Efficacy, Safety, and Treatment-Free Remission Outcomes of Front-Line Chronic Myeloid Leukemia Treatments - a Systematic Literature Review
Authors: Lundqvist Isabelle , Walsh Shaun , Dobariya Nikunj , Kodjamanova Petya , Jadhav Kejal , Gilbert Pauline 
Published: December 2024

Introduction: Tyrosine kinase inhibitors (TKIs) transformed the treatment of chronic myeloid leukemia in chronic phase (CML-CP), extending the life expectancy of patients to be comparable to the general population. Over time, emphasis of treatment goals has shifted to improving patients' quality of life (QOL)/tolerability, achieving stable deep molecular response (DMR) and treatment free remission (TFR). To meet current and future needs of patients with CML-CP, treatment options that provide rapid and sustained DMR are needed. This systematic literature review was conducted to understand and summarize the clinical evidence of currently available frontline CML-CP treatments.

Methods: Electronic databases (Embase®, MEDLINE®, Cochrane) and grey-literature were searched for English language publications from clinical-trials, published by the date of search, 12 Oct 2023, for evidence on clinical efficacy and QOL. Evidence on TFR was included from observational studies published until 08 Feb 2024. Based on pre-defined selection criteria, publications were included for extracting the available evidence.

Results: Out of 3,312 citations screened, 34 studies were included wherein 12 randomized-clinical trials reported outcomes on efficacy and safety, and two on QOL. TFR was reported in 22 observational and non-randomized studies.

At 12 months, the range of major molecular response (MMR) for approved doses of TKIs, nilotinib (44.0%-52.2%), bosutinib (41.0%-47.2%), and dasatinib (23.6%-81.8%), was more favourable than imatinib (22.0%-39.0%). Patients achieving molecular response (MR) 4.5 at 12 months ranged between 6.1%-8.1% with bosutinib, 14.3%-35.2% with dasatinib, 2.6%-6.9% with nilotinib, and 3.3%-15.0% with imatinib. Limited long-term evidence is reported, with MR4.5 at 5 years and 10 years achieved in 31.4% and 39.2% patients on imatinib and 53.5% and 61.0% patients on nilotinib, respectively.

Rate of overall survival at different follow-up time-points was similar across treatments. Tolerability of different treatments was comparable; however, treatment discontinuation due to adverse-event (AE) at 12 months was higher with bosutinib (13.8%-19.0%), dasatinib (5.0%-13.0%), nilotinib (5.0%) vs imatinib (1.5%-10.0%). AEs commonly (≥1%) leading to treatment discontinuation were: increased alanine aminotransferase/aspartate aminotransferase, thrombocytopenia, neutropenia, vomiting, increased lipase and pleural effusion for bosutinib; pleural effusion and drug-related cytopenia with dasatinib; diarrhea, thrombocytopenia, neutropenia, muscle spasms and myalgia with imatinib; and thrombocytosis with nilotinib. QOL scores reportedly improved from baseline with bosutinib, nilotinib, and imatinib, but change from baseline was not clinically meaningful as measured with FACT-Leu, EQ-5D, and SF-36.

Criteria for patients to be eligible for TFR attempt varied in different studies with the most commonly used criteria being treatment duration &gt;3 years and MR4.5 maintained for ≥2 years with a follow-up till loss of MMR after treatment discontinuation. Cumulative TFR eligibility by 10 years was generally higher, 47.3% to 48.6% with nilotinib and 29.7% with imatinib. Among total attempts, at 12 months, patients still in TFR varied from 59.2% with dasatinib to 76.5% with nilotinib. Long-term data on TFR is limited, but overall proportion of patients in TFR decreased with increased follow-up: with imatinib, 43.4% at five years, 40.9% at seven years, and 34.5% at nine years; with nilotinib 42.6% at five years.

Conclusions: Effectiveness of approved doses of dasatinib, nilotinib, and bosutinib was superior to imatinib in first line CML-CP, whereas tolerability, including AE related treatment discontinuation was reported to be better with imatinib and nilotinib. Literature suggests that a TFR attempt benefits patients by controlling disease progression while also eliminating treatment related AEs and long duration of DMR enhances TFR maintenance. Treatment options with more promising DMR outcomes that can enable patients with CML-CP achieve their treatment goals, including improved QOL, lower treatment switch rates due to intolerance, and achieving TFR eligibility are needed. Further research comparing the long-term TFR outcomes and incremental benefits of existing and new TKIs will help guide optimal treatment strategies for patients with frontline CML-CP.