Olverembatinib-Therapy in Patients with Accelerated-Phase Chronic Myeloid Leukaemia: A Multi-Centre Retrospective Study from China

Background Olverembatinib is a novel 3G-TKI, which has shown efficacy and safety in patients with CML-CP or CML-AP harboring T315I mutation, resistance or intolerance to imatinib or 2G-TKI. However, there are limited data on olverembatinib-therapy in patients with CML-AP.

Objectives To retrospectively analyze efficacy and safety and explore co-variates associated with outcomes of olverembatinib to classify patients into risk cohorts to predict progression-free survival (PFS) and survival in patients with CML-AP.

Methods We collected data of CML-AP patients receiving olverembatinib from university hospitals or academic centers in China. CML-AP was diagnosed according to ELN 2020 criteria. Cumulative incidences of MCyR, CCyR, MMR and MR⁴ were calculated using the Fine-Gray test considering competing events defined as a transplant or death. PFS and survival were calculated by Kaplan-Meier method. X-tile plots were used to determine optimal cut-off value continuous co-variates. Multi-variable Cox regression analyses were used to explore co-variates associated with outcomes on olverembatinib.

Results Eighty-nine patients with CML-AP receiving olverembatinib from 19 centers were included. Forty-six (52%) were from clinical trials; 43 (48%), from real world post marketing. Twenty-one (24%) was newly diagnosed CML-AP and 68 (76%) transformed from CML-CP to CML-AP. Sixty-six (74%) were male. Median age at the start of olverembatinib was 44 (Interquartile range [IQR], 34-58) years. Median interval from CML diagnosis to olverembatinib was 6.2 (IQR, 2.3-10.2) years. Thirty-six (40%) patients had ≥ 1 comorbidity(ies). 39 (44%) had 2 prior TKIs; 38 (43%), ≥ 3 prior TKIs. BCR::ABL1 mutation detected by Sanger sequencing prior to olverembatinib was available for 86 patients: 44 (51%) harbored a single T315I mutation; 16 (19%), T315I plus additional mutations; 12 (14%), other mutations; 14 (16%), no mutation.

Five (6%) patients received oral olverembatinib at alternate-day (QOD) dose of 20 mg; 19 (21%), 30 mg QOD; 58 (65%), 40 mg QOD; 7 (8%), 50 mg QOD. Median follow-up was 23 (IQR, 5-62) months. Among 42 patients with no MaHR at baseline, 25 (60%) achieved MaHR and CHR within 3 months. 5-year cumulative incidences of MCyR, CCyR, MMR and MR^4.0 were 49% (95% CI: 36, 63%]), 49% (36, 62%), 49% (36, 62%) and 39% (26, 53%), respectively. 22 patients progressed to AP again or blast phase, 19 died of disease progression (n = 15, 79%), cardiovascular events (CVEs) (n = 2, 10%), coronavirus disease 2019 (n = 1, 5%) or unknown (n = 1, 5%). 5-year probabilities of PFS and OS were 65% (54, 79%) and 65% (54, 80%), respectively.

In multi-variable analyses haemoglobin < 117 g/L (Hazard ratio [HR] = 5.2 [1.8, 14.8], p = 0.002), blood basophils ≥ 9% (HR = 3.6 [1.3, 9.6], p = 0.011) and additional cytogenetic abnormalities (ACAs) in Ph⁺ cells (HR = 4.0 [1.8, 10.1], p = 0.004) at baseline were significantly-associated with worse PFS. Comorbidity(ies) (HR = 3.0 [1.1, 8.2], p = 0.038) and blood basophils ≥ 8% (HR = 4.1 [1.4, 12.1], p = 0.010) at baseline were significantly-associated with worse survival. Based on number of baseline adverse prognostic co-variates, patients were classified into the low- (none, n = 18, 24%), intermediate- (one or two, n = 51, 69%) and high-risk (three, n = 5, 7%) cohorts with significant difference in PFS (p < 0.001) with 5-year PFS rates of 100% (100, 100%), 59% (45, 78%) and 0, respectively; the low- (≤ one, n = 69, 85%) and high-risk (two, n = 12, 15%) cohorts with significant difference in survival (p = 0.001) with 5-year survival rates of 73% (61, 87%) and 0.

Seventy-three (82%) patients experienced at least 1 treatment-related adverse events (TRAE). Thirty-three (37%) developed grade 3/4 hematological TRAE including leucopenia (n = 18, 20%) and thrombocytopenia (n = 33, 37%). The most common nonhematologic TRAE was skin hyperpigmentation in 48 (55%) patients, followed by hypertriglyceridemia (42%) and hypocalcaemia (36%). CVEs were observed in 19 (23%) patients including hypertension (14%), sinus tachycardia (6%), pericardial effusion (5%), cerebral infarction or atrial fibrillation (2% each), and myocardial infarction (1%).

Conclusions Olverembatinib is an effective 3G-TKI with well tolerance in patients with CML-AP. Anemia, increasing blood basophils and ACAs in Ph⁺ cells at baseline were significantly-associated with worse PFS; comorbidity(ies) and increasing blood basophils, worse survival.