Chronic Myeloid Leukemia in 2011 An Update on Treatment and Monitoring Michael Deininger MD PhD Chief, Division of Hematology and Hematologic Malignancies M. M. Wintrobe Professor of Medicine A Time Line Of Chronic Myeloid Leukemia Neoplastic nature recognized and term leukemia coined Concept of leukemia as a disease entity Leukemia originates from the bone marrow Ph chromosome CML originates in a stem cell t(9;22) Mouse model reproduces CML; tyrosine kinase activity essential BCR-ABL 1845 1847 1865 1872 1959 1960 1968 1969 1973 1975 1985 1990 2001 2006 First published use of arsenic to treat leukemia Busulfan introduced Hydrea introduced Allotransplant for CML Imatinib approved Interferon-α Dasatinib Nilotinib approved 1
Topics to cover 1. Current therapy of CML 2. Prognostic implications of BCR-ABL quantitative PCR 3. International Scale to express BCR-ABL 4. Triggers for additional diagnostic measures Most CML Patients are Diagnosed in the Chronic Phase Chronic phase Blastic phase 2
The Cytogenetic Hallmark of CML is the Philadelphia Chromosome (Ph) 9q+ Ph 9 22 22q- = Philadelphia chromosome Courtesy of Christl Müller, Leipzig Ph is the result of t(9;22)(q34;q11) q11{ BCR BCR ABL 22 Ph q34{ ABL 9 ABL BCR 9q+ 3
Breakpoints of The Ph Translocation and BCR-ABL mrnas ABL Ib Ia a2a3 a11 e1 e1 e2 BCR b2 b3 e19 e1a2 b2a2 b3a2 e19a2 m-bcr M-bcr µ-bcr BCR-ABL BCR-ABL Kinase Activity Is Essential for CML Pathogenesis K562 32D 32p210 BCR-ABL BCR-ABL- Imatinib (µm) 0.1 0.5 1.0 5.0 10 BCR-ABL NALM-1 cells (Ph+) Deininger et al Blood 1997 4
CML Originates From a BCR-ABL Transformed Hematopoietic Stem Cell CD34+ CD38- Lin- CD34+ CD38+ GMP Lin+ Monocytes CMP MKP Granulocytes LT- HSC ST- HSC MEP EB Platelets BCR-ABL Red cells Imatinib Greatly Improved Survival In Chronic Phase CML (MDACC data) Quintas-Cardama et al, 2006 5
Therapy Standards Chronic phase Imatinib Nilotinib Dasatinib (IFN) (Hydrea) Advanced phase Dasatinib Nilotinib Allotransplant (Imatinib) (Hydrea) ABL Kinase Inhibitors DCC-2036 ponatinib HG-7-85-01 danusertib PPY-A (SGX393- DCC-2036 like) 6
Tyrosine Kinase Inhibitors For CML: Major Randomized First Line Studies IRIS TOPS Study Comparison Pts/ Randomization ENESTnd IM 400mg QD IFN/Ara-C IM 400mg QD IM 400 BID IM 400mg QD NIL 300mg BID NIL 400mg BID DASISION IM 400mg QD DAS 100mg QD SPIRIT IM 400mg QD IM 600mg QD IM 400mg QD + IFN IM 400mg QD + AraC Major endpoints Authors 1106/1:1 PFS O Brien et al. NEJM 2003 476/1:2 MMR at 12 months 846/1:1:1 MMR at 12 months 519/1:1 CCyR at 12 months 636/1:1:1:1 PFS, OS, EFS Cortes et al. JCO 2010 Saglio et al. NEJM 2010 Kantarjian et al. NEJM 2010 Preudhomme et al. NEJM 2010 Annual Events On First-line Imatinib (IRIS Study 8 year update) Deininger et al. ASH 2009 7
Overall Survival On First-line Imatinib Deininger et al. ASH 2009 Not All Data Are As Good As The IRIS Data Hammersmith Hospital Experience 63% Event: Also off IM due to lack of MCyR or toxicity de Lavallade et al. 2008 8
The Community Experience: Only A Minority Of Patients Do Well Enough To Remain On IM Lucas et al. Leukemia. 2008 Oct;22(10):1963-6 Tyrosine Kinase Inhibitors For CML: Major Randomized First Line Studies IRIS TOPS Study Comparison Pts/ Randomization ENESTnd IM 400mg QD IFN/Ara-C IM 400mg QD IM 400 BID IM 400mg QD NIL 300mg BID NIL 400mg BID DASISION IM 400mg QD DAS 100mg QD SPIRIT IM 400mg QD IM 600mg QD IM 400mg QD + IFN IM 400mg QD + AraC Major endpoints Authors 1106/1:1 PFS O Brien et al. NEJM 2003 476/1:2 MMR at 12 months 846/1:1:1 MMR at 12 months 519/1:1 CCyR at 12 months 636/1:1:1:1 PFS, OS, EFS Cortes et al. JCO 2010 Saglio et al. NEJM 2010 Kantarjian et al. NEJM 2010 Preudhomme et al. NEJM 2010 9
CML: A Chronic Disease Requiring Chronic Therapy Imatinib cannot be stopped Prevalence of CML/10 5 (Pas de Calais Nord, France) 12 10 8 6 4 2 0 1998 2000 2002 2004 2006 Corm et al, ASCO 2008, #7088 In 2040 there will be 250,000 CML patients in the US. DASISION: First-Line Dasatinib vs Imatinib in CML-CP ASH 2010 21 10
DASISION: First-Line Dasatinib vs Imatinib in CML-CP ASH 2010 22 DASISION: First-Line Dasatinib vs Imatinib in CML-CP ASH 2010 23 11
DASISION: First-Line Dasatinib vs Imatinib in CML-CP ASH 2010 25 DASISION: First-Line Dasatinib vs Imatinib in CML-CP ASH 2010 26 12
Tyrosine Kinase Inhibitors For CML: Major Randomized First Line Studies IRIS TOPS Study Comparison Pts/ Randomization ENESTnd IM 400mg QD IFN/Ara-C IM 400mg QD IM 400 BID IM 400mg QD NIL 300mg BID NIL 400mg BID DASISION IM 400mg QD DAS 100mg QD SPIRIT IM 400mg QD IM 600mg QD IM 400mg QD + IFN IM 400mg QD + AraC Major endpoints Authors 1106/1:1 PFS O Brien et al. NEJM 2003 476/1:2 MMR at 12 months 846/1:1:1 MMR at 12 months 519/1:1 CCyR at 12 months 636/1:1:1:1 PFS, OS, EFS Cortes et al. JCO 2010 Saglio et al. NEJM 2010 Kantarjian et al. NEJM 2010 Preudhomme et al. NEJM 2010 DASISION (CA180-056) Study Design: An Ongoing Global Phase 3 Study DASISION: First-Line Dasatinib vs Imatinib in CML-CP Treatmentnaïve CML-CP patients (N=519) 108 centers 26 countries Dasatinib 100 mg QD (n=259) Randomized* Imatinib 400 mg QD (n=260) *Stratified by Hasford risk score Follow-up 5 years Primary endpoint Other key endpoints Confirmed CCyR by 12 mos Rates of CCyR and MMR, times to CCyR and MMR, time in CCyR (measure of duration), progression-free survival, overall survival ASH 2010 28 13
DASISION: First-Line Dasatinib vs Imatinib in CML-CP CCyR Rates (ITT) By Month Of Treatment 100 80 60 % 40 54 31 Dasatinib 100mg QD 78 73 59 Imatinib 400mg QD 83 85 72 67 80 20 0 Mo 3 Mo 6 Mo 9 Mo 12 Any time Based on time-to CCyR analysis, likelihood of achieving a CCyR at any time was 1.5-fold higher with dasatinib than with imatinib (stratified log-rank P<0.0001; HR=1.5) Among patients who achieved a CCyR, median time to CCyR was 3.1 mos for dasatinib and 5.8 mos for imatinib ASH 2010 30 DASISION: First-Line Dasatinib vs Imatinib in CML-CP MMR Rates (ITT) By Month Of Treatment 100 80 Dasatinib 100 mg QD Imatinib 400 mg QD P<0.0001 P=0.0002 60 % 40 20 0 8 0.4 27 39 ASH 2010 31 8 18 Mo 3 Mo 6 Mo 9 Mo 12 Any time Any time 46 MMR, BCR-ABL 0.1% 28 57 41 13 7 BCR-ABL 0.0032% Based on time-to MMR analysis, likelihood of achieving a MMR was 1.8-fold higher with dasatinib vs imatinib (stratified log-rank P<0.0001; HR=1.8) Among patients who achieved a MMR, median time to MMR was 8.3 mos for dasatinib and 11.8 mos for imatinib 14
DASISION: First-Line Dasatinib vs Imatinib in CML-CP Transformation To Advanced Phase CML (ITT) 100 6 % 4 2 Dasatinib 100 mg QD Imatinib 400 mg QD 2.3 3.5 0 n/n 6/259 9/260 5 patients who achieved a CCyR transformed to AP/BP CML (2 dasatinib, 3 imatinib) No patient who achieved a MMR transformed to AP/BP CML to date Patients were followed for transformation for up to 60 days after the last dose of study drug; clonal evolution without additional criteria for AP CML was NOT counted as transformation ASH 2010 33 Monitoring Response: Sensitivity Of Strategies 100% Diagnosis: 10 12 Leukemia cells 10% 1% 0.1% Blood counts Cytogenetics PCR Undetectable range Complete hematologic response Complete cytogenetic response Major molecular response Complete molecular response 15
The Need To Confirm Cytogenetic Results % Ph+ metaphases detected (20 analyzed) Y Data 120 100 80 60 40 20 0-20 2D Graph pq ˆ3 ˆ pˆ ± zα / 2 = ± n 50% Ph+ P = can mean. 35 65% 95% CI 0 20 40 60 80 100 120 % Ph+ metaphases X Data present Col 1 vs Col 2 Col 1 vs Col 3 Byung Park, OHSU Cytogenetics vs. BCR-ABL qpcr Ross et al. Leukemia 2006 16
Is There A Role For Peripheral Blood FISH For Monitoring Response? In Favor Widely accessible Excellent correlation with marrow cytogenetics in patients on IFN-α Le Gouill, S. et al. J Clin Oncol; 18:1533-1538. 2000 r = 0.98 Against IFN-α results not fully confirmed in patients on imatinib Lack of validation in prospective clinical endpoints Does not detect clonal evolution Limited sensitivity and dynamic range compared to qpcr FISH only in case of failed cytogenetics or unavailability of qpcr! IRIS Study: Progression Free Survival by Molecular Response at 12 months on First-line Imatinib % without progression 100 90 80 70 60 50 40 30 20 10 0 CCyR with >=3 log reduction CCyR with <3 log reduction No CCyR Estimated rate at 54 month 95% 89% 72% } } p=0.068 p<0.001 0 6 12 18 24 30 36 42 48 54 60 Months since randomization 17
IRIS Study: Prognostic Significance of Molecular Response on First-line Imatinib P=0.014 P=0.0006 P=0.019 P=0.001 Hughes et al. Blood 2010 Lack of MMR at 18 months predicts loss of CCyR Hughes et al. Blood 2010 18
Recommendations for Monitoring Response CBC Frequency Weekly until blood count stable Every 4-6 (12) weeks thereafter Cytogenetics 3,6, 12, 18 months or until CCyR qpcr Every 3-6 months after documentation of CCyR Therapeutic Milestones Month Optimal Suboptimal Failure 3 <35% Ph+ 36-65%Ph+ No CyR 6 12 CCyR or better MMR or better 1-35% Ph+ Less than MMR 66-95% Ph+ >35% Ph+ 18 CMR 0% Ph+ >0% Ph+ Baccarani et al on behalf of the ELN. J Clin Oncol. 2009;27(35):6041-51 19
Therapeutic Milestones Month Optimal Suboptimal Failure 3 <35% Ph+ 36-65%Ph+ No CyR 6 CCyR or better 1-35% Ph+ 66-95% Ph+ 12 MMR or better Less than MMR >35% Ph+ 18 CMR 0% Ph+ >0% Ph+ Baccarani et al on behalf of the ELN. J Clin Oncol. 2009;27(35):6041-51 Therapeutic Milestones Month Optimal Suboptimal Failure 3 <35% Ph+ 36-65%Ph+ No CyR 6 CCyR or better 1-35% Ph+ 66-95% Ph+ 12 MMR or better Less than MMR >35% Ph+ 18 CMR 0% Ph+ >0% Ph+ Baccarani et al on behalf of the ELN. J Clin Oncol. 2009;27(35):6041-51 20
Therapeutic Milestones Month Optimal Suboptimal Failure 3 <35% Ph+ 36-65%Ph+ No CyR 6 CCyR or better 1-35% Ph+ 66-95% Ph+ 12 MMR or better Less than MMR >35% Ph+ 18 CMR 0% Ph+ >0% Ph+ Baccarani et al on behalf of the ELN. J Clin Oncol. 2009;27(35):6041-51 Therapeutic Milestones Month Optimal Suboptimal Failure 3 <35% Ph+ 36-65%Ph+ No CyR 6 CCyR or better 1-35% Ph+ 66-95% Ph+ 12 MMR or better Less than MMR >35% Ph+ 18 CMR 0% Ph+ >0% Ph+ Baccarani et al on behalf of the ELN. J Clin Oncol. 2009;27(35):6041-51 21
Therapeutic Milestones Month Optimal Suboptimal Failure 3 <35% Ph+ 36-65%Ph+ No CyR 6 CCyR or better 1-35% Ph+ 66-95% Ph+ 12 MMR or better Less than MMR >35% Ph+ 18 CMR 0% Ph+ >0% Ph+ Baccarani et al on behalf of the ELN. J Clin Oncol. 2009;27(35):6041-51 Therapeutic Milestones Month Optimal Suboptimal Failure 3 6 12 18 Favorable outcome likely: keep going! Favorable outcome uncertain: consider alternative! Favorable outcome unlikely: change strategy! Baccarani et al on behalf of the ELN. J Clin Oncol. 2009;27(35):6041-51 22
PCR vs. Cytogenetic Monitoring qrt-pcr Cytogenetics Convenience Dynamic Range Sensitivity Standardization Familiarity Additional genetic info qpcr for BCR-ABL Lack of Standardization Different technology platforms Different control genes Different primers No uniform standard Different results reporting Lack of quality control US 10 years behind Europe and Australia 23
Standardization of qpcr: The International Scale (IS) Different control genes 100% [IRIS baseline] 10% Different primers/probes Reference samples 1% 0.1% [MMR/3 log reduction] Different cycler technologies 0.01% 0.001% Courtesy of Dr. Nick Cross, Southhamptom The International Scale for BCR-ABL: Before Standardisation 10 BCR-ABL level 1 0.1 0.01 0.001 Lab 1 Lab 2 Lab 3 Lab 4 Lab 5 0 CML cell dilution 24
The International Scale for BCR-ABL: Conversion 10 BCR-ABL level 1 0.1 0.01 0.001 Lab 1 Lab 2 Lab 3 Lab 4 Lab 5 0 CML cell dilution The IS for BCR-ABL: Conversion in a Test of a WHO- approved Reference Standard White et al. Blood 2010 25
Standardization: What Is Achievable? 100 10 1.0 0.1 0.01 MMR 0.001 0.001 0.01 0.1 1.0 10 100 Courtesy of Dr. Nick Cross, Southhamptom Standardization: Dependence On Log- Linearity Over 0.1-10% 10% IS 10 log %BCR- ABL/control gene 10 log %BCR- ABL/control gene 0 1 2 3 0 1 2 3 10 log dilution 10 log dilution 26
Standardization: What Is Achievable? CoVar between different labs comparable to different runs in same lab Reproducibility within 5-fold above MMR level? Uniform results reporting Uniform reflex triggers for additional diagnostics Which increase of BCR-ABL is the right trigger for BCR-ABL mutation screening? 10-fold (NCCN guidelines) 5-fold (ELN recommendations) 2-fold (if you live in Australia, Branford et al, Blood 2004) Mutations (%) resistance (%) No mutations (%) resistance (%) More than 2-fold rise 34/56 (61) 31/34 (91) 22/56 (39) 13/22 (59) Stable or decreasing 1/158 (0.6) 1/1 (100) 157/158 (99) 1/157 (0.6) 27
Sensitivity and Specificity of BCR-ABL Increase for Detection of BCR-ABL Mutations RQ-PCR Increase (fold change) Sensitivity (95% CI) (%) Specificit y (%) Negative Predictive Value (95% CI) (%) Odds Ratio (95% CI) P 2.0 77 (62-88) 44 88 (80-94) 2.6 (1.2-5.4) 0.01 2.5 77 (62-88) 46 89 (81-94) 2.8 (1.4-5.9) 0.005 2.6 77 (62-88) 47 89 (81-94) 2.9 (1.4-6.0) 0.005 2.6* (include subsequent sample) 94 (82-99) 47 97 (91-99) 13 (3.9-43) <0.0001 3.0 74 (60-86) 48 88 (80-94) 2.7 (1.3-5.5) 0.008 3.5 64 (49-77) 54 86 (78-91) 2.1 (1.1-4.1) 0.03 4.0 60 (44-74) 60 85 (78-91) 2.2 (1.1-4.2) 0.02 4.5 55 (40-70) 64 85 (78-90) 2.2 (1.2-4.2) 0.02 5.0 47 (32-62) 68 84 (77-89) 1.9 (1.0-3.6) 0.06 10 26 (14-40) 83 82 (75-87) 1.7 (0.8-3.7) 0.2 Press et al. Blood 2009 Receiver Operating Characteristic Analysis To Define Optimal qpcr Trigger Press et al. Blood 2009 28
Summary (1) Imatinib produces durable responses in 2/3 of newly diagnosed chronic phase patients. Well-established established time-dependent milestones of response predict outcome. These milestones are the basis for current recommendations for monitoring. As the frontline therapy of CML is shifting toward nilotinib and dasatinib, they will have to be adjusted. Summary (2) qpcr monitoring is indicated once a patient has achieved CCyR. qpcr is superior to cytogenetics in terms of convenience, dynamic range and sensitivity. Lack of qpcr standardization, low assay quality and misinterpretation are a frequent cause of clinical confusion. Conversion of results allows expression on a uniform scale (IS). 29