In the phase I Tasigna trial, no dose-limiting toxicities were observed at doses up to 600 mg daily.1 The most common adverse events reported with Tasigna therapy were myelosuppression, including thrombocytopenia,
neutropenia, and anemia. Transient indirect hyperbilirubinemia and rashes were also observed (Figure 1 and Table 1).1,2
Figure 1. Phase I Hematologic Adverse Events
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| 400 mg Twice Daily (N = 32) | 600 mg Twice Daily (N = 18) | Any Dose (N = 119) |
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|---|---|---|---|---|---|---|
| Adverse Eventa | Grade 1 or 2 % | Grade 3 or 4 % | Grade 1 or 2 % | Grade 3 or 4 % | Grade 1 or 2 % | Grade 3 or 4 % |
| Rash (all types) | 22 | 0 | 28 | 6 | 20 | 2 |
| Pruritus | 6 | 3 | 22 | 6 | 15 | 2 |
| Dry skin | 6 | 0 | 11 | 0 | 12 | 0 |
| Constipation | 0 | 0 | 22 | 0 | 8 | 0 |
| Nausea, vomiting, or both | 13 | 0 | 6 | 0 | 8 | 0 |
| Increase in both total and conjugated bilirubin | 6 | 3 | 17 | 11 | 5 | 3 |
| Fatigue | 16 | 0 | 6 | 0 | 5 | 1 |
| Increase in unconjugated bilirubin | 6 | 3 | 0 | 11 | 2 | 4 |
| Alopecia | 0 | 0 | 6 | 0 | 6 | 0 |
| Increase in lipase level | 0 | 9 | 0 | 11 | 0 | 5 |
| Increase in level of ALT, AST, or both | 3 | 3 | 0 | 0 | 1 | 3 |
| aLaboratory adverse events were reported only if they required therapy, constituted a serious adverse event, were clinically significant, or prompted withdrawal from the study. ALT, alanine aminotransferase; AST, aspartate aminotransferase. |
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Results from the Tasigna phase II trial, including patients with CML-CP and CML-AP, indicate an adverse event profile similar to that of the Tasigna phase I trial.1-4 The median exposure to Tasigna for patients with CML-CP and CML-AP in this safety analysis was 261 days (range 1-502) and 202 days (range 2-611), respectively. Discontinuation for adverse events regardless of causality was observed in 15% of patients with CML-CP.
Figure 2. Phase II Grade 3/4 Hematologic Adverse Events With Tasigna
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Tasigna therapy is associated with high rates of anemia, neutropenia, and thrombocytopenia (Figure 2) (National Cancer Institute Common Toxicity Criteria grade 3/4).2 Myelosuppression rates are higher in patients with CML-AP compared with patients with CML-CP.
Most nonhematologic adverse events, excluding laboratory abnormalities, reported with Tasigna® at frequencies ³5% among all patients (n = 280 CML-CP, n = 119 CML-AP) were mild to moderate (grades 1 and 2) (Table 2)3,4 <1% of patients experienced any nonhematologic adverse event at grade 3 or 4.2,3,4
| System Organ Class | Frequency | Adverse Reaction | All Grades % | Grade 3/4 % | Chronic Phase Grade 3/4 % | Accelerated Phase Grade 3/4 % |
|---|---|---|---|---|---|---|
| Nervous system disorders | Very common | Headache | 64 (16) | 6 (3) | 5 (2) | 1 (1) |
| Gastrointestinal disorders | Very common | Nausea | 78 (20) | 4 (1) | 3 (1) | 1 (1) |
| Very common | Constipation | 47 (12) | 0 | 0 | 0 | |
| Very common | Diarrhea | 43 (11) | 7 (2) | 6 (2) | 1 (1) | |
| Common | Vomiting | 30 (11) | 2 (<1) | 2 (<1) | NR | |
| Common | Abdominal pain | 8 (2) | 1 | NR | 1 | |
| Skin and subcutaneous tissue disorders |
Very common | Rash | 105 (26) | 9 (3) | 9 (3) | 0 |
| Very common | Pruritis | 91 (23) | 3 (1) | 3 (1) | 0 | |
| Common | Alopecia | 10 (3) | 0 | NR | 0 | |
| Musculoskeletal and connective tissue disorders |
Common | Myalgia | 34 (9) | 4 (1) | 3 (1) | 1 (1) |
| Common | Arthralgia | 6 (2) | 0 | NR | 0 | |
| Common | Muscle spasms | 11 (3) | 0 | NR | 0 | |
| Common | Extremity pain | 19 (5) 2 | 2 (<1) | 2 (<1) | 0 | |
| General disorders and administration site conditions |
Very common | Fatigue | 64 (16) | 4 (1) | 3 (1) | 1 (1) |
The most frequent biochemical abnormality observed with Tasigna therapy was elevated lipase, which occurred at grade 3 or 4 in 13% of patients with CML-CP and in 18% of patients with CML-AP. Other biochemical abnormalities with Tasigna therapy are listed in Table 3.3,4
| Biochemical Parameters | CML-CP (n = 280) % | CML-AP (n = 119) % |
|---|---|---|
| Elevated lipase | 13 | 13 |
| Elevated SGOT (AST) | 0 | 0 |
| Elevated SGPT (ALT) | 3 | 2 |
| Elevated bilirubin (total) | 8 | 9 |
| SGOT, serum glutamate-oxaloacetate transaminase; SGPT, serum glutamate-pyruvate transaminase. | ||
In the phase II Tasigna® trial, the change from baseline in mean time-averaged QT interval corrected using Fridericia’s formula (QTcF) at steady state was 6 milliseconds and 8 milliseconds, respectively, in patients with imatinib-resistant or imatinib-intolerant CML-CP or CML-AP. QTcF exceeding 500 milliseconds was observed in <1% of patients. In healthy volunteers treated with Tasigna at doses similar to that administered to patients, no clinically relevant arrhythmias were observed and no episode of torsades de pointes (transient or sustained) was observed. In patients receiving Tasigna, pleural or pericardial effusions or complications of fluid retention occurred in <1% of patients.
Congestive heart failure was observed in <1% of patients. Gastrointestinal and central nervous system hemorrhage was reported in 3% and 1% of patients, respectively.
Myelosuppression levels induced by Tasigna are acceptable and manageable (Table 4).2 Complete blood counts should be performed every 2 weeks for the first 2 months of Tasigna therapy and then once a month thereafter.
| CML-CP at 400 mg twice daily | ANC <1.0 × 109/L and/or platelet counts <50 × 109/L |
|
| CML-AP at 400 mg twice daily | ANC <0.5 × 109/L and/or platelet counts <10 × 109/L |
|
| ANC, absolute neutrophil count. | ||
Nonhematologic adverse events usually can be managed by dose interruption. When the toxicity is resolved, therapy with Tasigna can be resumed at 400 mg once daily. Reescalation of the Tasigna dose to 400 mg twice daily should be considered if clinically appropriate.
References:
1. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosomepositive ALL. N Engl J Med. 2006;354:2542-2551.
2. Tasigna® (nilotinib) Summary of Product Characteristics. Basel, Switzerland: Novartis; 2007.
3. Kantarjian H, Giles F, Gattermann M, et al. Nilotinib formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007:110:3540-3546.
4. le Coutre P, Ottman OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or intolerant accelerated phase chronic myelogenous leukemia [published online ahead of print December 10, 2007]. Blood. doi:blood-2007-04-083196v2.
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