At the 2017 Annual European Hemophilia Association (EHA) meeting held between the 21st and the 25th of June in Madrid, Spain, many lectures focused on what is becoming one of the most promising targets in the field of hematologic malignancies, the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2). The first Bcl-2 inhibitor, AbbVie’s Venclexta (venetoclax), was approved in 2016 for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletions (del[17p]). It is now being investigated in other blood cancers, including multiple myeloma, non-Hodgkin lymphoma, and acute myeloid leukemia (AML).

AML is a disease that has been characterized by a stagnant pipeline and, consequently, the treatment paradigm has not substantially changed over time. Since the 1970s, the standard of care in newly diagnosed fit patients has been a 3 + 7 induction regimen (three days of an anthracycline + seven days of cytarabine), aimed at achieving a complete hematologic remission (CR), followed by consolidation therapy with cytarabine, or an allogeneic hematopoietic cell transplantation (HCT). In recent years, dose-schedule optimization of the 3 + 7 regimen has led to better outcomes in patients eligible for induction therapy, although there still remains a high unmet need for patients unfit for this regimen. These ineligible patients are currently treated with hypomethylating agents (HMA) (azacitidine and decitabine) or low dose cytarabine (LDAC), both with poor outcomes (ORR <20% and survival <6 months).

In the last decade, a better understanding of the molecular basis of AML has encouraged the development of new targeted therapies. Among the different targets, Bcl-2 has a substantial role in the pathogenesis and prognosis of AML.

On June 24th, Dr. Keith Pratz, MD, presented results from a Phase Ib study that evaluated the safety and efficacy of Venclexta in combination with either decitabine or azacitidine in treatment-naive AML patients ineligible for standard induction therapy. The trial enrolled 100 patients with a median age of 73.9 years (47 with intermediate-risk cytogenetics and 53 with poor-risk cytogenetics) who were divided into four arms (D1, D2, E1, E2; 25 patients each) and received either a decitabine-based regimen in combination with Venclexta (Arm D1: decitabine 20mg/m2/day on days 1–5 of each 28 day cycle + Venclexta 400mg daily; Arm D2: decitabine 20mg/m2/day on days 1–5 of each 28 day cycle + Venclexta 800mg daily), or an azacitidine-based regimen with Venclexta (Arm E1: azacitidine 75 mg/m2/day on days 1–7 of each 28 day cycle + Venclexta 400mg daily; Arm E2: azacitidine 75 mg/m2/day on days 1–7 of each 28 day cycle + Venclexta 800mg daily). After a median follow-up time of 5.4 months, remission was achieved in 68% of the patients (defined as CR + CR with incomplete blood count recovery [CRi]). The highest CR/CRi (76%) was registered in a decitabine-based regimen (arm D1), while CR/CRi of 68%, 72%, and 56% were observed in arms D2, E1, and E2, respectively. Overall, the response was higher in intermediate-risk patients (CR/CRi of 78% versus 60% for poor-risk patients). The median duration of response and overall survival (OS) had not been reached at the time of the analysis, the probability of survival at 6- and 12-months were 79% and 70%, respectively, much higher than historical data reported for elderly AML patients. The incidence of adverse events (AEs) was generally comparable between the four arms. Overall, the most common treatment-emergent AEs were nausea (59%), diarrhea (42%), febrile neutropenia (41%), constipation (39%), fatigue (31%), and decreased white blood cell count (31%).

In another talk at EHA, Dr. Andrew H. Wei, PhD, presented updated Phase I/II data for the combination of Venclexta (600mg daily) and LDAC (20mg/m2 days 1–10 of each 28 day cycle) in 61 untreated AML patients ineligible for standard induction chemotherapy. The findings confirmed that the combination of the Bcl-2 inhibitor with a mild chemotherapy regimen is able to induce an antitumor response in frail patients (Venclexta + LDAC CR/CRi = 62%, the value was higher for intermediate-risk patients [76%]). In this trial, the median time to response was only one month and the median OS for all patients was 12 months, while in the subset of patients who achieved CR/CRi has yet to be reached.

These preliminary data suggest that the doublet Venclexta + HMA/LDAC might change the treatment landscape for elderly AML patients. In both the trials presented at EHA, the treatment exhibited an acceptable safety profile and durable efficacy, thus confirming the potential of Bcl-2 as a target in additional blood cancers, outside of their currently approved use in CLL. Based on the results from these two trials, AbbVie has now commenced two phase III randomized studies which are promising candidates in AML and could lead to an additional indication for Venclexta. AbbVie’s candidate may provide an exciting new approach to the treatment of elderly AML patients, a subset of patients with a limited life expectancy, offering a tolerable treatment which may extend survival and, in some cases, lead to remission.

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