Impact of Cytogenetic Abnormalities (CA) on Outcome of Patients (Pts) with Relapsed/Refractory (R-R) Acute Lymphoblastic Leukemia (ALL) Treated with Inotuzumab Ozogamicin (INO) in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab: Results from a Phase 2 Study

Background:

The combination of INO with hyper-mini-CVD with or without blinatumomab offers a safe and effective treatment modality for pts with R-R ALL. However, the outcomes of some pts remain poor and the predictors of survival are not well understood. CA are frequently used as predictors of outcomes in leukemia. We present an exploratory analysis evaluating the relationship between baseline CA and outcome in pts with R-R ALL treated at our institution in a phase 2 study of INO in combination with mini-hyper-CVD with or without blinatumomab.

Methods:

Ninety-six pts with R-R ALL received low-intensity chemotherapy referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m² x 4 doses). INO was given on Day 3 of each of the first 4 courses at 1.8-1.3 mg/m² for course 1 followed by 1.3-1.0 mg/m² for subsequent courses. From pt #68 onwards, INO was reduced and fractionated into biweekly doses (0.6 mg/m² and 0.3 mg/m² during course 1 and 0.3 mg/m² and 0.3 mg/m² during subsequent courses), and blinatumomab for up to 4 courses after INO therapy was added. By performing univariate and multivariate analyses of factors associated with survival, we identified 11q23 rearrangements and low hypodiploidy / near triploidy (Ho-Tr) as high-risk CA. Pts were categorized based on their CA as low-risk if they carry diploid, complex or other cytogenetics. Pts with 11q23 rearrangements and those with Ho-Tr were classified as having high-risk CA. Response rates and overall survival (OS) outcomes are compared between the two cytogenetic risk categories.

Results:

Pts characteristics are summarized in Table 1. Karyotype was diploid in 23 (24%) pts, complex in 12 (13%) pts, and other in 21 (22%) pts. Ten (10%) pts had Ho-Tr, 10 (10%) pts had KMT2A rearrangements, 3 (3%) pts had high hypertriploidy (HeH), 2 (2%) pts had near triploidy (Tt) and 15 (16%) pts had insufficient metaphases/ not determined karyotype. TP53 mutation was detected in a significantly higher proportion of pts with Ho-Tr (6 out of 7 tested pts or 86%) compared to pts with other cytogenetic abnormalities (10 out of 40 tested pts or 25%) (p=0.002). We performed univariate and multivariate analyses for the association of different cytogenetics with survival. By multivariate analysis, baseline cytogenetics independently associated with worse survival included Ho-Tr [HR= 18.262 (95% CI= 5.935–56.196); p<0.001], and KMT2A [HR= 3.744 (95% CI= 1.256–11.165); p=0.018]. Based on these findings, we stratified pts based on their CA into high-risk or low-risk disease. The overall response rate (ORR) was 73% in pts with high-risk CA compared to 82% in pts with low-risk CA (p=0.316). The complete remission (CR) rate was significantly higher in pts with low-risk CA compared to those with high-risk CA, 64% vs 36% (p=0.024). The rate of MRD negativity was numerically higher both at response as well as overall in the low-risk group compared to the high-risk group; 54% vs 44% and 86% vs 69%, respectively (Table 3). Four pts underwent allogeneic stem cell transplant (ASCT) in the high-risk group (17%), compared to 40 in the low risk group (55%) (p=0.003). At a median follow-up of 36 months, the median OS for pts with high-risk CA was 4 months compared to 23 months for pts with low-risk CA (p < 0.001) (Figure 1). The 3-year OS rates were 3% and 53%, respectively.

Conclusion:

Our analysis identified baseline KMT2A rearrangements and Ho-Tr as independent predictive of poor outcome in pts with R-R ALL treated with the combination therapy of INO with mini-hyper-CVD with or without blinatumomab. Pts with these poor-risk features should be considered for alternative strategies such as CAR T-cells therapies and clinical trials such as adding menin inhibitors to the regimen in pts with KMT2A rearrangement.