abt-199 and ponatinib

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Imidazoles; Male; Middle Aged; Mutation; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyridazines; Retrospective Studies; Sulfonamides; Young Adult

Topics: Adult; Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Imidazoles; Middle Aged; Neoplasm Recurrence, Local; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyridazines; Sulfonamides; Survival Analysis; Treatment Outcome

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.. 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.. 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.. Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Fusion Proteins, bcr-abl; Humans; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Middle Aged; Protein Kinase Inhibitors; Pyridazines; Retrospective Studies; Sulfonamides; Survival Rate

Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) remains a challenge. Although the addition of targeted tyrosine kinase inhibitors (TKIs) to standard cytotoxic therapy has greatly improved upfront treatment, treatment-related morbidity and mortality remain high. TKI monotherapy provides only temporary responses and renders patients susceptible to the development of TKI resistance. Thus, identifying agents that could enhance the activity of TKIs is urgently needed. Recently, a selective inhibitor of B cell lymphoma 2 (BCL-2), ABT-199 (venetoclax), has shown impressive activity against hematologic malignancies. We demonstrate that the combination of TKIs with venetoclax is highly synergistic in vitro, decreasing cell viability and inducing apoptosis in Ph(+)ALL. Furthermore, the multikinase inhibitors dasatinib and ponatinib appear to have the added advantage of inducing Lck/Yes novel tyrosine kinase (LYN)-mediated proapoptotic BCL-2-like protein 11 (BIM) expression and inhibiting up-regulation of antiapoptotic myeloid cell leukemia 1 (MCL-1), thereby potentially overcoming the development of venetoclax resistance. Evaluation of the dasatinib-venetoclax combination for the treatment of primary Ph(+)ALL patient samples in xenografted immunodeficient mice confirmed the tolerability of this drug combination and demonstrated its superior antileukemic efficacy compared to either agent alone. These data suggest that the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph(+)ALL and should be further evaluated for patient care.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Dasatinib; Humans; Imidazoles; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Myeloid Cell Leukemia Sequence 1 Protein; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Proto-Oncogene Proteins c-bcl-2; Pyridazines; src-Family Kinases; STAT5 Transcription Factor; Sulfonamides; Translational Research, Biomedical; Xenograft Model Antitumor Assays