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Acute myeloid leukemia (AML) is a rapidly progressive malignancy without effective therapies for refractory disease. So far, chimeric antigen receptor (CAR) T cell therapy in AML has not recapitulated the efficacy seen in B cell malignancies. Here we report a pilot study of autologous anti-CD123 CAR T cells in 12 adults with relapsed or refractory AML. CAR T cells targeting CD123+cells were successfully manufactured in 90.4% of runs. Cytokine release syndrome was observed in 10 of 12 infused individuals (83.3%, 90% confidence interval 0.5–0.97). Three individuals achieved clinical response (25%, 90% confidence interval 0.07–0.53). We found that myeloid-supporting cytokines are secreted during cell therapy and support AML blast survival via kinase signaling, leading to CAR T cell exhaustion. The prosurvival effect of therapy-induced cytokines presents a unique resistance mechanism in AML that is distinct from any observed in B cell malignancies. Our findings suggest that autologous CART manufacturing is feasible in AML, but treatment is associated with high rates of cytokine release syndrome and relatively poor clinical efficacy. Combining CAR T cell therapies with cytokine signaling inhibitors could enhance immunotherapy efficacy in AML and achieve improved outcomes (ClinicalTrials.gov identifier: NCT03766126).

•Gilteritinib maintenance therapy after allogeneic HCT in FLT3-ITDAML is not associated with any difference in HRQOL compared with placebo.•Despite a higher incidence of adverse events, gilteritinib was not associated with any patient-reported impact of side effects.

•FF-10101 is an irreversible inhibitor of FLT3 active against most types of FLT3 activating mutations.•FF-10101 induced responses in patients who had progressed on other FLT3 inhibitors, as well as in some patients with wild-type FLT3.

Patients with acute myeloid leukaemia (AML) positive for internal tandem duplication (ITD) mutations of FLT3have poor outcomes. Quizartinib, an oral, highly potent, selective, type 2 FLT3 inhibitor, plus chemotherapy showed antitumour activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML. The aim of the study was to compare the effect of quizartinib versus placebo on overall survival in patients with FLT3-ITD-positive newly diagnosed AML aged 18–75 years.

1.FLT3-ITD MRD correlates with relapse free survival.2.FLT3-ITD MRD can identify which patients benefit from gilteritinib maintenance.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

•Effective therapies for refractory myeloid leukemia and myelodysplasia are limited.•Refractory patients can achieve remission with myeloablative allogeneic transplantation.•Clofarabine/busulfan conditioning is tolerated and effective in refractory patients.•Graft-versus-host disease is of high concern with active disease at transplantation.

CPX-351 and venetoclax and azacitidine (ven/aza) are both indicated as initial therapy for acute myeloid leukemia (AML) in older adults. In the absence of prospective randomized comparisons of these regimens, we used retrospective observational data to evaluate various outcomes for patients with newly diagnosed AML receiving either CPX-351 (n = 217) or ven/aza (n = 439). This study used both a nationwide electronic health record (EHR)-derived de-identified database and the University of Pennsylvania EHR. Our study includes 217 patients who received CPX-351 and 439 who received ven/aza. Paitents receiving ven/aza were older, more likely to be treated in the community, and more likely to have a diagnosis of de novo acute myeloid leukemia. Other baseline covariates were not statistically significantly different between the groups. Median overall survival (OS) for all patients was 12 months and did not differ based on therapy (13 months for CPX-351 vs 11 months for ven/aza; hazard ratio, 0.88; 95% confidence interval, 0.71-1.08; P = .22). OS was similar across multiple sensitivity analyses. Regarding safety outcomes, early mortality was similar (10% vs 13% at 60 days). However, documented infections were higher with CPX-351 as were rates of febrile neutropenia. Hospital length of stay, including any admission before the next cycle of therapy, was more than twice as long for CPX-351. In this large multicenter real-world dataset, there was no statistically significant difference in OS. Prospective randomized studies with careful attention to side effects, quality of life, and impact on transplant outcomes are needed in these populations.

The phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation–positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P = .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.gov as #NCT02421939.

The phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation–positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P= .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.govas #NCT02421939.

The phase 3 Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation (ADMIRAL) trial demonstrated the superiority of the FLT3 inhibitor, gilteritinib, to salvage chemotherapy (SC) in patients with FLT3-mutated relapsed or refractory (R/R) AML. Baseline comutations, FLT3-internal tandem duplication (ITD) allelic ratio and length, and treatment-emergent mutations were analyzed in patients in the ADMIRAL trial. Baseline comutations were grouped according to gene subgroups (DNA methylation/hydroxymethylation, transcription, chromatin–spliceosome, receptor tyrosine kinase-Ras signaling, TP53-aneuploidy, NPM1, DNMT3A, DNMT3A/NPM1, WT-1, and IDH1/IDH2). Across all but 1 gene subgroup (TP53-aneuploidy), higher pretransplant response rates and a trend toward longer overall survival were observed with gilteritinib vs SC. Patients with DNMT3A/NPM1 comutations who received gilteritinib had the most favorable outcomes of any molecular subgroup analyzed. Survival outcomes with gilteritinib were not adversely affected by FLT3-ITD allelic ratio, FLT3-ITD length, or multiple FLT3-ITD mutations. Among patients who relapsed on gilteritinib, Ras/mitogen-activated protein kinase (MAPK) pathway and FLT3 F691L gene mutations were the most common mutational events associated with treatment resistance. However, the occurrence of Ras/MAPK pathway gene mutations at baseline did not preclude a clinical benefit from gilteritinib. Acquisition of multiple Ras/MAPK pathway gene mutations at relapse suggests a high level of pathway reactivation is needed to overcome the gilteritinib treatment effect. These findings provide insight into the R/R AML molecular profile and the impact of FLT3 inhibitors on mutational evolution associated with treatment resistance and benefit of gilteritinib across a wide spectrum of molecular and genetic subgroups in FLT3-mutated R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02421939.

Therapeutic outcomes for acute myeloid leukemia patients with Fms-like tyrosine kinase 3 (FLT3) mutations have improved substantially since the discovery of small molecule tyrosine kinase inhibitors. Today, use of FLT3 inhibitors is standard in frontline intensive chemotherapy as well as patients with relapsed or refractory acute myeloid leukemia and FLT3mutations and increasingly used as for prolonged remission maintenance posttransplant and/or postconsolidation. Yet, FLT3 inhibitors alone are not curative, and best outcomes are seen when the drugs are used as part of combination regimens. Optimizing therapy for patients with FLT3 mutations remains a work in progress. Overall, modern therapeutic approaches generate cure rates for this group at levels that argue against considering these mutations adverse risk. Still, such survivals require intensive therapy and often transplant. Therefore, efforts are underway to determine if lower toxicity regimens can attain comparable outcomes, at least for patients responding optimally. This review will review the various FLT3 inhibitors that are approved or in development, highlight the areas where they have been shown to add value, and identify areas where their use remains controversial.

Research has resulted in regulatory approval of nine agents for acute myeloid leukaemia indications by the US Food and Drug Administration since 2017: the Bcl-2 inhibitor, venetoclax; two FLT3 inhibitors, midostaurin and gilteritinib; two IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor); the anti-CD33 antibody–drug conjugate, gemtuzumab ozogamicin; the oral, poorly absorbable hypomethylating agent, azacitidine; the liposomal formulation of cytarabine and daunorubicin (5:1 ratio), CPX-351; and the hedgehog signalling pathway inhibitor, glasdegib. A 100% absorbable oral formulation of the hypomethylating agent decitabine was approved for the treatment of myelodysplastic syndrome and chronic myelomonocytic leukaemia, and might be used as an alternative to parenteral hypomethylating agents. Several of the approvals are as single-agent therapies or in specific combinations for narrow indications, thus offering poor treatment value. In this Review, we discuss ongoing research into combinations containing these commercially available targeted therapies for acute myeloid leukaemia.

Hematopoietic cell transplant (HCT) is a potentially curative treatment for hematologic malignancies, diseases largely of older adults. However, older adults are often excluded from this life-saving treatment because of a higher risk of post-HCT mortality and physical decline. Here we examined how fitness changes in older adults post-HCT and how post-HCT frailty status influences survival.

The Blood and Marrow Transplant Clinical Trials Network study 1506 (NCT02997202) was a multi-center phase III randomized trial comparing gilteritinib versus placebo after allogeneic hematopoietic cell transplantation (HCT) in patients with FLT3-ITD-positive AML. The primary analysis comparing relapse-free survival (RFS) did not reach statistical significance, with higher treatment-emergent adverse events (TEAE) with gilteritinib. In patients with detectable FLT3-ITDmeasurable residual disease (MRD) peri-HCT, gilteritinib was associated with significantly longer RFS, demonstrating efficacy of MRD monitoring and intervention with FLT3 inhibition in MRD positive patients. The impact of gilteritinib maintenance on health-related quality of life (HRQoL) is not known; and the aim of this prespecified exploratory analysis is to describe the effect of gilteritinib versus placebo on HRQoL.

•Single-cell sequencing exposes previously unmeasurable complexity of tumor heterogeneity and clonal evolution on quizartinib.•Single-cell sequencing reveals on- and off-target mechanisms of resistance to quizartinib, which can preexist therapy.

•Quizartinib enabled more patients to undergo hematopoietic stem cell transplantation (HSCT) versus chemotherapy.•Continuation of quizartinib after HSCT was tolerable, with no new safety signals.•Quizartinib before and after HSCT may confer clinical benefits in relapsed/refractory FLT3-ITD acute myelogenous leukemia.

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49–8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9–8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1–7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.

FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have activity in acute myeloid leukemia (AML) patients with FLT3 internal tandem duplication (ITD) mutations, but efficacy is limited by resistance-conferring kinase domain mutations. This phase 1/2 study evaluated the safety, tolerability, and efficacy of the oral FLT3 inhibitor PLX3397 (pexidartinib), which has activity against the FLT3 TKI–resistant F691L gatekeeper mutation in relapsed/refractory FLT3-ITD–mutant AML. Ninety patients were treated: 34 in dose escalation (part 1) and 56 in dose expansion (part 2). Doses of 800 to 5000 mg per day in divided doses were tested. No maximally tolerated dose was reached. Plasma inhibitory assay demonstrated that patients dosed with ≥3000 mg had sufficient levels of active drug in their trough plasma samples to achieve 95% inhibition of FLT3 phosphorylation in an FLT3-ITD AML cell line. Based on a plateau in drug exposure, the 3000-mg dose was chosen as the recommended phase 2 dose. The most frequently reported treatment-emergent adverse events were diarrhea (50%), fatigue (47%), and nausea (46%). Based on modified response criteria, the overall response rate to pexidartinib among all patients was 21%. Twenty-three percent of patients treated at ≥2000 mg responded. The overall composite complete response rate for the study was 11%. Six patients were successfully bridged to transplantation. Median overall survival (OS) of patients treated in dose expansion was 112 days (90% confidence interval [CI], 77-150 days), and median OS of responders with complete remission with or without recovery of blood counts was 265 days (90% CI, 170-422 days). This trial was registered at www.clinicaltrials.gov as #NCT01349049.

FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitors (TKIs) have activity in acute myeloid leukemia (AML) patients with FLT3 internal tandem duplication (ITD) mutations, but efficacy is limited by resistance-conferring kinase domain mutations. This phase 1/2 study evaluated the safety, tolerability, and efficacy of the oral FLT3 inhibitor PLX3397 (pexidartinib), which has activity against the FLT3 TKI–resistant F691L gatekeeper mutation in relapsed/refractory FLT3-ITD–mutant AML. Ninety patients were treated: 34 in dose escalation (part 1) and 56 in dose expansion (part 2). Doses of 800 to 5000 mg per day in divided doses were tested. No maximally tolerated dose was reached. Plasma inhibitory assay demonstrated that patients dosed with ≥3000 mg had sufficient levels of active drug in their trough plasma samples to achieve 95% inhibition of FLT3 phosphorylation in an FLT3-ITD AML cell line. Based on a plateau in drug exposure, the 3000-mg dose was chosen as the recommended phase 2 dose. The most frequently reported treatment-emergent adverse events were diarrhea (50%), fatigue (47%), and nausea (46%). Based on modified response criteria, the overall response rate to pexidartinib among all patients was 21%. Twenty-three percent of patients treated at ≥2000 mg responded. The overall composite complete response rate for the study was 11%. Six patients were successfully bridged to transplantation. Median overall survival (OS) of patients treated in dose expansion was 112 days (90% confidence interval [CI], 77-150 days), and median OS of responders with complete remission with or without recovery of blood counts was 265 days (90% CI, 170-422 days). This trial was registered at www.clinicaltrials.govas #NCT01349049.

Since the discovery of FMS-like tyrosine kinase-3 (FLT3)–activating mutations as genetic drivers in acute myeloid leukemia (AML), investigators have tried to develop tyrosine kinase inhibitors that could effectively target FLT3 and alter the disease trajectory. Giltertinib (formerly known as ASP2215) is a novel compound that entered the field late, but moved through the developmental process with remarkable speed. In many ways, this drug's rapid development was facilitated by the large body of knowledge gained over the years from efforts to develop other FLT3 inhibitors. Single-agent gilteritinib, a potent and selective oral FLT3 inhibitor, improved the survival of patients with relapsed or refractory FLT3-mutated AML compared with standard chemotherapy. This continues to validate the approach of targeting FLT3 itself and establishes a new backbone for testing combination regimens. This review will frame the preclinical and clinical development of gilteritinib in the context of the lessons learned from its predecessors.

Since the discovery of FMS-like tyrosine kinase-3 (FLT3)–activating mutations as genetic drivers in acute myeloid leukemia (AML), investigators have tried to develop tyrosine kinase inhibitors that could effectively target FLT3 and alter the disease trajectory. Giltertinib (formerly known as ASP2215) is a novel compound that entered the field late, but moved through the developmental process with remarkable speed. In many ways, this drug’s rapid development was facilitated by the large body of knowledge gained over the years from efforts to develop other FLT3 inhibitors. Single-agent gilteritinib, a potent and selective oral FLT3 inhibitor, improved the survival of patients with relapsed or refractory FLT3-mutated AML compared with standard chemotherapy. This continues to validate the approach of targeting FLT3 itself and establishes a new backbone for testing combination regimens. This review will frame the preclinical and clinical development of gilteritinib in the context of the lessons learned from its predecessors.

Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3 and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3 mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at <200 mg). These studies suggest that gilteritinib has broad activity against FLT3 mutations and limited vulnerability to resistance-causing FLT3 TKD mutations, particularly when used at higher doses.

Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at <200 mg). These studies suggest that gilteritinib has broad activity against FLT3 mutations and limited vulnerability to resistance-causing FLT3 TKD mutations, particularly when used at higher doses.

The natural history of FLT3-mutated AML is changing after the approval of midostaurin for frontline therapy and gilteritinib for relapsed or refractory patients. Recently reported, positive randomized trials of the drugs gilteritinib, quizartinib, and sorafenib predict even wider use of FLT3 inhibitors going forward. FLT3 inhibitors now emerge as an important, if not indispensable, part of therapy for a large subset of high-risk patients.

The natural history of FLT3-mutated AML is changing after the approval of midostaurin for frontline therapy and gilteritinib for relapsed or refractory patients. Recently reported, positive randomized trials of the drugs gilteritinib, quizartinib, and sorafenib predict even wider use of FLT3 inhibitors going forward. FLT3 inhibitors now emerge as an important, if not indispensable, part of therapy for a large subset of high-risk patients.

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

Activating mutations in Fms-like tyrosine kinase 3 (FLT3) occur in ∼30% of adult cases of acute myeloid leukemia (AML). Selective second- and third-generation FLT3 inhibitors have shown significant clinical activity in patients with relapsed FLT3-mutant AML. However, clearance of FLT3-mutant clones does not consistently occur, and disease will progress in most patients after an initial response. This scenario challenges the model of FLT3-mutant AML being oncogene addicted, and it suggests that redundant signaling pathways regulate AML cell survival after FLT3 inhibition. We show that primary FLT3-mutant AML cells escape apoptosis induced by FLT3 inhibition in vitro in the presence of cytokines produced normally in the bone marrow, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3). Despite reactivating canonical FLT3-signaling pathways, GM-CSF and IL-3 maintain cell survival without rescuing proliferation. Cytokine-mediated resistance through GM-CSF and IL-3 is dependent on JAK kinase, STAT5, and proviral integration site of Moloney murine leukemia virus (PIM) but not MAPK or mammalian target of rapamycin signaling. Cotreatment with FLT3 inhibitors and inhibitors of JAK or PIM kinases blocks GM-CSF and IL-3 rescue of cell survival in vitro and in vivo. Altogether, these data provide a strong rationale for combination therapy with FLT3 inhibitors to potentially improve clinical responses in AML.

Activating mutations in Fms-like tyrosine kinase 3 (FLT3) occur in ∼30% of adult cases of acute myeloid leukemia (AML). Selective second- and third-generation FLT3 inhibitors have shown significant clinical activity in patients with relapsed FLT3-mutant AML. However, clearance of FLT3-mutant clones does not consistently occur, and disease will progress in most patients after an initial response. This scenario challenges the model of FLT3-mutant AML being oncogene addicted, and it suggests that redundant signaling pathways regulate AML cell survival after FLT3 inhibition. We show that primary FLT3-mutant AML cells escape apoptosis induced by FLT3 inhibition in vitro in the presence of cytokines produced normally in the bone marrow, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3). Despite reactivating canonical FLT3-signaling pathways, GM-CSF and IL-3 maintain cell survival without rescuing proliferation. Cytokine-mediated resistance through GM-CSF and IL-3 is dependent on JAK kinase, STAT5, and proviral integration site of Moloney murine leukemia virus (PIM) but not MAPK or mammalian target of rapamycin signaling. Cotreatment with FLT3 inhibitors and inhibitors of JAK or PIM kinases blocks GM-CSF and IL-3 rescue of cell survival in vitro and in vivo. Altogether, these data provide a strong rationale for combination therapy with FLT3 inhibitors to potentially improve clinical responses in AML.

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•Quizartinib enabled more patients to undergo hematopoietic stem cell transplantation (HSCT) versus chemotherapy.•Continuation of quizartinib after HSCT was tolerable, with no new safety signals.•Quizartinib before and after HSCT may confer clinical benefits in relapsed/refractory FLT3-ITD acute myelogenous leukemia.

•Older prefrail and frail patients have inferior survival after HCT due to relapse.•Septuagenarians have inferior survival after HCT due to nonrelapse mortality.•Age, frailty phenotype, Karnofsky Performance Status, and Disease Risk Index determine survival for older HCT recipients.•Disease risk index and frailty phenotype determine relapse for older HCT recipients.