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Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Purpose: Isocitrate dehydrogenase 1 (IDH1) mutations occur in 5% to 10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML. Patients and Methods: We conducted a multicenter, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to 12 28-day cycles. The first dose level was 500 mg daily, with level reduction to 250 mg daily, if needed, in a 3 × 3 de-escalation design. Ten additional patients would then receive the MTD or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib. Results: Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose-limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500 mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and 2-year CI of all cGVHD was 63%. Two-year CI of relapse and nonrelapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and 2-year overall survival (OS) was 88%. Conclusions: Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase I study.

Background: Patients with acute myeloid leukemia (AML) face an abrupt life-threatening illness and experience immense physical and psychological symptoms. However, no data describe how patients with AML cope longitudinally with their illness or the relationship between longitudinal coping and outcomes. Methods: We conducted a secondary analysis of longitudinal data from 160 patients with high-risk AML enrolled in a supportive care intervention trial to describe coping strategies longitudinally across the illness course. We used the Brief COPE questionnaire, the Hospital Anxiety and Depression Scale, the Post-Traumatic Stress Disorder (PTSD) Checklist-Civilian Version, and the Functional Assessment of Cancer Therapy-Leukemia to measure coping strategies, psychological distress, and quality of life (QoL) at baseline and at weeks 2, 4, 12, and 24 after diagnosis. Electronic health records were used to assess healthcare utilization and end-of-life (EoL) outcomes, and multivariate analyses were used to assess the relationship between coping and outcomes. Results: Longitudinal utilization of approach-oriented coping strategies was significantly associated with less distress (anxiety: β, –0.18; PPPPPPP=.049). Conclusions: Longitudinal use of approach-oriented coping strategies was associated with less psychological distress, better QoL, and a lower likelihood of ICU admission, suggesting a possible target for supportive oncology interventions. Coping strategies did not impact EoL outcomes, and further research is needed to elucidate which patient factors impact EoL decision-making.

Prevention of relapse is a major therapeutic challenge and an unmet need for patients with acute myeloid leukemia (AML). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. When combined with azacitidine, it leads to prolonged overall survival and rapid, durable remissions in treatment-naive AML patients ineligible for intensive chemotherapy. VIALE-M is a randomized, double-blind, two-arm study to evaluate the safety and efficacy of venetoclax in combination with oral azacitidine (CC-486) as maintenance therapy in patients in complete remission with incomplete blood count recovery after intensive induction and consolidation therapies. The primary end point is relapse-free survival. Secondary outcomes include overall survival, minimal residual disease conversion and improvement in quality-of-life. Trial Registration Number: NCT04102020 ( ClinicalTrials.gov )

BCR-ABL1 kinase inhibitors have improved the prognosis of Philadelphia-chromosome-positive (Ph+)-acute lymphoblastic leukemia (ALL). Ph-like (or BCR-ABL1-like) ALL does not express BCR-ABL1 but commonly harbors other genomic alterations of signaling molecules that may be amenable to therapy. Here, we report a case with a NUP214-ABL1 fusion detected at relapse by multiplexed, targeted RNA sequencing. It had escaped conventional molecular work-up at diagnosis, including cytogenetic analysis and fluorescence in situ hybridization for ABL1 rearrangements. The patient had responded poorly to initial multi-agent chemotherapy and inotuzumab immunotherapy at relapse before the fusion was revealed. The addition of dasatinib targeting NUP214-ABL1 to inotuzumab resulted in complete molecular remission, but recurrence occurred rapidly with dasatinib alone. However, deep molecular remission was recaptured with a combination of blinatumomab and ponatinib, so he could proceed to allotransplantation. This case illustrates that next-generation sequencing approaches designed to discover cryptic gene fusions can benefit patients with Ph-like ALL.

PURPOSE The immunogenicity and reactogenicity of SARS-CoV-2 vaccines in patients with cancer are poorly understood. METHODS We performed a prospective cohort study of adults with solid-organ or hematologic cancers to evaluate anti–SARS-CoV-2 immunoglobulin A/M/G spike antibodies, neutralization, and reactogenicity ≥ 7 days following two doses of mRNA-1273, BNT162b2, or one dose of Ad26.COV2.S. We analyzed responses by multivariate regression and included data from 1,638 healthy controls, previously reported, for comparison. RESULTS Between April and July 2021, we enrolled 1,001 patients; 762 were eligible for analysis (656 had neutralization measured). mRNA-1273 was the most immunogenic (log10 geometric mean concentration [GMC] 2.9, log10 geometric mean neutralization titer [GMT] 2.3), followed by BNT162b2 (GMC 2.4; GMT 1.9) and Ad26.COV2.S (GMC 1.5; GMT 1.4; P < .001). The proportion of low neutralization (< 20% of convalescent titers) among Ad26.COV2.S recipients was 69.9%. Prior COVID-19 infection (in 7.1% of the cohort) was associated with higher responses ( P < .001). Antibody titers and neutralization were quantitatively lower in patients with cancer than in comparable healthy controls, regardless of vaccine type ( P < .001). Receipt of chemotherapy in the prior year or current steroids were associated with lower antibody levels and immune checkpoint blockade with higher neutralization. Systemic reactogenicity varied by vaccine and correlated with immune responses ( P = .002 for concentration, P = .016 for neutralization). In 32 patients who received an additional vaccine dose, side effects were similar to prior doses, and 30 of 32 demonstrated increased antibody titers (GMC 1.05 before additional dose, 3.17 after dose). CONCLUSION Immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer. These data suggest utility of antibody testing to identify patients for whom additional vaccine doses may be effective and appropriate, although larger prospective studies are needed.

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.

With the Food and Drug Administration approval of 9 agents for different acute myeloid leukemia (AML) indications, the prognosis and management of AML is evolving rapidly. Herein, we review the important milestones in the history of AML research and therapy, discuss insights regarding prognostic assessment and prediction of treatment outcome, detail practical supportive care measures, and summarize the current treatment landscape and areas of evolving research.

Background: LY3410738 is a potent, selective, covalent, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. We present initial results from the first-in-human phase 1 dose escalation study of oral LY3410738 in patients (pts) with R/R IDH1/2m hematologic cancers. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in IDH1/2m R/R AML (NCT04603001). Key objectives included determining the RP2D, safety, PK, PD (inhibition of plasma D-2-HG), and preliminary antitumor activity. Results: As of 28 July 2022, 114 pts including 108 R/R AML pts received LY3410738 dosed at 5-600 mg QD or 40-300 mg BID. Pts were median 73 years of age (range, 22-92) with a median of 2 prior therapies (range, 1-10); 29% received a prior IDH inhibitor and 58% a prior BCL2 inhibitor. Median time on treatment was 2.3 months (range, 0.1-15). No DLTs or treatment related deaths were observed. Treatment emergent adverse events ≥20% were diarrhea (22%), fatigue (21%), and anemia (20%). Differentiation syndrome was reported in 11 pts (10%); 4 grade 1/2 (4%), 7 grade 3 (6%). LY3410738 exposure was dose proportional. In pts with IDH1m cancers, LY3410738 achieved sustained D-2-HG inhibition at all dose levels including in pts who received prior IDH1 inhibitor. In pts with IDH2m cancers, a higher dose (≥150 mg daily dose) was required for D-2-HG inhibition. Responses were observed in both IDH1m and IDH2m AML (Table). Higher doses were required for IDH2m AML, especially IDH2 R140m pts. Efficacy appears higher in venetoclax naïve pts and limited in IDH inhibitor pre-treated pts. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1m R132, IDH2m R172, and IDH2m R140 mutations. Preliminary efficacy was also seen in all genotypes, in a dose dependent manner. RP2D evaluation is ongoing. Table: Response in R/R AML IDH Inhibitor Naive (N=68) IDH1 R132 IDH2 R172 IDH2 R140 No prior Venetoclax (n=13) Prior Venetoclax (n=19) Total (N=32) Low Dosesa (n=5) (High Dosesb) Total (N=13) Low Dosesa (n=9) (High Dosesb) Total (N=23) No prior Venetoclax (n=3) Prior Venetoclax (n=5) No prior Venetoclax (n=6) Prior Venetoclax (n=8) CR+CRh, n (%) 5 (38%) 2 (11%) 7 (22%) - 3 (100%) 2 (40%) 5 (38%) - 2 (33%) - 2 (9%) CR, n (%) 3 (23%) 2 (11%) 5 (16%) - 2 (67%) 2 (40%) 4 (31%) - 2 (33%) - 2 (9%) CRh, n (%) 2 (15%) - 2 (6%) - 1 (33%) - 1 (8%) - - - - CRc (CR+CRh+CRi/CRp), n (%) 6 (46%) 6 (32%) 12 (38%) - 3 (100%) 3 (60%) 6 (46%) - 2 (33%) - 2 (9%) MFLS, n (%) 1 (8%) 3 (16%) 4 (13%) 2 (40%) - - 2 (15%) 1 (11%) - - 1 (4%) IDH Inhibitor Pre-Treated (N=33) IDH1 R132 IDH2 R172 IDH2 R140 No prior Venetoclax (n=2) Prior Venetoclax (n=8) Total (N=10) Low Dosesa (n=6) (High Dosesb) Total (N=8) Low Dosesa (n=4) (High Dosesb) Total (N=15) No prior Venetoclax (n=1) Prior Venetoclax (n=1) No prior Venetoclax (n=3) Prior Venetoclax (n=8) CR+CRh, n (%) - - - - - - - - - 1 (13%) 1 (7%) CR, n (%) - - - - - - - - - - - CRh, n (%) - - - - - - - - - 1 (13%) 1 (7%) CRc (CR+CRh+CRi/CRp), n (%) - - - - - - - 1 (25%) - 1 (13%) 1 (7%) MLFS, n (%) - - - - - - - - - - - Among the 108 treated R/R AML pts, 101 were efficacy evaluable (42 IDH1 R132, 21 IDH2 R172, 38 IDH2 R140); 68 pts were IDH inhibitor naïve and 33 had received a prior IDH inhibitor treatment. Efficacy evaluable pts are those who had completed the first bone marrow assessment or had discontinued treatment prior to first bone marrow assessment aTotal daily low doses: ≤75 mg Arm A, ≤30 mg Arm B bTotal daily high doses: ≥150 mg Arm A, ≥60 mg Arm B Arm A: not requiring a strong CYP3A4 inhibitor Arm B: requiring a strong CYP3A4 inhibitor Citation Format: Courtney D. DiNardo, Pau Montesinos, Lina Benajiba, Ana Triguero, Christian Recher, Andre C. Schuh, Maël Heiblig, Ashish Bajel, Arnaud Pigneux, Juan M. Alonso-Domiguez, Amir T. Fathi, Carolyn Grove, Hsin-An Hou, Michael Heuser, Sarit Assouline, Shaun Fleming, Dong-Yeop Shin, Kendra Sweet, Olatoyosi Odenike, Jessica Altman, Melissa Gaik Ming Ooi, Lao Zhentang, Nobert Vey, Joshua Zeidner, Amandeep Salhotra, Eunice Wang, Gary Schiller, Kimmo Porkka, Tsila Zuckerman, Violaine Havelange, Brian A. Jonas, Sujaatha Narayanan, Jun Ho Jang, Je-Hwan Lee, Anna M. Szpurka, Dana Heirich, Hsiao Rong Chen, Violet Hanft, Junjie Zhao, Ivelina Gueorguieva, Yin Zhang, Eytan M. Stein. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced myeloid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT026.

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.

Background Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows. Methods Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network. Results Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of “abnormal” results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network. Conclusion Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology.

PURPOSE Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (m IDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition–related differentiation and apoptosis. PATIENTS AND METHODS This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m2 on days 1-7 in 28-day cycles in patients with newly diagnosed m IDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922 ). RESULTS Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m IDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. CONCLUSION Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m IDH1 mutation clearance.

The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.

Hyperleukocytosis in acute myeloid leukemia (AML) is associated with inferior outcomes. There is limited high quality evidence to support the benefits of leukapheresis. We retrospectively collected data from patients with newly-diagnosed AML who presented with a white cell count (WBC) >50 x 10(9)/L to 12 centers in the United States and Europe from 2006 to 2017 and received intensive chemotherapy. Logistic regression models estimated odds ratios for 30-day mortality and achievement of composite complete remission (CRc). Cox proportional hazard models estimated hazard ratios for overall survival (OS). Among 779 patients, clinical leukostasis was reported in 27%, and leukapheresis was used in 113 patients (15%). Thirty-day mortality was 16.7% (95% CI: 13.9-19.3%). Median OS was 12.6 months (95% CI: 11.5-14.9) among all patients, and 4.5 months (95% CI: 2.7-7.1) among those >= 65 years. Use of leukapheresis did not significantly impact 30-day mortality, achievement of CRc, or OS in multivariate analysis based on available data or in analysis based on multiple imputation. Among patients with investigator-adjudicated clinical leukostasis, there were statistically significant improvements in 30-day mortality and OS with leukapheresis in unadjusted analysis, but not in multivariate analysis. Given the significant resource use, cost, and potential complications of leukapheresis, randomized studies are needed to evaluate its value.

Patients with cancer are more likely to have impaired immune responses to SARS-CoV-2 vaccines. We study the breadth of responses against SARS-CoV-2 variants after primary vaccination in 178 patients with a variety of tumor types and after booster doses in a subset. Neutralization of alpha, beta, gamma, and delta SARS-CoV-2 variants is impaired relative to wildtype, regardless of vaccine type. Regardless of viral variant, mRNA1273 is the most immunogenic, followed by BNT162b2, and then Ad26.COV2.S. Neutralization of more variants (breadth) is associated with a greater magnitude of wildtype neutralization, and increases with time since vaccination; advancing age associates with a lower breadth. The concentrations of anti-spike protein antibody are a good surrogate for breadth (positive predictive value of =90% at >1,000 U/mL). Booster SARS-CoV-2 vaccines confer enhanced breadth. These data suggest that achieving a high antibody titer is desirable to achieve broad neutralization; a single booster dose with the current vaccines increases the breadth of responses against variants., Graphical abstract, Naranbhai et al. examine how well current wildtype-based SARS-CoV-2 vaccines perform in patients with cancer in neutralizing viral variants. The findings support preferring the most immunogenic wildtype vaccines (i.e., mRNA1273 or BNT162b2) for patients at high risk to generate breadth against variants.

Racial disparities in cancer care and outcomes have been well documented in various malignancies, with Black patients having the highest death rate and shortest survival of any racial/ethnic group in the United States (US) for most cancers. However, there have been limited studies on racial/ethnic disparities in myelodysplastic syndromes (MDS). Our study characterized and compared differences in baseline demographics, clinical characteristics, socioeconomic factors, and overall survival (OS) between Black and White patients with MDS in the US. We used the Surveillance, Epidemiology, and End Results (SEER) Program and included 37,562 patients (Black, 8.1 %; White, 91.9 %) diagnosed between 2001 and 2013. We observed significant differences in baseline characteristics between cohorts. In a univariate analysis, Black race was associated with longer survival (hazard ratio [HR]: 0.83; 95 % confidence interval [CI], 0.79-0.86; p 0.001). The association between race and survival was attenuated but remained significant in various models to adjust for differences in baseline characteristics (HR in multivariable analysis, 0.92; 95 % CI, 0.87-0.96); p 0.001). Subgroup analysis by histology revealed differences in the association between race and OS. Refractory anemia (RA), RA with ring sideroblasts, and MDS-not otherwise specified, a category in SEER representing a poorly defined MDS subset for 52 % of cases in our study, favored Black patients. RA with excess blasts favored White patients. The overall finding that Black race is associated with better OS outcomes, when compared with White patients, needs to be interpreted with caution and nuanced by histology. Additional research to explore these associations is warranted.

Background Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody-drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing R/R AML. Methods Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7. Results There were no dose-limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease-free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion. Conclusions The combination of BV with MEC was found to be safe in patients with CD30-expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777). Lay summary The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.

BACKGROUND It has been shown previously that integrated palliative care for patients with acute myeloid leukemia (AML) during intensive chemotherapy leads to improvements in quality of life (QOL) and mood. Coping has been shown to mediate palliative care interventions in advanced cancer; the mechanisms by which improvements occur among patients with AML remain unexplained. METHODS The authors conducted a secondary analysis of data from a multisite randomized trial of integrated palliative and oncology care (IPC; n = 86) versus usual care (n = 74) for hospitalized patients with AML undergoing intensive chemotherapy. IPC patients met with palliative care at least twice weekly during their initial and subsequent hospitalizations. Patients completed the Functional Assessment of Cancer Therapy-Leukemia, the Hospital Anxiety and Depression Scale, and the Brief Coping Orientation to Problems Experienced Inventory to assess QOL, mood, and coping at the baseline and at weeks 2, 4, 12, and 24. Linear regression models were used to assess the effect of IPC on coping. Causal mediation regression models were used to examine whether changes in coping mediated intervention effects on patient-reported outcomes at week 2. RESULTS One hundred sixty eligible patients (68.1%) were enrolled. Those randomized to IPC reported improvements in approach-oriented coping (P < .01) and reductions in avoidant coping (P < .05). These changes in coping mediated the intervention effects on QOL (95% CI, 2.14 to 13.63), depression (95% CI, -2.05 to -0.27), and anxiety symptoms (95% CI, -1.25 to -0.04). Changes in approach-oriented and avoidant coping accounted for 78% of the total palliative care intervention effect on QOL, for 66% of the effect on depression, and for 35% of the effect on anxiety symptoms. CONCLUSIONS Palliative care integrated during intensive chemotherapy for patients with AML facilitates coping strategy use. Improvement in coping skills accounts for a substantial proportion of the effect from a palliative care intervention on patient-reported outcomes.

Background: Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy. Methods: This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea). Eligible patients were aged 18 years or older and had newly diagnosed, mutant-IDH2 acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. In the phase 1b dose-finding portion, patients received oral enasidenib 100 mg/day or 200 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m2 per day for 7 days of each cycle. In phase 2, patients were randomly assigned (2:1) via an interactive web response system to enasidenib plus azacitidine or azacitidine-only, stratified by acute myeloid leukaemia subtype (de novo or secondary). The primary endpoint in the phase 2 portion was the overall response rate in the intention-to-treat population at a prespecified interim analysis (Aug 20, 2019) when all patients had at least 1 year of follow-up. Safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT02677922, and is ongoing. Findings: Between June 3, 2016, and Aug 2, 2018, 322 patients were screened and 107 patients with mutant-IDH2 acute myeloid leukaemia were enrolled. At data cutoff for the interim analysis, 24 patients (including two from the phase 1 portion) were still receiving their assigned treatment. Six patients were enrolled in the phase 1b dose-finding portion of the trial and received enasidenib 100 mg (n=3) or 200 mg (n=3) in combination with azacitidine. No dose-limiting toxicities occurred and the enasidenib 100 mg dose was selected for phase 2. In phase 2, 101 patients were randomly assigned to enasidenib plus azacitidine (n=68) or azacitidine only (n=33). Median age was 75 years (IQR 71–78). 50 (74%; 95% CI 61–84) patients in the enasidenib plus azacitidine combination group and 12 (36%; 20–55) patients in the azacitidine monotherapy group achieved an overall response (odds ratio 4·9 [95% CI 2·0–11·9]; p=0·0003). Common treatment-related grade 3 or 4 adverse events with enasidenib plus azacitidine were thrombocytopenia (25 [37%] of 68 vs six [19%] of 32 in the azacitidine-only group), neutropenia (25 [37%] vs eight [25%]), anaemia (13 [19%] vs seven [22%]), and febrile neutropenia (11 [16%] vs five [16%]). Serious treatment-related adverse events were reported in 29 (43%) patients in the combination group and 14 (44%) patients in the azacitidine-only group; serious treatment-related adverse events occurring in more than 5% of patients in either group were febrile neutropenia (nine [13%] in the combination group vs five [16%] in the azacitidine-only group), differentiation syndrome (seven [10%] vs none), and pneumonia (three [4%] vs two [6%]). No treatment-related deaths were reported. Interpretation: Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia.

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age

Myelodysplastic syndromes (MDS) comprise a spectrum of clonal blood cancers characterized by ineffective clonal hematopoiesis and the risk of progression to acute myeloid leukemia (AML) [1]. The me...

Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.

Older patients with AML face difficult treatment decisions as they can be treated either with ‘intensive’ chemotherapy requiring prolonged hospitalization, or ‘non-intensive’ chemotherapy. Although clinicians often perceive intensive chemotherapy as more burdensome, research is lacking on patients’ quality of life (QOL) and psychological distress. We conducted a longitudinal study of older patients (≥60 years) newly diagnosed with AML receiving intensive (cytarabine/anthracycline combination) or non-intensive (hypomethylating agents) chemotherapy. We assessed patients’ QOL [Functional-Assessment-of-Cancer-Therapy-Leukemia] and psychological distress [Hospital-Anxiety-and-Depression-Scale] at baseline and 2, 4, 8, 12, and 24 weeks after diagnosis. We enrolled 75.2% (100/133) of eligible patients within 72-hours of initiating intensive (n = 50) or non-intensive (n = 50) chemotherapy. Patient QOL improved over time (β = 0.32, P = 0.013). At baseline, 33.3% (33/100) and 30.0% (30/100) of patients reported clinically significant depression and anxiety symptoms, respectively, with no differences between groups. Patients’ depression symptoms did not change over time, while their anxiety symptoms decreased over time (β = −0.08, P

Certain Penicillium species are emerging opportunistic pathogens. While these can be common causes of airborne contamination of clinical cultures, an increasing number of reports describe clinically significant disease in the immunocompromised population, particularly in patients with hematologic malignancy. The typical site of infection is respiratory, but disseminated infection is also reported with some frequency. Therefore, culture growth of Penicillium in respiratory and other clinical samples from immunocompromised patients requires thorough investigation with clinical correlation. Here we report a case of angioinvasive Penicillium cluniae infection of the right shin in a patient with acute myeloid leukemia and review reported cases of invasive Penicillium infection (excluding Talaromyces marneffei) in hematologic malignancy patients to characterize the emerging pathogen in this vulnerable population.

Context: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ~3% of patients with MDS and are associated with increased transformation to acute myeloid leukemia (AML). IVO is an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme and is FDA-approved for mIDH1 R/R AML and mIDH1 newly diagnosed AML in patients ≥75 years old or with comorbidities precluding the use of intensive induction chemotherapy. In the first-in-human, phase 1 study of IVO in patients with mIDH1 advanced hematologic malignancies (NCT02074839), 12 patients with R/R MDS, with median age 72.5 years (range 52–78), received IVO 500 mg once daily (QD). All patients received prior MDS treatment. Investigator-assessed ORR (CR + PR + marrow CR, per IWG 2006) was 75% (95% CI 43–95), with median duration of response of 21.4 months (95% CI 2.3–NE). Nine (75%) patients were transfusion-independent for ≥56 days during treatment. No dose-limiting toxicities or adverse events leading to treatment discontinuation were reported among patients with MDS. Based on these encouraging data, the FDA granted Breakthrough Therapy Designation to IVO in mIDH1 MDS; the study was amended to enroll additional patients with mIDH1 R/R MDS. Objective: To evaluate safety, tolerability, clinical activity, and pharmacokinetics/pharmacodynamics of IVO in patients with mIDH1 R/R MDS. Design: A sub-study of the single-arm, open-label, phase 1 dose escalation and expansion study of IVO in mIDH1 advanced hematologic malignancies, evaluating patients with R/R MDS. Patients must have R/R disease after prior standard therapy; high disease burden based on cytopenia and/or transfusion dependence at baseline; an Eastern Cooperative Oncology Group performance status score of 0–2; and be amenable to bone marrow aspirate and/or core biopsy at specified study timepoints. Patients with documented AML are not eligible. IVO 500 mg QD orally on days 1–28 of 28-day cycles. Results: Study is open; enrollment of ~23 patients from the US and France planned. Results not yet available. Conclusions: This sub-study will provide additional insights into safety, tolerability, clinical activity, and pharmacokinetics/pharmacodynamics of treatment with IVO in patients with mIDH1 R/R MDS. Funding: Agios; Servier.

Introduction Remissions following therapy for acute myeloid leukemia (AML) are often not durable, and conventional treatments can have substantial toxicity. The last few years have witnessed an emergence of promising therapies for patients with AML. Antibody-based therapies can target leukemic cells via a variety of mechanisms. Conjugation of antibodies with cytotoxic agents or alteration of antibody segments to allow concurrent activation of T cells have transformed and expanded the therapeutic potential of antibody-based treatment. Identification and characterization of antigens specific to AML cells have helped to identify targets for antibody-drug conjugate (ADC) therapy. In addition, bispecific T cell engagers (BiTE) and dual-affinity retargeting (DART) therapies are emerging as therapeutically effective targeted immune-based treatment for patients with AML. Incorporating the target antigen-binding domain of an antibody, these molecules then engage and active the human immune system against leukemic cells expressing that target.

Differentiation Syndrome (DS) has been identified in a subset of patients undergoing treatment with novel classes of differentiating therapies for acute myeloid leukemia (AML) such as IDH and FLT3 inhibitors. While DS is a well-known treatment-related complication in acute promyelocytic leukemia (APL), efforts are still ongoing to standardize diagnostic and treatment parameters for DS in AML. Though the rates of incidence vary, many of the signs and symptoms of DS are common between APL and AML. So, DS can lead to fatal complications in AML, but prompt management is usually effective and rarely necessitates interruption or discontinuation of AML therapy.

Background Patients with acute myeloid leukemia (AML) receiving intensive chemotherapy face a life-threatening illness, isolating hospitalization, and substantial physical and psychological symptoms. However, data are limited regarding risk factors of posttraumatic stress disorder (PTSD) symptoms in this population. Methods The authors conducted a secondary analysis of data from 160 patients with high-risk AML who were enrolled in a supportive care trial. The PTSD Checklist-Civilian Version was used to assess PTSD symptoms at 1 month after AML diagnosis. The Brief COPE and the Functional Assessment of Cancer Therapy-Leukemia were to assess coping and quality of life (QOL), respectively. In addition, multivariate regression models were constructed to assess the relation between PTSD symptoms and baseline sociodemographic factors, coping, and QOL. Results Twenty-eight percent of patients reported PTSD symptoms, describing high rates of intrusion, avoidance, and hypervigiliance. Baseline sociodemographic factors significantly associated with PTSD symptoms were age (B = -0.26; P = .002), race (B = -8.78; P = .004), and postgraduate education (B = -6.30; P = .029). Higher baseline QOL (B = -0.37; P ≤ .001) and less decline in QOL during hospitalization (B = -0.05; P = .224) were associated with fewer PTSD symptoms. Approach-oriented coping (B = -0.92; P = .001) was associated with fewer PTSD symptoms, whereas avoidant coping (B = 2.42; P ≤ .001) was associated with higher PTSD symptoms. Conclusions A substantial proportion of patients with AML report clinically significant PTSD symptoms 1 month after initiating intensive chemotherapy. Patients' baseline QOL, coping strategies, and extent of QOL decline during hospitalization emerge as important risk factors for PTSD, underscoring the need for supportive oncology interventions to reduce the risk of PTSD in this population.

IMPORTANCE: Patients with acute myeloid leukemia (AML) receiving intensive chemotherapy experience substantial decline in their quality of life (QOL) and mood during their hospitalization for induction chemotherapy and often receive aggressive care at the end of life (EOL). However, the role of specialty palliative care for improving the QOL and care for this population is currently unknown. OBJECTIVE: To assess the effect of integrated palliative and oncology care (IPC) on patient-reported and EOL outcomes in patients with AML. DESIGN, SETTING, AND PARTICIPANTS: We conducted a multisite randomized clinical trial of IPC (n = 86) vs usual care (UC) (n = 74) for patients with AML undergoing intensive chemotherapy. Data were collected from January 2017 through July 2019 at 4 tertiary care academic hospitals in the United States. INTERVENTIONS: Patients assigned to IPC were seen by palliative care clinicians at least twice per week during their initial and subsequent hospitalizations. MAIN OUTCOMES AND MEASURES: Patients completed the 44-item Functional Assessment of Cancer Therapy–Leukemia scale (score range, 0-176) to assess QOL; the 14-item Hospital Anxiety and Depression Scale (HADS), with subscales assessing symptoms of anxiety and depression (score range, 0-21); and the PTSD Checklist–Civilian version to assess posttraumatic stress disorder (PTSD) symptoms (score range, 17-85) at baseline and weeks 2, 4, 12, and 24. The primary end point was QOL at week 2. We used analysis of covariance adjusting and mixed linear effect models to evaluate patient-reported outcomes. We used Fisher exact test to compare patient-reported discussion of EOL care preferences and receipt of chemotherapy in the last 30 days of life. RESULTS: Of 235 eligible patients, 160 (68.1%) were enrolled; of the 160 participants, the median (range) age was 64.4 (19.7-80.1) years, and 64 (40.0%) were women. Compared with those receiving UC, IPC participants reported better QOL (adjusted mean score, 107.59 vs 116.45; P = .04), and lower depression (adjusted mean score, 7.20 vs 5.68; P = .02), anxiety (adjusted mean score, 5.94 vs 4.53; P = .02), and PTSD symptoms (adjusted mean score, 31.69 vs 27.79; P = .01) at week 2. Intervention effects were sustained to week 24 for QOL (β, 2.35; 95% CI, 0.02-4.68; P = .048), depression (β, −0.42; 95% CI, −0.82 to −0.02; P = .04), anxiety (β, −0.38; 95% CI, −0.75 to −0.01; P = .04), and PTSD symptoms (β, −1.43; 95% CI, −2.34 to −0.54; P = .002). Among patients who died, those receiving IPC were more likely than those receiving UC to report discussing EOL care preferences (21 of 28 [75.0%] vs 12 of 30 [40.0%]; P = .01) and less likely to receive chemotherapy near EOL (15 of 43 [34.9%] vs 27 of 41 [65.9%]; P = .01). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of patients with AML, IPC led to substantial improvements in QOL, psychological distress, and EOL care. Palliative care should be considered a new standard of care for patients with AML. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02975869

Acute myeloid leukemia (AML) remains a therapeutically challenging malignancy with high rate of relapse and poor outcomes. There has been increased understanding of the molecular characteristics of AML and the various roles of the immune system in its pathogenesis, the result of which has led to the study and development of multiple immune-based approaches for this disease. In this review, we aim to provide an overview of the recent advancements made in antibody-based approaches to the treatment of AML including monoclonal antibodies, antibody-drug conjugates, and immune checkpoint inhibition. In addition, we provide insight and discuss the promise of these agents, some of which may soon enter the therapeutic armamentarium we currently employ against this lethal disease.

Antifungal prophylaxis during induction for acute myeloid leukemia (AML) varies according to local rates of invasive fungal infections (IFIs). We evaluated fluconazole prophylaxis and no antifungal prophylaxis, as a natural interrupted time-series study to assess survival and infection complications.We identified patients with AML ≥ 18 years old undergoing induction chemotherapy during 2 time periods: period 1, fluconazole prophylaxis from August 1, 2013 to September 30, 2015, and period 2, no prophylaxis from October 1, 2015 to December 31, 2017. The primary outcome was incidence of proven or probable IFI. Secondary outcomes included types of IFIs and 60-day overall survival (OS). IFI was defined by the 2002 European Organization for Research and Treatment of Cancer/Mycoses Study Group Consensus criteria.One hundred forty-four patients received induction chemotherapy over the 2 time periods. In the prophylaxis versus no-prophylaxis groups, the rate of proven or probable IFIs was 4 (5%) of 87 versus 12 (21%) of 57 (P = .01). The total number of proven IFIs was 3 (3%) of 87 versus 4 (7%) of 57 (P = .44), whereas probable IFIs were 1 (1%) of 87 versus 8 (14%) of 57 (P .01). No difference was observed in fungemia. Incidence of IFIs was too low to detect resistance patterns. OS at 60 days was improved in with fluconazole prophylaxis compared with no prophylaxis (hazard ratio, 0.329; 95% confidence interval, 0.12-0.89; P = .028).Observed rates of proven or probable IFI were lower in the fluconazole prophylaxis group versus the no-prophylaxis group. Sixty-day OS was higher with fluconazole prophylaxis. Further study is required to evaluate how fluconazole may impart the differences in survival seen in this analysis.

Background Acute myeloid leukemia (AML) cells harboring mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) produce the oncometabolite 2-hydroxyglutarate (2HG). This study prospectively evaluated the 2HG levels, IDH1/2 mutational status, and outcomes of patients receiving standard chemotherapy for newly diagnosed AML. Methods Serial samples of serum, urine, and bone marrow aspirates were collected from patients newly diagnosed with AML, and 2HG levels were measured with mass spectrometry. Patients with baseline serum 2HG levels greater than 1000 ng/mL or marrow pellet 2HG levels greater than 1000 ng/2 × 106 cells, which suggested the presence of an IDH1/2 mutation, underwent serial testing. IDH1/2 mutations and estimated variant allele frequencies were identified. AML characteristics were compared with the Wilcoxon test and Fisher's exact test. Disease-free survival and overall survival (OS) were evaluated with log-rank tests and Cox regression. Results Two hundred and two patients were treated for AML; 51 harbored IDH1/2 mutations. IDH1/2-mutated patients had significantly higher 2HG levels in serum, urine, bone marrow aspirates, and aspirate cell pellets than wild-type patients. A serum 2HG level greater than 534.5 ng/mL was 98.8% specific for the presence of an IDH1/2 mutation. Patients with IDH1/2-mutated AML treated with 7+3-based induction had a 2-year event-free survival (EFS) rate of 44% and a 2-year OS rate of 57%. There was no difference in complete remission rates, EFS, or OS between IDH1/2-mutated and wild-type patients. Decreased serum 2HG levels on day 14 as a proportion of the baseline were significantly associated with improvements in EFS (P = .047) and OS (P = .019) in a multivariate analysis. Conclusions Among patients with IDH1/2-mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy.

Patients with primary refractory or relapsed-acute myeloid leukemia (RR-AML), particularly older adults, have dismal outcomes and limited therapy options [1]. Given the tolerability of hypomethylat...

Acute myeloid leukemia (AML) with mutated NPM1 is a newly recognized separate entity in the revised 2016 World Health Organization classification and is associated with a favorable prognosis. Although previous studies have evaluated NPM1 in a binary fashion, little is known about the significance of its mutant allele burden at diagnosis, nor has the effect of comutations (other than FLT3) been extensively evaluated. We retrospectively used targeted sequencing data from 109 patients with de novo AML with mutated NPM1 to evaluate the potential significance of NPM1 variant allele frequency (VAF), comutations, and clinical parameters with regard to patient outcomes. We observed that high NPM1 VAF (uppermost quartile) correlated with shortened overall survival (median, 12.1 months vs not reached; P < .0001) as well as event-free survival (median, 7.5 vs 65.44 months; P < .0001) compared with the other NPM1-mutated cases. In both univariate and multivariable analyses, high NPM1 VAF had a particularly adverse prognostic effect in the subset of patients treated with stem-cell transplantation in first remission (P = .0004) and in patients with mutated DNMT3A (P < .0001). Our findings indicate that the prognostic effect of NPM1 mutation in de novo AML may be influenced by the relative abundance of the mutated allele.

Despite increasing understanding of the pathobiology of acute myeloid leukemia (AML), outcomes remain dismal particularly for patients over the age of 60 years, a population enriched for therapy-related AML (tAML) and secondary AML (sAML). For decades, the standard of care for AML has been the combination of cytarabine and daunorubicin, typically delivered in combination as "7 + 3" induction. In 2017, a liposomal-encapsulated combination of daunorubicin and cytarabine (CPX-351, Vyxeos) was approved by the US Food and Drug Administration (FDA) for use in the treatment of newly diagnosed tAML or AML with myelodysplasia-related changes (AML-MRCs). CPX-351 was designed to deliver a fixed 5:1 molar ratio of cytarabine and daunorubicin, respectively, based on the hypothesis that ratiometric dosing may be more effective than the delivery of either drug at their maximum tolerated dose. In a Phase III trial of older patients with sAML aged 60-75 years, CPX-351 was compared to "7 + 3" and was associated with a higher overall survival, event-free survival, and higher rates of complete remission (CR) and CR with incomplete hematologic recovery (CRi). These data were the basis for the approval of this new drug for use in the treatment of AML, but questions remain regarding how to best administer this agent across AML subgroups. Future directions include evaluating dose intensification with CPX-351, combining this agent with targeted therapies, and better understanding the mechanism of improved responses in tAML and AML-MRC, two entities that are historically less responsive to cytotoxic agents. In summary, CPX-351 offers an exciting new change to the landscape of AML therapy.

A multitude of regulatory approvals has recently changed the therapeutic landscape of acute myeloid leukemia. Among these was upfront therapy with the Hedgehog inhibitor glasdegib with low-dose cytarabine. Understanding the process of and rationale for approval of this promising combination is timely and valuable for the oncology community. See related article by Norsworthy et al., p. 6021

Background: Ivosidenib (IVO) and enasidenib (ENA) are oral inhibitors of mutant IDH1 (mIDH1) and mutant IDH2 (mIDH2), respectively, FDA-approved for the treatment of relapsed/refractory IDH-mutant acute myeloid leukemia (AML). Here we report updated response and survival results from a phase 1 study of these agents when combined with intensive chemotherapy in patients with newly diagnosed m IDH1/2 AML. Methods: The design of this open-label, multicenter, phase 1 study (NCT02632708) has been previously described. Briefly, eligible patients with newly diagnosed m IDH1 or m IDH2 AML were treated with induction therapy (daunorubicin 60 mg/m 2/day or idarubicin 12 mg/m 2/day × 3 days with cytarabine 200 mg/m 2/day × 7 days) in combination with either IVO 500 mg once daily (for m IDH1) or ENA 100 mg once daily (for m IDH2). After induction, patients received up to 4 cycles of consolidation therapy while continuing the mIDH inhibitor. Patients who completed or were ineligible for consolidation continued on maintenance IVO or ENA until the end of the study. IDH mutation clearance and measurable residual disease (MRD) negativity were assessed using BEAMing digital PCR and multiparameter flow cytometry (Stein et al. Blood 2021). Results: As of 16-Jan-2020, 153 patients had been treated: 60 in the IVO cohort (median age 62.5 years, range 24-76) and 93 in the ENA cohort (median age 63.0 years, range 27-77); 2 patients assigned to start ENA on Day 8 had an ongoing adverse event or died on Day 8, and therefore never received ENA and were not included in the efficacy analysis. Secondary AML (sAML; arising after an antecedent hematologic disorder, or after exposure to genotoxic injury) was present in 18/60 (30.0%) IVO-treated patients and in 35/93 (37.6%) ENA-treated patients. In patients with sAML, 4 (22.2%) and 17 (48.6%) IVO-treated and ENA-treated patients, respectively, had previously received a hypomethylating agent. IVO or ENA combined with induction and consolidation were well tolerated (Stein et al . Blood 2021). Among the 60 IVO-treated patients, a response of complete remission (CR), CR with incomplete hematologic recovery (CRi), or CR with incomplete platelet recovery (CRp) was achieved in 37/42 (88.1%) patients with de novo AML and in 10/18 (55.6%) patients with sAML. Among the 91 ENA-treated patients, a response of CR, CRi, or CRp was achieved in 45/56 (80.4%) patients with de novo AML and in 22/35 (62.9%) patients with sAML. Best overall response is reported in Table 1. Patients achieving CR, CRi, or CRp who had available samples were analyzed for IDH mutation clearance and MRD negativity. In those treated with IVO, the IDH1 mutation was cleared in 16/41 (39.0%) patients, and 16/20 (80.0%) were considered MRD negative. In those treated with ENA, the IDH2 mutation was cleared in 15/64 (23.4%) patients, and 10/16 (62.5%) were MRD negative (Stein et al . Blood 2021). Thirty-five (58.3%) IVO-treated patients received ≥1 cycle of consolidation therapy, 18 (30.0%) patients received maintenance after consolidation, 1 (1.7%) patient received maintenance after induction, and 29 (48.3%) patients proceeded to hematopoietic stem cell transplantation (HSCT). Forty-six (49.5%) ENA-treated patients received ≥1 cycle of consolidation therapy, 17 (18.3%) patients received maintenance after consolidation, 7 (7.5%) patients entered maintenance without consolidation, and 43 (46.2%) patients proceeded to HSCT. Median durations of follow-up were 21.2 and 23.7 months for IVO and ENA, respectively. For patients who entered maintenance, median duration of active maintenance was 13.8 and 11.0 months for IVO and ENA, respectively. Of patients who achieved CR, 7/42 (16.7%) of those treated with IVO and 7/51 (13.7%) of those treated with ENA experienced relapse or death. Overall survival is reported in Figure 1. Updated data from July 2021 will be presented. Conclusion: IVO or ENA in combination with induction and consolidation therapy have shown acceptable safety profiles, with ≥80% CR+CRi/CRp remission rates in patients with m IDH de novo AML. With over 21 months of follow-up, overall survival rates were high, with 12-month survival probabilities of >75% for both the IVO- and ENA-treated patients. The clinical benefit of adding IVO or ENA to induction, consolidation, and maintenance therapy for patients with newly diagnosed m IDH AML is being further evaluated in the ongoing HOVON150AML randomized phase 3 trial (NCT03839771). Figure 1 Figure 1. Disclosures Stein: Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; PinotBio: Consultancy; Daiichi Sankyo: Consultancy. DiNardo: Takeda: Honoraria; Novartis: Honoraria; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding. Fathi: Kite: Consultancy, Honoraria; Foghorn: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Trillium: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Blueprint: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria. Mims: Syndax Pharmaceuticals: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Kura Oncology: Consultancy; Leukemia and Lymphoma Society: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding; Glycomemetics: Research Funding; Xencor: Research Funding; Daiichi-Saynko: Consultancy. Savona: Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Stone: Boston Pharmaceuticals: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; Janssen: Consultancy; Jazz: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Onconova: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Winer: Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy. Döhner: AstraZeneca: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Pfizer: Research Funding; Ulm University Hospital: Current Employment; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria. Pollyea: Syndax: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Karyopharm: Consultancy, Honoraria; Foghorn: Honoraria; Kiadis: Honoraria; Syros: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Teva: Research Funding; Amgen: Honoraria; Aprea: Honoraria; Jazz: Honoraria; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. McCloskey: Jazz: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; Amgen: Speakers Bureau; Incyte: Speakers Bureau; COTA: Other: Equity Ownership; BMS: Honoraria, Speakers Bureau. Odenike: AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy; Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding. Ossenkoppele: Agios: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Astellas: Consultancy, Honoraria. Patel: Aptevo Therapeutics: Research Funding; BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Peerview: Honoraria. Roshal: Celgene: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Physicians' Education Resource: Other: Provision of services. Frattini: Celgene/BMS: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Cellectis, Inc.: Current Employment, Current equity holder in publicly-traded company. Lersch: Celgene, a Bristol-Myers Squibb Company: Current Employment. Nabhan: Agios: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Almon: Agios: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Saatcioglu: Servier Pharmaceuticals: Current Employment. Zhang: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Cooper: Agios: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; Servier: Current Employment. Kantarjian: Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Aptitude Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; Astellas Health: Honoraria; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Tallman: Kura: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; NYU Grand Rounds: Honoraria; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. OffLabel Disclosure: Ivosidenib and enasidenib are indicated for the treatment of adult patients with relapsed or refractory AML with a susceptible IDH1 mutation (ivosidenib) or an IDH2 mutation (enasidenib) as detected by an FDA-approved test. Enasidenib and ivosidenib are investigational products in tumors other than relapsed/refractory AML.

Background: Patients with acute myeloid leukemia (AML) who receive intensive chemotherapy must cope with immense physical and psychological symptoms associated with a variety of patient-reported outcomes (PROs) such as quality of life (QOL). Although coping is critical to the management of an AML diagnosis and its treatment, data characterizing the use of coping strategies and its associations with PROs in the AML population are limited. Hence, we characterize coping strategy use among patients with AML and examine the associations between coping strategy use, psychological distress, and QOL. Methods: We used cross-sectional secondary data analyses to describe coping in 160 patients with newly diagnosed high-risk AML enrolled in a multi-site randomized supportive care trial. We used the Brief COPE, Hospital Anxiety and Depression Scale (HADS), PTSD Checklist-Civilian Version (PCL-C), and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) within 72 hours of patient initiation of chemotherapy, to measure coping strategies, psychological distress and QOL, respectively. We grouped coping strategies into two higher-order domains of coping based on prior literature: approach-oriented coping (i.e., use of emotional support, active coping, positive reframing, acceptance) or avoidant coping (i.e., self-blame, denial, behavioral disengagement). We used the median split method for the distribution of coping domains. We used multivariate regression models adjusting for age, gender and diagnosis type (newly diagnosed vs. relapsed/refractory AML) to assess the relationship between coping and PROs. Results: Participants (median age of 64.4 years) were mostly non-Hispanic White (86.3%), male (60.0%), and married (73.8%). Most (51.9%) reported high utilization of approach-oriented coping strategies (e.g., emotional support) whereas 38.8% reported high utilization of avoidant coping strategies (e.g., denial) (Figure 1). At the time of AML diagnosis, use of approach-oriented coping was associated with less psychological distress and better QOL (Table 1). Use of avoidant coping was associated with more psychological distress and worse QOL. Additionally, patients who used multiple approach-oriented coping strategies had less psychological distress and better QOL (Table 2). In contrast, patients who used multiple avoidant coping strategies had more psychological distress, and worse QOL. Conclusions: Our study illustrates that most patients with high-risk AML utilize both approach-oriented and avoidant coping strategies. Our results also reveal links between approach-oriented coping strategies, less psychological distress, and better QOL. These findings underscore the need for early integration of supportive oncology interventions that help patients to cultivate approach-oriented coping strategies. Figure 1 Figure 1. Disclosures Brunner: Novartis: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Acceleron: Consultancy; Agios: Consultancy; Keros Therapeutics: Consultancy; GSK: Research Funding; Aprea: Research Funding; AstraZeneca: Research Funding; Janssen: Research Funding. Fathi: AbbVie: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Blueprint: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Trillium: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Foghorn: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding. LeBlanc: Seattle Genetics: Consultancy, Other: Advisory board, Research Funding; Pfizer: Consultancy, Other: Advisory Board; AstraZeneca: Consultancy, Honoraria, Other: Advisory board, Research Funding; UpToDate: Patents & Royalties; American Cancer Society: Research Funding; Agios: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Other: Travel fees, Research Funding, Speakers Bureau; Daiichi-Sankyo: Consultancy, Honoraria, Other: Advisory board; Flatiron: Consultancy, Other: Advisory board; Astellas: Consultancy, Honoraria, Other: Advisory board; AbbVie: Consultancy, Honoraria, Other: Advisory board; Travel fees, Speakers Bureau; Otsuka: Consultancy, Honoraria, Other; Jazz Pharmaceuticals: Research Funding; Duke University: Research Funding; Helsinn: Consultancy, Research Funding; Heron: Consultancy, Honoraria, Other: advisory board; CareVive: Consultancy, Other, Research Funding; NINR/NIH: Research Funding; Amgen: Consultancy, Other: travel.

Disease relapse after hematopoietic cell transplantation (HCT) is a major cause of treatment failure for patients with acute myeloid leukemia (AML). Maintenance therapy after HCT for patients with targetable mutations such as mutated IDH1 or IDH2 may improve outcomes, and clinical trials evaluating this strategy are ongoing. However, clinical outcomes of IDH1- and IDH2-mutated AML patients after HCT have not been well described. The primary objective of this study was to describe the clinical characteristics and post-HCT outcomes of IDH-mutated AML patients. Survival outcomes included progression-free survival (PFS), overall survival, and cumulative incidences of relapse and nonrelapse mortality. In this multicenter retrospective analysis, 112 adult patients with IDH1- or IDH2-mutated AML who underwent HCT and did not receive an IDH inhibitor as maintenance therapy after HCT were identified at Massachusetts General Hospital, Dana Farber Cancer Institute, and Ohio State University. Mutation testing was performed using next-generation sequencing panels. Patient characteristics were collected retrospectively, and their survival outcomes were analyzed. Univariate and multivariate analyses were performed. The median patient age was 64.1 years. The median follow-up was 27.5 months. Among patients, 78.5% had intermediate- or adverse-risk disease by European LeukemiaNET criteria. Fifty-eight percent of patients received intensive induction chemotherapy, 82% of patients underwent HCT during first complete remission (CR) or CR with incomplete hematologic recovery (CRi), and 34% of patients received myeloablative conditioning. Frequently detected co-mutations were DNMT3A (35.7%), NPM1 (33.1%), and FLT3-ITD (13.4%); TP53 mutations were detected in 3.6% of patients. For IDH1-mutated patients transplanted during first CR/CRi, the 1- and 2-year PFS was 75% and 58%, respectively. For IDH2-mutated patients transplanted in first CR/CRi, the 1- and 2-year PFS was 64% and 58%, respectively. The 2-year cumulative incidence of relapse was 31% and 25% for IDH1- and IDH2-mutated cohorts, respectively. Multivariable analysis suggested first CR/CRi and age ≤60 was associated with improved outcomes for IDH2-mutated patients. To date, this is the largest multicenter study of outcomes of IDH-mutated AML patients after HCT. Our analysis provides important benchmarks for analysis and interpretation of results emerging from clinical trials evaluating maintenance IDH1 and IDH2 inhibitor therapy for AML patients after HCT.