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1.
Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma
Westin, J. R., Locke, F. L., Dickinson, M., Ghobadi, A., Elsawy, M., van Meerten, T., Miklos, D. B., Ulrickson, M. L., Perales, M. A., Farooq, U., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;:Of1-of12
Abstract
PURPOSE Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. PATIENTS AND METHODS Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2-3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). RESULTS Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and <65 years. CONCLUSIONS Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.
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2.
Updated Indications for Immune Effector Cell Therapy: 2023 Guidelines from the American Society for Transplantation and Cellular Therapy
Kanate, A. S., Majhail, N., DeFilipp, Z. M., Dhakal, B., Dholaria, B., Hamilton, B., Herrera, A. F., Inamoto, Y., Jain, T., Perales, M. A., et al
Transplantation and cellular therapy. 2023
Abstract
The American Society for Transplantation and Cellular Therapy (ASTCT) published its guidelines on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) and immune effector cell therapy (IECT) in 2020. Since then we have witnessed rapid advancements in the field of IECT, resulting in several new chimeric antigen receptor T-cell (CAR-T) products and disease indications being approved by the U.S. Food and Drug Administration (FDA). To keep abreast of these practice changes, the ASTCT Committee on Practice Guidelines commissioned a focused update covering CAR-T therapy indications. This brief manuscript presents updated ASTCT recommendations on indications for CAR-T therapy. Only FDA approved indications for CAR-T were recommended and categorized as "standard of care" (S), where indication is well defined and supported by evidence. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.
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3.
Paving the Road for CAR-Ts: ASTCT 80/20 Task Force consensus on challenges and solutions to improving efficiency of clinical center certification and maintenance of operations for commercially approved immune effector cell therapies
Nikiforow, S., Frigault, M. J., Frey, N. V., Gardner, R. A., Komanduri, K. V., Perales, M. A., Kebriaei, P., Warkentin, P. I., Pasquini, M., Aho, J. L., et al
Transplantation and cellular therapy. 2023
Abstract
As the number and type of regulatory authority-approved cellular therapies grow, clinical treatment centers face a heavy burden of duplicative documentation around initial qualification, ongoing auditing, and reporting-with overlapping requirements from each manufacturer to ensure safe use of their specific product, which in the United States are stipulated under individual Food and Drug Administration (FDA) Biologic License Applications (BLA). The American Society for Transplantation and Cellular Therapy (ASTCT) convened the 80/20 Taskforce to consider challenges and potential solutions to these issues. The taskforce proposed that 80% of manufacturers' requirements for onboarding and ongoing operations of commercially available products could be standardized and streamlined. Taskforce members interviewed dozens of stakeholders, including clinicians at large academic medical centers already utilizing commercial and investigational immune effector cell (IEC) products, regulators, members of accrediting bodies and professional cellular therapy societies, and manufacturers of IEC therapies for oncologic indications. In November 2021, the taskforce organized and led virtual discussions in a public forum and at a private ASTCT 80/20 workshop at the online AcCELLerate Forum, a cellular-therapy stakeholders' meeting organized by the ASTCT, the National Marrow Donor Program (NMDP) and Center for International Blood and Marrow Transplant Research (CIBMTR). At the workshop, approximately 60 stakeholders worked to identify and prioritize common challenges in onboarding and maintenance of operations at clinical sites for commercial FDA-approved and future IEC therapies and ways to streamline the process. It was agreed that standardization would improve efficiency of onboarding, allowing more cost-effective, sustainable growth of approved IEC therapies at treatment centers, and facilitate wider access while maintaining safety and clinical success. This early but extensive survey of stakeholders resulted in five overarching suggestions for both established and emerging treatment centers: 1. Eliminate duplication in accreditation and auditing of clinical sites; 2. Define expectations for education and management of CAR-T cell therapy toxicities to potentially replace product-specific REMS programs; 3. Streamline current REMS education, testing and data reporting; 4. Standardize IT platforms supporting enrollment, clinical site-to-manufacturer communication, and logistics of maintaining chain of identity/chain of custody across multiple transportation steps; 5. Encourage use of universal nomenclature by cell therapy manufacturers. Future discussions need to engage a broader range of stakeholders including administrators, pharmacists, nurses, data coordinators, surgeons, pathologists, and those developing promising cellular therapies for solid tumors, as well as teams from smaller academic or community cancer center settings. Continued collaboration with stakeholders outside of clinical sites will include accrediting bodies/auditors, established and emerging cell therapy companies, software developers, professional societies, and the patients who receive these therapies. Active dialogue with government regulators remains essential. Such joint efforts are critical as the number of IEC therapies for myriad oncologic and non-oncologic indications grows.
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4.
Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma
Kersten, M. J., Qiao, Y., Shah, R., Solem, C., Snider, J. T., To, C., Cheng, P., Spooner, C., Perales, M. A.
Transplantation and cellular therapy. 2023
Abstract
The quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology provides a comprehensive framework for treatment comparison that partitions survival time into distinct health states reflecting both treatment toxicity and disease progression. ZUMA-7 (ClinicalTrials.gov identifier NCT03391466), a phase 3 randomized open-label multicenter study, was conducted to evaluate the efficacy of axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor T cell therapy, compared with standard of care (SOC) involving platinum-based salvage chemotherapy with autologous stem cell transplantation (ASCT) consolidation as a second-line treatment for relapsed/refractory (R/R) large B cell lymphoma (LBCL), and met its primary endpoint of improved event-free survival (EFS). We aimed to use the Q-TWiST method to compare the quality-adjusted survival of R/R LBCL patients treated with axi-cel and those treated with SOC who were enrolled in ZUMA-7. The preplanned analysis of overall survival (OS) was partitioned into 3 mutually exclusive health states: time with grade ≥3 adverse events before the event as defined in the EFS analysis (TOX), time without severe toxicity before the event (TWiST), and time after the event (REL). Q-TWiST was computed as a weighted sum of mean TOX, TWiST, and REL values multiplied by state-specific quality of life (QoL) utility scores. Q-TWiST was evaluated in the intention-to-treat cohort at median follow-up. A relative Q-TWiST gain of 10% was deemed "clinically important" and a gain of ≥15% was deemed "clearly clinically important" based on established categorization. Sensitivity analyses with follow-up ranging from 3 months to the maximum follow-up and subgroup analyses by age and R/R status were explored. At a median follow-up of 23.5 months, the axi-cel cohort showed a significantly longer time without severe toxicity compared with the SOC cohort, with a mean TWiST duration of 11.18 months versus 5.39 months, respectively. The mean TOX was 1.16 months versus .74 months, and mean REL was 6.02 months versus 10.66 months. Quality-adjusted survival was significantly longer with axi-cel by 3.7 months (95% CI, 2.3 to 5.2 months), representing a relative gain of 21.9%. This was reflected across all subgroups, with estimated Q-TWiST gains of 3.1 months (95% CI, 1.5 to 4.9 months) for patients age <65 years, 5.2 months (95% CI, 2.4 to 7.9 months) for those age ≥65 years, 3.2 months (95% CI, 1.4 to 4.9 months) for those with primary refractory disease, 9.1 months (95% CI, 3.9 to months 13.5) for those who relapsed within 6 months, and 4.1 months (95% CI, 1.1 to 7.1 months) for those who relapsed between 6 and 12 months. The Q-TWiST gain for axi-cel also was statistically significant across follow-up durations, increasing from .2 month (95% CI, .1 to .3 month) at a 3-month follow-up to 4.9 months (95% CI, 2.4 to 7.8 months) at the maximum follow-up of 37.7 months. Axi-cel was associated with a statistically significant and "clearly clinically important" gain in quality-adjusted survival, regardless of the relative decline in QoL associated with treatment toxicity, disease progression, or additional cancer treatment. This finding adds to the existing evidence supporting a benefit for axi-cel as a second-line treatment for patients with R/R LBCL.
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5.
Allogeneic transplant following CAR T-cell therapy for large B-cell lymphoma
Zurko, J., Ramdial, J., Shadman, M., Ahmed, S., Szabo, A., Iovino, L., Tomas, A. A., Sauter, C., Perales, M. A., Shah, N. N., et al
Haematologica. 2022
Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) can potentially salvage large B-cell lymphoma (LBCL) patients experiencing treatment failure after chimeric antigen receptor T-cell therapy (CAR-T). Nonetheless, data on the efficacy and toxicities of alloHCT after receipt of CAR-T are limited. We report a multicenter retrospective study assessing the safety, toxicities, and outcomes of alloHCT in LBCL patients following CAR-T failure. Eighty-eight patients with relapsed, refractory LBCL received an alloHCT following anti-CD19 CAR-T failure. The median number of lines of therapy between CAR-T infusion and alloHCT was 1 (range 0-7). Low intensity conditioning was used in 77% (n=68) and peripheral blood was the most common graft source (86%, n=76). The most common donor types were matched unrelated donor (39%), followed by haploidentical (30%) and matched related donor (26%). Median follow-up of survivors was 15 months (range 1-72). One-year overall survival, progression-free survival, and graft-versus-host disease-free relapse-free survival were 59%, 45%, and 39% respectively. One-year non-relapse mortality and progression/relapse were 22% and 33% respectively. On multivariate analysis.
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6.
Allogeneic Hematopoietic Cell Transplantation After CAR T-cell Therapy in Large B-cell Lymphoma: Allogeneic-HCT after CAR T-cell therapy
Fried, S., Shouval, R., Walji, M., Flynn, J. R., Yerushalmi, R., Shem-Tov, N., Danylesko, I., Tomas, A. A., Fein, J. A., Devlin, S. M., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has transformed the care of relapsed-refractory large B-cell lymphoma (LBCL). However, approximately 60% of CAR-T recipients will ultimately experience disease recurrence or progression. Salvage therapies after CAR-T treatment failures are of limited efficacy and have a short duration of response. OBJECTIVES To evaluate the role of allogeneic hematopoietic cell transplantation (allo-HCT) after CAR T-cell therapy in LBCL patients. STUDY DESIGN A multicenter observational study reporting the outcome of 39 adult LBCL patients receiving allo-HCT following anti CD19-CAR T-cell therapy. RESULTS The median age was 47 years (range 20-68). HLA-matched sibling, HLA-matched unrelated, and alternative donors were utilized in 36%, 36%, and 28% of transplant recipients, respectively. Conditioning regimens were primarily of low or intermediate intensity. Disease status at allo-HCT was CR (41%), PR (38%), or progressive disease (21%). Allo-HCT was performed at a median of 127 days (82-206) after CAR-T therapy. A high incidence of hepatic toxicity (28%), including sinusoidal obstruction syndrome (15.4% [95% CI: 6.2 - 28.5]), was observed. The one-year cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host disease was 38.5% (95% CI: 23.2-53.6) and 15.4% (95%CI: 6.1-28.5), respectively. The 2-year cumulative incidence of moderate-severe chronic GvHD was 11.1% (95% CI: 3.3-24.3). Overall, 2-year non-relapse mortality and relapse/ progression incidence were 26% (95% CI: 13-41) and 43% (95% CI: 27-59), respectively. With a median follow-up of 32 months, the 2-years overall survival (OS) and progression-free survival (PFS) were 45% (95% CI: 31-66) and 31% (95%CI: 19-50), respectively. In multivariable analyses, pre-HCT elevated LDH and transformed lymphoma were predictive of OS and PFS, respectively. CONCLUSION Allo-HCT after CD19-CAR-T treatment failure is feasible with a relatively promising efficacy but possibly high toxicity rates.
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7.
ASTCT Committee on Practice Guidelines Survey on Evaluation & Management of Diffuse Large B-cell Lymphoma after failure of Chimeric antigen receptor T cell therapy (CAR-T) therapy
Ahmed, N., Kumar, A., Kharfan-Dabaja, M. A., DeFilipp, Z., Herrera, A., Hashmi, S., Dholaria, B., Perales, M. A., Carpenter, P. A., Hamadani, M.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Chimeric antigen receptor T cell therapy (CAR-T) is a major advance in managing aggressive relapsed and/or refractory B-cell lymphomas; however, relapses are frequent and pose a major therapeutic challenge. There is substantial variability across transplant and cellular therapy programs in assessing and managing post-CAR-T failures. METHODS The American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines conducted an online cross-sectional survey between August 2021 and October 2021, to determine the U.S. lymphoma and transplant and cellular therapy physicians' practice patterns for the detection and diagnosis of CAR-T failure, and management strategies for diffuse large B cell lymphoma (DLBCL) in this particular setting. RESULTS Email surveys were sent to 901 potential participants, of which 174 (19%) completed the survey. Responders were mainly White (51.2%), male (70.7%), and with >10 years of practice experience (51.2%). 87% of the responders were affiliated with university/teaching centers; 54.6% had general oncology practices and 45.4% had lymphoma-focused transplant/cellular therapy practices. The most common periods to perform surveillance scans were at 3 months and 12 months after CAR-T infusion. 88.5% of responders would often or always consider a biopsy to confirm relapse and 89% would routinely check for the persistence of the antigen targeted by the CAR (e.g. CD19 in the case of CD19 CAR-T). The most popular first salvage regimen for relapse or progression was an alternate CAR-T therapy (dual or alternate target) regardless of CD19 positivity. 27% of responders chose this regimen for CD19 positive relapse, while 31% of responders did so for CD19 negative relapse. 88.5% of responders favored consolidative allogeneic hematopoietic cell transplantation (alloHCT) after response to salvage, whereas 51.2% of physicians would consider autologous hematopoietic cell transplant (AHCT) in transplant naïve patients. CONCLUSIONS There is substantial cross-center variation in surveillance, diagnosis, and management of CAR-T failure. Prospective clinical trials evaluating novel agents in this setting are urgently needed to identify best management strategies.
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8.
CAR T Cell Therapy During the COVID-19 Pandemic
Bachanova, V., Bishop, M. R., Dahi, P., Dholaria, B., Grupp, S. A., Hayes-Lattin, B., Janakiram, M., Maziarz, R. T., McGuirk, J. P., Nastoupil, L. J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
The COVID-19 pandemic has significantly impacted the delivery of cellular therapeutics, including chimeric antigen receptor (CAR) T cells. This impact has extended beyond patient care to include logistics, administration, and distribution of increasingly limited health care resources. Based on the collective experience of the CAR T-cell Consortium investigators, we review and address several questions and concerns regarding cellular therapy administration in the setting of COVID-19 and make general recommendations to address these issues. Specifically we address: 1) necessary resources for safe administration of cell therapies; 2) determinants of cell therapy utilization; 3) selection among patients with B-cell non-Hodgkin lymphomas and 4) B-cell acute lymphocytic leukemia; 5) supportive measures during cell therapy administration; 6) use and prioritization of tocilizumab, and 7) collaborative care with referring physicians. These recommendations were carefully formulated with the understanding that resources allocation is of the utmost importance and the decision to proceed with CAR T cell therapy will require extensive discussion of potential risks and benefits. Though these recommendations are fluid, at this time it is our opinion that the COVID-19 pandemic should not serve as reason to defer CAR T cell therapy for patients truly in need of a potentially curative therapy.
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9.
Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplant
Prockop, S., Doubrovina, E., Suser, S., Heller, G., Barker, J., Dahi, P., Perales, M. A., Papadopoulos, E., Sauter, C., Castro-Malaspina, H., et al
The Journal of clinical investigation. 2019
Abstract
BACKGROUND Adoptive transfer of donor-derived EBV-specific T-cells (EBV-CTLs) can eradicate EBV associated lymphomas post hematopoietic cell (HCT) or solid organ (SOT) transplants but is not available for most patients. METHODS We developed a 3rd-party, allogeneic, off-the-shelf bank of 330 GMP grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (N=33) or SOT (N=13) with established EBV associated lymphomas, who failed rituximab therapy, with 3rd-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation. RESULTS The EBV-CTLs did not induce significant toxicities or graft injury. One patient developed grade I skin GVHD requiring topical therapy. Complete and sustained partial remissions were achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, overall survival was 88.9% and 81.8% respectively at 1 year. Although only 1/11 patients (9.1%) with progression of disease (POD) after cycle 1 who received additional EBV-CTLs from the same donor survived, 3 of 5 with POD subsequently treated with EBV-CTLs from a different donor achieved CR or durable PR (60%) and survive > 1 year. Maximal responses were achieved after a median of 2 cycles. CONCLUSIONS Third party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab refractory EBV-associated lymphoma post transplant.Phase II protocols (NCT01498484 and NCT00002663) were approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, Food and Drug Administration and National Marrow Donor Program.This work was supported through NIH grants CA23766, NIH R21CA162002, Aubrey Fund, The Claire Tow Foundation, Major Family Foundation, Max Cure Foundation, Richard "Rick" J. EIsemann Pediatric Research Fund, Banbury Foundation, Edith Robertson Foundation, Larry Smead Foundation. In June 2015 Atara Biotherapeutics licensed the EBV-CTL bank and is developing this as ATA-129.
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10.
Clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)-an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT)
Kansagra, A. J., Frey, N. V., Bar, M., Laetsch, T. W., Carpenter, P. A., Savani, B. N., Heslop, H. E., Bollard, C. M., Komanduri, K. V., Gastineau, D. A., et al
Bone marrow transplantation. 2019
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Editor's Choice
Abstract
On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.
PICO Summary
Population
Children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia
Intervention
Expert opinion on clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia
Comparison
None
Outcome
An initial roadmap for navigating common clinical practice scenarios since the approval of the first commercially available CAR-T product for B-ALL.