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

Abstract

Background Hematopoietic stem cell transplantation (HSCT) is the current mainstay treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, tyrosine kinase inhibitors (TKI) also play a significant role in the treatment of these patients. We conducted this systematic review and meta-analysis to compare the efficacy of allogeneic (allo-) HSCT, autologous (auto-) HSCT, and chemotherapy (CMT) alone–all in combination with TKIs in adult Ph+ ALL patients. Materials and methods This systematic review identified studies from the EMBASE and MEDLINE databases from inception to April 2021 using search terms related to “ALL” and “HSCT.” Eligible studies could be randomized controlled trials or cohort studies that included adult Ph+ ALL patients who received a TKI and either allo-HSCT, auto-HSCT, or CMT alone, and that reported the number of patients in each group for each of our primary outcomes of interest: overall survival (OS) or disease-free survival (DFS). Point estimates and associated 95% confidence intervals (CI) from each study were combined using the Hantel-Maenszel method. Results After two rounds of review, 26 cohort studies were determined to be eligible for the meta-analysis. Adult Ph+ ALL patients who received HSCT had better survival outcomes than those who did not receive any HSCT (pooled odds ratio [OR] for OS of 1.61, 95%CI: 1.08–2.40; I2 = 59%, and for DFS of 3.23, 95%CI: 2.00–5.23; I2 = 62% for allo-HSCT; and, pooled OR for OS of 7.04, 95%CI: 1.97–25.15; I2 = 0%, and for DFS of 5.78, 95%CI: 1.04–32.19; I2 = 42% for auto-HSCT). Allo-HSCT recipients had comparable OS and DFS, but lower relapse rate compared to auto-HSCT recipients. Funnel plot generally demonstrated no presence of publication bias. Conclusions This systematic review and meta-analysis demonstrated superior results of HSCT in Ph+ ALL patients compared to CMT alone. Moreover, auto-HSCT could be implemented with comparable survival outcomes to allo-HSCT in patients with no available donor or when haploidentical HSCT is not feasible.

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in Adults

“…The allo-HSCT rate was particularly low (17% and 20%) in these studies [ 41 , 45 ]. These data are supported by two recent meta-analyses that compared efficacy of allo-HSCT to chemotherapy or auto-HSCT [ 31 , 75 ]. Analysis combining data from pre-TKIs and TKIs eras found significant survival benefit of allo-HSCT due to lower CIR, but with higher TRM rates.…”

“…In a retrospective study from the European Society for Blood and Marrow Transplantation (EBMT), pre-transplant TKI administration was associated with significant better OS survival (HR = 0.68; p = 0.04) and lower cumulative incidence of relapse (CIR) (HR = 0.5; p = 0.01) in multivariate analysis [ 26 ]. Imatinib administration also improves long-term outcome of patients receiving chemotherapy only while no long-term survivors were observed in the pre-TKIs era [ 22 , 23 , 31 ].…”

“…As in the pre-TKIs era, most of the data show survival benefit for imatinib recipients undergoing allo-HSCT ( Table 3 ) [ 7 , 18 , 20 , 26 , 73 ]. However, some studies did not find any significant survival advantage for allo-HSCT in the setting of imatinib administration as imatinib improved long-term survival in patients receiving only chemotherapy [ 21 , 22 , 23 , 31 ]. In a randomized pediatric/adolescents and young adults (AYA) trial, patients treated with imatinib and chemotherapy had the same 5-year DFS and EFS rates than patients undergoing allo-HSCT [ 74 ].…”

“…When analysis was restrained to TKIs recipients (mostly imatinib), odds ratio of OS and DFS between allo-HSCT and chemotherapy groups decreased. Moreover, when analysis was restrained to 2G and 3G-TKI, there was no more survival advantage for allo-HSCT compared to chemotherapy as post remission treatment [ 31 ]. Altogether, these results demonstrate survival advantage for allo-HSCT in the imatinib setting even if this benefit seems less significant than in the pre-TKIs era.…”

Outcomes of Philadelphia Positive Acute Lymphoblastic Leukemia in Adolescent and Young Adults

“…Two recent meta-analyses demonstrate a survival advantage for Allo-SCT with the use of imatinib, but the advantage seems to disappear with newer TKIs due to their greater efficacy compared to imatinib, as well as the TRM rate of Allo-SCT [22,23]. Considering the financial burden of newer TKIs and novel therapies in resource-limited countries, Allo-SCT continues to be an attractive option for our patients when under treatment with curative intent.…”