The oral CDK9 inhibitor voruciclib combined with venetoclax for patients with relapsed/refractory acute myeloid leukemia
Abstract: The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) promotes cell survival in acute myeloid leukemia (AML), and its overexpression is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase 9 inhibitor, indirectly decreases Mcl-1 protein expression and h...
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Elsevier
2025-08-01
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| Series: | Blood Neoplasia |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950328025000433 |
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| author | Yesid Alvarado-Valero Rachel J. Cook Shira N. Dinner Michael Keng Kebede H. Begna Nathalie Javidi-Sharifi Sameem Abedin Monzr M. Al Malki Vijaya Raj Bhatt Prabhu Rajagopalan Min Tang Sandra E. Wiley Richard G. Ghalie Matthew S. Davids |
| author_facet | Yesid Alvarado-Valero Rachel J. Cook Shira N. Dinner Michael Keng Kebede H. Begna Nathalie Javidi-Sharifi Sameem Abedin Monzr M. Al Malki Vijaya Raj Bhatt Prabhu Rajagopalan Min Tang Sandra E. Wiley Richard G. Ghalie Matthew S. Davids |
| author_sort | Yesid Alvarado-Valero |
| collection | DOAJ |
| description | Abstract: The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) promotes cell survival in acute myeloid leukemia (AML), and its overexpression is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase 9 inhibitor, indirectly decreases Mcl-1 protein expression and has synergistic activity with venetoclax in AML preclinical models. We hypothesized that voruciclib in combination with venetoclax would induce responses in patients with AML with disease progression after venetoclax therapy. This dose-escalation study evaluated voruciclib administered on days 1 to 14 of 28-day cycles with venetoclax daily. The study enrolled 41 adult patients with AML after failure of previous standard therapies. Patients had a median of 2 (range, 1-7) previous lines of therapy, 19 patients (46%) had ≥3 previous lines of therapy, and 39 (95%) had previous venetoclax. No dose-limiting toxicities were reported in 7 dose levels evaluated. The most common adverse events were nausea (34%), febrile neutropenia (32%), diarrhea (22%), dyspnea (22%), hypokalemia (22%), and thrombocytopenia (22%). Antileukemic activity was observed in 10 (24%) patients, including 3 with complete marrow remission and 7 with stable disease lasting ≥3 months. We observed a rebound of circulating blasts during the 14 days of single-agent venetoclax dosing in 40% of evaluable patients. Mcl-1 protein expression and RNA polymerase II Ser-2 phosphorylation decreased on voruciclib. Overall, the combination of voruciclib with venetoclax was tolerable in patients with relapsed/refractory AML, had antileukemic activity, and showed on-target effects in heavily pretreated patients with disease progression after venetoclax. This trial was registered at www.ClinicalTrials.gov as #NCT03547115. |
| format | Article |
| id | doaj-art-f3fa1dfcd04744e1b89d09df953a5805 |
| institution | DOAJ |
| issn | 2950-3280 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Neoplasia |
| spelling | doaj-art-f3fa1dfcd04744e1b89d09df953a58052025-08-20T03:17:28ZengElsevierBlood Neoplasia2950-32802025-08-012310010810.1016/j.bneo.2025.100108The oral CDK9 inhibitor voruciclib combined with venetoclax for patients with relapsed/refractory acute myeloid leukemiaYesid Alvarado-Valero0Rachel J. Cook1Shira N. Dinner2Michael Keng3Kebede H. Begna4Nathalie Javidi-Sharifi5Sameem Abedin6Monzr M. Al Malki7Vijaya Raj Bhatt8Prabhu Rajagopalan9Min Tang10Sandra E. Wiley11Richard G. Ghalie12Matthew S. Davids13Department of Leukemia, MD Anderson Cancer Center, Houston, TX; Correspondence: Yesid Alvarado-Valero, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030;Center for Hematologic Malignancies, Oregon Health & Sciences University, Portland, ORHematology Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Chicago, ILDivision of Hematology and Oncology, University of Virginia Medical Center Comprehensive Cancer Center, Charlottesville, VADivision of Hematology, Mayo Clinic, Rochester, MNDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MADivision of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WIDepartment of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CADivision of Oncology & Hematology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NEPR Consulting, Mountain Lakes, NJMEI Pharma, Inc, San Diego, CAMEI Pharma, Inc, San Diego, CAMEI Pharma, Inc, San Diego, CADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MAAbstract: The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) promotes cell survival in acute myeloid leukemia (AML), and its overexpression is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase 9 inhibitor, indirectly decreases Mcl-1 protein expression and has synergistic activity with venetoclax in AML preclinical models. We hypothesized that voruciclib in combination with venetoclax would induce responses in patients with AML with disease progression after venetoclax therapy. This dose-escalation study evaluated voruciclib administered on days 1 to 14 of 28-day cycles with venetoclax daily. The study enrolled 41 adult patients with AML after failure of previous standard therapies. Patients had a median of 2 (range, 1-7) previous lines of therapy, 19 patients (46%) had ≥3 previous lines of therapy, and 39 (95%) had previous venetoclax. No dose-limiting toxicities were reported in 7 dose levels evaluated. The most common adverse events were nausea (34%), febrile neutropenia (32%), diarrhea (22%), dyspnea (22%), hypokalemia (22%), and thrombocytopenia (22%). Antileukemic activity was observed in 10 (24%) patients, including 3 with complete marrow remission and 7 with stable disease lasting ≥3 months. We observed a rebound of circulating blasts during the 14 days of single-agent venetoclax dosing in 40% of evaluable patients. Mcl-1 protein expression and RNA polymerase II Ser-2 phosphorylation decreased on voruciclib. Overall, the combination of voruciclib with venetoclax was tolerable in patients with relapsed/refractory AML, had antileukemic activity, and showed on-target effects in heavily pretreated patients with disease progression after venetoclax. This trial was registered at www.ClinicalTrials.gov as #NCT03547115.http://www.sciencedirect.com/science/article/pii/S2950328025000433 |
| spellingShingle | Yesid Alvarado-Valero Rachel J. Cook Shira N. Dinner Michael Keng Kebede H. Begna Nathalie Javidi-Sharifi Sameem Abedin Monzr M. Al Malki Vijaya Raj Bhatt Prabhu Rajagopalan Min Tang Sandra E. Wiley Richard G. Ghalie Matthew S. Davids The oral CDK9 inhibitor voruciclib combined with venetoclax for patients with relapsed/refractory acute myeloid leukemia Blood Neoplasia |
| title | The oral CDK9 inhibitor voruciclib combined with venetoclax for patients with relapsed/refractory acute myeloid leukemia |
| title_full | The oral CDK9 inhibitor voruciclib combined with venetoclax for patients with relapsed/refractory acute myeloid leukemia |
| title_fullStr | The oral CDK9 inhibitor voruciclib combined with venetoclax for patients with relapsed/refractory acute myeloid leukemia |
| title_full_unstemmed | The oral CDK9 inhibitor voruciclib combined with venetoclax for patients with relapsed/refractory acute myeloid leukemia |
| title_short | The oral CDK9 inhibitor voruciclib combined with venetoclax for patients with relapsed/refractory acute myeloid leukemia |
| title_sort | oral cdk9 inhibitor voruciclib combined with venetoclax for patients with relapsed refractory acute myeloid leukemia |
| url | http://www.sciencedirect.com/science/article/pii/S2950328025000433 |
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