Treatment-free Remission Definition and Explanation

Treatment-free remission, or TFR, is defined as stopping tyrosine kinase inhibitor (TKI) therapy after achieving a sustained deep molecular response (DMR) and remaining in a deep molecular response without treatment. TFR is an emerging treatment goal for patients with chronic myeloid leukemia in chronic phase (CML-CP).1

 

Opportunity for TASIGNA TFR in the First- and Second-line

Consider the opportunity to achieve deep molecular response and treatment-free remission with TASIGNA for eligible adult Ph+ CML-CP patients.2-4 Starting your adult Ph+ CML patients on TASIGNA—both newly diagnosed and imatinib-treated patients—may give them the opportunity for treatment-free remission eligibility in the future.

Adobe
Consider discussing deep molecular response and treatment-free remission as goals of therapy. Build a path toward TFR with your adult Ph+ CML-CP patients.
Click here to download a one-page document to aid your conversations with CML patients.

Opportunity for TASIGNA TFR in the Future for Newly Diagnosed Patients

ENESTfreedom evaluated the discontinuation of front-line TASIGNA treatment in eligible adult Ph+ CML-CP patients treated with 300 mg twice daily for a minimum of 3 years, who sustained a deep molecular response (DMR) for a minimum of one year immediately prior to discontinuation of therapy and met other stringent eligibility criteria. Stopping TASIGNA therapy to attempt treatment-free remission should be initiated by physicians experienced treating Ph+ CML patients. Frequent monitoring during the treatment-free phase is critical. See additional details below.2

Patients who lose MMR must promptly re-initiate treatment within 4 weeks of when loss of remission is known to have occurred. TASIGNA therapy should be re-initiated at 300 mg twice daily or at a reduced dose level of 400 mg once daily if the patient had a dose reduction prior to discontinuation of therapy. Patients who re-start TASIGNA therapy should have their BCR-ABL transcript levels monitored monthly until MMR is re-established and every 12 weeks thereafter.2

For first-line TASIGNA patients who lose MR4 (BCR-ABL/ABL ≤0.01%IS) but not MMR (MR3 or BCR-ABL/ABL ≤0.1%IS) during the treatment-free phase, BCR-ABL transcript levels should be monitored every 2 weeks until BCR-ABL levels return to a range between MR4 and MR4.5. Patients who maintain BCR-ABL levels between MMR and MR4 for a minimum of 4 consecutive measurements can return to the original monitoring schedule.2

TASIGNA TFR in the Second-line Following Prior Imatinib Therapy

ENESTop evaluated the discontinuation of treatment in eligible adult Ph+ CML-CP patients who have been treated with TASIGNA for a minimum of 3 years after starting on imatinib. These patients sustained a deep molecular response (DMR) on TASIGNA for a minimum of one year immediately prior to discontinuation of therapy and met other stringent eligibility criteria. Stopping TASIGNA therapy to attempt treatment-free remission should be initiated by physicians experienced treating Ph+ CML patients. Frequent monitoring during the treatment-free phase is critical. See additional details below.2

For second-line TASIGNA patients with confirmed loss of MR4 (BCR-ABL/ABL ≤0.01%IS) during the treatment-free phase (two consecutive measures separated by at least 4 weeks showing loss of MR4) or loss of major molecular response (MR3 or BCR-ABL/ABL ≤0.1%IS) must promptly re-initiate treatment within 4 weeks of when loss of remission is known to have occurred. TASIGNA therapy should be re-initiated at either 300 mg or 400 mg twice daily. Patients who re-start TASIGNA therapy should have their BCR-ABL transcript levels monitored monthly until previous major molecular response or MR4 level is re-established and every 12 weeks thereafter.2

TFR eligibility and monitoring requirements: TASIGNA first- and second-line adult patients2

 

Started on TASIGNA: ENESTfreedom TFR Study

Switched to TASIGNA: ENESTfreedom TFR Study

Enrollment Criteria

  • Adults with Ph+ CML-CP
  • e13a2/b2a2 and/or e14a2/b3a2 transcripts
  • ≥2 years on frontline TASIGNA
  • MR4.5 at screening

Adults with Ph+ CML-CP e13a2/b2a2 and/or e14a2/b3a2 transcripts

≥3 years of TKI therapy (first imatinib for >4 weeks, then TASIGNA for ≥2 years)

No documented MR4.5 at time of switch to TASIGNA

Achieved MR4.5 on TASIGNA

Consolidation Phase

  • 52 weeks, sustained DMRa
  • IS RQ-PCR every 12 weeks
  • 52 weeks, no confirmed loss of MR4.5b
  • IS RQ-PCR every 12 weeks

Molecular Monitoring During TFR Phase

IS RQ-PCR every 4 weeks for 1 year, then every 6 weeks for 1 year, and every 12 weeks thereafterc

Importance of Molecular Monitoring Prior to and During TFR

Frequent monitoring of BCR-ABL transcript levels in patients eligible for treatment discontinuation must be performed with a quantitative diagnostic test validated to measure molecular response levels with a sensitivity of at least MR4.5. BCR-ABL transcript levels must be assessed prior to and during treatment discontinuation. Patients eligible to attempt TFR should be aware of the importance of close monitoring.

Re-initiation

Prompt re-initiation of TASIGNA is necessary if a patient loses MMR (MR3.0).

Prompt re-initiation of TASIGNA is necessary if a patient loses MMR (MR3.0) or with confirmed loss of MR4.0.

  • During TFR patients may experience musculoskeletal symptoms more frequently than before treatment discontinuation, e.g., myalgia, pain in extremity, arthralgia, bone pain, spinal pain or musculoskeletal pain. In both ENESTfreedom and ENESTop, symptoms were transient, and none led to study discontinuation.2

How often should a patient undergo molecular monitoring after reaching TFR?

Molecular monitoring for patients eligible for TFR who
discontinue first- or second-line TASIGNA1-3

Year 1 (first 48 weeks)

Monthly

Year 2 (second 48 weeks)

Every 6 weeks

Year 3 and later (after 96 weeks)

Every 3 months

Eligible patients who discontinue first-line or second-line TASIGNA therapy must have their BCR-ABL transcript levels and complete blood count with differential monitored according to the above schedule. Monitoring of BCR-ABL transcript levels must be performed with a quantitative diagnostic test validated to measure molecular response levels on the International Scale (IS) with a sensitivity of at least MR4.5 (BCR-ABL/ABL ≤0.0032% IS).2

aIn ENESTfreedom, sustained DMR defined as (looking at last 4 quarterly PCR assessments): MR4.5 in the last assessment, no assessment worse than MR4.0, and ≤2 assessments between MR4.0 and MR4.5. In ENESTfreedom, patients who did not sustain DMR during the consolidation phase continued to receive TASIGNA. If DMR was reached and sustained during this continuation phase, then those patients could enter the TFR-2 phase of the trial (data not yet available for this phase).

bIn ENESTop, confirmed loss of MR4.5 was defined as BCR-ABL1IS >0.0032%, confirmed in a second assessment within 4 weeks. Patients with confirmed loss of MR4.5 during the consolidation phase continued TASIGNA treatment in the prolonged continuation phase until 192 weeks after the last patient entered the TFR-2 phase (data not yet available for this phase).

cPatients with a loss of MR4.0 during the TFR phase undergo PCR monitoring every 2 weeks.

CP, chronic phase; DMR, deep molecular response; MMR, major molecular response; MR4, molecular response 4 (4-log reductions); MR4.5, molecular response 4.5 (4.5-log reductions); TFR, treatment-free remission.

ENESTfreedom is a single-arm, phase II trial assessing the potential for treatment-free remission in 215 patients with Ph+ CML-CP following frontline nilotinib treatment. The primary efficacy endpoint was the proportion of patients who were in MMR without reinitiation of treatment at week 48 of the TFR phase.

ENESTop is a single-arm, phase II trial assessing treatment-free remission in 163 patients with Ph+ CML-CP who had switched from imatinib to nilotinib. The primary efficacy endpoint was the proportion of patients with successful TFR at 48 weeks, defined as no loss of MMR or confirmed loss of MR4 (2 consecutive RQ-PCR tests) within the first 48 weeks of TFR.

  1. Hughes TP and Ross DM. Blood. 2016 Jul 7;128(1):17-23.
  2. TASIGNA® (nilotinib) Summary of Product Characteristics. Basel, Switzerland: Novartis Pharma AG; May 2017.
  3. Hochhaus A, et al. ENESTfreedom Study. Leukemia [published online March 17, 2017]. 2017:1-7. doi:10.1038/leu.2017.63.
  4. Hughes TP, et al. ENESTop Study. ASCO; June 3-7, 2016; Chicago, Illinois. Poster 7054.