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A predictive classifier of poor prognosis in transplanted patients with juvenile myelomonocytic leukemia: a study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire
Meyran, D., Arfeuille, C., Chevret, S., Neven, Q., Caye-Eude, A., Lainey, E., Petit, A., Rialland, F., Michel, G., Plantaz, D., et al
Haematologica. 2024
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Editor's Choice
Abstract
Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myeloproliferative neoplasm requiring hematopoietic stem cell transplantation (HSCT) in most cases. We retrospectively analyzed 119 JMML patients who underwent first allogeneic HSCT between 2002 and 2021. The majority (97%) carried a RAS-pathway mutation, and 62% exhibited karyotypic alterations or additional mutations in SETBP1, ASXL1, JAK3 and/or the RAS pathway. Relapse was the primary cause of death, with a 5-year cumulative incidence of 24.6% (95%CI: 17.1-32.9). Toxic deaths occurred in 12 patients, resulting in treatmentrelated mortality (TRM) of 9.0% (95%CI: 4.6-15.3). The 5-year overall (OS) and event-free survival were 73.6% (95%CI: 65.7-82.4) and 66.4% (95%CI: 58.2-75.8), respectively. Four independent adverse prognostic factors for OS were identified: age at diagnosis >2 years, time from diagnosis to HSCT >6 months, monocyte count at diagnosis >7.2x109/L, and the presence of additional genetic alterations. Based on these factors, we proposed a predictive classifier. Patients with three or more predictors (21% of the cohort) had a 5-year OS of 34.2%, whereas those with none (7%) had a 5-year OS of 100%. Our study demonstrates improved transplant outcomes compared to prior published data, which can be attributed to the synergistic impacts of a low TRM and a reduced yet still substantial relapse incidence. By integrating genetic information with clinical and hematological features, we have devised a predictive classifier. This classifier effectively identifies a subgroup of patients who are at a heightened risk of unfavorable post-transplant outcomes who would benefit novel therapeutic agents and post-transplant strategies.
PICO Summary
Population
Consecutive children diagnosed with Juvenile myelomonocytic leukemia (JMML) in centres in France (n=119)
Intervention
First allogeneic HSCT between 2002 and 2021
Comparison
None
Outcome
The majority (97%) carried a RAS-pathway mutation, and 62% exhibited karyotypic alterations or additional mutations in SETBP1, ASXL1, JAK3 and/or the RAS pathway. Relapse was the primary cause of death, with a 5-year cumulative incidence of 24.6% (95%CI: 17.1-32.9). Toxic deaths occurred in 12 patients, resulting in treatment related mortality (TRM) of 9.0% (95%CI: 4.6-15.3). The 5-year overall (OS) and event-free survival were 73.6% (95%CI: 65.7-82.4) and 66.4% (95%CI: 58.2-75.8), respectively. Four independent adverse prognostic factors for OS were identified: age at diagnosis >2 years, time from diagnosis to HSCT >6 months, monocyte count at diagnosis >7.2x109/L, and the presence of additional genetic alterations. Based on these factors, we proposed a predictive classifier. Patients with three or more predictors (21% of the cohort) had a 5-year OS of 34.2%, whereas those with none (7%) had a 5-year OS of 100%.
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Unrelated cord blood transplantation in children, adolescents, and young adults with acute leukemia or myelodysplastic syndrome: a retrospective comparative study from the French Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) between Real-World Data and previously reported results of a Randomized Clinical Trial
Teyssier, A. C., Michel, G., Jubert, C., Rialland, F., Visentin, S., Ouachée, M., Bilger, K., Gandemer, V., Beguin, Y., Marie-Cardine, A., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND We previously reported results of a French randomized clinical trial (RCT) comparing the risk of transplantation failure (including transplant-related mortality (TRM), engraftment failure, and autologous recovery) in single and double unrelated cord blood (UCB) transplantation in children and young adults with hematologic malignancies. We concluded that single-UCB transplantation with an adequate cell dose is the standard of care, leading to a 70% two-year overall survival (OS). It remains unclear, however, whether RCT participants have better outcomes than comparable patients not treated in the setting of a clinical trial. We previously reported results of a French randomized clinical trial (RCT) comparing the risk of transplantation failure (including transplant-related mortality (TRM), engraftment failure, and autologous recovery) in single and double unrelated cord blood (UCB) transplantation in children and young adults with hematologic malignancies. We concluded that single-UCB transplantation with an adequate cell dose is the standard of care, leading to a 70% two-year overall survival (OS). It remains unclear, however, whether RCT participants have better outcomes than comparable patients not treated in the setting of a clinical trial. We compared the characteristics and outcomes of RCT participants (n = 137) to a Francophone population-based registry of patients (real-world (RW) group) fulfilling the eligibility criteria used in our RCT and transplanted with one or two UCB units after a myeloablative conditioning (MAC) regimen between March 2015 (end of inclusion in the RCT) and February 2019 (n = 141). The primary endpoint was the two-year cumulative incidence (CI) of transplantation strategy failure as defined in our RCT. The two groups were comparable in terms of age, disease distribution, hematologic status at transplantation, follow-up, and HLA compatibility. Patients in the RW group were more likely to be transplanted with a single-unit UCB (87.9% versus 49.6%, p < 0.001) and to receive a radiation-free regimen (39.0% vs. 60.6%, p < 0.001). The two-year CI of transplantation strategy failure, TRM, and the two-year probability of OS were similar between the two groups, although the relapse risk was higher in the RW group (31.2% ± 7.7% vs. 20.4% ± 6.8%, p = 0.01), resulting in a significantly lower DFS (59.2% ± 8.4% vs. 69.3% ± 8.0%, p = 0.047). This difference remained statistically significant only in the group of patients with acute lymphoid leukemia (ALL) who did not receive the conditioning regimen recommended by the RCT (fludarabine 75 mg/m2, total body irradiation 12 Gy, cyclophosphamide 120 mg/kg). The results of our RCT appear to be reproducible in real-world conditions, provided that the same cord blood selection criteria and conditioning regimen are used. OBJECTIVES AND STUDY DESIGN We compared the characteristics and outcomes of RCT participants (n = 137) to a Francophone population-based registry of patients (real-world (RW) group) fulfilling the eligibility criteria used in our RCT and transplanted with one or two UCB units after a myeloablative conditioning (MAC) regimen between March 2015 (end of inclusion in the RCT) and February 2019 (n = 141). The primary endpoint was the two-year cumulative incidence (CI) of transplantation strategy failure as defined in our RCT. RESULTS The two groups were comparable in terms of age, disease distribution, hematologic status at transplantation, follow-up, and HLA compatibility. Patients in the RW group were more likely to be transplanted with a single-unit UCB (87.9% versus 49.6%, p < 0.001) and to receive a radiation-free regimen (39.0% vs. 60.6%, p < 0.001). The two-year CI of transplantation strategy failure, TRM, and the two-year probability of OS were similar between the two groups, although the relapse risk was higher in the RW group (31.2% ± 7.7% vs. 20.4% ± 6.8%, p = 0.01), resulting in a significantly lower DFS (59.2% ± 8.4% vs. 69.3% ± 8.0%, p = 0.047). This difference remained statistically significant only in the group of patients with acute lymphoid leukemia (ALL) who did not receive the conditioning regimen recommended by the RCT (fludarabine 75 mg/m2, total body irradiation 12 Gy, cyclophosphamide 120 mg/kg). CONCLUSION The results of our RCT appear to be reproducible in real-world conditions, provided that the same cord blood selection criteria and conditioning regimen are used.
PICO Summary
Population
Children, adolescents and young adults with acute leukaemia or myelodysplastic syndrome
Intervention
Participants in a randomised controlled trial (RCT) (n=137)
Comparison
Patients from a real-world cohort reported to a Francohpone regisistry, receiving onr or two cord blood units after myeloablative conditioning (RW group, n=141)
Outcome
The two groups were comparable in terms of age, disease distribution, hematologic status at transplantation, follow-up, and HLA compatibility. Patients in the RW group were more likely to be transplanted with a single-unit UCB (87.9% versus 49.6%) and to receive a radiation-free regimen (39.0% vs. 60.6%). The two-year CI of transplantation strategy failure, Transplant related mortality, and the two-year probability of overall survival were similar between the two groups, although the relapse risk was higher in the RW group (31.2% ± 7.7% vs. 20.4% ± 6.8%), resulting in a significantly lower DFS (59.2% ± 8.4% vs. 69.3% ± 8.0%). This difference remained statistically significant only in the group of patients with acute lymphoid leukemia (ALL) who did not receive the conditioning regimen recommended by the RCT (fludarabine 75 mg/m2, total body irradiation 12 Gy, cyclophosphamide 120 mg/kg).
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Reduced-toxicity myeloablative conditioning regimen using fludarabine and full doses of intravenous busulfan in pediatric patients not eligible for standard myeloablative conditioning regimens: Results of a multicenter prospective phase 2 trial
Rialland, F., Grain, A., Labopin, M., Michel, G., Gandemer, V., Paillard, C., Pochon, C., Clement, L., Brissot, E., Jubert, C., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Data regarding the safety and efficacy of reduced-toxicity conditioning regimen (RTC) prior to allogeneic stem cell transplantation (allo-SCT) to treat hematological malignancies in pediatric patients are limited. This prospective multicenter, phase 2 trial investigated a RTC regimen based on the combination of intravenous busulfan (3.2 mg/kg/d x 4 days), fludarabine (30 mg/m(2)/d x 5 days) and antithymocyte globulin (Thymoglobulin®, Genzyme; 5 mg/kg total dose) with the aim of delivering high dose myeloablation that would allow optimal disease control while minimizing toxicity, in a subgroup of children at very high risk of non-relapse mortality (NRM). The primary endpoint was NRM at 1 year after allo-SCT. A total of 48 high risk patients were included (median age, 13 years; range, 3-24). At 1 year, the cumulative incidence of recurrence/disease progression and NRM were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively. We conclude that the RTC regimen used in this prospective trial is safe, with a < 10% NRM rate noted among high-risk children and adolescents, paving the way for larger phase 3 trials incorporating novel agents pre- and post-allo-SCT.(ClinicalTrials.gov Identifier: NCT01572181).
PICO Summary
Population
Children and adolescents with haematological malignancies, but not eligible for standard myeloablative conditioning regimens, in 16 centres in France (n=48)
Intervention
30 mg/m2/d fludarabine for 5 consecutive days (day -6 to -2), 3.2 mg/kg/day IV Busulfan administered four times daily in a 2 h infusion for 4 consecutive days (day -5, -4, -3, and -2), and 2.5 mg/Kg/d antithymocyte globulin for 2 consecutive days (day -2 and -1).
Comparison
None
Outcome
At 1 year, the cumulative incidence of recurrence/disease progression and non-relapse mortality (NRM) were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively.
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Hematopoietic cell transplantation in severe combined immunodeficiency: the SCETIDE 2006-2014 European cohort
Lankester, A. C., Neven, B., Mahlaoui, N., von Asmuth, E. G., Courteille, V., Alligon, M., Albert, M. H., Serra, I. B., Bader, P., Balashov, D., et al
The Journal of allergy and clinical immunology. 2021
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Editor's Choice
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. OBJECTIVE To perform a comprehensive multicenter analysis of genotype-specific HSCT outcome including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. METHODS HSCT outcome was studied in 338 patients with genetically confirmed SCID, transplanted in 2006-2014 and registered in the SCETIDE registry. In a representative subgroup of n=152 patients data on IR and long-term clinical outcome were analyzed. RESULTS 2-years OS was similar with matched family and unrelated donors and superior to mismatched donor HSCT (p < 0.001). The 2-year EFS was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (p < 0.001). Genetic subgroups did not differ in 2-year OS (p=0.1) and EFS (p=0.073). In multivariate analysis, pretransplant infections and use of MMRD were associated with less favorable OS and EFS. With a median follow-up of 6.2 years [range 2.0-11.8 years], 73/152 IR cohort patients were alive and well without immunoglobulin dependency. IL2R?-JAK3-IL7R deficient SCID, myeloablative conditioning, matched donor HSCT, and naïve CD4 T lymphocytes > 0.5x10e3/µL at +1-year were identified as independent predictors of favorable clinical and immunological outcome. CONCLUSION Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long term outcome, treatment strategies should aim for optimal naïve CD4 T lymphocyte regeneration.
PICO Summary
Population
Patients with severe combined immunodeficiency (SCID) transplanted in the years 2006-2014 and reported to the SCETIDE registry (n=338) Long-term outcomes were assessed in a representative subgroup (n=152)
Intervention
Assessment of the impact of donor source and SCID genetic diagnosis on transplant outcomes
Comparison
None
Outcome
2-years OS was similar with matched family and unrelated donors and superior to mismatched donor HSCT. The 2-year EFS was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT. Genetic subgroups did not differ in 2-year OS and EFS. In multivariate analysis, pretransplant infections and use of MMRD were associated with less favorable OS and EFS. With a median follow-up of 6.2 years [range 2.0-11.8 years], 73/152 IR cohort patients were alive and well without immunoglobulin dependency IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor–deficient SCID, myeloablative conditioning, matched donor HSCT, and naïve CD4 T lymphocytes > 0.5x10e3/µL at +1-year were identified as independent predictors of favorable clinical and immunological outcome.
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Myeloablative unrelated cord blood transplantation in adolescents and young adults with acute leukemia
Hayashi, H., Volt, F., Sanz, J., Petersen, E., Dhedin, N., Hough, R., Milpied, N., Angelucci, E., Yakoub-Agha, I., Michallet, M., 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
Outcomes for adolescents and young adults (AYA) with leukemia differ from other age groups but are still underrepresented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYA with acute leukemia reported to Eurocord/EBMT. Patients (n=504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15-25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. Primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIF) of non-relapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute GVHD grade II-IV at day-100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (HR 2.74, p <0.001) and more recent UCBT (HR 1.43, p=0.01) were associated with increased OS and a similar effect of these factors was observed on LFS. Contrastingly, the use of ATG had a negative effect in LFS. The risk of acute GVHD grade II-IV increased with the use of double UCBT (HR 1.65, p =0.02) and decreased with more recent transplantation period (HR 0.65, p=0.02) and ATG use (HR 0.55, p =0.01). Outcomes of AYA UCBT improved in more recent years becoming comparable to pediatric results. Demonstrating the feasibility of UCBT in AYA facilitates stem cell source selection and provides the basis for future prospective studies.
PICO Summary
Population
Adolescents and young adults with acute leukaemia (n=504)
Intervention
Unrelated cord blood transplantation after myeloablative conditioning
Comparison
None
Outcome
Three-year overall survival (OS) was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIF) of non-relapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute GVHD grade II-IV at day-100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT and more recent UCBT were associated with increased OS and a similar effect of these factors was observed on LFS. Contrastingly, the use of ATG had a negative effect in LFS. The risk of acute GVHD grade II-IV increased with the use of double UCBT and decreased with more recent transplantation period and ATG use.