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The BYOND study evaluated the efficacy and safety of bosutinib 500 mg once daily in patients with chronic myeloid leukemia (CML) resistant/intolerant to prior tyrosine kinase inhibitors (TKIs). These post-hoc analyses assessed the efficacy and safety of bosutinib by resistance or intolerance to prior TKIs (imatinib-resistant vs dasatinib/nilotinib-resistant vs TKI-intolerant), and cross-intolerance between bosutinib and prior TKIs (imatinib, dasatinib, nilotinib), in patients with Philadelphia chromosome-positive chronic phase CML. Data are reported after ≥3 years' follow-up. Of 156 patients with Philadelphia chromosome-positive chronic phase CML, 53 were imatinib-resistant, 29 dasatinib/nilotinib-resistant, and 74 intolerant to all prior TKIs; cumulative complete cytogenetic response rates at any time were 83.7%, 61.5%, and 86.8%, and cumulative major molecular response rates at any time were 72.9%, 40.7%, and 82.4%, respectively. Of 141, 95, and 79 patients who received prior imatinib, dasatinib, and nilotinib, 64 (45.4%), 71 (74.7%), and 60 (75.9%) discontinued the respective TKI due to intolerance; of these, 2 (3.1%), 5 (7.0%), and 0 had cross-intolerance with bosutinib. The response rates observed in TKI-resistant and TKI-intolerant patients, and low cross-intolerance between bosutinib and prior TKIs, further support bosutinib use for patients with Philadelphia chromosome-positive chronic phase CML resistant/intolerant to prior TKIs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02228382., Competing Interests: Declaration of Competing Interest B. Douglas Smith: honoraria for consulting to Agios, Celgene, Jazz Pharmaceuticals, Novartis and Pfizer, and received research support from Pfizer. Tim H. Brümmendorf: consultant for Janssen, Merck, Novartis, Pfizer, and Takeda, and received research support from Novartis and Pfizer. Gail J. Roboz: consultancy, advisory board or data and safety monitoring committee for AbbVie, Actinium, Agios, Amphivena, Argenx, Array Biopharma, Astex, Astellas, AstraZeneca, Bayer, Celgene, Celltrion, Daiichi Sankyo, Eisai, Epizyme, Helsinn, Janssen, Jasper Therapeutics, Jazz, MEI Pharma – IDMC Chair, Novartis, Orsenix, Otsuka, Pfizer, Roche/Genentech, Sandoz, Takeda – IRC Chair, Trovagene. Received research support from Cellectis and Pfizer. Carlo Gambacorti-Passerini: provides consultancy to Bristol-Myers Squibb and received honoraria and research support from Pfizer. Aude Charbonnier: provides consultancy to Novartis and Pfizer; speaker’s bureau for Incyte; received research support from Pfizer. Andrea Viqueira, Eric Leip, Simon Purcell, and Erinn Goldman: employees of and have stock/stock options in Pfizer. Francis Giles: consultant to Actuate Therapeutics Inc, provides expert testimony to Novartis, and received research support from Pfizer. Thomas Ernst and Andreas Hochhaus: received research support from Bristol-Myers Squibb, Incyte, Novartis, and Pfizer. Gianantonio Rosti: received research support from Pfizer and served on the speaker bureau for Bristol-Myers Squibb, Incyte, Novartis, and Pfizer., (Copyright © 2024. Published by Elsevier Ltd.)

The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson's r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10 -14 ). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using azacitidine combinations., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Treatment with hypomethylating agents (HMAs) improves overall survival (OS) in patients who achieve a response of stable disease (SD) or better (complete remission [CR], partial remission [PR], or hematologic improvement [HI]). It is not well established if patients who achieve SD at 4-6 months of therapy should be offered different therapies to optimize their response or continue with the same regimen. Clinical data were obtained from the MDS Clinical Research Consortium database. SD was defined as no evidence of progression and without achievement of any other responses. Of 291 patients treated with AZA or DAC, 55% achieved their best response (BR) at 4-6 months. Among patients with SD at 4-6 months, 29 (20%) achieved a better response at a later treatment time point. Younger patients with lower bone marrow blast percentages, and intermediate risk per IPSS-R were more likely to achieve a better response (CR, PR, or HI) after SD at 4-6 months. Patients with SD who subsequently achieved CR had superior OS compared to patients who remained with SD (28.1 vs. 14.4 months, respectively, p=.04). In conclusion, patients treated with HMAs who achieves CR after a SD status had longer survival with continuous treatment after 6 months., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

This study compares outcomes of low-intensity versus standard-intensity induction strategies for older patients with acute myeloid leukemia at the Weill Cornell Leukemia Program. From 1999 to 2009, 298 adults ≥ 60 years with AML underwent induction chemotherapy with low-intensity and standard-intensity regimens, based on physician and patient preferences and investigational protocol availability. Overall, 33% of the cohort achieved complete remission with initial treatment, 23% with low-intensity induction and 53% with standard-intensity induction (P<0.0001). The median overall survival was 6.5 months and there was no significant difference in overall survival between patients initially treated with a low-intensity regimen compared to those receiving standard-intensity induction. There were no differences in 30- or 60-day mortality between the two groups., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Advanced myelodysplastic syndrome (MDS) carries a poor prognosis. In this phase I/II study, arsenic trioxide was combined with low-dose cytarabine in 49 previously untreated patients with intermediate-2 and high-risk MDS. Complete remission was achieved in 8 (17%) patients, including 3/14 (21%) with treatment-related disease, 4/31 (13%) with unfavorable cytogenetics and 2/36 (6%) with baseline poor performance status. Mortality within the first 4 weeks was 8%. The regimen was active and had a tolerable extramedullary toxicity profile, but it was cumbersome and intensive compared to other currently available treatments., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Patients with indolent non-Hodgkin lymphoma (I-NHL) often receive multiple courses of cytotoxic chemotherapy over several years. Radioimmunotherapy (RIT) has become an important part of treatment for relapsed patients and tositumomab/lodine I-131 tositumomab is a promising regimen currently being incorporated into first-line therapy. While treatment-related myelodysplasia (tMDS) and acute myeloid leukemia (tAML) are well-known, poor-prognosis complications of conventional chemotherapy and radiation therapy, they have not been previously observed as a consequence of initial treatment with RIT-based regimens. We describe four patients with tMDS/tAML who received a sequential chemotherapy and tositumomab/lodine I-131 tositumomab program as their initial and only lymphoma treatment. Our findings suggest that the potential risk of these important complications must be considered in the development of this novel therapeutic strategy in the first-line setting.

Angiogenesis is part of the pathophysiology of myelofibrosis with myeloid metaplasia (MMM). PTK787/ZK 222584 (PTK/ZK) is a novel inhibitor of vascular endothelial growth factor receptors. Twenty-nine patients with MMM received a continuous dosing schedule of PTK/ZK doses of 500 or 750 mg twice daily (BID). Transient potentially PTK/ZK related mild nausea, vomiting, dizziness, fatigue, thrombocytopenia, or anorexia occurred in 15% of patients. Dose limiting toxicities of dyspepsia, proteinurea, and/or mucositis were observed in patients treated with 750 mg BID. One (3%) and five (17%) patients achieved complete remission and clinical improvement, respectively. PTK/ZK has modest activity in patients with MMM.

A phase II study of troxacitabine, a non-natural dioxolane nucleoside L-enantiomer, was conducted in patients with chronic myelogenous leukemia in blastic phase (CML-BP). Patients were untreated for BP, or treated with imatinib mesylate (IM) as sole prior therapy for BP. Troxacitabine was given as an intravenous infusion over 30 min daily for 5 days at a dose of 8.0 mg/m(2) per day. Thirty-one patients, 29 (93%) of whom had failed prior IM therapy, received 51 courses of therapy. Grade 3 or 4 toxicities included stomatitis (4%), hand-foot syndrome (18%), and skin rash (12%). Four patients (13%) responded. Troxacitabine-based combinations merit study in IM-resistant CML.