Relapse Prevention with Tyrosine Kinase Inhibitors after Allogeneic Transplantation for Philadelphia Chromosome–Positive Acute Lymphoblast Leukemia: A Systematic Review

Abstract

Relapse after stem cell transplantation for Philadelphia chromosomeÀpositive (Ph+) acute lymphoblastic leukemia (ALL) remains a significant challenge. In this systematic review, we compare survival outcomes of second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib with first-generation TKI imatinib when these agents are used after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Ph+ ALL. In addition, we review the literature on TKI use to prevent relapse in patients who proceed to allo-HSCT beyond first complete response (>CR1). We performed database searches (inception to January 2018) using PubMed, Cochrane Library, and Embase. After exclusions, 17 articles were included in this analysis. Imatinib was used post-transplant either prophylactically or preemptively in 12 studies, 7 prospective studies and 5 retrospective studies. Overall survival (OS) for most prospective studies at 1.5 to 3 and 5 years ranged between 62% to 92% and 74.5% to 86.7%. Disease-free survival at 1.5 to 5 years was 60.4% to 92%. Additionally, imatinib failed to show survival benefit in patients who were >CR1 at the time of allo-HSCT. The cumulative OS for most retrospective studies using imatinib at 1 to 2 and 3 to 5 years was 42% to 100% and 33% to 40% respectively. Event-free survival at 1 to 2 and 3 to 5 years was 33.3% to 67% and 20% to 31% respectively. Dasatinib was used as maintenance treatment in 3 retrospective studies (n = 34). The OS for patients with Ph+ ALL using dasatinib as maintenance regimen after allo-HSCT at 1.4 to 3 years was 87% to 100% and disease-free survival at 1.4 to 3 years was 89% to 100%. Ninety-three percent of patients with minimal residual disease (MRD) positive status after allo-HSCT became MRD negative. Three prospective studies used nilotinib. In 2 studies where investigators studied patients with advanced chronic myeloid leukemia and Ph+ ALL, the cumulative OS and event-free survival at 7.5 months to 2 years were 69% to 84% and 56% to 84%, respectively. In the third study (n = 5) in patients with Ph+ ALL, nilotinib use resulted in OS at 5 years of 60%. Our review showed that use of TKIs (all generations) after allo-HSCT for patients in CR1 improved OS when given as a prophylactic or preemptive regimen. Limited data suggest that second-generation TKIs (ie, dasatinib) have a better OS, especially in patients with MRD-positive status. Imatinib did not improve OS in patients who were >CR1 at the time of allo-HSCT; for this population, no data were available with newer generation TKIs. The evaluation of survival benefit with newer generation TKIs and their efficacy in patients in >CR1 needs further study in large randomized clinical trials.

Use of tyrosine kinase inhibitors for paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia: a systematic review and meta-analysis

“…7 Systematic review by Warraich et al comprising 18 prospective and retrospective studies with 462 participates showed that utilisation of TKI (all generations) post allo-HSCT for adults patients in CR1 improved OS when given as prophylactic or pre-emptive regimen. 27 However, it is unclear whether this observed improvement of TKIs is significant in children. To our knowledge, our research is the first systematic review to investigate whether adding TKIs to conventional chemotherapy is indeed beneficial in paediatric Ph+ALL.…”

Dasatinib in the Management of Pediatric Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

“…TKIs-based maintenance post-HSCT can reduce relapse risk and should be considered a valuable option ( 56 ). Future studies addressing the same issue in a pediatric population are needed, although some clinical experiences support the positive role of the drug in this clinical setting ( 57 ).…”

Role of Inflammatory Factors during Disease Pathogenesis and Stem Cell Transplantation in Myeloproliferative Neoplasms

“…Efficacy of RUX in GVHD is attributed to the immunosuppressive properties of the drug and the inhibition of a wide number of cytokines involved in GVHD. However, the application of RUX in MF cannot be compared to the use of BCR-ABL-specific tyrosine kinase inhibitors (TKIs), such as imatinib, in patients transplanted for CML or Ph+ acute lymphoblastic leukemia (ALL) [ 128 , 129 ]. The efficacy of TKIs in CML and Ph+ ALL is attributed to a direct inhibition of the aberrant fusion protein, and a molecular response to the treatment is generally observed, whereas RUX is only acting on enhanced signal transduction without a significant decrease of the malignant clone [ 116 ], at least in most patients.…”