1. Fuerst, Mark L.

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CHICAGO-More than half of eligible Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients can maintain treatment-free remission (TFR) after stopping nilotinib, according to a new study (Abstract 7001) presented at the 2016 American Society of Clinical Oncology Annual Meeting.

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"This is the first trial to show that, after a short treatment duration with nilotinib of 3.6 years, more than 50 percent of patients who stopped therapy were able to remain treatment-free at 48 weeks," said lead author Andreas Hochhaus, MD, Head of the Department of Hematology and Medical Oncology, Jena University Hospital, Germany. "Findings from the nilotinib TFR trial add to the existing body of research exploring the discontinuation of tyrosine kinase inhibitor (TKI) treatment in CML and may help to establish safe and appropriate criteria for eligible patients to stop treatment."


CML in the Chronic Phase

ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Following REsponsE in De nOvo CML-CP Patients) is an open-label phase II study involving 215 Ph+ CML patients in the chronic phase, conducted at 132 sites across 19 countries. ENESTfreedom evaluated stopping treatment in 190 adults, median age 55, with Ph+ CML after the patients had achieved a response of MR4.5 with nilotinib and a sustained deep molecular response for 1 year as a first-line treatment.


Results from the ENESTfreedom study found that 51.6 percent of the 190 CML patients who achieved a sustained deep molecular response following at least 3 years of first-line treatment with nilotinib were able to discontinue therapy and remain in TFR for 48 weeks. Of the 190 patients who entered the study, 97 are still in TFR, said Hochhaus.


ENESTfreedom did not meet its primary objective, the percentage of patients in major molecular response (MMR) at 48 weeks in the TFR phase. The median treatment duration in this trial was 3.6 years, which is a short length of TKI exposure prior to attempting TFR, noted Hochhaus.


Of the 86 patients who restarted treatment with nilotinib due to loss of MMR, 98.8 percent were able to regain MMR and 88.4 percent were able to regain MR4.5. By weeks 8 and 15 of treatment reinitiation with nilotinib, 50 percent of retreated patients already achieved MMR and MR4.5, respectively. One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with nilotinib.


No new major safety findings were observed in the study in patients treated with nilotinib beyond those in the known safety profile of the drug. In ENESTfreedom, one-quarter of patients experienced musculoskeletal pain during the first year of the TFR phase versus 16.3 percent while still taking nilotinib in the 1-year consolidation phase. Most adverse events were grade 1 or 2 and occurred in the first 24 weeks of TFR, he said, noting that musculoskeletal pain is part of TKI withdrawal syndrome. Rash and pancreatitis were also increased in the TFR phase.


"TFR is clinically meaningful. A high rate of sustained MR4.5 leads to stable disease," Hochhaus concluded. The study is ongoing, with planned follow-up to evaluate the ability of patients to sustain remission for longer durations following discontinuation of nilotinib.


Ongoing Treatment

An important part of the nilotinib TFR studies is regular and frequent molecular monitoring with a well-validated assay able to measure BCR-ABL transcript levels down to MR4.5, Hochhaus explained.


Frequent patient monitoring during TFR allows timely determination of loss of MR4.0 and MMR and the need for treatment initiation. Researchers need to standardize sensitivity results from laboratories to exactly define a deep molecular response, which is not done at the moment, according to Hochhaus. "We need to harmonize results between laboratories," he emphasized.


Stopping CML treatment is currently not a clinical recommendation and should only be attempted in the context of a clinical study, Hochhaus cautioned. Discontinuation of treatment in ENESTfreedom was conducted under the conditions of the trials and in patients who met the rigorous predefined criteria of the trials.


CML Outlook

"The outlook is good for CML patients," Hochhaus said. "This is a chronic disease that may not require lifelong treatment in the future. The best patients will be able to discontinue treatment and will be stable in remission."


CML patients who do better in a treatment-free program are those who had longer treatment, achieved deeper responses, and had low-risk Sokal scores. Some patients may relapse and require new treatment.


Hochhaus projected that CML treatment will be akin to follicular lymphoma therapy. "CML patients will receive treatment, then stop, and if need be, be retreated.


"We need a multivariate analysis that considers the biology of the disease," Hochhaus continued. "All CML patients have persistent disease. Most probably the autoimmune system deals with persistent stem cells."


In addition, researchers are working on combination treatments of interferon with TKIs. "For the minority of patients who fail treatment, we need to identify them early and treat aggressively," Hochhaus concluded.


Mark L. Fuerst is a contributing writer.