TASIGNA prolongs the QT interval. Prior to TASIGNA administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to monitor the QTc at baseline,...+
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Treatment-Free Remission
First-Line TFR
TASIGNA IS THE ONLY TKI WITH TREATMENT-FREE REMISSION (TFR) DATA IN ITS LABEL1
TFR in CML is the ability for eligible patients who achieved sustained MR4.5 to maintain MMR (first line) or MR4 (second line) after discontinuing TASIGNA. 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::ABL1/ABL1 ≤0.01% IS) 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::ABL1 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 patients on first-line TASIGNA1
Entry criteria
To enter the study, adult patients with Ph+ CML-CP had to have:
- At least 2 years on first-line 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
- 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 (41.6%) 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
- 101 patients discontinued the TFR phase4
- 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 36.4% for patients with at least one RQ-PCR value showing loss of MR4.5 during the first 48 weeks of TFR
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])
- 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 first-line TASIGNA for ≥ 2 years. Patients who had achieved MR4.5 (measured with the MolecularMD MRDx® BCR::ABL1 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 cut-off 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
Treatment-Free Remission Checklist
Use this helpful guide to see if TASIGNA may be an option for your patients seeking TFR.
Second-Line TFR
Eligibility Criteria for Discontinuation of Treatment in Second-line Patients1:
Consider discontinuation of treatment in patients with Ph+ CML-CP who are resistant or intolerant to treatment with imatinib who have achieved a sustained molecular response (MR4.5) on TASIGNA and 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::ABL1/ABL1 ≤0.0032% IS)
- Sustained an MR4.5 for a minimum of 1 year immediately prior to discontinuation of therapy
- Been confirmed to express the typical BCR::ABL1 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
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Consider all of your adult patients for TFR eligibility* |
*Patients with CML-CP, aged 21-83, irrespective of Sokal risk score, who meet all eligibility requirements for discontinuation of treatment outlined in the TASIGNA Prescribing Information may be considered for TFR attempt.
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 first line 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
- 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)
- 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
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 first line 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::ABL1 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
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No patients in ENESTfreedom or ENESTop progressed to AP/BC at 5 years4,7 |
Monitoring TFR
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.
1L, first-line; 2L, second-line; AEs, adverse events; AP, accelerated phase; BC, blast crisis; bid, twice daily; ENESTfreedom; Evaluating Nilotinib Efficacy and Safety in Clinical Trials—freedom; ENESTtop, Evaluating Nilotinib Efficacy and Safety in clinical Trials—stop; IS, international scale; MMR, major molecular response; MR, molecular response; qd, once daily; RQ-PCR, real-time quantitative polymerase chain reaction; TFR, treatment-free remission.
References: 1. Tasigna. Prescribing information. Novartis Pharmaceuticals Corp. 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.
INDICATIONS for TASIGNA
Adult and Pediatric Patients With Newly Diagnosed Ph+ CML-CP
TASIGNA is indicated for the treatment of adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP).
Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP
TASIGNA is indicated for the treatment of adult patients with CP and accelerated phase (AP) Ph+ CML resistant or intolerant to prior therapy that included imatinib.
Pediatric Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP
TASIGNA is indicated for the treatment of pediatric patients greater than or equal to 1 year of age with CP and AP Ph+ CML with resistance or intolerance to prior tyrosine kinase inhibitor (TKI) therapy.
IMPORTANT SAFETY INFORMATION for TASIGNA
WARNING: QT PROLONGATION AND SUDDEN DEATHS
- TASIGNA prolongs the QT interval. Prior to TASIGNA administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, and following any dose adjustments
- Sudden deaths have been reported in patients receiving TASIGNA. Do not administer TASIGNA to patients with hypokalemia, hypomagnesemia, or long QT syndrome
- Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors
- Avoid food 2 hours before and 1 hour after taking the dose
CONTRAINDICATIONS
Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.
WARNINGS AND PRECAUTIONS
Myelosuppression
Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Perform complete blood counts every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding TASIGNA temporarily or dose reduction.
QT Prolongation
TASIGNA prolongs the QT interval. ECGs should be performed at baseline, 7 days after initiation, periodically as clinically indicated, and following dose adjustments. Correct hypokalemia or hypomagnesemia prior to administration and monitor periodically.
Significant prolongation of the QT interval may occur when TASIGNA is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided. The presence of hypokalemia and hypomagnesemia may further enhance this effect.
Sudden Deaths
Sudden deaths have been reported in patients with Ph+ CML treated with TASIGNA. The relatively early occurrence of some of these deaths relative to the initiation of TASIGNA suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.
Cardiac and Arterial Vascular Occlusive Events
Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial in patients with newly diagnosed Ph+ CML and observed in the postmarketing reports of patients receiving TASIGNA therapy. Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events.
If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively managed during TASIGNA therapy according to standard guidelines.
Pancreatitis and Elevated Serum Lipase
TASIGNA can cause increases in serum lipase. Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated.
Hepatotoxicity
TASIGNA may result in hepatotoxicity as measured by elevations in bilirubin, AST/ALT, and alkaline phosphatase. Grade 3/4 elevations of bilirubin, AST, and ALT were reported at a higher frequency in pediatric patients than in adults. Monitor hepatic function tests monthly or as clinically indicated.
Electrolyte Abnormalities
The use of TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating TASIGNA and monitor these electrolytes periodically during therapy.
Tumor Lysis Syndrome
Tumor lysis syndrome cases have been reported in patients taking TASIGNA who have resistant or intolerant Ph+ CML. Malignant disease progression, high white blood cell counts, and/or dehydration were present in most of these cases. Maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA.
Hemorrhage
Serious hemorrhage, including fatal events, from any site, including the GI tract, was reported in patients with Ph+ CML receiving TASIGNA. Monitor patients for signs and symptoms of bleeding and medically manage as needed.
Total Gastrectomy
Since the exposure of TASIGNA is reduced in patients with total gastrectomy, perform more frequent monitoring of these patients. Consider dose increase or alternative therapy in patients with total gastrectomy.
Lactose
Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.
Monitoring Laboratory Tests
Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Perform chemistry panels, including electrolytes, calcium, magnesium, liver enzymes, lipid profile, and glucose prior to therapy and periodically. ECGs should be obtained at baseline, 7 days after initiation, and periodically thereafter, as well as following dose adjustments.
Monitor lipid profiles and glucose periodically during the first year of TASIGNA therapy and at least yearly during chronic therapy. Assess glucose levels before initiating treatment with TASIGNA and monitor during treatment as clinically indicated. If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines.
Fluid Retention
Grade 3/4 fluid retention including pleural effusion, pericardial effusion, ascites, and pulmonary edema have been reported in patients with Ph+ CML receiving TASIGNA. Monitor patients for signs of severe fluid retention (eg, unexpected rapid weight gain or swelling) and for symptoms of respiratory or cardiac compromise (eg, shortness of breath); evaluate etiology and treat patients accordingly.
Effects on Growth and Development in Pediatric Patients
Growth retardation has been reported in pediatric patients with Ph+ CML in chronic phase treated with TASIGNA. Monitor growth and development in pediatric patients receiving TASIGNA treatment.
Embryo-Fetal Toxicity
TASIGNA can cause fetal harm. Advise females to inform their doctor if they are pregnant or become pregnant. Inform female patients of the risk to the fetus and potential for loss of the pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 14 days after receiving the last dose of TASIGNA. Advise lactating women not to breastfeed during treatment with TASIGNA and for at least 14 days after the last dose.
Monitoring of BCR-ABL Transcript Levels
Monitor BCR-ABL transcript levels in patients eligible for treatment discontinuation using an FDA-authorized test validated to measure molecular response (MR) levels with a sensitivity of at least MR4.5. In patients who discontinue TASIGNA therapy, assess BCR-ABL transcript levels monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter during treatment discontinuation.
Following a loss of MMR (first line/second line) or confirmed loss of MR4 (2 consecutive measures separated by at least 4 weeks showing loss of MR4 in second line), patients should reinitiate TASIGNA within 4 weeks of when the loss of remission is known to have occurred.
Monitor CBC and BCR-ABL transcripts in patients who reinitiate treatment with TASIGNA due to loss of MR quantitation every 4 weeks until MMR is reestablished and then every 12 weeks.
For patients who fail to achieve MMR after 3 months of treatment reinitiating, BCR-ABL kinase domain mutation testing should be performed.
ADVERSE REACTIONS
The most commonly reported nonhematologic adverse reactions (≥20%) in adult and pediatric patients receiving TASIGNA were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats.
Hematologic adverse drug reactions (all grades) include myelosuppression: thrombocytopenia, neutropenia, and anemia.
Musculoskeletal symptoms (eg, myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain) have been reported in eligible patients who discontinued TASIGNA therapy after attaining a sustained MR4.5. The rate of new musculoskeletal symptoms (all grades) generally decreased from the first year (34%-48%) to the second year (9%-15%) after treatment discontinuation.
DOSE ADJUSTMENTS OR MODIFICATIONS
TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hepatic impairment, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities (lipase, bilirubin, or hepatic transaminase elevations) or concomitant use of strong CYP3A4 inhibitors.
DRUG INTERACTIONS
Avoid concomitant use of strong CYP3A4 inhibitors with TASIGNA, or reduce TASIGNA dose if co-administration cannot be avoided. Avoid concomitant use of strong CYP3A4 inducers with TASIGNA. Use short-acting antacids or H2 blockers as an alternative to proton pump inhibitors.
Please see full Prescribing Information, including Boxed WARNING, by clicking here.
