We evaluated the outcome of ab T cell-depleted haploidentical hematopoietic stem cell transplantation (HSCT) in a cohort of children with chemorefractory acute myelogenous leukemia (AML). Twenty-two patients with either primary refractory (n = 10) or relapsed refractory (n = 12) AML in active disease status received a transplant from haploidentical donors. The preparative regimen included cytoreduction with fludarabine and cytarabine and subsequent myeloablative conditioning with treosulfan and thiotepa. Antithymocyte globulin was substituted with tocilizumab in all patients and also with abatacept in 10 patients. Grafts were peripheral blood stem cells engineered by ab T cell and CD19 depletion. Post-transplantation prophylactic therapy included infusion of donor lymphocytes, composed of a CD45RA-depleted fraction with or without a hypomethylating agent. Complete remission was achieved in 21 patients (95%). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 18%, and the cumulative incidence of chronic GVHD was 23%. At 2 years, transplantation-related mortality was 9%, relapse rate was 42%, event-free survival was 49%, and overall survival was 53%. Our data suggest that ab T cell-depleted haploidentical HSCT provides a reasonable chance of long-term survival in a cohort of children with chemorefractory AML and creates a solid basis for further improvement.
Both acute GVHD and chronic GVHD remain the leading cause of morbidity and death after allogeneic HSCT. We conducted a retrospective analysis comparing two GVHD‐prophylaxis regimens: 35 patients received “Regimen 1” (horse ATG, tacrolimus, and methotrexate) and 46 “Regimen 2” (rabbit ATG, rituximab, and peritransplant bortezomib). All 81 patients with a median age of 9 (0.6‐23) years with ALL (n = 31) or AML (n = 50) in complete remission received TCRαβ/CD19‐depleted transplants between May 2012 and October 2016, from 40 HLA‐matched unrelated and 41 haploidentical donors. After a median follow‐up of 3.9 years, the CI of acute GVHD II‐IV was 15% (95% CI: 7‐30) in the “Regimen 2” group and 34% (95% CI: −54) in the “Regimen 1” group, P = .05. “Regimen 2” was also more effective in the prevention of chronic GVHD; the CI at 1 year after HSCT was 7% (95% CI: 2‐19) vs 31% (95% CI: 19‐51), P = .005. The CI of relapse at 3 years adjusted for the GVHD‐prophylaxis regimen groups 31% (95% CI: 19‐51) for the “Regimen 1” vs 21% (95% CI: 11‐37) for the “Regimen 2”, P = .3. The retrospective observation suggests that the use of the rATG, rituximab, and bortezomib was associated with significantly lower rate of GVHD without the loss of anti‐leukemic activity.
Purpose: to analyze the radiation-induced organ-specific toxicity and survival outcomes in pediatric patients after hematopoietic stem cell transplantation (HSCT) with TCRαβ /CD19- depletion and myeloablative total body irradiation (TBI)-based conditioning regimen. Methods and Materials: We analyzed retrospectively a cohort of 197 patients (pts) with different hematological malignances. ALL - 150 pts: 1st CR - 40 pts; 2nd CR - 77; advanced - 33 pts; AML - 24 pts: active disease - 20 pts, 1st CR - 1 pt; 2nd CR - 3 pts; others (JMML, NHL etc.) - 23 pts. All the patients received allo-HSCT with TCRαβ /CD19- Depletion at Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology between 07/2014 and 04/2020. TBI (1200 cGy given twice daily in 6 fractions or once daily given in 4 fractions) was used as a part of HSCT conditioning regimens. The TBI technique included the irradiation of whole body using IMRT (TomoTherapy Helical System and IMRT Vmat on Elekta Linac) with following organ sparing: lungs, kidneys, lenses. The lung dose was prescribed as V8<40% (i.e the volume of each lung receiving 8 Gy, not to exceed 40%). The mean kidney dose was prescribed at < 8Gy. Forty-four patients received additional simultaneous integrated boost (SIB) up to 15 Gy or consecutive boost up to 18 Gy to different sites (bone marrow, etc.). Age of patients was from 3 to 21 y.o. (median - 10 y.o.). 26 pts were treated under anesthesia. Haploidentical HSCT was performed in 172 pts, allo-HSCT from matched unrelated donor was performed in 14 pts, from matched related donor - in 12 pts. We register acute toxicity (nausea/vomit/diarrhea, headache, veno-occlusive disease (VOD)) - during radiation therapy and 30 days after SCT, subacute toxicity - up to 100th day after SCT and late toxicity - at least 100 days after SCT according RTOG scale. Results: Follow-up period was from 0,3 to 7,2 years (median follow up period - 2 years). OS for all the patients was 66,7%±3,8%; EFS was 63,0%±3,6%; the transplant-related mortality rate was 8,9±2,1%. OS in patients with acute leukemia was 69,9±4,2% in ALL-group and 44,8±11,0% in AML-group (p=0,015). Mean survival time for patients with ALL was 4,3 years. EFS for pts with ALL was 66,7±4,1%; TRM = 8,4±2,3%. EFS for pts with AML was 43,1±10,3%; TRM = 16,3±7,5%. TRM in patients with 1st and 2nd CR was 5,5%±2,9%. TBI-related toxicity not significantly contribute to TRM, as most cases were infection-related. Acute toxicity during radiation therapy was registered among 100% of pts, in 97% of pts acute toxicity didn't exceed grade 1-2 according to RTOG scale. Among 3% of pts - grade 3 acute toxicity (nausea/vomiting/headache/diarrhea) was observed. We also registered VOD in 3 pts (all of them received SIB to bone marrow). Subacute toxicity was registered in 0.5% of patients (n=1) (interstitial pneumonia 3-4 stage according RTOG). Radiation-induced kidney toxicity was not registered. Conclusion: The developed TBI method included in conditioning regimen before allogenic SCT with TCRαβ /CD19-depletion in pediatric pts has tolerable organ-specific toxicity and predictable results of survival outcomes. Disclosures No relevant conflicts of interest to declare.
Introduction HSCT from matched family donors results in most favorable outcomes among children with severe aplastic anemia (SAA). Despite overall success, morbidity, associated with acute and chronic graft-versus-host disease (GVHD) is not completely prevented with current standard of pharmacologic prophylaxis. Depletion of ab T cells from the graft prevents GVHD, and improves outcome of hematopoietic stem cell transplantation from haploidentical donors, while infusions of donor memory lymphocytes (mDLI) (CD45RA-depleted) are able to transfer pathogen-specific immunity without the risk of GVHD. We evaluated the outcomes of ab T cell depletion and add-back of intermediate-dose mDLI among the pediatric SAA recipients of matched related grafts. Materials and methods A total of 16 children with SAA (8 female, 8 male, median age 10,9 y) underwent allogenic HSCT from matched family donors (MFD) between february 2015 and may 2021. For 15 (94%) pts it was the first allo HSCT, for 1 pts it was the second HSCT. TCR αβ+/CD19+ depletion of HSCT with CliniMACS technology was implemented in all cases. The median dose of CD34+ cells was 7,1 x10 6/kg (range 2,6-13), αβ T cells - 28x10 3/kg (range 5,6-184). All pts received an additional injection of memory T-cell (CD45RA-depleted) on day 0 at 1 million T cells per kg. All patients received cyclophosphamide at 100 mg/kg, fludarabine at 100 mg/m 2, rituximab 100mg/m 2 and serotherapy with either rabbit ATG at 5 mg/kg (n-2) or horse ATG at 100 mg/kg (n-14). Post-transplant GVHD prophylaxis included calcineurin (CNI)-based regimen and abatacept 10mg/kg on days -1, +7, +14 and +28. All pts received a graft from a 10/10 HLA-matched sibling. Median time of follow-up for survivors was 1,1 years (range: 0.14 - 6.38). Results Primary engraftment was achieved in all evaluable patients (100%) with full donor chimerism, and the median time to neutrophil and platelet recovery was 11 (10-20) and 14 (11-20) days, respectively. One patient had aGVHD grade I, there were no incidence of grade II-IV aGVHD and TRM. Event-free and overall survival were 100%. CMV viremia was detected among two patients after a median of 40 (35-73) days after HSCT. No cases of ADV and Epstein-Barr virus (EBV) viremia and EBV disease were recorded. The median recovery of T cells on day+60 was 0,26 (0,04-0,9). Conclusion ab T cell-depleted transplantation with intermediate dose memory T cell add-back definitively prevents GVHD and provides a platform for safe HSCT from matched family donors in patients with SAA. Disclosures Maschan: Miltenyi Biotec: Speakers Bureau.
receiving bulk HPC infusion. In addition, CD4+ cell count on day 180, TRM and relapse rates were similar between the two groups. We also observed that with current mobilization techniques it was unlikely that more than 60% of normal donors would be able to collect more than 7x10E6 CD34+ cells/kg recipient weight for adult recipients.
Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is indicated for patients with relapsed or refractory acute lymphoblastic leukemia. Patients with persistence of minimal residual disease (MRD) before HCT are at increased risk of disease relapse. Multiparameter flow cytometry (MFC) is the most commonly used method of MRD detection in clinical practice. This study aimed to evaluate MRD status before HCT on outcome of ALL patients receiving allogeneic HSCT from haploidentical donors with TCRαβ+/CD19+ depletion of the graft. Materials and methods A total of 120 pts with ALL (T-lineage ALL (T-ALL)- 37, B cell precursor (BCP)-ALL-83, 45 female, 75 male, median age 8.7 years (0.5-20) underwent allogeneic HSCT between June 2013 and June 2019. All pts received Haplo graft and were in morphologic remission. Disease status at transplant was CR1 in 35 pts, CR2 in 68 pts and CR>2 in 17 pts. Transplantation in CR1 was performed according to risk stratification scheme in the current institutional ALL protocol (Moscow-Berlin 2008, 2015). MRD detection in the bone marrow prior to НSСТ was performed in all pts by MFC according the AIEOP BFM FLOW Network SOP. MRD negativity was defined as <0.001% of all bone marrow nucleated cells. Seventy-nine patients were MRD negative before HSCT, 41 were MRD-positive. The median MRD level (among MRD-positive patients) prior HCT was 0.025%. Thirty (25%) pts received treosulfan-based myeloablative preparative regimen, while TBI-based regimen was used in 90 (75%) pts. Two regimens of GvHD prophylaxis were used. Regimen 1 (n=27): thymoglobulin 5mg/kg, rituximab 200 mg/m2 and bortezomib on day +2, +5; regimen 2 (n=93): tocilizumab at 8 mg/kg on day -1 and post-transplant bortezomib, 89 pts receive additional abatacept at 10 mg/kg on day +2, +7, +14, +28. TCR αβ+/CD19+ depletion of HSCT with CliniMACS technology was implemented in all cases. The median dose of CD34+ cells was 9.3 x106/kg (range 4.3-19.8), αβ T cells - 30x103/kg (range 1-361). Median time of follow-up for survivors was 1.6 years (range: 0.13 - 4.8). Results Primary engraftment was achieved in 116 of 120 pts (3 pts died before engraftment due to septic events, one relapsed early), the median time to neutrophil and platelet recovery was 13 and 14 days, respectively. All engrafted pts had verified morphologic remission and achieved sustained complete donor chimerism by day +30, seven of them had detectable MRD (5 of them were MRD-positive before HCT). Transplant-related mortality was 5 % (95% CI: 2-11). The cumulative incidence (CI) of relapse at 1.5 years was 25%(95%CI:18-35) for the whole cohort. Among patients, who had MRD-negative remission prior to HSCT, CI of relapse was 14 % (95%CI:8-26) with median time of relapse of 0.54 months, as compared to MRD-positive cohort, with CI of relapse of 44 % (95%CI:31-63) with median time to relapse 0.29 months, p=0.0004. pEFS (event=death or relapse) was 70% (95%CI: 61-78) for the whole cohort, in MRD (-) group pEFS was 79% (95%CI: 68-88), as compared to 56%(95%CI:40-72) in the MRD(+) group, p=0.025. CI of relapse in BCP-ALL pts, who had MRD-negative remission prior to HCT was 12 %(95%CI:6-25), in MRD(+) group 49% (95%CI:33-72), p=0.0002, in T-ALL pts in MRD (-) and MRD (+) groups CI of relapse was 17 % (95%CI:6-51) and 38 % (95%CI:20-76), respectively, p=0.14. Conclusion These results suggest that MRD detection by multiparameter flow cytometry prior to HSCT is a highly significant prognostic factor in the setting of haploidentical HSCT on the platform of ab T cell depletion. We expect that further improvement of the outcome can be achieved based on the combination of current safe haplo HSCT platform and novel targeted immunotherapy approaches. Figure Disclosures Maschan: Miltenyi Biotec: Other: lecture fee.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.