Prognostic factors for progression in patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia in complete molecular response within 3 months of therapy with tyrosine kinase inhibitors

Abstract

BACKGROUND The achievement of a 3‐month complete molecular response (CMR) is a major prognostic factor for survival in patients with Philadelphia chromosome (Ph)‐positive acute lymphoblastic leukemia (ALL). However, 25% of patients relapse during therapy with tyrosine kinase inhibitors (TKIs). METHODS The authors reviewed 204 patients with Ph‐positive ALL who were treated between January 2001 and December 2018 using the combination of hyper‐CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus a TKI (imatinib, 44 patients [22%]; dasatinib, 88 patients [43%]; or ponatinib, 72 patients [35%]). Progression‐free survival (PFS) was defined as the time from the start date of therapy to the date of relapse, death, or last follow‐up. Overall survival (OS) was defined as the time from the start date of therapy to the date of death or last follow‐up. RESULTS Overall, a 3‐month CMR was observed in 57% of patients, including 32% of those who received imatinib, 52% of those who received dasatinib, and 74% of those who received ponatinib. The median follow‐up was 74 months (imatinib, 180 months; dasatinib, 106 months; ponatinib, 43 months). Among 84 patients in 3‐month CMR, 17 (20%) proceeded to undergo allogeneic stem cell transplantation (ASCT). The 5‐year PFS and OS rates were 68% and 72%, respectively. By multivariate analysis, ponatinib therapy was the only significant favorable independent factor predicting for progression (P = .028; hazard ratio, 0.388; 95% CI, 0.166‐0.904) and death (P = .042; hazard ratio, 0.379; 95% CI, 0.149‐0.966). ASCT was not a prognostic factor for PFS and OS by univariate analysis. CONCLUSIONS In patients with Ph‐positive ALL, ponatinib is superior to other types of TKIs in inducing and maintaining a CMR, thus preventing disease progression. ASCT does not improve outcome once a 3‐month CMR is achieved.

Is stem cell transplantation still needed for adult Philadelphia chromosome-positive acute lymphoblastic leukemia receiving tyrosine kinase inhibitors therapy?: A systematic review and meta-analysis

“…Moreover, our study results supported the stronger efficacy of dasatinib and ponatinib than imatinib, in line with the result from a recent study [43]. However, the data on comparing the efficacy between each TKI are scarce, and more head-to-head studies are needed to investigate this issue.…”

“…of the status of transplantation. Results also suggested that negative minimal residual disease (MRD) status is also predictive of better survival outcomes and lower incidence of relapse compared to those with positive MRD in Ph + ALL, suggesting the potential of utilizing MRD status to classify patient subpopulation who would benefit from allo-HSCT [41][42][43]. Unfortunately, the data are still limited and more studies should explore further this subgroup of patients [11,14,16,34,37].…”

“…There have been interests in combining chemotherapy with immunotherapy such as blinatumomab and inotuzumab ozogamicin, and later generations of TKIs with greater potency such as ponatinib and asciminib to overcome resistance mutations such as T315I [44][45][46]. This could help patients achieving negative minimal residual disease status, leading to better outcomes and even dismissing the need for HSCT [43]. A phase 3 randomized controlled study comparing ponatinib and imatinib induction, consolidation, and maintenance in Ph + ALL patients is ongoing (NCT03589326) [47].…”

“…Third, most of the included studies did not include analyses based on the MRD status. As positive MRD status is associated with poorer survival outcomes and greater incidence of relapse, this could affect the benefit of HSCT and confound the result of the meta-analysis [41][42][43].…”

Oncogene-independent resistance in Philadelphia chromosome - positive (Ph+) acute lymphoblastic leukemia (ALL) is mediated by activation of AKT/mTOR pathway

“…When dasatinib was combined with intensive chemotherapy, the 3-year event-free survival and OS rates were 55% and 69%, respectively. In case of ponatinib a complete molecular response was increased to 74% in Ph+ ALL patients ( 13 ).…”