Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of ...the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG). Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells <5%) as events, the 5-year event-free survival was 97.9% (95% confidence interval: 95.5-100%), confirming, since the year 2000, an at least 95% chance of cure. In the overall cohort (n=234, median follow up 7.9 years), event-free survival was not associated with age, but chronic-graft-
-host disease (cGvHD) was independently associated with recipient's age >15 years (hazard ratio=4.37;
=0.002) and lower (5-15
20 mg/kg) ATG dose (hazard ratio=4.55;
=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells <50%. Myeloablative transplantation with matched-sibling donor currently has a higher event-free survival (98%) in patients under 30 years of age than that reported for non-myeloablative conditioning (88%). Nevertheless, the risk of cGvHD in older patients and the need to preserve fertility might be indications for a non-myeloablative conditioning.
This multicenter prospective phase 2 trial analyzed disease-free survival (DFS) in myelofibrosis patients receiving ruxolitinib for 6 months before transplantation. Seventy-six patients were ...recruited. Age-adjusted dynamic international prognostic scoring system was intermediate-1, intermediate-2, and high in 27 (36%), 31 (41%), and 18 (24%) patients. All patients received ruxolitinib from inclusion to conditioning regimen (fludarabine-melphalan) or to progression. A donor was found in 64 patients: 18 HLA-matched sibling donor (MSD), 32 HLA-matched unrelated (UD10/10), and 14 HLA mismatched unrelated donor (UD9/10. Among 64 patients with a donor, 20 (31%) achieved a partial response before transplantation and 59 (92%) could be transplanted after ruxolitinib therapy (18/18 MSD, 30/21 UD10/10, 11/34 UD9/10), of whom 19 (32%) were splenectomized. Overall survival from inclusion was 68% at 12 months. One-year DFS after transplantation was 55%: 83%, 40%, and 34% after MSD, UD10/10 or UD9/10, respectively. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) was 66% and non-relapse-mortality was 42% at 12 months. Short course of ruxolitinib before transplantation is followed by a high rate of transplantation. With the platform used in this protocol, outcome was much better in patients transplanted with HLA-matched sibling donor as compared to unrelated donor.
The impact of cytogenetic abnormalities in multiple myeloma after allogeneic stem cell transplantation has not been clearly defined. This study examines whether allogeneic stem cell transplantation ...could be of benefit for myeloma patients with high-risk cytogenetic abnormalities.
This is a retrospective multicenter analysis of the registry of the Société Française de Greffe de Moelle et de Thérapie Cellulaire, including 143 myeloma patients transplanted between 1999 and 2008.
The incidences of cytogenetic abnormalities were 59% for del(13q), 25% for t(4;14), 25% for del(17p) and 4% for t(14;16). When comparing the population carrying an abnormality to that without the same abnormality, no significant difference was found in progression-free survival, overall survival or progression rate. Patients were grouped according to the presence of any of the poor prognosis cytogenetic abnormalities t(4;14), del(17p) or t(14;16) (n=53) or their absence (n=32). No difference in outcomes was observed between these two groups: the 3-year progression-free survival, overall survival and progression rates were 30% versus 17% (P=0.9), 45% versus 39% (P=0.8) and 53% versus 75% (P=0.9), respectively.
These data indicate that allogeneic stem cell transplantation could potentially be of benefit to high-risk myeloma patients.
Abstract
The genetic diversity of the human leukocyte antigen (HLA) system was shaped by evolutionary constraints exerted by environmental factors. Analyzing HLA diversity may allow understanding of ...the underlying pathways and offer useful tools in transplant setting. The aim of this study was to investigate the HLA haplotype diversity in patients with sickle cell disease (SCD,
N
= 282) or β‐thalassemia (β‐Thal,
N
= 60), who received hematopoietic cell transplantation (HCT) reported to Eurocord and the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM‐TC). We identified 405 different HLA‐A‐B‐DRB1 haplotypes in SCD and 108 in β‐Thal patients. Using data from African and European populations of the “1000 Genomes Project” for comparison with SCD and β‐Thal, respectively, we found that the haplotypes HLA‐A*30‐B*14‐DRB1*15 (OR 7.87, 95% CI: 1.66–37.3,
p
b
= 0.035), HLA‐A*23‐B*08 (OR 6.59, 95% CI: 1.8–24.13,
p
b
= 0.023), and HLA‐B*14‐DRB1*15 (OR 10.74, 95% CI: 3.66–31.57,
p
b
= 0.000) were associated with SCD, and the partial haplotypes HLA‐A*30‐B*13 and HLA‐A*68‐B*53 were associated with β‐Thal (OR 4.810, 95% CI: 1.55–14.91,
p
b
= 0.033, and OR 17.52, 95% CI: 2.81–184.95,
p
b
= 0.011). Our results confirm the extreme HLA genetic diversity in SCD patients likely due to their African ancestry. This diversity seems less accentuated in patients with β‐Thal. Our findings emphasize the need to expand inclusion of donors of African descent in HCT donor registries and cord blood banks.
To analyze the impact of pre- and posttransplantation factors on the outcome of allogeneic transplantation after nonmyeloablative conditioning regimens.
Ninety-two allogeneic transplantations after ...nonmyeloablative preparative regimens were reported to the Société Française de Greffe de Moelle Registry registry. Initial diagnoses were lymphoid diseases (n = 22), myeloma (n = 14), acute leukemia and myelodysplasia (n = 41), chronic myelogenous leukemia (n = 12), and solid tumors (n = 3). Forty-six patients had previously received a transplant, and 49 had progressive disease before transplantation. Three types of conditioning regimens were used with fludarabine or antithymocyte globulins. Eighty-nine patients underwent transplantation, 60 from peripheral-blood progenitor cells. Eighty-six patients received graft-versus-host disease (GHVD) prophylaxis for a median duration of 53 days.
Seventy-nine patients engrafted, with 40 complete and 21 mixed chimerisms. The acute GHVD rate at 3 months was 50% +/- 11%. Fifty-two patients achieved complete remission and 12, partial remission. At 18 months after transplantation, the overall survival (OS) and the transplant-related mortality (TRM) were 32% +/- 12% and 38% +/- 14%, respectively. Initial diagnosis and disease status before transplantation significantly influenced survival. Age and GHVD prophylaxis type significantly influenced TRM. We also showed an impact of GHVD prophylaxis duration on OS and TRM. In multivariate analysis, three factors remained of prognostic value on OS: initial diagnosis, disease status at transplantation, and GHVD prophylaxis duration.
This series shows encouraging results from nonmyeloablative conditioning regimens before allotransplantation and demonstrates the impact of some pre- and posttransplantation factors on outcome after transplantation.
Introduction: Hematopoietic stem cell transplantation (HSCT) remains a key treatment of high-risk childhood leukemia despite a wide range of long-term complications. Chronic graft-versus-host disease ...(cGvHD) is a severe complication of HSCT characterized by the immune response of transplanted cells against the recipient's organs. Adults undergoing HSCT are particularly susceptible to experiencing cGvHD. This complication is generally considered to be much less common when HSCT is performed during childhood and adolescence, though very limited long-term data is available. The present study from the LEA program aims to provide a better understanding of cGvHD and its long-term impact in long-term childhood leukemia survivors.
Methods: LEA is a long-term follow-up program involving all childhood acute leukemia survivors treated in the French participating centers since 1980 (clinicaltrials.gov identifier: NCT01756599). The patients eligible to the present study were all patients included in the LEA cohort treated with HSCT. The primary objective of this cross-sectional study was to provide a long-term and comprehensive cGvHD evaluation in childhood leukemia survivors. Secondary objectives included identifying risk factors for cGvHD, assessing the impact of the disease on quality of life (QoL), and evaluating its evolution over time. The long-term cGvHD data were generated during an in-person dedicated follow-up visit by a clinician using 1) a dedicated questionnaire, and 2) the eGVHD application (UZ Leuven, Belgium) for standardizing the evaluation. QoL was evaluated using the SF36 questionnaire.
Results: The study included a cohort of 446 patients treated for acute lymphoblastic leukemia (59%), acute myeloid leukemia (34%), or another hematological malignancy (7%). The age at HSCT was 8.9 ±0.3 years (mean ±standard error of mean). The dedicated long-term evaluation of cGvHD was performed 8.8 ±0.3 years after HSCT. The stem cell source was matched sibling donor (32%), mismatched related donor (9%), unrelated donor (37%), and cord blood (22%). HSCT was performed in first complete remission in 47% of patients. Myeloablative conditioning and total body irradiation were administered to 91% and 56% of patients, respectively. Anti-thymocyte globulin and ciclosporin were given to 49% and 94% of patients, respectively. At the time of the study, most patients never experienced (n=324, 73%) or recovered (n=28, 6%) from cGvHD. However, a significant proportion of patients (n=94, 21%) suffered long-term cGvHD of variable severity (45% mild, 33% moderate, and 22% severe) (Figure 1). Patients mostly had isolated organ defects (most frequently skin, eyes, and mouth defects). Multiple organs defects were also reported in some patients without recurrent patterns. At the time of cGvHD evaluation, patients suffering cGvHD mostly remained untreated (83%, n=78). Systemic treatment (ruxolitinib, ciclosporine, ibrutinib, and sirolimus), as well as local treatment were used in 11% and 5% of patients, respectively. cGvHD was significantly associated with several other long-term complications (thyroid function defects, cataract, lung function defects, osteonecrosis, diabetes). In a multivariate analysis (Table 1), age at HSCT was significantly associated with long-term cGvHD (odds ratio 1.06 for each additional year, 95% confidence interval 1.01-1.1, p=0.01). Sex, type of leukemia, time from HSCT, stem cell source, relapse, number of HSCT and total body irradiation were not significantly associated with long-term cGvHD risk. Long-term cGvHD had a marked detrimental effect on QoL, even after adjusting to the total number of other long-term complications. The physical and psychic SF36 adjusted composite scores in patients with versus without cGvHD were 50 ±1.5 versus 55 ±0.7 (p=0.01) and 38 ±1.9 versus 43 ±1.0 (p=0.01), respectively.
Conclusion: This study shows that cGvHD is a frequent and severe complication in long-term survivors of childhood leukemia treated with HSCT. Higher age at HSCT is the main risk factor for long-term cGVHD in this population. Long-term cGvHD significantly and independently jeopardizes the survivors' QoL. This complication is probably underrecognized and undertreated. There is a great need for a systematic and standardized cGvHD evaluation in this population.
In this SFGM-TC registry study, we report the results after stem cell transplantation (HSCT) in 305 myelofibrosis patients, in order to determine potential risk factors associated with outcomes, ...especially regarding previous treatment with ruxolitinib. A total of 102 patients were transplanted from an HLA-matched-sibling donor (MSD), and 143 patients received ruxolitinib. In contrast with previous studies, our results showed significantly worse outcomes for ruxolitinib patients regarding overall survival (OS) and non-relapse mortality (NRM), especially in the context of unrelated donors (URD). When exploring reasons for potential confounders regarding the ruxolitinib effect, an interaction between the type of donor and the use of ATG was found, therefore subsequent analyses were performed separately for each type of donor. Multivariable analyses did not confirm a significant negative impact of ruxolitinib in transplantation outcomes. In the setting of URD, only age and Fludarabine-Melphalan (FM) conditioning were associated with increased NRM. For MSD, only Karnoksfy <70% was associated with reduced OS. However, a propensity score analysis showed that ruxolitinib had a negative impact on OS but only in non-responding patients, consistent with previous data. To conclude, with all the precautions due to confounders and bias, ruxolitinib itself does not appear to increase mortality after HSCT.
Tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™) are the first representatives of a new class of gene therapies produced by ex-vivo genetic modification of human autologous T ...lymphocytes, now using viral vectors. In 2020, there are three independent CAR-T cell databases in France: DESCAR-T (database supported by LYSARC, GRAALL and the IFM), ProMISe (EBMT database) and ATIH (database of the Agence Technique de l'Information sur l'Hospitalisation). Only the EBMT database is common to France and the French-speaking countries that are members of the SFGM-TC. In 2019, a workshop was held to draft a manual for entering data specific to CAR-T cells in the EBMT ProMISe database. As a follow-up to this article, we present a medical report template containing all the data required to enter the data of patients treated with CAR-T in the EBMT registry, in the CRF of the DESCAR-T registry and in the ATIH registry. This document aims to improve the completeness and quality of the data while optimizing data entry time.
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy in patients with primary or secondary myelofibrosis. Ruxolitinib, a JAK-inhibitor, has been ...approved in myelofibrosis patients and is effective to alleviate symptoms of the disease in a substantial proportion of patients. In a French phase 2 study, the use of ruxolitinib as a bridge to HSCT was followed by a high transplantation rate, with one third of patients presenting clinical improvement before HSCT (partial response or spleen size reduction) (BMT 2021, Robin et al). The aim of the current study is to compare post-transplantation outcomes between patients who received ruxolitinib before HSCT and those who did not.
Methods: This retrospective study includes patients with primary or secondary myelofibrosis registered in the SFGM-TC registry including patients from France, Belgium and Switzerland. Patients who received HSCT between July 2010 and December 2019 with available information regarding ruxolitinib treatment were included. The impact of ruxolitinib was analyzed by multivariable Cox regression and a propensity score.
Results: 305 patients could be included, of whom 143 received ruxolitinib prior to HSCT (RuxoG). All patient characteristics are given in RuxoG followed by no ruxolitinib group (noRuxo). The diagnosis before HSCT was primary myelofibrosis (83% vs 75%), secondary myelofibrosis (13% vs 19%) or transformed into AML (4% vs 6%). Karnofsky score at transplant was < 70% in 9% and 11%. In RuxoG. median age was older (60.29 vs. 58.75, p=0.069) and delay from diagnosis longer (20.42 vs 13.26 months, p=0.040). RuxoG patients had less frequently anemia < 10 g/dl (84% vs 98%, p=0.027) or thrombocytopenia < 50 G/L (22% vs 32%, p=0.066) and presented more frequently splenomegaly or pre-graft splenectomy (83% vs 63%, p=0.0007). DIPSS score was well balanced in both groups, being high or intermediate-2 in 100 patients (79% vs 86%, p=0.23), from the 235 patients with available data. Myeloablative conditioning regimen was used in 16% vs 26% (p=0.049), and conditioning regimen consisted of on fludarabine-busulfan in 33% vs 61%, fludarabine-melphalan in 47% vs 22% or other in 20% vs 16% (p<0.0001). The donor was HLA-matched in 93% and 85%, with 31% vs 35% being matched sibling donor. Partial response or any other response before HSCT was reported in 41% (RuxoG) and 29% (noRuxo). Regarding post-transplant outcomes, cumulative incidence of grade 2-4 or 3-4 acute GVHD at day 100 was 46.5% and 32.2% in RuxoG and 40.4% and 20.7% in noRuxo group (p=0.11 and p=0.023, respectively). Chronic GVHD incidence at 24 months was 33.2% in RuxoG and 43.3% in noRuxo group (p=0.15) Overall survival was improved for noRuxo versus RuxoG, with 60 month OS at 40.3% and 57.0% (p=0.0067) (Figure 1). Causes of death were: HSCT related in 35 and 41 patients, related to GVHD in 65% and 43%, respectively. A multivariate Cox full model after selection and imputation showed that prior ruxolitinib significantly increased the risk of mortality (Table 1). Age, conditioning regimen, thrombocytopenia, performance status and type of donor were also prognostic. The propensity score confirmed that prior ruxolitinib was associated with higher risk of mortality (HR: 1.60, 95%CI:1.06 to 2.42; p=0.024) including after adjustment for the delay from diagnosis to transplantation (HR: 1.59 95%CI: 1.05 to 2.42, p=0.028). Of note, in patients responding to prior ruxolitinib, this deleterious effect was not observed.
Conclusion: Patients who received ruxolitinib before HSCT were at higher risk of acute GVHD and post-transplant mortality, but this was not observed in patients responding to ruxolitinib and it does not translate into higher risk of chronic GVHD. Main hypotheses to explain these finding could be: 1) specific disease, patient or transplant characteristics in RuxoG; 2) the longer delay to transplantation or 3) a specific effect of ruxolitinib. This study suggests that myelofibrosis patients responding to ruxolitinib should have the transplant without waiting disease progression.
Display omitted
Forcade: Novartis: Other: travel grant. Loschi: AbbVie: Ended employment in the past 24 months, Honoraria; CELGENE/BMS: Honoraria; Gilead: Ended employment in the past 24 months, Honoraria; Novartis: Ended employment in the past 24 months, Honoraria; Servier: Ended employment in the past 24 months, Honoraria; MSD: Honoraria. Duléry: Takeda Gilead Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Robin: NEOVII MEDAC NOVARTIS: Research Funding.
PDF
