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In the randomized phase III IDHENTIFY trial, the IDH2 inhibitor enasidenib (ENA) showed improvement in event-free but not overall survival compared with conventional care regimens (CCR) among patients with relapsed/refractory (R/R), IDH2 -mutant AML. We constructed a partitioned survival model to evaluate the cost-effectiveness of enasidenib for the treatment of older patients with R/R, and  IDH2 -mutant AML. In the base-case scenario, ENA exhibited an incremental effectiveness of 0.234quality-adjusted life-years (QALYs) compared to CCR, and an incremental cost of $126,800, leading to an incremental cost-effectiveness ratio of $540,300/QALY(95% CI: $197,800-$4,777,000/QALY). In probabilistic sensitivity analysis, CCR was favored in 99.8% of simulations. The cost of ENA would need to be decreased by 72% to be cost-effective at a willingness-to-pay threshold of $150,000/QALY. Our findings suggest that ENA is unlikely to be a cost-effective treatment for older patients with IDH2- mutant R/R AML under current pricing.

Clinical trials are crucial for improving patient outcomes. Although a significant number of trials are discontinued prematurely, our understanding of factors influencing early termination is limited. We conducted a comprehensive search of ClinicalTrials.gov to identify leukemia trials from 2000 to 2020, followed by data abstraction performed by two independent reviewers. Among 3522 leukemia clinical trials identified, 28.4% were terminated prematurely. Slow accrual was the leading cause of termination 38.2%. The termination rate increased significantly from 17.0% between 2000 and 2005 to 30.9% between 2010 and 2015 ( p  < .001). Large trials had a lower termination rate than small trials ( p  < .001). Academic-sponsored trials had the highest termination rates compared to other sponsors' trials ( p  < .001). Early-phase trials showed higher termination rates compared to late-phase ( p  < .001). Other significant factors included a sequential assignment, single-center, and non-randomized trials ( p  < .001). Much of leukemia trials are terminated prematurely, with slow accrual being the most common reason for early termination.

We investigated immune cytopenia in multiple myeloma (MM) patients with concurrent acquired aplastic anemia (AA), focusing on three clinical cases treated with plasma cell-directed therapy. All three patients achieved partial response in MM and one patient experienced complete resolution of AA. Two patients had partial improvement in transfusion requirement but continued to suffer from severe AA, leading to immunosuppressive therapy (IST) with improvement of transfusion requirement in both patients. In vitro serum testing of these patients demonstrated platelet mitochondrial dysfunction and platelet apoptosis but did not show sera-specific inhibition of erythroid colony formation in progenitor cells. The levels of IL8 and IL15 were elevated in MM patients with AA, implicating their potential roles in this co-occurrence. Response to IST points to the possibility of myeloma-dysregulated immune system leading to autoreactive T-cell destruction of hematopoietic stem and progenitor cells, offering insights for developing new treatment for cytopenia in MM.

Tyrosine kinase inhibitors (TKIs) have significantly improved the survival of patients with chronic myeloid leukemia (CML), however, older patients are often underrepresented in pivotal trials. Approximately 20% of older adults never start treatment and face significant barriers to accomplish favorable outcomes. The treatment goal is to improve survival, prevent progression, and preserve quality of life. This is achieved through optimizing TKI doses and employing discontinuation strategies to attain treatment-free remission (TFR), a goal increasingly pursued by older patients. Imatinib may be favored as the front-line option for older individuals due to its side effect profile and cost. Bosutinib's favorable cardiovascular tolerability makes it a suitable second-line agent, but lower-dose dasatinib may likewise be an attractive option. The prevalence of comorbidities can preclude the use of second generation TKIs in some older patients. Optimal care for older patients with CML centers on personalized treatment, close monitoring, and proactive support.

Introduction: Relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remains a therapeutic challenge. Preclinical data in both B- and T-ALL suggests synergy of venetoclax (VEN) with vincristine (VCR). We designed a phase I/II trial (EA9152) of the combination of L-VCR and VEN for patients with r/r B-or T-cell ALL or LL. Here, we report the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644)., Methods: In a 3+3 dose escalation design, r/r ALL subjects were given single-agent VEN doses reaching 400, 600, or 800 mg for the three respective dose levels. Weekly L-VCR at 2.25 mg/m 2 IV was started on D15 of cycle 1. The primary phase I objective was to determine the maximum tolerated dose (MTD) of the combination., Results: Among the 18 patients in phase I, grade ≥ 3 treatment-related adverse events were reported in 89% of treated patients. Two patients (two of three) at dose level 3 experienced dose-limiting toxicities. Therefore, the MTD of the combination was determined to be dose level 2 (VEN 600 mg). Twenty-two percent of evaluable patients ( N  = 4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD)., Conclusion: The combination of VEN and L-VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses. With the removal of L-VCR from the US market, the phase 2 portion of this trial is actively enrolling with vincristine sulfate., 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.)

The FLT3 inhibitor quizartinib has been shown to improve overall survival when added to intensive induction chemotherapy ("7 + 3") in patients 18-75 years old with newly diagnosed AML harboring a FLT3- ITD mutation. However, the health economic implications of this approval are unknown. We evaluated the cost-effectiveness of quizartinib using a partitioned survival analysis model. One-way and probabilistic sensitivity analyses were conducted. In the base case scenario, the addition of quizartinib to 7 + 3 resulted in incremental costs of $289,932 compared with 7 + 3 alone. With an incremental gain of 0.84 quality-adjusted life years (QALYs) with quizartinib + 7 + 3 induction vs. 7 + 3 alone, the incremental cost-effectiveness ratio for the addition of quizartinib to standard 7 + 3 was $344,039/QALY. Only an 87% reduction in the average wholesale price of quizartinib or omitting quizartinib continuation therapy after completion of consolidation therapy and allogeneic hematopoietic cell transplant would make quizartinib a cost-effective option.

In 2022, the American Council for Graduate Medical Education (ACGME) recommended that core faculty (CF) in medical subspecialty fellowships receive at least 0.1 full-time equivalent (FTE) salary support, with plans to enforce compliance in July 2023. After early feedback raised concerns about potential unintended consequences, ACGME deferred enforcement to July 2024. Hence, there is an urgent need to understand the ramifications of providing FTE support for CF. In 2020, the Yale hematology and medical oncology (HO) fellowship program began providing 0.1 FTE support to all CF. Perceptions regarding this were assessed via surveys distributed to all CF in 2021 and 2022 and to all HO fellows in 2021. The vast majority (83.3%) of CF survey respondents reported improved job satisfaction and an increased sense of involvement in the fellowship program as a result of the new 0.1 FTE-supported CF program. Most CF increased attendance at fellowship conferences, devoted more time to mentorship, and increased participation in recruitment. In free text comments, CF respondents described that providing 0.1 FTE support made them "feel rewarded," gave them "a sense of commitment" to the fellowship, and helped "offset clinical requirements." HO fellows reported "a positive impact" of the new program with faculty being "more present at lectures." The median number of times faculty were available to interview fellowship applicants rose markedly after introduction of the program. The FTE-supported CF program was viewed enthusiastically by fellows and faculty, resulting in increased CF involvement in fellowship education and recruitment., (© 2024. The Author(s) under exclusive licence to American Association for Cancer Education.)

Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic ≥G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.)

Purpose: Gilteritinib is a type 1 FLT3 inhibitor active as monotherapy for relapsed or refractory FLT3 -mutated AML. We investigated the safety, tolerability, and efficacy of gilteritinib incorporated into intensive induction and consolidation chemotherapy, and as maintenance therapy for adult patients with newly diagnosed, non-favorable-risk AML., Methods: In this phase IB study (2215-CL-0103; ClinicalTrials.gov identifier: NCT02236013), 103 participants were screened and 80 were allocated to treatment. The study was divided into four parts: dose escalation, dose expansion, investigation of alternate anthracycline and gilteritinib schedule, and continuous gilteritinib during consolidation., Results: After dose escalation, 120 mg gilteritinib once daily was chosen for further study. There were 58 participants evaluable for response at this dose, 36 of whom harbored FLT3 mutations. For participants with FLT3 -mutated AML, the composite complete response (CRc) rate was 89% (83% were conventional complete responses), all achieved after a single induction cycle. The median overall survival time was 46.1 months. Gilteritinib was well-tolerated in this context although the median time to count recovery during induction was approximately 40 days. Longer time-to-count recovery was associated with higher trough levels of gilteritinib, which, in turn, were associated with azole use. The recommended regimen is gilteritinib at a dose of 120 mg once daily from days 4 to 17 or 8 to 21 of a 7 + 3 induction with either idarubicin or daunorubicin and from day 1 continuously with high-dose cytarabine consolidation. Maintenance therapy with gilteritinib was well-tolerated., Conclusion: These results demonstrated the safety and tolerability of gilteritinib incorporated into an induction and consolidation chemotherapy regimen, and as single-agent maintenance therapy for patients with newly diagnosed FLT3 -mutant AML. The data herein provide an important framework for the design of randomized trials comparing gilteritinib with other FLT3 inhibitors.

Background: Polycythemia vera (PV) and essential thrombocythemia (ET) are linked to increased risk of cardiovascular morbidity and mortality. In addition to the reduction in of arterial thrombotic events, statins may prevent venous thrombosis including among patients with cancer. As previous registry- and claims-based studies revealed that the use of statins may improve the survival of patients with various malignancies we evaluated their impact on outcomes of older adults with PV and ET., Methods: We identified 4010 older adults (aged 66-99 years at diagnosis) with PV (n = 1809) and ET (n = 2201) in a population-based cohort study using the Surveillance, Epidemiology, and End Results-Medicare database with median follow-up of 3.92 (interquartile range: 2.58-5.75) years. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) approaches were utilized to assess potential association between statins and overall survival. Multivariable competing risk models with death as a competing risk were used to evaluate possible relationship between statins and the incidence of thrombosis., Results: 55.8% of the patients used statins within the first year after PV/ET diagnosis, and statin use was associated with a 22% reduction in all-cause mortality (PSM: hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.63-0.98, p = 0.03; IPTW: HR = 0.79, 95% CI: 0.64-0.97, p = 0.03). Statins also reduced the risk of thrombosis in this patient population (PSM: HR = 0.63, 95% CI: 0.51-0.78, p < 0.01; IPTW: HR = 0.57, 95% CI: 0.49-0.66, p < 0.01) as well as in PV and ET subgroups., Conclusions: These findings suggest that it may be important to incorporate statins into the therapeutic strategy for older adults with PV and ET., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Tyrosine kinase inhibitor (TKI) use is critical in the care of patients with chronic myeloid leukemia (CML). Quantitative polymerase chain reaction (qPCR) testing for BCR-ABL1 every 3 months during the first year of TKI treatment is recommended to assure achievement of milestone response goals. Real-world evidence for the patterns of qPCR monitoring and TKI adherence in the older patient population is lacking. Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 1192 patients aged ≥66 years (median age, 74 years) with newly diagnosed CML who were followed up for ≥13 months from TKI initiation. In total, 965 patients (81.0%) had ≥1 test, with 425 (35.7%) and 540 (45.3%) of the patients tested during 1, 2, and ≥3 quarters (optimal monitoring) of the first year from TKI initiation, respectively. In multivariable analysis, diagnosis in later years and influenza vaccination before diagnosis, a proxy for health care access, were associated with optimal qPCR monitoring. Use of low-income subsidy and residing in census tracts with the lowest socioeconomic status were associated with less optimal monitoring. Patients with optimal monitoring were 60% more likely to be TKI adherent (odds ratio, 1.60; 95% CI, 1.11-2.31; P = .01) and had improved 5-year survival (hazard ratio, 0.66; 95% CI, 0.49-0.90; P < .01) than those without such monitoring. In this large, real-world study of CML management patterns, many older patients had suboptimal molecular monitoring, which was associated with decreased TKI adherence and worse survival., (© 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.)

Abstract: Myelodysplastic syndromes are a heterogeneous group of bone marrow disorders characterized by ineffective hematopoiesis, progressive cytopenias, and an innate capability of progressing to acute myeloid leukemia. The most common causes of morbidity and mortality are complications related to myelodysplastic syndromes rather than progression to acute myeloid leukemia. Although supportive care measures are applicable to all patients with myelodysplastic syndromes, they are especially essential in patients with lower-risk disease who have a better prognosis compared with their higher-risk counterparts and require longer-term monitoring of disease and treatment-related complications. In this review, we will address the most frequent complications and supportive care interventions used in patients with myelodysplastic syndromes, including transfusion support, management of iron overload, antimicrobial prophylaxis, important considerations in the era of COVID-19 (coronavirus infectious disease 2019), role of routine immunizations, and palliative care in the myelodysplastic syndrome population., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myelogenous leukemia (AML) in the phase 3 ADMIRAL trial. In this study, we assessed survival and relapse rates of patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received post-transplantation gilteritinib maintenance therapy. ADMIRAL was a global phase 3 randomized controlled trial that enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or to preselected high- or low-intensity salvage chemotherapy (1 or 2 cycles). Patients in the gilteritinib arm who proceeded to HSCT could receive post-transplantation gilteritinib maintenance therapy if they were within 30 to 90 days post-transplantation and had achieved composite complete remission (CRc) with successful engraftment and no post-transplantation complications. Adverse events (AEs) during HSCT were recorded in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent AEs were evaluated in patients who restarted gilteritinib as post-transplantation maintenance therapy. Patients in the gilteritinib arm underwent HSCT more frequently than those in the chemotherapy arm (26% [n = 64] versus 15% [n = 19]). For all transplantation recipients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplantation CRc, post-transplantation survival was comparable in the 2 arms. Patients who resumed gilteritinib after HSCT had a low relapse rate after pretransplantation CRc (20%) or CR (0%). The most common AEs observed with post-transplantation gilteritinib therapy were increased alanine aminotransferase level (45%), pyrexia (43%), and diarrhea (40%); grade ≥3 AEs were related primarily to myelosuppression. The incidences of grade ≥III acute graft-versus-host disease and related mortality were low. Post-transplantation survival was similar across the 2 study arms in the ADMIRAL trial, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as post-transplantation maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplantation-eligible patients., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Patients with classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary and secondary myelofibrosis (MF), are known to have an increased risk of second malignancies (SMs). Hydroxyurea (HU) is a guideline-recommended cytoreductive therapy for patients at high risk for MPNs. Controversy exists as to whether HU use is associated with a higher risk of SMs, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We conducted a retrospective cohort study of older patients diagnosed with MPN (age ≥66 years) between 2010 and 2017 and included the data in the Surveillance, Epidemiology, and End Results Medicare-linked database. Multivariable competing risk analyses adjusting for patient characteristics were used to assess the impact of HU on the development of SM. We identified 4023 patients (1688 with PV, 1976 with ET, and 359 with MF) with a median age of 77 (interquartile range [IQR], 71-83) years at the time of MPN diagnosis. After a median follow-up of 3.25 (IQR, 2.10-5.00) years, 489 patients developed an SM (346 solid, 73 lymphoid, and 70 myeloid malignancies). The cumulative incidence probability of SM was 19.88% (95% confidence interval [CI], 17.16%-22.75%) among 2683 HU users and 22.31% (95% CI, 17.51%-27.47%) among 1340 nonusers, respectively (Gray's test, P < .01). We did not identify significant differences in the incidence of solid or hematologic SMs, including AML/MDS (hazard ratio, 1.33; 95% CI, 0.77-2.29; P = .30), between HU users and nonusers. Our results suggest that the use of HU does not increase the risk of SM in older patients with MPN., (© 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.)

Ivosidenib + azacitidine (IVO/AZA) is approved in the United States for newly diagnosed, older or intensive chemotherapy-ineligible patients with IDH1 -mutated acute myeloid leukemia. We created a partitioned survival analysis model to evaluate the health economic implications of this approval. Model outputs were used to calculate the incremental cost-effectiveness ratio (ICER) of IVO/AZA versus AZA. One-way and probabilistic sensitivity analyses were conducted. In the base case scenario, IVO/AZA and AZA resulted in life-time costs of $403,062 and $161,887, respectively. With an incremental gain of 0.95 QALYs, the ICER of IVO/AZA was $252,782/QALY. In sensitivity analyses, only a reduction in the price of IVO by 59.3% lowered the ICER to below $150,000/QALY and 99.95% of model calculations yielded ICERs of >$150,000/QALY. In a model in which all patients received IVO monotherapy after progression on AZA monotherapy, the ICER was $155,453/QALY and various model inputs that would make IVO/AZA cost-effective were identified.

Biologic disease-modifying agents (bDMARDs) are highly effective in controlling the symptoms of autoimmune rheumatic diseases. The decision on whether to continue bDMARDs following a cancer diagnosis can be challenging for patients and physicians. Here, we describe a case of a middle-aged male with ankylosing spondylitis who was controlled on infliximab (IFX) and found to have a myeloid neoplasm with Platelet-Derived Growth Factor Receptor Beta rearrangement. The patient was started on a tyrosine kinase inhibitor imatinib. Given its significant positive effect on patient's quality of life, IFX was continued with a favorable outcome. This case highlights the importance of shared decisionmaking in balancing risks and benefits of immunosuppressants in appropriate cases of hematologic malignancy.

The phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation-positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P = .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.gov as #NCT02421939., (© 2022 by The American Society of Hematology.)

Acute promyelocytic leukemia (APL) is associated with a favorable long-term prognosis if appropriate treatment is initiated promptly. Outcomes in clinical trials and population-based registries vary; potential explanations include a delay in treatment and lower adherence to guideline-recommended therapy in real-world practice. We used the Vizient Clinical Data Base to describe demographic characteristics, baseline clinical characteristics, and treatment patterns in patients newly diagnosed with APL during the study period of April 2017 to March 2020. Baseline white blood cell count was used to assign risk status and assess treatment concordance with National Comprehensive Cancer Network guidelines. Logistic regression models examined adjusted associations between patient, hospital, disease characteristics, and adverse outcomes (in-hospital death or discharge to hospice). Among 1464 patients with APL, 205 (14.0%) experienced an adverse outcome. A substantial subset (20.6%) of patients did not receive guideline-concordant regimens. Odds of adverse outcomes increased with failure to receive guideline-concordant treatment (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.43-3.75; P = .001), high-risk disease (OR, 2.48; 95% CI, 1.53-4.00; P < .001), and increasing age (≥60 years: OR, 11.13; 95% CI, 4.55-27.22; P < .001). Higher hospital acute myeloid leukemia (AML) patient volume was associated with lower odds of adverse outcome (OR, 0.44; 95% CI, 0.20-0.99 [for ≤50 vs >200 AML patients per year]; P = .046). In conclusion, in this large database analysis, 14.0% of patients newly diagnosed with APL died or were discharged to hospice. A substantial proportion of patients did not receive guideline-concordant therapy, potentially contributing to adverse outcomes., (© 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.)

Background: Disease relapse remains the major cause of death among patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who receive an allogeneic hematopoietic cell transplant (allo-HCT). Maintenance treatment with FLT3 inhibitors and hypomethylating agents (HMA) has been studied in various clinical trials with mixed results., Objective: To synthesize the current evidence on the efficacy and safety of FLT3 inhibitors and HMA for maintenance therapy after allo-HCT in AML and MDS., Methods: For this systematic review and meta-analysis Cochrane Library, Google Scholar, Ovid Medline, Ovid Embase, PubMed, Scopus, and Web of Science Core Collection were searched from inception to March 2021 for studies on maintenance therapies after allo-HCT in AML and MDS. Studies were excluded if they were reviews, commentaries, case series with <5 patients, or basic research articles, not published in English, not on post-allo-HCT maintenance with FLT3 inhibitors or HMA in AML or MDS, or if they were clinical trials without published results or duplicate publications from the same patient cohort. Studies with insufficient reporting of the primary endpoint (2-year overall survival [OS]) and studies using FLT3 inhibitors or HMA for pre-emptive treatment of imminent relapse based on positive measurable residual disease testing were excluded. Random-effects models were used to pool response rates for the primary outcome of 2-year OS. Hazard ratios (HR) for death and relapse were calculated for studies that included a control group. Rates of relapse-free survival (RFS), non-relapse mortality, and acute and chronic graft-versus-host-disease (GVHD) were studied as secondary endpoints. Downs and Black checklist and risk of bias assessments were used to gauge the quality of individual studies. The study protocol has been registered on PROSPERO (CRD42020187298)., Results: Our search strategy identified 5559 studies. Twenty-one studies with a total of 809 patients were included in the meta-analysis. The 2-year OS rates were 81.7% (95% confidence interval [CI], 73.8%-87.7%) and 65.7% (95% CI, 55.1%-74.9%) among patients treated with FLT3 inhibitors and HMA, respectively. In sensitivity analyses restricted to studies that included a control group, maintenance therapy with FLT3 inhibitors (HR for death = 0.41; 95% CI, 0.26-0.62) or HMA (HR = 0.45; 95% CI, 0.31-0.66) appeared superior to no maintenance therapy. The 2-year RFS rates were 79.8% (95% CI, 75.0%-83.9%) and 62.4% (95% CI, 50.6%-72.9%) among patients treated with FLT3 inhibitors and HMA, respectively. Rates of any grade acute and chronic GVHD were 33.1% (95% CI, 25.4%-41.8%; grade 3/4: 16.5%) and 42.5% (95% CI, 26.3%-60.4%) among FLT3 inhibitor and 42.7% (95% CI, 33.5%-52.4%; grade 3/4: 8.1%) and 41.5% (95% CI, 32.0%-51.6%) among HMA-treated patients, respectively., Conclusion: Maintenance therapy with either FLT3 inhibitors or HMA after allo-HCT can lead to prolonged and improved OS and RFS with a favorable safety profile. Additional studies are needed to define the optimal duration of treatment, the role of measurable residual disease status, and transplant characteristics in patient selection., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The role of allogeneic hematopoietic cell transplant (allo-HCT) as consolidation after initial venetoclax therapy and the efficacy of venetoclax salvage therapy for relapse after allo-HCT in patients with acute myeloid leukemia (AML) are unclear. We conducted a retrospective study of patients with AML or myelodysplastic syndrome (MDS) who received venetoclax either before or after allo-HCT at Memorial Sloan Kettering Cancer Center and Yale University from 11 August 2016 to 16 November 2020. Among 39 heavily pretreated patients who received venetoclax before allo-HCT, median OS from allo-HCT was not reached after a median follow up of 12.5 months resulting in a 12-month OS estimate of 79.0%. In 37 patients who had received venetoclax-based combinations as salvage therapy after allo-HCT, the overall response rate was 32% with a median OS of 4.7 months (12-month OS estimate: 43.4%). Four patients underwent a second allo-HCT following venetoclax-based salvage therapy suggesting it as a potential salvage treatment option.

Introduction: The choice of BCR-ABL1 tyrosine kinase inhibitors (TKI) for the first line of therapy (LOT) for chronic-phase chronic myeloid leukemia (CML) is tailored to disease risk and patient characteristics like comorbidities, which become more prevalent with age. However, contemporary evaluations of frontline TKI choice and the factors associated with TKI switching in this specific patient population are lacking., Methods: We sought to describe TKI use in older patients (age: 66-99 years) with CML in the United States. Using the Surveillance, Epidemiology, and End Results-Medicare-linked database, we identified 810 older (median age: 75 years, interquartile range: 70-80 years) patients diagnosed during 2007-2015., Results: Imatinib was the most common frontline TKI (63.1%) throughout the study period, but its utilization as such decreased from 76% in 2010 to 47% in 2015. Most patients (65.3%) used only one TKI, but 12.5% of the 281 patients who switched from frontline TKI received ⩾4 LOT. Among the 167 patients switching from frontline imatinib, 18.6% eventually returned to imatinib with nearly all as the third LOT, supporting its favorable safety profile and indicating that the initial switch from imatinib might have been premature. Older patients within our cohort, white patients and those with greater comorbidity were less likely to switch from frontline TKI. Diagnosis year, geographic region, and surrogates for socioeconomic status and healthcare access had no impact on TKI switching., Conclusion: As expected, our findings highlight the frequent use of imatinib as the treatment option for older CML patients despite the availability of second-generation TKIs., Competing Interests: Conflict of interest statement: A.M.Z. received research funding (institutional) from Celgene, Acceleron, Abbvie, Otsuka, Pfizer, Medimmune/AstraZeneca, Boehringer Ingelheim, Trovagene, Incyte, Takeda, and ADC Therapeutics. A.M.Z. had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene, Ariad, Incyte, Agios, Boehringer Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Seattle Genetics, BeyondSpring, and Takeda. A.D. received research funding from Celgene Corp. N.A.P. consulted for and received honoraria from Alexion, Pfizer, Agios Pharmaceuticals, Blueprint Medicines, Incyte, Novartis, Celgene, Bristol Myers Squib (BMS), CTI BioPharma, and PharmaEssentia. N.A.P. received research funding (all to the institution) from Boehringer Ingelheim, Astellas Pharma, Daiichi Sankyo, Sunesis Pharmaceuticals, Jazz Pharmaceuticals, Pfizer, Astex Pharmaceuticals, CTI biopharma, Celgene, Genentech, AI Therapeutics, Samus Therapeutics, Arog Pharmaceuticals, and Kartos Therapeutics. X.M. received research funding (institutional) from Celgene/BMS and is a consultant for BMS. None of these relationships were related to the development of this work. Other authors have nothing to disclose., (© The Author(s), 2021.)

Existing studies regarding the role of DNA methyltransferase inhibitors (DNMTi) and lenalidomide in refractory anemia with ring sideroblasts (RARS) are limited. Using the surveillance, epidemiology, and end results-medicare database, we assembled a population-based cohort of older adults diagnosed with non-del(5q) lower-risk myelodysplastic syndromes during 2007-2015. Of 2167 patients, 30% had RARS. About 16% of RARS and non- ring sideroblasts (RS) patients received DNMTi. RARS patients were more likely to receive lenalidomide (11.1% vs. 7.1%, p  < 0.01). Among patients who were transfusion-dependent at treatment initiation, 55.6% of those treated with DNMTi only and 42.5% treated with lenalidomide only achieved red blood cell transfusion independence (RBC-TI) for a median duration of 21 and 12 weeks, respectively. RS status did not impact rate of RBC-TI. RARS patients had a significantly better survival, and the median survival of RARS patients varied by treatment group. In this population-based study of older RARS patients, DNMTi and lenalidomide were clinically active.

Allogeneic hematopoietic cell transplant (allo-HCT) remains the only potentially curative therapeutic modality for patients with primary or secondary myelofibrosis (MF). However, many patients are considered ineligible for allo-HCT, and transplant-related mortality can be substantial. Data on the efficacy and safety of allo-HCT are mixed and largely derived from retrospective studies. We aimed to synthesize the available evidence on the safety and efficacy of allo-HCT in MF and to identify patient, disease, and transplant characteristics with prognostic impact on outcomes of patients with MF undergoing allo-HCT. For this systematic review and meta-analysis, Cochrane Library, Google Scholar, Ovid Medline, Ovid Embase, PubMed, Scopus, and Web of Science Core Collection were searched from inception to October 11, 2020, for studies on allo-HCT in MF. Random-effects models were used to pool response rates for the co-primary outcomes of 1-year, 2-year, and 5-year overall survival (OS). Rates of non-relapse mortality and acute and chronic graft-versus-host-disease (GVHD) were studied as secondary endpoints. Subgroup analyses on the effect of conditioning regimen intensity, baseline dynamic international prognostic scoring system (DIPSS) score, and patient age were performed. The study protocol has been registered on PROSPERO (CRD42020188706). Forty-three studies with 8739 patients were identified and included in this meta-analysis. Rates of 1-year, 2-year, and 5-year OS were 66.7% (95% confidence interval [CI], 63.5%-69.8%), 64.4% (95% CI, 57.6%-70.6%), and 55.0% (95% CI, 51.8%-58.3%), respectively. Rates of 1-year, 2-year, and 5-year nonrelapse mortality were 25.9% (95% CI, 23.3%-28.7%), 29.7% (95% CI, 24.5%-35.4%), and 30.5% (95% CI, 25.9%-35.5%), respectively. The combined rate of graft failure was 10.6% (95% CI, 8.9%-12.5%) with primary and secondary graft failure occurring in 7.3% (95% CI, 5.7%-9.4%) and 5.9% (95% CI, 4.3%-8.0%) of patients, respectively. Rates of acute and chronic graft-versus-host disease were 44.0% (95% CI, 39.6%-48.4%; grade III/IV: 15.2%) and 46.5% (95% CI, 42.2%-50.8%; extensive or moderate/severe: 26.1%), respectively. Subgroup analyses did not show any significant difference between conditioning regimen intensity (myeloablative versus reduced-intensity), median patient age, and proportion of DIPSS-intermediate-2/high patients. The quality of the evidence is limited by the absence of randomized clinical trials in the field and the heterogeneity of patient and transplant characteristics across included studies. Given the poor prognosis of patients not receiving transplants and in the absence of curative nontransplantation therapies, our results support consideration of allo-HCT for eligible patients with MF., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

CEBPA-mutant acute myeloid leukemia (AML) encompasses clinically and biologically distinct subtypes of AML in both adults and children. CEBPA-mutant AML may occur with monoallelic (moCEBPA) or biallelic (biCEBPA) mutations, which can be somatic or germline, with each entity impacting prognosis in unique ways. BiCEBPA AML is broadly associated with a favorable prognosis, but differences in the type and location of CEBPA mutations as well as the presence of additional leukemogenic mutations can lead to heterogeneity in survival. Concurrent FLT3-ITD mutations have a well-documented negative effect on survival in adult biCEBPA AML, whereas support for a negative prognostic effect of mutations in TET2, DNMT3A, WT1, CSF3R, ASXL1, and KIT is mixed. NPM1 and GATA2 mutations may have a positive prognostic impact. MoCEBPA AML has similar survival outcomes compared to AML with wild-type CEBPA, and risk stratification is determined by other cytogenetic and molecular findings. Germline CEBPA mutations may lead to familial biCEBPA AML after acquisition of second somatic CEBPA mutation, with variable penetrance and age. BiCEBPA AML in children is likely a favorable-risk diagnosis as it is in adults, but the role of a single CEBPA mutation and the impact of concurrent leukemogenic mutations are not clear in this population. Laboratory evaluation of the CEBPA gene includes PCR-based fragment-length analysis, Sanger sequencing, and next-generation sequencing. Phenotypic analysis using multiparameter flow cytometry can also provide additional data in evaluating CEBPA, helping to assess for the likelihood of mutation presence., (© 2021 John Wiley & Sons Ltd.)

Polycythemia vera (PV) and essential thrombocythemia (ET) are both driven by JAK-STAT pathway activation and consequently much of the recent research efforts to improve the management and outcomes of patients with these neoplasms have centered around inhibition of this pathway. In addition to newer JAK inhibitors and improved interferons, promising novel agents exploiting a growing understanding of PV and ET pathogenesis and disease evolution mechanisms are being developed. These agents may modify the disease course in addition to cytoreduction. Histone deacetylase, MDM2 and telomerase inhibitors in patients with PV/ET have demonstrated clinically efficacy and serve as chief examples. Hepcidin mimetics, limiting iron availability to red blood cell precursors, offer an exciting alternative to therapeutic phlebotomy and have the potential to revolutionize management for patients with PV. Many of these newer agents are found to improve hematologic parameters and symptom burden, but their role in thrombotic risk reduction and disease progression control is currently unknown. The results of larger, randomized studies to confirm the early efficacy signals observed in phase 1/2 trials are eagerly awaited.

The World Health Organization classification and definition of "myeloid sarcoma" is imprecise and misleading. A more accurate term is "extramedullary acute myeloid leukemia tumor (eAML)." The pathogenesis of eAML has been associated with aberrancy of cellular adhesion molecules, chemokine receptors/ligands and RAS-MAPK/ERK signaling. eAML can present with or without synchronous or metachronous intramedullary acute myeloid leukemia (AML) so a bone marrow evaluation is always recommended. Accurate diagnosis of eAML requires tissue biopsy. eAML confined to one or a few sites is frequently treated with local therapy such as radiotherapy. About 75-90% of patients with isolated eAML will develop metachronous intramedullary AML with a median latency period ranging from 4 to 12 months; thus, patients with isolated eAML may also be treated with systemic anti-leukemia therapy. eAML does not appear to have an independent prognostic impact; selection of post-remission therapy including allogeneic hematopoietic cell transplant (alloHCT) is typically guided by intramedullary disease risk. Management of isolated eAML should be individualized based on patient characteristics as well as eAML location and cytogenetic/molecular features. The role of PET/CT in eAML is also currently being elucidated. Improving outcomes of patients with eAML requires further knowledge of its etiology and mechanism(s) as well as therapeutic approaches beyond conventional chemotherapy, ideally in the context of controlled trials., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) comprise the BCR-ABL-negative classical myeloproliferative neoplasms (MPNs). These clonal myeloid diseases are principally driven by well-described molecular events; however, factors leading to their acquisition are not well understood. Beyond increasing age, male sex, and race/ethnicity differences, few consistent risk factors for the MPNs are known. PV and ET have an incidence of 0.5 to 4.0 and 1.1 to 2.0 cases per 100,000 person-years, respectively, and predict similar survival. PMF, which has an incidence of about 0.3 to 2.0 cases per 100,000 person-years, is associated with the shortest survival of the MPNs., Competing Interests: Disclosures/competing interests A.M. Zeidan received research funding (institutional) from Celgene, Acceleron, Abbvie, Otsuka, Pfizer, Medimmune/AstraZeneca, Boehringer Ingelheim, Trovagene, Incyte, Takeda, and ADC Therapeutics. A.M. Zeidan had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene, Ariad, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Seattle Genetics, BeyondSpring, and Takeda. N.A. Podoltsev consulted for and received honoraria from Alexion, Pfizer, Agios Pharmaceuticals, Blueprint Medicines, Incyte, Novartis, Celgene, Bristol-Myers Squib, CTI BioPharma, and PharmaEssentia. N.A. Podoltsev received research funding (all to the institution) from Boehringer Ingelheim, Astellas Pharma, Daiichi-Sankyo, Sunesis Pharmaceuticals, Jazz Pharmaceuticals, Pfizer, Astex Pharmaceuticals, CTI biopharma, Celgene, Genentech, AI Therapeutics, Samus Therapeutics, Arog Pharmaceuticals, and Kartos Therapeutics. None of these relationships were related to the development of this article. All other authors report no relevant disclosures/competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose of Review: Maintenance therapy for acute myeloid leukemia (AML) has been studied for decades with mixed results. However, the application of modern agents has renewed interest and the recent data from randomized trials has provided evidence for the use of maintenance therapy in certain populations of AML patients., Recent Findings: Unselected patients are unlikely to benefit from maintenance therapy as has been previously and consistently demonstrated. The increasing availability of newer and targeted agents like oral hypomethylating agents, protein modifiers, as well as FLT3, IDH1/2 BCL-2 and immune checkpoint inhibitors have restoked interest in maintenance therapy for which randomized, placebo-controlled trials have recently demonstrated benefits, including in the post-transplant setting. Patients with high-risk disease, suboptimal consolidation or remission associated with measurable residual disease (MRD) appear to be beneficiaries of this strategy. The influence of MRD status and the platform by which it is measured are important factors in the current understanding of when maintenance therapy works and how future studies should be designed., Summary: The recent positive findings in support of maintenance therapy for certain AML patient populations are practice changing and bolster the need for properly designed, randomized studies using unified and standardized MRD techniques., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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 × 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.

Background: The etiology of myeloproliferative neoplasms (MPN) is obscure, and no previous studies have evaluated the role of diet., Methods: In the NIH-AARP Diet and Health Study, a prospective cohort of 463,049 participants ages 50 to 71 years at baseline (1995-1996), we identified 490 MPN cases after a median follow-up of 15.5 years, including 190 with polycythemia vera (PV) and 146 with essential thrombocythemia (ET). We examined possible associations between various dietary factors and the risk of MPN as a group, as well as PV and ET, using multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) and adjust for potential confounding variables., Results: An increased risk was observed between fruit consumption and the risk of MPN overall (third tertile vs. first tertile, HR = 1.32; 95% CI, 1.04-1.67; P trend = 0.02) and PV (third tertile vs. first tertile, HR = 2.00; 95% CI, 1.35-2.95; P trend < 0.01). Increased risk of PV was also observed among those with high intake of sugar (HR = 1.77; 95% CI, 1.12-2.79), sugar from natural sources (HR = 1.77; 95% CI, 1.16-2.71), sugar from natural beverage sources (HR = 1.57; 95% CI, 1.08-2.29), and fructose (HR = 1.84; 95% CI, 1.21-2.79)., Conclusions: The intake of fat and protein did not appear to influence PV risk-neither did meat or vegetable consumption. None of the dietary factors studied was associated with the risk of ET. The role of sugar intake in the etiology of PV in older individuals warrants further investigation., Impact: Our results indicate that high sugar intake is associated with an increased risk of polycythemia vera., (©2020 American Association for Cancer Research.)

Mutations in the tumor suppressor gene TP53 are detected in 5-10% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes. TP53 mutations have been associated with complex karyotypes, therapy-related malignancies, lower response rates to cytotoxic chemotherapy, and an overall adverse prognosis. In this single-center retrospective study, we analyzed the clinicopathologic characteristics and outcomes of 83 patients with TP53 -mutated myeloid malignancies treated at Yale Cancer Center between 9/2015 and 5/2019. Complex karyotypes ( n  = 75; 90%) and therapy-related malignancies ( n  = 32; 39%) were common. Median overall survival (OS) was 7.6 months. Intensive chemotherapy did not improve OS compared to lower-intensity treatment for AML patients. Patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT) had a significantly longer median OS, despite relatively limited follow-up. In conclusion, our data confirm the limited efficacy of intensive chemotherapy approaches for TP53 -mutated patients with myeloid neoplasms and suggest that a minority of patients achieve long-term survival with alloHSCT.

The etiology of Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) is largely unknown. We assessed potential associations between lifestyle factors and MPN risk in the NIH-AARP Diet and Health Study. In this prospective cohort with 463,049 participants aged 50-71 years at baseline (1995-1996) and a median follow-up of 15.5 years, we identified 490 MPN cases, including 190 with polycythemia vera (PV) and 146 with essential thrombocythemia (ET). Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Smoking was not associated with MPN risk in the overall cohort, but analyses stratified by sex suggested that smoking increased the risk of MPN in women (former smoker vs. nonsmokers, HR = 1.43, 95% CI: 1.03-2.00, p = 0.03; current smokers vs. nonsmokers, HR = 1.71, 95% CI: 1.08-2.71, p = 0.02). Coffee consumption was inversely associated with the risk of PV (high vs. low intake, HR = 0.53, 95% CI: 0.33-0.84, p-trend < 0.01), but not the risk of ET or MPN overall. Further analysis revealed an inverse association between the amount of caffeine intake and PV risk (high vs. low intake, HR = 0.55, 95% CI: 0.39-0.79, p-trend < 0.01). While the consumption of caffeinated coffee appeared to confer a protective effect against PV, the consumption of decaffeinated coffee did not. This large prospective study identified smoking as a risk factor for MPN in women and suggests that caffeine intake is associated with a lower risk of PV., (© 2020 UICC.)

The classical myeloproliferative neoplasms (MPNs), specifically chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), represent clonal myeloid disorders whose pathogenesis is driven by well-defined molecular abnormalities. In this comprehensive review, we summarize the epidemiological literature and present our own analysis of the most recent the Surveillance, Epidemiology, and End Results (SEER) program data through 2016. Older age and male gender are known risk factors for MPNs, but the potential etiological role of other variables is less established. The incidences of CML, PV, and ET are relatively similar at 1.0-2.0 per 100,000 person-years in the United States, while PMF is rarer with an incidence of 0.3 per 100,000 person-years. The availability of tyrosine kinase inhibitor therapy has dramatically improved CML patient outcomes and yield a life expectancy similar to the general population. Patients with PV or ET have better survival than PMF patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The hypomethylating agents (HMAs) azacitidine and decitabine have been the de facto standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive therapy. Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified 2263 older adults (age ≥66 years) diagnosed with AML during 2005-2015 who received a first-line HMA; 1154 (51%) received azacitidine, and 1109 (49%) received decitabine. Median survival from diagnosis was 7.1 and 8.2 months (P < .01) for azacitidine- and decitabine-treated patients, respectively. Mortality risk was higher with azacitidine vs decitabine (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.01-1.21; P = .02). The findings were similar when evaluating only patients completing ≥4 cycles (42% of patients treated with either azacitidine or decitabine). These findings lost significance when evaluating those completing a standard 7-day schedule of azacitidine (34%) vs 5-day schedule for decitabine (66%) (HR, 0.95; 95% CI, 0.83-1.08; P = .43). Red blood cell (RBC) transfusion independence (TI) was achieved in one-third of patients with no difference between the 2 HMAs. In conclusion, the majority of older AML patients did not receive the minimum of 4 cycles of HMA often needed to elicit clinical benefit. We observed no clinically meaningful differences between azacitidine- and decitabine-treated patients in their achievement of RBC TI or survival., (© 2020 by The American Society of Hematology.)

Hypomethylating agents (HMA) showed overall survival (OS) benefits in patients with higher-risk myelodysplastic syndromes (HR-MDS) in clinical trials. We conducted a retrospective cohort study of Surveillance, Epidemiology, and End Results (SEER)-Medicare data of patients ≥66 years diagnosed with refractory anemia with excess blasts (RAEB), a proxy for HR-MDS, in 01/2001-04/2004 (pre-period) or 01/2006-12/2011 (post-period). Association between post-period diagnosis and OS was examined using propensity scores (PS)-matched samples. Among 1876 RAEB patients, median OS was 9 months and 30.8% received HMAs (3.6% in pre-period; 43.0% in post-period) with no association between post-period diagnosis and OS. In the top PS quartile, post-period diagnosis was associated with a 74% lower risk of death (Hazard ratio [HR] = 0.26, 95%-CI: 0.10-0.69, p  = 0.007), while outcomes were worse in the lowest PS quartile (HR = 2.80, 95%-CI: 1.06-7.36, p  = 0.037). HMA lead to a 3-month OS benefit for patients most likely to receive HMA but not for unselected RAEB cohort.

Introduction : The myelodysplastic syndromes (MDS) vary in their risk of disease progression; progression includes increasingly severe bone marrow failure, reclassification as acute myeloid leukemia (AML), and death. Prognostic tools guide recommendations for allogeneic stem cell transplantation (alloSCT), the only curative option. AlloSCT is typically reserved for patients with higher-risk MDS as defined by existing prognostic tools, although additional clinical and biological factors in lower-risk patients may influence this dogma. Areas covered : This review discusses the current understanding of MDS risk stratification as it pertains to the use of alloSCT in subpopulations of MDS patients with a particular focus on the use of alloSCT in patients with lower-risk disease. Expert commentary : Though high-quality data are lacking, some lower-risk MDS patients may benefit from alloSCT, which offers the only prospect of cure. Understanding the etiologic role and prognostic impact of recurring genetic events may improve existing risk stratification and become integral facets of prognostic schemata. The identification of additional factors influencing the prognoses of patients currently lumped together as 'lower-risk' will likewise improve the selection of MDS patients for early intervention or aggressive therapies such as alloSCT.