Other Uses

TFR in CML is the ability for eligible patients who achieved sustained MR4.5 to maintain MMR (frontline) or MR4 (second line) after discontinuing TASIGNA^® (nilotinib) capsules. These patients no longer take oral therapy but continue to be actively managed through frequently scheduled monitoring to identify possible loss of molecular response.¹

Eligibility Criteria for Discontinuation of Treatment in Frontline Patients¹:

Consider discontinuation of treatment in patients with newly diagnosed Ph+ CML-CP who have:

• Been treated with TASIGNA for at least 3 years
• Maintained a molecular response of at least MR4 (corresponding to = BCR-ABL/ABL ≤0.01% IS) for one 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 of treatment-free remission discontinuation that resulted in relapse

ENESTfreedom: the first clinical trial specifically designed to study TFR in CML in frontline TASIGNA¹

Entry criteria

To enter the study, adult patients with Ph+ CML-CP had to have:

• At least 2 years on frontline TASIGNA
• Typical BCR-ABL1 transcripts (e13a2/b2a2 or e14a2/b3a2)
• MR4.5 at screening

Phase 1: Consolidation phase

215 patients entered a 52-week consolidation phase, where they had to maintain a deep response (assessed every 12 weeks) per the following criteria:

• Assessments had to be MR4 or deeper
• No more than 2 assessments could fall between MR4 and MR4.5
• The last assessment had to be MR4.5 

Phase 2: TFR phase

190/215 patients completed the consolidation phase to enter the TFR phase, where they discontinued TASIGNA (with frequently scheduled monitoring).1

ENESTfreedom TFR results through 5 years

• At week 48 of the TFR phase, 52% of patients remained in MMR without treatment reinitiation (n=98/190)^1,2
• At week 96 of the TFR phase, 48.9% of patients remained in MMR without treatment reinitiation (n=93/190)^1,3
• At the 5-year cut-off, 79 out of the 190 patients (43%) who entered the TFR phase remained in MMR or better without TASIGNA treatment, with 76 (40%) remaining in MR4.5⁴
• Of the 190 patients who entered the TFR phase, 81 (42.6%) were still in TFR at data cut-off⁴
• Patients underwent frequently scheduled monitoring⁴
• 109 patients discontinued the TFR phase⁴

TFR rates were higher in patients who maintained MR4.5⁴

• TFR rate at 5 years was higher for patients who had remained in MR4.5 at week 48 of the TFR phase than for patients who had not (86.0% for patients in MR4.5 vs 33.3% for patients in MR4 and 20.0% for patients in MMR at week 48 of the TFR phase)
• Patients with stable MR4.5 during the first 48 weeks of the TFR phase had a TFR rate of 86.7%, compared with 36.3% for patients with at least one RQ-PCR value showing loss of MR4.5 during the first 48 weeks of TFR

Higher TFR rate in the low-risk Sokal group⁴

TFR rate n/N (% [95% CI]) based on Sokal risk scores at diagnosis (n=190):

• Low-risk Sokal Group: Rates at 5 years for TASIGNA: 32/63 (50.8 [37.9, 63.6])
• Intermediate-risk Sokal Group: Rates at 5 years for TASIGNA: 19/50 (38.0 [24.7, 52.8])
• High-risk Sokal Group: Rates at 5 years for TASIGNA: 8/29 (27.6 [12.7, 47.2])
• Missing data: 20/48 (41.7 [27.6, 56.8])

Most patients attempting TFR who lost response regained MMR or MR4.5 with prompt reinitiation⁴

• 91 patients restarted TASIGNA treatment after loss of MMR
  • 90 (98.9%) regained MMR, 91.2% within the first 12 weeks of restarting TASIGNA
  • 84 (92.3%) regained MR4.5
• No progressions to AP/BC were reported at the 5-year analysis, including patients who reinitiated treatment

Potential for low-grade musculoskeletal symptoms

• Advise patients that musculoskeletal symptoms (eg, myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain) may occur more frequently than before TFR¹
• In the subset of 86 patients remaining in TFR >3.7 years, the most frequent AEs involved musculoskeletal pain, which increased in frequency from 16.3% of patients (n=14) during the consolidation phase to 41.9% of patients (n=36) in the first 48 weeks of TFR. This percentage then decreased to 9.3% (n=8), 3.5% (n=3), 5.8% (n=5), and 4.7% (n=4) over the second, third, fourth, and fifth 48-week periods of TFR⁴
• In the subset of 91 patients who entered the treatment reinitiation phase, the most frequent all-grade AE of special interest reported was musculoskeletal pain (19.8%, n=18)⁴

ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-freedom) is an open-label, multicenter, single-arm, Phase 2 trial of 215 adult patients with Ph+ CML-CP treated with frontline TASIGNA for ≥ 2 years. Patients who had achieved MR4.5 (measured with the MolecularMD MRDx^® BCR-ABL test) were enrolled in a 52-week consolidation phase and could enter the TFR phase after achieving a sustained molecular response. Efficacy results were based on the number of patients who remained in the TFR phase with MMR at 96 weeks. Patients with a loss of MMR during the TFR phase reinitiated TASIGNA within 5 weeks at 300 mg bid or at a reduced dose of 400 mg qd if required from the perspective of tolerance.¹

MR4.5 is defined as a value of ≤0.0032% of BCR-ABL1 ratio on the IS or undetectable BCR-ABL1 level with assay sensitivity of at least 4.5 log, which corresponds to a ≥4.5 log reduction of the BCR-ABL1 transcript level from a standardized baseline.^4,5

5-YEAR ANALYSIS: The analysis included updated results based on a data cutoff date of February 3, 2020, at which time all patients who entered the TFR phase had completed 5 years of TFR, switched to the reinitiation phase, or discontinued from the study.⁴

An FDA-authorized test with a detection limit below MR4.5 must be used to determine eligibility for discontinuation. Patients must be frequently monitored by the FDA-authorized test to detect possible loss of molecular response.¹

Eligibility Criteria for Discontinuation of Treatment in Second-line Patients¹:

Consider discontinuation of treatment in patients with Ph+ CML-CP that are resistant or intolerant to treatment with imatinib who have achieved a sustained molecular response (MR4.5) on TASIGNA who have:

• Been treated with TASIGNA for a minimum of 3 years
• Been treated with imatinib only prior to treatment with TASIGNA
• Achieved a molecular response of MR4.5 (corresponding to = BCR-ABL/ABL ≤0.0032% IS)
• Sustained an MR4.5 for a minimum of one year 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 of treatment-free remission discontinuation that resulted in relapse

ENESTop: the first clinical trial specifically designed to study TFR in CML in second-line TASIGNA⁶

Entry criteria

To enter the study, adult patients with Ph+ CML-CP had to have:

• At least 3 years of TKI therapy (imatinib for >4 weeks frontline and TASIGNA for 2 years second line)
• Typical BCR-ABL1 transcripts (e13a2/b2a2 or e14a2/b3a2)
• No documented MR4.5 at time of switch to TASIGNA
• MR4.5 at screening

Phase 1: Consolidation phase

163 patients entered a 52-week consolidation phase, where they had to maintain a deep response (assessed every 12 weeks) per the following criteria⁶:

• The last 4 quarterly assessments had to be MR4.5¹

Phase 2: TFR phase 

126/163 patients completed the consolidation phase to enter the TFR phase, where they discontinued TASIGNA (with frequently scheduled monitoring).1

ENESTop TFR results through 5 years⁷

• 43% of patients achieved TFR for 5 years after discontinuing TASIGNA with frequently scheduled monitoring (n=54/126; 95% CI, 34.1%-52.0%)
• 47% of patients lost MMR/MR4 and promptly reinitiated TASIGNA (n=59/126)

Patients who achieved TFR for 5 years after discontinuing TASIGNA with frequently scheduled monitoring (n=54/126; 95% CI, 34.1%-52.0%)> 47% of patients lost MMR/MR4 and promptly reinitiated TASIGNA (n=59/126)

Rapid response upon prompt TASIGNA reinitiation¹

• 93% of patients regained MMR at 24 weeks after TASIGNA reinitiation (n=52/56)
• 91% of all patients regained MR4.5 by 48 weeks after TASIGNA reinitiation (n=51/56)
• Patients who required reinitiation of TASIGNA were monitored for BCR-ABL1 levels every 4 weeks for the first 24 weeks, and then every 12 weeks thereafter

Patients who regained MMR at 24 weeks after TASIGNA reinitiation (n=52/56) 91% of all patients regained MR4.5 by 48 weeks after TASIGNA reinitiation (n=51/56) Patients who required reinitiation of TASIGNA were monitored for BCR-ABL1 levels every 4 weeks for the first 24 weeks, and then every 12 weeks thereafter

ENESTop (Evaluating Nilotinib Efficacy and Safety in clinical Trials-stop) is an open-label, multicenter, single-arm, Phase 2 trial of 163 adult patients with Ph+ CML-CP treated with TKI therapy for ≥3 years (imatinib for >4 weeks frontline and TASIGNA for ≥2 years second line) who had no documented MR4.5 on imatinib at the time of switch to TASIGNA, and achieved MR4.5 (measured with the MolecularMD MRDx^® BCR-ABL test) with TASIGNA. Patients were enrolled in a 52-week consolidation phase, and could enter the TFR phase after achieving a sustained molecular response. Efficacy results were based on the number of patients who remained in the TFR phase with MMR or MR4 at 96 weeks. Patients with 2 consecutive measurements of BCR-ABL1/ABL1 >0.01% IS or loss of MMR during the TFR phase reinitiated TASIGNA.¹

No patients in ENESTfreedom or ENESTop progressed to AP/BC at 5 years^4,7

Ongoing management is key to TFR in CML: how to actively manage patients in TFR with TASIGNA¹

Monitor patients in TFR by BCR-ABL1 level

Ongoing management informs when to increase testing frequency, and when to reinitiate TASIGNA should a patient lose molecular response.

TASIGNA for pediatric patients with newly diagnosed Ph+ CML-CP or resistant or intolerant Ph+ CML-CP¹

The safety and efficacy of TASIGNA in pediatric patients with Ph+ CML-CP have been investigated in two studies: Study CAMN107A2120 (NCT01077544), an open-label, single-arm, multi-center study that evaluated the pharmacokinetics, safety, and preliminary efficacy of TASIGNA in pediatric patients with Ph+ CML resistant or intolerant to imatinib or dasatinib (n=11), and Study CAMN107A2203 (NCT01844765), an open-label, single-arm, multi-center study evaluating the efficacy and safety of TASIGNA in pediatric patients (from 2 to less than 18 years of age) with Ph+ CML-CP resistant or intolerant to imatinib or dasatinib (n=33) and newly diagnosed Ph+ CML-CP (n=25). In both studies, patients received TASIGNA treatment at a dose of 230 mg/m² twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). Data up to 12 cycles was pooled from a total of 69 pediatric patients (from 2 to less than 18 years of age) with either newly diagnosed Ph+ CML-CP (n=25; 6 children from 2 to less than 12 years and 19 adolescents from 12 to less than 18 years) or imatinib/dasatinib resistant or intolerant Ph+ CML-CP (n=44; 18 children from 2 to less than 12 years and 26 adolescents from 12 to less than 18 years).

In patients with resistant or intolerant CML, the major molecular response [(MMR); BCR-ABL/ABL ≤0.1% IS)] rate was 40.9% (18/44, 95% CI: 26.3%, 56.8%) at 12 cycles (28 days per cycle). In patients with newly diagnosed CML, the MMR rate was 60.0% (15/25, 95% CI: 38.7%, 78.9%) at 12 cycles. In patients with resistant or intolerant CML, the cumulative MMR rate was 47.7% (21/44) by Cycle 12. In patients with newly diagnosed CML, the cumulative MMR rate was 64.0% (16/25) by Cycle 12.  

Among the 21 patients with resistant or intolerant CML who were in MMR at any time on treatment, the median time to first MMR was 2.8 months (range, 0.0 to 11.3). For the 17 patients with newly diagnosed CML who achieved MMR, the median time to first MMR was 5.6 months (range, 2.7 to 16.6). 

Study CAMN107A2203 provided long term data with follow up of approximately 5 years.

By the time of final analysis, the median time on treatment with Tasigna was 51.9 months (range, 1.4 to 61.2 months) for patients with newly diagnosed CML and 60.5 months (range, 0.7 to 63.5 months) for patients with resistant or intolerant CML. 

In the patients with resistant or intolerant CML, the major molecular response (MMR; BCR-ABL/ABL ≤0.1% IS) rates were 57.6%, 57.6% by Cycles 24, and 36, respectively. The MMR rate increased to 60.6% by Cycle 48 and was the same until end of study (Cycle 66). In the patients with newly diagnosed CML, the MMR rates were 68.0% by Cycle 24. The MMR rate increased to 76.0% by Cycle 36 and was the same until end of study (Cycle 66). 

Among patients with resistant or intolerant CML, 12.1% of patients achieved BCR-ABL/ABL ≤0.0032% IS (MR4.5) by Cycle 66. Among patients with newly diagnosed CML, the percentage of patients who achieved MR4.5 was 44%. 

None of the 20 patients with resistant or intolerant CML who achieved MMR at any time on treatment by Cycle 66 had confirmed loss of MMR by the end of Cycle 66 or at the time of early discontinuation. Among the 19 patients with newly diagnosed CML who achieved MMR at any time on treatment by the end of Cycle 66, three patients had confirmed loss of MMR. The median durations of MMR could not be estimated in either population as more than half responders did not have a confirmed loss of response by the study end. Range of duration of response was 0.03 to 61 months for resistant or intolerant CML patients and 2.8 to 57.9 months for newly diagnosed CML patients. One patient with resistant or intolerant CML progressed to AP/BC after 10.1 months on treatment. 

In pediatric patients with Ph+ CML-CP, the most common (greater than 20%) non-hematologic adverse reactions were hyperbilirubinemia, headache, alanine aminotransferase increased, rash, pyrexia, nausea, aspartate aminotransferase increased, pain in extremity, upper respiratory tract infection, vomiting, diarrhea, and nasopharyngitis. The most common (greater than 5%) Grade 3/4 non-hematologic adverse reactions were hyperbilirubinemia, rash, alanine aminotransferase increased, and neutropenia.

Laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 16%) and transaminase elevation (AST Grade 3/4: 2.9%, ALT Grade 3/4: 10%), were reported at a higher frequency than in adult patients.

The most common hematological laboratory abnormalities (greater than or equal to 30% of patients, of all Grades) were decreases in total white blood cells (54%), platelet count (44%), absolute neutrophils (44%), hemoglobin (38%), and absolute lymphocytes (36%).

Discontinuation of study treatment due to adverse reactions occurred in 15 patients (22%). The most frequent adverse reactions leading to discontinuation were hyperbilirubinemia (9%) and rash (6%).

Increase in QTcF greater than 30 msec from baseline was observed in 19 patients (28%). No patient had an absolute QTcF of greater than 500 msec or QTcF increase of greater than 60 msec from baseline.

TFR, treatment-free remission; MR, molecular response; MMR, major molecular response; bid, twice daily; qd, once daily; IS, International Scale; RQ-PCR, real-time quantitative PCR; AP, accelerated phase; BC, blast crisis; AEs, adverse events.   

References:

1. Tasigna [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021.
2. Hochhaus A, Masszi T, Giles FJ, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31(7):1525-1531.
3. Ross DM, Masszi T, Gomez Casares MT, et al. Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study. J Cancer Res Clin Oncol. 2018;144(5):945-954.
4. Radich JP, Hochhaus A, Masszi T, et al. Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial. Leukemia. 2021;35(5):1344-1355.
5. Data on file. Study CAMN107A2303 60-month analysis. Novartis Pharmaceuticals Corp; 2014.
6. Mahon FC, Boquimpani C, Kim DW, et al. Treatment-free remission after second-line nilotinib treatment in patients with chronic myeloid leukemia in chronic phase: results from a single-group, phase 2, open-label study. Ann Intern Med. 2018;168(7):461-470.
7. Hughes H, Clementino N, Fominykh M, et al. Long-term treatment-free remission in patients with chronic myeloid leukemia after second-line nilotinib: ENESTop 5-year update. Leukemia. 2021;35:1631-1642.