Results of POLARIS-1, a global Phase 3 study (Part A): Olverembatinib combined with low-intensity chemotherapy in patients with newly diagnosed (ND) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) Free

Introduction Ph⁺ ALL is the most common genetic subtype of adult ALL, is associated with high relapse risk and poor outcomes, and is increasingly being managed with targeted therapies. Olverembatinib is a third-generation tyrosine kinase inhibitor with potent inhibitory activity against wild-type and mutant BCR-ABL1. The aim of this global phase 3 study, POLARIS-1, is to assess the efficacy and safety of olverembatinib plus reduced-intensity chemotherapy in patients with ND Ph⁺ ALL.

Methods Part-A of this multicenter phase 3 clinical trial, POLARIS-1, enrolled patients with confirmed BCR-ABL1 genetic variants, ECOG PS ≤ 2, and adequate organ function. Olverembatinib 40 or 30 mg was administered orally QOD in 28-day cycles. Induction therapy comprised 3 cycles of VD or VDP: vincristine 1.4 mg/m²(maximum 2 mg) on days (D) 1, 8, 15, and 22; dexamethasone 10 mg on D1–14, 5 mg on D15–21, and 2.5 mg on D22–28; and daunorubicin 25 mg/m²(maximum 40 mg; 20 mg for patients ≥ 70 years) on D1–3. Consolidation alternated 3 cycles of high-dose methotrexate (1.0 g/m², 1 day) with 3 cycles of cytarabine (1,000 mg/m²every 12 hours; 250 mg/m² every 12 hours for patients > 60 years, 3 days). Maintenance therapy of mercaptopurine plus methotrexate and VP was alternated for 12 cycles at standard dosages. The primary endpoint was MRD negativity (BCR-ABL/ABL1 ≤ 0.01% by qPCR) by the end of 3 induction cycles. Correlative analyses were performed using baseline sample genetic profiles.

Results As of July 18, 2025, 55 patients were enrolled (median age 43 years; 63.6% female). BCR-ABL1 variant subtypes were p190 in 36 patients (65.5%), p210 in 16 (29.1%), p230 in 1 (1.8%), and p190+p210 in 2 (3.6%); the mean treatment duration was 9.6 months. Among 53 efficacy-evaluable patients, complete remission (CR) or CR with incomplete hematologic recovery was achieved in 50patients (94.3%) by the end of induction. MRD negativity rates increased over time: 19 (35.8%) at cycle (C) 1, 28 (52.8%) at C2, and 30 (56.6%) at C3. MRD-negative CR rates were 19 (35.8%) after C1, 27 (50.9%) after C2, and 28 (52.8%) after C3, showing deeper responses with longer treatment. Best MRD negativity and MRD-negative CR rates by the end of 3 cycles were 35 (66.0%) and 34 (64.2%), respectively. Among 55 safety-evaluable patients, 54 (98.2%) had ≥ 1 TEAE, including (> 50%) neutropenia (72.7%), leukopenia (70.9%), anemia (69.1%), hypokalemia (69.1%), thrombocytopenia (61.8%), neuropathy peripheral (52.7%), hyperuricemia (52.7%), and ALT increased (50.9%). Grade ≥ 3 TEAEs with incidence > 15% were neutropenia (63.6%), thrombocytopenia (56.4%), leukopenia (54.5%), anemia (49.1%), pneumonia (30.9%), hypokalemia (20%), and hepatic function abnormal (16.4%). Two patients died because of TEAEs (1 pneumonia; 1 pulmonary edema with septic shock), assessed as unrelated or unlikely related to olverembatinib. One patient had grade 2 coronary artery disease possibly related to olverembatinib. Olverembatinib plus chemotherapy was generally well tolerated. Treatment discontinuation occurred because of HSCT (n = 5, 9.1%), disease progression (n = 4, 7.3%; 1 refractory, 3 CNS/bone marrow relapse), and toxicity (n = 5, 9.1% [1 with polyserositis (probably related to olverembatinib) and 4 with peripheral neuropathy, pneumonia, or pulmonary edema (unlikely related to olverembatinib)]. A total of 6 (10.9%) patients withdrew from study for reasons unrelated to efficacy. No significant differences in efficacy or safety were observed between olverembatinib 30 and 40 mg. The PK profile of olverembatinib plus chemotherapy was similar to that of monotherapy. Copy number alterations in IKZF1, CDKN2A/B, PAX5, PAR1, EBF1, ETV6, BTG1, and RB1 genes were analyzed at baseline using multiplex ligation-dependent probe amplification and next-generation sequencing. Among 50 tested patients, 10 had the IKZF1^plus genotype, of whom 9 achieved MRD-negative status by the end of induction and 1 was not efficacy evaluable. All 7 patients with co-occurring IKZF1 and BTG1 deletions achieved MRD-negative status within the induction period.

Conclusions In patients with ND Ph⁺ ALL treated with olverembatinib plus chemotherapy, the MRD-negative CR rate was 64.2% by the end of induction, including in patients with inferior prognostic genotypes. The regimen extended the window for further treatment and demonstrated a favorable safety profile. (NCT06051409; HQP1351AG301).