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Abstract Asparaginase (ASP)-containing regimens for acute lymphoblastic leukemia (ALL) are associated with venous thromboembolism (VTE). We evaluated the prevalence, risk factors, role of prophylaxis and clinical impact of VTE among adolescents and young adult (AYA) patients (15–50 years) treated on Dana-Farber Cancer Institute (DFCI) ALL protocols. The 1- and 2-year cumulative incidence of VTE were 31.9% (95% CI: 27.0%, 36.9%) and 33.5% (95% CI: 28.5%, 38.5%) respectively, with most events occurring during ASP-based consolidation phase (68.6%). VTE was more frequent in patients with overweight/obese vs. normal BMI (39.2% vs. 29.0%, p = 0.048). In a 1-year landmark analysis, the 4-year overall survival was 91.5%, without difference between patients with vs. without VTE (93.8% vs. 90.0%, p = 0.93). Relapse and non-relapse mortality rates were also similar. Among patients treated at Dana-Farber/Harvard Cancer Center, cerebral sinus vein thrombosis occurred in 3.6% of patients (8.5% of VTE events) in comparison to pulmonary embolism (32.9%) and deep vein thromboses (58.6%, 24.4% line-associated). In a Cox regression model for VTE free-time, elevated BMI was associated with shorter VTE free-time (HR 1.94 [95% CI 1.13-3.35], p = 0.018), while low molecular weight heparin (LMWH) prophylaxis as time-varying covariate was not. In conclusion, we found that VTE was frequent in AYAs treated on DFCI ALL protocols but did not impact survival outcomes. Overweight/obese BMI increased risk for VTE.

Abstract Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM.

Neutrophils are versatile immune cells that may also serve as antigen-presenting cells (APC). Here the authors show that engaging FcγRs on neutrophils with immune complexes or an anti-FcγR-antigen conjugate induces neutrophil APC with comparable functions as classical dendritic cells, and with therapeutic potentials for cancer and infectious diseases.

Abstract Recently, a novel knowledge bank (KB) approach to predict outcomes of individual patients with acute myeloid leukemia (AML) was developed using unbiased machine learning. To validate its prognostic value, we analyzed 1612 adults with de novo AML treated on Cancer and Leukemia Group B front-line trials who had pretreatment clinical, cytogenetics, and mutation data on 81 leukemia/cancer-associated genes available. We used receiver operating characteristic (ROC) curves and the area under the curve (AUC) to evaluate the predictive values of the KB algorithm and other risk classifications. The KB algorithm predicted 3-year overall survival (OS) probability in the entire patient cohort (AUCKB = 0.799), and both younger (

Abstract Background Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study. Methods We classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes. Results Our classification identified core-binding factor and NPM1-mutated/FLT3-ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of > 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17–42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%. Conclusions By classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies. Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).

We conducted a randomized controlled trial in older adults with hematologic malignancies to determine the impact of geriatrician consultation embedded in our oncology clinic alongside standard care. From February 2015 to May 2018, transplant-ineligible patients aged ≥75 years who presented for initial consultation for lymphoma, leukemia, or multiple myeloma at Dana-Farber Cancer Institute (Boston, MA, USA) were eligible. Pre-frail and frail patients, classified based on phenotypic and deficit-accumulation approaches, were randomized to receive either standard oncologic care with or without consultation with a geriatrician. The primary outcome was 1-year overall survival. Secondary outcomes included unplanned care utilization within 6 months of follow-up and documented end-of-life (EOL) goals-of-care discussions. Clinicians were surveyed as to their impressions of geriatric consultation. One hundred sixty patients were randomized to either geriatric consultation plus standard care (n=60) or standard care alone (n=100). The median age of the patients was 80.4 years (standard deviation = 4.2). Of those randomized to geriatric consultation, 48 (80%) completed at least one visit with a geriatrician. Consultation did not improve survival at 1 year compared to standard care (difference: 2.9%, 95% confidence interval: -9.5% to 15.2%, P=0.65), and did not significantly reduce the incidence of emergency department visits, hospital admissions, or days in hospital. Consultation did improve the odds of having EOL goals-of-care discussions (odds ratio = 3.12, 95% confidence interval: 1.03 to 9.41) and was valued by surveyed hematologic-oncology clinicians, with 62.9%-88.2% of them rating consultation as useful in the management of several geriatric domains.

The aim of this study was to evaluate the prognostic impact of FLT3-ITD in core-binding factor acute myeloid leukemia (CBFAML) in an international, multicenter survey of 97 patients of whom 52% had t(8;21)(q22;q22) and 48% had inv(16)(p13q22)/t(16;16)(p13;q22). The median age of the patients was 53 years (range, 19-81). Complete remission after anthracycline-based induction (n=86) and non-intensive therapy (n=11) was achieved in 97% and 36% of the patients, respectively. The median follow-up was 4.43 years (95% confidence interval [95% CI]: 3.35-7.39 years). The median survival after intensive and non-intensive treatment was not reached and 0.96 years, respectively. Among intensively treated patients, inv(16) with trisomy 22 (n=11) was associated with a favorable 4-year relapse-free survival rate of 80% (95% CI: 59-100%) as compared to 38% (95% CI: 27-54%; P=0.02) in all other patients with CBFAML/ FLT3-ITD (n=75). Overall, 24 patients underwent allogeneic hematopoietic cell transplantation (HCT), 12 in first complete remission and 12 after relapse. Allogeneic HCT in first complete remission was not beneficial (P=0.60); however, allogeneic HCT seemed to improve median survival in relapsed patients compared to that of patients treated with chemotherapy (not reached vs. 0.6 years, respectively; P=0.002). Excluding patients with inv(16) with trisomy 22, our data indicate that compathe outcome of CBF-AML patients with FLT3-ITD may be inferior to that of patients without FLT3-ITD (based on previously published data), suggesting that prognostically CBF-AML patients with FLT3-ITD should not be classified as favorable-risk. FLT3-inhibitors may improve the outcome of these patients.

Expression levels of long non-coding RNA (lncRNA) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNA in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged

Leukemia stem cells (LSC) are more resistant to standard chemotherapy and their persistence during remission can cause relapse, which is still one of the major clinical challenges in the treatment of acute myeloid leukemia (AML). A better understanding of the mutational patterns and the prognostic impact of molecular markers associated with stemness could lead to better clinical management and improve patients’ outcomes. We applied a previously described 17-gene expression score comprising genes differently expressed between LSC and leukemic bulk blasts, for 934 adult patients with de novo AML, and studied associations of the 17-gene LSC score with clinical data and mutation status of 81 genes recurrently mutated in cancer and leukemia. We found that patients with a high 17-gene score were older and had more mutations. The 17-gene score was found to have a prognostic impact in both younger (aged

Acute myeloid leukemia (AML) with t(6;9)(p22;q34) is a distinct entity accounting for 1-2% of AML cases. A substantial proportion of these patients have a concomitant FLT3-ITD. While outcomes are dismal with intensive chemotherapy, limited evidence suggests allogeneic hematopoietic cell transplantation (allo-HCT) may improve survival if performed early during first complete remission. We report on a cohort of 178 patients with t(6;9)(p22;q34) within an international, multicenter collaboration. Median age was 46 years (range: 16-76), AML was de novo in 88%, FLT3-ITD was present in 62%, and additional cytogenetic abnormalities in 21%. Complete remission was achieved in 81% (n=144), including 14 patients who received high-dose cytarabine after initial induction failure. With a median follow up of 5.43 years, estimated overall survival at five years was 38% (95%CI: 31-47%). Allo-HCT was performed in 117 (66%) patients, including 89 in first complete remission. Allo-HCT in first complete remission was associated with higher 5-year relapse-free and overall survival as compared to consolidation chemotherapy: 45% (95%CI: 35-59%) and 53% (95%CI: 42-66%) versus 7% (95%CI: 3-19%) and 23% (95%CI: 13-38%), respectively. For patients undergoing allo-HCT, there was no difference in overall survival rates at five years according to whether it was performed in first [53% (95%CI: 42-66%)], or second [58% (95%CI: 31-100%); n=10] complete remission or with active disease/relapse [54% (95%CI: 34-84%); n=18] (P=0.67). Neither FLT3-ITD nor additional chromosomal abnormalities impacted survival. In conclusion, outcomes of t(6;9)(p22;q34) AML are poor with chemotherapy, and can be substantially improved with allo-HCT.

Abstract: Prior to novel targeted agents for chronic lymphocytic leukemia (CLL), the best chemoimmunotherapy regimen in patients with non-del(11q) disease was unclear. The role of lenalidomide was also not defined. This phase 2 study randomized 342 untreated patients with non-del(11q) CLL requiring therapy to fludarabine plus rituximab (FR; n = 123), FR plus lenalidomide consolidation (FR+L; n = 109), or FR plus cyclophosphamide (FCR; n = 110) and compared 2-year progression-free survival (PFS) rates of each to the historical control rate with FC (60%). Patients with del(11q) in at least 20% of pretreatment cells continued with FCR (n = 27) or were reassigned to FCR+L (n = 31) and excluded from the primary analysis. Among non-del(11q) patients, 2-year PFS rates were 64% (90% confidence interval [CI], 57-71; FR), 72% (90% CI, 65-79; FR+L), and 74% (90% CI, 66-80; FCR); FR+L and FCR had rates significantly greater than historical control. Median PFS was significantly shorter with FR compared with FR+L (P = .04) and FCR (P < .001): 43 (95% CI, 33-50), 61 (95% CI, 45-71), and 97 (95% CI, 61 to not reached) months, respectively. Median follow-up was 73 months and median overall survival (OS) was only reached with FCR (101 months; 95% CI, 96 to not reached). With FR+L, the risk of death decreased over time and was lower than with FR at later time points (P = .01), but not significantly different from FCR (P = .21). Future studies incorporating short courses of lenalidomide into other novel treatment regimens are justified.

Abstract: The probability that adult patients with de novo acute myeloid leukemia (AML) receiving intensive chemotherapy in the absence of allogeneic hematopoietic stem cell transplantation (Allo-HCT) in first complete remission (CR1) will be disease-free at 10 years after diagnosis, a long-term surrogate of cure, is unknown. To address this question, we examined 2551 AML patients (1607 aged

Abstract: Midostaurin was a prototype kinase inhibitor, originally developed as a protein kinase C inhibitor and subsequently as an angiogenesis inhibitor, based on its inhibition of vascular endothelial growth factor receptor. Despite promising preclinical data, early clinical trials in multiple diseases showed only modest efficacy. In 1996, the relatively frequent occurrence of fms-like tyrosine kinase 3 (FLT3) activating mutations in acute myeloid leukemia (AML) was first recognized. Several years later, midostaurin was discovered to be a potent inhibitor of the FLT3 tyrosine kinase and to have activity against mutant forms of KIT proto-oncogene receptor tyrosine kinase, which drive advanced systemic mastocytosis (SM). Through a series of collaborations between industry and academia, midostaurin in combination with standard chemotherapy was evaluated in the Cancer and Leukemia Group B 10603/RATIFY study, a large, phase 3, randomized, placebo-controlled trial in patients with newly diagnosed FLT3-mutated AML. This was the first study to show significant improvements in overall survival and event-free survival with the addition of a targeted therapy to standard chemotherapy in this population. Around the same time, durable responses were also observed in other trials of midostaurin in patients with advanced SM. Collectively, these clinical data led to the approval of midostaurin by the US Food and Drug Administration and the European Medicines Agency for both newly diagnosed FLT3-mutated AML and advanced SM.

Abstract Background Compared with World Health Organization-defined acute myeloid leukaemia (AML) not otherwise specified, patients with AML with myelodysplasia-related changes (AML-MRC) are generally older and more likely to have poor-risk cytogenetics, leading to poor response and prognosis. More than one-half of all older (≥65 years) patients in the phase 3 AZA-AML-001 trial had newly diagnosed AML-MRC. Methods We compared clinical outcomes for patients with AML-MRC treated with azacitidine or conventional care regimens (CCR; induction chemotherapy, low-dose cytarabine, or supportive care only) overall and within patient subgroups defined by cytogenetic risk (intermediate or poor) and age (65–74 years or ≥75 years). The same analyses were used to compare azacitidine with low-dose cytarabine in patients who had been preselected to low-dose cytarabine before they were randomized to receive azacitidine or CCR (ie, low-dose cytarabine). Results Median overall survival was significantly prolonged with azacitidine (n = 129) versus CCR (n = 133): 8.9 versus 4.9 months (hazard ratio 0.74, [95%CI 0.57, 0.97]). Among patients with intermediate-risk cytogenetics, median overall survival with azacitidine was 16.4 months, and with CCR was 8.9 months (hazard ratio 0.73 [95%CI 0.48, 1.10]). Median overall survival was significantly improved for patients ages 65–74 years treated with azacitidine compared with those who received CCR (14.2 versus 7.3 months, respectively; hazard ratio 0.64 [95%CI 0.42, 0.97]). Within the subgroup of patients preselected to low-dose cytarabine before randomization, median overall survival with azacitidine was 9.5 months versus 4.6 months with low-dose cytarabine (hazard ratio 0.77 [95%CI 0.55, 1.09]). Within the low-dose cytarabine preselection group, patients with intermediate-risk cytogenetics who received azacitidine had a median overall survival of 14.1 months versus 6.4 months with low-dose cytarabine, and patients aged 65–74 years had median survival of 14.9 months versus 5.2 months, respectively. Overall response rates were similar with azacitidine and CCR (24.8% and 17.3%, respectively), but higher with azacitidine versus low-dose cytarabine (27.2% and 13.9%). Adverse events were generally comparable between the treatment arms. Conclusions Azacitidine may be the preferred treatment for patients with AML-MRC who are not candidates for intensive chemotherapy, particularly patients ages 65–74 years and those with intermediate-risk cytogenetics. Trial registration This study was registered at clinicalTrials.gov on February 16, 2010 ( NCT01074047 ).

Abstract: The Cancer and Leukemia Group B (CALGB), now part of the Alliance for Clinical Trials in Oncology, conducted a multicenter, single-arm, phase 2 study in patients ≥60 years with FMS-like tyrosine kinase 3 (FLT3)–mutated acute myeloid leukemia (AML). In this study, sorafenib was added to daunorubicin and cytarabine-based induction and consolidation chemotherapy and was also continued for 12 months of maintenance therapy. The primary end point of the study was overall survival (OS) at 1 year in the FLT3 internal tandem duplication (FLT3-ITD) cohort. Fifty-four patients with a median age of 67 years (range, 60.3-82.7 years) were enrolled; 39 were FLT3-ITD patients (71%) and 15 were FLT3-TKD (29%) patients. The observed 1-year OS (95% confidence interval [CI]) was 62% (45%-78%) for the FLT3-ITD patients (meeting the primary end point 62% vs 30% for a historical control group, P < .0001) and 71% (42%-92%) for the FLT3-TKD patients. The median disease-free survival and OS were 12.2 months (95% CI, 5-16.9) and 15.0 months (95% CI, 10.4-20.1), respectively, in the FLT3-ITD group and 9.6 (95% CI, 1.9 to not available [NA]) and 16.2 months (95% CI, 5.0 to NA) for the FLT3-TKD group. This study suggests that the addition of sorafenib to chemotherapy for FLT3-ITD AML is feasible and may improve the survival of older adults with FLT3-mutated AML. This trial was registered at www.clinicaltrials.gov as #NCT01253070.

Acute myeloid leukemia (AML) is a heterogenous and complex disease characterized by rapid cellular proliferation, an aggressive clinical course, and generally high mortality. While progress has been made in the understanding of the genetic and molecular biology of the disease, the standard of care for patients had only changed minimally over the past 40 years. Recently, rapid movement of potentially useful agents from bench to bedside has translated into new therapies either recently approved or in clinical trials. These therapies include improved chemotherapies, mutationally targeted inhibitors, pro-apoptotic agents, microenvironment targeting molecules, cell cycle checkpoint inhibitors, and epigenetic regulators. Furthermore, advances in immunotherapy employ monoclonal and bispecific antibodies, chimeric antigen receptor (CAR) T cells, checkpoint inhibitors, and vaccines provide an alternative pathway for AML treatment. In this review, we discuss the recent results of completed or ongoing clinical trials with these novel therapeutic agents in AML.

All-trans-retinoic acid (ATRA) is the standard of care for the management of acute promyelocytic leukemia (APL), but can be associated with differentiation syndrome (DS). Over a seven-year period, we sought to determine the impact of ATRA initiation time on the development of DS. ATRA administration time had no impact on DS occurrence (p = =0.13), APL risk (p = =0.28) or regimen received (p = =0.1). Patients with higher mean body mass index (BMI) were more likely to develop moderate or severe DS (p = =0.02). Early treatment of APL is essential and maybe strongly considered in patients with elevated BMI. Keywords: Acute promyelocytic leukemia (APL), All-trans retinoic acid (ATRA), Differentiation syndrome

Long non-coding ribonucleic acids (RNAs) are a novel class of RNA molecules, which are increasingly recognized as important molecular players in solid and hematologic malignancies. Herein we investigated whether long non-coding RNA expression is associated with clinical and molecular features, as well as outcome of younger adults (aged

Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine’s clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves.

Achievement of complete remission is essential for long-term survival of acute myeloid leukemia patients. We evaluated the prognostic significance of cytogenetics at complete remission in 258 adults with de novo acute myeloid leukemia and abnormal pre-treatment karyotypes, treated on Cancer and Leukemia Group B front-line studies, with cytogenetic data at onset of morphological complete remission. Thirty-two patients had abnormal karyotypes at time of initial complete remission. Of these, 28 had at least 1 abnormality identified pre-treatment, and 4 acute myeloid leukemia-related abnormalities not detected pre-treatment. Two hundred and twenty-six patients had normal remission karyotypes. Patients with abnormal remission karyotypes were older (P