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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.

Haploidentical hematopoietic cell transplantation (haplo-HCT) is being increasingly used in acute leukemia patients as an alternative transplant modality when matched sibling or matched unrelated donors are unavailable. As several potential haploidentical relative donors are typically available for a given patient, optimizing donor selection to improve clinical outcome is crucial. The impact of donor age and kinship on the outcome of acute leukemia patients is not clearly established in this setting. Using the multinational registry of the acute leukemia working party of the European society for blood and marrow transplantation we retrospective analyzed the clinical outcome of 1270 acute myeloid leukemia and acute lymphoblastic leukemia patients who underwent haplo-HCT between 2005 and 2015. Patients over the age of 40 were significantly affected by increasing donor age resulting in higher non-relapse mortality (NRM) [Hazard ratio (HR)=1.86, confidence interval (CI) 95%, 1.18-2.94; P = .007], inferior leukemia-free survival (LFS) (HR = 1.59, CI 95%, 1.13-2.24; P = .007), and overall survival (OS) (HR = 1.74, CI 95%, 1.22-2.47; P = .002) when donors were over the age of 40. Additionally, kinship was found to be prognostically significant as patients transplanted from children donors over the age of 35 experienced an increased rate of NRM (HR = 1.82, CI 95%, 1.13-2.9; P = .01), inferior LFS (HR = 1.5, CI 95%, 1.05-2.13; P = .03), and OS (HR = 1.5, CI 95%, 1.04-2.15; P = .03). For patients younger than 40 years, donor age and kinship were mostly not clinically impactful. Our data establish donor age and kinship as significant determinants of outcome following haplo-HCT for acute leukemia patients.

The optimal conditioning regimen to employ before hematopoietic stem cell transplantation in acute lymphoblastic leukemia (ALL) is still undecided, and while cyclophosphamide/total body irradiation (Cy/TBI) is the most commonly used myeloablative regimen, there are concerns regarding long-term toxicity for patients conditioned with this regimen. Thiotepa-based conditioning is an emerging radiation-free regimen with recent publications indicative of comparable clinical outcomes to TBI-based conditioning. In this analysis of the acute leukemia working party of the EBMT, we performed a retrospective matched-pair analysis, evaluating the outcome of adult patients with ALL who received thiotepa-based conditioning (n = 180) with those receiving Cy/ TBI conditioning (n = 540). The 2-year leukemia-free survival and overall survival (OS) rates of both conditioning regimens were comparable, 33% for thiotepa [95% confidence interval (CI): 26.4-42.8] versus 39% for Cy/TBI (95% CI: 34.8-44.5] (P = .33) and 46.5% [95% CI: 38.6-56.1] versus 48.8% [95% CI: 44.2-54] (P = .9), respectively. There was no significant difference between the two regimens in the incidence of either acute graft versus host disease (GVHD) or chronic GVHD. Multivariate analysis demonstrated increased relapse incidence for thiotepa conditioning compared to Cy/TBI (HR = 1.78, 95% CI, 1.07-2.95; P = .03) which did not affect OS. Our results indicate that thiotepa-based conditioning may not be inferior to Cy/TBI for adult patients with ALL.

Up to 20% of acute myeloid leukemia (AML) patients present initially with hyperleukocytosis, placing them at increased risk for early mortality during induction. Yet, it is unknown whether hyperleukocytosis still retains prognostic value for AML patients undergoing hematopoietic stem cell transplantation (HSCT). Furthermore, it is unknown whether hyperleukocytosis holds prognostic significance when modern molecular markers such as FLT3-ITD and NPM1 are accounted for. To determine whether hyperleukocytosis is an independent prognostic factor influencing outcome in transplanted AML patients we performed a retrospective analysis using the registry of the acute leukemia working party of the European Society of Blood and Marrow Transplantation. A cohort of 357 patients with hyperleukocytosis (159 patients with white blood count [WBC] 50 K-100 K, 198 patients with WBC >= 100 K) was compared to 918 patients without hyperleukocytosis. Patients with hyperleukocytosis were younger, had an increased rate of favorable risk cytogenetics, and more likely to be FLT3 and NPM1 mutated. In multivariate analysis, hyperleukocytosis was independently associated with increased relapse incidence (hazard ratio [HR] of 1.55, 95% confidence interval [CI], 1.14-2.12; P = .004), decreased leukemia-free survival (HR of 1.38, 95% CI, 1.07-1.78; P = .013), and inferior overall survival (HR of 1.4, 95% CI, 1.07-1.84; P = .013). Hyperleukocytosis retains a significant prognostic role for AML patients undergoing HSCT.

Introduction: Notwithstanding recent advances in the molecular characterization of acute myeloid leukemia (AML), the 2016 world health organization (WHO) classification system of AML still recognizes AML, not otherwise specified (NOS) as a major category. AML, NOS patients are further morphologically subcategorized according to the French, American, and British (FAB) classification system, widely used by pathologists and hematologists. While recent data proposes that the FAB classification does not provide additional prognostic information for patients for whom NPM1 status is available (Walter, 2013), it is unknown whether FAB classification still retains a prognostic role in the current era of molecular and cytogenetic prognostication in predicting outcome of AML patients undergoing an allogeneic stem cell transplant (ASCT). Thus, we set out to determine whether the FAB classification system complemented with molecular stratification provides prognostic information in AML, NOS patients undergoing an ASCT in CR1. Patients and Methods: Using the European Society of Blood and Bone Marrow Transplantation (EBMT) registry we identified patients with available FAB data and the following inclusion criteria: age over 18, de-novo non-M3 AML, and ASCT in complete remission (CR1) from a fully matched sibling or a 10/10 HLA matched unrelated donor. Patients with recurrent genetic abnormalities, AML with myelodysplasia-related changes, and patients with therapy-related myeloid neoplasms were excluded from the analysis. Multivariate analyses was used to assess whether the FAB type was independently associated with leukemia free survival (LFS), overall survival (OS), relapse incidence (RI), and non-relapse mortality (NRM). Age, gender, cytogenetics, donor type, FLT3 status, NPM1 status, and conditioning intensity were covariates for regression modeling. Results: A cohort of 1690 patients transplanted between 2005-2014, at a median age of 50 years (range 18-74 years) with a median follow up duration of 34.7 months, was analyzed (baseline characteristics of the cohort summarized per FAB category are shown in table 1). The different FAB subtypes had comparable rates of donor type (62% HLA identical sibling donors for the entire cohort), and conditioning intensity (55% underwent myeloablative conditioning). FAB M6/M7 patients underwent transplant at an older age while FAB M0 and M7 had increased rates of poor risk cytogenetics (26% and 60%, respectively). NPM1 mutations were more prevalent among FAB M4 (53%) whereas FAB M1 patients had increased rates of mutated FLT3 (55%). Multivariate analysis of the entire cohort showed that FAB M6/M7 was significantly associated with decreased LFS compared to the other FAB subtypes grouped together (hazard ratio (HR) of 1.41, 95% confidence interval (CI), 1.01-1.99; p=0.046), and increased NRM (HR, 1.79; 95% CI, 1.06-3.01; p=0.028). Next, to align our data with the recently introduced 2016 WHO AML, NOS classification we restricted our analysis to the NPM1 negative subset of the cohort (n=712), and found on multivariate regression analysis that FAB M6/M7 was significantly associated with increased NRM (HR, 2.17; 95% CI, 1.14-4.16; p=0.019) compared to the other FAB subtypes. RI, LFS, and OS rates were not significantly different between FAB M6/M7 and the other FAB subtypes. Finally, we wanted to ascertain whether in FLT3 mutated patients FAB classification retains prognostic significance post-transplant. We did not find any statistically significant difference in terms of outcome between M6/M7 versus all other FAB subtypes, possibly due to the small cohort of M6/M7 FLT3+ patients (n=18). Conclusion: FAB classification may predict outcome following transplantation in NPM1 negative AML, NOS patients. Table Baseline characteristics of study cohort per FAB category Table. Baseline characteristics of study cohort per FAB category Figure Clinical outcome in NPM1 negative AML, NOS patients after ASCT* *Adjusted for age, gender, donor type, cytogenetics, FLT3 status and conditioning regimen Figure. Clinical outcome in NPM1 negative AML, NOS patients after ASCT*. / *Adjusted for age, gender, donor type, cytogenetics, FLT3 status and conditioning regimen Disclosures No relevant conflicts of interest to declare.

ABO incompatibility is commonly observed in stem cell transplantation and its impact in this setting has been extensively investigated. HLA-mismatched unrelated donors (MMURD) are often used as an alternative stem cell source but are associated with increased transplant related complications. Whether ABO incompatibility affects outcome in MMURD transplantation for acute myeloid leukemia (AML) patients is unknown. We evaluated 1,013 AML patients who underwent MMURD transplantation between 2005 and 2014. Engraftment rates were comparable between ABO matched and mismatched patients, as were relapse incidence [34%; 95% confidence interval (CI), 28-39; for ABO matched vs. 36%; 95% CI, 32-40; for ABO mismatched; P = .32], and nonrelapse mortality (28%; 95% CI, 23-33; for ABO matched vs. 25%; 95% CI, 21-29; for ABO mismatched; P = .2). Three year survival was 40% for ABO matched and 43% for ABO mismatched patients (P = .35), Leukemia free survival rates were also comparable between groups (37%; 95% CI, 32-43; for ABO matched vs. 38%; 95% CI, 33-42; for ABO mismatched; P = .87). Incidence of grade II-IV acute graft versus host disease was marginally lower in patients with major ABO mismatching (Hazard ratio of 0.7, 95% CI, 0.5-1; P = .049]. ABO incompatibility probably has no significant clinical implications in MMURD transplantation. ispartof: American Journal of Hematology vol:92 issue:8 pages:789-796 ispartof: location:United States status: published