Venetoclax and BCR-ABL Tyrosine Kinase Inhibitor Combinations: Outcome in Patients with Philadelphia Chromosome-Positive Advanced Myeloid Leukemias

Abstract

Background: Philadelphia chromosome-positive (Ph+) advanced leukemias, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in myeloid blast phase (MBP), have poor outcomes. Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKI) in preclinical studies. However, clinical activity of venetoclax and TKI-based regimens is unknown. Methods: We conducted a retrospective study on patients with Ph+ AML (n = 7) and CML-MBP (n = 9) who received venetoclax combined with TKI-based regimens at our institution. Results: Median patient age was 42 years, and the median number of prior therapy cycles was 5 (range 2–8). Nine patients received decitabine-based, and 7 received intensive chemotherapy-based regimens. Ten patients (63%) received ponatinib. The overall response rate (ORR) in 15 evaluable patients was 60% (1 complete remission [CR], 6 CR with incomplete hematologic recovery [CRi], 1 morphologic leukemia-free state, and 1 partial response). The ORR was 43% in Ph+ AML and 75% in CML-MBP. The median overall survival (OS) for all patients was 3.6 months, for AML OS was 2.0 months, and for CML-MBP OS was 10.9 months. The median relapse-free survival for AML and CML-MBP was 3.6 and 3.9 months, respectively. Compared to nonresponders, patients achieving CR/CRi had higher baseline Ph+ metaphases and BCR-ABL1 PCR. Conclusions: Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP.

Emerging agents and regimens for AML

“…Given the proven synergies of BCL-2 inhibition, multiple combinations with targeted agents, and venetoclax are under investigation. There are many ongoing combinations of therapies targeting BCL-2 and other pathways, including FLT3 inhibitors (gilteritinib) and IDH1 and 2 inhibitors (Ivosidenib and enasidenib) (will be discussed in the later sections), MCL-1 inhibitors (VU661013, A-1210477); MEK1/2 inhibitor (cobimetinib), and MDM2 inhibitor (idasanutlin) (reviewed in [20]), combination with TKI in Ph + acute leukemia [21] and other emerging pre-clinical combinations including small-molecule inhibitors of CDK9 (the orally active A-1592668 and the related analog A-1467729) leading to down-expression of MCL-1 [22]; the Exportin inhibitor, Selinexor, [23]; BET inhibitors, ABBV-075, [24]; SRC family kinases (SFK) and Bruton's tyrosine kinase (BTK) inhibitor, ArQule 531 (ARQ 531), [25]; and it is expecting much more novel combinations to come.…”

Sustained Complete Remission with Incomplete Hematologic Recovery (CRi) in a Patient with Relapsed AML and Concurrent BCR-ABL1 and CBFB Rearrangement Treated with a Combination of Venetoclax and 5-Azacytidine

“…These results indicate a potential extension of venetoclax-combined regimens to younger AML patients, possibly in association with FLT3- or IDH1- and IDH2-inhibitors [10]. The MD Anderson Cancer recently has reported clinical outcomes of 7 refractory/relapsed Philadelphia chromosome-positive (Ph+) AML patients treated with venetoclax combined with a TKI [11]. Importantly, in this series, only 2 patients achieved CR/CRi.…”

Impact of frontline treatment approach on outcomes of myeloid blast phase CML

“…Ongoing studies are evaluating lower-intensity therapy (HMA + venetoclax) combined with ponatinib for patients with Ph + myeloid malignancies, including CML-MBP (NCT04188405), which may further improve outcomes for this disease. Retrospective and prospective studies also support the use of venetoclax-based combination regimens in CML-BP and advanced Ph + leukemias [ 37 , 38 ].…”