Assessing Molecular Relapse-Free Survival in Latin American Chronic Myeloid Leukemia Patients Undergoing TKI Dose Reduction
Authors: Luft Melina Gisel , Tannuri Ricardo Khalil , Mela Osorio María Jose , Riva Maria Elisa , Moiraghi Beatriz , Varela Ana Ines , Prado Ana Inés , Ventriglia Veronica , Freitas Maria Josefina , Gelo Olivia Maria , Sackmann Massa Federico , Tosin Maria Fernanda , Perez Mariel Ana , Stevenazzi Mariana , Matosas Victoria , Barreto Carolina , Pavlovsky Miguel Arturo , Fernandez Isolda Isabel , Pavlovsky Carolina 
Published: December 2024

Introduction: Tyrosine Kinase inhibitors (TKIs) treatment in chronic myeloid leukemia (CML) patients have achieved a life expectancy similar to the general population. In clinical practice, TKIs dose reduction (DR) frequently occurs due to numerous adverse events with profound impact on quality of life. However, there is not enough scientific and literary evidence supporting this strategy. We report our real-world experience in Latin America with low dose TKIs and the molecular recurrence-free survival (MRFS) in this population.

Material and Methods: Retrospective, multicentric, observational study of a real world cohort of CML chronic phase patients treated with reduced TKI dose between 2000 and 2024. Data was collected from 9 institutions in Latin America. Patients ≥ 18 years who received lower doses of TKI were included, regardless of molecular response (MR) and status at the time of tapering. A DR was defined as Imatinib &lt; 400 mg/day, Dasatinib &lt; 100 mg/day, Nilotinib &lt; 600 mg/day, Bosutinib &lt; 500 mg/day and Ponatinib &lt; 45 mg/day.

The causes of DR and subsequent response evolution were analyzed. MRFS was calculated using Kaplan-Meier curves. An event was defined by the loss of stable molecular response or loss of major molecular response (MMR).

Results: Sixty-five patients were included, with a median age of 54 years (18-86). Dose reduction TKIs treatment distribution was as follows: Imatinib 11 patients (16.9%) and 54 (83.1%) were under treatment with later lines: Dasatinib 28 (43%); Nilotinib 20 (31%); Ponatinib 5 (7.7%) and Bosutinib 1 (1.5%).

The DR was due to toxicity in 51 patients (78.4%): 12 (18.5 %) hematological and 39 (60%) non-hematological: (hepatotoxicity 12.3%, pleural effusion 15.4%, gastrointestinal intolerance 10.8%, skin disorders 4.6%, pulmonary hypertension 4.6%, renal failure 4.6%, myalgia 4.6 %, cardiovascular toxicity 1.5% and pancreatitis 1.5%). Other reasons for DR were persistent deep molecular response or comorbidities (21.5%).

TKIs at dose reduction were: Dasatinib 25 mg/50 mg (n:25); Nilotinib 300 mg/450 mg (n:19); Imatinib 200 mg/300 mg (n:11); Ponatinib 15 mg (n:5) and Bosutinib 400 mg (n:1). Sixty three patients (97%) maintained previous MR or achieved MMR after DR, regardless of the cause and previous molecular status. Fifty two patients (81.5%) achieved or maintained MMR at DR with a median duration of 6,7 years (0,3 -13,7). The median follow-up of the entire cohort was 3,23 years ( 0,21-13,7). The MRFS at 5 years was 98,4%. No patient died or progressed to advanced phases.

Conclusions: In this study we have observed that DR is effective in maintaining MR and also achieving MMR in a high percentage of patients. The main reason for DR were non-hematological toxicities. Although more evidence is required to incorporate this approach into clinical practice guidelines, our experience might trigger the design of prospective trials to test the use of lower doses of TKI in our region, with possible impact not only on quality of life but also on financial resources in low-income countries.