Dr. Rezvani is an Assistant Professor of Medicine in the Division of Blood & Marrow Transplantation at Stanford University. His focus includes clinical care of patients undergoing allogeneic and autologous hematopoietic cell transplantation, as well as clinical research aimed at improving outcomes and reducing complications of these transplants. He has conducted both retrospective and prospective clinical research in support of these aims. He also teaches and serves as a research mentor for fellows in the Division of Blood & Marrow Transplant at Stanford.
- Cancer > Blood and Marrow Transplant
- Medical Oncology
Inpatient Medical Director, Blood & Marrow Transplant Unit, Stanford University (2017 - Present)
Honors & Awards
Member, Alpha Omega Alpha medical honor society (2001)
Boards, Advisory Committees, Professional Organizations
Member, Protocol Development Committee, Protocol 1703, Blood & Marrow Transplant Clinical Trials Network (BMT-CTN) (2017 - Present)
Editorial consultant, American College of Physicians PIER (2008 - 2016)
Member, Conflict of Interest Committee, Blood & Marrow Transplant Clinical Trials Network (BMT-CTN) (2018 - Present)
Member, Toxicity and Supportive Care Committee, Blood & Marrow Transplant Clinical Trials Network (BMT-CTN) (2015 - 2018)
Fellowship, Fred Hutchinson Cancer Research Center/University of Washington, Medical Oncology (2008)
Residency, Duke University Medical Center, Internal Medicine (2004)
M.D., Temple University, Medicine (2001)
B.A., Stanford University, Slavic Languages and Literature (1997)
Current Research and Scholarly Interests
Clinical research in allogeneic hematopoietic cell transplantation
Autologous Transplantation in Follicular Lymphoma with Early Therapy Failure: A National LymphoCare Study and Center for International Blood and Marrow Transplant Research Analysis
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2018; 24 (6): 1163–71
Patients with follicular lymphoma (FL) experiencing early therapy failure (ETF) within 2 years of frontline chemoimmunotherapy have poor overall survival (OS). We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National LymphoCare Study (NLCS) to determine whether autologous hematopoietic cell transplant (autoHCT) can improve outcomes in this high-risk FL subgroup. ETF was defined as failure to achieve at least partial response after frontline chemoimmunotherapy or lymphoma progression within 2 years of frontline chemoimmunotherapy. We identified 2 groups: the non-autoHCT cohort (patients from the NLCS with ETF not undergoing autoHCT) and the autoHCT cohort (CIBMTR patients with ETF undergoing autoHCT). All patients received rituximab-based chemotherapy as frontline treatment; 174 non-autoHCT patients and 175 autoHCT patients were identified and analyzed. There was no difference in 5-year OS between the 2 groups (60% versus 67%, respectively; P = .16). A planned subgroup analysis showed that patients with ETF receiving autoHCT soon after treatment failure (≤1 year of ETF; n = 123) had higher 5-year OS than those without autoHCT (73% versus 60%, P = .05). On multivariate analysis, early use of autoHCT was associated with significantly reduced mortality (hazard ratio, .63; 95% confidence interval, .42 to .94; P = .02). Patients with FL experiencing ETF after frontline chemoimmunotherapy lack optimal therapy. We demonstrate improved OS when receiving autoHCT within 1 year of treatment failure. Results from this unique collaboration between the NLCS and CIBMTR support consideration of early consolidation with autoHCT in select FL patients experiencing ETF.
View details for PubMedID 29242111
Outcomes of Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: a CIBMTR analysis
2018; 2 (8): 933–40
The application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults.
View details for PubMedID 29685953
Infusion of donor-derived CD8(+) memory T cells for relapse following allogeneic hematopoietic cell transplantation
2018; 2 (6): 681–90
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
Viral Isolates in the Cerebrospinal Fluid of Hematopoietic Stem Cell Transplant Recipients, 2007-2015
ELSEVIER SCIENCE INC. 2018: S378–S379
View details for Web of Science ID 000425476000551
Phase I/II Trial for Patients with Advanced Hematologic Malignancies Undergoing Myeloablative Allogeneic HCT with a T Cell Depleted Graft with Infusion of Conventional T Cells and Regulatory T Cells
ELSEVIER SCIENCE INC. 2018: S145
View details for Web of Science ID 000425476000186
Acute Graft-versus-Host Disease
NEW ENGLAND JOURNAL OF MEDICINE
2018; 378 (6): 585–86
View details for PubMedID 29419277
Allogeneic transplantation for advanced acute myeloid leukemia: The value of complete remission.
Patients with acute myeloid leukemia (AML) without complete remission (CR) or in first relapse (Rel1) can have extended leukemia control and survival after allogeneic hematopoietic cell transplantation (HCT). For patients in Rel1 or primary induction failure (PIF), transplantation versus treatment to achieve a second CR (CR2) and subsequent HCT might yield similar outcomes, but available comparative data are scarce.Survival was analyzed in 4682 HCT recipients according to disease status: PIF (N = 1440), Rel1 (failing ≥1 reinduction; N = 1256), and CR2 (N = 1986).Patient, disease, and transplantation characteristics were similar, except that patients in CR2 more often had performance scores of 90% to 100%, de novo AML, and longer CR1 duration. Adverse cytogenetics were more common in patients who experienced PIF. The 5-year survival rate adjusted for performance score, cytogenetic risk, and donor type for CR2 was 39% (95% confidence interval [CI], 37%-41%) compared with 18% (95% CI, 16%-20%) for HCT in Rel1 and 21% (95% CI, 19%-23%) in PIF (P < .0001).Although survival is superior for patients who undergo HCT in CR2, transplantation for selected patients in Rel1 or PIF may still be valuable. These data can guide decision making about additional salvage therapy versus prompt HCT for patients not in CR, but they also highlight that AML is intrinsically more treatable in patients who have favorable-risk cytogenetics, those with longer CR1 duration, and younger patients with better performance status. Cancer 2017. © 2017 American Cancer Society.
View details for DOI 10.1002/cncr.30536
View details for PubMedID 28117884
HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity.
2017; 1 (17): 1347–57
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
Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.
Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.
View details for PubMedID 27802969
- A new standard for HIV-associated lymphoma. Blood 2016; 128 (8): 1026-1027
Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors
2016; 127 (7): 938-947
We evaluated 917 adult lymphoma patients who received haploidentical (n = 185) or HLA-matched unrelated donor (URD) transplantation either with (n = 241) or without antithymocyte globulin (ATG; n = 491) following reduced-intensity conditioning regimens. Haploidentical recipients received posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, whereas URD recipients received calcineurin inhibitor-based prophylaxis. Median follow-up of survivors was 3 years. The 100-day cumulative incidence of grade III-IV acute GVHD on univariate analysis was 8%, 12%, and 17% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .44). Corresponding 1-year rates of chronic GVHD on univariate analysis were 13%, 51%, and 33%, respectively (P < .001). On multivariate analysis, grade III-IV acute GVHD was higher in URD without ATG (P = .001), as well as URD with ATG (P = .01), relative to haploidentical transplants. Similarly, relative to haploidentical transplants, risk of chronic GVHD was higher in URD without ATG and URD with ATG (P < .0001). Cumulative incidence of relapse/progression at 3 years was 36%, 28%, and 36% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .07). Corresponding 3-year overall survival (OS) was 60%, 62%, and 50% in the 3 groups, respectively, with multivariate analysis showing no survival difference between URD without ATG (P = .21) or URD with ATG (P = .16), relative to haploidentical transplants. Multivariate analysis showed no difference between the 3 groups in terms of nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). These data suggest that reduced-intensity conditioning haploidentical transplantation with posttransplant cyclophosphamide does not compromise early survival outcomes compared with matched URD transplantation, and is associated with significantly reduced risk of chronic GVHD.
View details for DOI 10.1182/blood-2015-09-671834
View details for PubMedID 26670632
Microbiota Manipulation With Prebiotics and Probiotics in Patients Undergoing Stem Cell Transplantation
CURRENT HEMATOLOGIC MALIGNANCY REPORTS
2016; 11 (1): 19-28
Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy that often comes at the cost of complications such as graft-versus-host disease and post-transplant infections. With improved technology to understand the ecosystem of microorganisms (viruses, bacteria, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota's contribution to the development of post-transplant complications. Antibiotics have traditionally been the mainstay of microbiota-altering therapies available to physicians. Recently, interest is increasing in the use of prebiotics and probiotics to support the development and sustainability of a healthier microbiota. In this review, we will describe the evidence for the use of prebiotics and probiotics in combating microbiota dysbiosis and explore the ways in which they may be used in future research to potentially improve clinical outcomes and decrease rates of graft-versus-host disease (GVHD) and post-transplant infection.
View details for DOI 10.1007/s11899-016-0302-9
View details for Web of Science ID 000372595100004
Long-term sustained disease control in patients with mantle cell lymphoma with or without active disease after treatment with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.
2015; 121 (20): 3709-3716
Previously, early results were reported for allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning with 2 Gy of total body irradiation with or without fludarabine and/or rituximab in 33 patients with mantle cell lymphoma (MCL).This study examined the outcomes of 70 patients with MCL and included extended follow-up (median, 10 years) for the 33 initial patients. Grafts were obtained from human leukocyte antigen (HLA)-matched, related donors (47%), unrelated donors (41%), and HLA antigen-mismatched donors (11%).The 5-year incidence of nonrelapse mortality was 28%. The relapse rate was 26%. The 5-year rates of overall survival (OS) and progression-free survival (PFS) were 55% and 46%, respectively. The 10-year rates of OS and PFS were 44% and 41%, respectively. Eighty percent of surviving patients were off immunosuppression at the last follow-up. The presence of relapsed or refractory disease at the time of HCT predicted a higher rate of relapse (hazard ratio [HR], 2.94; P = .05). Despite this, OS rates at 5 (51% vs 58%) and 10 years (43% vs 45%) were comparable between those with relapsed/refractory disease and those undergoing transplantation with partial or complete remission. A high-risk cytomegalovirus (CMV) status was the only independent predictor of worse OS (HR, 2.32; P = .02). A high-risk CMV status and a low CD3 dose predicted PFS (HR, 2.22; P = .03).Nonmyeloablative allogeneic HCT provides a long-term survival benefit for patients with relapsed MCL, including those with refractory disease or multiple relapses. Cancer 2015;121:3709-3716. © 2015 American Cancer Society.
View details for DOI 10.1002/cncr.29498
View details for PubMedID 26207349
Allogeneic hematopoietic cell transplantation after failed autologous transplant for lymphoma using TLI and anti-thymocyte globulin conditioning
BONE MARROW TRANSPLANTATION
2015; 50 (10): 1286-1292
We describe 47 patients with lymphoma and failed prior autologous hematopoietic cell transplantation (HCT) who received TLI-ATG (anti-thymocyte globulin) conditioning followed by allogeneic HCT. Thirty-two patients had non-Hodgkin lymphoma (NHL; diffuse large B-cell lymphoma (n=19), T-cell NHL (n=6), mantle cell lymphoma (n=4) or other B-cell subtypes (n=3)), and 15 had Hodgkin lymphoma. The median follow-up was 4.9 (range, 2.1-11.9) years. The cumulative incidence of grade II-IV acute GvHD at day +100 was 12%, and the cumulative incidence of extensive chronic GvHD at 1 year was 36%. The 3-year cumulative incidences of overall survival (OS), PFS and non-relapse mortality (NRM) were 81%, 44% and 7%, respectively. Fifteen patients died (relapse, n=10; NRM, n=5). Among the 25 patients with relapse after allogeneic HCT, 11 (44%) achieved durable (>1 year) CRs following donor lymphocyte infusion or chemoradiotherapy. The majority of surviving patients (75%; n=24) were able to discontinue all immunosuppression. For patients with relapsed lymphoma after autologous HCT, allogeneic HCT using TLI-ATG conditioning is a well-tolerated, predominantly outpatient therapy with low NRM (7% at 3 years), a low incidence of GvHD, durable disease control and excellent OS (81% at 3 years).
View details for DOI 10.1038/bmt.2015.149
View details for PubMedID 26146806
Long-term outcomes of patients with persistent indolent b cell malignancies undergoing nonmyeloablative allogeneic transplantation.
Biology of blood and marrow transplantation
2015; 21 (2): 281-287
Relapse is least common in patients with indolent B cell (iB) malignancies (ie, iB non-Hodgkin lymphoma [NHL]) who undergo nonmyeloablative allogeneic transplantation (NMAT) in complete remission (CR). However, for the many patients unable to achieve this state, outcomes are poorly described and methods to improve results are unknown. We sought to describe the long-term follow-up and predictive factors for these poor-risk patients unable to achieve CR before NMAT. We identified and evaluated patients with iB-NHL including chronic lymphocytic leukemia treated with fludarabine/total body irradiation-based NMAT that had evidence of persistent disease before NMAT. From December 1998 to April 2009, 89 patients were identified, most commonly with small/chronic lymphocytic lymphoma (n = 62) and follicular lymphoma (n = 24). Pretransplant anti-CD20 radioimmunotherapy (RIT) using standard yttrium-90-ibritumomab tiuxetan was administered to 18 patients (20%) who more frequently had chemoresistant disease (81% versus 39%, P = .003), disease bulk > 5 cm (61% versus 15%, P < .001), thrombocytopenia < 25k/μL (33% versus 7%, P = .002), and Hematopoietic Cell Transplant Comorbidity Index scores ≥ 3 (72% versus 37%, P = .006). After adjusting for these imbalances, RIT-treated patients had improved rates of progression-free survival (PFS) (hazard ratio [HR] = .4; 95% confidence interval [CI], .2 to .9, P = .02) and overall survival (OS) (HR = .3; 95% CI, .1 to .8, P = .008) compared with the non-RIT group. The 3-year adjusted estimates of PFS and OS for the RIT and non-RIT groups were 71% and 87% versus 44% and 59%, respectively. The use of RIT was the only factor independently associated with improved PFS and OS. Rates of nonrelapse mortality and graft-versus-host disease (GVHD) were similar between the 2 groups, although over 70% of patients developed clinically significant acute or chronic GVHD. In conclusion, despite relatively high rates of GVHD, patients with persistent iB-NHL can derive durable benefit from NMAT.
View details for DOI 10.1016/j.bbmt.2014.10.024
View details for PubMedID 25445025
Impact of donor age on outcome after allogeneic hematopoietic cell transplantation.
Biology of blood and marrow transplantation
2015; 21 (1): 105-112
As older patients are eligible for allogeneic hematopoietic cell transplantation (HCT), older siblings are increasingly proposed as donors. We studied the impact of donor age on the tempo of hematopoietic engraftment and donor chimerism, acute and chronic graft-versus-host disease (GVHD), and nonrelapse mortality (NRM) among 1174 consecutive patients undergoing myeloablative and 367 patients undergoing nonmyeloablative HCT from HLA-matched related or unrelated donors with granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell allografts. Sustained engraftment rates were 97% and 98% in patients undergoing myeloablative and nonmyeloablative conditioning, respectively, for grafts from donors < 60 years old (younger; n = 1416) and 98% and 100%, respectively, for those from donors ≥60 years old (older; n = 125). No significant differences were seen in the tempo of neutrophil and platelet recoveries and donor chimerism except for an average 1.3-day delay in neutrophil recovery among myeloablative patients with older donors (P = .04). CD34(+) cell dose had an independent effect on the tempo of engraftment. Aged stem cells did not convey an increased risk of donor-derived clonal disorders after HCT. Myeloablative and nonmyeloablative recipients with older sibling donors had significantly less grade II to IV acute GVHD than recipients with grafts from younger unrelated donors. Rates of grade III and IV acute GVHD, chronic GVHD, and NRM for recipients with older donors were not significantly different from recipients with younger donors. In conclusion, grafts from donors ≥60 years old do not adversely affect outcomes of allogeneic HCT compared with grafts from younger donors.
View details for DOI 10.1016/j.bbmt.2014.09.021
View details for PubMedID 25278458
Allogeneic hematopoietic cell transplantation for indolent non-Hodgkin lymphoma: indications and outcomes
CURRENT OPINION IN HEMATOLOGY
2013; 20 (6): 509-514
Allogeneic hematopoietic cell transplantation (HCT) can potentially cure indolent non-Hodgkin lymphoma (NHL). However, the optimal timing and indications remain unclear. Here, we review recent published reports on the subject and summarize our approach.Recent prospective clinical trials of allogeneic HCT in indolent NHL are marked by substantial variation in eligibility criteria, patient populations, and transplant approach. Nonetheless, several common themes are apparent. Indolent NHL is highly susceptible to immunologic graft-versus-lymphoma effects and relapse rates after allogeneic HCT are uniformly low. Allogeneic HCT early in the disease course produces the highest overall and progression-free survival, but also increases patient exposure to potential transplant-related complications such as chronic graft-versus-host disease. In contrast, allogeneic HCT can be reserved as a 'last resort' for patients who are refractory to conventional chemotherapy, delaying their exposure to graft-versus-host disease and other transplant-associated risks. No trials have directly addressed the optimal timing of allogeneic HCT in indolent NHL nor prospectively compared different transplant approaches.Excellent outcomes have been reported with allogeneic HCT for indolent NHL, both early and late in the disease course. The optimal timing of allogeneic HCT is unknown and depends heavily on patient preferences.
View details for DOI 10.1097/MOH.0b013e328365a151
View details for Web of Science ID 000326746100004
View details for PubMedID 24104411
Inducible costimulator (ICOS) up-regulation on activated T cells in chronic graft-versus-host disease after dog leukocyte antigen-nonidentical hematopoietic cell transplantation: a potential therapeutic target.
2013; 96 (1): 34-41
Inducible costimulator (ICOS), a member of the CD28 family of costimulatory molecules, is induced on CD4 and CD8 T cells after their activation. ICOS functions as an essential immune regulator and ICOS blockade is a potential approach to immune modulation in allogeneic transplantation. Here, we describe the expression profile of ICOS in dogs and determine whether ICOS expression is up-regulated during chronic graft-versus-host disease (GVHD) and host-versus-graft reactions in the canine hematopoietic cell transplantation model.Monoclonal antibodies (mAbs) against cell surface-expressed ICOS were produced and tested in vitro for suppression of canine mixed leukocyte reactions (MLR). Expression of ICOS on CD3 cells was evaluated by flow cytometry using peripheral blood, lymph nodes, and splenocytes obtained from dogs undergoing graft-versus-host and host-versus-graft reactions.Canine ICOS was expressed in an inducible pattern on T cells activated by concanavalin A, anti-CD3 mAb in combination with anti-CD28 mAb, and alloantigen stimulation. Immunosuppressive effects of ICOS blockade were observed in MLR using peripheral blood mononuclear cells from dog leukocyte antigen-nonidentical dogs. Immunosuppressive effects of ICOS blockade were observed in MLR when anti-ICOS was combined with suboptimal concentrations of cytotoxic T-lymphocyte antigen 4-Ig or cyclosporine. ICOS expression was significantly up-regulated on T cells in dogs undergoing graft rejection or chronic GVHD after allogeneic hematopoietic cell transplantation.These studies suggest that ICOS plays a role in graft rejection and GVHD in an outbred animal model, and ICOS blockade may be an approach to prevention and treatment of chronic GVHD.
View details for DOI 10.1097/TP.0b013e318295c025
View details for PubMedID 23694952
Cyclophosphamide followed by Intravenous Targeted Busulfan for Allogeneic Hematopoietic Cell Transplantation: Pharmacokinetics and Clinical Outcomes
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2013; 19 (7): 1033-1039
Targeted busulfan ((T)BU) and cyclophosphamide (CY) for allogeneic hematopoietic cell transplantation carries a high risk of sinusoidal obstruction syndrome (SOS) in patients undergoing transplantation for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from (T)BU/CY to CY/(T)BU) would reduce SOS and day +100 nonrelapse mortality. We enrolled 51 patients with myelofibrosis (n = 20), acute myelogenous leukemia (n = 20), or myelodysplastic syndrome (n = 11) in a prospective trial of CY/(T)BU conditioning for allogeneic hematopoietic cell transplantation. CY 60 mg/kg/day i.v. for 2 days was followed by daily i.v. BU for 4 days, targeted to a concentration at steady state (Css) of 800-900 ng/mL. Compared with (T)BU/CY-conditioned patients, CY/(T)BU-conditioned patients had greater exposure to CY (P < .0001) and less exposure to 4-hydroxycyclophosphamide (P < .0001). Clinical outcomes were compared between cases and controls (n = 271) conditioned with (T)BU/CY for the same indications. In patients with myelofibrosis, CY/(T)BU conditioning was associated with a significantly reduced incidence of SOS (0% versus 30% after (T)BU/CY; P = .006), whereas the incidence of SOS was low in both cohorts with acute myelogenous leukemia/myelodysplastic syndrome. Day +100 mortality was significantly lower in the CY/(T)BU cohort (2% versus 13%; P = .01). CY/(T)BU conditioning had a marked affect on the pharmacokinetics of CY and was associated with significantly lower incidence of SOS and day +100 mortality, suggesting that CY/(T)BU is superior to (T)BU/CY as conditioning for patients with myelofibrosis.
View details for DOI 10.1016/j.bbmt.2013.04.005
View details for Web of Science ID 000321093500008
View details for PubMedID 23583825
Prevention of graft-vs.-host disease
EXPERT OPINION ON PHARMACOTHERAPY
2012; 13 (12): 1737-1750
Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for many malignant and non-malignant hematologic disorders. However, graft-vs.-host disease (GVHD) remains a major complication of allogeneic HCT and limits the success of this approach.This paper reviews recent developments in the prevention of acute and chronic GVHD. In the setting of acute GVHD prevention, recent trials of T-cell depletion using Fresenius-ATG are reviewed, as well as studies testing total lymphoid irradiation, mesenchymal stromal cells, rituximab, statins, sirolimus and other investigational agents. In the setting of chronic GVHD, results with Fresenius-ATG are reviewed, as well as B-cell depletion with rituximab, and the potential role of the B-cell regulatory cytokine BAFF in chronic GVHD is also discussed. Finally, the emerging role of resident skin and gut bacterial flora-the so-called microbiome-in the pathogenesis of GVHD is covered.Current methods of acute GVHD prevention are highly successful, and a number of investigational approaches promise to further reduce the risk of this complication. By contrast, chronic GVHD is more poorly understood and more difficult to prevent. Future studies are required to delineate the roles of these approaches and to abrogate GVHD without sacrificing the beneficial immunologic graft-vs.-tumor effect.
View details for DOI 10.1517/14656566.2012.703652
View details for Web of Science ID 000306524600007
View details for PubMedID 22770714
The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation
2012; 119 (11): 2657-2664
Studies by the International Working Group showed that the prognosis of myelofibrosis patients is predicted by the Dynamic International Prognostic Scoring System (DIPSS) risk categorization, which includes patient age, constitutional symptoms, hemoglobin, leukocyte count, and circulating blasts. We evaluated the prognostic usefulness of the DIPSS in 170 patients with myelofibrosis, 12 to 78 years of age (median, 51.5 years of age), who received hematopoietic cell transplantation (HCT) between 1990 and 2009 from related (n = 86) or unrelated donors (n = 84). By DIPSS, 21 patients had low-risk disease, 48 had intermediate-1, 50 had intermediate-2, and 51 had high-risk disease. Five-year incidence of relapse, relapse-free survival, overall survival, and nonrelapse mortality for all patients were 10%, 57%, 57%, and 34%, respectively. Among patients with DIPSS high-risk disease, the hazard ratio for post-HCT mortality was 4.11 (95% CI, 1.44-11.78; P = .008), and for nonrelapse mortality was 3.41 (95% CI, 1.15-10.09; P = .03) compared with low-risk patients. After a median follow-up of 5.9 years, the median survivals have not been reached for DIPSS risk groups low and intermediate-1, and were 7 and 2.5 years for intermediate-2 and high-risk patients, respectively. Thus, HCT was curative for a large proportion of patients with myelofibrosis, and post-HCT success was dependent on pre-HCT DIPSS classification.
View details for DOI 10.1182/blood-2011-08-372904
View details for Web of Science ID 000301941700035
View details for PubMedID 22234678
Accurate Targeting of Daily Intravenous Busulfan with 8-Hour Blood Sampling in Hospitalized Adult Hematopoietic Cell Transplant Recipients
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2012; 18 (2): 265-272
Daily intravenous (i.v.) busulfan is increasingly being used in hematopoietic cell transplantation (HCT) conditioning regimens. Intravenous busulfan doses administered at the traditional frequency of every 6 hours can be targeted ((T)Bu) to a patient-specific concentration at steady state (C(ss)) using therapeutic drug monitoring (TDM). In this report, we describe our experiences with TDM of daily i.v. busulfan in an adult population, with the specific aims of (1) evaluating covariates associated with busulfan clearance, and (2) assessing the feasibility of TDM for outpatient administration of daily (T)Bu with pharmacokinetic sampling over 6 hours. A retrospective pharmacokinetic analysis was conducted in 87 adults receiving daily (T)Bu as part of cyclophosphamide followed by (T)BU (CY/(T)BU), fludarabine monophosphate (fludarabine) followed by (T)BU, or (T)BU concurrent with fludarabine conditioning. The desired C(ss) was achieved in 85% of patients receiving daily i.v. busulfan. Busulfan clearance was not associated with sex or age, but was associated with the day of dosing and conditioning regimen (P = .0016). In patients receiving CY/(T)BU, no differences in clearance were found between dosing days (P > .36); however, clearance decreased significantly in patients receiving fludarabine-based regimens (P = .0016). Busulfan clearance and C(ss) estimates from pharmacokinetic sampling over 8, 11, or 24 hours were comparable (P > .4). However, pharmacokinetic modeling of individual patient concentration-time data over 6 hours could not reliably estimate busulfan clearance or C(ss).
View details for DOI 10.1016/j.bbmt.2011.06.013
View details for Web of Science ID 000299398500015
View details for PubMedID 21736869
Decreased Serum Albumin as a Biomarker for Severe Acute Graft-versus-Host Disease after Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2011; 17 (11): 1594-1601
Biomarkers capable of predicting the onset and severity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT) would enable preemptive and risk-stratified therapy. Severe aGVHD leads to gastrointestinal protein loss, resulting in hypoalbuminemia. We hypothesized that decreases in serum albumin at onset of aGVHD would predict the risk of progression to severe aGVHD. We identified 401 patients who developed aGVHD grades II-IV after reduced-intensity allogeneic HCT and reviewed all available serum albumin values from 30 days before HCT to 45 days after initiation of treatment for aGVHD. A ≥0.5 g/dL decrease in serum albumin concentration from pretransplantation baseline to the onset of treatment for aGVHD predicted the subsequent development of grade III/IV aGVHD (versus grade II aGVHD) with a sensitivity of 69% and a specificity of 73%. Overall mortality at 6 months after initiation of aGVHD treatment was 36% versus 17% for patients with and without ≥0.5 g/dL decreases in serum albumin, respectively (P = .0009). We conclude that change in serum albumin concentration from baseline to initiation of aGVHD treatment is an inexpensive, readily available, and predictive biomarker of GVHD severity and mortality after reduced-intensity allogeneic HCT.
View details for DOI 10.1016/j.bbmt.2011.07.021
View details for Web of Science ID 000296829000006
View details for PubMedID 21806949
BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY
2011; 24 (2): 203-216
Rituximab has become a ubiquitous component of treatment regimens for follicular non-Hodgkin lymphoma. Despite widespread clinical use, the mechanisms by which tumor cells resist rituximab-mediated destruction remain unclear. Rituximab relies in part on immune effector mechanisms for its antitumor effect, and thus resistance may be mediated not only by intrinsic tumor-cell alterations but also by the host immunological environment. In this article, we explore the mechanisms of action of rituximab, the incidence of rituximab resistance, and potential mechanisms of resistance. Finally, we discuss novel approaches to modulate the antibody, the tumor cell, and the host immunologic environment to overcome rituximab resistance. Further research into the mechanisms of rituximab resistance will be essential to improving the efficacy of anti-CD20 therapy in NHL, and may also pay dividends in the optimization of monoclonal antibody therapy across a wide range of diseases.
View details for DOI 10.1016/j.beha.2011.02.009
View details for Web of Science ID 000292355200010
View details for PubMedID 21658619
Allogeneic hematopoietic cell transplantation: the state of the art
EXPERT REVIEW OF HEMATOLOGY
2010; 3 (3): 285-299
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative procedure for a variety of hematologic malignancies. The field has evolved substantially over the past decade, with advances in patient and donor selection, stem cell sources, supportive care, prevention of complications and reduced-toxicity preparative regimens. As a result, the indications for HCT and the pool of eligible patients have expanded significantly. In this article, we provide an overview of the major aspects of allogeneic HCT, and focus specifically on areas of active research and on novel approaches to challenges in the field. Specifically, we will discuss approaches to reduce the toxicity of the preparative regimen, with the goal of increasing the safety and applicability of HCT. The availability of suitable donors may be an obstacle to wider application of HCT. We review three major approaches to broadening the donor pool: the use of HLA-mismatched unrelated donors, umbilical cord blood and HLA-haploidentical family donors. Graft-versus-host disease remains a major cause of morbidity and mortality after HCT. We review recent advances in the understanding of this phenomenon, and novel prophylactic and therapeutic approaches that hold the promise of further improving the safety of the procedure. We conclude with a speculative outline of the next 5 years of research in the field of HCT.
View details for DOI 10.1586/EHM.10.21
View details for Web of Science ID 000284801600012
View details for PubMedID 20871781
Treatment Change as a Predictor of Outcome among Patients with Classic Chronic Graft-versus-Host Disease
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
2008; 14 (12): 1380-1384
We analyzed outcomes for 668 patients who had systemic treatment for chronic graft-versus-host disease (cGVHD) to assess the utility of early treatment change for exacerbation of cGVHD as a surrogate for survival endpoints in clinical trials. Fifty-six percent of patients had treatment change within 2 years after diagnosis of cGVHD. The median onset of treatment change was 4.4 months (range: 0.3-50 months). The cumulative incidence of nonrelapse mortality (NRM) at 2 years was 16%, and overall survival (OS) at 2 years was 74%. In time-dependent Cox models, treatment change was associated with an increase in risk of NRM (hazard ratio, 2.53; 95% confidence interval, 1.7-3.7; P < .0001). The hazard ratio was attenuated by 6% per month of delay in treatment change. Our results confirm that exacerbation of cGVHD is associated with an increased risk of NRM and with decreased OS, but the strength of this association is not large enough to allow the use of early exacerbation as a surrogate for survival endpoints in clinical trials. Other measures of clinical benefit, such as response, will need to be developed as endpoints in phase II trials for patients with cGVHD.
View details for DOI 10.1016/j.bbmt.2008.09.017
View details for Web of Science ID 000261754600008
View details for PubMedID 19041060
Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience
7th International Meeting on AAA Proteins
WILEY-BLACKWELL PUBLISHING, INC. 2008: 395–403
Patients with relapsed diffuse large B-cell lymphoma (DLBCL) who have failed or are ineligible for autologous haematopoietic cell transplantation (HCT) have a poor prognosis. We examined the outcomes of non-myeloablative allogeneic HCT in this setting. Thirty-one patients with DLBCL and one patient with Burkitt lymphoma received allogeneic HCT following 2 Gy total body irradiation with or without fludarabine. Median age was 52 years. Twenty-four patients (75%) had undergone prior autologous HCT. Disease status at HCT was complete response (14/32, 44%), partial response (9/32, 28%), or refractory (9/32, 28%). Cumulative incidences of acute graft-versus-host disease (GVHD) grades II-IV, grades III-IV, and chronic GVHD were 53%, 19%, and 47% respectively. With a median follow-up of 45 months, 3-year estimated overall (OS) and progression-free survival (PFS) was 45% and 35% respectively. Three-year cumulative incidences of relapse and non-relapse mortality were 41% and 25% respectively. In multivariate models, chemosensitive disease and receipt of >or=4 lines of treatment before HCT were associated with better OS. Patients with chemosensitive disease had 3-year OS and PFS of 56% and 43% respectively. Non-myeloablative allogeneic HCT can produce long-term disease-free survival in patients with chemosensitive relapsed DLBCL who have failed or are ineligible for autologous HCT.
View details for DOI 10.1111/j.1365-2141.2008.07365.x
View details for Web of Science ID 000260117300012
View details for PubMedID 18759762
View details for PubMedCentralID PMC2654416
Separation of graft-vs.-tumor effects from graft-vs.-host disease in allogeneic hematopoietic cell transplantation
Center of Excellence Meeting
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. 2008: 172–79
Allogeneic hematopoietic cell transplantation (HCT) is an increasingly widely used treatment modality in hematological malignancies. Alloreactivity mediated by donor T cells (and, in some settings, by donor natural killer cells) can produce durable immunologic control or eradication of residual malignancy after allogeneic HCT. However, graft-vs.-tumor (GVT) effects are variably effective and are often accompanied by deleterious alloreactivity against normal host tissue, manifesting as graft-vs.-host disease (GVHD). A major focus of current research in HCT is the separation of beneficial GVT effects from GVHD. Here we review a number of approaches currently under investigation to specifically augment GVT effects, including the identification of minor histocompatibility antigens (mHA), adoptive immunotherapy with tumor-specific or mHA-specific cytotoxic T lymphocytes, vaccination of the donor or recipient to stimulate tumor-specific immunity, and adoptive transfer of natural killer cells. In addition, we review strategies being investigated to specifically suppress GVHD while sparing GVT, including the manipulation and infusion of regulatory T cells, the use of novel pharmacologic and biologic agents, and the use of mesenchymal stem cells. Ultimately, advances in separation of GVT from GVHD will further enhance the potential of allogeneic HCT as a curative treatment for hematological malignancies.
View details for DOI 10.1016/j.jaut.2007.12.002
View details for Web of Science ID 000253769900010
View details for PubMedID 18242060
Using allogeneic stem cell/T-cell grafts to cure hematologic malignancies
EXPERT OPINION ON BIOLOGICAL THERAPY
2008; 8 (2): 161-179
Background: Allogeneic stem cell and T-cell-based therapies are widely used in the treatment of hematologic malignancies and can treat or cure otherwise refractory disease. However, in spite of major advances in the understanding and practice of allogeneic hematopoietic cell transplantation (HCT), several important challenges remain. Objective: Here the authors review the use of allogeneic HCT and T-cell-based therapy, with the goal of providing an overview of the uses and limitations of this approach as well as a survey of areas of active research. Methods: The authors review and summarize recent publications and expert opinions in the field of allogeneic HCT, along with a brief historical perspective, with a focus on challenges and recent advances in the field. Results/conclusion: Present areas of research include efforts to expand the donor pool through the use of umbilical cord blood and human leukocyte antigen-haploidentical donors, the use of reduced-intensity conditioning regimens, which allow treatment of previously ineligible patients, enhancement of immune reconstitution after transplantation, more effective prevention and treatment of acute and chronic graft-versus-host disease, and the augmentation of the immunologic graft-versus-tumor response and its uncoupling from deleterious graft-versus-host alloreactivity.
View details for DOI 10.1517/147125126.96.36.199
View details for Web of Science ID 000252878300004
View details for PubMedID 18194073
Nonmyeloablative allogeneic hematopoietic cell transplantation in relapsed, refractory, and transformed indolent non-Hodgkin's lymphoma
48th Annual Meeting of the American-Society-of-Hematology
AMER SOC CLINICAL ONCOLOGY. 2008: 211–17
Few effective treatment options exist for chemotherapy-refractory indolent or transformed non-Hodgkin's lymphoma (NHL). We examined the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) in this setting.Sixty-two patients with indolent or transformed NHL were treated with allogeneic HCT from related (n = 34) or unrelated (n = 28) donors after conditioning with 2 Gy of total-body irradiation with or without fludarabine. Nine unrelated donors were mismatched for >/= one HLA antigen. Sixteen patients had histologic transformation before HCT. Twenty patients (32%) had progressive disease after previous high-dose therapy with autologous HCT. Median age was 54 years, and patients had received a median of six lines of treatment before HCT. Median follow-up time after HCT was 36.6 months.At 3 years, the estimated overall survival (OS) and progression-free survival (PFS) rates were 52% and 43%, respectively, for patients with indolent disease, and 18% and 21%, respectively, for patients with transformed disease. Patients with indolent disease and related donors (n = 26) had 3-year estimated OS and PFS rates of 67% and 54%, respectively. The incidences of grade 2 to 4 acute graft-versus-host disease (GVHD), grade 3 and 4 acute GVHD, and extensive chronic GVHD were 63%, 18%, and 47%, respectively. Among survivors, the median Karnofsky performance status at last follow-up was 85%.Nonmyeloablative allogeneic HCT can produce durable disease-free survival in patients with relapsed or refractory indolent NHL, even in this relatively elderly and heavily pretreated cohort. Outcomes were particularly good in patients with untransformed disease and related donors, whereas patients with transformed disease did poorly. Long-term survivors reported good overall functional status.
View details for DOI 10.1200/JCO.2007.11.5477
View details for Web of Science ID 000254177100010
View details for PubMedID 18056679