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1.
Allogeneic transplant and CAR-T therapy after autologous transplant failure in DLBCL: a noncomparative cohort analysis
Hamadani, M., Gopal, A. K., Pasquini, M., Kim, S., Qiu, X., Ahmed, S., Lazaryan, A., Bhatt, V. R., Daly, A., Lulla, P., et al
Blood Advances. 2022;6(2):486-494
Abstract
Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR)-T cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto)HCT. Although the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis, we report outcomes of patients with DLBCL (≥18 years) undergoing a reduced intensity alloHCT or CAR-T therapy with axicabtagene ciloleucel during 2012 to 2019 after a prior auto-HCT failure and apply the CIBMTR prognostic model to CAR-T recipients. A total of 584 patients were included. The 1-year relapse, nonrelapse mortality, overall survival (OS), and progression-free survival for CAR-T treatment after autoHCT failure were 39.5%, 4.8%, 73.4%, and 55.7%, respectively. The corresponding rates in the alloHCT cohort were 26.2%, 20.0%, 65.6%, and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3%, respectively (P = .002). The corresponding rates for low-, intermediate-, and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (P < .001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in a subset of patients with DLBCL relapsing after a prior autoHCT. The simple CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high-risk patients.
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2.
Donor lymphocyte infusions after haploidentical stem cell transplantation with PTCY: A study on behalf of the EBMT cellular therapy & immunobiology working party
Santoro, N., Mooyaart, J. E., Devillier, R., Koc, Y., Vydra, J., Castagna, L., Gülbas, Z., Martin, J. D., Araujo, M. C., Kulagin, A., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Donor lymphocyte infusion (DLI) is a treatment option to prevent or treat relapse after allogeneic hematopoietic cell transplantation (HCT). We here report data for 173 patients who received one or multiple DLIs after haploidentical-HCT with post-transplant cyclophosphamide (PTCY) at 47 EBMT centers from 2009 to 2018. Indication for DLI was: prophylactic for 59(34.3%), preemptive for 20(11.6%), and therapeutic for 93(54.1%). For the prophylactic group, the median number of DLIs was 1 (IQR:1-2.5) with a median first dose of 0.1 × 10(6) CD3+ T cell/kg, for the preemptive 2 (IQR:1-3) with 0.5 × 10(6) CD3+ T cell/kg, for the therapeutic 1 (IQR:1-3) with 1 × 10(6)CD3+ Tcell/kg, respectively. OS after first DLI was 61% (46-75%) for prophylactic, 40% (19-61%) for preemptive, and 22% (13-31%) for therapeutic. CI of II-IV aGVHD and cGVHD was 17%(7-27%) and 53% (40-67%) for the prophylactic, 20% (2-38%) and 21% (3-39%) for the preemptive, 17% (9-24%) and 24% (15-33%) for the therapeutic group, respectively. Our data show great variability in the indications and modalities of DLI across responding EBMT centers. Survival rates remain relatively low in patients with active disease. While the cumulative incidence of aGVHD appears acceptable, we showed a high incidence proportion of cGVHD in the prophylactic group, compared with preemptive and therapeutic DLI. These data should be investigated further in prospective clinical trials.
PICO Summary
Population
Adults drawn from 47 EBMT centres receiving donor lymphocyte infusions (DLIs) after haploidentical transplant with post-transplant cyclophosphamide (n=173)
Intervention
DLIs for a prophylactic indication (n=59)
Comparison
DLIs for a pre-emptive indication (n=20), or a therapeutic indication (n=93)
Outcome
For the prophylactic group, the median number of DLIs was 1 (IQR:1-2.5) with a median first dose of 0.1 × 10(6) CD3+ T cell/kg, for the pre-emptive 2 (IQR:1-3) with 0.5 × 10(6) CD3+ T cell/kg, for the therapeutic 1 (IQR:1-3) with 1 × 10(6)CD3+ Tcell/kg, respectively. Overall survival after first DLI was 61% (46-75%) for prophylactic, 40% (19-61%) for pre-emptive, and 22% (13-31%) for therapeutic. Cumulative incidence of II-IV acute GVHD and chronic GVHD was 17%(7-27%) and 53% (40-67%) for the prophylactic, 20% (2-38%) and 21% (3-39%) for the pre-emptive, 17% (9-24%) and 24% (15-33%) for the therapeutic group, respectively.
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3.
Decrease post-transplant relapse using donor-derived expanded NK-cells
Ciurea, S. O., Kongtim, P., Soebbing, D., Trikha, P., Behbehani, G., Rondon, G., Olson, A., Bashir, Q., Gulbis, A. M., Indreshpal, K., et al
Leukemia. 2021
Abstract
In this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1?×?10(5)-1?×?10(8) cells/kg/dose) were administered on days -2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database.After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p?=?0.014), and disease-free survival (DFS) was 66% vs. 44% (p?=?0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p?=?0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype.Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION NCT01904136 ( https://clinicaltrials.gov/ct2/show/NCT01904136 ).
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4.
Autologous Transplant versus Chimeric Antigen Receptor T-cell Therapy for Relapsed DLBCL in Partial Remission
Shadman, M., Pasquini, M. C., Ahn, K. W., Chen, Y., Turtle, C. J., Hematti, P., Cohen, J. B., Khimani, F., Ganguly, S., Merryman, R. W., et al
Blood. 2021
Abstract
The relative efficacy of autologous hematopoietic cell transplant (auto-HCT) versus chimeric antigen receptor T-cell (CAR-T) therapy in diffuse large B-cell lymphoma (DLBCL) patients who achieve a partial remission (PR) after salvage chemotherapy is not known. Using the Center for International Blood & Marrow Transplant Research registry database, we identified adult DLBCL patients who received either an auto-HCT (2013-2019) or CAR-T treatment with axicabtagene ciloleucel (2018-2019) while in a PR by CT or PET scan. We compared the clinical outcomes between the two cohorts using univariable and multivariable regression models after adjustment for relevant baseline and clinical factors. In the univariable analysis, the 2-year progression-free survival (52% vs. 42% ; p=0.1) and the rate of 100-day non-relapse mortality (4% vs. 2% ; p=0.3) were not different between the 2 cohorts but consolidation with auto-HCT was associated with a lower rate of relapse/progression (40% vs. 53% ; p=0.05) and a superior overall survival (OS) (69% vs. 47% ; p=0.004) at 2-years. In the multivariable regression analysis, treatment with auto-HCT was associated with a significantly lower risk of relapse/progression rate (HR=1.49; p=0.01) and a superior OS (HR=1.63; p=0.008). In patients with DLBCL in a PR after salvage therapy, treatment with auto-HCT was associated with a lower incidence of relapse and a superior OS compared with CAR-T. These data support the role of auto-HCT as the standard-of-care in transplant-eligible patients with relapsed DLBCL in PR after salvage therapy.
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Is Autologous Transplant in Relapsed DLBCL Patients Achieving Only a PET+ PR Appropriate in the CAR-T cell Era?
Shah, N. N., Ahn, K. W., Litovich, C. A., He, Y., Sauter, C. S., Fenske, T. S., Hamadani, M.
Blood. 2020
Abstract
For relapsed, chemosensitive diffuse large B-cell lymphoma (DLBCL) consolidation with autologous hematopoietic cell transplantation (auto-HCT) is a standard option. Since the approval of anti-CD19 CAR T-cells in 2017, the Center for International Blood and Marrow Transplant Research (CIBMTR) reported a 45% decrease in the number of auto-HCT for DLBCL in the U.S. in 2018. Using the CIBMTR database, we report outcomes for auto-HCT in relapsed chemosensitive DLBCL in a partial response (PR). 249 relapsed DLBCL patients undergoing auto-HCT from 2003-13 with a PET/CT+ PR prior to transplant were identified. The study cohort was divided into two groups: (a) early chemo-immunotherapy failure (ECF) defined as patients with primary refractory disease (PRefD) or relapse within 12 months of diagnosis, (b) late chemoimmunotherapy failure defined as patients relapsing ≥12 months. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS) and relapse. 182 patients had ECF and 67 were no ECF. ECF patients were younger (57 versus (vs) 63 years, p<0.01) and 79% of had PRefD. The adjusted 5-year probabilities for PFS and OS (ECF vs no ECF) was not different: 41% vs 41% (p=0.93) and 51% vs 63% (p=0.09), respectively. On multivariate analysis, ECF patients had increased risk of death (HR=1.61, 95%CI 1.05-2.46, p=0.03) but no increased risk in PFS or relapse. In conclusion, for relapsed, chemosensitive DLBCL patients with residual PET/CT+ disease prior to auto-HCT, the adjusted 5-year PFS (41%) was comparable irrespective of time to relapse. These data support ongoing application of auto-HCT in chemosensitive DLBCL.
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The Role of Donor Lymphocyte Infusion (DLI) in Post Hematopoietic Cell Transplant (HCT) Relapse for Chronic Myeloid Leukemia (CML) in the Tyrosine Kinase Inhibitor (TKI) Era
Schmidt, S., Liu, Y., Hu, Z. H., Williams, K. M., Lazarus, H. M., Vij, R., Kharfan-Dabaja, M. A., Orti, G., Wiernik, P. H., Weisdorf, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Treatment for relapse of chronic myeloid leukemia (CML) following hematopoietic cell transplantation (HCT) includes tyrosine kinase inhibitors (TKI) with or without donor lymphocyte infusions (DLI), however the most effective treatment strategy is unknown. This study was performed through the Center for International Blood and Marrow Transplant Research (CIBMTR) database. We retrospectively reviewed all patients reported to the CIBMTR registry from 2002-2014 who underwent HCT for CML and were alive 30 days post relapse. A total of 215 HCT recipients relapsed and were analyzed in the following groups 1) TKI alone n=128, 2) TKI with DLI n=48, and 3) DLI without TKI n=39. In multivariate analysis, disease status prior to HCT had a significant effect on overall survival (OS). Patients that received a DLI alone compared to a TKI with DLI had inferior survival HR 2.28 (95% CI 1.23-4.24; p=0.009). Those who received TKI alone had similar survival compared to those who received TKI with DLI (p=0.81). These data supports that despite use of TKI pre-transplantation, TKI salvage therapy continues to provide significant survival following relapse in patients with CML following HCT. These data does not suggest that adding a DLI to TKI adds an improvement in OS.
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7.
Impact of T-cell dose on the outcome of T-cell replete HLA matched allogeneic peripheral blood stem cell transplantation
Saad, A., Lamb, L., Wang, T., Hemmer, M. T., Spellman, S., Couriel, D., Alousi, A., Pidala, J., Abdel-Azim, H., Agrawal, V., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
BACKGROUND Data on whether T-cell dose of allogeneic peripheral blood stem cell (PBSC) product influences transplant outcome are conflicting. METHODS Using CIBMTR database, we identified 2,736 adult patients who underwent first allogeneic peripheral blood stem cell (PBSC) transplant for acute leukemia (AML, ALL) or myelodysplastic syndrome (MDS) between 2008-2014 using an HLA-matched sibling donor (MSD) or 8/8-matched unrelated donor (MUD). We excluded ex-vivo and in-vivo T-cell depleted transplants. Correlative analysis was performed between CD3+ T-cell dose and risk of graft-versus-host-disease (GVHD), relapse, non-relapse mortality (NRM), disease free survival (DFS) and overall survival (OS). RESULTS Using maximum likelihood estimation method, we identified CD3+ T-cell cell dose cutoff that separated risk of acute GVHD (aGVHD) grade II-IV in both MSD and MUD groups. A CD3+ T-cell dose cutoff of 14x10(7) cells/kg identified MSD/low CD3+ (n=223) and MSD/high CD3+ (n=1214), and a dose of 15x10(7) cells/kg identified MUD/low CD3+ (n=197) and MUD/high CD3+ (n=1102). With univariate analysis, MSD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 33% vs 25% when compared to MSD/low CD3+ group (P value =0.009). There was no other difference between both groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. MUD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 49% vs 41% when compared to MUD/low CD3+ group (P value =0.04). There was no other difference between both groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of MSD and MUD groups failed to show an association between CD3+ T-cell dose and risk of either aGVHD grade II-IV (p value =0.1 and 0.07 respectively) or cGVHD (p value=0.8 and 0.3 respectively). Sub-analysis of CD4, CD8 and CD4/CD8 ratio failed to identify cutoff values predictive of transplant outcome. Using log-rank test, the sample size was, however, suboptimal to identify difference at these cutoff cell dose. CONCLUSION In this registry study, CD3+ T-cell dose of PBSCT product did not influence risk of aGVHD or cGVHD or other transplant outcomes when using HLA-matched sibling or 8/8 unrelated donors. Subset analysis of CD4+ and CD8+ T-cell dose was not possible for small sample size.
PICO Summary
Population
Patients reported to CIBMTR database with acute leukaemia (ALL or AML) or myelodysplastic syndrome between 2008-2014 (n=2736)
Intervention
First allogeneic peripheral blood stem cell using an HLA-matched sibling donor (MSD)
Comparison
8/8-matched unrelated donor (MUD)
Outcome
Using maximum likelihood estimation method, we identified CD3+ T-cell cell dose cutoff that separated risk of acute GVHD (aGVHD) grade II-IV in both MSD and MUD groups. A CD3+ T-cell dose cutoff of 14x10(7) cells/kg identified MSD/low CD3+ (n=223) and MSD/high CD3+ (n=1214), and a dose of 15x10(7) cells/kg identified MUD/low CD3+ (n=197) and MUD/high CD3+ (n=1102). With univariate analysis, MSD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 33% vs 25% when compared to MSD/low CD3+ group. MUD/high CD3+ group had higher cumulative incidence of day 100 aGVHD grade II-IV of 49% vs 41% when compared to MUD/low CD3+ group. Multivariate analysis of MSD and MUD groups failed to show an association between CD3+ T-cell dose and risk of either aGVHD grade II-IV or cGVHD. Sub-analysis of CD4, CD8 and CD4/CD8 ratio failed to identify cutoff values predictive of transplant outcome.
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Association of Second Allogeneic Hematopoietic Cell Transplant vs Donor Lymphocyte Infusion With Overall Survival in Patients With Acute Myeloid Leukemia Relapse
Kharfan-Dabaja, M. A., Labopin, M., Polge, E., Nishihori, T., Bazarbachi, A., Finke, J., Stadler, M., Ehninger, G., Lioure, B., Schaap, N., et al
JAMA oncology. 2018
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Abstract
Importance: The optimal treatment approach to patients with acute myeloid leukemia (AML) who relapse after an allogeneic hematopoietic cell transplant (allo-HCT) remains elusive. No randomized clinical trial comparing survival outcomes of a second allo-HCT (allo-HCT2) vs donor lymphocyte infusion (DLI) has been conducted to date. Objective: To compare overall survival (OS) after an allo-HCT2 or DLI in relapsed AML after a first allo-HCT. Design, Setting, and Participants: A retrospective registry study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation involving 418 adults who received an allo-HCT2 (n = 137) or DLI (n = 281) for postallograft-relapsed AML. Analysis was assessed on the principle of intent-to-first received intervention. The data were collected from November 21, 2015, to May 15, 2017, and analysis was performed June 1, 2017. Main Outcomes and Measures: Number of patients with relapsed AML who are alive after 2 years and 5 years from receiving an allo-HCT2 or DLI. Results: Of the 418 patients, 228 (54.5%) were men; mean age was 46.2 years (interquartile range, 36.5-56.9 years). There was no apparent difference in OS whether an allo-HCT2 or DLI was prescribed (2-year OS with allo-HCT2, 26%; 5-year OS with allo-HCT2, 19%; 2-year OS with DLI, 25%; 5-year OS with DLI, 15%; P = .86). Overall survival was better if either of these procedures was offered when the patient was in complete remission (hazard ratio, 0.55; 95% CI, 0.41-0.74; P < .001). Conversely, OS was low for patients relapsing within less than 6 months after an allo-HCT1, regardless of the treatment prescribed (5-year OS: allo-HCT2, 9%; 95% CI, 1%-17% vs DLI, 4%; 95% CI, 1%-8%; P = .86). Conclusion and Relevance: Heterogeneity of the patient-, disease-, and treatment-related characteristics limit the ability to recommend one approach over another. Findings of this study highlight that best outcomes seem to be achieved in patients relapsing 6 or more months from an allo-HCT1 or those in complete remission at the time of either allo-HCT2 or DLI.
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Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation in acute leukaemia - a matched pair analysis by the Acute Leukaemia Working Party of EBMT
Schmid, C., Labopin, M., Schaap, N., Veelken, H., Schleuning, M., Stadler, M., Finke, J., Hurst, E., Baron, F., Ringden, O., et al
British journal of haematology. 2018
Abstract
Strategies for relapse prevention after allogeneic transplantation in acute leukaemia are warranted. A registry-based matched-pair analysis evaluated the efficacy of prophylactic donor lymphocyte infusion (proDLI). Adults receiving proDLI in complete remission (CR) and controls were pair-matched for age, diagnosis, cytogenetics, stage, donor, gender, conditioning and T-cell depletion. Eighty-nine pairs were identified (median follow-up: 6.9 years). Within the entire cohort, no difference was observed. However, among patients with high-risk acute myeloid leukaemia (AML) (unfavourable cytogenetics and/or transplanted beyond first CR), proDLI recipients had improved overall survival (69.8% vs. 40.2% in controls, P = 0.027). ProDLI has moderate efficacy, but can contribute to improved outcome in high-risk AML.