Real-World Management of Chronic Myeloid Leukemia in Bosnia and Herzegovina: Treatment Patterns, Molecular Monitoring, and Outcomes

Introduction

Chronic myeloid leukemia (CML) patients in low- and middle-income countries have limited access to tyrosine kinase inhibitor (TKI) therapies. Long delays in the start of TKI treatment may have significant consequences on patients' outcomes; therefore, monitoring and therapy management of these patients is undoubtedly challenging. The aim of the study was to conduct a comprehensive long-term analysis of CML management in a developing country in the era of limited TKIs.

Methods

Newly diagnosed CML patients in chronic phase (n=265) treated with imatinib (Glivec or generics) or nilotinib (Tasigna) in the period from 6/2005 to 6/2022 in the Federation of Bosnia and Herzegovina were included in this multicenter study. Glivec was available from 6/2005 to 9/2013, generic imatinib from 9/2013 to present, and Tasigna from 11/2011 to present. From 2005 to 2013, the waiting list was created due to the limited number of TKIs. Introduction of generic imatinib in 9/2013 led to the cancellation of the waiting list; branded imatinib was ceased and patients were switched to generics.

Patient cohort consisted of 171 patients started on front-line imatinib, 60 patients on front-line nilotinib, 19 patients who died while waiting for TKI, 7 patients who discontinued therapy (pregnancy (n=3) or voluntarily (n=4)), and 8 patients did not have complete data. Patients were categorized based on the type of therapy: Group 1 (front-line imatinib, n=171) and Group 2 (front-line nilotinib, n=60). In Group 1, patients were furthermore subcategorized: Group 1a (front-line Glivec, n=83) and Group 1b (front-line generic imatinib, n=88). Patients from Group 1 and Group 2 were additionally categorized and compared according the length of wait period before therapy initiation: <6 months wait (n=120 vs. n=43), 6-12 months wait (n=20 vs. n=7), and >13 months wait (n=31 vs. n=10).

BCR-ABL1 was confirmed by nested PCR/FISH/karyotype and BCR-ABL1 QPCR was evaluated every three months from 2012. Complete cytogenetic response (CCyR) was defined as <1% BCR-ABL1-positive nuclei of at least 200 nuclei by FISH or 20 metaphases using CBA. Major molecular response (MMR) was defined as ≤0.1% BCR-ABL1 expression. Standard patients' variables were collected and survival probabilities were estimated using the Kaplan-Meier method and compared with the log-rank test. The study was conducted according to the Declaration of Helsinki.

Results

We compared overall survival (OS), CCyR, and MMR in 265 patients based on the type of therapy (branded or generic imatinib and nilotinib) and delayed treatment. We first compared outcomes of patients based on initiating therapy alone, imatinib (Group 1, 42 months median follow-up) and nilotinib (Group 2, 45 months median follow-up).

In Group 1, 39% (n=66) of patients were switched to nilotinib. In Group 2, 7% (n=4) were switched to imatinib. In Group 1, 27 patients died on front-line imatinib, 14 patients on second-line nilotinib, and one on third-line imatinib (overall 25%); in Group 2, 6 patients died on front-line nilotinib, and 1 on second-line imatinib (overall 12%). At 120 months, OS was 69% vs. 81% for Group 1 and Group 2, respectively (p=0.057); CCyR at 36 months was 73% vs. 89%, respectively (p=0.000); MMR at 36 months was 69% vs. 88%, respectively (p=0.000).

Comparing the outcomes of branded (Group 1a) vs. generic imatinib (Group 1b), we found that at 72 months, OS, CCyR, and MMR were not significantly different (85% vs. 84%, p=0.876; 90% vs. 90%, p=0.051; 88% vs. 92%, p=0.11, respectively).

Among imatinib treated patients, subgroups <6 months wait, 6-12 months wait, and >13 months wait showed deleterious effects on long-term patients outcomes; OS at 120 months was 78%, 76%, and 42% (p=0.040), CCyR at 48 months was 90%, 87%, and 58% (p=0.000), MMR at 60 months was 87%, 65%, and 44% (p=0.000), and MR⁴ at 60 months was 74%, 42%, and 37% (p=0.020). However, patients treated with nilotinib after the delay showed no significant differences in OS, CCyR, and MMR compared to immediate nilotinib treatment.

Conclusion

The long-term study from Bosnia showed that OS, cytogenetic, and molecular reponses were similar to previously published real-world data. Outcomes on generic imatinib were comparable to branded imatinib. However, nilotinib showed superiority over imatinib, especially in patients whose start of treatment was delayed.

No relevant conflicts of interest to declare.