Meeting News CoveragePerspective

Nilotinib induces treatment-free remission in patients with chronic phase CML

CHICAGO — Frontline nilotinib led to treatment-free remission after relatively short exposure in a majority of patients with chronic myeloid leukemia in chronic phase, according to the results of the single-arm phase 2 ENESTfreedom study presented at the ASCO Annual Meeting.

Further, almost every patient who required treatment re-initiation again achieved major molecular response.

“[More than half] of patients remained in tumor-free remission for 48 weeks. ...The remission that was observed is clinically meaningful and should warrant consideration for a response from the FDA,” Andreas Hochhaus, MD, interim head of hematology and medical oncology and professor of internal medicine at University Medical Center in Jena, Germany, said during a presentation.

Data show 40% to 60% of patients with CML in chronic phase (CML-CP) who achieve sustained deep molecular response after long-term treatment with imatinib (median duration, 5-7 years) maintain treatment-free remission after treatment stopped.

Hochhaus and colleagues conducted the ENESTfreedom study to examine the occurrence of treatment-free remission following frontline nilotinib (Tasigna, Novartis) for patients with CML-CP.

The analysis included 215 patients who had received at least 2 years of frontline imatinib and had achieved a molecular response 4.5 (BCR-ABL1IS 0.0032%). Patients continued nilotinib for 1 year and underwent examination using real-time quantitative–polymerase chain reaction assessments at 12-week intervals.

Patients entered the treatment-free remission phase if assessments showed no worse than molecular response 4 (BCR-ABL1IS 0.01%), two or fewer assessments between molecular response 4 and 4.5, and molecular response 4.5 in the last assessment.

One hundred ninety patients (median age, 55 years) met these criteria and discontinued nilotinib. The median time from first molecular response 4.5 to study entry was 18 months, and the median nilotinib duration prior to treatment-free remission was 43 months (range, 33-89).

After 48 weeks, 51.6% (95% CI, 44.2-58.9) of patients in the treatment-free remission phase experienced major molecular response and had not re-initiated treatment with nilotinib.

Eighty-six patients experienced a loss of major molecular response (BCR-ABL1IS 0.1%), which triggered re-initiation of nilotinib. Of these patients, 85 regained major molecular response after a median of 7.9 weeks, and 76 regained molecular response 4.5 after a median of 13.1 weeks.

The other patient discontinued from the study due to their own choice 7.1 weeks after re-initiation, before they had regained major molecular response.

During the treatment-free remission phase, 24.7% of patients experienced musculoskeletal pain, 1.1% of which was grade 3 or higher.

No new safety signals were observed on treatment.

“CML patients who experience deep and sustained molecular response should be eligible for further trials. However, monitoring is critical especially during the first 6 months following the end of treatment,” Richard A. Larson, MD, professor of medicine in the department of hematologic malignancies at University of Chicago, said during the discussion portion of the session. “Discontinuing treatment may seem counterproductive to patients who experience good outcomes, but continuing treatment past tumor-free remission can lead to increased adverse events and high long-term costs for patients. Some patients with CML with deep molecular response to TKI can safely stop therapy." – by Nick Andrews

Reference:

Hochhaus A, et al. Abstract 7001. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclos ure: Hochhaus reports honoraria, research funding and travel expenses from, as well as consultant/advisory board roles with ARIAD, Bristol-Myers Squibb, Novartis and Pfizer. Please see the abstract for a list of all other researchers’ relevant financial disclosures. Larson reports consultant/advisory roles with Amgen, ARIAD, Bristol-Myers Squibb, Celgene, CVS/Caremark and Novartis and research funding paid to his institution from Amgen, Astellas Pharma, Celgene, Daiichi Sankyo and ERYTECH Pharma.

CHICAGO — Frontline nilotinib led to treatment-free remission after relatively short exposure in a majority of patients with chronic myeloid leukemia in chronic phase, according to the results of the single-arm phase 2 ENESTfreedom study presented at the ASCO Annual Meeting.

Further, almost every patient who required treatment re-initiation again achieved major molecular response.

“[More than half] of patients remained in tumor-free remission for 48 weeks. ...The remission that was observed is clinically meaningful and should warrant consideration for a response from the FDA,” Andreas Hochhaus, MD, interim head of hematology and medical oncology and professor of internal medicine at University Medical Center in Jena, Germany, said during a presentation.

Data show 40% to 60% of patients with CML in chronic phase (CML-CP) who achieve sustained deep molecular response after long-term treatment with imatinib (median duration, 5-7 years) maintain treatment-free remission after treatment stopped.

Hochhaus and colleagues conducted the ENESTfreedom study to examine the occurrence of treatment-free remission following frontline nilotinib (Tasigna, Novartis) for patients with CML-CP.

The analysis included 215 patients who had received at least 2 years of frontline imatinib and had achieved a molecular response 4.5 (BCR-ABL1IS 0.0032%). Patients continued nilotinib for 1 year and underwent examination using real-time quantitative–polymerase chain reaction assessments at 12-week intervals.

Patients entered the treatment-free remission phase if assessments showed no worse than molecular response 4 (BCR-ABL1IS 0.01%), two or fewer assessments between molecular response 4 and 4.5, and molecular response 4.5 in the last assessment.

One hundred ninety patients (median age, 55 years) met these criteria and discontinued nilotinib. The median time from first molecular response 4.5 to study entry was 18 months, and the median nilotinib duration prior to treatment-free remission was 43 months (range, 33-89).

After 48 weeks, 51.6% (95% CI, 44.2-58.9) of patients in the treatment-free remission phase experienced major molecular response and had not re-initiated treatment with nilotinib.

Eighty-six patients experienced a loss of major molecular response (BCR-ABL1IS 0.1%), which triggered re-initiation of nilotinib. Of these patients, 85 regained major molecular response after a median of 7.9 weeks, and 76 regained molecular response 4.5 after a median of 13.1 weeks.

The other patient discontinued from the study due to their own choice 7.1 weeks after re-initiation, before they had regained major molecular response.

During the treatment-free remission phase, 24.7% of patients experienced musculoskeletal pain, 1.1% of which was grade 3 or higher.

No new safety signals were observed on treatment.

“CML patients who experience deep and sustained molecular response should be eligible for further trials. However, monitoring is critical especially during the first 6 months following the end of treatment,” Richard A. Larson, MD, professor of medicine in the department of hematologic malignancies at University of Chicago, said during the discussion portion of the session. “Discontinuing treatment may seem counterproductive to patients who experience good outcomes, but continuing treatment past tumor-free remission can lead to increased adverse events and high long-term costs for patients. Some patients with CML with deep molecular response to TKI can safely stop therapy." – by Nick Andrews

Reference:

Hochhaus A, et al. Abstract 7001. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Disclos ure: Hochhaus reports honoraria, research funding and travel expenses from, as well as consultant/advisory board roles with ARIAD, Bristol-Myers Squibb, Novartis and Pfizer. Please see the abstract for a list of all other researchers’ relevant financial disclosures. Larson reports consultant/advisory roles with Amgen, ARIAD, Bristol-Myers Squibb, Celgene, CVS/Caremark and Novartis and research funding paid to his institution from Amgen, Astellas Pharma, Celgene, Daiichi Sankyo and ERYTECH Pharma.

    Perspective
    Ehab Atallah

    Ehab Atallah

    This is the first and the largest study looking at treatment free remission in patients with CML receiving nilotinib (Tasigna, Novartis). It is exciting on one hand that 50% of patients did not need to restart treatment. It is less exciting on the other hand, though, because of 100 patients with chronic myeloid leukemia, only 40 patients would achieve a sustained deep molecular response to be eligible to stop nilotinib. Of those,  only 20 would be able to successfully stop TKI therapy. For the 20% of patients who could stop safely, it would be a very big step for them in terms of improved quality of life, the potential for pregnancy if desired and lowered expenses. Cost to patient and society is one of the reasons discontinuing TKIs is desirable.  There are approximately 30,000 patients in the United States who take medication for CML, and those drugs on average cost $100,000 per year.

    One of the stopping TKI trials which is currently enrolling patients in the US is The LAST trial ( Life after stopping tyrosine kinase inhibitors). This study is an NIH funded trial and is open to enrollment at 14 centers across the US. Patients who stop treatment need to be monitored monthly for the first 6 months, then every 2 months for the next 18 months. After that, it is every 3 months for the third year, which is why we believe that it is best to stop treatment in a clinical trial setting. Most recurrence happens in the first 6 months, which is why that period has the most intense monitoring.

    A total of 100 patients have been accrued on the trial thus far, with a target accrual of 174 patients by the end of the year. We hope that, with this trial, we will be able to better identify which patients will be able to safely stop TKI treatment.

    Many challenges remain in the therapy of patients with CML. We need to understand which patients can safely stop treatment. For those patients who do not achieve a deep molecular response, adding other therapies that would get them there.  Finally, our goal should remain to cure patients with CML i.e. no evidence of CML and off TKI therapy.

    • Ehab Atallah, MD
    • Medical College of Wisconsin

    Disclosures: Atallah reports that he is the principal investigator on the LAST trial.

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