Clinical Outcome in Pediatric Patients with Philadelphia Chromosome Positive ALL Treated with Tyrosine Kinase Inhibitors Plus Chemotherapy—The Experience of a Polish Pediatric Leukemia and Lymphoma Study Group

Abstract

The treatment of children with Philadelphia chromosome positive acute lymphoblastic leukemia (ALL Ph+) is currently unsuccessful. The use of tyrosine kinase inhibitors (TKIs) combined with chemotherapy has modernized ALL Ph+ therapy and appears to improve clinical outcome. We report herein the toxicity events and results of children with ALL Ph+ treated according to the EsPhALL2010 protocol (the European intergroup study of post-induction treatment of Philadelphia chromosome positive ALL) in 15 hemato-oncological centers in Poland between the years 2012 and 2019. The study group included 31 patients, aged 1–18 years, with newly diagnosed ALL Ph+. All patients received TKIs. Imatinib was used in 30 patients, and ponatinib was applied in one child due to T315I and M244V mutation. During therapy, imatinib was replaced with dasatinib in three children. The overall survival of children with ALL Ph+ treated according to the EsPhALL2010 protocol was 74.1% and event-free survival was 54.2% after five years. The cumulative death risk of the study group at five years was estimated at 25.9%, and its cumulative relapse risk was 30%. Our treatment outcomes are still disappointing compared to other reports. Improvements in supportive care and emphasis placed on the determination of minimal residual disease at successive time points, which will impact decisions on therapy, may be required.

Resistance Mechanisms in Pediatric B-Cell Acute Lymphoblastic Leukemia

“…In Poland, children with the presence of Ph (+) have been treated according to the EsPhALL2010 Protocol since 2012. The estimated 5-year survival rate for children is 74.1% [ 118 ].…”

“…The greatest range of these ailments, in grades from I to III, was observed after imatinib. A patient who received ponatinib developed dermatitis of grade IV [ 118 ].…”

Targeted Therapy in the Treatment of Pediatric Acute Lymphoblastic Leukemia—Therapy and Toxicity Mechanisms

“…The authors reported the severity of adverse events of imatinib therapy was mild and mostly Grades 1–2. The most frequently reported forms of toxicity were infections (38.7%), hepatotoxicity (35.5%), and gastrointestinal disorder (22.5%) [ 26 ].…”

“…Identification of the BCR-ABL 1 fusion gene has been associated with a poor prognosis among pediatric patients and, in the pre-tyrosine-kinase inhibitors (TKIs) era, survival was 62% [ 24 ]. Incorporation of the therapy of molecular TKIs significantly improved treatment outcomes [ 25 , 26 ]. However, due to the potential resistance mechanisms and long-term molecular toxicity, further clinical trials concerning TKIs are essential.…”

Protein Kinases in Leukemias

“…In contrast, some PK inhibitors, such for Btk, have also been proposed as antithrombotic drugs [ 3 ]. In parallel, the use of a PK inhibitor in acute myeloblastic leukemia (AML) FLT3-ITD or acute lymphoblastic leukemia (ALL) Ph + demonstrates a broad benefit in terms of patient management and toxicity but also reveals new resistance as well as unchanged long-term survival [ 4 , 5 , 6 ].…”