A Meta-Analysis and Meta-Regression of the Efficacy of Front-Line Treatment Combinations with Ponatinib Versus 1st- and 2nd-Generation Tyrosine Kinase Inhibitors for Ph+ Acute Lymphoblastic Leukemia

Background: The current standard induction therapy for de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is a tyrosine kinase inhibitor (TKI) in combination with chemotherapy or corticosteroids. Three generations of TKIs are currently available for the treatment of Ph+ ALL. Ponatinib, a third generation multi-targeted TKI, is a more potent inhibitor of BCR/ABL than previous generations. It also is effective in cases where there is a threonine-to-isoleucine substitution at position 315 (T315I mutation), which confers resistance to all first- and second-generation TKIs (i.e., imatinib, dasatinib, and nilotinib). However, evidence on the comparative effectiveness of front-line combination therapy with ponatinib relative to other TKIs in de novo Ph+ ALL has not been well-established.

Aims: The purpose of this study is to evaluate the effectiveness, as measured by complete molecular response (CMR) and 2- and 3-year overall survival (OS), of front-line treatment combinations with ponatinib versus first- and second-generation TKIs in de novo Ph+ ALL.

Methods: Twenty-six studies of front-line Ph+ ALL treatment with TKI in combination with chemotherapy or corticosteroids (18 studies of imatinib, 5 of dasatinib, 2 of nilotinib, and 1 of ponatinib) were identified from published targeted literature reviews and recently published trials. These consisted of 25 phase 2 through 4 trials and 1 retrospective analysis. Study arms in which patients received chemotherapy or corticosteroids only, a single TKI agent, or in which they received autologous stem cell transplant exclusively were excluded. Data on aggregated patient characteristics were extracted and summarized using the median (range). The proportions of patients achieving CMR (following induction or consolidation therapy) and 2- and 3-year OS were also extracted from all study arms and summarized by TKI group (ponatinib versus all other first and second generation TKIs) using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the ponatinib trial. Multivariate logistic meta-regressions were conducted to examine the association between each TKI treatment group and CMR rates, 2-year OS, and 3-year OS, separately, adjusting for age and gender.

Results: A total of 32 TKI treatment arms were included in the analysis. The median (range) of age across trial arms was 46 years (36-69 years) and proportion of male patients was 53% (42-67%). The pooled proportion of patients achieving CMR with ponatinib was higher than that with first and second generation TKIs (79% versus 34%). The pooled 2- and 3-year OS with ponatinib were also higher than those with other TKIs (2-year: 83% versus 58%; 3-year: 79% versus 50%). Relative to other TKIs, ponatinib was associated with a statistically significant 6.09-fold increase in the odds of achieving CMR (N=25) [odds ratio=6.09 (95% CI: 1.16-31.90), p=0.034]. While ponatinib was not significantly associated with an increase in the odds of 2-year OS (N=27) [odds ratio=3.70 (95% CI: 0.93-14.73), p=0.062], it was associated with a statistically significant 4.49-fold increase in the odds of 3-year OS (N=19) [odds ratio=4.49 (95% CI: 1.00-20.13), p=0.050] compared to earlier generation TKIs.

Conclusion: Frontline treatment with ponatinib in combination with chemotherapy or corticosteroids was associated with significantly better odds of CMR and 3-year OS in patients newly diagnosed with Ph+ ALL than combination therapy with earlier generations of TKIs. In particular, ponatinib was associated with a 6-fold increase in CMR, the most important factor in predicting long-term survival outcomes. The improved efficacy of ponatinib in Ph+ ALL may be particularly important for patients who are ineligible to undergo stem cell transplantation due to lack of suitably matched donors, advanced age, or significant comorbidities. In such cases, combination therapy with TKI may be a suitable alternative. Though the number of studies included was small and few covariates could be used to adjust for heterogeneity across trials, the results suggest that ponatinib in combination with chemotherapy may represent an effective front-line treatment option for patients with Ph+ ALL. Prospective head-to-head clinical trials are needed to confirm these results.

Sponsor: ARIAD Pharmaceuticals, Inc.

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