Next Article in Journal
Long-Term Survival and Risk of Second Malignant Neoplasms Among Childhood Cancer Patients in 16 provinces of Spain
Previous Article in Journal
Honokiol and Its Emerging Role in Breast Cancer Therapy
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 18
Issue 12
10.3390/cancers18121990
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Olverembatinib: A New Treatment for Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

by
Xavier Thomas
Hospices Civils de Lyon, Department of Clinical Hematology, Centre Hospitalier Universitaire, F-69003 Lyon, France
Cancers 2026, 18(12), 1990; https://doi.org/10.3390/cancers18121990
Submission received: 16 May 2026 / Revised: 11 June 2026 / Accepted: 17 June 2026 / Published: 18 June 2026
(This article belongs to the Special Issue Advances in Acute Lymphoblastic Leukemia Treatment)
Browse Figures
Versions Notes

Simple Summary

The prognosis of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) improved dramatically over the last decades with the introduction of tyrosine kinase inhibitors (TKIs). However, resistance or intolerance to TKIs remains a challenge. The novel third-generation TKI, olverembatinib, showed the potential to address unmet clinical needs in this situation. Fist clinical trials suggest impressive anti-leukemic activity, conferring to olverembatinib the potential to change to standard of care for patients with Ph+ ALL, especially those harboring an unfavorable mutation. The aim of this review is to summarize the first results obtained with olverembatinib and to discuss the potential therapeutic strategies using this novel agent for the treatment of Ph+ ALL.

Abstract

Background/Objectives: The prognosis of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has improved with the addition of tyrosine kinase inhibitors (TKIs) to conventional chemotherapy. However, there are limited therapeutic options for patients resistant or intolerant to current TKIs. Methods: A comprehensive search was made on PubMed.ncbi.nlm.nih.gov for published studies and ClinicalTrials.gov for registered trials, regarding the first results of and promising strategies with olverembatinib, a novel third-generation TKI, for the treatment of Ph+ ALL. Results: First trials involving olverembatinib showed significant anti-leukemic clinical activity both in newly diagnosed and relapsed/refractory patients with Ph+ ALL, especially those harboring the T315I mutation. Furthermore, olverembatinib demonstrated a favorable tolerability compared with the other TKIs. Conclusions: This augurs a new era in the standard of care for many patients with unmet clinical needs. However, further studies are warranted to assess olverembatinib’s real value and its cost-effectiveness.

1. Introduction

Olverembatinib, an oral, third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI), also known as HQP1351 and GZD824, is currently being mainly investigated in the treatment of chronic myeloid leukemia (CML) and more recently Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The drug, initially developed by Ascentage Pharma, has demonstrated promising anti-leukemic activity in heavily pre-treated patients. In November 2021, it was approved, at the dosage of 40 mg every other day (QOD), in China for the treatment of adult patients with TKI-resistant chronic- and accelerated-phase CML harboring the threonine-to-isoleucine mutation at position 315 (T315I), and in adult CML patients intolerant to first- and second-generation TKIs [1]. More recently, olverembatinib has been granted orphan drug designation and fast track designation by the US Food and Drug Administration (FDA) and orphan designation by the European Medicines Agency (EMA). Since 2024, the drug has been developed by Takeda in all territories outside of China, Taiwan and Russia.
This review provides a comprehensive overview of olverembatinib’s therapeutic potential and summarizes its first results in the treatment of Ph+ ALL.

2. Historical Considerations

ALL is a malignant hematological disease characterized by aberrations in proliferation and differentiation of lymphoblasts. Among adults with B-lineage ALL, Ph+ ALL characterized by the presence of a Philadelphia chromosome [t(9;22)] cytogenetic abnormality, resulting in the molecular juxtaposition of two genes, BCR and ABL, to form an aberrant BCR::ABL gene on chromosome 22, represents more than 25% of the cases. Historically, the prognosis of Ph+ ALL was considered very dismal, with a long-term survival rate of less than 10% after standard intensive chemotherapy [2,3], and could only reach 30 to 40% in patients able to undergo allogeneic stem cell transplantation (SCT) in first complete remission (CR) [4]. Prognosis improved substantially after 2000 with the addition of BCR::ABL1 TKIs to intensive chemotherapy, beginning with imatinib [5,6,7], and then second-generation TKIs dasatinib [8,9] and nilotinib [10]. A benefit was mainly demonstrated when TKI was started immediately, administered continuously, and continued indefinitely, leading, in combination with chemotherapy, to morphological CR rates of more than 90% and long-term survival rates reaching 50%. Given the efficacy of TKIs, some studies considered TKI-based regimens when combined with low-intensity chemotherapy [6,9,10] or no chemotherapy [11,12,13,14]. While a complete molecular response was observed in 20 to 50% of cases, the emergence of a T315I mutation was detected in up to 75% of patients relapsing after treatment with first- or second-generation TKIs [15]. Recently, ponatinib, a third-generation BCR::ABL1 TKI, combined with chemotherapy, showed complete molecular remission rate ranging from 71 to 86% and a long-term survival rate from 75 to 92% in newly diagnosed Ph+ ALL patients [16,17]. Its activity was demonstrated against both wild-type and mutated ABL1 kinase domain including the T315I mutation. Superiority of ponatinib over first- or second-generation TKIs was confirmed in a randomized trial [18] and meta-analysis [19]. Therapeutic strategies also potentially moved to combinations with monoclonal antibodies targeting CD20 (rituximab) [20], CD19 (blinatumomab, a bispecific T-cell engager targeting CD3 and CD19) [13,21], or CD22 (inotuzumab ozogamicin, an antibody–drug conjugate) [22] in both the salvage and frontline settings. Recently, blinatumomab was combined with ponatinib in a chemotherapy-free regimen. This treatment resulted in a molecular remission rate of 85% and a 3-year survival rate of 90%. These results suggested a decreased need for allogeneic SCT in remission (historically considered the gold standard for all patients with Ph+ ALL), especially for those achieving measurable residual disease (MRD) negativity at a sensitivity of 10−6 [23]. Positive results were also obtained when blinatumomab was only combined with dasatinib [24]. Results of significant clinical studies obtained over the years for the treatment of Ph+ ALL are summarized in Table 1.
However, despite the impact of TKIs in the treatment of Ph+ ALL, significant unmet needs remain, especially for patients whose disease is resistant or refractory to these therapies or who develop mutations following these treatments. Besides T315I mutation, patients displaying additional IKZF1 plus CDKN2A/B and/or PAX5 deletions or VPREB1 deletion were poor responders [25]. Introduction of novel therapeutic agents appears therefore required. In this setting, asciminib and olverembatinib have recently been developed. Asciminib inhibits the ABL1 kinase activity through binding to an allosteric site, the ABL myristoyl pocket, unlike the remaining BCR::ABL1 TKIs which bind to the ATP binding site of the BCR::ABL1 oncoprotein [26] (Figure 1). Olverembatinib is a pan BCR::ABL1 TKI which first trials demonstrated efficacy in Ph+ hemopathies previously treated with two or more TKIs, including hemopathies harboring severe mutations [1].

3. Olverembatinib: A New Third-Generation BCR::ABL1 TKI

Olverembatinib is an ATP binding-site inhibitor. It targets both wild-type BCR::ABL1 kinase and a broad spectrum of BCR::ABL1 mutants, including mutant T315I, known as the gatekeeper mutation, which confers resistance against all first- and second-generation TKIs [27,28]. The drug can also target other kinases, such as KIT, FLT3, FGFR1, and PDGFRα, potentially opening treatment opportunities for the management of acute myeloid leukemia or other malignancies, including gastro-intestinal stromal tumors (GISTs), endometrial cancer, and renal cell carcinoma [29]. Its molecular formula is C29H27F3N6O (Figure 2). In vitro, olverembatinib showed more activity than all other TKIs against BCR::ABL1-positive cells expressing various variants including T315I [30]. This includes ponatinib and asciminib. Comparisons with ponatinib point to differences in binding to the active and inactive conformations of wild-type and mutant BCR::ABL1 mutants [31]. Olverembatinib binds to both phosphorylated and non-phosphorylated conformations, while ponatinib binds only to non-phosphorylated wild-type and T315I mutant ABL1. Oral bioavailability of olverembatinib is compatible with alternate-day dosing and an appropriate half-life [27]. The absorption is slow with a mean terminal elimination half-life of 20 h. Olverembatinib is mainly metabolized by CYP3A4. Its administration should be cautious with strong CYP3A4 inhibitors or inducers, which may substantially alter olverembatinib pharmacokinetics and potentially exacerbate olverembatinib-induced toxic reactions. Coadministration of olverembatinib with itraconazole increases the maximum plasma concentration and duration of exposure of olverembatinib, while coadministration with rifampin decreases both its concentration and duration of exposure, which should drive to appropriate dose modifications if coadministration is required [32]. Pre-clinical studies showed inhibition of Ba/F3 murine cells expressing the native BCR::ABL1 gene and resistance to mutations including T315I which contraindicates treatment with imatinib and second-generation TKIs, V299L and F317L mutations which contraindicate dasatinib and bosotinib, Y253H, E255K/V, and F359V/C/L mutations which contraindicate nilotinib, and A337T, P465S, M244V, and F359V/I/C which contraindicate asciminib [27]. Inhibition was then confirmed in mice xenografted with human ALL cells and on human CML cells. Olverembatinib was effective against Ba/F3 cells co-expressing BCR::ABL1T315I and luciferase, and increased lifespan of leukemic mice compared to controls [27]. Anti-leukemic effects of olverembatinib in Ba/F3 murine cells harboring T315I mutation were potentiated by combination with asciminib [33]. A potential impact of olverembatinib on leukemic blast clearance from the cerebrospinal fluid was suggested in an early clinical study involving relapsed patients with central nervous system (CNS) involvement [34]. Anti-leukemic effects of olverembatinib have also been demonstrated independently of BCR::ABL1 kinase, through inhibition of both PI3K/AKT and SRC kinase pathways [28].

4. Lessons from CML

The translocation of the ABL1 gene from chromosome 9 to the BCR gene at its site on chromosome 22 creates the BCR::ABL1 fusion gene, which transforms hematopoietic stem cells into leukemic cells through uncontrolled tyrosine kinase activity [35]. Ponatinib is currently the standard therapeutic option in CML patients harboring the T315I mutation. Major cytogenetic response (MCyR) and major molecular response (MMR) rates after 12 months of treatment reach 70% and 40% respectively [36]. Although harboring a different mechanism of action, asciminib demonstrated similar efficacy than ponatinib [37,38]. However, patients who are resistant or intolerant to ponatinib and asciminib need further therapeutic options. Olverembatinib, another third-generation TKI, appears potentially effective in this situation. It was first investigated in chronic-phase CML and accelerated-phase CML. A phase 1/2 study in CML patients with TKI resistance, of whom more than 60% harbored the T315I mutation, demonstrated olverembatinib efficacy [39]. Forty mg once every two days in 28-day cycles was established as the phase 2 dose, leading to drug approval in China with this schedule [40]. However, a real-world study suggested that an approach starting at a lower dose might allow similar efficacy with improved tolerability [41]. Patients starting at 30 mg once every two days experienced fewer dose reductions or treatment discontinuations, and maintained this initial dose through follow-up. This was confirmed by another study, which however showed that a higher concentration of olverembatinib was needed to inhibit leukemia cells with T315I mutation [42]. In chronic-phase CML patients, complete hematologic response (CHR), MCyR, complete cytogenetic response (CCyR), and MMR after 37 months of follow-up were 100%, 79%, 69% and 56%, respectively. They were 73%, 47%, 47% and 45%, respectively, in accelerated-phase CML. Grade ≥ 3 non-hematologic and hematologic treatment-related adverse events were seen in 49% and 56% of patients in chronic- and accelerated-phases, respectively. However, olverembatinib was well tolerated. Most treatment-related adverse events resolved over time. The most frequent non-hematologic side effects with olverembatinib therapy were skin hyperpigmentation manifested as lentiginous nevi, elevated creatine phosphokinase, hypocalcemia, and hypertriglyceridemia [39,43,44]. Arterial and venous occlusive events of special concern with ponatinib have yet to be investigated. Results after a longer duration of follow-up were consistent with the first analyses [43]. The phase 2 Chinese pivotal study (NCT04126681) randomized patients to a 2:1 ratio to either olverembatinib or investigator’s choice of best available treatment (but excluding bosutinib, ponatinib or asciminib) [45]. Olverembatinib significantly prolonged event-free survival (EFS) versus best available treatment (21 months versus 3 months) in the intention-to-treat population. Achieving cytogenetic and molecular responses over 36 months were also significantly higher with olverembatinib. An American study confirmed the results from the Chinese studies and demonstrated that a dosage of 30 mg was effective in patients without T315I mutation, while higher dosages were required in patients harboring the mutation [42]. Furthermore, this study found a strong anti-leukemic activity in chronic-phase CMLs known for resistance to ponatinib andasciminib [42]. Most cases of ponatinib and/or asciminib resistance that responded to olverembatinib had the T315I variant. Interesting results were also obtained by Chinese studies combining olverembatinib with venetoclax or hypomethylating agents in blastic-phase CML [46,47]. A study evaluating health-related quality of life (HRQoL) scores showed that being younger than 40 years and in chronic-phase CML was associated with greater improvements in HRQoL than being older and in accelerated-phase CML, as patients underwent more cycles of olverembatinib therapy [48].

5. Olverembatinib in Ph+ ALL

Ponatinib has shown efficacy in Ph+ ALL and currently represents the treatment of choice in frontline therapy or in relapsed/refractory Ph+ ALL after initial treatment involving first- or second-generation TKIs. Combined with chemotherapy regimens, CR rates reached 80 to 90% and 41% of relapsed/refractory Ph+ ALL achieved major hematologic responses [36]. However, ponatinib was not easily available in mainland China. This led, especially in China, to the development of olverembatinib in these indications. Combined with a pediatric-inspired chemotherapy protocol, olverembatinib used at 40 mg once every two days demonstrated increased MCyR achievement from 15% on day 14 to 85% on day 90 when compared to chemotherapy combined with another TKI [49]. Although tested on a small series, overall response rate (ORR) was 100% and CR was achieved regardless of the P190 or P210 transcript subtypes. Promising results were confirmed in further small series combining olverembatinib with standard or low-intensity chemotherapy in patients with newly diagnosed or relapsed/refractory Ph+ ALL [34,50,51,52]. High early and sustainable MCyR rates were achieved. Like in CML studies, most observed adverse events were mild and manageable. Common treatment-related adverse events included skin hyperpigmentation, hypertriglyceridemia, proteinuria, thrombocytopenia, and neutropenia. Various possible strategies have been proposed to manage myelosuppression during treatment, including low-intensity chemotherapy scheme, hematopoietic growth factor support, scheduled breaks in therapy, or dose reduction after achieving molecular response. Olverembatinib was also tested alone or combined with only vincristine and steroids in relapsed/refractory patients, including patients harboring T315I mutation and patients with prior treatment by ponatinib [53]. MCyR could be achieved in about 67% of cases and responses were obtained in some previously treated with ponatinib. In another study, 43% of patients resistant to ponatinib achieved MCyR, 29% achieved CCyR, and 22% achieved MMR after olverembatinib therapy [42]. Relapsing patients without T315I mutation obtained higher CCyR and MCyR rates than those harboring the mutation (33% versus 20% and 50% versus 20%, respectively). Olverembatinib was also incorporated within a regimen including high-intensity chemotherapy cycles and the bispecific T-cell engager (BiTE) antibody blinatumomab in patients with newly diagnosed Ph+ ALL [54]. MCyR rate was 35% after one cycle of treatment and reached 70% after another cycle. The one-year EFS and overall survival (OS) reached 100% at a median follow-up of one and half years. Beside combination with blinatumomab, first case reports revealed a complementary action when combining olverembatinib with the anti-CD22 antibody, inotuzumab ozogamicin [55]. Similar results were obtained with the combination of olverembatinib, venetoclax and dexamethasone (OVD regimen) for induction and consolidation phases with a course of treatment every 28 days (NCT06082934) [56]. In this trial, olverembatinib was used at 40 mg orally every other day, along with intravenous dexamethasone (10 mg on days 1 to 14 and 5 mg on days 15 to 28). Venetoclax was administered at 100 mg on day 4, 200 mg on day 5, and 400 mg on days 6 to 17. After CR achievement, olverembatinib was administered at 40 mg every other day on days 1 to 28 and venetoclax 400 mg daily for the first two weeks of each cycle. All patients achieved CR and MRD-negativity, and 80% of them obtained MMR. Favorable outcomes with olverembatinib and venetoclax-based regimen were confirmed by other studies suggesting complementary mechanisms of action [57]. Responses to olverembatinib therapy were noted not only in relapsed patients harboring the T315I mutation [55], but also for patients harboring other mutations, such as the E255V mutation [58]. Main registered current studies involving olverembatinib in the treatment of Ph+ ALL are summarized in Table 2. Most of them tend to test olverembatinib in frontline therapy. The position of olverembatinib within regimens was evaluated in induction and consolidation phases, but also as maintenance therapy including the post-transplant phase (NCT07074496, NCT05466175, NCT06658925). Maintenance therapy with TKIs after allogeneic HSCT in Ph+ ALL can decrease relapse incidence and improve OS. It was shown that the efficacy of this maintenance therapy was better was started within the three months after transplantation [59]. In a recent retrospective study using olverembatinib alone as maintenance post-transplant, the 3-year OS and relapse-free survival (RFS) was 92% and 79%, respectively [60]. The efficacy of olverembatibib as maintenance therapy after transplantation was similar to that reported with ponatinib and appeared well tolerated [61]. Combinations mostly involve low-intensity chemotherapy (NCT07152041, NCT07493161), including inhibitors of BCL2 (NCT05495035, NCT06481228, NCT06754267, NCT06082934, NCT05594784) and monoclonal antibodies (NCT05931757, NCT07178912, NCT06220487, NCT07443488). Two phase 2 studies combining olverembatinib with inotuzumab ozogamicin as a bridging therapy prior to transplantation recently conducted enrolling patients with persistent MRD (NCT05603156) after at least three rounds of chemotherapy, and patients with relapsed/refractory Ph+ ALL (ChiCTR2200061432). Treatment resulted in a high complete molecular response (CMR) rate, a high bridging transplantation rate, and a good tolerance [62]. Another proposed study takes into account genetic alterations (NCT07454226). Patients with ABL class fusions (ABL1, ABL2, PDGFRA, PDGFRB) receive olverembatinib, while those with JAK pathway alterations (CRLF2 rearrangement, JAK mutation/fusion, EPOR fusion, SH2B3 deletion, IL7R mutation) receive gecacitinib (also known as jaktinib), a novel inhibitor targeting both JAK and ACVR1.

6. Discussion

The novel third-generation TKI, olverembatinib, appears well tolerated and efficacious both in newly diagnosed and heavily pre-treated TKI-resistant patients with Ph+ ALL. Olverembatinib exerts sustainable anti-leukemic activity in patients including those with the T315I mutation and other mutations conferring resistance to other TKIs. In newly diagnosed patients with Ph+ ALL, olverembatinib combined with low-intensity chemotherapy gave 64% of MRD-negativity by the end of induction, including patients with unfavorable prognostic genotypes (POLARIS 1 study, NCT06051409) [63]. Furthermore, olverembatinib tolerability compared favorably with the other TKIs (Table 3). The most common adverse event was skin hyperpigmentation, which was not noted with other TKIs. The precise mechanism of this adverse event is not known and should be elucidated, but could be explained by the inhibition of various kinases. Severe thrombocytopenia is another event that appeared more frequent than what was observed with ponatinib, but severe cardiovascular events were less frequent than those reported in ponatinib studies [36]. Molecular features, including the presence of ASXL1, FAT4 and/or TET2 mutations, were recently identified as independent predictors for glucolipid metabolic disorders and cerebrovascular adverse events, and therefore guide early risk identification and targeted surveillance [64]. Although effectiveness of olverembatinib was comparable to that observed with ponatinib and asciminib in newly diagnosed patients [36,65], very encouraging effects were noted in patients previously treated with those agents, suggesting especially a higher specific targeting of the T315I mutation with olverembatinib [42,53]. Overall, olverembatinib good tolerance combined with its profile as multikinase inhibitor suggests a potential utility in the treatment of this disease.
Despite those encouraging results, some issues should be mentioned. First, which patients will benefit from the introduction of olverembatinib has yet to be defined. Should it be given to all patients with Ph+ ALL or reserved for those previously heavily treated and having developed resistance or intolerance to prior therapy. In the first situation olverembatinib would become a new standard of care in this disease. In ALL, it is effectively generally admitted to use agents with the larger spectrum of activity from frontline therapy in order to avoid resistance or relapse always harder to eradicate. Persistence or reappearance of MRD is the most important adverse prognostic factor in ALL. Combinations yielded deeper responses and remissions are therefore required to allow organization of allogeneic SCT, which remains the main goal of therapy in high-risk patients, and to perform it in the best conditions. In the later situation, olverembatinib would be limited to salvage therapy. Patients who are resistant to ponatinib or to asciminib need further therapeutic options [66] and olverembatinib has demonstrated a potential efficacy in this setting [42]. The mechanism that could explain the superiority of olverembatinib over ponatinib remains unknown. However, olverembatinib can bind to both non-phosphorylated and phosphorylated BCR::ABL1, while ponatinib only bind to non-phosphorylated BCR::ABL1 [27,31]. Theoretically, therapies with an alternative mechanism of action are considered the best choice in case of relapse or resistance. Unlike ABL-TKIs, which target the ATP binding site, asciminib is a novel drug that shows a therapeutic effect by binding to the myristoyl pocket, which regulates ABL activity [65]. However, asciminib did not demonstrate any superiority comparatively to other novel inhibitors. Asciminib showed similar effects than the third-generation TKI ponatinib [37,38], but the progression-free survival (PFS) was lower for ponatinib pre-treated patients than for ponatinib naïve patients [67,68]. Regarding olverembatinib, efficacy was noted in some cases pre-treated by asciminib, while no cases were reported until now in the opposite situation.
Second, which dosing should be used? Clinical experience already underscores the importance of flexible TKI dosing [30]. Olverembatinib 30 mg QOD as a starting dose demonstrated equivalent efficacy and better tolerability compared with 40 mg QOD. Starting olverembatinib at a lower dose with the flexibility to escalate based on suboptimal response seems therefore consistent with real-world practice patterns [41]. Maintaining a good quality of life and adherence to treatment appears as important as achieving deep molecular responses. However, 40 mg QOD demonstrated a better efficacy in patients harboring an unfavorable mutation. A tentative of algorithm regarding olverembatinib dosing that should be used is presented in Figure 3.
Third, questions remain about how best to use olverembatinib: as a single agent or in combination therapy, and what combination therapy, for induction, consolidation, and/or maintenance, or as part of a large combination or succession of treatments. Administration should certainly follow the same rules as other TKIs. Treatment should be started immediately and administered continuously for induction and consolidations rather than intermittently, and continued indefinitely. Although intensive chemotherapy remains still required in Ph+ ALL with IKZF1 deletion plus additional genetic aberrations including CDKN2A, CDKN2B, or PAX5, an important current point in the treatment of Ph+ ALL is the transition of patients to a chemotherapy-free era. Recently blinatumomab and venetoclax were integrated into chemotherapy-free regimens with TKIs serving as the backbone in the treatment of Ph+ ALL. A combination of blinatumomab with TKIs already demonstrated interesting results with a MCyR rate of 75% and a one-year OS rate of 73% in relapsed/refractory patients [69]. In the frontline setting, the combination of ponatinib with blinatumomab showed 46% to 59% of MCyR after induction [23,70] and 96% of MRD-negativity [23]. The 3-year EFS and OS rates were 78% and 88%, respectively [71]. In this setting, olverembatinib combined with blinatumomab already showed promising results [54]. Several ongoing trials should confirm these preliminary results (NCT05931757, NCT07178912). Olverembatinib combined with venetoclax and dexamethasone is another current attractive chemotherapy-free regimen (NCT06082934). Addition of venetoclax or another BCL2 inhibitor, which exhibits a high activity in relapsed/refractory ALL [72], completes effectively achievement of rapid and profound remissions. The first assessment of the OVD regimen in frontline therapy showed achievement of MRD-negativity in all patients at day 14 and CMR in 90% of them at day 90 that were maintained throughout the follow-up period [56]. The effectiveness and safety of olverembatinib combined with blinatumomab and venetoclax is currently evaluated in several ongoing trials.
Finally, the ability to target sanctuary sites remains, like for other TKIs, another major challenge. Primary results of the NCT05495035 clinical trial combining olverembatinib with APG-2575 (lisaftoclax) showed that both agents were detectable in the cerebrospinal fluid indicating CNS penetration, positioning this combination as a highly promising strategy in Ph+ ALL with CNS involvement [73]. Besides the increased efficacy of novel TKIs, other ways are currently explored to overcome TKI resistance in Ph+ ALL. In this setting thermal-based therapy was recently presented as offering a promising adjuvant approach [74]. Heat stress was shown to suppress proliferation of BCR::ABL1-driven leukemic cells, including drug resistant mutant in vitro and decrease tumor burden in vivo.

7. Conclusions

Overall, first clinical trials with overembatinib suggest impressive anti-leukemic activity in patients with Ph+ ALL. Olverembatinib has the potential to change the standard of care for adults with Ph+ ALL, and could hold in combination therapy the promise of substantial benefit, especially in patients harboring an unfavorable mutation. Larger series and longer follow-up intervals are warranted to confirm olverembatinib value, further assess its toxicity profile, especially in the cardiovascular setting, and its cost-effectiveness, an essential consideration in resource-limited and/or low-income countries [75].

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

A comprehensive search was made on PubMed.ncbi.nlm.nih.gov for published studies and ClinicalTrials.gov for registered trials.

Conflicts of Interest

The author declares no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
ALLAcute lymphoblastic leukemia
BiTEBispecific T-cell engager
CCyRComplete cytogenetic response
CHRComplete hematologic response
CMLChronic myeloid leukemia
CMRComplete molecular response
CNSCentral nervous system
CRComplete remission
EFSEvent-free survival
EMAEuropean Medicines Agency
FDAFood and Drug Administration
GISTGastro-intestinal stromal tumor
HRQoLHealth-related quality of life
MCyRMajor cytogenetic response
MMRMajor molecular response
MRDMeasurable residual disease
ORROverall response rate
OSOverall survival
Ph+Philadelphia chromosome-positive
QODEvery other day
RFSRelapse-free survival
SCTStem cell transplantation
TKITyrosine kinase inhibitor

References

  1. Dhillon, S. Olverembatinib: First approval. Drugs 2022, 82, 469–475. [Google Scholar] [CrossRef] [PubMed]
  2. Hoelzer, D.; Thiel, E.; Löffler, H.; Büchner, T.; Ganser, A.; Heil, G.; Koch, P.; Freund, M.; Diedrich, H.; Rühl, H.; et al. Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 1988, 71, 123–131. [Google Scholar] [CrossRef][Green Version]
  3. Thomas, X.; Thiebaut, A.; Olteanu, N.; Danaïla, C.; Charrin, C.; Archimbaud, E.; Fiere, D. Philadelphia chromosome positive adult acute lymphoblastic leukemia: Characteristics, prognostic factors and treatment outcome. Hematol. Cell Ther. 1998, 40, 119–128. [Google Scholar] [PubMed]
  4. Dombret, H.; Gabert, J.; Boiron, J.M.; Rigal-Huguet, F.; Blaise, D.; Thomas, X.; Delannoy, A.; Buzyn, A.; Bilhou-Nabera, C.; Cayuela, J.M.; et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia–results of the prospective multicenter LALA-94 trial. Blood 2002, 100, 2357–2366. [Google Scholar] [CrossRef] [PubMed]
  5. Daver, N.; Thomas, D.; Ravandi, F.; Cortes, J.; Garris, R.; Jabbour, E.; Garcia-Manero, G.; Borthakur, G.; Kadia, T.; Rytting, M.; et al. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica 2015, 100, 653–661. [Google Scholar] [CrossRef] [PubMed]
  6. Chalandon, Y.; Thomas, X.; Hayette, S.; Cayuela, J.M.; Abbal, C.; Huguet, F.; Raffoux, E.; Leguay, T.; Rousselot, P.; Lepretre, S.; et al. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood 2015, 125, 3711–3719. [Google Scholar] [CrossRef] [PubMed]
  7. Fielding, A.K.; Rowe, J.M.; Buck, G.; Foroni, L.; Gerrard, G.; Litzow, M.R.; Lazarus, H.; Luger, S.M.; Marks, D.I.; McMillan, A.K.; et al. UKALLXII/ECOG2993: Addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood 2014, 123, 843–850. [Google Scholar] [CrossRef] [PubMed]
  8. Ravandi, F.; Othus, M.; O’Brien, S.M.; Forman, S.J.; Ha, C.S.; Wong, J.Y.C.; Tallman, M.S.; Paietta, E.; Racevskis, J.; Uy, G.L.; et al. US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv. 2016, 1, 250–259. [Google Scholar] [CrossRef] [PubMed]
  9. Rousselot, P.; Coudé, M.M.; Gokbuget, N.; Gambacorti Passerini, C.; Hayette, S.; Cayuela, J.M.; Huguet, F.; Leguay, T.; Chevallier, P.; Salanoubat, C.; et al. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL. Blood 2016, 128, 774–782. [Google Scholar] [CrossRef] [PubMed]
  10. Chalandon, Y.; Rousselot, P.; Chevret, S.; Cayuela, J.M.; Kim, R.; Huguet, F.; Chevallier, P.; Graux, C.; Thiebaut-Bertrand, A.; Chantepie, S.; et al. Nilotinib with or without cytarabine for Philadelphia-positive acute lymphoblastic leukemia. Blood 2024, 143, 2363–2372. [Google Scholar] [CrossRef] [PubMed]
  11. Vignetti, M.; Fazi, P.; Cimino, G.; Martinelli, G.; Di Raimondo, F.; Ferrara, F.; Meloni, G.; Ambrosetti, A.; Quarta, G.; Pagano, L.; et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: Results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood 2007, 109, 3676–3678. [Google Scholar] [CrossRef] [PubMed]
  12. Foà, R.; Vitale, A.; Vignetti, M.; Meloni, G.; Guarini, A.; De Propris, M.S.; Elia, L.; Paoloni, F.; Fazi, P.; Cimino, G.; et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2011, 118, 6521–6528. [Google Scholar] [CrossRef] [PubMed]
  13. Foà, R.; Bassan, R.; Elia, L.; Piciocchi, A.; Soddu, S.; Messina, M.; Ferrara, F.; Lunghi, M.; Mulè, A.; Bonifacio, M.; et al. Long-term results of the dasatinib-blinatumomab protocol for adult Philadelphia-positive ALL. J. Clin. Oncol. 2024, 42, 881–885. [Google Scholar] [CrossRef] [PubMed]
  14. Martinelli, G.; Papayannidis, C.; Piciocchi, A.; Robustelli, V.; Soverini, S.; Terragna, C.; Marconi, G.; Lemoli, R.M.; Guolo, F.; Fornaro, A.; et al. INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia. Blood Adv. 2022, 6, 1742–1753. [Google Scholar] [CrossRef] [PubMed]
  15. Nicolini, F.E.; Mauro, M.J.; Martinelli, G.; Kim, D.W.; Soverini, S.; Müller, M.C.; Hochhaus, A.; Cortes, J.; Chuah, C.; Dufva, I.H.; et al. Epidemiologic study on survival of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia patients with BCR-ABL T315I mutation. Blood 2009, 114, 5271–5278. [Google Scholar] [CrossRef] [PubMed]
  16. Kantarjian, H.; Short, N.J.; Jain, N.; Sasaki, K.; Huang, X.; Haddad, F.G.; Khouri, I.; DiNardo, C.D.; Pemmaraju, N.; Wierda, W.; et al. Frontline combination of ponatinib and hyper-CVAD in Philadelphia chromosome-positive acute lymphoblastic leukemia: 80-months follow-up results. Am. J. Hematol. 2023, 98, 493–501. [Google Scholar] [CrossRef] [PubMed]
  17. Ribera, J.M.; Morgades, M.; Ribera, J.; Montesinos, P.; Cano-Ferri, I.; Martinez, P.; Esteve, J.; Esteban, D.; Garcia-Fortes, M.; Alonso, N.; et al. Ponafil trial for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: Long-term results. Hemasphere 2024, 8, e67. [Google Scholar] [CrossRef] [PubMed]
  18. Jabbour, E.; Kantarjian, H.M.; Aldoss, I.; Montesinos, P.; Leonard, J.T.; Gomez-Almaguer, D.; Baer, M.R.; Gambacorti-Passerini, C.; McCloskey, J.; Minami, Y.; et al. Ponatinib vs imatinib in frontline Philadelphia chromosome-positive acute lymphoblastic leukemia: A randomized clinical trial. JAMA 2024, 331, 1814–1823. [Google Scholar] [CrossRef] [PubMed]
  19. Jabbour, E.; DerSarkissian, M.; Duh, M.S.; McCormick, N.; Cheng, W.Y.; McGarry, L.J.; Souroutzidis, A.; Huang, H.; O’Brien, S.; Ravandi, F.; et al. Efficacy of ponatinib versus earlier generation tyrosine kinase inhibitors for front-line treatment of newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Clin. Lymphoma Myeloma Leuk. 2018, 18, 257–265. [Google Scholar] [CrossRef] [PubMed]
  20. Rios-Olais, F.A.; Rodriguez-Rodriguez, S.; Mora-Canas, A.; Ramos-Penafiel, C.O.; Urbalejo-Ceniceros, V.I.; Lopez-Garcia, Y.K.; Gomez-De Leon, A.; Delgado-Lopez, N.; Castellanos-Mares, M.; Figueroa-Hernandez, P.C.; et al. Impact of the addition of rituximab in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Leuk. Lymphoma 2025, 66, 561–564. [Google Scholar] [CrossRef] [PubMed]
  21. Martinelli, G.; Boissel, N.; Chevallier, P.; Ottmann, O.; Gökbuget, N.; Rambaldi, A.; Ritchie, E.K.; Papayannidis, C.; Tuglus, C.A.; Morris, J.D.; et al. Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia: Final analysis of ALCANTARA study. Eur. J. Cancer 2021, 146, 107–114. [Google Scholar] [CrossRef] [PubMed]
  22. Ueda, T.; Fukushima, K.; Kusakabe, S.; Yoshida, K.; Suga, M.; Nakai, R.; Koike, M.; Hino, A.; Akuta, K.; Toda, J.; et al. Inotuzumab ozogamicin and blinatumomab sequential therapy for relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. Leuk. Res. Rep. 2022, 17, 100294. [Google Scholar] [CrossRef] [PubMed]
  23. Jabbour, E.; Short, N.J.; Jain, N.; Huang, X.; Montalban-Bravo, G.; Banerjee, P.; Rezvani, K.; Jiang, X.; Kim, K.H.; Kanagal-Shamanna, R.; et al. Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: A US, single-centre, single-arm, phase 2 trial. Lancet Haematol. 2023, 10, e24–e34. [Google Scholar] [CrossRef] [PubMed]
  24. Foà, R.; Bassan, R.; Vitale, A.; Elia, L.; Piciocchi, A.; Puzzolo, M.C.; Canichella, M.; Viero, P.; Ferrara, F.; Lunghi, M.; et al. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N. Engl. J. Med. 2020, 383, 1613–1623. [Google Scholar] [CrossRef] [PubMed]
  25. Chiaretti, S.; Ansuinelli, M.; Vitale, A.; Elia, L.; Matarazzo, M.; Piciocchi, A.; Fazi, P.; Di Raimondo, F.; Santoro, L.; Fabbiano, F.; et al. A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia: Final results of the GIMEMA LAL1509 protocol. Haematologica 2021, 106, 1828–1838. [Google Scholar] [CrossRef] [PubMed]
  26. Luskin, M.R.; Murakami, M.A.; Keating, J.; Flamand, Y.; Winer, E.S.; Garcia, J.S.; Stahl, M.; Stone, R.M.; Wadleigh, M.; Jaeckle, S.L.; et al. Asciminib plus dasatinib and prednisone for Philadelphia chromosome-positive acute leukemia. Blood 2025, 145, 577–589. [Google Scholar] [CrossRef] [PubMed]
  27. Ren, X.; Pan, X.; Zhang, Z.; Wang, D.; Lu, X.; Li, Y.; Wen, D.; Long, H.; Luo, J.; Feng, Y.; et al. Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib. J. Med. Chem. 2013, 56, 879–894. [Google Scholar] [CrossRef] [PubMed]
  28. Ye, W.; Jiang, Z.; Lu, X.; Ren, X.; Deng, M.; Lin, S.; Xiao, Y.; Lin, S.; Wang, S.; Li, B.; et al. GZD824 suppresses the growth of human B cell precursor acute lymphoblastic leukemia cells by inhibiting the SRC kinase and Pl3K/AKT pathways. Oncotarget 2017, 8, 87002. [Google Scholar] [CrossRef] [PubMed]
  29. Wang, Y.; Zhang, L.; Tang, X.; Luo, J.; Tu, Z.; Jiang, K.; Ren, X.; Xu, F.; Chan, S.; Li, Y.; et al. GZD824 as a FLT3, FGFR1 and PDGFRα inhibitor against leukemia in vitro and in vivo. Transl. Oncol. 2020, 13, 100766. [Google Scholar] [CrossRef] [PubMed]
  30. Senapati, J.; Sasaki, K.; Issa, G.C.; Lipton, J.H.; Radich, J.P.; Jabbour, E.; Kantarjian, H.M. Management of chronic myeloid leukemia in 2023–common ground and common sense. Blood Cancer J. 2023, 13, 58. [Google Scholar] [CrossRef] [PubMed]
  31. O’Hare, T.; Shakespeare, W.C.; Zhu, X.; Eide, C.A.; Rivera, V.M.; Wang, F.; Adrian, L.T.; Zhou, T.; Huang, W.S.; Xu, Q.; et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009, 16, 401–412. [Google Scholar] [PubMed]
  32. Wang, H.; Yang, Y.; Chen, Z.; Fu, L.; Yu, M.; Jiang, L.; Wang, C.; Men, L.; Minto, I.; Yang, D.; et al. Pharmacokinetics of olverembatinib (HQP1351) in the presence of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampin) in healthy volunteers. Clin. Transl. Sci. 2024, 17, e70021. [Google Scholar] [CrossRef] [PubMed]
  33. Wang, G.; Lv, J.; Tang, C.; Min, P.; Rui, L.; Zhang, F.; Wang, L.; Ge, Y.; Lian, K.; Liang, E.; et al. ATP-site inhibitor olverembatinib, HQP1351, enhanced the effect of allosteric inhibitor on the resistance conferred by the compound mutations of BCR-ABL. Cancer Res. 2021, 81, 1463. [Google Scholar] [CrossRef]
  34. Li, X.; Zhang, J.; Liu, F.; Liu, T.; Zhang, R.; Chen, Y.; Guo, Y.; Fang, Y.; Xu, X.; Pui, C.H.; et al. Olverembatinib treatment in pediatric patients with relapsed Philadelphia-chromosome-positive acute lymphoblastic leukemia. Clin. Lymphoma Myeloma Leuk. 2023, 23, 660–666. [Google Scholar] [CrossRef] [PubMed]
  35. Laurent, E.; Talpaz, M.; Kantarjian, H.; Kurzrock, R. The BCR gene and Philadelphia chromosome-positive leukemogenesis. Cancer Res. 2001, 61, 2343–2355. [Google Scholar] [PubMed]
  36. Cortes, J.E.; Kim, D.W.; Pinilla-Ibarz, J.; Le Coutre, P.; Paquette, R.; Chuah, C.; Nicolini, F.E.; Apperley, J.F.; Khoury, H.J.; Talpaz, M.; et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 2013, 369, 1783–1796. [Google Scholar] [CrossRef] [PubMed]
  37. Hochhaus, A.; Rea, D.; Boquimpani, C.; Minami, Y.; Cortes, J.E.; Hughes, T.P.; Apperley, J.F.; Lomaia, E.; Voloshin, S.; Turkina, A.; et al. Asciminib vs bosutinib in chronic-phase chronic myeloid leukemia previously treated with at least two tyrosine kinase inhibitors: Longer-term follow-up of ASCEMBL. Leukemia 2023, 37, 617–626. [Google Scholar] [CrossRef] [PubMed]
  38. Atallah, E.; Mauro, M.J.; Hochhaus, A.; Boquimpani, C.; Minami, Y.; Maheshwari, V.K.; Saini, L.; Corbin, R.; Rea, D. Matching-adjusted indirect comparison of asciminib versus other treatments in chronic-phase chronic myeloid leukemia after failure of two prior tyrosine kinase inhibitors. J. Cancer Res. Clin. Oncol. 2023, 149, 6247–6262. [Google Scholar] [CrossRef] [PubMed]
  39. Jiang, Q.; Huang, X.; Chen, Z.; Niu, Q.; Shi, D.; Li, Z.; Hou, Y.; Hu, Y.; Li, W.; Xu, N.; et al. Novel BCR-ABL1 tyrosine kinase inhibitor (TKI) HQP1351 (olverembatinib) is efficacious and well tolerated in patients with T315I-mutated chronic myeloid leukemia (CML): Results of pivotal (phase II) trials. Blood 2020, 136, 50–51. [Google Scholar] [CrossRef]
  40. Jiang, Q.; Li, Z.; Qin, Y.; Li, W.; Xu, N.; Liu, B.; Zhang, Y.; Meng, L.; Zhu, H.; Du, X.; et al. Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: Results of an open-label, multicenter phase 1/2 trial. J. Hematol. Oncol. 2022, 15, 113. [Google Scholar] [CrossRef] [PubMed]
  41. Zhang, X.; Yang, Y.; Liu, B.; Du, X.; Wang, X.; Zhu, H.; Yu, L.; Li, Z.; Zhao, S.; Yang, L.; et al. Optimizing olverembatinib dose in chronic phase chronic myeloid leukemia. Haematologica 2025, 110, 2986–2996. [Google Scholar] [CrossRef] [PubMed]
  42. Jabbour, E.; Oehler, V.G.; Koller, P.B.; Jamy, O.; Lomaia, E.; Hunter, A.M.; Uspenskaya, O.; Samarina, S.; Mukherjee, S.; Cortes, J.E.; et al. Olverembatinib after failure of tyrosine kinase inhibitors, including ponatinib and asciminib: A phase 1b randomized clinical trial. JAMA Oncol. 2025, 11, 28–35. [Google Scholar] [CrossRef] [PubMed]
  43. Qian, J.; Shi, D.; Li, Z.; Qin, Y.; Zhao, T.; Liu, B.; Chen, Z.; Niu, Q.; Men, L.; Wang, H.; et al. Updated safety and efficacy results of phase 1 study of olverembatinib (HQP1351), a novel third-generation BCR-ABL tyrosine kinase inhibitor (TKI), in patients with TKI-resistant chronic myeloid leukemia (CML). Blood 2021, 138, 311. [Google Scholar] [CrossRef]
  44. Jiang, Q.; Li, Z.; Hou, Y.; Hu, Y.; Li, W.; Liu, X.; Xu, N.; Zhang, Y.; Song, Y.; Meng, L.; et al. Updated results of pivotal phase 2 trials of olverembatinib (HQP1351) in patients (Pts) with tyrosine kinase inhibitor (TKI)-resistant chronic- and accelerated-phase chronic myeloid leukemia (CML-CP and CML-AP) with T315I mutation. Blood 2022, 140, 203–204. [Google Scholar] [CrossRef]
  45. Jiang, Q.; Li, Z.; Zhang, G.; Hu, Y.; Li, W.; Song, Y.; Li, J.; Zhou, L.; Liu, B.; Liu, X.; et al. Olverembatinib (HQP1351) demonstrates efficacy vs. best available therapy (BAT) in patients (pts) with tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia chronic-phase (CML-CP) in a registrational randomized phase 2 study. Blood 2023, 142, 869. [Google Scholar] [CrossRef]
  46. Zhang, T.; Zhou, H.; Xu, M.; Qian, C.; Sun, A.; Wu, D.; Xue, S. Combination venetoclax and olverembatinib (HQP1351) as a successful therapeutic strategy for relapsed/refractory (R/R) mixed-phenotype blast phase of chronic myeloid leukemia. Ann. Hematol. 2023, 102, 973–975. [Google Scholar] [CrossRef] [PubMed]
  47. Wen, Z.; Zhou, X.; Fan, Z.; Liu, Q.; Sun, J.; Liu, X.; Xu, N. Outcomes of olverembatinib based regimen in patients with Philadelphia chromosome-positive advanced leukemias: A real-world, single-center experience. Blood 2022, 140, 12217. [Google Scholar] [CrossRef]
  48. Yu, L.; Li, W.; Xu, N.; Liu, X.; Liu, B.; Zhang, Y.; Meng, L.; Zhu, H.; Du, X.; Chen, S.; et al. Patient-reported outcomes in adults with tyrosine kinase inhibitor-resistant chronic myeloid leukemia receiving olverembatinib therapy. Cancer 2025, 131, e35652. [Google Scholar] [CrossRef] [PubMed]
  49. Zhu, K.; Zhang, T.; Wang, Z.; Liu, Q.; Zhou, H. Frontline combination of olverembatinib and PDT-all-2016 pediatric inspired protocol in Philadelphia chromosome-positive acute lymphoblastic leukemia. HemaSphere 2023, 7, e68180f9. [Google Scholar] [CrossRef]
  50. Tan, X.; Wen, Q.; Chen, G.; Wan, K.; Liu, X.; Ma, Y.Y.; Wang, M.H.; Zhang, X.; Zhang, C. Novel third-generation tyrosine kinase inhibitor for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: A case study. Anticancer Drugs 2023, 34, 599–604. [Google Scholar] [PubMed]
  51. Lou, Y.; Xu, G.; Wang, H.; Mao, L.; Tong, H.; Jin, J. Olverembatinib plus low-intensive regimen in frontline therapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: A case series from a single center. Blood 2022, 140, 11683–11684. [Google Scholar] [CrossRef]
  52. Zhao, Y.; Zhai, W.; Pang, A.; Yang, D.; He, Y.; Wei, J.; Ma, Q.; Chen, X.; Han, M.; Feng, S.; et al. Efficacy and safety of olverembatinib-based therapies in patients with Ph/BCR-ABL1-positive acute lymphoblastic leukemia. Blood 2023, 142, 5893. [Google Scholar] [CrossRef]
  53. Liu, W.; Liu, Y.; Zhu, Y.; Weng, X.; Wang, C.; Ouyang, W.; Xu, J.; Wang, J.; Mi, J.Q. The first report of third-generation TKI olverembatinib in adult Ph/BCR-ABL1-positive acute lymphoblastic leukemia with T315I mutation and relapsed disease. Blood 2022, 140, 3266–3267. [Google Scholar] [CrossRef]
  54. Zhu, Y.; Huang, J.; Wang, Y.; Han, Y.; Xue, S.; Yang, Y.; Zhu, Y.; Cai, W.; Chen, S. Olverembatinib treatment in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Ann. Hematol. 2024, 103, 4643–4648. [Google Scholar] [CrossRef] [PubMed]
  55. Liu, W.; Wang, C.; Ouyang, W.; Hao, J.; Ren, J.; Peng, L.; Tang, S.; Liu, Y.; Zhu, Y.; Weng, X.; et al. Efficacy and safety of olverembatinib in adult BCR-ABL1-positive ALL with T315I mutation or relapsed/refractory disease. Br. J. Haematol. 2024, 205, 2228–2233. [Google Scholar] [CrossRef] [PubMed]
  56. Tang, H.; Jia, W.; Jia, S.; Dong, R.; Gao, S.; Feng, J.; Dong, H.; Gu, H.; Zhang, T.; Yuan, R.; et al. A new chemotherapy-free regimen of olverembatinib in combination with venetoclax and dexamethasone for newly diagnosed Ph+ acute lymphoblastic leukemia: Preliminary outcomes of a prospective study. Am. J. Hematol. 2024, 99, 1177–1179. [Google Scholar] [CrossRef] [PubMed]
  57. Gong, X.; Liu, W.; Liu, Y.; Fang, Q.; Gu, R.; Liu, K.; Lin, D.; Zhou, C.; Zhang, G.; Gong, B.; et al. Olverembatinib combined with venetoclax and reduced-intensity chemotherapy for adult newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: A single-center, single-arm, phase 2 trial. Leukemia 2025, 39, 1838–1847. [Google Scholar] [CrossRef] [PubMed]
  58. Ding, J.; Li, W. Case report: Olverembatinib monotherapy: The chemotherapy-free regimen for an elderly patient with relapsed Ph-positive acute lymphoblastic leukemia. Front. Pharmacol. 2023, 14, 1320641. [Google Scholar] [CrossRef] [PubMed]
  59. Saini, N.; Marin, D.; Ledesma, C.; Delgado, R.; Rondon, G.; Popat, U.R.; Bashir, Q.; Hosing, C.M.; Nieto, Y.; Alousi, A.M.; et al. Impact of TKIs post-allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive ALL. Blood 2020, 136, 1786–1789. [Google Scholar] [CrossRef] [PubMed]
  60. Kong, J.; Zheng, F.M.; Yan, C.H.; Wang, J.Z.; Fu, H.X.; Wang, Z.D.; Suo, P.; Hu, G.H.; Lv, M.; Chen, H.; et al. Efficacy and safety of olverembatinib as maintenance therapy after allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Ann. Hematol. 2025, 104, 801–808. [Google Scholar] [PubMed]
  61. Candoni, A.; Chiusolo, P.; Lazzarotto, D.; Sartor, C.; Dargenio, M.; Chiaretti, S.; Skert, C.; Giglio, T.; Trappolini, S.; Fracchiolla, N.S.; et al. Ponatinib as a prophylactic or pre-emptive strategy to prevent cytological relapse after allogeneic stem cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia transplanted in complete cytological remission. Cancers 2024, 16, 2108. [Google Scholar] [CrossRef] [PubMed]
  62. Zhang, X.; Cao, Y.; Wei, J.; Zhai, W.; Ma, Q.; Liang, C.; Chen, X.; Cao, W.; Yang, D.; Pang, A.; et al. Efficacy and safety of the third-generation tyrosine kinase inhibitor olverembatinib in combination with inotuzumab ozogamicin for the treatment of adult Philadelphia chromosome-positive acute lymphoblastic leukemia patients with refractory/relapsed disease or persistent minimal residual disease bridging to hematopoietic stem cell transplantation. Am. J. Hematol. 2025, 100, 1924–1928. [Google Scholar] [CrossRef] [PubMed]
  63. Chen, S.; Wu, Y.; Weng, J.; Zhang, C.; Zhou, H.; Doronin, V.; Hong, M.; Wang, Y.; Wei, X.; Osipov, I.; et al. 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). Blood 2025, 146, 1574. [Google Scholar] [CrossRef]
  64. Zhang, X.; Yu, L.; Li, Z.; Qin, Y.Z.; Jiang, Q. Clinical and molecular features associated with glucolipid metabolic disorders and cardio-/cerebro-vascular adverse events in CML patients receiving olverembatinib therapy. Blood 2025, 146, 5561. [Google Scholar] [CrossRef]
  65. Hughes, T.P.; Mauro, M.J.; Cortes, J.E.; Minami, H.; Rea, D.; DeAngelo, D.J.; Breccia, M.; Goh, Y.T.; Talpaz, M.; Hochhaus, A.; et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N. Engl. J. Med. 2019, 381, 2315–2326. [Google Scholar] [CrossRef] [PubMed]
  66. Kubota, Y. Olverembatinib for heavily pretreated BCR::ABL1-positive leukemia, including resistance or intolerance to ponatinib and/or asciminib. Ann. Transl. Med. 2025, 13, 13. [Google Scholar] [CrossRef] [PubMed]
  67. Khadadah, F.M.; Cerquozzi, S.; Olney, H.J.; Fraga, C.; Dudebout, J.; Xenocostas, A.; Finn, N.; Ethier, V.; Savoie, M.L.; Busque, L.; et al. Canadian real-world experience of asciminib treatment in heavily pre-treated chronic myeloid leukemia (CML) patients who failed multiple lines of tyrosine kinase inhibitor (TKI) therapy. Leuk. Res. 2023, 133, 107374. [Google Scholar] [CrossRef] [PubMed]
  68. Luna, A.; Perez-Lamas, L.; Boque, C.; Giraldo, P.; Xicoy, B.; Ruiz Nuno, C.; Vega, M.M.; Alvarez-Larran, A.; Salamanca, A.; Garcia-Noblejas, A.; et al. Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia. Ann. Hematol. 2022, 101, 2263–2270. [Google Scholar] [CrossRef] [PubMed]
  69. Assi, R.; Kantarjian, H.; Short, N.J.; Daver, N.; Takahashi, K.; Garcia-Manero, G.; DiNardo, C.; Burger, J.; Cortes, J.; Jain, N.; et al. Safety and efficacy of blinatumomab in combination with atyrosine kinase inhibitor for the treatment of relapsed Philadelphia chromosome-positive leukemia. Clin. Lymphoma Myeloma Leuk. 2017, 17, 897–901. [Google Scholar] [CrossRef] [PubMed]
  70. Chiaretti, S.; Leoncin, M.; Elia, L.; Soddu, S.; Piciocchi, A.; Matarazzo, M.; Di Trani, M.; Martinelli, M.; Borlenghi, E.; Parisi, M.; et al. Efficacy and toxicity of frontline ponatinib plus blinatumomab for adult Ph+ ALL patients of all ages. Intermediate analysis of the GIMEMA ALL2820. Blood 2024, 144, 835. [Google Scholar] [CrossRef]
  71. Kantarjian, H.; Short, N.J.; Haddad, F.G.; Jain, N.; Huang, X.; Montalban-Bravo, G.; Kanagal-Shamanna, R.; Kadia, T.M.; Daver, N.; Chien, K.; et al. Results of the simultaneous combination of ponatinib and blinatumomab in Philadelphia chromosome-positive ALL. J. Clin. Oncol. 2024, 42, 4246–4251. [Google Scholar] [CrossRef] [PubMed]
  72. Wang, H.; Yang, C.; Shi, T.; Zhang, Y.; Qian, J.; Wang, Y.; Hu, Y.; Mao, L.; Ye, X.; Liu, F.; et al. Venetoclax-ponatinib for T315I/compound-mutated Ph+ acute lymphoblastic leukemia. Blood Cancer J. 2020, 12, 20. [Google Scholar]
  73. Zhang, J.; Guo, H.; Chen, Z.; Chen, X.; Zou, Y.; Yang, W.; Zhai, Y.; Zhu, X. Efficacy and safety of olverembatinib combined with lisaftoclax in pediatric patients with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia: A phase 1b study. In Proceedings of the European Hematology Association 2026, Stockholm, Sweden, 11–14 June 2026. abstract PF389. [Google Scholar]
  74. Yang, C.; Kang, Z.Y.; Zhu, C.Y.; Ma, Y.; Yu, P.H.; Yang, T.; Liu, Y.Q.; Zhang, Z.Y.; Suzuki, N.; Ogra, Y.; et al. Heat stress targets and degrades BCR::ZBL1 oncoproteins to overcome drug-resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 2025, 39, 2140–2151. [Google Scholar] [CrossRef] [PubMed]
  75. Marchetti, M. Cost-effectiveness of kinase inhibitors for hematologic malignancies: A systematic and critical review. Expert Rev. Pharmacoecon. Outcomes Res. 2017, 17, 469–480. [Google Scholar] [CrossRef] [PubMed]
Cancers 18 01990 g001
Figure 1. Mechanism of action of TKIs. Olverembatinib exerts its therapeutic effect by directly competing with ATP for the binding site within the catalytic domain of the BCR-ABL1 kinase. This competitive inhibition prevents the autophosphorylation and activation of the kinase, therefore blocking the downstream signaling pathways. Unlike olverembatinib and approved TKIs, asciminib inhibits the ABL1 kinase activity through binding to the ABL myristoyl pocket.
Figure 1. Mechanism of action of TKIs. Olverembatinib exerts its therapeutic effect by directly competing with ATP for the binding site within the catalytic domain of the BCR-ABL1 kinase. This competitive inhibition prevents the autophosphorylation and activation of the kinase, therefore blocking the downstream signaling pathways. Unlike olverembatinib and approved TKIs, asciminib inhibits the ABL1 kinase activity through binding to the ABL myristoyl pocket.
Cancers 18 01990 g001
Cancers 18 01990 g002
Figure 2. Chemical structure of olverembatinib.
Figure 2. Chemical structure of olverembatinib.
Cancers 18 01990 g002
Cancers 18 01990 g003
Figure 3. Algorithm regarding olverembatinib dosing according to Ph+ ALL status.
Figure 3. Algorithm regarding olverembatinib dosing according to Ph+ ALL status.
Cancers 18 01990 g003
Table 1. Examples of results from clinical studies reflecting the evolution of treatment and prognosis over the years for Ph+ ALL (from the 80s to the present).
Table 1. Examples of results from clinical studies reflecting the evolution of treatment and prognosis over the years for Ph+ ALL (from the 80s to the present).
TreatmentStatusResultsRef.
Chemo ± HSCTNDCR: 64%; Med DFS: 6 m; Med OS: 9 m[3]
NDCR: 62%; 3 y-OS: 19%; MRD-neg: 38%; 3 y-OS(Allo): 28%[4]
Imatinib + Chemo ± HSCTNDCR: 93%; MRD-neg: 88%; 5 y-DFS: 43%; 5 y-OS: 43%[5]
NDCR: 91%; MMR: 64%; 5 y-EFS: 32%; 5 y-OS: 43%[6]
NDCR: 92%; 4 y-OS: 38%[7]
Second-gen TKI + Chemo ± HSCTNDCR: 88%; 3y-EFS: 55%; 3 y-OS: 69%; 3 y-RFS: 62%; 1 y-RFS (post-transpl): 71%; 1 y-OS (post-transpl): 87%[8]
NDCR: 97%; MMR: 71%; 4 y-OS: 79%; 4 y-RFS: 76%[10]
TKI + reduced-intensity chemoNDCR: 98%; MMR: 66%; 5 y-EFS: 42%; 5 y-OS: 48%[6]
ND oldCR: 96%; MRD < 10−3: 65%[9]
NDCR: 99%; MMR: 77%; 4 y-OS: 73%; 4 y-RFS: 59%[10]
TKI (Chemo-free)ND oldCR: 100%; Med MRD reduction: 2.0–2.9[11]
NDCR: 100%; MRD < 10−3: 19%; 1.5 y-DFS: 51%; 1.5 y-OS: 69%[12]
ND oldCR: 86%; CMR: 41%; Med EFS: 14.3 m; Med OS: NR[14]
Ponatinib + chemo ± HSCTNDCR: 100%; CMR: 86%; 6 y-EFS: 65%; 6 y-OS: 75%[16]
NDCMR (post-ind): 47%; CMR (post-conso): 71%; 2 y-EFS: 70%; 2 y-OS: 96%[17]
Introduction of BlinaR/RCR: 36%; CMR: 31%; Med RFS: 6.8 m; Med OS: 9 m; Dur CMR: 9.7 m[21]
Dasa + Blina (Chemo-free)ND4.5 y-DFS: 76%; 4.5 y-OS: 81%; 4.5 y-EFS: 75%[13]
Pona + Blina (Chemo-free)ND + R/RCMR: 87%; CMR (R/R): 79%[23]
Abbreviations: Allo, allogeneic transplantation; Blina, blinatumomab; Chemo, chemotherapy; CMR, complete molecular response; CR, complete remission; conso, consolidation; Dasa, dasatinib; DFS, disease-free survival; Dur, duration; EFS, event-free survival; HSCT, hematopoietic stem cell transplantation; ind, induction; m, month; Med, median; MMR, major molecular response; MRD, measurable residual disease; ND, newly diagnosed; neg, negative; old, older patients; OS, overall survival; Pona, ponatinib; RFS, relapse-free survival; R/R, relapsed/refractory; second-gen, second-generation; transpl, transplantation; TKI, tyrosine kinase inhibitor; y, year.
Table 2. Current registered treatments involving olverembatinib in Ph+ ALL.
Table 2. Current registered treatments involving olverembatinib in Ph+ ALL.
Registration Number
(Sponsor)
Status		Indication
(Phase)
Treatment		Main Outcome Measures
NCT05495035
(Institute of Hematology and Blood Diseases Hospital)
Recruiting		R/R pediatric Ph+ ALL
(Phase 1b)
Olv, APG-2575		DLT, ORR, maximum plasma concentration, AUC
NCT07152041
(Institute of Hematology and Blood Diseases Hospital)
Recruiting		ND pediatric Ph+ ALL
(Phase 3)
Olv, Blina, Ven		d19 MRD, d48 end-of-induction MRD, EFS, OS, cumulative incidence of relapse
NCT06481228
(Institure of Hematology and Blood Diseases Hospital)
Recruiting		Adult Ph+ ALL
(NA)
Olv, Ven, reduced intensity chemo followed by CAR T-cell therapy as consolidation		Reduction in cycles of chemo, shortened length of hospitalization, improved QoL
NCT06754267
(First Affiliated Hospital of Zheijiang University)
Recruiting		ND adult Ph+ ALL
(Phase 2)
Olv, Ven, Prednisone		Safety and efficacy
NCT07074496
(First Affiliated Hospital of Soochow University—Fundamenta Therapeutics, Ltd.)
Active not recruiting		ND Ph+ ALL
(Early phase 1)
Chemo followed by ThisCAR19A therapy, Olv as maintenance		Efficacy, safety and PK of CAR T combined with Olv
NCT05931757
(First Affiliated Hospital of Soochow University)
Recruiting		ND adult Ph+ ALL
(Phase 2)
Olv, Blina		Efficacy and safety
NCT06082934
(Xijing Hospital)
Recruiting		ND Ph+ ALL
(Phase 1/2)
Olv, Ven, Dex		CR, MRD, MCyR, PFS
NCT05594784
(Institute of Hematology & Blood Diseases Hospital)
Completed		ND Ph+ ALL
(Phase 2)
Olv, Ven, reduced-intensity chemo		Efficacy and safety
NCT07178912
(MD Anderson Cancer Center)
Not yet recruiting		ND and R/R Ph+ ALL
(Phase 2)
Olv, sc Blina		ND: MCyR
R/R: ORR
NCT05466175
(Chen Suning)
Not yet recruiting		ND Ph+ ALL
(Phase 2)
Olv, Chemo followed by cycles of Hyper-CVAD, a maintenance with Olv		Efficacy and safety
NCT06051409
(Ascentage Pharma Group Inc.)
Recruiting		ND Ph+ ALL
(Phase 3)
Olv, chemo vs. Imatinib, chemo		Randomization
Efficacy and safety
NCT07454226
(Institute of Hematology & Blood Diseases Hospital)
Recruiting		ND Ph+ ALL
(Phase 2)
Olv or Gecacitinib according to ABL class fusions, Chemo, Ven		Efficacy and safety
MRD-neg at 3 months
NCT06220487
(Nanfang Hospital, Southern Medical University)
Recruiting		ND Ph+ ALL
(Phase 2)
Olv, Blina, Chidamide		MCyR at 3 months, OS, EFS, AE, IKZF1/CD20 subgroups
NCT07443488
(Institute of Hematology & Blood Diseases Hospital)
Not yet recruiting		Ph+ ALL not achieving MRD-neg after induction chemo
(Phase 2)
Olv, Ino as first-line consolidation		MRD clearance rate
NCT06658925
(Institute of Hematology & Blood Diseases Hospital)
Not yet recruiting		Ph+ ALL treated by Allo HSCT
(Phase 2)
Olv as post-transplant maintenance		Prevention of recurrence
NCT07493161
(Institute of Hematology & Blood Diseases Hospital)
Recruiting		ND Ph+ ALL
(NA)
Olv, Ven, Blina, low-intensity chemo		Rate of BCR::ABL1 ≤ 0.01% at d90, EFS
NCT04260022
(Ascentage Pharma Group Inc.)
Recruiting		Refractory Ph+ ALL and CML
(phase 1b)
Olv		PK, safety and efficacy
NCT05603156
(Institute of Hematology and Blood Diseases Hospital)
Recruiting		Ph+ ALL with MRD positive
(NA)
Olv, Ino		Efficacy and safety for MRD clearance before HSCT
Abbreviations: AE, adverse events; Allo HSCT, allogeneic hematopoietic stem cell transplantation; AUC, aera under the plasma concentration versus time curve; Blina, blinatumomab; chemo, chemotherapy; CAR T, chimeric antigenic receptor T; CR, complete remission; d, day; Dex, dexamethasone; DLT, dose-limiting toxicity; EFS, event-free survival; Hyper-CVAD, chemotherapy combining cycles of cyclophosphamide, vincristine, adriamycin, dexamethasone followed by cycles of methotrexate and cytarabine; Ino, inotuzumab ozogamicin; MCyR, major cytogenetic response; MRD, measurable residual disease; NA, not applicable; ND, newly diagnosed; neg, negativity; Olv, olverembatinib; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; Ph+ ALL, Philadlphia chromosome-positive acute lymphoblastic leukemia; PK, pharmacokinetics; QoL, quality of life; R/R, relapsed/refractory; sc, sub-cutaneous; Ven, venetoclax.
Table 3. Comparison of olverembatinib with ponatinib and asciminib in newly diagnosed Ph+ ALL.
Table 3. Comparison of olverembatinib with ponatinib and asciminib in newly diagnosed Ph+ ALL.
FeaturesOlverembatinibPonatinibAsciminib
Examples of responses in combination with reduced intensity treatment [Ref]CR: 100%
MCyR: 85%
[54]		ORR: 94%
MRD-neg: 34%
[18]		MRD-neg: 89%
MMR: 74%
[26]
Main adverse eventsSkin hyperpigmentation
Cytopenias
Hypertriglyceridemia		Pancreatitis
Arterial occlusive events
Venous occlusive events
Cytopenias		Arthralgias
Cytopenias
Pancreatitis
Dosing40 mg QOD
30 mg QOD in newly diagnosed patients or in case of good molecular response		30–45 mg QD
15–30 mg QD if good molecular response		80 mg QD or 40 mg every 12 h
200 mg every 12 h if T315I mutation
Abbreviations: CR, complete remission; MCyR, major cytogenetic response; MMR, major molecular response; MRD-neg, measurable residual disease negativity; ORR, overall response rate; QD, daily; QOD, once every two days; Ref, reference.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Thomas, X. Olverembatinib: A New Treatment for Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Cancers 2026, 18, 1990. https://doi.org/10.3390/cancers18121990

AMA Style

Thomas X. Olverembatinib: A New Treatment for Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Cancers. 2026; 18(12):1990. https://doi.org/10.3390/cancers18121990

Chicago/Turabian Style

Thomas, Xavier. 2026. "Olverembatinib: A New Treatment for Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia" Cancers 18, no. 12: 1990. https://doi.org/10.3390/cancers18121990

APA Style

Thomas, X. (2026). Olverembatinib: A New Treatment for Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Cancers, 18(12), 1990. https://doi.org/10.3390/cancers18121990

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop