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Hematopoietic stem cell transplantation for pediatric patients with non-anaplastic peripheral T-cell lymphoma. An EBMT pediatric diseases working party study
Moser, O., Ngoya, M., Galimard, J. E., Dalissier, A., Dalle, J. H., Kalwak, K., Wössmann, W., Burkhardt, B., Bierings, M., Gonzalez-Vicent, M., et al
Bone marrow transplantation. 2024
Abstract
Peripheral T-cell lymphomas (PTCL) other than anaplastic large-cell lymphoma are rare in children, and the role of hematopoietic stem cell transplantation (HSCT) has not been clarified yet. In a retrospective analysis of registry-data of the European Society for Blood and Marrow Transplantation we analyzed 55 patients aged < 18 years who received allogeneic (N = 46) or autologous (N = 9) HSCT for PTCL. Median age at HSCT was 13.9 years; 33 patients (60%) were in first remission, and 6 (19%) in progression at HSCT. Conditioning was myeloablative in 87% of the allogeneic HSCTs and in 27 (58.7%) based on total body irradiation. After allogeneic HSCT the 5-year overall- and progression-free survival was 58.9% (95% CI 42.7-71.9) and 52.6% (95% CI 36.8-66.1), respectively. 5-year relapse incidence was 27.6% (95% CI 15.1-41.6), the non-relapse mortality rate was 19.8% (95% CI 9.7-32.6). Five of the six patients with progression at HSCT died. Seven of nine patients after autologous HSCT were alive and disease-free at last follow-up. Our data suggest a role of allogeneic HSCT in consolidation-treatment of patients with high-risk disease, who reach at least partial remission after primary- or relapse-therapy, whereas patients with therapy-refractory or progressive disease prior to transplantation do not profit from HSCT.
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Ovarian tissue cryopreservation for fertility preservation before hematopoietic stem cell transplantation in patients with sickle cell disease: safety, ovarian function follow-up, and results of ovarian tissue transplantation
Missontsa, M. M., Bernaudin, F., Fortin, A., Dhédin, N., Pondarré, C., Yakouben, K., Neven, B., Castelle, M., Cavazzana, M., Lezeau, H., et al
Journal of assisted reproduction and genetics. 2024
Abstract
PURPOSE To describe the experience of performing ovarian tissue cryopreservation (OTC) before hematopoietic stem cell transplantation (HSCT), among girls/women with severe sickle cell disease (SCD)(SS or S/β(0)-thalassemia) who are, besides the usual surgical risk, at risk of SCD-related complications during the fertility preservation procedure for improving their counseling and management. METHODS This retrospective study included 75 patients (girls/women) with SCD who have had OTC before myeloablative conditioning regimen (MAC) for HSCT. Characteristics of patients and data on OTC, ovarian status follow-up, and results of ovarian tissue transplantation (OTT) were collected in medical records. RESULTS At OTC, the median (IQR 25-75; range) age of the patients was 9.6 (6.9-14.1; 3.6-28.3) years, 56/75 were prepubertal, and no SCD or surgery-related complications occurred. The median follow-up post-HSCT was > 9 years. At the last follow-up, among prepubertal patients at HSCT, 26/56 were ≥ 15 years old and presented with a premature ovarian insufficiency (POI), except 2, including the patient who had received an OTT to induce puberty. Eight were 13-15 years old and presented for POI. The remaining 22 patients were under 13. Among the 19 patients who were menarche at HSCT, 2 died 6 months post-HSCT and we do not have ovarian function follow-up for the other 2 patients. All the remaining patients (n = 15) had POI. Five patients had OTT. All had a return of ovarian function. One patient gave birth to a healthy baby. CONCLUSION OTC is a safe fertility preservation technique and could be offered before MAC independent of the patient's age.
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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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Cytogenetic abnormalities predict survival after allogeneic hematopoietic stem cell transplantation for pediatric acute myeloid leukemia: a PDWP/EBMT study
Sharma, A., Galimard, J. E., Pryce, A., Bhoopalan, S. V., Dalissier, A., Dalle, J. H., Locatelli, F., Jubert, C., Mirci-Danicar, O., Kitra-Roussou, V., et al
Bone marrow transplantation. 2024
Abstract
Poor-risk (PR) cytogenetic/molecular abnormalities generally direct pediatric patients with acute myeloid leukemia (AML) to allogeneic hematopoietic stem cell transplant (HSCT). We assessed the predictive value of cytogenetic risk classification at diagnosis with respect to post-HSCT outcomes in pediatric patients. Patients younger than 18 years at the time of their first allogeneic HSCT for AML in CR1 between 2005 and 2022 who were reported to the European Society for Blood and Marrow Transplantation registry were subgrouped into four categories. Of the 845 pediatric patients included in this study, 36% had an 11q23 abnormality, 24% had monosomy 7/del7q or monosomy 5/del5q, 24% had a complex or monosomal karyotype, and 16% had other PR cytogenetic abnormalities. In a multivariable model, 11q23 (hazard ratio [HR] = 0.66, P = 0.03) and other PR cytogenetic abnormalities (HR = 0.55, P = 0.02) were associated with significantly better overall survival when compared with monosomy 7/del7q or monosomy 5/del5q. Patients with other PR cytogenetic abnormalities had a lower risk of disease relapse after HSCT (HR = 0.49, P = 0.01) and, hence, better leukemia-free survival (HR = 0.55, P = 0.01). Therefore, we conclude that PR cytogenetic abnormalities at diagnosis predict overall survival after HSCT for AML in pediatric patients.
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Efficacy of haematopoietic stem cell boost as a rescue for poor graft function after haematopoietic stem cell transplantation: A multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)
Gaffet, M., Wiedemann, A., Dalle, J. H., Bilger, K., Forcade, E., Robin, M., Cornillon, J., Labussière-Wallet, H., Ceballos, P., Bulabois, C. E., et al
British journal of haematology. 2023;201(6):1153-1158
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Editor's Choice
Abstract
Haematopoietic stem cell reinjection may be a curative option for poor graft function after haematopoietic stem cell transplantation; however, literature supporting its use remains limited. We conducted a multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, including 55 patients. We demonstrated response rates of nearly 40% and two-year survival of more than 60% in the context of an otherwise deadly complication and we observed that the timing of injection and the degree of cytopenia are strongly associated with outcomes. This study shows the feasibility of the procedure informing on its epidemiology, outcomes and prognostic factors, setting the stage for future guidelines.
PICO Summary
Population
Children and adults with poor graft function following allogeneic transplant, from 12 centres in France (n=55)
Intervention
Haematopoietic stem cell boost injection
Comparison
None
Outcome
Response rate was nearly 40% and two year survival was more than 60%
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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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Recent results of hematopoietic stem cell transplantation for thalassemia with busulfan-based conditioning regimen in France: improved thalassemia free survival despite frequent mixed chimerism. A retrospective study from the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)
Rossi, M., Szepetowski, S., Yakouben, K., Paillard, C., Sirvent, A., Castelle, M., Pegon, C., Piguet, C., Grain, A., Angoso, M., et al
Bone marrow transplantation. 2023
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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.