Venetoclax and azacitidine (VenAZA) combination therapy in young unfit patients with AML: a perspective from a developing country

Despite improvements in leukemia therapy, acute myeloid leukemia (AML) remain a difficult disease to treat with a majority of patients having disease relapse without an allogeneic stem cell transplantation within 3 years [1]. Treatment options in AML have improved over the years with the introduction of hypomethylating agents and recently with the FDA approval of Venetoclax, a B cell lymphoma protein 2 (Bcl2) inhibitor [2]. The combination of Venetoclax and Azacitidine (VenAZA) upfront therapy has led to improvement in remission rates and overall survival compared to azacitidine monotherapy in elderly patients ( 75 years) with AML and in those who are unfit for conventional high dose induction chemotherapy [3]. Patients with AML in India are around a decade younger compared to patients in the west, with almost 30% of them presenting with baseline neutropenic infections like fungal pneumonia and multi drug resistance bacteremia, making them high risk candidates for upfront high dose induction chemotherapy [4]. In similar settings the induction mortality in these patients with conventional chemotherapy remains high (around 20–30% across different studies), often due to worsening of the neutropenic infections present at chemotherapy initiation, which are largely refractory to antimicrobials till neutrophil recovery [5]. In our department a majority of young patients with AML (>40%, unpublished data) have severe neutropenic infections at diagnosis (neutropenic sepsis with shock and multiorgan dysfunction; fungal pneumonia based on imaging or broncho-alveolar lavage findings together with respiratory distress; multi drug resistant bacteremia; organ dysfunction like acute kidney injury, type 1 respiratory failure, hepatic dysfunction etc.) making them unfit for upfront conventional chemotherapy. We report here the retrospective analysis of the first 7 relatively young patients with AML (median age of 45 years, range 27–60 years) treated in our department with the VenAZA combination therapy from Jan 2019 to March 2020, 6 of who had conditions preventing the use of upfront high dose induction chemotherapy and 1 with primary induction failure (Table 1). The study was approved by the Institutional ethics committee and informed consent was taken from all the patients for the off label use of Venetoclax and for the use of patient data in scientific reproduction. We collected data about the patient’s demographics, clinical characteristics at presentation (neutropenic infections, organ dysfunction), disease parameters (baseline complete blood count and blast percentage, cytogenetics and mutational profile on the diagnostic bone marrow), treatment parameters and outcomes (time to hematological recovery, bone marrow remission status and survival outcomes). The 2017 European Leukemia Network (ELN) recommendation were used to assess response status [6]. Four patients had intermediate risk AML based on ELN 2017 criteria; one had favorable risk and two patients had adverse risk AML with one having primary induction failure. Azacitidine was administered at 75mg/m/day for 7 days subcutaneously every 28 days and Venetoclax was initiated within the first week of Azacitidine therapy. Venetoclax was started at 50mg (lowest tablet denomination feasible) after withholding concomitant azole antifungals and bridging the venetoclax ramp up period with alternative antifungal prophylaxis or therapy that do not alter in vivo venetoclax drug concentration (micafungin or caspofungin) with increments over a week to reach a maximum dose of 400mg which was continued for 28 days each cycle. Azole antifungals were re-initiated after a steady venetoclax dose was achieved. Dose adjustments were done for concomitant azole therapy; a maximum dose of 100mg per day of venetoclax was administered for concomitant voriconazole and alternate day 50mg/100mg for concomitant posaconazole therapy (given the unavailability of tablet denominations to administer daily 70mg venetoclax with posaconazole). None of the patients in this cohort had a white blood cell (WBC) count > 30 10/L before the initiation of Venetoclax. Adequate tumor lysis syndrome (TLS) prophylaxis like hydration,