Antifungal prophylaxis and novel drugs in acute myeloid leukemia: the midostaurin and posaconazole dilemma
ANNALS OF HEMATOLOGY
Authors: Stemler, Jannik; Koehler, Philipp; Maurer, Christian; Mueller, Carsten; Cornely, Oliver A.
With the advent of new targeted drugs in hematology and oncology patient prognosis is improved. Combination with antifungal prophylaxis challenges clinicians due to pharmacological profiles prone to drug-drug interactions (DDI). Midostaurin is a novel agent for FLT3-TKD/-ITDmut-acute myeloid leukemia (AML) and metabolized via cytochrome P450 3A4 (CYP3A4). Posaconazole is a standard of care antifungal agent used for prophylaxis during induction treatment of AML and a strong CYP3A4 inhibitor. Concomitant administration of both drugs leads to elevated midostaurin exposure. Both drugs improve overall survival at low numbers needed to treat. The impact of CYP3A4-related DDI remains to be determined. Severe adverse events have been observed; however, it remains unclear if they can be directly linked to DDI. The lack of prospective clinical studies assessing incidence of invasive fungal infections and clinical impact of DDI contributes to neglecting live-saving antifungal prophylaxis. Management strategies to combine both drugs have been proposed, but evidence on which approach to use is scarce. In this review, we discuss several approaches in the specific clinical setting of concomitant administration of midostaurin and posaconazole and give examples from everyday clinical practice. Therapeutic drug monitoring will become increasingly important to individualize and personalize antineoplastic concomitant and antifungal treatment in the context of DDI. Pharmaceutical companies addressing the issue in clinical trials may take a pioneer role in this field. Other recently developed and approved drugs for the treatment of AML likely inhere potential of DDI marking a foreseeable issue in future treatment of this life-threatening disease.
Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients
AMERICAN JOURNAL OF HEMATOLOGY
Authors: Morsia, Erika; McCullough, Kristen; Joshi, Maansi; Cook, Joselle; Alkhateeb, Hassan B.; Al-Kali, Aref; Begna, Kebede; Elliott, Michelle; Hogan, William; Litzow, Mark; Shah, Mithun; Pardanani, Animesh; Patnaik, Mrinal; Tefferi, Ayalew; Gangat, Naseema
Venetoclax and hypomethylating agent (HMA) combination therapy is FDA-approved for elderly or unfit acute myeloid leukemia (AML) patients unable to withstand intensive chemotherapy. The primary objective of the current study was to impart our institutional experience with the above regimen, outlining response, survival outcomes, and its determinants amongst 86 treatment- naive and relapsed/refractory AML patients. A total of 44 treatment-naive AML patients, median age 73.5 years, enriched with secondary, therapy related and ELN adverse risk disease (n = 27) were studied. The CR/CRi rates of 50% (22 of 44 patients) were superior to 23% in a matched AML cohort treated with HMA alone (P= .005). Response rates were similar withTP53,FLT3,NPM1andIDHmutations (P= .31). Moreover,CEPBAmutations (P= .03) and neutropenia (P= .05) emerged as predictors of complete response. Survivalwas prolonged in patients achieving CR/CRi (17 vs 3 months without CR/CRi,P < .001; conversely adverse ELN risk portended inferior survival. Amongst 42 relapsed/refractory AML patients, half received >= 2 prior therapies excluding transplant, and 15 (35.7%) had received HMA. A group of 14 patients (33.3%) attained CR/CRi; age > 65 years, AML with myelodysplasia,JAK2,DNMT3A, andBCORmutations predicted complete response. Survival distinctions were based on CR/CRi (median survival 15 vs 3 months with/without CR/CRi;P < .001), andTP53mutation status (P= .04). In summary, we corroborate existing reports demonstrating superior response and prolonged survival with venetoclax and HMA in treatment -naive and relapsed/refractory AML patients regardless of genotype. Additionally, we identify unique predictors of response to therapy which require validation.