BackgroundOlverembatinib, a novel 3G-TKI, has promising outcome in patients with TKI resistant and/or intolerant chronic or accelerated phase CML. However, there are rare data in patients with Ph-positive acute leukemia.

Objectives To assess the efficacy and safety olverembatinib-based therapy in patients with CML in myeloid blast phase (CML-MBP) or lymphoid blast phase (CML-LBP) and relapsed or refractory acute lymphoblastic leukemia (R/R Ph-positive ALL), and explore co-variates associated with survival.

Methods Data of patients withCML-MBP, CML-LBP or R/R Ph-positive ALL receiving olverembatinib-based therapy from academic centers in China were retrospectively interrogated. Diagnosis was according to the WHO 2016 criteria. Event-free survival (EFS) was defined as interval from starting olverembatinib-based therapy to no MaHR by 3 months, relapse (> 5% blasts in bone marrow or occurrence of blast in blood or new extramedullary disease), or death from any cause or censored at the last follow-up. Survival was defined as interval from starting olverembatinib-based therapy to death from any cause or censored at the last follow-up. Cox regression model was utilized to identify co-variates associated with survival.

Results A total of 153 patients with CML-MBP (n = 68, 44%), CML-LBP (n = 39, 25%) or R/R Ph-positive ALL (n = 46, 30%) were enrolled, 20 of them were newly diagnosed CML-MBP or CML-LBP. 86 (56%) were male. Median age was 50 (IQR, 34-58) years. 52 (34%) had ≥ 1 comorbidity(ies). Median interval from diagnosis of CML to starting olverembatinib-based therapy was 12 (IQR, 6-47) months. 39 (25%) had 2 prior TKIs; 24 (16%), ≥ 3 prior TKIs. 15 (10%) patients had no response to prior TKI-therapy; 66 (43%) achieved the best response of CHR; 42 (27%), ≥ MCyR. BCR::ABL1 mutation status detected by Sanger sequencing at baseline was available for 137 patients: 45 (33%) harbored a single T315I mutation; 6 (4%), T315I plus additional mutations; 25 (18%), other mutations; 61 (45%), no mutation.

29 (19%) patients received olverembatinib monotherapy; 124 (81%), olverembatinib combined with AML-like or ALL-like chemotherapy. With a median follow-up of 9 (IQR, 5-15) months, 82 (77%) patients with CML-MBP or CML-LBP returned to chronic phase; 40 (59%) with CML-MBP, 31 (79%) with CML-LBP and 38 (83%) with R/R Ph-positive ALL achieved MaHR by 3 months (p = 0.007); 19 (19/64, 30%) with CML-MBP, 20 (20/37, 54%) with CML-LBP and 36 (36/44, 82%) with R/R Ph-positive ALL, MCyR (p < 0.001). 44 (29%) patients with in the chronic phase or MaHR received transplant, 34 experienced relapse, 61 died of acute leukemia (n = 48, 79%), severe infection (n = 6, 10%), transplant-related mortality (n = 5, 8%), or COVI-19 (n = 2, 3%). At last follow-up, 65 (42%) patients still on olverembatinib-based therapy. Patients with CML-LBP showed the longest EFS (24 vs. 3 vs. 7 months, p = 0.013) and survival (not reached vs. 9 vs. 15 months, p = 0.021) compared to those with CML-MBP and R/R Ph-positive ALL. 1-year probabilities of EFS (59% vs. 29% vs.39%, p = 0.013) and survival (74% vs. 39% vs.53%, p = 0.027) in the patients with CML-LBP were the highest. Patients receiving transplant had higher 1-year probabilities of EFS (72% vs. 27%, p < 0.001) and survival (84% vs. 40%, p < 0.001) than those receiving non-transplant therapy.

In multi-variable analyses CML-MBP or R/R Ph-positive ALL (vs. CML-LBP, HR = 3.1 [1.3, 7.8], p = 0.014; HR = 4.3 [1.5, 12.8], p = 0.008), poor response to prior TKI-therapy (p = 0.012), no MaHR (HR = 2.2 [1.2, 4.1], p = 0.015) or BCR::ABL1 > 10% (HR = 2.8 [1.2, 6.7], p = 0.020) by 3 months, and non- transplant therapy (HR = 3.3 [1.3, 8.3], p = 0.012) were significantly-associated with worse survival.

Of 141 evaluable patients, 115 (82%) experienced ≥ 1 treatment-related adverse events (TRAE). 84 (62%) patients developed grade 4 hematological TRAE. The most common non-hematologic TRAE was pulmonary infection (29%), followed by increased aminotransferase (21%) and fatigue (20%). Cardio-cerebrovascular TRAE were observed in 23 (16%) patients including hypertension (n = 12, 52%), heart failure (n = 6, 26%), deep venous thrombosis (n = 5, 22%), and cerebral infarction (n = 2, 9%).

Conclusions Olverembatinib-based therapy is effective and tolerable in Ph-positive acute leukemia. CML-MBP, R/R Ph-positive ALL, inferior response to prior TKI-therapy, no MaHR or BCR::ABL1 > 10% by 3 months, and non-transplant therapy predicted worse survival.

Disclosures

No relevant conflicts of interest to declare.

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2024
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