Is CML a curable disease? David Ross

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Is CML a curable disease?:

Is CML a curable disease? David Ross SA Pathology Saturday 16 th August 2014

NO:

NO Gratwohl Haem 2006 91:513; Sekhri Leuk Res 2009 33:1291. Latest reported relapse at 24 years post-allograft

Overview:

Overview What is a ‘ cure ’ ? MRD despite deep molecular response Possible future strategies for ‘ cure ’

Cure:

Cure Absence of disease-related symptoms and signs Freedom from progression No need for treatment Permanent

CMR:

CMR Complete Molecular Response No detectable BCR-ABL mRNA RQ-PCR method with sensitivity ≥4.5-log Confirmed on two consecutive measurements Undetectable MRD (UMRD) Molecular Undetectable Leukaemia (MUL) Branford Clin Cancer Res 2007 13:7080

Slide6:

CHR CCR CMR MR4.5 Estimated <10 6 residual leukaemic cells

Less is better:

Less is better Mutations occur stochastically – fewer cells means fewer opportunities CML LSCs have increased ROS and increased mutation rate Imatinib does not correct ROS-induced mutagenesis in the most primitive CML cells (mouse model) Bolton-Gillespie Blood 2013 121:4175

Allografting:

Allografting Achievement of UMRD required for EFS Relapse risk: UMRD 5% detectable MRD 70% Rate of unstable UMRD is lower than in imatinib-treated patients BCR-ABL DNA not detected in 8/9 patients in long-term remission Radich Blood 1995 85:2632; Mughal BJH 2001 115:569; Lange Leukemia 2005 19:1262; Simoes Blood 2010 116:1329

Stopping Imatinib:

Stopping Imatinib All reported cases of cessation in CCR or MMR led to relapse Doubling time ~ 10 days First reported TFR cases had UMRD Mahon Blood 2007 109:58; Branford Blood 2012 119:4264

ALLG CML8 study clinical outline:

ALLG CML8 study clinical outline Clinical trial of withdrawing imatinib from chronic phase CML patients with sustained undetectable BCR-ABL by RQ-PCR for at least two years Close RQ-PCR monitoring for two years Completed accrual of 40 patients: 21 patients received IFN before imatinib 19 patients received imatinib in early CP Ross Blood 2013 122:515.

Relapse:

Relapse Defined as: Loss of MMR (BCR-ABL IS >0.1%) OR Any two consecutive positive results Imatinib re-commenced at previous dose

Patients (n=40):

Patients (n=40) Male sex 48% Median age 61 years Median interval (months) Imatinib prior to study entry 70 (44-108) Time to UMRD 32 (3-73) UMRD prior to study entry 36 (24-82) Follow-up 40 (12-72)

CML8 TFR:

CML8 TFR Ross Blood 2013 122:515.

Patient-specific DNA PCR:

Patient-specific DNA PCR BCR ABL

Slide15:

Years in treatment-free remission Ross Blood 2013 122:515.

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P<0.001 P<0.001 10 0.1 0.001 1 0.01 BCR-ABL DNA% Not detected 0.0001 UMRD at study entry Molecular relapse UMRD after retreatment NS Ross Blood 2013 122:515.

Atypical relapse:

Atypical relapse

A-STIM:

A-STIM Single case of lymphoid blast crisis developing abruptly after regaining UMRD Started imatinib 10 years after original diagnosis Rousselot JCO 2014 32:424.

Interferon-α:

Interferon- α Mahon JCO 2001 20:214

Interferon-α:

Interferon- α Burchert JCO 2010 28:1429. IFN-IM combination then IFN maintenance after IM cessation

Stopping of 2G TKI:

Stopping of 2G TKI ENESTop MR4.5 after second-line nilotinib One year nilotinib ‘ consolidation ’ then stop if MRD criteria met ENESTfreedom MR4.5 after first-line nilotinib (ENESTnd) Similar design EuroSKI registry

Dasatinib after imatinib failure:

Dasatinib after imatinib failure Ross Haem 2011 96:1720.

Biology of TFR Possible models for MRD:

Ross & Melo ASHEP 2011. Biology of TFR Possible models for MRD

Conclusions:

Conclusions Some patients appear to be ‘ cured ’ with follow-up of >5 years after stopping imatinib TFR after imatinib is often (or always) associated with detectable MRD by highly sensitive BCR-ABL DNA PCR Many questions remain:

Question #1:

Question #1 What MRD threshold is good enough to achieve TFR? UMRD is arbitrary and varies from test to test MR4.5 being tested in prospective trials Probably also depends on duration of MR

Question #2:

Question #2 What is the latest that relapse can occur? How should we monitor patients in TFR? Latest reported relapse from TFR at 42 months Latest reported loss of MMR (A-STIM) at 17 months

Question #3:

Question #3 Why do some people with stable UMRD relapse early while others remain in TFR? Pre-determined by disease biology? Immune control? Persistence of differing subclones or cell types?

Thanks:

Thanks SA Pathology, Adelaide Tim Hughes Sue Branford Junia Melo Flinders Uni, Adelaide Alec Morley Paul Bartley Sue Latham SAHMRI, Adelaide Deb White Phuong Dang Jarrad Goyne Salisbury, UK Nick Cross Joannah Score ALLG, Australia & NZ

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