ABSTRACT:QuANTUM-First was a randomized trial that demonstrated that the addition of quizartinib, a potent and selective FMS-like tyrosine kinase 3 (FLT3) inhibitor, to induction and consolidation chemotherapy, followed by monotherapy maintenance, improved the survival for patients with newly diagnosed FLT3-internal tandem duplication (FLT3-ITD)-mutated acute myeloid leukemia. We conducted a post hoc analysis of the trial data focusing on measurable residual disease (MRD) as assayed using an amplicon-based next-generation sequencing assay, and on the impact of molecular biomarkers such as FLT3-ITD insertion length and comutations. This is, to our knowledge, the first prospective, randomized trial of an FLT3 inhibitor in newly diagnosed patients in which FLT3-ITD MRD data were collected throughout therapy. We established that quizartinib induces deeper remissions with respect to FLT3-ITD MRD vs placebo, and that the amount of MRD at the completion of induction correlates with relapse and survival. We found that longer FLT3-ITD insertion mutations correlated with worse outcome, quizartinib was beneficial irrespective of insertion mutation length, and the FLT3-ITD MRD assay was more sensitive when bone marrow was used vs peripheral blood. Regardless of the presence of NPM1 (nucleophosmin 1) comutation, quizartinib increased the rates of MRD negativity at the end of induction vs placebo. Finally, comparison of the FLT3-ITD mutation length between the polymerase chain reaction (PCR) with capillary electrophoresis assay obtained at screening and the PCR next-generation sequencing MRD assay performed at the end of induction showed a 96.2% concordance with the exact ITD length. This trial was registered at www.clinicaltrials.gov as #NCT02668653.

QuANTUM-First (ClinicalTrials.gov identifier: NCT02668653) was a randomized phase III trial in patients with newly diagnosed FLT3-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) treated with quizartinib or placebo plus standard induction and consolidation chemotherapy and/or allogeneic hematopoietic cell transplantation (allo-HCT), followed by single-agent maintenance therapy. We evaluated the impact of allo-HCT performed in first complete remission (CR1) or composite CR1 (CRc1) on overall survival (OS), considering treatment randomization. Post-hoc extended Cox regression multivariable analyses were conducted in patients who achieved complete remission/composite complete remission by the end of induction, including allo-HCT in CR1/CRc1 as a time-dependent variable to identify prognostic and predictive factors for OS. There were 297 patients with complete remission by the end of induction (quizartinib, N=147; placebo, N=150); of these, 157 (52.9%) underwent allo-HCT in CR1 (quizartinib, N=84; placebo, N=73). There were 368 patients with composite complete remission by the end of induction (quizartinib, N=192; placebo, N=176); of these, 196 (53.3%) underwent allo-HCT in CRc1 (quizartinib, N=110; placebo, N=86). Multivariable analyses revealed quizartinib treatment and allo-HCT in either CR1 (hazard ratio [HR]=0.553, 95% confidence interval [95% CI]: 0.383-0.798, P=0.0015 and HR=0.527, 95% CI: 0.349-0.796, P=0.0023, respectively) or CRc1 (HR=0.645, 95% CI: 0.470‒0.886, P=0.0068 and HR=0.557, 95% CI: 0.391-0.793, P=0.0012, respectively) as significant predictive factors for a longer OS. No new safety signals were identified. Patients who underwent protocol-specified allo-HCT in CR1/CRc1 experienced post-transplant-related complications, mostly grade ≥2 graft-versus-host disease, as expected. This post-hoc analysis further supports the use of quizartinib and allo-HCT in CR1/CRc1 as an efficacious and well-tolerated treatment strategy for newly diagnosed FLT3-ITD-positive AML patients fit for intensive chemotherapy.

Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status and AML monocytic differentiation are implicated in resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts in differentiation not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of patients treated on a clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Git) to characterize immunophenotypic, transcriptional, and genetic clonal evolution on therapy. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, it selected for RAS mutations, RAS pathway activation and RAS-associated monocytic differentiation. In an in vitro model of monocytic differentiation associated with heightened RAS pathway activation, we demonstrated that MEK inhibition re-sensitized to Ven/Gilt. These data indicate RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to monocytic differentiation and can be overcome by RAS pathway inhibition. ### Competing Interest Statement C.C.S. has provided educational talks for Astellas Pharma, served on advisory boards for Genentech/Abbvie and received research funding from Abbvie. B.C., Y.S. and J.H. are employees of Abbvie. M.S. and H.H. are or were previously employees of Genentech.

Importance Acute promyelocytic leukemia (APL) is an acute illness that presents with cytopenia, infections, and disseminated intravascular coagulation. Achieving remission has been shown to make a major difference in patient outcomes; however, early death rates in the first month have been as high as 30% due to acute presentation, comorbidities, the rarity of APL, and clinician inexperience. Objective To develop treatment strategies that would decrease estimated 1-month mortality from 30% to below 15%. Design, Setting, and Participants In this nonrandomized clinical trial, a treatment algorithm that focused on supportive care was used to prevent early death in patients with APL treated at academic and community health centers between August 2017 and July 2021. Because of the rarity of the disease, expert support was available 24/7 from 7 designated APL experts at 6 participating academic lead centers, and included an additional 293 community centers. When a patient presented with APL, an expert was contacted and a consensus treatment plan was developed using the algorithm and expert suggestions. There were no exclusion criteria and all patients with a confirmed diagnosis of APL regardless of age or comorbid conditions were enrolled. Expert support was provided throughout induction. Initial data analysis was conducted May 2023. Main Outcomes and Measures One-month mortality; additional objectives were to compare outcomes in academic and community centers and assess 1-year and overall survival. Results A total of 201 patients were enrolled from 43 centers; 62 at lead centers and 139 from 37 community centers. The median age was 53 years (range, 18-91 years), with 72 patients (35.8%) who were aged 60 years or older; 105 patients (52.2%) were male. Fifty-two patients (26.4%) were diagnosed with high-risk APL. The 1-month mortality rate was 6 deaths of 201 patients (3.0%; 95% CI, 1.1%-6.4%) after adjusting for 1 interim analysis. In a secondary analysis using the Kaplan-Meier method, the 1-month overall survival (OS) rate was 97.0% (95% CI, 93.5%-98.6%) and the 1-year OS rate was 94.5% (95% CI, 90.3%-96.9%). Conclusions and Relevance In this nonrandomized clinical trial, use of an algorithm combined with expert support resulted in a dramatic decrease in early death in academic and community centers. Population-wide survival improved in this highly curable disease, which suggests that implementing an accessible support system with APL experts for comanagement is the most logical next step.

ABSTRACT:The prognosis for relapsed or refractory (R/R) nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML) is poor and represents an urgent unmet medical need. Revumenib, a potent, selective menin inhibitor, was recently approved for the treatment of R/R acute leukemia with a KMT2A translocation in patients aged ≥1 year based on results from the phase 1/2 AUGMENT-101 study. Here, we present results from patients with R/R NPM1m AML enrolled in the phase 2 portion of AUGMENT-101. Enrolled patients received revumenib with or without a strong CYP3A4 inhibitor every 12 hours in 28-day cycles. Primary end points were rate of complete remission (CR) or CR with partial hematologic recovery (CRh; CR + CRh), safety, and tolerability. Secondary end points included overall response rate (ORR) and duration of response. As of 18 September 2024, 84 patients received ≥1 dose of revumenib. Median age was 63 years; 1 patient was aged <18 years. The protocol-defined, efficacy-evaluable population for the primary analysis included 64 adult patients (≥3 previous lines of therapy, 35.9%; previous venetoclax, 75.0%). The CR + CRh rate was 23.4% (1-sided P = .0014); the ORR was 46.9%. Median duration of CR + CRh was 4.7 months. Of 30 responders, 5 (16.7%) proceeded to hematopoietic stem cell transplant (HSCT) and 3 resumed revumenib after HSCT. Treatment-related adverse events led to treatment discontinuation in 4 patients (4.8%). Revumenib demonstrated clinically meaningful responses in this heavily pretreated, older population with NPM1m AML, including remissions that enabled HSCT. The safety profile of revumenib was consistent with previously reported results. This trial was registered at www.clinicaltrials.gov as #NCT04065399.

Combining FLT3 inhibitors with intensive chemotherapy and transplant has substantially improved AML outcomes, prompting a recent re-evaluation of FLT3-ITD's historically negative prognostic effect. Treatment approaches may soon undergo major changes as emerging data suggest maximal intensity does not benefit all patients and MRD potentially can guide several treatment choices. Finally, recent data also suggest FLT3 inhibitors could transform outcomes in patients unsuitable for intensive therapy. If confirmed, this has important implications for fit patients and could revolutionize the treatment paradigm.

Context.—:The phase 3 study Quizartinib With Standard of Care Chemotherapy and as Continuation Therapy in Patients With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia (AML) (QuANTUM-First; NCT02668653) demonstrated improved overall survival (OS) in newly diagnosed patients with FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication-positive AML treated with the FLT3 inhibitor quizartinib over placebo, leading to the approval of quizartinib in this population. Objective.—:To describe the bridging study between the Navigate clinical trial assay (CTA) used for patient selection in QuANTUM-First and the LeukoStrat CDx [companion diagnostic] FLT3 Mutation Assay, necessary to establish concordance between these 2 assays to support the QuANTUM-First supplemental premarket application for the CDx. Design.—:Assay agreement was established if lower bounds of the 95% CI for both positive and negative percentage agreement were 90% or greater. Treatment efficacy was evaluated to assess if OS in the intent-to-treat (ITT) CDx+ population (CTA+, CDx+) and the QuANTUM-First ITT were comparable. Results.—:The lower bounds of the 95% CI were greater than 90% for positive percentage agreement (94.7%) and negative percentage agreement (100%) based on results from 1029 patients, demonstrating agreement between CTA and CDx. The OS benefit provided by quizartinib in the ITT CDx+ population in the bridging study, with a median OS of 29.4 months for quizartinib versus 14.8 months for placebo (hazard ratio, 0.794; 2-sided stratified log-rank P = .06), was comparable with the OS benefit in the QuANTUM-First ITT. Conclusions.—:The LeukoStrat CDx FLT3 Mutation Assay aids in selecting newly diagnosed patients with FLT3 internal tandem duplication-positive AML for quizartinib therapy.

Abstract: Little is known about the impact of recent advances in acute myeloid leukemia (AML) treatment on racial/ethnic disparities in survival outcomes. We performed a retrospective cohort study of patients with newly diagnosed AML using data from a nationwide electronic health record–derived deidentified database. Patients were categorized based on their diagnosis date relative to venetoclax approval, as pre–novel therapy era (Pre era; 2014-2018; n = 2998) or post–novel therapy era (Post era; 2019-2022; n = 2098). Patients in the Post era were older and had more comorbidities than Pre era. Non-Hispanic Black (NHB) and Hispanic patients were younger and more likely to have lower socioeconomic status than non-Hispanic White (NHW) patients, with no differences in the distributions of key disease features. After accounting for age and comorbidity, overall survival (OS) was higher in patients in Post era than Pre era (adjusted hazard ratio [aHR], 0.90; 95% confidence interval [CI], 0.83-0.96). In Pre era, NHB had a 22% higher hazard of death than NHW (aHR, 1.22; 95% CI, 1.04-1.43), whereas worse OS was not observed for NHB in Post era (aHR, 0.86; 95% CI, 0.69-1.08; predicted 2-year survival, 45.3% vs 39.9%). Utilization of novel therapeutics in frontline therapy did not differ by race/ethnicity. Among patients receiving venetoclax-based induction, particularly those without TP53, RAS, or FLT3-ITD mutations, results suggested higher OS for NHB than NHW patients (aHR, 0.67; 95% CI, 0.45-1.01). Additional studies are needed to elucidate factors contributing to these observed survival differences and to inform strategies to optimize outcomes for all patients with AML.

BMT CTN 1506 ("MORPHO"; NCT02997202) was a randomized phase 3 study of gilteritinib compared to placebo as maintenance therapy after hematopoietic stem cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary endpoint was to determine the impact on survival of pre- and/or post-HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post-hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively impacted RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared to 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild type clones (as assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multi-clonal disease. These data demonstrate the potential of using FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML.

TPS6580 Background: Quizartinib (Quiz) is an oral, selective, type-II FLT3 inhibitor with potent activity against wild-type (wt) FLT3, FLT3-ITDs, and other kinase domain variants. Quiz is approved for patients (pts) with FLT3 -ITD+ newly diagnosed (ND) AML based on results from the QuANTUM-First trial (NCT02668653). Mutations in the FLT3 gene are observed in ~30% of AML cases, most commonly as ITDs, but they are not the only mechanism affecting FLT3 activation. Elevated expression of the FLT3 receptor is observed in nearly all cases of AML, and high levels of FLT3 gene expression are detected in 70–100% of AML blasts, independent of the presence of FLT3 gene mutations, potentially contributing to leukemic cell survival and proliferation. Evidence from preclinical and clinical studies supports Quiz activity in FLT3 -ITD–negative ( FLT3 -ITDneg) AML. In the phase 2 QUIWI trial, the addition of Quiz to standard chemotherapy and as single-agent maintenance significantly prolonged overall survival (OS) vs placebo (Pbo) in ND FLT3 -ITDneg AML. QuANTUM-Wild is a global, phase 3, double-blind, Pbo-controlled trial evaluating Quiz with standard induction/consolidation chemotherapy and as maintenance in ND FLT3 -ITDneg AML (NCT06578247). Methods: Eligible pts are aged 18–70 years with FLT3 -ITD allelic frequency < 5%. Treatment includes standard induction with cytarabine and an anthracycline plus Quiz/Pbo, followed by up to 4 cycles of consolidation (+/– allo-HSCT) with high-dose cytarabine and Quiz/Pbo, and then single-agent maintenance with Quiz/Pbo in 28d cycles for up to 36 cycles. Pts are randomized 2:2:1 into 3 arms: Arm A (Quiz in all phases), Arm B (Pbo in all phases), or Arm C (Quiz in induction/consolidation and Pbo in maintenance). Quiz is administered at 60 mg/day, reduced to 30 mg if combined with strong CYP3A inhibitors. The primary endpoint is OS, and secondary endpoints include event-free survival (EFS), relapse-free survival (RFS), complete remission (CR) rate and duration, measurable residual disease (by FLT3 -ITD in all pts and by NPM1 and CBF if present), and safety. Planned enrollment is ~700 pts, with 280 each in Arms A and B, and 140 pts in Arm C. The primary OS analysis compares Arms A and B, while Arm C is descriptive. Enrollment is expected to continue through 2028. © American Society of Hematology (2024). Reused with permission. Clinical trial information: 2023-507936-20-00; NCT06578247 .

Importance Acute promyelocytic leukemia (APL) is an acute illness that presents with cytopenia, infections, and disseminated intravascular coagulation. Achieving remission has been shown to make a major difference in patient outcomes; however, early death rates in the first month have been as high as 30% due to acute presentation, comorbidities, the rarity of APL, and clinician inexperience. Objective To develop treatment strategies that would decrease estimated 1-month mortality from 30% to below 15%. Design, Setting, and Participants In this nonrandomized clinical trial, a treatment algorithm that focused on supportive care was used to prevent early death in patients with APL treated at academic and community health centers between August 2017 and July 2021. Because of the rarity of the disease, expert support was available 24/7 from 7 designated APL experts at 6 participating academic lead centers, and included an additional 293 community centers. When a patient presented with APL, an expert was contacted and a consensus treatment plan was developed using the algorithm and expert suggestions. There were no exclusion criteria and all patients with a confirmed diagnosis of APL regardless of age or comorbid conditions were enrolled. Expert support was provided throughout induction. Initial data analysis was conducted May 2023. Main Outcomes and Measures One-month mortality; additional objectives were to compare outcomes in academic and community centers and assess 1-year and overall survival. Results A total of 201 patients were enrolled from 43 centers; 62 at lead centers and 139 from 37 community centers. The median age was 53 years (range, 18-91 years), with 72 patients (35.8%) who were aged 60 years or older; 105 patients (52.2%) were male. Fifty-two patients (26.4%) were diagnosed with high-risk APL. The 1-month mortality rate was 6 deaths of 201 patients (3.0%; 95% CI, 1.1%-6.4%) after adjusting for 1 interim analysis. In a secondary analysis using the Kaplan-Meier method, the 1-month overall survival (OS) rate was 97.0% (95% CI, 93.5%-98.6%) and the 1-year OS rate was 94.5% (95% CI, 90.3%-96.9%). Conclusions and Relevance In this nonrandomized clinical trial, use of an algorithm combined with expert support resulted in a dramatic decrease in early death in academic and community centers. Population-wide survival improved in this highly curable disease, which suggests that implementing an accessible support system with APL experts for comanagement is the most logical next step. Trial Registration ClinicalTrials.gov Identifier: NCT03253848

Background: Rearrangements of the lysine methyltransferase 2A (KMT2Ar) gene occur in ≤10% of acute leukemias (ALs) and are associated with a poor prognosis. In patients (pts) with KMT2Ar AL, the menin-KMT2A fusion protein interaction is a key driver of leukemogenesis. Revumenib, an oral, potent, and selective menin inhibitor, demonstrated a high rate of complete remission (CR) or CR with partial hematologic recovery (CR+CRh; 23%) and overall response rate (ORR; 63%) with a tolerable safety profile in pts with R/R KMT2Ar AL in the phase 2 interim analysis of AUGMENT-101 (NCT04065399). The KMT2Ar cohorts met prespecified stopping rules for efficacy, and the data from this analysis (n=57) were the basis for a New Drug Application to the FDA. Here we report longer follow-up and a larger data set, including safety and efficacy results for all pts with KMT2Ar enrolled in the phase 2 study (N=116), representing the largest evaluation of menin inhibition in pts with R/R KMT2Ar AL to date. Methods: Pts aged ≥30 d with R/R KMT2Ar AL were enrolled and received revumenib 163 mg (95 mg/m2 if body weight <40 kg) every 12 h (q12h) with a strong CYP3A4 inhibitor azole in 28-d continuous cycles. Treatment continued until lack of at least morphological leukemia-free state (MLFS) after 4 cycles, disease progression, or unacceptable adverse events (AEs). Primary objectives were safety and tolerability and rate of CR+CRh. Key secondary endpoints included rate of composite CR (CRc [CR+CRh+CR with incomplete platelet recovery+CR with incomplete count recovery), ORR (CRc+MLFS+partial remission), and duration of response (DoR). The efficacy population included pts with centrally confirmed KMT2Ar and ≥5% baseline bone marrow blasts. Measurable residual disease (MRD) was assessed locally by flow cytometry or PCR at the discretion of investigators. Results: At the time of the interim analysis (data cutoff [DCO]: July 24, 2023), 13 pts achieved CR+CRh (23%), 6 of whom remained in follow-up with no relapse or death at that time. In this current analysis, with 7 additional mo of follow-up (DCO: February 29, 2024), the updated median duration of CR+CRh in these 13 responders was 13.0 mo (95% CI, 3.4 mo-not reached [NR]); 5 remained in follow-up with no relapse or death, while 1 more pt had relapsed. A total of 116 pts with R/R KMT2Ar AL received ≥1 dose of revumenib and were included in the safety population. Median age was 35.5 y (range, 0.6-75.0); 28 (24%) pts were <18 y, and 14 (12%) were ≥65 y. A total of 95 (82%) pts had AML, and 21 (18%) had ALL or MPAL; 67 (58%) were female, and 18 (16%) were non-White. Pts were heavily pretreated (median of 2 prior therapies [range, 1-11]), with 51 (44%) receiving ≥3 prior lines, 73 (63%) receiving prior venetoclax, and 59 (51%) underwent prior hematopoietic stem cell transplant (HSCT). In the efficacy population (n=97), 22 pts (23% [95% CI, 15%-32%]) achieved CR+CRh with a median DoR of 6.4 mo (95% CI, 1.9 mo-NR). CRc rate was 42% (95% CI, 32%-53%); ORR was 64% (95% CI, 54%-73%). Of 18 CR+CRh responders with MRD results available, 11 (61%) achieved MRD negativity; 21/36 (58%) MRD-evaluable CRc responders achieved MRD negativity. Of 62 pts who achieved ORR, 21 (34%) proceeded to HSCT. Nine pts resumed revumenib post HSCT. In the safety population (N=116), 106 (91%) pts experienced a grade ≥3 treatment-emergent AE (TEAE) and 63 (54%) experienced a grade ≥3 treatment-related AE (TRAE). The most common (≥10%) grade ≥3 TEAEs were febrile neutropenia (45 [39%]), anemia (23 [20%]), platelet count decreased (19 [16%]), differentiation syndrome (17 [15%]; only 1 grade 4, no grade 5), neutrophil count decreased (17 [15%]), white blood cell count decreased (17 [15%]), sepsis (16 [14%]), and QTc prolongation (15 [13%]; all grade 3). Sixteen pts (14%) discontinued treatment due to a TEAE, and 6 (5%) discontinued due to a TRAE. Nineteen (16%) and 4 (3%) pts experienced a TEAE or TRAE leading to death, respectively. Conclusions: Revumenib monotherapy provides clinically meaningful responses in heavily pretreated pts with R/R KMT2Ar acute leukemias, including high rates of MRD negativity and ability to proceed to HSCT. Continued treatment and follow-up of pts after the interim analysis demonstrate the durability of ongoing response. The safety profile of revumenib with this longer follow-up is consistent with prior reports. This trial represents the largest evaluation of a targeted therapy for pts with R/R KMT2Ar acute leukemias to date.

Introduction Venetoclax (ven) in combination with hypomethylating agents (HMA) is the standard of care for the treatment of acute myeloid leukemia (AML) in patients (pts) who are ineligible for intensive chemotherapy. The most serious complication of ven is tumor lysis syndrome (TLS). The phase 1b trial of ven and HMA in AML pts included strict prophylactic measures to prevent TLS. Reported rates of TLS in real world cohorts vary widely and prophylactic measures are not standardized. Methods Here we describe TLS prophylaxis (ppx) and incidence in a cohort of 100 consecutive pts age ≥18 years at the University of Pennsylvania who received inpatient or outpatient ven and HMA for up front treatment of AML between 1/2017-8/2022. TLS ppx was at the discretion of the treating team. TLS was retrospectively defined by Cairo Bishop and Howard Criteria (table 1). Howard TLS (H-TLS) criteria differs from Cairo Bishop TLS (CB-TLS) in that it requires two lab abnormalities be present in the same 24-hour period, uses calcium corrected for albumin and does not include ≥25% changes from baseline lab values. Results 92 pts had a white blood cell count (WBC) <25,000 cells/μL on the first day of treatment (table 1). 34 pts developed laboratory (lab) CB-TLS; 8 of these pts met criteria for clinical CB-TLS due to acute kidney injury (AKI). 13 pts developed CB-TLS prior to starting ven. While the original phase 1b trial mandated frequent lab monitoring as well as starting allopurinol ≥72 hours prior to ven and suggested a target of 2L of intravenous (IV) fluid per day starting the night prior to ven, TLS ppx was variable in our pts. 56 pts received allopurinol ≥72 hours prior to starting ven, 21 received ≥2L of IV fluid per day starting at least the day prior to ven, and 56 had TLS labs measured every 8-12 hours during the first 3 days following ven initiation. CB-TLS was associated with a higher ECOG score and baseline lactate dehydrogenase as well as FLT3 and NPM1 mutations. The CB-TLS group had a higher mean WBC count but there was no difference in the proportion of pts with WBC counts ≥25,000 cells/μL. There was a trend towards increased CB-TLS in pts with WBC counts ≥15,000 cells/μL; this reached statistical significance when comparing the percent of pts with non-spontaneous CB-TLS with WBC count ≥15,000 cells/μL to the rest of the cohort (33% vs 13%, p=0.034). To characterize TLS severity, we categorized the pts with CB-TLS into three groups: insignificant TLS, significant TLS, and those whose lab abnormalities were explained by a different pathology. We defined significant TLS as pts who required hospitalization (if started treatment outpatient) or ICU transfer, received rasburicase, developed AKI, or had treatment held due to TLS. 17 pts had insignificant TLS, 14 had significant TLS, and 3 were ultimately felt not to have TLS (table 2). We also compared pts who developed CB-TLS with those who met criteria for H-TLS. Of the 34 pts who met lab CB-TLS criteria, only 6 also met Howard criteria. All 6 of these pts had significant TLS. Of the 8 pts with significant TLS who only met Cairo Bishop criteria, 6 developed spontaneous TLS >3 days prior to starting treatment with ven that would have met H-TLS criteria at onset. Their lab abnormalities were not as severe by ≤3 days prior to ven start when the formal time frame for defining TLS begins. Discussion Other studies have shown lab TLS rates of 0-40% in AML pts receiving ven with HMA, with the majority reporting rates <10%. Our data show a higher rate of lab CB-TLS than other published cohorts. However, our data also show that most pts do not develop significant TLS despite less aggressive ppx than was used in the original ven trial and suggest that less aggressive ppx is appropriate for most pts. There was a high rate of spontaneous TLS in our cohort. Debate exists over the most appropriate WBC threshold for ven initiation; our data suggest an association of WBC count <15,000 cells/μL with lower TLS risk. Of the pts who developed significant TLS, a majority had spontaneous TLS; only 5 pts had significant TLS occur after starting ven. We also found that the Howard criteria for TLS better identify pts who will have adverse outcomes from TLS and may be a more clinically meaningful set of criteria to use in future studies.

PURPOSE:The management of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have evolved substantially in recent years with the development of targeted therapies and novel nontargeted approaches. However, many questions remain about how to best use current therapies, and there is a large unmet need for effective therapies, particularly for patients with higher-risk MDS, AML, and those with MDS/AML relapsed/refractory (R/R) to prior therapy. METHODS AND RESULTS:A panel of experts was assembled to discuss current controversies and unanswered questions in the care of patients with MDS and AML. Workshop topics included: molecular testing and new classification systems, clonal hematopoiesis, treatment of MDS (lower-risk and higher-risk), frontline treatment of AML, treatment of special populations, treatment of R/R AML, and novel approaches. CONCLUSIONS:We identified many areas of ongoing controversy in the diagnosis and management of MDS and AML related to classification and risk assessment, treatment selection, sequencing of therapies, and monitoring of responses. Many clinical trials are ongoing to further improve outcomes for patients with MDS and AML, and we noted potential areas of debate related to study design, selection of endpoints, and assessment of responses. The controversies and gaps in knowledge identified by this panel will inform a follow-up conference in 2025 that will employ a modified Delphi method with a goal of developing and publishing formal consensus recommendations that can provide actionable guidance to clinicians in practice.

Abstract: We conducted a post hoc analysis of data from Blood and Marrow Transplant Clinical Trials Network 1506 (MORPHO), a randomized trial of gilteritinib vs placebo as posttransplantation maintenance for patients with FLT3-ITD–mutated acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT), focusing the interactions between conditioning regimen intensity, measurable residual disease (MRD), and NPM1 comutation status reported from diagnosis. Comparing FLT3-ITD MRD before and after conditioning, there was no difference between myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) in eradication or reduction of FLT3-ITD MRD. For participants who were FLT3-ITD MRD negative before HCT, there was no difference in the cumulative incidence of relapse during follow-up between those receiving MAC vs RIC. NPM1 comutation was associated with the largest magnitude of relapse-free survival benefit from post-HCT gilteritinib, and in these participants, post-HCT gilteritinib in the setting of RIC appeared to be as effective as MAC at preventing relapse. MAC appeared superior to RIC in preventing relapse only in participants who were NPM1 wild type at diagnosis and FLT3-ITD MRD positive before HCT. Our findings suggest that only a subset of patients with FLT3-ITD AML undergoing HCT may benefit from MAC and that, similar to AML therapy before HCT, the intensity of the HCT regimen should be adapted according to the molecular features of the disease. This trial was registered at www.clinicaltrials.gov as #NCT02997202.

Background FLT3-ITD is among the most common mutations in AML but has not historically been routinely assessed in patients in remission. In the phase 3 QuANTUM-First trial, quizartinib, a type-II FLT3 inhibitor, significantly improved OS vs placebo when added to intensive chemotherapy and used as maintenance monotherapy in patients with FLT3-ITD+ ND-AML. We analyzed the impact of FLT3-ITD–specific MRD in QuANTUM-First. Methods Genomic DNA was collected from patients with remission after induction and after consolidation (pretransplant for HCT patients) and analyzed with a FLT3-ITD PCR-NGS assay. ITD mutations after induction were cross-validated against enrollment; ITD variant allele frequencies (VAFs) were calculated with a sensitivity of ~10–5; MRD was classified as undetectable below 0 or as MRD– using a predefined 10–4 cutoff. Composite complete remission (CRc) rates (CR+CRi) by MRD status were compared between arms by stratified CMH test. ITD VAFs were compared between arms by Wilcoxon rank-sum test. Results Of 539 randomized patients (quizartinib/placebo, 268/271), 368 (68.3%) achieved CRc. MRD analysis was performed on 321 (87.2%) of the 368 (quizartinib/placebo, 162/159) during induction response assessments and on 337 patients (quizartinib/placebo, 172/165) at end of consolidation prior to continuation; 166 (quizartinib/placebo, 87/79) received HCT. The CRc rate at end of induction with ITD MRD <10-4 was similar between arms (quizartinib/placebo, 25.4%/21.8%; P=.3430), but proportionally more patients had CRc with undetectable MRD (0 cutoff) with quizartinib (12.3% vs 7.0%, respectively; P=.0403). For patients with CRc after induction, the median best ITD VAF by end of consolidation was lower with quizartinib than placebo (0% vs 0.0017%; P=.0006). Using the undetectable ITD (0 VAF) cutoff at end of induction, a longer OS was observed with quizartinib vs placebo regardless of MRD status (HR: 0.79 in MRD− 0.75 in MRD+). In MRD+ patients, median OS was not reached with quizartinib and was 35.4 months with placebo. Results were similar using an MRD– cutoff of 10-4. Conclusions These findings demonstrate the prognostic utility of ITD-specific MRD measurements in the management of patients with FLT3-ITD+ AML and suggest that long-term OS benefits with quizartinib derive in part from a deep and sustained reduction of FLT3-ITD.

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.

Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of