Dr. Dahiya is a cancer specialist with board certification in internal medicine, hematology, and medical oncology. He is an Associate Professor at Stanford University School of Medicine and Clinical Director of Cancer Cell Therapy in the Stanford BMT and Cell Therapy division.
Dr. Dahiya strives to support each patient with a personalized and compassionate care plan that optimizes healing and quality of life.
Prior to joining Stanford, Dr. Dahiya was an associate professor of medicine at the Greenebaum Comprehensive Cancer Center at the University of Maryland School of Medicine, where he developed the Cellular Immunotherapy Program and served as the Director of Cellular Immunotherapy in leukemia and lymphoma.
Dr. Dahiya’s research focuses on cellular immunotherapy for hematologic malignancies. He has led and participated in several investigator-initiated studies and sponsored clinical trials with cell therapies (CAR-T, CAR-NK, TCR-T) for hematologic malignancies. His research group is also involved in various translational research activities for the standard of care and research CAR-T therapy. Dr. Dahiya’s group was the first group to show the role of fibrinogen in Neurotoxicity associated with CAR-T therapy. They showed vascular injury as manifested by high fibrinogen levels is associated with higher Neurotoxicity in patients who receive CAR-T therapy. More recently his group led a novel study of assessing the immune response to COVID-19 disease. They evaluated the immune response in critically ill and non-critically ill patients hospitalized with COVID-19 disease and showed a differential immune response between the groups. Dr. Dahiya’s group also showed and established poor immunogenicity of COVID-19 vaccines in CART recipients. As such, passive immunity and other strategies to address the issues of immunogenicity are being explored.
He has published more than 50 articles in peer-reviewed journals including the New England Journal of Medicine, Journal of Clinical Oncology, Blood, Blood Advances, Lancet, Leukemia Research, Neuro-Oncology, and many more. He reviews article submissions for the journals Critical Reviews in Oncology and Hematology, Thoracic Cancer, and Blood. He serves as the hematology lead editor for the journal Critical Reviews in Oncology and Hematology.
He has presented his research findings at conferences such as the annual meetings of the American Society of Hematology, American Society of Clinical Oncology, and American Society for Transplantation and Cell Therapy.
Dr. Dahiya is a member of the American Society of Hematology and the American Society of Transplantation and Cell Therapy.
- Blood and Marrow Transplantation
- Cellular Therapy
Associate Professor - University Medical Line, Medicine - Blood & Marrow Transplantation
Fellowship: Stanford University Bone Marrow Transplant Fellowship (2017) CA
Board Certification: American Board of Internal Medicine, Medical Oncology (2016)
Board Certification: American Board of Internal Medicine, Hematology (2016)
Fellowship: Baystate Medical Center (2016) MA
Fellowship: Cleveland Clinic Graduate Medical Education (2013) OH
Board Certification: American Board of Internal Medicine, Internal Medicine (2012)
Residency, Baystate Medical Center/Tufts University School of Medicine, Internal Medicine Residency (2012)
Internship: Western Reserve Care System (2010) OH
Medical Education: Maulana Azad Medical College (2008) India
Evaluate Safety of Axicabtagene Ciloleucel Reinfusion (Axi-Cel-2) in Patients With Relapsed and/or Refractory Second Line High-Risk Non-Hodgkin Lymphoma After Standard of Care Axi-Cel
This is a phase Ib study to establish safety of Axi-Cel-2 in patients with Large B Cell Lymphoma (LBCL) who are at high risk of relapse.
Study of KITE-363 or KITE-753 in Participants With Relapsed and/or Refractory B-cell Lymphoma
The goal of this clinical study is to learn more about the safety and dosing of the study drugs, KITE-363 and KITE-753, in participants with relapsed and/or refractory B-cell lymphoma.
Challenges and solutions to superior chimeric antigen receptor-T design and deployment for B-cell lymphomas.
British journal of haematology
Chimeric antigen receptor-T (CAR-T) therapies represent a major breakthrough in cancer medicine, given the ex vivo-based technology that harnesses the power of one's own immune system. These therapeutics have demonstrated remarkable success for relapsed/refractory B-cell lymphomas. Although more than a decade has passed since the initial introduction of CAR-T therapeutics for patients with leukaemia and lymphoma, there is still significant debate as to where CAR-T therapeutics fit into the management paradigm, as consensus guidelines are limited. Competing interventions deployed in subsequent lines of therapy for aggressive lymphoma include novel targeted agents, bispecific antibodies, and time-honoured stem cell transplant. In this focused review, we discuss the major obstacles to advancing the therapeutic reach for CAR-T products in early lines of therapy. Such barriers include antigen escape, "cold" tumour microenvironments, host inflammation and CAR-T cell exhaustion. We highlight solutions including point-of-care CAR-T manufacturing and early T lymphopheresis. We review the evidence basis for early CAR-T deployment for B-cell lymphomas in light of the recent Food and Drug Administration (FDA) approval of three first-in-class anti-CD3/CD20 bispecific antibodies-mosunetuzumab, epcoritamab and glofitamab. We propose practical recommendations for 2024.
View details for DOI 10.1111/bjh.19001
View details for PubMedID 37488074
Imaging Biomarkers to Predict Outcomes in Patients With Large B-Cell Lymphoma With a Day 28 Partial Response by 18F-FDG PET/CT Imaging Following CAR-T Therapy.
Clinical lymphoma, myeloma & leukemia
BACKGROUND: CD19 directed CAR-T therapy for Large B-cell lymphoma (LBCL) has shown great therapeutic response in patients with relapsed/refractory disease with response rates of 60-80%. However, in patients with a partial response (PR) on initial day 28 post CAR-T therapy imaging, clinical uncertainty remains as half of these patients will ultimately have relapsed disease. PATIENTS: In 24 patients receiving CD19 directed CAR-T therapy for relapsed/refractory LBCL achieving a PR on day 28, we utilize imaging biomarkers by 18F-FDG PET/CT imaging at pre CAR-T therapy baseline and day 28 to determine factors that may predict best overall response (B-OR), progression free survival (PFS), and overall survival (OS). METHODS: Out of 75 patients receiving CAR-T therapy at a single institution, we retrospectively identified and reviewed 25 (33%) as achieving a PR on day 28. PR was defined using the 2014 Lugano classification system. All patients received standard of care CD19 directed CAR-T therapy with axicabtagene ciloleucel. Two independent nuclear medicine physicians measured baseline (pre-CAR-T therapy) and day 28 PET/CT SUVmax, SUVmean and TMV (cm3) of each lesion (node, organ or marrow uptake, if any) using ROVER software. All statistical tests were two-sided and conducted at the 0.05 level of significance. R version 1.3.1099 (R-studio) was used for statistical modeling. CONCLUSION: We demonstrate that a higher day 28 SUVmax was significantly higher in those with a B-OR of PR and in our modeling, a lower day 28 SUVmax may predict favorable PFS and OS. Additionally, lower TMV, both at baseline and day 28, may also be predictive of longer PFS and OS, while lower TLG at baseline, but not day 28 is significantly associated with a B-OR of CR. While further study is warranted, these imaging biomarkers may allow for early identification of those with a day 28 PR at highest risk for relapse leading to early intervention to improve long term outcomes.
View details for DOI 10.1016/j.clml.2023.06.005
View details for PubMedID 37453865
Chimeric antigen receptor (CAR) T cells for the treatment of a kidney transplant patient with post-transplant lymphoproliferative disorder (PTLD).
Human vaccines & immunotherapeutics
Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD treatments associated with more pronounced and durable responses. To date, reports on the use of CD19-targeted chimeric antigen receptor (CAR) T (CAR-T) cells in patients after solid organ transplant (SOT) have been anecdotal, clinical presentations and outcomes have been heterogenous, and a longitudinal analysis of CAR-T cell expansion and persistence in PTLD patients has not been reported. Our report describes a patient with a history of renal transplant who received CD19-directed CAR-T cell therapy for the treatment of refractory PTLD, diffuse large B cell lymphoma (DLBCL)-type. We show that even with the background of prolonged immunosuppression for SOT, it is possible to generate autologous CAR-T products capable of expansion and persistence in vivo, without evidence of excess T-cell exhaustion. Our data indicate that CAR-T cells generated from a SOT recipient with PTLD can yield deep remissions without increased toxicity or renal allograft dysfunction. Future clinical studies should build on these findings to investigate CAR-T therapy, including longitudinal monitoring of CAR-T phenotype and function, for PTLD in SOT recipients.
View details for DOI 10.1080/21645515.2023.2216116
View details for PubMedID 37278257
Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma.
The New England journal of medicine
In an analysis of the primary outcome of this phase 3 trial, patients with early relapsed or refractory large B-cell lymphoma who received axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, as second-line treatment had significantly longer event-free survival than those who received standard care. Data were needed on longer-term outcomes.In this trial, we randomly assigned patients with early relapsed or refractory large B-cell lymphoma in a 1:1 ratio to receive either axi-cel or standard care (two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation in patients who had a response). The primary outcome was event-free survival, and key secondary outcomes were response and overall survival. Here, we report the results of the prespecified overall survival analysis at 5 years after the first patient underwent randomization.A total of 359 patients underwent randomization to receive axi-cel (180 patients) or standard care (179 patients). At a median follow-up of 47.2 months, death had been reported in 82 patients in the axi-cel group and in 95 patients in the standard-care group. The median overall survival was not reached in the axi-cel group and was 31.1 months in the standard-care group; the estimated 4-year overall survival was 54.6% and 46.0%, respectively (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.54 to 0.98; P = 0.03 by stratified two-sided log-rank test). This increased survival with axi-cel was observed in the intention-to-treat population, which included 74% of patients with primary refractory disease and other high-risk features. The median investigator-assessed progression-free survival was 14.7 months in the axi-cel group and 3.7 months in the standard-care group, with estimated 4-year percentages of 41.8% and 24.4%, respectively (hazard ratio, 0.51; 95% CI, 0.38 to 0.67). No new treatment-related deaths had occurred since the primary analysis of event-free survival.At a median follow-up of 47.2 months, axi-cel as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma resulted in significantly longer overall survival than standard care. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).
View details for DOI 10.1056/NEJMoa2301665
View details for PubMedID 37272527
Circulating Tumor DNA Adds Specificity to PET following Axicabtagene Ciloleucel in Large B-cell Lymphoma.
We examined the meaning of metabolically active lesions on 1 month restaging nuclear imaging of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving axicabtagene ciloleucel (axi-cel) by assessing the relationship between total metabolic tumor volume (MTV) on positron emission tomography (PET) scans and circulating tumor DNA (ctDNA) in the plasma. In this prospective multicenter sample collection study, MTV was retrospectively calculated via commercial software at baseline, 1 and 3 months post chimeric antigen receptor (CAR) T-cell therapy; ctDNA was available pre and post axi-cel. Spearman correlation coefficient (rs) was used to study the relationship between the variables and a mathematical model was constructed to describe tumor dynamics 1 month post CAR T-cell therapy. The median time between baseline scan and axi-cel infusion was 33 (range, 1-137) days for all 57 patients. For 41 of the patients with imaging within 33 days of axi-cel or imaging before that time but no bridging therapy, the correlation at baseline became stronger (rs 0.61, P< 0.0001) compared to all patients (rs 0.38, P= 0.004). Excluding patients in complete remission with no measurable residual disease, ctDNA and MTV at 1 month did not correlate (rs 0.28, P= 0.11), but did correlate at 3 months (rs 0.79, P= 0.0007). Modeling of tumor dynamics, which incorporated ctDNA and inflammation as part of MTV, recapitulated outcomes of patients with positive radiologic 1-month scans. Our results suggested that non-progressing hypermetabolic lesions on 1 month PET represent ongoing treatment response and their composition may be elucidated by concurrent ctDNA.
View details for DOI 10.1182/bloodadvances.2022009426
View details for PubMedID 37126659
Second-line treatment with CAR T-cell therapy for large B-cell lymphoma.
Clinical advances in hematology & oncology : H&O
2023; 21 (4): 170-178
The landscape for the treatment of patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) has continued to evolve. However, challenges continue to exist, particularly in patients who do not respond to first-line anti-CD20 monoclonal antibody and anthracycline-based therapy or those who experience early relapse. In such patients, the treatment paradigm has changed little in the past 2 decades, with salvage chemotherapy followed by myeloablative chemotherapy and autologous hematopoietic stem cell transplant resulting in historical durable response rates of approximately 40%. Given the success of chimeric antigen receptor (CAR) T-cell therapy in the third- or later-line in the R/R LBCL setting, 3 recent clinical trials (ZUMA-7, BELINDA, and TRANSFORM) have sought to address the clinical need for improved therapies in the high-risk second-line setting for primary R/R disease in the first 12 months. In this review, we analyze these 3 pivotal trials with a focus on clinical trial design, CAR T-cell product attributes, efficacy data, safety data, and patient-reported outcomes when compared with standard of care.
View details for PubMedID 37039724
Second-line Treatment With CAR T-Cell Therapy for Large B-Cell Lymphoma
CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY
2023; 21 (4): 170-178
View details for Web of Science ID 000969484500002
Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication.Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines.Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis.In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.
View details for DOI 10.1200/JCO.22.01797
View details for PubMedID 36753699
- Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (axi-cel) in Patients with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): Real-World Practice Patterns and Outcomes AMER SOC HEMATOLOGY. 2022: 4657-4660
- Higher Rates of Severe Infection and Persistent Cytopenias in Long-Term CAR19 Responders Than after Autologous HCT: A Single Institution Study of 139 Subjects AMER SOC HEMATOLOGY. 2022: 7545-7547
- The Development of Carhlh after Axicabtagene Ciloleucel Is Associated with Poor Outcomes AMER SOC HEMATOLOGY. 2022: 12775-12777
- Analysis of Bendamustine Lymphodepletion, CD19 CART Expansion, Safety and Efficacy in Patients with Rel/Ref NonHodgkin Lymphoma AMER SOC HEMATOLOGY. 2022: 10371-10373
- A Phase 2/3, Randomized, Double Blind, Placebo-Controlled, Multicenter Study of NKTR-255 Vs Placebo Following CD-19 Directed CAR-T Therapy in Patients with Relapsed/Refractory Large B-Cell Lymphoma AMER SOC HEMATOLOGY. 2022: 7488-7490
Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma.
Here we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy versus standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 (NCT03391466) study of axicabtagene ciloleucel (axi-cel) versus SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and ≥1 follow-up PRO completion. Prespecified hypotheses for QLQ-C30 Physical Functioning, Global Health Status/QoL, and EQ-5D-5L visual analogue scale (VAS) were tested using mixed-effect models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 Global Health Status/QoL (estimated difference 18.1 [95% CI, 12.3-23.9]), Physical Functioning (13.1 [95% CI, 8.0-18.2]), and EQ-5D-5L VAS (13.7 [95% CI, 8.5-18.8]; P<.0001 for all). At day 150, scores significantly favored axi-cel versus SOC for Global Health Status/QoL (9.8 [95% CI, 2.6-17.0]; P=.0124) and EQ-5D-5L VAS (11.3 [95% CI, 5.4-17.1]; P=.0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/R LBCL.
View details for DOI 10.1182/blood.2022015478
View details for PubMedID 35839452
- Vaccine-induced T-cell responses against SARS-CoV-2 and its Omicron variant in patients with B cell-depleted lymphoma after CART therapy. Blood 2022; 140 (2): 152-156
T cell responses against SARS-CoV-2 and its Omicron variant in a patient with B cell lymphoma after multiple doses of a COVID-19 mRNA vaccine.
Journal for immunotherapy of cancer
2022; 10 (7)
Anti-SARS-CoV-2 antibodies are crucial for protection from future COVID-19 infections, limiting disease severity, and control of viral transmission. While patients with the most common type of hematologic malignancy, B cell lymphoma, often develop insufficient antibody responses to messenger RNA (mRNA) vaccines, vaccine-induced T cells would have the potential to 'rescue' protective immunity in patients with B cell lymphoma. Here we report the case of a patient with B cell lymphoma with profound B cell depletion after initial chemoimmunotherapy who received a total of six doses of a COVID-19 mRNA vaccine. The patient developed vaccine-induced anti-SARS-CoV-2 antibodies only after the fifth and sixth doses of the vaccine once his B cells had started to recover. Remarkably, even in the context of severe treatment-induced suppression of the humoral immune system, the patient was able to mount virus-specific CD4+ and CD8+ responses that were much stronger than what would be expected in healthy subjects after two to three doses of a COVID-19 mRNA vaccine and which were even able to target the Omicron 'immune escape' variant of the SARS-CoV-2 virus. These findings not only have important implications for anti-COVID-19 vaccination strategies but also for future antitumor vaccines in patients with cancer with profound treatment-induced immunosuppression.
View details for DOI 10.1136/jitc-2022-004953
View details for PubMedID 35851312
View details for PubMedCentralID PMC9295666
KITE-363: A phase 1 study of an autologous anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory (R/R) B-cell lymphoma (BCL).
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680305078
The Novel Therapeutic Landscape for Relapsed/Refractory Diffuse Large B Cell Lymphoma.
Clinical lymphoma, myeloma & leukemia
2022; 22 (6): 362-372
Diffuse large B cell lymphoma (DLBCL) is an aggressive malignancy that has been traditionally treated with anthracycline-based chemotherapy, but approximately one-third of patients relapse after first-line therapy or have primary refractoriness. In this focused review, we discuss the 7 novel Food & Drug Administration (FDA)-approved medications for relapsed/refractory (R/R) DLBCL. We describe 5 CD19-targeted therapies, 3 of which are chimeric antigen receptor (CAR)-T cell therapies. We also highlight novel non-cell-based targeted therapies and discuss optimal sequencing considerations based on the goal of treatment, with an emphasis on CAR-T cell therapy as curative intent. We consider the limited tolerability of certain novel agents, prospects for elderly patients, and financial aspects of these approaches. We discuss advantages and limitations of these targeted therapies based on seminal clinical trials. Finally, we summarize ongoing trials involving promising agents making their way into the pharmacologic pipeline. These therapies include allogeneic CAR-T treatments and multi-antigen targeting therapies such as the CD19/CD22 CAR-T and the CD3/CD20 bispecific antibodies mosunetuzumab and odronextamab. We summarize our approach based on the best available evidence as we enter 2022.
View details for DOI 10.1016/j.clml.2021.11.010
View details for PubMedID 34922844
Low utility of the H-Score and HLH-2004 criteria to identify patients with secondary hemophagocytic lymphohistiocytosis after CAR-T cell therapy for relapsed/refractory diffuse large B-Cell lymphoma.
Leukemia & lymphoma
2022; 63 (6): 1339-1347
Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation disorder. Use of chimeric antigen receptor T-cell therapy (CAR-T) is associated with cytokine release syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) and secondary HLH. However, application of HLH scoring systems (H-score, HLH-2004 criteria) are not validated in this setting. We analyzed the utility of applying the H-score and the HLH-2004 criteria to identify patients with possible HLH post-CAR-T for Relapsed/Refractory Diffuse Large B-cell Lymphoma. Only two of four patients with post CAR-T HLH met five or more of the diagnostic criteria for HLH by HLH 2004 criteria. In contrast all four post CAR-T HLH patients had a high H-score (>169); however, an additional ten patients that did not have HLH also had a high H-score. Thus, in this patient population, both scoring systems were demonstrated to have low prognostic significance in differentiating between high grade CRS and HLH.
View details for DOI 10.1080/10428194.2021.2024817
View details for PubMedID 35045791
Brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma: Real-world experience from the United States lymphoma CAR T consortium.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680304110
Severity of Cytokine Release Syndrome Influences Outcome After Axicabtagene Ciloleucel for Large B cell Lymphoma: Results from the US Lymphoma CAR-T Consortium.
Clinical lymphoma, myeloma & leukemia
BACKGROUND: The majority of patients with large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, develop cytokine release syndrome (CRS). Whether the lack of development of CRS with axi-cel is associated with inferior lymphoma outcomes is unknown. Additionally, relationship between CRS grade and lymphoma outcome is not well established.METHODS: The US Lymphoma CAR T Consortium includes seventeen US academic centers that contribute data independently of manufacturers. We analyzed the modified intent-to-treat population of 275 patients receiving axi-cel in two different ways: 1) Two group analysis comparing no CRS with any grade CRS; 2) Three group analysis comparing grade 0 CRS with grade 1 to 2 CRS, and grade 3-5 CRS.RESULTS: In this large multi-center observational cohort of 275 patients receiving axi-cel, 9% (n = 24) did not develop CRS, 84% (n = 232) developed grade 1-2 CRS, and 7% (n = 19) developed grade 3 to 5 CRS. Patients without CRS, compared with those having any grade CRS, had similar overall response rates (ORR), lower complete response (CR) rates and inferior progression free survival (PFS) with no statistically significant difference in overall survival (OS). Patients experiencing grade 1 to 2 CRS had superior CR rate and PFS, as compared to those without CRS or with grade 3 to 5 CRS. Grade 3 to 5 CRS was associated with a worse OS.CONCLUSION: Overall, durable responses were seen in patients that did not develop CRS, however grade 1 to 2 CRS was associated with better outcomes while those with grade 3 to 5 experienced the worse outcomes.
View details for DOI 10.1016/j.clml.2022.05.004
View details for PubMedID 35780055
Humoral immunity against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine.
Clinical & translational immunology
2022; 11 (5): e1391
Solid organ transplant recipients (SOTR) receiving post-transplant immunosuppression show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines can overcome the reduced immune responsiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants.We analysed humoral immune responses against SARS-CoV-2 and its variants in 53 SOTR receiving SARS-CoV-2 vaccination.Following the initial vaccination series, 60.3% of SOTR showed no measurable neutralisation and only 18.9% demonstrated neutralising activity of > 90%. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titres against microbial recall antigens were higher. By contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titres against SARS-CoV-2 and its delta variants and fewer linear B-cell epitopes, indicating reduced B-cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titres and neutralising activity across alpha, beta and delta variants and to the induction of anti-SARS-CoV-2 CD4+ T cells in a subgroup of patients analysed. By contrast, we observed significantly lower antibody titres after the third dose with the omicron variant compared to the ancestral SARS-CoV-2 and the improvement in neutralising activity was much less pronounced than for all the other variants.Only a small subgroup of solid organ transplant recipients is able to generate functional antibodies after an initial vaccine series; however, an additional vaccine dose resulted in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron where antibody responses and neutralising activity remained suboptimal.
View details for DOI 10.1002/cti2.1391
View details for PubMedID 35505864
View details for PubMedCentralID PMC9052011
Ocular adverse events associated with chimeric antigen receptor T-cell therapy: a case series and review.
The British journal of ophthalmology
Chimeric antigen receptor T-cell (CAR T) therapy has been shown to improve the remission rate and survival for patients with refractory haematological malignancies. The aim of this study is to describe ocular adverse effects associated with CAR T therapy in patients with haematological malignancies.This is a retrospective, single-institution, case series. Patients aged 18 years or older who received standard of care CAR T therapy for relapsed/refractory large B-cell lymphoma with a documented ophthalmic evaluation were included. The primary outcome was clinician ophthalmic examination findings.A total of 66 patients received CAR T-cell therapy from February 2018 to October 2019 with 11 receiving an ophthalmic examination. Eleven patients (n=22 eyes) who received CAR T-cell therapy were included in review. The median time from CAR T-cell infusion date to ocular examination was 57.5 days. The median patient age at the time of examination was 60.5 years. Ten patients had subjective symptoms prompting ophthalmic examination. Two patients reported floaters and photopsias. One patient had worsening ocular graft-versus-host disease. Two patients were identified with possible reactivation of viral infections, including herpes zoster ophthalmicus and regressing acute retinal necrosis.The increasing use of CAR T therapy for malignancies underscores the importance of ophthalmologists and oncologists understanding the potential toxicities associated with its use, particularly ocular toxicities and when to refer for an ophthalmic examination.
View details for DOI 10.1136/bjophthalmol-2021-320814
View details for PubMedID 35144919
- Impaired immune response to COVID-19 vaccination in patients with B-cell malignancies after CD19 CAR T-cell therapy. Blood advances 2022; 6 (2): 686-689
Deep dissection of the antiviral immune profile of patients with COVID-19.
2021; 4 (1): 1389
In light of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants potentially undermining humoral immunity, it is important to understand the fine specificity of the antiviral antibodies. We screened 20 COVID-19 patients for antibodies against 9 different SARS-CoV-2 proteins observing responses against the spike (S) proteins, the receptor-binding domain (RBD), and the nucleocapsid (N) protein which were of the IgG1 and IgG3 subtypes. Importantly, mutations which typically occur in the B.1.351 "South African" variant, significantly reduced the binding of anti-RBD antibodies. Nine of 20 patients were critically ill and were considered high-risk (HR). These patients showed significantly higher levels of transforming growth factor beta (TGF-β) and myeloid-derived suppressor cells (MDSC), and lower levels of CD4+ T cells expressing LAG-3 compared to standard-risk (SR) patients. HR patients evidenced significantly higher anti-S1/RBD IgG antibody levels and an increased neutralizing activity. Importantly, a large proportion of S protein-specific antibodies were glycosylation-dependent and we identified a number of immunodominant linear epitopes within the S1 and N proteins. Findings derived from this study will not only help us to identify the most relevant component of the anti-SARS-CoV-2 humoral immune response but will also enable us to design more meaningful immunomonitoring methods for anti-COVID-19 vaccines.
View details for DOI 10.1038/s42003-021-02852-1
View details for PubMedID 34916602
View details for PubMedCentralID PMC8677724
Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma.
The New England journal of medicine
BACKGROUND: The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor.METHODS: In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed.RESULTS: A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group (with a complete response in 65% and 32%, respectively). In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group. Adverse events of grade 3 or higher occurred in 91% of the patients who received axi-cel and in 83% of those who received standard care. Among patients who received axi-cel, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21%. No deaths related to cytokine release syndrome or neurologic events occurred.CONCLUSIONS: Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).
View details for DOI 10.1056/NEJMoa2116133
View details for PubMedID 34891224
- Long-Term Outcomes of Patients with Large B-Cell Lymphoma Treated with Standard-of-Care Axicabtagene Ciloleucel: Results from the US Lymphoma CAR-T Cell Consortium AMER SOC HEMATOLOGY. 2021: 3826-+
- Brexucabtagene Autoleucel for Relapsed/Refractory Mantle Cell Lymphoma: Real World Experience from the US Lymphoma CAR T Consortium AMER SOC HEMATOLOGY. 2021
The impact of bridging therapy prior to CD19-directed chimeric antigen receptor T-cell therapy in patients with large B-cell lymphoma.
British journal of haematology
2021; 195 (3): 405-412
In the relapsed/refractory setting for treatment of large B-cell lymphoma (LBCL), chimeric antigen receptor T-cell (CAR-T) therapy has emerged as an effective treatment modality. Patients often have aggressive disease that requires prompt treatment in the form of bridging therapy (BT) for disease stabilisation while CAR-T cells are manufactured. Patients (n = 75) undergoing CAR-T therapy infusion for LBCL at our institution were identified. A total of 52 (69·3%) received BT and 23 (30·7%) received no BT (NBT). BT modalities included systemic BT (SBT) in 28 patients, radiation BT (RBT) in 14, and high-dose steroid BT (HDS) in 10. There was no difference in incidence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome between BT and NBT (P = 0·18 and P = 0·53 respectively). Prolonged cytopenias at Day 180 were more common in BT than NBT (50% vs. 13·3%, P = 0·04). The SBT and RBT subgroups had more cytopenias at Day 180 compared to the HDS and NBT subgroups (58·3% and 57·1% vs. 20% and 13·3% respectively, P = 0·04). Disease response at last follow-up, progression-free survival and overall survival were similar between BT, NBT, and BT subgroups. In summary, BT can be safely considered in patients undergoing CAR-T therapy. However, those undergoing BT with SBT or RBT are at higher risk of prolonged cytopenias after CAR-T therapy.
View details for DOI 10.1111/bjh.17738
View details for PubMedID 34500492
Anti-SARS-CoV-2 Immune Responses in Patients Receiving an Allogeneic Stem Cell or Organ Transplant.
2021; 9 (7)
Patients after autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) are at an increased risk of COVID-19-related morbidity and mortality, compounded by an immune system weakened by the underlying malignancy and prior treatments. Allogeneic transplantation, including stem cell and solid organ transplants, requires intensive immunosuppressive prophylaxis, which may further undermine the development of a protective vaccine-induced anti-viral immunity. Herein, we report on short- and long-term antiviral immune responses in two peri-stem cell transplant recipients and a third patient who received a COVID-19 vaccination after kidney transplantation. Our data indicate that: (1) patients post-alloSCT may be able to mount an anti-COVID-19 immune response; however, a sufficient time interval between transplant and exposure may be of critical importance; (2) alloSCT recipients with preexisting anti-SARS-CoV-2 immunity are at risk for losing protective humoral immunity following transplantation, particularly if the stem-cell donor lacks antiviral immunity, e.g., vaccine-derived immunity; and (3) some post-transplant patients are completely unable to build an immune response to a COVID-19 vaccine, perhaps based on the prophylactic suppression of T cell immunity.
View details for DOI 10.3390/vaccines9070737
View details for PubMedID 34358153
View details for PubMedCentralID PMC8310198
Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel Infusion in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE: Although the majority of patients with relapsed or refractory large B-cell lymphoma respond to axicabtagene ciloleucel (axi-cel), only a minority of patients have durable remissions. This prospective multicenter study explored the prognostic value of circulating tumor DNA (ctDNA) before and after standard-of-care axi-cel for predicting patient outcomes.METHODS: Lymphoma-specific variable, diversity, and joining gene segments (VDJ) clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axi-cel infusion. We assessed the prognostic value of ctDNA to predict outcomes and axi-cel-related toxicity.RESULTS: A tumor clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axi-cel infusion and developing cytokine release syndrome and/or immune effector cell-associated neurotoxicity syndrome. Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated nondetectable ctDNA 1 week after axi-cel infusion (P < .0001). At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median progression-free survival and OS of 3 months versus not reached (P < .0001) and 19 months versus not reached (P = .0080), respectively. In patients with a radiographic partial response or stable disease on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed (P = .0001). ctDNA was detected at or before radiographic relapse in 29 of 30 (94%) patients. All durably responding patients had undetectable ctDNA at or before 3 months after axi-cel infusion.CONCLUSION: Noninvasive ctDNA assessments can risk stratify and predict outcomes of patients undergoing axi-cel for the treatment of large B-cell lymphoma. These results provide a rationale for designing ctDNA-based risk-adaptive chimeric antigen receptor T-cell clinical trials.
View details for DOI 10.1200/JCO.21.00377
View details for PubMedID 34133196
Length of Stay and Hospital Costs for Patients Undergoing Allogeneic Stem-Cell Transplantation.
JCO oncology practice
2021; 17 (3): e355-e368
Patients who undergo allogeneic hematopoietic stem-cell transplantation (allo-HSCT) usually require a prolonged hospital stay that varies greatly across patients. Limited information exists on the factors associated with hospital length of stay (LOS) after allo-HSCT and the impact on transplant-related costs. The objective of this study was to determine predictors for longer LOS for allo-HSCT and to assess their impact on the cost of transplant stay.Using the National Inpatient Sample database, adult patients hospitalized for allo-HSCT were identified using International Classification of Diseases, Ninth Revision, primary and secondary procedure codes.Between 2002 and 2015, 68,296 hospitalizations for allo-HSCT were identified. Peripheral blood was the most common stem-cell source (80%) followed by bone marrow (15%) and cord blood (5%). Median LOS was 25.8 days (interquartile range [IQR], 21-34.0 days), and the overall inpatient mortality rate was 8%. Stem-cell source was a significant predictor for longer LOS, being significantly longer for cord blood (median, 36.9 days; IQR, 26.7-49.9 days) compared with bone marrow (median, 27.2 days; IQR, 21.5-35.2 days) and peripheral blood (median 25.4 days; IQR, 20.8-32.7 days). Other predictors for longer LOS were patient characteristics such as age and race, transplant/post-transplant characteristics, and complications such as total body irradiation use, acute graft-versus-host disease, and infections. Longer LOS was also found to be associated with higher hospital costs.In patients who undergo allo-HSCT, LOS can be predicted using patient- and transplant-related characteristics as well as post-transplant complications. LOS is also a driver for increased cost, and further efforts are needed to mitigate transplant complications and resource utilization.
View details for DOI 10.1200/OP.20.00170
View details for PubMedID 32735507
The association of leukocyte immunoglobulin-like receptor subfamily B-4 expression in acute myeloid leukemia and central nervous system involvement.
2021; 100: 106480
Central nervous system (CNS) involvement in patients with acute myeloid leukemia (AML) varies, ranging from 0.6%-46%. Leukocyte immunoglobulin-like receptor B4 (LILRB4) has been shown to be critical in orchestration of infiltration of AML cells into the CNS in animal models, however it is unknown if an association exists between LILRB4 and CNS involvement (CNS+) in human patients with AML. LILRB4 was measured by flow cytometry in a heterogeneous population of fifty-six AML patients. Patients were then followed clinically for the development of CNS + . LILRB4 was positive in 91 % of patients with CNS + compared to 38 % without CNS involvement (p < 0.002). In logistic analysis: age, BMI, serum albumin and positive LILRB4 were predictive for CNS+ [OR, 95 % CI, p-value]: 0.95, 0.92-0.99, p < 0.01; 0.85, 0.73-0.998, p < 0.05; 0.23, 0.066-0.78, p < 0.02; 16.46, 1.93-140.2, p < 0.02, respectively. This finding of the association of LILRB4 with CNS + in combination with earlier findings suggests that LILRB4 has a mechanistic role in infiltration of the CNS and may provide insight into the pathogenesis of AML seeding the CNS. Moreover, this proof of concept and the findings in the present study may lead to the development of innovative and novel therapies to improve the lives of patients with AML.
View details for DOI 10.1016/j.leukres.2020.106480
View details for PubMedID 33285315
- Chimeric antigen receptor T-cell therapy after allogeneic stem cell transplant for relapsed/refractory large B-cell lymphoma. British journal of haematology 2021; 192 (1): 212-216
- Outcomes of Patients with Large B-cell Lymphoma Progressing after Axicabtagene Ciloleucel. Blood 2020
- Severe dysautonomia as a manifestation of neurotoxicity after CAR-T cell therapy for diffuse large B-cell lymphoma. American journal of hematology 2020; 95 (6): E146-E148
Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE: Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication.PATIENTS AND METHODS: Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution's guidelines. Responses were assessed as per Lugano 2014 classification.RESULTS: Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel-treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis.CONCLUSION: The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.
View details for DOI 10.1200/JCO.19.02104
View details for PubMedID 32401634
Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.
Lancet (London, England)
Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness.In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing.Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality.Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.
View details for DOI 10.1016/S0140-6736(20)31187-9
View details for PubMedID 32473681
Radiation Therapy as a Bridging Strategy for CAR T Cell Therapy With Axicabtagene Ciloleucel in Diffuse Large B-Cell Lymphoma.
International journal of radiation oncology, biology, physics
2019; 105 (5): 1012-1021
Axicabtagene ciloleucel (axi-cel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Bridging therapy may be required for lymphoma control during the manufacturing interval between collection of autologous T cells and final CAR T product administration. The optimal bridging therapy is not known and patients are often chemorefractory. We present a case series of patients receiving radiation as a bridge to axi-cel.Between December 2017 and October 2018, 12 patients were intended to receive bridging radiation before axi-cel. The group was characterized by highly aggressive disease including 6 of 12 with "double hit" lymphoma and 6 of 12 with disease ≥10 cm in diameter. All patients received 2 to 4 Gy/fraction to a median dose of 20 Gy (range, 6-36.5 Gy). Half of patients received either 30 Gy in 10 fractions or 20 Gy in 5 fractions. Seven patients received concurrent chemotherapy. Eleven patients underwent axi-cel infusion and one did not. Median follow-up was 3.3 months (range, 1.1-12.0 months).No significant toxicities were identified during bridging radiation, and no patient experienced in-field progression of disease before axi-cel infusion. One patient experienced abdominal pain, which resolved after dose reduction. Two patients had out-of-field progression of disease during the bridging period. After axi-cel infusion, 3 of 11 patients (27%) experienced severe cytokine release syndrome or neurotoxicity. At 30 days, the objective response rate was 81.8% (11 of 12 evaluable; 1 stable disease, 1 out-of-field progression), with complete response in 27% (3 of 11). At last follow-up, the best objective response rate was 81.8%, with a complete response attained in 45% (5 of 11). Lymphocyte counts decreased slightly in 10 of 12 patients during radiation (median, 0.25 k/uL).Radiation (with or without concurrent chemotherapy) can be safely administered as a bridge to axi-cel in high-risk lymphoma. Caution should be taken if irradiation is started before apheresis, and lymphocyte counts should be monitored closely throughout. Future investigation is warranted to optimize the use of bridging radiation before CAR T therapy.
View details for DOI 10.1016/j.ijrobp.2019.05.065
View details for PubMedID 31175906
View details for PubMedCentralID PMC6872916
- Detectable Circulating Tumor DNA 28 Days after the CD19 CAR T-Cell Therapy, Axicabtagene Ciloleucel, Is Associated with Poor Outcomes in Patients with Diffuse Large B-Cell Lymphoma AMER SOC HEMATOLOGY. 2019
- Characteristics and Outcomes of Patients Receiving Bridging Therapy While Awaiting Manufacture of Standard of Care Axicabtagene Ciloleucel CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Results from the US Lymphoma CAR-T Consortium AMER SOC HEMATOLOGY. 2019
- Experience with Axicabtagene Ciloleucel (Axi-cel) in Patients with Secondary CNS Involvement: Results from the US Lymphoma CAR T Consortium AMER SOC HEMATOLOGY. 2019
- Rapid relapse of large B-cell lymphoma after CD19 directed CAR-T-cell therapy due to CD-19 antigen loss. American journal of hematology 2019; 94 (10): E273-E275
- Refractory postallogeneic stem cell transplant pure red cell aplasia in remission after treatment with daratumumab. American journal of hematology 2019; 94 (8): E216-E219
Monitoring ctDNA in r/r DLBCL patients following the CAR T-cell therapy axicabtagene ciloleucel: Day 28 landmark analysis.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for Web of Science ID 000487345806314
- Circulating tumor DNA assessment in patients with diffuse large B-cell lymphoma following CAR T-cell therapy LEUKEMIA & LYMPHOMA 2019; 60 (2): 503-506
Circulating tumor DNA assessment in patients with diffuse large B-cell lymphoma following CAR T-cell therapy.
Leukemia & lymphoma
View details for PubMedID 29966461
Continuing challenges and current issues in acute lymphoblastic leukemia
LEUKEMIA & LYMPHOMA
2018; 59 (3): 526–41
Conventional cytotoxic chemotherapy used to treat acute lymphoblastic leukemia (ALL) has resulted into high cure rates for pediatric patients, however outcomes for adult patients remain suboptimal. The 5-year overall survival is only 30-40% in adults and elderly patients with ALL compared to 90% in children. We have seen major advances in our understanding and management of ALL related to identification of new cytogenetic and molecular abnormalities and development of novel targeted agents for the treatment of ALL. The addition of tyrosine kinase inhibitors, monoclonal antibodies and novel immune therapies (e.g. bispecific T cell engager [BiTE] and chimeric antigen receptor [CAR] T cells) has resulted in improved outcomes. These new developments are changing the treatment paradigm of adults ALL from a 'one size fits all' approach to a more individualized treatment approach based on immunophenotypic, cytogenetic and molecular features. In this article we review recent diagnostic and therapeutic advances along with the challenges in the treatment of patients with ALL.
View details for PubMedID 28604239
- Circulating tumor DNA assessment in patients with diffuse large B-cell lymphoma following CAR-T therapy. AMER SOC CLINICAL ONCOLOGY. 2017
Correlation of higher levels of soluble TNF-R1 with a shorter survival, independent of age, in recurrent glioblastoma.
Journal of neuro-oncology
The circulating levels of soluble tumor necrosis factor receptor-1 (sTNF-R1) and sTNF-R2 are altered in numerous diseases, including several types of cancer. Correlations with the risk of progression in some cancers, as well as systemic manifestations of the disease and therapeutic side-effects, have been described. However, there is very little information on the levels of these soluble receptors in glioblastoma (GBM). Here, we report on an exploratory retrospective study of the levels of sTNF-Rs in the vascular circulation of patients with GBM. Banked samples were obtained from 112 GBM patients (66 untreated, newly-diagnosed patients and 46 with recurrent disease) from two institutions. The levels of sTNF-R1 in the plasma were significantly lower in patients with newly-diagnosed or recurrent GBM than apparently healthy individuals and correlated with the intensity of expression of TNF-R1 on the tumor-associated endothelial cells (ECs) in the corresponding biopsies. Elevated levels of sTNF-R1 in patients with recurrent, but not newly-diagnosed GBM, were significantly associated with a shorter survival, independent of age (p = 0.02) or steroid medication. In contrast, the levels of circulating sTNF-R2 were significantly higher in recurrent GBM than healthy individuals and there was no significant correlation with expression of TNF-R2 on the tumor-associated ECs or survival time. The results indicate that larger, prospective studies are warranted to determine the predictive value of the levels of sTNF-R1 in patients with recurrent GBM and the factors that regulate the levels of sTNF-Rs in the circulation in GBM patients.
View details for DOI 10.1007/s11060-016-2319-2
View details for PubMedID 27858267
Treatment of Cerebral Radiation Necrosis With Bevacizumab: The Cleveland Clinic Experience
AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS
2015; 38 (3): 304-310
Cerebral radiation necrosis (RN) is a devastating complication of radiation therapy for brain tumors. Recent studies have explored the role of bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor in the treatment of RN of the brain. We report 24 patients with cerebral RN who were treated with bevacizumab.Twenty-four patients diagnosed with cerebral RN and treated with different schedules of bevacizumab between July 2007 and June 2012, were identified from the Cleveland Clinic Brain Tumor and Neuro-Oncology Center's database. Pretreatment and posttreatment magnetic resonance imaging (MRI) studies were compared to evaluate bevacizumab efficacy.Posttreatment MRI demonstrated a radiographic improvement in 23 of 24 patients on the postcontrast T1-weighted MRI and fluid-attenuated inversion-recovery sequences. Using the McDonald criteria, the average change in the T1-weighted postcontrast MRI was a decrease of 48.1%, and the average change in the fluid-attenuated inversion-recovery images was a decrease of 53.7%. There was a mean daily dose reduction of 9.4 mg of dexamethasone after initiation of bevacizumab in patients who were on steroids at the start of bevaciuzmab therapy for RN. Treatment with bevacizumab was well tolerated with only 1 grade 3 adverse event.The current study demonstrates that bevacizumab treatment results in excellent clinical and radiologic response in patients with RN caused by common forms of radiation therapy. The safety profile of bevacizumab use in RN is acceptable. In the current study, we found no difference between different schedules of bevacizumab in treatment outcomes.
View details for DOI 10.1097/COC.0b013e31829c3139
View details for Web of Science ID 000355142900013
View details for PubMedID 23799286
Bevacizumab in high-grade gliomas: past, present, and future.
Expert review of anticancer therapy
2015; 15 (4): 387-397
The survival of patients with high-grade gliomas (anaplastic gliomas and glioblastoma) remains poor despite current treatment modalities. However, an enhanced understanding of gliomagenesis is supporting the development of targeted molecular therapies with the potential for improving clinical outcomes. Glioblastoma (GBM) is characterized by extensive microvascular proliferation and the production of large amounts of VEGF. Bevacizumab is a humanized IgG1 monoclonal antibody that selectively binds with high affinity to human VEGF and neutralizes VEGF's biologic activity. Preclinical data indicate that angiogenesis is essential for the proliferation and survival of GBM cells. A number of studies have evaluated the outcomes of both newly diagnosed and recurrent GBM patients with bevacizumab in a prospective manner. Here, we discuss the role of bevacizumab in the treatment of anaplastic gliomas and GBM in the recurrent and upfront setting.
View details for DOI 10.1586/14737140.2015.1028376
View details for PubMedID 25797685
Efficacy and patient-reported outcomes with dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma: a phase II multicenter study.
Journal of neuro-oncology
2015; 122 (1): 111-119
Standard initial therapy for patients with pure and mixed anaplastic oligodendrogliomas (AO/MAO) includes chemotherapy and radiation therapy. Anaplastic oligodendrogliomas with 1p/19q co-deletion are more responsive to chemotherapy. There is concern for potential long-term CNS toxicity of radiation. Hence an approach using chemotherapy initially and reserving radiation for progressive disease is attractive. This multicenter phase II trial included patients with newly diagnosed AO/MAO with central pathology review and 1p/19q assay. Temozolomide was given 150 mg/m(2) days 1-7 and 15-21, every 28 days for 8 cycles. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate, overall survival (OS), treatment toxicity and health-related quality of life (HRQL). Data from 62 patients enrolled between December 2001 and April 2007 at seven centers were analyzed. Among patients with measurable disease, 8 % achieved complete remission, 56 % had stable disease and 36 % had progression. The median PFS and OS were 27.2 months (95 % CI 11.9-36.3) and 105.8 months (95 % CI 51.5-N/A), respectively. Both 1p loss and 1p/19q co-deletion were positive prognostic factors for PFS (p < 0.001) and OS (p < 0.001); and there was some suggestion that 1p/19q co-deletion also predicted better response to chemotherapy (p = 0.007). Grade 3/4 toxicities were mainly hematological. Significantly improved HRQL in the future uncertainty domain of the brain cancer module was seen after cycle 4 (p < 0.001). This trial achieved outcomes similar to those reported previously. Toxicities from dose-intense temozolomide were manageable. Improvement in at least one HRQL domain increased over time. This trial supports the further study of first-line temozolomide monotherapy as an alternative to radiation therapy for patients with newly diagnosed AO/MAO with 1p 19q co-deleted tumors.
View details for DOI 10.1007/s11060-014-1684-y
View details for PubMedID 25534576
Sleep disturbances in cancer patients: Underrecognized and undertreated
CLEVELAND CLINIC JOURNAL OF MEDICINE
2013; 80 (11): 722-732
Sleep-related complaints are extremely common in patients with cancer but often are not recognized, and even if they are, they are seldom treated. Recognizing insomnia in cancer patients is imperative, as appropriate treatment can improve quality of life.
View details for DOI 10.3949/ccjm.80a.12170
View details for Web of Science ID 000336727900008
View details for PubMedID 24186891
Recurrent or refractory primary central nervous lymphoma: therapeutic considerations
EXPERT REVIEW OF ANTICANCER THERAPY
2013; 13 (9): 1109-1119
Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin lymphoma (NHL) that involves the brain, leptomeninges, eyes or spinal cord without evidence of systemic disease. Despite the high complete remission rate achieved with aggressive first-line therapy, 10-35% of PCNSL are treatment refractory and 35-60% of patients relapse. Standard therapy for recurrent or refractory disease has not yet been established, although retrospective data suggests improvement in survival with salvage therapy. The reported survival after relapse of PCNSL varies between 2 months and 24 months, with most series reporting an average of 4-12 months. The outcomes depend on whether treatment is instituted or not, suggesting a need for treatment guidelines for these patients. We review therapeutic approaches and their outcomes in recurrent or refractory PCNSL.
View details for DOI 10.1586/14737140.2013.829634
View details for Web of Science ID 000336053400017
View details for PubMedID 24053208
Primary Central Nervous System Lymphoma in the Elderly: The Cleveland Clinic Experience
2013; 33 (8): 3251-3258
Primary central nervous system lymphoma (PCNSL) is a type of extranodal non-Hodgkin lymphoma that involves only the central nervous system. Untreated PCNSL in the elderly has a rapidly fatal course.In this retrospective study, we evaluated the demographics, management, and outcomes of patients over 60 years of age with PCNSL at our institution.A total of 54 patients with a median age of 67 years were included in the analysis. The initial treatment regimens included whole-brain radiation therapy (WBRT), chemotherapy with or without consolidation WBRT. The median progression-free survival (PFS) was 8.0 months (95% confidence interval CI=2.7-22 months) and the median overall survival (OS) was 38 months (95% CI=18-65 months). On multivariable analysis, age younger than 70 years and Karnofsky Performance Status (KPS) no less than 70 were favorable prognostic factors for both OS and PFS.Aggressive treatment strategies for elderly patients with PCNSL with good performance status can lead to improved outcomes in this patient population.
View details for Web of Science ID 000322559300038
View details for PubMedID 23898087
- Primary central nervous system posttransplantation lymphoproliferative disorder in an elderly liver transplant recipient. Journal of the American Geriatrics Society 2012; 60 (9): 1777-8