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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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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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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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Impact of graft function on health status and quality of life in 112 very long-term survivors who received an HSCT for Inborn Errors of Immunity, a prospective study of the CEREDIH
Petit, A., Neven, B., Min, V., Mahlaoui, N., Moshous, D., Castelle, M., Allouche, M., Stérin, A., Visentin, S., Saultier, P., et al
Transplantation and cellular therapy. 2023
Abstract
Overall survival rate after Hematopoietic stem cell transplantation (HSCT) for Inborn Errors of Immunity (IEI) has improved considerably and its indications have broadened. As a consequence, addressing the issue of long-term health-related quality of life (HRQoL) has become crucial. Our study focuses on the health and HRQoL of post-HSCT survivors. We conducted a multicenter prospective follow-up study enrolling IEI patients transplanted in childhood, before 2009. Self-reported data from the French Childhood Immune Deficiency Long-term Cohort (F-CILC) and 36-item Short Form (SF-36) questionnaires were compiled. 112 survivors were included with a median duration period from HSCT of 15 years (range: 5-37), of whom 55 were transplanted for a combined immunodeficiency. We show that in patients evaluated at least 5 years after HSCT, 55% are still affected by a poor or very poor health status. Poor and very poor health status correlated with an abnormal graft function defined as host or mixed chimerism and/or abnormal CD3+ count and/or diagnosis of chronic GVHD (Poor health: OR 2,6 CI 95%: 1,1-5,9 p:0,028; Very poor health: OR 3,6 CI 95%: 1,1-13, p:0,049). Poor health directly linked to a poorer HRQoL. Significant improvements in graft procedures have translated in better survival rates, but we show here that about half of the transplanted patients remain affected by an altered health status with a correlation to both abnormal graft function and impaired HRQoL. Additional studies are needed to confirm the impact of those improvements on long-term health status and HRQoL.
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Hematopoietic stem cell transplantation for acute lymphoblastic leukemia: why do adolescents and young adults outcomes differ from those of children? A retrospective study on behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)
Grain, A., Rialland-Battisti, F., Chevallier, P., Blin, N., Dalle, J. H., Michel, G., Dhédin, N., Peffault de Latour, R., Pochon, C., Yakoub-Agha, I., et al
Journal of cancer research and clinical oncology. 2022
Abstract
PURPOSE In the acute lymphoblastic leukemia (ALL) landscape, adolescents and young adults (AYA) often present high-risk diseases and increased chemotherapy-related toxicity. Studies analyzing the outcomes of AYA after hematopoietic stem cell transplantation (HSCT) are scarce. Our study aimed to compare the outcomes of children and AYA with ALL after HSCT and to determine the factors influencing potential differences. METHOD 891 patients, from the SFGM-TC registry, aged between 1 and 25 years who received HSCT between 2005 and 2012 were included. The outcomes of AYA were compared to the ones of their younger counterparts. RESULTS Five-year OS and GRFS were lower in AYA: 53.1% versus 64% and 36% versus 47% (p = 0.0012 and p = 0.007, respectively). WhileCIR was similar in both groups, 5 year-treatment related mortality was higher in AYA: 19% versus 13% (p = 0.04). The lower GRFS in AYA was mainly explained by a higher chronic graft versus host disease (cGvHD) incidence: 32% versus 19% (p < 0.001). Use of peripheral blood stem cells and use of anti-thymoglobulin appeared to be the main factors impacting cGvHD occurrence in AYA. CONCLUSION AYA have worse outcomes than children after HSCT for ALL because of a greater risk of TRM due to cGvHD. HSCT practices should be questioned in this population.
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Improved outcome in children compared to adolescents and young adults after allogeneic hematopoietic stem cell transplant for acute myeloid leukemia: a retrospective study from the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC)
Pochon, C., Detrait, M., Dalle, J. H., Michel, G., Dhédin, N., Chalandon, Y., Brissot, E., Forcade, E., Sirvent, A., Izzadifar-Legrand, F., et al
Journal of cancer research and clinical oncology. 2021
Abstract
BACKGROUND There are currently few data on the outcome of acute myeloid leukemia (AML) in adolescents after allogeneic HSCT. The aim of this study is to describe the outcome and its specific risk factors for children, adolescents and young adults after a first allogeneic HSCT for AML. METHODS In this retrospective study, we compared the outcome of AML patients receiving a first allogeneic HSCT between 2005 and 2017 according to their age at transplantation's time: children (15 years, n?=?564), adolescent and post-adolescent (APA) patients (15-25 years, n?=?647) and young adults (26-40 years; n?=?1434). RESULTS With a median follow-up of 4.37 years (min-max 0.18-14.73 years), the probability of 2-year overall survival (OS) was 71.4% in children, 61.1% in APA patients and 62.9% in young adults (p?=?0.0009 for intergroup difference). Both relapse and non-relapse mortality (NRM) Cumulative Incidence (CI) estimated at 2 years were different between the age groups (30.8% for children, 35.2% for APA patients and 29.4% for young adults-p?=?0.0254, and 7.0% for children, 10.6% for APA patients and 14.2% for young adults, p?0.0001; respectively). Whilst there was no difference between the three groups for grade I to IV acute GVHD CI at 3 months, the chronic GVHD CI at 2 years was higher in APA patients and young adults (31.4% and 36.4%, respectively) in comparison to the children (17.5%) (p?0.0001). In multivariable analysis, factors associated with death were AML cytogenetics (HR1.73 [1.29-2.32] for intermediate risk 1, HR 1.50 [1.13-2.01] for intermediate risk 2, HR 2.22 [1.70-2.89] for high cytogenetics risk compared to low risk), use of TBI?=?8 Grays (HR 1.33 [1.09-1.61]), disease status at transplant (HR 1.40 [1.10-1.78] for second Complete Remission (CR), HR 2.26 [1.02-4.98] for third CR and HR 3.07 [2.44-3.85] for active disease, compared to first CR), graft source (HR 1.26 [1.05-1.50] for Peripheral Blood Stem Cells compared to Bone Marrow) and donor age (HR 1.01 (1-1.02] by increase of 1 year). CONCLUSION Age is an independent risk factor for NRM and extensive chronic GVHD. This study suggests that APA patients with AML could be beneficially treated with a chemotherapy-based MAC regimen and bone marrow as a stem cells source.
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Innate lymphoid cell recovery and occurrence of GvHD after hematopoietic stem cell transplantation
Piperoglou, C., Larid, G., Vallentin, B., Balligand, L., Crinier, A., Banzet, N., Farnarier, C., Gomez-Massa, E., Adalia, A. C., Michel, G., et al
Journal of leukocyte biology. 2021
Abstract
Lymphocytes are essential for microbial immunity, tumor surveillance, and tissue homeostasis. However, the in vivo development and function of helper-like innate lymphoid cells (ILCs) in humans remain much less well understood than those of T, B, and NK cells. We monitored hematopoietic stem cell transplantation (HSCT) to determine the kinetics of ILC development in both children and adults. It was found that, unlike NK cells, helper-like ILCs recovered slowly, mirroring the pattern observed for T cells, with normalization achieved at 1 year. The type of graft and the proportion of CD34(+) cells in the graft did not significantly affect ILC reconstitution. As HSCT is often complicated by acute or chronic graft-versus-host disease (GVHD), the potential role of ILC subsets in maintaining tissue integrity in these conditions was also analyzed. It was found that GVHD was associated with lower levels of activated and gut-homing NKp44(+) ILCP, consistent with a non-redundant role of this ILC subset in preventing this life-threatening disorder in lymphopenic conditions.
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Low Body Mass Index Is Associated with Increased Risk of Acute GVHD after Umbilical Cord Blood Transplantation in Children and Young Adults with Acute Leukemia: A Study on Behalf of Eurocord and the EBMT Pediatric Disease Working Party
Paviglianiti, A., Dalle, J. H., Ayas, M., Boelens, J. J., Volt, F., Iori, A. P., de Souza, M. P., Diaz, M. A., Michel, G., Locatelli, F., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018;24(4):799-805
Abstract
Body mass index (BMI) may influence outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of BMI on survival in children undergoing HSCT is not well defined, with conflicting results being reported on this issue. We analyzed 855 patients age 2 to 20 years with diagnosis of acute leukemia who underwent umbilical cord blood transplantation (UCBT) from 1990 to 2015. Patients were classified according to BMI as normal (fifth to 85th percentile), underweight (less than fifth percentile), overweight (85th to 95th percentile), and obese (>95th percentile) using growth charts for age and sex. All patients received single-unit UCBT after a myeloablative conditioning regimen. Diagnosis was acute lymphoblastic leukemia in 68% of the patients. Sixty-one percent of patients (n = 523) were in the normal BMI category, 11% (n = 96) were underweight, 16% (n = 137) overweight, and 12% (n = 99) obese. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was 35% (32% to 38%). According to pretransplantation BMI, aGVHD was 46% (33% to 59%) for underweight, 34% (31% to 42%) for normal, 36% (18% to 38%) for overweight, and 27% (15% to 37%) for obese (P = .04). In multivariate analysis, a BMI less than the fifth percentile was associated with higher incidence of acute grade II to IV GVHD compared with normal-BMI patients (hazard ratio, 1.61; 95% confidence interval, 1.15 to 2.26; P = .006). Our results show that being underweight at the time of transplantation is associated with an increased risk of aGVHD, highlighting the importance of nutritional status before UCBT.
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An Integrative Scoring System for Survival Prediction Following Umbilical Cord Blood Transplantation in Acute Leukemia
Shouval, R., Ruggeri, A., Labopin, M., Mohty, M., Sanz, G., Michel, G., Kuball, J., Chevallier, P., Al-Seraihy, A., Milpied, N. J., et al
Clinical Cancer Research. 2017;23(21):6478-6486
Abstract
Purpose: Survival of acute leukemia (AL) patients following umbilical cord blood transplantation (UCBT) is dependent on an array of individual features. Integrative models for risk assessment are lacking. We sought to develop a scoring system for prediction of overall survival (OS) and leukemia-free survival (LFS) at 2 years following UCBT in AL patients.Experimental Design: The study cohort included 3,140 pediatric and adult AL UCBT patients from the European Society of Blood and Marrow Transplantation and Eurocord registries. Patients received single or double cord blood units. The dataset was geographically split into a derivation (n = 2,362, 65%) and validation set (n = 778, 35%). Top predictors of OS were identified using the Random Survival Forest algorithm and introduced into a Cox regression model, which served for the construction of the UCBT risk score.Results: The score includes nine variables: disease status, diagnosis, cell dose, age, center experience, cytomegalovirus serostatus, degree of HLA mismatch, previous autograft, and anti-thymocyte globulin administration. Over the validation set an increasing score was associated with decreasing probabilities for 2 years OS and LFS, ranging from 70.21% [68.89-70.71, 95% confidence interval (CI)] and 64.76% (64.33-65.86, 95% CI) to 14.78% (10.91-17.41) and 18.11% (14.40-22.30), respectively. It stratified patients into six distinct risk groups. The score's discrimination (AUC) over multiple imputations of the validation set was 68.76 (68.19-69.04, range) and 65.78 (65.20-66.28) for 2 years OS and LFS, respectively.Conclusions: The UCBT score is a simple tool for risk stratification of AL patients undergoing UCBT. Widespread application of the score will require further independent validation. Clin Cancer Res; 23(21); 6478-86. ©2017 AACR.Copyright ©2017 American Association for Cancer Research.
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Impact of CTLA4 genotype and other immune response gene polymorphisms on outcomes after single umbilical cord blood transplantation
Cunha, R., Zago, M. A., Querol, S., Volt, F., Ruggeri, A., Sanz, G., Pouthier, F., Kogler, G., Vicario, J. L., Bergamaschi, P., et al
Blood. 2017;129(4):525-532
Abstract
We evaluated the impact of recipient and cord blood unit (CBU) genetic polymorphisms related to immune response on outcomes after unrelated cord blood transplantations (CBTs). Pretransplant DNA samples from 696 CBUs with malignant diseases were genotyped for NLRP1, NLRP2, NLRP3, TIRAP/Mal, IL10, REL, TNFRSF1B, and CTLA4. HLA compatibility was 6 of 6 in 10%, 5 of 6 in 39%, and >=4 of 6 in 51% of transplants. Myeloablative conditioning was used in 80%, and in vivo T-cell depletion in 81%, of cases. The median number of total nucleated cells infused was 3.4 x 107/kg. In multivariable analysis, patients receiving CBUs with GG-CTLA4 genotype had poorer neutrophil recovery (hazard ratio [HR], 1.33; P = .02), increased nonrelapse mortality (NRM) (HR, 1.50; P < .01), and inferior disease-free survival (HR, 1.41; P = .02). We performed the same analysis in a more homogeneous subset of cohort 1 (cohort 2, n = 305) of patients who received transplants for acute leukemia, all given a myeloablative conditioning regimen, and with available allele HLA typing (HLA-A, -B, -C, and -DRB1). In this more homogeneous but smaller cohort, we were able to demonstrate that GG-CTLA4-CBU was associated with increased NRM (HR, 1.85; P = .01). Use of GG-CTLA4-CBU was associated with higher mortality after CBT, which may be a useful criterion for CBU selection, when multiple CBUs are available.