Chronic Myeloid Leukaemia

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1 Chronic Myeloid Leukaemia Molecular Response: What is really important? Jeff Szer The Royal Melbourne Hospital

PROBABILITY, % PROBABILITY OF SURVIVAL AFTER MYELOABLATIVE TRANSPLANTS FOR CML IN CHRONIC PHASE, 1996-2001 - By Donor Type and Disease Duration - 100 80

2 PROBABILITY, % PROBABILITY OF SURVIVAL AFTER MYELOABLATIVE TRANSPLANTS FOR CML IN CHRONIC PHASE, By Donor Type and Disease Duration HLA-identical sibling, <1y (N = 2,720) 60 HLA-identical sibling, 1y (N = 1,317) P = Unrelated, 1y (N = 951) YEARS Unrelated, <1y (N = 677)

3 PROBABILITY, % SURVIVAL AFTER MYELOABLATIVE TRANSPLANTS FOR CML CP, from IBMTR and SURVIVAL WITH IMATINIB FROM BRIAN DRUKER Imatinib survival HLA-identical sibling, <1y (N = 2,720) HLA-identical sibling, 1y (N = 1,317) Unrelated, 1y (N = 951) Unrelated, <1y (N = 677) YEARS

6 BCR-ABL Transcripts (log 10 ) Disease Burden Is Reduced Over Time With Imatinib Therapy Highly sensitive techniques are required to detect MRD Disease burden and tests Cytogenetics FISH 1-2-log reduction RT-PCR ~5 Log reduction Dx Months on Treatment Time Dx, diagnosis; FISH, fluorescence in situ hybridization. Radich JP. Blood. 2009;114:

9 Prognostic Significance of Molecular Response Early molecular response is associated with: Higher probability of MMR 1,2 Higher rates of event-free survival (EFS) 2,3,4 and progression-free survival (PFS) 3 Achievement of MMR is associated with: Higher rates of EFS 4 and PFS 5 Longer duration of CCyR 6,7,8,9 Durable MMR is associated with prolonged PFS Branford S, et al. Leukemia. 2003;(17): ; 2. Quintas-Cardama A, Blood. 2009;113: ; 3. Müller MC, et al. Blood. 2008;112(11):129; 4 Hughes TP, et al. Blood. 2008;112(11): ; 5. Press RD, et al. Blood. 2006;107(11): ; 6. Iacobucci I, et al, Clin Cancer Res. 2006:12, : 7. Cortes J, et al, Clin Cancer Res;2005;11: ; 8. Paschka P, et al. Leukemia; 2003;17:1687; 9. Press RD, et al. Clin Cancer Res. 2007;13: ; 10.Kantarjian H, et al. Cancer. 2008;112:

13 Importance of Depth of Response (MMR) Hughes T et al. N Engl J Med. 2003;349:

14 BCR- ABL1/ABL1 transcript ratio Degree of Molecular Response at Early Time Points is Associated With Achievement of MMR N=258, mgIM, mg. Med FU 53 months Probability of outcome according to transcript ratio at specified time points, % MMR (BCR-ABL1/ABL1 < 0.05%) Event 3 mo 6 mo 12 mo 3 mo 6 mo 12 mo 0.1% > 0.1% to 1% > 1% to 10% > 10% Quintas-Cardama A, et al. Blood. 2009;113:

15 % EFS % PFS Degree of Molecular Response at Early Timepoints Predicts PFS and EFS: German CML IV study BCR-ABL% (IS) at 6 months y PFS: 93% vs 72%; P = < 10% 10% Patients randomized to imatinib-based therapies on the CML Study IV y EFS: 88% vs 77%; P = Months 5 arm study. Data presented for IM 400mg ± IFN only Müller MC, et al. Blood. 2008;112(11):129.

16 Without Event, % EFS on IRIS: 6-Month Landmark Analysis N=553; 476 had PCR studies % 85% 85% P = BCR-ABL % (IS) 0.1% (n = 86) > 0.1-1% (n = 89) > 1-10% (n = 43) > 10% (n = 38) Months Since Start of Treatment 56% EFS, event-free survival. Hughes TP, et al. Blood. 2008; 112(11):

17 Without Event, % EFS on IRIS: 12-Month Landmark Analysis % 91% P = % 53% BCR-ABL % (IS) 0.1% (n = 153) > 0.1-1% (n = 90) > 1-10% (n = 36) > 10% (n = 22) Months Since Start of Treatment EFS, event-free survival. Hughes TP, et al. Blood. 2008;112(11):

18 PFS, % MMR is Associated With Decreased Risk for Progression 85pts achieving CCyR (72 CP 400mg and 13 AP 600mg) Log drop 3 (n = 42) 60 3 > log-drop 2 (n = 15) 40 log-drop < 2 (n = 28) 20 0 P < Months From First CCyR CCyR, complete cytogenetic response. Press RD, et al. Blood. 2006;107(11):

19 Cumulative Proportion of CCyR Duration MMR at 12 Months is Associated With Longer Duration of CCyR 1.05 GIMEMA study 97pts with late stage CP P =.021 Pts with MMR at 12 mo: longer CCyR and less likely to lose it Pts with log reduction 3 (MMR) at 12 months Pts with log reduction < 3 at 12 months CCyR Months from CCyR Iacobucci I, et al. Clin Cancer Res. 2006;12:

20 MMR is Associated With Durable CCyR Best BCR- ABL ratio Evaluable patients, n Loss of CCyR Total, n (%) P No MMR* (37) MMR* (5) <.0001 *MMR defined as BCR-ABL/ABL % <.05. An increase in CCyR durability in patients with an MMR (< 0.05% BCR-ABL/ABL) at 6 (P =.02) and 12 (P =.0004) months was also reported Cortes J, et al. Clin Cancer Res. 2005;11:

21 MMR is Associated With Decreased Risk for Cytogenetic Relapse Total n=48, 29 with PCR 29 CP Patients with a CCyR 1 BCR-ABL (%) 0.1 n = 16 BCR-ABL (%) > 0.1 n = 13 0/16 Relapse 0% 6/13 Relapse 46% P = CML Patients with a CCyR 2 76/90 patients BCR-ABL (%) /90 patients BCR-ABL (%) > /76 Relapse 16% 8/14 Relapse 57% P = Paschka P, et al. Leukemia; 2003;17: Press RD, et. al. Clin Cancer Res. 2007;13:

22 Proportion Progression-free Survival Durable MMR is Associated With Increased PFS P = Durable MMR (months) Total Failure < Months from 1 st Major Molecular Response Kantarjian H, et al. Cancer. 2008;112:

23 ELN Definitions of Response on First-Line Imatinib: Role of MMR Optimal Response Suboptimal Response Failure Warnings Baseline NA NA NA High Risk CCA/Ph+ * 3 Months CHR and at least minor CyR (Ph+ 65%) No CyR (Ph+ > 95%) Less than CHR NA 6 Months At least PCyR (Ph+ 35%) Less than PCyR (Ph+ > 35%) No CyR (Ph+ > 95%) NA 12 Months CCyR PCyR (Ph+ 1-35%) Less than PCyR (Ph+ > 35%) Less than MMR 18 Months MMR Less than MMR Less than CCyR NA Any time Stable or improving MMR Loss of MMR Mutations Loss of CHR Loss of CCyR Mutations CCA/Ph+ * Any rise in transcript levels CCA/Ph- װ * CCA/Ph+ = Clonal chromosome abnormalities in Ph+ cells; CCA/Ph+ is a warning factor at diagnosis although its occurrence during treatment (ie, clonal progression) is a marker of treatment failure. Two consecutive cytogenetic tests are required and must show the same CCA in at least two Ph cells. MMR indicates a ratio of BCR-ABL1 to ABL1 or other housekeeping genes, 0.1% on the international scale. BCR-ABL1 kinase domain mutations still sensitive to imatinib. BCR-ABL1 kinase domain mutations poorly sensitive to imatinib. װ CCA/Ph- = Clonal chromosome abnormalities in Ph- cells. Baccarani M, et al. J Clin Oncol (35):6041

24 Achievement of CMR Rate of MMR and depth of molecular response increase over time on imatinib 1 Majority of newly diagnosed patients achieve MMR within 12 months on nilotinib 2,3,4 Many patients will achieve undetectable BCR-ABL transcript levels on tyrosine kinase inhibitors The definition of complete molecular response (CMR) is evolving with the development of more sensitive molecular monitoring techniques Current definition: Undetectable BCR-ABL by RQ-PCR and/or nested PCR (sensitivity > 10 4 ) 5 1. O Brien SG, et al. Blood. 2008;112(11): Rosti G, et al. Blood. 2008;112(11): Rosti G, et al. Haematologica. 2009;94(s2): Cortes J, et al. Blood. 2008;112(11): Baccarani M, et al. J Clin Oncol (35):6041.

25 Undetectable BCR-ABL, % MMR at 12 Months is Predictive of CMR* Pre P <.0001 MMR by 12 months (n = 24) No MMR by 12 months (n = 29) Years on Imatinib * > 4.5-log reduction in BCR-ABL levels from a standardized baseline. 72% 5% Branford S, et al. Clin Cancer Res. 2007;13:

26 Importance of Depth of Response (CMR) Survival was 100% only in the group of patients who achieved CMR Kantarjian H. et al, Cancer 2008;112(4):837

27 CMR and TWISTER

28 Imatinib cessation study Patient characteristics Two cohorts: imatinib de novo (IM only, n=15) and imatinib after prior interferon therapy (IFN-IM, n=17). Peripheral blood (PB) RQ-PCR for BCR-ABL performed centrally. Age (years) IM only IFN-IM n=15 n= Molecular relapse was defined as a single RQ-PCR result above the level of major molecular response (MMR) or any two consecutive positive results. Imatinib re-treatment was commenced in patients who relapsed. DM Ross, 1,2 S Branford, 1 A Grigg, 2 A Schwarer, 2 C Arthur, 2 K Loftus, 3 AK Mills, 2 R Filshie, 2 R Columbus, 2 JF Seymour, JV Melo, 1 TP Hughes 1,2, ESH 2009 Sex 6M/9F 9M/8F Duration of imatinib Rx (months) Duration of CMR (months) p=0.??

29 Percentage in CMR Molecular relapse-free survival Molecular relapse-free survival in all 32 patients Molecular relapse-free survival in each cohort Estimated proportion of patients Survival in Analysis stable CMR Median follow-up 13 months 1.0 Survival Analysis Survival Survival 0.6 IM only cohort 0.51 Mean ± 95% confidence interval IFN-IM cohort Days off imatinib Time Days off imatinib Time Estimated proportion of patients remaining in stable CMR = 46% at 13 months (95% CI 21-71%) DM Ross, 1,2 S Branford, 1 A Grigg, 2 A Schwarer, 2 C Arthur, 2 K Loftus, 3 AK Mills, 2 R Filshie, 2 R Columbus, 2 JF Seymour, JV Melo, 1 TP Hughes 1,2, ESH 2009

30 BCR-ABL mrna level (%) Does detectable mrna really mean relapse? Relapse was defined as detectable mrna in two consecutive samples. Seven patients had detectable mrna on one occasion, not meeting the study definition of relapse imatinib re-started #6 Two of the 7 patients subsequently relapsed (in both cases 4 months later, see figure). The other 5 patients remain in CMR after 3-10 months of follow-up Undet #14 In these two patients there was no progressive increase in the BCR-ABL mrna level between samples at relapse. Both achieved CMR after restarting imatinib Undet Months since imatinib cessation The measured BCR-ABL mrna level is shown as a solid line. The broken line indicates the calculated detection limit of RQ-PCR. Arrows indicate when imatinib was re-started. DM Ross, 1,2 S Branford, 1 A Grigg, 2 A Schwarer, 2 C Arthur, 2 K Loftus, 3 AK Mills, 2 R Filshie, 2 R Columbus, 2 JF Seymour, JV Melo, 1 TP Hughes 1,2, ESH 2009

31 BCR-ABL level (%) BCR-ABL DNA was detected before mrna relapse 12 patients were tested with patient-specific DNA PCR for BCR-ABL. Six of the 12 patients relapsed. BCR-ABL DNA was detected before mrna in 5 out of 6 patients. In the sixth patient there was a single positive mrna result, but the subsequent 3 months of mrna samples were negative, whereas DNA was persistently detectable DNA and mrna results in patients with molecular relapse RNA DNA RNA DNA RNA DNA RNA DNA RNA DNA RNA DNA Months since imatinib cessation Patient #4 MMR BCR-ABL not detected BCR-ABL detected Sample not available DNA mrna DM Ross, 1,2 S Branford, 1 A Grigg, 2 A Schwarer, 2 C Arthur, 2 K Loftus, 3 AK Mills, 2 R Filshie, 2 R Columbus, 2 JF Seymour, JV Melo, 1 TP Hughes 1,2, ESH Months since imatinib cessation 6

32 Elimination of MRD is not required for stable CMR Comparison of DNA and mrna in the other 6 patients who have not relapsed Five patients had BCR-ABL DNA detected on at least one occasion during follow-up so far. The 12 th patient had no detectable BCR- ABL DNA on any occasion over the first 12 months since imatinib cessation. Patient #9 remained in CMR off imatinib, but had a stable level of BCR-ABL DNA detectable over 12 months of follow-up. The estimated detection limit of BCR-ABL mrna is indicated by the broken line. DM Ross, 1,2 S Branford, 1 A Grigg, 2 A Schwarer, 2 C Arthur, 2 K Loftus, 3 AK Mills, 2 R Filshie, 2 R Columbus, 2 JF Seymour, JV Melo, 1 TP Hughes 1,2, ESH 2009

33 Conclusions Approximately 50% of patients remain in CMR if imatinib treatment is withdrawn from selected patients in a stable CMR. The majority of relapses occur within the first 6 months after imatinib withdrawal. Rising BCR-ABL DNA levels may herald molecular relapse. Many patients in CMR have detectable MRD within 1-2 log of the detection limit of BCR-ABL mrna, yet have not relapsed. If the level of MRD is not the sole predictor of relapse risk further investigation is required to identify other, possibly immunological, factors that may influence the risk of relapse. DM Ross, 1,2 S Branford, 1 A Grigg, 2 A Schwarer, 2 C Arthur, 2 K Loftus, 3 AK Mills, 2 R Filshie, 2 R Columbus, 2 JF Seymour, JV Melo, 1 TP Hughes 1,2, ESH 2009

34 ENESTcmr

35 ENESTcmr Study Schema Next Phase CP-CML Imatinib 400 or 600 mg QD for at least 2 years Stable dose: No Imatinib dose change within 6 months of study entry No major toxicity on Imatinib within 3 months of study entry CCyR and persistent disease R A N D O M I Z E 1:1 Year 1 Nilotinib 400 mg bid Potential Outcomes Imatinib (same dose) Potential Outcomes Primary Endpoint Year 2 Years 3 & 4 NO CMR Continue Nilotinib CMR Continue Nilotinib CMR Continue Imatinib NO CMR Crossover to Nilotinib* End of Study

36 2 nd Generation

38 Failure to achieve MMR at 12 months to 2G TKI impacts on survival Mutations status important Jabbour et al Blood. 2009;114: Tam et al Blood. 2008;112:

45 2 nd Generation: 1st line

46 Molecular Response % Cortes J, et al. Blood 2009; 114(22), , Months N Evaluable Nilotinib in Early CP CML Molecular Responses (ITT) CMR MMR

47 Proportion Survival Nilotinib in ECP CML:Long-Term Outcome % 92% Overall Event-free Progression-free No No. Events Months Definitions: Event: Loss of CHR, loss of MCyR, off for toxicity, AP/BP, death Progression: Transformation to AP/BP Cortes J, et al. Blood 2009; 114(22), , Abs #341

51 Recommendations for Monitoring Molecular Response and Rising BCR-ABL Levels Molecular Monitoring every 3 months 1 Achieve MMR: screen every 6 months 1 No MMR? Sequence for TKI mutations Persistent MMR Highly promising 2 Rising RQ-PCR Repeat at 1-3 month intervals 2 > 10x rise is concerning 2 mutational testing 1. Baccarani M, et al. J Clin Oncol (35): Radich JP, et al. Blood. 2009;114:

53 Conclusion There is now sufficient evidence to say that the depth of molecular response and the speed of attaining that response in CML is important and should be closely monitored Some patients with a deep response may stay free of apparent disease for prolonged periods The place of allogeneic stem cell transplants in chronic phase CML is becoming increasingly controversial

IRIS 8-Year Update. Management of TKI Resistance Will KD mutations matter? Sustained CCyR on study. 37% Unacceptable Outcome 17% 53% 15%

IRIS 8-Year Update. Management of TKI Resistance Will KD mutations matter? Sustained CCyR on study. 37% Unacceptable Outcome 17% 53% 15% Management of TKI Resistance Will KD mutations matter? IRIS 8-Year Update 17% 53% 5% 15% 37% Unacceptable Outcome No CCyR Lost CCyR CCyR Other 3% 7% Safety Lost-regained CCyR Sustained CCyR on study Deininger