Olverembatinib (HQP1351): a third-generation tyrosine kinase inhibitor in the treatment of hematologic and solid malignancies—a comprehensive review of clinical outcomes

Abstract

The increasing prevalence of cancers, their economic impact and the complications associated with existing treatments, have stimulated research to better understand the mechanisms involved in their aetiology and the development of more effective diagnostic and treatment methods. Olverembatinib (HQP1351 or GZD824) is a new third-generation tyrosine kinase inhibitor (TKI), that is being investigated for its potential application in the treatment of several cancers, with a focus on chronic myeloid leukemia (CML). This review attempts to summarise the pre-clinical and clinical studies in hematological and non-hematological malignancies of this agent.

Introduction

With an estimation of more than 50,000 patients diagnosed daily and around 27,000 deaths per day, cancer remains an important public health challenge, and is predicted to account for morbidity and mortality of about 20 and 7.3 million by 2040, respectively [1, 2]. An important approach for decreasing global cancer mortality is the application of particular and individualized therapeutic strategies. The development of treatments over the past two decades highlights the transformative strategies in treatments that have enhanced clinical outcomes and improved the quality of life in affected individuals [3]. Imatinib is a tyrosine kinase inhibitor (TKI) that was approved by the FDA in 2001 for the treatment of chronic myeloid leukemia (CML) as the first specific targeting protein kinase to treat a disease [4].

Despite its success, mutations in the BCR::ABL1 gene has been recognized as an escape mechanism that limits imatinib inhibition [5]. Most of these mutations are addressed by second-generation TKIs such as nilotinib, dasatinib, and bosutinib [6]. However, they all face failure in the presence of the T315I mutation, known as the “gatekeeper” mutation [6]. Ponatinib, a third-generation TKI, was approved as an effective ABL1 inhibitor against the T315I mutation [7]. In clinical studies, Ponatinib has demonstrated high activity in patients with CML harboring T315I, with major cytogenetic response (MCyR) rates of ~ 70% and major molecular response (MMR) rates of ~ 40% after 12 months of therapy. In Ph + ALL, Ponatinib combined with chemotherapy has yielded complete remission rates of > 80%, although long-term molecular responses remain limited. Olverembatinib (HQP-1351, formerly known as GZD-824) is another third-generation TKI that targets a broad range of BCR::ABL1 mutants, including T315I, as well as the unmutated (wild-type) form of the BCR::ABL1 kinase [8, 9]. This drug’s inhibition effect is not limited to the BCR::ABL1 gene; it also targets other kinases, including KIT, FLT3, FGFR1, and PDGFRα [8, 10]. In addition to CML, olverembatinib has shown promising results in the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and solid tumors such as gastrointestinal stromal tumors (GIST) [11–13]. Our review aims to provide a comprehensive overview of olverembatinib’s therapeutic potential across various hematologic and non-hematologic cancers.

Olverembatinib in BCR::ABL1-driven leukemia

Chronic myeloid leukemia (CML)

A reciprocal translocation of chromosome 22 with chromosome 9 leads to a transformed chromosome called the Philadelphia chromosome (Ph) [14]. The joining of the ABL1 gene from chromosome 9 to the BCR gene at the translocation site of chromosome 22 creates the BCR:: ABL1 fusion gene [15, 16]. The oncoprotein synthesized from this gene transforms hematopoietic stem cells into leukemia cells through uncontrolled tyrosine kinase activity and the development of CML [17]. For context, Ponatinib remains the current standard option for CML patients with the T315I mutation. In the pivotal PACE trial, Ponatinib achieved a complete hematologic response in 92% and MCyR in 54% of chronic-phase patients with T315I, though vascular adverse events limited long-term use. Olverembatinib, was produced by Ascentage Pharma as a therapeutic option in CML, and obtained its initial approval in China on 24 November 2021 for adults with TKI-resistant CML in the chronic phase (CML-CP) or accelerated phase (CML-AP) possessing the T315I mutation [18].

The in vivo pharmacokinetic profile of olverembatinib oral administration showed robust oral bioavailability and an appropriate half-life [8]. Based on the findings of the studies conducted by Lu et al. and Jiangthe et al., oral administration of 40 mg of olverembatinib every other day was used for phase 2 of the study in patients with CML [19, 20]. After demonstrating its efficacy and tolerability in Phase II trials, olverembatinib received its initial approval in China [21–23]. Then, in November 2023, it was approved for a new indication in adult patients with CML-CP resistance and/or intolerant of first- and second-generation TKIs [23].

Ren et al., studied 10a (designated as GZD824) and demonstrated its ability to inhibit the proliferation of murine Ba/F3 cells expressing the native BCR::ABL1 gene and 15 resistance-relevant BCR::ABL1 mutations, including the T315I. This compound’s antiproliferative effect was reported to be selective for BCR::ABL1-positive human CML cells, including K562 and Ku812 and SUP-B15 human ALL cells. This was attributed to its suppression of BCR::ABL1 activation and its downstream signaling pathways. Furthermore, the tumor growth suppression in mice xenografted with K562 and Ku812, as well as in mice with BCR::ABL1 positive Ba/F3 allografts, revealed positive results. This study also demonstrated the dose-dependent survival prolongation of the mice allografted with Ba/F3 cells harboring the T315I mutant of the BCR::ABL1 gene, treated with 10a [8].

In a phase 1/2 study, a total of 101 CML patients with TKI resistance, including 86 with CP-CML and 15 with AP-CML, were enrolled in a phase I study. While having the T315I mutation in the BCR::ABL1 gene was not an inclusion criterion, 62.4% of participants harbored this mutation. They received increasing doses of olverembatinib (1–60 mg) every other day (QOD) in 28-day cycles across 11 cohorts. Entry into the next phase of the cohort study required a confirmed safety of olverembatinib. After establishing 40 mg as the phase II dose, 64 CML patients with resistance to TKIs, all of whom had the T315I mutation, were enrolled in phase II. All 165 patients were meticulously followed for an extended period. After a median follow-up period of 37 months from the beginning treatment with an effective dose (≥ 30 mg) in CP-CML, 100%, 79.3%, 69.4%, 55.6%, 44.4%, and 38.9% of evaluable patients experienced complete hematologic remission (CHR), MCyR, complete cytogenetic response (CCyR), MMR, MR4 (BCR::ABL1 mRNA IS level of less than 0.01%), and MR4.5 (BCR::ABL1 mRNA IS level of less than 0.0032%), respectively. The corresponding rates in evaluable AP-CML patients were 73%, 47.4%, 47.4%, 44.7%, 36.8%, and 34.2% after a median follow-up period of 27 months from the beginning treatment with ≥ 30 mg QOD. The 3-year cumulative incidence rate of all 165 participants of phase I and II is shown in Table 2 [20]. Among CP-CML patients, those with a single T315I mutation and those with no BCR::ABL1 mutation respectively had the highest and lowest 3-year cumulative rates of achieving MCyR and CCyR, as well as molecular responses defined by BCR::ABL1 mRNA IS levels (MMR, MR4, and MR4.5). Among AP-CML patients, those with a single T315I mutation had the highest 2-year cumulative rates, while unmutated or patients with other mutations didn’t achieve any molecular or cytogenetic responses. In multivariate analyses, the BCR::ABL1 mutation status, determined through both Sanger sequencing and NGS at the beginning of the study, demonstrated an independent correlation with the cumulative incidences of achieving MMR, MR4.0, and MR4.5. Additionally, a total of 12 patients progressed to the blast phase. Among CP-CML patients, 3 of the 7 deaths were due to disease progression, and 4 patients from the 11 AP-CML population who had progressed to CML-BP passed away [20].

Table 2.

Clinical outcomes of olverembatinib administration in the treatment of hematologic malignancies

Type of malignancy	Type of study	Regimen	Dosage		Outcomes		Refs.
CML	Clinical trial	Olverembatinib	1 to 60 mg		The highest MCyR rate was at 50 mg QOD and high MCyR rate accompanied by a controllable risk of grade ≥ 3 thrombocytopenia was at 40 mg.		[19]
CML	Clinical trial	Olverembatinib	40 mg		The 3-year cumulative incidence rates of MCyR, CCyR, MMR, MR4.0, MR4.5, PFS and OS were 79.0, 69.0, 56.0, 44.0, 39.0%, 92%, and 94% in CP-CML, respectively, and 47.4%, 47.4%, 44.7%, 39.3%, 32.1%, 60%, and 70% in AP-CML.		[20]
CML	Clinical trial	Olverembatinib	40 mg		The rates of CHR, MCyR, CCyR, and MMR were 96.8%, 75.6%, 65.9%, and 48.8% in CP-CML respectively, and 60.9%, 52.2%, 39.1%, and 26.1% in AP-CML. The mean 3-month PFS was 100% in AP and CP-CML and 6-month PFS was 95.5% in AP and 96.7% in CP-CML		[21]
CML	Clinical trial	Olverembatinib	40 mg		CHR, CCyR, MCyR, and MMR were achieved in 100%, 68.3%, 75.6%, and 56.1% of CP-CML respectively, and in 65.2%, 47.8%, 52.2%, and 39.1% of AP-CML At 12 months, the PFS rate and OS were 89.3% and 100% in CP-CML, respectively, and 74.1% and 91.3% in AP-CML		[22]
CML	Clinical trial	Olverembatinib	40 mg		CHR, CCyR, MCyR, and MMR were achieved in 100%, 70.7%, 82.9%, and 58.5% of CP-CML, respectively, and in 73.9%, 52.2%, 52.2%, and 47.8% of AP-CML At 36 months, the PFS rate and OS were 86.3% and 95.1% in CP-CML, and 57.1% and 69.6% in AP-CML		[26]
CML	Clinical trial	Olverembatinib	1 to 60 mg		At 36 months the cumulative incidence rates of MCyR, CCyR, and MMR, and PFS were 77.7%, 66.7%, 70%, and 96.3% in CP-CML, respectively, and 41.7%, 41.7%, 41.7%, and 71.4 in AP-CML		[24]
CML	Clinical trial	Olverembatinib	1 to 60 mg		At 48 months, the cumulative rates of MCyR, CCyR, and MMR, and PFS were 80.3%, 75.1%, 56.2%, and 85.6% in CP-CML, respectively, and 41.7%, 41.7%, 41.7%, and 50% in AP-CML		[25]
CML	Clinical trial	Olverembatinib	40 mg		CHR, MCyR, CCyR, MMR, MR4, MR4.5, and CMR rates were 85%, 47.7%, 36.4%, 27.3%, 21.6%, 21.6%, and 20.5%, respectively. Estimated EFS at 6, 12, and 24 months was 73%, 58.7%, and 46.9%, respectively.		[31]
CML	Case report	Olverembatinib + venetoclax	Case 1	20 mg QOD	CHR and CCyR were achieved after a month, and an MR4.5 after haplo-HSCT		(32)
			Case 2	20 mg QOD	decreased bone marrow blast cells from 70% to 7% in 8 days, achieved CHR and CMR after MUD-SCT
CML (MBP and LBP)/ Ph + ALL	Retrospective	Olverembatinib ± chemotherapy	Not mentioned		MaHR achievement were 59% for CML-MBP, 79% for CML-LBP, and 83% for R/R Ph-positive ALL. MCyR was achieved in 54%, 30%, and 82% of patients with CML-LBP, CML-MBP, and R/R Ph-positive ALL.		[34]
CML (LBP)/ Ph + ALL	Retrospective	Olverembatinib ± VP or hyper-CVAD	30 or 40 mg QOD		R/R (11, Ph + ALL; 4, CML-BP): CR rate of 86% The one-year relapse-free survival (RFS) rate was 52%, and survival was 68% molecular resistance (16 patients): the one-year RFS rate was 67% and survival was 93%. . The rate of CMR achievement in patients on the combined regimen was 50%.		[35]
CML/Ph + ALL	Clinical trial	Olverembatinib	30, 40 or 50 mg QOD		CP-CML: CCyR: 60.8% MMR: 42.4%	Ph + ALL: MMR: 33% (4/12) 4/8 patients with asciminib resistance had a CCyR	(27)
CML/Ph + ALL	Clinical trial	Olverembatinib	30, 40 or 50 mg QOD		CCyR, MCyR, and MMR occurred in 58.8%, 64.7%, and 42.9%		[28]
CML/Ph + ALL	Clinical trial	Olverembatinib	30, 40 or 50 mg QOD		57% of CP-CML patients experienced CCyR and 43% experienced MMR. CCyR, MCyR, and MMR occurred in 27.3%, 36.4%, and 23.1% of Ph + ALL patients.		[29]
CML-LBP	Case report	Olverembatinib + VA	40 mg QOD		CHR achieved after the first cycle and partial cytogenetic remission. No molecular response was reported.		[30]
CML/Ph + ALL	Clinical trial	Olverembatinib (monotherapy/+demethylating agent/+ VDP and stem cell transplantation)	Not mentioned		CR/Cri, CCyR, and MMR were reported as 100%, 62.5%, and 75%, respectively. Five relapsed Ph + ALL patients achieved CMR.		[33]
AML	Case series	Mitoxantrone, Venetoclax, Homoharringtonine, and Olverembatinib (HQP1351) (MVHO)	20-30 mg/m 2		eight patients (8/19) achieved MRD negative remission; the ORR was 94.4% after one cycle, The cumulative incidence of relapse (CIR) was 6.7%, and the OS was 100%		[94]
ALL	Clinical trial	Olverembatinib	40 mg QOD		All patients (16 individuals) achieved CR; ORR was 100%. CMR achievement increased from 15.4% on day 14 to 84.6% on day 90		[47]
ALL	Clinical trial	Olverembatinib (induction:1 mg/kg/d of prednisone for 14 days, then tapered and stopped at 28 days and vindesine 4 mg/d at days 1, 8 and 15, consolidation: high-dose of cytarabine and methotrexate)	40 mg QOD		All patients (4 individuals) reached CR with a CCyR after induction therapy. Two patients reached MMR and one with CMR. Before allo-HSCT, all the patients achieved CMR. All the patients have survived disease-free for 3–6 months		[50]
ALL	Clinical trial	Olverembatinib + VP (Prednisone: 1 mg/kg daily for 14 days, then tapered, Vindesine: 4 mg on days 1, 8, and 15)	40 mg QOD		All patients (n = 12) achieved complete remission with a complete cytogenetic response after induction therapy; two reached major molecular remission and one achieved complete molecular remission		[51]
ALL	Clinical trial	Olverembatinib ± VP	40 mg QOD		all experienced CR (n = 10), except for one patient with the T315I mutation who had also previously failed treatment with ponatinib, two of them had molecular relapse, while the rest were persistently molecular positive. Of these patients, 66.7% achieved CMR in a median duration of 3 months.		[52]
ALL	Retrospective	Induction: Olverembatinib + VP (vindesine 4 mg d1, d8, prednisone 1 mg/kg/d d1-14, and tamper) or blinatumomab or prednisone alone. Consolidation: (1) Olverembatinib + blinatumomab or Hyper-CVAD A/B, (2) high-dose methotrexate and eliminated minimal residual disease with blinatumomab for bridging to allo-HSCT	40 mg QOD		All patients achieved CR (n = 20). The CMR rate after one cycle was 35%, which increased to 70% after another cycle of treatment.		[53]
ALL	Clinical trial	Olverembatinib, venetoclax (100 mg on day 4, 200 mg on day 5, and 400 mg on days 6–17), and dexamethasone (10 mg on days 1–14 and 5 mg on days 15–28).	40 mg QOD		By the middle of the first 28-day cycle, all patients (n = 10) achieved CR/CRi and MRD negativity, and 80% of them achieved MMR. The rate of CMR increased from 50% at this time to 70% by the end of the first cycle. After 2 cycles of treatment, all patients achieved CMR and entered the continuous phase, except for one patient who achieved CMR after 4 cycles. no changes in MRD negativity and CMR rates were observed, and no relapses occurred.		[54]
ALL	Clinical trial	Olverembatinib ± Lisaftoclax (200, 400, and 600 mg)	40 mg QOD		One-third of 6 evaluable patients achieved an ORR (33.3%) at the end of the first course which increased to 83.3% after a 42-day treatment cycle. Out of 7 evaluable patients, five achieved MRD negativity at the end of the monotherapy course. An additional 4 patients reached MRD negativity after one course of treatment with the combination regimen.		[69]
ALL	Case report	Olverembatinib	40 mg QOD		CMR achieved (second-CMR) after two cycles of olverembatinib monotherapy.		[72]
ALL	Retrospective	Olverembatinib	35 mg QOD (range, 15–40)		The hematologic relapse rate was 7.7%, with no event in the preemptive group. The 3-year probability of overall survival and relapse free survival after allo-HCT was 91.7% and 79.1%, respectively.		[73]
ALL	Retrospective observational	Olverembatinib + VP	40 mg QOD (20 mg QOD after HSCT)		The achievement of CMR and negative MRD was higher among patients with positive MRD compared to the other patients (CMR: 47.1% vs. 35.7% and negative MRD: 60% vs. 42.9%, respectively). After a median follow-up time of 16.3 months, in overt R/R patients, the median EFS was 3.9 months and the overall survival was 8.3 months. For MRD-positive patients, these metrics were 11.5 months and 18.4 months, respectively		[12]
ALL	Case report	Olverembatinib + inotuzumab ozogamicin	40 mg QOD		achieved morphological remission with a negative MRD and undetectable BCR::ABL transcripts		[74]
ALL	Case report	olverembatinib + blinatumomab (9 µg/day for 7 days, and 28 µg/day for the next 21 days)	40 mg QOD		Two cases achieved CR and MRD negativity		[70]

After a median treatment duration of 30.7 months, all of the patients experienced non-hematologic treatment-related adverse events (TRAEs), and 49.1% of them had a grade ≥ 3. The prevalence of grade ≥ 3 non-hematologic AEs in AP-CML was higher than CP-CML. Hematologic AEs involved 83.6% of patients, and 56.4% of them had a grade ≥ 3. Any grade and grade ≥ 3 hematologic AEs were more prevalent among patients with AP-CML. The most prevalent non-hematologic AEs (any grades; grade ≥ 3) were skin hyperpigmentation (84.2%, 0%), followed by hypertriglyceridemia (57.6%, 7.3%), and proteinuria (50.9%, 3.6%). Reported hematologic AEs (any grades; grade ≥ 3) were thrombocytopenia (76.4%, 51.5%), anemia (54.5%, 23%), leukopenia (33.9%, 20.6%), and neutropenia (15.8%, 11.5%). Serious AEs reported with a rate of more than one were thrombocytopenia (9.0%), anemia (6.0%), pneumonia (3.0%), pyrexia (2%), and atrial fibrillation (2%) [20]. During the study, the frequency of most AEs decreased except for skin hyperpigmentation and proteinuria. Cardiovascular events such as hypertension, arrhythmia, and ventricular extrasystoles are completely or almost completely resolved following episodic suspension of olverembatinib therapy. Of note, one patient experienced acute myocardial infarction (MI) and subsequently discontinued treatment, and pericardial effusion was the cause of death for one of the deceased individuals [20].

During this period, 101 patients were also separately analyzed at one cutoff point [24] (Table 2). With ongoing treatment of those 101 patients for a median duration of 44.7 months, at second cutoff point, 100% of patients with CP-CML, achieved CHR, 80%, 71%, and 55% achieved CCyR, MCyR, and MMR, respectively. Consistent with the first analysis, in patients with AP-CML compare to CP-CML, the rates of these cytogenetic and molecular responses were lower (86%, 40%, 40%, and 40% respectively). For AP-CML patients with the T315I mutation, CHR was 80% compared to 100% in unmutated form. The CHR rates in CP-CML with and without the T315I mutation was 100%. Other response rates were generally higher in T315I mutant patients compared to those without the T315I mutation [25]. The most common TRAEs of both cutoff points in the separate analysis of 101 patients were consistent with the TRAEs in all 165 patients. These included thrombocytopenia, anemia, and leukopenia as hematologic AEs, and skin hyperpigmentation, hypertriglyceridemia, and proteinuria as non-hematologic AEs [24, 25]. Separately analysis of 64 patients at three cutoff points also demonstrated the higher response rates in CP-CML than in AP-CML (Table 2). At every cutoff, most prevalent hematologic AEs of AP-CML and CP-CML were thrombocytopenia and anemia. After skin hyperpigmentation, the second most common non-hematologic AEs in CP-CML was elevated creatine phosphokinase, while at the first cutoff of AP-CML, it was hypocalcemia, and at the two later cutoffs, it was hypertriglyceridemia [21, 22, 26].

Another phase 1 study was conducted in non-Chinese individuals. In this study, 80 AP-CML and CP-CML with and without T315I mutation, blast-phase CML (BP-CML), and Ph + ALL who had history of treatment with at least 2 TKIs randomly received 30, 40, or 50 mg olverembatinib QOD. The non-Chinese nature of the study’s participants was important in demonstrating the absence of racial differences in the pharmacokinetic characteristics of olverembatinib. Moreover, the study results indicated that a dosage of 30 mg of olverembatinib every other day was effective in patients with CP-CML without the T315I mutation, whereas those with the T315I mutation may require a higher dose of 40 mg every other day [27].

Two other studies were also conducted on non-Chinese patients. The first included 23 patients with CP-CML and 7 patients with AP-CML, BP-CML, and Ph + ALL (4, 2, and 1, respectively). The second included 57 CP-CML and 19 Ph + ALL patients. In three studies olverembatinib exhibited strong antileukemic activity in CP-CML with resistance to asciminib and ponatinib [27–29]. In three study of non-Chinese patients [27–29], the most common hematologic TRAE was thrombocytopenia, consistent with findings in the Chinese population [20]. Meanwhile, the most common non-hematologic TRAE was elevated blood creatine phosphokinase.

A case study involving a patient with unmutated newly diagnosed CML-LBP was treated with olverembatinib at a dose of 40 mg QOD and the VA regimen (including azacytidine and venetoclax) in two cycles. He achieved CHR after the first cycle and experienced partial cytogenetic remission, while no molecular response was reported [30]. Higher observed molecular and cytogenetic responses in T315I mutant CML from former studies [24, 25], as well as no molecular response in unmutated CML from this case report, may underscore the specificity of olverembatinib in targeting the T315I mutation [30]. However, the response rates in non-Chinese patients were similar between CP-CML with T315I mutation and those without [27–29].

Participants of another study included 144 resistant and/or intolerant CML patients, of whom 39 had the T315I mutation. Ninety-six patients treated with 40 mg olverembatinib QOD, demonstrated higher CHR, MCyR, CCyR, MMR, MR4, MR4.5, and CMR compare to 48 others were in the BAT group, receiving one of the following drugs: TKIs, interferon, hydroxyurea, or homoharringtonine. Furthermore, the median event-free survival (EFS) of olverembatinib-treated patients was 21.22 months, significantly higher than that of the BAT arm. 85.4% of 96 patients treated with olverembatinib experienced a grade ≥ 3 AE. Additionally, 7 serious adverse events were reported in this group, including 1 case of acute myocardial infarction, 3 cases of coronary heart disease, 2 cases of cerebral infarction, and 1 case of congestive heart failure [31].

Two BP-CML cases reported by Zhang et al., treated with combination of venetoclax and olverembatinib (20 mg QOD) demonstrated promising results. One patient in the chronic phase experienced grade 3–4 thrombocytopenia with nilotinib, failed to achieve CHR after initial treatment with imatinib, and achieved 17 months of lasting CHR upon a second attempt. After experiencing a relapse, he received flumatinib, which was discontinued following the occurrence of grade 3 thrombocytopenia. As a result, imatinib was continued until the patient presented with BP-CML. The treatment plan at this point was this combination regimen of olverembatinib and venetoclax. The patient achieved both CHR and CCyR after one month. The results at the last follow-up after haplo-HSCT indicated MR4.5 [32].

Another case was a 13-year-old patient with BP-CML who achieved his first CHR after one cycle of a regimen that included VP (vindesine and prednisone) and nilotinib. However, severe jaundice led to switching the treatment from nilotinib to flumatinib. After 2 months of receiving flumatinib, BP-CML relapsed with a secondary Y253H mutation. The combination regimen of olverembatinib and venetoclax decreased bone marrow blast cells from 70% to 7% in just 8 days. Furthermore, he achieved CHR and complete molecular remission (CMR) after MUD-SCT [32]. Olverembatinib administration also demonstrated notable results in Ph + CML patients who were in post-transplantation relapse. Two patients with AP-CML received olverembatinib as monotherapy. Six patients with MBP-CML and another patient with CML-MLBP were treated with olverembatinib alongside demethylating agents. Two patients with LBP-CML underwent treatment combining VDP and stem cell transplantation with olverembatinib. After a median follow-up of 4 months, among the 8 evaluable CML patients, an impressive overall response rate (ORR) of 100% was observed. In addition, the rates of CR/CRi (complete remission/complete remission with incomplete count recovery), CCyR, and MMR were reported as 100%, 62.5%, and 75%, respectively [33].

We will review of olverembatinib in ALL, and in this section Ph + ALL patients in 2 combination studies are reported. In a combination study by Bao et al., in addition to 107 patients with CML-MBP and CML-LBP, of whom 20 were newly diagnosed, 46 patients with relapsed/refractory (R/R) Ph + ALL were enrolled. The T315I mutation was found as a single mutation in 45 patients and alongside additional mutations in 6 out of 137 evaluated patients with prior TKI therapy, 15 had no response, 66 achieved CHR, and 42 reached at least an MCyR. Treatment regimens included olverembatinib as monotherapy for 29 patients, while others received it combined with chemotherapy resembling that used for ALL or AML. After a median follow-up of 9 months, 77% of patients with CML reverted to a chronic phase. In this study 34 patients experienced relapse and the causes of death for the 61 decedents were acute leukemia (48 patients), severe infections (6 patients), transplant-related mortality (5 patients), and COVID-19 (2 patients) [34].

Notably, among all patients, those with CML-LBP had the highest rates of EFS, survival, and one-year probabilities of EFS and survival. Additionally, transplantation was associated with higher one-year probabilities of EFS and survival compared to patients who did not undergo transplantation. An important aspect of this study was identifying factors associated with poorer survival, which included having CML-MBP or R/R Ph-positive ALL compared to CML-LBP, inadequate response to previous TKI therapy, failure to achieve MaHR or having BCR::ABL1 mRNA IS > 10% within three months, and not receiving transplantation. The most frequently reported non-hematological TRAEs included pulmonary infections, increased aminotransferase levels, and fatigue in 29%, 21%, and 20% of patients, respectively. Cardio-cerebrovascular TRAEs were observed in 16%. Additionally, grade 4 hematological TRAEs occurred in 84 patients (62%) [34].

Another combination study involved 24 patients with Ph + ALL who had failed TKI-based chemotherapy and 7 patients with TKI-resistant CML-LBP. Among the 30 evaluated patients, 24 had mutations, while the T315I mutation was found in 15 of them. The regimen of 15 patients with R/R patients, comprising 11 with Ph + ALL and 4 with CML-BP, was a combination of VP with olverembatinib at doses of either 30 or 40 mg QOD. Four weeks of induction therapy resulted in a CR rate of 86%. Five of these patients underwent allo-HSCT. Additionally, half of the remaining eight patients in CR continued their treatment with an olverembatinib-based consolidation phase combined with VP, while the other half continued with hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone). After a median follow-up of 8 months, transplant patients remained in CMR, while six patients in consolidation therapy with olverembatinib relapsed, resulting in four deaths [35]. Poorer survival of non-transplant patients is consistent with the multivariable analyses of the study by Bao M et al. [34].

Among the other 16 patients who had molecular resistance, including 4 with molecular resistance to imatinib, 9 to dasatinib, and 3 to flumatinib, 2 received olverembatinib monotherapy, 7 received it combined with VP, and 7 with hyper-CVAD. After a median follow-up of 9 months, one patient in the monotherapy regimen received CAR T-cell therapy following hematologic relapse, while another underwent transplantation after not achieving CMR. The rate of CMR achievement in patients on the combined regimen was 50%. One patient experienced a hematological relapse, and two patients had single central nervous system leukemia (CNSL). After transplantation of 3 patients who were in CMR and 4 patients who were not in CMR, one patient developed CNSL, while the others remained in CMR. Although hematologic adverse events (AEs) observed in this population were easily manageable, severe nonhematologic AEs included stable angina pectoris, severe pneumonia, and fatal Klebsiella sepsis, each affecting one patient [35].

In the latest published study on olverembatinib in patients with CML, 146 participants (114 CP-CML and 32 AP-CML) from phase 1 and 2 studies conducted in China [20] completed the 36-month Chinese version of the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Core 30 Questionnaire (QLQ-C30) to assess health-related quality of life (HRQoL) scores. Over time, global health, physical functioning, and emotional functioning, as well as fatigue, dyspnea, diarrhea, and financial difficulties, significantly improved. A separate analysis of CP-CML patients demonstrated improvement in the same items; however, in AP-CML patients, not only did no items improve, but cognitive functioning and constipation worsened. Multivariate analyses indicated that being younger than 40 years and in the chronic phase of CML were associated with greater improvements in various aspects of HRQoL as patients underwent more cycles of olverembatinib therapy [36].

Another group of 102 patients (85 CP-CML and 17 AP-CML) was assessed using the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS). The SAS and SDS scores were decreased over 36 months after beginning the treatment with olverembatinib. While significant improvement in depression symptoms over time was only seen in CP-CML, both AP-CML and CP-CML patients experienced a significant decrease in anxiety symptoms over time [36].

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL)

ALL results from the abnormal proliferation of immature lymphoid cells within the bone marrow, peripheral blood, and various other organs [37]. While the highest incidence rate of ALL is in children, approximately 80% of ALL-related deaths are in adults [38]. American Cancer Society estimated 6,550 new cases of ALL and 1,330 ALL-related deaths in 2024 [39]. The introduction of TKIs has improved outcomes for Philadelphia chromosome-positive patients who previously had a poor prognosis [40]. However, those treated with earlier-generation TKIs face the challenge of relapse due to the T315I mutation [41–43]. It is noteworthy that Ponatinib has shown considerable efficacy in Ph + ALL. When combined with intensive chemotherapy regimens, complete remission rates of approximately 80–90% have been reported, and in the PACE trial, 41% of relapsed/refractory Ph + ALL patients achieved major hematologic responses. However, durability of molecular remission remains a challenge, and cardiovascular toxicity is an important consideration. Another group at risk of relapse (approximately 25%) is children with pre-B ALL who have been treated with chemotherapy despite the initial responsiveness [44]. In an in vitro part of the study conducted by Ye W et al., GZD824 (olverembatinib) induced apoptosis in the Ph- pre-B ALL cell line (NALM6), the Ph + pre-B ALL cell line (SUPB15), and Ph- and Ph + pre-B ALL cells derived from five patients. In addition, GZD824 induced cell cycle arrest in NALM6 and SIPB15 cell lines. Notably, Ph- cells exhibited greater sensitivity to GZD824 compared to Ph + cells. In an in vivo part, GZD824 succeeded in reducing tumor loads in xenografted mice with Ph- pre-B ALL, in contrast to its effect on xenografted mice with Ph + pre-B ALL. This TKI suppresses the proliferation of pre-B ALL cells by inhibiting the SRC kinase and PI3K/AKT signaling pathways [45].

Another in vitro study demonstrated that combining olverembatinib with either vincristine or doxorubicin significantly increases apoptosis in Ph + ALL SUP-B15 cells compared to each agent alone. Notably, vincristine exhibited a higher synergistic effect than doxorubicin when combined with olverembatinib. Western blot analysis demonstrated that these combinations resulted in inhibited expression and phosphorylation of BCR::ABL1 and its downstream targets, including STAT5, AKT, and ERK1/2. Additionally, similar to the combination of olverembatinib and Lisaftoclax observed in AML cells, these regimens also led to a decrease in antiapoptotic proteins such as MCL-1, BCL-2, and BCL-xL and an increase in proapoptotic proteins such as BAX and PUMA in ALL cells [46].

We have reviewed studies exclusively evaluating the efficacy and safety of olverembatinib, either alone or in combination with other treatments, in patients diagnosed with ALL. In a study conducted by Zhu et al., 13 patients with Ph + ALL received ≤ 3 courses of chemotherapy according to the PDT-ALL-2016 (a pediatric-inspired regimen) protocol with olverembatinib (40 mg QOD). All patients, regardless of having the P190 or P210 transcript, achieved CR, in other words, ORR was 100% [47]. Treatment with chemotherapy and other TKIs, previously demonstrated higher CMR rates in patients with P190 transcript compared to those with the P210 transcript, although their CR rates did not differ [48]. CMR achievement in Zhu K et al. study increased from 15.4% on day 14 to 84.6% on day 90. Two patients experienced skin hyperpigmentation, and another one developed hypertension. Among all, 6 patients underwent allo-HSCT, and pulmonary embolism following the transplantation caused the death of one of them [47].

Complete remission was also reported at 14 days post-olverembatinib therapy (40 mg daily) along with prednisone, vindesine, and intrathecal injection of dexamethasone, cytarabine, and methotrexate in 4 patients with newly diagnosed Ph + ALL in a study by Tan X et al. CCyR, MMR, and CMR were achieved in 4, 2, and 1 patient, respectively. According to the potential independent risk of MRD persistence (defined as more than 10,000 blasts) in causing relapse, achieving MRD negativity is an important part of ALL treatment in both pediatric and adult patients [49]. While at day 14, only patients with P190 achieved MRD negativity, by day 28, all of them had negative MRD and remained in complete remission. The only adverse event experienced by 2 patients during treatment with olverembatinib was fever [50].

Four weeks of treatment with olverembatinib (40 mg QOD) and VP in 12 Ph + ALL patients in a study by Lou et al. led to CHR in all of them and CMR in 60%. Consolidation therapy for 4 patients involved allo-HSCT, while the others were treated with blinatumomab or intensive chemotherapy. They received olverembatinib and low-intensive regimens during the maintenance phase. CMR increased from 60% to 100% at 8 weeks. Notably, after a median follow-up of 5 months, all patients remained in CMR. In addition, most of the AEs observed in this study were mild and manageable [51].

Another study started treating Ph + ALL adult patients with olverembatinib as a single agent (40 mg QOD) or combined with VP (vincristine and prednisone) in December 2021. Among the four patients with hematological relapsed Ph + ALL, half of them were in their first relapse and harbored the T315I mutation. One of them was in the second relapse after unsuccessful treatment with two types of TKIs and chemotherapy, and another one was in the third relapse involving both the CNS and bone marrow. They all experienced CR, except for one patient with the T315I mutation who had also previously failed treatment with ponatinib. The other six patients included in this study had the T315I mutation. Additionally, two of them had molecular relapse, while the rest were persistently molecular positive. Of these patients, 66.7% achieved CMR in a median duration of 3 months. One of those who didn’t respond to olverembatinib had prior treatment with ponatinib. While cytopenia, raised transaminase levels, hypertension, and cardiovascular events were reported as adverse events, they were less frequent than those observed with ponatinib [52].

In a study that included non-Chinese CP-CML and Ph + ALL patients, among evaluable Ph + ALL patients resistant to ponatinib, 42.9% achieved MCyR, 28.6% achieved CCyR, and 22.2% achieved MMR after olverembatinib treatment. In contrast to CP-CML we reported in its section, none of the evaluable Ph + ALL patients resistant to asciminib achieved CCyR or MMR, and only one patient achieved MCyR. While response rates of CP-CML with and without T315I were similar, unmutated Ph + ALL patients had higher CCyR (33.3% vs. 20%) and MCyR (50% vs. 20%) compared to those with the T315I mutation. Furthermore, the results of 2 Ph + ALL patients treated with blinatumomab and 30 mg olverembatinib QOD demonstrated CHR in both and negative MRD in one of them [29].

Combinations of olverembatinib with VP, blinatumomab, or prednisone were used as induction regimens for patients with newly diagnosed Ph + ALL in a study conducted by Zhu Y et al. They continued the administration of olverembatinib in the next cycle, combined with VP, blinatumomab, hyper-CVAD, or methotrexate in consolidation therapy. After one cycle of induction therapy, all 20 patients achieved CR, which was maintained at the last follow-up. The CMR rate after one cycle was 35%, which increased to 70% after another cycle of treatment. Four patients received CAR-T therapy, and five received allo-HSCT. At a median follow-up of 17.2 months, the 1-year OS and 1-year EFS reached 100%. The most common TRAEs experienced were anemia (30%), neutropenia (25%), febrile neutropenia (25%), and skin hyperpigmentation (25%). Grade ≥ 3 AEs occurred in a total of four patients, including one case of anemia, one case of febrile neutropenia, and two cases of pneumonia [53].

In a phase 1/2 study by Tang H et al., 10 newly diagnosed Ph + ALL patients received olverembatinib in the OVD regimen (olverembatinib, venetoclax, and dexamethasone) during both the induction and continuous treatment phases. By the middle of the first 28-day cycle, all patients achieved CR/CRi and MRD negativity, and 80% of them achieved MMR. The rate of CMR increased from 50% at this time to 70% by the end of the first cycle. After two cycles of treatment, all patients achieved CMR and entered the continuous phase, except for one patient who achieved CMR after four cycles. Allo-HCT was considered for this patient. After a median follow-up of 7.4 months, no changes in MRD negativity and CMR rates were observed, and no relapses occurred. During continuous treatment, grade 4 neutropenia was reported in three patients, and short episodes of neutropenia without developing a fever in two others. Grade 3 non-hematological AEs included pneumonia in two patients and febrile neutropenia, lower extremity weakness, and hypertension in one patient. The other non-hematological AEs were grade 1 or 2, which were more common than grade 3. The treatment of three patients who experienced hematological toxicity, pneumonia, or hypertension was suspended for 7, 13, and 37 days, respectively. In addition, the doses of venetoclax or olverembatinib were reduced in one patient who experienced grade 4 neutropenia and another patient with grade 3 hypertension. Two notable points of this study were the increase in hemoglobin and platelet levels within the first 13 days of induction therapy, reducing the requirement for transfusions, and the rapid CMR achievement in a patient who underwent total gastrectomy, indicating that olverembatinib absorption was not affected [54]. More recently, a single-center, single-arm phase 2 trial further evaluated olverembatinib in combination with venetoclax and reduced-intensity chemotherapy as frontline therapy in adult patients with newly diagnosed Ph + ALL. In this study, 79 patients (median age: 42 years) received at least three cycles of the olverembatinib–venetoclax–based regimen. The primary endpoint of complete molecular response (CMR) at 3 months was achieved in 62.0% of patients, notably without the need for intensive chemotherapy or immunotherapy. No induction-phase deaths were observed, and with a median follow-up of 12 months, the estimated 1-year OS and EFS were 93.1% and 89.1%, respectively. Transcriptomic analyses suggested complementary mechanisms between TKIs and venetoclax, supporting the biological rationale for this novel combination. This trial provides important evidence for an alternative first-line treatment strategy in ND Ph + ALL, especially in patients unfit for intensive therapy [55].

Li et al., studied seven patients under 18 years old who were enrolled, including 5 with Ph+-B-ALL P190, 1 with Ph+-B-ALL e1a3, and 1 with NUP214::ABL1 T-ALL. Olverembatinib alone or combined with other treatment was used as a second or third line of treatment for relapsed Ph + ALL following prior intensive chemotherapy and dasatinib in 5 patients. One patient received a combination regimen of olverembatinib after a third relapse following treatment with intensive chemotherapy, dasatinib, flumatinib, and ponatinib. A patient with T-ALL who had not relapsed was treated with olverembatinib as a second-line therapy after suffering grade 4 toxicity to dasatinib. Out of the five patients assessed for treatment response, 4 achieved complete remission with undetectable minimal residual disease. Notably, 2 of them were patients in the monotherapy olverembatinib regimen. The only unfavorable response to olverembatinib was seen in a patient who had relapsed for the third time. Reported toxicities included grade 2 extremity pain in 2 patients and myopathy in another patient. One of the patients experiencing extremity pain also had grade 3 fever and pneumonia [56].

One factor associated with a higher risk of initial CNS involvement in ALL patients is Ph positivity [57, 58]. Additionally, CNS leukemia may relapse and cause treatment failure [59–61]. Despite their associated toxicity, systemic and intrathecal chemotherapy, and even cranial irradiation for some high-risk cases, may not prevent CNS relapse [62–68]. Another positive impact of olverembatinib in this study was its assistance in clearing leukemic blasts from the cerebrospinal fluid (CSF) of 4 patients with combined CNS and hematological relapse. Notably, 3 of these patients had elevated leukemia blast counts in the CSF despite after intrathecal therapy [56].

A separate study of olverembatinib in patients under 18 years old with R/R Ph + ALL enrolled 10 patients, including nine patients with the p190 transcript, one with the p210, and 3 with the T315I mutation. Patients received 40 mg of olverembatinib alone QOD during the first course. All of them, except the one who discontinued olverembatinib therapy after experiencing a seizure, then received the same dose of olverembatinib combined with Lisaftoclax in the 3 + 3 dose escalation model at doses of 200, 400, and 600 mg. One-third of 6 evaluable patients achieved an ORR (33.3%) at the end of the first course. This increased to 83.3% after a 42-day treatment cycle with olverembatinib and Lisaftoclax. Out of 7 evaluable patients, five achieved MRD negativity at the end of the monotherapy course. An additional four patients reached MRD negativity after one course of treatment with the combination regimen. 70% of patients experienced grade ≥ 3 neutropenia, while anemia and thrombocytopenia each occurred in 30% of patients. Severe non-hematologic AEs included a grade 3 increase in alanine aminotransferase, which occurred in one patient and led to discontinuation of the treatment [69].

In the group of patients with relapsed Ph + ALL after transplantation, treatment was a combination of blinatumomab and olverembatinib for one patient and olverembatinib after anti-CD19 CAR-T for two patients. The last two didn’t receive olverembatinib and were treated with intensive chemotherapy and donor lymphocyte infusion (DLI) consecutively. All these patients with different regimens achieved CMR [33]. The combination of olverembatinib (40 mg QOD) and blinatumomab (9 µg/day for 7 days, and 28 µg/day for the next 21 days) as a second line of treatment was also administered to a patient with morphological relapse Ph + ALL (p190) with secondary T315I and another one with refractory Ph + ALL (p210). A former case was treated with VEP (vincristine, epirubicin, and prednisone) and dasatinib during the induction phase, which was continued with CAM and dasatinib as a consolidation phase. She achieved CR after induction therapy, although MRD flow remained positive. Her second CR was achieved after receiving this combination regimen. Additionally, MRD turned negative this time [70]. In the latter case, this combination also resulted in CR achievement and MRD negativity after not responding to two cycles of regimens that included vincristine, idarubicin, dexamethasone, and cyclophosphamide, along with nilotinib. They did not experience any significant adverse events. In addition, both patients underwent HSCT following one cycle of consolidation therapy with olverembatinib. Notably, persistent CR chimerism and the absence of MRD were maintained until the last assessment conducted six months and eight months post-transplant, respectively [70].

In addition, complete remission following olverembatinib-based therapy for relapsed Ph+-B-ALL was achieved in 5 adult patients. For the patient with 2 mutations, T315I and Q252H, who was in his 4th relapse, it took 7 months to achieve CMR. CMR was also the best response for the patient with the E255K mutation. Two unmutated Ph+-B-ALL patients with p190 achieved MMR one month after allo-HSCT. However, another patient with a single T315I mutation relapsed for the second time [71]. Another patient treated with olverembatinib for relapsed Ph+-B-ALL (P190) was a 79-year-old woman. Initially, she achieved a CMR after just one cycle of treatment, which included VP and flumatinib. Induction therapy continued with the same regimen of consolidation therapy for seven cycles, after which she underwent eleven cycles of maintenance therapy with flumatinib alone. Nineteen months post-CMR, the leukemia relapsed with a secondary E255V mutation. In the second-line treatment, she received two cycles of olverembatinib (40 mg QOD), which successfully led to achieving a second CMR [72].

Participants in the study by Zhao et al. included 33 patients with Ph + ALL. Three of these patients had newly diagnosed Ph + ALL, while the others included 19 patients with prior standard chemotherapy and 11 patients with prior hematopoietic stem cell transplantation. Among these 30 individuals, 5 were in relapse, 19 had positive MRD, and the remaining 6 had negative MRD. During the first course of olverembatinib administration, 5 patients were treated with olverembatinib alone, while the others received olverembatinib combined with blinatumomab, inotuzumab, VD (Velcade^® and dexamethasone), VDCP (vincristine, daunorubicin, cyclophosphamide, and prednisone), CAM (complementary and alternative medicine), and interferon. All patients achieved remission, which included CR, CRi, or a morphologic leukemia-free state (MLFS). At this time, the MRD of 22 patients was negative, including 6 patients from the negative MRD group. One patient was lost to follow-up, and 5 patients with negative MRD underwent HSCT. The second regimen for the remaining patients included olverembatinib alone for 9 patients, while 18 patients received olverembatinib combined with blinatumomab, inotuzumab, VD, and CAM. 100% remission and 77.78% MRD negativity were reported after the second course of treatment. Hematologic AEs commonly reported in studies involving CML patients treated with olverembatinib, such as leukopenia, neutropenia, anemia, and thrombocytopenia, were also observed in this study. In addition, hepatotoxicity, nephrotoxicity, myalgia, arthralgia, rash, and edema were common nonhematologic AEs, most of which were mild [73].

Administration of olverembatinib in 31 Ph + ALL patients, including 17 with positive MRD and 14 with overt R/R, showed promising results. Among these patients, 14 and 10 had the T315I mutation, respectively. The achievement of CMR and negative MRD was higher among patients with positive MRD compared to the other patients (CMR: 47.1% vs. 35.7% and negative MRD: 60% vs. 42.9%, respectively). After a median follow-up time of 16.3 months, in overt R/R patients, the median EFS was 3.9 months, and the overall survival was 8.3 months. For MRD-positive patients, these metrics were 11.5 months and 18.4 months, respectively. While the EFS of the group that underwent allo-HSCT was not reached, the results showed a further improvement in the survival of this group [12]. Tong Liu et al. reported the case of a 31-year-old man diagnosed with Ph+-B-ALL (P210). His first-line treatment consisted of one cycle of VCP (cyclophosphamide, vincristine, and prednisone acetate) combined with imatinib, leading to morphological remission, although BCR/ABL1 transcript quantification remained at 11.4%. As a result of complications from COVID-19 pneumonia, the patient continued treatment with only oral imatinib for two months instead of proceeding to a second cycle, resulting in relapse with secondary E255M mutation. At this stage, the treatment regimen was switched to hyper-CVAD along with dasatinib, which successfully induced hematological remission. However, after three weeks on monotherapy with dasatinib, the leukemia recurred with the emergence of the T315I mutation. To address this recurrence, the patient was treated with anti-CD22 antibodies (inotuzumab ozogamicinand) and olverembatinib at a dose of 40 mg QOD. Following one cycle of therapy, he achieved morphological remission with a negative MRD and undetectable BCR::ABL1 mRNA IS transcripts. In contrast to the study by Li X et al., in this study, notwithstanding treatment with olverembatinib, blast cells were detected in the CSF at a rate of 25.11% [56, 74]. However, they were cleared through intensive lumbar puncture (LP) and intrathecal injection. The blood-brain barrier may act differently against olverembatinib in patients under 18 compared to older patients. In addition, during the treatment with olverembatinib and anti-CD22 antibody, the patient experienced elevated liver enzymes (AST, ALT, ALP, GGT) and bilirubin levels, along with the development of veno-occlusive disease (VOD). This condition gradually improved after suspending treatment and administering steroids and ursodeoxycholic acid. Treatment was subsequently resumed with VCP and continued with three cycles alternating Hyper-CVAD courses with high-dose methotrexate and cytarabine, while olverembatinib remained a consistent part of the regimen. The results demonstrated sustained complete remission, with no detectable levels of the BCR::ABL transcripts [74]. Figure 1 shows most prevalent TRAEs of Olverembatinib in CML and ALL.

Fig. 1.

most prevalent Treatment Related Adverse Events (TRAEs) of Olverembatinib in 1.CML: a Thrombocytopenia, b Skin hyperpigmentation, c Hypertriglyceridemia, and 2.ALL: a Neutropenia, b Anemia, C. Thrombocytopenia

Olverembatinib in acute myeloid leukemia (AML)

The aggregation of atypical hematopoietic precursors, coupled with excessive proliferation, inhibited differentiation, and decreased apoptosis in the bone marrow and peripheral blood, leads to an aggressive hematologic malignancy known as AML [75, 76]. Although specific targeted therapies have been developed, the 5-year survival of patients younger than 20 years and elderly individuals is about 67 and 25%, respectively [77].The FMS-like tyrosine kinase 3 (FLT3) gene encodes a receptor tyrosine kinase (RTK), mostly expressed on immature hematopoietic progenitors and hematopoietic stem cells (HSCs). Its expression diminishes during the completion of the differentiation process in the cells [78]. FLT3 signaling is begun when FLT3 ligand (FLT3 L) binds to FLT3, inducing FLT3 dimerization and activation by autophosphorylation at tyrosine residues. PI3K/AKT, MAPK, and JAK2/STAT5 are the activated downstream signaling pathways, which lead to cell proliferation and inhibition of apoptosis [79]. Activating mutations in FLT3 constitute 30% of all AML cases, specifically FLT3 internal tandem duplication (ITD) and FLT3 tyrosine kinase domain (TKD) mutations. FLT3-ITD is prevalent in 20–25% of newly diagnosed AML patients, whereas FLT3-TKD mutations account for 5–10% of all cases [80]. The FLT3-ITD mutation correlates with a diminished likelihood of CR, an elevated mortality rate, and an augmented chance of relapse, hence indicating a poor prognosis in AML [81, 82]. Although multiple FLT3 inhibitors, such as Midostaurin, quizartinib, gilteritinib, and crenolanib, have been created and revealed a substantial clinical advantage in AML cases with FLT3 mutation [83–85], brief response length and almost certain relapse in most cases remain a major concern in the management of FLT3-mutant AML [86–88]. For instance, midostaurin, when added to standard chemotherapy, improves overall survival but does not prevent relapse in most patients; quizartinib has shown higher composite remission rates in relapsed/refractory AML but resistance emerges rapidly; gilteritinib provides improved survival in relapsed/refractory settings but with modest long-term disease control; and crenolanib has activity against both ITD and TKD mutations yet is still largely investigational. Against this backdrop, Olverembatinib represents a potentially valuable addition, as its dual activity on FLT3 signaling and synergy with BCL-2 inhibition may overcome resistance that limits existing FLT3 inhibitors. Anti-apoptotic protein B-cell lymphoma 2 (BCL-2) is correlated with resistance to treatment and serves as a biomarker indicative of poorer responses to chemotherapy in AML [89, 90]. Venetoclax, a BCL-2 inhibitor, has been shown to synergistically enhance the anti-leukemic efficacy of FLT3 inhibitors in AML with FLT3-ITD mutation, demonstrated in preclinical models [91–93]. In this context, Fang et al. designed a preclinical study to evaluate FLT-3 inhibition by olverembatinib alone or combined with Lisaftoclax (APG-2575) in FLT3-ITD mutant AML. Administration of AML cell lines in vivo and ex-vivo (both patient and cell line-derived xenograft models) in their study showed that olverembatinib induces apoptosis and inhibits FLT3 signaling in AML cell lines with FLT3-ITD mutation. Also, its monotherapy showed a substantial decrease in the proliferation of FLT3-ITD mutant AML xenograft tumors and extended survival in animal models. On the other hand, the addition of Lisaftoclax to olverembatinib induced apoptosis in AML cells with FLT3-ITD mutation and suppressed the growth of xenograft tumors, as well as enhanced survival of tumor-bearing-mice and synergistic anti-leukemic outcomes in a patient-derived FLT3-ITD mutant AML xenograft model. The mechanism justifying this process is that olverembatinib downregulates expression of myeloid-cell leukemia 1 (MCL-1) through suppression of FLT3-STAT5 (signal transducer and activator of transcription 5) signaling and, therefore, increased Lisaftoclax-induced apoptosis in AML cells with mutation [11].

Hu et al. assessed the role of combined Liposomal Mitoxantrone, Venetoclax, Homoharringtonine, and Olverembatinib (HQP1351) (MVHO) regimens in pediatric cases with refractory or relapsed AML. Their study included refractory or new AML cases with unfavorable prognoses and detrimental genomic anomalies in patients who failed to attain full remission (CR) following the first chemotherapy. Their combined regimen included Olverembatinib (HQP1351) 20-30 mg/m ² for four doses from day 1 to day 7, apart from the other therapeutics. Among eighteen pediatric patients, eight patients achieved minimum residual disease (MRD) negative remission; the ORR was 94.4% after one cycle. Three patients discontinued treatment due to lack of response or disease progression, whereas twelve patients had hematopoietic stem cell transplantation (HSCT), resulting in one patient experiencing relapse. The remaining two patients are undergoing further MVHO cycles. The cumulative incidence of relapse (CIR) was 6.7%, and the OS was 100%. Among 26 cycles of MVHO treatment, there were no associated fatal infections or bleeding events, although episodes of infection, grade 4 neutropenia, and thrombocytopenia were reported. Briefly, their investigation suggested that the MVHO regimen, including olverembatinib, may act as a proper therapeutic strategy in pediatric AML [94].

In addition, the efficacy of the olverembatinib and Lisaftoclax combination on the proliferation and apoptosis of venetoclax-resistant AML cell lines elucidated a promising future for overcoming venetoclax resistance in patients with AML. It was found to work synergistically on antiproliferation in a primary venetoclax-resistant AML cell line (OCI-AML-3) as well as two acquired venetoclax-resistant MOLM13 and MV-4-11. In addition, cell apoptosis, measured by flow cytometry, was significantly more prevalent among cells treated with olverembatinib and Lisaftoclax compared to those treated with single agents or the DMSO (vehicle) across the three venetoclax-resistant AML cell lines [95].

Resistance to venetoclax may be explained by significantly elevated levels of phosphorylated FLT-3, AKT, and MCL-1 detected in these cell lines. Western blot analysis illustrated that the combination therapy effectively reduced both the expression and phosphorylation of FLT3 and its downstream signaling molecules, such as STAT, AKT, and ERK, synergistically. Furthermore, this treatment regimen promoted the upregulation of proapoptotic proteins (BAX, BAK, BID, PUMA, and Noxa) and the downregulation of antiapoptotic proteins (BCL-2, BCL-xL, and MCL-1) in venetoclax-resistant AML cell lines [95].

Olverembatinib and non-hematologic malignancies

Although most of the studies on Olverembatinib have been focused on hematologic malignancies, research on its effects in several non-hematologic malignancies has also been conducted. These malignancies include GIST [96, 97], Endometrial Cancer [98], and renal cell carcinoma (RCC) [99].

GISTs, which are mostly found in the stomach, although rare, represent the most common mesenchymal tumors of the gastrointestinal tract [100]. Several mutations are involved in the pathogenesis of GISTs, including the KIT and platelet-derived growth factor receptorα (PGFRA), the most common mutations [101]. Wild-type (WT) GIST is considered a group of tumors that lack these common mutations, are primarily observed in pediatrics rather than adults, and are less responsive to common chemotherapies [102]. Succinate dehydrogenase (SDH) complex mutations are also seen in other tumors, such as paragangliomas, renal carcinomas, pituitary gland tumors, and SDH-deficient GISTs [103]. SDH-deficient GISTs, a subset of WT GISTs, are mainly prevalent in younger ages, highly metastatic, and have low TKI response rates [104]. Since there isn’t a promising targeted therapy for this type of GIST, Qiu et al. evaluated the impact of Olverembatinib on patients with SDH-deficient GIST and paraganglioma.

With a median treatment duration of 15.6 months and administration of Olverembatinib in a dosage ranging from 30 to 50 mg, partial response (PR) was observed as the best response in 6 of 26 SDH-deficient GIST patients. Eighteen patients experienced stable disease (SD) > 4 cycles, and the.

clinical benefit rate (CBR; complete response [CR] + PR + SD > 4 cycles) was more than 90%. In a median follow-up of 17.0 months, the median PFS was 25.7 months. Six patients with paraganglioma participated in the trial; optimal responses were noted in five, with SD persisting for over four cycles, resulting in a clinical benefit rate of 80%. The median progression-free survival was 8.25 months. This study showed a positive effect of olverembatinib on CBR and PFS, noting that the drug was well tolerated in their study population [105]. In another study, the synergistic effect of Olverembatinib and Lisaftoclax on GIST cell lines with resistance to imatinib (GIST430, GIST48, and GIST48B) was assessed. A tumor growth inhibition (TGI) of 76.8% was reached following the combination of olverembatinib at 15 mg/kg with Lisaftoclax at 50 mg/kg (both daily for three weeks), while it was around 57% and 31% for olverembatinib and Lisaftoclax, respectively. Therefore, a synergistic antitumor phenomenon through the combination of these two agents in GIST with resistance to Imatinib was demonstrated [96], (Tables 1, 2 and 3).

Table 1.

Preclinical studies on olverembatinib

Type of malignancy	Type of study	regimen	Dosage	Cell line	Mechanism	Outcome	Complications	Refs.
CML and ALL	In vivo, in vitro	Olverembatinib (GZD824 (10a))	In vivo:1.0 mg/kg to 20 mg/kg. In vitro: 0.2, 0.13 nM.	Murine BaF3 cells with T315I, L248 V, G250E, Q252H, Y253H/F, E255K/V, F317L/V, M351T, E355G, F359 V, H396R, and F486S mutations, human CML cells, and SUP-B15. K562 and Ku812 human CML xenograft models and BCR::ABL1-positive Ba/F3 allograft model.	Suppression of BCR::ABL activation and downstream signaling pathways	Inhibiting proliferation of BCR::ABL positive murine and CML cells and SUP-B15 cells. Tumor growth suppression in xenografted mice with K562 and Ku812, and allografted mice with BCR::ABL1-positive Ba/F3. dose-dependent survival prolongation of the allografted mice.	No toxicity, or significant body loss, and mortality were reported	[8]
CML, ALL	In vitro	Olverembatinib		Ba/F3 cell lines with wild-type ABL1 or ABL1 with single variants or compound variants.		Suppressing proliferation of tumor cells containing various variants, including T315I and multiple compound variants, more potently compared to ponatinib and asciminib.	-	[27]
AML	in vitro and in vivo	Olverembatinib ± Lisaftoclax (APG-2575)	In vitro: 10 nM APG-2575 or 3 nM HQP1351, alone or in combination. In vivo: MV-4-11 model: (1) monotherapy: 10 or 30 mg/kg HQP1351 orally, QOD for 22 consecutive days. (2) combination: 10 mg/kg HQP1351 QOD and 100 mg/kg APG-2575 QD alone or in combination for 19 consecutive days. MOLM-13 model: (1) monotherapy: 3, 10, or 30 mg/kg HQP1351 orally QOD for 21 consecutive days. (2) combination: 10 mg/kg HQP1351, or 100 mg/kg APG-2575 alone or in combination by oral administration for 21 consecutive days	Human AML cell lines, MV-4–11, MOLM-13	inhibiting FLT3 signaling, HQP1351 downregulates MCL-1 and BCL-xL expression and enhances APG-2575 induced apoptosis in FLT3-ITD mutant AML cells	potentiate cellular apoptosis	No additional toxicity	[11]
AML	In vitro	Olverembatinib ± Lisaftoclax	Olverembatinib: 0.5 µM and 10 nM. Lisaftoclax: 0.5 µM and 3 µM	OCI-AML-3, MOLM13 and MV-4-11	inhibited expression and phosphorylation of FLT3 and proteins in downstream signaling pathways such as STAT, AKT, and ER. Antiapoptotic proteins BCL-2, BCL-xL, and MCL-1 were suppressed. tly increased expression levels of proapoptotic proteins BAX, BAK, BID, PUMA, and Noxa resulting in in remarkable augmentation of cleaved caspase-3 and poly (ADP-ribose) polymerase 1 (PARP)	Overcome venetoclax resistance	-	[95]
ALL	In vitro and in vivo	olverembatinib	Up to 3 µΜ	NALM6, SUP-B15, and Pre-B ALL cells derived from five patient	inhibition of the SRC kinase and PI3K/AKT pathways	inducing cell-cycle arrest and apoptosis in vitro.	-	[45]
ALL	In vitro	Olverembatinib ± vincristine or doxorubicin	Olverembatinib: 100 nM, Vincristine:300 nM doxorubicin: 100 nM	Ph+ALL SUP-B15 cell	Both combinations showed synergistic effects in inhibiting protein expression and phosphorylation of BCR::ABL1, and downstream STAT5, decreased phosphorylation of AKT and ERK1/2, decreased protein levels of antiapoptotic MCL-1, BCL-2, and BCL-xL and increased protein levels of proapoptotic BAX and p53 upregulated modulator of apoptosis (PUMA) which led to marked augmentation of cleavage of caspase-3 and poly (ADP-ribose) polymerase 1 (PARP)	synergistic antitumor effects by enhancing apoptosis and antiproliferation	-	[46]
GIST	In vivo, In vitro	Olverembatinib + Lisaftoclax	In vivo: Olverembatinib: 15 mg/kg, Lisaftoclax: 50 mg/kg	imatinib-resistant GIST cells, particularly in GIST430, GIST48, and GIST48B lines	Downregulation of BCL-xL and MCL-1 protein expression via inhibition of KIT and STAT3. Lisaftoclax disrupted the BCL-2: BIM complex. Therefore, selective inhibition of BCL-2, aided by TKI-mediated MCL-1 and BCL-XL inhibition, markedly augmented cleavage of caspase-3 PARP-1	triggering apoptosis and antitumor effects	-	[96]
EC	In vitro	Olverembatinib	0 to 100 µM	HEC-1-A, HEC-1-B, RL95-2, KLE, MFE296, Ishikawa and ARK-1 as well as the normal immortalized endometrial cell line E6E7hTERT and healthy omentum-derived human peritoneal mesothelial (HPMC) and Normal Omentum Fibroblast (NOF)	ROR1/Wnt, GCN2-ATF4, EMT and PI3K-AKT were altered	inhibited the proliferation, suppressing metastasis and modulating immune responses	-	[98]
RCC	In vitro	olverembatinib + anti-PD-1 antibody	-	Murine RCC lines RANCA and RAG	Inhibition of VEGFR, FGFR, and induction of apoptosis; increased immune cell populations	antitumor effects and tumor growth inhibition	-	[99]

Table 3.

Registered clinical trials on olverembatinib

Registration number	Types	Phase	Status	Patient no.	Intervention	Main indicators (time frame)
NCT05311943	CML-CP, Resistant or intolerant to at least two second-generation TKIs	III	Recruiting	40	Olverembatinib, 40 mg QOD	MMR (12 months)
NCT06817720	Newly diagnosed CML in chronic Phase	II	Not yet recruiting	50	Olverembatinib, 30 mg QOD	Safety and adverse events
NCT06423911	CML-CP without the T315I mutation T315I mutated CML-CP	III	Recruiting	285	Olverembatinib, QOD Or Bosutinib	MMR rate (24 weeks)
NCT06757855	Blast Phase Ph + CML	I II	Not yet recruiting	29	Olverembatinib, 40 mg QOD, Combined with Venetoclax and Azacitidine	Maximum tolerated dose and CHR (six weeks)
NCT06390306	CML-MBP		Not yet recruiting	30	Ponatinib or Olverembatinib, daily, combined with venetoclax and azacitidine	MaHR (At the end of cycle 2)
NCT04126681	CML-CP, Resistant or intolerant to first and second-generation TKIs	II	Active, not recruiting	144	Olverembatinib, Hydroxyurea or Interferon-based therapy, Homoharringtonine, and Imatinib, Dasatinib or Nilotinib	EFS (By the end of Cycle 24)
NCT03883100	CML-AP with T315I mutation	II	Active, not recruiting	23	Olverembatinib, 40 mg QOD	MaHR (By the end of cycle 24)
NCT03883087	CML-CP with T315I mutation	II	Active, not recruiting	41	Olverembatinib, 40 mg QOD	MCyR (By the end of cycle 24)
NCT06401603	CML-AP, CML-MBP, or Ph + AML	I	Recruiting	30	Decitabine, Lisaftoclax, and Olverembatinib	Safety and adverse events
NCT06481228	Newly diagnosed adult Ph + B-ALL	Not applicable	Recruiting	82	Venetoclax, Olverembatinib, and CAR-T cells	Disease-free Survival (Up to 2 years after enrollment)
NCT06051409	Newly diagnosed adult Ph + ALL	III	Recruiting	350	Olverembatinib, QOD	MRD negativity rate (Cycles 1 to cycle 3)
NCT05931757	Newly diagnosed adult Ph + ALL	II	Not yet recruiting	22	Olverembatinib, 40 mg QOD and Blinatumomab IV	CMR (during 3 cycles of blinatumomab)
NCT06754267	Ph + B-ALL	II	Recruiting	36	Venetoclax, Olverembatinib, and Predinisone	CMR (At the end of cycle 3)
NCT06082934	Newly diagnosed adult Ph + ALL	I II	Recruiting	30	Olverembatinib, 40 mg QOD, Combined with Venetoclax and Dexamethasone	CR, CRi, MRD negativity, CMR, and PFS (3 years)
NCT06658925	Adult Ph + ALL after allo-HSCT	II	Not yet recruiting	50	Olverembatinib, 20–40 mg QOD	Relapse-free survival (2 year after HSCT)
NCT05594784	Newly diagnosed 14 Years and older Ph + ALL	II	Recruiting	60	Olverembatinib, Venetoclax, Prednisone, and Vincristine	CMR (at 3 months)
NCT06220487	Newly diagnosed adult Ph + B-ALL	II	Recruiting	67	Olverembatinib, 40 mg QOD, combination with Prednisone, Blinatumomab, and Chidamide	CMR (at 3 months)
NCT06640361	GIST, SDH-deficient and at least one prior systemic therapy failure	III	Recruiting	40	Olverembatinib, 40 mg QOD	PFS (36 months)
NCT05521204	FGFR1-Rearranged Myeloid/Lymphoid Neoplasms	II	Recruiting	20	Olverembatinib	ORR

Endometrial cancer (EC) is one of the most common gynecological cancers, as well as one of the most frequent malignancies overall among women [106, 107]. In addition to the increase in the incidence, the rate of presentation with advanced-stage EC is about 10–15% [1, 108, 109]. For years, the treatment of relapsed or advanced EC was limited and mostly dependent on carboplatin and paclitaxel [110]. A recent study has demonstrated that a combination of Lenvatinib (a multi-kinase inhibitor) with pembrolizumab would be efficient and gained approval for advanced EC cases except for individuals with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) [111, 112].

The receptor tyrosine kinase-like orphan receptor (ROR1), a prognostic biomarker for EC, has been found to have an inhibitory role in the proliferation of EC cell lines and could be a proper target for treatment, especially for chemoresistance EC [113]. This could be a route for Olverembatinib to have antitumor activity in EC treatment. Liu et al. designed a preclinical study to estimate the efficacy of Olverembatinib in EC. In this study, seven EC cell lines, including HEC-1-A, HEC-1-B, MFE296, RL95-2, Ishikawa, KLE, and ARK-1, alongside normal cell lines, were used. A greater sensitivity in EC cells than normal endometrial cells to Olverembatinib was detected, which can justify the inhibitory effect of this agent on the proliferation of all EC cell lines. Also, the migration in Ishikawa and ARK1 cells and invasion in the ARK1 cells were considerably inhibited and, therefore, showed a suggestive inhibitory effect for Olverembatinib for further investigations [98].

RCC is the most common forms of renal cancer [114]. Through the identification of biological features of RCC, the treatment has experienced a major development over the past decades [115]. Although the development of immunotherapy, including immune checkpoint inhibitors (ICIs), has significantly enhanced, still a considerable proportion of patients show resistance to these treatments [116]. Recently, a treatment strategy, including immunotherapy combined with TKIs (e.g., Axitinib, Lenvatinib, and Cabozantinib), has been proven as a proper option for treating RCC [117–120]. To assess the role of Olverembatinib as a novel TKI in the treatment of RCC, Wang et al. combined this agent with immunotherapy and examined the effect on murine RCC lines. An antitumor impact was seen by targeting tumor growth, angiogenesis, and immune regulation. A higher tumor growth inhibition was seen by coadministration of Olverembatinib with an anti-PD-1 antibody [99].

Conclusion

In summary, Olverembatinib (alone or combined with other agents, including immunotherapy or chemotherapy regimens) has shown promising results in both clinical and preclinical studies, particularly concerning hematologic malignancies with additional chromosomal aberrations (ACA), such as T315I mutant CML patients (Tables 1, 2 and 3). However, further research on a larger scale and across diverse ethnicities, along with the current trials, is necessary.

Author contributions

The study was conceptualized by S.S. , S.Y., SM.R, M.H, F.D, and G.A.F was involved in data collection, manuscript writing, and revision. S.S. contributed to manuscript writing, editing, and correspondence with the journal. S.Y., F.D, M.H, and G.A.F conducted the literature review, edited the manuscript, and provided critical revisions. H.M. contributed to data analysis, manuscript editing, and critical revision, supervised the case analysis, provided critical insights, and revised the manuscript. All authors have read and approved the final manuscript and agree to be accountable for all aspects of the work.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.