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Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n = 55) or refractory myelodysplastic syndrome (MDS; n = 12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P = .05) and 2-year OS (39% versus 70%; P = .04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.

PURPOSE The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated ( FLT3 mut) acute myeloid leukemia (AML) but seldom reduces FLT3 mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3 mut AML. METHODS This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505 ) enrolled patients with FLT3 wild-type and FLT3 mut (escalation) or FLT3 mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III–defined response criteria. RESULTS Sixty-one patients were enrolled (n = 56 FLT3 mut); 64% (n = 36 of 56) of FLT3 mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3 mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10−2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3 mut patients was 10.0 months. CONCLUSION The combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.

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.

Mixed phenotype acute leukemia (MPAL) is a leukemia whose biologic drivers are poorly understood, therapeutic strategy remains unclear, and prognosis is poor. We performed multiomic single cell (SC) profiling of 14 newly diagnosed adult MPAL patients to characterize the immunophenotypic, genetic, and transcriptional landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. However, progressive acquisition of mutations is associated with increased expression of immunophenotypic markers of immaturity. Using SC transcriptional profiling, we find that MPAL blasts express a stem cell-like transcriptional profile distinct from other acute leukemias and indicative of high differentiation potential. Further, patients with the highest differentiation potential demonstrated inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in this cohort, is applicable to bulk RNA sequencing data and was predictive of survival in an independent patient cohort, suggesting utility for clinical risk stratification.

Gilteritinib is a potent and selective FLT3 kinase inhibitor with single-agent clinical efficacy in relapsed/refractory FLT3-mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in NRAS or KRAS. Less frequently, secondary FLT3-F691L gatekeeper mutations or BCR–ABL1 fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of RAS mutations in FLT3-mutated subclones, the expansion of alternative wild-type FLT3 subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML.Significance:Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in FLT3-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML.See related commentary by Wei and Roberts, p. 998.This article is highlighted in the In This Issue feature, p. 983

Supplementary Tables 1-6

Supplementary Figures S1-S7

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.

Limited treatment options exist for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Venetoclax (VEN) in combination with a hypomethylating agent (HMA) or low-dose cytarabine (LDAC) has been recently approved for treatment-naïve patients unfit for intensive induction. Limited data are available to characterize the efficacy of VEN combinations in R/R AML. We retrospectively analyzed 77 patients with a median of 1 prior therapy (range 0-5) treated with VEN combinations for R/R AML or AML secondary to myelodysplastic syndrome (MDS) progressing after HMA monotherapy. The median overall survival (OS) was 13.1 months (95% CI 9.2-15.1). The median progression-free survival (PFS) was 12 months (95% CI 8.2-15.4) with a median duration of response of 8.9 months (95% CI 5.7-13.9). Overall response rate (ORR) was 68% with a composite complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 53%. VEN combination therapy is efficacious in R/R AML and further prospective studies are warranted.

Introduction Granulocyte colony-stimulating factor (G-CSF) hastens neutrophil engraftment and reduces infections after allogeneic hematopoietic cell transplant (alloHCT), yet the optimal start date is unknown. Additionally, concurrent G-CSF and methotrexate for graft-vs-host disease (GVHD) prophylaxis may potentiate myelosuppression, and prolonged G-CSF is costly. Our institution changed from day + 4 to day + 12 G-CSF initiation following reduced intensity (RIC) alloHCT with methotrexate GVHD prophylaxis. Methods We retrospectively compared day + 4 and day + 12 G-CSF initiation after RIC alloHCT from 2017–2021. The primary endpoint was the time to neutrophil engraftment. Secondary endpoints included length of stay (LOS) and the time to platelet engraftment as well as the incidence of infectious events, acute GVHD (aGVHD), and mucositis. Results Thirty-two patients were included in each group with similar baseline characteristics. We observed faster neutrophil engraftment (median 12 vs. 15 days, p = 0.01) and platelet engraftment (median 13 vs. 15 days, p = 0.026) with day + 4 vs. day + 12 G-CSF initiation. Median LOS was 23 days (range, 19–32) with day + 4 initiation vs. 24 days (21–30) with day + 12 (p = 0.046). The incidence of culture-negative febrile neutropenia (p = 0.12), any grade aGVHD (p = 0.58), and grade 2-4 mucositis (p = 0.8) were similar between groups. Conclusion Compared to day + 4, day + 12 G-CSF initiation following RIC alloHCT had a longer time to neutrophil and platelet engraftment. Day + 12 initiation also resulted in longer LOS, which while statistically significant, was potentially of limited clinical significance. These findings are hypothesis generating.

Patients undergoing haploidentical or mismatched unrelated donor (haplo/MMUD) allogeneic hematopoietic cell transplantation (alloHCT) receiving post-transplant cyclophosphamide (PTCy) are at high risk of cytomegalovirus (CMV) infection. Experience with letermovir (LET) in this population is limited. This single center retrospective cohort study compared CMV and transplant outcomes between LET and a historical control with high-dose valacyclovir (HDV) prophylaxis in adults undergoing haplo/MMUD alloHCT. Thirty-eight CMV seropositive patients were included, 19 in each arm. LET reduced the incidence of CMV infection (5% vs. 53%, RR 0.01, 95% CI 0.014-0.71

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 FLT3 mutations 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.

Purpose:Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML), where ITD mutations in tyrosine kinase receptor FLT3 are associated with poor prognostic outcomes. Several FLT3 inhibitors (FLT3i) are in clinical trials for high-risk FLT3-ITD–positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of FLT3-ITD mutations might not guarantee effective clinical response. Motivated by the heterogeneity of FLT3-ITD mutations, we investigated the effects of FLT3-ITD structural features on the response of AML patients to treatment.Experimental Design: We developed the HeatITup (HEAT diffusion for Internal Tandem dUPlication) algorithm to identify and quantitate ITD structural features including nucleotide composition. Using HeatITup, we studied the impact of ITD structural features on the clinical response to FLT3i and induction chemotherapy in FLT3-ITD–positive AML patients.Results:HeatITup accurately identifies and classifies ITDs into newly defined categories of “typical” or “atypical” based on their nucleotide composition. A typical ITD's insert sequence completely matches the wild-type FLT3, whereas an atypical ITD's insert contains nucleotides exogenous to the wild-type FLT3. Our analysis shows marked divergence between typical and atypical ITD mutation features. Furthermore, our data suggest that AML patients carrying typical FLT3-ITDs benefited significantly more from both FLT3i and induction chemotherapy treatments than patients with atypical FLT3-ITDs.Conclusions:These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing toward personalized treatment of AML patients, and enable researchers and clinicians to unravel ITD complexity using the provided software.See related commentary by Gallipoli and Huntly, p. 460

Figure S1: Characterization of FLT3-ITD clones in the FLT3i cohort. Table S1: Confusion matrix of HeatITup and genetic reviewers manual annotation for sequences in Figure 3. Table S2: Univariate Cox regression analyses for the FLT3-ITD-positive UPENN cohort. Table S3: Cox regression analysis of FLT3-ITD duplication length for the non-FLT3i-treated cohort. Table S4: Cox regression analysis of FLT3-ITD classification for the non-FLT3i-treated cohort. Table S5: Cox regression analysis of FLT3-ITD duplication length with classification for the non-FLT3i-treated cohort. Table S6: Cox regression analysis of FLT3-ITD classification for the top third longest ITD duplications in the non-FLT3i-treated cohort (Benjamini-Hochberg adjusted p-values from long non-FLT3i-treated cohort analyses). Table S7: Cox regression analysis of FLT3-ITD spacer sequence exogenous fraction for the non-FLT3i-treated cohort. Table S8: Cox regression analysis of FLT3-ITD spacer sequence exogenous fraction for the top third longest ITD duplications in the non-FLT3i-treated cohort. Table S9: Cox regression analysis of FLT3i treatment for the UPENN cohort. Table S10: Cox regression analysis of FLT3-ITD duplication length for the FLT3i-treated cohort (Benjamini-Hochberg adjusted p-values from FLT3i cohort analyses). Table S11: Cox regression analysis of FLT3-ITD classification for the FLT3i-treated cohort (Benjamini-Hochberg adjusted p-values from FLT3i cohort analyses). Table S12: Cox regression analysis of FLT3-ITD spacer sequence exogenous fraction for the FLT3i-treated cohort.

Purpose: Bexarotene is a retinoic X receptor agonist that has been shown in vitro to inhibit growth and induce differentiation of myeloid leukemic cell lines. We therefore conducted a phase I dose escalation study to assess the maximum tolerated dose, toxicities, and activity of bexarotene in patients with non-M3 acute myeloid leukemia (AML).Experimental Design: We enrolled patients with active non-M3 AML who had either relapsed or refractory disease or were not eligible for standard cytotoxic chemotherapy. Cohorts of three to six patients received escalating doses of daily oral bexarotene ranging from 100 to 400 mg/m2 until evidence of disease progression or unacceptable adverse events occurred.Results: Twenty-seven patients, with median age of 69 years (range, 51-82 years), were treated. Twenty-four (89%) patients had undergone prior chemotherapy. At the highest dose level tested (400 mg/m2), three of six patients had to reduce their dose of bexarotene due to grade 3 adverse events. The maximum tolerable dose of bexarotene was determined to be 300 mg/m2. Clinical activity was manifested by 4 (15%) patients with reduction in bone marrow blasts to ≤5%, 11 (41%) patients with improved platelet counts, and 7 (26%) patients with improved neutrophil counts. Three patients with relapsed AML survived >1 year while taking bexarotene. Leukemic blast differentiation was suggested by the presence of the leukemic cytogenetic abnormality in mature circulating granulocytes and the occurrence of differentiation syndrome.Conclusions: The recommended dose of bexarotene for future studies is 300 mg/m2/d. Bexarotene is well tolerated in patients with non-M3 AML and has evidence of antileukemic activity.

Purpose: Integration of signal transduction inhibitors into chemotherapy regimens generally has generally not led to anticipated increases in response and survival. However, it remains unclear whether this is because of inadequate or inconsistent inhibition of target or other complex biology. The mTOR signaling pathway is frequently activated in acute myelogenous leukemia (AML) and we previously showed the safety of combining the mTOR inhibitor, sirolimus, with mitoxantrone, etoposide, and cytarabine (MEC) chemotherapy. However, we did not reliably determine the extent of mTOR inhibition on that study. Here, we sought to develop an assay that allowed us to serially quantify the activation state of mTOR kinase during therapy.Experimental Design: To provide evidence of mTOR kinase activation and inhibition, we applied a validated whole blood fixation/permeabilization technique for flow cytometry to serially monitor S6 ribosomal protein (S6) phosphorylation in immunophenotypically identified AML blasts.Results: With this approach, we show activation of mTOR signaling in 8 of 10 subjects' samples (80%) and conclusively show inhibition of mTOR in the majority of subjects' tumor cell during therapy. Of note, S6 phosphorylation in AML blasts is heterogeneous and, in some cases, intrinsically resistant to rapamycin at clinically achieved concentrations.Conclusions: The methodology described is rapid and reproducible. We show the feasibility of real-time, direct pharmacodynamic monitoring by flow cytometry during clinical trials combining intensive chemotherapy and signal transduction inhibitors. This approach greatly clarifies pharmacokinetic/pharmacodynamic relationships and has broad application to preclinical and clinical testing of drugs whose direct or downstream effects disrupt PI3K/AKT/mTOR signaling. Clin Cancer Res; 18(6); 1716–25. ©2011 AACR.

CCR Translation for This Article from Single-Cell Pharmacodynamic Monitoring of S6 Ribosomal Protein Phosphorylation in AML Blasts during a Clinical Trial Combining the mTOR Inhibitor Sirolimus and Intensive Chemotherapy

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CCR Translation on this Article from A Phase I Study of Bexarotene, a Retinoic X Receptor Agonist, in Non-M3 Acute Myeloid Leukemia

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myelogenous leukemia (AML) in the phase 3 ADMIRAL trial. In this study, we assessed survival and relapse rates of patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received post-transplantation gilteritinib maintenance therapy. ADMIRAL was a global phase 3 randomized controlled trial that enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or to preselected high- or low-intensity salvage chemotherapy (1 or 2 cycles). Patients in the gilteritinib arm who proceeded to HSCT could receive post-transplantation gilteritinib maintenance therapy if they were within 30 to 90 days post-transplantation and had achieved composite complete remission (CRc) with successful engraftment and no post-transplantation complications. Adverse events (AEs) during HSCT were recorded in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent AEs were evaluated in patients who restarted gilteritinib as post-transplantation maintenance therapy. Patients in the gilteritinib arm underwent HSCT more frequently than those in the chemotherapy arm (26% [n = 64] versus 15% [n = 19]). For all transplantation recipients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplantation CRc, post-transplantation survival was comparable in the 2 arms. Patients who resumed gilteritinib after HSCT had a low relapse rate after pretransplantation CRc (20%) or CR (0%). The most common AEs observed with post-transplantation gilteritinib therapy were increased alanine aminotransferase level (40%), pyrexia (43%), and diarrhea (40%); grade ≥3 AEs were related primarily to myelosuppression. The incidences of grade ≥III acute graft-versus-host disease and related mortality were low. Post-transplantation survival was similar across the 2 study arms in the ADMIRAL trial, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as post-transplantation maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplantation-eligible patients.

Key Points 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.

Purpose This analysis evaluated the relationship between concentrations of quizartinib and its active metabolite AC886 and QT interval corrected using Fridericia’s formula (QTcF) in patients with relapsed/refractory acute myeloid leukemia (AML) treated in the phase 3 QuANTUM-R study (NCT02039726). Methods The analysis dataset included 226 patients with AML. Quizartinib dihydrochloride was administered as daily doses of 20, 30, and 60 mg. Nonlinear mixed-effects modeling was performed using observed quizartinib and AC886 concentrations and time-matched mean electrocardiogram measurements. Results Observed QTcF increased with quizartinib and AC886 concentrations; the relationship was best described by a nonlinear maximum effect (Emax) model. The predicted mean increase in QTcF at the maximum concentration of quizartinib and AC886 associated with 60 mg/day was 21.1 ms (90% CI, 18.3–23.6 ms). Age, body weight, sex, race, baseline QTcF, QT-prolonging drug use, hypomagnesemia, and hypocalcemia were not significant predictors of QTcF. Hypokalemia (serum potassium Conclusion QTcF increase was dependent on quizartinib and AC886 concentrations, but patient factors, including sex and age, did not affect the concentration–QTcF relationship. Because concomitant strong cytochrome P450 3A (CYP3A) inhibitor use significantly increases quizartinib concentration, these results support the clinical recommendation of quizartinib dose reduction in patients concurrently receiving a strong CYP3A inhibitor. Clinical Trial Registration NCT02039726 (registered January 20, 2014).

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

The FLT3 inhibitor gilteritinib has clinical activity in patients with FLT3‐mutated (FLT3 mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML). The impact of FLT3 mutation clearance and the achievement of composite complete remission (CRc) and complete remission/complete remission with partial hematologic recovery (CR/CRh) on overall survival (OS) in patients with FLT3 mut+ R/R AML treated with single‐agent gilteritinib in a phase 1/2 trial were evaluated. Using next‐generation sequencing, a FLT3‐ITD variant allele frequency of ≤10−4 was used to define FLT3‐ITD clearance in patients with no morphologic leukemia (ie, CRc). A total of 108 patients with FLT3‐ITD‐positive (FLT3‐ITD+) R/R AML were analyzed; 95 of these patients had received ≥80‐mg/day gilteritinib. Ten of the 95 patients had FLT3‐ITD clearance; eight of these 10 patients achieved CRc and were considered negative for measurable residual disease. There was a trend toward longer OS in patients who attained CRc with FLT3‐ITD clearance (131.4 weeks) versus those who achieved CRc and did not have FLT3‐ITD clearance (n = 41; 43.3 weeks; HR = 0.416; p = 0.066). Among patients treated with ≥80‐mg/day gilteritinib who achieved CR/CRh (n = 24), seven had FLT3‐ITD clearance. Among patients who received 120‐mg/day gilteritinib, those who achieved CR/CRh had a longer median OS (70.6 weeks) and higher 52‐week survival probability (66.7%) than patients who did not achieve CR/CRh (n = 71; median OS, 41.7 weeks; 52‐week survival probability, 20.2%). Overall, these data suggest that gilteritinib can induce deep molecular responses in patients with FLT3‐ITD+ R/R AML, and in the setting of CRc or CR/CRh, these responses may be associated with prolonged survival., In patients with FLT3‐mutated relapsed/refractory acute myeloid leukemia, the FLT3 inhibitor gilteritinib induced deep molecular responses characterized by FLT3–internal tandem duplication (FLT3‐ITD) mutation clearance. Among patients who achieved morphologic remission with gilteritinib therapy, FLT3‐ITD mutation clearance was associated with a trend toward longer survival.

Approval of midostaurin, a multikinase inhibitor, in combination with chemotherapy for the treatment of adults with newly diagnosed FLT3 mutation–positive acute myeloid leukemia, was based on the p...

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.

Children and adults with Philadelphia chromosome–like B cell acute lymphoblastic leukemia (Ph-like B-ALL) experience high relapse rates despite best-available conventional chemotherapy. Ph-like ALL is driven by genetic alterations that activate constitutive cytokine receptor and kinase signaling, and early-phase trials are investigating the potential of the addition of tyrosine kinase inhibitors (TKIs) to chemotherapy to improve clinical outcomes. However, preclinical studies have shown that JAK or PI3K pathway inhibition is insufficient to eradicate the most common cytokine receptor–like factor 2–rearranged (CRLF2-rearranged) Ph-like ALL subset. We thus sought to define additional essential signaling pathways required in Ph-like leukemogenesis for improved therapeutic targeting. Herein, we describe an adaptive signaling plasticity of CRLF2-rearranged Ph-like ALL following selective TKI pressure, which occurs in the absence of genetic mutations. Interestingly, we observed that Ph-like ALL cells have activated SRC, ERK, and PI3K signaling consistent with activated B cell receptor (BCR) signaling, although they do not express cell surface μ-heavy chain (μHC). Combinatorial targeting of JAK/STAT, PI3K, and “BCR-like” signaling with multiple TKIs and/or dexamethasone prevented this signaling plasticity and induced complete cell death, demonstrating a more optimal and clinically pragmatic therapeutic strategy for CRLF2-rearranged Ph-like ALL.

Pegaspargase (PEG) increases venous thromboembolism (VTE) in acute lymphoblastic leukemia (ALL) potentially due to depletion of anticoagulation factors, including antithrombin (AT). The benefit and cost of AT supplementation in adults is unclear. We aimed to characterize VTE incidence and risk factors following AT and determine the characteristics and costs of supplementation. Fifty-three adults received PEG and AT. VTE occurred in 21% (grade ≥3 8%). T cell ALL and patients receiving prednisone during induction were at highest risk. Repeat AT levels post supplementation were subtherapeutic forty-four percent of the time. A median of 18 days elapsed between PEG and two sequential therapeutic AT levels despite supplementation. Patients received a median of 2 AT doses per PEG dose at a median cost of $11,145. VTE remains common in adults despite AT supplementation. More aggressive AT supplementation may reduce VTE but warrant prospective evaluation given the significant cost.

Quizartinib is an FMS‐like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3‐internal tandem duplication–mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM‐R study. Quizartinib was given as a single dose or multiple once‐daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed‐effects modeling was performed using observed concentrations of quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (Cmax) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and Cmax were

Background and Objective Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib. Methods The pharmacokinetic profile of gilteritinib was assessed from five clinical studies. Results Dose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20–450 mg). Median maximum concentration was reached 2–6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function. Conclusions Gilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment. Clinical Trial Registration NCT02014558, NCT02456883, NCT02571816. Electronic supplementary material The online version of this article (10.1007/s40262-020-00888-w) contains supplementary material, which is available to authorized users.

PURPOSE The anti-CD19 chimeric antigen receptor T-cell therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemotherapy refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is a life-threatening treatment-related toxicity that limits the full therapeutic potential in adults. We report outcomes for adults with r/r ALL treated with an optimized CTL019 dosing and CRS management strategy. METHODS Adults with r/r B-cell ALL received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over 3 days (day 1, 10%; day 2, 30%; day 3, 60%), which allowed for day 2 and day 3 doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. RESULTS Thirty-five adults with r/r ALL received CTL019 in 1 of 3 dosing cohorts. The low-dose cohort (n = 9) received single or fractionated dosing and had manageable toxicity with a 33% complete remission (CR) rate. In the high-dose single infusion cohort, 3 of 6 patients with refractory CRS concurrent with culture-positive sepsis died, and 3 achieved CR. The 20 patients in the high-dose fractionated (HDF) cohort had a 90% CR rate and manageable CRS. The HDF cohort had the highest survival, with a 2-year overall survival of 73% (95% CI, 46% to 88%) and event-free survival of 49.5% (95% CI, 21% to 73%). CONCLUSION Fractionated dosing of CTL019 with intrapatient dose modification optimizes safety without compromising efficacy in adults with r/r ALL.