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Myelodysplastic syndromes (MDS) have historically been challenging diseases for drug development due to their biology, preclinical modeling, and the affected patient population. In April 2022, the FDA convened a panel of regulators and academic experts in MDS to discuss approaches to improve MDS drug development. The panel reviewed challenges in MDS clinical trial design and endpoints and outlined considerations for future trial design in MDS to facilitate drug development to meaningfully meet patient needs. Challenges for defining clinical benefit in patients with MDS include cumbersome response criteria, standardized transfusion thresholds, and application and validation of patient reported outcome instruments. Clinical trials should reflect the biology of disease evolution, the advanced age of patients with MDS, and how patients are treated in real-world settings to maximize the likelihood of identifying active drugs. In patients with lower-risk disease, response criteria for anemic patients should be based on baseline transfusion dependency, improvement in symptoms, and quality of life. For higher-risk patients with MDS, trials should include guidance to prevent dose reductions or delays that could limit efficacy, specify minimal durations of treatment (in the absence of toxicity or progression), and have endpoints focused on overall survival and durable responses. MDS trials should be designed from the outset to allow the practicable application of new therapies in this high-needs population, with drugs that can be administered and tolerated in community settings, and with endpoints that meaningfully improve patients’ lives over existing therapies.

Supplementary Figure 1

Rate of CR+CRh by subgroup

Supplementary Table S2

Preferred Terms included in grouped terms

Supplemental Table 1 describes the adverse events with corresponding risk differences between treatment arms during induction of pivotal trial ALFA-0701.

Supplementary Table S1

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody–drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51–0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53–0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242–6. ©2018 AACR.

Supplementary tables and figures

Supplemental Table 4 and the accompanying text describe the grouped terms used for the adverse reactions described in Table 2 and the reasons for using grouped terms.

On November 21, 2018, the FDA approved glasdegib (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, in combination with low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy. Evidence of clinical benefit came from Study BRIGHT AML 1003, a randomized trial comparing glasdegib+LDAC with LDAC alone for treatment of newly diagnosed AML in 115 patients either ≥ 75 years old or ≥ 55 years old with preexisting comorbidities. Efficacy was established by improved overall survival (OS) with the combination compared with LDAC alone (HR, 0.46; 95% confidence interval, 0.30–0.71; one-sided stratified log-rank P = 0.0002). Median OS was 8.3 months with the combination and 4.3 months with LDAC alone. Common adverse reactions included cytopenias, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. The label includes a boxed warning for embryo-fetal toxicity and a warning for QT interval prolongation. There is a limitation of use for patients with moderate-to-severe hepatic and severe renal impairment; trials studying glasdegib in these patient populations are required as a condition of this approval.See related commentary by Fathi, p. 6015

On November 28, 2018, the FDA approved gilteritinib (Xospata; Astellas), a small-molecule FMS-like tyrosine kinase 3 (FLT3) inhibitor, for treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation as detected by an FDA-approved test. In the ADMIRAL study, patients were randomized 2:1 to receive gilteritinib or standard chemotherapy and stratified by response to first-line treatment and intensity of prespecified chemotherapy. Efficacy was established on interim analysis on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence to transfusion independence in 138 patients in the gilteritinib arm. With median follow-up of 4.6 months [95% confidence interval (CI), 2.8–15.8 months] at interim analysis, the CR + CRh rate was 21% (95% CI, 15%–29%), median duration of CR + CRh was 4.6 months (range, 0.1–15.8+), and conversion from transfusion dependence to transfusion independence was 31%. Revised labeling approved on May 29, 2019 included the results of the final analysis, showing an improvement in overall survival (OS) with gilteritinib compared with chemotherapy (HR, 0.64; 95% CI, 0.49–0.83; one-sided P = 0.0004; median OS, 9.3 vs. 5.6 months). The OS benefit was observed in both high and low chemotherapy intensity subgroups. Labeling includes a boxed warning for differentiation syndrome and warnings for posterior reversible encephalopathy syndrome, QT prolongation, pancreatitis, and embryo-fetal toxicity. Safe use requires frequent monitoring of electrocardiograms and blood chemistries. Assessments of long-term safety are pending.

The FDA approved ivosidenib (Tibsovo; Agios), a small-molecule inhibitor of isocitrate dehydrogenase (IDH)1 on July 20, 2018, for treatment of adults with relapsed or refractory acute myeloid leukemia (R/R AML) with susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of ivosidenib was established on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence (TD) to transfusion independence (TI) in Study AG120-C-001, a single-arm trial. With median follow-up of 8.3 months for 174 adults with IDH1-mutated R/R AML treated with 500 mg ivosidenib daily, the CR + CRh rate was 33% [95% confidence interval (CI), 26–40], median duration of response was 8.2 (95% CI, 5.6–12) months, and conversion from TD to TI occurred in 37% of patients. These endpoints reflect short-term benefit in patients with an unmet medical need; long-term efficacy outcomes were not assessed. Serious adverse reactions (AR) in ≥5% of patients were differentiation syndrome (10%), leukocytosis (10%), and QT interval prolongation (7%). Common (≥20%) ARs of any grade were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, QT interval prolongation, rash, pyrexia, cough, and constipation. Assessment of long-term safety of ivosidenib is a condition of this approval.

Supplementary Figure from FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes

Supplementary Figure 1. Detailed flow diagram for ascertainment of DS cases.

Supplemental Table 2 describes the adverse events with corresponding risk differences between treatment arms during consolidation 1 of pivotal trial ALFA-0701.

Supplementary Figure 2. Relative risk of DS for frequently co-mutated genes.

Purpose:Differentiation syndrome (DS) is a serious adverse reaction of isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib in patients with (IDH)1- and IDH2-mutated acute myeloid leukemia (AML), respectively.Experimental Design:During FDA review of marketing applications for ivosidenib and enasidenib, data from pivotal trials were queried to identify cases of DS in patients with relapsed or refractory (R/R) AML. One hundred seventy-nine patients with R/R AML received ivosidenib and 214 received enasidenib. Adverse events, labs, and vital signs in the first 90 days of treatment were screened per diagnostic criteria, and narratives were reviewed to adjudicate DS cases.Results:We identified 72 of 179 (40%) potential cases for ivosidenib and 86 of 214 (40%) for enasidenib; 34 of 179 (19%) and 41 of 214 (19%) were adjudicated as DS. Leukocytosis was present in 79% and 61% of cases, respectively. Median (range) time to onset was 20 (1–78) and 19 (1–86) days. Grade ≥ 3 adverse reactions occurred in 68% and 66%; 6% and 5% were fatal. Univariate analyses suggested baseline bone marrow blasts ≥ 48% and peripheral blood blasts ≥ 25% and 15% for ivosidenib and enasidenib, respectively, were associated with increased risk of DS. Complete remission (CR) + CR with partial hematologic recovery rates were lower in patients with versus without DS [ivosidenib 18% (95% confidence interval, 7%–35%) vs. 36% (28%–45%); enasidenib 18% (7%–33%) vs. 25% (18%–32%)].Conclusions:DS is a common and potentially fatal adverse reaction of IDH inhibitors, and use of standardized diagnostic criteria may aid in earlier diagnosis and treatment.See related commentary by Zeidner, p. 4174

Supplementary Tables

Supplementary Figure 3. Blood count trajectory for patients with or without DS.

Supplementary Table from FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes

On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93–1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.

Supplemental Table 3 describes the adverse events with corresponding risk differences between treatment arms during consolidation 2 of pivotal trial ALFA-0701.

PURPOSE To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy. METHODS We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models. We performed patient-level responder analyses to compare OS by response using pooled data from all studies. RESULTS In trial-level analyses, association between HR for OS and OR for CR was moderate (R2 = 0.49; 95% CI, 0.05 to 0.86), as was the association with OR for CR + CRi or CRp (R2 = 0.48; 95% CI, 0.05 to 0.99). For OS versus EFS, a strong association was observed (R2 = 0.87; 95% CI, 0.47 to 0.98) when EFS definitions were harmonized across trials using raw data. In the patient-level responder analyses, patients who achieved CR had better OS compared with CRi or CRp responders (0.73; 95% CI, 0.64 to 0.84) and nonresponders (HR, 0.33; 95% CI, 0.31 to 0.37). CONCLUSION On a trial level, there is a moderate association between OS and CR rate. A strong association between EFS and OS was observed. However, CIs were wide, and results became moderate using alternative definitions for EFS. Patient-level analyses showed CR responders have better OS compared with CRi or CRp responders and nonresponders. A therapy in newly diagnosed AML with benefit in EFS or substantial benefit in CR rate would be likely to have an OS effect.

On December 18, 2020, US Food and Drug Administration (FDA) approved a supplemental application for ponatinib extending the indication in patients with chronic-phase chronic myeloid leukemia (CP-CML) to patients with resistance or intolerance of at least 2 prior kinase inhibitors. Ponatinib was initially approved in December 2012 but was briefly voluntarily withdrawn due to serious safety concerns including the risk of arterial occlusive events (AOE). It returned to the market in December 2013 with an indication limited to patients with T315I mutation or for whom no other tyrosine kinase inhibitor (TKI) therapy was indicated with revised warnings and precautions. A post-marketing requirement was issued to identify the optimal safe and effective dose for CP-CML. Thus, the OPTIC trial was performed, which randomized patients to 1 of 3 doses, 45 mg, 30 mg, or 15 mg, with a dose reduction to 15 mg on achievement of MR2 (BCR-ABLIS ≤1%). Patients enrolled were treated with at least 2 prior TKIs or had a T315I mutation. Patients with a history of clinically significant, uncontrolled, or active cardiovascular disease were excluded. Efficacy was established on an interim analysis based on the rate of MR2 at 12 months in the modified intent-to-treat population of 261 patients, with 88, 86, and 87 patients in the 45, 30, and 15 mg cohorts, respectively. With a median follow-up of 28 months, the rate of achievement of MR2 at 12 months was 42%, 28%, and 24% in the respective cohorts. The safety profile was consistent with that observed in prior evaluations of ponatinib with notable adverse reactions including pancreatitis, hypertension, hyperlipidemia, liver dysfunction, and AOE. Of patients treated at the 45/15 mg dose, AOEs were seen in 13%, with a higher rate being observed in patients age 65 or older compared to younger patients. A readjudication of AOEs seen on the prior pivotal phase 2 study resulted in a rate of 26%. Overall, the results supported a modification of the recommended dose for patients with CP-CML to 45 mg until the achievement of MR2 followed by a reduction to 15 mg. The expansion of the indication to patients with exposure to 2 prior TKIs was approved given data showing that ponatinib could be successfully used for the treatment of this population with appropriate monitoring and screening for risk factors.

The FDA has an accelerated approval program for drugs that have been identified as promising treatments for serious conditions when the available data suggest that the benefits outweigh the foreseeable risks. All of the currently available treatment options for chronic myeloid leukemia (CML) initially went through the accelerated approval program. Here, a group of academic CML experts, patient panelists, and members from the FDA convened to discuss the utility of the accelerated approval program as it pertains to CML, and the utility of this program in future drug development in this disease. The results of that discussion are summarized here.

On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93–1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.

On November 28, 2018, the FDA approved gilteritinib (Xospata; Astellas), a small-molecule FMS-like tyrosine kinase 3 (FLT3) inhibitor, for treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation as detected by an FDA-approved test. In the ADMIRAL study, patients were randomized 2:1 to receive gilteritinib or standard chemotherapy and stratified by response to first-line treatment and intensity of prespecified chemotherapy. Efficacy was established on interim analysis on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence to transfusion independence in 138 patients in the gilteritinib arm. With median follow-up of 4.6 months [95% confidence interval (CI), 2.8–15.8 months] at interim analysis, the CR + CRh rate was 21% (95% CI, 15%–29%), median duration of CR + CRh was 4.6 months (range, 0.1–15.8+), and conversion from transfusion dependence to transfusion independence was 31%. Revised labeling approved on May 29, 2019 included the results of the final analysis, showing an improvement in overall survival (OS) with gilteritinib compared with chemotherapy (HR, 0.64; 95% CI, 0.49–0.83; one-sided P = 0.0004; median OS, 9.3 vs. 5.6 months). The OS benefit was observed in both high and low chemotherapy intensity subgroups. Labeling includes a boxed warning for differentiation syndrome and warnings for posterior reversible encephalopathy syndrome, QT prolongation, pancreatitis, and embryo-fetal toxicity. Safe use requires frequent monitoring of electrocardiograms and blood chemistries. Assessments of long-term safety are pending.

Purpose: Differentiation syndrome (DS) is a serious adverse reaction of isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib in patients with (IDH)1- and IDH2-mutated acute myeloid leukemia (AML), respectively. Experimental Design: During FDA review of marketing applications for ivosidenib and enasidenib, data from pivotal trials were queried to identify cases of DS in patients with relapsed or refractory (R/R) AML. One hundred seventy-nine patients with R/R AML received ivosidenib and 214 received enasidenib. Adverse events, labs, and vital signs in the first 90 days of treatment were screened per diagnostic criteria, and narratives were reviewed to adjudicate DS cases. Results: We identified 72 of 179 (40%) potential cases for ivosidenib and 86 of 214 (40%) for enasidenib; 34 of 179 (19%) and 41 of 214 (19%) were adjudicated as DS. Leukocytosis was present in 79% and 61% of cases, respectively. Median (range) time to onset was 20 (1–78) and 19 (1–86) days. Grade ≥ 3 adverse reactions occurred in 68% and 66%; 6% and 5% were fatal. Univariate analyses suggested baseline bone marrow blasts ≥ 48% and peripheral blood blasts ≥ 25% and 15% for ivosidenib and enasidenib, respectively, were associated with increased risk of DS. Complete remission (CR) + CR with partial hematologic recovery rates were lower in patients with versus without DS [ivosidenib 18% (95% confidence interval, 7%–35%) vs. 36% (28%–45%); enasidenib 18% (7%–33%) vs. 25% (18%–32%)]. Conclusions: DS is a common and potentially fatal adverse reaction of IDH inhibitors, and use of standardized diagnostic criteria may aid in earlier diagnosis and treatment. See related commentary by Zeidner, p. 4174

Wide adoption of electronic health records (EHRs) has raised the expectation that data obtained during routine clinical care, termed “real-world” data, will be accumulated across health care systems and analyzed on a large scale to produce improvements in patient outcomes and the use of health care resources. To facilitate a learning health system, EHRs must contain clinically meaningful structured data elements that can be readily exchanged, and the data must be of adequate quality to draw valid inferences. At the present time, the majority of EHR content is unstructured and locked into proprietary systems that pose significant challenges to conducting accurate analyses of many clinical outcomes. This article details the current state of data obtained at the point of care and describes the changes necessary to use the EHR to build a learning health system.

Standardizing response criteria for myelodysplastic syndromes (MDS), a clinically and biologically heterogeneous group of disorders, has been historically challenging. The International Working Group (IWG) response criteria, first proposed in 2000 and modified in 2006 and 2018, represent the best effort by a group of international experts to define a set of clinically meaningful end-points in MDS. These criteria have been adopted in many MDS clinical trials, allowing for comparisons of response across trials. However, clinical experience has also revealed some limitations of these criteria, and most of the end-points proposed by the IWG require further validation. In this review, we present a critical analysis of the current MDS response criteria from both a practical standpoint and based on currently available clinical trial data. Potential areas for improvement in the criteria are highlighted, which may be considered in future iterations of the response criteria.

The Food and Drug Administration Oncology Center of Excellence initiated Project 2025 to develop 5-year goals in specific areas of oncology drug development. This meeting, in October 2020, brought together a panel of regulators and academic experts in acute myeloid leukemia (AML) to discuss opportunities to maximize the success that has recently occurred in AML drug development. The panel discussed challenges and opportunities in clinical trial design and novel endpoints, and outlined key considerations for drug development to facilitate continued growth in the field.

The FDA approved ivosidenib (Tibsovo; Agios), a small-molecule inhibitor of isocitrate dehydrogenase (IDH)1 on July 20, 2018, for treatment of adults with relapsed or refractory acute myeloid leukemia (R/R AML) with susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of ivosidenib was established on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence (TD) to transfusion independence (TI) in Study AG120-C-001, a single-arm trial. With median follow-up of 8.3 months for 174 adults with IDH1-mutated R/R AML treated with 500 mg ivosidenib daily, the CR + CRh rate was 33% [95% confidence interval (CI), 26–40], median duration of response was 8.2 (95% CI, 5.6–12) months, and conversion from TD to TI occurred in 37% of patients. These endpoints reflect short-term benefit in patients with an unmet medical need; long-term efficacy outcomes were not assessed. Serious adverse reactions (AR) in ≥5% of patients were differentiation syndrome (10%), leukocytosis (10%), and QT interval prolongation (7%). Common (≥20%) ARs of any grade were fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, nausea, mucositis, QT interval prolongation, rash, pyrexia, cough, and constipation. Assessment of long-term safety of ivosidenib is a condition of this approval.

INTRODUCTION: Obesity has become increasingly prevalent worldwide and is a risk factor for many malignancies. We studied the correlation between body mass index (BMI) and the incidence of acute promyelocytic leukemia (APL), non-APL acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and control hospitalized patients without leukemia in the same community. METHODS: Multi-center, retrospective analysis of 71,196 patients: APL (n=200), AML (n=437), ALL (n=103), non-leukemia hospitalized (n=70,456) admitted to University of Maryland and Johns Hopkins Cancer Centers, and University of Maryland Medical Center. RESULTS: Patients with APL had a significantly higher unadjusted mean and median BMI (32.5 kg/m(2) and 30.3 kg/m(2)) than those with AML (28.3 kg/m(2) and 27.1 kg/m(2)), ALL (29.3 kg/m(2) and 27.7 kg/m(2)), and others (29.3 kg/m(2) and 27.7 kg/m(2)) (p

Simple Summary Around 12–38% of acute promyelocytic leukemia (APL) patients carry the FLT3-ITD mutation, which has been associated with several poor-prognosis indicators such as high white blood cell counts, M3v variant morphology, and the bcr3 isoform. We aimed to retrospectively study the impact of FLT3-ITD mutations in APL patients in regard to clinical features, treatment courses, and outcomes. We demonstrate that Sanz high-risk status APL correlates with high FLT3-ITD allelic burdens, with every 1% increase in allelic burden correlating with a 0.6 × 109/L increase in white blood cell count (WBC). The presence of FLT3-ITD was associated with decreased remission rates and higher 5-year mortality from the time of diagnosis. These findings provide novel revelations regarding the features of FLT3-ITD APL, particularly in regard to allelic burden, that warrant further study. Abstract The significance of FLT3-ITD in acute promyelocytic leukemia (APL) is not well-established. We performed a bi-center retrospective study of 138 APL patients, 59 (42.8%) of whom had FLT3-ITD. APL patients with FLT3-ITD had higher baseline white blood cell counts (WBCs) (p < 0.001), higher hemoglobin, (p = 0.03), higher aspartate aminotransferase (p = 0.001), lower platelets (p = 0.004), lower fibrinogen (p = 0.003), and higher incidences of disseminated intravascular coagulation (p = 0.005), M3v variant morphology (p < 0.001), and the bcr3 isoform (p < 0.001). FLT3-ITD was associated with inferior post-consolidation complete remission (CR) (p = 0.02) and 5-year overall survival (OS) of 79.7%, compared to 94.4% for FLT3-WT (wild-type) (p = 0.02). FLT3-ITD was strongly associated with baseline WBCs ≥ 25 × 109/L (odds ratio (OR): 54.4; 95% CI: 10.4–286.1; p < 0.001). High FLT3-ITD allelic burdens correlated with high-risk (HR) Sanz scores and high WBCs, with every 1% increase in allelic burden corresponding to a 0.6 × 109/L increase in WBC. HR APL was associated with a 38.5% increase in allelic burden compared with low-risk (LR) APL (95% CI: 19.8–57.2; p < 0.001). Our results provide additional evidence that FLT3-ITD APL is a distinct subtype of APL that warrants further study to delineate potential differences in therapeutic approach.

Acute promyelocytic leukemia (APL) is an uncommon cancer, comprising approximately 10% of acute myeloid leukemia (AML) with annual incidence of approximately 1500 cases in the United States (U.S.) ...

Background: Ivosidenib (Servier Pharmaceuticals LLC) and enasidenib (Celgene) are inhibitors of mutant IDH1 and IDH2, respectively, approved for the treatment of relapsed/refractory (R/R) AML with an IDH1 or IDH2 mutation (ivosidenib is also approved for front-line use in patients ≥ 75 years or with comorbidities). While these drugs were approved based on durable complete remission (CR) + CR with partial hematologic recovery (CRh) rate, only 23-43% of patients responded. Thus, there is a need for a biomarker to better predict response. We previously presented a genomic model of response to enasidenib using linear discriminate analysis (Ghazanchyan et al., ASH 2018). In the two-part study presented here, we improved this modeling by adding clinical data, using machine learning-based approaches to model response to both enasidenib and ivosidenib, and generated an independent validation cohort using clinical samples. Methods: In part I, models were generated using data submitted to FDA in the marketing applications for ivosidenib and enasidenib (studies AG120-C-001 [NCT02074839] and AG221-C-001 [NCT01915498], respectively). Analysis inclusion criteria were available genomic data, IDH mutation positivity per the companion diagnostics, and receipt of at least the approved dose of IDH inhibitor. Patients in the ivosidenib cohort had untreated (n=33) or R/R AML (n=173); patients in the enasidenib cohort had R/R AML. Patients achieving a best response of CR or CRh were considered responders; all other patients were considered nonresponders. Genomic data for the ivosidenib cohorts were generated with the Foundation Medicine FoundationOne Heme panel (FMI) in dose escalation (n=38) and Brigham and Women's Hospital Rapid Heme Panel (RHP) in dose expansion (n=168); these cohorts were analyzed separately to account for differences between panels. Genomic data for the enasidenib cohort (n=75) were generated with the FMI panel. Machine learning-based feature selection approaches were used prior to modeling to identify important clinical data variables (i.e., baseline demographics and disease characteristics). Each analysis cohort was split into a training set (80% patients) and a testing set (20% patients). Machine learning modeling was performed with the decision-tree based algorithm XGBoost using repeated stratified cross validation. In part II of the study, we generated an independent validation cohort consisting of patients with IDH-mutated myeloid malignancies treated with ivosidenib or enasidenib at collaborating institutions (n=14). Bone marrow or peripheral blood samples were processed for deep whole exome sequencing to an average coverage of 441X. Custom analysis pipelines for filtering and annotation were developed to harmonize exome and panel data. Results: In part I, separate machine learning models were generated for each cohort using clinical data only, genomic data only, and clinical and genomic data together. Use of clinical and genomic data together, compared with either data type alone, resulted in improved model performance with accuracies of 89-100% in the testing sets. The most important clinical and genomic features for each cohort are shown in Figure 1. In part II, the independent validation cohort, collaborators provided response data and clinical data for variables found to be important in the models. Patient demographics and response rates are shown in Table 1. Mutational profiles for model genes mutated in ≥ 2 patients are shown in Figure 2. The models for CR+CRh response using both clinical and genomic data in the validation cohort had accuracies of 50-75% (66.7% ivosidenib BWH; 50% ivosidenib FMI; and 75% enasidenib). The combined accuracy improved to 80% when restricted to AML cases (excluding CMML and MDS) treated with ivosidenib (using the BWH model) or enasidenib (n=10). Conclusions: This study demonstrates the potential of harnessing machine learning for biomarker discovery to improve response prediction for the treatment of AML. The modeling approaches improved with inclusion of multiple data types, highlighting the importance of multi-faceted approaches for biomarker development in AML. The models presented have encouraging accuracies in a small independent validation cohort, suggesting potential clinical utility of machine learning-based biomarkers for identifying patients likely to respond to IDH inhibitors. Figure 1 Figure 1. Disclosures Kural: Senseonics: Current equity holder in publicly-traded company; NanoDimensions: Current equity holder in publicly-traded company; Bionano Genomics: Current equity holder in publicly-traded company. Ghiaur: Menarini Richerche: Research Funding; Syros Pharmaceuticals: Consultancy. Kazandjian: Arcellx: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lai: Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Astellas: Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wynne: Servier Pharmaceuticals: Honoraria; Carisma Therapeutics: Patents & Royalties. OffLabel Disclosure: This presentation references off label use of enasidenib in patients with MDS and CMML.

Background: Hypomethylating agents (HMAs) have changed the treatment landscape for patients with higher-risk myelodysplastic syndromes (HR-MDS) in the past two decades. However, less than half of patients respond to HMA therapy and even the best responses are transient and non-curative. Therapeutic options for those who have failed HMAs are limited, and these patients have very poor prognosis. To speed the development of novel therapeutics, varying response rate definitions and event-free survival (EFS) have been suggested as clinical benefit endpoints for regulatory approvals. However, the relationship between complete remission (CR), partial remission (PR), hematologic improvement (HI), event-free survival (EFS) and overall survival (OS) in MDS has not been conclusively established. To evaluate the relationship between these endpoints, we conducted patient-level response analyses of MDS trials submitted to the FDA. Methods: We searched for trials submitted with New Drug Applications for treatment of MDS between 2000 and 2020. Trials which supported the efficacy of approved treatments for HR-MDS were included. Patients with chronic myelomonocytic leukemia (CMML), bone marrow blasts ≥ 20%, or missing bone marrow blast information were excluded. A patient-level responder analysis was performed to compare OS and EFS between responders and non-responders, regardless of treatment assignment in the pooled dataset. Separate analyses were formed for CR, PR, and HI. Response rates were defined per protocol; criteria included IWG 2000, IWG 2006, and custom criteria. EFS was defined as time from randomization, or first dose of study drug for single-arm trials, to treatment failure (defined as date of transformation to AML, given availability across trials) or death from any cause. For each trial, the hazard ratio of response vs. no-response on OS and EFS was estimated using a Cox model with response as a time-varying covariate and treatment, sex, age, and percentage blast count as baseline covariates. The resulting hazard ratios were combined assuming a common effect of response on clinical outcome to estimate a pooled hazard ratio. Unadjusted distributions of OS and EFS by response were obtained using the Kaplan-Meier method. Results: We identified 8 trials with a total of 772 patients with HR-MDS investigating 3 experimental agents (azacitidine, decitabine, and decitabine + cedazuridine) for the treatment of HR-MDS. Three trials were randomized trials to assess efficacy (N=116, 124, 215), two were randomized crossover trials to assess bioequivalence (N=116, 61), and 3 were single arm trials (N=29, 34, 77). Across all trials, the population characteristics were: median age 69 years (range: 23-92); 70% male, 67% White, 29% Asian, 2% Black; 17% High Risk per IPSS, 25% Intermediate-1, 33% Intermediate-2, 2% Low Risk, and 24% unknown. IPSS information was missing for 3 trials (187 patients). We assessed the effect of CR vs. PR vs. HI in a pooled analysis. Patients who achieved a CR had better OS (HR=0.40 [95% CI: 0.25-0.64]) and EFS (HR=0.39 [95% CI: 0.24-0.63]) compared with non-responders, defined as patients who failed to achieve CR, PR, or HI. Patients who achieved a PR had better OS (HR=0.51 [95% CI: 0.28-0.92]) and EFS (HR=0.66 [95% CI: 0.37-1.17]) compared to non-responders. Patients who achieved an HI response had better OS (HR=0.60 [95% CI: 0.46-0.76]) and EFS (HR=0.60 [95% CI: 0.47-0.76]) compared to non-responders. Patients who achieved a CR+PR had a trend for longer OS (HR=0.73 [95% CI: 0.49-1.11]) and EFS (HR=0.76 [95% CI: 0.51-1.14]) compared with those who achieved HI alone. Between-study variances of these effects were not able to be reliably estimated due to the low number of responses per trial and low number of trials included in the analysis. Figures 1 and 2 present unadjusted Kaplan-Meier estimates of OS and EFS by response group. Conclusions: Patient-level responder analyses suggest that CR, PR, and HI responders have better OS and EFS compared with non-responders. A limitation of these analyses is that response criteria are not standardized across trials. Future work includes standardizing response criteria across trials. However, our results suggest that CR, PR, and HI may be associated with long-term benefit in patients with HR-MDS. While HI responses had better OS compared to no response, CR and CR+PR remain the response endpoints associated with greatest long-term benefit. Figure 1 Figure 1. Disclosures Vallejo: AstraZeneca: Other: Spouse is employed by AstraZeneca..

Timed sequential therapy (TST) aims to improve outcomes in acute myelogenous leukemia (AML) by harnessing drug-induced cell cycle kinetics of AML, where a second drug is timed to coincide with peak leukemia proliferation induced by the first drugs. We analyzed outcomes in 301 newly diagnosed AML patients treated from 2004–2013 with cytarabine, anthracycline, and etoposide TST induction. Median age was 52 (range 20–74) and complete remission rate 68%. With median follow-up 5.8 years, 5-year DFS and overall survival (OS) were 37% (95% CI 31–45%) and 32% (95% CI 27–38%), respectively. In multivariate analysis, older age, unfavorable cytogenetics, and WBC ≥ 50 × 109/L resulted in worse OS. Among patients not undergoing blood and marrow transplant, a propensity score analysis, which reduces imbalance in baseline characteristics, showed consolidation with TST compared with 1 or more cycles high-dose cytarabine trended toward lower DFS and post-remission survival with hazard ratio (HR) 1.9 (95% CI 0.9–4.0), and 1.6 (95% CI 0.7–3.6), respectively. Our results demonstrate the efficacy and feasibility of TST induction for newly diagnosed patients with AML, with results comparable to that seen in clinical trials with other TST therapies and 7 + 3.

Background: Ethnic and racial minorities are underrepresented in oncologic clinical trials. One potential barrier to participation may be narrow eligibility criteria which contribute to an increased rate of screen failure among minorities. Prior work in multiple myeloma demonstrated a higher rate of screen failure among black or African-American (AA) patients and lower rate of screen failure among Asian patients compared with white patients (1). Here, we examine screen failure rates by race in patients screened for participation in clinical trials of acute myeloid leukemia (AML). Methods: Trials submitted to the U.S. Food and Drug Administration (FDA) to support approval of new treatments for AML between 2016-2019 were examined. Trials which included information on screen failures and race were included. Trial, screen failure status, basic demographic information (age, gender, race, and ethnicity), country of participant, and reason for screen failure (if relevant) were abstracted from the trials. Screen failure rates were calculated based on this information. Results: Twenty-one trials of AML therapies were identified, of which screen failure and race information were available in fourteen. Of these, information on reason for screen failure was available in nine. A total of 6,471 patients were identified across fourteen trials (Table 1). Race was recorded as unknown for 2,934 (46%) of patients. A total of 3,372 (52%) screen failures occurred. Minorities were more likely to be screen failures at 201/603 (33%) compared to whites at 27%. Of minorities, screen failures occurred in 29% of black/AA patients, 36% of Asians, and 36% of patients of any other race. A total of 579 patients were included in the nine trials that included data on reasons for screen failures (Table 2). Lack of appropriate mutation (i.e. IDH1/2, FLT3) was the most common reason for screen failure overall and was more common in black/AA (41%) and Asian patients (66%) compared to white patients (29%). Other issues related to the disease course (e.g. not at the appropriate point in treatment, not treated within the time limit set in the protocol) led to screen failure in 28% black/AA patients versus 9-22% for other races (19% overall). White patients were more likely than patients of other races to be screen failures due to cardiac issues (4%) and laboratory abnormalities (6%). Conclusions: Minority patients were numerically more likely to be screen failures compared to whites in trials of AML therapeutics, which exemplifies the known issue of lower minority recruitment in clinical trials. Minority patients were more likely to be screen failures due to lack of appropriate mutation and less likely due to lab abnormalities or cardiac issues. The significance of this finding is uncertain given the limited information on reasons for screen failure and the small number of minority patients in the database. Further investigation into screen failures in minority patients with AML is indicated. These results underscore the importance of including racial and ethnic minorities in all phases of translational and clinical research to further precision oncology for all patients since oncogenic driver mutation frequencies may vary among different populations. (1) Kanapuru B, Fernandes L FDA analysis of multiple myeloma trials supporting approval; Presented at FDA-AACR workshop to examine under-representation of African Americans in multiple myeloma clinical trials 2/13/20 Disclosures No relevant conflicts of interest to declare.

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, with an incidence that increases with age, and a generally poor prognosis. The disease is clinically and genetically heterogeneous, and recent advances have improved our understanding of the cytogenetic abnormalities and molecular mutations, aiding in prognostication and risk stratification. Until recently, however, therapeutic options were mostly limited to cytotoxic chemotherapy. Since 2017, there has been an explosion of newly approved treatment options both nationally and internationally, with the majority of new drugs targeting specific gene mutations and/or pivotal cell survival pathways. In this review article, we will discuss these new agents approved for the treatment of AML within the last 2 years, and will outline the mechanistic features and clinical trials that led to their approvals.

On November 21, 2018, the FDA approved glasdegib (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, in combination with low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy. Evidence of clinical benefit came from Study BRIGHT AML 1003, a randomized trial comparing glasdegib+LDAC with LDAC alone for treatment of newly diagnosed AML in 115 patients either ≥ 75 years old or ≥ 55 years old with preexisting comorbidities. Efficacy was established by improved overall survival (OS) with the combination compared with LDAC alone (HR, 0.46; 95% confidence interval, 0.30–0.71; one-sided stratified log-rank P = 0.0002). Median OS was 8.3 months with the combination and 4.3 months with LDAC alone. Common adverse reactions included cytopenias, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. The label includes a boxed warning for embryo-fetal toxicity and a warning for QT interval prolongation. There is a limitation of use for patients with moderate-to-severe hepatic and severe renal impairment; trials studying glasdegib in these patient populations are required as a condition of this approval. See related commentary by Fathi, p. 6015

Pre-clinical data in non-M3 AML supports the use of differentiation therapy, but clinical activity has been limited. Myeloid growth factors can enhance anti-leukemic activity of differentiating agents in vitro . We conducted companion phase II trials investigating sargramostim (GM-CSF) 125 μg/m 2 /day plus 1) bexarotene (BEX) 300 mg/m 2 /day or 2) entinostat (ENT) 4–8 mg/m 2 /week in patients with MDS or relapsed/refractory AML. Primary endpoints were response after at least two treatment cycles and toxicity. 26 patients enrolled on the BEX trial had a median of 2 prior treatments and 24 enrolled on the ENT trial had a median of 1. Of 13 response-evaluable patients treated with BEX, the best response noted was hematologic improvement in neutrophils (HI-N) seen in 4 (31%) patients; none achieved complete (CR) or partial remission (PR). Of 10 treated with ENT, there was 1 (10%) partial remission (PR) and 2 (20%) with HI-N. The secondary endpoint responses of HI-N with each combination were accompanied by a numerical increase in ANC (BEX: 524 to 931 cells/mm 3 , p = 0.096; ENT: 578 to 1 137 cells/mm 3 , p = 0.15) without increasing marrow blasts. Shared grade 3–4 non-hematologic toxicities included febrile neutropenia, bone pain, fatigue, and dyspnea. GM-CSF plus either BEX or ENT are well tolerated in resistant and refractory MDS and AML and showed modest clinical and biologic activity, most commonly HI-N.