I. Yakoub-Agha

Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Sociéte Française de Greffe de Moelle et de Thérapie Cellulaire

This retrospective report assessed the impact of rabbit antithymocyte globulins (ATG), incorporated within a standard myeloablative conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT) using human leukocyte antigen-matched unrelated donors (HLA-MUD), on the incidence of acute and chronic graft-vs-host disease (GVHD). In this series of leukemia patients, 120 patients (70%) did not receive ATG (‘no-ATG’ group), whereas 51 patients received ATG (‘ATG’ group). With a median follow-up of 30.3 months, the cumulative incidence of grade 3–4 acute GVHD was 36% in the no-ATG group and 20% in the ATG group (P=0.11). The cumulative incidence of extensive chronic GVHD was significantly lower in the ATG group as compared to the no-ATG group (4 vs 32%, respectively; P=0.0017). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of extensive chronic GVHD (relative risk)=7.14, 95% CI: 1.7–33.3, P=0.008). At 2 years, the probability of nonrelapse mortality, relapse, overall and leukemia-free survivals was not significantly different between the no-ATG and ATG groups. We conclude that the addition of ATG to GVHD prophylaxis resulted in decreased incidence of extensive chronic GVHD without an increase in relapse or nonrelapse mortality, and without compromising survival after myeloablative allo-SCT from HLA-MUD.

Outcomes and prognostic factors of adults with acute lymphoblastic leukemia who relapse after allogeneic hematopoietic cell transplantation. An analysis on behalf of the Acute Leukemia Working Party of EBMT

To describe outcomes, treatment and prognostic factors that influence survival of adult patients with acute lymphoblastic leukemia (ALL), who relapsed after allogeneic hematopoietic cell transplantation (HCT), we retrospectively analyzed 465 ALL adult patients from European Group for Blood and Marrow Transplantation (EBMT) centers who relapsed after a first HCT performed in complete remission (CR1 65%, CR2/3 35%). Salvage treatments were: supportive care (13%), cytoreductive therapy (43%), donor lymphocyte infusion without or with prior chemotherapy (23%) and second HCT (20%). Median time from HCT to relapse was 6.9 months, median follow-up was 46 months and median survival after relapse was 5.5 months. Estimated 1-, 2- and 5-year post-relapse survival was 30±2%, 16±2% and 8±1%, respectively. In a multivariate analysis, adverse factors for survival were: late CR (CR2/3) at transplant (P<0.012), early relapse after transplant (<6.9 months, P <0.0001) and peripheral blast percent at relapse (P <0.0001). On the basis of multivariate model for survival, three groups of patients were identified with estimated 2 year survival of 6±2, 17±3 and 30±7%. Outcome of ALL patients relapsing after HCT is dismal and there is a need for new therapies. Our study provides the standard expectations in ALL relapse and may help in the decision of post-relapse therapy.

Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma

Allogeneic hematopoietic cell transplantation (allo-HCT) is indicated for patients with relapsed or refractory Hodgkin lymphoma (HL). Although long-term disease control can be achieved, relapse is still frequent. The programmed cell death protein 1 (PD-1) pathway-blocking antibody nivolumab has shown substantial therapeutic activity and an acceptable safety profile in patients with relapsed or refractory HL who did not receive allo-HCT. However, PD-1 blocking strategy can increase the risk of graft-versus-host disease (GVHD) in murine models. We retrospectively assessed the efficacy and toxicity of nivolumab as a single agent in 20 HL patients relapsing after allo-HCT. GVHD occurred in 6 patients (30%) after nivolumab initiation. All 6 patients had prior history of acute GVHD. The patients with nivolumab-induced GVHD were managed by standard treatment for acute GVHD. Two patients died as a result of GVHD, 1 of progressive disease and 1 of complications related to a second allo-HCT. Overall response rate was 95%. At a median follow-up of 370 days, the 1-year progression-free survival rate was 58.2% (95% CI, 33.1%-76.7%) and the overall survival rate was 78.7% (95% CI, 52.4%-91.5%). Among 13 patients still in response, 6 received a single dose of nivolumab and 7 remain on nivolumab. Compared with standard options for this indication, our results show that nivolumab is effective with an acceptable safety profile.

Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD

To assess the impact of homeostatic expansion on the occurrence of acute GVHD after reduced intensity conditioning (RIC) transplantation, systemic levels of IL-7 and IL-15 and expression of their specific receptor chains were prospectively investigated in 45 fully HLA-matched allograft recipients. IL-7 and IL-15 levels peaked at four- to fivefold over pre-conditioning values. IL-7 levels were inversely correlated to absolute T-cell counts. Peak IL-15 levels positively correlated to concurrent CRP levels, but normalized earlier than IL-7. These results indicate that the kinetic course of IL-7 depends mainly on initiation of T-cell recovery, while IL-15 depends more on peri-transplant inflammation after RIC. Longer duration of the rise in IL-7 levels was associated with preservation of a normal CD4/CD8 ratio. In all, 16 (35%) patients developed grade 2–4 acute GVHD at a median of 42 days post graft, preceded by higher IL-7 levels and more downregulation of IL-7 receptor α chain on CD4+ T cells than in patients without acute GVHD, suggesting enhanced homeostatic expansion. In multivariate analysis, IL-7 level measured on day +30 was the foremost predictive factor for grade 2–4 acute GVHD (P=0.002). Measurement of IL-7 level after RIC transplantation might help predict risk of subsequent acute GvHD.

Impact of rabbit ATG-containing myeloablative conditioning regimens on the outcome of patients undergoing unrelated single-unit cord blood transplantation for hematological malignancies

This study aimed to assess the impact of antithymocyte globulin (ATG) on patient outcome in a retrospective series of 91 patients (median age: 12 years) who underwent unrelated single-unit cord blood transplantation (allo-CBT) following a myeloablative conditioning regimen. Cord blood units were HLA-matched (6/6, n=18; 21%), one-Ag mismatched (n=30, 35%) or two-Ag mismatched (n=38; 44%). In this series, the OS, nonrelapse mortality (NRM) and cumulative incidence of relapse were 47±6%, 23±4% and 48±5%, respectively. Among 46 patients who received ATG as part of the conditioning regimen, the incidence of acute and chronic GVHD was lower than that in the group of 45 patients who did not receive ATG (20% vs 43%; P=0.03). However, multivariate statistical analysis revealed that the ATG use was associated with decreased OS and EFS rates and a high incidence of NRM (hazard ratio (HR)=1.99, 95% confidence interval (CI): 1.11–3.59, P=0.02), (HR=1.83, 95% CI: 1.08–3.10, P=0.02) and (HR=2.54, 95% CI: 1.03–6.26, P=0.04), respectively. Therefore, our results do not support the use of ATG as part of a myeloablative-conditioning regimen before single-unit allo-CBT in younger patients with hematological malignancies.

Enteral nutrition: a first option for nutritional support of children following allo-SCT?

Parenteral nutrition (PN) is the treatment of choice for nutritional support of patients undergoing allo-SCT following myeloablative conditioning (MAC). Here we prospectively assessed the outcomes of early enteral nutrition (EN) in a paediatric cohort. From 2003 to 2010, all 65 consecutive children undergoing MAC allo-SCT at our referral centre began EN the day after transplantation. Post-transplant and nutritional outcomes of patients receiving only EN (EN group, n=50) were compared with those of patients requiring additional PN (EN-PN group, n=15). In the EN group time to platelet recovery (P=0.01) and length of hospitalisation (P<0.001) were shorter, while in the EN-PN group the proportion of unrelated donors (P=0.02) and the frequency of severe acute GVHD (aGVHD; P=0.004) were higher. All patients were alive at day 100. PN was started 14 days after transplant because of poor digestive tolerance to EN or severe gut aGVHD. The body mass index Z-score in the EN-PN group decreased from transplant to discharge (P=0.02). In only 23% of cases was PN required for severely ill patients. Our results suggest that EN might be considered to be an option for nutritional support in children undergoing MAC allo-SCT, while PN should be used only as a rescue option, possibly in combination with EN.

Outcomes of adults with active or progressive hematological malignancies at the time of allo-SCT: a survey from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Previous data suggested that allo-SCT might be an effective therapy in the setting of chemo-refractory/relapsed diseases because of the potent long-term immune-mediated tumor control. This retrospective study aimed to analyze the outcome of adult patients who received allo-SCT in a chemo-refractory/relapsed status. The series included 840 patients with active or progressive disease at the time of transplant. Median age was 50 years. With a median follow-up of 40 months, 3-year OS, disease-free survival (DFS), and non-relapse mortality rates were 29±2, 23±2, and 30±2%, respectively. At the last follow-up, 252 patients (30%) were still alive (of whom 201 were in CR (24%). In a Cox multivariate analysis, the use of a reduced-intensity conditioning (RIC) before allo-SCT and use of an HLA-identical sibling donor remained independently associated with a better OS (hazard ratio (HR)=0.82; 95% confidence interval (CI), 0.69–0.98, P=0.03; and HR=0.79; 95% CI, 0.66–0.93, P=0.006, respectively). Also, a diagnosis of myelodysplastic syndrome/myeloproliferative disorder, Hodgkin lymphoma and non-Hodgkin lymphoma compared with acute leukemia had a favorable impact on OS (HR=0.55; 95% CI, 0.45–0.68, P<0.0001; HR=0.49; 95% CI, 0.31–0.75, P=0.001; and HR=0.47; 95% CI, 0.35–0.63, P<0.0001, respectively). In conclusion, this study suggests that allo-SCT may be of benefit in some subgroups of patients with active or progressive hematological malignancies at the time of allo-SCT.

Long-term survival of patients with CLL after allogeneic transplantation: a report from the European Society for Blood and Marrow Transplantation

Even with the availability of targeted drugs, allogeneic hematopoietic cell transplantation (allo-HCT) is the only therapy with curative potential for patients with CLL. Cure can be assessed by comparing long-term survival of patients to the matched general population. Using data from 2589 patients who received allo-HCT between 2000 and 2010, we used landmark analyses and methods from relative survival analysis to calculate excess mortality compared with an age-, sex- and calendar year-matched general population. Estimated event-free survival, overall survival and non-relapse mortality (NRM) 10 years after allo-HCT were 28% (95% confidence interval (CI), 25–31), 35% (95% CI, 32–38) and 40% (95% CI, 37–42), respectively. Patients who passed the 5-year landmark event-free survival (N=394) had a 79% probability (95% CI, 73–85) of surviving the subsequent 5 years without an event. Relapse and NRM contributed equally to treatment failure. Five-year mortality for 45- and 65-year-old reference patients who were event-free at the 5-year landmark was 8% and 47% compared with 3% and 14% in the matched general population, respectively. The prospect of long-term disease-free survival remains an argument to consider allo-HCT for young patients with high-risk CLL, and programs to understand and prevent late causes of failure for long-term survivors are warranted, especially for older patients.

Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques : insuffisance corticotrope et ostéoporose

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview on secondary adrenal insufficiency and osteoporosis post-transplant.

[Allogeneic stem cell transplantation from an HLA-haploidentical related donor: SFGM-TC recommendations (part 2)].

Haploidentical allogeneic stem cell transplantation (CST) has globally taken off in the past decade. It appears to be a valid alternative to other sources of stem cells; however, further research is necessary to validate the use of this approach in standard patient care. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. This is part two of the recommendations regarding allogeneic stem cell transplantation from an HLA-haploidentical related donor.