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A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60–87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45–64)) and the study group arms (53% (95%CI: 47–60) and 59% (95%CI: 58–63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7–14.0) in the CSA, 7.6% (95%CI: 4.5–12.8) in study group A and 11.1% (95%CI: 9.0–13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0–26.9), 17.0% (95%CI: 2.0–23.9), and 19.5% (95%CI: 16.7–22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.

Leukemia : normal and malignant hemopoiesis ; a peer-reviewed journal 36(9), 2242-2249 (2022). doi:10.1038/s41375-022-01648-4, Published by Springer Nature, London

Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60–82%) compared to patients with GG (51%, 95% CI: 41–61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280–0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. The SNP rs460089 was found as an independent predictor of TFR.

The ideal post-remission strategy in patients with intermediate-risk (IR) acute myeloid leukemia (AML) in first complete remission (CR) has been a matter of debate. To address this question, one hundred and forty-three patients with AML, IR cytogenetics in first CR or CRi, aged ≤ 60 years with an available HLA-matched sibling or unrelated donor were randomized 1:1 to either receive allogeneic HCT or high-dose cytarabine for consolidation and salvage HCT only in case of relapse. According to the intent-to-treat analysis, the probability of survival at 2 years was 71% (95%-CI 60-81%) and 84% (95%.CI 73-92%) in Arm A (Primary allogeneic HCT) and Arm B (Chemo-consolidation), respectively (p=.120). Disease-free survival after HCT in CR1 at 2 years was 69% (95%-CI 57-80%) compared to 41% (95%-CI 29-54%; p=.001). The cumulative incidence of relapse was 20% (95% CI 13-31%) and 57% (95%-CI 46-71%; p

Journal of neurology 269(7), 3389-3399 (2022). doi:10.1007/s00415-022-11034-w, Published by Steinkopff, [Darmstadt]

Introduction: The licenced starting dose of bosutinib is 400 mg QD for first line therapy and 500 mg QD in later lines in CML. Gastrointestinal (GI) adverse events (AE) are observed in up to 90% in similar patient cohorts (BYOND, Hochhaus et al; Leukemia 2020). The goal of this study was to evaluate whether a bosutinib step-in dosing regimen decreases GI toxicity while maintaining optimal efficacy in patients (pts) with CML after failure or intolerance to 2G-TKIs. Methods: This is the first and final analysis of the BODO "Bosutinib Dose Optimization Study" trial (NCT02577926), which is a multicenter, open-label single arm phase II study testing tolerability and efficacy of 2 nd& 3 rd line bosutinib step-in dosing in chronic phase CML pts intolerant and/or refractory to previous imatinib, and/or nilotinib, and/or dasatinib therapy. Bosutinib was commenced with 300 mg QD and was (in the absence of >G1 toxicities) dose-increased by increments of 100 mg daily dosing every 14 days if applicable up to a maximum dose of 500 mg QD. The primary endpoint (PE) was the incidence of grade 2 to 4 GI toxicity AEs within 6 months after registration. 127 pts were planned to be recruited. However, due to slow recruitment, the trial had to be stopped prematurely after inclusion of 57 pts. The 95% confidence interval (CI) around the estimated rate of the PE was calculated in accordance with Clopper and Pearson. Results: Pts´ characteristics are presented in Table 1. 23 (40.4%) pts were intolerant, 20 resistant (35.1%), and 14 (24.6%) both intolerant and resistant to previous TKI treatment. 20 (35.1%) pts entered the study in molecular response (at least MMR at screening). The probability of MMR after 24 months of treatment was 79% (95% CI: 65.8% to 87.5%); probabilities of MMR, MR4, MR4.5 are shown in Figure 1. Six out of 7 intolerant pts without MMR at baseline reached MMR or better molecular response with bosutinib. Thirty pts were refractory to previous therapy (19 being resistant; 11 being resistant and intolerant) lacking baseline MMR, of which 19 pts achieved MMR or better (2 pts with MR4.5, 2 with MR4 and 15 with MMR). Eight out of 30 pts did not achieve MMR and 3 experienced complications (2 pts with SAEs that led to discontinuation and 1 death). No patient progressed to accelerated/blast phase on treatment. Two pts died (1 CML progression (no MMR with bosutinib, death 6 months after allogenic stem cell transplant); 1 cerebral cavernoma unrelated to bosutinib). In the overall patient population (N = 57), all pts had ≥1 any grade TEAE and 71.9% of patients had ≥1 grade 3/4 TEAE. SAEs occurred in 28.1% of pts. A total of 949 AEs were reported during the study. The most frequently reported AEs (SOC terms) were GI disorders (n=346, 36.5%) and investigations (n=206, 21.7%). Among the GI events (n=346) diarrhea (55.5%), nausea (16.2%) and abdominal pain (9.8%) were most common; among investigations (n=206) liver enzyme increases were most frequent (ALT increase (26.7%), AST increase 17%). The PE was evaluated for 50 out of 57 pts (4 pts with treatment < 14 days + 3 pts with observation < 6 months were excluded from the analysis). Twenty pts did not develop any clinically relevant GI-toxicity during the first 6 months. Thus, the rate of GI-toxicity (grade 2 to 4) within the first 6 months of treatment was 60.0% (95% confidence interval: 45.2% to 73.6%), accordingly, the alternative hypothesis of the trial (GI-toxicity was assumed to be less than 40%) could not be accepted. However, only in 1 patient GI-toxicity led to discontinuation. Twenty-five pts discontinued bosutinib prematurely (17 due to AEs; 5 with insufficient response; 3 with other reasons). Conclusion: This is 1 of the largest cohorts published on the efficacy and safety of bosutinib after intolerance/failure to first-line 2G-TKIs. Given the limitations of a single-arm study with incomplete recruitment, we could not demonstrate an advantage of the step-in dosing concept chosen here to reduce the frequency of grade 2-4 GI toxicity overall. However, using this regimen, bosutinib was able to induce optimal responses in almost two thirds of pts previously resistant to 2G-TKIs while GI toxicity rarely led to treatment discontinuation. We conclude that treatment with bosutinib is safe (rates of AEs being similar to other trials (e.g. BYOND)) and efficacious as 2 nd and 3 rd line therapy after failure of previous 2G-TKI therapy whereas an advantage of run-in dosing regimens remains to be proven. Figure 1 Figure 1. Disclosures Isfort: Mundipharma: Other: Travel reimbursement; Amgen: Other: Travel reimbursement; Roche: Other: Travel reimbursement; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hexal: Other: Travel reimbursement; Alexion: Other: Travel reimbursement; BMS: Honoraria; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement. Wolf: Roche: Honoraria, Research Funding; MSD: Honoraria, Research Funding; BMS-Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Gilead: Honoraria; Incyte: Honoraria; GEMOAB: Honoraria. Teichmann: Pfizer: Membership on an entity's Board of Directors or advisory committees. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Burchert: Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Pfizer: Honoraria; Incyte: Honoraria; Gilead: Honoraria; BMS: Honoraria. Hochhaus: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Saussele: Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria. Kiani: Novartis Pharma GmbH: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Göthert: Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel reimbursement; Incyte: Consultancy, Honoraria, Other: Travel reimbursement; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel reimbursement; Proteros Biostructures: Consultancy; AOP Orphan Pharmaceuticals: Honoraria, Other: Travel reimbursement; zr pharma&: Honoraria. Schafhausen: Swedish Orphan Biovitrum AB: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees. Brümmendorf: Novartis: Honoraria, Patents & Royalties, Research Funding; Janssen: Honoraria; Bristol Myers: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Repeat Diagnostics: Research Funding; Takepart Media: Honoraria.