CML is a bi- or triphasic illness, with most patients diagnosed in a relatively indolent chronic or stable phase
progression of CML to blast crisis occurred in 5% to 10% of patients in the first 2 years after diagnosis, and thereafter, the annual progression rate increased from 20% to 25%.best known of these is the Sokal score
By using these scores we can categorize patients in 3 categories which are low intermediate and high risk for which the median survival of patients are 5,4 and 3 yrs respectively
Hydroxyurea, a well-tolerated oral agent that inhibits DNA synthesis by inhibiting ribonucleotidereductase, remains in use as an initial therapy to control blood counts pending definitive diagnosis and therapy
Although the 5-year survival for IFN-α-treated patients (57%) is better than the 5-year survival of patients treated with hydroxyurea or busulfan (42%, P <.00001),29 the clinical use of IFN-α is limited by its toxicity profile and has largely been supplanted by BCR-ABL kinase inhibitor therapy.
When we compare these historical treatments with modern perpectives
Currently available therapies for CML range from relatively nontoxic AlthoughSo it is not first line treatment
Response in cml is assessed using these parameters
Based on remarkable activity in phase 1 and 2 clinical trials,30,31 a phase 3 randomized study (n = 1,106) compared imatinib at 400 mg/d to IFN-α plus Ara-C in newly diagnosed patients with chronic phase CML. Patients could crossover for lack of response, loss of response, or intolerance to therapy. The IRIS study was stopped early because of the superior efficacy of imatinib compared with the interferon/Ara-C combination.
With a median follow-up of 19 months, patients randomized to imatinib had statistically significant better results than patients treated with IFN-α plus Ara-C in all parameters
Two new tyrosine kinase inhibitors, dasatinib (Sprycel) and nilotinib (Tasigna), initially FDA-approved for patients with imatinib resistance or intolerance, have been compared to imatinib in newly diagnosed patients with chronic phase diseaseENESTnd was an international, multicenter, open-label, randomized phase III trial[3-5] that evaluated the efficacy and safety of nilotinib 300 mg or 400 mg twice daily vsimatinib 400 mg once daily in patients with newly diagnosed Ph-positive chronic-phase CML
phase III DASISION (CA180-056) trial[6,7] compared dasatinib 100 mg once daily with imatinib 400 mg once daily as first-line therapy for newly diagnosed CML-CP
In both studies, with a median follow-up of approximately 14 months, dasatinib at 100 mg/d and nilotinib at 300 mg twice daily or 400 mg twice daily achieved higher rates of complete cytogenetic responses, MMR, and improvements in progression-free survival
In 2010 a Bayesian mixed comparison meta-analysis was done to assess
300 mg twice daily dose of nilotinib was generally better tolerated than the 400 mg twice daily dose with similar response rates, the 300 mg twice daily dose has been recommended as a starting dose for newly diagnosed patients. Only a minority of patients experience grade 3/4 toxicity, and most side effects can be managed successfully with supportive measuresSpecific side effects from nilotinib, including increases in bilirubin, amylase, or lipase, generally do not require specific intervention unless they progress to grade 3/4 toxicity or become symptomatic.
Ten percent of patients treated with dasatinib will develop pleural effusions. These can generally be managed with diuretics or a short course of low-dose prednisone, and rarely require thoracentesis. Recurrent pleural effusions may also be less problematic with dose reductions to 70 mg/d.
Monitoring the reponse to Imatinib requires blood counts and differentials, cytogenetics, and molecular testing forBCR-ABL1 transcript level and for BCR-ABL1 kinase domain mutationsBlood counts and differentialsare required frequently during the first 3 months until a CHR hasbeen achieved and confirmed. Cytogenetics, performed with chromosomebanding analysis (CBA) of marrow cell metaphases, is required at 3 and 6months, then every 6 months until a CCgR has been achieved and confirmed,then every 12 months if regular molecular monitoring cannot be assuredReal-time, quantitative polymerase chain reaction assessmentof BCR-ABL1 transcript levels is recommended every 3 months until aMMolR has been achieved and confirmed then at least every 6 months
Onthe basis of the degree of HR, CgR, and MolR, and on the basis of the Time when these responses are achieved, the overall response to imatinib can be defined as optimal, suboptimal, and failure
DR. VARUN GOEL MEDICAL ONCOLOGISTRAJIV GANDHI CANCER INSTITUTE, DELHI
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
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 phase 6-12 months Blastic phase 3-6 months
Baseline Prognostic Factors Phase of Disease CML-CP blast crisis (5 - 10% cases in the first 2 yrs after 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
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 <50, 1 when >/ + 0,0420x spleen + 0,0584x blasts + 0,0413x eosinophils + 0,2039x basophils /0 when basophils <3%, 1 when basophils >3%/ + 1,0956x platelet /0 when platelet <15000G/l, 1 when >/) x 1000
Calculation of Disease RRRelative Risk Sokal score Hasford ScoreLow <0.8 <780Intermediate 0.8-1.2 781-1480High >1.2 >1480Low intermediate and high risk of disease progression,with median survivals of 5, 4 and 3 years, respectively.
Historical treatment Historically, mainstays of therapy for CML were busulfan, hydroxyurea and interferon-α
Conventional DrugsBusulphan Hydroxyurea Alkylating agent ● Often used initially for white cell count acts on stem cell reduction Side effect : ● Acts by inhibiting the enzyme ribonucleotide reductase prolonged myelosuppression ● Dose: 1-6g/d orally, depending on the Pulmonary fibrosis white cell count Skin pigmentation ● Side effects: suppression of infertility hematopoiesis, often with megaloblastic erythropoiesis ● It does not alter long-term prognosis
INTERFERON 5yr SurvivalChemotherapy 42%IFN alpha 57% The Chronic Myeloid leukemia Trialists’ Colaborative group. Interferon alpha Vs chemotherapy for CML: a meta-analysis of seven randomised trials. J Natl Cancer Inst 1997;89:1616-20.clinical use of IFN-α is limited by its toxicity profile INTERFERON + CYTOSINE ARABINOSIDE Cyogenetic Response IFN+AraC IFN Complete 15% 9% Partial 26% 15% Minor 25% 28% 3 yr survival 85.7% 79.1% Guilhot et al. N Engl J Med 1997;337:223-29
CML: Overview of Historical vs Modern PerspectiveParameter Historical Perspective Modern Perspective (Until 2000) (Since 2000)Course Fatal IndolentPrognosis Poor Excellent10-yr survival 10% 84% to 90%Frontline treatment Allogeneic SCT, Imatinib or dasatinib or interferon alfa nilotinibSecond-line treatment Not established Allogeneic 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.
Treatment of Chronic PhaseDisease The basis of current therapy for CML in CP is the three TKIs— imatinib, dasatinib, and nilotinib—and alloHSCT. Allogeneic HCT is regarded as the only curative therapy but associated with morbidities. Ability of tyrosine kinase inhibitor therapy to achieve long-term disease control have made these drugs the treatment of choice.
Definition of Response in CML Response by Type Definitions Hematologic Complete WBC < 10 X 109/L Basophils < 5% No myelocytes, promyelocytes, myeloblasts in the differential Platelet count < 450 x 109/L Spleen nonpalpable Cytogenetic Complete No Ph+ metaphases Partial 1% to 35% Ph+ metaphases Minor 36% to 65% Ph+ metaphases Minimal 66% to 95% Ph+ metaphases None > 95% Ph+ metaphases Molecular Complete Undetectable 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.
Imatinib(Gleevec) first tyrosine kinase inhibitor developed approved by the U.S. FDA in 2001 targets the molecular pathogenetic event in CML Imatinib functions byblocking the binding of ATPto the BCR-ABL tyrosinekinase, inhibiting its activity.
The IRIS Study Design R Imatinib A (n = 553) N D Crossover O M IFN- + I Ara-C Z (n = 553) E Crossover for: Lack of response Loss of response Intolerance of treatmentDruker BJ, et al. N Engl J Med. 2006;355:2408-2417.
Summary of 19 Month Data Imatinib vs. INF/ARAC <0.001100 97 95 92 <0.00180 74 7660 Imatinib40 INF/ARAC20 15 8.5 3.3 0 FFP OS AP/BC CCR Quality of Life O’Brien S.G. N Engl J Med. 348:994. Hahn, E.A. et al. JCO 2003;21:2138-46
IRIS Study – 8 year follow-up Event-free survival 81% Overall survival 85% Transformation-free survival 92% If MMR at 12 months 100% Annual rate of transformation: 1.5%; 2.8%; 1.8%; 0.9%; 0.5%; 0%; 0%; 0.4% Deininger M et al, ASH 2009
ENESTnd: Nilotinib vs Imatinib in Newly Diagnosed CML Primary endpoint: MMR at 12 mos; secondary endpoint: CCyR by 12 mos Other endpoints: time/duration of MMR and CGCR, EFS, PFS, time to AP/BP, OS Stratification by Sokal risk; MMR defined as ≤ 0.1% BCR-ABL(/ABL ratio) on international scale R A Nilotinib 300 mg BID (n = 282) Newly diagnosed N CML-CP in D 217 centers and O Nilotinib 400 mg BID (n = 281) 35 countries M I (N = 846) Z Imatinib 400 mg QD (n = 283) ELarson RA, et al. ASCO 2010. Abstract 6501. Saglio G, et al. N Engl J Med. 2010;362:2251-2259.
Results from the ENESTnd trial at 12 months of treatmentSaglio G, et al. N Engl J Med. 2010;362:2251-2259. Hughes TP, et al. ASH 2010. Abstract 207.Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270
DASISION (CA180-056): Dasatinib vs Imatinib in Treatment-Naive CML Stratified by Hasford risk score N = 519 Dasatinib 100 mg QD (n = 259) 108 centers Follow-up 26 countries 5 yrs Imatinib 400 mg QD (n = 260) Primary endpoint: confirmed CCyR by 12 mos Secondary/other endpoints: rates of CCyR and MMR; times to confirmed CCyR, CCyR, and MMR; time in confirmed CCyR and CCyR; PFS; OSKantarjian H, et al. N Engl J Med. 2010;362:2260-2270.
Meta-analysis: Frontline Imatinib vs Dasatinib vs Nilotinib for CML Bayesian mixed comparison meta-analysis to assess relative efficacy of BCR-ABL inhibitors across randomized clinical trials of patients with previously untreated CP-CML Imatinib 400 mg QD Dasatinib 100 mg QD Nilotinib 300 mg BID Nilotinib 400 mg BID After systemic review, data from 3 published studies used to construct evidence network for CCyR at 6 mos, CCyR at 12 mos, and MMR at 12 mos[2-4] 1. Mealing S, et al. ASH 2010. Abstract 3436. 2. Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270.3. Saglio G, et al. N Engl J Med. 2010;362:2251-2259. 4. Baccarani M, et al. Blood. 2009;113:4497-4504.
Meta-analysis of Frontline Imatinibvs Dasatinib vs Nilotinib for CML:Summary Data suggest CCyR and MMR rates significantly higher with dasatinib or nilotinib vs imatinib for frontline CP- CML treatment Relative efficacy of dasatinib and nilotinib similar Insufficient data at present to distinguish between these agents by indirect comparisonMealing S, et al. ASH 2010. Abstract 3436.
Comparisons of Imatinib to Nilotinib- side effects Imatinib 400 Nilotinib 300 Nilotinib 400 P Value/Comments mg/d mg bid mg bid Nausea, Rash, headache, pruritus, diarrhea, All grades, most being alopecia, elevations of alanine vomiting, grade 1/2; adverse events Adverse events aminotransferase, aspartate muscle were similar with both aminotransferase, and spasms, and doses of nilotinib bilirubin, increased glucose edemaDiscontinuation for 7% 5% 9% adverse events Neutropenia 20% 12% 10% Grade 3/4Thrombocytopenia 9% 10% 12% Grade 3/4 Anemia 5% 3% 3% Grade 3/4
DASISION: Differences in Adverse Event Rates With Dasatinib vs Imatinib Patients, n DAS IM Fluid retention l 60 111 Superficial edema l 25 92 Pleural effusion l 31 0 Myalgia l 56 99 Nausea l 23 55Any grade Vomiting l 12 27 Diarrhea l 47 50 Fatigue l 21 28 Headache l 32 27 Rash l 29 44 Neutropenia l 57 52 Grade 3/4 Thrombocytopenia l 49 27 Anemia l 29 18 -0.4 -0.2 0.0 0.2 0.4 Rate difference (dasatinib-imatinib) with exact 95% CI Favors dasatinib Favors imatinibShah N, et al. ASH 2010. Abstract 206..
Frontline Rx With Imatinib vs Second-Generation TKIs Parameter Imatinib Second-Generation TKIs Efficacy Excellent Even better 12-mo outcome, % CGCR 65-70 80-85 MMR 20-25 40-45 AP-BP 3.5 0.4-2.0 Tolerance Excellent Even better Follow-up, yrs 10 6-7 Cost, $/yr 54,000 90,000-96,000Larson RA, et al. ASCO 2010. Abstract 6501. Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270.
Recommendations for Monitoring CML Therapy Hematologic response: diagnosis, then every 15 days until CHR confirmed, then at least every 3 mos Cytogenetic response: Diagnosis, 3 and 6 mos, then every 6 mos until CCgR confirmed, then every 12 mos if regular molecular monitoring cannot be assured; always for occurrences of treatment failure and for occurrences of unexplained anemia, leukopenia or thrombocytopenia Molecular (RT-PCR): every 3 mos until MMR confirmed then every 6 mos Molecular (mutation assessment): suboptimal response or failure; always required before changing to other TKIsBaccarani M, et al. J Clin Oncol. 2009;27:6041-6051.
Recommendations for Response Assessment ResponseEvaluation Time Optimal Suboptimal Failure Warning High risk; Baseline NA NA NA CCA/Ph+ CHR and at least No CgR 3 mos minor CgR < CHR NA (Ph+ > 95%) (Ph+ ≤ 65%) At least partial < Partial CgR No CgR 6 mos CgR NA (Ph+ > 35%) (Ph+ > 95%) (Ph+ ≤ 35%) Partial CgR < Partial CgR 12 mos CCgR < MMR (Ph+ 1% to 35%) (Ph+ > 35%) 18 mos MMR < MMR < CCgR NA Stable or Loss of CHR, loss of Increase inAny time during Loss of MMR; improving MMR CCgR, mutations, transcript levels, treatment mutations CCA/Ph+ CCA/Ph- Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051.
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.
Options for Patients who failed Initial Imatinib 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
When Does Imatinib Dose Escalation Work? Imatinib dose escalation in 84 patients with imatinib failure 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.
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.
PFS and OS With Dasatinib inChronic-Phase CML by ImatinibFailure Imatinib Intolerance Imatinib Resistance 96% 100% 100% 100 92% 100 98% 94% 80 88% 80 75% 60 60 40 PFS 40 PFS OS OS 20 20 0 0 0 3 6 9 12 15 18 21 24 28 30 33 0 3 6 9 12 15 18 21 24 28 30 33 Mos Mos Progression defined as increasing WBC count, loss of CHR/MCyR, AP/BP, or death.Stone RM, et al. ASH 2007. Abstract 734..
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 domain mutant subclone3. If other mutations are present, they may influence choice in favour of either nilotinib or dasatinib4. Toxicity: Myelo- Hepatic Pancreatic Pleural Diarrhoea QTc interval suppression effusions prolongationDasatinib +++ - - ++ - +Nilotinib + ++ + - - +
Imatinib Resistance – Common Mutations InfluencingTherapeutic Decisions Nilotinib DasatinibT 3151 X XF 317L XE 255 V/K XY 253H XF 359 V/C X
Emerging TKIs in the Newly Diagnosed andRelapsed/Refractory Bosutinib, an experimental TKI, shows modestly improved efficacy with more toxicity compared with imatinib as first-line therapy for chronic-phase CML Bosutinib is approximately as active as nilotinib and dasatinib as second-line treatment, with activity in some Bcr-Abl mutations resistant to these 2 agents Ponatinib, another experimental TKI, produced high rates of major cytogenetic responses across subgroups of heavily pretreated patients with CML, including those with the T315I mutation
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
Survival after BMT for CML by CML-CP scoreDonor type Matched Sib 0 Matched Unrelated 2Age <30 0 30 – 40 1 >40 2Donor recipient gender Female Male 1 Other 0Interval from Diagnosis < 1 year 0 > 1 year 1Performance Status KPS > 85 0 Passweg, J.R. et al. BJH 125:613, 2004 other 1
CML Treatment Paradigm Chronic-phase CML Advanced-phase CML Complete diagnostic workup Tumor burden by RQ-PCR CHEMO + TKI vs TKI alone Imatinib 400 mg daily Imatinib 400 mg BID Nilotinib 300 mg BID Dasatinib 70 mg BID Dasatinib 100 mg daily Nilotinib 400 mg BID Dasatinib No Goals Nilotinib Heme CR in 1-2 mos Cyto response in 3-6 mos CCyR in 12-15 mos MMR in ~ 12 mos Allogeneic BMT @ progression