Differential regulation of BAX and BAK apoptotic activity revealed by small molecules.Science advances • March 05, 2025
Kaiming Li, Yu Yap, Donia Moujalled, Fransisca Sumardy, Yelena Khakham, Angela Georgiou, Michelle Jahja, Thomas Lew, Melanie De Silva, Meng-xiao Luo, Jia-nan Gong, Zheng Yuan, Richard Birkinshaw, Peter Czabotar, Kym Lowes, David C Huang, Benjamin Kile, Andrew Wei, Grant Dewson, Mark Van Delft, Guillaume Lessene
Defective apoptosis mediated by B cell lymphoma 2 antagonist/killer (BAK) or B cell lymphoma 2-associated X protein (BAX) underlies various pathologies including autoimmune and degenerative conditions. On mitochondria, voltage-dependent anion channel 2 (VDAC2) interacts with BAK and BAX through a common interface to inhibit BAK or to facilitate BAX apoptotic activity. We identified a small molecule (WEHI-3773) that inhibits interaction between VDAC2 and BAK or BAX revealing contrasting effects on their apoptotic activity. WEHI-3773 inhibits apoptosis mediated by BAX by blocking VDAC2-mediated BAX recruitment to mitochondria. Conversely, WEHI-3773 promotes BAK-mediated apoptosis by limiting inhibitory sequestration by VDAC2. In cells expressing both pro-apoptotic proteins, apoptosis promotion by WEHI-3773 dominates, because activated BAK activates BAX through a feed-forward mechanism. Loss of BAX drives resistance to the BCL-2 inhibitor venetoclax in some leukemias. WEHI-3773 overcomes this resistance by promoting BAK-mediated killing. This work highlights the coordination of BAX and BAK apoptotic activity through interaction with VDAC2 that may be targeted therapeutically.
Olutasidenib alone or combined with azacitidine in patients with mutant IDH1 myelodysplastic syndrome.Blood AdvancesBlood Advances • April 07, 2025
Jorge Cortes, Jay Yang, Gail Roboz, Shira Dinner, Eunice Wang, Andrew Wei, Hua Tian, Francois Di Trapani, Maria Baer, William Donnellan, Justin Watts
Olutasidenib, a potent, selective, oral small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), is FDA-approved for mIDH1 relapsed/refractory (R/R) acute myeloid leukemia based on results from the pivotal AML cohort of a multi-arm phase 1/2 trial that also enrolled patients with MDS (NCT02719574). We report pooled data evaluating olutasidenib as monotherapy or combined with azacitidine in R/R and treatment-naĂŻve (TN) higher-risk MDS harboring mIDH1. Endpoints included safety, overall response rate (ORR), complete remission (CR) rate, time-to-response (TTR), duration of response (DOR), overall survival (OS), and transfusion-independence. Twenty-two patients (median age 74 years, 59% male) with IPSS-R intermediate- to very high-risk MDS (n=6 monotherapy [4 R/R, 2 TN]; n=16 combination [11 R/R, 5 TN]) were analyzed. The most frequent AEs were fatigue and cytopenias. Differentiation syndrome occurred in 3 patients (14%); 1(5%) grade 3 severity. QT prolongation occurred in 1 patient receiving combination therapy. ORR was 59% (CR: 27%, 6/22; marrow CR: 32%, 7/22) in intent-to-treat (n=22, ITT) and 68% (CR: 32%, 6/19; marrow CR: 37%, 7/19) in response-evaluable (n=19) patients. ORR (ITT population) was 33% (2/6) for monotherapy (3/6 patients received ÂŁhalf the recommended dose) and 69% (11/16) for combination therapy. Median TTR was 2 months (range 1-13), median DOR 14.6 months (95% CI, 5.8-32.8), and median OS 27.2 months (95% CI, 6.9-37). 62% and 67% of patients who were transfusion-dependent at baseline achieved 56-day RBC and platelet transfusion independence, respectively. Olutasidenib with or without azacitidine demonstrated encouraging clinical activity and tolerability in patients with higher-risk mIDH1 MDS. NCT02719574.
Time to complete remission is an independent determinant of survival after intensive chemotherapy in AML. Blood • January 27, 2025
Rithin Nedumannil, Michael Ashby, James Rowland, Jacques A Malherbe, Jared Fairbank, Kelli Gray, Sun Loo, Matthew Wright, John Reynolds, Devendra Hiwase, Paula Marlton, Shaun Fleming, Ashish Bajel, Andrew Wei
The purpose of this study was to explore and determine the optimal landmark for defining complete remission after intensive induction therapy that best correlates with long-term survival outcome among patients with newly diagnosed acute myeloid leukemia (AML).
Standardization of Bone Marrow Reporting for Myelodysplastic Syndromes/Neoplasms on Behalf of the International Consortium for Myelodysplastic Syndromes/Neoplasms.Archives Of Pathology & Laboratory Medicine • January 15, 2025
Savanah Gisriel, Fnu Aakash, John Bennett, Robert Hasserjian, Sanam Loghavi, Amy Dezern, Valeria Santini, Michael Savona, Andrew Brunner, Rena Buckstein, Andrew Wei, Matteo Della Porta, Rami Komrokji, Uma Borate, Mikkael Sekeres, Uwe Platzbecker, Pierre Fenaux, Gail Roboz, Arjan Van De Loosdrecht, Amer Zeidan, Mina Xu
Standardized bone marrow reporting specifically for myelodysplastic syndromes/neoplasms (MDS) is currently lacking in the literature and much needed in practice. To propose a standardized approach to MDS evaluation in bone marrow specimens by (1) enhancing interinstitutional and intrainstitutional collaborations and clinical decision-making among hematopathologists and clinical hematologists and (2) allowing for efficient data extraction for clinical trials, institutional databases, and registry templates. This suggested approach is summarized in a modifiable, user-friendly template for hematopathologists to reference as they examine bone marrows (in the Supplemental Digital Content). We built upon the bone marrow template reporting guideline outlined by the College of American Pathologists Pathology and Laboratory Quality Center for Evidence-Based Guidelines and gathered expert insight from hematopathologists and hematologists-oncologists who specialize in MDS. This proposed approach to MDS evaluation in the bone marrow standardizes reporting, which enhances communication among health care professionals and allows for efficient data extraction.
Frailty and geriatric assessments in older patients diagnosed with acute myeloid leukaemia: an Australasian Leukaemia and Lymphoma Group consensus statement.Internal Medicine Journal • December 05, 2024
Briony Shaw, Victoria Ling, Ruth Hubbard, Ashish Bajel, Devendra Hiwase, Paula Marlton, Sushrut Patil, Travis Perera, Jacinta Perram, Shuh Tan, Xuan Tan, Andrew Wei, Nada Hamad, Chong Chua
The treatment of acute myeloid leukaemia (AML) is rapidly changing, and treatment decisions are more complex, with increasing therapeutic options available for those 'unfit' for intensive cytotoxic therapy. With the median age of 69 years at diagnosis, frailty is expected to be highly prevalent in patients with AML. An individualised approach is required, accounting for disease biology, chronological age, functional status, social factors, patient-directed goals of care and co-morbidities. This Australasian Leukaemia and Lymphoma Group (ALLG) consensus statement aims to highlight the importance of performing geriatric and frailty assessments (FAs) in older patients diagnosed with AML and provide practical recommendations on integrating FAs into routine clinical practice within the Australian and New Zealand context. We recommend FAs be widely implemented and tailored to the resources of individual centres to provide an objective measure of fitness of older patients with AML to assist therapeutic decisions at diagnosis as well as at serial timepoints throughout the disease course. Deficits in domains identified by FAs can specifically be targeted through supportive care interventions aiming to improve tolerance of therapy. FAs should be incorporated into clinical trials and be prioritised for funding and resources.
