Olverembatinib (HQP1351) plus blinatumomab (Blincyto) generated promising response rates, bridging to CAR T-cell therapy success rates, and a manageable safety profile in patients with relapsed/refractory Philadelphia chromosome (Ph)–positive lymphoid blast-phase chronic myeloid leukemia (CML) and Ph-positive B-cell precursor acute lymphoblastic leukemia (B-ALL), according to data from the phase 1b HQP1351CU101 trial (NCT04260022) presented at the 2026 ASCO Annual Meeting.¹
Additionally, the ongoing phase 3 POLARIS-2 (NCT06423911) trial is evaluating olverembatinib in patients with chronic-phase (CP) CML who have been previously treated with TKIs. This trial is currently enrolling, according to a poster presented at ASCO 2026.2
In HQP1351CU101, among evaluable patients (n = 11), the combination of olverembatinib and blinatumomab produced a complete response (CR) or CR with incomplete count recovery (CRi) rate of 90.9%.1 Moreover, evaluable patients (n = 12) achieved a minimal residual disease (MRD)–negativity rate of 66.7%, and 80% of evaluable patients (n = 10) achieved MRD negativity by flow cytometry at a sensitivity of 10⁻⁴.
“We believe olverembatinib is one of the best TKIs available, [because it] overcomes resistance and intolerance,” Elias Jabbour, MD, said in an exclusive interview with OncLive®. “With the best TKI, [olverembatinib], and the best CD19 inhibitor, [blinatumomab], among a series of patients with refractory disease, we have almost everyone responding…. At the last follow-up, we had patients with ongoing responses. These are good data.”
Jabbour is a professor of leukemia at The University of Texas MD Anderson Cancer Center in Houston.
Of the 13 patients enrolled, 5 remained on treatment at data cutoff; among the 8 who discontinued, 3 were bridged to CAR T-cell therapy, 2 were bridged to allogeneic stem cell transplantation, 1 had progressive disease, and 2 discontinued for other reasons.
Regarding safety, olverembatinib-associated and blinatumomab-associated treatment-related adverse effects (TRAEs) of any grade occurred 69.2% of patients each. Grade 3 or higher olverembatinib-associated TRAEs occurred in 46.2% of patients, and 38.5% of patients had TRAEs associated with blinatumomab. Serious TRAEs associated with these respective agents occurred in 1 patient each. The most common grade 3 or higher TRAE was neutropenia, which was associated with these respective agents in 23.1% of patients each. Notably, blinatumomab-related grade 3 or higher cytokine release syndrome (CRS) occurred in 23.1% of patients. Olverembatinib-related grade 3 or higher TRAEs of increased blood creatine phosphokinase levels, increased lipase levels, thrombocytopenia, and pancreatitis occurred at rates of 7.7%.
“There were no safety concerns,” Jabbour asserted. “We have not seen CRS or immune effector cell–associated neurotoxicity syndrome of grade 3 or 4. That gives us proof that the combination is tolerable.”
What was the design of the HQP1351CU101 trial evaluating olverembatinib plus blinatumomab in CML and B-ALL?
The multicenter, open-label study enrolled patients who were at least 18 years of age with TKI-resistant or -intolerant or MRD-positive disease. If patients had uncontrolled cardiovascular disease or significant central nervous system pathology, they were excluded from the trial.
The study used a 3+3 dose-escalation design. Patients received olverembatinib at a starting dose of 30 mg every other day, with escalation to 40 mg every other day if no dose-limiting toxicities occurred among the first 3 patients, combined with standard-dose blinatumomab for up to 5 cycles that were 6 weeks long. Patients who completed the combination phase moved to a maintenance phase, receiving 30-mg or 40-mg doses of olverembatinib alone every other day.
Olverembatinib’s Development in CML and B-ALL: Need-to-Knows
- Olverembatinib plus blinatumomab produced a 90.9% CR/CRi rate in relapsed/refractory Ph-positive ALL and CML.
- The regimen served as an effective bridge, with 23.1% of patients proceeding to CAR T-cell therapy and 15.4% of patients receiving to allogeneic transplant.
- Grade 3 or higher toxicities were manageable and included neutropenia and cytokine release syndrome, with no new safety signals identified.
- Olverembatinib is being evaluated in the ongoing POLARIS-2 trial vs bosutinib in patients with CP CML.
Safety, tolerability, and efficacy were all primary end points.
Baseline characteristics revealed that patients had a median age of 48 years (range, 32-68) and were mostly male (61.5%). Additionally, 38.5% of patients were White. Patients had also received a median of 2 prior TKIs (range, 1-5), and 61.5% of patients had received prior blinatumomab. Disease biology was predominantly Ph-positive B-ALL (92.3%), with fewer patients having CML (7.7%). Most patients were MRD positive at baseline (61.5%) and carried p190 BCR::ABL1 transcript type (69.2%), with fewer harboring T315I mutations (15.4%).
“The next step [for olverembatinib and the combination] is to take them into the frontline [setting],” Jabbour added.
What are the design and significance of POLARIS-2?
Based on the data from HQP1351CU101, POLARIS-2 is a global, multicenter, open-label study being conducted in 2 parts.2 The study is enrolling patients who are at least 18 years of age and have an ECOG performance status of 2 or less, with adequate organ function.
Across both parts, patients must have experienced treatment failure or intolerance with the most recent TKI they received. If patients have had previous accelerated- or blast-phase CML or are planned for stem cell transplant, they will not be included in either part of the trial.
Part A of the trial is enrolling patients with CP CML previously treated with at least 2 approved TKIs (n = 285). If patients have received prior bosutinib (Bosulif) or harbored a bosutinib-resistant mutation, they will not be included in Part A. Patients are being randomly assigned to receive olverembatinib at 30 mg every other day or bosutinib at 500 mg daily. Patients randomly assigned to receive bosutinib who develop treatment failure, as defined by 2025 European LeukemiaNet guidelines, will be allowed to cross over to receive olverembatinib treatment.
In Part B, patients are required to have CP CML harboring a T315I mutation and have previously received at least 1 prior approved TKI (n = 48). These patients are being enrolled into a single-arm olverembatinib cohort.
The primary end point of both parts of the trial is 24-week major molecular response rate.
“If [POLARIS-2] is completed and favorable, [olverembatinib] will be a new drug approved for us,” Jabbour explained. “If we can get a [TKI] approved that is as potent as ponatinib [Iclusig] and safer, that will be one of the best drugs we have for CML. Olverembatinib has [been] shown to be at least as effective, if not more effective, than ponatinib with a great safety profile.”
POLARIS-2 is active and open to enrollment across sites in the United States, Canada, Mexico, Brazil, Australia, South Korea, Japan, Singapore, Hong Kong, Taiwan, India, Spain, France, Italy, Belgium, United Kingdom, Poland, Germany, and Turkey.
References
- Jabbour E, Baer M, Hunter A, et al. Olverembatinib (HQP1351) combined with blinatumomab in patients with lymphoid blast phase chronic myeloid leukemia (CML-LBP) or Philadelphia chromosome–positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCP-ALL). J Clin Oncol. 2026:44(6513). doi:10.1200/JCO.2026.44.16_suppl.6513
- Jabbour E, Kantarjian H, Turkina A, et al. A phase 3 study of olverembatinib (HQP1351) in patients with chronic-phase chronic myeloid leukemia: POLARIS-2 trial in progress. J Clin Oncol. 2026:44(6608). doi:10.1200/JCO.2026.44.16_suppl.TPS6608
