Nilotinib Label Updated to Provide Treatment Discontinuation Recommendations for CML With Sustained Molecular Response


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On December 22, 2017, the product label for nilotinib (Tasigna) was updated to include information on nilotinib discontinuation, postdiscontinuation monitoring, and guidance for treatment reinitiation in patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) who have achieved a sustained molecular response (MR4.5).1,2 Nilotinib is currently indicated for treatment of newly diagnosed adult patients with Ph-positive CML in chronic phase and treatment of chronic phase and accelerated phase Ph-positive CML in adult patients resistant to or intolerant of prior therapy including imatinib.

OF NOTE

Common adverse events reported in patients discontinuing nilotinib include musculoskeletal symptoms, including body aches, bone pain, and extremity pain.

According to the update, patients with newly diagnosed patients with Ph-positive CML in chronic phase and patients with resistant or intolerant Ph-positive CML in chronic phase who have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation after at least 3 years of nilotinib. To be considered for treatment discontinuation, patients must have typical BCR-ABL transcripts; a U.S. Food and Drug Administration (FDA)--authorized test with a detection limit below at least MR4.5 must be used to determine discontinuation eligibility. Patients must be frequently monitored by this test to detect possible loss of remission.

The new recommendations are based on the findings in two single-arm trials that enrolled patients with Ph-positive CML in chronic phase and evaluated treatment-free remission: -ENESTfreedom3 and ENESTop. In ENESTfreedom, among the 190 newly diagnosed patients who discontinued nilotinib after receiving it for at least 3 years and met other specified criteria, 51.6% remained in the treatment-free remission phase after 48 weeks and 48.9% remained in the treatment-free remission phase after 96 weeks. At the 96-week data cutoff, among patients who restarted treatment due to loss of molecular response, 98.9% regained major molecular response (MMR), and 92% regained MR4.5 by the cutoff date.

In ENESTop, of the 126 patients who discontinued nilotinib after at least 3 years after switching from imatinib, 57.9% remained in the treatment-free remission phase after 48 weeks and 53.2% remained in the treatment-free remission phase after 96 weeks. At the 96-week data cutoff, among patients who restarted treatment due to loss of molecular response, 92.9% regained molecular response (MR4.0 or M4.5). 

Eligibility for Discontinuation of Treatment

Discontinuation of treatment should be considered in patients with newly diagnosed Ph-positive CML in chronic phase who meet the following criteria:

  • Been treated with nilotinib for at least 3 years
  • Maintained a molecular response of at least MR4.0 (corresponding to BCR-ABL/ABL ≤ 0.01% international scale) for 1 year prior to discontinuation of therapy
  • Achieved an MR4.5 for the last assessment taken immediately prior to discontinuation of therapy
  • Been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2)
  • No history of accelerated phase or blast crisis
  • No history of prior attempts at treatment-free remission discontinuation that resulted in relapse.

Discontinuation of treatment should be considered in patients who are resistant or intolerant to treatment with imatinib and who have achieved a sustained molecular response (MR4.5) on nilotinib who meet the following criteria:

  • Been treated with nilotinib for a minimum of 3 years
  • Been treated with imatinib only prior to treatment with nilotinib
  • Achieved a molecular response of MR.4.5 (corresponding to BCR-ABL/ABL ≤ 0.0032% international scale)
  • Sustained an MR4.5 for a minimum of 1 year immediately prior to discontinuation of therapy
  • Been confirmed to express the typical BCR-ABL transcripts
  • No history of accelerated phase or blast crisis
  • No history of prior attempts at treatment-free remission discontinuation that resulted in relapse.

BCR-ABL transcript levels and complete blood cell count with differential must be monitored in patients who have discontinued nilotinib monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter. Upon the loss of MR4.0 (corresponding to BCR-ABL/ABL ≤ 0.01% international scale) during the treatment-free phase, BCR-ABL transcript levels should be monitored every 2 weeks until BCR-ABL levels remain lower than MMR (corresponding to MR3.0 or BCR-ABL/ABL ≤ 0.1% international scale) for four consecutive measurements. The patient can then proceed to the original monitoring schedule.

Treatment Reinitiation With Loss of MMR After Nilotinib Discontinuation

Newly diagnosed patients who lose MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy. Patients who reinitiate nilotinib therapy should have their BCR-ABL transcript levels monitored monthly until MMR is reestablished and every 12 weeks thereafter.

NILOTINIB LABEL UPDATE IN CML

  • The product label for nilotinib (Tasigna) was updated to include information on nilotinib discontinuation, postdiscontinuation monitoring, and guidance for treatment reinitiation in patients with Ph-positive CML who have achieved a sustained molecular response (MR4.5).
  • The new recommendations are based on the findings in two single-arm trials that enrolled patients with Ph-positive CML in chronic phase and evaluated treatment-free remission: ENESTfreedom and ENESTop.

Patients who are resistant to or intolerant of prior treatment that included imatinib with a confirmed loss of MR4.0 (2 consecutive measures separated by at least 4 weeks showing loss of MR4.0) or loss of MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy. Patients who reinitiate nilotinib should have their BCR-ABL transcript levels monitored monthly until previous MMR or MR4.0 is re-established and every 12 weeks thereafter.

Common adverse events reported in patients discontinuing nilotinib include musculoskeletal symptoms, including body aches, bone pain, and extremity pain. The long-term outcomes of patients discontinuing vs continuing treatment are unknown at this time. ■

REPORT ADVERSE EVENTS

Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

REFERENCES

1. U.S. Food and Drug Administration: Nilotinib label update to include treatment discontinuation recommendations for CML with sustained molecular responses. Available at www.fda.gov. Accessed April 19, 2018.

2. Tasigna (nilotinib) capsules prescribing information, Novartis, December 2017. Available at www.accessdata.fda.gov. Accessed April 19, 2018.

3. Hochhaus A, Masszi T, Giles FJ, et al: Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase. Leukemia 31:1525-1531, 2017.


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