A Single Center Retrospective Analysis of Adherence to Molecular Monitoring Guidelines in Patients with Chronic Myeloid Leukemia
Authors: Dela Cruz Josephine Pineda , Staszewski Harry 
Published: October 2019

Introduction
In 2016, it is predicted that there will be 8,220 new cases of Chronic Myelogenous Leukemia (CML) in the United States, with an estimated 1,070 deaths from this disease (Siegel RL, et al, CA Cancer J Clin 2016, 66:7-30). Due to the prognostic significance of cytogenetic and molecular response to frontline Tyrosine Kinase Inhibitors (TKIs), expert panels such as the European LeukemiaNet and the National Comprehensive Cancer Network (NCCN) recommend strict guidelines to ensure adequate surveillance of patient's response to TKI therapy (Deininger M, et al, Blood 2009, 114: Abstract 1126).
In this retrospective observational study, we studied adherence to current NCCN Guidelines in the management of CML.
Methods
Using both electronic and archived paper medical records, we identified 26 patients diagnosed with CML from 3/3/2003 to 12/9/2015 who were followed in a single community practice. Information at initial diagnosis regarding age, CML phase, spleen size, and initial TKI therapy selected were obtained. Monitoring parameters including frequency of follow-ups, complete blood counts, chromosomal analysis, molecular testing, and repeat bone marrow aspirates were reviewed. Evaluation for response to treatment with time to Complete Hematologic Response (CHR), time to Major Molecular Response (MMR), and time to Complete Molecular Response (CMR) were noted. Evaluations of treatment adherence and testing for BCR-ABL kinase mutations when milestones were missed or molecular progressions detected were recorded. Reasons for change in therapy and choice of subsequent treatment were also documented.
Results
The median age at diagnosis of CML was 53, with a male to female ratio of 1.6:1. In this group of 26 patients, only a single patient was diagnosed in the accelerated phase, the rest were in the chronic phase of CML. In 92%, clinical spleen size was logged. However, a single standardized method was not utilized which precluded calculation of Sokal scores for risk classification. In 88.5%, bone marrow aspirates were obtained to establish disease phase and enable bone marrow cytogenetic studies. Out of 26 patients, 16 (61.5%) were initially treated with imatinib, 6 (23%) were treated with dasatinib and 4 (15.4%) were treated with nilotinib. Attempts to achieve superior cytogenetic and deeper molecular response with dasatinib or nilotinib, coupled with lower rates of progression to advanced phases, were most frequently cited as reasons for choosing non-imatinib front line therapy. Only 50% of patients had complete compliance with periodic molecular testing at 3, 6 and 12 months during the first 2 years of diagnosis. The frequency of molecular and cytogenetic response assessments were often less than recommended. Only 2 of the patients studied underwent repeat bone marrow testing, with one enrolled in a clinical trial requiring periodic repeat bone marrow biopsies. The median time to achieve CHR was 27 days, median time to reach MMR was 26.5 weeks and median time to CMR was 7.9 months. Attempts to confirm patient compliance with oral TKI therapy were documented in 22 of the patients (84.6%). Three patients underwent testing for BCR-ABL kinase mutations at the time of molecular progression, however, none tested positive for resistance mutations. No patient had a hematological or cytogenetic relapse, and two patients switched from nilotinib to imatinib because of poor compliance due to toxicity.
Conclusion
Clinical practice guidelines promote evidence-based recommendations to guide clinicians in the management of CML. TKI therapy has evolved to be the primary treatment for chronic phase CML, and monitoring response to TKI therapy by setting cytogenetic and molecular milestones has improved quality of care and success with treatment. Unfortunately, real-world application of strict time lines for testing may not be feasible in all circumstances. Patient non-compliance with testing and marrow exams, interval illness and hospitalization, and errors in laboratory testing have served as barriers to adherence to NCCN guidelines. Despite a 50% compliance rate, there were no major untoward events (i.e. transformation to accelerated or blast phase) appreciated in this subset of patients.

Disclosures
No relevant conflicts of interest to declare.