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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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Uterine volume is dramatically decreased after Hematopoietic Stem Cell Transplantation during childhood regardless of the conditioning regimen
Courbiere, B., Drikes, B., Grob, A., Hamidou, Z., Saultier, P., Bertrand, Y., Gandemer, V., Plantaz, D., Plat, G., Poiree, M., et al
Fertility and sterility. 2023
Abstract
OBJECTIVE To study the impact of hematopoietic stem cell transplantation (HSCT) on uterine volume of childhood acute leukemia (AL) survivor depending on age at HSCT and the type of myeloablative conditioning (MAC) regimen. DESIGN Prospective cohort study EXPOSURE A multicentric prospective national study compared uterine volume in a cohort of childhood AL survivor adult women treated with HSCT, matched 1:1 to control women. Pelvic MRI scans included diffusion-weighted imaging sequences. Scans were centralized for a double-blinded reading by two radiologists. MAIN OUTCOME MEASURES Uterine volume, uterine body-to-cervix ratio, and apparent diffusion coefficient (ADC). RESULTS Mean age at HSCT was 9.1 + 0.3 years with a mean follow-up duration of 16.4 + 0.5 years. The cohort of 88 HSCT survivor women was composed of two sub-groups depending on the MAC regimen received: an alkylating agents-based regimen group (n=34) and a TBI-based regimen group (n=54). Among the 88 women, 77 were considered as having a "correct hormonal balance" with estrogens supplied by hormone replacement therapy (HRT) for premature ovarian insufficiency (POI), or thanks to a residual ovarian function. In the control group (n=88), the mean uterine volume was 79.7 + 3.3 mL. Uterine volume was significantly decreased in all HSCT survivor women (p < 0.0001). After alkylating agents-based regimen, uterine volume was 45.3 + 5.6 mL, corresponding to a significant volume reduction of 62.6 % [55.5 - 69.6] compared to the control group. After TBI, uterine volume was 19.6 + 1.9 mL, corresponding to a significant volume reduction of 75.3 % [70.5 - 80.2] compared to the control group. After alkylating agents-based regimen, uterine volume was dramatically decreased in POI women without HRT compared to those with a correct hormonal balance (15.2 + 2.6 Vs 49.3 + 6 mL, p < 0.05). In contrast, after TBI, uterine volume was similar in all women, with no positive effect of hormonal impregnation on uterine volume (respectively 16.3 + 2.6 Vs 20.1 + 2.2 mL). CONCLUSION Uterine volume was diminished after HSCT, regardless of the conditioning regimen. The physiopathology needs to be further investigated: specific impact of high dose of alkylating agent, impact of hormone deprivation around puberty, poor compliance to HRT, or different myometrial impact of HRT compared to endogenous ovarian estrogens?
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Low rate of nonrelapse mortality in under 4-year-olds with ALL given chemo-conditioning for HSCT: Phase III FORUM study
Bader, P., Poetschger, U., Dalle, J. H., Moser, L. M., Balduzzi, A. C., Ansari, M., Buechner, J., Güngör, T., Ifversen, M., Kriván, G., et al
Blood advances. 2023
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). In young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of two TBI-free conditioning regimens in children with ALL <4 years old. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children were transplanted and observed for ≥6 months (median follow-up: 3 years). 3-year OS was 0.63 (95% confidence interval [95% CI]: 0.52-0.72) and 0.76 (95% CI: 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (p = 0.075), respectively. 3-year EFS was 0.52 (95% CI: 0.41-0.61) and 0.51 (95% CI: 0.39-0.62), respectively (p = 0.794). Cumulative incidence of non-relapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI: 0.02-0.12) versus 0.03 (95% CI: <0.01-0.09) (p = 0.406) and 0.42 (95% CI: 0.31-0.52) versus 0.45 (95% CI: 0.34-0.56) (p = 0.920), respectively. Grade >1 acute graft-versus-host disease (GvHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% receiving Flu/Thio/Treo (p = 0.049), while grade 3-4 occurred in 10% and 9% (p = 0.813). 3-year incidence of chronic GvHD was 0.07 (95% CI: 0.03-0.13) versus 0.05 (95% CI: 0.02-0.11), respectively (p = 0.518). In conclusion, both chemo-conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure.
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Monitoring for virus-specific T-cell responses and viremia in allogeneic HSCT recipients: a survey from the EBMT Cellular Therapy & Immunobiology Working Party
Greco, R., Hoogenboom, J. D., Bonneville, E. F., Anagnostopoulos, A., Cuoghi, A., Dalle, J. H., Weissinger, E. M., Lang, P., Galaverna, F., Martino, M., et al
Bone marrow transplantation. 2023;:1-4
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Ovarian function and spontaneous pregnancy after hematopoietic stem cell transplantation for leukemia before puberty An L.E.A. cohort study
Chabut, M., Schneider, P., Courbiere, B., Saultier, P., Bertrand, Y., Tabone, M. D., Pochon, C., Ducassou, S., Paillard, C., Gandemer, V., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Ovarian function impairment and infertility are among the most frequent late effects after hematopoietic stem cell transplantation (HSCT). OBJECTIVE The aim of this study was to evaluate ovarian function, occurence of premature ovarian insufficiency (POI), and spontaneous pregnancy in a large cohort of adult survivor women who had received HSCT for leukemia before puberty. STUDY DESIGN We conducted a retrospective observational study in women from the national cohort L.E.A., the long term French follow-up program after childhood leukemia. RESULTS The median follow-up duration was 18 years [14.2-23.3] after HSCT. Among 178 women, 106 (60%) needed pubertal induction with hormone substitution treatment, whereas 72 (40%) had spontaneous menarche. After spontaneous menarche, 33 (46%) developed POI, mostly within 5 years of HSCT. Older age at time of HSCT and cryopreservation of ovarian tissue appeared as significant risk factors for POI. More than 65% of patients who underwent HSCT before the age of 4.8 years had spontaneous menarche and almost 50% didn't have POI at last evaluation whereas more than 85% with HSCT after the age of 10.9 years didn't have spontaneous menarche and needed induction of puberty with hormone replacement therapy. Twenty-two women (12%) had at least one spontaneous pregnancy, with 17 live-births, 14 miscarriages, 4 legal abortions and 2 therapeutic abortions. CONCLUSION These results add supplementary data to better counsel patients and their families on the chances of ovarian residual function and pregnancy post-HSCT as well as on the potential interest of fertility preservation.
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Long term follow-up after haematopoietic stem cell transplantation for mucopolysaccharidosis type I-H: a retrospective study of 51 patients
Gardin, A., Castelle, M., Pichard, S., Cano, A., Chabrol, B., Piarroux, J., Roubertie, A., Nadjar, Y., Guemann, A. S., Tardieu, M., et al
Bone marrow transplantation. 2022
Abstract
Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8-16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation (n = 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy.
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Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study
Mohty, M., Blaise, D., Peffault de Latour, R., Labopin, M., Bourhis, J. H., Bruno, B., Ceballos, P., Detrait, M., Gandemer, V., Huynh, A., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin <2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT.
PICO Summary
Population
Adults and children receiving defibrotide for treatment or prophylaxis of veno-occlusive disease / sinusoidal obstruction syndrome (VOD/SOS) between July 2014 to March 2020 at 53 French HCT centres (n=798)
Intervention
Defibrotide for severe/very severe VOD/SOS (n=251); Defibrotide for mild/moderate VOD/SOS (n=81)
Comparison
Defibrotide for VOD/SOS prophylaxis (n=381)
Outcome
In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated complete remission (CR) at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%.
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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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Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan
Sobkowiak-Sobierajska, A., Lindemans, C., Sykora, T., Wachowiak, J., Dalle, J. H., Bonig, H., Gennery, A., Lawitschka, A.
Frontiers in pediatrics. 2022;10:808103
Abstract
Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include: (i) the epidemiology of cGvHD; (ii) an overview of advances in our understanding cGvHD pathogenesis; (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers; (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD; and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapse/infection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individual's GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.
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HLA-matched related-donor hematopoietic stem cell transplantation is a suitable treatment in adolescents and adults with sickle cell disease: comparison of myeloablative and non-myeloablative approaches
Dhedin, N., Chevillon, F., Castelle, M., Lavoipière, V., Vasseur, L., Dalle, J. H., Joseph, L., Beckerich, F., Buchbinder, N., Coman, T., et al
American journal of hematology. 2022