Venetoclax-Ponatinib for T315I/Compound-Mutated Ph+Acute Lymphoblastic Leukemia

The outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) have greatly improved in tyrosine kinase inhibitors (TKIs) era and is just moving to a chemo-free era using dasatinib and blinatumomab (Foà R, N Engl J Med. 2020; Ravandi F, Blood. 2019). However, the outcome of T...

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Published in:Blood 2021-11, Vol.138 (Supplement 1), p.3395-3395
Main Authors: Wang, Huafeng, Qian, Jiejing, Yang, Chang, Zhang, Yi, Wang, Yungui, Shi, Ting, HU, Yongxian, Mao, Liping, Ye, Xiujin, Liu, Fang, Xi, Zhenfang, Shou, Lihong, Fu, Caiyun, Naranmandura, Hua, Jin, Jie, Zhu, Hong-Hu
Format: Article
Language:English
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Summary:The outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) have greatly improved in tyrosine kinase inhibitors (TKIs) era and is just moving to a chemo-free era using dasatinib and blinatumomab (Foà R, N Engl J Med. 2020; Ravandi F, Blood. 2019). However, the outcome of T315I/compound-mutated Ph+ ALL patients is dismal (Cortes JE, N Engl J Med. 2013), representing an unmet need. Recently, Scherr et al reported the curative potential of venetoclax-TKIs-dexamethasone in a BCR-ABL+ mouse model (Scherr M, Leukemia. 2019). Here, we firstly reported outcome of 19 T315I/compound-mutated relapsed/refractory （R/R）Ph+ ALL patients treated with venetoclax(100mg d1, 200mg d2, 400mg d3-28), ponatinib (45mg d1-28) and dexamethasone (0.15mg/kg d1-21,0.075mg/kg d22-28）(VPD regimen) (Figure 1A) between January 2020 and May 2021. They had already received a median of 3 lines of salvage therapy. After one cycle, 17 patients (89.5%) achieved CR/CRi [13 minimal residual disease (MRD)–negative by flow cytometry;11 major molecular remission (MMR);8 complete molecular remission (CMR)] (Figure 1B). Subsequently relapse occurred in 1/6 [allogeneic hematopoietic cell transplantation (allo-HSCT) group)] and 7/11 (VDP consolidation group). At a median follow-up of 259 days, the median EFS and OS of patients from the starting VPD treatment was 242 and 400 days. Adverse events of VPD regimen were listed in Figure 1C. Grade 3-4 neutropenia, anemia and thrombocytopenia occurred in 73.7%,36.8% and 52.6% patients. 5.3% and 16% patients have grade 3-4 rash and infection separately. No tumor lysis syndrome or death occurred. 7/19 patients were treated safety outpatient. Moreover, venetoclax had a strong synergistic effect with ponatinib and dexamethasone on inducing apoptosis of primary blast cells and BaF3 cells expressing p190 BCR/ABL with T315I-mutation in vitro, with a combination index of 0.019 when the suppressing rate is 0.05, while the effect was significant decreased when ponatinib was replaced by dasatinib (Figure 1D-F), a prominent change of mitochondrial membrane potential as well as the cleavage of PARP were also observed in triple-combination treatment group (Figure 1G-H). For T315I/compound-mutated Ph+ ALL, VPD regimen exhibited 89.5% CR/CRi rate, with deep molecular remission (57.9% MMR), while ponatinib alone showed 41% hematologic response (Cortes JE, N Engl J Med. 2013), which supported by the preclinical data suggesting TKIs and venetoclax are h
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2021-152836