Profiles in CML: Diagram of Practice Difficulties.


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Perpetual Myelogenous Leukemia (CML) Abnormal clonal hematopoietic foundational microorganism issue, ... Shortened forms: CML-CP, interminable myeloid leukemia-endless stage; CyR, cytogenetic reaction; ...
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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

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Chronic Myelogenous Leukemia (CML) Abnormal clonal hematopoietic undifferentiated cell issue, expanded proliferation,
 diminished apoptosis and attachment Chronic, quickened, and blastic stages Ph t(9;22) (q34;q11) cytogenetic and
 BCR-ABL atomic variations from the norm

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

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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.

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The Philadelphia Chromosome and BCR-ABL Chromosome 22 Chromosome 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 PROTEIN WITH TYROSINE KINASE ACTIVITY BCR-ABL quality structure t(9;22) translocation Faderl S, et al. N Engl J Med. 1999;341:164-172. Melo JV. Blood . 1996;88:2375-2384.

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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.

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The Clinical Course of Untreated CML Advanced Phases Chronic Phase Accelerated Phase Blast Crisis Median term 5–6 years Median span 6–9 months Median survival 3–6 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.

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Incidence and Mortality Of CML Based on current information, middle survival is required to surpass 15–20 years. Parker SL, et al. CA Cancer J Clin. 1997;47:5-27. Jemal An, et al. CA Cancer J Clin . 2007;57:43-66..

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

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IRIS Study in Chronic Phase CML—7-Year Update 1106 patients initially selected, 553 for every arm Estimated general survival at 7 years: 86% Late-movement occasions Kaplan-Meier evaluation of occasion free survival at 7 years: 81% Kaplan-Meier assessed rate without quickened stage/impact emergency at 7 years: 93% Safety Grade 3/4 occasions diminished in frequency after years 1–2 No one of a kind, already unreported unfavorable occasions developed O\'Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Dynamic 186.

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IRIS Overall Survival (ITT Principle) Imatinib Arm Estimated general survival at 7 years is 86% (94% considering just CML-related passings) Probability of Survival: passings connected with CML Overall survival Months Since Randomization Abbreviation: ITT, expectation to treat. With authorization from O\'Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Conceptual 186.

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Annual Event Rates—Imatinib Arm KM assessed EFS at 7 years = 81% KM evaluated rate without AP/BC at 7 years = 93% Event Loss of CHR, Loss of MCR, AP/BC, Death amid treatment AP/BC % with Event a Year a Total occasions (n = 5), including loss of MCR (n = 3) and passings (n = 2, one of which was coded a movement to AP/BC in a patient in CHR 6 months before death). Shortenings: AP/BC, quickened stage/impact emergency; CHR, complete hematologic reaction; EFS, occasion free survival; MCR, major cytogenic reaction; KM, Kaplan-Meier. With consent from O\'Brien SG, et al. 50th Annual ASH Meeting; December 6-9, 2008. Theoretical 186.

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IRIS 7-Year Update—Key Findings Overall survival: 86% without event survival: 81% 7% movement to quickened stage/impact emergency (AP/BC) Complete cytogenetic reaction (CCR) accomplished by 456/553 (82%) patients 17% in this manner lost CCR 3% advanced to AP/BC 2% kicked the bucket from CML Time to CCR did not associate with the rate of movement to AP/BC Major sub-atomic reaction rates and profundity of sub-atomic reaction expanded after some time While imatinib is effective, it doesn\'t work for all patients O\'Brien SG, et al. 50th ASH Annual Meeting; December 6-9, 2008. Conceptual 186.

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Imatinib Resistance BCR-ABL particular Mutations >50 portrayed with variable degrees of effect ~50% of patients Amplification or overexpression ~7-10 % 50%–60% BCR-ABL free Cellular pharmacology Drug import/trade Other pathways Wnt, score Autocrine components Lyn (other Src-family kinases) 40%–50% Courtesy of M. Talpaz, MD.

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C An\' A\' M C An A\' M C An A L C M C An A\' C\' An A\' M C An A B C An A M\' C An\' A C\' An A\' C An 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 transformations (\'). 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. Tumor Cell . 2002;117-125. Hochhaus An, et al. Leukemia . 2002;16:2190-2196. Al-Ali HK, et al. Hematol J . 2004;5:55-60.

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Role of Kinase Conformation in Imatinib Resistance Point changes in BCR-ABL kinase space limits its capacity to embrace an idle compliance Mutations that straightforwardly influence imatinib restricting Mutations that influence the adaptation required to tie imatinib With authorization from Schindler T, et al. Science. 2000;289:1938-1942. With consent from Lombardo LJ, et al. J Med Chem . 2004;47:6658-6661.

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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 After 48 h of Drug Exposure 0.6 E255K 0.4 Wild-sort BCR-ABL 0.2 M351T 0 0.5 2.5 5 25 50 Concentration of Dasatinib (nM) With consent from Shah NP, et al. Science . 2004;305:399-401.

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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 strong shading compares to the first amino corrosive change; the broken shading relates to the second amino corrosive change if pertinent. With consent from Cortes J, et al. Blood . 2007; 110:4005-4011 .

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Case 1: AK Neil P. Shah, MD, PhD Assistant Professor Division of Hematology/Oncology UCSF School of Medicine San Francisco, California

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AK 33-Year-Old Male Referred for as of late found leukocytosis of 253K noted in blood work performed after he exhibited to his essential consideration doctor with left shoulder torment and progressing night sweats Palpable splenomegaly Differential: 3% basophils, juvenile granulocytes, and 2% impacts Bone marrow biopsy uncovered: hypercellular marrow with 4% impacts and a M:E proportion of 10:1, steady with a myeloproliferative issue Cytogenetics: t(9;22) in each of the 20 metaphases dissected AK has 2 kin and no other huge restorative history

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Decision Point 1 What is the suitable first-line treatment for this patient? Hematopoietic undifferentiated cell transplantation Imatinib Dasatinib Nilotinib Interferon alpha

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AK Imatinib 400 mg day by day is started AK endures treatment well, except for fringe edema, mellow sickness, and muscle spasms 1 month later, CBC uncovers a complete hematologic reaction (CHR) 6 months in the wake of starting treatment, AK keeps on having a CHR. Bone marrow goal is performed, and the t(9;22) translocation is distinguished in 5/20 metaphases 12 months subsequent to starting treatment, just 2/20 bone marrow metaphases contain the t(9;22) translocation 6 months after the fact, regardless of keeping on having a CHR, marrow metaphase investigation uncovers the t(9;22) translocation in 18/20 metaphases

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Decision Point 2 What is your next stride? Survey persistent consistence Do a mutational examination Increase imatinib dose Switch to dasatinib or nilotinib Refer for allogeneic foundational microorganism transplantation All of the above

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AK expresses that he has been exceptionally agreeable with treatment BCR-ABL kinase space change test is requested; the imatinib measurements is expanded to 800 mg day by day AK encounters expanded exhaustion, sickness, and edema on this dosage 3 months after imatinib dosage heightening CBC: WBC of 18K with youthful structures and 3% basophils Mutation investigation: E255K transformation in a vast extent of cells

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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-circle; C, synergist area; An, actuation circle. 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. Disease Cell . 2002;117-125. Hochhaus An, et al. Leukemia . 2002;16:2190-2196. Al-Ali HK, et al. Hematol J . 2004;5:55-60. Kindness of Tim Hughes, MD.

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Role of Kinase Conformation in Imatinib Binding Imatinib ties to a dormant adaptation of BCR-ABL, and is balanced out by a H-bond with Thr315 Helix C Imatinib P-circle Activation circle With consent from O\'Hare T, et al. Disease

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