Presentation on theme: "Managing Side Effects of TKIs"— Presentation transcript:
1Managing Side Effects of TKIs Ming YAO M.D.Division of HematologyDepartment of Internal MedicineNational Taiwan University Hospital
2Goals of Managing Side Effects of TKIs in CML Optimize patient’s adherence to TKIMaximize safety and efficacy of TKIsCase of a non-compliant CML patientA 38-year-old man, took imatinib 400 mg per day from Jul, as initial treatment of CML, MMR achieved one year post Imatinib tx. He took imatinib irregularly since Jul-2009 due to GI upset. Loss of CCyR was noted then regained MMR after resuming imatinib.
3General Concepts in Managing Side Effects of TKIs Side effects vary from person to person.Individuals may tolerate one drug much better than another.Side effects generally increase as dose increases.Management of side effects essential to encourage compliance or adherence.
4General Principles in Managing Side Effects of TKIs Generally, grade 3/4 AEs are addressed via dose interruption followed by resumption of treatment at a reduced dose after resolution of toxicity;Dose reduction and temporary discontinuation of TKIs have been used effectively to treat events of neutropenia and thrombocytopenia in the clinical trial setting. The time frame of recovery of individual patients guides dosing decisions.Common mild or moderate AEs are addressed via speciﬁc treatments or supportive care.
5Common Adverse Reactions Reported in Newly Diagnosed CML Clinical Trials ofImatinib 400 mg Once Daily ( >10% of Patients)Probably Hematlogic AEs RelatedALL GRADES (%)GRADES 3/4 (%)(N 551)Fatigue391.8Headache370.5Dizziness190.9Cough200.2Nasopharyngitis31URI21Pyrexia18Sore throatInﬂuenza14Sinusitis11Hemorrhage29GI hemorrhage2CNS hemorrhage<1
6ImatinibManagement of Select Side Effects Associated with Imatinib Treatment of CML-CPHematologic● Grade 3/4 neutropenia (ANC<1,000/uL):Dose interruption until ANC > 1,500/UlGrowth factors can be used in combination with imatinibfor patients with resistant neutropenia.● Grade 3/4 thrombocytopenia (PLT<50K/uL):Keep Imatinib with PLT transfusion orDose interruption until PLT > 75K/uL
7Imatinib-induced Thrombocytopenia 46-year-old man, CML, ever treated w INF, PCyRStart imatinib 400mg /d in late CP3 months post imatinib, Gr 4 thrombocytopenia but achieved CCyR and MMRHe received regular PLT conc. transfusion and kept on imatinib 400mg /dResolution of thrombocytopenia at one year post imatinibHe remained MMR and continued imatinib for 10 years
8Common Adverse Reactions Reported in Newly Diagnosed CML Clinical Trials ofImatinib 400 mg Once Daily ( >10% of Patients)ALL GRADES (%)GRADES 3/4 (%)(N=551)Fluid retention622.5Superﬁcial edema601.5Other ﬂuid retention 71.3Weight increased162Nonhematologic—Speciﬁc interventions (Grade 2 or 3 severity)● Edema: Diuretics, supportive care● Fluid retention (pleural effusion, pericardial effusion, edema, and ascites):Weighed and monitored closely; salt restrictionDiuretics, supportive care, dose reduction, interruption, or discontinuation. Consider echocardiogram to check left ventricular ejection fraction.
10Common Adverse Reactions Reported in Newly Diagnosed CML Clinical Trials ofImatinib 400 mg Once Daily ( >10% of Patients)ALL GRADES (%)GRADES 3/4 (%)(N=551)Nausea501.3Diarrhea453.3Abdominal pain374.2Vomiting232Dyspepsia19Constipation110.7● GI upset:Take medication with a meal and large glass of watersplit dosing, eg 200mg bidtaking the imatinib prior to going to bed.antiemetic● Diarrhea: Supportive care
11Common Adverse Reactions Reported in Newly Diagnosed CML Clinical Trials ofImatinib 400 mg Once Daily ( >10% of Patients)ALL GRADES (%)GRADES 3/4 (%)(N=551)Muscle cramps492.2Musculoskeletal pain475.4Joint pain312.5Myalgia241.5Bone pain111.6● Muscle cramps and musculoskeletal pain :increased ﬂuid intakecalcium and potassium supplementstonic water (quinine content)NSAID
12Common Adverse Reactions Reported in Newly Diagnosed CML Clinical Trials ofImatinib 400 mg Once Daily ( >10% of Patients)ALL GRADES (%)GRADES 3/4 (%)(N=551)Skin rashes402.9Insomnia15Depression0.5● Rash:Most cases of skin toxicity are mild to moderate in severityand appear soon after treatment begins.Topical or systemic steroidsDose reduction, interruption, or discontinuation for severecase (rare)
13ImatinibIf any of the grade 2 or 3 toxicities are not responsive to symptomatic measures, treat as grade 4.Nonhematologic—Grade 4Hold drug until grade 1 or better, then consider resuming dose at 25%–33% dose reduction (not less than 300mg). Consider change to dasatinib, nilotinib, or clinical trial.Nonhematologic — Liver● Grade 2: Hold drug until grade <1. Resume at 25%–33% dose reduction (not less than 300 mg). Evaluate forother hepatotoxic drugs that may be contributing to toxicity, including acetaminophen.Consider change to DASA, NILO, or clinical trial.● Grade 3/4: Consider change to DASA, NILO, or clinical trial.
14Imatinib intolerance68-year-old woman CML-CP began imatinib (IM)400 mg/dQuickly developed gr. 1 periorbital edema, loose stools, and a slight elevation in bilirubin; reassurance !CCyR in 3M post IMAfter 6 Ms of therapy, she had a gr. 3 skin rash covering 30%-60% of her body. IM was suspended, treated with topical and oral steroids until the rash completely resolvedResume IM at 300 mg/d, rashes recurred, stop IM againAfter several attempts to restart IM, which rapidly resulted in a recurrent rash, the patient was considered to be intolerant to IM.Shift to to nilotinib, 400 mg twice daily. Six years after diagnosis, she is maintaining an MMR and is tolerating the nilotinib well.
15Dasatinib Common Side Effects (All Patients, All Grades) Fluid retention (edema) 37%Diarrhea 31%Headache 24%Nausea 22%Pleural effusion 22%Rash 22%Fatigue 21%Hemorrhage 21%Dyspnea 20%Musculoskeletal pain 14%Bleeding and thrombocytopenia (platelet dysfunction in vitro), platelets can drop very quickly, hemorrhage possible, monitor carefully.Fluid retention can be severe, including pleural or pericardial effusion. If develop dyspnea (shortness of breath), do chest x-ray. May occur months into therapy.Side effects less severe at 140 mg once a day dose vs. 70 mg twice a day.Possible prolongation of QTc interval
16Dasatinib-induced pleural effusions Dasatinib-induced pleural effusions are potentially serious and require prompt diagnosis and treatment.For patients with grade 2-3 pleural effusion, dasatinib therapy should be discontinued; a short course of diuretics or use of an oral steroid, such as prednisone 20 mg/day three times daily, should be administered.Patients should be educated to report symptoms of chest pain, dyspnea, and dry cough as soon as they occur.A lower dasatinib dose should be used when treatment is resumed.Comorbid conditions (autoimmune disease, hypertension, cardiovascular disease) may play a role in the development of pleural effusions. Patients with these conditions, therefore, may need closer monitoring.
17Dasatinib-induced pleural effusions &Thrombocytopenia 42-year-old man, CML APCHR but only PCyR after IM 600mg/d for one yearShift to dasatinib (DA)140 mg/dGr 4 thrombocytopenia w Gr 3 pleural effusionHold DA then he was back to Gr 1 AEsResume DA at 100 mg/d, CCyR achieved (6M post DA)Gr 4 AEs again, PLT transfusion w diureticsLoss of CCyR (18M post DA)Allogeneic HSCT w unrelated donorRemained CMR 7 years post-allo-HSCT
18Nilotinib Common Side Effects (All Patients, All Grades) Rash 33%Pruritis (itching) 29%Nausea 31%Headache 31%Fatigue 28%Diarrhea 22%Constipation 21%Vomiting 21%Arthralgias 18%Cough 17%Special considerations in using nilotinib are related to QT interval prolongation.Patients with hypokalemia, hypomagnesemia, or long QT syndrome should be avoided or employed with caution.Nilotinib should not be used with strong CYP3A4 inhibitors.ECG should be conducted before starting nilotinib, 7 days after initiation of therapy, with any dose changes, and regularly during treatment.
19Nilotinib: Hepatotoxicity Use with caution in patients with known hepatic impairment.Liver enzyme and bilirubin elevations are often transient, resolve with short treatment break.Elevated lipase and amylase may occur.Pancreatitis has also occurred.● Elevated serum levels of lipase, amylase, bilirubin, and/or hepatic transaminases (grade >3 ) serum levels return to grade < 1. Resume nilotinib at 400 mg once daily.
20Nilotinib induced Hyperbilirubinemia 42-year-old man, CML CPNilotinib 300 mg bid as 1st line treatmentCCyR with CMR achieved 3M post NIGr 3 Hyperbilirubinemia & Gr 2 ALT elevationAdjust NI to 400 mg/dGr 2 Hyperbilirubinemia without malaise, so hold NIresumed NI at 400 mg/d when AE returned to Gr 1Resolution of Hyperbilirubinemia 6M after resuming NINow on NI 400 mg/d, CML remains CMR
21SummaryAll 3 TKI’s well-tolerated compared to traditional chemotherapy and interferon.With aggressive adverse effects management, most patients have good quality of life.Adverse effects generally decrease over time.Management of side effects is essential to encourage compliance or adherence.