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Tyrosine Kinase Inhibitor (TKI) Therapeutic Flow Chart for the Treatment of CML

A. Flow Chart

•Imatinib
1sta

•Dasatinib
2ndb •Nilotinib

•Nilotinib
3rdb •Dasatinib

•Bosutinib

•Ponatinib

B. Rationale and Supporting Evidence
a
First-line Therapy
• Imatinib, the first approved TKI for CML, has been shown to provide durable responses in an 8-year follow up of the IRIS study with OS 93% [1]
• Most long-term safety data of all agents (no new safety signals noted)
• Dasatinib, a second-generation TKI, is supported by a 3-year follow up of DASISION with OS 93%; MMR 46% at 12 months [2]
• Nilotinib, a second-generation TKI, is supported by a 3-year follow up of ENESTnd with OS 94%; MMR 44% at 12 months [3]
• Impact of early response (MMR at 12 months) on survival remains to be determined
• It is theorized that high-risk patients may benefit from a second-generation TKI as first-line therapy, but there is no supporting data and the optimal treatment for these patients
remains to be determined
• Unless a contraindication exists, imatinib should be the preferred first-line therapy
b
Second-line and Subsequent Therapies
• Guidelines (ELN, NCCN) recommend that choice of TKI take the following into consideration: side effect profile, kinase mutation profile, drug interactions, adherence issues, pre-existing
comorbidities [4, 5, 6]
• Second-line TKI recommended for patients on imatinib who do not meet treatment milestones at 12 months (BCR-ABL1 transcripts > 10% (IS), lack of at least partial cytogenetic response
(PCyR) of bone marrow cytogenetics).
th
• Evidence for use of bosutinib as a 4 TKI is supported by a small subset (n=3) of patients within a phase 2 trial (Khoury, 2012) and a retrospective evaluation (n=30) of patients in Spain (Garcia-
Gutierrez, 2015)
• Refer to Tyrosine Kinase Inhibitor Comparison Chart for CML for notable differences among agents

October 2015 Page 1

Disease progression to accelerated or blast phase. Absence of MMR in the presence of a CCyR is not considered a treatment failure.  Recommendations for response monitoring are found in Table 1.  Rising levels of BCR-ABL1 transcript (1-log increase) without a MMR.  At 12 months and beyond from the initiation of TKI therapy. If there is no CCyR or MMR.  Every 3 months after initiation of treatment. every 3 months for 2 years and every 3-6 months thereafter.  1-log increase in BCR-ABL1 transcript levels and loss of MMR. QPCR should be repeated in 1-3 months. Table 1. Monitoring  Refer to TKI Comparison Chart for baseline and follow-up toxicity monitoring recommendations for each agent. If collection of bone marrow is not feasible. if QPCR (IS) is not available. October 2015 Page 2 . bone marrow cytogenetics should be repeated at 3 months after change of therapy to alternate TKI to document CCyR.  For patients with less than CCyR at 12 months and beyond.  Any sign of loss of response (defined as hematologic or cytogenetic relapse). BCR-ABL1 kinase domain Chronic phase mutation analysis  Inadequate initial response to TKI therapy (BCR-ABL1 transcripts > 10% (IS) or lack of PCyR at 3 and 6 months or less than a CCyR or BCR-ABL1 transcripts > 1% (IS) at 12 months). Recommendations for Monitoring Response to TKI Therapy and Mutational Analysis Test Recommendations Bone Marrow Cytogenetics  At diagnosis to establish disease phase.C.  If there is a rising level of BCR-ABL1 transcript (1-log increase) with a MMR. After CCyR has been achieved. QPCR (IS)  At diagnosis. FISH on peripheral blood specimen using dual probes for BCR and ABL1 genes is an acceptable method of confirming diagnosis of CML  At 3 months and 6 months after initiation of TKI therapy.

AP or BP therapy ALL IFN-α therapy with imatinib R/I 2. newly diagnosed Ph+ CML 1. do not Less than 4% excreted No renal excretion If CrCl 30-50 ml/min. Ph+ CML in BC. AP. film-coated tabs use 400 mg tab for large doses to ↓ iron exposure Boxed warnings None None QT prolongation. 70. HES and/or CEL 7. no studies done dose 400 mg once daily. max dose 400 mg Formulations 100. 500 mg tablets 15. 100. use Lower dose 200 mg once daily 30 mg once daily impairment severe hepatic impairment with caution Dosing in renal If CrCl 40-59 ml/min. CP. 20. Ph+ CML CP in peds Dosing (oral) CP 400 mg once daily 100 mg once daily 300 mg BID 500 mg once daily w/food 45 mg once daily AP 600 mg once daily to 140 mg once daily 400 mg BID 45 mg once daily BP 400 mg BID 140 mg once daily 45 mg once daily Dosing in hepatic 25% dose reduction in Adjustment not needed. no impairment exceed 600 mg daily. Tyrosine Kinase Inhibitor Comparison Chart for CML Generic name Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Trade name Gleevec Sprycel Tasigna Bosulif Iclusig FDA approved 1. GIST 9. Ph+ ALL with R/I to prior in CP for whom no other TKI is 4. 80. 200mg hard caps 100. 140 mg 150. long QT syndrome October 2015 Page 3 . AP after 2. renally. D. starting with 50% ↓. AP or BP or T315I Ph+ 2. Ph+ ALL 3. CML CP and AP in adults 1. newly diagnosed Ph+ CML 1. DFSP 8. heart sudden death failure. 50. newly diagnosed Ph+ CML 2. Treatment of T315I+ CML indications in CP in CP R/I to imatinib-based with R/I to prior therapy in CP. None Vascular occlusion. 400 mg scored tabs. Ph+ CML in CP. AP or BP 1. hepatotoxicity Contraindications None None Hypokalemia. then ↑ as dose 300 mg once daily tolerated. starting Renal excretion ~5%. start If CrCl < 30 ml/min. Hypersensitivity None hypomagnesemia. 45 mg tablets Coating contains ferric oxide. Ph+ CML in CP. studies done If CrCl 20-39 ml/min. ASM 6. MDS/MPD therapy indicated 5. BP-CML or Ph+ALL 3.

Constipation (24-47%). Hemorrhage (11%) Neutropenia (31%). Pruritus (32%). Nausea (46%). Thrombocytopenia (41%). Vomiting (54%). Diarrhea (45%). Fluid retention (34%). Rash (11%) (10%). Rash (40%) Diarrhea (18%). Headache (33%). Vomiting (39%). Rash (36%). Fatigue (19%). Headache (12%). Neutropenia (22%). Headache (25-39%). Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Precautions/ Fluid retention Myelosuppression Myelosuppression GI toxicity Arterial/Venous occlusion a warnings Myelosuppression Bleeding-related events QT prolongation Myelosuppression Heart failure CHF/LV dysfunction Fluid retention ↑ serum lipase Hepatotoxicity Hepatotoxicity Hepatotoxicity QT prolongation ↑ LFT’s Fluid Retention HTN b Bleeding-related events CHF/MI/LV dysfunction Electrolyte abnormality Pregnancy category D Pancreatitis Pregnancy category D Pregnancy category D Pregnancy category D Neuropathy GI irritation Lactose-containing Lactose-containing Ocular toxicity Hypothyroidism Pulmonary Arterial Total gastrectomy Hemorrhage Hypertension (PAH) Hypothyroidism Fluid retention Hypothyroidism Cardiac arrhythmias Myelosuppression Tumor Lysis Syndrome Impaired wound healing Pregnancy category D Adverse events Newly diagnosed (> 10%): Newly diagnosed (> 10%): Newly diagnosed (> 10%): Imatinib R/I (>20%): TKI R/I (> 20%): Fluid retention (62%). Constipation (15%). H2A. Anemia (4%) Pyrexia (26%). acetaminophen antacids. H2A. QT prolongators. Headache (35%). Muscle cramps (49%). Thrombocytopenia (19%). Other CML trials (> 10%): Imatinib R/I (> 20%): Imatinib R/I (>10%): Pyrexia (23-32%) Fluid retention (72%). Thrombocytopenia (30%). Anemia (11%). CYP3A4 inhib/inducer. Diarrhea (43%) Musculoskeletal pain (19%). Rash (34-54%). Nausea (19%). Nausea (71%). Diarrhea (82%). CYP3A4 CYP3A or P-gp inhibitors CYP3A4 inhibitors. CYP3A inducers CYP3A4 inducers PPIs and P-gp PPIs P-gp substrates October 2015 Page 4 . Anemia (11%) Drug-drug CYP3A4 inhib/inducers. Fluid retention (23%). (12%). PPIs inhibitors. Fatigue (32%). Abdominal pain (34-49%). Myelosuppression (36%) Rash (36%). Fatigue (24%) Nausea (22-32%). Fatigue (31-39%). Abdominal pain (37%). Pruritus (19%). Musculoskeletal pain (12%). Nausea (37%). Neutropenia Rash (35%). Arthralgia (13-26%). Muscle cramps (28%). HTN (53-71%). Dry skin (24-39%). Headache (28%). Rash (17%). interactions Warfarin. antacids. Nausea (49%). Thrombocytopenia Anemia (27%). Diarrhea (27%).

LFT’s q month (or ACI). Fasting lipid panel. CBC q 2 weeks x 2 mos. the monitoring Fasting lipid panel ACI. Ankle-brachial index. therapy should BP check ACI. Take with or without food. CBC. LFT’s. including BP. changes. Ankle-brachial index. BP check ACI BP check ACI BP check ACI BP check s/sx of CHF/LV dysfxn. Fasting lipid panel. including BP. use Echocardiogram ACI with low Ankle-brachial index. Mg). Fasting glucose ACI. Echocardiogram ACI. BP check BP check ACI. CV monitoring at 1 month CV monitoring at 1 month CV monitoring at 1 month CV monitoring at 1 month toxicity Biweekly x 2nd month then Clinical CV assessment. Serum lipase q 2 weeks x 2 s/sx bleeding Serum lipase periodically. fasting glucose. clinical threshold for patient with ECG ACI and with any dose ECG ACI. monitoring periodically (q 2-3 mos). cardiopulmonary sx. serum lipase. LFTs LFT’s. then monthly (or LFTs periodically ACI). Clinical CV assessment. Clinical CV assessment ACI. ECG ACI. GI issues (D/N/V) CBC. Ankle-brachial index ACI ECG ACI do not hold ECG ACI. Recs provided LFT’s q month (or ACI). Electrolytes periodically. Clinical CV assessment. 7 days after Echocardiogram ACI. BP check continue during Fasting glucose ACI. CBC. fasting lipid panel ACI fasting lipid panel. CBC. Pregnancy test (if applicable) fasting glucose ACI. Clinical CV assessment. Fasting lipid panel ACI. then s/sx bleeding. monthly (and ACI). Fasting glucose ACI. Echocardiogram ACI. monthly. Clinical CV assessment. while awaiting Serum TSH on day 1 of each CBC weekly x 1 month. CV monitoring at 3-6 CV monitoring at 3-6 CV monitoring at 3-6 CV monitoring at 3-6 d d d d should be used Serum TSH on day 1 of each months months months months f as a guide. Mg). uric acid. cardiopulmonary sx. threshold for patient with start & with dose changes. Ankle-brachial index ACI Electrolytes (esp K. monitoring TFT’s (thyroidectomy pts). Echocardiogram ACI prescriptions Ankle-brachial index ACI GI toxicity (D/N/V) s/sx of neuropathy. Take on empty stomach. Ankle-brachial index. Fasting glucose. eye exam. Electrolytes periodically. serum lipase. f monitoring Serum TSH on day 1 of each cycle . then LFT’s q month x 3 (and ACI). Ankle-brachial index ACI. Echocardiogram ACI. Clinical CV assessment. Fasting glucose. then f cycle . Fasting lipid panel. CBC. Fasting lipid panel ACI. including BP. including BP. months. ECG ACI. Eye exam ACI October 2015 Page 5 . Echocardiogram ACI. process. Clinical CV assessment. Fasting glucose ACI. CBC q 2 weeks x 3 mos. Electrolytes (esp K. Clinical CV assessment. judgement. Clinical CV assessment. Baseline CV monitoring Baseline CV monitoring Baseline CV monitoring Baseline CV monitoring toxicity LFT’s. ECG. Clinical CV assessment. Echocardiogram ACI with low ECG baseline. Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Drug-food Take with food and water. Pregnancy test (if applicable) Pregnancy test (if applicable) Pregnancy test (if applicable) Pregnancy test (if applicable) d d d d Follow-up CBC weekly x 1 month. Take with or without food interactions Avoid grapefruit products Avoid grapefruit products Avoid grapefruit products Avoid grapefruit products REMS None Medication guide Medication guide None Medication guide d d d d Baseline CBC. cycle Clinical CV assessment. Take with food. monthly (or ACI).

TKI-Associated CV Toxicity in CML.4718 BIG4 f pricing as of 10/8/2015. CEL=chronic eosinophilic leukemia. mostly associated b c with thrombocytopenia. CML PAH. et al. 12. Khoury HJ. gr 3.8% in CML trials. et al. ACI = as clinically indicated. et al. Patient at significant risk of Patient at baseline risk of Patient harbors T315I that may direct TKI peripheral edema elevated bilirubin. PAH = pulmonary arterial hypertension. Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Sensitivity to BCR. Hughes T.1200/JCO. Blood 2012. HES=hypereosinophilic syndrome.9% in GIST trials. MPD=myeloproliferative diseases. BC=blast crisis. although some events are independent of platelet count. Deininger M. et al.2015. Fallahi P. a DFSP=dermatofibrosarcoma protuberans. JClin Oncol 2009. ASM=aggressive systemic mastocytosis. Thyroid Dysfunctions Induced by TKIs. pleural/pericardial effusions. ALL=acute lymphoblastic leukemia. Expert Opin Drug Saf 2014. Blood d e 2009. et al. NEngl J Med 2012. CP=chronic phase.62. October 2015 Page 6 . Moslehi JJ. 33: DOI: 10. or a high bleed risk Patient not a candidate for involving CNS any other TKI ECOG PS of study 0-2 0-2 0-2 0-1 0-2 participants Monthly cost 400 mg PO daily 100 mg PO daily 300 mg PO BID 500 mg PO daily 45 mg PO daily e estimates $140/day $204/day $209/day $184/day $240/day Key: CML=chronic myelogenous leukemia. GIST=gastrointestinal stromal tumor. preference uncontrolled DM. Y253H V299L F317L T315I c ABL1 mutations E255K/V F317L Y253H F359C/V F359C/I/V Handling Avoid exposure to Avoid exposure to ?? Avoid exposure to Avoid exposure to crushed/broken tablets crushed/broken tablets crushed/broken tablets crushed/broken tablets Clinical situations Patient with significant Patient with pancreatitis. Muller MC. Cortes JE. IFN=interferon. MDS=myelodysplastic syndrome. J Clin Oncol 2015. AP=accelerated phase. 4 bleeds: 1. Ph+=Philadelphia chromosome positive. QT-prolongation mutation. R/I = resistance/intolerance. 13: 723.

Early Response with Dasatinib or Imatinib in Chronic Myeloid Leukemia: 3-year follow up from a Randomized Phase 3 Trial (DASISION). 108: 28-37. Inc. 17. 2015 May.1002/ajh. et al. Massachusetts. Bosutinib appears to be safe with low cross intolerance.D. Hughes T. Radich JP. Nilotinib (Tysigna) Prescribing Information. Imatinib in Patients with Newly Diagnosed Philadelphia chromosome-positive Chronic Myeloid Leukemia in Chronic Phase: ENESTnd 3-year follow up.90(5):429-33. Ann Hematol 2015. et al. A Review of the European LeukemiaNet Recommendations for the Management of CML. 26: 2197. Kantarjian HM. August 2015. 10.23973. January 2015. Monitoring CML Patients Responding to Treatment with Tyrosine Kinase Inhibitors: Review and Recommendations for Harmonizing Current Methodology for Detecting BCR-ABL Transcripts and Kinase Domain Mutations and for Expressing Results. 369: 1783. et al. Jabbour E. O’Brien SG. Baccarani M. Saglio G. New York. N Engl J Med 2013. International Randomized Study of Interferon vs. et al. Bristol-Myers Squibb. 2. Am J Hematol. et al. J Natl Compr Canc Netw. Am J Hematol 2014. 27: 4204. Saglio G. Pfizer Labs. 122: 872. Martinez-Trillo A. 7. New Jersey. Bosutinib (Bosulif) Prescribing Information. Cambridge. Clark RE. Akhtari M. Kim DW. et al. Kim DW. Dasatinib Treatment of Chronic-Phase Chronic Myeloid Leukemia: Analysis of Responses According to Preexisting BCR-ABL mutations. Results of the Spanish Compassionate Use Program. Novartis Pharmaceuticals Corporation. Chronic Myeloid Leukemia: 2014 Update on Diagnosis. Larson RA. Abboud CN. Blood 2013. 8. Imatinib (Gleevec) Prescribing Information. East Hanover. Impact of Baseline BCR-ABL Mutations on Response to Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase. 6. New Jersey. 4. Princeton. J Clin Oncol 2009. Kantarjian HM. 12. Chronic Myelogenous Leukemia. Garcia-Gutierrez V. ARIAD Pharmaceuticals. et al. Blood 2006. 119: 3403. Khoury RJ. doi: 10. 123: 494. et al. Ponatinib (Iclusig) Prescribing Information. Baccarani M. th 18. 89: 548. Hughes T. Branford S. 94: S141. Cortes JE. October 2015 Page 7 . Leukemia 2012. Rosti G. 15. New York. Hochhaus A. Castagnetti F. Jabbour E. Muller MC. Rosti G. Novartis Pharmaceuticals Corporation. 2014. Nilotinib vs. Blood 2009. 16. Blood 2014. Cortes JE. Deininger MW. 114: Abstract 1126. 5. version 1. Deininger M. Blood 2009. Gugliotta G. Epub 2015 Mar 30. Monitoring and Management. 13. et al. Bosutinib is Active in Chronic Phase Chronic Myeloid Leukemia after Imatinib and Dasatinib and/or Nilotinib Therapy Failure. 14. 11. Deininger M. Cortes JE. European LeukemiaNet Recommendations for the Management of Chronic Myeloid Leukemia. Kantarjian H. Dasatinib (Sprycel) Prescribing Information. Blood 2012. East Hanover. in Patients Treated in 4 Line.2015. STI571 (IRIS) 8-year follow up: Sustained Survival and Low Risk for Progression of Events in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib. September 2014. 9. January 2015. Pinilla-Ibarz J. 3. References 1. New Jersey. O'Brien S. 114: 4944. et al. 12:1590. November 2014. Hochhaus A. A Phase 2 of Ponatinib in Philadelphia Chromosome-Positive Leukemias. Guilhot F. Maestro B. et al.