The Role of Donor Selection for a Second Allogeneic Stem Cell Transplantation in Patients with AML Relapsing after a First Transplant; A Study on Behalf of the Acute Leukemia Working Party of EBMT

Abstract Introduction. Recurrent disease is the major cause of treatment failure after allogeneic stem cell transplantation (SCT) in patients with AML. Second SCT (SCT2) is a valid treatment option in this setting but outcome is relatively poor. Haplo-identical (haplo) SCT is increasingly used over the last decade due to the introduction of non T-depleted methods. Prior studies have shown similar outcome when using the same or different HLA-matched donor for SCT2. However, there is relatively limited data on the use of haplo-donors. Methods and Results. The study included 556 patients with AML relapsing after a first allogeneic SCT (SCT1) given in CR1 from an HLA-matched sibling (sib, n= 294) or a matched unrelated donor (MUD, n=262) and given SCT2 during the years 2006-2016. The median age at SCT2 was 46 years (20-73). 247 patients were in CR2 (44%) and 309 had active leukemia (55%) at the time of SCT2. The conditioning regimen was myeloablative (MAC, 66%) or reduced-intensity (RIC, 34%) for SCT1, and 41% and 59%, respectively for SCT2. 19% of all patients had acute GVHD grade II-IV and 20% had chronic GVHD after SCT1 and before relapse. Patients were divided into 3 groups based on the donor selected for SCT2; 1) same donor (n=163, sib/sib-112, MUD/MUD-51), 2) different HLA-matched donor (n=305, sib/different sib-44, sib/MUD-93, MUD/ different MUD- 168), 3) haplo-donor (n=88, sib/haplo-45, MUD/haplo-43). All haploSCT were non T-depleted. There were some differences between the 3 groups in the timing of relapse and SCT2. The median time from SCT1 to relapse was similar; 10.6, 12.5 and 9.3 months, respectively (P=0.14). However, the median time from relapse to SCT2 was shorter for the same donor group; 2.8, 3.7 and 3.5 months, respectively (P<0.001) and the median time between SCT1 and SCT2 was longer for the different donor group; 14.3, 17.5 and 13.8 months, respectively (P=0.03). There were no difference between the groups in patient age, gender, disease status at SCT2 or conditioning regimen intensity for SCT1 or SCT2. The 2-year leukemia-free survival (LFS) after SCT2 was 23.5%, 23.7% and 21.8%, respectively (unadjusted P=0.30). Multivariate analysis of factors predicting relapse after SCT2 showed no effect of the second donor type, hazard ratio (HR) 0.96 (P=0.83) and 1.20 (P=0.47) for different matched donor and haplo-donor compared to the same donor, respectively. MUD donor in SCT1, CR2 compared to active disease and chronic GVHD after SCT1 were associated with reduced relapse risk after SCT2, HR 0.70 (P=0.02), 0.60 (P=0.001) and 0.66 (P=0.03), respectively. Age, gender, conditioning regimen used for SCT1 or SCT2 and time to first relapse or to SCT2 did not predict relapse rate after SCT2. The second donor type did predict for non-relapse mortality (NRM) after SCT2; HR 1.26 (P=0.41) and 2.18 (P=0.02) for different matched donor and haplo-donor compared to same donor, respectively. Advanced age and MAC in SCT1 also predicted for NRM, HR 1.40 (P<0.001) and 0.61 (P=0.04), respectively. The second donor also predicted for LFS after SCT2; HR 1.05 (P=0.77) and 1.55 (P=0.03), respectively. Advanced age and SCT2 in CR2 also predicted for LFS; HR 1.11 (P=0.06) and 0.66 (P=0.002), respectively. In all, there were no differences between same or different matched donors in SCT2 outcomes, but haploSCT2 was associated with higher NRM and lower LFS. Significant interaction was detected between second donor type and conditioning for SCT1. The inferior outcome after SCT2 with a haplo-donor was limited to patients given MAC in SCT1. In this setting it was associated with higher relapse and NRM rates and lower LFS, HR 1.86 (P=0.05), 3.40 (P=0.005) and 2.25 (P=0.001), respectively. However, there was no difference in any of these outcomes in patients given RIC in SCT1. Unadjusted analysis showed that in patients with no chronic GVHD after SCT1, haploSCT2 was associated with lower LFS, due to higher NRM. However, LFS was similar in patients with prior chronic GVHD. Multivariate analysis was not feasible due to low patient numbers. Conclusions. Second SCT with the same donor or different matched donor is associated with similar outcomes in patients with relapsed AML after a first SCT. However, SCT2 with a haplo-donor is associated with higher NRM and lower LFS, mostly in patients given MAC in SCT1. Prior chronic GVHD after SCT1 is associated with lower relapse rate after SCT2. The role of prior chronic GVHD in donor selection should be further investigated. Disclosures Finke: Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding. Gramatzki:Affimed: Research Funding. Stelljes:Novartis: Honoraria; Amgen: Honoraria; JAZZ: Honoraria; MSD: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Stoelzel:Neovii: Speakers Bureau. Mohty:MaaT Pharma: Consultancy, Honoraria

Long-term follow-up of autologous stem cell transplantation after intensive chemotherapy in patients with myelodysplastic syndrome or secondary acute myeloid leukemia.

International audienceWe report on the outcomes of 53 patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia secondary to MDS, autografted in first complete remission. Five (9.4%) died from the procedure whereas hematological reconstitution occurred in all the remaining patients. Forty patients (75%) relapsed, with 87.5% of the relapses occurring within 2 years of the autologous transplant. With a median follow-up of 6.2 years, the median actuarial disease-free survival and overall survival were 8 and 17 months after autograft, respectively. Karyotype was the only prognostic factor for disease-free and overall survival. The eight survivors (15%), including two patients with unfavorable or intermediate karyotype, remained in first complete remission 50+ to 119+ months after transplantation and are probably cured

Allogeneic stem cell transplantation benefits for patients >= 60 years with acute myeloid leukemia and FLT3 internal tandem duplication : a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 (FLT3-ITD) is associated with a high risk of relapse, and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in the elderly, we made a selection from the European Society for Blood and Marrow Transplantation registry of de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3-ITD in patients aged 60 or over and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%), while donors consisted of an unrelated donor in 161 (55%) patients. Two hundred and twelve patients received their transplantation in first remission, 37 in second remission and 42 in a more advanced stage of the disease. The 2-year leukemia-free survival rate was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively (P= 60 with FLT3-ITD acute myeloid leukemia in first remission, similarly to current treatment recommendations for younger patients.Peer reviewe

Organ complications after CD19 CAR T-cell therapy for large B cell lymphoma: a retrospective study from the EBMT transplant complications and lymphoma working party.

We investigated ≥ grade 3 (CTC-AE) organ toxicities for commercial CD19 chimeric antigen receptor T cell (CAR-T cell) products in 492 patients (Axi-Cel; n = 315; Tisa-Cel; n = 177) with Large B-cell Lymphoma in the European Society for Blood and Marrow Transplantation (EBMT) CAR-T registry. The incidence of ≥ grade 3 organ toxicities during the first 100 days after CAR-T was low and the most frequent were: renal (3.0%), cardiac (2.3%), gastro-intestinal (2.3%) and hepatic (1.8%). The majority occurred within three weeks after CAR-T cell therapy. Overall survival was 83.1% [79.8-86.5; 95% CI] at 3 months and 53.5% [49-58.4; 95% CI] at one year after CAR-T. The most frequent cause of death was tumour progression (85.1%). Non-relapse mortality was 3.1% [2.3-4.1; 95% CI] at 3 months and 5.2% [4.1-6.5; 95% CI] at one year after CAR-T. The most frequent causes of non-relapse mortality were cell-therapy-related toxicities including organ toxicities (6.4% of total deaths) and infections (4.4% of total deaths). Our data demonstrates good safety in the European real-world setting

Salvage use of allogeneic hematopoietic stem cell transplantation after reduced intensity conditioning from unrelated donors in multiple myeloma. A study by the Plasma Cell Disorders subcommittee of the European Group for Blood and Marrow Transplant Chronic Malignancies Working Party

Non peer reviewe

Comparison of reduced-intensity conditioning regimens in patients with acute lymphoblastic leukemia >45 years undergoing allogeneic stem cell transplantation—a retrospective study by the Acute Leukemia Working Party of EBMT

The optimal reduced-intensity conditioning (RIC) for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic stem cell transplantation (allo-HSCT) remains unclear. We retrospectively analyzed 417 patients > 45 years with ALL in first complete remission who underwent a matched-sibling 76 or unrelated allo-HSCT and compared outcomes between fludarabine/busulfan (FLUBU, n=127), fludarabine/melphalan (FLUMEL, n=190) and fludarabine-TBI (FLUTBI, n=100) conditioning. At 2 years, there were no differences between the groups in terms of cumulative incidence (CI) of relapse (40% for FLUBU vs 36% for FLUMEL vs 41% for FLUTBI, p=0.21); transplant-related mortality (TRM) (18% for FLUBU, 22% for FLUMEL, 14% for FLUTBI, p=0.09); overall survival (OS) (55% for FLUBU, 50% for FLUMEL, 60% for FLUTBI, p=0.62) or leukemia-free survival (LFS) (43% for FLUBU, 42% for FLUMEL, 45% for FLUTBI, p=0.99), but GVHD-relapse-free survival (GFRS) was significantly lower in the FLUTBI group than FLUBU and FLUMEL group (18% vs 35% vs 28%, p=0.02). However, this difference was lost in the multivariate analysis when adjusted for the in vivo T-cell depletion. Finally, the FLUMEL regimen was shown to be an independent risk factor for a higher TRM (HR 1.97, 95% CI 1.05-3.72, p=0.04). We conclude that the 3 most popular RIC regimens yield similar transplant outcomes

Late relapse after hematopoietic stem cell transplantation for acute leukemia: a retrospective study by SFGM-TC.

peer reviewedLate relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010, and December 31, 2016, using data from the French national retrospective register ProMISe provided by the SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy). We included patients presenting with LR, defined as a relapse occurring at least 2 years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, a total of 7582 AHSCTs were performed in 29 centers, and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered to have LR, representing an incidence of 4.2% for the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia and 40 (13.8%) with acute lymphoid leukemia. The median interval from AHSCT to LR was 38.2 months (interquartile range [IQR], 29.2 to 49.7 months), and 27.2% of the patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of the patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (IQR, 5.6 to 46.4 months). The most common salvage therapy was induction regimen (55.5%), with complete remission (CR) obtained in 50.7% of cases. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (IQR, 7.1 to 49.1 months). Nonrelapse mortality after second AHSCT was 18.2%. The Cox model identified the following factors as associated with delay of LR: disease status not in first CR at first HSCT (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.04 to 1.64; P = .02) and the use of post-transplantation cyclophosphamide (OR, 2.23; 95% CI, 1.21 to 4.14; P = .01). Chronic GVHD appeared to be a protective factor (OR, .64; 95% CI, .42 to .96; P = .04). The prognosis of LR is better than in early relapse, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity

Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease

BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODS: We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. RESULTS: A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). CONCLUSIONS: Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy

Prophylaxie et traitement de la maladie du greffon contre l'hôte aïgue (étude observationnelle menée pendant 2 ans au CHU de Montpellier)

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF