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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.
Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma
Westin, J. R., Oluwole, O. O., Kersten, M. J., Miklos, D. B., Perales, M. A., Ghobadi, A., Rapoport, A. P., Sureda, A., Jacobson, C. A., Farooq, U., et al
The New England journal of medicine. 2023
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.).
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3.
Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis in HLA-matched and haploidentical donor transplants for patients with Hodgkin lymphoma: a comparative study of the LWP EBMT.: GVHD prophylaxis for patients with Hodgkin lymphoma
Montoro, J., Boumendil, A., Finel, H., Bramanti, S., Castagna, L., Blaise, D., Dominietto, A., Kulagin, A., Yakoub-Agha, I., Tbakhi, A., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCy) has emerged as a promising approach for preventing graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is a lack of studies examining the impact of this GVHD prophylaxis when different donor types are used in patients with Hodgkin lymphoma (HL). OBJECTIVE To compare the outcomes of patients with HL undergoing HSCT from both HLA-matched donors, which include matched sibling donors (MSD) and matched unrelated donors (MUD), and haploidentical donors, using PTCy as GVHD prophylaxis approach in all cohorts. STUDY DESIGN We retrospectively compared transplant outcomes of allo-HSCT from 166 HLA-matched donors (96 siblings and 70 unrelated) and 694 haploidentical donors using PTCy-based GVHD prophylaxis in patients with HL registered in the EBMT database from 2010 to 2020. RESULTS Haploidentical transplantation showed significantly lower platelet engraftment (86% vs 94%, p<0.001) and higher rates of grades II-IV acute GVHD (24% vs 34%, p=0.01) compared to HLA-matched transplantation. The 2-year cumulative incidence of non-relapse mortality (NRM) was significantly lower in the HLA-matched cohort compared to haploidentical cohort (10% vs 18%, p=0.02), resulting in a higher overall survival (OS) rate (82% vs 70%, p=0.002). There were no significant differences observed in terms of relapse, progression-free survival, or GVHD-free relapse-free survival between the groups. In multivariable analysis, haploidentical transplantation was associated with an increased risk of grades II-IV acute GVHD, NRM, and worse OS compared to HLA-matched transplantation. CONCLUSIONS Our findings suggest that, in the context of PTCy-based GVHD prophylaxis, transplantation from HLA-matched donors appears to be a more favorable option compared to haploidentical transplantation.
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4.
Allogeneic hematopoietic stem cell transplantation for NK/T-cell lymphoma: an international collaborative analysis
Berning, P., Schmitz, N., Ngoya, M., Finel, H., Boumendil, A., Wang, F., Huang, X. J., Hermine, O., Philippe, L., Couronné, L., et al
Leukemia. 2023;:1-10
Abstract
Natural killer/T-cell lymphomas (NKTCL) represent rare and aggressive lymphoid malignancies. Patients (pts) with relapsed/refractory disease after Asparaginase (ASPA)-based chemotherapy have a dismal prognosis. To better define the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), we conducted a retrospective analysis of data shared with the European Society for Blood and Marrow Transplantation (EBMT) and cooperating Asian centers. We identified 135 pts who received allo-HSCT between 2010 and 2020. Median age was 43.4 years at allo-HSCT, 68.1% were male. Ninety-seven pts (71.9 %) were European, 38 pts (28.1%) Asian. High Prognostic Index for NKTCL (PINK) scores were reported for 44.4%; 76.3% had >1 treatment, 20.7% previous auto-HSCT, and 74.1% ASPA-containing regimens prior to allo-HSCT. Most (79.3%) pts were transplanted in CR/PR. With a median follow-up of 4.8 years, 3-year progression-free(PFS) and overall survival were 48.6% (95%-CI:39.5-57%) and 55.6% (95%-CI:46.5-63.8%). Non-relapse mortality at 1 year was 14.8% (95%-CI:9.3-21.5%) and 1-year relapse incidence 29.6% (95%-CI:21.9-37.6%). In multivariate analyses, shorter time interval (0-12 months) between diagnosis and allo-HSCT [HR = 2.12 (95%-CI:1.03-4.34); P = 0.04] and transplantation not in CR/PR [HR = 2.20 (95%-CI:0.98-4.95); P = 0.056] reduced PFS. Programmed cell death protein 1(PD-1/PD-L1) treatment before HSCT neither increased GVHD nor impacted survival. We demonstrate that allo-HSCT can achieve long-term survival in approximately half of pts allografted for NKTCL.
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5.
Integrated analysis of randomized controlled trials evaluating bortezomib + lenalidomide + dexamethasone or bortezomib + thalidomide + dexamethasone induction in transplant-eligible newly diagnosed multiple myeloma
Rosiñol, L., Hebraud, B., Oriol, A., Colin, A. L., Ríos Tamayo, R., Hulin, C., Blanchard, M. J., Caillot, D., Sureda, A., Hernández, M. T., et al
Frontiers in oncology. 2023;13:1197340
Abstract
OBJECTIVE Providing the most efficacious frontline treatment for newly diagnosed multiple myeloma (NDMM) is critical for patient outcomes. No direct comparisons have been made between bortezomib + lenalidomide + dexamethasone (VRD) and bortezomib + thalidomide + dexamethasone (VTD) induction regimens in transplant-eligible NDMM. METHODS An integrated analysis was performed using patient data from four trials meeting prespecified eligibility criteria: two using VRD (PETHEMA GEM2012 and IFM 2009) and two using VTD (PETHEMA GEM2005 and IFM 2013-04). RESULTS The primary endpoint was met, with VRD demonstrating a noninferior rate of at least very good partial response (≥ VGPR) after induction vs VTD. GEM comparison demonstrated improvement in the ≥ VGPR rate after induction for VRD vs VTD (66.3% vs 51.2%; P = .00281) that increased after transplant (74.4% vs 53.5%). Undetectable minimal residual disease rates post induction (46.7% vs 34.9%) and post transplant (62.4% vs 47.3%) support the benefit of VRD vs VTD. Treatment-emergent adverse events leading to study and/or treatment discontinuation were less frequent with VRD (3%, GEM2012; 6%, IFM 2009) vs VTD (11%, IFM 2013-04). CONCLUSION These results supported the benefit of VRD over VTD for induction in transplant-eligible patients with NDMM. The trials included are registered with ClinicalTrials.gov (NCT01916252, NCT01191060, NCT00461747, and NCT01971658).
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6.
Lenalidomide and dexamethasone with or without ixazomib maintenance tailored by residual disease status in myeloma
Rosiñol, L., Oriol, A., Ríos-Tamayo, R., Blanchard, M. J., Jarque, I., Bargay, J., Hernandez Garcia, M. T., Cabañas, V., Carrillo-Cruz, E., Sureda, A., et al
Blood. 2023
Abstract
From November 2014 to May 2017, 332 patients homogeneously treated with VRD induction, ASCT and VRD consolidation were randomized to receive maintenance therapy with RD (161 patients) vs IRD (171 patients). RD consisted of lenalidomide 15 mg/d from days 1-21 plus dexamethasone 20 mg/d on days 1-4 and 9-12 at 4-weeks intervals while in the IRD arm oral ixazomib at a dose of 4 mg on days 1,8, and 15 was added. MRD negative patients after 24 cycles were discontinued while those who were MRD positive remained on maintenance with RD for 36 more cycles. The MRD negativity from baseline increased from 50.9% to 71.8% with RD and from 59.6% to 72.4% with IRD at 2 years. After a median follow-up of 69 months from the initiation of maintenance, the PFS was similar in both arms, median not reached in either arm with a 6-years PFS rate of 61.3% and 55.6% for RD and IRD, respectively (HR 1.136 [95% CI 0.809 - 1.603]). No significant differences in PFS between RD and IRD were observed in any prognostic subgroup. After 2 years of maintenance, treatment was discontinued in 163 patients who were MRD negative while 63 MRD positive patients were continued on RD therapy. Maintenance discontinuation in MRD negative patients resulted in a low progression rate (17.2% at 4 years), even in patients with high-risk features. In summary, our results show the efficacy of RD maintenance and support the safety of maintenance discontinuation in MRD negative patients at 2 years. This trial is registered at ClinicalTrials.gov (NCT02406144) and EudraCT (2014-00055410).
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7.
Role of allogeneic hematopoietic cell transplant for relapsed/refractory aggressive B-cell lymphomas in the CART era
Mussetti, A., Bento, L., Bastos-Oreiro, M., Rius Sansalvador, B., Albo, C., Bailen, R., Barba, P., Benzaquén, A., Briones, J., Caballero, A. C., et al
Bone marrow transplantation. 2023
Abstract
Anti-CD19 chimeric antigen receptor T cells (CART) has rapidly been adopted as the standard third-line therapy to treat aggressive B-cell lymphomas (ABCL) after failure of second-line therapy despite the lack of direct comparisons with allogeneic hematopoietic cell transplantation (alloHCT)-based strategies. Using the Grupo Español de Trasplante y Terapia Celular (GETH-TC) registry, we selected patients with the following characteristics: CART or alloHCT performed between 2016 and 2021; ≥18 years old; ABCL diagnosis; ≥2 lines of therapy; and either anti-CD19 CART or alloHCT as therapy at relapse. The analysis included a total of 316 (CART = 215, alloHCT = 101) patients. Median follow-up was 15 and 36 months for the CART and alloHCT cohorts, respectively. In the multivariate analysis, CART was confirmed to be similar to alloHCT for the primary study endpoint (progression-free survival) (hazard ratio [HR] 0.92, CI95%:0.56-1.51, p = 0.75). Furthermore, when the analysis was limited to only patients with chemo-sensitive diseases (complete and partial response) at infusion (CART = 26, alloHCT=93), no differences were reported (progression-free survival at month +18: 65% versus 55%, p = 0.59). However, CART had lower non-relapse mortality (HR 0.34, 95% CI: 0.13-0.85, p = 0.02). Given the lower toxicity and similar survival outcomes, these results suggest the use of CART before alloHCT.
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8.
Circulating Tumor Cells for the Staging of Patients With Newly Diagnosed Transplant-Eligible Multiple Myeloma
Garcés, J. J., Cedena, M. T., Puig, N., Burgos, L., Perez, J. J., Cordon, L., Flores-Montero, J., Sanoja-Flores, L., Calasanz, M. J., Ortiol, A., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2022;:Jco2101365
Abstract
PURPOSE Patients with multiple myeloma (MM) may show patchy bone marrow (BM) infiltration and extramedullary disease. Notwithstanding, quantification of plasma cells (PCs) continues to be performed in BM since the clinical translation of circulating tumor cells (CTCs) remains undefined. PATIENTS AND METHODS CTCs were measured in peripheral blood (PB) of 374 patients with newly diagnosed MM enrolled in the GEM2012MENOS65 and GEM2014MAIN trials. Treatment included bortezomib, lenalidomide, and dexamethasone induction followed by autologous transplant, consolidation, and maintenance. Next-generation flow cytometry was used to evaluate CTCs in PB at diagnosis and measurable residual disease (MRD) in BM throughout treatment. RESULTS CTCs were detected in 92% (344 of 374) of patients with newly diagnosed MM. The correlation between the percentages of CTCs and BM PCs was modest. Increasing logarithmic percentages of CTCs were associated with inferior progression-free survival (PFS). A cutoff of 0.01% CTCs showed an independent prognostic value (hazard ratio: 2.02; 95% CI, 1.3 to 3.1; P = .001) in multivariable PFS analysis including the International Staging System, lactate dehydrogenase levels, and cytogenetics. The combination of the four prognostic factors significantly improved risk stratification. Outcomes according to the percentage of CTCs and depth of response to treatment showed that patients with undetectable CTCs had exceptional PFS regardless of complete remission and MRD status. In all other cases with detectable CTCs, only achieving MRD negativity (and not complete remission) demonstrated a statistically significant increase in PFS. CONCLUSION Evaluation of CTCs in PB outperformed quantification of BM PCs. The detection of ≥ 0.01% CTCs could be a new risk factor in novel staging systems for patients with transplant-eligible MM.
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9.
An Analysis of the Worldwide Utilization of Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia
Tokaz, M. C., Baldomero, H., Cowan, A. J., Saber, W., Greinix, H., Koh, M. B., Kröger, N., Mohty, M., Galeano, S., Okamoto, S., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Acute myeloid leukemia (AML) has an aggressive course and a historically dismal prognosis. For many patients, hematopoietic stem cell transplantation (HSCT) represents the best option for cure, but access, utilization and health inequities on a global scale remain poorly elucidated. OBJECTIVE To describe patterns of global HSCT use in AML for a better understanding of global access, practices, and unmet needs internationally. STUDY DESIGN Estimates of AML incident cases in 2016 were obtained from the Global Burden of Disease (GBD) 2019 study. HSCT activities were collected from 2009-2016 by the Worldwide Network for Blood and Marrow Transplantation (WBMT) through its member organizations. The primary endpoint was global and regional use (number of HSCT) and utilization of HSCT (number of HSCT/ number of incident cases) for AML. Secondary outcomes included trends from 2009 to 2016 in donor type, stem cell source and remission status at time of HSCT. RESULTS Global AML incidence has steadily increased, from 102,000 (95% uncertainty interval (UI): 90,200-108,000) in 2009 to 118,000 (104,000-126,000) in 2016 (+16.2%). Over the same period, a +54.9% increase from 9,659 to 14,965 HSCT/year was observed globally, driven by an increase in allogeneic (+64.9%) with a reduction in autologous (-34.9%) HSCT. While the highest numbers of HSCT continue to be performed in high-resource regions, the largest increases were seen in resource-constrained regions [+94.6% in Africa/East Mediterranean Region (AFR/EMR); +34.7% in America-Nord Region (AMR-N)]. HSCT utilization was skewed towards high-resource regions [in 2016: AMR-N 18.4%, Europe (EUR) 17.9%, South-East Asia/Western Pacific Region (SEAR/WPR) 11.7%, America-South Region (AMR-S) 4.5% and AFR/EMR 2.8%]. For patients <70 years of age, this difference in utilization was widened; AMR-N had the highest allogeneic utilization rate, increasing from 2009 to 2016 (30.6% to 39.9%) with continued low utilization observed in AFR/EMR (1.7% to 2.9%) and AMR-S (3.5% to 5.4%). Across all regions, total HSCT for AML in 1(st) complete remission (CR1) increased (from 44.1% to 59.0%). Patterns of donor stem cell source from related versus unrelated donors varied widely by geographic region. SEAR/WPR had a +130.2% increase in related donor from 2009 to 2016 and >95% HSCT donors in AFR/EMR were from related; in comparison, AMR-N and EUR have a predilection for unrelated HSCT. Globally, allogeneic HSCT stem cell source was predominantly peripheral blood (69.7% of total HSCT in 2009 increased to 78.6% in 2016). Autologous HSCT decreased in all regions from 2009 to 2016 except in SEAR/WPR (+18.9%). CONCLUSIONS HSCT remains a central curative treatment modality in AML. Allogeneic HSCT for AML is rising globally but there are marked variations in regional utilization and practices, including types of graft source. Resource-constrained regions have the largest growth in HSCT use, but utilization rates remain low with a predilection for familial related donor sources and are typically offered in CR1. Further studies are necessary to elucidate the reasons, including economic factors, to understand and address these health inequalities and improve discrepancies in use of HSCT as a potentially curative treatment globally.
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10.
The outcome of patients with Hodgkin lymphoma and early relapse after autologous stem cell transplant has improved in recent years
Bazarbachi, A., Boumendil, A., Finel, H., Khvedelidze, I., Romejko-Jarosinska, J., Tanase, A., Akhtar, S., Ben Othman, T., Ma'koseh, M., Afanasyev, B., et al
Leukemia. 2022
Abstract
Hodgkin lymphoma (HL) patients who relapse after autologous-stem-cell- transplantation (auto-SCT) have traditionally had a poor prognosis. We analyzed 1781 adult HL patients who relapsed between 2006 and 2017 after a first auto-SCT. The 4-year overall survival (OS) after relapse continuously increased from 32% for patients relapsing in 2006-2008, to 63% for patients relapsing in 2015-2017 (p = 0.001). The improvement over time was predominantly noted in patients who had an early relapse (within 12 months) after auto-SCT (p = 0.01). On multivariate analysis, patients who relapsed in more recent years and those with a longer interval from transplant to relapse had a better OS, whereas increasing age, poor performance status, bulky disease, extranodal disease and presence of B symptoms at relapse were associated with a worse OS. Brentuximab vedotin (BV), checkpoint inhibitors (CPI) and second transplant (SCT2; 86% allogeneic) were used in 233, 91 and 330 patients respectively. The 4-year OS from BV, CPI, and SCT2 use was 55%, 48% and 55% respectively. In conclusion, the outcome after post-transplant relapse has improved significantly in recent years, particularly in the case of early relapse. These large-scale real-world data can serve as benchmark for future studies in this setting.