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Profiles in CML: Overview of Practice Challenges. Moshe Talpaz, MD Professor Department of Internal Medicine, Hematology-Oncology University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan. Chronic Myelogenous Leukemia (CML).

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Profiles in CML: Overview of Practice Challenges


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    1. Profiles in CML: Overview of Practice Challenges Moshe Talpaz, MDProfessor Department of Internal Medicine, Hematology-OncologyUniversity of Michigan Comprehensive Cancer CenterAnn Arbor, Michigan

    2. Chronic Myelogenous Leukemia (CML) • Abnormal clonal hematopoietic stem cell disorder, increased proliferation,
 decreased apoptosis and adhesion • Chronic, accelerated, and blastic phases • Ph t(9;22) (q34;q11) cytogenetic and
 BCR-ABL molecular abnormalities

    3. CML—A Myeloproliferative Disorder Normal CML Chronic-Phase Courtesy of John K. Choi, MD, PhD.

    4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 X Y 19 20 21 22 CML Is Linked to a Single Cytogenetic 
Abnormality—The Philadelphia Chromosome Stoll C, et al. Blood. 1978;52:828-838.

    5. The Philadelphia Chromosome and BCR-ABL Chromosome 22 Chromosome 9 9 q+ 9 2-11 c-BCR 1 c-ABL Ph (or 22q-) 22 2-11 p210BCR-ABL 2-11 BCR p190BCR-ABL BCR-ABL Exons Introns CML breakpoints ALL breakpoints ABL FUSION PROTEINWITH TYROSINEKINASE ACTIVITY BCR-ABL gene structure t(9;22) translocation Faderl S, et al. N Engl J Med. 1999;341:164-172. Melo JV. Blood. 1996;88:2375-2384.

    6. q34 Chromosome 22 (q34;q11) Chromosome 9 t(9;22) BCR wwwww BCR-ABL q11 wwwwwwwww wwwwwww wwwwwwww ABL BCR ABL 210 KD protein Faderl S, et al. N Engl J Med. 1999;341:164-172. Melo JV. Blood. 1996;88:2375-2384.

    7. The Clinical Course of Untreated CML Advanced Phases Chronic Phase Accelerated Phase Blast Crisis Median duration5–6 years Median duration6–9 months Median survival3–6 months Faderl S, et al. Ann Intern Med. 1999;131:207-219. Pasternak, G et al. J Cancer Res Clin Oncol. 1998;124:643-660.

    8. Incidence and Mortality Of CML Based on current data, median survival is expected to exceed 15–20 years. Parker SL, et al. CA Cancer J Clin. 1997;47:5-27. Jemal A, et al. CA Cancer J Clin. 2007;57:43-66..

    9. Survival in Early Chronic Phase CML With permission from Quintas-Cardama A, et al. Mayo Clin Proc. 2006;81:973-988.

    10. IRIS Study in Chronic Phase CML—7-Year Update 1106 patients originally enrolled, 553 per arm Estimated overall survival at 7 years: 86% Late-progression events Kaplan-Meier estimate of event-free survival at 7 years: 81% Kaplan-Meier estimated rate without accelerated phase/blast crisis at 7 years: 93% Safety Grade 3/4 events decreased in incidence after years 1–2 No unique, previously unreported adverse events emerged O’Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Abstract 186.

    11. IRIS Overall Survival (ITT Principle)Imatinib Arm Estimated overall survival at 7 years is 86% (94% considering only CML-related deaths) Probability of Survival Survival: deaths associated with CML Overall survival Months Since Randomization Abbreviation: ITT, intent to treat. With permission from O’Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Abstract 186.

    12. Annual Event Rates—Imatinib Arm • KM estimated EFS at 7 years = 81% • KM estimated rate without AP/BC at 7 years = 93% Event Loss of CHR, Loss of MCR, AP/BC, Death during treatment AP/BC % with Event a Year aTotal events (n = 5), including loss of MCR (n = 3) and deaths (n = 2, one of which was coded a progression to AP/BC in a patientin CHR 6 months prior to death). Abbreviations: AP/BC, accelerated phase/blast crisis; CHR, complete hematologic response; EFS, event-free survival; MCR, major cytogenic response; KM, Kaplan-Meier. With permission from O’Brien SG, et al. 50th Annual ASH Meeting; December 6-9, 2008. Abstract 186.

    13. IRIS 7-Year Update—Key Findings • Overall survival: 86% • Event-free survival: 81% • 7% progression to accelerated phase/blast crisis (AP/BC) • Complete cytogenetic response (CCR) achieved by 456/553 (82%) patients • 17% subsequently lost CCR • 3% progressed to AP/BC • 2% died from CML • Time to CCR did not correlate with the rate of progression to AP/BC • Major molecular response rates and depth of molecular response increased over time • While imatinib is efficacious, it does not work for all patients O’Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Abstract 186.

    14. Imatinib Resistance • BCR-ABL specific • Mutations • >50 described with variable degrees of impact • ~50% of patients • Amplification or overexpression • ~7-10 % 50%–60% • BCR-ABL independent • Cellular pharmacology • Drug import/export • Other pathways • Wnt, notch • Autocrine factors • Lyn (other Src-family kinases) 40%–50% Courtesy of M. Talpaz, MD.

    15. C C A A A‘ A‘ M M M M M CC A A A A A‘ M M C C C A A A L C C C C M M M C C C C A A‘ CC C‘ A A‘ M C C A A B C C C C A A M‘ C A‘ A C C‘ A AA‘ C A A M‘ A C M P-Loop KD A-Loop M244V L248V D267G T315I M351T L387F/M G250E/R T277A F317L E355G H396R Q252H F311L L324Q F359C/V A397P Y253F/H V379I E255K/V 24 Mutations in 19 Amino Acids 5 patients had 2 or more mutations (‘). Gorre ME, et al. Science. 2001;293:876-880. von Bubnoff N, et al. Lancet. 2002;359:487-491. Branford S, et al. Blood. 2002;99:3472-3475. Hofmann W-K, et al. Blood. 2002;99:1860-1862. Roche-Lestienne C, et al. Blood. 2002;100:1014-1018. Shah NP, et al. Cancer Cell. 2002;117-125. Hochhaus A, et al. Leukemia. 2002;16:2190-2196. Al-Ali HK, et al. Hematol J. 2004;5:55-60.

    16. Role of Kinase Conformation in Imatinib Resistance Point mutations in BCR-ABL kinase domain restricts its ability to adopt an inactive conformation Mutations thatdirectly affect imatinib binding Mutations that affect the conformation requiredto bind imatinib With permission from Schindler T, et al. Science. 2000;289:1938-1942. With permission from Lombardo LJ, et al. J Med Chem. 2004;47:6658-6661.

    17. Ba/F3 Bcr-Abl E255K T315I M351T M244V G250E Q252H Q252R Y253F Y253H E255V F317L E355G F359V H396R F486S Dasatinib Inhibits the Growth of Most
Imatinib Mesylate—Resistant BCR-ABL—Expressing Ba/F3 Cell Lines In Vitro 1.2 Parental Ba/F3 cells 1.0 T315I 0.8 Relative Growth After48 h of Drug Exposure 0.6 E255K 0.4 Wild-typeBCR-ABL 0.2 M351T 0 0 0.5 2.5 5 25 50 Concentration of Dasatinib (nM) With permission from Shah NP, et al. Science. 2004;305:399-401.

    18. Imatinib 20 Dasatinib Nilotinib 15 % BCR-ABL Mutation 10 5 0 F3111 F317L V299L T315I E255K G250E M351T E355G/A F359C/V H396R/P Y253H/F Spectrum and Frequency of BCR-ABL Kinase Domain Mutations Developing During Treatment with Imatinib, Dasatinib, and Nilotinib The solid color corresponds to the 1st amino acid change; the broken color corresponds to the 2nd amino acid change if applicable. With permission from Cortes J, et al. Blood. 2007; 110:4005-4011.

    19. Case 1: AK Neil P. Shah, MD, PhDAssistant Professor Division of Hematology/OncologyUCSF School of MedicineSan Francisco, California

    20. AK33-Year-Old Male • Referred for recently discovered leukocytosis of 253K noted in blood work performed after he presented to his primary care physician with left shoulder pain and ongoing night sweats • Palpable splenomegaly • Differential: 3% basophils, immature granulocytes, and 2% blasts • Bone marrow biopsy revealed: hypercellular marrow with 4% blasts and an M:E ratio of 10:1, consistent with a myeloproliferative disorder • Cytogenetics: t(9;22) in all 20 metaphases analyzed • AK has 2 siblings and no other significant medical history

    21. Decision Point 1 What is the appropriate first-line treatment for this patient? • Hematopoietic stem cell transplantation • Imatinib • Dasatinib • Nilotinib • Interferon alpha

    22. AK • Imatinib 400 mg daily is initiated • AK tolerates therapy well, with the exception of peripheral edema, mild nausea, and muscle cramps • 1 month later, CBC reveals a complete hematologic response (CHR) • 6 months after initiating therapy, AK continues to have a CHR. Bone marrow aspiration is performed, and the t(9;22) translocation is detected in 5/20 metaphases • 12 months after initiating therapy, only 2/20 bone marrow metaphases contain the t(9;22) translocation • 6 months later, despite continuing to have a CHR, marrow metaphase analysis reveals the t(9;22) translocation in 18/20 metaphases

    23. Decision Point 2 What is your next step? • Assess patient compliance • Do a mutational analysis • Increase imatinib dosage • Switch to dasatinib or nilotinib • Refer for allogeneic stem cell transplantation • All of the above

    24. AK • AK states that he has been very compliant with therapy • BCR-ABL kinase domain mutation test is ordered; the imatinib dose is increased to 800 mg daily • AK experiences increased fatigue, nausea, and edema on this dose • 3 months after imatinib dose escalation • CBC: WBC of 18K with immature forms and 3% basophils • Mutation analysis: E255K mutation in a large proportion of cells

    25. L248V G383D L298V F311L/I L387F/M G250E/A/F A397P E453G/K E292V T315I/N M388L Q252H/R E459K/Q E450G/Q H396R/P Y253H/F F317L F486S S417Y L364I E255K/V x A C P V379I D276G M351T M244V E355G/D T277A V289A E279K F359C/V/D/I E281A (Incomplete) Map of BCR-ABL Kinase Domain Mutations Associated with Clinical Resistance to Imatinib Abbreviations: P, P-loop; C, catalytic domain; A, activation loop. Gorre ME, et al. Science. 2001;293:876-880. von Bubnoff N, et al. Lancet. 2002;359:487-491. Branford S, et al. Blood. 2002;99:3472-3475. Hofmann W-K, et al. Blood. 2002;99:1860-1862. Roche-Lestienne C, et al. Blood. 2002;100:1014-1018. Shah NP, et al. Cancer Cell. 2002;117-125. Hochhaus A, et al. Leukemia. 2002;16:2190-2196. Al-Ali HK, et al. Hematol J. 2004;5:55-60. Courtesy of Tim Hughes, MD.

    26. Role of Kinase Conformation in Imatinib Binding Imatinib binds to an inactive conformation of BCR-ABL, and is stabilized by a H-bond with Thr315 Helix C Imatinib P-loop Activation loop With permission from O’Hare T, et al. Cancer Res. 2005;652:4500-4505.

    27. Differential Binding of Dasatinib and Imatinib to ABL Kinase With permission from Schindler T, et al. Science. 2000;289:1938-1942. With permission from Lombardo LJ, et al. J Med Chem. 2004;47:6658-6661.

    28. How Resistant is the E255K Mutation to Imatinib in Vitro?

    29. Resistance to Imatinib of CellsBearing BCR-ABL Mutations Measured by determining concentration dependence of normalized viable cell counts. Shah NP, et al. Cancer Cell. 2002;2:117-125.

    30. Decision Point 3 How would you treat this imatinib-resistantpatient with a E255K mutation? • Hematopoietic stem cell transplantation • Switch to dasatinib • Switch to nilotinib

    31. How Resistant is the E255K Mutation to Dasatinib in Vitro?

    32. Ba/F3 Bcr-Abl E255K T315I M351T M244V G250E Q252H Q252R Y253F Y253H E255V F317L E355G F359V H396R F486S Efficacy of Dasatinib Against Imatinib-Resistant Kinase Domain Mutations in Vitro 1.2 Parental Ba/F3 cells 1.0 T315I 0.8 Relative Growth After48 h of Drug Exposure 0.6 E255K 0.4 unmutatedBCR-ABL 0.2 0 0 0.5 2.5 5 25 50 Concentration of Dasatinib (nM) With permission from Shah NP, et al. Science. 2004;305:399-401.

    33. How Responsive is the E255K Mutation to Dasatinib in Patients?

    34. Complete CyRPartial CyR Complete HR No response Dasatinib 70 mg Twice Daily in CML-CPResponse by Individual Baseline BCR-ABL Mutation Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; CyR, cytogenetic response; HR, hematologic response. With permission from Stone R, et al. 49th ASH; December 8-11, 2007. Abstract 734.

    35. How Is Longer-Term Survival Impacted by Dasatinib in Chronic Phase CML Patients?

    36. Dasatinib 100 mg in Imatinib-Resistantand -Intolerant CML-CPOverall Survival 100 80 60 0 % Alive 100 mg once daily 24-month overall survival = 91% 0 3 6 9 12 15 18 21 24 27 30 Months Abbreviation: CML-CP, chronic myeloid leukemia-chronic phase. With permission from Shah NP, et al. 50th ASH; December 6-9, 2008. Abstract 3225.

    37. Survival of Patients Who Discontinued Imatinib Study Therapy 100 Survival 85% at 5 years after discontinuing study 90 80 70 60 % Survival (all deaths) 50 40 Survival approximately 50% at 5 years after stopping imatinib study drug 30 Safety (n = 30) Efficacy (n = 82) Bone marrow transplant (n = 16) Other reason (n = 80) 20 10 0 0 12 24 36 60 72 84 96 48 Months After Stopping Imatinib Study Therapy With permission from O’Brien SG, et al. 50th ASH; December 6-9, 2008. Abstract 186.

    38. How Resistant is the E255K Mutation to Nilotinib in Vitro?

    39. Activity of Nilotinib on Imatinib-Resistant BCR-ABL Mutants in Vitro Ba/F3 cell proliferation 3000 Imatinib Nilotinib 2500 2000 IC50 (nM) on Proliferation 1500 1000 500 0 F359V E255V T315I + IL3 M237I F317L L387F L248V F311V F317V S348L F468S F317C F359C Y253H E255D E255K E255R E275K E281K E292K E355A A380S G250E G250V E276G K285N D325N M351T E355G M388L M244V G250A Q252H Maternal BCR-ABL wt 72-hour proliferation assay with BCR-ABL–expressing Ba/F3 cells Weisberg E, et al. Br J Cancer. 2006;94:1765-1769. O’Hare T, et al. Cancer Res. 2005;65:4500-4505. Weisberg E, et al. Cancer Cell. 2005;7:129-141.

    40. How Responsive is the E255K Mutationto Nilotinib in Patients?

    41. Phase II Nilotinib in CML-CPResponse and ProgressionBased on Mutation IC50 • Response rates and progression rates were similar in patients without baseline mutations and in patients with mutations with IC50 ≤150 nM for nilotinib • Less favorable responses seen in patients with Y253H, E255K/V, and F359C/V • 8 of 26 patients were dose escalated to 600 mg BID • Highest rates of progression for E255K/V and F359C/V Abbreviations: CCyR, complete cytogenetic response; CML-CP, chronic myeloid leukemia-chronic phase. With permission from Hughes TP, et al. Blood. 2007;110(11). Abstract 320. Blood. 2007;110(11). Abstract 320.

    42. AK • Dasatinib 100 mg daily is initiated • Therapy is tolerated well except for an occasional mild headache • 2 weeks later, AK once again has a normal CBC • After 6 months, bone marrow aspiration reveals no karyotypically abnormal cells • 12 months later, AK continues to have a complete cytogenetic response on dasatinib

    43. Conclusions • Loss of response to imatinib is frequently associated with the evolution of resistance-conferring BCR-ABL kinase domain mutations • Mutations confer varying degrees of resistance to imatinib, and many are not likely to respond to imatinib dose escalation • Dasatinib and nilotinib are effective against most imatinib-resistant BCR-ABL kinase domain mutants in vitro and in patients • Survival data with dasatinib compare favorably with transplant after 2 years • Patients with select imatinib-resistant BCR-ABL kinase domain mutations should be preferentially treated with either dasatinib or nilotinib • Consultation with a chronic myeloid leukemia expert is indicated when treating patients with imatinib resistance

    44. Case 2: WL Michael J. Mauro, MD Associate Professor Center for Hematologic Malignancies, Knight Cancer Institute Oregon Health & Science University Portland, Oregon

    45. WL45-Year-Old Female • Diagnosed with chronic myeloid leukemia (CML) • WBC 150k • Left shift, 3% blasts, 3% basophils, platelets 700k • Splenomegaly 8 cm below left costal margin • Bone marrow shows typical CML chronic phase (CML-CP) • 95% cellular, myeloid hyperplasia, 5% blasts • Karyotype: 100% classic t(9:22) • Matched unrelated donor option identified; no sibling donor Patient asks about initial treatment options

    46. Decision Point 1 • What should be the initial therapy for this patient? • Imatinib 400 mg/day • Imatinib 600 mg/day • Imatinib 800 mg/day • Immediate matched unrelated donor stem cell transplantation

    47. Imatinib 400 mg/day is the Indicated Dose for Initial Therapy in This Patient • Imatinib 400 mg/day • Imatinib 600 mg/day • Imatinib 800 mg/day • Immediate matched unrelated donor stem cell transplantation

    48. WLFollow-Up at Month 3 • Imatinib 400 mg/day was advised • At month 3 • Complete hematologic response with mild leukopenia (WBC 2.5–4k, ANC >1500) • Periorbital edema and myalgias present • Peripheral blood qPCR is performed • Results: 1.0 log reduction from baseline How is she doing? Any recommendations, changes?

    49. Decision Point 2 • Response to 3-month results? • Decrease imatinib dose to 300 mg/day dueto reduced WBC • Continue imatinib at 400 mg/day • Increase imatinib dose due to failure • Change to nilotinib or dasatinib due to failure • Move to matched unrelated donor stem cell transplantation