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Treatment of Newly Diagnosed CML Mechanisms of Imatinib Resistance Neil Shah, MD, PhD Assistant Professor Division of Hematology/Oncology UCSF School of Medicine San Francisco, CA Chronic Myelogenous Leukemia Background Chronic Myelogenous Leukemia (CML) • • • • CML is a malignant myeloproliferative disorder that originates from neoplastic transformation of hematopoietic progenitor cells All patients express the BCR-ABL hybrid gene and its protein product – an active tyrosine kinase protein that triggers intracellular abnormal signaling pathways, resulting in disordered myelopoiesis with accelerated cell growth, decreased apoptosis, and weakened cellular adhesion Characterized by either a biphasic or triphasic progressive course The cytogenetic hallmark of the disease is the presence of the Philadelphia chromosome Kantarjian et al., 2007. CML – Phases of Disease Phase Chronic Phase Accelerated Phase Blast Phase Characteristics • Indolent course, often asymptomatic and found incidentally on routine physical exam • Predominance of mature white blood cells • Approximately 90% of patients are diagnosed at this stage • Median survival is 4–7 years (pre-tyrosine kinase inhibitor [TKI] therapy) • Transition generally occurs over a period of 1 year or more. Duration is 6 months to 1 year • Associated with progressive leukocytosis, thrombocytosis or thrombocytopenia, basophilia, increased blasts, splenomegaly, fever, bone pain • Clonal evolution may be present • Lasts only a few months – survival is poor if untreated • Associated with increasing blasts (>20%), progressive splenomegaly despite treatment, and clonal evolution National Comprehensive Cancer Network, 2007; National Cancer Institute, 2007; Calabretta & Perrotti, 2004; Cortes et al., 2006. Historical Perspective Medical Treatment of CML 1954 FDA approval of busulfan for the palliative treatment of CML 1960 Philadelphia chromosome discovered in CML cells 1983 First published report on interferon activity in CML – First molecular description of the BCR-ABL gene 1993 Preclinical testing of STI571 (imatinib) – the first therapy developed to target a known gene-based cause of cancer 1995 Interferon alfa-2a approved for treatment of Philadelphia chromosome-positive CML patients who are minimally pretreated (within 1 year of diagnosis) 2001 Imatinib FDA-approved as first-line therapy for CML 2006 Dasatinib FDA-approved for treatment of all phases of CML in with resistance or intolerance to prior imatinib therapy 2007 Nilotinib FDA-approved for imatinib-resistant or -intolerant chronic and accelerated phase CML Savona & Talpaz, 2006. Selection of Initial Treatment Strategies for Patients with CML Treatment Selection • Options for treating patients with newly diagnosed CML have changed since the introduction of imatinib • NCCN recommendations for treatment of newly diagnosed CML (chronic or accelerated phase) include three primary options: – Imatinib – Stem cell transplant – Clinical trial NCCN, 2007. Imatinib Mesylate for Patients with Newly Diagnosed CML in Chronic Phase: Long-Term Benefit (Update from the IRIS Study) Patients on Study/Discontinuations At 6 Years First-line imatinib (N = 553) • On imatinib study treatment 66% • Discontinuation/crossover 34% – Side effects/other AEs 5% – Deaths (CML - unrelated) 2% – Lack of efficacy/progression 14% – Withdrawal of consent 6% – Other reason (incl. SCT, lost to follow-up) 8% AE, adverse event; CML, chronic myeloid leukemia; SCT, stem cell transplant Event-Free Survival and Survival Without AP/BC on First-Line Imatinib (IRIS Study) 100 90 % without event 80 70 Estimated rate at 60 months (with 95% CI) 60 Survival without AP/BC Event-free Survival 50 40 93% 83% (90-96) (80-87) Events 6.3% AP/BC (N = 35) 5.1% loss of MCyR (N = 28) 2.5% loss of CHR (N = 14) 1.6% CML-unrelated deaths (N = 9) 30 20 10 0 0 6 12 18 24 30 36 42 48 54 60 66 Months since randomization Druker et al., 2006. Overall Survival on First-Line Imatinib (ITT Principle) 100 90 80 % aAlive 70 60 50 40 Estimated rate at 60 months (with 95% CI) 30 20 Without CML-related deaths 95.4% (93-98) Overall Survival 89.4% (86-92) 10 0 0 6 12 18 24 30 36 42 48 Months since randomization 54 60 66 Druker et al., 2006. Declining Annual Event Rates 8 7.5 % Annual Rates 7 Event 6 • • 4.8 5 • • 4 AP/BC 3.3 2.8 3 2 Loss of CHR Loss of MCyR AP/BC Death during treatment 1.6 1.5 1.5 0.9 1 0.8 0.5 0.4 0 0 Year 1st 2nd 3rd 4th 5th 6th Epidemiology Estimated New Cases Estimated Deaths CML Both Men Women Both Men Women 1997 4,300 2,400 1,900 2,400 1,400 1,000 2007 4,570 2,570 2,000 490 240 250 The annual mortality rate has been reduced from 15% to 20% to ~2% and median survival is expected to exceed 15 to 20 years based on current data. Parker et al., 1997. Jemal et al., 2007. Alvarez et al., 2007. IRIS Study at 6-Year Follow-up Conclusions • Imatinib is confirmed as the standard first-line therapy for all CML patients – 88% overall survival with imatinib exceeds that of all other CML therapies with less than 5% patients dying from CML – During the 6th year there was 0% transformation to AP/BC – 82% of patients treated with imatinib achieved a CCyR – 63% of all imatinib randomised patients are still in CCyR and on study treatment – Responses are durable and the annual risk of progression is decreasing with time – No new safety findings seen with long term follow-up Allogeneic Stem Cell Transplantation Influence of Age on Survival Post-HSCT in Chronic Phase (CP) CML < 20 years (N = 14) Probability of Survival 1.0 ≥ 20 and < 30 years (N = 50) 0.8 0.6 ≥ 30 and < 40 years (N = 81) 0.4 ≥ 50 years (N = 19) ≥ 40 and < 50 years (N = 51) 0.2 0 0 5 10 Years 15 20 N = 215, 1982-1997. Thomas ED et al. Ann Intern Med. 1986;104:155-163 and findings noted by Radich J, MD (written communication, January 2007). Findings noted by Radich J, MD (written communication, January 2007). Related Transplants (≥ 1992) Cumulative Proportion Surviving Survival in Early Chronic Phase by Year of Referral Years from Referral Univ. of Texas, MD Anderson Cancer Center Database 1965-2005 Selection of Initial Treatment Options for CML Patients: Conclusions • With six years of follow-up data available, imatinib can be considered standard first-line therapy for adult CML patients – 88% overall survival with imatinib in chronic phase CML exceeds that of all other CML therapies (< 5% patients dying from CML) – During the 6th year of imatinib therapy, there was 0% transformation to AP/BC • Bone marrow transplantation has known curative potential, but is associated with substantial treatmentrelated morbidity and mortality • Patients with advanced phase CML should be considered for allo-SCT following TKI-induced remission whenever possible Laboratory Tests to Determine Response Methods of Assessing Treatment Response Type of Response Test Hematologic Complete Blood Count Cytogenetic Bone Marrow Metaphase* Molecular Peripheral Blood PCR * Cytogenetic response is based on analysis of at least 20 metaphases Deininger, 2005; National Comprehensive Cancer Network, 2007. The Philadelphia Chromosome and BCR-ABL Chromosome 22 9 q+ 9 Chromosome 9 c-BCR 1 2-11 Ph (or 22q-) 22 2-11 2-11 BCR BCR-ABL c-ABL P210 BCR-ABLl P185 BCR-ABL Exons ABL Fusion protein with tyrosine kinase activity t (9;22) translocation Introns CML breakpoints ALL breakpoints BCR-ABL gene structure Faderl et al.,1999; Melo, 1996. Diagnostic Evaluation: Bone Marrow Diagnostic Study Aspirate Biopsy Clinical Significance • Evaluation of morphological abnormalities of hematopoietic precursors (myeloid vs. lymphoid and stage of maturation). • Used for flow cytometry, fluorescence in situ hybridization (FISH), or polymerase chain reaction (PCR) analysis and cytogenetics. • Evaluate cellularity, topography, presence of fibrosis • Evaluate for possible non-random chromosomal abnormalities. Usually based on evaluation of 20 or more metaphases. Cytogenetics • Two metaphases is considered non-random. • Useful for detection of emerging additional chromosomal abnormalities in patients with or without the presence of the Philadelphia chromosome. • Still the only FDA-approved test for defining complete cytogenetic remission. FISH • Low false positive rate. • Does not replace regular cytogenetics to detect additional cytogenetic abnormalities. Hughes, 2006. Definitions of Treatment Response Level of Response Definition Complete hematological response Normal CBC and differential, no extramedullary disease Major cytogenetic response 0-35% Ph-positive metaphases* - Partial cytogenetic response 1%-35% Ph-positive metaphases* - Complete cytogenetic response 0% Ph-positive metaphases* Major molecular response ≥ 3-log reduction of BCR-ABL mRNA from baseline Complete molecular remission Negativity by RT-PCR * Cytogenetic response is based on analysis of at least 20 metaphases Deininger, 2005; National Comprehensive Cancer Network, 2007. Frequency of Response Evaluation • NCCN recommends hematologic, cytogenetic, and molecular measures at baseline and at regular intervals after initiation of TKI therapy – Hematological parameters are monitored regularly to evaluate for response and treatment toxicity – Bone marrow metaphase cytogenetics at diagnosis and every 6 and 12 months thereafter until a complete cytogenetic response is achieved – PCR at diagnosis and every 3 months thereafter NCCN, 2007. Molecular Analysis in CML • Real-time PCR reaction is highly useful for analysis of treatment response in CML, since the majority of chronic phase patients will achieve a CCyR • PCR should be assessed on peripheral blood and should be consistently performed by a single specialized laboratory to minimize variance • The real time PCR provides additional prognostic discrimination to the karyotype • Increasing BCR-ABL levels measured by PCR may provide an early indication for disease resistance or progression Hughes, 2006. Imatinib Overall Estimated Log Reduction of BCR-ABL: IRIS Study Updated Results 100 8% 90 19% 18% 13% 29% Patients (%) 80 20% 70 34% 60 25% 50 4 log 3 to < 4 log 2 to < 3 log < 2 log No CCyR 40 30 20 75% 50% 32% 26% 24% 3 6 12 18 24 10 0 Time (months) Adapted from Hughes T et al. N Engl J Med. 2006;349:1423-1432. CML Monitoring Strategy Test Time Indication Cytogenics Diagnosis Establish disease stage Q 6 months Assess imatinib response until CCyR After CCyR Q 12 months to look for newly acquired cytogenetic changes post-BCR-ABL increases Diagnosis Establish BCR-ABL transcript level After CCyR Q 3 months Monitor for MMR (> 3 log decrease) or increase in BCR-ABL Diagnosis Advanced phase disease Anytime If no/poor response, relapse, or increasing BCR-ABL PCR ABL point mutation analysis National Comprehensive Cancer Network. Clinical Practice Guideline in Oncology v.1.2007: Chronic Myelogenous Leukemia. Definitions of Imatinib Resistance Imatinib Resistance and Intolerance in Chronic Phase CML: Definitions • Resistance can be defined as primary (lack of acceptable initial response) or secondary (loss of an established response) – Primary hematologic resistance refers to failure to achieve a CHR within 3-6 months of initiating imatinib (~2-4 % of cases*) – Primary cytogenetic resistance can be defined as: • Lack of any cytogenetic response by 6 months (~22% of cases* - IRIS study) • Lack of MCyR by 12 months (~15% of cases* - IRIS) • Lack of CCyR by 18 months (~25% of cases* - IRIS) • Secondary resistance refers to progression after an established hematologic or cytogenetic response • Intolerance can be defined as the inability to tolerate at least 400 mg imatinib daily despite reasonable supportive measures (< 5% with G3/G4 toxicities; % of patients with persistent G2 toxicities leading to drug discontinuation presently not well-defined) *These categories are NOT mutually exclusive Imatinib Event-free Survival by MCyR at 12 Months Patients without events (%) 100 90 80 P <.001 70 60 50 40 30 Estimated rate at 42 months 20 MCyR No MCyR 10 N = 436 N = 66 91% (95% CI, 88-94) 66% (95% CI, 53-78) 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Time (months since randomization) Adapted from O’Brien SG et al. N Engl J Med. 2003;348:994-1004; Findings noted by Druker B, MD (written communication, January 2007). EFS by Response at 12 Months Impact of Major Molecular Remission (MMR) 100 90 80 70 60 50 Estimated rate at 54 months 40 CCyR with ≥ 3 log reduction 30 97% 89% 72% CCyR with <3 log reduction No CCyR 20 P = 0.017 P < 0.001 10 0 0 6 12 18 24 30 36 42 Months since randomization 48 54 60 Imatinib Survival Without Accelerated Phase/Blast Crisis by Molecular Response: IRIS Study Patients without AP/BC (%) 100 90 80 70 60 50 Response at 18 months 40 Estimated rate at 60 months P = 0.11 30 CCyR with 3 log reduction (N = 139) 100% 20 CCyR with < 3 log reduction (N = 54) 98% No CCyR 87% P < 0.001 54 60 10 (N = 88) 0 0 6 12 18 24 30 36 42 48 66 Time (months since randomization) Druker B et al. N Engl J Med. 2006;355:2408-2417. Imatinib Resistance at 42-48 Months Not resistant to imatinib Resistant to imatinib Early Chronic Phase = 16% Late Chronic Phase = 26% Accelerated Phase = 73% • • Blast Phase = 95% Early chronic phase patients (disease duration not greater than 6 months) were followed for 42 months All other patients had been previously treated with interferon and were followed for 48 months Shah et al. Hematology (Am Soc Hematol Educ Program). ;183-187, 2005. Clinical Resistance to Imatinib Mechanisms Clinical Resistance to Imatinib Mechanisms • Primary Resistance – Insufficient inhibition of BCR-ABL • Can be due to low plasma levels, activity of drug pumps, etc Primary Cytogenetic Resistance Correlation of Response with Imatinib Plasma Levels Day 29 551 pts Rx with imatinib 400 mg/D Trough PK plasma levels on day 1 and 29 100 1 yr 4 yr Percentage 80 60 40 20 0 <647 ng/ml 6471170 ng/ml >1170 ng/ml <647 ng/ml 6471170 ng/ml CCR MMR P = 0.005 P = 0.03 >1170 ng/ml Larson et al. ASH 2006.(Abst# 429) Clinical Resistance to Imatinib Mechanisms • Primary Resistance – Insufficient inhibition of BCR-ABL • Can be due to low plasma levels, activity of drug pumps, etc – Individual variation in normal bone marrow reserve (low levels of normal hematopoietic stem cells in some patients) Clinical Resistance to Imatinib Mechanisms • Primary Resistance – Insufficient inhibition of BCR-ABL • Can be due to low plasma levels, activity of drug pumps, etc – Individual variation in normal bone marrow reserve (low levels of normal hematopoietic stem cells in some patients) • Secondary resistance – Outgrowth of one or more clones harboring an imatinib-resistant BCR-ABL kinase domain mutation (most common) BCR-ABL Kinase Domain Mutations Associated with Clinical Resistance to Imatinib (Incomplete Map) L298V E292V x P C A Gorre et al, 2001; von Bubnoff et al, 2002; Branford et al, 2002; Hofmann et al, 2002; Roche-L’Estienne et al, 2002; Shah et al, 2002; Hochhaus et al, 2002; Al-Ali et al, 2004 Courtesy Tim Hughes Clinical Resistance to Imatinib Mechanisms • Primary Resistance – Insufficient inhibition of BCR-ABL • Can be due to low plasma levels, activity of drug pumps, etc – Individual variation in normal bone marrow reserve (low levels of normal hematopoietic stem cells in some patients) • Secondary resistance – Outgrowth of one or more clones harboring an imatinib-resistant BCR-ABL kinase domain mutation (most common) – Overproduction of BCR-ABL (e.g. via genomic amplification) BCR-ABL Gene Amplification Associated With Clinical Imatinib Resistance MB13 Imatinib MB14 Imatinib Chemotherapy Gorre et al, Science, 293:876, 2001 Clinical Resistance to Imatinib Mechanisms • Primary Resistance – Insufficient inhibition of BCR-ABL • Can be due to low plasma levels, activity of drug pumps, etc – Individual variation in normal bone marrow reserve (low levels of normal hematopoietic stem cells in some patients) • Secondary resistance – Outgrowth of one or more clones harboring an imatinib-resistant BCR-ABL kinase domain mutation (most common) – Overproduction of BCR-ABL (e.g. via genomic amplification) – BCR-ABL-independent mechanisms (poorly understood) Role of Kinase Conformation in Imatinib Resistance • Point mutations in BCR-ABL kinase domain can destabilize the inactive conformation Mutations that directly affect imatinib binding Mutations that affect the conformation required to bind imatinib Shah NP et al. Cancer Cell. 2002;2:117-125. Mode of Dasatinib Binding to ABL Kinase Nilotinib has a Better Fit to the Binding Pocket Imatinib (Glivec®) IC50 669 nM Nilotinib (Tasigna®) IC50 25nM • Rationally designed highly specific inhibitor of BCR-ABL • 30x more potent than imatinib; maintains target specificity • No significant effect on other kinases • (Src, FLT3, VEGFR, EGFR, InsR, RET, MET, IGFR, etc) Comparison of Imatinib and Two New BCR-ABL Inhibitors: Nilotinib and Dasatinib 25-fold more potent than imatinib 325-fold more potent than imatinib • Preclinical evidence predicts that nilotinib and dasatinib will have significant activity against BCR-ABL kinase domain mutations and BCR-ABL overexpression, the two most common mechanisms of imatinib resistance • Both agents lack activity against the BCR-ABL T315I mutation Shah et al. 2004; Weisberg et al. 2005; O'Hare et al.2005; Permission pending. Bosutinib A Dual Inhibitor of Src and Abl Kinases Cl Cl HN O O N O CN N N Src Enzyme (Elisa) IC50 = 1.2 nM Src Enzyme (Lance) IC50 = 3.8 nM Abl Enzyme IC50 = 1.4 nM K562 Cell IC50 = 20 nM KU812 Cell IC50 = 4.3 nM Boschelli et al. J Med Chem. 2005;48:3891-3902. Golas et al. Cancer Res. 2003;63:375-381. Golas et al. Cancer Res. 2005;65:5358-5364. Puttini et al. Cancer Res 2006; 66:11314-22 SKI-606 (Bosutinib) Preclinical Summary • Orally bioavailable, potent dual Src/Abl inhibitor • Minimal inhibitory activity against PDGF-R, c-kit • Inhibits BCR-ABL signaling in CML cells • Active against imatinib-resistant mutants of BCR-ABL, except T315I Investigational Abl Kinase Inhibitors • Second generation - T315I-ineffective (in vitro) – Bosutinib – INNO-406 • Third generation - T315I-effective (in vitro) – MK-0457 (VX-680) – PHA-739358 – XL228 – AP23464 MK-0457 in Advanced Leukemias • Aurora kinase/BCR-ABL inhibitor • N = 44; median follow-up 6 months • All imatinib pretreated • 50% dasatinib pretreated; 50% nilotinib pretreated • Major toxicity – myelosuppression • Doses > 20 mg/day (primarily in T315I-positive patients) – 3 patients achieved MinHR – 3 patients achieved MHR – 1 patient achieved MinCyR – 2 patients achieved PCyR – 1 patient achieved CCyR Giles et al., 2007. Imatinib Intolerance Definitions • For clinical trial purposes of second generation TKIs, a strict definition of imatinib intolerance has been utilized – e.g. grade 3/4 non-hematologic toxicity or grade 4 hematologic toxicity persisting for >7 days • With the approval of dasatinib and nilotinib, imatinib intolerance should include an inability to tolerate a minimally effective dose of imatinib (at least 300 mg daily) – It is not expected that a trial of a second generation agent (to determine if the side effect profile is preferable to imatinib) will impair the long-term outcome of the patient, or the ability of the patient to be successfully retreated retreated with imatinib if the second generation agent is found not to be more tolerable Key Concepts • Long-term data confirm a survival advantage in CP patients treated with imatinib – CML-related deaths after six years are lower than what would be expected with allo-SCT • Careful monitoring is essential to determine if patients are responding adequately to TKI therapy, and to identify patients who may benefit from alternative treatment strategies • The mechanism of action of dasatinib and nilotinib and other novel TKIs involves their activity against imatinib-resistant BCR-ABL kinase domain mutants and increased potency of BCR-ABL inhibition • Patients who are unable to tolerate at least 300 mg imatinib daily, or who are considering skipping doses due to side effects, may be considered imatinib-intolerant and eligible for alternative treatment strategies • Allo-SCT should be used as a bridge to consolidate TKI-mediated remissions in advanced phase CML whenever possible Case Study • A 32-year old man is referred for recently discovered leukocytosis of 234K, which was noted in blood work performed after he presented to his primary care physician with left shoulder pain and ongoing night sweats • He was found to have substantial splenomegaly • His differential was notable for the presence of 4% basophils, immature granulocytes, and 8% blasts • Bone marrow biopsy reveals a hypercellular marrow with 9% blasts and an M:E ratio of 10:1, consistent with a myeloproliferative disorder • Cytogenetics reveal a t (9;22) in all 20 metaphases analyzed • He has four siblings, and no other medical history, and would like to know how he should be treated Case Study Question 1 Which therapeutic option would you recommend? Allo-SCT as soon as possible, with imatinib until pre-transplant workup can be completed Imatinib 400 mg daily with deferral of allo-SCT unless there is evidence of resistance to imatinib/TKI therapy Imatinib 600 mg daily with deferral of Allo-SCT unless there is evidence of resistance to imatinib/TKI therapy Dasatinib 100 mg daily Nilotinib 400 mg bid Interferon 3 MU tiw Clinical trial Case Study Question 1 Which therapeutic option would you recommend? Allo-SCT as soon as possible, with imatinib until pre-transplant workup can be completed Imatinib 400 mg daily with deferral of allo-SCT unless there is evidence of resistance to imatinib/TKI therapy Imatinib 600 mg daily with deferral of Allo-SCT unless there is evidence of resistance to imatinib/TKI therapy Dasatinib 100 mg daily Nilotinib 400 mg bid Interferon 3 MU tiw Clinical trial Recommended approach: • • Imatinib 400 mg daily Clinical trial Case Study • The patient initiates imatinib 400 mg daily, which he tolerates generally well, with the exception of peripheral edema and nausea • One month later, CBC reveals a complete hematologic response (CHR) • He visits your office three months after initiating imatinib, and continues to have a CHR Case Study Question 2 How would you monitor the patient’s disease? A. B. CBC alone every 6-12 weeks Choice (A) with a bone marrow biopsy every six months until achievement of a CCyR C. CBC every 6-12 weeks with peripheral blood BCR-ABL FISH every three months D. Choice (C) with a bone marrow biopsy every six months until achievement of a CCyR E. CBC every 6-12 weeks with peripheral blood BCR-ABL PCR every three months F. Choice (E) with a bone marrow biopsy every six months until achievement of a CCyR Case Study Question 2 How would you monitor the patient’s disease? A. B. CBC alone every 6-12 weeks Choice (A) with a bone marrow biopsy every six months until achievement of a CCyR C. CBC every 6-12 weeks with peripheral blood BCR-ABL FISH every three months D. Choice (C) with a bone marrow biopsy every six months until achievement of a CCyR E. CBC every 6-12 weeks with peripheral blood BCR-ABL PCR every three months F. Choice (E) with a bone marrow biopsy every six months until achievement of a CCyR Recommended approach: E + F • CBC q 6-12 weeks with peripheral blood BCR-ABL PCR q 3 months, with bone marrow biopsy q 6 months until achievement of a CCyR Case Study • Six months after initiating imatinib therapy, the patient continues to have a CHR • PCR analysis reveals a one-log decline in disease burden compared with baseline • You inform him that a bone marrow biopsy will be performed to allow an accurate assessment of his chromosome response • You state that you wish to observe some level of cytogenetic response • The patient is wondering about the likelihood of having no cytogenetic response at this time Case Study Question 3 You inform him that the percent of chronic phase CML patients who receive imatinib as primary therapy and have no cytogenetic response after six months is approximately: 4% 8% 13% 18% 22% 27% Case Study Question 3 You inform him that the percent of chronic phase CML patients who receive imatinib as primary therapy and have no cytogenetic response after six months is approximately: 4% 8% 13% 18% 22% 27% Answer: • 22% Case Study Question 4 In reality, the patient’s marrow reveals 9 of 20 Ph+ metaphases. Your recommendation at this time is: Continue imatinib 400 mg daily Increase imatinib to 400 mg twice daily Switch to dasatinib 100 mg once daily Switch to dasatinib 70 mg twice daily Switch to nilotinib 400 mg twice daily Referral for allo-SCT Case Study Question 4 In reality, the patient’s marrow reveals 9 of 20 Ph+ metaphases. Your recommendation at this time is: Continue imatinib 400 mg daily Increase imatinib to 400 mg twice daily Switch to dasatinib 100 mg once daily Switch to dasatinib 70 mg twice daily Switch to nilotinib 400 mg twice daily Referral for allo-SCT Recommended approach: • Continue 400 mg daily Case Study • • • Twelve months after initiating imatinib, the patient’s bone marrow biopsy reveals 3/20 Ph+ metaphases. Six months later, bone marrow biopsy reveals 8/20 Ph+ metaphases. The patient assures you that he has been compliant with therapy. Case Study Question 5 You inform him that his loss of cytogenetic response is most likely due to: A low plasma level of imatinib A resistant mutation in the BCR-ABL kinase domain Overexpression of BCR-ABL Activation of a parallel oncogenic pathway, such as SRC Case Study Question 5 You inform him that his loss of cytogenetic response is most likely due to: A low plasma level of imatinib A resistant mutation in the BCR-ABL kinase domain Overexpression of BCR-ABL Activation of a parallel oncogenic pathway, such as SRC Answer: • A resistant mutation in the BCR-ABL kinase domain Case Study • You send his blood for mutation testing – Results indicate the presence of an imatinib-resistant BCR-ABL kinase domain mutation, L387M • He wants to know if there are other promising drugs available for him • You inform him that two agents, dasatinib and nilotinib, are approved for patients with imatinib-resistant chronic phase CML • He asks how these drugs will work when imatinib has failed Case Study Question 6 You inform him that dasatinib and nilotinib are effective because: A. They are effective against all imatinib-resistant mutations B. They are effective against most imatinib-resistant mutations C. They are more potent than imatinib A+C B+C None of the above Case Study Question 6 You inform him that dasatinib and nilotinib are effective because: A. They are effective against all imatinib-resistant mutations B. They are effective against most imatinib-resistant mutations C. They are more potent than imatinib A+C B+C None of the above Answer: B + C • They are effective against most imatinib-resistant mutations AND they are more potent than imatinib Treatment of Newly Diagnosed CML Mechanisms of Imatinib Resistance Concluding Remarks