Frequency of Molecular Monitoring Correlates with Long Term Outcomes in Chronic Phase Chronic Myelogenous Leukemia Treated with First-Line Imatinib: Results of a Community Survey

Molecular monitoring is recognized as an important part of evaluating treatment response in Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase (Ph+ CML-CP). The latest guidelines from the National Comprehensive Cancer Network (NCCN) recommend quantitative polymerase chain reaction (QPCR) testing in the first 3 months with a goal of <10% Bcr-Abl transcripts using the international scale (IS), and then testing every 3 months to achieve at some point and maintain a 3 log reduction in transcripts (Major Molecular Response). Regular molecular monitoring provides an opportunity to detect resistance or adherence problems early. However, it remains unknown how patterns of use of molecular monitoring impact long term outcomes in non-research community settings.

Community physicians who treat CML patients were invited to retrospectively submit information on Ph+ CML-CP patients in their practice who were ≥18 years old when started on first-line imatinib between 2006–2011 and who had ≥6 months of follow-up. Patients enrolled in clinical trials were excluded. Clinical characteristics at treatment initiation were collected. For each 3 month period after treatment initiation while the patient was on tyrosine kinase inhibitor (TKI) therapy, information was collected on molecular monitoring performed to assess treatment response. Information on death and progression to accelerated phase or blast crisis was collected over the entire follow-up period. Patients were grouped by the average number of QPCR tests received on TKI therapy (scaled to rate per year): the 0 tests group if they never had a QPCR test; the 1–2 tests group if they had on average more than 0 but 2 or less QPCR tests/year; and the 3–4 tests group if they had on average more than 2 but 4 or less QPCR test/year. Progression, mortality, and combined progression/mortality rates were reported for each group. In addition, Cox proportional hazards models were used to test the association between progression and progression-free survival and the average number of QPCR tests per year, controlling for the average number of cytogenetic tests per year, and for potential confounders including age, race, initial imatinib dose, Sokal score, and enlarged spleen at diagnosis. Results were reported as hazard ratios (HR) with 95% confidence intervals (CI).

38 hematologists and oncologists from community practices throughout the US submitted information on 402 patients initiated on first-line imatinib. Patients were followed retrospectively for a median duration of 36 months. Of these, 52 (13%) had no molecular monitoring, 164 (41%) had 1–2 tests/year, and the remaining 186 (46%) had 3–4 tests/year. The figure below shows progression, mortality, and progression/mortality by frequency of molecular testing. The progression/mortality rates tended to decrease with the number of tests received. Adjusting for cytogenetic testing frequency and potential confounders aside from the Sokal score, a higher average number of QPCR tests per year was significantly associated with a lower rate of progression and longer progression-free survival. Each additional QPCR test per year significantly decreased the risk of progression by 45% (HR=0.55; CI [0.35, 0.87], p=0.011), and progression/mortality by 48% (HR=0.52; CI [0.35, 0.79], p=0.002]. Since 48% of patients did not have a reported Sokal score at diagnosis, a separate analysis was done to also adjust for the Sokal score among those without missing data, with nearly identical results.

Ph+ CML-CP patients who underwent QPCR testing every 3–4 months experienced decreased progression and longer progression-free survival compared to those patients monitored less frequently, with the impact of molecular monitoring being independent of the frequency of cytogenetic testing. It is possible that molecular monitoring identifies impending treatment failure earlier and enables adjustment of therapy before hematologic and cytogenetic failure occur. This analysis underscores the value of molecular monitoring every 3 months for Ph+ CML-CP patients on TKI therapy and also demonstrates that a significant number of Ph+ CML-CP patients are not undergoing QPCR at the frequencies recommended in published guidelines. Additional community based education on CML monitoring is needed to assure optimal outcomes.

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Goldberg:Novartis Oncology: Research Funding, Speakers Bureau. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Ericson:Novartis Pharmaceuticals Corp: Employment, Own stock in Novartis Other. Macalalad:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Guerin:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Liu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Kaminsky:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Wu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding.