Chronic Myeloid Leukemia CML and Targeted Therapy n
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Chronic Myeloid Leukemia (CML) and Targeted Therapy n CML – Proliferative disorder of hematopoietic stem cells – Well-characterized clinical course n Philadelphia (Ph) chromosome – Unique chromosomal abnormality n 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 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 n Median age range at presentation: 45 to 55 years n Incidence increases with age – 12%– 30% of patients are >60 years old n Male-to-female ratio– 1. 3: 1 n At presentation – 50% diagnosed by routine laboratory tests – 85% diagnosed during chronic phase
Clinical Presentation of CML n Common Symptoms – Fatigue – Weight loss/anorexia – Abdominal fullness Common Signs – Palpable splenomegaly n Common Laboratory Findings – Abnormal differential – Anemia – Leukocytosis – Basophilia – Thrombocytosis
CML: Peripheral Blood Smear Courtesy of John K. Choi, MD, Ph. D, 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 Parameter Chronic WBC count 20 x 109/L Blasts 1%– 15% Basophils Platelets Accelerated Blast Crisis — 15% 30% 20% — or normal or 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 <5 d Platelet 1000 x 109/L despite adequate therapy Marrow collagen fibrosis Anemia unrelated to therapy Progressive splenomegaly Leukocyte doubling time <5 d 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 IFN- = interferon-alpha.
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 22 q-) bcr-abl FUSION PROTEIN WITH TYROSINE KINASE ACTIVITY
bcr-abl Gene and Fusion Protein Tyrosine Kinases Chromosome 22 Chromosome 9 c-bcr 1 2 -11 Exons Introns CML Breakpoints ALL Breakpoints 2 -11 p 210 Bcr-Abl p 185 Bcr-Abl c-abl
p 210 Bcr-Abl Fusion Protein Tyrosine Kinase Extracellular space Cytoplasm Y 177 BAP-1 SH 3 SH 2 SH 1 GRB 2 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 n 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: n Disappearance of splenomegaly n Normal physical examination 0% Ph+ cells 1%– 35% Ph+ cells 36%– 95% Ph+ cells
Therapeutic Options for CML n Allogeneic stem cell transplantation (SCT) n IFN- –based treatments n Chemotherapy with hydroxyurea, busulfan n Imatinib mesylate (formerly STI 571)
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, <1 y (N = 2, 876) 60 HLA-identical sibling, 1 y (N = 1, 391) Unrelated, <1 y (N = 613) 40 Unrelated, 1 y (N = 936) 20 P = 0. 0001 0 0 1 2 3 4 5 6 YEARS SUM 02_3. ppt
Advances in SCT n 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) n 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 n IFN- has multiple biologic effects – Inhibition of proliferation – Regulation of cytokine expression – Modulation of immune system n Higher doses correlate with better response and greater toxicity n Cytogenetic response may take 12 to 18 months n Survival advantage in low-risk patients with early chronic phase CML n IFN- in combination with cytarabine (ara-C) may be superior to IFN- alone
IFN- : Clinical Results in CML 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: 1392 -1397. 7. Ohnishi K et al. Blood. 1995; 86: 906 -916. 8. Silver RT et al. Blood. 1996; 88 (suppl 1)638 a. 9. Tura S et al. Blood. 1998; 92(suppl 1) 317 a. 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 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 n 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 n >90% of patients experience constitutional symptoms n >50% of patients require IFN- dose reduction n >25% of patients discontinue treatment due to severe drug-induced toxicity
Chemotherapy: Chronic Phase CML n Oral cytotoxic agents – Hydroxyurea – Busulfan n Hematologic response in up to 90% of patients n Rare MCR (0. 9%– 5%) n Palliative care—no effect on disease progression MCR = major cytogenetic response.
Pegylated IFN- n IFN- coupled to polyethylene glycol (PEG) n Has a longer half-life than IFN- and is administered once a week n Phase III trials do not find an efficacy advantage over interferon
Imatinib Mesylate Gleevec
Imatinib Mesylate (Formerly STI 571) Tyrosine Kinase Inhibitor for CML
The Ideal Target for Molecular Therapy n An abnormality present in the majority of patients with a specific disease n Determined to be the causative abnormality n Has unique activity that is – Required for disease induction – Dispensable for normal cellular function
Bcr-Abl as a Therapeutic Target for CML n Bcr-Abl is detected in 95% of patients with CML n Bcr-Abl is the causative abnormality of CML n Bcr-Abl tyrosine kinase is constitutively activated intracellularly – Tyrosine kinase activity is required for CML cell function n Abl null mice are viable n Imatinib mesylate: targets the cause of CML
Structure of Imatinib Mesylate • CH 3 SO 3 H C 29 H 31 N 7 O • CH 4 SO 3 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 is characterized by a 9; 22 translocation known as the Ph chromosome n The product of this fusion gene is Bcr-Abl tyrosine kinase, which is leukemogenic n Imatinib mesylate is a selective inhibitor of Bcr-Abl kinase n Inhibition of Bcr-Abl kinase should be an effective therapy for CML n Imatinib mesylate has shown antileukemic activity in in vitro and in vivo studies
Cellular Selectivity of Imatinib Mesylate: IC 50 M Kinases Inhibited Kinases Not Inhibited v-Abl 0. 1– 0. 3 Flt-3 p 210 Bcr-Abl 0. 25 p 185 Bcr-Abl 0. 25 TEL-Abl 0. 35 PDGF-R 0. 1 TEL-PDGF-R 0. 15 c-Kit 0. 1 v-Src JAK-2 >10 c-Fms, v-Fms EGF receptor c-erb. B 2>100 Insulin receptor IGF-I receptor >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 U 937* KG 1* SU DHL 1* KCL 22† K 562† KU 812† 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 400 mg and 600 mg Doses n Rapidly and completely absorbed after oral administration n Absolute bioavailability 98% n Terminal half-life (t 1/2) 18– 22 h; volume of distribution 435 L; and clearance 14 L/h n Linear and dose-proportional increase in AUC with doses 25 mg to 1000 mg n Imatinib mesylate is metabolized in the liver by the P 450 enzyme system n Imatinib mesylate can alter the metabolism of drugs that are substrates of CYP 3 A 4 and may alter CYP 2 D 6 substrates AUC = area under the concentration time curve.
Phase I Studies with Imatinib Mesylate n Study design – Open-label, dose escalation n Study objectives – Safety – Tolerability – Evidence of antileukemic activity n 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 300 mg– 1000 mg/day (n=55) Blast Crisis Myeloid Phenotype (n=39) Blast Crisis Lymphoid Phenotype (n=20) Hematologic response Complete 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 800 mg
Imatinib Mesylate: Rapid Responses Hematologic Response 100 Cytogenetic Response 100 % Ph+ 10 60 40 20 1 0 WBC x 103 80 30 60 90 120 Days on Imatinib Mesylate 150 0 100 200 300 Days on Imatinib Mesylate 400
Imatinib Mesylate: Phase I Conclusions n Generally well tolerated with a mild side-effects profile n In all phases of CML, imatinib mesylate achieved – Hematologic responses – Cytogenetic responses n Time to response was rapid
Phase II Studies With Imatinib Mesylate n 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 n Study design and objectives – Open-label, multicenter, noncontrolled – Imatinib mesylate dose: 400 mg to 600 mg – Assess safety, efficacy, and survival rate
Imatinib Mesylate: Phase II Study 0110—Patients With CML in Chronic Phase After IFN- Failure n Treatment schedule: 400 mg daily n Accrual time: December 1999 to May 2000 n 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 n Primary endpoint: cytogenetic response
Patient Demographics n Enrolled patients: N=532, confirmed chronic phase CML n=454 (85%) n Median age [yrs] (range) 57 (18– 90) n IFN- failure – Hematologic failure 152 (29%) – Cytogenetic failure 188 (35%) – IFN- intolerance 192 (36%) n Months from diagnosis (range) 32 (3– 218) n Months of prior IFN- * (range) 14 (>1– 135) n WBC (x 109/L) (range) 14 (1. 8– 260) n Platelets (x 109/L) (range) 296 (75– 2081) n Additional chromosomal abnormalities 87 (16%) *IFN- at doses >25 MIU/week.
Response Criteria in Chronic Phase CML Patients (Study 0110) n CHR – WBC <10 x 109/L – Platelets <450 x 109/L – No blasts, basophils <20% – No extramedullary disease n Cytogenetic responses – Complete cytogenetic response (CCR)0% Ph+ – Partial cytogenetic response (PCR) 1% to 35% Ph+ – Major cytogenetic response (MCR) 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
Patients Without Progression (%) Durable Response in Chronic Phase Patients (Study 0110) Months Since Start of Treatment Kantarjian H et al. N Engl J Med. 2002; 346: 645 -653. 2002 Massachusetts Medical Society. All rights reserved.
First-Line Use of Imatinib Mesylate in Early Chronic Phase CML n 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: 400 mg daily – MCR rate: 77% at 3 month follow-up – CCR rate: 36% – Severe adverse events in 5% of patients n 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) n 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 n Secondary objectives include: – Quality of life (Qo. L) – Rate and duration of CHR – Rate and duration of CCR
Imatinib Mesylate as First-Line Therapy (IRIS Study) n 1, 106 adult patients were randomized to either – Imatinib mesylate 400 mg/day – IFN- with a target dose of 5 MU/m 2/day and ara-C 20 mg/m 2/day for 10 days every months n 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) n Treatment schedule: 400 mg (n=77) or 600 mg (n=158) daily n Patient selection: – Blood or bone marrow blasts 15% but <30% – Blasts + promyelocytes in peripheral blood or bone marrow 30% – Peripheral basophils 20% 9 – Thrombocytopenia <100 x 10 /L unrelated to therapy n Primary endpoint: hematologic response
Response Criteria (Study 0109) n 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) n 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 400 mg 600 mg 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) 400 mg 600 mg 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 0. 2 0. 1 0. 0 Hematologic Response at 3 Months Yes No 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 Hematologic Response 1. 0 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 Cytogenetic Response at 3 Months Yes No 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) n Treatment schedule: 400 mg (n=37) or 600 mg (n=223) daily n 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 n Primary endpoint: hematologic response
Response Criteria (Study 0102) n 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) n 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 0. 8 0. 7 0. 6 Yes No 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 Hematologic Response at 3 Months 1. 0 0. 9 0. 8 0. 7 0. 6 Untreated Pretreated 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
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 20 21 10 15 13. 5 0 Chronic Phase Accelerated Phase Blast Crisis
Resistance to Imatinib Mesylate Predominately Occurs During Advanced Phase CML n Advanced stage cancers are characterized by multiple genetic changes n Patients in advance phase often relapse with the development of chemotherapy resistance n Some patients in blast crisis CML initially respond to imatinib mesylate but then tend to relapse
Resistance to Imatinib Mesylate n 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 al 2 No. of patients resistant to imatinib mesylate 11 40 6 6 Branford et al 3 12 9 Shah et al 4 31 26 van Bubnoff et al 5 8 7 T 315 I (6) T 315 I(2); Y 253 F (1); E 255 K(2); E 255 V (1) T 315 I (1); G 250 E (2); Y 253 H (1); E 255 k (3); F 317 L (1); M 351 T (1) T 315 I (9); Q 252 H (6); E 255 K (5); M 351 T (4) G 250 E (2) T 315 I (1); others 1. Gorre ME et al. Science. 2001; 293: 876. 2. Kreil S et al. Blood. 2001; 98: 435 a. 3. Branford S et al. Blood. 2001; 98: 769 a. 4. Shah N et al. Blood. 2001; 98: 770 a. 5. van Bubnoff N et al. Blood. 2001; 98: 771 a.
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 n Other mechanisms of resistance are predicted to exist: – Amplification of the bcr-abl gene – Unknown n 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 n Ph+ cell lines – Bcr-Abl overexpression – Gene amplification – Drug reflux mediated by P-glycoprotein – Other n In vivo murine model – Binding in the plasma of alpha 1 -acid glycoprotein to imatinib mesylate
Avoiding and Managing Resistance to Imatinib Therapy n The earlier CML is treated, the more likely resistance can be avoided n A major benefit of regular cytogenetic monitoring is early detection of impending resistance/relapse n 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) 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.
Lab Abnormalities in Phase II Trials
Myelosuppression: Sometimes a Good Thing n More common in advanced phases of CML n Identified risk factors are those associated with advanced phase CML n Onset within 4 weeks in blast crisis; later in earlier phases n 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/mm 3 or PLTs <50, 000/mm 3 Withhold imatinib mesylate and allow recovery to ANC >1500/mm 3 and PLTs >100, 000/mm 3 Normal Recovery (2 -4 weeks) Resume imatinib at 400 mg ANC = absolute neutrophil count; PLTs = platelets. Slow Recovery (>4 weeks) Resume imatinib at 300 mg Escalate imatinib to 400 mg, as long as recovery continues
Managing Myelosuppression: Advanced Phases PLTs <10, 000/mm 3 or <50, 000/mm 3 with bleeding Withhold until bleeding stops Continue at 600 mg and transfuse PLTs Hypercellular BM or blasts >30% Continue at 600 mg and monitor BM if ANC <500/mm 3 Hypocellular BM and ANC <500/mm 3 for >2 -4 weeks Dose interrupt Reduce dose Continue at 600 mg and administer myeloid growth factors
Practical Considerations for Nonhematologic Side Effects n GI upset, nausea, vomiting, diarrhea – Take dose with a meal and large glass of water – Take at least 2 hours before bedtime – Take 800 mg dose as 400 mg bid – Use antiemetic and antidiarrheal medications for severe effects
Practical Considerations for Nonhematologic Side Effects (cont. ) n 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. ) n Muscle cramps/bone pain/arthralgia – Ca++ supplements – Nonsteroidal anti-inflammatory drugs (NSAIDs) • +/- proton pump inhibitors • +/- histamine H-2 inhibitors – Mild narcotics
Management of Hepatotoxicity n 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 n For persistently elevated LFTs, perform hepatic evaluation AST = aspartate transaminase; ALT = alanine transaminase.
Management of Dermatologic Side Effects n Skin rash is generally mild – Maculopapular rash – Occurs most often on the arms and trunk – Treat with antihistamines, topical or oral steroids n Severe, desquamative rash is much rarer – Treat with systemic steroids
Optimal Dosing of Imatinib Mesylate n Starting dose in chronic phase: 400 mg once daily n Starting dose in advanced phases: 600 mg once daily n Consider dose escalation (400 mg to 600 mg, 600 mg to 800 mg) 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. ) n Dose interruption or discontinuation is only recommended for the management of severe adverse events n 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/mm 3 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/mm 3 and/or PLTs <100, 000/mm 3, 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/mm 3 and/or PLTs <100, 000/mm 3 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 n 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 n Perform more frequently – If ANC <1500/mm 3 – And/or PLTs <100, 000/mm 3 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 n 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 n 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 m. RNA transcript levels n Frequent cytogenetic or molecular monitoring has prognostic value for predicting clinical responses and disease status
Imatinib Metabolism and Elimination n Cytochrome P 450 3 A 4 isoenzyme(CYP 3 A 4) – Major metabolic enzyme responsible for metabolizing imatinib and many other agents – A cause of many drug interactions n Other cytochrome P 450 enzymes play a minor role in metabolism (CYP 1 A 2, CYP 2 D 6, CYP 2 C 9, CYP 2 C 19) n 81% of imatinib eliminated within 7 days – 68% in feces – 13% in urine
Drug–Drug Interactions n CYP 3 A 4 inhibitors – Increase imatinib concentrations – Ketoconazole (antifungal), erythromycin (antibiotic), diltiazem (cardiovascular), verapamil (CV), nifedipine (CV), grapefruit juice, cyclosporine (transplant), cimetidine (H-2 blocker) n CYP 3 A 4 inducers – Decrease imatinib concentrations – Phenytoin (anti-seizure), carbamazepine (anti-seizure), dexamethasone (steroid), St. John’s Wort, rifampin
Drug–Drug Interactions (cont. ) n Imatinib mesylate may affect levels of other CYP 3 A 4, CYP 2 C 9, or CYP 2 D 6 substrates n Use caution when coadministering these substrates that have a narrow therapeutic window – Substitute low-molecular weight or standard heparin for warfarin (CYP 3 A 4 and CYP 2 C 9 substrate)
Imatinib Mesylate has Revolutionized the Treatment of CML n Therapy specifically designed to target the molecular cause of CML – Potent and selective inhibitor of Bcr-Abl n Outstanding rates of rapid hematologic and cytogenetic responses in all stages of disease n Significant Improvement in survival and delay in the time of disease progression in all phases of CML n Excellent side-effect profile – Most adverse events were mild to moderate in severity n 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 + otherapies
Concepts for the Future: Optimizing Therapy n 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 n Additional molecular targets – Kit – PDGF-R n Relationship to prognosis and malignant transformation is unknown n Tumors associated with these targets – Sarcomas – Lung cancer – Prostate cancer – Gliomas and neuroblastomas – Breast cancer – Seminomas and germ-cell tumors n Evidence for mutations leading to constitutive activation
Imatinib Mesylate: Kit Targets n GISTs – Study 2222 • Immunohistochemically Kit+, unresectable or metastatic disease n 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 n Prostate cancer – Study 0201 • Single-agent therapy in hormone-refractory prostate cancer (HRPC) – Study 0210 • Neoadjuvant therapy in prostate cancer n Glioma – Study 0204 • Imatinib mesylate in adult glioma – Study of recurrent pediatric glioma planned n Breast cancer – Study 0206 • Imatinib mesylate in combination with standard chemotherapy in advanced breast cancer
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