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.

在酪氨酸激酶抑制剂（TKI）开发后的时代，对于既往未经治疗的费城染色体阳性急性淋巴细胞白血病（Ph + ALL）临床健康患者的当前治疗标准是第一代或第二代 TKI 联合化疗或皮质类固醇，然后进行同种异体干细胞移植（allo-HCT）。然而，复发仍然会发生，主要是因为白血病进展过程中 T315I 突变的演变以及诱导后完全分子缓解 (CMR) 率低下。¹早期和持续的 CMR 可能有助于识别从异基因 HCT 中获益有限的人群。²鉴于化疗和移植的各种并发症对生活质量产生不利影响，医生正在探索“免化疗”诱导方案以及在CR1期省略移植。最近，blinatumomab 和 venetoclax 被整合到无化疗方案中，以 TKI 为骨干，从而彻底改变了难治性 Ph + ALL 或 Ph + ALL 复发患者的治疗格局。此外，在一线环境中对 blinatumomab 联合 TKI 进行的研究代表了治疗 de novo Ph + ALL 的一项有前途的创新。³ Olverembatinib是我国自主研发的第三代TKI，目前尚未报道对Ph+ALL有效。

因此，我们设计了一项前瞻性1/2期临床研究，以评估olverembatinib联合维奈托克和地塞米松（即OVD方案）对未经治疗的Ph + ALL患者的有效性和安全性。本研究按照赫尔辛基宣言原则进行，并经西京医院伦理委员会批准。所有患者均提供知情同意书。根据既定标准评估完全缓解/计数不完全恢复的完全缓解（CR/CRi）。采用十色流式细胞仪评估微小残留病（MRD）；它在骨髓中有核细胞中可以达到<1×10 ^-4的敏感性。通过定量聚合酶链式反应测定评估，BCR-ABL1 转录水平分别低于 0.01% 和 0.1%，表明 CMR 和主要分子缓解 (MMR)。无进展生存期被认为是从诊断到疾病进展或因任何原因死亡的时间。总生存期确定为从诊断到死亡或最后一次随访的时间，以先发生者为准。美国国家癌症研究所不良事件通用术语标准（5.0 版）用于评估不良事件。

OVD方案包括诱导治疗和持续治疗，每28天一个疗程。在诱导周期期间，患者每隔一天口服 40 mg olverembatinib，同时静脉注射地塞米松（第 1-14 天 10 mg，第 15-28 天 5 mg）。接受两剂olverembatinib后，采用每日剂量递增策略（第4天100 mg，第5天200 mg，第6-17天400 mg）给予venetoclax。当诱导治疗三个周期内达到CR/CRi时，患者进入持续治疗阶段。在此阶段，患者在第 1-28 天每隔一天接受 40 mg olverembatinib，并在每个周期的前 2 周每天接受 400 mg Venetoclax，直到出现进展、无法耐受的毒性或最多 3 年停药。仅当三个周期的诱导治疗后未达到 CMR 和阴性 MRD 时才考虑 CR1 阶段的 Allo-HCT。地塞米松可作为诱导治疗前的预处理施用。中枢神经系统（CNS）白血病按照国家综合癌症网络指南提出的标准方案进行管理。对于服用 CYP3A4 抑制剂的患者，根据药物相互作用的标准指南调整 olverembatinib 和 Venetoclax 的剂量。

本研究于 2022 年 8 月至 2023 年 11 月期间在两个医疗中心招募了 10 名患者（表 S1）；其中包括 6 名女性和 4 名男性（中位年龄 41 岁；范围 27-60 岁）。3 名患者的东部肿瘤合作组表现状态≥3。两名患者具有 BCR/ABL p210，而其余患者具有 BCR/ABL p190。接受的治疗周期中位数为 8.5 个（范围 1-17）。

在第一个周期的第 14 天，所有 10 名患者均达到 CR/CRi 并表现出阴性 MRD。此外，分别在 8 名和 5 名患者中观察到 MMR 和 CMR。很大一部分患者（即 90% [ n  = 9]）在接受两个周期的治疗后达到了 CMR；其中包括 7 名患者 (70%) 在一个周期后达到 CMR。7 号患者具有复杂的核型，在四个周期的治疗后实现了 CMR。值得注意的是，接受全胃切除术的 9 号患者也在 14 天内实现了快速 CMR，这表明胃切除术可能不会对给药药物的吸收产生影响。在开始诱导治疗后 13 天内（范围为 4-13 天），所有患者的血红蛋白水平和血小板计数开始增加，从而迅速过渡到独立输血。5 名患者需要输注红细胞（范围：1.5-8 单位），6 名患者需要输注血小板（范围：0-20 单位）。达到CR/CRi后，所有患者均接受持续的olverembatinib和venetoclax联合治疗。7 号患者被考虑进行异基因 HCT。所有患者均存活，没有任何复发迹象，中位随访时间为 7.4 个月（范围：1.8-16 个月）。在诱导阶段获得的阴性 MRD 和 CMR 结果在最后一次随访中持续存在，并且中枢神经系统受累无法检测到（图 1，表 S2）。

OVD 方案的耐受性是可以接受的（表 S3）。考虑到第一个周期血细胞减少和白血病之间的潜在相关性，我们评估了 OVD 方案第二个周期的血液学不良事件。三名患者在持续治疗期间出现 4 级中性粒细胞减少症，两名患者出现暂时性发作，但没有发热性中性粒细胞减少症。大多数非血液学不良事件为 1-2 级。两名患者出现 3 级肺炎，三名患者分别出现 3 级发热性中性粒细胞减少症、下肢无力和高血压。没有观察到肿瘤溶解综合征或任何原因导致的死亡病例。在所有患者中，有3名患者因血液毒性、肺炎或高血压而因不良事件导致停药，停药时间分别为7、13和37天。由于一名患者出现 4 级中性粒细胞减少症，另一名患者出现 3 级高血压，两名患者的 Venetoclax 或 olverembatinib 剂量减少。

这项研究首次评估了无化疗 OVD 方案在新发 Ph + ALL 患者中的初步有效性和安全性。所有患者均在13天内实现了输血独立，并在第14天表现出阴性MRD；9 名患者在 90 天内达到了 CMR。所有这些结果在整个随访期间均得到维持。先前的一项研究表明，快速达到深度 CMR 可能表明该亚组患者首次缓解后，allo-HCT 的长期结果良好，但获益有限。²此外，观察到的不良事件在可接受的限度内。因此，这些患者（包括诊断时身体状况不佳的患者）在病情缓解后无需住院即可接受治疗，生活质量迅速提高。此外，治疗成本并没有显着高于历史对照。其他策略，例如使用基于 ponatinib 的疗法（与 hyper-CVAD 或 blinatumomab 组合）作为一线治疗，在 Ph + ALL 患者中取得了优异的效果，显示 CR/CRi 率接近 100%，并且CMR 率为 84%–87%。^3-5此外，venetoclax 对复发性或难治性 ALL 表现出高活性。⁶与特定的标准治疗相比，OVD 方案（由我们首先设计）在未经治疗的 Ph + ALL 患者中引起了更高、更快的反应，并表现出更可靠的安全性，尽管患者数量有限且随访有限。

总之，我们的研究首次证明了 OVD 方案相对于未经治疗的 Ph + ALL 患者的特定标准治疗具有显着优势。初步结果表明，接受 OVD 方案的患者迅速从输血中解脱出来，并获得快速和深度的缓解。这一治疗方案将进一步加速初诊Ph+ALL患者向无化疗时代过渡，让他们在持续治疗阶段能够接受家庭治疗，而不是住院治疗。预计 OVD 方案的长期有效性，我们打算增加参与者注册并延长随访时间。