A Phase 2 Study of Olverembatinib for the Treatment of Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement
Authors: Chen Suning , Wu Depei , CAI Wenzhi , Dou Xueqing , Liu Zhenfang , Zhu Yu , Wang Ying , Yang Chunmei , Hu Jiong , Miao Miao , Deng Xiuzhi , Chen Chunyan 
Published: December 2024

Introduction
Myeloid/lymphoid neoplasms with FGFR1 rearrangement (MLN-FGFR1) are rare hematologic malignancies with poor prognoses. On the basis of cases reported in the literature, front-line use of tyrosine kinase inhibitors (TKIs) such as ponatinib, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT), is the only potential approach leading to long-term disease-free survival. Pemigatinib, a selective inhibitor of FGFR1-FGFR3, has shown remarkable complete remission (CR) rates and complete cytogenetic remission (CCyR) in patients with chronic-phase (CP) disease but poorer responses in those with blast-phase (BP) disease. Olverembatinib is a well-tolerated and effective third-generation TKI that has been approved in China for chronic myeloid leukemia. Beyond its use in Philadephia-chromosome positive leukemia, olverembatinib has demonstrated antitumor activity in FGFR1-mutated cells in parallel to ponatinib.
Methods
Study Design
This was a phase 2, open-label, multicenter study evaluating the efficacy and safety of olverembatinib in adults with MLN-FGFR1. Key eligibility criteria included: age
≥ 18 years; newly diagnosed or relapsed MLN-FGFR1 without prior ponatinib treatment; estimated life expectancy ≥ 3 months; ECOG PS 0-2 for patients in CP and 0-3 for those in BP. For treatment, patients in CP received olverembatinib 40 mg on alternate days (QOD) orally, whereas those in BP received olverembatinib 40 mg QOD combined with regimens for acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) . Allo-HSCT was recommended for all eligible patients following at least 2 years post-transplant maintenance with olverembatinib.
Endpoints
The primary endpoint was the CR rate as defined by the MLN International Working Group in 2023. Key secondary endpoints included CCyR, complete molecular response (CMR), and adverse events (AEs).
Results
Baseline characteristics
As of July 18, 2024, 10 patients were enrolled, of whom 7 were in CP (2 with extramedullary disease) and 3 were in BP (2 B-cell ALL and 1 AML).Three patients were previously treated, and one had prior HSCT. The median age was 48 years, and 5 patients were men. Five patients (50.0%) had peripheral blood eosinophilia, of whom four were in CP. ZMYM2 was the most commonly observed fusion partner, as detected in 7 patients. RUNX1 mutation was detected in 4/7 (57.1%) patients. At this writing, four patients had bridged to allo-HSCT upon achievement of CR.
Response
Seven patients were analyzed for efficacy. All patients (100%) achieved CR, among whom one achieved CCyR (Pt 04 who received olverembatinib alone) and one achieved CMR (Pt 08 who received olverembatinib combined with inotuzumab ozogamicin) at 2 months' evaluation. Best responses were 5 CMR, 1 CCyR, and 1 CR ( Pt 03 who died of COVID-19 at 3 months).With a median (range) follow-up of 8 (2-25) months, five patients were still alive with no detected disease. Among the four patients who had received HSCT, three had CMR, and one died of transplant-related infection. Olverembatinib was well tolerated, with reduced platelet counts (grade 3) in one patients, as well as elevated γ-glutamyl transpeptidase (grade 2), fatigue (grade 1)， myalgia (grade 1) and rash in one patient each among the five patients who were treated with olverembatinib alone.
Conclusions
Olverembatinib showed a favorable CR rate and good tolerance in the treatment MLN-FGFR1, potentially enabling allo-HSCT in greater numbers of eligible patients.