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,...+
Primary end point: 1-Year Response of TASIGNA vs Imatinib1,2
ENESTnd is a randomized, controlled, open-label, multicenter Phase 3 trial of 846 adult patients with newly diagnosed Ph+ CML-CP that included 3 treatment groups. The data presented reflect TASIGNA at the recommended dose of 300 mg twice daily (n=282) versus imatinib 400 mg once daily (n=283). The daily dose of imatinib could be escalated to 800 mg (400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for RQ-PCR testing. The primary end point was MMR at 12 months. MMR was defined as ≥3 logs below baseline (BCR::ABL1 ≤0.1% IS) as measured by RQ-PCR assay. Patients who did not undergo RQ-PCR assessment at 12 months were considered to have had no response.1,3
- Many patients who achieved MMR at 12 months had EMR at 3 months14
- 24 TASIGNA patients (9%) did not achieve EMR vs 88 imatinib patients (33%)14
A descriptive analysis of patients receiving TASIGNA 300 mg bid (n=258) or imatinib 400 mg qd (n=264) in ENESTnd with typical b2a2 and/or b3a2 BCR::ABL1 transcripts and evaluable RQ-PCR samples at 3 months. Data were grouped based on BCR::ABL1 transcript levels at 3 months: ≤1%, >1% to ≤10%, ≤10%, and >10% IS. At 3 months, 24 patients in the TASIGNA arm and 19 patients in the imatinib arm had unevaluable BCR::ABL1 transcript levels (atypical transcripts at baseline, missing RQ-PCR samples, or discontinued therapy) and were excluded from the analysis.14
DEEP RESPONSE MATTERS
TASIGNA delivered deeper responses: Higher cumulative rate of MR4.5 across all time points4
First line: Cumulative rate of MR4.5 with TASIGNA vs imatinib4
Among 2nd-generation TKIs approved for CML, only TASIGNA has data showing MR4.5 in >60% of patients by 10 years4
10-YEAR ANALYSIS: Final analysis of the core study followed the last patient’s last visit, when all patients had completed ≥10 years or treatment discontinued earlier.4
MR4.5 is defined as ≥4.5-log reduction in BCR::ABL1 transcript levels. Best BCR::ABL1 ratio includes patients who achieved MR of ≤0.0032% IS at any time up to the data cut-off date.2
First-Line Progressions to AP/BC
DEEPER RESPONSES HAVE BEEN LINKED TO REDUCED NUMBER OF PROGRESSIONS TO AP/BC5
TASIGNA had fewer progressions to AP/BC vs imatinib at long-term follow-up
ITT population: 11 patients on TASIGNA progressed to AP/BC while 24 patients on imatinib progressed to AP/BC at 10 years.4
101 patients (36% of 279) stayed on TASIGNA through 10 years compared with 90 patients (32% of 280) on imatinib.4
There were no progressions following the first 6 months on core treatment with TASIGNA.6
No patients who achieved MR4.5 progressed to AP/BC at any time during core treatment throughout 10 years of follow-up2,6
First-Line Overall Survival
First line: ENESTnd shows OS among patients receiving TASIGNA and imatinib7
Among 2nd-generation TKIs approved for CML, only TASIGNA has 10-year data linking EMR to OS7
Estimated overall survival rates at 10 years in ENESTnd
- 87.6% (95% CI, 83.5%-91.7%) with TASIGNA vs 88.3% (95% CI, 84.2%-92.4%) with imatinib4
- A total of 32 and 29 deaths from any cause were reported in the TASIGNA and imatinib arms, respectively4
- Median overall survival was not reached for either arm. Estimated overall survival rates at 5 years were 93.7% with TASIGNA vs 91.7% with imatinib2,6
Fewer CML-related deaths with TASIGNA vs imatinib
- At the time of the 120-month final analysis, the estimated overall survival rate was 97.8% for patients on TASIGNA and 93.8% for patients on imatinib6
First line: CML-related death was nearly 3 times as common with imatinib vs TASIGNA at 10-year follow-up6
CML-related deaths were those in which the principal cause of death was marked as “study indication” in the case report/record form by the investigator; or the death occurred subsequent to documented progression to AP/BC, and the cause of death was reported as “unknown” or not reported by the investigator.5
Switch to TASIGNA to advance along the journey of treatment goals8-10
Switch to TASIGNA at the first sign of:
- Failure to achieve key molecular milestones
- Increased TKI dose
- Relapse or loss of response
- Persistent side effects
- Decreased TKI dose
- Concomitant medications to manage side effects
Side effects with imatinib can impact your patients
Selected Safety Information for TASIGNA
- Severe (Grade 3 or 4) fluid retention has occurred in patients taking TASIGNA (see Warning/Precaution regarding Fluid Retention)3,10
- In study A2101, in adult patients with CML-CP resistant to or intolerant to prior therapy that included imatinib, patients receiving TASIGNA experienced: ALT elevation 69%; AST elevation 55%; rash 36%; diarrhea 28%; arthralgia 26%; myalgia 19%3,10
Cross-intolerance data after first-line imatinib11
In a post hoc analysis, among 60 patients with CML-CP intolerant to imatinib, zero patients required a dose reduction or discontinuation of TASIGNA due to the same Grade 3/4 nonhematologic adverse events.
Of 31 CML-CP patients with imatinib-related hematologic AEs, 12 events led to dose reduction and 7 events led to discontinuation of TASIGNA.
Second-Line MCyR and MMR
SECOND LINE: FAST AND SUSTAINED RESPONSES FOR PATIENTS WHO SWITCHED TO TASIGNA
A single-arm, open-label, multicenter study in 321 patients with imatinib-resistant or -intolerant Ph+ CML-CP and 137 patients with Ph+ CML-AP. Patients received TASIGNA 400 mg bid for a minimum follow-up of 24 months (median duration 18.4 months). The definition of imatinib resistance included failure to achieve CHR by 3 months, cytogenetic response by 6 months, or MCyR by 12 months; or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance was defined as discontinuation of treatment due to toxicity and lack of MCyR at time of study entry. The efficacy end point in CML-CP was unconfirmed MCyR, which included complete and partial cytogenetic responses. The efficacy end point in CML-AP was confirmed hematologic response, defined as either a CHR or NEL. Cytogenetic responses were based on the percentage of Ph+ metaphases among ≥20 metaphase cells in each bone marrow sample (CCyR, 0% Ph+ metaphases; PCyR, 1%-35% Ph+ metaphases).3
Cytogenetic response rate (unconfirmed) (%) (95% CI)3:
- Major: 51% (46%-57%)
- Complete: 37% (32%-42%)
- Partial: 15% (11%-19%)
Among the patients who achieved MCyR, 62% had MCyR lasting more than 18 months6
Median time to MCyR:
- 1.4 months in responders with CHR at baseline3
- 2.8 months in responders without CHR at baseline3,10
Estimated Second-Line Overall Survival
OVERALL SURVIVAL FOR PATIENTS IN CHRONIC PHASE WHO SWITCHED TO TASIGNA
Second line: Estimated survival rates among imatinib-resistant or -intolerant patients in chronic phase treated with TASIGNA13
The safety and efficacy of TASIGNA in pediatric patients with Ph+ CML-CP have been investigated in 2 studies: Study CAMN107A2120 (NCT01077544), an open-label, single-arm, multicenter 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, multicenter 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 were 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::ABL1/ABL1 ≤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::ABL1/ABL1 ≤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::ABL1/ABL1 ≤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, 3 patients had confirmed loss of MMR. The median durations of MMR could not be estimated in either population as more than half of 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.
AEs, adverse events; ALT, alanine aminotransferase; AP, accelerated phase; AST, aspartate aminotransferase; BC, blast crisis; bid, twice daily; CCyR, complete cytogenetic response; CHR, complete hematologic response; CI, confidence interval; ENETSnd, Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients; IS, international standard; ITT, Intention-to-treat; MCyR; major cytogenetic response; MMR, major molecular response; MR, molecular response; NEL, no evidence of leukemia; OS, overall survival; PCyR, partial cytogenetic response; Ph+ CML-CP, Philadelphia chromosome-positive chromic myeloid leukemia in chronic phase; qd, once daily; QTcF, corrected QT interval by Fredericia; RQ-PCR, real-time quantitative polymerase chain reaction; TKI, tyrosine kinase inhibitor.
References: 1. Saglio G, Kim DW, Issaragrisil S, et al; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251-2259. 2. Data on file. Study CAMN107A2303 60-month analysis. Novartis Pharmaceuticals Corp; 2014. 3. Tasigna. Prescribing information. Novartis Pharmaceuticals Corp. 4. Kantarjian HM, Hughes TP, Larson RA, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021;35(2):440-453. 5. Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044-1054. 6. Data on file. Study CAMN107A2303 120-month analysis. Novartis Pharmaceuticals Corp; 2020. 7. Data on file. Study CAMN107A2303: KM estimates of OS by BCR-ABL ratio. Novartis Pharmaceuticals Corp; 2019. 8. Hochhaus A, Saussele S, Rosti G, et al; the ESMO Guidelines Committee. Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv41-iv51. 9. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-884. 10. Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117(4):1141-1145. 11. Cortes JE, Hochhaus A, le Coutre PD, et al. Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib. Blood. 2011;117(21):5600-5606. 12. O’Brien SG, Guilhot F, Larson RA, et al; the IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;384(11):994-100. 13. Data on file. Study CAMN107A2101. Novartis Pharmaceuticals Corp; 2009.
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
Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome.
WARNINGS AND PRECAUTIONS
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.
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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.