Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Chronic Myeloid Leukemia (CML) and Targeted Therapy CML – Proliferative disorder of hematopoietic stem cells – Well-characterized clinical course Philadelphia (Ph) chromosome – Unique chromosomal abnormality Bcr-Abl tyrosine kinase – A single molecular abnormality that causes transformation of a hematopoietic progenitor into a malignant clone Incidence of Hematologic Malignancies Type of Leukemia Overall CML CLL AML ALL Incidence per 100,000* 6–10 1–2 2–3 2–3 1–2 *1990, Western hemisphere. CLL = chronic lymphoid leukemia; AML = acute myeloid leukemia; ALL = acute lymphoid leukemia. Black RJ et al. Eur J Cancer. 1997;33:1075-1107. Epidemiology of CML Median age range at presentation: 45 to 55 years Incidence increases with age – 12%–30% of patients are >60 years old Male-to-female ratio–1.3:1 At presentation – 50% diagnosed by routine laboratory tests – 85% diagnosed during chronic phase Clinical Presentation of CML Common Symptoms – Fatigue – Weight loss/anorexia – Abdominal fullness Common Signs – Palpable splenomegaly Common Laboratory Findings – Abnormal differential – Leukocytosis – Thrombocytosis – Anemia – Basophilia CML: Peripheral Blood Smear Courtesy of John K. Choi, MD, PhD, University of Pennsylvania. Clinical Course: Phases of CML Advanced phases Chronic phase Median 5–6 years stabilization Accelerated phase Blast crisis Median duration 6–9 months Median survival 3–6 months Typical Laboratory Parameters by Phase of CML Phase of CML Parameter Chronic WBC count 20 x 109/L Blasts Accelerated Blast Crisis — — 1%–15% 15% 30% 20% — or Basophils Platelets or normal Bone marrow Myeloid hyperplasia Cytogenetics Ph+ Bcr-Abl + WBC = white blood cell; Ph+ = Ph chromosome–positive. + + Definition of Accelerated Phase M.D. Anderson Cancer Center (Kantarjian 1988) PB blasts 15% PB blasts + promyelocytes 30% PB basophils 20% Platelet count 100 x 109/L unrelated to therapy Sokal (Sokal 1988) IBMTR (Speck 1984) PB or BM blasts 5% – PB basophils 20% Thrombopenia unrelated to therapy PB or BM blasts 10% PB or BM blasts+promyelocytes 20% Cytogenetic karyotypic evolution Thrombopenia unresponsive to BU or HU therapy Cytogenetic karyotypic evolution Persistent thrombocytosis Myelofibrosis Anemia unresponsive to BU or HU therapy Progressive splenomegaly Rapid doubling time of leukocytes <5d Platelet 1000 x 109/L despite adequate therapy Marrow collagen fibrosis Anemia unrelated to therapy Progressive splenomegaly Leukocyte doubling time <5d PB basophils + eosinophils 20% Frequent Pelger-Huët–like neutrophils; nucleated erythrocytes; megakaryocyte nuclear fragments Leukocyte count difficult to control with BU or HU therapy Fever not otherwise explained Development of chloromas PB = peripheral blood; BM = bone marrow; HU = hydroxyurea; BU = busulfan. Kantarjian HM et al. Cancer. 1988;61:1441-1446. Sokal JE et al. Semin Hematol. 1988;25:49-61. Speck B et al. Semin Hematol. 1984;21:48-52. Therapies for Advanced Stages of CML Usual Therapy Accelerated phase Blast crisis IFN- = interferon-alpha. Various single-agent or combination chemotherapy, IFN- Acute leukemia type multiagent chemotherapy Hematologic Response (complete) <50% Cytogenetic Response Survival anecdotal <18 months 20%–40% (5%–30%) anecdotal 3–6 months Ph Chromosome Cytogenetic Abnormality of CML: The Ph Chromosome 1 6 2 7 3 8 13 14 19 20 4 9 15 21 5 10 16 22 11 17 x 12 18 Y Prevalence of the Ph Chromosome in Hematologic Malignancies Leukemia % of Ph+ Patients CML 95 ALL (Adult) 15–30 ALL (Pediatric) 5 AML 2 Faderl S et al. Oncology. 1999;13:169-180. The Ph Chromosome: t(9;22) Translocation 9 9 q+ 22 Ph ( or 22q-) bcr bcr-abl abl FUSION PROTEIN WITH TYROSINE KINASE ACTIVITY bcr-abl Gene and Fusion Protein Tyrosine Kinases Chromosome 22 Chromosome 9 c-bcr 1 2-11 2-11 Exons Introns CML Breakpoints ALL Breakpoints 2-11 p210Bcr-Abl p185Bcr-Abl c-abl p210Bcr-Abl Fusion Protein Tyrosine Kinase Extracellular space Cytoplasm Y177 BAP-1 SH3 SH2 SH1 GRB2 CBL SHC CRKL Faderl S et al. N Engl J Med. 1999;341:164-172. Molecular Methods for Detecting bcr-abl at the Ph Chromosome Fluorescence in situ hybridization (FISH) Interphase Courtesy of Charles Sawyers, UCLA. Metaphase Therapeutic Options Goals of Therapy for CML: Response Criteria Hematologic Response Cytogenetic Response – Complete: Normal peripheral blood count WBC <10 x 109/L Platelets <450 x 109/L No immature cells – Major: Complete: Partial: – Minor: Disappearance of splenomegaly Normal physical examination 0% Ph+ cells 1%–35% Ph+ cells 36%–95% Ph+ cells Therapeutic Options for CML Allogeneic stem cell transplantation (SCT) IFN-–based treatments Chemotherapy with hydroxyurea, busulfan Imatinib mesylate (formerly STI571) 100% Chronic Myelogenous Leukemia Survival by Disease Stage 90% S u r v i v a l 100% 90% 80% 80% P=0.0001 70% 60% 70% 60% First Chronic Phase (n=1903) 50% 50% 40% 40% Accelerated and 2nd CP (n=744) 30% 30% 20% 20% Blast Phase (n=159) 10% 10% 0% 0% 0 1 2 3 Years After Transplant June 2001, based on transplants 1987 - Feb 2001 4 5 S u r v i v a l PROBABILITY OF SURVIVAL AFTER ALLOGENEIC TRANSPLANTS FOR CML IN CHRONIC PHASE BY DONOR TYPE AND DISEASE DURATION, 1994-1999 100 PROBABILITY, % 80 HLA-identical sibling, <1y (N = 2,876) HLA-identical sibling, 1y (N = 1,391) 60 Unrelated, <1y (N = 613) 40 Unrelated, 1y (N = 936) 20 P = 0.0001 0 0 1 2 3 4 5 6 YEARS SUM02_3.ppt Advances in SCT Donor lymphocyte infusion (DLI) after SCT – Used to prevent or treat relapse after SCT – Can induce a graft-versus-leukemia effect – High rate of graft-versus-host disease (GVHD) Non-myeloablative SCT – Low-dose, less toxic preparative regimens – Provides immunosuppression to allow donor cells to engraft, while graft-versus-leukemia effect eradicates tumor – Permits SCT use in patients not eligible for conventional SCT – Is still investigational IFN-: Chronic Phase CML IFN- has multiple biologic effects – Inhibition of proliferation – Regulation of cytokine expression – Modulation of immune system Higher doses correlate with better response and greater toxicity Cytogenetic response may take 12 to 18 months Survival advantage in low-risk patients with early chronic phase CML IFN- in combination with cytarabine (ara-C) may be superior to IFN- alone IFN-: Clinical Results in CML IFN- IFN- + ara-C (results from 7 clinical trials)1-7 (results from 4 clinical trials)8-11 CHR (%) 31–80 64–92 Cytogenetic responses (%) Any Major 18–58 6–38 41–74 10–50 3-year survival rates (%)10 79 86 Response CHR = complete hematologic response. 1. Kantarjian HM et al. Ann Intern Med. 1995;122:254-261. 2. Ozer H et al. Blood. 1993;82:2975-2984. 3. Mahon F et al. Blood. 1994;84:3592. 4. Hehlmann R et al. Blood. 1994;84:4064-4077. 5. Italian Cooperative Study Group on CML. N Engl J Med. 1994;330:820. 6. Allan NC et al. Lancet. 1995;345:13921397. 7. Ohnishi K et al. Blood. 1995;86:906-916. 8. Silver RT et al. Blood. 1996;88 (suppl 1)638a. 9. Tura S et al. Blood. 1998;92(suppl 1) 317a. 10. Guilhot F et al. N Engl J Med. 1997;337:223-229. 11. Kantarjian HM et al. J Clin Oncol. 1999;17:284-292. Achieving a Cytogenetic Response Correlates with Increased Survival Major response 1.0 0.9 Proportion Surviving 0.8 0.7 P <.001 0.6 0.5 0.4 Minor or no response 0.3 0.2 0.1 0.0 0.0 12 24 36 Months After Treatment Guilhot F et al. N Engl J Med. 1997;337:223-229. 48 60 IFN-: Safety and Tolerability in Patients With CML Chronic adverse events include fatigue, depression, insomnia, and weight loss as well as gastrointestinal disorders, neurologic symptoms, psychiatric disorders, dermatologic effects, renal dysfunction, and hematologic cytopenias >90% of patients experience constitutional symptoms >50% of patients require IFN- dose reduction >25% of patients discontinue treatment due to severe drug-induced toxicity Chemotherapy: Chronic Phase CML Oral cytotoxic agents – Hydroxyurea – Busulfan Hematologic response in up to 90% of patients Rare MCR (0.9%–5%) Palliative care—no effect on disease progression MCR = major cytogenetic response. Pegylated IFN- IFN- coupled to polyethylene glycol (PEG) Has a longer half-life than IFN- and is administered once a week Phase III trials do not find an efficacy advantage over interferon Imatinib Mesylate Gleevec Imatinib Mesylate (Formerly STI571) Tyrosine Kinase Inhibitor for CML The Ideal Target for Molecular Therapy An abnormality present in the majority of patients with a specific disease Determined to be the causative abnormality Has unique activity that is – Required for disease induction – Dispensable for normal cellular function Bcr-Abl as a Therapeutic Target for CML Bcr-Abl is detected in 95% of patients with CML Bcr-Abl is the causative abnormality of CML Bcr-Abl tyrosine kinase is constitutively activated intracellularly – Tyrosine kinase activity is required for CML cell function Abl null mice are viable Imatinib mesylate: targets the cause of CML Structure of Imatinib Mesylate • CH3SO3H C29H31N7O•CH4SO3 Class: Phenylaminopyrimidines, 589.7 mw Mechanism of Action of Imatinib Mesylate Goldman JM, Melo JV. N Engl J Med. 2001;344:1084-1086. Rationale for Use of Imatinib Mesylate in CML CML is characterized by a 9;22 translocation known as the Ph chromosome The product of this fusion gene is Bcr-Abl tyrosine kinase, which is leukemogenic Imatinib mesylate is a selective inhibitor of Bcr-Abl kinase Inhibition of Bcr-Abl kinase should be an effective therapy for CML Imatinib mesylate has shown antileukemic activity in in vitro and in vivo studies Cellular Selectivity of Imatinib Mesylate: IC50 M Kinases Inhibited Kinases Not Inhibited v-Abl p210Bcr-Abl p185Bcr-Abl TEL-Abl PDGF-R TEL-PDGF-R c-Kit Flt-3 c-Fms, v-Fms EGF receptor c-erbB2 Insulin receptor IGF-I receptor v-Src JAK-2 0.1–0.3 0.25 0.25 0.35 0.1 0.15 0.1 >10 >10 >100 >100 >100 >100 >10 >100 PDGF-R = platelet-derived growth factor receptor; EGF = epidermal growth factor; IGF-I = insulin-like growth factor-I. Druker BJ et al. Nat Med. 1996;2:561-566. Imatinib Mesylate Inhibits the Growth of Bcr-Abl–Positive Cells U937* KG1* SU DHL1* KCL22† K562† KU812† Imatinib Mesylate Concentration (M) *Bcr-Abl–negative cell lines. Gambacorti-Passerini C et al. Blood Cells Mol Dis. 1997;23:380-394. †Bcr-Abl–positive cell lines. Imatinib Mesylate: Achieving Steady-State Pharmacokinetics at 400mg and 600mg Doses Rapidly and completely absorbed after oral administration Absolute bioavailability 98% Terminal half-life (t1/2) 18–22 h; volume of distribution 435 L; and clearance 14 L/h Linear and dose-proportional increase in AUC with doses 25mg to 1000mg Imatinib mesylate is metabolized in the liver by the P450 enzyme system Imatinib mesylate can alter the metabolism of drugs that are substrates of CYP3A4 and may alter CYP2D6 substrates AUC = area under the concentration time curve. Phase I Studies with Imatinib Mesylate Study design – Open-label, dose escalation Study objectives – Safety – Tolerability – Evidence of antileukemic activity Eligibility Chronic Phase CML – Ph+ CML – WBC >20,000, <15% blasts – IFN- failure Acute Leukemia CML in Blast Crisis Ph+ ALL Ph+ AML Phase I Studies With Imatinib Mesylate: Results Hematologic and Cytogenetic Responses IFN-–Resistant Chronic Phase CML 300mg–1000mg/day (n=55) Blast Crisis Myeloid Phenotype (n=39) Blast Crisis Lymphoid Phenotype (n=20) Hematologic response Complete 98% 98% 54% 13% 70% 20% Cytogenetic response Major Complete 49% 31% 14% 4% 40% 20% Most adverse events were mild to moderate in severity (grades 1–2) A maximal tolerated dose (MTD) was not reached Higher frequency and severity of adverse events with doses 800mg Imatinib Mesylate: Rapid Responses Hematologic Response 100 Cytogenetic Response 100 % Ph+ 10 60 40 20 1 0 WBC x 103 80 0 Days on Imatinib Mesylate Days on Imatinib Mesylate Imatinib Mesylate: Phase I Conclusions Generally well tolerated with a mild side-effects profile In all phases of CML, imatinib mesylate achieved – Hematologic responses – Cytogenetic responses Time to response was rapid Phase II Studies With Imatinib Mesylate 3 large international trials have been conducted – 0110: Patients with CML in chronic phase after failure of IFN- therapy – 0109: Patients with CML in accelerated phase – 0102: Patients with CML in myeloid blast crisis Study design and objectives – Open-label, multicenter, noncontrolled – Imatinib mesylate dose: 400mg to 600mg – Assess safety, efficacy, and survival rate Imatinib Mesylate: Phase II Study 0110—Patients With CML in Chronic Phase After IFN- Failure Treatment schedule: 400mg daily Accrual time: December 1999 to May 2000 Patients with CML in chronic phase: – Hematologic failure • Lack of complete cytogenetic response (CHR) after 6 months IFN- • Loss of CHR – Cytogenetic failure • No cytogenetic response after 12 months of IFN- • Loss of a cytogenetic response – IFN- intolerant Primary endpoint: cytogenetic response Patient Demographics Enrolled patients: N=532, confirmed chronic phase CML n=454 (85%) Median age [yrs] (range) 57 (18–90) IFN- failure – Hematologic failure – Cytogenetic failure – IFN- intolerance Months from diagnosis (range) Months of prior IFN-* (range) WBC (x109/L) (range) Platelets (x109/L) (range) Additional chromosomal abnormalities *IFN- at doses >25 MIU/week. 152 (29%) 188 (35%) 192 (36%) 32 (3–218) 14 (>1–135) 14 (1.8–260) 296 (75–2081) 87 (16%) Response Criteria in Chronic Phase CML Patients (Study 0110) CHR – WBC <10 x 109/L – Platelets <450 x 109/L – No blasts, basophils <20% – No extramedullary disease Cytogenetic responses – Complete cytogenetic response (CCR) – Partial cytogenetic response (PCR) – Major cytogenetic response (MCR) 0% Ph+ 1% to 35% Ph+ CCR + PCR Results in Chronic Phase CML Patients (Study 0110) Total Hematologic Failures Resistant Cytogenetic Failures Relapsed IFN- Intolerant Resistant Relapsed Cytogenetic Response Major 60 41 57 55 83 66 Complete 41 25 41 31 76 47 Partial 19 16 16 24 7 19 5 8 1 8 2 2 11 16 16 9 2 11 95 89 99 97 98 93 Minor Minimal Hematologic Response Complete Kantarjian H et al. N Engl J Med. 2002;346:645-653. 2002 Massachusetts Medical Society. All rights reserved. Proportion of Patients Who Responded Time to MCR and CCR in Chronic Phase CML (Study 0110) MCR CCR 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months Since Start of Treatment 13 14 15 Durable Response in Chronic Phase Patients (Study 0110) n 100 o is 90 s e rg 80 o rp 70 tu 60 o h t 50 iw s 40 tn e 30 it a 20 p fo 10 % 0 0 = Censored observations 2 4 6 8 10 12 14 16 18 Months since start of Months Since Start of Treatment treatment tttreatment Kantarjian H et al. N Engl J Med. 2002;346:645-653. 2002 Massachusetts Medical Society. All rights reserved. 20 22 First-Line Use of Imatinib Mesylate in Early Chronic Phase CML Front-line use of imatinib mesylate in early chronic phase is supported by the results of a single institution study recently presented at ASH 2001 – Median time from diagnosis: 1 month – Dose: 400mg daily – MCR rate: 77% at 3 month follow-up – CCR rate: 36% – Severe adverse events in 5% of patients A large multinational multicenter phase III clinical trial comparing imatinib mesylate vs IFN- plus ara-C as first-line therapy is ongoing (Study 106) International Multicenter Clinical Trial: Imatinib as First-Line Therapy in CML (IRIS Study) Study design and objectives: – Imatinib mesylate versus IFN- + ara-C in newly diagnosed previously untreated, chronic phase CML patients – Phase III, multicenter, randomized, open-label – Primary objectives: time-to-treatment failure which includes • Failure to achieve a CHR at 6 months • Failure to achieve an MCR at 6 months • Loss of CHR • Progression, intolerance of treatment, or death Secondary objectives include: – Quality of life (QoL) – Rate and duration of CHR – Rate and duration of CCR Imatinib Mesylate as First-Line Therapy (IRIS Study) 1,106 adult patients were randomized to either – Imatinib mesylate 400mg/day – IFN- with a target dose of 5MU/m2/day and ara-C 20mg/m2/day for 10 days every months Treatment with each drug will be continued until: – Crossover – Progression – Death – Intolerance to treatment Study Design for Phase III Trial Imatinib mesylate S R If: • Progression • Intolerance of treatment • Failure to achieve MCR at 24 months Crossover IFN- + ara-C S = screening R = randomization Progression: • Death • Accelerated phase or blast crisis • Loss of MCR or CHR • Increasing WBC count Multicenter Clinical Trial with Accelerated Phase CML Patients (Study 0109) Treatment schedule: 400mg (n=77) or 600mg (n=158) daily Patient selection: – Blood or bone marrow blasts 15% but <30% – Blasts + promyelocytes in peripheral blood or bone marrow 30% – Peripheral basophils 20% – Thrombocytopenia <100 x 109/L unrelated to therapy Primary endpoint: hematologic response Response Criteria (Study 0109) CHR – Marrow blasts <5%, no peripheral blood blasts – ANC 1.5 x 109/L and platelet count 100 x 109/L – No extramedullary disease • No evidence of leukemia: as for CHR except for (ANC >1.0 x 109/L) and platelets (>20 x 109/L) • Return to chronic phase (RTC) Cytogenetic responses – Complete cytogenetic response (CCR) 0% Ph+ – Partial cytogenetic response (PCR) 1% to 35% Ph+ – Major cytogenetic response (MCR) CCR + PCR Clinical Results in Patients With Accelerated CML (Study 0109) Results 400mg 600mg Overall Hematologic response Complete 65% 27% 71% 37% 69% 34% No evidence of leukemia 10% 13% 12% Return to chronic phase 27% 21% 23% Major cytogenetic response Complete Partial 16% 11% 5% 28% 19% 8% 24% 17% 7% Higher Doses of Imatinib Delays the Time to Disease Progression (Study 0109) 400mg 600mg 1.0 Proportion of Patients Without Progression 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Months Since Start of Treatment Increased Survival: Achieved with a cytogenetic response at 3 Months (Study 0109) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 Hematologic Response at 3 Months Yes No 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Months Since Start of Treatment Cytogenetic Response Proportion of Patients Alive Proportion of Patients Alive Hematologic Response 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 Cytogenetic Response at 3 Months 0.2 Yes No 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Months Since Start of Treatment Multicenter Clinical Trial In Blast Crisis CML Patients (Study 0102) Treatment schedule: 400mg (n=37) or 600mg (n=223) daily Patient selection: – Blast crisis: blood or bone marrow blasts 30%; extramedullary involvement other than spleen or liver – Prior treatment: previously treated/no prior treatment except hydroxyurea, IFN-, busulfan, low-dose ara-C Primary endpoint: hematologic response Response Criteria (Study 0102) CHR – Marrow blasts <5%, no peripheral blood blasts – ANC 1.5 x 109/L and platelet count 100 x 109/L – No extramedullary disease • No evidence of leukemia: as for CHR except for (ANC >1.0 x 109/L) and platelets (>20 x 109/L) • Return to chronic phase (RTC) Cytogenetic responses – Complete cytogenetic response (CCR) 0% Ph+ – Partial cytogenetic response (PCR) 1% to 35% Ph+ – Major cytogenetic response (MCR) CCR + PCR Clinical Results in Blast Crisis CML Patients (Study 0102) Results by Subgroup Previously Untreated Previously Treated Overall 34% 8% 20% 4% 29% 6.5% 4% 1% 3% Return to chronic phase (RTC) 22% 15% 20% Major cytogenetic response (MCR) Complete Partial 14.5% 7% 8% 16% 6% 9.5% 15% 6.5% 8.5% Hematologic response Complete No evidence of leukemia Achieving a Hematologic Response in Blast Crisis Correlates with Survival (Study 0102) 1.0 0.9 Yes No 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Months Since Start of Treatment Overall Survival Proportion of Patients Alive Proportion of Patients Alive Hematologic Response at 3 Months 1.0 0.9 Untreated Pretreated 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Months Since Start of Treatment Overview of Clinical Results with Imatinib % of Patients (CI95%) Hematologic response Complete response No evidence of leukemia Return to chronic phase (RTC) Major cytogenetic response (MCR) Complete Partial Study 0110 Chronic Phase IFN- Failure (n=454) Study 0109 Accelerated Phase (n=235) Study 0102 Blast Crisis (n=260) 95% _ 95% – – 71% (61.8–75.7) 34% 12% 23% 29% (23.4–34.8) 7% 3% 20% 60% – 41% 19% 26% (17.8–30.6) 17% 7% 15% (10.9–19.9) 7% 8% Improved Hematologic Responses Occurs in All Phases of CML with Imatinib Mesylate Percentage of Patients Responding Hematologic response, original report 100 90 80 70 60 50 40 30 20 10 0 95 Hematologic response, latest report 71 88 63 29 26 Chronic Phase Accelerated Phase Blast Crisis Percentage of Patients Responding Improved Cytogenetic Responses Occurs in All Phases of CML With Imatinib Major cytogenetic response, original report 70 60 60 Major cytogenetic response, latest report 50 40 49 26 30 15 20 21 10 13.5 0 Chronic Phase Accelerated Phase Blast Crisis Resistance to Imatinib Mesylate Predominately Occurs During Advanced Phase CML Advanced stage cancers are characterized by multiple genetic changes Patients in advance phase often relapse with the development of chemotherapy resistance Some patients in blast crisis CML initially respond to imatinib mesylate but then tend to relapse Resistance to Imatinib Mesylate Studies of patients resistant to imatinib mesylate (most of them in blast crisis) indicated that for some patients, point mutations in the ATP-binding domain of the kinase were involved in the resistance to imatinib mesylate Study No. of patients with a mutation Mutations (number of patients) Gorre et al 1 Kreil et al2 No. of patients resistant to imatinib mesylate 11 40 6 6 Branford et al3 12 9 Shah et al4 31 26 van Bubnoff et al 5 8 7 T315I (6) T315I(2); Y253F (1); E255K(2); E255V (1) T315I (1); G250E (2); Y253H (1); E255k (3); F317L (1); M351T (1) T315I (9); Q252H (6); E255K (5); M351T (4) G250E (2) T315I (1); others 1. Gorre ME et al. Science. 2001;293:876. 2. Kreil S et al. Blood. 2001;98:435a. 3. Branford S et al. Blood. 2001;98:769a. 4. Shah N et al. Blood. 2001;98:770a. 5. van Bubnoff N et al. Blood. 2001;98:771a. Evolution of Resistance to Imatinib Mesylate in CML Chronic Phase Ph-negative Ph-positive Ph+ blasts Ph+ imatinibresistant blasts Courtesy of Charles L. Sawyers, MD. Relapse Bone marrow to peripheral blood Hematopoietic differentiation Blast Crisis Resistance to Imatinib Mesylate Other mechanisms of resistance are predicted to exist: – Amplification of the bcr-abl gene – Unknown Results obtained so far indicate that, in blast crisis CML, where the cancer is more complex than in earlier phases, it still remains dependent on activation of Bcr-Abl Other Possible Mechanisms of Resistance to Imatinib Mesylate Mechanisms of resistance Ph+ cell lines – Bcr-Abl overexpression – Gene amplification – Drug reflux mediated by P-glycoprotein – Other In vivo murine model – Binding in the plasma of alpha 1-acid glycoprotein to imatinib mesylate Avoiding and Managing Resistance to Imatinib Therapy The earlier CML is treated, the more likely resistance can be avoided A major benefit of regular cytogenetic monitoring is early detection of impending resistance/relapse To manage resistance occurring during therapy • Dose escalate, use intermittent dosing • Add additional drugs, switch to non-cross–resistant drugs Drug-Relevant Adverse Events in Phase II Trials Most Common Adverse Experiences Reported in Clinical Trials (10% of all patients in any trial)(1) Preferred term Nausea Fluid retention Superficial edemas Other fluid retention events (2) Muscle cramps Diarrhea Vomiting Hemorrhage CNS hemorrhage Gastrointestinal hemorrhage Musculoskeletal pain Skin rash Headache Fatigue Arthralgia Dyspepsia Myalgia Weight increased Myeloid Blast Crisis N=260 (%) All Grade grades 3/4 69 3 69 10 65 5 16 6 26 0.4 41 3 52 4 48 17 5 3 5 3 42 9 34 4 26 4 28 3 24 4 10 0 8 0 5 0.8 Accelerated Phase N=235 (%) All Grade 3/4 grades 71 5 71 6 69 3 9 3 37 0.4 53 4 55 3 39 8 1 0.4 3 1 43 9 43 5 29 2 36 3 29 6 20 0 20 2 11 2 Chronic Phase IFN- Failure N=532 (%) All grades Grade 3/4 58 56 55 3 50 37 30 16 0.6 0.4 32 39 30 31 30 21 21 24 (1) All adverse events occurring in 10% of patients are listed regardless of suspected relationship to treatment. (2) Other fluid retention events include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. 2 2 1 0.6 1 1 0.9 0.8 0.6 0 1 3 0.2 0.6 0.6 0 0.2 4 Lab Abnormalities in Phase II Trials Myeloid Blast Crisis N=260 (%) Accelerated Phase N=235 (%) Chronic Phase, IFN- Failure N=532 (%) Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Neutropenia 16 47 23 35 26 8 Thrombocytopenia 27 33 31 12 17 <1 Anemia 40 11 33 6 5 <1 Hematology parameters Myelosuppression: Sometimes a Good Thing More common in advanced phases of CML Identified risk factors are those associated with advanced phase CML Onset within 4 weeks in blast crisis; later in earlier phases Myelosuppression is a therapeutic effect of imatinib mesylate – Normal hematopoiesis is not suppressed – Imatinib targets only Ph+ cells, which leads to a cytogenetic response Managing Myelosuppression: Chronic Phase ANC <1000/mm3 or PLTs <50,000/mm3 Withhold imatinib mesylate and allow recovery to ANC >1500/mm3 and PLTs >100,000/mm3 Normal Recovery (2-4 weeks) Resume imatinib at 400mg ANC = absolute neutrophil count; PLTs = platelets. Slow Recovery (>4 weeks) Resume imatinib at 300mg Escalate imatinib to 400mg, as long as recovery continues Managing Myelosuppression: Advanced Phases PLTs <10,000/mm3 or <50,000/mm3 with bleeding Withhold until bleeding stops Continue at 600mg and transfuse PLTs Hypercellular BM or blasts >30% Continue at 600mg Continue at 600mg and monitor BM if ANC <500/mm3 Hypocellular BM and ANC <500/mm3 for >2-4 weeks Dose interrupt Reduce dose Continue at 600mg and administer myeloid growth factors Practical Considerations for Nonhematologic Side Effects GI upset, nausea, vomiting, diarrhea – Take dose with a meal and large glass of water – Take at least 2 hours before bedtime – Take 800mg dose as 400mg bid – Use antiemetic and antidiarrheal medications for severe effects Practical Considerations for Nonhematologic Side Effects (cont.) Edema/fluid retention – Mild (generally periorbital) • Limit salt intake • Use diuretics and topical steroids – Severe (pulmonary edema, pleural/pericardial effusion, ascites): • Use diuretics • Dose reduction/interruption/continuation • Weigh patient regularly Practical Considerations for Nonhematologic Side Effects (cont.) Muscle cramps/bone pain/arthralgia – Ca++ supplements – Nonsteroidal anti-inflammatory drugs (NSAIDs) • +/- proton pump inhibitors • +/- histamine H-2 inhibitors – Mild narcotics Management of Hepatotoxicity Liver function tests (LFTs) including AST, ALT, bilirubin – Grade 2 • Dose adjustment not necessary • Minimize alcohol • Substitute other nonhepatotoxic drugs • Avoid acetaminophen – Grades 3/4 • Dose interrupt • Resume at reduced dose when LFTs normalize • Resume initial dose after 6-12 weeks of normal LFTs For persistently elevated LFTs, perform hepatic evaluation AST = aspartate transaminase; ALT = alanine transaminase. Management of Dermatologic Side Effects Skin rash is generally mild – Maculopapular rash – Occurs most often on the arms and trunk – Treat with antihistamines, topical or oral steroids Severe, desquamative rash is much rarer – Treat with systemic steroids Optimal Dosing of Imatinib Mesylate Starting dose in chronic phase: 400mg once daily Starting dose in advanced phases: 600mg once daily Consider dose escalation (400mg to 600mg, 600mg to 800mg) for: – Disease progression – Failure to achieve a hematologic response after at least 3 months – Loss of a previously achieved hematologic response Optimal Dosing of Imatinib Mesylate (cont.) Dose interruption or discontinuation is only recommended for the management of severe adverse events Preliminary results from ASH 2001 support the use of higher doses in nonresponding patients in chronic phase – 67% of patients achieved or regained a CHR – 30% achieved or improved their cytogenetic response Maximizing the Potential of Imatinib Mesylate Therapy WBC >20,000/mm3 WBC elevated, on HU Start imatinib mesylate Continue allopurinol until WBC normal; Maintain hydration to avoid TLS Start imatinib mesylate Continue HU for up to 3 weeks Monitor CBC Weeks 1-4: weekly (CP), at least weekly (AP, BC) Weeks 8-12: every 2 weeks WBC normal, on HU WBC <1500/mm3 and/or PLTs <100,000/mm3, on IFN- PLTs elevated, on anagrelide Start imatinib mesylate Discontinue IFN-; allow WBC to normalize Taper HU during week 1 More frequently if ANC <1500/mm3 and/or PLTs <100,000/mm3 Start imatinib mesylate Start imatinib mesylate After week 12: monthly Continue anagrelide up to 5 weeks Adapted from Druker BJ. In preparation. WBC = white blood cell; TLS = tumor lysis syndrome; CBC = complete blood count; HU = hydroxyurea; CP = chronic phase; AP = accelerated phase; BC = blast crisis; PLTs = platelets; ANC = absolute neutrophil count; IFN- = interferon-alpha. Hematologic Response: Monitoring to Maximize Patient Outcome Hematologic monitoring, consisting of CBC and differential, should begin immediately – Weeks 1–4: monitor CBC weekly – Weeks 5–12: monitor CBC every 2 weeks – After week 12: monitor CBC monthly Perform more frequently – If ANC <1500/mm3 – And/or PLTs <100,000/mm3 ANC = absolute neutrophil count; PLTs = platelets. Cytogenetic Response: Monitoring to Maximize Patient Outcome “A systematic plan must be established for evaluating the degree and duration of cytogenetic and molecular response”1 Recommended cytogenetic monitoring schedule based on imatinib mesylate clinical trials – Cytogenetic analysis for the Ph chromosome should be performed every 3 months 1. Silver RT et al. Blood. 1999;94:1517-1536. Molecular Monitoring for a Response is Critical for the Optimal Treatment of CML Molecular analyses may be performed – FISH to assess the presence and copy number of the bcr-abl fusion gene – RT-PCR to quantify bcr-abl mRNA transcript levels Frequent cytogenetic or molecular monitoring has prognostic value for predicting clinical responses and disease status Imatinib Metabolism and Elimination Cytochrome P450 3A4 isoenzyme(CYP3A4) – Major metabolic enzyme responsible for metabolizing imatinib and many other agents – A cause of many drug interactions Other cytochrome P450 enzymes play a minor role in metabolism (CYP1A2, CYP2D6, CYP2C9, CYP2C19) 81% of imatinib eliminated within 7 days – 68% in feces – 13% in urine Drug–Drug Interactions CYP3A4 inhibitors – Increase imatinib concentrations – Ketoconazole (antifungal), erythromycin (antibiotic), diltiazem (cardiovascular), verapamil (CV), nifedipine (CV), grapefruit juice, cyclosporine (transplant), cimetidine (H-2 blocker) CYP3A4 inducers – Decrease imatinib concentrations – Phenytoin (anti-seizure), carbamazepine (anti-seizure), dexamethasone (steroid), St. John’s Wort, rifampin Drug–Drug Interactions (cont.) Imatinib mesylate may affect levels of other CYP3A4, CYP2C9, or CYP2D6 substrates Use caution when coadministering these substrates that have a narrow therapeutic window – Substitute low-molecular weight or standard heparin for warfarin (CYP3A4 and CYP2C9 substrate) Imatinib Mesylate has Revolutionized the Treatment of CML Therapy specifically designed to target the molecular cause of CML – Potent and selective inhibitor of Bcr-Abl Outstanding rates of rapid hematologic and cytogenetic responses in all stages of disease Significant Improvement in survival and delay in the time of disease progression in all phases of CML Excellent side-effect profile – Most adverse events were mild to moderate in severity Convenient once-daily oral dosing Possible Concepts for the Future: Individualizing Therapy Biologically Early Biologically Late Bcr-Abl: unique molecular abnormality Additional molecular abnormality Molecular remission with imatinib mesylate Lack of molecular remission Imatinib mesylate as single-agent therapy Imatinib mesylate + other therapies Concepts for the Future: Optimizing Therapy Define the molecular signature of specific response Dx expression analysis Responsive genotype “Conservative” therapy Unresponsive genotype MRD monitoring “Hi-risk” MRD = minimal residual disease. Courtesy of Jerry Radich, Fred Hutchinson Cancer Research Center. “Aggressive” therapy Imatinib Mesylate: Solid Tumors Additional molecular targets – Kit – PDGF-R Relationship to prognosis and malignant transformation is unknown Tumors associated with these targets – Sarcomas – Lung cancer – Prostate cancer – Gliomas and neuroblastomas – Breast cancer – Seminomas and germ-cell tumors Evidence for mutations leading to constitutive activation Imatinib Mesylate: Kit Targets GISTs – Study 2222 • Immunohistochemically Kit+, unresectable or metastatic disease SCLC – Study 0202 • Newly diagnosed, extensive stage disease • Sensitive relapse (any stage) – Study 0205 • Newly diagnosed, extensive stage disease in combination with cisplatin/etoposide GISTs = gastrointestinal stromal tumors; SCLC = small-cell lung cancer. Imatinib Mesylate: PDGF-R Targets Prostate cancer – Study 0201 • Single-agent therapy in hormone-refractory prostate cancer (HRPC) – Study 0210 • Neoadjuvant therapy in prostate cancer Glioma – Study 0204 • Imatinib mesylate in adult glioma – Study of recurrent pediatric glioma planned Breast cancer – Study 0206 • Imatinib mesylate in combination with standard chemotherapy in advanced breast cancer