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Background The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide prophylaxis is gaining traction in patients with acute lymphoblastic leukemia (ALL). Methods The Acute Leukemia Working Party/European Society for Blood and Marrow Transplantation registry was used to evaluate the outcomes of adult patients with ALL who underwent haplo-HCT during 2011 through 2015 and compared them with the outcomes of those who underwent transplantation during 2016 through 2018. Results The analysis consisted of 195 patients, including 79 who underwent transplantation during 2011 through 2015 and 116 who underwent transplantation during 2016 through 2018. Overall, the 2-year leukemia-free survival and relapse incidence rates were 56.5% and 21%, respectively. The 100-day incidence of grade 2 through 4 acute graft-vs-host disease (GVHD) was 34.5%. The rates of nonrelapse mortality (NRM) and overall survival (OS) were 22.5% and 64.7%, respectively. Patients who underwent transplantation during 2016 through 2018 experienced improved rates of leukemia-free survival (64.9% vs 47.3%; P = .019) and OS (75.5% vs 53.5%; P = .006). Patients who underwent transplantation during 2016 through 2018 developed more grade 2 through 4 acute GVHD (42% vs 26.4%; P = .047). The incidence of relapse, GVHD-free/relapse-free survival, grade 3 and 4 acute GVHD, chronic GVHD, and extensive chronic GVHD did not differ significantly between groups. In multivariate analysis, more recently transplanted patients had a significantly reduced risk of NRM (hazard ratio, 0.44; 95% CI, 0.22-0.89; P = .022) and improved OS (hazard ratio, 0.47; 95% CI, 0.26-0.86; P = .014). A comparable analysis of patients who had acute myeloid leukemia during the same timeframes did not reveal any statistically significant differences in any outcomes. Conclusions The outcome of adult patients with ALL who receive posttransplant cyclophosphamide has improved over time, with an impressive 2-year OS of 75% and, most recently, an NRM rate of only 17%.

Introduction: Achievement of an initial complete remission (CR) following induction chemotherapy is tightly correlated with survival in acute myeloid leukemia (AML) patients, yet patients in CR with incomplete hematologic recovery (CRi) still experience improved outcomes compared with nonresponding patients. Whether CRi predicts prognosis in patients referred to an allogeneic stem cell transplantation (allo-SCT) is incompletely defined. In this analysis, we evaluated whether clinical outcomes of transplanted AML patients in CR and CRi were significantly different. Methods: A retrospective single-center analysis of all de novo AML patients who underwent an allo-SCT between 2001 and 2015. The cohort included all adult patients with AML who underwent a first allo-SCT either in first or second CR or CRi at the time of transplantation. Results: The study cohort included 186 CR patients and 44 CRi patients. In univariate analysis, CRi was associated with inferior 3-year survival and 3-year nonrelapse mortality (NRM) compared to CR (41 vs. 62%; p = 0.022 and 27 vs. 10%; p = 0.006, respectively). In multivariate analysis, CRi was associated with decreased rates of survival (hazard ratio [HR] 2.01; 95% CI, 1.24–3.25; p = 0.005) and NRM (HR, 3.5; 95% CI, 1.6–7.8; p = 0.002). Conclusion: CRi in transplanted AML patients is potentially a potent predictor of increased NRM and survival.

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.

A substantial segment of patients with acute myeloid leukemia (AML) will relapse following an initial response to induction therapy or will prove to be primary refractory. High-dose cytarabine and mitoxantrone (HiDAC/MITO) is an established salvage therapy for these patients. We studied all adult patients with relapsed/refractory (R/R) AML who were treated with HiDAC/MITO in our center between the years 2008-2017. To determine whether responding patients harbored a unique molecular signature, we performed targeted next-generation sequencing (NGS) on a subset of patients. The study cohort consisted of 172 patients with a median age of 54 years (range 18–77). The composite complete remission rate was 58%; 11 patients (6%) died during salvage therapy. Median survival was 11.4 months with a 1-year survival rate of 48%. In multivariate analysis favorable risk cytogenetics [Odds ratio (OR)=0.34, confidence interval (CI) 95%, 0.17–0.68; P = 0.002], and de-novo AML (OR = 0.4, CI 95%, 0.16–0.98; P = 0.047) were independently associated with a favorable response. Patients who attained a complete remission had a median survival of 43.7 months compared with 5.2 months for refractory patients (p < 0.0001). Neither the FLT3-ITD and NPM1 mutational status nor the indication for salvage therapy significantly impacted on the response to HiDAC/MITO salvage. NGS analysis identified 20 different mutations across the myeloid gene spectrum with a distinct TP53 signature detected in non-responding patients. HiDAC/MITO is an effective salvage regimen in R/R AML, however patients with adverse cytogenetics or secondary disease may not benefit as much from this approach.

Reduced-intensity conditioning (RIC) allows for the use of allogeneic hematopoietic stem cell transplantation (HSCT) in older patients with acute myelogenous leukemia (AML). We compared outcomes between 713 patients age ≥70 years and 16,161 patients age 50 to 69 years who underwent HSCT between 2004 and 2014. A higher proportion of the older patients were male and had secondary AML, active disease, a peripheral blood stem cell graft, a matched unrelated donor, an RIC regimen, and a lower Karnofsky Performance Status (KPS) score (P.001). In multivariate analysis, the incidences of acute and chronic graft-versus-host disease and relapse were similar in the 2 age groups. Nonrelapse mortality at 2 years was 34% (95% confidence interval [CI], 31% to 38%) in patients age ≥70 years and 24% (95% CI, 25% to 32%) in those age 50 to 69 years (P.001). Survival at 2 years in the 2 groups was 38% (95% CI, 34% to 42%) and 50% (95% CI, 49% to 50%), respectively (P.001). In patients with active disease, the corresponding percentages were 35% (95% CI, 29% to 41%) in those age ≥70 years and 33% (95% CI, 31% to 34%) in those age70 years (P = .36). In patients age ≥70 years, a KPS score of ≥80% was associated with improved survival (hazard ratio, 1.53; 95% CI, 1.14 to 2.06; P = .003). In summary, patients age ≥70 years had worse outcomes, except for those with active AML.

Achievement of initial remission remains the most important clinical factor predicting long term survival in acute myeloid leukemia (AML) patients treated with intensive chemotherapy. Yet, whether the patient subset in need of a second cycle of intensive induction chemotherapy to reach remission experiences inferior outcomes compared to patients reaching remission after a single cycle of therapy, remains uncertain.Retrospective analysis of 302 consecutive AML patients treated with intensive induction chemotherapy in our institution in 2007-2020.Median patient age was 55 years with a median follow-up duration of 23 months. In terms of European LeukemiaNet (ELN) 2017 classification, 122 patients (40%) were designated as favorable risk disease, 108 patients (36%) were intermediate risk, and 71 patients (24%) were adverse risk. A hundred and seventy-seven patients (60%) attained remission following initial chemotherapy while 58 patients (20%) required an additional cycle of intensive chemotherapy for remission. Patients requiring 2 cycles to reach remission were less likely to be NPM1 mutated (33% versus 51%; P=.025) or be in the ELN 2017 favorable risk category (25% versus 57%; P.001). In multivariate analysis achievement of remission following 2 cycles of intensive compared with a single cycle resulted in significantly inferior survival [hazard ratio (HR)=1.67, 95% CI, 1.07-2.59; P=.025] whereas leukemia-free survival was not significantly impacted (HR=1.26, 95% CI, 0.85-1.85) (P=.23). Relapse rates also did not differ to a significant degree between groups (45% versus 47%, P=.8).Attainment of an early remission significantly impacts long term survival in AML patients.

Key Points Gilteritinib induces 2 distinct marrow responses in FLT3-mutated AML: responses with and without differentiation. Ongoing clonal hematopoiesis is ubiquitous during gilteritinib therapy and may promote genetic evolution and drug resistance.

Baseline cytogenetic studies at diagnosis remain the single most important determinant of outcome in patients with acute myeloid leukemia (AML). However, the prognostic role of the complete gamut of cytogenetic aberrations in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently undefined. In addition, their significance in conjunction with FLT3-ITD status has not been addressed thus far. Using the ALWP/EBMT registry we conducted a retrospective analysis to determine the clinical outcomes of AML patients undergoing allo-HSCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-HSCT from either a matched sibling or a matched unrelated donor. Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Trisomy 14, del(9q), and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITD status was constructed with significant prognostic implications. Our analysis supports the added prognostic significance of FLT3-ITD to baseline cytogenetics in patients undergoing allo-HSCT.

Acute leukemia is an aggressive blood malignancy with low survival rates. A high expression of stem-like programs in leukemias predicts poor prognosis and is assumed to act in an aberrant fashion in the phenotypically heterogeneous leukemia stem cell (LSC) population. A lack of suitable genome engineering tools that can isolate LSCs based on their stemness precludes their comprehensive examination and full characterization. We hypothesized that tagging endogenous stemness-regulatory regions could generate a genome reporter for the putative leukemia stemness-state. Our analysis revealed that the ERG + 85 enhancer region can serve as a marker for stemness-state and a fluorescent lentiviral reporter was developed that can accurately recapitulate the endogenous activity. Using our novel reporter, we revealed cellular heterogeneity in several leukemia cell lines and patient-derived samples. Alterations in reporter activity were associated with transcriptomic and functional changes that were closely related to the hematopoietic stem cell (HSC) identity. Notably, the differentiation potential was skewed towards the erythro-megakaryocytic lineage. Moreover, an ERG + 85High fraction of AML cells could regenerate the original cellular heterogeneity and was enriched for LSCs. RNA-seq analysis coupled with in silico drug-screen analysis identified 4HPR as an effective inhibitor of ERG + 85High leukemia growth. We propose that further utilization of our novel molecular tool will identify crucial determinants of LSCs, thus providing a rationale for their therapeutic targeting.

Purpose: Posttransplant cyclophosphamide (PTCy) is increasingly being utilized as a principle GvHD prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) is a valid option in the absence of a matched related donor. Experimental Design: We compared the outcomes of patients with acute leukemia who underwent haplo bone marrow (haplo-BM, N = 401) versus UD mobilized peripheral blood stem cells (UD-PB, N = 192) transplantation in the setting of PTCy. Results: The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively (P < 0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively (P < 0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively (P = 0.21). In the multivariate analysis, the risk of grade 2–4 acute GvHD (HR = 0.53, P = 0.01) and chronic GvHD (HR = 0.50, P = 0.02) was significantly lower in the haplo-BM group compared with the UD-PB group. There was no significant difference between the study groups with respect to relapse incidence, nonrelapse mortality, leukemia-fee survival, overall survival, or GvHD-free and relapse-free survival. Conclusions: The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared with a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into a difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.

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.

Background Relapsed/refractory acute myeloid leukemia (R/R AML) remains a significant therapeutic challenge and while meaningful therapeutics gains have been achieved with the introduction of novel agents, clinical outcomes remain unsatisfactory. Anthracyclines constitute an essential component of induction chemotherapy for AML patients, however owing in part to the cardiotoxicity concerns, they are not broadly prescribed in R/R AML settings. Bisantrene, an anthracene with anthracycline-like activity, was shown in earlier studies to be an effective salvage therapy in R/R AML with no discernible cardiotoxicity. In this study, we assessed the clinical efficacy of bisantrene in a cohort of heavily pre-treated R/R AML patients. Aims To investigate the safety and efficacy of bisantrene in adult patients with R/R AML. Methods This phase 2, single center study (NCT03820908) enrolled adult R/R AML to receive bisantrene (250 mg/m2 daily for 7 days) which was administered via an intravenous infusion over 2 hours on days 1-7. Patient therapy was limited to one completed cycle of bisantrene including those who had achieved a partial response. Disease assessment included routine blood work and bone marrow studies which were performed at baseline and subsequently at blood count recovery or suspected disease progression. Next generation sequencing (NGS) was performed at baseline for all patients with adequate pre-study samples. Results In all, 10 patients were recruited to the study with a median of 3 lines of prior therapy including 7 patients who had relapsed following allogeneic stem cell transplantation. With regard to disease burden, three patients had an antecedent myeloid disorder while 4 patients had extramedullary disease at study recruitment. The most frequently reported grade ≥3 treatment attributed hematologic AE was thrombocytopenia whereas the most frequently reported grade ≥3 treatment attributed non-hematologic AE was mucositis. Of the ten patients, one (10%) achieved a complete remission and three patients achieved a partial remission resulting in an overall response rate of 40% with one patient being bridged to transplantation. NGS of patient samples identified a wide array of mutations associated with activated signaling, splicing, and epigenetic modification (table 1). Conclusion In conclusion, in the present study bisantrene induced clinical responses in 4 of 10 patients with R/R AML with acceptable toxicity. Given its marked activity in patients with leukemia cutis, chroromas and CNS disease, we speculate that bisantrene-based chemotherapy may have a significant applicability in patients with extramedullary disease. In view of the observed efficacy and low related toxicity, a follow-up study combining bisantrene with complementary anti-leukemic therapy is planned. Disclosures Canaani: Abbvie: Consultancy, Honoraria, Research Funding. Benjamini:Abbvie Inc: Consultancy, Research Funding. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding.

Despite considerable advances in our understanding of the molecular and epigenetic underpinnings of the myelodysplastic syndromes (MDS), this diverse group of myeloid neoplasms remains a significant clinical challenge. Considerable barriers to timely development of effective therapy include the diverse molecular landscape encountered in MDS patients, the difficulty in translating specific molecular aberration into a clinically meaningful animal model, as well as challenges in patient recruitment into clinical trials. These speak to the need to discover efficacious novel therapeutic targets which would in turn translate into improved patient outcomes in terms of both survival and quality of life. In this review, we outline recently published data pertaining to therapeutic advances in TGF-β pathway inhibition, STAT3, Hedgehog signaling, and additional therapeutic venues being actively explored in MDS.

Relapse has become the leading cause of treatment failure after stem cell transplantation. Besides cellular therapies and novel agents, immunotherapeutic strategies have entered clinical practice in order to reduce or prevent relapse. Here, we summarize the presentations on checkpoint inhibitors, vaccination strategies, and novel antibody therapies, which were presented and discussed at the third International Workshop on Biology, Prevention, and Treatment of Relapse after Stem Cell Transplantation.

Background: Venetoclax-based combinations were recently approved to treat patients (pts) with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. Limited prospective 'real-world' data is available on treatment patterns of venetoclax-based therapy in routine clinical practice. We investigated patterns of patient selection, efficacy, toxicity, patient related outcome and post-remission management in a nationwide multicenter prospective observational trial. Methods: Newly diagnosed pts with AML were enrolled at the time of venetoclax-based therapy initiation from 10 medical centers in Israel. Demographic, clinical and patient-related baseline characteristics were documented. Treatment patterns, safety and efficacy outcomes are reported. Results: Between August 12, 2019, and June 17, 2021(data cut) ,127 AML pts were enrolled to receive venetoclax based therapy. Baseline patient and disease characteristics are reported in Table 1. The main reasons for physician's choice of venetoclax-based therapy were age ≥75, comorbidities and ECOG ≥2 (patient related factors) in 76% of cases and adverse disease biology predicting poor response to intensive chemotherapy (disease related factors) in 24% of cases. Most pts started therapy in an inpatient setting, 82 (64.6%) with a median hospitalization duration of 14 days, while 44 pts (34.6%) started therapy as out pts. Pts received a median of 3.8 cycles of therapy (range 1-21). Most pts (97%) received venetoclax in combination with hypomethylating agents. The full dose of 400mg QD after a median ramp-up duration of 3 days was achieved in 88% of the pts. Dose interruptions and dose modifications during follow-up occurred in 59 (46%) and 30 (24%) of pts, respectively. To allow for adequate follow up for response assessment, efficacy analysis was limited to pts enrolled prior to December 31, 2020, and included 108 pts with a median follow-up of 8 months (range 1-20). As of data cut, 93 pts completed cycle 1 of therapy, 66 pts completed cycle 3 and 39 pts completed cycle 6. 29 pts (27%) are still active on treatment. Best composite complete remission [CCR = complete remission (CR) plus CR with incomplete count recovery (CRi)] was achieved in 62 (57%) pts. CCR rates were assessed in different pre-defined subgroups. Best CCR in pts selected for therapy based on disease-related and patient-related factors were 70% and 54% respectively. Best CCR in pts with AML arising from MPN and pts with other AML were 45% and 58% respectively. Estimated median overall survival (OS) of all pts was 9.6 months (range 7.4-10.6) (Figure 1). Achieving CCR was associated with a superior probability for survival. Estimated median OS was 13.6 months (range 10.6 - not reached) in pts achieving CCR and 4.2 months (range 1.2-10.3) in non-CCR (p Allogeneic transplantation following venetoclax based treatment was offered to 16 (26%) pts with a median age of 71 years (range 43-77). Last documented response prior to transplant was CR in 5 (32%) pts, CRi 9 (56%), MLFS 1 (6%) and PR in 1 (6%) patient. Among grade ≥3 AEs were febrile neutropenia in 28% and infections in 21% of pts. Clinical and laboratory tumor lysis syndrome (TLS) was documented in 2 and 4 pts, respectively. Antifungal prophylaxis was administered in 20% of pts and granulocyte colony-stimulating factor (GCSF) support was used in 17% of pts in response. Early death rate at 30 and 60 days were 7% and 13%, respectively. Conclusion: This prospective real-world analysis reveals unique patterns of patient selection and venetoclax treatment utilization in a medical system with wide access for this indication. Venetoclax-based therapies are effective and associated with manageable toxicity, including in AML patient populations that were excluded from previous registration trials with comparable CCR and early death rates. Factors associated with patient selection in the 'real-world' setting and immature follow up data most probably led to a shorter estimated median OS in this analysis as compared to controlled trials. The REVIVE study continues to expand and is expected to provide additional insights on treatment patterns, management as well as clinical and patient related outcomes. Figure 1 Figure 1. Disclosures Wolach: Janssen: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Astellas: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Neopharm: Consultancy. Levi: AbbVie: Consultancy, Research Funding. Lavie: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Other: Fees for lectures; Roche: Other: Fees for lectures; Novartis: Other: Fees for lectures. Tavor: AbbVie: Consultancy. Hellmann: AbbVie: Consultancy. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Zuckerman: Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen: Honoraria; Cellect Biotechnology: Honoraria; BioSight Ltd: Honoraria; AbbVie: Honoraria; Orgenesis Inc.: Honoraria. Stemer: AbbVie: Consultancy. Berelovich: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ofek: AbbVie: Current Employment, Current equity holder in publicly-traded company. Frankel: AbbVie: Current Employment, Current equity holder in publicly-traded company. Grunspan: AbbVie: Current Employment, Other: May hold equity. Ofran: Medison Israel: Consultancy; Pfizer: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; Janssen: Consultancy. Moshe: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Astellas: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures.

Background. Early mortality remains a challenging therapeutic facet of the initial induction phase of intensive chemotherapy in patients with acute myeloid leukemia (AML). The impact of standard molecular evaluation and risk category of the European LeukemiaNet (ELN) 2017 classification model on early mortality have not been rigorously evaluated thus far. Aim. Evaluate the impact of standard clinical, laboratory, cytogenetic, and molecular parameters on the likelihood of early death following induction chemotherapy in a cohort of uniformly treated AML patients receiving standard intensive induction chemotherapy. Methods. We reviewed the medical records of 320 consecutive adult patients with newly diagnosed AML treated with intensive induction chemotherapy in our center from 2007 to 2021. The Kaplan-Meier method was used to determine overall survival and the log-rank test was used to compare differences between groups. All tests were two-sided and a p-value < 0.05 was considered statistically significant. Results. From October 2007 to January 2021, 320 adult patients with AML were treated with standard anthracycline and cytarabine-based intensive induction chemotherapy . Median age was 56 years (range, 18 to 92); 33 patients (10%) died during induction. As outlined in table 1, patient age, white blood cell count, hemoglobin level, platelet level, creatinine, uric acid, lactate dehydrogenase serum levels, FLT3-ITD and CEBPA mutational status did not significantly impact on early mortality. NPM1 mut patients had a lower likelihood of early death compared to NPM1 wt (5% versus 13%; p=0.023) whereas patients with high-risk cytogenetic studies experienced higher rates of induction mortality compared with intermediate and favorable risk patients (20% versus 8% and 7%, respectively; p=0.049). Adverse risk ELN 2017 were significantly more likely to die during induction compared with intermediate and favorable risk patients (20% versus 10% and 4%, respectively; p=0.001). Patients treated in 2007-2011 experienced a significantly higher rate of induction death compared with patients in 2012-2021 (17% versus 8%; p=0.039). Multivariate analysis confirmed adverse ELN 2017 [odds ratio (OR), 6.7; 95% confidence interval (CI), 1.77-25.3; p=0.005) and treatment timeframe (OR, 0.36; 95% CI, 0.15-0.87; p=0.023) as pivotal predictors of early mortality. Conclusion. Our data underscore the tight association of the ELN 2017 risk model with early induction mortality in AML patients receiving intensive induction chemotherapy. With the introduction of novel agents as well as innovative regimens combining these agents, it is becoming clear that better prognostic tools are needed at the provider level to navigate the rapidly changing therapeutic landscape seen in current management of AML patients. Our findings further underpin the importance of integrated prognostication models and their profound implications on the immediate peri-induction setting in AML patients. Figure 1 Figure 1. Disclosures Avigdor: Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria.

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.

Hematopoietic stem cell transplantation (HSCT) is being increasingly explored as a treatment modality for older patients with acute lymphoblastic leukemia (ALL). Yet, concerns regarding the long term outcome of transplantation in older patients limit the wide spread applicability of this approach. In this analysis we set out to determine the outcome of ALL patients over the age of 60 who underwent reduced intensity HSCT. Herein, we present the experience of the acute leukemia working party (ALWP) of the EBMT in this age group. We analyzed a cohort of 142 patients transplanted in first remission with a median age of 62 (range 60–76 years) and a median follow-up period of 36 months post-transplant. At 3 years, overall survival (OS) and leukemia-free survival were 42% and 35%, respectively. Multivariate analyses identified cytomegalovirus (CMV) donor-recipient matching (CMV D+/R+) to be significantly associated with inferior OS. Patients transplanted from unrelated donors experienced increased grade II-IV acute graft versus host disease compared to those receiving grafts from matched related donors [Hazard ratio (HR) of 3.7, 95% confidence interval (CI), 1.75–7.8; p = 0.0005). Outcome was not impacted by Philadelphia chromosome status. A select subset of older ALL patients will benefit from extended survival and a disease free state following HSCT.

Background: The outcome of elderly patients with Acute Myeloid Leukemia (AML) is poor and treatment options in these high-risk groups are limited. Recently, venetoclax combinations with hypomethylating agents or low dose cytarabine were approved to treat patients with AML ineligible for intensive chemotherapy. However limited prospective data is available on the safety and efficacy of venetoclax treatment in routine clinical practice. Israel is among the first countries to have approved venetoclax-based combinations as first line therapy for AML and this treatment is fully reimbursed via the national health system. Here we present the initial results of a prospective, multicenter, nationwide trial that sought to assess the use of venetoclax-based therapy in a real-world setting. Methods: A prospective observational nationwide multicenter trial. Newly diagnosed patients with AML were enrolled at the time of venetoclax-based therapy initiation. Demographic, clinical and patient-related baseline characteristics were documented. Treatment patterns, safety and efficacy outcomes are reported. Patient related outcomes were assessed at baseline and after cycle 3 using the EQ-5D-5L and EORTC QLQ-C30 questionnaires. Results: A total of 70 patients were enrolled between August 2019 and June 2020 (data cut off) with a median age of 75 years (range 45-88) and a median follow-up of 74 days (8-232). Two-thirds of patients were males (62.9%). Over one-quarter (28.6%) of patients had an ECOG performance status of 2 or higher; the median modified Charlson Comorbidity Index (CCI) was 0 (range 1-4) with 27.1% with a CCI ≥2. De-novo AML was documented in 44.3%, secondary AML was diagnosed in 52.8% (secondary to MDS (27.1%), MPNs (11.4%) and therapy related AML (14.3%)). European LeukemiaNet (ELN) risk category was favorable, intermediate and adverse in 8.6%, 30% and 42.9%, respectively (Table 1). Time from diagnosis to initiation of therapy was 8 days (median, range 1-38). The main reasons for choosing venetoclax-based low intensity therapy as reported by treating physicians were patient related factors (mainly age>75 years, performance status) in the majority of cases and adverse disease biology predicting poor response to intensive chemotherapy in 17.1%. Of the 57 patients with available data, 38 (67%) initiated therapy in an inpatient setting with a median hospitalization duration of 12 days (range 1-62 days) and 19 (33%) patients started therapy as outpatients. By data cutoff, of 63 patients that initiated therapy 45, 23 and 7 patients completed cycle 1, cycle 3 and cycle 6 assessments, respectively. Complete remission (CR) or CR with incomplete count recovery (CRi) was achieved in 23/44 (52.3%) patients that were assessed for best response. Of responding patients, 6 (23%, 5 CRi and 1 Partial Remission (PR)) went on to receive an allogeneic transplantation (median age 70.5 years). Ninety percent of patients received venetoclax in combination with hypomethylating agents (azacytidine n=56, decitabine n=1). The full dose of 400mg was administered in 87% of cases with a median ramp-up duration of 3 days. Dose interruptions, dose modifications and dose discontinuations during follow-up were frequent and occurred in 41%, 35% and 27%, respectively. During therapy 63.5% of patients experienced adverse events (AE) of any grade; severe AE's were recorded in 41.3% of patients. Febrile neutropenia was documented in 22.2% and Tumor Lysis Syndrome (TLS) was documented in 2 patients (grade 2; 3.2%). Early death rates at 30 and 60 days were 6.3% and 11.1%, respectively. Conclusion: In the real-world setting venetoclax-based therapies are effective and associated with manageable toxicity including in the outpatient setting. In routine practice patient-related factors and disease-related factors (disease-risk) both seem to play a role in choice of therapy. Venetoclax treatment in real-life practice in Israel appears to follow general recommendations, is tolerable with approximately 90% of patients achieving target dose. These observational data are expected to provide information on patient selection patterns, efficacy and safety and patient related outcomes in patients not in clinical trial. Table Disclosures Wolach: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures and Consultancy, Research Funding; Astellas: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Amgen: Other: Fees for lectures and Consultancy; Janssen: Other: Fees for lectures and Consultancy. Levi:Abbvie Inc: Consultancy, Research Funding. Canaani:Abbvie: Consultancy, Honoraria, Research Funding. Tadmor:AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Tavor:Abbvie: Consultancy, Honoraria, Research Funding. Hellmann:Abbvie: Research Funding. Stemer:Abbvie: Research Funding. Cohen:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Afik:Abbvie Inc: Current equity holder in publicly-traded company. Ofek:Abbvie Inc: Current Employment. Banayan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Kan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Grunspan:Abbvie Inc: Current Employment, Current equity holder in publicly-traded company. Ofran:AbbVie: Membership on an entity's Board of Directors or advisory committees. Moshe:Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding.

Background Chemotherapy based approaches still constitute an essential feature in the treatment paradigm of adult acute lymphoblastic leukemia (ALL). The German Multicenter Study Group (GMALL) is a well-established and commonly used protocol for ALL (Gökbuget 2012). Over the years evolving versions of the protocol have been developed with the aim of improving patient outcome (Apel 2014). In view of the recent advancements in the treatment of adult ALL we now analyzed our more recent data. Aims Assess the clinical outcomes of adult ALL patients treated on the GMALL protocol in real world settings, and establish prognostic parameters associated with long term survival and risk of relapse. Methods Retrospective analysis of all adult ALL patients who were treated with GMALL in our institution between the years 2008-2020. Demographic, clinical, cytogenetic, treatment, and transplant related data were collected using our institution's electronic medical records system. Baseline characteristics were evaluated by Fisher's exact test and Wilcoxon rank sum tests. Kaplan-Meier estimates were used to estimate overall survival (OS) and relapse-free survival (RFS). Hazard ratios and 95% confidence intervals were generated using a Cox proportional hazards model. Results The analysis comprised 81 evaluable patients with a median age of 36 years (range 18-73), 36% were adolescents and young adults (AYA). Forty-three were B-ALL (53%), 12 (15%) patients were Philadelphia chromosome positive ALL (Ph+ ALL), and 26 (32%) were T-ALL. Median duration of follow-up was 24.4 months (range 0.7-112.1 months), at the time of data analysis 51 patients (63.8%) were alive. Seventy patients (88%) attained a first remission (CR1) and 4 (5%) died during the first two induction phases. The 2-year and 5-year overall survival rates were 62% and 44%, respectively. Estimated 2-year and 5-year leukemia-free survival rates were 52% and 35%, respectively. Overall, disease relapse (31%), lethal infection (28%), and graft-versus-host disease (14%) accounted for most patient deaths. Of patients achieving CR1, 20 (29%) eventually relapsed after a median time of 9.8 months (range 1.1-69.3). Fifty-five patients (68%) underwent an allogeneic stem cell transplantation using matched sibling (47%), matched unrelated (31%), haploidentical (7%), partially mismatched (12%), and cord blood donors (3%). Of the 50 patients transplanted in CR1, 15 relapsed (30%) after a median time of 10.9 months (range 3.8-32.8). Multivariate analysis revealed that in terms of overall survival, increasing patient age was associated with inferior outcome [Hazard ratio (HR)=1.026, confidence interval (CI) 95%, 1.002-1.05, p=0.035) as was outcome for patients whose baseline cytogenetic analysis detected a higher number of clones (HR=2.69, CI 95%, 1.57-4.62, p=0.0002). T-ALL patients experienced longer survival compared with B-ALL (87 months versus 56 months, p=0.019) while patients transplanted using cord blood donors had inferior survival, 12.8 months, compared with matched sibling donors, 71.3 months, and fully matched unrelated donors, 73.4 months (p=0.001, and p=0.003, respectively). Relapse-free survival was significantly better in patients with T-ALL compared with B-ALL (90 months vs. 50 months, p=0.039), and in patients without t(12;21)(p13;q22) (75 months vs. 11.7 months, p=0.034). Gender, AYA status, extramedullary disease at diagnosis, initial white blood cell count, treatment delays, presence of MLL rearrangement, specific measurable residual disease modality used, GMALL risk category, and cytogenetic hyperdiploidy did not significantly impact on survival or disease relapse. Treatments for relapse following GMALL included blinatumomab (6), inotuzumab (3), nelarabine (3), and CAR-T (2). Conclusions While results are improving for patients treated on GMALL, a substantial patient segment still experiences relapse. It is conceivable that in the near future new novel therapeutic modalities for adult ALL involving the use of monoclonal antibodies and CAR-T cell therapy will help reduce relapse rates and further improve the current outcomes of patients treated on the GMALL protocol. Disclosures Avigdor: Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. Canaani:Abbvie: Consultancy, Honoraria, Research Funding.

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.

Background: Patients with acute myeloid leukemia (AML) are surviving longer. There are no data on changes in myocardial mechanics from standard of care low-dose anthracycline-based induction chemotherapy in older patients with AML. The aim of this study was to demonstrate the potential utility of strain imaging in detecting early changes in left ventricular function in this patient population after induction chemotherapy. Methods: Thirty two patients enrolled in the ECOG-ACRIN E2906 study (cytarabine and daunorubicin vs clofarabine [Genzyme/Sanofi]) from 2011 to 2014 were evaluated retrospectively. Two-dimensional transthoracic echocardiography (TTE) imaging with Doppler and two-dimensional speckle-tracking echocardiography (2DSTE) using EchoInsight software (Epsilon imaging) were performed before and after induction chemotherapy. Results: Eighteen patients received cytarabine and daunorubicin (7 + 3) and 14 received clofarabine. The clofarabine group was older than the 7 + 3 cohort (67.8 ± 4.0 vs 63.7 ± 3.8, P = .007). There were no other significant differences in cardiac risk factors between groups. The 7 + 3 group had a decrease in average peak systolic global longitudinal (-19.1 ± 2.8 to -17.2 ± 3.0, P = .01) and circumferential strain (-29.4 ± 6.3 to -23.9 ± 4.3, P = .011). These changes were not demonstrated in the clofarabine group and were not associated with a decline in left ventricular ejection fraction (LVEF). Conclusions: In older AML patients, standard cytarabine and daunorubicin chemotherapy causes early changes in global longitudinal and circumferential strain not seen with clofarabine therapy. These findings demonstrate subclinical left ventricular dysfunction after exposure to low cumulative doses of anthracycline-based induction chemotherapy and may help us better identify those patients at risk for adverse long-term cardiovascular outcomes.

Although having promising anti-myeloma properties, the pan-histone deacetylase inhibitor (HDACi) panobinostat lacks therapeutic activity as a single agent. The aim of the current study was to elucidate the mechanisms underlying multiple myeloma (MM) resistance to panobinostat monotherapy and to define strategies to overcome it. Sensitivity of MM cell lines and primary CD138+ cells from MM patients to panobinostat correlated with reduced expression of the chemokine receptor CXCR4, whereas overexpression of CXCR4 in MM cell lines increased their resistance to panobinostat. Decreased sensitivity to HDACi was associated with reversible G0/G1 cell growth arrest while response was characterized by apoptotic cell death. Analysis of intra-cellular signaling mediators revealed the pro-survival mTOR pathway to be regulated by CXCR4 overexpression. Combining panobinostat with mTOR inhibitor everolimus abrogated the resistance to HDACi and induced synergistic cell death. The combination of panobinostat/everolimus resulted in sustained DNA damage and irreversible suppression of proliferation accompanied by robust apoptosis. Gene expression analysis revealed distinct genetic profiles of single versus combined agent exposure. Whereas panobinostat increased the expression of the cell cycle inhibitor p21, co-treatment with everolimus abrogated the increase in p21 and synergistically downregulated the expression of DNA repair genes and mitotic checkpoint regulators. Importantly, the combination of panobinostat with everolimus effectively targeted CXCR4-expressing resistant MM cells in vivo in the BM niche. In summary, our results uncover the mechanism responsible for the strong synergistic anti-MM activity of dual HDAC and mTOR inhibition and provide the rationale for a novel potential therapeutic approach to treat MM.

The therapeutic paradigm for treatment of acute myeloid leukemia (AML) is rapidly changing with the advent of a new generation of drugs targeting diverse aspects of leukemogenesis. Whereas standard treatment for AML until recently consisted of a classic chemotherapy backbone, the incorporation of novel agents targeting pathogenic mutations, myeloid surface markers, and apoptosis-related proteins may become a reality in the next few years. In this review, we outline the therapeutic landscape of recently approved novel agents for AML, including FLT3 inhibitors, isocitrate dehydrogenase 1/2 (IDH1/2) inhibitors, Bcl-2 antagonists, hedgehog signaling inhibitors, and immunotherapy-based approaches. Some of the future challenges in the field would be to delineate which specific patient subsets derive the most clinical benefit from a given novel agent and, furthermore, which drug combinations will yield the maximal antileukemia effect without increased toxicity. To this end, it is expected that advances in genomic and epigenomic classification of AML will facilitate a rational and optimal choice of these novel agents for AML patients.

BACKGROUND Outcomes for patients with acute myeloid leukaemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) have significantly improved in recent years. OBJECTIVES To assess the incremental improvement of transplanted AML patients in the last two decades. METHODS Patients included in this analysis were adult AML patients who underwent allo-SCT from an HLA-matched sibling donor (MSD) or HLA-matched unrelated donor (MUD) in first remission. Patient outcomes were assessed between three cohorts according to the year of transplant (1993-2002, 2003-2007 and 2008-2012). RESULTS The analysis comprised a total of 20 187 patients of whom 4763 were transplanted between 1993 and 2002, 5835 in 2003 and 2007, and 9589 in 2008 and 2012. In multivariate analysis, leukaemia-free survival (LFS) rates were significantly improved in more recently transplanted patients compared to patients transplanted in 1993-2002 [Hazard ratio (HR) = 0.84, confidence interval (CI) 95%, 0.77-0.92; P = 0.003], a benefit which also extended to improved overall survival (OS; HR = 0.8, CI 95%, 0.73-0.89; P

Gilteritinib is a potent and selective FLT3 kinase inhibitor with single-agent clinical efficacy in relapsed/refractory FLT3-mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in NRAS or KRAS. Less frequently, secondary FLT3-F691L gatekeeper mutations or BCR–ABL1 fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of RAS mutations in FLT3-mutated subclones, the expansion of alternative wild-type FLT3 subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML.Significance:Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in FLT3-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML.See related commentary by Wei and Roberts, p. 998.This article is highlighted in the In This Issue feature, p. 983

AML is a malignancy of hematopoietic immature precursors (myeloblasts) that accumulate in the BM at the expense of their normal counterparts.

Therapy for the myelodysplastic syndromes (MDS) is an evolving area of research which has made significant use of the increased understanding of the complex biology of these disorders. Novel agents targeting multiple pathogenic pathways are being actively tested in preclinical and clinical settings and hold the potential to be available to clinicians before long.Herein we provide an historical framework for understanding the current use of hypomethylating agents in MDS and discuss recent developments in the field of targeted therapy in MDS including data from published and ongoing clinical studies with oral hypomethylating agents, PI3/polo-like kinase inhibitors, TGF-β inhibitor/ligand traps, and immune checkpoint inhibitors. A comprehensive review of recent literature was undertaken using PubMed and Medline. Expert commentary: Management of MDS patients will evolve substantially in the near future with the incorporation of molecular data into patient stratification models and with the introduction of novel targeted agents.

Quizartinib elicits differential responses that correlate with karyotype and genotype of the leukemic clone

FLAMSA followed by sequential reduced intensity conditioning and treosulfan/fludarabine are frequently used conditioning approaches used in centers of the European Society for Blood and Marrow Transplantation (EBMT) for older patients with acute myeloid leukemia (AML). It is currently unknown whether any of these regimens is superior to the others in terms of disease control and toxicity. Using the Acute Leukemia Working Party/EBMT multicenter registry we compared the outcomes of AML patients 45–65 of age transplanted between the years 2007 and 2016. A total of 629 patients were included in the analysis: 281 in the Treo/Flu group, 203 in the FLAMSA/TBI group, and 145 in the FLAMSA/Busulfan group. In multivariate analysis, FLAMSA/TBI conditioned patients had a decreased risk of relapse (hazard ratio (HR) = 0.43; 95% confidence interval (CI), 0.25–0.75; p = 0.002) and superior leukemia-free survival (HR = 0.67; 95% CI, 0.45–0.98; p = 0.042) compared to Treo/Flu conditioned patients. Rates of acute graft-versus-host disease (GVHD) were significantly higher in the FLAMSA/TBI group compared to the Treo/Flu group (HR = 2.004; 95% CI, 1.09–3.67; p = 0.024). Overall survival, non-relapse mortality, and chronic GVHD were not significantly impacted by the specific regimen used. The choice of either FLAMSA/TBI, FLAMSA/Bu, or Treo/Flu results in no major impact on survival of older AML patients.

International audience; Acute myeloid leukemia (AML) patients harboring the FLT3-ITD mutation are considered a high risk patient subset preferentially allocated for allogeneic stem cell transplantation in first remission. Whether FLT3-ITD retains a prognostic role in haploidentical stem cell transplantation (haplo-SCT) is unknown. To analyze the prognostic impact of FLT3-ITD in haplo-SCT, we performed a retrospective analysis of the multicenter registry of the acute leukemia working party of the European Society for Blood and Marrow Transplantation. We included all adult AML patients with known FLT3 status who underwent a first T-cell replete related haplo-HCT in first complete remission from 2005 to 2016. We evaluated 293 patients of whom 202 were FLT3wt and 91 were FLT3-ITD mutated. FLT3-ITD patients were more likely to be NPM1 mutated as well as be in the intermediate risk cytogenetic risk category. In multivariate analysis, patients with FLT3-ITD had comparable rates of relapse incidence [ Hazard ratio (HR) 51.34, confidence interval (CI) 95%, 0.67-2.7; P=.9] and leukemia-free survival (HR=.99, CI 95%, 0.62-1.57; P=.9) to those of FLT3(wt) patients. Overall survival, the incidence of nonrelapse mortality, and graft versus host disease-free/relapse-free survival were not significantly impacted by FLT3-ITD status. Furthermore, relapse and overall survival were comparable between FLT3-ITD patients transplanted from various donor pools, namely matched siblings, unrelated donors, haplo-SCT). Finally, subset analysis of patients with intermediate risk cytogenetics confirmed the absence of a prognostic impact of FLT3-ITD also for this patient segment. In AML patients undergoing T-cell replete haplo-SCT, the FLT3-ITD mutation possibly does not retain its prognostic significance.

Poster-Abstract

Background Allogeneic haematopoietic stem cell transplantation (alloHSCT) is considered a standard treatment for patients with Philadelphia chromosome–positive acute lymphoblastic leukaemia (Ph+ ALL) achieving complete remission after induction containing tyrosine kinase inhibitors (TKIs). Methods We retrospectively compared results of myeloablative alloHSCT from either matched sibling donor (MSD) or unrelated donor (URD) with autologous (auto) HSCT for adults with Ph+ ALL in molecular remission, treated between 2007 and 2014. Results In univariate analysis, the incidence of relapse at 2 years was 47% after autoHSCT, 28% after MSD-HSCT and 19% after URD-HSCT (P = 0.0002). Respective rates of non-relapse mortality were 2%, 18%, and 22% (P = 0.001). The probabilities of leukaemia-free survival were 52%, 55% and 60% (P = 0.69), while overall survival rates were 70%, 70% and 69% (P = 0.58), respectively. In multivariate analysis, there was a trend towards increased risk of overall mortality after MSD-HSCT (hazard ratio [HR], 1.5, P = 0.12) and URD-HSCT (HR, 1.6, P = 0.08) when referred to autoHSCT. The use of total body irradiation (TBI)–based regimens was associated with reduced risk of relapse (HR, 0.65, P = 0.02) and overall mortality (HR, 0.67, P = 0.01). Conclusion In the era of TKIs, outcomes of myeloablative autoHSCT and alloHSCT for patients with Ph+ ALL in first molecular remission are comparable. Therefore, autoHSCT appears to be an attractive treatment option potentially allowing for circumvention of alloHSCT sequelae. Irrespective of the type of donor, TBI-based regimens should be considered the preferable type of conditioning for Ph+ ALL.

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

Introduction Baseline karyotype at diagnosis remains the pivotal determinant of outcome in patients with acute myeloid leukemia (AML). The Medical Research Council (MRC) prognostic model is currently the benchmark for risk assessment in this patient population. However, the prognostic role of the complete spectrum of chromosomal abnormalities in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) is currently unknown. Furthermore, their significance in conjunction with FLT3-ITD status has not been addressed thus far. Methods Using the Acute Leukemia Working Party/European Society for Blood and Marrow Transplantation multicenter database a retrospective analysis was performed to assess the clinical outcomes of AML patients undergoing allo-SCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-SCT in first remission from either a matched sibling or a matched unrelated donor in 2006-2016. Results Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Del (9q), trisomy 14, and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITD status was constructed with significant prognostic implications. Conclusion Our analysis endorses the prognostic significance of the MRC predictive model in patients undergoing allo-SCT in CR1 with some specific modifications. Furthermore, consideration of FLT3-ITD and karyotypic complexity improved the projective capacity of the MRC model in transplanted patients.

The role of corticosterone (Cort), the immune system's major stress hormone, in the regulation of hematopoietic stem and progenitor cells (HSPCs) and their dynamic bone marrow (BM) microenvironment is currently unknown. We report that corticotropin-releasing factor receptor 1 (CRFR1) mutant mice with chronically low Cort levels showed aberrant HSPC regulation, having higher HSPC numbers and upregulation of the chemokine CXCL12, phenotypes that were restored by Cort supplementation. Expanded stromal progenitors known to support HSPCs were also observed in these low-Cort-containing mice. A similar phenotype was induced in wild-type (WT) mice by Metyrapone, a Cort synthesis inhibitor. Conversely, high Cort exposure induced HSPC apoptosis, reduced long-term BM repopulation and decreased stromal progenitor cell numbers. We documented circadian oscillations of Cort in WT BM but not in CRFR1 mutant mice, leading to diminished circadian BM CXCL12 fluctuations and increased number of circulating HSPCs in these mice. Finally, low Cort induced expansion of stromal progenitors, CXCL12 expression, HSPC proliferation and BM repopulation capacity, involving Notch1 signaling. This was associated with upregulation of the Notch ligand, Jagged1, in BM myeloid cells. Our results suggest that daily physiologic Cort oscillations are critical for balanced HSPC proliferation and function involving Notch1 signaling and their supportive BM microenvironment. © 2013 Macmillan Publishers Limited All rights reserved.

Purpose of review High relapse rates and therapy-related toxicity contribute to suboptimal outcomes in acute myeloid leukemia (AML) patients attaining a remission following initial induction therapy and postallogeneic stem cell transplant. Maintenance therapy holds the potential for a prolonged remission interval analogue to that seen in other hematologic malignancies. Herein we present and analyze the current data in the field. Recent findings Maintenance treatment approaches utilizing conventional chemotherapy, immunomodulation, hypomethylating agents, targeted small molecules, and tyrosine kinase inhibitors have been explored in this setting. The published data have not yet demonstrated convincing efficacy to merit establishment of this approach as standard of care. The role of hypomethylating agents and novel tyrosine kinase inhibitors is being actively studied in phase II/III trials and may improve patient outcome. Summary Maintenance therapy has not been shown to improve patient outcome in AML. The results of ongoing and future studies with novel agents may facilitate incorporation of this approach to standard care of AML.

Background: Abnormalities in repolarization may reflect underlying myocardial pathology and play a prominent role in arrhythmogenesis The T-wave amplitude has been associated with cardiovascular outcome in patients with acute myocardial infarction (MI) Additionally, T-wave amplitude is considered a predictor of arrhythmias, as well as being related to an individual’s inflammatory status. The combined influence of different variables, such as inflammation, cardiovascular risk factors and physical fitness status, on the T-wave amplitude has not been evaluated to date. The aim of this study was to identify factors that affect the T-wave amplitude. Methods: Data from 255 consecutive apparently healthy individuals included in the Tel Aviv Medical Center Inflammation Survey (TAMCIS) were reviewed. All patients had undergone a physical examination and an exercise stress test, and different inflammatory and metabolic biomarkers (fibrinogen, potassium, and high-sensitivity C-reactive protein) were measured. Results: Multivariate stepwise analysis revealed that the body mass index and the resting heart rate were significantly associated with the T-wave amplitude (β =− 0.34, P < 0.001; β =− 0.19, P = 0.03, respectively) in males, while the recovery rate and the usage of statins significantly affected the T-wave amplitude in females (β = 0.36, P = 0.002; β = 0.35, P = 0.002, respectively). Inflammatory variables had no significant affect on the T-wave amplitude of either gender. Conclusions: In conclusion, the T-wave amplitude is linked to an individual’s physical fitness and not to his/her inflammatory status. Ann Noninvasive Electrocardiol 2012;17(3):214–218 ECG; repolarization; T wave; inflammation

Adult hematopoietic stem cells (HSC) continuously replenish the blood with immune and blood cells with a finite life span, from the bone marrow (BM) reservoir of immature and maturing leukocytes. Regulation of HSC migration and development is essential for their function and blood cell production. These diverse and multiple states require a tight regulation to efficiently address host defense and repair requirements. Numerous recent studies disclose a central role for bone related cells in regulation of HSC and hematopoiesis. During ontogeny HSC home and seed the fetal BM in the last gestation period when the bone is already ossified. Ossification involves bone forming osteoblast- and bone degrading osteoclast activity and is considered essential for the formation of BM cavities and hematopoiesis. This synchronized association implies the need for active bone cells and bone turnover for HSC regulation. Osteoblastic cells and SDF- 1+/nestin+ reticular adventitial and CAR cells are crucial for regulation of HSC lodgment, self-renewal and function. Bone resorbing osteoclasts regulate bone turnover and progenitor cell detachment and release from the BM. Sympathetic signals from the nervous system activated by circadian rhythms or stress conditions control both bone turnover and HSC migration and development. In this review we discuss pathways and mechanisms involved in this orchestrated regulatory network. A special focus is made on the pivotal role of the SDF-1/CXCR4 axis as a determinant of HSC fate. Inflammation, DNA damage, cytokine mobilization, microgravity and aging are discussed as specific physiologic and pathologic events entailing dysregulation of the tightly balanced Bone-Brain-Blood triad.

Background: MicroRNA-132 (miR-132) targets acetylcholinesterase (AChE) and potentiates the cholinergic blockade of inflammatory reactions in cultured cells and experimental mice, but the implications of this interaction to human inflammatory disease remained unexplored. This study aimed to test whether miR-132 is causally involved in anti-inflammatory reactions of patients with inflammatory bowel disease (IBD) and modulates vagal tone and consequently inflammation in patients with IBD. Methods: We prospectively measured inflammation readouts and the cholinergic status (total capacity for hydrolyzing acetylcholine in one’s circulation), and AChE activity in 2 independent cohorts of patients with IBD and quantified miR-132 levels in intestinal tissue biopsies removed at colonoscopy from inflamed and apparently quiescent tissues of tested volunteers. Results: MiR-132 levels are higher in inflamed compared with apparently quiescent intestinal biopsies from patients with IBD. Correspondingly, the cholinergic status and AChE activity was significantly lower in patients with IBD suffering from moderate–severe disease as compared with healthy controls or patient with IBD presenting low disease severity. Patients with IBD (n ¼ 16) presented lower AChE activity compared with healthy controls (n ¼ 33; 289 6 128 AU versus 391 6 102 AU, P ¼ 0.001), and a negative correlation between AChE activity and C-reactive protein levels (r ¼ 20.47, P ¼ 0.01). Corroborating these observations in an additional cohort of participants, C-reactive protein and AChE activity were negatively correlated in patients with moderate–severe disease (n ¼ 16; r ¼ 20.6, P ¼ 0.04) and positively correlated in healthy controls (n ¼ 74, r ¼ 0.24, P ¼ 0.046). Conclusions: Taken together, these findings support an inflammation-dependent homeostatic role for the regulation by miR-132 of AChE in IBD, opening new venues for therapeutic interference. (Inflamm Bowel Dis 2013;0:1–8)

To determine the role of bone marrow biopsy (BMBX), performed in association with comprehensive blood and imaging tests, in the evaluation of patients with fever of unknown origin (FUO).We reviewed the medical records of 475 hospitalized patients who underwent BMBX in our medical center from January 1, 2005, to April 30, 2010. We identified 75 patients who fulfilled the accepted classic Petersdorf criteria for FUO. All patients underwent in-hospital investigation for fever, including chest and abdominal computed tomography.In 20 patients (26.7%), BMBX established the final diagnosis. Sixteen patients had hematologic disorders, including 8 patients with non-Hodgkin lymphoma, 2 with acute leukemia, 1 with multiple myeloma, 1 with myelodysplastic syndrome, and 4 with myeloproliferative disorders. The remaining patients with diagnostic BMBX specimens had solid tumors (2 patients), granulomatous disease (1 patient), and hemophagocytic syndrome (1 patient). Multivariate analysis revealed the following as the significant positive predictive parameters for a diagnostic BMBX specimen: male sex (odds ratio [OR], 7.35; 95% confidence interval [CI], 1.19-45.45), clinical lymphadenopathy (OR, 21.98; 95% CI, 1.97-245.66), anemia (OR, 2.21; 95% CI, 1.28-3.80), and increased lactate dehydrogenase levels (OR, 1.003; 95% CI, 1.001-1.006).Bone marrow biopsy is still a useful ancillary procedure for establishing the diagnosis of FUO, particularly if used in the appropriate clinical setting. Clinical and laboratory parameters associated with hematologic disease are predictive of a diagnostic BMBX specimen in patients with FUO.

Introduction Cytarabine in high doses (> 1 g/m2) is commonly combined with other cytotoxic chemotherapy agents to treat acute myeloid leukemia (AML) in the initial and salvage settings. Single-agent high dose cytarabine (HiDAC) is traditionally reserved for consolidation therapy for patients in remission. At our institution we also use single agent HiDAC to treat patients with active disease. We reviewed our experience to assess the outcomes. Methods We identified patients (pts) with AML diagnosed from 2009-2014 and treated at the Hospital of The University of Pennsylvania with anthracycline plus infusional cytarabine induction (7+3) who received subsequent single agent HiDAC for active disease. Pts included were those with evidence of residual leukemia on nadir biopsy after one cycle of therapy or those with refractory disease (positive nadir after 2 cycles of therapy or disease at the time of or within 30 days of count recovery). Comparisons of categorical covariates by subgroup were evaluated using the Fisher's exact test. Patients In total, 44 pts with median age of 54 (range 23-69) years were identified. Twenty-five (56%) pts had de novo AML, and 19 (43%) had AML secondary to prior myelodysplasia (MDS) or a myeloproliferative neoplasm (MPN). Twenty-two pts (50%) had unfavorable cytogenetics, 8 (18%) were FLT3 -ITD positive, and 4 (9%) were NPM1 mutant (Table 1). Indications for HiDAC salvage included positive nadir marrow or frankly progressive disease at day 14 of 1 (n=28) or refractory disease (n=16) Outcome Six pts (14%) died during index hospital admission for HiDAC therapy (5 from sepsis, 1 from multi-organ failure). Twelve (27%) pts achieved CR following HiDAC salvage and 4 (9%) achieved CRp. Pts with de novo AML were more likely to achieve a CR/CRp (11/24; 46%) compared to those with secondary AML (antecedent myeloid disorder or prior chemotherapy/radiation therapy) (5/20, 25%; p=0.037). CR/CRp rates were higher for pts with a white blood cell (WBC) count ≤10K/µL at initial diagnosis (50% vs. 20%; p=0.039). Pts treated for residual disease at first nadir were more likely to respond to HiDAC (n=13/28, 46%) than pts treated for refractory disease (3/16, 19%; p=0.104). Cytogenetic risk, age, presence of extramedullary disease, and FLT3 -ITD/NPM1 mutation status were not associated with response in this small sample (Table 2). No features predicted early mortality. Conclusion Our data suggest that pts with AML who received HiDAC therapy for active disease after 1-2 cycles of anthracycline plus infusional cytarabine induction have CR rates of 36% with single agent HiDAC with a 14% rate of early mortality. De-novo disease, initial WBC count < 10K/µL and treatment for residual disease at first nadir predict for a better response. Pts presenting with refractory disease are less likely to respond to this approach, consistent with previously published data with HiDAC combination regimens. HiDAC monotherapy for persistent AML following initial induction is a reasonable therapeutic option. Figure 1. Patient Characteristics Figure 1. Patient Characteristics Figure 2. Response to HiDAC monotherapy Figure 2. Response to HiDAC monotherapy Disclosures Loren: Merck: Research Funding. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Frey:Novartis: Research Funding. Porter:Novartis: Patents & Royalties, Research Funding.

OBJECTIVE: The recently introduced Bayer wide-range C-reactive protein (wr-CRP) assay might be relevant for the real-time low-cost and online determination of inflammatory bowel disease (IBD) activity. Our aim was to examine whether wr-CRP can substitute for the Dade Behring high sensitivity C-reactive protein (hs-CRP) assay in IBD patients. METHODS: A total of 71 patients with IBD, of whom 48 had Crohn’s disease CD and 23 had ulcerative colitis (UC) with various intensities of disease activity participated in the study. The CRP of patients who were under treatment at the Department of Gastroenterology and Liver Diseases were measured using both wr-CRP and the hs-CRP. RESULTS: A significant (r = 0.995; P < 0.001) correlation was noted between the hs-CRP and wr-CRP measurements for the whole sample as well as for the two diseases, CD (r = 0.994; P < 0.001) and UC (r = 0.997; P < 0.001), which were analyzed separately. CONCLUSION: The Bayer wr-CRP assay might be a useful low-cost and real-time inflammation-sensitive biomarker in patients with IBD.