1. DR. VARUN GOEL MEDICAL ONCOLOGISTRAJIV GANDHI CANCER INSTITUTE, DELHI

2. Overview Introduction Prognostic Factors Conventional Drugs Presently First-line Therapy in CML Toxicity Profiles of TKI Therapy Monitoring of Patients With CML Resistance and Second-line Therapy in CML Allogeneic Hematopoietic Stem Cell Transplantation in CML 3. INTRODUCTION Chronic myeloid leukemia is a clonal hematopoietic disorder caused by an acquired genetic defect in a pluripotent stem cell. The disease usually evolves into an accelerated phase that often terminates in acute phase chronic phase (90%)3-5 years accelerated phase6-12 months Blastic phase3-6 months 4. Baseline Prognostic Factors Phase of Disease CML-CP blast crisis (5 - 10% cases in the first 2 yrsafter diagnosis), the annual progression rate increased to 20 - 25%. To guide patient management, various prognostic scales have been developed to predict the probability of disease progression. Risk stratification Sokal Hasford 5. WHO criteria of the differentphases of CML 6. Risk stratification Sokal Score: Exponential of Total (Age, Spleen, Platelet count, Blood myeloblasts) = (11x age + 35x spleen + 89x blasts + 0,4x platelet 550)/1000 Hasford Score: Applicable to patients treated with interferons Includes above factors + blood basophils and eosinophils Expressed as total x 1000 = (0,666x age /0 when age / + 0,0420x spleen +0,0584x blasts + 0,0413x eosinophils + 0,2039x basophils /0when basophils 3%/ + 1,0956xplatelet /0 when platelet /) x 1000 7. Calculation of Disease RRRelative Risk Sokal score Hasford ScoreLow1480Low intermediate and high risk of disease progression,with median survivals of 5, 4 and 3 years, respectively. 8. Historical treatment Historically, mainstays of therapy for CML were busulfan, hydroxyurea and interferon- 9. Conventional DrugsBusulphanHydroxyurea Alkylating agent Often used initially for white cell count acts on stem cellreduction Side effect : Acts by inhibiting the enzyme ribonucleotide reductase prolongedmyelosuppression Dose: 1-6g/d orally, depending on the Pulmonary fibrosis white cell count Skin pigmentation Side effects: suppression of infertilityhematopoiesis, often with megaloblastic erythropoiesis It does not alter long-term prognosis 10. INTERFERON 5yr SurvivalChemotherapy42%IFN alpha 57%The Chronic Myeloid leukemia Trialists Colaborative group. Interferon alpha Vs chemotherapy forCML: a meta-analysis of seven randomised trials. J Natl Cancer Inst 1997;89:1616-20.clinical use of IFN- is limited by its toxicity profileINTERFERON + CYTOSINE ARABINOSIDECyogenetic Response IFN+AraC IFN Complete 15%9% Partial26%15% Minor25%28% 3 yr survival85.7%79.1% Guilhot et al. N Engl J Med 1997;337:223-29 11. CML: Overview of Historical vsModern PerspectiveParameter Historical Perspective Modern Perspective (Until 2000) (Since 2000)Course FatalIndolentPrognosisPoor Excellent10-yr survival 10%84% to 90%Frontline treatment Allogeneic SCT,Imatinib or dasatinib or interferon alfa nilotinibSecond-line treatment Not establishedAllogeneic SCT or novel TKIs Faderl S, et al. Ann Intern Med. 1999;131:207-219. Druker BJ, et al. N Engl J Med. 2001;344:1031-1037. 12. Treatment of Chronic PhaseDisease The basis of current therapy for CML in CP is the threeTKIs imatinib, dasatinib, and nilotinibandalloHSCT. Allogeneic HCT is regarded as the only curative therapybut associated with morbidities. Ability of tyrosine kinase inhibitor therapy to achievelong-term disease control have made these drugs thetreatment of choice. 13. Definition of Response in CML Response by TypeDefinitions Hematologic CompleteWBC < 10 X 109/L Basophils < 5% No myelocytes, promyelocytes, myeloblasts in the differential Platelet count < 450 x 109/L Spleen nonpalpable CytogeneticComplete No Ph+ metaphasesPartial1% to 35% Ph+ metaphasesMinor36% to 65% Ph+ metaphasesMinimal66% to 95% Ph+ metaphasesNone > 95% Ph+ metaphases Molecular CompleteUndetectable BCR-ABL mRNA transcripts by real time quantitative and/or nested PCR in 2 consecutive blood samples of adequate quality (sensitivity > 104) Major Ratio of BCR-ABL to ABL (or other housekeeping genes) 0.1% on the international scaleBaccarani M, et al. J Clin Oncol. 2009;27:6041-6051. 14. Imatinib(Gleevec) first tyrosine kinase inhibitordeveloped approved by the U.S. FDA in 2001 targets the molecular pathogeneticevent in CML Imatinib functions byblocking the binding of ATPto the BCR-ABL tyrosinekinase, inhibiting its activity. 15. The IRIS Study Design R Imatinib A (n = 553) N DCrossover O MIFN- + I Ara-C Z(n = 553) ECrossover for:Lack of responseLoss of responseIntolerance of treatmentDruker BJ, et al. N Engl J Med. 2006;355:2408-2417. 16. Summary of 19 Month Data Imatinib vs. INF/ARAC 35%)(Ph+ > 95%) (Ph+ 35%)Partial CgR< Partial CgR 12 mosCCgR < MMR(Ph+ 1% to 35%)(Ph+ > 35%)18 mos MMR < MMR< CCgRNAStable or Loss of CHR, loss ofIncrease inAny time during Loss of MMR; improving MMR CCgR, mutations,transcript levels,treatmentmutations CCA/Ph+ CCA/Ph-Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051. 29. Mechanisms of Resistance to Imatinib BCR-ABL dependent Amplification/overexpression Mutations in ABL Remigration of BCR-ABL to cytoplasm BCR-ABL independent Increased MDR expression Increased alpha-1 acid glycoprotein Overexpression of Src-related kinases Quiescent stem cells (persistence)le Coutre P, et al. Blood. 2000;95:1758-1766. Weisberg E, et al. Blood. 2000;95:3498-3505. Mahon FX, et al.Blood. 2000;96:1070-1079. Gambacorti-Passerini C, et al. J Natl Cancer Inst. 2000;92:1641-1650. Vigneri P, etal. Nat Med. 2001;7:228-234. 30. Options for Patients who failed InitialImatinib Increase dose of imatinib Second line: Dasatinib, Nilotinib Allogeneic Stem Cell Transplant (BMT/PBSCT) Classical drugs: Cytarabine, Hydroxyurea, Busulphan,Intereron-alpha Experimental agents, Autografting.BCSH, 2007 31. When Does Imatinib Dose Escalation Work? Imatinib dose escalation in 84 patients with imatinibfailure CG failure (n = 63):imatinib associated with CGCR in 52% MCyR durable at 2 yrs in 88% of patients Hematologic failure (n = 21): only transient responses; CGCR in 5% However, results of new TKIs betterJabbour E, et al. Blood. 2009;113:2154-2160. 32. Nilotinib in Chronic-Phase CML Post-Imatinib: OS and PFS Patient population (n = 321) 70% imatinib resistant 30% imatinib intolerant Median duration of nilotinib: 18.4 mos 2-yr survival rates PFS: 64% OS: 87%Kantarjian HM, et al. Blood 2011;117:1141-1145. 33. PFS and OS With Dasatinib inChronic-Phase CML by ImatinibFailure Imatinib Intolerance Imatinib Resistance96%100% 100% 100 92%10098%94%80 88%8075%606040PFS 40 PFSOS OS20 20 00 0 3 6 9 12 15 18 21 24 28 30 330 3 6 9 12 15 18 21 24 28 30 33 MosMos Progression defined as increasing WBC count, loss of CHR/MCyR, AP/BP, or death.Stone RM, et al. ASH 2007. Abstract 734.. 34. Choosing a second generation TKI for patients intolerant of or resistant to imatinib1.Efficacy: Little to choose between dasatinib, nilotinib2.All three agents are ineffective in patients with a T315I kinase domainmutant subclone3.If other mutations are present, they may influence choice in favour ofeither nilotinib or dasatinib4.Toxicity:Myelo- Hepatic Pancreatic Pleural Diarrhoea QTc intervalsuppressioneffusionsprolongationDasatinib+++- -++- +Nilotinib + ++ + - - + 35. Imatinib Resistance Common Mutations InfluencingTherapeutic Decisions NilotinibDasatinibT 3151 XXF 317LXE 255 V/KXY 253H XF 359 V/CX 36. Emerging TKIs in the Newly Diagnosed andRelapsed/RefractoryBosutinib, an experimental TKI, shows modestlyimproved efficacy with more toxicity comparedwith imatinib as first-line therapy for chronic-phaseCML Bosutinib is approximately as active as nilotinib anddasatinib as second-line treatment, with activity insome Bcr-Abl mutations resistant to these 2 agents Ponatinib, another experimental TKI, producedhigh rates of major cytogenetic responses acrosssubgroups of heavily pretreated patients with CML,including those with the T315I mutation 37. Transplantation for CML Indications :- Failure of second-generation TKI (donor search should be undertaken after failure of imatinib) imatinib failure and T315I BCR-ABL1 mutation Curative Treatment for most patients High rate of morbidity and mortality Problems of: Toxicity of preparative regimen Graft-vs-Host disease Relapse 38. Survival after BMT for CML by CML-CP scoreDonor typeMatched Sib 0Matched Unrelated 2Age40 2Donor recipient genderFemale Male 1Other 0Interval from Diagnosis< 1 year0> 1 year1Performance StatusKPS > 850Passweg, J.R. et al. BJH 125:613, 2004other 1 39. CML Treatment ParadigmChronic-phase CMLAdvanced-phase CMLComplete diagnostic workupTumor burden by RQ-PCRCHEMO + TKI vs TKI aloneImatinib 400 mg daily Imatinib 400 mg BIDNilotinib 300 mg BIDDasatinib 70 mg BIDDasatinib 100 mg dailyNilotinib 400 mg BIDDasatinib NoGoals NilotinibHeme CR in 1-2 mosCyto response in 3-6 mosCCyR in 12-15 mosMMR in ~ 12 mosAllogeneic BMT@ progression 40. THANK YOU