The implementation of targeted therapies for acute myeloid leukemia has been challenged by complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here, we report initial findings from the Beat AML program on a cohort of 672 tumor specimens collected from 562 patients. We assessed these specimens using whole exome sequencing, RNA-sequencing, and ex vivo drug sensitivity analyses. Our data reveal Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Combining venetoclax, a selective BCL-2 inhibitor, with low-dose navitoclax, a BCL-X L /BCL-2 inhibitor, may allow targeting of both BCL-2 and BCL-X L without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adultequivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population. Statement of Significance In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histological and genomic subtypes and in those who failed available therapies including stem cell transplant. Research.

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Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) remains a challenge. Although the addition of targeted tyrosine kinase inhibitors (TKIs) to standard cytotoxic therapy has greatly improved upfront treatment, treatment-related morbidity and mortality remain high. TKI monotherapy provides only temporary responses and renders patients susceptible to the development of TKI resistance. Thus, identifying agents that could enhance the activity of TKIs is urgently needed. Recently, a selective inhibitor of B cell lymphoma 2 (BCL-2), ABT-199 (venetoclax), has shown impressive activity against hematologic malignancies. We demonstrate that the combination of TKIs with venetoclax is highly synergistic in vitro, decreasing cell viability and inducing apoptosis in Ph(+)ALL. Furthermore, the multikinase inhibitors dasatinib and ponatinib appear to have the added advantage of inducing Lck/Yes novel tyrosine kinase (LYN)-mediated proapoptotic BCL-2-like protein 11 (BIM) expression and inhibiting up-regulation of antiapoptotic myeloid cell leukemia 1 (MCL-1), thereby potentially overcoming the development of venetoclax resistance. Evaluation of the dasatinib-venetoclax combination for the treatment of primary Ph(+)ALL patient samples in xenografted immunodeficient mice confirmed the tolerability of this drug combination and demonstrated its superior antileukemic efficacy compared to either agent alone. These data suggest that the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph(+)ALL and should be further evaluated for patient care.

BackgroundHematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management.Case PresentationHerein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient’s leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient’s blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time.ConclusionsThis case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0258-1) contains supplementary material, which is available to authorized users.

Acute myeloid leukemia (AML) is a genetically heterogeneous disease with a clinical course predicted by recurrent cytogenetic abnormalities and/or gene mutations. The NPM1 insertion mutations define the largest distinct genetic subset, ∼30% of AML, and is considered a favorable risk marker if there is no (or low allelic ratio) FLT3 internal tandem duplication (FLT3 ITD) mutation. However, ∼40% of patients with mutated NPM1 without FLT3 ITD still relapse, and the factors that drive relapse are still not fully understood. We used a next‐generation sequencing panel to examine mutations at diagnosis; clearance of mutations after therapy, and gain/loss of mutations at relapse to prioritize mutations that contribute to relapse. Triple mutation of NPM1, DNMT3A and IDH1/2 showed a trend towards inferior overall survival in our discovery dataset, and was significantly associated with reduced OS in a large independent validation cohort. Analysis of relative variant allele frequencies suggests that early mutation and expansion of DNMT3A and IDH1/2 prior to acquisition of NPM1 mutation leads to increased risk of relapse. This subset of patients may benefit from allogeneic stem cell transplant or clinical trials with IDH inhibitors.

Risk stratification in acute myeloid leukemia (AML) remains principle for survival prognostication and treatment selection. The 2022 European LeukemiaNet (ELN) recommendations were recently published, with notable updates to risk group assignment. The complexity of risk stratification and comparative outcomes between the 2022 and 2017 ELN guidelines remains unknown. This comparative analysis evaluated outcomes between the 2017 and 2022 ELN criteria in patients enrolled within the multi-center Beat AML cohort. Five-hundred thirteen patients were included. Most patients had one (36% [N=183]) or two (31% [N=159]) ELN risk-defining abnormalities. In patients with two or more ELN-risk defining mutations (58% [N=297]), 44% (N=132) had mutations spanning multiple ELN risk categories. Compared to ELN 2017 criteria, the updated ELN 2022 guidelines changed assigned risk group in 15% (N=75) of patients, including 10% (N=16/160), 26% (N=29/112), and 6% (N=13/224) of ELN 2017 favorable, intermediate, and adverse-risk patients. Median OS across ELN 2022 favorable, intermediate, and adverse-risk groups was not reached (estimated 5-year OS: 53% [standard error: 0.06%]), 16.8 (95% CI: 11-48) and 9.7 (95% CI: 8.3-10.8) months, respectively. The ELN 2022 guidelines more accurately stratified survival between patients with intermediate or adverse-risk AML treated with IC (HR: 1.58 [95% CI: 1.12-2.25], p-value: 0.01) compared to ELN 2017 guidelines (HR 1.27 [95% CI: 0.88-1.85], p-value: 0.20). The updated ELN 2022 guidelines better stratify survival, namely between patients with intermediate or adverse-risk AML treated with IC. The increased complexity of risk stratification with inclusion of additional cytogenetic and molecular aberrations necessitates clinical workflows simplifying risk stratification.

Background: There remains an unmet need for novel therapeutic strategies for relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LLy). Venetoclax (Ven) is a highly selective BCL-2 inhibitor with established efficacy in adults with hematologic malignancies. Navitoclax (Nav) is a BCL-2/BCL-XL/BCL-W inhibitor with promising effects, but prolonged thrombocytopenia limits its continuous use at higher doses (J Clin Oncol. 2012;30:488). In a previous report of 32 patients (pts) with ALL, Ven+Nav was well tolerated without unexpected toxicity and with promising preliminary efficacy (EHA 2019. Abstr #PS940). Here we report updated outcomes for 36 pts with ALL or LLy treated with Ven+Nav and chemotherapy. Methods: This phase 1, multicenter, open-label, dose escalation study enrolled pts aged ≥4 years with R/R ALL or LLy (NCT03181126). Pts received the weight-adjusted equivalent of 200 mg Ven on day 1 and 400 mg equivalent daily thereafter. From day 3 onward, oral daily Nav was administered at 25, 50, or 100 mg for pts weighing ≥45 kg or at 25 or 50 mg for pts weighing 20 to &lt;45 kg according to Bayesian optimal interval design. Pts could receive 2 cycles of chemotherapy with asparaginase, vincristine, and dexamethasone and additional cycles at the investigators' discretion. Disease assessment by flow cytometry occurred on days 8 and 36 and as clinically indicated. Minimal residual disease (MRD) evaluation (&lt;10-4 cutoff for undetectable MRD) was performed at time of disease assessment if clinically indicated. Results: As of May 6, 2019, 36 pts have been enrolled with B-cell ALL (B-ALL, n=18), T-cell ALL (T-ALL, n=16), or LLy (n=2). The median age was 29 years (range, 6-72 years), including 7 pediatric pts (Table), and pts had a median of 4 prior therapies (range, 1-10) including 5 (14%) with prior stem cell transplant (SCT) and 6 (17%) with prior CAR-T therapy. Median time on study was 2.1 months (range, 1.3 - 8.3 months). The most common treatment-emergent adverse events (AEs) were nausea (47%), vomiting (42%), diarrhea (42%), hypokalemia (42%), abdominal pain (36%), febrile neutropenia (33%), alanine aminotransferase increase (31%), and neutropenia (31%). The only grade 3/4 non-hematologic AE related to Ven occurring in more than 1 pt was vomiting (3 [8%]); only hematologic events related to Nav occurred in &gt;1 pt. Dose-limiting toxicities included ischemic bowel and delayed count recovery (n=1 each, 100 mg Nav, ≥45 kg); drug-induced hepatitis (n=1, 50 mg Nav, ≥45 kg); and delayed count recovery (n=1, 25 mg, &lt;45 kg). Three pts had fatal AEs not related to disease progression that included 2 cases of sepsis and 1 case of cardiac arrest in a pt with known underlying arrhythmia. Four other pts died in the setting of disease progression (ischemic bowel, sepsis, respiratory failure, and other) while receiving study drugs or within 30 days of stopping study drugs. The overall response rate (ORR) was 56% (20/36) in the total population, with best responses of complete response (CR)/CR with incomplete marrow recovery (CRi)/CR with incomplete platelet recovery (CRp) in 18 pts (50%; Table). In pediatric patients, the ORR was 86% (6/7) with best responses of CR/CRi/CRp in 5 pts (71%). Of the 18 pts with CR/CRi/CRp, 10 (56%) had undetectable MRD. Twenty-five percent of pts went on to SCT or CAR-T after achieving good response. There was no significant pharmacokinetic interaction between venetoclax and navitoclax. Preliminary assessment of mitochondrial priming by BH3 profiling confirmed that pt ALL cells showed dependence on BCL-XL and/or BCL-2. Genomic analyses are underway. Conclusions:Ven+Nav in combination with chemotherapy is well tolerated, with few discontinuations or dose reductions from AEs in pts with R/R ALL or LLy. The preliminary efficacy of Ven+Nav was promising in this heavily pretreated population of pts including those with prior SCT or CAR-T, with high rates of CR/CRi/CRp, and 10/18 (56%) with undetectable MRD. Additional correlative biomarker analyses are ongoing and will be presented. Disclosures Stock: Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Jabbour:Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Bajel:AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: travel funding. Rubnitz:AbbVie: Research Funding. Leonard:Amgen: Research Funding. Mullighan:Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel. Khaw:Amgen: Other: travel accommodations, Research Funding; Bristol Myers Squibb: Research Funding; Jazz Pharmaceuticals: Research Funding; AbbVie: Research Funding; Novartis: Other: travel accommodations. Opferman:AbbVie: Research Funding. Salem:AbbVie: Employment, Other: Stock/stock options. Schmidt:AbbVie: Employment, Other: stock or options. Tong:AbbVie: Employment, Other: stock or options. Zhou:AbbVie: Employment, Other: Stock or options. Ross:AbbVie: Employment, Other: Stock/stock options. Bensman:AbbVie: Employment, Other: stock or options. Jacobson:AbbVie: Employment, Other: Stock or options. Alexander:AbbVie: Other: travel funding.