Venetoclax and Cobimetinib in Relapsed/Refractory AML: A Phase 1b Trial.

BACKGROUND: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies. PATIENTS AND METHODS: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle. RESULTS: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway. CONCLUSION: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.

The Clinical Utility of FLT3 Mutation Testing in Acute Leukemia: A Canadian Consensus.

FMS-like tyrosine kinase 3 (FLT3) mutations are detected in approximately 20-30% of patients with acute myeloid leukemia (AML), with the presence of a FLT3 internal tandem duplication (FLT3-ITD) mutation being associated with an inferior outcome. Assessment of FLT3 mutational status is now essential to define optimal upfront treatment in both newly diagnosed and relapsed AML, to support post-induction allogeneic hematopoietic stem cell transplantation (alloSCT) decision-making, and to evaluate treatment response via measurable (minimal) residual disease (MRD) evaluation. In view of its importance in AML diagnosis and management, the Canadian Leukemia Study Group/Groupe canadien d'étude sur la leucémie (CLSG/GCEL) undertook the development of a consensus statement on the clinical utility of FLT3 mutation testing, as members reported considerable inter-center variability across Canada with respect to testing availability and timing of use, methodology, and interpretation. The CLSG/GCEL panel identified key clinical and hematopathological questions, including: (1) which patients should be tested for FLT3 mutations, and when?; (2) which is the preferred method for FLT3 mutation testing?; (3) what is the clinical relevance of FLT3-ITD size, insertion site, and number of distinct FLT3-ITDs?; (4) is there a role for FLT3 analysis in MRD assessment?; (5) what is the clinical relevance of the FLT3-ITD allelic burden?; and (6) how should results of FLT3 mutation testing be reported? The panel followed an evidence-based approach, taken together with Canadian clinical and laboratory experience and expertise, to create a consensus document to facilitate a more uniform approach to AML diagnosis and treatment across Canada.

Changing frontline AML treatment patterns from 2013 to 2022.

The treatment patterns for patients with newly diagnosed acute myeloid leukemia (AML) were compared between 2013 and 16 and 2021-22 in a real-world setting. A significantly higher proportion of patients age 70 and over received non-intensive therapy (NIT) in 2021-22 as compared with 2013-16 (65 % vs 44 %, p = 0.014), with a corresponding reduction in the proportion receiving either intensive therapy or no antileukemic treatment. Treatment patterns among patients < age 70 were unchanged. The complete response rate in the NIT group was 69 % in 2021-22 vs. 24 % in 2013-16 (p < 0.001); the overall survival (OS) of NIT patients was 11.5 months in 2021-22 vs. 7.8 months in 2013-16. Older patients from rural areas were more likely to decline therapy than those from urban regions. The increase in the proportion of patients opting for NIT may be related to the availability of more effective treatment options. Although outcomes are improving, the OS with NIT remains suboptimal.

Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial.

This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with incomplete platelet count recovery) rate was 26.0% and morphologic leukemia-free state (MLFS) rate was 12%. For anticipated recommended phase 2 doses (venetoclax 600 mg + idasanutlin 150 mg; venetoclax 600 mg + idasanutlin 200 mg), the combined CRc rate was 34.3% and the MLFS rate was 14.3%. Pretreatment IDH1/2 and RUNX1 mutations were associated with higher CRc rates (50.0% and 45.0%, respectively). CRc rate in patients with TP53 mutations was 20.0%, with responses noted among those with co-occurring IDH and RUNX1 mutations. In 12 out of 36 evaluable patients, 25 emergent TP53 mutations were observed; 22 were present at baseline with low TP53 variant allele frequency (median 0.0095% [range, 0.0006-0.4]). Venetoclax-idasanutlin showed manageable safety and encouraging efficacy in unfit patients with R/R AML. IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were preexisting. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations. This trial was registered at www.clinicaltrials.gov as #NCT02670044.

Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial.

The aim of this study was to characterize the mutational landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the randomized CALGB 10603/RATIFY trial evaluating intensive chemotherapy plus the multi-kinase inhibitor midostaurin versus placebo. We performed sequencing of 262 genes in 475 patients: mutations occurring concurrently with the FLT3-mutation were most frequent in NPM1 (61%), DNMT3A (39%), WT1 (21%), TET2 (12%), NRAS (11%), RUNX1 (11%), PTPN11 (10%), and ASXL1 (8%) genes. To assess effects of clinical and genetic features and their possible interactions, we fitted random survival forests and interpreted the resulting variable importance. Highest prognostic impact was found for WT1 and NPM1 mutations, followed by white blood cell count, FLT3 mutation type (internal tandem duplications vs. tyrosine kinase domain mutations), treatment (midostaurin vs. placebo), ASXL1 mutation, and ECOG performance status. When evaluating two-fold variable combinations the most striking effects were found for WT1:NPM1 (with NPM1 mutation abrogating the negative effect of WT1 mutation), and for WT1:treatment (with midostaurin exerting a beneficial effect in WT1-mutated AML). This targeted gene sequencing study provides important, novel insights into the genomic background of FLT3-mutated AML including the prognostic impact of co-mutations, specific gene-gene interactions, and possible treatment effects of midostaurin.

Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results.

In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3-ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3-ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole (n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3-ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.

Improved survival with enasidenib versus standard of care in relapsed/refractory acute myeloid leukemia associated with IDH2 mutations using historical data and propensity score matching analysis.

BACKGROUND: The present study evaluated the relative survival benefits associated with enasidenib and current standard of care (SoC) therapies for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and an isocitrate dehydrogenase 2 (IDH2) mutation who are ineligible for hematopoietic stem cell transplantation (HSCT). METHODS: Propensity score matching (PSM) analysis compared survival outcomes observed with enasidenib 100 mg daily in the phase I/II AG221-C-001 trial and SoC outcomes obtained from a real-world chart review of patients in France. RESULTS: Before matching, enasidenib (n = 195) was associated with numerically improved overall survival (OS) relative to SoC (n = 80; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.61-1.11). After matching and adjusting for covariates (n = 78 per group), mortality risk was significantly lower with enasidenib than with SoC (HR, 0.67; 95% CI, 0.47-0.97). The median OS was 9.26 months for enasidenib (95% CI, 7.72-13.24) and 4.76 months for SoC (95% CI, 3.81-8.21). Results remained robust across all sensitivity analyses conducted. CONCLUSIONS: PSM analyses indicate that enasidenib significantly prolongs survival relative to SoC among patients with R/R AML and an IDH2 mutation who are ineligible for HSCT. Future prospective studies are needed to validate these findings using other data sources and to assess the comparative efficacy of enasidenib for other treatment outcomes.

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.

Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial.

The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.

Outcomes of patients with relapsed or refractory acute myeloid leukemia: a population-based real-world study.

With standard therapies for patients with acute myeloid leukemia (AML), many patients either do not achieve complete response (CR) or relapse after CR. There are a scarcity of real-world data on outcomes of unselected patients with relapsed/refractory acute myeloid leukemia (RR-AML). We retrospectively evaluated treatment patterns and survival outcomes of unselected patients aged ≥18 years diagnosed with RR-AML identified from the Alberta Cancer Registry, Alberta, Canada, between January 2013 and December 2016. We included 199 patients who met predefined criteria for RR-AML. Following RR-AML diagnosis, 23% of patients received intensive therapy (IT), 33% non-intensive therapy (NIT), and 44% best supportive care (BSC). The unadjusted median overall survival (OS) of the study cohort was 5.3 months from the time of RR-AML diagnosis, with a 5-year OS rate of 12.6% (95% confidence interval 7.5-21.1). According to treatment intensity after RR-AML, the median OS outcomes were 13.6, 9.4, and 2.0 months for IT, NIT, and BSC groups, respectively (P<0.001). Patients who received treatment (IT or NIT) had better survival than those who received only BSC. This study emphasizes the need for newer therapy options for patients with RR-AML.

Anticoagulation prophylaxis reduces venous thromboembolism rate in adult acute lymphoblastic leukaemia treated with asparaginase-based therapy.

Venous thromboembolism (VTE) is a well-known complication in adults receiving asparaginase (ASNase)-based intensification chemotherapy for acute lymphoblastic leukaemia (ALL). The optimal preventative strategy is unclear. Our objective is to determine the effects of low-molecular-weight heparin (LMWH) as primary VTE prophylaxis. A single-centred retrospective cohort study of adult patients with Philadelphia chromosome negative (Ph-) ALL who received ASNase-based intensification from 2001 to 2017, with prophylaxis given from 2011 to 2017. In all, 214 patients were included in this study with 99 in the historical control group and 125 in the prophylaxis group. The mean (range) enoxaparin dose was 0·79 (0·39-1·2) mg/kg. Of the 125 patients in the prophylaxis group 17 (13·6%) developed VTE during the intensification phase, while 27/99 patients (27·3%) in the control cohort experienced at least one thrombotic event (odds ratio [OR] 0·42, 95% confidence interval [CI] 0·21-0·83). Overall, the main sites of VTE incidences included deep vein thrombosis in the lower extremity (54·6%), pulmonary embolism (13·6%) and catheter-related thrombosis (22·7%). In addition, we found that after adjusting for age, T-phenotype ALL was associated with VTE development (OR 3·07, 95% CI 1·04-9·08). There was no documented major bleeding in the prophylaxis group. LMWH prophylaxis reduced the incidence of symptomatic VTE in adult patients with ALL receiving intensification chemotherapy with ASNase.

Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.

Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic options.

Chronic myeloid leukemia cells are armed with several resistance mechanisms that can make current drugs ineffective. A better understanding of resistance mechanisms is yielding new approaches to management of the disease. Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm the hallmark of which, the breakpoint cluster region-Abelson (BCR-ABL) oncogene, has been the target of tyrosine kinase inhibitors (TKIs), which have significantly improved the survival of patients with CML. However, because of an increase in TKI resistance, it is becoming imperative to identify resistance mechanisms so that drug therapies can be better prescribed and new agents developed. In this review, we discuss the various BCR-ABL-dependent and -independent mechanisms of resistance observed in CML, and the range of therapeutic solutions available to overcome such resistance and to ultimately improve the survival of patients with CML.

A phase II open-label study of aprepitant as anti-emetic prophylaxis in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy.

Despite the widespread use of 5-HT3 antagonists as anti-emetic prophylaxis in patients with acute myeloid leukemia (AML) receiving induction chemotherapy, nausea and vomiting persist in many cases. We performed a Phase II single-arm study evaluating the use of aprepitant on days 1-5, in combination with a 5-HT antagonist on days 1-3, in AML patients undergoing induction chemotherapy with daunorubicin on days 1-3 plus cytarabine, given as a continuous infusion, on days 1-7. This was compared to a retrospective cohort of AML patients that received the same chemotherapy regimen with a 5-HT antagonist but without aprepitant. The cumulative incidence of vomiting/retching by the end of day 5 was significantly lower in the aprepitant vs. the control group (26.3 vs. 52.8%, p = 0.013). The cumulative incidence of nausea by the end of day 5 was 61% in the aprepitant group vs. 75% in the control group. The total use of supplemental anti-emetics on days 2-5 was also significantly lower in the aprepitant group (p = 0.01). In contrast, the cumulative incidence of vomiting/retching by the end of day 8, the incidence of vomiting/retching on days 6-8, and the use of anti-emetics on days 6-8, were not significantly different between the two groups. The results suggest that the use of aprepitant may be associated with a lower rate of emesis during aprepitant dosing days, but not afterward. However, this requires confirmation in a randomized trial.

Advances in biology of acute lymphoblastic leukemia (ALL) and therapeutic implications.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and also occurs in adults. Although the outcomes of multi-agent chemotherapy regimens have greatly improved, high toxicity and relapses in many patients necessitate the development of novel therapeutic approaches. Advances in molecular profiling and cytogenetics have identified a broad range of genetic abnormalities, including gene mutations, chromosome translocations and aneuploidy, which has provided a more comprehensive understanding of the biology and pathogenesis of ALL. This understanding has also led to new targeted therapeutic approaches, including the use of selective small molecule inhibitors, nucleic acid-based therapies and immune-based therapies mediated by specific monoclonal antibodies and cellular immunotherapy, which are poised to revolutionize the treatment of various ALL subtypes. The main focus of this review is to highlight the latest advances in ALL biology, including the identification of prognostic factors and putative therapeutic targets. We also review the current status of, and ongoing progress in, the development of targeted therapies for ALL.

Treatment of older patients with acute myeloid leukemia (AML): revised Canadian consensus guidelines.

The treatment of acute myeloid leukemia (AML) in older patients is undergoing rapid changes, with a number of important publications in the past five years. Because of this, a group of Canadian leukemia experts has produced an update to the Canadian Consensus Guidelines that were published in 2013, with several new agents recommended, subject to availability. Recent studies have supported the survival benefit of induction chemotherapy for patients under age 80, except those with major co-morbidities or those with adverse risk cytogenetics who are not candidates for allogeneic hematopoietic stem cell transplantation (HSCT). Midostaurin should be added to induction therapy for patients up to age 70 with a FLT3 mutation, and gemtuzumab ozogamicin for de novo AML up to age 70 with favorable or intermediate risk cytogenetics. Daunorubicin 60 mg/m2 is the recommended dose for 3+7 induction therapy. Acute promyelocytic leukemia should be treated with arsenic trioxide plus all-trans retinoic acid, regardless of age, with cytotoxic therapy added upfront only for those with initial white blood count > 10. HSCT may be considered for selected suitable patients up to age 70-75. Haploidentical donor transplants may be considered for older patients. For non-induction candidates, azacitidine is recommended for those with adverse risk cytogenetics, while either a hypomethylating agent (HMA) or low-dose cytarabine can be used for others. HMA may also be used for relapsed/refractory disease after chemotherapy. For patients with secondary AML, CPX-351 is recommended for fit patients age 60-75.

Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.

BACKGROUND: Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS: We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS: A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS: The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).