Wen-Kai Weng, MD, PhD
Associate Professor of Medicine (Blood and Marrow Transplantation and Cellular Therapy) and, by courtesy, of Dermatology
Medicine - Blood & Marrow Transplantation
Web page: http://med.stanford.edu/profiles/Wen-Kai_Weng/
Bio
Dr. Wen-Kai Weng specializes in the treatment of non-Hodgkin's lymphoma (NHL), his basic research interest is immunotherapy for lymphoma and cancer, with two components: tumor specific targeting therapy and allogeneic transplant. He is currently working on new strategies to target patient-specific tumor using antibody along with effector cells. He is also conducting clinical study looking at the clinical efficacy of allogeneic transplant in patients with cutaneous lymphoma.
Clinical Focus
- Cancer > Blood and Marrow Transplant
- Cancer > Lymphoma
- Cutaneous T-Cell Lymphoma
- Medical Oncology
- Chimeric Antigen Receptor (CAR) T-cell Therapy
- Immunotherapy
Academic Appointments
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Associate Professor - University Medical Line, Medicine - Blood & Marrow Transplantation
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Associate Professor - University Medical Line (By courtesy), Dermatology
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Member, Stanford Cancer Institute
Administrative Appointments
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Scientific Advisory Board, Lymphoma Research Foundation (2011 - 2012)
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Co-Director, Stanford Multidisciplinary Cutaneous Lymphoma Clinic (2014 - Present)
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Director, Blood and Marrow Transplantation/Cellular Therapy (BMT/CT) Fellowship Program (2015 - Present)
Honors & Awards
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Predoctoral National Research Service Award, NIH/NIAID (1994-1995)
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Doctoral Dissertation Award, University of Minnesota Graduate School (1995)
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Charles and Dorothy Andrew Bird Award, Sigma Xi Scientific Research Society (1996)
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Fellowship, Lymphoma Research Foundation (2002-2004)
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K08 Clinical Scientist Career Development Award, NIH/NCI (2005-2009)
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Developmental Research Award, Stanford University Cancer Center (2009-2010)
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ITI Seed Grant Award, Institute for Immunity, Transplantation and Infection, Stanford University (2011-2012)
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Developmental Research Award, Stanford Cancer Institute (2012-2013)
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Translational Research Grant, Stanford Cancer Institute (2014-2015)
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Division Teaching Award, BMT, Stanford University (2009, 2010, 2012, 2015, 2016, 2018, 2019)
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Department of Medicine Master Teacher Award, Stanford University (2022)
Boards, Advisory Committees, Professional Organizations
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Co-Director, Stanford Cancer Immunotherapy and Blood & Marrow Transplantation Symposium (2018 - Present)
Professional Education
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Board Certification: American Board of Internal Medicine, Medical Oncology (2021)
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Fellowship, Stanford University, Medical Oncology (2002)
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Residency, University of Texas-Houston, Internal Medicine (1999)
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Internship, University of Texas-Houston, Internal Medicine (1997)
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PhD, University of Minnesota, Pathobiology/Immunology (1996)
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MD, ChungShan Medical and Dental College, Medicine (1988)
Patents
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Ronald Levy, Wen-Kai Weng. "United States Patent 9109255 Methods and compositions for determining responsiveness to antibody therapy", Aug 18, 2015
Current Research and Scholarly Interests
My clinical focus is non-Hodgkin's lymphoma (NHL) and am currently conducting clinical trials with novel therapies on these patients. My basic research interest is immunotherapy for lymphoma, with two components: tumor vaccines and allogeneic transplant. For the tumor vaccine, I am working with my colleagues in Oncology to conduct a clinical trial using a CpG-activated tumor vaccine in mantel cell NHL patients who undergo autologous transplantation. The goal is to sensitize the autologous T cells to recognize the malignant lymphoma cells and to expand these tumor-specific T cells immediate after autologous transplant.
Second, I am conducting a study using a novel non-myeloablative preparative regimen prior to allogeneic transplant in patients with mycosis fungoides/Sezary syndrome, a cutaneous T cell NHL. While these patients exhibit little sensitivity to traditional chemotherapy, graft-versus-lymphoma effect provided by allogeneic transplant seems to have an excellent disease control effect. I also use high throughput sequencing technology to assess the minimal residual disease and the immune reconstitution after allogeneic transplant.
Clinical Trials
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A Safety and Efficacy Study Evaluating CTX131 in Adult Subjects With Relapsed or Refractory Solid Tumors
Recruiting
This is an open-label, multicenter, Phase 1/2 study evaluating the safety and efficacy of CTX131™ in subjects with relapsed or refractory solid tumors.
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CIBMTR Research Database
Recruiting
The primary purpose of the Research Database is to have a comprehensive source of observational data that can be used to study HSC transplantation and cellular therapies. A secondary purpose of the Research Database is to have a comprehensive source of data to study marrow toxic injuries. Objectives: To learn more about what makes stem cell transplants and cellular therapies work well such as: * Determine how well recipients recover from their transplants or cellular therapy; * Determine how recovery after a transplant or cellular therapy can be improved; * Determine how a donor's or recipient's genetics impact recipient recovery after a transplant or cellular therapy; * Determine how access to transplant or cellular therapy for different groups of patients can be improved; * Determine how well donors recover from the collection procedures.
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A Long-term Follow-up Study of Subjects Who Received CRISPR CAR T Cellular Therapies
Not Recruiting
This study will evaluate the long-term safety and efficacy of CRISPR CAR T cellular therapies
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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A Phase 3 Study of Brentuximab Vedotin (SGN-35) in Patients at High Risk of Residual Hodgkin Lymphoma Following Stem Cell Transplant (The AETHERA Trial)
Not Recruiting
This is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial to evaluate the efficacy and safety of brentuximab vedotin (SGN-35) and best supportive care (BSC) compared to placebo and BSC in treatment of residual Hodgkin lymphoma (HL) following autologous stem cell transplant (ASCT).
Stanford is currently not accepting patients for this trial. For more information, please contact Sarah Robeson, (650) 725 - 1647.
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A Pilot Study of Imatinib Mesylate in Steroid Refractory Chronic Graft Versus Host Disease
Not Recruiting
To determine if subjects with steroid refractory cGVHD can tolerate imatinib mesylate and whether their cGVHD responds to imatinib mesylate.
Stanford is currently not accepting patients for this trial. For more information, please contact Joanne Otani, (650) 721 - 2372.
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A Safety and Efficacy Study Evaluating CTX130 in Subjects With Relapsed or Refractory T or B Cell Malignancies (COBALT-LYM)
Not Recruiting
This is a single-arm, open-label, multicenter, Phase 1 study evaluating the safety and efficacy of CTX130 in subjects with relapsed or refractory T or B cell malignancies.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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A Study of Ruxolitinib in Combination With Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease (REACH-1)
Not Recruiting
The purpose of this study was to assess the efficacy of ruxolitinib in combination with corticosteroids in subjects with Grades II to IV steroid-refractory acute graft-versus-host disease (GVHD).
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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A Trial of the FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor Gilteritinib Administered as Maintenance Therapy Following Allogeneic Transplant for Patients With FLT3/Internal Tandem Duplication (ITD) Acute Myeloid Leukemia (AML)
Not Recruiting
The purpose of this study was to compare relapse-free survival between participants with FLT3/ITD AML in first morphologic complete remission (CR1) who underwent hematopoietic stem cell transplant (HCT) and were randomized to receive gilteritinib or placebo beginning after the time of engraftment for a two year period.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Acute Graft-versus-Host Disease Treatment (BMT CTN 0802)
Not Recruiting
The study is a Phase III, randomized double blind, placebo controlled, and trial evaluating the addition of Mycophenolate mofetil (MMF) vs. placebo to systemic corticosteroids as initial therapy for acute Graft Vs Host Disease (GVHD). The primary endpoint will be GVHD free survival at Day 56 post randomization.
Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, (650) 723 - 0822.
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Allo vs Hypomethylating/Best Supportive Care in MDS (BMTCTN1102)
Not Recruiting
This study is designed as a multicenter trial, with biological assignment to one of two study arms; Arm 1: Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT), Arm 2: Non-Transplant Therapy/Best Supportive Care.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
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Allogeneic HCT Using Nonmyeloablative Host Conditioning With TLI & ATG vs SOC in AML
Not Recruiting
Acute myeloid leukemia (AML) is a cancer of the bone marrow that mostly affects older adults. Even with the best chemotherapy, two-year disease-free survival is achieved in a minority of patients. Bone marrow transplantation from a sibling donor may improve cure rates; however, patients over 50 years of age have a high risk of complications and therefore generally are excluded from this treatment option. Recently our group developed a transplantation strategy for older cancer patients that protects against transplant-associated complications, yet does not interfere with the ability of the transplanted donor cells to destroy cancer cells. With this new method, we can now safely evaluate transplantation as a curative therapy for AML patients over the age of 50. We have assembled clinical and scientific researchers throughout the state of California to study and compare bone marrow transplantation using our new approach with the best standard of care chemotherapy in AML patients over the age of 50. The results of this study have the potential to establish a new treatment standard that will improve survival of older AML patients.
Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, 650-725-1647.
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Allogeneic Transplantation Using Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) for Older Patients With Hematologic Malignancies
Not Recruiting
To measure how frequently and to what degree a complication of transplant cell acute graft versus host disease (GvHD) occurs.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
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Autologous Followed by Non-myeloablative Allogeneic Transplantation for Non-Hodgkin's Lymphoma
Not Recruiting
The purpose of this trial is to develop an alternative treatment for patients with poor risk non-Hodgkin's lymphoma. This trial uses a combination of high dose chemotherapy with stem cell transplant using the patient's own cells. This is followed with non-myeloablative transplant using stem cells from a related or unrelated donor to try and generate an anti-lymphoma response from the new immune system.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
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Bone Marrow Grafting for Leukemia and Lymphoma
Not Recruiting
The purpose of this study is to obtain tissue samples for ongoing studies regarding transplant outcomes and complications.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
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Brentuximab Vedotin (SGN-35) in Patients With Mycosis Fungoides With Variable CD30 Expression Level
Not Recruiting
The purpose of this study is to learn the effects of brentuximab vedotin (SGN-35), an investigational medication, on patients with cutaneous T cell lymphoma (CTCL), specifically mycosis fungoides (MF) and Sezary syndrome (SS). Despite a wide range of therapeutic options, the treatments are associated with short response duration, thus this condition is largely incurable. This investigational drug may offer less toxicity than standard treatments and have better tumor specific targeting.
Stanford is currently not accepting patients for this trial. For more information, please contact Kokil Bakshi, 650-421-6370.
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CD8+ Memory T-Cells as Consolidative Therapy After Donor Non-myeloablative Hematopoietic Cell Transplant in Treating Patients With Leukemia or Lymphoma
Not Recruiting
This phase 2 trial studies how well cluster of differentiation 8 (CD8)+ memory T-cells work as a consolidative therapy following a donor non-myeloablative hematopoietic cell transplant in treating patients with leukemia or lymphoma. Giving total lymphoid irradiation and anti-thymocyte globulin before a donor hematopoietic cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them. Giving an infusion of the donor's white blood cells, such as CD8+ memory T-cells, may boost this effect and may be an effective treatment to kill any cancer cells that may be left in the body (consolidative therapy).
Stanford is currently not accepting patients for this trial. For more information, please contact Leah Galvez, 650-725-7951.
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Chronic Graft-versus-Host Disease Treatment (BMT CTN 0801)
Not Recruiting
This study is designed as a combined Phase II/III, randomized, open label, multicenter, prospective comparative study of sirolimus plus prednisone versus sirolimus/calcineurin-inhibitor plus prednisone for the treatment of chronic GVHD. Patients will be stratified by transplant center and will be randomized to an experimental arm of one of the two pre-specified experimental arms (sirolimus + prednisone or the comparator arm of sirolimus + calcineurin inhibitor + prednisone) in a 1:1 ratio.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
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Clinical and Pathologic Studies in Non-Hodgkin's Lymphoma Patients Receiving Antibody Treatment
Not Recruiting
To characterize the molecular and cell biology of the tumor cells in lymphoma. The mechanism of monoclonal antibody treatment by rituximab or epratuzumab will also be examined.
Stanford is currently not accepting patients for this trial. For more information, please contact Mayita Romero, (650) 725 - 6452.
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Continued, Long-Term Follow-Up and Lenalidomide Maintenance Therapy for Patients on BMT CTN 0702 Protocol (BMT CTN 07LT)
Not Recruiting
This study is designed to compare long-term outcomes among patients randomized on the BMT CTN 0702 protocol (NCT01109004), "A Trial of Single Autologous Transplant with or without Consolidation Therapy versus Tandem Autologous Transplant with Lenalidomide Maintenance for Patients with Multiple Myeloma". It is hypothesized that use of novel anti-myeloma agents will improve long-term progression-free survival (PFS) after high-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) as compared to a second autologous transplantation.
Stanford is currently not accepting patients for this trial. For more information, please contact Kashif Naseem, 650-724-3155.
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Cyclosporine Eye Drops in Preventing Graft-Versus-Host Disease of the Eye in Patients Who Have Undergone Donor Stem Cell Transplant for Hematologic Cancer or Bone Marrow Failure Disorder
Not Recruiting
RATIONALE: Cyclosporine eye drops may prevent graft-versus-host disease of the eye in patients who have undergone donor stem cell transplant for hematologic cancer or bone marrow failure disorder. PURPOSE: This randomized phase I trial is studying how well cyclosporine eye drops work in preventing graft-versus-host disease of the eye in patients who have undergone donor stem cell transplant for hematologic cancer or bone marrow failure disorder.
Stanford is currently not accepting patients for this trial. For more information, please contact Joanne Otani, (650) 721 - 2372.
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Donor Atorvastatin Treatment for Preventing Severe Acute Graft-Versus-Host Disease in Patients Undergoing Myeloablative Peripheral Blood Stem Cell Transplantation
Not Recruiting
This phase II trial studies donor atorvastatin treatment for the prevention of severe acute graft-versus-host disease (GVHD) in patients undergoing myeloablative peripheral blood stem cell (PBSC) transplantation. Giving chemotherapy and total-body irradiation (TBI) before a donor PBSC transplant helps stop the growth of cancer cells. It may also prevent the patient's immune system reject the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving atorvastatin to the donor before transplant may prevent this from happening.
Stanford is currently not accepting patients for this trial. For more information, please contact Leah Galvez, 650-725-7951.
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Donor Regulatory T Cells in Treating Patients With Visceral Acute Graft-versus-Host Disease After Stem Cell Transplant
Not Recruiting
This phase I trial studies the side effects and best dose of donor regulatory T cells in treating patients with graft-versus-host disease affecting the liver or gastrointestinal organs (visceral) within 100 days (acute) after undergoing a stem cell transplant. Graft-versus-host disease occurs when donor immune cells infused in a stem cell transplant attack the gut, skin, liver, or other organ systems of the patient. Regulatory T cells are a type of immune cell that may be able to reduce the attack of the donor's immune cells on the patient's normal cells and help treat graft-vs-host disease.
Stanford is currently not accepting patients for this trial. For more information, please contact Joanne Otani, 650-721-2372.
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Double Cord Versus Haploidentical (BMT CTN 1101)
Not Recruiting
Hematopoietic cell transplants (HCT)are one treatment option for people with leukemia or lymphoma. Family members,unrelated donors or banked umbilical cordblood units with similar tissue type can be used for HCT. This study will compare the effectiveness of two new types of bone marrow transplants in people with leukemia or lymphoma: one that uses bone marrow donated from family members with only partially matched bone marrow; and, one that uses two partially matched cord blood units.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
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Expanded Access Protocol for Tabelecleucel for Patients With Epstein-Barr Virus-Associated Viremia or Malignancies
Not Recruiting
The primary objective of this protocol is to provide expanded access to tabelecleucel to participants with Epstein-Barr virus-associated diseases and malignancies for whom there are no other appropriate therapeutic options, and who are not eligible to enroll in clinical studies designed to support the development and registration of tabelecleucel.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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High Dose Chemotherapy and Allogeneic Hematopoietic Cell Transplant for Non-Hodgkin's Lymphoma
Not Recruiting
To evaluate the role of allogeneic hematopoietic cell transplantation in the treatment of NHL.
Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, (650) 723 - 0822.
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Ibrutinib in Combination With Corticosteroids vs Placebo in Combination With Corticosteroids in Participants With New Onset Chronic Graft Versus Host Disease (cGVHD)
Not Recruiting
To evaluate the safety and efficacy of ibrutinib in combination with prednisone in subjects with newly diagnosed moderate to severe cGVHD.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Ibrutinib in Treating Patients With Refractory or Relapsed Lymphoma After Donor Stem Cell Transplant
Not Recruiting
This phase II trial studies how well ibrutinib works in treating patients after a donor stem cell transplant for lymphoma that is not responding to treatment or has come back. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial.
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Intravenous Administration of RGI-2001 in Patient Undergoing Allogenic Hematopoietic Stem Cell Transplantation (AHSCT)
Not Recruiting
The clinical trial is a Phase 1/2a, open-label, multi-center, dose-escalation study to evaluate the safety, tolerability and pharmacokinetic profile of RGI-2001 in patients undergoing AHSCT, with radiation or non-radiation myeloablative preparative treatment. The study will be separated into two parts; a dose escalation phase to assess safety, followed by a large expansion phase to further evaluate the pharmacologic effects of either a Maximum Tolerated Dose, Maximum Feasible Dose or optimal pharmacologically active dose of RGI-2001. The initial dose escalation safety portion of the study (Part 1) will include higher risk patients and limit the unrelated donor transplants. After safety is established in part 1 of the study, the second portion of the study will expand the enrollment criteria and allow transplantation by either related or unrelated donors. This study will endeavor to identify the dose range at which RGI-2001 has an acceptable safety profile, at which biologic activity is observed, and to guide possible dose levels to utilize in later phase studies based on biological activity.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, (650) 723 - 0822.
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Nilotinib and Imatinib Mesylate After Donor Stem Cell Transplant in Treating Patients With ALL or CML
Not Recruiting
This phase I/II trial is studying the side effects and best way to give nilotinib when given alone or sequentially after imatinib mesylate after donor stem cell transplant in treating patients with acute lymphoblastic leukemia or chronic myelogenous leukemia. Nilotinib and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, (650) 723 - 0822.
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Non-myeloablative Allogeneic Transplantation for the Treatment of Multiple Myeloma
Not Recruiting
Mixed chimerism transplantation is an approach to allogeneic transplants that attempts to decrease regimen-related toxicity by using non-myeloablative preparatory regimens; establish mixed chimerism using low dose total body irradiation along with immunosuppression using cyclosporine and mycophenolate mofetil; suppress graft-vs-host and host-vs-graft reactions to allow a mixed chimeric state to be established, encourage tolerance and prevent graft-vs-host disease (GvHD) during the mixed chimerism period and use donor lymphocyte infusions to convert the patient to a full chimera while developing a graft-vs-tumor effect.
Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, (650) 723 - 0822.
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Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN 1203)
Not Recruiting
Acute Graft-versus-Host-Disease (GVHD) is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to determine if any of three new GVHD prophylaxis approaches improves the rate of GVHD and relapse free survival at one year after transplant compared to the current standard prophylaxis regimen.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
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Obinutuzumab in cGVHD After Allogeneic Peripheral Blood Stem Cell Transplantation
Not Recruiting
This research study is studying a drug called obinutuzumab as a means of preventing chronic Graft vs. Host Disease (cGVHD).
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Peripheral Blood Stem Cell Transplant vs Bone Marrow Transplant in Individuals With Hematologic Cancers (BMT CTN 0201)
Not Recruiting
The study is designed as a Phase III, randomized, open label, multicenter, prospective, comparative trial of granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSC) versus marrow from unrelated donors for transplantation in patients with hematologic malignancies. Recipients will be stratified by transplant center and disease risk and will be randomized to either the PBSC or marrow arm in a 1:1 ratio.
Stanford is currently not accepting patients for this trial. For more information, please contact Kate Tierney, (650) 725 - 7063.
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Ph II of Non-myeloablative Allogeneic Transplantation Using TLI & ATG In Patients w/ Cutaneous T Cell Lymphoma
Not Recruiting
Non-myeloablative approach for allogeneic transplant is a reasonable option, especially given that the median age at diagnosis is 55-60 years and frequently present compromised skin in these patients, which increases the risk of infection. Therefore, we propose a clinical study with allogeneic hematopoietic stem cell transplantation (HSCT) using a unique non-myeloablative preparative regimen, TLI/ATG, to treat advanced mycosis fungoides/Sezary syndrome (MF/SS).
Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Chin, 650-721-4183.
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Phase 1 Infused Donor T Regulatory Cells in Steroid Dependent/Refractory Chronic GVHD
Not Recruiting
Chronic graft versus host disease (cGVHD) is a common complication of bone marrow or hematopoietic cell transplant from another person (allogeneic transplant). This study will determine if subjects with steroid dependent/refractory cGVHD can tolerate infusion of donor regulatory T cells and whether their cGVHD responds to the infusion.
Stanford is currently not accepting patients for this trial. For more information, please contact Joanne Otani, 650-721-2372.
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Phase 1-2 MAHCT w/ TCell Depleted Graft w/ Simultaneous Infusion Conventional and Regulatory T Cell
Not Recruiting
For patients with hematologic malignancies undergoing allogeneic myeloablative (MA) HCT with a T cell depleted graft, the infusion of naturally occurring regulatory T cells with conventional T cells (T cell add back) in pre-defined doses and ratios will reduce the incidence of acute graft vs host disease while augmenting the graft vs leukemia effect and improving immune reconstitution.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
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Phase 1-2 of a CpG-Activated Whole Cell Vaccine Followed by Autologous Immunotransplant for MCL
Not Recruiting
Mantle cell lymphoma (MCL) is a sub-type of non-Hodgkin's lymphoma (NHL) which is generally considered incurable with current therapy. Participants will receive an autologous vaccine against their individual lymphoma after undergoing stem cell transplantation. This vaccination may prolong the time which patients will stay in remission from their disease.
Stanford is currently not accepting patients for this trial. For more information, please contact Ami Okada, (650) 725 - 4968.
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Phase 2 Poor Risk DLBCL of TLI and ATG Followed by Matched Allogeneic HT as Consolidation to Autologous HCT
Not Recruiting
The purpose of this study is to determine if double autologous then allogeneic hematopoietic cell transplant may offer an improved treatment option for patients with relapsed diffuse large B-cell lymphoma (DLBCL) who are not likely to be cured by the conventional transplantation regimen.
Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, (650) 723 - 0822.
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Phase 2 Study of Autologous Followed by Nonmyeloablative Allogeneic Transplantation Using TLI & ATG
Not Recruiting
To evaluate the toxicity and tolerability of this tandem autologous/allogeneic transplant approach for patients with advanced stage multiple myeloma.
Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, (650) 723 - 0822.
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Post T-plant Infusion of Allogeneic Cytokine Induced Killer (CIK) Cells as Consolidative Therapy in Myelodysplastic Syndromes/Myeloproliferative Disorders
Not Recruiting
Allogeneic stem cell transplantation (transplant of blood cells from another individual) is a treatment option for patients with myelodysplasia or myeloproliferative Disorders. During the course of this study, it will be evaluated whether a particular type of blood cell, called a cytokine-induced killer (CIK) cell, may add benefit to allogeneic stem cell transplantation. CIK cells are present in small quantities in the bloodstream but their numbers can be expanded after a brief period of nurturing in a laboratory.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
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Safety and Efficacy Study of an Anti-CD20 Monoclonal Antibody (AME-133v) to Treat Non-Hodgkin's Lymphoma
Not Recruiting
This study is designed to provide evidence of the safety and a preliminary understanding of the efficacy of AME 133v.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Ahern, (650) 493 - 5000.
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Sirolimus & Mycophenolate Mofetil as GvHD Prophylaxis in Myeloablative, Matched Related Donor HCT
Not Recruiting
A continuation study of sirolimus and mycophenolate mofetil (MMF) for graft-vs-host disease (GvHD) prophylaxis for patients undergoing matched related allogeneic hematopoietic stem cell transplantation (HSCT) for acute and chronic leukemia, myelodysplastic syndrome (MDS), high risk non-Hodgkin lymphoma (NHL), or Hodgkin lymphoma (HL)
Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, (650) 723 - 0822.
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Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors
Not Recruiting
This randomized phase III trial studies how well standard-dose combination chemotherapy works compared to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement or did not respond to treatment. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim or pegfilgrastim, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. It is not yet known whether high-dose combination chemotherapy and stem cell transplant are more effective than standard-dose combination chemotherapy in treating patients with refractory or relapsed germ cell tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Stem Cell Transplant With Lenalidomide Maintenance in Patients With Multiple Myeloma (BMT CTN 0702)
Not Recruiting
The study is designed as a Phase III, multicenter trial of tandem autologous transplants plus maintenance therapy versus the strategy of single autologous transplant plus consolidation therapy with lenalidomide, bortezomib and dexamethasone (RVD) followed by maintenance therapy or single autologous transplant plus maintenance therapy as part of upfront treatment of multiple myeloma (MM). Lenalidomide will be used as maintenance therapy for three years in all arms.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, (650) 723 - 0822.
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Study of Brexucabtagene Autoleucel (KTE-X19) for the Treatment of Individuals With Relapsed/Refractory B-Cell Malignancies
Not Recruiting
The primary objectives of this study are: Cohort 1: to provide access to brexucabtagene autoleucel (KTE-X19) for individuals with relapsed or refractory (r/r) mantle cell lymphoma (MCL) until KTE-X19 is commercially available Cohort 2: To provide access to KTE-X19 for individuals with r/r MCL whose commercially manufactured product did not meet commercial release specification(s)
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Study of Brexucabtagene Autoleucel (KTE-X19) in Participants With Relapsed/Refractory Mantle Cell Lymphoma (Cohort 3)
Not Recruiting
The goal of this clinical study is to test how well the study drug, brexucabtagene autoleucel (KTE-X19), works in participants with relapsed/refractory (r/r) mantle cell lymphoma (MCL).
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Study of Effectiveness of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Patients With Relapsed/Refractory Diffuse Large B Cell Lymphoma
Not Recruiting
The goal of this clinical study is to assess whether axicabtagene ciloleucel therapy improves the clinical outcome compared with standard of care second-line therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Study of Safety and Efficacy of KTE-C19 in Combination With Atezolizumab in Adults With Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Not Recruiting
The primary objective of phase 1 is to evaluate the safety of KTE-C19 and atezolizumab combination regimens. The primary objective of phase 2 is to evaluate the efficacy of KTE-C19 and atezolizumab, as measured by complete response rate in participants with refractory diffuse large B-cell lymphoma (DLBCL). Participants who received an infusion of KTE-C19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968 (NCT05041309).
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Targeted Therapy of Bronchiolitis Obliterans Syndrome
Not Recruiting
This phase II trial studies how well giving fluticasone propionate, azithromycin, and montelukast sodium (FAM) together works in treating patients with bronchiolitis obliterans who previously underwent stem cell transplant. FAM may be an effective treatment for bronchiolitis obliterans
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
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TLI & ATG for Non-Myeloablative Allogeneic Transplantation for MDS and MPD
Not Recruiting
To evaluate the feasibility and safety of TLI/ATG conditioning for allogeneic HCT for elderly patients with advanced stage MDS and MPD.
Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.
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Transplantation for Patients With Chronic Lymphocytic Leukemia
Not Recruiting
To evaluate the role of high dose therapy and autologous or allogeneic hematopoietic cell transplantation for the treatment of chronic lymphocytic leukemia.
Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, (650) 723 - 0822.
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Vaccine Therapy and GM-CSF in Treating Patients With Progressive Non-Hodgkin's Lymphoma
Not Recruiting
RATIONALE: Vaccines made from a person's cancer cells may make the body build an effective immune response to kill cancer cells. Colony-stimulating factors, such as GM-CSF, may increase the number of immune cells found in bone marrow or peripheral blood and may stimulate the immune system in different ways and stop cancer cells from growing. PURPOSE: This phase II trial is studying how well giving vaccine therapy together with GM-CSF works in treating patients with progressive B-cell non-Hodgkin's lymphoma.
Stanford is currently not accepting patients for this trial. For more information, please contact Mayita Romero, (650) 725 - 6452.
2024-25 Courses
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Independent Studies (5)
- Directed Reading in Medicine
MED 299 (Aut, Win, Spr, Sum) - Early Clinical Experience in Medicine
MED 280 (Aut, Win, Spr, Sum) - Graduate Research
MED 399 (Aut, Win, Spr, Sum) - Medical Scholars Research
MED 370 (Aut, Win, Spr, Sum) - Undergraduate Research
MED 199 (Aut, Win, Spr, Sum)
- Directed Reading in Medicine
All Publications
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Phase II study of novel CXCR2 agonist and Plerixafor for rapid stem cell mobilization in patients with multiple myeloma.
Blood cancer journal
2024; 14 (1): 173
Abstract
MGTA-145 or GROβT, a CXCR2 agonist, has shown promising activity for hematopoietic stem cell (HSC) mobilization with plerixafor in pre-clinical studies and healthy volunteers. Twenty-five patients with multiple myeloma enrolled in a phase 2 trial evaluating MGTA-145 and plerixafor for HSC mobilization (NCT04552743). Plerixafor was given subcutaneously followed 2 h later by MGTA-145 (0.03 mg/kg) intravenously with same day apheresis. Mobilization/apheresis could be repeated for a second day in patients who collected <6 ×106 CD34+ cells/kg. Lenalidomide and anti-CD38 antibody were part of induction therapy in 92% (n = 23) and 24% (n = 6) of patients, respectively. Median total HSC cell yield (CD34+ cells/kg × 106) was 5.0 (range: 1.1-16.2) and day 1 yield was 3.4 (range: 0.3-16.2). 88% (n = 22) of patients met the primary endpoint of collecting 2 ×106 CD34+ cells/kg in ≤ two days, 68% (n = 17) in one day. Secondary endpoints of collecting 4 and 6 × 106 CD34+ cells/kg in ≤ two days were met in 68% (n = 17) and 40% (n = 10) patients. Grade 1 or 2 adverse events (AE) were seen in 60% of patients, the most common AE being grade 1 pain, usually self-limited. All 19 patients who underwent transplant with MGTA-145 and plerixafor mobilized HSCs engrafted successfully, with durable engraftment at day 100. 74% (17 of 23) of grafts with this regimen were minimal residual disease negative by next generation flow cytometry. Graft composition for HSCs and immune cells were similar to a contemporaneous cohort mobilized with G-CSF and plerixafor.
View details for DOI 10.1038/s41408-024-01152-1
View details for PubMedID 39384609
View details for PubMedCentralID 10040899
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ASTCT and USCLC Clinical Practice Recommendations for Allogeneic Stem Cell Transplant in Mycosis Fungoides and Sézary Syndrome.
Transplantation and cellular therapy
2024
Abstract
Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). While MF generally follows an indolent course, a subset of patients will experience progressive and/or treatment-refractory disease. Sézary syndrome is an aggressive CTCL associated with high morbidity and mortality secondary to immune compromise and opportunistic infection. Although allogeneic hematopoietic cell transplant (allo-HCT) is currently the only available potentially curative treatment modality for MF/SS and is included in NCCN and ASTCT treatment guidelines, there is no published guidance regarding referral criteria, timing and allo-HCT approach to help guide clinicians caring for these patients.Delphi survey of 32 specialists in dermatology (n=9), transplant hematology/oncology (n=10), non-transplant hematology/oncology (n=8), and radiation oncology (n=5) from across the United States. Consensus required agreement of ≥75% of participants.Sixteen consensus statements were generated on four topics: 1) criteria for referral for consideration for allo-HCT, 2) allo-HCT preparative regimens and procedures 3) disease status at the time of allo-HCT, and 4) multidisciplinary management in the pre- and post-transplant settings.These clinical practice guidelines provide a framework for decision-making regarding allo-HCT for MF/SS and highlight areas for future prospective investigation.
View details for DOI 10.1016/j.jtct.2024.08.020
View details for PubMedID 39222792
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CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study.
Lancet (London, England)
2024
Abstract
Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study.In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment.From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome.This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach.National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.
View details for DOI 10.1016/S0140-6736(24)00746-3
View details for PubMedID 38996463
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A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia.
Blood
2024
Abstract
While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).
View details for DOI 10.1182/blood.2024024952
View details for PubMedID 38968138
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Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma.
Journal for immunotherapy of cancer
2024; 12 (7)
Abstract
Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy.84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC.Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts.Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.
View details for DOI 10.1136/jitc-2024-008975
View details for PubMedID 38955420
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Management of post-autologous transplant relapse in patients with T-cell lymphomas.
American journal of hematology
2024
Abstract
Autologous hematopoietic cell transplantation (AHCT) is often used as a consolidation for patients with peripheral T-cell lymphomas (PTCLs) due to the poor prognosis associated with this heterogenous group of disorders. However, a significant number of patients will experience post-AHCT disease relapse. Here, we report a retrospective study of consecutive 124 patients with PTCLs who underwent AHCT from 2008 to 2020. With a median follow-up of 6.01 years following AHCT, 49 patients (40%) experienced disease relapse. As expected, more patients who were not in first complete remission experienced post-AHCT relapse. Following relapse, majority of the patients (70%) receiving systemic therapies intended as bridging to curative allogeneic HCT. However, only 18 (53%) patients eventually underwent allogeneic HCT. The estimated 3-year OS among patients proceeding to allogeneic HCT was 72% (95% CI 46%-87%). Our report details the pattern of post-AHCT relapse and the management of relapsed disease using different therapeutic modalities.
View details for DOI 10.1002/ajh.27345
View details for PubMedID 38661220
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Tabelecleucel for EBV+ PTLD following allogeneic HCT or SOT in a multicenter expanded access protocol.
Blood advances
2024
Abstract
Patients with Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disease (EBV+ PTLD) in whom initial treatment fails have few options and historically low median overall survival (OS) of 0.7 months following allogeneic hematopoietic cell transplant (HCT) and 4.1 months following solid organ transplant (SOT). Tabelecleucel is an off-the-shelf, allogeneic EBV-specific cytotoxic T-lymphocyte immunotherapy for EBV+ PTLD. Previous single-center experience showed responses in patients with EBV+ PTLD following HCT or SOT. We now report outcomes from a multicenter expanded access protocol (NCT02822495) in HCT (n = 14) and SOT (n = 12) recipients treated with tabelecleucel for EBV+ PTLD that was relapsed/refractory to rituximab ± chemotherapy. The investigator-assessed objective response rate was 65.4% overall (including 38.5% with a complete and 26.9% with a partial response), 50.0% in HCT, and 83.3% in SOT. The estimated 1- and 2-year OS rates (95% CI) were both 70.0% (46.5, 84.7) overall, both 61.5% (30.8, 81.8) in HCT, and both 81.5% (43.5, 95.1) in SOT (median follow-up: 8.2, 2.8, and 22.5 months, respectively). Patients responding to tabelecleucel had higher 1- and 2-year OS rates (94.1%) than non-responders (0%). Treatment was well tolerated with no reports of tumor flare, cytokine release syndrome, or rejection of marrow and SOT. Results demonstrate clinically meaningful outcomes across a broad population treated with tabelecleucel, indicating a potentially transformative and accessible treatment advance for relapsed/refractory EBV+ PTLD following HCT or SOT.
View details for DOI 10.1182/bloodadvances.2023011626
View details for PubMedID 38625984
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CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity.
Blood advances
2024
Abstract
Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas. CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell (MCL), follicular (FL), and large B-cell lymphoma (LBCL) over the course of five years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL compared to other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required four-fold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and the requirement for granulocyte colony stimulating factor (GCSF) after day 14 post-infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.
View details for DOI 10.1182/bloodadvances.2024012637
View details for PubMedID 38498731
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A US Multicenter Collaborative Study on Outcomes of Hematopoietic Cell Transplantation in Hepatosplenic T-Cell Lymphoma.
Transplantation and cellular therapy
2024
Abstract
Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive type of peripheral T-cell lymphoma with median overall survival (OS) of approximately 1 year. Data on the effectiveness of hematopoietic cell transplantation (HCT) is limited, as is the choice between autologous HCT (auto-HCT) and allogeneic HCT (allo-HCT) in the treatment of this disease.To evaluate the outcome of patients with HSTCL who underwent either auto-HCT or allo-HCT.We performed a multi-institutional retrospective cohort study to assess outcomes of HCT in HSTCL patients.Fifty-three patients with HSTCL were included in the study. Thirty-six patients received an allo-HCT and 17 an auto-HCT. Thirty-five (66%) were males. Median age at diagnosis was 38 (range 2-64) years. Median follow-up for survivors was 75 months (range 8-204). The median number of prior lines of therapy was 1 (range 1-4). Median OS and progression-free survival (PFS) for the entire cohort were 78.5 months (95% CI: 25-79) and 54 months (95% CI: 18-75), respectively. There were no significant differences in OS (HR: 0.63, 95% CI: 0.28-1.45, p=0.245) or PFS (HR: 0.7, 95% CI: 0.32-1.57, p=0.365) between the allo-HCT and auto-HCT groups, respectively. In the allo-HCT group, the 3-year cumulative incidence of relapse was 35% (95% CI: 21-57), while 3-year cumulative incidence of NRM was 16% (95% CI: 7-35). In the auto-HCT group, the 3-year cumulative incidence of relapse and NRM were 43% (95% CI: 23-78) and 14% (95% CI: 4-52), respectively.Both Auto-HCT and Allo-HCT are effective consolidative strategies in patients with HSTCL, and patients should be promptly referred for HCT evaluation.
View details for DOI 10.1016/j.jtct.2024.02.021
View details for PubMedID 38431075
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Clinical characteristics, treatment patterns, and outcomes of cytotoxic cutaneous T-cell lymphomas.
American journal of hematology
2024
View details for DOI 10.1002/ajh.27266
View details for PubMedID 38391088
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Clinical Features of Neurotoxicity Following CD19 CAR T-cell Therapy in Mantle Cell Lymphoma.
Blood advances
2024
Abstract
CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development following CD19 CAR T-cell therapy in patients with MCL. All patients (n = 26) who received standard of care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (≥ grade 3) ICANS. All ICANS patients had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. 92% of EEGs revealed interictal changes; no patients experienced frank seizures due to ICANS. 86% of severe ICANS patients with post-infusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of post-infusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in severe ICANS patients, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.
View details for DOI 10.1182/bloodadvances.2023011896
View details for PubMedID 38295285
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Single Center Randomized Trial of T-reg graft alone versus T-reg graft Plus Tacrolimus for the Prevention of Acute GVHD.
Blood advances
2023
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies for which graft-versus-host disease (GVHD) remains a major complication. The use of donor T regulatory cells (Tregs) to prevent GVHD appears promising, including in our previous evaluation of an engineered graft product (T-reg graft) consisting of the timed, sequential infusion of CD34+ hematopoietic stem cells and high-purity Tregs followed by conventional T cells. However, whether immunosuppressive prophylaxis can be removed from this protocol remains unclear. We report the results of the first stage of an open-label single-center phase 2 study (NCT01660607) investigating T-reg graft in myeloablative HCT of HLA-matched and 9/10 matched recipients. Twenty-four patients were randomized to receive T-reg graft alone (n=12) or T-reg graft plus single-agent GVHD prophylaxis (n=12) to determine if T-reg graft alone was non-inferior in preventing acute GVHD. All patients developed full donor myeloid chimerism. Patients with T-reg graft alone versus with prophylaxis had an incidence of grade II-IV acute GVHD of 58% versus 8% (p=0.005) and grade III-IV of 17% versus 0% (p=0.149), respectively. The incidence of moderate to severe chronic GVHD was 28% in the T-reg graft alone arm versus 0% with prophylaxis (p=0.056). Among patients with T-reg graft and prophylaxis, CD4+ T cell:Treg ratios were reduced after transplantation, gene-expression profiles showed reduced CD4+ proliferation, and the achievement of full donor T cell chimerism was delayed. This study indicates that T-reg graft with single-agent tacrolimus is preferred to T-reg graft alone for the prevention of acute GVHD. Clinical Trial #: NCT01660607.
View details for DOI 10.1182/bloodadvances.2023011625
View details for PubMedID 38091578
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Improved outcomes for relapsed/refractory Hodgkin lymphoma after autologous transplantation in the era of novel agents.
Blood
2023
Abstract
The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade following the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for R/R cHL patients who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011-2020 (N=183) compared to 2001-2010 (N=159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era (4-year estimates 89.1% vs 79.0%, HR 0.53, 95% CI 0.33-0.85, p=0.011) with a trend towards lower non-relapse mortality beyond 2 years post-transplant. Among patients who progressed after AHCT, 4-year post-progression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients transplanted in the modern era, age ³45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, while receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS (HR 0.21, 95% CI 0.05-0.80, p=0.030). Extranodal disease at relapse was associated with inferior OS (HR 3.12, 95% CI 1.25-7.77, p=0.014). Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.
View details for DOI 10.1182/blood.2022018827
View details for PubMedID 36857637
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Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia in the Modern Era.
Transplantation and cellular therapy
2022
Abstract
Allogeneic hematopoietic cell transplantation (HCT) remains an important treatment for adults with acute lymphoblastic leukemia (ALL). We hypothesized that advances in ALL and transplantation have resulted in improved HCT outcomes in recent years.To evaluate the characteristics and outcomes of adult ALL patients undergoing allogeneic HCT over the last decade.Patients with ALL aged ≥18 years old who underwent allogeneic HCT at Stanford University between 2008 and 2019 were included in this study. Patients were divided into two Eras based on year of HCT: 2008-2013 (Earlier Era) and 2014-2019 (Later Era).A total of 285 patients were included: 119 patients underwent HCT in the Earlier Era and 166 in the Later Era. Patients transplanted in the Later Era were more likely to be Hispanic (38% vs. 21%) and to have HCT-Comorbidity Index of ≥ 3 (31% vs. 18%). Donor source for HCT also differed with an increase in the use of HLA-mismatched donor sources (38% vs. 24%), notably umbilical cord blood (UCB) in the Later Era (16% vs. 0%). Patients in the Later Era were less likely to undergo transplant with active disease (4% vs.16%); pre-HCT rates of measurable residual disease (MRD) were similar across the Eras (38% vs. 40%). In unadjusted analyses, overall survival (OS) improved across Eras, with 2-year estimates for the Later and Earlier Eras of 73% (95% CI, 66%-80%) vs. 55% (95% CI, 46%-64%), respectively. Multivariable analysis confirmed the association between Later Era and OS (HR = 0.52, 95% CI, 0.34-0.78). Finally, among patients relapsing after HCT (25% in Later Era and 33% in Earlier Era), the utilization of novel immunotherapies increased in the Later Era (44% vs. 3%), as did the median OS following post-HCT relapse (16 months vs. 8 months, p < 0.001).OS following HCT for adult ALL has improved in recent years. This is due, in part, to a significant improvement in the ability to effectively salvage adults with ALL relapsing after HCT.
View details for DOI 10.1016/j.jtct.2022.05.010
View details for PubMedID 35584783
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Real-world Experience of Cryopreserved Allogeneic Hematopoietic Grafts in the COVID-19 Pandemic: A Single Center Report.
Transplantation and cellular therapy
1800
Abstract
BACKGROUND: As a result of the COVID-19 widespread pandemic, cryopreservation of allogeneic donor apheresis products was implemented to mitigate the challenges of donor availability and product transport. Although logistically beneficial, the impact of cryopreservation on clinical outcomes and graft composition remains unclear.OBJECTIVES: To compare the outcomes and graft composition with cryopreserved versus fresh allografts in the setting of allogeneic hematopoietic cell transplantation (allo-HCT).STUDY DESIGN: We retrospectively analyzed the clinical outcomes of 30 consecutive patients who received cryopreserved allografts between March and August 2020 as compared to 60 consecutive patients who received fresh allografts prior to the COVID-19 pandemic. Primary endpoints were hematopoietic engraftment, graft failure (GF) and secondary outcomes were overall survival (OS), relapse free survival (RFS) and non-relapse mortality (NRM). In addition, extended immunophenotype analysis was performed on cryopreserved versus prospectively collected fresh apheresis samples.RESULTS: Compared to fresh allografts, both neutrophil and platelet recovery were delayed in recipients of cryopreserved reduced intensity conditioning (RIC) allo-HCT with median times to engraftment of 24 days vs 18 days (P = .01) and 27 days vs 18 days (P = .069), respectively. We observed primary GF in 4 of 30 patients in the cryopreserved cohort (13.3%) vs only one of 60 patients (1.7 %) in the fresh cohort (P = .03). Cryopreserved RIC allo-HCT was associated with significantly lower median total, myeloid and T-cell donor chimerism at 1 month. OS and RFS were inferior for cryograft recipients with hazard ratio [HR (95%Cl)]: 2.16 (1.00, 4.67) and 1.90 (0.95, 3.79), respectively. Using an extended immunophenotype analysis we compared 14 samples from the cryopreserved cohort to 6 prospectively collected fresh apheresis donor samples. These analyses showed both decrease in total cell viability and significantly reduced absolute numbers of NK cells (CD3-CD56+) in the cryopreserved apheresis samples.CONCLUSION: In this single institution study we note delayed engraftment and a trend toward clinical inferiority of cryopreserved vs fresh allografts. Further evaluation of the use of cryopreserved allografts and their impact on clinical and laboratory outcomes is warranted.
View details for DOI 10.1016/j.jtct.2022.01.010
View details for PubMedID 35042013
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Incidence and risk factors associated with bleeding and thrombosis following chimeric antigen receptor T-cell therapy
BLOOD ADVANCES
2021; 5 (21): 4465-4475
View details for DOI 10.1182/bloodadvances.2021004716.
View details for Web of Science ID 000718993700016
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Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia.
Blood advances
2021; 5 (16): 3147-3151
Abstract
Monitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting.
View details for DOI 10.1182/bloodadvances.2021004234
View details for PubMedID 34424318
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NUTRITIONAL DEFICIENCY CONTRIBUTING TO REFRACTORY ERYTHRODERMA IN HEMATOPOETIC CELL TRANSPLANT PATIENTS: DISTINCTIVE CLINICAL AND HISTOPATHOLOGICAL FINDINGS.
Journal of the American Academy of Dermatology
2021
View details for DOI 10.1016/j.jaad.2021.07.077
View details for PubMedID 34450206
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CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial.
Nature medicine
2021
Abstract
Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19- or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n=17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n=21), 62% of patients responded with 29% CR. Relapses were CD19-/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22-/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.
View details for DOI 10.1038/s41591-021-01436-0
View details for PubMedID 34312556
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Outcomes after delayed and second autologous stem cell transplant in patients with relapsed multiple myeloma.
Bone marrow transplantation
2021
Abstract
We evaluated the outcomes of 168 patients undergoing delayed or second autologous stem cell transplant (ASCT) for relapsed multiple myeloma (MM) from 2010 to 2019. Overall, 21% (n=35) patients had received a prior transplant and 69% (n=116) underwent transplant at first relapse. Overall, 27% patients had high-risk cytogenetics and 15% had ISS stage III disease. Stem cell collection was performed after relapse in 72% and 35% of patients received maintenance therapy. Median PFS from salvage treatment and transplant were 28 and 19 months, respectively. Median OS from salvage treatment and transplant was 69 and 55 months. Multivariate analysis revealed that ASCT in first relapse was associated with superior PFS (HR 0.63, p=0.03) and OS (HR 0.59, p=0.04) compared to later lines of therapy. In addition, PFS of ≥36 months with prior therapy was associated with improved PFS (HR 0.62, p=0.04) and OS (HR 0.41, p=0.01). Ninety-five patients underwent delayed transplant at first relapse, median PFS and OS from start of therapy was 30 and 69 months, and median OS from diagnosis was 106 months. These data may serve as a guide when counseling patients undergoing ASCT for relapsed MM and provide a benchmark in designing clinical trials of transplantation/comparative treatments for relapsed MM.
View details for DOI 10.1038/s41409-021-01371-1
View details for PubMedID 34163014
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Stem Cell Mobilization in Multiple Myeloma: Comparing Safety and Efficacy of Cyclophosphamide +/- Plerixafor vs. G-CSF +/- Plerixafor in the Lenalidomide Era.
Transplantation and cellular therapy
2021
Abstract
Growth factor and chemotherapy-based stem cell mobilization strategies are commonly used for patients with multiple myeloma. We retrospectively compared 398 patients mobilized between 2017-2020 using either cyclophosphamide (4g/m2) plus granulocyte colony stimulating factor (GCSF) or G-CSF alone, with on demand plerixafor (PXF) in both groups. While total CD34+yield was higher after chemo-mobilization compared to GCSF+/-PXF (median 13.6 vs. 4.4 * 106/kg,P< .01), achievement of≥2 * 106CD34+ cells (95% vs 93.7%,P= .61), and rates of mobilization failure (5% vs. 6.3%,P= .61) were similar. Fewer patients required PXF with chemo-mobilization (12.3% vs 49.5%,P< .01), and apheresis sessions were fewer (median: 1, range 1-4 vs. 2, range 1-5). Complications were higher after chemo-mobilization (30% vs. 7.4%,P< .01), including neutropenic fever, ED visits, and hospitalizations. Prior lenalidomide≤6 cycles did not impair cell yield in either group.Median cost of mobilization was 17.4% lower in the GCSF +/- PXF group (P= .01).Differences in time to engraftment were not clinically significant. Given similar rates mobilization success, engraftment time, and less toxicity and lower costs compared to chemo-mobilization, G-CSF with on-demand PXF may be preferable in myeloma patients with adequate disease control and limited lenalidomide exposure.
View details for DOI 10.1016/j.jtct.2021.04.016
View details for PubMedID 33915323
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Radiation Therapy for Primary Cutaneous Gamma Delta Lymphoma Prior to Stem Cell Transplantation.
Cancer investigation
2021: 1–11
Abstract
We present a patient with widespread PCGD-TCL of the bilateral arms and legs, who underwent radiotherapy with 34Gy in 17 fractions using circumferential VMAT and 3-D printed bolus to the 4 extremities prior to planned stem cell transplant, who was then found to have progression in the liver, lung, and skin, followed by drastic regression of all in and out-of-field lesions on imaging 1.5months later. The cause of regression may be related to a radiation-induced abscopal effect from the immunomodulatory effects of radiation, or related to immune reactivation in the setting of cessation of systemic immunosuppressive agents.
View details for DOI 10.1080/07357907.2021.1919696
View details for PubMedID 33899635
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Use of Backup Stem Cells for Stem Cell Boost and Second Transplant in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation.
Transplantation and cellular therapy
2021
Abstract
Autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient stem cells in case there is a need for stem cell boost for delayed/poor engraftment or for future second ASCT. However, collecting and storing backup stem cells in all patients requires significant resources and cost, and the rates of backup stem cell utilization are not well studied. We sought to examine the utilization of backup stem cells (BSCs) in patients with MM undergoing ASCT. Patients with MM aged ≥18 years old who underwent first ASCT at our institution from January 2010 through December 2015 and collected sufficient stem cells for at least 2 transplants were included in this single-center retrospective study. This timeframe was selected to allow for adequate follow-up. A total of 393 patients were included. The median age was 58 years (range, 25-73). After a median follow-up of 6 years, the median progression-free survival (PFS) of the cohort was 3 years. Sixty-one percent (n=240) of patients progressed or relapsed. Chemotherapy-based mobilization was used in almost all patients (98%). The median total CD34+ cells collected was 18.2*106/kg (range, 3.4-112.4). A median of 5.7*106 CD34+ cells/kg (range, 1.8-41.9) was infused during the first ASCT, and a median of 10.1*106 CD34+ cells/kg (range, 1.5-104.5) was cryopreserved for future use. Of the patients, 6.9% (n=27) used backup stem cells, with 2.3% (n=10) using them for stem cell boost, 4.6% (n=18) for a second salvage ASCT, including 1 patient for both stem cell boost and second ASCT. Rates of backup stem cell use among patients aged <60, 60-69, and ≥70 years were 7.8%, 5.7%, and 5.9%, respectively. There was a trend toward higher rates of backup stem cell use for second ASCT in patients who were younger, had suboptimal disease control at time of first ASCT, and longer PFS. The median dose of stem cell boost given was 5.6*106 CD34+ cells/kg (range, 1.9-20). The median time from stem cell boost to neutrophil, hemoglobin, and platelet engraftment was 4 (range, 2-11), 15 (range, 4-34), and 12 (range, 0-34) days, respectively. Lower CD34+ dose and older age at time of ASCT predicted need for stem cell boost. With new salvage therapies for relapsed MM, the rates of second ASCT are very low. The low rates of use suggest that institutional policies regarding universal BSC collection and long-term storage should be reassessed and individualized. However, need for stem cell boost in 2.3% of patients may present a challenge to that.
View details for DOI 10.1016/j.jtct.2021.02.026
View details for PubMedID 33775587
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Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma
BLOOD ADVANCES
2021; 5 (1): 143–55
View details for DOI 10.1182/bloodadvances.2020002732
View details for Web of Science ID 000607932700016
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Pembrolizumab in mycosis fungoides with PD-L1 structural variants.
Blood advances
2021; 5 (3): 771–74
View details for DOI 10.1182/bloodadvances.2020002371
View details for PubMedID 33560388
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Incidence and Risk Factors Associated with Bleeding and Thrombosis Following Chimeric Antigen Receptor T Cell Therapy.
Blood advances
2021
Abstract
Bleeding and thrombotic events are an emerging toxicity associated with chimeric antigen receptor (CAR) therapies. To determine their incidence, we retrospectively analyzed consecutive adult patients (n=127) with large B-cell lymphoma (LBCL) or B-cell acute lymphoblastic leukemia (B-ALL) treated between 2017-2020 with axicabtagene ciloleucel (axi-cel) (N=89) or a bispecific CD19/CD22 CAR (N=38). 12 (9.4%) and 8 (6.3%) patients developed bleeding and thrombosis within first 3 months, respectively. In the axi-cel subgroup, these occurred in 11.2% and 6.7%, respectively. Bleeding occurred between days 8-30 (median 17.5), and thrombosis between days 2-91 (median 29). Bleeding sites included genitourinary (N=6), soft tissue (N=2), intracranial (N=2), gastrointestinal (N=1), pulmonary (N=1), and were associated with features of consumptive coagulopathy. On univariate analysis, patients with bleeding were older (median 72 vs. 60 yrs, P<0.01), had lower baseline platelets (86 vs. 178 K/uL, P<0.01), lower platelet nadir after CAR-T (median 17.5 vs. 48 K/uL; P<0.01), lower fibrinogen nadir (median 122 vs. 340 ug/mL; P<0.01) and elevated LDH (P=0.01). ICANS grade ≥3 was associated with increased bleeding (50% vs. 15%; P=0.01), thrombosis (50% vs. 16%; P=0.04), PT prolongation, hypofibrinogenemia and elevated D-dimer. A paucity of events limited multivariate analysis, however low pre-treatment platelets were associated with bleeding in a multivariate logistic regression model. Patients with thrombocytopenia or severe ICANS are at increased risk of bleeding complications and should be closely monitored particularly within the first month after CAR therapy. Future studies in larger cohorts should assess risk factors for systemic coagulopathies in CAR-T therapy, including their association with neurotoxicity.
View details for DOI 10.1182/bloodadvances.2021004716
View details for PubMedID 34521106
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Outcomes with Autologous or Allogeneic Stem Cell Transplantation in Patients with Plasma Cell Leukemia in the Era of Novel Agents.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
2020
Abstract
Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell disorder. The optimal treatment approach, including whether to pursue an autologous (autoSCT) or allogeneic (alloSCT) transplant is not clear as there is lack of clinical trial based evidence. This single center retrospective study describes the outcomes of 16 patients with PCL (N=14 primary PCL) who underwent either autoSCT (N=9) or alloSCT (N=7) for PCL in the era of novel agents, between 2007 and 2019. Median age of the cohort was 58 years. High-risk cytogenetics were seen in 50% of patients. All patients received a proteasome inhibitor (PI) and/or immunomodulatory drug (IMiD) based regimen before transplant. At transplant, 10 (62%) patients obtained at least a very good partial response. Response after autoSCT (3 month) was at least VGPR in 6 (67%, CR=5) patients. All patients undergoing alloSCT achieved CR at 3 months. Maintenance was used in 5 patients (56%) after autoSCT. Median PFS from transplant in the autoSCT vs. alloSCT group was 6 vs. 18 months, p=0.09, while median OS from transplant was 19 vs. 40 months (p=0.41), respectively. The median OS from diagnosis was 27 vs. 49 months, p=0.50, respectively. Of all the deaths, 10 (91%) patients died of relapsed disease. In conclusion, alloSCT was not observed to offer any significant survival advantage over autoSCT in PCL, which is comparable to other recent reports and relapse remains the primary cause of death.
View details for DOI 10.1016/j.bbmt.2020.08.035
View details for PubMedID 32961371
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Outcomes with autologous stem cell transplant vs. non-transplant therapy in patients 70 years and older with multiple myeloma.
Bone marrow transplantation
2020
Abstract
We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality (TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients <70 years (n = 631) (median PFS from transplant: 36 vs. 47 months, p = 0.25). In this retrospective analysis, ASCT was associated with low TRM and better PFS in fit older adults with MM compared to non-transplant therapy, with comparable benefits as seen in younger patients.
View details for DOI 10.1038/s41409-020-01026-7
View details for PubMedID 32782351
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Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial.
The Journal of experimental medicine
2020; 217 (9)
Abstract
Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.
View details for DOI 10.1084/jem.20191712
View details for PubMedID 32558897
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CD22-Directed CAR T-Cell Therapy Induces Complete Remissions in CD19-Directed CAR-Refractory Large B-Cell Lymphoma.
Blood
2020
Abstract
The prognosis for patients with large B-cell lymphoma (LBCL) progressing after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first three consecutive patients with autologous CAR19-refractory LBCL treated with a single infusion of autologous 1×106 CAR+ T-cells/kg targeting CD22 (CAR22) as part of a phase I dose escalation study. CAR22 therapy was relatively well tolerated, without any observed non-hematologic adverse events higher than grade 2. Following infusion, all three patients achieved complete remission, with all responses ongoing at the time of last follow up (mean 7.8 months, range 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range 85.4-350 cells/µL), and persisted beyond three months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA (ctDNA) beyond six months post-infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients who have failed prior CAR T-cell therapies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT04088890).
View details for DOI 10.1182/blood.2020009432
View details for PubMedID 33512414
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Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma.
Blood advances
2020; 4 (18): 4474–82
Abstract
The majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients. Cyclosporine or tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. Patients tolerated the transplant well, with 1- and 2-year nonrelapse mortality of 3% and 14%, respectively. The day +180 cumulative incidence of grade 2 to 4 acute GVHD was 16%, and the 2-year incidence of moderate/severe chronic GVHD was 32%. With a median posttransplant follow-up of 5.4 years, the 2-, 3-, and 5-year overall survival rates were 68%, 62%, and 56%. Using high-throughput sequencing of the T-cell receptor for minimal residual disease monitoring, we observed that 43% achieved molecular remission, which was associated with a lower incidence of disease progression or relapse (9% vs 87%; P = .02). Our study also showed that patients who were aged ≥65 years at the time of allotransplant had similar clinical outcomes compared with younger patients. Thus, we have developed an alternative and potentially curative nonmyeloablative allogeneic transplant regimen for patients with advanced stage MF/SS. This trial was registered at www.clinicaltrials.gov as #NCT00896493.
View details for DOI 10.1182/bloodadvances.2020001627
View details for PubMedID 32941647
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Pityriasis rubra pilaris-like graft-vs-host disease following allogeneic stem cell transplant in two patients.
Clinical case reports
2019; 7 (12): 2491-2494
Abstract
Chronic cutaneous graft-vs-host disease (GVHD) has several atypical variants. We describe two cases of GVHD with clinical and histopathologic features of pityriasis rubra pilaris (PRP), which responded to additional immunosuppression. Recognition of this newly described PRP-like clinical presentation of GVHD may prompt early consideration of additional steroid-sparing therapies.
View details for DOI 10.1002/ccr3.2458
View details for PubMedID 31893086
View details for PubMedCentralID PMC6935619
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Volumetric Modulated Arc Therapy and 3-Dimensional Printed Bolus in the Treatment of Refractory Primary Cutaneous Gamma Delta Lymphoma of the Bilateral Legs
PRACTICAL RADIATION ONCOLOGY
2019; 9 (4): 220–25
View details for DOI 10.1016/j.prro.2019.02.016
View details for Web of Science ID 000472574100020
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Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients
JCI INSIGHT
2019; 4 (10)
View details for DOI 10.1172/jci.insight.127244
View details for Web of Science ID 000468146300016
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Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort.
Blood advances
2019; 3 (16): 2454–64
Abstract
Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining graft-versus-tumor activity across various hematologic malignancies. We report our comprehensive experience using TLI-ATG conditioning in 612 patients with hematologic malignancies who underwent allogeneic transplantation at Stanford University from 2001 to 2016. All patients received granulocyte colony-stimulating factor-mobilized peripheral blood grafts and cyclosporine and mycophenolate mofetil for GVHD prophylaxis. The median age was 60 years (range, 21-78), with a median follow-up of 6.0 years (range, 1.0-16.4). Common diagnoses included acute myeloid leukemia (AML; n = 193), myelodysplastic syndrome (MDS; n = 94), chronic lymphocytic leukemia (CLL; n = 80), non-Hodgkin lymphoma (NHL; n = 175), and Hodgkin lymphoma (HL; n = 35). Thirty-four percent of patients had a comorbidity index ≥3, 30% had a high to very high disease risk index, and 56% received unrelated donor grafts, including 15% with HLA-mismatched donors. Ninety-eight percent underwent transplant in the outpatient setting, and 57% were never hospitalized from days 0 through 100. The 1-year rates of nonrelapse mortality (NRM), grade II-IV acute GVHD, and extensive chronic GVHD were 9%, 14%, and 22%, respectively. The 4-year estimates for overall and progression-free survival were 42% and 32% for AML, 30% and 21% for MDS, 67% and 43% for CLL, 68% and 45% for NHL, and 78% and 49% for HL. Mixed chimerism correlated with the risk of relapse. TLI-ATG conditioning was well tolerated, with low rates of GVHD and NRM. Durable remissions were observed across hematologic malignancies, with particularly favorable outcomes for heavily pretreated lymphomas. Several efforts are underway to augment donor chimerism and reduce relapse rates while maintaining the favorable safety and tolerability profile of this regimen.
View details for DOI 10.1182/bloodadvances.2019000297
View details for PubMedID 31427277
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Infusion of donor-derived CD8(+) memory T cells for relapse following allogeneic hematopoietic cell transplantation
BLOOD ADVANCES
2018; 2 (6): 681–90
Abstract
Murine models showed that CD8+CD44hi memory T (TM) cells could eradicate malignant cells without inducing graft-versus-host disease (GVHD). We evaluated the feasibility and safety of infusing freshly isolated and purified donor-derived phenotypic CD8+ TM cells into adults with disease relapse after allogeneic hematopoietic cell transplantation (HCT). Phenotypic CD8 TM cells were isolated after unmobilized donor apheresis using a tandem immunomagnetic selection strategy of CD45RA depletion followed by CD8+ enrichment. Fifteen patients received CD8+ TM cells at escalating doses (1 × 106, 5 × 106, or 10 × 106 cells per kg). Thirteen received cytoreduction before CD8+ TM cell infusion, and 9 had active disease at the time of infusion. Mean yield and purity of the CD8+ TM infusion were 38.1% and 92.8%, respectively; >90% had CD8+ T effector memory phenotype, cytokine expression, and secretion profile. No adverse infusional events or dose-limiting toxicities occurred; GVHD developed in 1 patient (grade 2 liver). Ten patients (67%) maintained or achieved response (7 complete response, 1 partial response, 2 stable disease) for at least 3 months after infusion; 4 of the responders had active disease at the time of infusion. With a median follow-up from infusion of 328 days (range, 118-1328 days), median event-free survival and overall survival were 4.9 months (95% confidence interval [CI], 1-19.3 months) and 19.6 months (95% CI, 5.6 months to not reached), respectively. Collection and enrichment of phenotypic CD8+ TM cells is feasible, well tolerated, and associated with a low incidence of GVHD when administered as a manipulated infusion of donor lymphocytes in patients who have relapsed after HCT. This trial was registered at www.clinicaltrials.gov as #NCT01523223.
View details for PubMedID 29572391
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Potential Association of Anti-CCR4 Antibody Mogamulizumab and Graft-vs-Host Disease in Patients With Mycosis Fungoides and Sézary Syndrome.
JAMA dermatology
2018
View details for PubMedID 29800117
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Effect of voriconazole on risk of nonmelanoma skin cancer after hematopoietic cell transplantation
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
2017; 77 (4): 706–12
Abstract
Voriconazole has previously been associated with increased risk for cutaneous squamous cell carcinoma (SCC) in solid organ transplant recipients. Less is known about the risk in patients after hematopoietic cell transplantation (HCT).We evaluated the effect of voriconazole on the risk for nonmelanoma skin cancer (NMSC), including SCC and basal cell carcionoma, among those who have undergone allogeneic and autologous HCT.In all, 1220 individuals who had undergone allogeneic HCT and 1418 who had undergone autologous HCT were included in a retrospective cohort study. Multivariate analysis included voriconazole exposure and other known risk factors for NMSC.In multivariate analysis, voriconazole use increased the risk for NMSC (hazard ratio, 1.82; 95% confidence interval, 1.13-2.91) among those who had undergone allogeneic HCT, particularly for SCC (hazard ratio, 2.25; 95% confidence interval, 1.30-3.89). Voriconazole use did not appear to confer increased risk for NMSC among those who had undergone autologous HCT.This is a retrospective study.Voriconazole use represents an independent factor that may contribute to increased risk specifically for SCC in the allogeneic HCT population.
View details for PubMedID 28780363
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Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index in Nonmyeloablative Allogeneic Stem Cell Transplantation
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2017; 23 (10): 1744–48
Abstract
The Hematopoietic Cell Transplantation (HCT)-Specific Comorbidity Index (HCT-CI) has been extensively studied in myeloablative and reduced-intensity conditioning regimens, with less data available regarding the validity of HCT-CI in nonmyeloablative (NMA) allogeneic transplantation. We conducted a retrospective analysis to evaluate the association between HCT-CI and nonrelapse mortality (NRM) and all-cause mortality (ACM) in patients receiving the total lymphoid irradiation and antithymocyte globulin (TLI/ATG) NMA transplantation preparative regimen. We abstracted demographic and clinical data from consecutive patients, who received allogeneic HCT with the TLI/ATG regimen between January 2008 and September 2014, from the Stanford blood and marrow transplantation database. We conducted univariable and multivariable Cox proportional hazards regression models to evaluate the association between HCT-CI and NRM and ACM. In all, 287 patients were included for analysis. The median age of the patients was 61 (range, 22 to 77) years. The median overall survival was 844 (range, 374 to 1484) days. Most patients had Karnofsky performance score of 90 or above (85%). Fifty-two (18%) patients relapsed within 3 months and 108 (38%) patients relapsed within 1 year, with a median time to relapse of 163 (range, 83 to 366) days. Among the comorbidities in the HCT-CI identified at the time of HCT, reduced pulmonary function was the most common (n = 89), followed by prior history of malignancy (n = 39), psychiatric condition (n = 38), and diabetes (n = 31). Patients with higher HCT-CI scores had higher mortality risks for ACM (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.14 for HCT-CI score 1 or 2 and HR, 1.85; 95% CI, 1.11 to 3.08 for HCT-CI score ≥ 3, compared with 0, respectively). Among individual HCT-CI variables, diabetes (HR, 2.31; 95% CI, 1.79 to 2.89; P = .003) and prior solid tumors (HR, 1.75; 95% CI, 1.02 to 3.00; P = .043) were associated with a higher risk of ACM. Higher HCT-CI scores were significantly associated with higher risk of death. HCT-CI is a valid tool for predicting ACM in NMA TLI/ATG allogeneic HCT.
View details for PubMedID 28668491
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Gain of CD26 expression on the malignant T-cells in relapsed erythrodermic leukemic mycosis fungoides.
Journal of cutaneous pathology
2017
Abstract
Loss of CD26 surface expression on the circulating malignant T-cell is the most widely accepted diagnostic marker in patients with leukemic cutaneous T-cell lymphoma (CTCL). CTCL cases with reemergence of CD7 and/or CD26 surface expression are unusual and of uncertain prognosis. We report the case of an erythrodermic leukemic mycosis fungoides patient who had achieved temporary remission after a several months on multimodality immunotherapy and extracorporeal photopheresis, but who relapsed with aggressive disease phenotypically characterized by CD4+ T-cells with high CD26 expression. Polymerase chain reaction (PCR) studies and high throughput sequencing analyses from peripheral blood mononuclear cells at presentation and relapse consistently showed an identical clonal T-cell receptor (TCR) suggesting evolution of her original malignant clone which lacked CD26 expression. Interestingly, quantitative expression of the sialomucin, CD164, mirrored her clinical picture, thus favoring its reliability as a novel biomarker in CTCL.
View details for DOI 10.1111/cup.12899
View details for PubMedID 28083948
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HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity.
Blood advances
2017; 1 (17): 1347–57
Abstract
Many patients lack a fully HLA-matched donor for hematopoietic cell transplantation (HCT), and HLA mismatch is typically associated with inferior outcomes. Total lymphoid irradiation and antithymocyte globulin (TLI-ATG) is a nonmyeloablative conditioning regimen that is protective against graft-versus-host disease (GVHD), and we hypothesized that the protective effect would extend beyond HLA-matched donors. We report outcomes for all consecutively transplanted patients at Stanford University from December 2001 through May 2015 who received TLI-ATG conditioning and HCTs from 8 to 9 out of 10 HLA-mismatched unrelated donors (MMUDs, N = 72) compared with 10 out of 10 HLA-matched unrelated donors (MUDs, N = 193). The median age of the patients was 60 years with a median follow-up of 2 years, and there was a similar distribution of lymphoid and myeloid malignancies in both cohorts. There were no significant differences between MMUD and MUD cohorts in overall survival (46% vs 46% at 5 years, P = .86), disease-free survival (38% vs 28% at 5 years, P = .25), nonrelapse mortality (17% vs 12% at 2 years, P = .34), acute GVHD grades III-IV (6% vs 3% at day +100, P = .61), or chronic GVHD (39% vs 35% at 5 years, P = .49). There was a trend toward less relapse in the MMUD cohort (45% vs 60% at 5 years, hazard ratio: 0.71, P = .094), which was significant for patients with lymphoid malignancies (29% vs 57% at 5 years, hazard ratio: 0.55, P = .044). Achieving full donor chimerism was strongly associated with lower relapse rates. TLI-ATG conditioning may overcome the traditionally poorer outcome associated with HLA-mismatched donors and may be particularly well suited for patients with lymphoid malignancies who lack HLA-matched donors.
View details for PubMedID 29296777
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Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project.
Journal of clinical oncology
2015; 33 (32): 3750-3758
Abstract
In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored.In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety.Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event.Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.
View details for DOI 10.1200/JCO.2014.60.3969
View details for PubMedID 26195720
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Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2.
Nature genetics
2015; 47 (9): 1056-1060
Abstract
Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.
View details for DOI 10.1038/ng.3370
View details for PubMedID 26258847
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Total lymphoid irradiation-antithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms.
Biology of blood and marrow transplantation
2014; 20 (6): 837-843
Abstract
Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative therapy for the myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but treatment toxicity has been a barrier to its more widespread use. The nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) permits the establishment of donor hematopoiesis necessary for the graft-versus-malignancy effect and is protective against acute graft-versus-host disease (aGVHD), but it has minimal direct cytotoxicity against myeloid diseases. We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS (n = 32), therapy-related myeloid neoplasms (n = 15), MPN (n = 9), and chronic myelomonocytic leukemia (n = 5). The median age of all patients was 63 years (range, 50 to 73). The cumulative incidence of aGVHD grades II to IV was 14% (95% confidence interval [CI], 4% to 23%) and for grades III to IV, 4% (95% CI, 0 to 9%), and it did not differ between patients who received allografts from related or unrelated donors. The cumulative incidence of nonrelapse mortality (NRM) at 100 days, 12 months, and 36 months was 0%, 7%, and 11%. Overall survival and progression-free survival were 41% (95% CI, 29% to 53%) and 35% (95% CI, 23% to 48%), respectively. The safety and tolerability of TLI-ATG, as exemplified by its low NRM, provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression.
View details for DOI 10.1016/j.bbmt.2014.02.023
View details for PubMedID 24607552
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European LeukemiaNet classification intermediate risk-1 cohort is associated with poor outcomes in adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation
BLOOD CANCER JOURNAL
2014; 4
View details for DOI 10.1038/bcj.2014.35
View details for PubMedID 24879117
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Cancer Vaccines and T Cell Therapy
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2013; 19 (1): S97-S101
View details for DOI 10.1016/j.bbmt.2012.09.020
View details for Web of Science ID 000313998100024
View details for PubMedID 23041602
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Minimal residual disease monitoring with high-throughput sequencing of T cell receptors in cutaneous T cell lymphoma
SCIENCE TRANSLATIONAL MEDICINE
2013; 5 (214): 214ra171
View details for DOI 10.1126/scitranslmed.3007420
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Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence
BLOOD
2012; 119 (25): 6145-6154
Abstract
B cells are involved in the pathogenesis of chronic GVHD (cGVHD). We hypothesized that prophylactic anti-B-cell therapy delivered 2 months after transplantation would decrease allogeneic donor B-cell immunity and possibly the incidence of cGVHD. Therefore, in the present study, patients with high-risk chronic lymphocytic leukemia (n = 22) and mantle-cell lymphoma (n = 13) received a total lymphoid irradiation of 80 cGy for 10 days and antithymocyte globulin 1.5 mg/kg/d for 5 days. Rituximab (375 mg/m(2)) was infused weekly on days 56, 63, 70, and 77 after transplantation. The incidence of acute GVHD was 6%. The cumulative incidence of cGVHD was 20%. Nonrelapse mortality was 3%. Rituximab treatment after allogeneic transplantation significantly reduced B-cell allogeneic immunity, with complete prevention of alloreactive H-Y Ab development in male patients with female donors (P = .01). Overall survival and freedom from progression at 4 years for chronic lymphocytic leukemia patients were 73% and 47%, respectively; for mantle-cell lymphoma patients, they were 69% and 53%, respectively.
View details for DOI 10.1182/blood-2011-12-395970
View details for PubMedID 22563089
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The histone deacetylase inhibitor, romidepsin, suppresses cellular immune functions of cutaneous T-cell lymphoma patients
AMERICAN JOURNAL OF HEMATOLOGY
2012; 87 (4): 354-360
Abstract
Romidepsin is the second histone deacetylase inhibitor (HDACi) approved for the treatment of advanced stages of cutaneous T-cell lymphoma (CTCL). Recent in vitro data suggest that HDACis suppress immune function although these findings have not been confirmed in patients. Thus, we serially examined the cellular immune function of eight CTCL patients undergoing treatment with three cycles of romidepsin. We measured the patients' natural killer (NK) and dendritic cell (DC) function and performed an in vitro terminal deoxynucleotidyl transferase dUTP nick end labeling assay to measure cellular apoptosis. Patients' NK cell cytolytic activity decreased from baseline to the third cycle of treatment (P = 0.018) but stimulation with a toll-like receptor (TLR) agonist increased this activity (P = 0.018). At baseline, a TLR agonist could both activate patients' DC (P = 0.043) and stimulate interleukin-12 protein production (P = 0.043) but both were suppressed after the first cycle of romidepsin. Finally, we observed increased specificity for romidepsin-induced CD4+ tumor cell apoptosis and dose-dependent increases in cellular apoptosis of healthy cells in multiple lineages (P < 0.05). These findings raise concern that HDACis suppress immune function in CTCL patients and they support the concurrent use of multiple immune stimulatory agents to preserve the host immune response.
View details for DOI 10.1002/ajh.23112
View details for Web of Science ID 000301429300003
View details for PubMedID 22367792
View details for PubMedCentralID PMC3638752
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Tandem chemo-mobilization followed by high-dose melphalan and carmustine with single autologous hematopoietic cell transplantation for multiple myeloma
BONE MARROW TRANSPLANTATION
2012; 47 (4): 516-521
Abstract
Single autologous hematopoietic cell transplant (AHCT) with high-dose melphalan prolongs survival in patients with multiple myeloma but is not curative. We conducted a study of intensive single AHCT using tandem chemo-mobilization with CY and etoposide followed by high-dose conditioning with melphalan 200 mg/m(2) plus carmustine 15 mg/kg. One hundred and eighteen patients in first consolidation (CON1) and 58 patients in relapse (REL) were transplanted using this intensified approach. Disease response improved from 32% very good PR (VGPR)+CR pre-mobilization to 76% VGPR+CR post transplant in CON1. With a median follow-up of 4.7 years, the median EFS was 2.8 years, and the median OS was 5.1 years in CON1. OS from time of transplant was significantly shorter for REL (3.4 years) compared with CON1 (5.1 years; P=0.02). However, OS from time of diagnosis was similar in REL (6.1 years) and CON1 (6.0 years; P=0.80). The 100-day non-relapse mortality in the CON1 and REL groups was 0% and 7%, respectively. In summary, intensified single AHCT with tandem chemo-mobilization and augmented high-dose therapy is feasible in multiple myeloma and leads to high-quality response rates.
View details for DOI 10.1038/bmt.2011.106
View details for PubMedID 21602899
- Transcriptome sequencing in Sezary syndrome identifies Sezary cell and mycosis fungoides-associated IncRNAs and novel transcripts BLOOD 2012; 120: 3288-3297
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Adoptive Immunotherapy with Cytokine-Induced Killer Cells for Patients with Relapsed Hematologic Malignancies after Allogeneic Hematopoietic Cell Transplantation
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2011; 17 (11): 1679-1687
Abstract
Donor leukocyte infusions induce remissions in some patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT); however, graft-versus-host disease (GVHD) remains the major complication of this strategy. Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes that express the CD3(+)CD56(+) phenotype and show marked up-regulation of the natural killer cell receptor NKG2D (CD314). CIK cells are non-major histocompatibility complex-restricted and NKG2D-dependent in target recognition and cytotoxicity. We explored the feasibility of ex vivo expansion of allogeneic CIK cells in patients with relapsed hematologic malignancies after allogeneic HCT. Eighteen patients (median age, 53 years; range, 20-69 years) received CIK cell infusions at escalating doses of 1 × 10(7) CD3(+) cells/kg (n = 4), 5 × 10(7) CD3(+) cells/kg (n = 6), and 1 × 10(8) CD3(+) cells/kg (n = 8). The median expansion of CD3(+) cells was 12-fold (range, 4- to 91-fold). CD3(+)CD56(+) cells represented a median of 11% (range, 4%-44%) of the harvested cells, with a median 31-fold (range, 7- to 515-fold) expansion. Median CD3(+)CD314(+) cell expression was 53% (range, 32%-78%) of harvested cells. Significant cytotoxicity was demonstrated in vitro against a panel of human tumor cell lines. Acute GVHD grade I-II was seen in 2 patients, and 1 patient had limited chronic GVHD. After a median follow-up of 20 months (range, 1-69 months) from CIK infusion, the median overall survival was 28 months, and the median event-free survival was 4 months. All deaths were due to relapsed disease; however, 5 patients had longer remissions after infusion of CIK cells than from allogeneic HCT to relapse. Our findings indicate that this form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD, supporting further investigation as an upfront modality to enhance graft-versus-tumor responses in high-risk patient populations.
View details for DOI 10.1016/j.bbmt.2011.05.012
View details for PubMedID 21664472
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Phase I/II Trial of GN-BVC, a Gemcitabine and Vinorelbine-Containing Conditioning Regimen for Autologous Hematopoietic Cell Transplantation in Recurrent and Refractory Hodgkin Lymphoma
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2010; 16 (8): 1145-1154
Abstract
Autologous hematopoietic cell transplantation with augmented BCNU regimens is effective treatment for recurrent or refractory Hodgkin lymphoma (HL); however, BCNU-related toxicity and disease recurrence remain challenges. We designed a conditioning regimen with gemcitabine in combination with vinorelbine in an effort to reduce the BCNU dose and toxicity without compromising efficacy. In this phase I/II dose escalation study, the gemcitabine maximum tolerated dose (MTD) was determined at 1250 mg/m(2), and a total of 92 patients were treated at this dose to establish safety and efficacy. The primary endpoint was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year freedom from progression (FFP), event-free survival (EFS), and overall survival (OS). Sixty-eight patients (74%) had 1 or more previously defined adverse risk factors for transplant (stage IV at relapse, B symptoms at relapse, greater than minimal disease pretransplant). The incidence of BCNU-related toxicity was 15% (95% confidence interval, 9%-24%). Only 2% of patients had a documented reduction in diffusing capacity of 20% or greater. With a median follow-up of 29 months, the FFP at 2 years was 71% and the OS at 2 years was 83%. Two-year FFP was 96%, 72%, 67%, and 14% for patients with 0 (n = 24), 1 (n = 37), 2 (n = 23), or 3 (n = 8) risk factors, respectively. Regression analysis identified PET status pretransplant and B symptoms at relapse as significant prognostic factors for FFP. This new transplant regimen for HL resulted in decreased BCNU toxicity with encouraging FFP and OS. A prospective, risk-modeled comparison of this new combination with other conditioning regimens is warranted.
View details for DOI 10.1016/j.bbmt.2010.02.022
View details for PubMedID 20197102
- The IgG Fc Receptor FcγRIIIa 158 V/F Polymorphism is Correlated with Rituximab-Induced Neutropenia after Autologous Transplantation in Patients with Non-Hodgkin Lymphoma JOURNAL OF CLINICAL ONCOLOGY 2010; 28: 279-284
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TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors
BLOOD
2009; 114 (5): 1099-1109
Abstract
A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)-matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.
View details for DOI 10.1182/blood-2009-03-211441
View details for PubMedID 19423725
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Tumor-specific recombinant idiotype immunisation after chemotherapy as initial treatment for follicular non-Hodgkin lymphoma
LEUKEMIA & LYMPHOMA
2009; 50 (1): 37-46
Abstract
Tumor-specific variable regions of the clonal immunoglobulin (idiotype, Id) expressed by B cell non-Hodgkin lymphoma (NHL) can be targeted by active immunotherapy. We conducted a phase I/II trial to determine the safety and immunogenicity of a patient-specific, recombinant, mammalian cell-derived Id protein conjugated to keyhole limpet hemocyanin (Id-KLH; MyVax personalised immunotherapy) in 22 patients with follicular NHL in first remission after chemotherapy. Subjects received five subcutaneous immunisations with MyVax plus locally administered granulocyte-macrophage colony-stimulating factor (GM-CSF). Among 21 evaluable patients, 62% mounted Id-specific immune responses. Evoked anti-Id antibodies recognised both recombinant Id and native Id, and could specifically stain autologous tumor cells. At median follow-up of more than 6 years, median progression-free survival is 38 months. Immunisation of follicular lymphoma patients with MyVax Id-KLH is safe and patients often mount tumor-specific immune responses. These results form the basis of a pivotal phase 3 trial of MyVax in follicular NHL.
View details for DOI 10.1080/10428190802563355
View details for Web of Science ID 000262789000009
View details for PubMedID 19125383
View details for PubMedCentralID PMC2914563
- Genetic polymorphism of the inhibitory IgG Fc receptor FcRIIb is not associated with clinical outcome in patients with follicular lymphoma treated with rituximab LEUKEMIA & LYMPHOMA 2009; 50 (5:723-727)
- Immunoglobulin G Fc Receptor Polymorphisms Do Not Correlate with Response to Chemotherapy or Clinical Course in Patients with Follicular Lymphoma LEUKEMIA & LYMPHOMA 2009; 50 (9): 1494-1500
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A Polymorphism in the Complement Component C1qA Correlates with Prolonged Response Following Rituximab Therapy of Follicular Lymphoma
CLINICAL CANCER RESEARCH
2008; 14 (20): 6697-6703
Abstract
Complement may play a role in the clinical response to rituximab and other monoclonal antibody-based therapies of cancer. The purpose of this study was to explore the relationship between the C1qA([276]) polymorphism and the clinical response to rituximab in patients with follicular lymphoma.Genotyping for C1qA([276A/G]) was done in 133 subjects with follicular lymphoma treated with single-agent rituximab, and correlation with clinical response was done using Cox regression analysis.Prolonged remission was observed among subjects that responded clinically to rituximab therapy and were carriers of the A allele compared with homozygous G subjects. Homozygous G subjects had a time to progression of 282 days, whereas A-allele carriers had a time to progression of 708 days [hazard ratio, (HR), 2.5; 95% confidence interval (95% CI), 2.0-3.1; P = 0.02]. Among subjects who achieved complete remission, homozygous G subjects had a time to progression of 250 days, whereas A-allele carriers had a time to progression of 1,118 days (HR, 4.5; 95% CI, 4.1-4.8, P = 0.04). The difference persisted after controlling for CD32 and CD16 polymorphisms. In patients who responded to rituximab used as first-line agent, a linear trend was observed among the C1qA([276]) genotypes, with homozygous A subjects achieving complete response at a higher rate compared with heterozygous or homozygous G subjects.Our findings indicate that polymorphisms in the C1qA gene may affect the clinical response and duration of response to rituximab therapy of follicular lymphoma. These results could have direct implications on designing antibodies with improved efficiency and enhance our understanding of the role of complement in monoclonal antibody therapy.
View details for DOI 10.1158/1078-0432.CCR-08-0745
View details for Web of Science ID 000260359600042
View details for PubMedID 18927313
View details for PubMedCentralID PMC2907116
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The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells
BLOOD
2008; 112 (3): 711-720
Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is a lymphoproliferative disorder characterized by the surface expression of CD20, CD5 antigens, as well as the receptor CD40. Activation of CD40 by its ligand (CD40L) induces proliferation and rescues the cells from spontaneous and chemotherapy-induced apoptosis. CD40 activation also induces secretion of cytokines, such as IL-6, IL-10, TNF-alpha, IL-8, and GM-CSF, which are involved in tumor cell survival, migration, and interaction with cells in the tumor microenvironment. Here we demonstrate that in primary B-CLL tumor cells, the novel antagonist anti-CD40 monoclonal antibody, HCD122, inhibits CD40L-induced activation of signaling pathways, proliferation and survival, and secretion of cytokines. Furthermore, HCD122 is also a potent mediator of antibody-dependent cellular cytotoxicity (ADCC), lysing B-CLL cells more efficiently than rituximab in vitro, despite a significantly higher number of cell surface CD20 binding sites compared with CD40. Unlike rituximab, however, HCD122 (formerly CHIR-12.12) does not internalize upon binding to the cells. Our data suggest that HCD122 may inhibit B-CLL growth by blocking CD40 signaling and by ADCC-mediated cell lysis.
View details for DOI 10.1182/blood-2007-04-084756
View details for Web of Science ID 000258257900039
View details for PubMedID 18497318
View details for PubMedCentralID PMC2481542
- Humoral immune response and immunoglobulin G Fc receptor genotype are associated with better clinical outcome following idiotype vaccination in follicular lymphoma patients regardless their response to induction chemotherapy. BLOOD 2007; 109: 951-3
- Immune-mediated antitumor effects with antibody therapy. American Society of Clinical Oncology Educational Book 2005: 200-4
- Clinical outcome of lymphoma patients after idiotype vaccination is correlated with humoral immune response and immunoglobulin G Fc receptor genotype. JOUNRAL OF CLINICAL ONCOLOGY 2004; 22: 4717
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Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma
JOURNAL OF CLINICAL ONCOLOGY
2003; 21 (21): 3940-3947
Abstract
Although rituximab is now routinely used in the treatment of B-cell non-Hodgkin's lymphoma, the mechanism of its antitumor effect is not clear. One potential mechanism of action involves antibody-dependent cellular cytotoxicity (ADCC). Two aspects of ADCC influence the effectiveness of this process: the susceptibility of tumor cells and the activation of effector cells via their immunoglobulin G fragment C receptors (Fc gamma Rs). Several Fc gamma R polymorphisms have been identified that may affect the killing function of natural killer cells and macrophages.The pretreatment tumor cells from 43 patients with follicular lymphoma were tested for their intrinsic susceptibility to rituximab-mediated ADCC. In addition, the Fc gamma RIIIa (CD16) and Fc gamma RIIa (CD32) polymorphisms were determined in an expanded group of 87 patients. The results were then correlated with clinical outcome of these patients.No difference was found between the susceptibility of tumors from patients who clinically responded to rituximab versus those who did not respond. Conversely, both the Fc gamma RIIIa 158 valine/valine and the Fc gamma RIIa 131 histidine/histidine genotypes were found to be independently associated with the response rate and freedom from progression.These data support the hypothesis that ADCC plays an important role in the clinical effect of rituximab at the level of the effector cell. It will be important to include information on Fc receptor polymorphisms in future trials of rituximab therapy.
View details for DOI 10.1200/JCO.2003.05.013
View details for Web of Science ID 000186295500010
View details for PubMedID 12975461
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Hepatitis C virus (HCV) and lymphomagenesis
LEUKEMIA & LYMPHOMA
2003; 44 (7): 1113-1120
Abstract
Hepatitis C virus (HCV) is the major cause for non-A, non-B hepatitis. Most HCV-infected individuals do not clear the virus resulting in a chronic infection that may potentially lead to liver cirrhosis and hepatocellular carcinoma. In addition to hepatic manifestations, HCV infection is associated with B cell lymphoproliferative disorders, including mixed cryoglobulinemia, usually a benign condition, and overt B cell lymphoma. A direct role of HCV infection in the genesis of these B cell lymphoproliferative disorders has been suggested initially by epidemiological studies and is supported by recent studies, which analyzed the monoclonal B cells that proliferate in these disorders. How HCV induces B cell lymphoproliferative disorders is still unclear, it is probably not due to direct change of phenotype in B cells after viral infection, but may be due to an HCV-antigen driven process. Support for this hypothesis comes from the analysis of monoclonal B cells found in these disorders, which use a restricted repertoire of immunoglobulin variable region genes that are similar to those used by B cells that secrete anti-HCV antibodies. The fact that monoclonal IgM is resolved in HCV-infected patients who responded to anti-viral treatment supports the linkage between antigen persistence and B cell proliferation. Finally, the linkage between benign B cell proliferation and overt lymphoma is supported by the identification of a pre-malignant B cell clone that subsequently converted to an overt B cell lymphoma. The molecular basis for viral induced B cell proliferation is still unknown. One possibility is that HCV stimulates the proliferation of monoclonal B cells via their HCV-specific B cell receptor (BCR) on the cell surface. Binding of the HCVenvelope proteins to a cellular ligand, CD81, may also enhance this antigen-driven process. A recent report on regression of splenic marginal zone lymphoma after anti-viral treatment with interferon and ribavirin has significantly strengthened the cause-effect relationship between HCV infection and lymphoma. Further studies should determine whether BCRs expressed on HCV-associated lymphomas, particularly those that regress in response to anti-viral therapy, bind HCV antigens that stimulate their proliferation.
View details for DOI 10.1080/1042819031000076972
View details for Web of Science ID 000182775000003
View details for PubMedID 12916862
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Expression of complement inhibitors CD46, CD55, and CD59 on tumor cells does not predict clinical outcome after rituximab treatment in follicular non-Hodgkin lymphoma
BLOOD
2001; 98 (5): 1352-1357
Abstract
Rituximab is a chimeric monoclonal antibody that targets B-cell-specific antigen CD20 and an effective treatment for B-cell non-Hodgkin lymphoma. Although it is readily used in clinical practice, the exact mechanism of its antitumor effect is unclear. One potential mechanism involves complement-mediated cytotoxicity. It has been shown that rituximab induces complement-mediated cytotoxicity in follicular lymphoma cells in vitro, and complement inhibitors CD55 and CD59 may regulate this process. To determine whether complement inhibitors play a role in regulating the antitumor effect of rituximab, the expression of complement inhibitors CD46, CD55, and CD59 was analyzed in pretreatment tumor cells from 29 rituximab-treated follicular lymphoma patients. Among them, 8 patients achieved complete responses, 11 patients achieved partial responses, and 10 patients showed no or minimal responses to rituximab treatment. Expression of surface CD20, CD46, CD55, and CD59 was determined by 2-color flow cytometry. Although the CD59 level was slightly lower in the complete response group, there was no statistically significant difference in the expression of individual complement inhibitor CD46 (mean channel fluorescence [MCF]: NR, 26.4; PR, 21.9; CR, 29.9), CD55 (MCF: NR, 16.4; PR, 14.9; CR, 23.2), or CD59 (MCF: NR, 41.6; PR, 40.6; CR, 30.6), the combination of any 2 inhibitors, or all 3 on tumor cells from 3 response groups. In addition, there was no difference in the rituximab-induced complement-mediated cytotoxicity in an in vitro assay using tumor cells from 3 response groups. Thus, CD46, CD55, and CD59 expression on pretreatment tumor cells, or their susceptibility to in vitro complement-mediated killing, does not predict clinical outcome after rituximab treatment.
View details for Web of Science ID 000170685000014
View details for PubMedID 11520782
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Differential induction of DNA-binding activities following CD19 cross-linking in human B lineage cells
JOURNAL OF IMMUNOLOGY
1997; 159 (11): 5502-5508
Abstract
The B cell-specific cell surface molecule CD19 is expressed at all stages of B cell development, including normal plasma cells, and mediates signal transduction via interaction with cytoplasmic effector proteins. Cross-linking CD19 on early human B lineage cells induces the formation of a CD19/Vav/phosphatidylinositol-3 kinase complex, tyrosine phosphorylation of CD19 and Vav, and activation of the Ras pathway. To further explore the ramifications of CD19 signaling, the current study examined whether phosphorylation of Elk-1, activation of activator protein-1 (AP-1), or activation of nuclear factor-kappaB (NF-kappaB) transcription factors occurred following CD19 cross-linking. The cells used were the BLIN-1 pre-B cell line expressing low levels of cell surface mu heavy chain associated with surrogate light chain and the 1E8 immature B cell line expressing cell surface mu/kappa. Lysates from CD19 cross-linked 1E8 cells induced robust phosphorylation of an Elk-1 fusion protein in vitro, whereas no phosphorylation of Elk-1 fusion protein occurred using lysates from CD19 cross-linked BLIN-1 cells. An electrophoretic mobility shift assay employing AP-1 and NF-kappaB consensus oligonucleotides was used to demonstrate that AP-1 -binding activity increased, while constitutive NF-kappaB-binding activity was not enhanced, following 2 h of CD19 cross-linking in 1E8 cells. Supershift experiments revealed that JunD and c-Fos proteins mediated anti-CD19 induced AP-1-binding activity in 1E8 cells. In contrast, CD19 cross-linking in BLIN-1 cells resulted in the induction of NF-kappaB, but had no apparent effect on AP-1-binding activity. These data suggest that CD19-mediated signal transduction activates different transcription factors at juxtaposed stages of B cell development that may culminate in the activation or suppression of distinct sets of genes.
View details for Web of Science ID 000071914800039
View details for PubMedID 9548490
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SIGNALING THROUGH CD19 ACTIVATES VAV MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY AND INDUCES FORMATION OF A CD19/VAV/PHOSPHATIDYLINOSITOL 3-KINASE COMPLEX IN HUMAN B-CELL PRECURSORS
JOURNAL OF BIOLOGICAL CHEMISTRY
1994; 269 (51): 32514-32521
Abstract
The B cell-specific cell surface molecule CD19 plays a role in regulating immunoglobulin (Ig) receptor signaling, and cross-linking CD19 activates several signaling molecules in mature human B cells. In surface Ig-negative B cell precursors, a protein tyrosine kinase (PTK)-dependent homotypic aggregation response can be triggered by cross-linking CD19. In the current study, we examined the outcome of PTK-mediated signal transduction following CD19 cross-linking on surface Ig negative and surface Ig positive B cell lines, as well as freshly isolated surface Ig-negative B cell precursors. PTK activation resulted in the tyrosine phosphorylation of multiple protein substrates and peaked at 0.5-1 min following CD19 cross-linking in all B-lineage cells examined. One of the tyrosine-phosphorylated substrates was identified as the hematopoietic-specific protein Vav, a guanine nucleotide exchange factor that activates the Ras pathway. Evidence consistent with Ras pathway activation was also demonstrated by MEK activation and subsequent phosphorylation of a MAP kinase fusion protein. CD19 cross-linking, sequential immunoprecipitation, and Western blotting revealed that: (a) Vav becomes associated with CD19, (b) phosphatidylinositol 3-kinase (PI 3-kinase) becomes associated with CD19, and (c) PI 3-kinase becomes associated with Vav. No such physical interaction occurred following control IgG1 cross-linking or cross-linking of class I major histocompatability complex cell surface molecules. Coupled with a previous report (Tuveson, D.A., Carter, R.H., Soltoff, S.P., and Fearon, D.T. (1993) Science 260, 986-988), our data support a model in which CD19 cross-linking induces the formation of a signaling complex that leads to the activation of two pathways involving Ras and PI 3-kinase.
View details for Web of Science ID A1994PX30400074
View details for PubMedID 7528218
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FUNCTIONAL EFFECT OF IL-7-ENHANCED CD19 EXPRESSION ON HUMAN B-CELL PRECURSORS
JOURNAL OF IMMUNOLOGY
1993; 151 (1): 138-148
Abstract
We have previously demonstrated that IL-7 can sustain the growth of normal human B cell precursors (BCP) for several weeks on bone marrow-derived stromal cells. Flow cytometric analysis of BCP recovered from IL-7 supplemented cultures revealed two- to threefold higher levels of cell surface CD19, compared with BCP maintained without IL-7. Short term culture of BCP showed that IL-7 enhancement of CD19 was dose-dependent, with increases detected by day 1 and plateauing by days 3 to 4. IL-7 increased cell-surface CD19 on small lymphoid cells, and to a greater degree on lymphoblasts, whereas cell-surface CD10 was unchanged. The CD34+/CD19+ pro-B cell population showed a greater increase in cell-surface CD19 compared with pre-B and immature B cells. IL-1, IL-3, IL-4, IL-6, and stem-cell factor had no effect on CD19. The potential functional significance of IL-7-enhanced cell-surface CD19 was examined using a F(ab')2 fragment of anti-CD19. This reagent had no effect on [3H]TdR incorporation in BCP cultured in the absence or presence of IL-7 for 5 days, but homotypic adhesion of BCP was induced at a concentration as low as 1.0 ng/ml F(ab')2 anti-CD19. IL-7 enhanced the F(ab')2 anti-CD19 induced homotypic adhesion of BCP in a dose-dependent manner. Blocking antibody studies indicated that members of the beta 1 or beta 2 integrin families did not mediate anti-CD19-induced homotypic adhesion, even though the adhesion was completely ablated by 10 mM EDTA. The pre-B and immature leukemic B cell lines NALM-6 and 1E8 expressed comparable levels of cell-surface CD19, and exhibited comparable increases after IL-7 stimulation. However, their homotypic adhesion responses to anti-CD19 were different. NALM-6 cells exhibited a strong homotypic adhesion response to anti-CD19 that was EDTA-resistant, and beta 1/beta 2 integrin independent. 1E8 cells only responded to anti-CD19 after IL-7 stimulation; this response was EDTA-sensitive and beta 1/beta 2 integrin independent. These collective results indicate that IL-7 not only acts as a growth factor for human BCP, but also regulates signal transduction through cell-surface CD19.
View details for Web of Science ID A1993LM57900015
View details for PubMedID 7686930