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Competing Interests: Competing interests: MO: consulting fees from Merck and Biosights; Data Safety Monitoring Board Member for BMS, Glycomimetics, Grifols. MP: clinical trial research funding (to institution) from Abbvie, Ascentage, Astex, Biosight, BMS, Immunogen, Pfizer.

Background/aims: Randomized clinical trials often use stratification to ensure balance between arms. Analysis of primary endpoints of these trials typically uses a "stratified analysis," in which analyses are performed separately in each subgroup defined by the stratification factors, and those separate analyses are weighted and combined. In the phase 3 setting, stratified analyses based on a small number of stratification factors can provide a small increase in power. The impact on power and type-1 error of stratification in the setting of smaller sample sizes as in randomized phase 2 trials has not been well characterized., Methods: We performed computational studies to characterize the power and cross-arm balance of modestly sized clinical trials (less than 170 patients) with varying numbers of stratification factors (0-6), sample sizes, randomization ratios (1:1 vs 2:1), and randomization methods (dynamic balancing vs stratified block)., Results: We found that the power of unstratified analyses was minimally impacted by the number of stratification factors used in randomization. Analyses stratified by 1-3 factors maintained power over 80%, while power dropped below 80% when four or more stratification factors were used. These trends held regardless of sample size, randomization ratio, and randomization method. For a given randomization ratio and sample size, increasing the number of factors used in randomization had an adverse impact on cross-arm balance. Stratified block randomization performed worse than dynamic balancing with respect to cross-arm balance when three or more stratification factors were used., Conclusion: Stratified analyses can decrease power in the setting of phase 2 trials when the number of patients in a stratification subgroup is small., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Acute myeloid leukemia (AML) remains one of the deadliest hematopoietic malignancies. A better understanding of the molecular biology governing AML may lead to improved risk stratification and facilitate the development of novel therapies. Proteins are responsible for much of the biology of cells. Several studies have examined the global proteome in bulk mononuclear cells (MNCs) from AML specimens, which are comprised a heterogenous population of cells at various stages of differentiation., Methods: Given the potential impact of the nonleukemic cells on protein expression profiles, we applied an integrative proteogenomic approach utilizing next-generation sequencing and mass spectrometry-based proteomics to identify novel protein biomarkers in unsorted MNCs and viable leukemic blasts (VLBs) isolated from blood and bone marrow specimens obtained at the time of AML diagnosis., Results: We identified significant differences in protein expression between VLBs and MNCs. Subsequent studies ( N  = 27) focused on proteomic profiling of VLBs that identified novel candidate biomarkers associated with mutational genotypes and clinical outcome, some of which were recapitulated in an independent cohort of patients. Using mass spectrometry, we also detected mutated protein products, some of which were predicted via in silico analyses to be potential neoantigens amenable to adoptive immunotherapy. As previously described, analyses comparing transcript and protein expression showed an overall modest correlation between mRNA and protein dataset, but enriching for genes associated with mutations significantly improved the protein-RNA correlation., Conclusion: Together, the results provide insight into the biology of VLBs and demonstrate the gains derived from examining the proteome in addition to genome and transcriptome., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity., Methods: KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41., Findings: From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission., Interpretation: Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing., Funding: Kura Oncology., Competing Interests: Declaration of interests ESW declares honoraria for educational talks from Aptitude, Astellas, Bioascend, CEA, CCO, Curio Sciences, Dava Oncology, Medscape, MD Education, OncLive, PER, Peerview, RTP, and Pfizer; participation on Data Safety Monitoring Committees and research grant committees for AbbVie and Gilead; advisory board participation for Abbvie, Astellas, Blueprint, Bristol Myers Squibb, Daiichi Sankyo, Gilead, GlaxoSmithKline, Immunogen, Janssen, Jazz, Kite, Novartis, NuProbe, PharmaEssentia, Pfizer, Qiagen, Rigel, Schrodinger, Sumitomo, Syndax, and Takeda; other financial and non-financial interests with UptoDate; and medical writing support for this work from Kura Oncology. GCI declares research funding to their institution from Astex, Cullinan Oncology, Kura Oncology, Merck, Novartis, and Syndax Pharmaceuticals; consultancy fees from AbbVie, Kura Oncology, Novartis, and Syndax Pharmaceuticals; support for attending meetings and travel from Kura Oncology; steering committee role with Kura Oncology and Novartis; receipt of material for sample analysis from NuProbe; and medical writing support for this work from Kura Oncology. HPE declares a leadership role with AbbVie (Chair, Independent Review Committee for VIALE A and VIALE C), Bristol Myers Squibb (Chair, AML Registry Steering Committee), and Glycomimetics (Scientific Steering Committee); speakers bureau for AbbVie, Bristol Myers Squibb, Incyte, Jazz, Novartis, and Servier; contracted research from AbbVie, ALX Oncology, Amgen, Aptose, Ascentage, Daiichi Sankyo, Forma, Gilead, Glycomimetics, Immunogen, Jazz, Kura Oncology, MacroGenics, Novartis, PTC, and Sumitomo Pharma; consultancy fees from AbbVie, Astellas, Bristol Myers Squibb, Daiichi Sankyo, Glycomimetics, Incyte, Jazz, Kura Oncology, Novartis, Pfizer, Servier, Stemline, and Sumitomo Pharma; and medical writing support for this work from Kura Oncology. JKA declares a leadership role with the American Society of Hematology (guidelines panel), National Comprehensive Cancer Network (acute myeloid leukaemia panel vice-chair), and National Cancer Institute (co-chair on Leukemia Steering Committee); honoraria from Astellas, HMP Education, MD Education, and VJ HemOnc; advisory board role with AbbVie, Aptitude Health, Astellas, BlueBird Bio, Curio, Daiichi Sankyo, Dark Blue Therapeutics, Gilead, Kura Oncology, Kymera, Rigel, Stemline Therapeutics, Syros, and Treadwell Therapeutics; meeting attendance and travel expenses from Astellas, Daiichi Sankyo, HMP Education, MD Education, and VJ HemOnc; medical writing support for this work from Kura Oncology; and participation on a Data Safety Committee for Glycomimetics. PM declares consultancy fees from Kura Oncology and Syndax Pharmaceuticals and medical writing support for this work from Kura Oncology. SDB declares honoraria from Astellas, Bristol Myers Squibb, Menarini, and Servier; consultancy fees from AbbVie, Bristol Myers Squibb, Forma, Remix, Rigel, and Servier; travel expenses from Janssen, Pfizer, Rigel, and Servier; and medical writing support for this work from Kura Oncology. RBW declares clinical trial support from Kura Oncology and medical writing support for this work from Kura Oncology. KP declares honoraria from Merck (investigator meeting lecture); advisory board role with AbbVie, Incyte, PharmaEssentia, Protagonist, and Sobi; and medical writing support for this work from Kura Oncology. MRS declares research funding to institution from ALX Oncology, Astex, Incyte, Takeda, and TG Therapeutics; consultancy fees from AbbVie, Bristol Myers Squibb, CTI BioPharma, Forma, Geron, GlaxoSmithKline, Karyopharm, Rigel, Ryvu, Taiho, and Treadwell; stock or stock options in Empath Bioscience, Karyopharm, and Ryvu; and medical writing support for this work from Kura Oncology. MVS declares research grant to their institution from AbbVie, Astellas, Celgene, Kura Oncology, and MRKR Therapeutics; travel expenses from Dava Oncology; and medical writing support for this work from Kura Oncology. MK declares consultancy fees from AbbVie, CTI Biopharma, Incyte, and Protagonist; advisory board role with CTI BioPharma, Incyte, Kura Oncology, and Morphosys; travel expenses from Protagonist; and medical writing support for this work from Kura Oncology. MRB declares research funding to their institution from AbbVie, Ascentage, Astellas, Gilead, Kura Oncology, and Takeda and medical writing support for this work from Kura Oncology. JMF declares leadership role with National Cancer Institute Leukemia Steering Committee and the National Heart, Lung, and Blood Institute national Myelodysplastic Syndrome Study Steering Committee; stock or stock options with Aurinia; honoraria from AmerisourceBergen/IntrinsiQ Specialty Solutions, Aptitude Health, and MJH LifeSciences; consultancy fees from Autolus, Bristol Myers Squibb, Remix, and Syndax; grants to institution for clinical trial support from Actinium, Astellas, Celgene, Chordia, Kura Oncology, Novartis, Pfizer, Roivant, Sellas, and Servier; and medical writing support for this work from Kura Oncology. GS declares contracts through their institution from AbbVie, Actinium, Actuate, Agios, Arog, Astellas, AlloVir, Amgen, Aptevo, AltruBio, AVM Bio, Bristol Myers Squibb/Celgene; BioMea, Biopath, Biosight, Cellularity, Celator, Constellation, Cogent, Cellectis, Cullinan, Daiichi Sankyo, Deciphera, Delta-Fly, Fate, Forma, FujiFilm, Gamida, Genentech-Roche, Rigel Glycomimetics, Geron, Gilead, Incyte, Janssen, Jazz, Karyopharm, Kite/Gilead, Kronos Bio, Kura Oncology, Immunogene, ImmuneOnc, Loxo, Marker, Mateon, Novartis, Onconova, Ono-UK, Orca, Pfizer, PrECOG, Regimmune, Samus, Sangamo, Sellas, Stemline, Syros, Takeda, Tolero, and Trovagene; consultancy fees from Bristol Myers Squibb, Curios, Daiichi, and Novartis; speakers bureau role for AbbVie, Agios, Amgen, Astellas, Blueprint Medicine, Bristol Myers Squibb, Celgene, Karyopharm, GlaxoSmithKline, Kite (Gilead), Jazz, Rigel, Seattle genetics, and Stemline; board or advisory committee membership for Agios, Autolus, AVM Biotech, Bristol Myers Squibb, Gamida, Gilead, GlaxoSmithKline, Incyte, Novartis, Orca, Rigel, and Stemline; board of trustees membership for Leukemia Lymphoma Society Los Angeles; secretary or treasurer membership for the American Society of Hematology Research Collaborative Board of Directors; and holds stock with Amgen, Bristol Myers Squibb, and Janssen/Johnson & Johnson. LA declares research funding to institution from AbbVie, Bristol Myers Squibb, Jazz Pharmaceuticals, and Novartis; consultancy fees from AbbVie, Jazz Pharmaceuticals, and Novartis; and medical writing support for this work from Kura Oncology. ER declares consulting fees from Astellas and Laboratories Delbert; honoraria from AbbVie, Astellas, Eurocept, and Jazz Pharmaceuticals; support for attending meetings and travel from AbbVie, Gilead, and Jazz Pharmaceuticals; and medical writing support for this work from Kura Oncology. MMP declares research funding to institution from Epigenetix, Kura Oncology, Polaris, Solutherapeutics, and Stem Line Pharma; medical writing support for this work from Kura Oncology; and Data Safety Monitoring Boards with CTI Biopharma. CP declares honoraria from AbbVie, Amgen, Astellas, Blueprint, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Incyte, Janssen, Jazz Pharmaceuticals, Laboratories Delbert, Menarini-Stemline, Novartis, Paladin Labs, Pfizer, and Servier; travel expenses from AbbVie, Amgen and Pfizer; medical writing support for this work from Kura Oncology; and Data Safety Monitoring Board or advisory board membership for AbbVie, Amgen, Astellas, Blueprint, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Incyte, Janssen, Jazz Pharmaceuticals, Laboratories Delbert, Paladin Labs, and Pfizer. JG declares research support to institution, consultancy fees, royalties, patents, and stock with Kura Oncology, and medical writing support for this work from Kura Oncology. TC declares research support to institution and royalties from, and patents and owns stock with Kura Oncology; and medical writing support for this work from Kura Oncology. BC, JR, BML, MH, PP, and OS declare medical writing support for this work from Kura Oncology. KN declares employment with Kura Oncology; received stock options from Kura Oncology; and medical writing support for this work from Kura Oncology. AM declares employment with Kura Oncology; owns stock with Kura Oncology; patents and patent applications with Kura Oncology; and medical writing support for this work from Kura Oncology. JMA declares employment and stock or stock options with and travel expenses from Kura Oncology, and medical writing support for this work from Kura Oncology. MT declares employment with Kura Oncology; stock and restricted stock units with Kura Oncology; reimbursement for conference fees, hotels and travel expenses from Kura Oncology; and medical writing support for this work from Kura Oncology. HSS declares employment, patents and patent applications, and owns stock with, Kura Oncology, and medical writing support for this work from Kura Oncology. DC declares employment with Kura Oncology; stock or stock options with Kura Oncology; and medical writing support for this work from Kura Oncology. ML declares employment, patents and patent applications, stock or stock options, support for attending meetings and travel, and other financial or non-financial interests with Kura Oncology; and medical writing support for this work from Kura Oncology. SD declares employment, patents and patent applications, stock or stock options, and other financial or non-financial interests with Kura Oncology; and medical writing support for this work from Kura Oncology. ATF declares consultancy fees from AbbVie, Amgen, Astellas, AstraZeneca, Autolus, Bristol Myers Squibb/Celgene, Daiichi Sankyo, EnClear, Forma, Genentech, Gilead, Immunogen, Ipsen, Kite, Mablytics, Menarini, Novartis, Orum, Pfizer, PureTech, Remix, Rigel, Servier, and Takeda; clinical trial support from AbbVie, Bristol Myers Squibb, and Servier; and medical writing support for this work from Kura Oncology. CB declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission., Methods: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1 -negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point., Results: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group., Conclusions: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.)., (Copyright © 2024 Massachusetts Medical Society.)

There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently few studies have stratified outcomes by class I obesity, class II obesity, and class III obesity, and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n = 729). Class III obesity was associated with an increased rate of early death (p = 0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The presence of measurable residual disease (MRD) is strongly associated with treatment outcomes in acute myeloid leukemia (AML). Despite the correlation with clinical outcomes, MRD assessment has yet to be standardized or routinely incorporated into clinical trials and discrepancies have been observed between different techniques for MRD assessment. In 62 patients with AML, aged 18-60 years, in first complete remission after intensive induction therapy on the randomized phase III SWOG-S0106 clinical trial (clinicaltrials gov. Identifier: NCT00085709), MRD detection by centralized, high-quality multiparametric flow cytometry was compared with a 29-gene panel utilizing duplex sequencing (DS), an ultrasensitive next-generation sequencing method that generates double-stranded consensus sequences to reduce false positive errors. MRD as defined by DS was observed in 22 (35%) patients and was strongly associated with higher rates of relapse (68% vs. 13%; hazard ratio [HR] =8.8; 95% confidence interval [CI]: 3.2-24.5; P<0.001) and decreased survival (32% vs. 82%; HR=5.6; 95% CI: 2.3-13.8; P<0.001) at 5 years. DS MRD strongly outperformed multiparametric flow cytometry MRD, which was observed in ten (16%) patients and marginally associated with higher rates of relapse (50% vs. 30%; HR=2.4; 95% CI: 0.9-6.7; P=0.087) and decreased survival (40% vs. 68%; HR=2.5; 95% CI: 1.0-6.3; P=0.059) at 5 years. Furthermore, the prognostic significance of DS MRD status at the time of remission for subsequent relapse was similar on both randomized arms of the trial. These findings suggest that next-generation sequencing-based AML MRD testing is a powerful tool that could be developed for use in patient management and for early anti-leukemic treatment assessment in clinical trials.

Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.)., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target. As such, newer approaches employing combinations of targeted therapy, or targeted therapy with standard therapies, need to be considered. The NCI has recently embarked on three second-generation precision medicine trials to address this need: ComboMATCH, iMATCH, and myeloMATCH. The design of these trials and necessary infrastructure are discussed in the following perspective., (©2023 The Authors; Published by the American Association for Cancer Research.)

Relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) is a genetically complex and heterogeneous disease with a poor prognosis and limited treatment options. Thus, there is an urgent need to develop therapeutic combinations to overcome drug resistance in AML. This open-label, multicenter, international, phase 1b study evaluated the safety, efficacy, and pharmacokinetics of venetoclax in combination with alvocidib in patients with R/R AML. Patients were treated with escalating doses of venetoclax (400, 600, and 800 mg QD, orally, days 1-28) and alvocidib (45 and 60 mg/m 2 , intravenously, days 1-3) in 28-day cycles. The combination was found to be safe and tolerable, with no maximum tolerated dose reached. Drug-related Grade ≥3 adverse events were reported in 23 (65.7%) for venetoclax and 24 (68.6%) for alvocidib. No drug-related AEs were fatal. Gastrointestinal toxicities, including diarrhea, nausea, and vomiting were notable and frequent; otherwise, the toxicities reported were consistent with the safety profile of both agents. The response rate was modest (complete remission [CR] + incomplete CR [CRi], 11.4%; CR + CRi + partial response rate + morphologic leukemia-free state, 20%). There was no change in alvocidib pharmacokinetics with increasing doses of venetoclax. However, when venetoclax was administered with alvocidib, AUC 24 and C max decreased by 18% and 19%, respectively. A recommended phase 2 dose was not established due to lack of meaningful increase in efficacy across all cohorts compared to what was previously observed with each agent alone. Future studies could consider the role of the sequence, dosing, and the use of a more selective MCL1 inhibitor for the R/R AML population., (© 2023 AbbVie Inc. Hematological Oncology published by John Wiley & Sons Ltd.)

Genomic data variability from laboratory reports can impact clinical decisions and population-level analyses; however, the extent of this variability and the impact on the data's value are not well characterized. This pilot study used anonymized genetic and genomic test reports from the Connect Myeloid Disease Registry (NCT01688011), a multicenter, prospective, observational cohort study of patients with newly diagnosed myelodysplastic syndromes, acute myeloid leukemia, or idiopathic cytopenia of undetermined significance, to analyze laboratory test variabilities and limitations. Results for 56 randomly selected patients enrolled in the Registry were independently extracted and evaluated (data cutoff, January 2020). Ninety-five reports describing 113 assay results from these 56 patients were analyzed for discrepancies. Almost all assay results [101 (89%)] identified the sequencing technology applied, and 94 (83%) described the test limitations; 95 (84%) described the limits of detection, but none described the limit of blank for detecting false positives. RNA transcript identifiers were not provided for 20 (43%) variants analyzed by next-generation sequencing and reported by the same laboratory. Of 42 variants with variant allele frequencies ≥30%, 16 (38%) of the variants did not have report text indicating that the variants might be germline. Variabilities and lack of standardization present challenges for incorporating this information into clinical care and render data collation ineffective and unreliable for large-scale use in centralized databases for therapeutic discovery., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Hematopoietic stem cell transplantation (HCT) is indicated for patients with higher-risk (HR) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Age, performance status, patient frailty, comorbidities, and nonclinical factors (eg, cost, distance to site) are all recognized as important clinical factors that can influence HCT referral patterns and patient outcomes; however, the proportion of eligible patients referred for HCT in routine clinical practice is largely unknown. This study aimed to assess patterns of consideration for HCT among patients with HR-MDS and AML enrolled in the Connect® Myeloid Disease Registry at community/government (CO/GOV)- or academic (AC)-based sites, as well as to identify factors associated with rates of transplantation referral. We assessed patterns of consideration for and completion of HCT in patients with HR-MDS and AML enrolled between December 12, 2013, and March 6, 2020, in the Connect Myeloid Disease Registry at 164 CO/GOV and AC sites. Registry sites recorded whether patients were considered for transplantation at baseline and at each follow-up visit. The following answers were possible: "considered potentially eligible," "not considered potentially eligible," or "not assessed." Sites also recorded whether patients subsequently underwent HCT at each follow-up visit. Rates of consideration for HCT between CO/GOV and AC sites were compared using multivariable logistic regression analysis with covariates for age and comorbidity. Among the 778 patients with HR-MDS or AML enrolled in the Connect Myeloid Disease Registry, patients at CO/GOV sites were less likely to be considered potentially eligible for HCT than patients at AC sites (27.9% versus 43.9%; P < .0001). Multivariable logistic regression analysis with factors for age (<65 versus ≥65 years) and ACE-27 comorbidity grade (<2 versus ≥2) showed that patients at CO/GOV sites were significantly less likely than those at AC sites to be considered potentially eligible for HCT (odds ratio, 1.6, 95% confidence interval, 1.1 to 2.4; P = .0155). Among patients considered eligible for HCT, 45.1% (65 of 144) of those at CO/GOV sites and 35.7% (41 of 115) of those at AC sites underwent transplantation (P = .12). Approximately one-half of all patients at CO/GOV (50.1%) and AC (45.4%) sites were not considered potentially eligible for HCT; the most common reasons were age at CO/GOV sites (71.5%) and comorbidities at AC sites (52.1%). Across all sites, 17.4% of patients were reported as not assessed (and thus not considered) for HCT by their treating physician (20.7% at CO/GOV sites and 10.7% at AC sites; P = .0005). These findings suggest that many patients with HR-MDS and AML who may be candidates for HCT are not receiving assessment or consideration for transplantation in clinical practice. In addition, treatment at CO/GOV sites and age remain significant barriers to ensuring that all potentially eligible patients are assessed for HCT., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Progress in acute myeloid leukaemia treatment is occurring at an unprecedented pace. The past decade has witnessed an increasingly improved scientific understanding of the underlying biology of acute myeloid leukaemia, leading to enhanced prognostication tools and refined risk assessments, and most especially incorporating measurable residual disease (MRD) into longitudinal risk assessments. The classification of acute myeloid leukaemia has recently been updated by WHO and the International Consensus Classification (ICC). Recommendations for prognostic stratification, response assessment, and MRD determination have also been updated by the European LeukemiaNet. Treatment options have evolved substantially in the last 5 years for patients with newly diagnosed acute myeloid leukaemia, leading to improved outcomes in intensively treated patients and those more appropriate for non-intensive chemotherapy. More effective targeted treatment options in the relapsed setting are also available, further advancing the treatment armamentarium and improving patient outcomes., Competing Interests: Declaration of interests CDD received funding (to institution) from Abbvie, Astex, BMS, Cleave, Foghorn, ImmuneOnc, Loxo, and Servier; received consulting and honorarium fees from Abbvie, BMS, Genmab, Gilead, GSK, Jazz, Kura, Novartis, Servier, and Takeda; and was on the scientific advisory board of Notable Labs. HPE received funding (to institution) from AbbVie, ALX Oncology, Amgen, Ascentage, Daiichi Sankyo, Forma, Gilead, Glycomimetics, Immunogen, Jazz, MacroGenics, Novartis, PTC, and Sumitomo Pharma; received consulting fees from AbbVie, Agios, Astellas, BMS/Celgene, Daiichi Sankyo, Glycomimetics, Immunogen, Incyte, Jazz, Kura Oncology, MacroGenics, Novartis, Pfizer, Servier, Syros, Takeda, Trillium; was on the speaker's bureau for AbbVie, BMS, Incyte, Jazz, Novartis, and Servier. SDF received funding (to institution) from BMS and Jazz; received consulting and honorarium fees from Novartis, and was on the advisory board of Neogenomics and MPAAC. AHW acts on the advisory boards for Novartis, Astra Zeneca, Astellas, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, Gilead, BMS, Shoreline, Macrogenics and Agios; receives funding (to institution) from Novartis, Abbvie, Servier, Janssen, BMS, Syndax, Astex, Astra Zeneca, and Amgen; serves on the speaker's bureaus for Abbvie, Novartis, BMS, Servier, and Astellas; and is an employee of the Walter and Eliza Hall Institute (WEHI). WEHI receives milestone and royalty payments related to the development of venetoclax. Current and past employees of WEHI may be eligible for financial benefits related to these payments. AHW receives financial benefits from WEHI., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Patients with acute myeloid leukaemia (AML) positive for internal tandem duplication (ITD) mutations of FLT3 have poor outcomes. Quizartinib, an oral, highly potent, selective, type 2 FLT3 inhibitor, plus chemotherapy showed antitumour activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML. The aim of the study was to compare the effect of quizartinib versus placebo on overall survival in patients with FLT3-ITD-positive newly diagnosed AML aged 18-75 years., Methods: We conducted a randomised, double-blind, placebo-controlled, phase 3 trial comparing quizartinib and placebo in combination with chemotherapy in induction and consolidation, followed by quizartinib or placebo single-agent continuation, in patients with FLT3-ITD-positive newly diagnosed AML at 193 hospitals and clinics in 26 countries in Europe; North America; and Asia, Australia, and South America. Patients aged 18-75 years were eligible. Patients were randomly assigned (1:1) to the quizartinib group or the placebo group by an independent biostatistician through an interactive web and voice response system, stratified by region, age, and white blood cell count at diagnosis. Patients, investigators, funders, and contract research organisations were masked to treatments assigned. Induction therapy comprised a standard 7 + 3 induction regimen of cytarabine 100 mg/m 2 per day (or 200 mg/m 2 per day allowed if institutional or local standard) by continuous intravenous infusion from day 1 to day 7 and anthracycline (daunorubicin 60 mg/m 2 per day or idarubicin 12 mg/m 2 per day) by intravenous infusion on days 1, 2, and 3, then quizartinib 40 mg orally or placebo once per day, starting on day 8, for 14 days. Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose cytarabine plus quizartinib (40 mg per day orally) or placebo, allogeneic haematopoietic cell transplantation (allo-HCT), or both as consolidation therapy, followed by continuation of single-agent quizartinib or placebo for up to 3 years. The primary outcome was overall survival, defined as time from randomisation until death from any cause and assessed in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of quizartinib or placebo. This study is registered with ClinicalTrials.gov (NCT02668653)., Findings: Between Sept 27, 2016, and Aug 14, 2019, 3468 patients with AML were screened and 539 patients (294 [55%] male patients and 245 [45%] female patients) with FLT3-ITD-positive AML were included and randomly assigned to the quizartinib group (n=268) or placebo group (n=271). 148 (55%) of 268 patients in the quizartinib group and 168 (62%) of 271 patients in the placebo group discontinued the study, primarily because of death (133 [90%] of 148 in the quizartinib group vs 158 [94%] of 168 in the placebo group) or withdrawal of consent (13 [9%] of 148 in the quizartinib group vs 9 [5%] of 168 in the placebo group). Median age was 56 years (range 20-75, IQR 46·0-65·0). At a median follow-up of 39·2 months (IQR 31·9-45·8), median overall survival was 31·9 months (95% CI 21·0-not estimable) for quizartinib versus 15·1 months (13·2-26·2) for placebo (hazard ratio 0·78, 95% CI 0·62-0·98, p=0·032). Similar proportions of patients in the quizartinib and placebo groups had at least one adverse event (264 [100%] of 265 in the quizartinib group and 265 [99%] of 268 in the placebo group) and one grade 3 or higher adverse event (244 [92%] of 265 in the quizartinib group and 240 [90%] of 268 in the placebo group). The most common grade 3 or 4 adverse events were febrile neutropenia, hypokalaemia, and pneumonia in both groups and neutropenia in the quizartinib group., Interpretation: The addition of quizartinib to standard chemotherapy with or without allo-HCT, followed by continuation monotherapy for up to 3 years, resulted in improved overall survival in adults aged 18-75 years with FLT3-ITD-positive newly diagnosed AML. Based on the results from the QuANTUM-First trial, quizartinib provides a new, effective, and generally well tolerated treatment option for adult patients with FLT3-ITD-positive newly diagnosed AML., Funding: Daiichi Sankyo., Competing Interests: Declaration of interests HPE reports research grants from AbbVie, Agios Pharmaceuticals, ALX Oncology, Amgen, Ascentage, Celgene, Daiichi Sankyo, Forma Therapeutics, Forty Seven, Gilead, GlycoMimetics, ImmunoGen, Jazz Pharmaceuticals, Kura Oncology, MacroGenics, Novartis, PTC Therapeutics, Servier, and Sumitomo Dainippon Pharma; consulting fees for participation on advisory boards for AbbVie, Agios Pharmaceuticals, Astellas, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Genentech, GlycoMimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, Kura Oncology, MacroGenics, Novartis, Pfizer, Servier, Syros Pharmaceuticals, Takeda, and Trillium Therapeutics; payment for speakers bureaus from AbbVie, Agios Pharmaceuticals, Bristol Myers Squibb, Celgene, Incyte, Jazz Pharmaceuticals, Novartis, and Servier; and has served as a steering committee member for GlycoMimetics, as chair of the Myeloid Neoplasms Repository study for Bristol Myers Squibb and Celgene, and as chair of the independent review committee of the VIALE A and VIALE C studies for AbbVie. PM reports research grants from AbbVie, Bristol Myers Squibb, Jazz Pharmaceuticals, Menarini, Stemline Therapeutics, Novartis, Pfizer, and Takeda; consulting fees from AbbVie, Astellas, BeiGene, Bristol Myers Squibb, Gilead, Incyte, Jazz Pharmaceuticals, Kura Oncology, Menarini, Stemline Therapeutics, Nerviano Medical Sciences, Novartis, Otsuka Pharmaceutical, Pfizer, Ryvu Therapeutics, and Takeda; and payment for speakers bureaus from AbbVie, Astellas, Bristol Myers Squibb, Gilead, Jazz Pharmaceuticals, and Pfizer. H-JK reports research grants from BL&H; consulting fees from AbbVie, AIMS BioScience, Amgen, AMLHub, Astellas, Aston BioSciences, Bristol Myers Squibb, Celgene, Boryung Pharmaceutical, Daiichi Sankyo, Handok, Ingenium, Janssen, LG Chem, Novartis, Pfizer, Sanofi Genzyme, SL VaxiGen, and VigenCell; is on a data safety monitoring board or advisory board for AbbVie, the Asia Pacific Leukemia Consortium, Astellas, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Handok, Janssen, Novartis, Pfizer, and Sanofi Genzyme; and is a leader in other board, society, committee, or advocacy groups for AMLHub, the Asia Pacific Leukemia Consortium, the Asia Pacific Blood and Marrow Transplantation Group, and the Korean Society of Blood and Marrow Transplantation. EP reports consulting fees from KCR US; payment for lectures from Amgen, Angelini, Astellas, Novartis, Pfizer, and Servier; and support for attending meetings from Angelini, Astellas, Bristol Myers Squibb, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier. RV reports consulting fees from AbbVie, Astellas, Pfizer, and PharmaS; and payment for lectures from AbbVie, Astellas, Merck Sharp & Dohme, Novartis, Pfizer, PharmaS, Servier, and Teva. JC reports research grants from AbbVie, Daiichi Sankyo, Novartis, Sun Pharma, and Pfizer; consulting fees from AbbVie, Bio-Path, Daiichi Sankyo, Gilead, Forma Therapeutics, Novartis, Pfizer, and Takeda; payment for lectures from Novartis, Pfizer, and Takeda; and has stock options with Bio-Path. AEP reports research grants from AbbVie, Actinium Pharmaceuticals, Astellas, Bayer, BioMed Valley Discoveries, and Daiichi Sankyo; personal fees from Actinium Pharmaceuticals, Agios Pharmaceuticals, Astellas, Daiichi Sankyo, Forma Therapeutics, Jazz Pharmaceuticals, Leukemia & Lymphoma Society (Beat AML Master Clinical Trial), Loxo Oncology, NewLink Genetics, Novartis, and Takeda; and non-financial support from Arog Pharmaceuticals, Astellas, Jazz Pharmaceuticals, NewLink Genetics, Novartis, and Takeda. MAS reports consulting fees from Bristol Myers Squibb, Kurome Therapeutics, and Novartis; and has stock options with Kurome Therapeutics. HD reports personal fees from Incyte and Servier. JW reports payment for participation on an advisory board from Abbvie and for participation on a data safety monitoring committee from AstraZeneca. MJL reports research grants from Astellas and FujiFilm Pharmaceuticals; consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Menarini, Pfizer, and Takeda; and payment for lectures from Astellas. RFS reports consulting fees from Daiichi Sankyo for participation on a steering committee and from AbbVie, Jazz Pharmaceuticals, and Pfizer for participation on advisory boards; payment for lectures from Daiichi Sankyo, Novartis, and Pfizer; is on a data safety monitoring board or advisory board for BerGenBio and Novartis; and has been provided with equipment by AbbVie, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, PharmaMar, Pfizer, and Roche. TM, JH, YMK, JECR, LL, AB, and AL are employees of Daiichi Sankyo. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Novel treatment strategies are needed for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell-engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations) were eligible and could be newly diagnosed or relapsed/refractory. Induction therapy consisted of dasatinib/prednisone. Patients not achieving response by day 56 proceeded to blinatumomab reinduction therapy. Patients achieving response with induction or reinduction therapy proceeded to blinatumomab/dasatinib postremission therapy for 3 cycles followed by dasatinib/prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at days 28, 56, and 84 and at additional time points based on response parameters. Measurable residual disease was assessed centrally by 8-color flow cytometry at day 28. A total of 24 eligible patients with newly diagnosed Ph+ ALL were enrolled with a median age of 73 years (range, 65-87 years). This combination was safe and feasible. With a median of 2.7 years of follow-up, 3-year overall survival and disease-free survival were 87% (95% confidence interval [CI], 64-96) and 77% (95% CI, 54-90), respectively. Although longer follow-up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial was registered at www.clinicaltrials.gov as #NCT02143414., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The presence of measurable residual disease (MRD) is strongly associated with treatment outcomes in acute myeloid leukemia (AML). Despite the correlation with clinical outcomes, MRD assessment has yet to be standardized or routinely incorporated into clinical trials. Discrepancies have been observed between different techniques for MRD assessment and there remains a need to compare centralized, high-quality multiparametric flow cytometry (MFC) and ultrasensitive next-generation sequencing (NGS) in AML patients with diverse mutational profiles. In 62 patients with AML, aged 18-60, in first complete remission after intensive induction therapy on the randomized phase 3 SWOG-S0106 clinical trial, MRD detection by MFC was compared with a 29 gene panel utilizing duplex sequencing (DS), an NGS method that generates double-stranded consensus sequences to reduce false positive errors. Using DS, detection of a persistent mutation utilizing defined criteria was seen in 22 (35%) patients and was strongly associated with higher rates of relapse (68% vs 13% at year 5; HR, 8.8; 95% CI, 3.2-24.5; P<0.001) and decreased survival (32% vs 82% at year 5; HR, 5.6; 95% CI, 2.3-13.8; P<0.001). MRD as defined by DS strongly outperformed MFC, which was observed in 10 (16%) patients and marginally associated with higher rates of relapse (50% vs 30% at year 5; HR, 2.4; 95% CI, 0.9-6.7; P=0.087) and decreased survival (40% vs 68% at year 5; HR, 2.5; 95% CI, 1.0-6.3; P=0.059). Furthermore, the prognostic significance of DS MRD status at the time of remission was similar on both randomized arms of the trial, predicting S0106 clinical trial outcomes. These findings suggest that DS is a powerful tool that could be used in patient management and for early treatment assessment in clinical trials.

Background: Studies have not systematically compared the ability to verify performance of prognostic transcripts in paired bulk mononuclear cells versus viable CD34-expressing leukemic blasts from patients with acute myeloid leukemia. We hypothesized that examining the homogenous leukemic blasts will yield different biological information and may improve prognostic performance of expression biomarkers., Methods: To assess the impact of cellular heterogeneity on expression biomarkers in acute myeloid leukemia, we systematically examined paired mononuclear cells and viable CD34-expressing leukemic blasts from SWOG diagnostic specimens. After enrichment, patients were assigned into discovery and validation cohorts based on availability of extracted RNA. Analyses of RNA sequencing data examined how enrichment impacted differentially expressed genes associated with pre-analytic variables, patient characteristics, and clinical outcomes., Results: Blast enrichment yielded significantly different expression profiles and biological pathways associated with clinical characteristics (e.g., cytogenetics). Although numerous differentially expressed genes were associated with clinical outcomes, most lost their prognostic significance in the mononuclear cells and blasts after adjusting for age and ELN risk, with only 11 genes remaining significant for overall survival in both cell populations (CEP70, COMMD7, DNMT3B, ECE1, LNX2, NEGR1, PIK3C2B, SEMA4D, SMAD2, TAF8, ZNF444). To examine the impact of enrichment on biomarker verification, these 11 candidate biomarkers were examined by quantitative RT/PCR in the validation cohort. After adjusting for ELN risk and age, expression of 4 genes (CEP70, DNMT3B, ECE1, and PIK3CB) remained significantly associated with overall survival in the blasts, while none met statistical significance in mononuclear cells., Conclusions: This study provides insights into biological information gained/lost by examining viable CD34-expressing leukemic blasts versus mononuclear cells from the same patient and shows an improved verification rate for expression biomarkers in blasts., (© 2023. The Author(s).)

Asparaginase is a key component of pediatric-inspired regimens in young adults with acute lymphoblastic leukemia (ALL). Truncation of asparaginase therapy is linked to inferior outcomes in children with ALL. However, a similar correlation in adults is lacking. Here, we studied the prevalence and risk factors associated with pegylated (PEG)-asparaginase discontinuation in young adults with ALL treated on the US intergroup Cancer and Leukemia Group B (CALGB) 10403 study and examined the prognostic impact of early discontinuation (ED) (defined as <4 of 5 or 6 planned doses) on survival outcomes. The analysis included 176 patients who achieved complete remission and initiated the delayed intensification (DI) cycle. The median number of PEG-asparaginase doses administered before DI was 5 (range, 1-6), with 57 (32%) patients with ED. The ED patients were older (median, 26 vs 23 years; P = .023). Survival was apparently lower for ED patients compared with those receiving ≥4 doses, but this finding was not statistically significant (hazard ratio [HR], 1.82; 95% confidence interval [CI], 0.97-3.43; P = .06), with corresponding 5-year overall survival (OS) rates of 66% and 80%, respectively. In patients with standard-risk ALL, the ED of PEG-asparaginase adversely influenced OS (HR, 2.3; 95% CI, 1.02-5.22; P = .04) with a trend toward inferior event-free survival (EFS) (HR, 1.84; 95% CI, 0.92-3.67; P = .08). In contrast, there was no impact of early PEG-asparaginase discontinuation on OS (P = .64) or EFS (P = .32) in patients with high-risk disease based on the presence of high-risk cytogenetics, Ph-like genotype, and/or high white blood cell count at presentation. In conclusion, early PEG-asparaginase discontinuation is common in young adults with ALL and may adversely impact survival of patients with standard-risk ALL., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

We have previously shown that complete response (CR) rates and overall survival of patients with acute myeloid leukemia have improved since the 1980s. However, we have not previously evaluated how the length of first CR (CR1) has changed over this time period. To address this, we analyzed 1,247 patients aged 65 or younger randomized to "7+3" arms from five SWOG studies: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), and S1203 (n=261). We evaluated length of CR1 and survival after relapse from CR1 over the four decades that these studies represent. Both length of CR1 and survival after relapse from CR1 have improved over the last four decades. The relative benefit associated with CR1 and the relative detriment associated with relapse have decreased over this period; while achieving CR1 and relapse from CR1 still have strong prognostic associations with outcomes, the magnitude of the association has decreased over time. Possible explanations for these patterns include higher CR rates with salvage therapies after relapse, more frequent use of hematopoietic cell transplant, and better supportive care.

In this secondary analysis of Hispanic adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated on Cancer and Leukemia Group B (CALGB) 10403, we evaluated outcomes and geographic enrollment patterns relative to US population data. We used demographic, clinical, and survival data on AYAs enrolled on CALGB 10403 (N = 295, 2007-2012). Surveillance, Epidemiology, and End Results registries provided overall survival (OS) for US AYA ALL by ethnicity/race. North American Association of Cancer Registries provided AYA ALL incidence overall and proportion among Hispanics by US state. Of AYAs enrolled on CALGB 10403, 263 (89%) reported ethnicity/race: 45 (17%) Hispanic, 172 (65%) non-Hispanic White (NHW), 25 (10%) non-Hispanic Black (NHB), and 21 (8%) other. Compared with NHWs, Hispanic and NHB patients had lower household income, and Hispanic patients were more likely to harbor high-risk CRLF2 aberrations. Relative to US estimates, where Hispanic patients represented 46% of newly diagnosed AYA ALL patients and experienced inferior OS compared with NHW (P < .001), Hispanic AYAs on CALGB 10403 did as well as NHW patients (3 year OS, 75% vs 74%; P = NS). Hispanic patients also had higher rates of protocol completion (P = .05). Enrollments on CALGB 10403 differed relative to the distribution of Hispanic AYA ALL in the United States: enrollment was highest in the Midwest; t and only 15% of enrollees were from states with a high proportion of Hispanic AYA ALL patients. In summary, Hispanic patients treated on CALGB 10403 did as well as NHWs and better than population estimates. Geographical misalignment between trial sites and disease epidemiology may partially explain the lower-than-expected enrollment of Hispanic AYA ALL patients., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome-negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population., Patients and Methods: Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome-negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis., Results: Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively., Conclusion: Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome-negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored., Competing Interests: Anjali S. AdvaniHonoraria: PfizerConsulting or Advisory Role: Novartis, GlycoMimetics, Kite, a Gilead company, Seattle Genetics, Amgen, Beam Therapeutics, Jazz Pharmaceuticals, Nkarta, Taiho OncologyResearch Funding: Pfizer (Inst), Millennium (Inst), KaloBios (Inst), Seattle Genetics (Inst), AbbVie (Inst), GlycoMimetics (Inst), MacroGenics (Inst), Pfizer (Inst), Amgen (Inst), Trillium Therapeutics (Inst), Seattle Genetics (Inst), Immunogen (Inst), SERVIER (Inst), Kite/Gilead (Inst), Incyte (Inst), OBI Pharma (Inst) Anna MoseleyConsulting or Advisory Role: BioSight Kristen M. O'DwyerConsulting or Advisory Role: Beam Therapeutics Brent L. WoodHonoraria: Amgen, Seattle Genetics, AbbVie, Janssen, Amgen, Astellas Pharma, Roche Diagnostics, Beckman CoulterConsulting or Advisory Role: SysmexResearch Funding: Amgen (Inst), Seattle Genetics (Inst), Pfizer (Inst), Juno Therapeutics (Inst), BioLineRx (Inst), BioSight (Inst), Stemline Therapeutics (Inst), Janssen Oncology (Inst), Novartis, Kite, a Gilead company (Inst), MacroGenics (Inst)Travel, Accommodations, Expenses: Amgen, Amgen Min FangConsulting or Advisory Role: UnityDxResearch Funding: Nucleix (Inst) Matthew J. WieduwiltStock and Other Ownership Interests: Reata PharmaceuticalsHonoraria: Gilead Sciences, ServierConsulting or Advisory Role: Gilead Sciences, ServierResearch Funding: NCI (Inst)Travel, Accommodations, Expenses: Gilead Sciences Ibrahim AldossHonoraria: Amgen, AbbVie, Kite, a Gilead company, Agios, Jazz PharmaceuticalsConsulting or Advisory Role: AmgenSpeakers' Bureau: PfizerResearch Funding: AbbVie, MacroGenics Jae H. ParkConsulting or Advisory Role: Amgen, Novartis, Pfizer, Kite, a Gilead company, Autolus, Takeda, Servier, Incyte, Intellia Therapeutics, Innate Pharma, Artiva, Bristol Myers Squibb/Celgene/Juno, Kura Oncology, Kura Oncology, Kura Oncology, Minerva Biotechnologies, Precision Biosciences, AffyImmune Therapeutics, BeiGeneResearch Funding: Juno Therapeutics (Inst), Genentech/Roche (Inst) Rebecca B. KlisovicConsulting or Advisory Role: Novartis, Visante, AbbVie, Bristol Myers Squibb, PfizerResearch Funding: Pfizer, ARIAD, Bristol Myers Squibb, Avillion, NovartisTravel, Accommodations, Expenses: Novartis Maria R. BaerResearch Funding: AbbVie (Inst), FORMA Therapeutics (Inst), Kite, a Gilead company (Inst), Takeda (Inst), Kura Oncology (Inst), Ascentage Pharma (Inst) Wendy StockHonoraria: Amgen, PfizerConsulting or Advisory Role: Agios, Amgen, Astra Zeneca, Beam, Glaxo Smith Kline, Jazz, Kite, Kronos, Kura, Morphosys, Newave, Pfizer, Pluristem, Servier, SyndaxPatents, Royalties, Other Intellectual Property: Royalties for a chapter in UpToDate Megan OthusConsulting or Advisory Role: GlycoMimetics, Cascadia Labs, Merck, Daiichi Sankyo, BioSightOther Relationship: Celgene, GlycoMimetics Cheryl L. WillmanPatents, Royalties, Other Intellectual Property: I have three patents for genomic diagnostics. They are all held by the University of New Mexico and have been licensed by TriCore Reference Laboratories. One generates minimal annual royalties (< $5,000 US dollars) Mark R. LitzowConsulting or Advisory Role: Omeros, Jazz PharmaceuticalsResearch Funding: Amgen, Astellas Pharma, Actinium Pharmaceuticals, Pluristem Therapeutics, AbbVie/Genentech, Tolero Pharmaceuticals, AbbVieOther Relationship: BioSight Richard M. StoneHonoraria: Prime Oncology, Medscape, Research to Practice, DAVA PharmaceuticalsConsulting or Advisory Role: Amgen, AbbVie, Agios, Celgene, Novartis, Actinium Pharmaceuticals, Arog, Astellas Pharma, MacroGenics, Takeda, BioLineRx, Daiichi-Sankyo, Trovagene, GEMoaB, Syntrix Biosystems, ElevateBio, Syndax, Syros Pharmaceuticals, BerGenBio, Janssen, Innate Pharma, Foghorn Therapeutics, Aprea Therapeutics, GlaxoSmithKline, CTI BioPharma Corp, Bristol Myers Squibb, Boston Pharmaceuticals, Onconova Therapeutics, Jazz PharmaceuticalsResearch Funding: Novartis (Inst), Agios (Inst), AbbVie/Genentech (Inst) Harry P. ErbaConsulting or Advisory Role: Agios, Astellas Pharma, Amgen, Celgene, Daiichi Sankyo, GlycoMimetics, Immunogen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, AbbVie/Genentech, Janssen Oncology, Pfizer, Trillium Therapeutics, Takeda, Kura OncologySpeakers' Bureau: Agios, Celgene, Incyte, Jazz Pharmaceuticals, Novartis, AbbVie/GenentechResearch Funding: AbbVie, Agios (Inst), Amgen (Inst), Daiichi Sankyo (Inst), FORMA Therapeutics (Inst), Gilead/Forty Seven (Inst), Immunogen (Inst), Jazz Pharmaceuticals (Inst), MacroGenics (Inst), Novartis (Inst), PTC Therapeutics (Inst), AbbVie (Inst), GlycoMimetics (Inst), ALX Oncology (Inst)Other Relationship: GlycoMimetics, CelgeneUncompensated Relationships: Daiichi SankyoNo other potential conflicts of interest were reported.

Introduction: The presence of ring sideroblasts (RS) and mutation of the SF3B1 gene are diagnostic of lower-risk (LR) myelodysplastic syndromes (MDS) and are correlated with favorable outcomes. However, information on testing and reporting in community-based clinical settings is scarce. This study from the Connect ® MDS/AML Disease Registry aimed to compare the frequency of RS and SF3B1 reporting for patients with LR-MDS, before and after publication of the 2016 World Health Organization (WHO) MDS classification criteria., Methods: Ring sideroblasts assessment and molecular testing data were collected from patients with LR-MDS at enrollment in the Registry. Patients enrolled between December 2013 and the data cutoff of March 2020 were included in this analysis., Results: Among 489 patients with LR-MDS, 434 (88.8%) underwent RS assessment; 190 were assessed prior to the 2016 WHO guidelines (Cohort A), and 244 after (Cohort B). In Cohort A, 87 (45.8%) patients had RS identified; 29 (33.3%) patients had RS < 15%, none of whom underwent molecular testing for SF3B1. In Cohort B, 96 (39.3%) patients had RS identified; 31 (32.3%) patients had < 15% RS, with 13 undergoing molecular testing of which 10 were assessed for SF3B1., Conclusions: In the Connect ® MDS/AML Registry, only 32% of patients with <15% RS underwent SF3B1 testing after the publication of the WHO 2016 classification criteria. There was no change in RS assessment frequency before and after publication, despite the potential impact on diagnostic subtyping and therapy selection, suggesting an unmet need for education to increase testing rates for SF3B1 mutations., (© 2020 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956., (© 2021 by The American Society of Hematology.)

Objectives: Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) represents a high-risk and somewhat diverse subtype of AML, and substantial confusion exists about the pathologic evaluation needed for diagnosis, which can include the patient's clinical history, cytogenetic analysis, mutational analysis, and/or morphologic evaluation. Treatment decisions based on incomplete or untimely pathology reports may result in the suboptimal treatment of patients with AML-MRC., Methods: Using a PubMed search, diagnosis of and treatment options for AML-MRC were investigated., Results: This article reviews the current diagnostic criteria for AML-MRC, provides guidance on assessments necessary for an AML-MRC diagnosis, summarizes clinical and prognostic features of AML-MRC, and discusses potential therapies for patients with AML-MRC. In addition to conventional chemotherapy, treatment options include CPX-351, a liposomal encapsulation of daunorubicin/cytarabine approved for treatment of adults with AML-MRC; targeted agents for patients with certain mutations/disease characteristics; and lower-intensity therapies for less fit patients., Conclusions: Given the evolving and complex treatment landscape and the high-risk nature of the AML-MRC population, a clear understanding of the pathology information necessary for AML-MRC diagnosis has become increasingly important to help guide treatment decisions and thereby improve patient outcomes., (© American Society for Clinical Pathology, 2020.)

Patients with high-risk acute promyelocytic leukemia (APL) have inferior outcomes compared with patients with low-risk APL, predominantly due to higher risk of early mortality related to hemorrhage. The majority of regimens contain prolonged maintenance, but the impact of this phase is not clear in the era of all trans retinoic acid (ATRA) and arsenic trioxide (ATO). We present a retrospective analysis of 10 patients that were treated for high risk APL based on the consolidation treatment phase of APL 0406 study without subsequent maintenance. With a median follow up of 38 months, all patients remain in remission., Competing Interests: Declaration of Competing Interest H.P.E. reports honoraria from Agios, Celgene, Incyte, Jazz, and Novartis for speaker bureau participation. He has served as a paid consultant for Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, Immunogen, Incyte, Jazz, MacroGenics, Novartis, Pfizer, and Seattle Genetics. He has received fees from Covance as Chair of the Independent Review Committee of the AbbVie-sponsored VIALE-A and VIALE-C phase III studies. The other authors declare no conflicts of interest., (Copyright © 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Background: The recently updated European LeukemiaNet risk stratification guidelines combine cytogenetic abnormalities and genetic mutations to provide the means to triage patients with acute myeloid leukemia for optimal therapies. Despite the identification of many prognostic factors, relatively few have made their way into clinical practice., Methods: In order to assess and improve the performance of the European LeukemiaNet guidelines, we developed novel prognostic models using the biomarkers from the guidelines, age, performance status and select transcript biomarkers. The models were developed separately for mononuclear cells and viable leukemic blasts from previously untreated acute myeloid leukemia patients (discovery cohort, N  = 185) who received intensive chemotherapy. Models were validated in an independent set of similarly treated patients (validation cohort, N  = 166)., Results: Models using European LeukemiaNet guidelines were significantly associated with clinical outcomes and, therefore, utilized as a baseline for comparisons. Models incorporating age and expression of select transcripts with biomarkers from European LeukemiaNet guidelines demonstrated higher area under the curve and C-statistics but did not show a substantial improvement in performance in the validation cohort. Subset analyses demonstrated that models using only the European LeukemiaNet guidelines were a better fit for younger patients (age < 55) than for older patients. Models integrating age and European LeukemiaNet guidelines visually showed more separation between risk groups in older patients. Models excluding results for ASXL1 , CEBPA , RUNX1 and TP53 , demonstrated that these mutations provide a limited overall contribution to risk stratification across the entire population, given the low frequency of mutations and confounding risk factors., Conclusions: While European LeukemiaNet guidelines remain a critical tool for triaging patients with acute myeloid leukemia, the findings illustrate the need for additional prognostic factors, including age, to improve risk stratification., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Diagnostic and molecular genetic testing are key in advancing the treatment of acute myeloid leukemia (AML), yet little is known about testing patterns outside of clinical trials, especially in older patients. We analyzed diagnostic and molecular testing patterns over time in 565 patients aged ≥ 55 years with newly diagnosed AML enrolled in the Connect ® MDS/AML Disease Registry (NCT01688011) in the United States. Diagnostic data were recorded at enrolment and compared with published guidelines. The percentage of bone marrow blasts was reported for 82.1% of patients, and cellularity was the most commonly reported bone marrow morphological feature. Flow cytometry, karyotyping, molecular testing, and fluorescence in situ hybridization were performed in 98.8%, 95.4%, 75.9%, and 75.7% of patients, respectively. Molecular testing was done more frequently at academic than community/government sites (84.3% vs 70.2%; P  < .001). Enrolment to the Registry after 2016 was significantly associated with molecular testing at academic sites (odds ratio [OR] 2.59; P  = .023) and at community/government sites (OR 4.85; P  < .001) in logistic regression analyses. Better understanding of practice patterns may identify unmet needs and inform institutional protocols regarding the diagnosis of patients with AML., Competing Interests: DAP: AbbVie, Bristol‐Myers Squibb, Daiichi Sankyo – advisory board member and consultancy; Agios, Forty Seven, Pfizer – advisory board member; Takeda – consultancy; Glycomimetics – data safety and monitoring committee. TIG: Bristol‐Myers Squibb – consultancy; MA: Bristol‐Myers Squibb – advisory board, AbbVie, Bristol‐Myers Squibb, Gilead, Seattle Genetrix, Takeda – speaker panel; CRC, JPM, GGM: no conflicts to disclose; RB: AbbVie, Astex Daiichi Sankyo, Forty Seven, NeoGenomics – consultancy; Bristol‐Myers Squibb – consultancy, honoraria, research funding; Xian‐Janssen – honoraria; KF: Bristol‐Myers Squibb – advisory board member. DLG: AbbVie – consultancy; Alexion – speakers bureau; Astellas, Bristol‐Myers Squibb – advisory board member. RSK: Alexion, Jazz Pharmaceuticals, Novartis – speakers bureau; Agios, Bristol‐Myers Squibb, Daiichi Sankyo, Inc., Incyte, Janssen, Pfizer – consultancy. DAR: Allergan, Amgen, Bristol‐Myers Squibb, Takeda – research funding and consultancy. GJR: AbbVie, Actinum, Agios, Amphivena, Argenx, Astex, Astellas, Bayer, Bristol‐Myers Squibb, Celltrion, Daiichi Sankyo, Eisai, Janssen, Jazz Pharmaceuticals, Novartis, MEI Pharma, Orsenix, Otsuka, Pfizer, Roche/Genentech, Sandoz, Takeda, Trovgene – consultancy, advisory board or data and safety monitoring committee; Cellectis – research funding. MRS: AbbVie – advisory board member, consulting; Boehringer Ingelheim – patents and royalties; Bristol‐Myers Squibb, Selvita – advisory board member; Incyte – advisory board member, research funding; Karyopharm – advisory board member, consultancy, equity ownership; Sunesis – research funding; Takeda, TG Therapeutics – advisory board member, research funding. BLS: Agios – speakers bureau; Alexion, Bristol‐Myers Squibb – advisory board member, consultancy, speakers bureau; Incyte – advisory board member, speakers bureau; Novartis – research funding. MAS: Bristol‐Myers Squibb, Pfizer, Takeda/Millenium – consulting. MAT: Adaptive, Bristol‐Myers Squibb, Doximity, GlaxoSmithKline, Strata Oncology, Syapse Precision Medicine Council, VIA Oncology, UpToDate – consultancy; Doximity – equity; AbbVie, Bristol Myers‐Squibb, CRAB CTC, Denovo, Hoosier Research Network, Lilly, LynxBio, Stata Oncology, Takeda, TG Therapeutics – institutional research funding; SEK: Agios and Bristol‐Myers Squibb – consultancy. CUL, MN, ASS, PK: Bristol‐Myers Squibb ‐ equity and employment. EDF: Bristol‐Myers Squibb – employment. DPS: Astex, Bristol‐Myers Squibb, Onconova, Pfizer, StemLine, Summer Road, Takeda – consultancy. HPE: Agios, Bristol‐Myers Squibb, Jazz Pharmaceuticals, Incyte, Novartis – speakers bureau; AbbVie, Agios, Amgen, Astellas, Bristol‐Myers Squibb, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz, MacroGenics, Novartis, Pfizer, Seattle Genetics – consultancy; AbbVie, Daiichi Sankyo, ImmunoGen, Macrogenics – research funding; Glycomimetics – data safety and monitoring committee; Covance – independent review committee., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT., Methods: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1., Results: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 ( P < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [ P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months)., Conclusion: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.

High-risk acute promyelocytic leukemia (APL) remains a therapeutic challenge, with higher associated rates of early mortality and relapse than standard-risk APL. All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) is a well-established treatment for patients with standard-risk APL, but it is not well defined for those with high-risk APL. In a prior study of patients with high-risk APL, the addition of gemtuzumab ozogamicin (GO) to ATO plus ATRA suggested benefit. The SWOG Cancer Research Network conducted a phase 2 study to confirm the efficacy and safety of the combination of ATRA plus ATO plus GO in treating high-risk APL patients. The primary end points were 3-year event-free survival (EFS) and early (6-week) death rates associated with this combination. Seventy patients were treated. With a median follow-up of 3.4 years, the 3-year EFS and overall survival estimates were 78% (95% confidence interval [CI], 67%-86%) and 86% (95% CI, 75%-92%), respectively. Overall, 86% of patients achieved complete response. The 6-week mortality rate was 11%. The most common treatment-emergent toxicities during the induction phase included febrile neutropenia, aspartate aminotransferase/alanine aminotransferase elevation, hyperglycemia, hypoxia, headache, and prolonged QT interval corrected for heart rate. Retinoic acid syndrome occurred in 9% of patients. Approximately 37% of patients did not complete all planned courses of postremission therapy. The combination of ATRA plus ATO plus GO in high-risk APL patients was effective and generally well tolerated, suggesting an opportunity to offer a chemotherapy-free induction platform for patients with this disease. This trial was registered at www.clinicaltrials.gov as #NCT00551460., (© 2020 by The American Society of Hematology.)

Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839., (© 2020 by The American Society of Hematology.)

Introduction: Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic neoplasm. The cytogenetic changes associated with AML affect the response rate and survival and are one of the most important independent prognostic factors. AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM accounts for 1% to 2% of all forms of AML and has been associated with a younger age at diagnosis, a poor response to standard induction chemotherapy, and very poor long-term prognosis., Patients and Methods: We performed a single-center, retrospective cohort study comparing the outcomes with hypomethylating agent (HMA) plus lenalidomide to those with standard intensive induction therapies for newly diagnosed and relapsed/refractory AML with inv(3)., Results: Of the 15 patients, 4 (26.7%) had received lenalidomide and HMA as primary therapy. The overall response rate (ORR) was 100% for the 4 patients who had received lenalidomide with HMA as first-line induction therapy. The ORR was 27.3% (3 of 11) for the patients who had received other induction regimens (P = .0256). The duration of response for first induction therapy was an average of 7.4 months after lenalidomide plus an HMA and a mean of 1.5 months after induction with other chemotherapy regimen (P = .057). The ORR for induction and reinduction therapy was also assessed, with an ORR of 21.4% (6 of 28) for alternative chemotherapy regimens and an ORR of 75% (6 of 8) for induction and reinduction with lenalidomide plus HMA (P = .0046)., Conclusions: The high ORR and reasonable duration of response could allow for potentially curative allogeneic hematopoietic cell transplantation for these patients with high-risk AML. Our initial data suggest that lenalidomide plus HMA is a promising approach for patients with AML with inv(3)., (Copyright © 2019. Published by Elsevier Inc.)

The preferred post-remission therapy for older patients with acute myeloid leukemia (AML) in first complete remission (CR1) remains uncertain. In this retrospective, multicenter study, we compared the outcomes for older AML patients (age 60-77 years) receiving allogeneic hematopoietic cell transplantation (alloHCT) (n = 431) with those treated on prospective National Clinical Trials Network induction and nontransplantation chemotherapy (CT) consolidation trials (n = 211). AlloHCT patients were younger (median age: 64.2 versus 67.9 years, p < 0.001), but more frequently had high-risk AML (high WBC, secondary AML, and unfavorable cytogenetics). Overall survival (OS) was worse in alloHCT during the first 9 months after CR1 (HR = 1.52, p = 0.02), but was significantly better thereafter (HR = 0.53, p < 0.0001) relative to CT. Treatment-related mortality (TRM) following HCT was worse in the first 9 months (HR = 2.8, 95% CI: 1.5-5.2, p = 0.0009), while post-HCT relapse was significantly less frequent beyond 9 months (HR = 0.42, 95% CI: 0.29-0.61, p < 0.0001). Despite higher early TRM, alloHCT recipients had superior long-term OS [29% (24-34%) versus CT 13.8% (9-21%) at 5 years]. Although this is a retrospective analysis with potential biases, it indicates that alloHCT led to heightened early risks from TRM, yet reduced relapse and superior long-term survival relative to CT in older AML patients in CR1.

Background: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene ( FLT3 ) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3 -mutated AML., Methods: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3 -mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission., Results: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%)., Conclusions: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3 -mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.)., (Copyright © 2019 Massachusetts Medical Society.)

This open-label, phase 1 study evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 232, an investigational oral, selective mouse double minute 2 homolog inhibitor in relapsed/refractory acute myeloid leukemia (AML). AMG 232 was administered orally once daily for 7 days every 2 weeks (7 on/off) at 60, 120, 240, 360, 480, or 960 mg as monotherapy (arm 1) or at 60 mg with trametinib 2 mg (arm 2). Dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics, clinical and pharmacodynamic response, and expression of p53 target genes were assessed. All 36 patients received AMG 232. No DLTs occurred in arm 1, and 360 mg was the highest test dose; dose escalation was halted due to gastrointestinal AEs at higher doses. One of ten patients in arm 2 had a DLT (grade 3 fatigue); 60 mg was the highest dose tested with trametinib. Common treatment-related AEs (any grade) included nausea (58%), diarrhea (56%), vomiting (33%), and decreased appetite (25%). AMG 232 exhibited linear pharmacokinetics unaffected by coadministration with trametinib. Serum macrophage inhibitor cytokine-1 and bone marrow expression of BAX , PUMA , P21 , and MDM2 increased during treatment. Of 30 evaluable patients, 1 achieved complete remission, 4 had morphologic leukemia-free state, and 1 had partial remission. Four of 13 (31%) TP53 -wild-type patients and 0 of 3 (0%) TP53 -mutant patients were responders. AMG 232 was associated with gastrointestinal AEs at higher doses but had acceptable pharmacokinetics, on-target effects, and promising clinical activity warranting further investigation in patients with relapsed/refractory AML. This trial was registered at www.clinicaltrials.gov as #NCT02016729., (© 2019 by The American Society of Hematology.)

The treatment of acute myeloid leukemia has been associated with dismal outcomes despite available therapies. The morbidity and mortality associated with acute myeloid leukemia (AML) are most profound in older patients who account for the majority of cases. The 5-year survival of AML patients over age 65 years has remained 5% for decades. However, for the first time since the development of 7+3 induction chemotherapy in the 1970s, there is reason to believe that outcomes can and will improve. The understanding of the biology of AML has led to the development of targeted therapies that have shown great promise in this regard. Therapeutic interventions can lead to meaningful responses with improvement in hematopoietic function and much more acceptable toxicity profiles compared with intensive therapy. The therapeutic paradigms for older AML patients have shifted. Nevertheless, the diagnosis most often comes late in life, when patients are more likely to have impaired functional status and suffer from other comorbid illnesses. Therefore, the oncologist must be fully engaged with the patient, discussing goals of therapy and end-of-life issues, in a shared decision making process., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: To study whether institutional clinical trial accrual volume affects clinical outcomes of younger (age less than 61 years) patients with acute myeloid leukemia., Patients and Methods: We investigated the impact of clinical trial accrual on response rates, early mortality and survival in patients with AML enrolled between 2002 and 2009 into two parallel cooperative group clinical trials SWOG S0106/ECOG-ACRIN E1900. Institutions were classified as low- (LAIs) (≤ 9 enrolled patients) or high-accruing institutions (HAIs) (≥10 enrolled patients). Fisher's exact text and logistic regression analysis were used to analyze the response and early mortality rates. The effect of accrual volume on survival was analyzed by log-rank tests and Cox regression models., Results: A total of 1252 patients from 152 institutions were included in the final analyses. The median clinical trial registrations in HAIs was 19 patients (range, 10 to 92) versus 3 (range, 1 to 9) patients in LAIs. In multivariate analyses, HAIs, as a quantitative covariate, was associated with improved complete remission rates (odds ratio (OR) 1.08, p = 0.0051), but no improvement median overall survival (HR 0.97, p = 0.065) or median event-free (hazard ratio (HR) 0.97, p = 0.05). Early mortality rates were similar between cohorts and academic affiliation had no impact on response rates or survival., Conclusion: Clinical trial accrual volume, had an independent, albeit modest, impact on complete remission rates, but not on overall survival and event-free in younger patients with AML., (Copyright © 2019 Elsevier Ltd. All rights reserved.)