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Update on the Side Effects of Tyrosine Kinase Inhibitors

Update on the Side Effects of Tyrosine Kinase Inhibitors. Dr Jenny Byrne Nottingham University Hospitals Trust. IRIS Study: Most Frequently Reported AEs. Imatinib is a Safe Drug. Only Serious Adverse Events (SAEs) were collected after 2005

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Update on the Side Effects of Tyrosine Kinase Inhibitors

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  1. Update on the Side Effects of Tyrosine Kinase Inhibitors Dr Jenny Byrne Nottingham University Hospitals Trust

  2. IRIS Study: Most Frequently Reported AEs Imatinib is a Safe Drug.... • Only Serious Adverse Events (SAEs) were collected after 2005 • Grade 3/4 adverse events decreased in incidence after years 1-2 IRIS 8 year update

  3. IRIS SAEs in Year 8 • No unique, previously unreported AEs attributed to imatinib observed over the past 24 months • Since year 5 only 9 SAEs with suspected relationship to imatinib have been reported (2%): • Congestive Heart Failure (n=3): all of the patients had pre-existing cardiac disease prior to study entry • Second malignancy (n=3)* • Myositis (n=1); elevated CK (n=1); multiple sclerosis (n=1) • Pancreatitis (n=1); vomiting (n=1) • Dermatitis (n=1) *With >400,000 patient years of estimated imatinib exposure, the analysis of clinical safety data from clinical trials and spontaneous reports did not provide evidence for an increased incidence of malignancies for patients treated with imatinib compared to that of the general population IRIS 8 year update

  4. But many patients have low level side effects... Which can affect their quality of life…

  5. ENRICH STUDY: Changes in Toxicity and QoL in Patients Switched from Imatinib to Nilotinib 45 / 52 patients had a total of 182 low-grade (grade 1/2), imatinib-related, nonhematologic AEs at baseline. Of the 182 AEs, 130 were grade 1 and 52 were grade 2. 71.4% ASH 2012

  6. ENRICH: Change in Severity of Most Frequently Reported Imatinib-Related Nonhematologic AEs* Cortes J, et al. Blood. 2012;120(21):[abstract 3782].

  7. ENRICH: Change from Baseline in QoL bCycle* Cortes J, et al. Blood. 2012;120(21):[abstract 3782].

  8. Nilotinib is Generally Better Tolerated…

  9. But what about Long Term Toxicity...?ENESTnd: 3-year adverse event data (any grade) Symptomatic QT prolongation Pancreatitis Hepatotoxicity Fluid retention Effusions Rash Nilotinib 300 mg BID (n=279) Significant bleeding Imatinib 400 mg BID (n=280) CNS haemorrhage Adverse event onset in third year of therapy GI haemorrhage Ischaemic heart disease PAOD* Patients (%) 0 10 20 30 40 50 60 70 80 90 100 *No patient discontinued the study as a result of PAOD. 6/7 patients (85%) with PAOD had pre-existing risk factors at baseline. CNS: Central nervous system; GI: Gastrointestinal; PAOD: Peripheral arterial occlusive disease. Larson RA et al.Leukemia 2012 [Epub ahead of print].

  10. ENESTnd:3-year grade 3/4 laboratory abnormalities AST increased ALT increased Bilirubin (total) increased Lipase (blood) increased Nilotinib 300 mg BID (n=279) Glucose increased Imatinib 400 mg BID (n=280) Adverse event onset in third year of therapy Haemoglobin Absolute neutrophils (seg. + bands) Platelet count (direct) 60 70 80 90 100 0 10 20 30 40 50 Patients (%) ALT: Alanine aminotransferase; AST: Aminotransferase; Seg.: segmented. Larson RA et al.Leukemia 2012 [Epub ahead of print].

  11. ENESTnd: arterial Events by 4 Years • Between years 3 and 4, five new patients had an IHD event (2 in the nilotinib 300 mg BID arm and 3 in the nilotinib 400 mg BID arm), and 2 new patients had a PAOD event (both in the nilotinib 400 mg BID arm) • 1 patient in the nilotinib 400 mg BID arm with previously reported PAOD had a newly reported drug-related SAE (arterial stenosis limb) leading to treatment discontinuation Mechanism not clear - ? Related to high glucose levels Worrying – need more data, especially as now approved 1st line Data cutoff: 27Jul 2012.

  12. Novartis Communication 25 Feb 2012: Atherosclerotic Related Events ‘Clinicians should vigorously manage cardiovascular risk factors and AREs according to standard international guidelines regarding treatment of hypertension, hyperlipidemia, and diabetes as well as smoking cessation’

  13. Is Dasatinib any better...?

  14. DASISION:2-year adverse event data • Grade 3/4 biochemical abnormalities occurred in ≤3% of patients and with similar frequency in treatment arms except hypophosphataemia (dasatinib: 7%; imatinib 25%) • Pulmonary arterial hypertension was diagnosed in 3 patients but did not lead to treatment discontinuation Fluid retention Superficial oedema Pleural effusion Myalgia Nausea Any grade Diarrhoea Dasatinib 100 mg QD (n=258) Vomiting Rash Imatinib 400 mg QD (n=258) Headache Fatigue Neutropenia Grade 3/4 Thrombocytopenia Anaemia 0 10 20 30 40 50 60 70 80 90 100 Patients (%) Kantarjian HM et al. Blood 2012; 119(5): 1123–1129.

  15. Dasatinib and Pleural Effusions • Occurs in approx. 20% of patients but only 5% Grade 3-4 • Thought to be caused by more potent inhibition of src • Pleural fluid shows marked lymphocytic infiltrate • Associated with peripheral blood lymphocytosis • More common with higher / split doses of dasatinib • Median time from start of drug to effusion is 5 weeks • Most occur within 12 months May resolve with steroid / diuretic combination and temporary stopping of dasatinib Others require drainage and permanent discontinuation

  16. Pulmonary Arterial Hypertension • Circulation 2012, Montani et al • French study of 9 cases between 2008-2010 • Estimated incidence 0.45% of patients exposed to dasatinib • Src inhibition thought to be implicated in pathogenesis • Late complication occurring 8-48 months after starting dasatinib • More common in females • Median age of patients 51 years • 6/9 patients also had concomitant pleural effusions but PAH persisted even after effusions resolved • ? Reversible on stopping dasatinib

  17. Evolution of clinical, functional, and hemodynamic parameters after dasatinibdiscontinuation Most patients improved after stopping dasatinib but none returned completely to normal

  18. How about the ‘new’ TKIs...? Bosulif (bosutinib) and Iclusig (ponatinib) both now licensed for 2nd line in the USA and are coming...

  19. Can we Predict their Side Effects..? Target kinases for the 5 Tyrosine Kinase Inhibitors 1. Manley PW, et al. Proc Am Assoc Cancer Res 2007;48:772. 2. Weisberg E, et al. Cancer Cell 2005;7:1129. 3. Remsing Rix LL, et al. Leukemia 2009;23:477. 4. O’Hare T. et al (2009) Cancer Cell. 16: 401-412

  20. Bosutinib Study 200 (2nd Line): Treatment-emergent Adverse Events Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.

  21. Bosutinib Study 200 (2nd Line): Gastrointestinal Adverse Events Start with low dose and build up gradually. Warn patients & give loperamide! Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.

  22. Bosutinib Study 200 (2nd Line): Other Grade 3–4 Laboratory Abnormalities ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio. Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.

  23. Study 200 (2nd Line): Grade 3–4 Hematologic Laboratory Abnormalities Generally less haematological toxicity than other 2nd line agents – may be useful for patients who cannot tolerate other TKIs due to low counts Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.

  24. Bosutinib Study 200 (2nd Line): Other Adverse Events of Interest Pleural effusion Observed in 10 (3%) patients (all grades) Grade 3–4 pleural effusion reported in 1 (<1%) patient Effects on QTcF interval On treatment, 25 (9%) patients had grade 1–2 prolongation and 1 (<1%) patient had grade 3–4 prolongation At treatment completion, 2 (2%) patients had grade 1–2 prolongation and none had grade 3–4 prolongation Brümmendorf et al. Oral presentation, EHA 2010; abstr 1136.

  25. Ponatinib PACE Study: Treatment Emergent AEs *Combines the terms erythematous, macular and papular rash 14

  26. Ponatinib Phase 2 PACE Study:Treatment Emergent Serious AEs • Serious adverse events of arterial thromboembolism, including arterial stenosis, were observed in patients with cardiovascular risk factors 15

  27. Iclusig Given FDA Approval but with Black Box Warning (Dec 2012) • Important for haematologists to be aware of these toxicities • Ponatinib forms part of the new SPIRIT 3 trial for newly diagnosed patients

  28. Summary • No drug is side effect free! • Side effect profile depends on the degree of inhibition of the kinases • Side effects rarely recur on switching to different TKI • Long term toxicity may be emerging but more data needed • Choice of drug needs careful consideration for each patient • Refractory patients: main consideration must be to achieve disease control • Intolerant patients: ideally choose drug depending on other comorbidities / risk factors (if funding allows) • Diabetes / cardiovascular risk factors: ? avoid nilotinib / ponatinib • Pulmonary issues: ? Avoid dasatinib • Low blood counts: consider bosutinib • May need to brush up on cardiology skills!

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