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Autologous stem cell transplant in fit patients with refractory or early relapsed diffuse large B-cell lymphoma that responded to salvage chemotherapy
Tun, A. M., Wang, Y., Maliske, S., Micallef, I., Inwards, D. J., Habermann, T. M., Porrata, L., Paludo, J., Bisneto, J. V., Rosenthal, A., et al
Haematologica. 2024
Abstract
Chimeric antigen receptor T-cell (CAR-T) therapy is the new standard of care in fit patients with refractory or early relapsed diffuse large B-cell lymphoma (DLBCL). However, there may still be a role for salvage chemotherapy (ST) and autologous stem cell transplant (ASCT) in certain circumstances (eg, lack of CAR-T resources, chemosensitive relapses, etc). We retrospectively studied 230 patients with refractory or early relapsed DLBCL who underwent ST and ASCT. Median line of ST was 1 (range 1-3). Best response before ASCT was complete response (CR) in 106 (46%) and partial response (PR) in 124 (54%) patients. Median follow-up after ASCT was 89.4 months. The median progression-free (PFS) and overall survival (OS) were 16.1 and 43.3 months, respectively. Patients relapsing between 6 to 12 months after frontline therapy had numerically better median PFS (29.6 months) and OS (88.5 months). Patients who required 1 line of ST, compared to those requiring >1 line, had better median PFS (37.9 vs 3.9 months; P = 0.0005) and OS (68.3 vs 12.0 months; P = 0.0005). Patients who achieved CR had better median PFS (71.1 vs 6.3 months; P.
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2.
ASTCT Clinical practice recommendations for transplant and cellular therapies in diffuse large B-cell lymphoma
Epperla, N., Kumar, A., Abutalib, S. A., Awan, F. T., Chen, Y. B., Gopal, A. K., Holter-Chakrabarty, J., Kekre, N., Lee, C. J., Lekakis, L., et al
Transplantation and cellular therapy. 2023
Abstract
Autologous hematopoietic cell transplantation (auto-HCT) has long remained the standard approach for patients with relapsed/refractory (R/R) chemosensitive diffuse large B-cell lymphoma (DLBCL). However, the advent of chimeric antigen receptor (CAR) T-cell therapy has caused a paradigm shift in the management of R/R DLBCL patients, especially with the recent approval of CD19-directed CAR T-cell therapy in the second line setting in high-risk groups (primary refractory and early relapse [≤12 months]). Consensus on the contemporary role, optimal timing, and sequencing of HCT and cellular therapies in DLBCL is lacking. Therefore, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines undertook this project to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 20 consensus statements with a few key statements as follows: 1) in the first-line setting, there is no role of auto-HCT consolidation for those achieving complete remission (CR) following R-CHOP or similar therapy in non-double hit/triple hit cases (DHL/THL) and in DHL/THL cases receiving intensive induction therapies, but auto-HCT may be considered in eligible patients receiving R-CHOP or similar therapies in DHL/THL cases. 2) Auto-HCT consolidation with thiotepa-based conditioning is standard-of-care for eligible patients with primary central nervous system achieving CR with first-line therapy. 3) In the primary refractory and early relapse setting, the preferred option is CAR T-cell therapy, while in late relapse (>12 months), consolidation with auto-HCT is recommended in those achieving chemosensitivity to salvage therapy (CR or partial response), and CAR T-cell therapy is recommended in those not achieving remission. These clinical practice recommendations will serve as a tool to guide clinicians managing patients with newly diagnosed and R/R DLBCL.
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Trends in utilization of stored cryopreserved autologous peripheral hematopoietic cells intended for a second (or beyond) autologous hematopoietic cell transplantation in patients with multiple myeloma: a single center experience
Yassine, F., Kharfan-Dabaja, M. A., Tsalantsanis, A., Roy, V., Zubair, A. C., Murthy, H. S., Ayala, E., Iqbal, M., Sher, T., Ailawadhi, S., et al
Bone marrow transplantation. 2023
Abstract
Due to the advent of effective novel therapies for multiple myeloma (MM), the use of cryopreserved autologous peripheral blood hematopoietic cells (APBHC) for a salvage autologous transplant (auto-HCT) is in decline. We evaluated utilization trends and costs associated with cryopreserved APBHC in patients with MM. We retrospectively evaluated the clinicopathologic data from 440 patients with MM who underwent APBHC mobilization and collection at Mayo Clinic Florida between 2010 and 2019. Based on institution-specific charges as of May 2021, the cost of 1 session of APBHC collection/apheresis was $4,680 and the cost of 1 year of APBHC cryopreservation was $4,790 per patient. Out of 347 patients who had APBHC in cryopreservation, 5 (1.4%) underwent a salvage auto-HCT and 61% of patients had ≥1 excess collection sessions for APBHC that ultimately went unused. The median cost of excess collection sessions was $4,680 per patient (range, $4,680-$32,760) and the median total cost for excess collection sessions plus costs for storage was $23,840 per patient (range, $4,680-$85,450). The sum of costs of excess collection sessions was $2,077,920 and the sum of costs of cryopreservation was $5,812,665. Institutional policies regarding universal APBHC collection and long-term storage should be reevaluated in the era of novel therapeutics.
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Allogeneic Hematopoietic Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm: a CIBMTR analysis
Murthy, H. S., Zhang, M. J., Chen, K., Ahmed, S., Deotare, U., Ganguly, S., Kansagra, A., Michelis, F. V., Nishihori, T., Patnaik, M. M., et al
Blood advances. 2023
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with standard conventional chemotherapy. Small observational studies have shown that allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We conducted an analysis of 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007-2018 using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Results: Median follow up of survivors was 49 months (range 6-121). 5-year overall survival (OS), disease-free survival (DFS), relapse, and non-relapse (NRM) rates were 51.2% (95% confidence interval [95%CI]: 42.5-59.8%), 44.4% (95%CI: 36.2-52.8%), 32.2% (95%CI: 24.7-40.3%), and 23.3% (95%CI: 16.9-30.4%), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age ≥60 was predictive for inferior OS (hazard ratio [HR]= 2.16, 95% CI 1.35-3.46, p= 0.001), and higher NRM [HR= 2.19, 95% CI 1.13-4.22, p= 0.02]. Remission status at time of allo-HCT (CR2/PIF/Relapse vs CR1) was predictive of inferior OS [HR= 1.87, 95% CI 1.14-3.06, p= 0.01] and DFS [HR= 1.75, 95% CI 1.11-2.76, p= 0.02]. Use of myeloablative conditioning with total body irradiation (TBI) was predictive for improved DFS and reduced risk of relapse. Conclusion: Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, while myeloablative conditioning with TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.
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5.
Impact of pre-transplant induction and consolidation cycles on AML allogeneic transplant outcomes: a CIBMTR analysis in 3113 AML patients
Boyiadzis, M., Zhang, M. J., Chen, K., Abdel-Azim, H., Abid, M. B., Aljurf, M., Bacher, U., Badar, T., Badawy, S. M., Battiwalla, M., et al
Leukemia. 2022
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Editor's Choice
Abstract
We investigated the impact of the number of induction/consolidation cycles on outcomes of 3113 adult AML patients who received allogeneic hematopoietic cell transplantation (allo-HCT) between 2008 and 2019. Patients received allo-HCT using myeloablative (MAC) or reduced-intensity (RIC) conditioning in first complete remission (CR) or with primary induction failure (PIF). Patients who received MAC allo-HCT in CR after 1 induction cycle had 1.3-fold better overall survival (OS) than 2 cycles to CR and 1.47-fold better than ≥3 cycles. OS after CR in 2 or ≥3 cycles was similar. Relapse risk was 1.65-fold greater in patients receiving ≥3 cycles to achieve CR. After RIC allo-HCT, the number of induction cycles to CR did not affect OS. Compared to CR in 1 cycle, relapse risk was 1.24-1.41-fold greater in patients receiving 2 or ≥3 cycles. For patients receiving only 1 cycle to CR, consolidation therapy prior to MAC allo-HCT was associated with improved OS vs. no consolidation therapy. Detectable MRD at the time of MAC allo-HCT did not impact outcomes while detectable MRD preceding RIC allo-HCT was associated with an increased risk of relapse. For allo-HCT in PIF, OS was significantly worse than allo-HCT in CR after 1-3 cycles.
PICO Summary
Population
Adults with acute lymphoblastic leukaemia who received allogeneic hematopoietic cell transplantation (allo-HCT) in 450 centres worldwide (n=3113)
Intervention
Patients achieving complete remission (CR) after 1 induction cycle (n=862)
Comparison
Patients requiring 2 cycles to CR (n=454) or 3 or more cycles to CR (n=157).
Outcome
Patients who received myeloablative (MAC) allo-HCT in CR after 1 induction cycle had 1.3-fold better overall survival (OS) than 2 cycles to CR and 1.47-fold better than ≥3 cycles. OS after CR in 2 or ≥3 cycles was similar. Relapse risk was 1.65-fold greater in patients receiving ≥3 cycles to achieve CR. After reduced-intensity conditioning (RIC) allo-HCT, the number of induction cycles to CR did not affect OS. Compared to CR in 1 cycle, relapse risk was 1.24-1.41-fold greater in patients receiving 2 or ≥3 cycles. For patients receiving only 1 cycle to CR, consolidation therapy prior to MAC allo-HCT was associated with improved OS vs. no consolidation therapy. Detectable MRD at the time of MAC allo-HCT did not impact outcomes while detectable MRD preceding RIC allo-HCT was associated with an increased risk of relapse. For allo-HCT in PIF, OS was significantly worse than allo-HCT in CR after 1-3 cycles.
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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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CNS Involvement at Initial Diagnosis and Risk of Relapse After Allogeneic HCT for Acute Lymphoblastic Leukemia in First Complete Remission
Kharfan-Dabaja, M. A., Labopin, M., Bazarbachi, A., Salmenniemi, U., Mielke, S., Chevallier, P., Thérèse Rubio, M., Balsat, M., Pioltelli, P., Menard, A. L., et al
HemaSphere. 2022;6(11):e788
Abstract
Outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult acute lymphoblastic leukemia (ALL) have improved over time. Studies have shown that total body irradiation (TBI) is the preferable type of myeloablative conditioning (MAC). However, outcomes based on central nervous system (CNS) involvement, namely CNS-positive versus CNS-negative, have not been compared. Here, we evaluated outcomes of 547 patients (CNS-positive = 96, CNS-negative = 451) who were allografted in the first complete remission (CR1) between 2009 and 2019. Primary endpoint was leukemia-free survival (LFS). Median follow-up was not different between the CNS-positive and CNS-negative groups (79 versus 67.2 months, P = 0.58). The CNS-positive group were younger (median age 31.3 versus 39.7 years, P = 0.004) and were allografted more recently (median year 2012 versus 2010, P = 0.003). In both groups, MAC was the preferred approach (82.3% versus 85.6%, P = 0.41). On multivariate analysis, the CNS-positive group had higher incidence of relapse (RI) (hazard ratio [HR] = 1.58 [95% confidence interval (CI) = 1.06-2.35], P = 0.025), but no adverse effect on LFS (HR = 1.38 [95% CI = 0.99-1.92], P = 0.057) or overall survival (OS) (HR = 1.28 [95% CI = 0.89-1.85], P = 0.18). A subgroup multivariate analysis limited to CNS-positive patients showed that a TBI-based MAC regimen resulted in better LFS (HR = 0.43 [95% CI = 0.22-0.83], P = 0.01) and OS (HR = 0.44 [95% CI = 0.21-0.92], P = 0.03) and lower RI (HR = 0.35 [95% CI = 0.15-0.79], P = 0.01). Another subgroup analysis in CNS-negative patients showed that MAC-TBI preparative regimens also showed a lower RI without a benefit in LFS or OS. While a MAC-TBI allo-HCT regimen may not be suitable to all, particularly for older patients with comorbidities, this approach should be considered for patients who are deemed fit and able to tolerate.
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Efficacy of a second allogeneic hematopoietic cell transplant in relapsed acute myeloid leukemia: results of a systematic review and meta-analysis
Kharfan-Dabaja, M. A., Reljic, T., Yassine, F., Nishihori, T., Kumar, A., Tawk, M. M., Keller, K., Ayala, E., Savani, B., Mohty, M., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only known treatment modality that can offer the possibility of cure for acute myeloid leukemia (AML). Unfortunately, relapse and/or disease progression still occurs in over one-third of cases even when patients are allografted in complete hematologic remission (CR). Treatment of AML relapsing after a first allo-HCT is particularly challenging. A second allo-HCT is offered to patients considered fit for the procedure, but reported outcomes have been conflicting. OBJECTIVES To perform a systematic review and meta-analysis to assess the totality of evidence on the role of a second allo-HCT in patients with AML. STUDY DESIGN AND METHODS We performed a comprehensive literature search using PUBMED/MEDLINE and EMBASE on August 25, 2021 and extracted clinical outcome data relating to benefits (CR, overall survival [OS], and progression-free/disease-survival [PFS/DFS]) and harms (acute and chronic graft-versus-host disease [GVHD], non-relapse mortality [NRM] and relapse). RESULTS The search identified 821 studies. Only 20 studies (n= 2,772 patients) met our inclusion criteria. A second allo-HCT resulted in pooled CR, OS, PFS/DFS, NRM and relapse rates of 67%, 34%, 30%, 27%, and 51%, respectively. OS was 2-fold higher when the second allo-HCT was performed in CR (38% vs. 17%) and 3-fold higher in patients who had a later relapse from the first allo-HCT (34% vs. 10%). There was no apparent difference in pooled OS (HR=1.01 (95%CI=0.78-1.31), p=0.94) whether the same original donor or a different one was used. CONCLUSION Notwithstanding several limitations apart from the high heterogeneity among included studies, this analysis shows that a second allo-HCT is a reasonable treatment option for relapsed AML. The procedure appears to be more effective when performed in CR and in patients who had a later relapse from the first allo-HCT. The high pooled relapse rates exceeding 50%, even when receiving the second allo-HCT in CR is worrisome and emphasizes the need to incorporate new therapies whether as post-transplant maintenance or consolidation, to mitigate relapse risk. This analysis was limited to patients receiving a second allo-HCT for the sole purpose of treating AML relapse. Accordingly, we caution against extrapolating these findings to other indications such as treatment of graft failure, poor graft function or mixed donor chimerism.
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Impact of conditioning regimen intensity on the outcomes of peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma patients undergoing allogeneic transplant
Savani, M., Ahn, K. W., Chen, Y., Ahmed, S., Cashen, A. F., Shadman, M., Modi, D., Khimani, F., Cutler, C. S., Zain, J., et al
British journal of haematology. 2022
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Abstract
There have been no large studies comparing reduced-intensity/non-myeloablative conditioning (RIC/NMA) to myeloablative conditioning (MAC) regimens in T-cell non-Hodgkin lymphoma (T-NHL) patients undergoing allogeneic transplant (allo-HCT). A total of 803 adults with peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma (age 18-65 years), undergoing allo-HCT between 2008-2019 and reported to the Center for International Blood and Marrow Transplant Research with either MAC (n = 258) or RIC/NMA regimens (n = 545) were evaluated. There were no significant differences between the two cohorts in terms of patient sex, race and performance scores. Significantly more patients in the RIC/NMA cohort had peripheral blood grafts, haematopoietic cell transplantation-specific comorbidity index (HCT-CI) of ≥3 and chemosensitive disease compared to the MAC cohort. On multivariate analysis, overall survival (OS) was not significantly different in the RIC/NMA cohort compared to the MAC cohort (hazard ratio (HR) = 1.01, 95% confidence interval (CI) = 0.79-1.29; p = 0.95). Similarly, non-relapse mortality (NRM) (HR = 0.85, 95% CI = 0.61-1.19; p = 0.34), risk of progression/relapse (HR = 1.29; 95% CI = 0.98-1.70; p = 0.07) and therapy failure (HR = 1.14; 95% CI = 0.92-1.41, p = 0.23) were not significantly different between the two cohorts. Relative to MAC, RIC/NMA was associated with a significantly lower risk of grade 3-4 acute graft-versus-host disease (HR = 0.67; 95% CI = 0.46-0.99, p = 0.04). Among chemorefractory patients, there was no difference in OS, therapy failure, relapse, or NRM between RIC/NMA and MAC regimens. In conclusion, we found no association between conditioning intensity and outcomes after allo-HCT for T-cell NHL.
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Allogeneic haematopoietic cell transplant in patients with relapsed/refractory anaplastic large cell lymphoma
Furqan, F., Ahn, K. W., Chen, Y., Kaur, M., Abutalib, S. A., Ahmed, N., Ahmed, S., Kharfan-Dabaja, M. A., Friedberg, J., Gregory, T., et al
British journal of haematology. 2022
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Editor's Choice
Abstract
The prognosis of relapsed/refractory (R/R) anaplastic large cell lymphoma (ALCL) is poor. Large studies evaluating outcomes of allogeneic haematopoietic cell transplantation (allo-HCT) in systemic R/R ALCL are not available. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we evaluated outcomes of 182 adults (aged ≥18 years) with R/R ALCL undergoing allo-HCT between 2008 and 2019. Non-relapse mortality (NRM), disease relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) were modelled using Cox proportional hazards models. The median (range) follow-up of survivors was 62 (3-148) months. The 1-year NRM was 18%. The 5-year REL, PFS and OS were 32%, 41% and 56% respectively. On multivariable regression analysis African American race (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.6-4.8; p < 0.001) and refractory disease at allo-HCT (HR 3.2, 95% CI 1.6-6.2; p < 0.001) were predictive of inferior OS. Similarly, African-American race (HR 2.1, 95% CI 1.3-3.4; p = 0.003), other minority race (HR 2.5, 95% CI 1.2-5.3; p = 0.02) and refractory disease (HR 2.2, 95% CI 1.2-4.3; p = 0.01) were predictive of inferior PFS. These data, demonstrate that allo-HCT can result in durable disease control in a sizable proportion of patients with R/R ALCL. Refractory disease and racial minority status predicted inferior allo-HCT outcomes. Whether the inferior outcomes of racial minorities with R/R ALCL after allo-HCT are driven by differences in disease biology or disparities in post allo-HCT care, or both, requires further investigation.
PICO Summary
Population
Adults with relapsed/refractory anaplastic large cell lymphoma identified from the CIBMTR database (n=182)
Intervention
Allogeneic HSCT
Comparison
None
Outcome
The median (range) follow-up of survivors was 62 (3-148) months. The 1-year non-relapse mortality (NRM) was 18%. The 5-year disease relapse/progression (REL), progression-free survival (PFS) and overall survival (OS) were 32%, 41% and 56% respectively. On multivariable regression analysis African American race (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.6-4.8) and refractory disease at allo-HCT (HR 3.2, 95% CI 1.6-6.2) were predictive of inferior OS. Similarly, African-American race (HR 2.1, 95% CI 1.3-3.4), other minority race (HR 2.5, 95% CI 1.2-5.3) and refractory disease (HR 2.2, 95% CI 1.2-4.3) were predictive of inferior PFS.