A Prognostic Model for Survival in Patients with Relapsed/Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia on the Combination of Low-Intensity Chemotherapy Plus Inotuzumab Ozogamicin with or without Blinatumomab

Background: The combination of low-intensity therapy (mini-hyper-CVD) with inotuzumab ozogamicin with or without sequential blinatumomab is effective in patients with relapsed/refractory Philadelphia-chromosome negative acute lymphoblastic leukemia (ALL). The development of a prognostic model on the novel combination therapy may identify patients who requires additional or alternative therapies.

Methods: Patients (pts) with relapsed/refractory Philadelphia chromosome-negative ALL who were treated with the combination of mini-hyper-CVD with inotuzumab ozogamicin plus/minus blinatumomab were analyzed. Briefly, the odd cycles of mini-hyper-CVD (cycles 1, 3, 5, 7) comprised cyclophosphamide (150 mg/m² every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracyclines. The even cycles (cycles 2, 4, 6, 8) comprised methotrexate (250 mg/m² on day 1) and cytarabine (0.5 g/m² given every 12 h on days 2 and 3). Rituximab and intrathecal chemotherapy were given for first 4 courses. Inotuzumab ozogamicin was originally given on day 3 of the first four cycles at the dose of 1.3-1.8 mg/m² at cycle 1, followed by 1.0-1.3 mg/m2 in subsequent cycles. The protocol was amended to minimize the risk of veno-occlusive disease. Inotuzumab ozogamicin was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m² at cycle 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m² at subsequent cycles; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles.

Backward multivariate Cox regression analysis was performed with a cutoff p value of 0.100 by univariate for variable selections from univariate to multivariate analysis. The optimal cutoffs were defined at the point with the most significant division by the log-rank test. CD22 expression was determined using multicolor flow cytometry analysis and reported as percentage of positive leukemic cells as a fraction of total gated events relative to internal control parameters. A new prognostic model was built based on identified prognostic factors by multivariate analysis. The developed prognostic model was planned to be validated with two independent dataset with salvage chemotherapy and inotuzumab single-agent.

Results: We analyzed 96 pts enrolled on the clinical trial of mini-hyper-CVD + inotuzumab ozogamicin +/- sequential blinatumomab from February, 2013 to September, 2019 (Table 1). Overall, the median follow-up is 36 months (range, 0.1-87.5). The overall response rate was 80% with negative measurable residual disease rate of 83% overall (52% at response after induction therapy). Multivariate analysis showed the percentage of CD22 expression less than 70% (P<0.001; hazard ratio [HR], 4.669; 95% confidence interval [CI], 2.187-9.967), the presence of low hypodiploidy/near triploidy (Ho-Tr) (P<0.001; HR, 3.744; 95% CI, 5.935-56.196), and the presence of KMT2A rearrangements (P=0.018; HR, 3.744; 95% CI, 1.256-11.165) as adverse prognostic factors for survival (Table 2). Based on the relative impact of each of these three factors on survival, we proposed a prognostic risk classification with 2 risk-categories. Low risk was defined as the absence of any high-risk features; high risk was defined as the presence of any one of the adverse prognostic factors (Table 3). Overall, the median survival was 17 months. The median survival were not reached and 5 months in the low- and high-risk disease with 3-year survival rates of 55% and 3%, respectively (P<0.001) (Figure 1). With allogeneic stem cell transplant (ASCT) censoring, the median survival were not reached and 4 months in the low- and high-risk disease with 3-year survival rates of 61% and 0%, respectively (P<0.001) (Figure 2). The 3-year OS rates with ASCT censoring for pts with low-risk and high-risk disease treated with salvage chemotherapy were 7% and 0%, respectively (p=0.031). The 3-year OS rates with ASCT censoring were 9% and 0% for pts treated with inotuzumab monotherapy, respectively (p=0.002).

Conclusion: The combination of low-intensity therapy with inotuzumab ozogamicin with or without sequential blinatumomab is highly effective. The presence of Ho-Tr, KMT2A rearrangement, or CD22 expression less than 70% confers poor outcome and identifies pts with poor-risk features who may be considered for alternative strategies such as CAR T-cells therapies and clinical trials.