On December 11, 2022 GSK plc (LSE/NYSE:GSK) reported new 48-week data from the MOMENTUM phase III trial that showed a majority of patients treated with investigational momelotinib maintained their responses across key clinical measures including Total Symptom Score (TSS), Transfusion Independence (TI) rate, and Splenic Response Rate (SRR) in myelofibrosis patients previously treated with an approved Janus kinase (JAK) inhibitor (Press release, GlaxoSmithKline, DEC 11, 2022, View Source [SID1234625050]). Additionally, new analyses from MOMENTUM showed that TI response with momelotinib at week 24 was associated with overall survival. These data were presented at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (10-13 December) in New Orleans.

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Hesham Abdullah, Senior Vice President, Global Head of Oncology Development, GSK, said: "Myelofibrosis patients have significant medical needs including progressive anemia resulting from the disease and often exacerbated by currently approved treatments. The data presented today reinforce the potential of momelotinib as a treatment option with a favorable impact on myelofibrosis symptoms and spleen volume, as well as on blood transfusions due to anemia."

MOMENTUM is a global, randomized, double-blind phase III clinical trial of momelotinib (MMB) versus danazol (DAN) in patients with myelofibrosis who were symptomatic and anemic and had been previously treated with an approved JAK inhibitor. The study was designed to evaluate the safety and efficacy of momelotinib for the treatment and reduction of the key manifestations of the disease: constitutional symptoms, blood transfusions (due to anemia) and enlarged spleen. Patients were randomized at 2:1 to receive either momelotinib or danazol (n=130 and n=65, respectively). After 24 weeks of treatment, patients on danazol were allowed to crossover to receive momelotinib. Early crossover to momelotinib was available for confirmed splenic progression.

Primary analysis at week 24 met the primary endpoint of TSS reduction of ≥50% over the 28 days immediately before the end of week 24 compared to baseline TSS, using the Myelofibrosis Symptom Assessment Form. It also met key secondary endpoints including TI rate for ≥12 weeks immediately before the end of week 24 with hemoglobin levels ≥8 g/dL and SRR based on splenic volume reduction of ≥35% at week 24 from baseline.

48-week follow-up data from MOMENTUM presented at ASH (Free ASH Whitepaper) demonstrated the following (oral presentation #627):

TSS response at week 24
and maintained below
baseline through week 48

TI response at week 24
and maintained response
through week 48

SRR response at week 24
and maintained below
baseline through week 48
MMB

31/32 (97%)*

36/40 (90%)

24/24 (100%)***

DAN with crossover to MMB at week 24

6/6 (100%)**

10/13 (77%)

2/2 (100%)

*12 of 61 (20%) non-responding patients who received momelotinib at week 24 had achieved a TSS response at week 48

**10 of 35 (29%) non-responding patients who received danazol and crossed over to momelotinib at week 24 achieved a new TSS response at week 48

***data available for 24 of 30 patients who received momelotinib and achieved splenic response at 24 weeks

In MOMENTUM, the most common Grade 3 or greater treatment emergent adverse events in the open-label period, similar to the double-blind period, were thrombocytopenia (9% for the continuous momelotinib treatment arm and 15% for the danazol to momelotinib treatment arm) and anemia (9% for the continuous momelotinib treatment arm and 2% for the danazol to momelotinib treatment arm). Additionally, these efficacy and safety results in patients with thrombocytopenia were consistent with the overall population.

An additional analysis from the MOMENTUM clinical trial evaluated the impact of TI response on overall survival (abstract #3028). As previously presented, patients receiving treatment with momelotinib were more likely to achieve transfusion independence during the study period than patients treated with danazol (TI response at week 24 of 31% and 20% for the momelotinib and danazol arms, respectively; non-inferiority p=0.0064). Momelotinib patients were also less likely to require a transfusion during the study period (35% of momelotinib patients had zero units transfused compared to 17% of danazol patients; odds ratio=2.7; p=0.0107), and more likely to reduce transfusion burden. Data presented at ASH (Free ASH Whitepaper) with additional survival follow up suggests that TI response with momelotinib at week 24 is associated with overall survival (HR=0.27 for TI vs. non-TI; CI 95% 0.09, 0.80) compared to patients who were not TI.

A New Drug Application and Marketing Authorization Application for momelotinib is currently under review with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), respectively. Momelotinib is not currently approved in any market.

About momelotinib
Momelotinib is an investigational oral treatment for myelofibrosis. Momelotinib not only inhibits the Janus kinase (JAK) 1 signalling pathway and JAK2 signalling pathways, but also activin A receptor type I (ACVR1).1,2,3,4 Inhibition of JAK1 and JAK2 may improve constitutional symptoms and splenomegaly.1,2,4 Additionally, direct inhibition of ACVR1 leads to a decrease in circulating hepcidin, which is often elevated in myelofibrosis and contributes to anemia.1,2,3,4

About myelofibrosis
Myelofibrosis is a rare and potentially fatal cancer characterized by the build-up of excessive scar tissue in the bone marrow, which interferes with the production of healthy blood cells and can lead to: severe low blood counts, including anemia and thrombocytopenia; constitutional symptoms such as weakness and fatigue; and splenomegaly or an enlarged spleen.5,6,7 Myelofibrosis affects about 1 in 500,000 people worldwide.8 At diagnosis, approximately 40% of patients are anemic and nearly all myelofibrosis patients will eventually develop anemia.9,10,11 Patients will often require blood transfusions, and more than 30% will discontinue treatment due to anemia.12 Anemia and transfusion dependence are strongly correlated with poor prognosis, reduced quality of life and shortened survival

On December 11, 2022 -Ajax Therapeutics, Inc., a biopharmaceutical company applying computational chemistry and structure-based technologies to develop novel, selective small molecules for myeloproliferative neoplasms (MPNs), reported the presentation of preclinical data on the company’s next generation Type II JAK2 inhibitor, AJ1-10502, at a poster session held today at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in New Orleans (Press release, Ajax Therapeutics, DEC 11, 2022, View Source [SID1234625049]).

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The poster, entitled "The Second Generation Type II JAK2 inhibitor, AJ1-10502, Demonstrates Enhanced Selectivity, Improved Therapeutic Efficacy and Reduced Mutant Cell Fraction Compared to Type I JAK2 inhibitors in Models of Myeloproliferative Neoplasms (MPNs)," highlights the improved efficacy and disease modifying features of Ajax’s Type II JAK2 inhibitor, AJ1-10502, when compared to the investigational, first generation Type II inhibitor, CHZ868, and the approved market-leading Type I inhibitor, ruxolitinib, in two different mouse models of MPNs.

In both MPN models studied, AJ1-10502 demonstrated dose dependent improvements in efficacy over ruxolitinib on key blood cell parameters, including reticulocytes and hematocrit, associated with MPNs, as well as superior reductions in spleen weights on par with JAK2 deletion. More importantly, AJ1-10502 caused significant reductions in mutant cell fraction within bone marrow and spleen not observed with ruxolitinib. Distinct from all currently approved JAK2 inhibitors, including ruxolitinib, that bind the Type I conformation of the JAK2 kinase and allow continued JAK/STAT signaling which leads to disease persistence, AJ1-10502 is designed to bind the Type II conformation of the JAK2 kinase. In preclinical studies, investigational Type II JAK2 inhibitors have been shown to overcome disease persistence to ruxolitinib and, most significantly, reduce mutant JAK2 allele burden that drives MPN disease progression. The ASH (Free ASH Whitepaper) poster presentation is available on Ajax’s website.

"We’re very encouraged by the first preclinical data on our Type II JAK2 inhibitor program being presented today at the ASH (Free ASH Whitepaper) Annual Meeting," said Craig E. Masse, PhD, Senior Vice President, Discovery Research at Ajax Therapeutics. "Our unique drug discovery capabilities, including state-of-the-art computational and structure-based technologies, have enabled us to develop Type II JAK2 inhibitors, such as AJ1-10502, that target JAK2 with greater precision and potency, while overcoming the limitations of current JAK2 therapies that interact with other JAK-family members and related kinases which limits their efficacy and leads to unwanted side effects."

"It’s exciting to see Ajax’s next generation Type II JAK2 inhibitor, AJ1-10502, demonstrate enhanced selectivity and efficacy with a much-improved safety profile than first generation Type II inhibitors," said Ross Levine, MD, Chair of Ajax’s Scientific Advisory Board and Deputy Physician-in-Chief, Translational Research, Laurence Joseph Dineen Chair in Leukemia Research and Member of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center. "This data supports our findings that Type II JAK2 inhibitors can significantly reduce the mutant allele burden that drives MPNs which is not observed with Type I JAK2 inhibitors, such as ruxolitinib. We believe that more selective and potent JAK2 inhibitors, like AJ1-10502, could provide much needed new targeted therapies for MPN patients who are not well served by currently approved JAK2 inhibitors."

On December 11, 2022 Cimeio Therapeutics, a biotechnology company developing a novel approach to cell therapies, reported data for its CD117 and CD123 Shielded Cell & Immunotherapy Pairs (SCIP) program during this weekend’s American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in New Orleans (Press release, Cimeio Therapeutics, DEC 11, 2022, View Source [SID1234625047]).

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The two studies demonstrate proof-of-concept that genetically engineered variants of cell surface receptors harboring single amino acid substitutions are fully functional but evade a paired immunotherapy directed against the wild-type (wt) molecule. This technology will enable the development of more efficient and safer targeted conditioning regimens for hematopoietic stem cell transplantation, gene therapies, and opens the path to more efficient cell and immunotherapy-based treatment approaches for hematological malignancies.

The first abstract was titled "Function-preserving single amino acid substitutions shield hematopoietic stem and progenitor cells from CD117 targeted immunotherapy in vivo." The receptor tyrosine kinase c-KIT (CD117) is expressed on normal hematopoietic stem cells (HSC) but also on leukemia cells. Consequently, it is an attractive target for an antibody-based conditioning therapy.

The study showed that cells expressing a genetically engineered variant of CD117 (shielded) are fully functional in vitro and contributed to the blood development (engraftment) in vivo, similar to unmodified HSCs expressing the wt receptor. Mice transplanted with a mix of human HSCs expressing either wt CD117 or the Cimeio shielded CD117 variant showed a selective depletion of wt CD117 cells, while those cells expressing the variant receptor were spared following the treatment with a monoclonal antibody directed against wt CD117.

The second abstract, titled "Engineered Single Amino Acid Substitutions Protect Hematopoietic Stem and Progenitor Cells From CD123 Targeted Immunotherapy," focused on targeting the interleukin-3 (IL-3) receptor alpha-chain (CD123), a cytokine receptor highly expressed on various hematological malignancies as well as normal hematopoietic cells. This abstract demonstrated that shielded CD123 cells were not depleted by a highly efficient CD123 targeted immunotherapy.

Collectively, these preclinical studies demonstrate the feasibility and efficacy of Cimeio’s SCIP platform, a novel and promising therapeutic approach to improve the outcomes for patients with benign and malignant hematological diseases in need of an HSC transplant.

"Many severe and late side effects following an HSC transplant are caused by untargeted and broadly toxic chemotherapeutics and radiation in conditioning regimens," said Suneet Agarwal, M.D., Ph.D., Co-Program Leader for the Stem Cell Transplant Center at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Associate Professor of Pediatrics at the Harvard Medical School, and member of the Cimeio Scientific Advisory Board. "The presented work is an encouraging and important step towards safer and efficient approaches to overcome these hurdles. Cimeio’s SCIP platform could allow more patients facing debilitating and fatal diseases to receive a life-saving HSC transplant."

Last month, Cimeio announced the issuance of a foundational patent that covers a method for in vivo selective depletion of edited primary hematopoietic cells or non-edited primary hematopoietic cells, the basis of its SCIP platform.

On December 10, 2022 Gracell Biotechnologies Inc. ("Gracell" or the "Company", NASDAQ: GRCL), a global clinical-stage biopharmaceutical company dedicated to developing highly efficacious and affordable cell therapies for the treatment of cancer, reported that the clinical data from its ongoing Phase 1, investigator-initiated trial (IIT) in China evaluating FasTCAR-enabled GC012F as first-line therapy in transplant-eligible, high-risk, newly diagnosed multiple myeloma (NDMM) patients (Press release, Gracell Biotechnologies, DEC 11, 2022, View Source [SID1234625037]). Data has been presented in an oral session at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, held Dec. 10-13 in New Orleans. Patients in the study achieved a 100% overall response rate (ORR) and 100% minimal residual disease (MRD) negativity in all dose levels.

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GC012F is an autologous CAR-T therapeutic candidate dual-targeting B cell maturation antigen (BCMA) and CD19, and utilizes Gracell’s proprietary FasTCAR next-day manufacturing platform.

As of the Oct. 14, 2022 data cutoff date, 16 transplant-eligible NDMM patients had received GC012F infusion in the clinical trial. All patients had multiple high-risk features. After receiving a conditioning lymphodepletion regimen of cyclophosphamide and fludarabine, patients were treated with GC012F as a single infusion with one of three dose levels: 1×105 cells/kg, 2×105 cells/kg and 3×105 cells/kg.

As of Oct. 14, 2022, among the 16 evaluable patients with the median follow-up time of eight months (ranging from 1.3 to 15.4 months):

ORR was 100%
87.5% (14/16) of patients achieved stringent complete response (sCR). Patients continue to be followed for deepening responses
100% of evaluable patients achieved MRD negativity in all dose levels
100% of evaluable patients achieved MRD negativity at months 1, 6 and 12
100% of patients experienced robust CAR-T cell expansion with long persistence in all dose levels
The clinical data also demonstrated an excellent safety profile:

Only 25% (4/16) of patients experienced Grade 1-2 cytokine release syndrome (CRS); no patients experienced Grade 3-5 CRS
No immune effector cell-associated neurotoxicity syndrome (ICANS) or other neurotoxicity of any grade had been observed
"This clinical data brings us great optimism. GC012F has demonstrated an impressive 100% ORR, 100% MRD negativity and 87.5% sCR, as well as an outstanding safety profile, among newly-diagnosed multiple myeloma patients, showing tremendous potential for substantial improvement over currently available therapies," said Dr. Wendy Li, Gracell’s Chief Medical Officer. "We are pleased to share this data with the leading experts in hematology and oncology at ASH (Free ASH Whitepaper) 2022. We believe that the data underscores GC012F’s significant potential as a safe and effective therapy for NDMM patients. In addition, GC012F is developed using our proprietary FasTCAR next-day manufacturing platform, which could greatly expedite the delivery of this much-needed therapy to patients."

About GC012F

GC012F is a FasTCAR-enabled BCMA/CD19 dual-targeting CAR-T product candidate that is currently being evaluated in IIT studies in China for the treatment of multiple myeloma and B-cell non-Hodgkin’s lymphoma. GC012F simultaneously targets CD19 and BCMA to drive fast, deep and durable responses, which can potentially improve efficacy and reduce relapse in multiple myeloma and B-NHL patients.

About FasTCAR

CAR-T cells manufactured on Gracell’s proprietary FasTCAR platform appear younger, less exhausted and show enhanced proliferation, persistence, bone marrow migration and tumor cell clearance activities as demonstrated in preclinical studies. With next-day manufacturing, FasTCAR is able to significantly improve cell production efficiency which may result in meaningful cost savings, and, together with fast release time, enables enhanced accessibility of cell therapies for cancer patients.

On December 11, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that it has released preliminary results of olverembatinib (HQP1351) in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), in an Oral Presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 64th Annual Meeting and Exposition (New Orleans, LA), marking the first data readout from the US study (Press release, Ascentage Pharma, DEC 11, 2022, View Source;ascentage-pharma-delivers-oral-report-on-the-first-dataset-from-the-us-study-of-olverembatinib-hqp1351-with-promising-efficacy-observed-in-patients-who-failed-prior-treatment-with-ponatinib-301699947.html [SID1234625036]).

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The ASH (Free ASH Whitepaper) Annual Meeting is one of the largest gatherings of the international hematology field, featuring world-class advances on cutting-edge scientific and clinical research in hematology. As a leading member of the Chinese hematology and oncology research community that has been increasingly active on the global stage, Ascentage Pharma had results from 5 of its clinical trials selected for 4 Oral Presentations at this year’s ASH (Free ASH Whitepaper) Annual Meeting, attracting widespread interest at the event. In total, Ascentage Pharma will have 8 presentations at ASH (Free ASH Whitepaper) 2022, including 4 Oral and 4 Poster Presentations (with 3 poster presentations submitted independently by investigators based on real-world evidence).

Preliminary results announced at this year’s meeting suggested that olverembatinib has favorable efficacy and a manageable safety profile in US patients with drug-resistant CML and Ph+ ALL, and showed the drug’s potential as a "salvage" therapy in patients with prior resistance to third-generation tyrosine kinase inhibitor (TKI) ponatinib and allosteric STAMP inhibitor asciminib. These data showed that close to 80% patients with CML had received at least three lines of treatment, and over 50% had failed prior treatment with ponatinib. Even in heavily pre-treated patients with drug-resistant CML, those with chronic-phase CML (CML-CP) achieved complete cytogenetic response (CCyR) and major molecular response (MMR) rates of 77.8% and 43.5%, respectively; while patients with CML-CP who had failed prior treatment with ponatinib have achieved a CCyR and an MMR rate of 83.3% and 42.9%, respectively.

In addition, olverembatinib was well-tolerated. The safety data from this US study were similar to previously published results from Chinese studies and showed no new safety signals. In particular, olverembatinib demonstrated excellent tolerability in patients who were intolerant of ponatinib, which also exemplifies olverembatinib’s positive safety profile.

Developed by Ascentage Pharma, olverembatinib is a potential best-in-class novel drug that has been designated a Major New Drug Project by China’s Ministry of Science and Technology. As the first approved third-generation BCR-ABL inhibitor in China and the second in any country globally, olverembatinib is recommended by both the Guidelines of the Chinese Society of Clinical Oncology (CSCO) and the China Anti-Cancer Association’s (CACA) Guidelines for the Holistic Integrative Management of Cancers, for the treatment of patients with TKI-resistant CML harboring the T315I mutation (while the CACA Guidelines also recommend olverembatinib for the treatment of patients with CML intolerant/resistant to at least two TKIs).

Globally, despite approvals for ponatinib and asciminib, patients with CML still have enormous unmet medical needs because of limited accessibility as well as adverse events of these two drugs. Taken together, these limitations have recently stimulated strong interest in clinical progress with olverembatinib among the global hematology community. At present, olverembatinib is being evaluated in a US Phase Ib study for the treatment of drug-resistant CML. Furthermore, olverembatinib has been granted one Fast Track designation and three Orphan Drug designations by the US Food and Drug Administration (FDA), and one Orphan Drug designation by the European Medicines Agency (EMA).

As olverembatinib is not yet approved anywhere outside China, Ascentage Pharma is pressing ahead with global clinical development of olverembatinib and advancing the drug toward approvals in a number of countries to help address the unmet medical needs of patients with CML globally. Driven by a sense of urgency to facilitate early access by patients with malignancies that currently lack treatment options, Ascentage Pharma and Tanner Pharma Group (a global pharmaceutical services provider of specialty access solutions) jointly launched an innovative Named Patient Program (NPP) for olverembatinib in July 2022. This collaboration will allow access to olverembatinib on a named patient basis in more than 140 countries and regions where the drug is not yet commercially accessible, in a manner that is reliable, responsible, ethical, and in accordance with all country-specific regulatory requirements.

"These findings suggest that olverembatinib is a potentially effective ‘salvage’ therapy for patients with prior CML treatment failure," according to Prof. Elias Jabbour, MD, Department of Leukemia, The University of Texas MD Anderson Cancer Center (Houston, TX). "The favorable safety and tolerability profile of olverembatinib are important because many patients with CML experience intolerance, including potentially concerning cardiovascular events, when using certain other BCR-ABL1 inhibitors."

"The first batch of data from the first US study of olverembatinib released at ASH (Free ASH Whitepaper) 2022 are very promising, indeed, as they show olverembatinib’s exciting potential as a best-in-class drug that can overcome resistance to ponatinib and asciminib in patients with CML and Ph⁺ ALL. We are encouraged by these results because they further validate that olverembatinib can potentially bring a long-awaited change to the treatment paradigm for CML and Ph⁺ ALL globally." according to Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma.

"At this year’s ASH (Free ASH Whitepaper) Annual Meeting, we released data of olverembatinib and our Bcl-2 inhibitor for CLL/SLL, lisaftoclax, in four Oral Presentations. We are very proud of this achievement, which underscores our robust capabilities in global innovation," she remarked. "Moving forward, we will remain committed to the mission of addressing unmet clinical needs in China and around the world, and continue to accelerate our clinical development programs with the hope of bringing more safe and effective therapeutics to patients in need," Dr. Zhai noted.

Data from the US studies of olverembatinib reported in Oral Presentations at this year’s ASH (Free ASH Whitepaper) Annual Meeting are as follows (for detailed results from the study of lisaftoclax and the China study of olverembatinib, please refer to other two press releases to be published during ASH (Free ASH Whitepaper) 2022):

Olverembatinib (HQP1351) Overcomes Ponatinib Resistance in Patients with Heavily Pretreated/Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Format: Oral Presentation
Abstract: #162387
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Novel Agents
Time: Saturday, December 10, 2022, 10:15 AM (Eastern Time) / Saturday, December 10, 2022, 11:15 PM (Beijing Time)
Highlights
– Olverembatinib is a novel third-generation BCR-ABL1 TKI with antitumor activity against CML and Ph+ ALL and a favorable safety profile.

– This multicenter, open-label, randomized trial is the first to report on the safety, efficacy, and pharmacokinetics (PK) of olverembatinib in patients with CML and Ph+ ALL outside China, who were intolerant or resistant to at least 2 BCR-ABL1 inhibitors, including ponatinib and asciminib, except for those whose disease harbors the T315I mutation, for whom the number of prior lines of therapy was not limited. Study participants were randomized in a ratio of 3:3:2 to receive olverembatinib 30, 40, or 50 mg QOD in 28-day cycles.

– As of Dec 5, 2022, a total of 51 patients have been enrolled, including 38 with CML-CP, and 13 with CML-AP, CML blast phase (-BP), or Ph+ ALL. The median treatment duration was 32.4 (range, 0-119) weeks. 54.9% (28/51) of patients were men, and the median age was 51 (range, 21-79). In all, 7 (13.7%), 14 (27.5%), and 25 (49%) patients received 2, 3, and ≥ 4 prior lines of treatment, respectively. A total of 28 (54.9%) patients were pretreated with the third-generation TKI ponatinib, including 21 (75.0%) with resistance and 7 (25.0%) with intolerance; a total of 19 (37.3%) had T315I mutations; 28 (54.9%) had cardiovascular diseases at baseline, and 18 (35.3%) had hypertension.

– PK analysis indicated a dose-proportional increase in olverembatinib plasma exposure from 30 to 50 mg QOD and comparable plasma exposures between the Chinese and US CML populations.

– Safety: Olverembatinib was well tolerated. 34 patients experienced treatment related adverse events (TRAEs) of any grade, the incidence of which tended to be dose-dependent. Most of the nonhematologic TRAEs were grade 1/2. Common grade 3/4 nonhematologic TRAEs included thrombocytopenia (18.9%), neutropenia (16.2%), and decreased leukopenia counts (13.5%). 8 olverembatinib-related serious adverse events (SAEs) were observed in 6 patients, and none of these SAEs led to treatment discontinuation.

– Preliminary efficacy: Olverembatinib conferred potent antileukemic activity in patients with CML and Ph+ ALL. Of 23 efficacy-evaluable patients with CML-CP, 14/18 (77.8%) had a CCyR; 10/23 (43.5%) had a MMR. Olverembatinib was effective in patients with either the T315I-mutant (87.5%, CCyR; 55.6%, MMR) or T315I un-mutant (70.0%, CCyR; 35.7%, MMR), and its effectiveness was not compromised by prior use of ponatinib or asciminib. Among patients who were previously treated with ponatinib, 10/12 (83.3%) experienced CCyR and 6/14 (42.9%) experienced MMR. In particular, among patients with diseases resistant to ponatinib, 7/9 (77.8%) experienced CCyR, and 5/10 (50%) experienced MMR. In patients who were previously treated with asciminib, 1 experienced CCyR and MMR. In the 7 efficacy-evaluable patients with Ph+ leukemia in progressive phase (including CML-AP, CML-BP, and Ph+ ALL), 2 experienced CCyR and MMR. Both patients were resistant to ponatinib and neither harbored the T315I mutation. Of them, 1 patient with Ph+ ALL achieved CCyR after just one cycle of treatment with olverembatinib.

– Conclusions: Olverembatinib monotherapy is efficacious and well tolerated in patients with TKI-refractory CML and Ph+ ALL. Even in patients with CML who were ponatinib or asciminib resistant, or who had T315I mutations, olverembatinib also showed strong efficacy.