Cytogenetic risk classification maintains its prognostic significance in transplanted FLT3-ITD mutated acute myeloid leukemia patients: On behalf of the acute leukemia working party/European society of blood and marrow transplantation.

FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutational status is a pivotal prognosticator in acute myeloid leukemia (AML) patients and significantly increases the risk of disease relapse. However, it remains unclear whether in FLT3-ITD patients referred for allogeneic stem cell transplantation (allo-SCT), baseline cytogenetics significantly impacts clinical outcome. Using the European Society of Blood and Marrow Transplantation registry, we performed a retrospective analysis of 1631 FLT3-ITD AML patients who underwent allo-SCT with the aim of determining the influence of cytogenetic risk category on patient outcomes. Median patient age was 49 years and median follow-up duration was 36 months. Two-year leukemia-free survival (LFS) and incidence of relapse were 54% and 31.6%, respectively. Non-relapse mortality was experienced by 14.4% with a 2-year overall survival (OS) of 60.1%. On multivariate analysis, LFS was significantly lower in patients with intermediate and adverse risk cytogenetics compared with those with favorable risk cytogenetics, (hazard ratio [HR] = 1.48, 95% confidence interval [CI], 1.06-2.06; p = .02), and (HR = 01.65, 95% CI, 1.13-2.40; p = .009), respectively. OS was significantly lower in patients with adverse risk cytogenetics compared with patients with favorable risk cytogenetics (HR = 1.74, 95% CI, 1.16-2.61; p = .008) with a trend toward lower OS in patients with intermediate risk cytogenetics compared to those with favorable risk cytogenetics (HR = 1.43, 95% CI, 1.00-2.05; p = .052). In addition, adverse risk patients and intermediate risk patients experienced higher relapse rates compared with favorable risk patients (HR = 1.83, 95% CI, 1.13-2.94; p = .013 and HR = 1.82, 95% CI, 1.19-2.77; p = .005). Overall, cytogenetic studies aid in refinement of risk stratification in transplanted FLT3-ITD AML patients.

Long-term outcome after allogeneic stem cell transplantation in multiple myeloma.

The role of allogeneic hematopoietic stem cell transplantation (allo-SCT) in multiple myeloma is controversial. We analyzed the results of 205 patients transplanted in one center during 2000-2017. Transplantation was performed on 75 patients without a previous autologous SCT (upfront-allo), on 74 as tandem transplant (auto-allo), and on 56 patients after relapse. Median overall survival (OS) was 9.9 years for upfront-allo, 11.2 years for auto-allo, and 3.9 years for the relapse group (p = 0.015). Progression-free survival (PFS) was 2.4, 2.4, and 0.9 years, respectively (p < 0.001). Non-relapse mortality at 5 years was 8% overall, with no significant difference between the groups. Post-relapse survival was 4.1 years for upfront-allo and auto-allo, and 2.6 years for the relapse group (p = 0.066). Survival of high-risk patients was reduced. In multivariate analysis, the auto-allo group had improved OS and chronic graft-versus-host disease was advantageous in terms of PFS, OS, and relapse incidence. Late relapses occurred in all groups. Allo-SCT resulted in long-term survival in a small subgroup of patients. Our results indicate that auto-allo-SCT is feasible and could be considered for younger patients in the upfront setting.

Allogeneic peripheral blood stem cell transplantation with anti-thymocyte globulin versus allogeneic bone marrow transplantation without anti-thymocyte globulin.

We compared severe graft-versus-host-disease (GvHD) free and relapse-free survival and other transplantation outcomes of acute myeloid leukemia (AML) patients given bone marrow (BM) without anti-thymocyte globulin (ATG) versus peripheral blood stem cells (PBSC) with ATG after myeloablative conditioning. In the cohort of patients receiving grafts from a human leukocyte antigen (HLA)-matched sibling donor, patients given PBSC with ATG (n=1,021) and those given BM without ATG (n=1,633) presented comparable severe GvHD-free relapse-free survival (GRSF)(hazard ratio [HR]=0.9, 95% confidence interval [CI]: 0.8-1.1, P=0.5) and overall survival (HR=1.0, 95% CI: 0.8-1.2, P=0.8). They had however, a lower incidence of chronic GvHD (cGvHD) (HR=0.7, 95% CI: 0.6-0.9, P=0.01). In the cohort of patients receiving grafts from HLA-matched unrelated donor , patients given PBSC with ATG (n=2,318) had better severe GvHD-free and relapse-free survival (GRFS) than those given BM without ATG (n=303) (HR=0.8, 95% CI: 0.6-0.9, P=0.001). They also had a lower incidence of cGvHD (HR=0.6, 95% CI: 0.5-0.8, P=0.0006) and better overall survival (HR=0.8, 95% CI: 0.6-1.0, P=0.04). In summary, these data suggest that PBSC with ATG results in comparable (in the case of sibling donor) or significantly better (in the case of unrelated donor) severe GRFS than BM without ATG in patients with AML in complete remission receiving grafts after myeloablative conditioning.

Association of uric acid levels before start of conditioning with mortality after allogeneic hematopoietic stem cell transplantation - a prospective, non-interventional study of the EBMT Transplant Complication Working Party.

Uric acid is a danger signal contributing to inflammation. Its relevance to allogeneic stem cell transplantation (alloSCT) derives from preclinical models where the depletion of uric acid led to improved survival and reduced graft-versus-host disease (GvHD). In a clinical pilot trial, peri-transplant uric acid depletion reduced acute GvHD incidence. This prospective international multicenter study aimed to investigate the association of uric acid serum levels before start of conditioning with alloSCT outcome. We included patients with acute leukemia, lymphoma or myelodysplastic syndrome receiving a first matched sibling alloSCT from peripheral blood, regardless of conditioning. We compared outcomes between patients with high and low uric acid levels with univariate- and multivariate analysis using a cause-specific Cox model. Twenty centers from 10 countries reported data on 366 alloSCT recipients. There were no significant differences in terms of baseline comorbidity and disease stage between the high- and low uric acid group. Patients with uric acid levels above median measured before start of conditioning did not significantly differ from the remaining in terms of acute GvHD grades II-IV incidence (Hazard ratio [HR] 1.5, 95% Confidence interval [CI]: 1.0-2.4, P=0.08). However, they had significantly shorter overall survival (HR 2.8, 95% CI: 1.7-4.7, P<0.0001) and progression free survival (HR 1.6, 95% CI: 1.1-2.4, P=0.025). Non-relapse mortality was significantly increased in alloSCT recipients with high uric acid levels (HR 2.7, 95% CI: 1.4-5.0, P=0.003). Finally, the incidence of relapse after alloSCT was increased in patients with higher uric acid levels (HR 1.6, 95% CI: 1.0-2.5, P=0.04). We conclude that high uric acid levels before the start of conditioning correlate with increased mortality after alloSCT.

Conditioning-based outcomes after allogeneic transplantation for myeloma following a prior autologous transplant (1991-2012) on behalf of EBMT CMWP.

OBJECTIVES: The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma-reduced intensity conditioning (RIC), non-myeloablative (NMA), myeloablative conditioning (MAC) or Auto-AlloHCT-on outcomes in patients who had had a prior autologous transplant. METHODS: A retrospective analysis of the EBMT database (1991-2012) was performed. RESULTS: A total of 344 patients aged between 40 and 60 years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto-Allo transplants. At a median follow-up of 54 months, the probabilities of overall survival (OS) at 5 years were 39% (95% CI 31%-47%), 45% (95% CI 32%-57%), 19% (95% CI 6%-32%) and 34% (95% CI 17%-51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P = .004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR = 4.1, P < .001) but not after 2002 (HR = 1.2, P = .276). CONCLUSION: From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches.

Cytogenetic risk score maintains its prognostic significance in AML patients with detectable measurable residual disease undergoing transplantation in remission: On behalf of the acute leukemia working party of the European society for blood and marrow transplantation.

While evidence for measurable residual disease (MRD) is a harbinger of inferior outcome in acute myeloid leukemia (AML) patients referred for allogeneic stem cell transplantation (allo-SCT), the exact clinical trajectory of specific patient subsets in this clinical setting is undefined. Using a recently published prognostic cytogenetic model (Canaani et al. Leukemia 2019) we evaluated whether this model applied also to studies of patients with positive MRD. The analysis comprised MRD+ patients in first complete remission undergoing allo-SCT from a matched sibling donor or unrelated donor. Seven hundred and seventy-five patients were evaluated with a median follow-up duration of 22 months. Cytogenetic risk score was favorable, intermediate/FLT3wt intermediate/FLT3-ITD3, and adverse in 15%, 28.3%, 37% and 19.7% of the patients, respectively. Favorable and intermediate/FLT3wt risk patients had 2-year leukemia-free survival rates of 78% and 61%, respectively, compared with only 50% and 37% for intermediate/FLT3-ITD3 and adverse risk patients, respectively (P < .001). In multivariate analysis adverse and intermediate/FLT3-ITD3 risk patients were more likely to experience disease relapse compared with favorable risk patients [hazard ratio (HR) = 3.9, 95% confidence interval (CI), 2.1-7.3; P < .001, and HR = 4.4, CI 95%, 2.4-7.8; P < .001, respectively]. The European society for blood and marrow transplantation cytogenetic risk score is a valuable adjunct for risk stratification of MRD+ AML patients.

Increased MHC Matching by C4 Gene Compatibility in Unrelated Donor Hematopoietic Stem Cell Transplantation.

HLA matching is a prerequisite for successful allogeneic hematopoietic stem cell transplantation (HSCT) because it lowers the occurrence and severity of graft-versus-host disease (GVHD). However, matching a few alleles of the classic HLA genes only may not ensure matching of the entire MHC region. HLA haplotype matching has been reported to be beneficial in HSCT because of the variation relevant to GVHD risk in the non-HLA region. Because polymorphism in the MHC is highly population specific, we hypothesized that donors from the Finnish registry are more likely to be matched at a higher level for the Finnish patients than donors from other registries. In the present study we determined 25 single nucleotide polymorphisms (SNPs) of the complement component 4 (C4) gene in the γ-block segment of MHC from 115 Finnish HSCT patients and their Finnish (n = 201) and non-Finnish (n = 280) donor candidates. Full matching of HLA alleles and C4 SNPs, independently or additively, occurred more likely in the Finnish-Finnish group as compared with the Finnish-non-Finnish group (P < .003). This was most striking in cases with HLA haplotypes typical of the Finnish population. Patients with ancestral HLA haplotypes (AH) were more likely to find a full HLA and C4 matched donor, regardless of donor origin, as compared with patients without AH (P < .0001). Despite the clear differences at the population level, we could not find a statistical association between C4 matching and clinical outcome. The results suggest that screening C4 SNPs can be advantageous when an extended MHC matching or HLA haplotype matching in HSCT is required. This study also supports the need for small population-specific stem cell registries.

Second allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia: a study on behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation.

Although second allogeneic haematopoietic cell transplantation (allo-HCT2) is a therapeutic option for patients relapsing after first HCT (allo-HCT1), there is limited data on allo-HCT2 in patients with acute lymphoblastic leukaemia (ALL). We retrospectively studied 245 patients receiving allo-HCT2 as a salvage treatment for relapse following allo-HCT1 between the 2000 and 2017. The median age at allo-HCT2 was 34·6 years (range: 18-74). One hundred and one patients (41%) received sibling donor and 144 (59%) unrelated donor allo-HCT2. Acute graft-versus-host disease (GVHD) grade II-IV and III-IV occurred in 33% and 17% of the patients, respectively. The incidence of 2-year total and extensive chronic GVHD was 38% and 19%, respectively. The 2- and 5-year cumulative incidence of non-relapse mortality, relapse incidence, leukaemia-free survival, overall survival and GVHD-free, relapse-free survival (GRFS) were 24% and 26%, 56% and 62%, 20% and 12%, 30% and 14% and 12% & 7%, respectively. In multivariate analysis, factors associated with overall survival were age, time from allo-HCT1 to relapse, conditioning for allo-HCT1, Karnofsky score at allo-HCT2 and donor type for allo-HCT2. In conclusion, outcomes of allo-HCT2 in ALL patients were poor, with only 14% overall survival and 7% GRFS at 5 years with very high relapse incidence.

A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis.

BACKGROUND: In a previously published study, the authors randomized 108 adult patients with a malignant hematologic disorder undergoing allogeneic bone marrow transplantation from a human leukocyte antigen-identical sibling to receive methylprednisolone (53 patients; MP+) or not to receive methylprednisolone (55 patients; MP-) as a part of graft-versus-host disease (GVHD) prophylaxis. All patients received cyclosporine and methotrexate. The cumulative incidence of acute GVHD was found to be significantly lower among the patients given MP. METHODS: In the current study, the authors performed a long-term follow-up to discover possible late effects of the intensified GVHD prophylaxis. RESULTS: The median follow-up for surviving patients was 24.5 years. In the MP+ group, the overall survival and recurrence-free survival were higher (P = .021 and P = .028, respectively) and the nonrecurrence mortality was lower (P = .003) than in the MP- group. There was a trend toward a lower cumulative incidence and a significantly lower prevalence (P = .031) of chronic GVHD in the MP+ group. There was no difference noted with regard to the rate of disease recurrence or in the incidence of secondary malignancies. Eleven patients in the MP- group but none in the MP+ group died >15 years after transplantation. At the end of follow-up, the overall survival rates in the MP+ and MP- groups were 55% and 20%, respectively, and the recurrence-free survival rates were 49% and 15%, respectively. CONCLUSIONS: Long-term survival was found to be higher among the patients given MP in addition to cyclosporine and methotrexate. There was marked late nonrecurrence mortality observed in the group not given MP. No adverse late effects caused by the addition of corticosteroid were observed. Cancer 2018;124:727-33. © 2017 American Cancer Society.

Extracorporeal photopheresis in the treatment of acute graft-versus-host disease: a single-center experience.

BACKGROUND: Steroid-refractory acute graft-versus-host disease (aGVHD) is a serious complication after hematopoietic stem cell transplantation. The long-term outcome of the patients is poor. Various immunosuppressive agents have been proposed as the second-line therapy but none of them has turned out more effective than the others. Extracorporeal photopheresis (ECP) is a treatment option that does not predispose the patients to severe side effects of the immunosuppressive drugs. STUDY DESIGN AND METHODS: We analyzed the treatment results of ECP in 52 patients with steroid-refractory or steroid-dependent aGVHD. Eighty-one percent of the patients suffered from a severe, Grade III or IV, aGVHD. ECP was started alone as the second-line treatment in 23 patients and in combination with an immunosuppressive drug in 18 patients. Eleven patients received ECP as the third-line or later treatment. RESULTS: A total of 62% of the patients responded, with 48% achieving complete response. In the patients with complete or partial response, the probabilities of survival at 4 years were 54 and 17%, respectively. The outcome of nonresponders was poor. The 1-year overall survivals of the patients with ECP as the second-line treatment either alone or in combination with an immunosuppressive drug or as the third-line treatment were 51, 28, and 18%, respectively. In multivariate analysis, starting ECP no later than 10 days after the start of the first-line treatment correlated with a good response and a consequent survival benefit. CONCLUSION: Extracorporeal photopheresis is an effective and well-tolerated treatment that should be considered as a second-line treatment for aGVHD.

Coinfusion of mobilized hematopoietic stem cells from an HLA-mismatched third-party donor with umbilical cord blood graft to support engraftment.

We evaluated the role of mismatched third-party hematopoietic stem cells (TPC) in shortening the neutropenia after umbilical cord blood transplantation (UCBT). A TPC graft was given to 7/37 children with UCBT to support engraftment due to anticipated increased risk of nonengraftment (N=6) or active infection (N=1). TPC grafts were collected with apheresis from haploidentical family members. The median UCB and CD34 cell counts were 5.10 (range, 4.13 to 9.98)×10/kg and 5.98 (range, 4.40 to 14.00)×10/kg, respectively. The median time to neutrophil engraftment was shorter in the patients with TPC (12 d; range, 9 to 24 d) than those without (23 d; range, 12 to 44 d) (P=0.010). TPC chimerism was lost in median at 28 (range, 24 to 103) days posttransplant. TPC grafts from mothers engrafted similarly as the grafts from other family members. UCB graft cell count and the use of methotrexate posttransplant strongly contributed to engraftment. TPC may form a valuable transient bridging graft over the neutropenia after UCBT in patients with anticipated high-risk of nonengraftment or toxicity due to pretransplant infections.

Clinically relevant germline variants in allogeneic hematopoietic stem cell transplant recipients.

Allogeneic hematopoietic stem cell transplantation (HSCT) provides patients with severe hematologic disease a well-established potential for curation. Incorporation of germline analyses in the workup of HSCT patients is not a common practice. Recognizing rare harmful germline variants may however affect patients' pre-transplantation care, choice of the stem cell donor, and complication risks. We analyzed a population-based series of germline exome data of 432 patients who had undergone HSCT. Our aim was to identify clinically relevant variants that may challenge the outcome of the HSCT. We focused on genes predisposing to hematological diseases, or solid tumors, and genes included in the American College of Medical Genetics secondary findings list v3.0. As population-specific controls, we used GnomAD non-cancer Finns (n = 10,816). We identified in our population-based analysis rare harmful germline variants in disease-predisposing or actionable toxicity-increasing genes in 17.8% of adult and pediatric patients that have undergone HSCT (15.1% and 22.9%, respectively). More than half of the patients with a family member as a donor had not received genetic diagnosis prior to the HSCT. Our results encourage clinicians to incorporate germline genetic testing in the HSCT protocol in the future in order to reach optimal long-term outcome for the patients.

Fludarabine/TBI 8 Gy versus fludarabine/treosulfan conditioning in patients with AML in first complete remission: a study from the Acute Leukemia Working Party of the EBMT.

The optimal reduced intensity conditioning (RIC) regimen is a matter of debate. We retrospectively compared conditioning with fludarabine plus fractionated total body irradiation of 8 Gy (FluTBI) and fludarabine plus treosulfan 30, 36 or 42 g/m2 (FluTreo) in 754 patients with AML above the age of 40 years undergoing an allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission (CR). After balancing patient characteristics by propensity score matching of 115 patients in each group, FluTBI was associated with a significantly lower probability of relapse compared to FluTreo (18.3% vs. 34.7%, p = 0.018) which was counteracted by a higher non-relapse mortality (NRM, 16.8% vs. 5.3%, p = 0.02). Thus, overall survival and graft-versus-host disease-free and relapse-free survival at 2 years were similar between groups (OS 66.9% vs. 67.8%, GRFS 50.3% vs. 45.6%). Univariate analysis by age group demonstrated a higher NRM exclusively in patients ≥55 years of age treated with FluTBI compared to FluTreo (27.6% vs. 5.8%, p = 0.02), while a similarly low NRM was observed in patients <55 years in both groups (6.0% vs. 4.7%, p = ns). We conclude that both conditioning regimens are effective and safe, but FluTBI may better be reserved for younger patients below the age of 55 years.

20-Year Steady Increase in Survival of Adult Patients with Relapsed Philadelphia-Positive Acute Lymphoblastic Leukemia Post Allogeneic Hematopoietic Cell Transplantation.

PURPOSE: Relapse after allogeneic hematopoietic cell transplantation (allo-HCT) remains the first cause of transplant failure in patients with Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). In other hematologic malignancies, therapeutic advances resulted in significant improvement over time in survival of patients relapsing after transplant. EXPERIMENTAL DESIGN: We compared outcomes at European Society for Blood and Marrow Transplantation (EBMT) participating centers of 899 adult patients with Ph+ ALL who relapsed between 2000 and 2019 after allo-HCT performed in first complete remission. Median follow-up for alive patients was 56 months. RESULTS: Overall, 116 patients relapsed between 2000 and 2004, 225 between 2005 and 2009, 294 between 2010 and 2014, and 264 between 2015 and 2019. Patient and transplant characteristics were similar over the four time periods except for a progressive increase in unrelated donors, peripheral blood stem cells, reduced intensity conditioning, and in vivo T-cell depletion and a progressive decrease in total body irradiation. The 2-year overall survival (OS) after relapse increased from 27.8% for patients relapsing between 2000 and 2004 to 54.8% for 2015 and 2019 (P = 0.001). A second allo-HCT within 2 years after relapse was performed in 13.9% of patients resulting in a 2-year OS of 35.9%. In multivariate analysis, OS from relapse was positively affected by a longer time from transplant to relapse and the year of relapse. CONCLUSIONS: We observed a major progressive improvement in OS from posttransplant relapse for patients with Ph+ ALL over the years, likely multifactorial including transplant-related factors, posttransplant salvage, and improvement in supportive care. These large-scale real-world data can serve as a benchmark for future studies in this setting. See related commentary by Gale, p. 813.

Measurable residual disease, FLT3-ITD mutation, and disease status have independent prognostic influence on outcome of allogeneic stem cell transplantation in NPM1-mutated acute myeloid leukemia.

Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified 1572 adult (age ≥ 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow-up for survivors was 23.7 months. FLT3-ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia-free survival (LFS) were negatively affected by concomitant FLT3-ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p < 0.0001, respectively), MRD positivity at transplant (HR 2.18, p < 10-5 and HR 1.71, p < 10-5 , respectively), and transplant in CR2 (HR 1.36, p = 0.026, and HR 1.26, p = 0.033, respectively), but positively affected by Karnofsky score ≥90 (HR 0.74, p = 0.012, and HR 0.7, p = 0.0002, respectively). Overall survival (OS) was also negatively influenced by concomitant FLT3-ITD (HR 1.6, p = 0.0001), MRD positivity at transplant (HR 1.61, p < 10-5 ), and older age (HR 1.22 per 10 years, p < 0.0001), but positively affected by matched sibling donor (unrelated donor: HR 1.35, p = 0.012; haploidentical donor: HR 1.45, p = 0.037) and Karnofsky score ≥90 (HR 0.73, p = 0.004). These results highlight the independent and significant role of FLT3-ITD, MRD status, and disease status on posttransplant outcomes in patients with NPM1-mutated AML allowing physicians to identify patients at risk of relapse who may benefit from posttransplant prophylactic interventions.

Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide versus Cyclosporine A and Methotrexate in Matched Sibling Donor Transplantation.

Cyclosporine A (CSA) and methotrexate (MTX) is the standard graft-versus-host disease (GVHD) prophylaxis regimen for matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). Recently, post-transplantation cyclophosphamide (PTCy) has been shown to be effective in GVHD prevention. In this registry-based study, we compared outcomes of 118 patients treated with PTCy and 1202 patients with CSA/MTX who underwent MSD allo-HCT for acute myelogenous leukemia. In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2 years compared with CSA/MTX (41.1% versus 21.3%; P = .039). The incidences of day +180 grade II-IV acute GVHD and 2-year chronic GVHD were comparable in the PTCy and CSA/MTX arms (25.2% versus 25.4% [P = .90] and 42.6% versus 42.6% [P = .84], respectively). Similarly, 2-year leukemia-free survival (LFS; 54.4% versus 74.32%; P = .052), overall survival (OS; 70.6% versus 79.7%; P = .15), and GVHD-free relapse-free survival (GRFS; 38.1% versus 52.5%; P = .49) were not statistically different in the 2 arms. Our data show that GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS as seen with conventional CSA/MTX in patients undergoing allo-HCT from an MSD. The higher rate of relapse observed with PTCy needs further evaluation in a prospective study. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Outcomes and toxicity of allogeneic hematopoietic cell transplantation in chronic myeloid leukemia patients previously treated with second-generation tyrosine kinase inhibitors: a prospective non-interventional study from the Chronic Malignancy Working Party of the EBMT.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a treatment option for patients with chronic myeloid leukemia (CML) who fail to respond to tyrosine kinase inhibitors (TKIs). While imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second-generation TKI (2GTKI). We present the results of a prospective non-interventional study performed by the EBMT on 383 consecutive CML patients previously treated with dasatinib or nilotinib undergoing allo-HCT from 2009 to 2013. The median age was 45 years (18-68). Disease status at transplant was CP1 in 139 patients (38%), AP or >CP1 in 163 (45%), and BC in 59 (16%). The choice of 2GTKI was: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. With a median follow-up of 37 months (1-77), 8% of patients developed either primary or secondary graft failure, 34% acute and 60% chronic GvHD. There were no differences in post-transplant complications between the three different 2GTKI subgroups. Non-relapse mortality was 18% and 24% at 12 months and at 5 years, respectively. Relapse incidence was 36%, overall survival 56% and relapse-free survival 40% at 5 years. No differences in post-transplant outcomes were found between the three different 2GTKI subgroups. This prospective study demonstrates the feasibility of allo-HCT in patients previously treated with 2GTKI with a post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients.

Allogeneic stem cell transplant in patients with acute myeloid leukemia and karnofsky performance status score less than or equal to 80%: A study from the acute leukemia working party of the European Society for Blood and Marrow Transplantation (EBMT).

Limited data are currently available on the outcome of patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) with a reduced performance status. We herein present the results of a registry study on 2,936 AML patients undergoing allo-SCT in first remission (CR1) with a Karnofsky Performance Status (KPS) score less than or equal to 80%. Two-year leukemia-free survival (LFS), overall survival (OS) and graft-versus-host disease (GVHD)-free, and relapse-free survival (GRFS) rates were 54%, 59%, and 41%, respectively. In multivariable analysis, patients with a KPS score = 80% had lower non-relapse mortality (NRM) and superior OS in comparison to patients with a KPS score <80% (p < 0.001). In the subgroup of patients with a KPS score =80%, a reduced-intensity conditioning (RIC) regimen was associated with an increased risk of relapse (p = 0.002) and lower GRFS (p < 0.001) compared to myeloablative conditioning (MAC). Differently, in patients with a KPS score <80%, a RIC regimen resulted in lower NRM (p < 0.001), whereas relapse incidence did not differ, thus leading to an improved GRFS (p = 0.008) as compared to MAC. A transplant from a matched sibling donor (MSD) was associated with a reduced incidence of grade III-IV acute GVHD (p < 0.01) and NRM (p < 0.01) in comparison to other donor types. In conclusion, allo-SCT appears feasible in AML patients with a jeopardized KPS score. Survival is significantly affected by the conditioning intensity, which should be adjusted according to the severity of KPS impairment.