![OPTIMAL WARNING FAILURE
BASELINE NA -HIGH RISK,
-CCA/Ph+
(Major route)
NA
3 mo Ph+ ≤ 35% and/or
BCR-ABL ≤ 10%
Ph + 36-95% and/or
BCR-ABL ≥ 10%
No CHR and/or
Ph + > 95%
6 mo Ph+ 0 and/or
BCR-ABL < 1%
Ph + 1-35% and/or
BCR-ABL 1-10%
Ph + > 35% and/or
BCR-ABL > 10%
12 mo BCR-ABL≤ 0.1% BCR-ABL 0.1-1 % Ph + ≥ 1%, and/or
BCR-ABL > 1%
24 mo BCR-ABL ≤ 0.1% BCR-ABL 0.1-1% BCR-ABL > 1%
EUROPEAN LEUKEMIANET 2013
RESPONSE TO TREATMENT FIRSTLINE
Baccarani M et al, Blood. 2013 Jun 26. [Epub ahead of print].Yellow = cytogenetic response](https://image.slidesharecdn.com/8ritchiecmlbtg2015-150518165038-lva1-app6891/85/When-to-stop-TKI-in-Chronic-Myelogenous-Leukemia-40-320.jpg)
When to stop TKI in Chronic Myelogenous Leukemia?
- 1. When to stop TKI in CMLWhen to stop TKI in CML
- 4. Three situationsThree situations When they don’t workWhen they don’t work When they are too toxicWhen they are too toxic When they appear to have affected a cureWhen they appear to have affected a cure
- 5. Three situationsThree situations When they don’t workWhen they don’t work When they are too toxicWhen they are too toxic When they appear to have affected a cureWhen they appear to have affected a cure
- 6. CML is cured by alloSCT by eradicationCML is cured by alloSCT by eradication CML clones via the GVL effect……right?CML clones via the GVL effect……right? Gratwohl Haem 2006 91:513; Sekhri Leuk Res 2009 33:1291. Latest reported relapse at 24 years post- allograft
- 7. CureCure Absence of disease-related symptomsAbsence of disease-related symptoms and signsand signs Freedom from progressionFreedom from progression No need for treatmentNo need for treatment PermanentPermanent
- 8. CMRCMR Complete Molecular ResponseComplete Molecular Response No detectable BCR-ABL mRNANo detectable BCR-ABL mRNA RQ-PCR method with sensitivityRQ-PCR method with sensitivity ≥4.5-log≥4.5-log Confirmed on two consecutive measurementsConfirmed on two consecutive measurements Undetectable MRD (UMRD)Undetectable MRD (UMRD) Molecular Undetectable Leukaemia (MUL)Molecular Undetectable Leukaemia (MUL) Treatment free remissionTreatment free remission Branford Clin Cancer Res 2007 13:7080
- 10. Less is betterLess is better Mutations occur stochastically – fewerMutations occur stochastically – fewer cells means fewer opportunitiescells means fewer opportunities CML LSCs have increased ROS andCML LSCs have increased ROS and increased mutation rateincreased mutation rate Imatinib does not correct ROS-inducedImatinib does not correct ROS-induced mutagenesis in the most primitive CMLmutagenesis in the most primitive CML cells (mouse model)cells (mouse model) Bolton-Gillespie Blood 2013 121:4175
- 11. AllograftingAllografting Achievement of UMRD required for EFSAchievement of UMRD required for EFS Relapse risk: UMRD 5%Relapse risk: UMRD 5% detectable MRD 70%detectable MRD 70% Rate of unstable UMRD is lower than inRate of unstable UMRD is lower than in imatinib-treated patientsimatinib-treated patients BCR-ABL DNA not detected in 8/9BCR-ABL DNA not detected in 8/9 patients in long-term remissionpatients in long-term remission Radich Blood 1995 85:2632; Mughal BJH 2001 115:569; Lange Leukemia 2005 19:1262; Simoes Blood 2010 116:1329
- 12. Ross & Melo ASHEP 2011. Biology of TFRBiology of TFR Possible modelsPossible models for MRDfor MRD
- 13. Stopping ImatinibStopping Imatinib All reported cases of cessation in CCR orAll reported cases of cessation in CCR or MMR led to relapseMMR led to relapse Doubling timeDoubling time ~~10 days10 days First reported TFR cases had UMRDFirst reported TFR cases had UMRD Mahon Blood 2007 109:58; Branford Blood 2012 119:4264
- 14. ALLG CML8 studyALLG CML8 study clinical outlineclinical outline Clinical trial of withdrawing imatinib from chronicClinical trial of withdrawing imatinib from chronic phase CML patients with sustained undetectablephase CML patients with sustained undetectable BCR-ABL by RQ-PCR for at least two yearsBCR-ABL by RQ-PCR for at least two years Close RQ-PCR monitoring for two yearsClose RQ-PCR monitoring for two years Completed accrual of 40 patients:Completed accrual of 40 patients: 21 patients received IFN before imatinib21 patients received IFN before imatinib 19 patients received imatinib in early CP19 patients received imatinib in early CP Ross Blood 2013 122:515.
- 15. RelapseRelapse Defined as:Defined as: Loss of MMR (BCR-ABLLoss of MMR (BCR-ABLISIS >0.1%)>0.1%) • OROR Any two consecutive positive resultsAny two consecutive positive results Imatinib re-commenced at previous doseImatinib re-commenced at previous dose
- 16. Patients (n=40)Patients (n=40) Male sex 48%Male sex 48% Median age 61 yearsMedian age 61 years Median interval (months)Median interval (months) Imatinib prior to study entryImatinib prior to study entry 70 (44-108)70 (44-108) Time to UMRDTime to UMRD 32 (3-73)32 (3-73) UMRD prior to study entryUMRD prior to study entry 36 (24-82)36 (24-82) Follow-upFollow-up 40 (12-72)40 (12-72)
- 17. CML8 TFRCML8 TFR Ross Blood 2013 122:515.
- 18. Patient-specific DNA PCRPatient-specific DNA PCR BCR ABL
- 19. Years in treatment-free remission Ross Blood 2013 122:515.
- 20. P<0.001P<0.001 10 0.1 0.001 1 0.01 BCR-ABLDNA% Not detected 0.0001 UMRD at study entry Molecular relapse UMRD after retreatment NS Ross Blood 2013 122:515.
- 21. A-STIMA-STIM Single case of lymphoid blast crisis developing abruptly after regaining UMRD Started imatinib 10 years after original diagnosis Rousselot JCO 2014 32:424.
- 22. Interferon-Interferon-αα Mahon JCO 2001 20:214
- 23. Stopping of 2G TKIStopping of 2G TKI ENESTopENESTop MR4.5 after second-line nilotinibMR4.5 after second-line nilotinib One year nilotinib ‘consolidation’ then stop if MRDOne year nilotinib ‘consolidation’ then stop if MRD criteria metcriteria met ENESTfreedomENESTfreedom MR4.5 after first-line nilotinib (ENESTnd)MR4.5 after first-line nilotinib (ENESTnd) Similar designSimilar design EuroSKI registryEuroSKI registry
- 24. Question #1Question #1 What MRD threshold is good enough toWhat MRD threshold is good enough to achieve TFR?achieve TFR? UMRD is arbitrary and varies from test to testUMRD is arbitrary and varies from test to test MR4.5 being tested in prospective trialsMR4.5 being tested in prospective trials Probably also depends onProbably also depends on speedspeed andand durationduration ofof MRMR
- 27. Question #2Question #2 What is the latest that relapse can occur?What is the latest that relapse can occur? How should we monitor patients in TFR?How should we monitor patients in TFR? Latest reported relapse from TFR at 42 monthsLatest reported relapse from TFR at 42 months Latest reported loss of MMR (A-STIM) at 17Latest reported loss of MMR (A-STIM) at 17 monthsmonths
- 28. Question #3Question #3 Why do some people with stable UMRDWhy do some people with stable UMRD relapse early while others remain in TFR?relapse early while others remain in TFR? Pre-determined by disease biology?Pre-determined by disease biology? Immune control?Immune control? Persistence of differing subclones or cell types?Persistence of differing subclones or cell types?
- 29. ConclusionsConclusions Some patients appear to be ‘cured’ withSome patients appear to be ‘cured’ with follow-up of >5 years after stopping imatinibfollow-up of >5 years after stopping imatinib TFR after imatinib is often (or always)TFR after imatinib is often (or always) associated with detectable MRD by highlyassociated with detectable MRD by highly sensitive BCR-ABL DNA PCRsensitive BCR-ABL DNA PCR
- 31. Imatinib is still a great drug IRIS and many, many, many ASH updates
- 32. 3 year Dasision data Jabbour; Blood 2014
- 34. Ischemic heartIschemic heart diseasedisease IschemicIschemic cerebrovascularcerebrovascular eventsevents PeripheralPeripheral arterialarterial diseasedisease 2020 1818 1010 22 00 1616 88 66 44 1414 1212 NumberofpatientsNumberofpatients Cardiovascular events (CVE) by 36 months (safety population)Cardiovascular events (CVE) by 36 months (safety population) Any CVEAny CVE NilotinibNilotinib Median exposure, 3.0 yMedian exposure, 3.0 y ImatinibImatinib Median exposure on study,Median exposure on study, 2.2 y2.2 y Crossover to Nilotinib MedianCrossover to Nilotinib Median exposure, 1.0 yexposure, 1.0 y 1212 22 22 77 44 00 1111 11 00 11 33 1515 More cases of CVEs were reported in patientsMore cases of CVEs were reported in patients randomized to nilotinib compared with imatinibrandomized to nilotinib compared with imatinib
- 37. What if you do wait until 6 months? 6 month landmark analysis 37 85
- 39. 3-Month Evaluation Recommended assessments Level of response achieved Follow-up assessments Treatment options Ongoing monitoring Ongoing management Cytogenetics if RQ-PCR using the IS is not available BCR-ABLIS ≤ 10% or PCyR BCR-ABLIS > 10% or < PCyR Continue same dose of TKI Evaluate patient compliance and drug-drug interactions RQ-PCR every 3 months RQ-PCR at least every 3 months Switch to alternate TKI (other than imatinib) OR Continue same dose/dose-escalatea Continue ongoing monitoring until 12-month evaluation Proceed according to recommendations for patients with BCR-ABLIS > 10% or < PCyR at 3 months RelapseNo relapse Event RQ-PCR using the IS OR Clinical trial Additional monitoring or mutational analysis as indicated Mutational analysis NCCN Clinical Practice Guidelines in Oncology. Chronic Myelogenous Leukemia. Version 1.2014. a Increase dose of imatinib if not candidate for alternate TKI or continue same dose of nilotinib or dasatinib (for patients on first-line nilotinib or dasatinib). AND Evaluate for HSCT
- 40. OPTIMAL WARNING FAILURE BASELINE NA -HIGH RISK, -CCA/Ph+ (Major route) NA 3 mo Ph+ ≤ 35% and/or BCR-ABL ≤ 10% Ph + 36-95% and/or BCR-ABL ≥ 10% No CHR and/or Ph + > 95% 6 mo Ph+ 0 and/or BCR-ABL < 1% Ph + 1-35% and/or BCR-ABL 1-10% Ph + > 35% and/or BCR-ABL > 10% 12 mo BCR-ABL≤ 0.1% BCR-ABL 0.1-1 % Ph + ≥ 1%, and/or BCR-ABL > 1% 24 mo BCR-ABL ≤ 0.1% BCR-ABL 0.1-1% BCR-ABL > 1% EUROPEAN LEUKEMIANET 2013 RESPONSE TO TREATMENT FIRSTLINE Baccarani M et al, Blood. 2013 Jun 26. [Epub ahead of print].Yellow = cytogenetic response
- 41. 00 halving time > 90 days, n=58 (64%)halving time > 90 days, n=58 (64%) halving time ≤ 90 days, n=33 (36%)halving time ≤ 90 days, n=33 (36%) PP < .0001< .0001 100100 9090 5050 1010 00 66 1212 1818 242433 99 1515 2121 8080 4040 3030 2020 7070 6060 Confirmed undetectable BCR-ABL by 2 yearsConfirmed undetectable BCR-ABL by 2 years – dynamics of response– dynamics of response 48% 5% Months after switch to nilotinibMonths after switch to nilotinib 91 evaluable patients91 evaluable patients Cumulativeincidence%Cumulativeincidence% 2020For distribution in response to an unsolicited request for medical information pending local NP4 approval.