1. Fuerst, Mark L.

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SAN DIEGO-More than half of all Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) patients who switch to nilotinib from imatinib due to intolerance, resistance or physician preference can safely stop treatment after sustaining deep molecular responses on nilotinib for at least 1 year, according to a new study presented at the American Society of Hematology (ASH) annual meeting.

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Tyrosine kinase inhibitors (TKIs) such as imatinib and nilotinib are so effective at controlling CML that some patients seek to avoid the drugs' side effects and save costs by discontinuing TKI treatment altogether once they have achieved a stable level of leukemia remission. Under current guidelines, most patients who achieve remission with TKI therapy are advised to continue taking the drugs indefinitely, but it is unclear whether continued therapy is necessary for all patients.


"Findings from this post-hoc analysis of ENESTop suggest that the reason for switching from imatinib to nilotinib did not impact a patient's chance of maintaining treatment-free remission (TFR). CML is considered a chronic disease due to the success of TKIs, but there remains a need for continued advancements and these findings are an exciting and important contribution to clinical research in CML treatment," said lead author Timothy P. Hughes, MD, Cancer Theme Leader at the South Australian Health and Medical Research Institute and Clinical Professor at the University of Adelaide, Australia.


Treatment-Free Remissions & CML

This new post-hoc analysis of ENESTop, an ongoing, single-arm, phase II study, evaluated rates of TFR at 48 weeks after stopping treatment with nilotinib among subgroups of patients who switched from imatinib due to intolerance, resistance or physician preference (Abstract 792). Eligible patients were adults with chronic phase CML who received 3 or more years of total TKI therapy (more than 4 weeks of imatinib, followed by 2 or more years of nilotinib) and achieved a sustained deep molecular response (MR4.5). Patients continued nilotinib treatment in a 1-year consolidation phase, and those without confirmed loss of MR4.5 were eligible to stop nilotinib in the TFR phase.


The analysis of 125 patients found that more than 50 percent of patients in each of the subgroups maintained TFR at 48 weeks, and the proportion of patients who maintained TFR at 48 weeks was similar across the three subgroups: 30 of 51 (58.8%) in the intolerance subgroup, 16 of 30 (53.3%) in the resistance subgroup, and 27 of 44 (61.4%) in the physician preference subgroup. One patient who stopped treatment was found to have had atypical transcripts and was excluded from this analysis.


No new major safety findings were observed in ENESTop in patients treated with nilotinib beyond those in the known safety profile of the drug. The rates of all grade musculoskeletal pain were 42.1 percent in the first year of the TFR phase versus 14.3 percent while still taking nilotinib in the consolidation phase. No patients progressed to advanced phase/blast crisis.


"Overall, the data are reassuring that patients who switch to nilotinib can achieve deep responses and are stable enough to achieve TFR," said Hughes.


Regular and frequent molecular monitoring with a well-validated assay able to measure BCR-ABL transcript levels down to MR4.5 is an important part of nilotinib TFR studies, explained Hughes. "Frequent patient monitoring during TFR allows timely determination of loss of major molecular response and the need for treatment initiation," he said, adding that most community oncologists can get access to a reputable laboratory to do molecular monitoring.


"Many CML patients with long exposure to TKIs and who are in deep remission for at least 1 year can be considered for TFR," said Hughes. "In my practice, of 200 CML patients, I have had 50 patients stop TKI therapy, with 25 patients stopping successfully and another 25 patients going back on TKI therapy."


Reducing TKI Dose

Many CML patients may be able to safely reduce TKI side effects by cutting their dose in half, according to another study presented at ASH (Abstract 938). The results suggest that a wider range of patients may be able to safely reduce TKI therapy than was previously thought feasible.


Of 174 CML patients, the vast majority (93%) showed no evidence of leukemia rebound 1 year after reducing their TKI dose, and many reported a significant decrease in TKI-associated side effects within the first 3 months. Just 12 patients showed signs of leukemia recurrence, all of whom regained a remission level of MR3 or better within 4 months of resuming a full TKI dose.


"Taken together, these findings might indicate that some patients are being unnecessarily over-treated," said study author Mhairi Copland, MD, PhD of the Institute of Cancer Sciences, University of Glasgow, U.K. "The other important implication is that patients do not have to have extremely low levels of leukemia on very sensitive tests in order to safely try reducing their TKI dose."


Patients who started with extremely low levels of leukemia (MR4) were significantly less likely to experience a leukemia rebound (seen in 2.4% of these patients) compared with those with low levels classified as MR3 (18.4%). However, Copland said the low rates of rebound overall suggest it is safe for MR3 patients to attempt to reduce their TKI dose if desired. Any benefits in terms of reducing side effects should become apparent within the first 3 months, she concluded.


Mark L. Fuerst is a contributing writer.