A multicenter phase Ib trial of the histone deacetylase inhibitor entinostat in combination with pembrolizumab in patients with myelodysplastic syndromes/neoplasms or acute myeloid leukemia refractory to hypomethylating agents.

Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic ≥G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752.

A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML.

ABSTRACT: Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

Samples from patients with AML show high concordance in detection of mutations by NGS at local institutions vs central laboratories.

Next-generation sequencing (NGS) to identify pathogenic mutations is an integral part of acute myeloid leukemia (AML) therapeutic decision-making. The concordance in identifying pathogenic mutations among different NGS platforms at different diagnostic laboratories has been studied in solid tumors but not in myeloid malignancies to date. To determine this interlaboratory concordance, we collected a total of 194 AML bone marrow or peripheral blood samples from newly diagnosed patients with AML enrolled in the Beat AML Master Trial (BAMT) at 2 academic institutions. We analyzed the diagnostic samples from patients with AML for the detection of pathogenic myeloid mutations in 8 genes (DNMT3A, FLT3, IDH1, IDH2, NPM1, TET2, TP53, and WT1) locally using the Hematologic Neoplasm Mutation Panel (50-gene myeloid indication filter) (site 1) or the GeneTrails Comprehensive Heme Panel (site 2) at the 2 institutions and compared them with the central results from the diagnostic laboratory for the BAMT, Foundation Medicine, Inc. The overall percent agreement was over 95% each in all 8 genes, with almost perfect agreement (κ > 0.906) in all but WT1, which had substantial agreement (κ = 0.848) when controlling for site. The minimal discrepancies were due to reporting variants of unknown significance (VUS) for the WT1 and TP53 genes. These results indicate that the various NGS methods used to analyze samples from patients with AML enrolled in the BAMT show high concordance, a reassuring finding given the wide use of NGS for therapeutic decision-making in AML.

Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial.

BACKGROUND: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population. METHODS: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy. RESULTS: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts. CONCLUSIONS: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

GABA-A Receptor Encephalitis After Autologous Hematopoietic Stem Cell Transplant forMultiple Myeloma: Three Cases and Literature Review.

BACKGROUND AND OBJECTIVES: The relationship between autologous hematopoietic stem cell transplant (aHSCT) for multiple myeloma (MM) and anti-GABAA receptor (GABAAR) encephalitis is unknown. We aimed to describe the clinical features, diagnostic process, and outcome of 3 cases of anti-GABAAR encephalitis in patients with a history of prior aHSCT for MM. METHODS: A case series of 3 patients. Anti-GABAAR antibody was tested at the University of Pennsylvania Laboratory. RESULTS: The patients were all male, aged 52 (case 1), 61 (case 2), and 62 (case 3) years at encephalitis symptom onset. The duration between completion of aHSCT and the onset of encephalitis was 43, 18, and 9 months, respectively. All 3 patients presented with new seizures and altered cognitive function. Other symptoms included headache and visual obscurations in cases 1 and 2 and intractable vertigo and mania in case 3. Brain MRI demonstrated nonenhancing multifocal T2-weighted/fluid-attenuated inversion recovery cortical and subcortical hyperintensities in all 3 patients. Cases 2 and 3 underwent brain biopsy before initiating immunomodulatory therapy, which demonstrated nonspecific encephalitis with astrogliosis in the white matter; these 2 patients were started on immunotherapy for the treatment of anti-GABAAR encephalitis after 22 days and 3 months, respectively, from the first presentation. Case 1 was started on empiric immunotherapy within 8 days of presentation without requiring brain biopsy, given characteristic MRI imaging. CSF analysis demonstrated the presence of anti-GABAAR antibodies in all 3 cases. Cases 1 and 3 also tested positive for anti-GABAAR antibodies in the serum (serum test was not performed in case 2). Cases 1 and 2 recovered to work full-time within 1 year. Case 3 reported occasional myoclonic-like movement. DISCUSSION: We highlight the importance of considering anti-GABAAR encephalitis in patients with seizures, multifocal nonenhancing brain lesions, and a history of aHSCT for MM. Awareness in recovered post-aHSCT patients with MM may be crucial because prompt recognition can avoid brain biopsy and delays in treatment. The rapid initiation of immunotherapy while awaiting autoantibody results will likely improve functional outcomes.

The genetic landscape of germline DDX41 variants predisposing to myeloid neoplasms.

Germline DDX41 variants are the most common mutations predisposing to acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in adults, but the causal variant (CV) landscape and clinical spectrum of hematologic malignancies (HMs) remain unexplored. Here, we analyzed the genomic profiles of 176 patients with HM carrying 82 distinct presumably germline DDX41 variants among a group of 9821 unrelated patients. Using our proposed DDX41-specific variant classification, we identified features distinguishing 116 patients with HM with CV from 60 patients with HM with variant of uncertain significance (VUS): an older age (median 69 years), male predominance (74% in CV vs 60% in VUS, P = .03), frequent concurrent somatic DDX41 variants (79% in CV vs 5% in VUS, P < .0001), a lower somatic mutation burden (1.4 ± 0.1 in CV vs 2.9 ± 0.04 in VUS, P = .012), near exclusion of canonical recurrent genetic abnormalities including mutations in NPM1, CEBPA, and FLT3 in AML, and favorable overall survival (OS) in patients with AML/MDS. This superior OS was determined independent of blast count, abnormal karyotypes, and concurrent variants, including TP53 in patients with AML/MDS, regardless of patient's sex, age, or specific germline CV, suggesting that germline DDX41 variants define a distinct clinical entity. Furthermore, unrelated patients with myeloproliferative neoplasm and B-cell lymphoma were linked by DDX41 CV, thus expanding the known disease spectrum. This study outlines the CV landscape, expands the phenotypic spectrum in unrelated DDX41-mutated patients, and underscores the urgent need for gene-specific diagnostic and clinical management guidelines.

A phase 1b study of glasdegib + azacitidine in patients with untreated acute myeloid leukemia and higher-risk myelodysplastic syndromes.

This phase 1b study evaluated glasdegib (100 mg once daily) + azacitidine in adults with newly diagnosed acute myeloid leukemia (AML), higher-risk myelodysplastic syndromes (MDS), or chronic myelomonocytic leukemia (CMML) who were ineligible for intensive chemotherapy. Of 72 patients enrolled, 12 were in a lead-in safety cohort (LIC) and 60 were in the AML and MDS (including CMML) expansion cohorts. In the LIC, the safety profile of glasdegib + azacitidine was determined to be consistent with those of glasdegib or azacitidine alone, with no evidence of drug-drug interaction. In the expansion cohort, the most frequently (≥ 10%) reported non-hematologic Grade ≥ 3 treatment-emergent adverse events were decreased appetite, electrocardiogram QT prolongation, and hypertension in the AML cohort and sepsis, diarrhea, hypotension, pneumonia, and hyperglycemia in the MDS cohort. Overall response rates in the AML and MDS cohorts were 30.0% and 33.3%, respectively; 47.4% and 46.7% of patients who were transfusion dependent at baseline achieved independence. Median overall survival (95% confidence interval) was 9.2 (6.2-14.0) months and 15.8 (9.3-21.9) months, respectively, and response was associated with molecular mutation clearance. Glasdegib + azacitidine in patients with newly diagnosed AML or MDS demonstrated an acceptable safety profile and preliminary evidence of clinical benefits.Trial registration: ClinicalTrials.gov NCT02367456.

A clinical, histopathological, and molecular study of two cases of VEXAS syndrome without a definitive myeloid neoplasm.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is caused by somatic mutations in UBA1 and is identified by a genotype-driven method. This condition affects unrelated men with adultonset inflammatory syndromes in association with hematologic manifestations of peripheral cytopenia and bone marrow myeloid dysplasia. Although bone marrow vacuolization restricted to myeloid and erythroid precursors has been identified in patients with VEXAS, the detailed clinical and histopathological features of peripheral blood and bone marrows remain unclear. The current case report describes the characteristic hematologic findings in patients with VEXAS, including macrocytic anemia, thrombocytopenia, marked hypercellular bone marrow with granulocytic hyperplasia, megaloblastic changes in erythroid precursors, and the absence of hematogones in addition to prominent vacuoles in myeloid and erythroid precursor cells. Characterizing the clinical and hematologic features helps to raise awareness and improve diagnosis of this novel, rare, but potentially underrecognized disease. Prompt diagnosis expands the general knowledgeable and understanding of this disease, and optimal management may prevent patients from developing complications related to this refractory inflammatory syndrome and improve the overall clinical outcome.

AML with germline DDX41 variants is a clinicopathologically distinct entity with an indolent clinical course and favorable outcome.

Germline DDX41 variants in myeloid neoplasms (MNs) are not uncommon, and we explored the prevalence and characterized the clinical and pathologic features in a cohort of 3132 unrelated adult MN patients. By targeted next-generation sequencing, we identified 28 patients (20 men and 8 women) with pathogenic germline DDX41 variants who developed acute myeloid leukemia (AML), in which only 3 (11%) had a family history (FH) of MNs. A subacute clinical course of cytopenia (mean duration of 11.2 months, range 0-72 months) prior to the initial AML diagnosis was accompanied by a low blast count (median at 30%, range 20-70%) in hypocellular marrows (93% of all patients), in vast contrast to the typical proliferative subtypes of AML in the elderly. Most patients had a normal karyotype (75%) and acquired a second DDX41 variant (69%). A favorable overall survival (OS) was observed in comparison to that of common subtypes of AML with wild-type DDX41 in age-matched patients. Our study demonstrated that the frequent germline pathogenic DDX41 variants characterized a clinically distinct AML entity. Features characteristic of DDX41-mutated AML include male predominance, often lack of FH, indolent course, low proliferative potential, frequent somatic DDX41 variants, and a favorable OS.

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

A phase 1b study of once-weekly carfilzomib combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma.

Twice-weekly carfilzomib with lenalidomide-dexamethasone (Rd) is an effective regimen for newly diagnosed multiple myeloma (NDMM). Here we evaluated once-weekly carfilzomib with Rd (once-weekly KRd) in NDMM patients. The NDMM patients were enrolled regardless of transplant eligibility. Patients received carfilzomib on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on carfilzomib days (also day 22 for cycles 1-8) for ≤18, 28-day cycles. Enrollment initiated in a carfilzomib 20/70 mg/m2 (20 mg/m2 on cycle one, day 1; 70 mg/m2 thereafter) NDMM dose-expansion arm, which was suspended because of serious adverse events. After evaluation of dose-limiting toxicities in a two-step-up dose-evaluation cohort, an NDMM dose-expansion arm (carfilzomib 20/56 mg/m2 ) was opened. Fifty-one NDMM patients were enrolled in dose-finding and dose-expansion cohorts. Results are presented for the carfilzomib 56 mg/m2 NDMM dose-expansion arm (n = 33). The grade ≥ 3 treatment-emergent AE (TEAE) rate was 63.6%. Twenty-five patients underwent stem cell collection; 18 proceeded to auto stem cell transplant, and five resumed KRd on study after autoSCT. The overall response rate (ORR) based on best overall response by cycle four was 97.0% (≥very good partial response [VGPR], 69.7%) in the NDMM 20/56 mg/m2 cohort. In patients who did not receive autoSCT (n = 15), the median number of cycles was 16.0; ORR was 93.3% (≥VGPR, 80.0%). At a median follow-up of 8.1 months, median progression-free survival was not reached. Once-weekly KRd (carfilzomib 56 mg/m2 ) had a favorable safety profile and promising activity in NDMM, supporting the use of this regimen in this setting.

Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial.

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome1,2. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.

Utility of Biomarkers in Cardiac Amyloidosis.

Cardiac amyloidosis is a growing field, with advancements in diagnosis and management. Cardiac biomarkers are used to predict survival and to develop severity staging systems. Cardiac biomarkers are also used in clinical practice to stratify patients for treatment and to evaluate response to therapies. The current review summarizes the major clinical utility of current biomarkers in patients with cardiac amyloidosis and provides insights about future areas of investigation.

Dasatinib overcomes stroma-based resistance to the FLT3 inhibitor quizartinib using multiple mechanisms.

FLT3-ITD mutations occur in 20-30% of AML patients and are associated with aggressive disease. Patients with relapsed FLT3-mutated disease respond well to 2nd generation FLT3 TKIs but inevitably relapse within a short timeframe. In this setting, until overt relapse occurs, the bone marrow microenvironment facilitates leukemia cell survival despite continued on-target inhibition. We demonstrate that human bone marrow derived conditioned medium (CM) protects FLT3-ITD+ AML cells from the 2nd generation FLT3 TKI quizartinib and activates STAT3 and STAT5 in leukemia cells. Extrinsic activation of STAT5 by CM is the primary mediator of leukemia cell resistance to FLT3 inhibition. Combination treatment with quizartinib and dasatinib abolishes STAT5 activation and significantly reduces the IC50 of quizartinib in FLT3-ITD+ AML cells cultured in CM. We demonstrate that CM protects FLT3-ITD+ AML cells from the inhibitory effects of quizartinib on glycolysis and that this is partially reversed by treating cells with the combination of quizartinib and dasatinib. Using a doxycycline-inducible STAT5 knockdown in the FLT3-ITD+ MOLM-13 cell line, we show that dasatinib-mediated suppression of leukemia cell glycolytic activity is STAT5-independent and provide a preclinical rationale for combination treatment with quizartinib and dasatinib in FLT3-ITD+ AML.

Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA.

Although no therapies are approved for light chain (AL) amyloidosis, cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is considered standard of care. Based on outcomes of daratumumab in multiple myeloma (MM), the phase 3 ANDROMEDA study (NCT03201965) is evaluating daratumumab-CyBorD vs CyBorD in newly diagnosed AL amyloidosis. We report results of the 28-patient safety run-in. Patients received subcutaneous daratumumab (DARA SC) weekly in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks thereafter for up to 2 years. CyBorD was given weekly for 6 cycles. Patients had a median of 2 involved organs (kidney, 68%; cardiac, 61%). Patients received a median of 16 (range, 1-23) treatment cycles. Treatment-emergent adverse events were consistent with DARA SC in MM and CyBorD. Infusion-related reactions occurred in 1 patient (grade 1). No grade 5 treatment-emergent adverse events occurred; 5 patients died, including 3 after transplant. Overall hematologic response rate was 96%, with a complete hematologic response in 15 (54%) patients; at least partial response occurred in 20, 22, and 17 patients at 1, 3, and 6 months, respectively. Renal response occurred in 6 of 16, 7 of 15, and 10 of 15 patients, and cardiac response occurred in 6 of 16, 6 of 13, and 8 of 13 patients at 3, 6, and 12 months, respectively. Hepatic response occurred in 2 of 3 patients at 12 months. Daratumumab-CyBorD was well tolerated, with no new safety concerns versus the intravenous formulation, and demonstrated robust hematologic and organ responses. This trial was registered at www.clinicaltrials.gov as #NCT03201965.

Clinical and economic analysis of patients with acute myeloid leukemia by FLT3 status and midostaurin use at a Comprehensive Cancer Center.

INTRODUCTION: Identification of cytogenetic and molecular abnormalities has become vital for the appropriate treatment of acute myeloid leukemia (AML). One of the most common molecular alterations in AML is the constitutive activation by internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3). METHODS: This observational, retrospective, cohort study at the Huntsman Cancer Institute (HCI) had two time periods: 1) a historical pre-midostaurin time period which consisted of the FLT3 mutated (FLT3m) and FLT3 wild type (FLT3wt) cohorts from January 1, 2007, to December 31, 2016, and 2) a post-midostaurin cohort which consisted of the FLT3 mutated midostaurin-user cohort (early mido) from May 01, 2017 to December 31, 2018. RESULTS: In total, 39 patients were included in the FLT3m cohort, 61 in the FLT3wt cohort, and seven in the early mido cohort. FLT3m patients spent fewer days in the hospital during the first consolidation regimen and received fewer consolidation cycles compared to FLT3wt patients. Overall survival (OS) was similar between FLT3m and FLT3wt patients. For patients without hematopoietic stem cell transplant, OS was significantly shorter for FLT3m patients compared to FLT3wt patients. Mean AML related inpatient charges and physician charges for FLT3m patients were significantly higher than FLT3wt patients. CONCLUSION: The FLT3 mutation is historically associated with a shorter time to transplant and increased total health care charges. More information is needed to evaluate the real-world treatment strategies for FLT3-mutated patients in the presence of FLT3 inhibitors and the impact of these treatment strategies on clinical and economic outcomes.