Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosome‐positive acute lymphoblastic leukaemia

Abstract

SummaryAcute lymphoblastic leukaemia (ALL) is a heterogeneous disease that is often associated with several chromosomal and molecular abnormalities. Patients who have the Philadelphia (Ph) chromosome and associated BCR-ABL1 oncogene have a particularly poor prognosis. Currently, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only known curative treatment for Ph+ ALL and facilitating allo-HSCT in eligible patients is a key treatment goal. However, many patients relapse after allo-HSCT, particularly those with measurable residual disease prior to transplantation, and a significant percentage of patients are ineligible for allo-HSCT, particularly older patients. Hence, many patients require additional/alternative therapies to prolong survival. Studies are ongoing to determine the most effective first-line drug regimens for patients who subsequently undergo allo-HSCT and ineligible patients. Tyrosine kinase inhibitors targeted to Bcr-Abl are important novel therapies for Ph+ ALL. Although imatinib administered in combination with chemotherapy is established as the current first-line strategy, relapse is common, even among allo-HSCT recipients. Emerging data indicate that more potent multi-targeted kinase inhibitors (including dasatinib, nilotinib, and bosutinib) have promising efficacy in the first-or second-line setting. Here, the evidence base for existing drug treatments for Ph+ ALL is discussed and emerging therapeutic strategies are explored.

Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR–ABL-positive acute lymphoblastic leukemia

“…The treatment of Ph þ ALL has changed dramatically since the introduction of imatinib and 490% of patients have achieved CR, 7,14,15 and allows SCT to be performed in a substantial proportion of patients in major or complete molecular remission. 8,[16][17][18] Actually, in the imatinib cohort, 97 of 100 patients (97%) achieved CR and 60 (60%) could receive allo-HSCT in their first CR. Several studies reported improved OS rates compared with that in the pre-imatinib era by incorporation of imatinib-based therapy.…”

Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia

“…These treatments do not induce lasting remission for patients in blast crisis and for patients with BCR-ABL-associated B-ALL. Imatinib administered in combination with chemotherapy during the induction or consolidation phase is associated with improved clinical responses, but relapse and drug resistance are common (for review, see Gruber et al 9 ). Drugs targeting either signaling molecules downstream of BCR-ABL, or molecular pathways that synergize with BCR-ABL in leukemia maintenance, will likely offer additional therapeutic options.…”

Treatment of Pediatric Acute Lymphoblastic Leukemia and Recent Advances

“…and Saha, 2005). Given the marked improvement in treatment results achieved with combinations of a tyrosine kinase inhibitor (imatinib) and intensive chemotherapy, transplantation is not recommended for the first remission of children with PH+ ALL, unless the early response to treatment was poor (Barr, 2010;Gruber et al, 2009;Koo, 2011;Liu et al, 2009;Milone and Enrico, 2009;Ottmann and Pfeifer, 2009;Schultz et al, 2009). Second generation tyrosine kinase inhibitors were developed because imatinib may induce specific resistance mainly due to ABL1 mutations.…”