Safety and feasibility of chimeric antigen receptor T cell therapy after allogeneic hematopoietic cell transplantation in relapsed/ refractory B cell non-Hodgkin lymphoma.
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ABSTRACT:
SUBMITTER: Jain T
PROVIDER: S-EPMC8224498 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
Publications
Safety and feasibility of chimeric antigen receptor T cell therapy after allogeneic hematopoietic cell transplantation in relapsed/ refractory B cell non-Hodgkin lymphoma.
Jain Tania T Sauter Craig S CS Shah Gunjan L GL Maloy Molly A MA Chan Jason J Scordo Michael M Avecilla Scott T ST Batlevi Yakup Y Dahi Parastoo B PB Batlevi Connie W CW Lia Palomba M M Giralt Sergio A SA Perales Miguel-Angel MA
Leukemia 20190521 10
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Project description:To clarify the role of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the chimeric antigen receptor T-cell therapy era, we analyzed the clinical characteristics and outcomes of 52 patients treated with allo-HSCT with relapsed/refractory diffuse large B cell lymphoma. Most enrolled patients had previously undergone intensive treatments, the median number of chemotherapy lines was 4, and the median time from diagnosis to allo-HSCT was 27.1 months. Patients were divided into remission-achieved (n = 30) and active-disease (n = 22) groups before allo-HSCT. Over a median follow-up period of 38.3 months, overall survival (OS) and event-free survival (EFS) rates were 38.4% and 30.6%, respectively. The cumulative incidence of relapse (CIR) and the non-relapsed mortality (NRM) were 36.7% and 32.7%, respectively. OS, EFS, and graft-versus-host disease-free, relapse-free survival (GRFS) outcomes were significantly superior in the remission-achieved group with lower CIR. In a multivariate analysis, a shorter interval from diagnosis to allo-HSCT reflected relatively rapid disease progression and showed significantly poor OS and EFS with higher CIR. Patients with active disease had significantly lower EFS, GRFS, and higher CIR. Previous autologous stem-cell transplantation was associated with better GRFS. Allo-HSCT is an established modality with a prominent group of cured patients and still has a role in the CAR T-cell era, particularly given its acceptable clinical outcomes in young patients with chemo-susceptible disease.
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Project description:Despite the favorable prognosis of most patients with Hodgkin's Lymphoma (HL), 15-20% of patients remain refractory to chemoradiotherapy, and 20-40% experience relapses following autologous stem cell transplantation (SCT) being used as salvage approach in this situation. Long-term survival of only 20% was reported for patients who failed this option. As some authors suggested the presence of a graft versus HL effect, allogeneic SCT was introduced as a further option. Myeloablative strategies were reported to be able to achieve cure in some younger patients, but high nonrelapse mortality remains a problem. Reduced intensity conditioning, in turn, was found to be associated with high posttransplant relapse rates. As there is currently no standard in the management of HL patients who failed autologous SCT, we here review the literature on allogeneic stem cell transplantation in HL patients with a special focus on the outcomes and risk factors being reported in the largest studies.
| S-EPMC2964008 | biostudies-other
Project description:Forty patients (median age, 31 years; range, 20 to 63) with Hodgkin lymphoma underwent an allogeneic stem cell transplant with the gemcitabine-fludarabine-melphalan reduced-intensity conditioning regimen. Thirty-one patients (77%) had undergone a prior autologous stem cell transplant, with a median time to progression after transplant of 6 months (range, 1 to 68). Disease status at transplant was complete remission/complete remission, undetermined (n = 23; 57%), partial remission (n = 14; 35%), and other (n = 3; 8%). Twenty-six patients (65%) received brentuximab vedotin before allotransplant. The overall complete response rate before allotransplant was 65% in brentuximab-treated patients versus 42% in brentuximab-naive patients (P = .15). At the latest follow-up (October 2015) 31 patients were alive. The median follow-up was 41 months (range, 5 to 87). Transplant-related mortality rate at 3 years was 17%. Pulmonary, skin toxicities, and nausea were seen in 13 (33%), 11 (28%), and 37 (93%) patients, respectively. At 3 years, estimates for overall and progression-free survival were 75% (95% CI, 57% to 86%) and 54% (95% CI, 36% to 70%). Overall incidence for disease progression was 28% (95% CI, 16% to 50%). We believe the gemcitabine-fludarabine-melphalan regimen allows moderate dose intensification with acceptable morbidity and mortality. The inclusion of gemcitabine affected nausea, pulmonary, and likely skin toxicity. Exposure to brentuximab vedotin allowed more patients to reach allogeneic stem cell transplantation in complete remission. With over 50% of patients progression-free at 3 years, allogeneic stem cell transplantation with reduced-intensity conditioning remains an effective and relevant treatment option for Hodgkin lymphoma in the brentuximab vedotin era.
| S-EPMC5193224 | biostudies-literature
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| S-EPMC6058792 | biostudies-literature
Project description:Allogeneic stem cell transplantation (allo-SCT) outcomes in patients with Hodgkin lymphoma (HL) remain poorly defined. We performed a meta-analysis of allo-SCT studies in HL patients. The primary endpoints were 6-month, 1-year, 2-year and 3-year relapse-free survival (RFS) and overall survival (OS). A total of 42 reports (1850 patients) was included. The pooled estimates (95% confidence interval) for 6-month, 1-year, 2-year and 3-year RFS were 77 (59-91)%, 50 (42-57)%, 37 (31-43)% and 31 (25-37)%, respectively. The corresponding numbers for OS were 83 (75-91)%, 68 (62-74)%, 58 (52-64)% and 50 (41-58)%, respectively. There was statistical heterogeneity among studies in all outcomes. In meta-regression, accrual initiation year in 2000 or later was associated with higher 6-month (P=0.012) and 1-year OS (P=0.046), and pre-SCT remission with higher 2-year OS (P=0.047) and 1-year RFS (P=0.016). In conclusion, outcomes of allo-SCT in HL have improved over time, with 5-10% lower non-relapse mortality and relapse rates, and 15-20% higher RFS and OS in studies that initiated accrual in 2000 or later compared with earlier studies. However, there is no apparent survival plateau, demonstrating the need to improve on current allo-SCT strategies in relapsed/refractory HL.
| S-EPMC5092068 | biostudies-literature
Project description:Although anti-CD19 chimeric antigen receptor (CAR) T-cell therapy shows good efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), it fails to improve long-term leukemia-free survival (LFS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CAR T-cell therapy has emerged as a promising strategy to prolong LFS. Nevertheless, which patients are likely to benefit from consolidative allo-HSCT, as well as the optimal therapeutic window, remain to be explored. Recent clinical data indicate that patients with complex karyotypes, adverse genes, and high pre-infusion minimal residual disease (MRD) by flow cytometry in the bone marrow, were at high risk of relapse after CAR T-cell therapy. High pre-lymphodepletion lactate dehydrogenase, low pre-lymphodepletion platelet count, absence of fludarabine in lymphodepletion, persistent leukemic sequence by high throughput sequencing in bone marrow after CAR T-cell infusion, and early loss of CAR T cells have also been linked to relapse after CAR T-cell therapy. In patients having these risk factors, consolidative allo-HSCT after CAR T-cell therapy may prolong LFS. Allo-HSCT provides optimal clinical benefit in patients with MRD-negative complete remission, typically within three months after CAR T-cell therapy. Herein, we summarize the clinical data on consolidative allo-HSCT after anti-CD19 CAR T-cell therapy, as well as the potential factors associated with allo-HSCT benefit. We also discuss the optimal therapeutic window and regimen of consolidative allo-HSCT. Finally, and most importantly, we provide recommendations for the assessment and management of r/r B-ALL patients undergoing anti-CD19 CAR T-cell therapy.
| S-EPMC7687790 | biostudies-literature
Project description:BackgroundWe previously demonstrated that brentuximab vedotin (BV) used as second-line therapy in patients with Hodgkin lymphoma is a tolerable and effective bridge to autologous hematopoietic cell transplantation (AHCT). Here, we report the post-AHCT outcomes of patients treated with second-line standard/fixed-dose BV and an additional cohort of patients where positron-emission tomography adapted dose-escalation of second-line BV was utilized.Patients and methodsPatients on the dose-escalation cohort received 1.8 mg/kg of BV intravenously every 3 weeks for two cycles. Patients in complete remission (CR) after two cycles received two additional cycles of BV at 1.8 mg/kg, while patients with stable disease or partial response were escalated to 2.4 mg/kg for two cycles. All patients, regardless of treatment cohort, proceeded directly to AHCT or received additional pre-AHCT therapy at the discretion of the treating physician based on remission status after second-line BV.ResultsOf the 20 patients enrolled to the BV dose-escalation cohort, 8 patients underwent BV dose-escalation. BV escalation was well-tolerated, but no patients who were escalated converted to CR. Of 56 evaluable patients treated across cohorts, the overall response rate (ORR) to second-line BV was 75% with 43% CR. Twenty-eight (50%) patients proceeded directly to AHCT without post-BV chemotherapy, and a total of 50 patients proceeded to AHCT. Thirteen patients received consolidative post-AHCT therapy with either radiation, BV, or a PD-1 inhibitor. After AHCT, the 2-year progression-free survival (PFS) and overall survival were 67% and 93%, respectively. The 2-year PFS among patients in CR at the time of AHCT (n = 37) was 71% compared with 54% in patients not in CR (p = 0.12). The 2-year PFS in patients who proceeded to AHCT directly after receiving BV alone was 77%.ConclusionsSecond-line BV is an effective bridge to AHCT that produces responses of sufficient depth to provide durable remission in conjunction with AHCT (clinicaltrials.gov: NCT01393717).
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Project description:Anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy has transformed the care of patients with relapsed/refractory large B cell lymphoma (LBCL). However, approximately 60% of CAR-T recipients ultimately will experience disease recurrence or progression. Salvage therapies after CAR-T treatment failures are of limited efficacy and have a short duration of response. The objective of the present study was to evaluate the role of allogeneic hematopoietic cell transplantation (allo-HCT) after CAR-T therapy in LBCL patients. This was a multicenter observational study reporting the outcome of 39 adult LBCL patients who underwent allo-HCT following anti-CD19 CAR-T therapy. The median patient age was 47 years (range, 20 to 68 years). HLA-matched sibling, HLA-matched unrelated, and alternative donors were used in 36%, 36%, and 28% of transplantations, respectively. Conditioning regimens were primarily of low or intermediate intensity. Disease status at allo-HCT was complete response in 41%, partial response in 38%, and progressive disease in 21%. Allo-HCT was performed at a median of 127 days (range, 82 to 206 days) after CAR-T therapy. A high incidence of hepatic toxicity (28%), including sinusoidal obstruction syndrome (15.4%; 95% confidence interval; [CI], 6.2% to 28.5%), was observed. The 1-year cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) was 38.5% (95% CI, 23.2% to 53.6%) and 15.4% (95% CI, 6.1% to 28.5%), respectively. The 2-year cumulative incidence of moderate-severe chronic GVHD was 11.1% (95% CI, 3.3% to 24.3%). Overall, 2-year nonrelapse mortality and relapse/progression incidence were 26% (95% CI, 13% to 41%) and 43% (95% CI, 27% to 59%), respectively. With a median follow-up of 32 months, the 2-year overall survival (OS) and progression-free survival (PFS) were 45% (95% CI, 31% to 66%) and 31% (95% CI, 19% to 50%), respectively. In multivariable analyses, pre-HCT elevated lactate dehydrogenase level and transformed lymphoma were predictive of OS and PFS, respectively. Our data suggest that allo-HCT after anti-CD19 CAR-T treatment failure is feasible with a relatively promising efficacy but possibly high toxicity rate.
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Project description:AbstractPatients with relapsed classic Hodgkin lymphomas (cHLs) receive salvage therapy with immune checkpoint inhibitors (ICIs) or chemotherapy (no-ICI). Patients responding to therapy often undergo consolidation with allogeneic blood or marrow transplantation (alloBMT). We previously reported that relapsed patients with cHL treated with ICI followed by alloBMT experienced improved 3-year progression-free survival (PFS) compared with patients treated with salvage chemotherapy without ICI followed by alloBMT. In this retrospective analysis, we report the 5-year overall survival (OS), PFS, and graft-versus-host disease (GVHD) incidence in patients with cHL treated with ICI before alloBMT with post-transplantation cyclophosphamide GVHD prophylaxis. Among the 147 relapsed/refractory patients with cHL, 71 (48.3%) received ICIs and 76 (51.7%) received chemotherapy without ICIs (no-ICI) before alloBMT. We observed an improved 5-year estimated OS of 91% (ICI) vs 66% (no-ICI; hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.16-0.98; P = .046) and a 5-year estimated PFS of 84% (ICI) vs 53% (no-ICI; HR, 0.4; 95% CI, 0.2-0.81; P = .011). The 12-month cumulative incidence of grade 3 to 4 GVHD was 20% (ICI) and 7% (no-ICI; subdistribution hazard ratio (SDHR), 3.16; 95% CI, 1.13-8.81; P = .03). More frequent grade 3 to 4 acute GVHD was likely due to the higher incidence of grade 3 to 4 acute GVHD in the subset of patients with pretransplant exposure to ICI and shortened duration (60 days) of immunosuppression vs patients with long immunosuppression (day 180). These data suggest that patients with cHL treated with ICI and alloBMT experience improved OS, and the GVHD risk can be mitigated by immunosuppression until day 180.
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