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Phase I study of zoledronic acid combined with escalated doses of interleukine-2 for early in vivo generation of Vγ9Vδ2 T-cells after haploidentical stem cell transplant with posttransplant cyclophosphamide
Jullien, M., Guillaume, T., Le Bourgeois, A., Peterlin, P., Garnier, A., Eveillard, M., Le Bris, Y., Bouzy, S., Tessoulin, B., Gastinne, T., et al
American journal of hematology. 2024
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Editor's Choice
Abstract
The presence of donor Vγ9Vδ2 T-cells after haploidentical hematopoietic stem cell transplant (h-HSCT) has been associated with improved disease-free survival. These cells kill tumor cells in a non-MHC restricted manner, do not induce graft-versus-host disease (GVHD), and can be generated by stimulation with zoledronic acid (ZA) in combination with interleukin-2 (IL-2). This monocentric phase I, open-label, dose-escalating study (ClinicalTrials.gov: NCT03862833) aimed at evaluating the safety and possibility to generate Vγ9Vδ2 T-cells early after h-HSCT. It applied a standard 3 + 3 protocol to determine the maximum tolerated dose (MTD) of increasing low-doses of IL-2 (5 days [d] per week, 4 weeks) in combination with a single dose of ZA, starting both the first Monday after d + 15 posttransplant. Vγ9Vδ2 T-cell monitoring was performed by multiparameter flow cytometry on blood samples and compared with a control cohort of h-HSCT recipients. Twenty-six patients were included between April 2019 and September 2022, 16 of whom being ultimately treated and seven being controls who received h-HSCT only. At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. MTD was not reached. A significantly higher number of Vγ9Vδ2 T-cells was observed during IL-2 treatment compared with controls. In conclusion, early in vivo generation of Vγ9Vδ2 T-cells is feasible after h-HSCT by using a combination of ZA and repeated IL-2 infusions. This study paves the way to a future phase 2 study, with the hope to document lesser posttransplant relapse with this particular adaptive immunotherapy.
PICO Summary
Population
Adults with haematological malignancy, eligible for haploidentical transplant from a single centre in France (n=26)
Intervention
Increasing low-doses of IL-2 (5 days per week, 4 weeks) in combination with a single dose of zoledronic acid (ZA) to generate Vγ9Vδ2 T-cells early after h-HSCT (n=16)
Comparison
Haploidentical HSCT only (n=7)
Outcome
At the three dose levels tested, 1, 0, and 1 dose-limiting toxicities were observed. Maximum tolerated dose was not reached.
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Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant
Cao, X. Y., Zhang, J. P., Zhao, Y. L., Xiong, M., Zhou, J. R., Lu, Y., Sun, R. J., Wei, Z. J., Liu, D. Y., Zhang, X., et al
Frontiers in immunology. 2023;14:1191382
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Editor's Choice
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival. METHODS A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy. RESULTS The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021). CONCLUSIONS Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.
PICO Summary
Population
Adults with acute lymphoblastic leukaemia who were minimal residual disease-positive after first transplant at a single centre in China (n=95)
Intervention
CAR-T therapy followed by consolidation allogeneic transplant, using a different donor
Comparison
None
Outcome
The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24) and OS(HR, 2.67, 95%CI, 1.24-5.74), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24).
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Prevention of CMV/EBV reactivation by double-specific T cells in patients after allogeneic stem cell transplantation: results from the randomized phase I/IIa MULTIVIR-01 study
Gerbitz, A., Gary, R., Aigner, M., Moosmann, A., Kremer, A., Schmid, C., Hirschbuehl, K., Wagner, E., Hauptrock, B., Teschner, D., et al
Frontiers in immunology. 2023;14:1251593
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Editor's Choice
Abstract
INTRODUCTION Allogeneic stem cell transplantation is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population. METHODS We report the results of a randomized controlled multi centre phase I/IIa study (MULTIVIR-01) using a newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. The study aimed at prevention and preemptive treatment of both viruses in patients after allogeneic stem cell transplantation targeting first infusion on day +30. Primary endpoints were acute transfusion reaction and acute-graft versus-host-disease after infusion of activated T cells. RESULTS Thirty-three patients were screened and 9 patients were treated with a total of 25 doses of the T cell product. We show that central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation. DISCUSSION Our study results indicate peptide stimulated epitope specific T cells derived from stem cell grafts can be administered safely for prevention and preemptive treatment of reactivation without evidence for induction of acute graft versus host disease. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov, identifier NCT02227641.
PICO Summary
Population
Adults undergoing allogeneic transplant from a matched donor who was seropositive for cytomegalovirus (CMV) and Epstein-barr virus (EBV) and enrolled in the MULTIVIR-01 study in centres in Germany (n=33)
Intervention
A newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. (n=16; 9 received full treatment)
Comparison
Control (n=13)
Outcome
Central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation
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Prophylactic donor lymphocyte infusion after haploidentical hematopoietic cell transplantation and post-transplant cyclophosphamide for treatment of high-risk myeloid neoplasms in children: A retrospective study
Qi, S. S., Chen, Z., Du, Y., Sun, M., Wang, Z., Long, F., Luo, L., Xiong, H.
Pediatric blood & cancer. 2023;:e30659
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Editor's Choice
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCy) has been recommended for prevention of graft-versus-host disease (GvHD) following haploidentical hematopoietic cell transplantation (haplo-HCT) for treatment of malignant blood diseases, but disease relapse remains a problem. Although donor lymphocyte infusion (DLI) is reported to be effective for treating post-transplantation relapse, the efficacy and safety of prophylactic-DLI (pro-DLI) post haplo-HCT, and PTCy in pediatric patients with hematological malignancies is unknown. METHODS We retrospectively analyzed the outcomes of 54 pediatric patients with high-risk myeloid neoplasms who received a PTCy regimen for GvHD prophylaxis and pro-DLI after haploidentical peripheral blood stem cell transplantation. The high-risk myeloid neoplasms in this cohort included acute myeloid leukemia (n = 46) and myelodysplastic syndromes (n = 8). RESULTS Median follow-up was for 19.7 (range: 3.4-46.6) months. The cumulative incidences of grade II-IV and III-IV acute GvHD were 37.0% (95% CI: 22.7%-48.7%) and 16.7% (95% CI: 6.1%-26.0%), respectively. There were no graft-failure events, and the 2-year rate of moderate/severe chronic GvHD was 8.1% (95% CI: 0%-16.7%). The 2-year non-relapse mortality, relapse, disease-free survival, GvHD-free relapse-free survival, and overall survival rates were 5.1% (95% CI: 0%-11.7%), 16.6% (95% CI: 5.3%-26.6%), 78.9% (95% CI: 68.0%-91.6%), 62.2% (95% CI: 49.4%-78.3%), and 87.3% (95% CI: 78.3%-97.4%), respectively. CONCLUSIONS Prophylactic donor lymphocyte infusion in the setting of haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide appears to be effective and safe in pediatric patients with high-risk myeloid neoplasms.
PICO Summary
Population
Children with high-risk myeloid neoplasms undergoing haploidentical peripheral blood transplant at a single centre in China (n=54)
Intervention
Post-transplant cyclophosphamide (PTCy) regimen for GvHD prophylaxis and prophylactic donor lymphocyte infusion (pro-DLI)
Comparison
None
Outcome
Median follow-up was for 19.7 (range: 3.4-46.6) months. The cumulative incidences of grade II-IV and III-IV acute GvHD were 37.0% (95% CI: 22.7%-48.7%) and 16.7% (95% CI: 6.1%-26.0%), respectively. There were no graft-failure events, and the 2-year rate of moderate/severe chronic GvHD was 8.1% (95% CI: 0%-16.7%). The 2-year non-relapse mortality, relapse, disease-free survival, GvHD-free relapse-free survival, and overall survival rates were 5.1% (95% CI: 0%-11.7%), 16.6% (95% CI: 5.3%-26.6%), 78.9% (95% CI: 68.0%-91.6%), 62.2% (95% CI: 49.4%-78.3%), and 87.3% (95% CI: 78.3%-97.4%), respectively.
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Immune Reconstitution Profiling Suggests Antiviral Protection After Transplantation with Omidubicel: a Phase 3 Substudy
Szabolcs, P., Mazor, R. D., Yackoubov, D., Levy, S., Stiff, P., Rezvani, A., Hanna, R., Wagner, J., Keating, A., Lindemans, C. A., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for hematological malignancies and non-malignant disorders. Rapid immune reconstitution (IR) following allogeneic HCT has been shown to be associated with improved clinical outcomes and lower infection rates. A global phase 3 trial (NCT02730299) of omidubicel, an advanced cell therapy manufactured from an appropriately human leukocyte antigen-matched single umbilical cord blood (UCB) unit, showed faster hematopoietic recovery, reduced rates of infection, and shorter hospitalizations in patients randomized to omidubicel compared with those randomized to standard UCB. OBJECTIVE This optional, prospective substudy of the phase 3 trial characterized the IR kinetics following HCT with omidubicel compared with UCB in a systematic and detailed manner. STUDY DESIGN In this substudy, 37 patients from 14 global sites were included (omidubicel: n=17, UCB: n=20). Peripheral blood samples were collected over 10 predefined time points from 7 to 365 days post-HCT. Flow cytometry immunophenotyping, T cell receptor excision circle quantification, and T cell receptor sequencing were employed to evaluate the longitudinal IR kinetics post-transplant and their association with clinical outcomes. RESULTS Patient characteristics in the two comparator cohorts were overall statistically similar, except for age and total body irradiation (TBI) based conditioning regimens. The median age (range) for patients who received omidubicel or UCB was 30 (13-62) years and 43 (19-55) years, respectively. The percentages of patients receiving TBI based conditioning regimens were 47% and 70% for omidubicel and UCB recipients, respectively. Graft characteristics differed in their cellular composition. Omidubicel recipients received a 33-fold higher median dose of CD34+ stem cells, while receiving one third of the median CD3+ lymphocyte dose infused to UCB transplanted patients. Compared with UCB, omidubicel recipients exhibited faster IR of all measured lymphoid and myelomonocytic subpopulations, predominantly in the first 14 days post-transplant. This effect involved circulating natural killer (NK) cells, helper T cells, monocytes, and dendritic cells, with superior long-term B cell recovery from Day 28. One-week post-HCT, omidubicel recipients exhibited 4.1 and 7.7 -fold increases in the median helper T and NK cell counts respectively, compared to their UCB transplanted counterparts. By three weeks post-HCT, omidubicel transplanted patients were 3-fold more likely to achieve clinically relevant helper T and NK cell counts of 100 cells/ µL or above. Similar to UCB, omidubicel yielded a balanced cellular subpopulation composition and diverse T cell receptor repertoire in the short to long term. Omidubicel's CD34+ cell content correlated with faster IR by Day 7 post-HCT, which in turn coincided with earlier hematopoietic recovery. Lastly, early NK and helper T cell reconstitution correlated with a decreased rate of post-HCT viral infections, suggesting a plausible explanation for this phenomenon among omidubicel recipients in the phase 3 study. CONCLUSIONS Our findings suggest that omidubicel efficiently promotes IR across multiple immune cells, including CD4+ T cells, B cells, NK cells, and dendritic cell subtypes as early as 7 days post-transplant, potentially endowing recipients of omidubicel with early protective immunity.
PICO Summary
Population
Adults with haematological malignancies enrolled in a randomised controlled trial (n=125) and selected for a substudy evaluating immune reconstitution kinetics (n=37)
Intervention
Omidubicel, an advanced cell therapy manufactured from an appropriately human leukocyte antigen-matched single umbilical cord blood unit (omidubicel, n=17)
Comparison
Standard cord blood transplantation (UCB, n=20)
Outcome
Compared with UCB, omidubicel recipients exhibited faster immune reconstitution (IR) of all measured lymphoid and myelomonocytic subpopulations, predominantly in the first 14 days post-transplant. This effect involved circulating natural killer (NK) cells, helper T cells, monocytes, and dendritic cells, with superior long-term B cell recovery from Day 28. One-week post-HCT, omidubicel recipients exhibited 4.1 and 7.7 -fold increases in the median helper T and NK cell counts respectively, compared to their UCB transplanted counterparts. By three weeks post-HCT, omidubicel transplanted patients were 3-fold more likely to achieve clinically relevant helper T and NK cell counts of 100 cells/ µL or above. Similar to UCB, omidubicel yielded a balanced cellular subpopulation composition and diverse T cell receptor repertoire in the short to long term. Omidubicel's CD34+ cell content correlated with faster IR by Day 7 post-HCT, which in turn coincided with earlier hematopoietic recovery. Lastly, early NK and helper T cell reconstitution correlated with a decreased rate of post-HCT viral infections, suggesting a plausible explanation for this phenomenon among omidubicel recipients in the phase 3 study.
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A Multicenter Phase 2 Clinical Trial of 10-Day Decitabine, Dose-Escalated Donor Lymphocyte Infusion, and Ruxolitinib for Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Cell Transplantation
Rashidi, A., Huselton, E. J., Stefanski, H. E., DeFor, T. E., Shanley, R., Choi, J., DiPersio, J. F., Juckett, M., Miller, J. S., Weisdorf, D. J., et al
Transplantation and cellular therapy. 2023;29(5):328.e1-328.e6
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Editor's Choice
Abstract
Post-transplantation relapse of acute myeloid leukemia and myelodysplastic syndromes has a poor prognosis. Donor lymphocyte infusion (DLI) is one treatment approach. However, efficacy is limited, and toxicity, mostly in the form of acute graft-versus-host disease (GVHD), is frequent. We tested a novel approach using 10-day decitabine, dose-escalated DLI, and ruxolitinib in a multicenter phase 2 trial aimed at increasing the efficacy of DLI and reducing its toxicity. Up to four 28-day cycles were administered. The primary endpoint was 6-month overall survival (OS). Of the 14 patients who started cycle 1, 13 received 1 DLI, 6 received 2 DLIs, and 1 received 3 4 DLIs. A preplanned interim analysis after enrolling 14 patients suggested futility, and the trial was closed to accrual. The final analysis showed a 6-month OS of 36% (95% confidence interval [CI], 18 to 72), a 1-year progression-free survival of 7% (95% CI, 1% to 47%), a 6-month cumulative incidence of grade II-IV acute GVHD of 57% (95% CI, 26% to 80%), and a 1-year nonrelapse mortality of 14% (95% CI, 2% to 38%). The combined modality treatment studied in this trial was ineffective and did not reduce DLI toxicity.
PICO Summary
Population
Patients with aged 12 years or over with relapsed acute myeloid leukaemia or myelodysplastic syndromes after allogeneic transplant, from three centres in USA (n=14)
Intervention
10-day decitabine, dose-escalated donor lymphocyte infusion (DLI), and ruxolitinib, for up to four 28-day cycles (n=13)
Comparison
None
Outcome
The trial was stopped for futility after interim analysis. The final analysis showed a 6-month OS of 36% (95% confidence interval [CI], 18 to 72), a 1-year progression-free survival of 7% (95% CI, 1% to 47%), a 6-month cumulative incidence of grade II-IV acute GVHD of 57% (95% CI, 26% to 80%), and a 1-year nonrelapse mortality of 14% (95% CI, 2% to 38%).
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The infusion of ex vivo, interleukin-15 and -21-activated donor NK cells after haploidentical HCT in high-risk AML and MDS patients-a randomized trial
Lee, K. H., Yoon, S. R., Gong, J. R., Choi, E. J., Kim, H. S., Park, C. J., Yun, S. C., Park, S. Y., Jung, S. J., Kim, H., et al
Leukemia. 2023
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Editor's Choice
Abstract
Clinical effect of donor-derived natural killer cell infusion (DNKI) after HLA-haploidentical hematopoietic cell transplantation (HCT) was evaluated in high-risk myeloid malignancy in phase 2, randomized trial. Seventy-six evaluable patients (aged 21-70 years) were randomized to receive DNKI (N = 40) or not (N = 36) after haploidentical HCT. For the HCT conditioning, busulfan, fludarabine, and anti-thymocyte globulin were administered. DNKI was given twice 13 and 20 days after HCT. Four patients in the DNKI group failed to receive DNKI. In the remaining 36 patients, median DNKI doses were 1.0 × 10(8)/kg and 1.4 × 10(8)/kg on days 13 and 20, respectively. Intention-to-treat analysis showed a lower disease progression for the DNKI group (30-month cumulative incidence, 35% vs 61%, P = 0.040; subdistribution hazard ratio, 0.50). Furthermore, at 3 months after HCT, the DNKI patients showed a 1.8- and 2.6-fold higher median absolute blood count of NK and T cells, respectively. scRNA-sequencing analysis in seven study patients showed that there was a marked increase in memory-like NK cells in DNKI patients which, in turn, expanded the CD8(+) effector-memory T cells. In high-risk myeloid malignancy, DNKI after haploidentical HCT reduced disease progression. This enhanced graft-vs-leukemia effect may be related to the DNKI-induced, post-HCT expansion of NK and T cells. Clinical trial number: NCT02477787.
PICO Summary
Population
Adults 21-70 years undergoing haploidentical transplant for high-risk myeloid malignancy from a single centre in Korea (n=76)
Intervention
Two doses of donor-derived natural killer cell infusion (DNKI) on day 13 and day 20 (n=40)
Comparison
No NK cell infusion (n=36)
Outcome
Intention-to-treat analysis showed a lower disease progression for the DNKI group (30-month cumulative incidence, 35% vs 61%; subdistribution hazard ratio, 0.50). Furthermore, at 3 months after HCT, the DNKI patients showed a 1.8- and 2.6-fold higher median absolute blood count of NK and T cells, respectively. scRNA-sequencing analysis in seven study patients showed that there was a marked increase in memory-like NK cells in DNKI patients which, in turn, expanded the CD8(+) effector-memory T cells.
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Prophylactic versus Preemptive modified donor lymphocyte infusion for high-risk acute leukemia after allogeneic hematopoietic stem cell transplantation: a multicenter retrospective study
Yang, L., Lai, X., Yang, T., Lu, Y., Liu, L., Shi, J., Zhao, Y., Wu, Y., Chen, Y., Yu, J., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
Donor lymphocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been widely used in preventing post-transplant relapse. We conducted this study to compare the superiority of prophylactic modified DLI (pro-DLI) and preemptive modified DLI (pre-DLI) in patients with high-risk relapse features acute leukemia. Pro-DLI was performed in 95 patients, whereas the pre-DLI cohort included 176 patients. In the pre-DLI cohort, 42 patients relapsed without chance for pre-DLI while 95 patients remained CR without detectable minimal residual disease (MRD). Thirty-nine patients in the pre-DLI cohort became minimal MRD positive/mixed chimerism and received pre-DLI. Pro-DLI cohort had higher 3-year progression-free-survival (PFS) (63.4%vs.53.0%, P = 0.026) and overall survival (OS) (65.2% vs. 57.0%, P = 0.14) compared to the pre-DLI cohort. The 3-year cumulative incidence of relapse (CIR) was 25.3% in the pro-DLI cohort which was significantly lower than 36.7% in the pre-DLI cohort (P = 0.02). The cumulative incidence of grade III-IV aGVHD, cGVHD and non-relapse mortality were comparable between cohorts. Multivariable analysis demonstrated strong protective effect of pro-DLI on OS (hazard ratio (HR) = 0.63, P = 0.04), PFS (HR = 0.54, P = 0.005) and CIR (HR = 0.50, P = 0.005). In high-risk patients with acute leukemia, early scheduled pro-DLI rather than pre-DLI after detectable MRD would reduce post-transplant relapse and improve long-term survival.
PICO Summary
Population
Patients with high-risk acute leukaemia undergoing allogeneic transplant with myeloablative conditioning, in continuous complete remission without GvHD, from six centres in China (n=280)
Intervention
Prophylactic modified donor lymphocyte infusion (pro-DLI, n=95)
Comparison
Preemptive modified donor lymphocyte infusion (pre-DLI, n=186)
Outcome
In the pre-DLI cohort, 42 patients relapsed without chance for pre-DLI while 95 patients remained in complete remission (CR) without detectable minimal residual disease (MRD). Thirty-nine patients in the pre-DLI cohort became minimal MRD positive/mixed chimerism and received pre-DLI. Pro-DLI cohort had higher 3-year progression-free-survival (PFS) (63.4%vs.53.0%) and overall survival (OS) (65.2% vs. 57.0%) compared to the pre-DLI cohort. The 3-year cumulative incidence of relapse (CIR) was 25.3% in the pro-DLI cohort which was significantly lower than 36.7% in the pre-DLI cohort (P = 0.02). The cumulative incidence of grade III-IV aGVHD, cGVHD and non-relapse mortality were comparable between cohorts. Multivariable analysis demonstrated strong protective effect of pro-DLI on OS (hazard ratio (HR) = 0.63), PFS (HR = 0.54) and CIR (HR = 0.50). In high-risk patients with acute leukemia, early scheduled pro-DLI rather than pre-DLI after detectable MRD would reduce post-transplant relapse and improve long-term survival.
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Donor-derived CD19 CAR-T Cells versus Chemotherapy Plus Donor Lymphocyte Infusion for Treatment of Recurrent CD19-positive B-ALL After Allogeneic Hematopoietic Stem Cell Transplantation
Tan, X., Wang, X. Q., Zhang, C., Zhao, X. L., Yao, H., Chen, G., Ma, Y. Y., Wen, Q., Gao, L., Gao, L., et al
Current medical science. 2023
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Editor's Choice
Abstract
OBJECTIVE This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells (CAR-T cells) versus chemotherapy plus donor lymphocyte infusion (chemo-DLI) for treating relapsed CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS Clinical data of 43 patients with B-ALL who relapsed after allo-HSCT were retrospectively analyzed. Twenty-two patients were treated with CAR-T cells (CAR-T group), and 21 with chemotherapy plus DLI (chemo-DLI group). The complete remission (CR) and minimal residual disease (MRD)-negative CR rates, leukemia-free survival (LFS) rate, overall survival (OS) rate, and incidence of acute graft-versus-host disease (aGVHD), cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were compared between the two groups. RESULTS The CR and MRD-negative CR rates in the CAR-T group (77.3% and 61.5%) were significantly higher than those in the chemo-DLI group (38.1% and 23.8%) (P=0.008 and P=0.003). The 1- and 2-year LFS rates in the CAR-T group were superior to those in the chemo-DLI group: 54.5% and 50.0% vs. 9.5% and 4.8% (P=0.0001 and P=0.00004). The 1- and 2-year OS rates in the CAR-T versus chemo-DLI group were 59.1% and 54.5% vs. 19% and 9.5% (P=0.011 and P=0.003). Six patients (28.6%) with grade 2-4 aGVHD were identified in the chemo-DLI group. Two patients (9.1%) in the CAR-T group developed grade 1-2 aGVHD. Nineteen patients (86.4%) developed CRS in the CAR-T group, comprising grade 1-2 CRS in 13 patients (59.1%) and grade 3 CRS in 6 patients (27.3%). Two patients (9.1%) developed grade 1-2 ICANS. CONCLUSION Donor-derived anti-CD19 CAR-T-cell therapy may be better, safer, and more effective than chemo-DLI for B-ALL patients who relapse after allo-HSCT.
PICO Summary
Population
Adults and children with relapsed CD19-positive ALL after allo-HSCT, from centres in China (n=43)
Intervention
CAR-T cell therapy (n-22),
Comparison
Chemotherapy plus donor lymphocyte infusion (DLI) treatment (n=21).
Outcome
The complete remission (CR) and minimal residual disease (MRD)-negative CR rates in the CAR-T group (77.3% and 61.5%) were significantly higher than those in the chemo-DLI group (38.1% and 23.8%). The 1- and 2-year leukaemia free surivival (LFS) rates in the CAR-T group were superior to those in the chemo-DLI group: 54.5% and 50.0% vs. 9.5% and 4.8%. The 1- and 2-year overall survival (OS) rates in the CAR-T versus chemo-DLI group were 59.1% and 54.5% vs. 19% and 9.5%. Six patients (28.6%) with grade 2-4 aGVHD were identified in the chemo-DLI group. Two patients (9.1%) in the CAR-T group developed grade 1-2 aGVHD. Nineteen patients (86.4%) developed CRS in the CAR-T group, comprising grade 1-2 CRS in 13 patients (59.1%) and grade 3 CRS in 6 patients (27.3%). Two patients (9.1%) developed grade 1-2 ICANS.
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Posoleucel, an Allogeneic, Off-the-Shelf Multivirus-Specific T-Cell Therapy, for the Treatment of Refractory Viral Infections in the Post-HCT Setting
Pfeiffer, T., Tzannou, I., Wu, M., Ramos, C., Sasa, G., Martinez, C., Lulla, P., Krance, R. A., Scherer, L., Ruderfer, D., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023;:Of1-of7
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Editor's Choice
Abstract
PURPOSE Viral infections are a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). In the absence of safe and effective antiviral treatments, virus-specific T cells have emerged as a promising therapeutic option. Posoleucel is a multivirus-specific T-cell therapy for off-the-shelf use against six viral infections that commonly occur in allo-HCT recipients: adenovirus, BK virus (BKV), cytomegalovirus, Epstein-Barr virus, human herpes virus-6, and JC virus. PATIENTS AND METHODS We conducted an open-label, phase II trial to determine the feasibility and safety of posoleucel in allo-HCT recipients infected with one or more of these viruses. Infections were either unresponsive to or patients were unable to tolerate standard antiviral therapies. Fifty-eight adult and pediatric patients were enrolled and treated. RESULTS Posoleucel was well tolerated, with no cytokine release syndrome or other infusion-related toxicities; two patients (3.4%) developed Grade 2 and one patient (1.7%) Grade 3 GvHD during the trial. The overall response rate 6 weeks after the first posoleucel infusion was 95%, with a median plasma viral load reduction of 97%. Of the 12 patients who had two or more target viral infections identified at study entry, 10 (83%) had a clinical response for all evaluable viruses. Of the 23 patients treated for refractory BKV-associated hemorrhagic cystitis, 74% had resolution of symptoms and macroscopic hematuria by 6 weeks post-infusion. CONCLUSIONS In this open-label trial, treatment of refractory viral infections/disease in allo-HCT recipients with posoleucel was feasible, safe, and effective.
PICO Summary
Population
Adult and pediatric allogeneic HSCT recipients infected with one or more of adenovirus, BK virus (BKV), cytomegalovirus, Epstein-Barr virus, human herpes virus-6, and JC virus (n=58)
Intervention
Single intravenous infusion of 2 × 107/m2 of posoleucel with the option to receive a second infusion after four weeks and additional infusions at biweekly intervals thereafter.
Comparison
None
Outcome
Posoleucel was well tolerated, with no cytokine release syndrome or other infusion-related toxicities; two patients (3.4%) developed Grade 2 and one patient (1.7%) Grade 3 GvHD during the trial. The overall response rate 6 weeks after the first posoleucel infusion was 95%, with a median plasma viral load reduction of 97%. Of the 12 patients who had two or more target viral infections identified at study entry, 10 (83%) had a clinical response for all evaluable viruses. Of the 23 patients treated for refractory BKV-associated hemorrhagic cystitis, 74% had resolution of symptoms and macroscopic hematuria by 6 weeks post-infusion.