A New Chemotherapy-Free Regimen of Olverembatinib in Combination with Venetoclax and Dexamethasone for Newly Diagnosed Ph Plus Acute Lymphoblastic Leukemia: Preliminary Outcomes of a Prospective Study

In the era following the development of tyrosine kinase inhibitors (TKIs), the current standard of treatment for clinically fit patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is first- or second-generation TKIs combined with chemotherapy or corticosteroids, followed by allogeneic stem cell transplantation (allo-HCT). However, relapse still occurs primarily because of the evolution of the T315I mutation during leukemia progression and the dismal rate of complete molecular remission (CMR) after induction.1 Early and persistent CMR may be helpful in identifying populations that experience limited benefits from allo-HCT.2 In light of the various complications of chemotherapy and transplantation that adversely affect the quality of life, doctors are exploring "chemotherapy-free" induction regimens and the omission of transplantation in the CR1 stage. Recently, blinatumomab and venetoclax were integrated into chemotherapy-free regimens, with TKIs serving as the backbone, thereby revolutionizing the treatment landscape of patients with refractory Ph + ALL or a Ph + ALL relapse. Furthermore, the investigation of blinatumomab plus TKIs in a frontline setting represents a promising innovation in the treatment of de novo Ph + ALL.3 Olverembatinib, a third-generation TKI developed independently in China, has not been reported to be effective against Ph + ALL. Therefore, we designed a prospective, phase 1/2 clinical study to assess the effectiveness and safety of olverembatinib plus venetoclax and dexamethasone (i.e., the OVD regimen) in patients with untreated Ph + ALL. This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Xijing Hospital. All patients provided informed consent. Complete remission/complete remission with incomplete count recovery (CR/CRi) was assessed on the basis of established criteria. Ten-color flow cytometry was used to assess minimal residual disease (MRD); it could reach a sensitivity of <1 × 10−4 among the nucleated cells in the bone marrow. CMR and major molecular remission (MMR) were indicated by BCR-ABL1 transcript levels of below 0.01% and 0.1%, respectively, as evaluated by a quantitative polymerase chain reaction assay. Progression-free survival was recognized as the time from diagnosis to disease progression or death from any cause. Overall survival was determined as the time from diagnosis to death or the last follow-up, whichever occurred first. The National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0) were used for assessing adverse events. The OVD regimen comprised induction and continuous therapies, with a course of treatment every 28 days. During the induction cycle, the patients received 40 mg of olverembatinib orally every other day, along with intravenous dexamethasone (10 mg on days 1–14 and 5 mg on days 15–28). After two doses of olverembatinib, venetoclax was administered using a daily ramp-up strategy (100 mg on day 4, 200 mg on day 5, and 400 mg on days 6–17). Whenever CR/CRi was achieved within three cycles of induction therapy, the patients entered the continuous treatment phase. In this phase, the patients received 40 mg of olverembatinib every other day on days 1–28 and 400 mg of venetoclax daily for the first 2 weeks of each cycle until progression, intolerable toxicity, or withdrawal for a maximum of 3 years. Allo-HCT in the CR1 stage was considered only if CMR and negative MRD were not achieved after three cycles of induction therapy. Dexamethasone could be administered as pretreatment prior to induction therapy. Central nervous system (CNS) leukemia was managed in accordance with the standard protocol proposed by the National Comprehensive Cancer Network Guidelines. For patients taking a CYP3A4 inhibitor, the olverembatinib and venetoclax dosages were adjusted according to the standard guidelines for drug–drug interactions. Ten patients were recruited in this study at two medical centers between August 2022 and November 2023 (Table S1); these comprised six women and four men (median age, 41 years; range, 27–60 years). The Eastern Cooperative Oncology Group performance status of three patients was ≥3. Two patients had BCR/ABL p210, whereas the remaining patients had BCR/ABL p190. The median number of treatment cycles received was 8.5 (range, 1–17). On day 14 of the first cycle, all 10 patients achieved CR/CRi and exhibited negative MRD. Moreover, MMR and CMR were observed in eight and five patients, respectively. A significant proportion of patients (i.e., 90% [n = 9]) achieved CMR after undergoing two cycles of treatment; these included seven patients (70%) who attained CMR after one cycle. Patient #7, with a complex karyotype, achieved CMR after four cycles of treatment. It is worth noting that patient #9, who underwent total gastrectomy, also achieved rapid CMR within 14 days, indicating that gastrectomy might not have had an impact on the absorption of the administered drugs. The hemoglobin levels and platelet counts began to increase in all patients within 13 days (range, 4–13 days) after starting induction therapy, which led to a rapid transition toward transfusion independence. Red blood cell transfusion was required in five patients (range, 1.5–8 units) and platelet transfusion was required in six patients (range, 0–20 units). After achieving CR/CRi, all patients received continuous olverembatinib and venetoclax combination therapy. Patient #7 was considered for allo-HCT. All patients survived without any signs of relapse, with a median follow-up of 7.4 months (range, 1.8–16 months). The negative MRD and CMR results obtained during the induction phase persisted throughout the last follow-up, along with undetectable CNS involvement (Figure 1, Table S2). The tolerability of the OVD protocol was acceptable (Table S3). Considering the potential correlation between cytopenia and leukemia during the first cycle, we evaluated the hematological adverse events from the second cycle of the OVD regimen. Three patients experienced grade 4 neutropenia during continuous treatment, and two experienced temporary bouts without febrile neutropenia. Most non-hematological adverse events were of grade 1–2. Two patients experienced grade 3 pneumonia, and three experienced grade 3 febrile neutropenia, lower extremity weakness, and hypertension, respectively. No cases of the tumor lysis syndrome or death from any cause were observed. Among all the patients, adverse event-induced discontinuation occurred in three patients because of hematological toxicity, pneumonia, or hypertension, with the discontinuation lasting for 7, 13, and 37 days, respectively. The doses of venetoclax or olverembatinib were reduced for two patients because of grade 4 neutropenia in one patient and grade 3 hypertension in the other. This study represents the first assessment of the preliminary effectiveness and safety of a chemotherapy-free OVD regimen among patients with de novo Ph + ALL. All patients achieved transfusion independence within 13 days and exhibited negative MRD on the 14th day; nine patients achieved CMR within 90 days. All of these results were maintained throughout the follow-up period. A previous study has suggested that the rapid attainment of deep CMR might indicate favorable long-term outcomes and limited benefits from allo-HCT after the first remission in this subset of patients.2 Furthermore, the adverse events observed were within acceptable limits. Accordingly, these patients (including those with a poor physical status at diagnosis) were able to receive treatment without hospitalization after achieving remission and attained a rapidly improved quality of life. Moreover, the cost of treatment was not significantly higher than that for historical controls. Other strategies, such as the use of ponatinib-based therapies (a combination with hyper-CVAD or blinatumomab) as the front-line treatment, have yielded excellent results in individuals with Ph + ALL, showcasing a CR/CRi rate nearing 100% and CMR rates of 84%–87%.3-5 Additionally, venetoclax exhibits a high activity against relapsed or refractory ALL.6 Compared to specific standard treatment, the OVD regimen (first designed by us) elicited a higher and faster response and exhibited a more reliable safety profile in patients with untreated Ph + ALL, despite the limited number of patients with a limited follow-up. In conclusion, our study is the first to demonstrate a remarkable advantage of the OVD regimen over specific standard treatment for patients with untreated Ph + ALL. Preliminary findings indicate that patients who underwent the OVD regimen achieved prompt release from transfusions along with rapid and profound remission. This treatment protocol will further accelerate the transition of patients with newly diagnosed Ph + ALL to a chemotherapy-free era, allowing them to receive domestic therapy instead of undergoing hospitalization during the continuous treatment phase. Anticipating the long-term effectiveness of the OVD protocol, we intend to increase participant enrollment and extend the follow-up duration. Informed consent was obtained from all the patients. Guangxun Gao, Shuya Zhou, and Hailong Tang conceptualized the study, and all authors analyzed and interpreted the patient data. Shan Gao performed the histopathological examination of the bone marrow. Hailong Tang and Guangxun Gao were the major contributors to the writing of the manuscript. All authors have read and approved the final version of the manuscript. This study was funded by the National Natural Science Foundation of China (81970190, 82100218), Clinical New Technology Application Innovation Project of the Fourth Military Medical University (2023XJSY12), Social Development Key Project of Shaanxi Province (2019ZDLSF02-02), Translational Project of the National Medical Center (2020ZKMC01), and Health Scientific Research Innovation Ability Improvement Project of Shaanxi Province (2023TD-03). The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Baseline characteristics of the 10 patients with Ph + ALL. Table S2. Efficacy of the olverembatinib, venetoclax, and dexamethasone regimen in the 10 patients with Ph + ALL. Table S3. Adverse events due to the olverembatinib, venetoclax, and dexamethasone regimen in the 10 patients with Ph + ALL. 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