Reduction of BCR-ABL Transcript Levels at 6, 12, and 18 Months (mo) Correlates with Long-Term Outcomes on Imatinib (IM) at 72 Mo: An Analysis from the International Randomized Study of Interferon versus STI571 (IRIS) in Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CML-CP)
Timothy P Hughes, MD1,*,
Andreas Hochhaus, MD2,
Susan Branford, PhD3,
Martin C Müller, MD4,*,
Letizia Foroni, MD, PhD, FRCPath5,*,
Brian J. Druker, MD6,
François Guilhot, MD7,
Richard A. Larson, MD8,
Stephen G OBrien, MD, PhD9,*,
Roger J. Waltzman, MD10,
Manisha Mone, PhD11,*,
Elisabeth Wehrle, PhD12,*,
Jerald P. Radich, MD13,* and
John M. Goldman, MD14,*
1 Haematology, Institute of Medical and Veterinary Science, Adelaide, Australia, 2 Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany, 3 Institute of Medical & Veterinary Science, Adelaide, Australia, 4 Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany, 5 Department of Haematology, Imperial College, London, United Kingdom, 6 Oregon Health & Science University Cancer Institute, Portland, OR, USA, 7 Clinical Investigational Centre INSERM 802, CHU de Poitiers, Poitiers, France, 8 University of Chicago, Chicago, IL, USA, 9 University of Newcastle, Newcastle, United Kingdom, 10 Global Medical Affairs, Novartis Pharma. Corporation, Florham Park, NJ, USA, 11 Novartis Pharmaceuticals, Florham Park, NJ, USA, 12 Novartis Pharma AG, Basel, Switzerland, 13 Fred Hutchinson Cancer Research Ctr., Seattle, WA, USA, 14 Department of Haematology, Hammersmith Hospital, London, United Kingdom
Background: An exploratory endpoint of the IRIS trial was measurementof BCR-ABL transcripts over time and its correlation with long-termoutcomes. BCR-ABL measured by polymerase chain reaction (PCR)was required per protocol only after achievement of a completecytogenetic response (CCyR). However, preplanned substudiesoccurred at sites in Germany and Australia who conducted PCRmeasurements on pts at intervals from the start of treatmentindependent of cytogenetic response (CyR). Additionally, otherIRIS investigators contributed non-protocol specified molecularassessments. This first entire PCR dataset from IRIS assessesthe prognostic value of molecular response (MR) at specifictime points.
Methods: 553 pts were enrolled onto the IM arm of IRIS; of these,476 pts with at least one PCR measurement form the basis forthis analysis. A major molecular response (MMR) is defined asthe ratio of BCR-ABL/control gene (BAC) of 0.1%. Analyses wereconducted at 6, 12 and 18 mo relating BAC percent reductionto event free survival (EFS), where events were defined as deathduring study treatment, loss of complete hematologic response,loss of Major CyR (MCyR), progression to accelerated phase (AP)or blast crisis (BC), or an increasing white blood cell countto > 20 x 109/L.
Results: Among pts receiving first line IM for CML-CP, MMR wasobserved in 13% of samples available for study at 3 mo, 33%at 6 mo, 50% at 12 mo, 65% at 18 mo, 75% at 48 mo, 85% at 60mo, and 86% at 72 mo. The degree of molecular response in ptswho achieved CCyR is described in Table 1. This exploratoryanalysis demonstrates close correlation between CCyR and BAC1% at 6 months and beyond.
Table 1. Correlation of CCyR with molecular response at 3, 6,12 and 18 mo.
Pts with CCyR and PCR samples available (n)
CCyRand 0.1% BAC [MMR], n (%)
CCyR and 1% BAC, n (%)
At 6 mo, half of the pts with BAC >10% who also had a cytogeneticassessment at the same time had at least a partial cytogeneticresponse (PCyR) with an EFS of 91% at 72 mo, and 64% of thesepts achieved MMR later. The other half of the pts with >10%BAC who did not have a PCyR at 6 mo had an EFS of 43%, and 31%later achieved MMR. A separate landmark analysis by CyR statusalone showed EFS rates at 72 mo of 92% for pts in CCyR, 86%for pts in PCyR, 60% for Minor/Minimal CyR and 49% for No CyR.At 12 mo, pts with BAC 1% had excellent long term outcomes(72 month EFS of >90%, >95% without progression to AP/BC).Those pts with BAC > 1– 10% (n = 36) had a 67% EFS,and 44% later achieved an MMR. These molecular analyses comparesimilarly to cytogenetic analyses alone (Baccarani et al; ASH2006), with 60 mo EFS of 93% for pts in CCyR, 78% for pts inPCyR and 61% for pts without PCyR At 18 mo, pts with MMR couldbe statistically distinguished from pts with BAC >0.1–1%; EFS was 98% versus 89%, p=0.0137 (with 6 events in eachgroup). The rate without AP/BC at 72 mo was not significantlydifferent (with only 2 events in the >0.1 – 1% group).Baccarani et al (ASH 2006) reported an EFS at 60 mo of 96% forpts in CCyR, 80% for pts in PcyR and 69% for pts without PCyR.
Table 2: Long-term outcomes (estimated rates at 72 mo) by MRlevels at 6, 12 and 18 mo.
EFS rate at 72 mo
WithoutAP/BC at 72 mo
12 mo landmark
EFSrate at 72 mo
Without AP/BC at 72 mo
EFS rate at 72 mo
WithoutAP/BC at 72 mo
*P=.0137. None of the othercomparisons between MMR and > 0.1–1% BAC were
Conclusion: In pts on first-line IM, MMR rates increase overtime, and in pts who achieved an MMR at any time point progressionis rare. Achievement of a CCyR correlated well with BAC of 1%from 6 mo onwards. Exploratory molecular analyses show pts withBAC >10% at 6 mo have EFS rates distinguishable by theircytogenetic status. At 12 mo, pts with a BAC > 1% or withoutCCyR, fare more poorly than those with BAC 1% or those in CCyR.At 18 mo pts with BAC 1% have excellent long term outcomes,with the best outcomes seen in those with BAC 0.1%. Molecularand cytogenetic evaluations are recommended until at least CCyRis achieved, with molecular assessments measured indefinitelythereafter.
Disclosures: Hughes:Novartis Pharmaceuticals: Honoraria, ResearchFunding, Speakers Bureau. Hochhaus:Novartis Pharmaceuticals:Honoraria, Research Funding; BMS: Honoraria, Research Funding;Innovive: Research Funding; Wyeth: Research Funding; Merck:Research Funding. Branford:Novartis Pharmaceuticals: Honoraria,Research Funding; BMS: Honoraria, Research Funding. Druker:MolecularMD: Scientific founder. OHSU/Dr. Druker have a financialinterest in MolecularMD. Technology used in this research hasbeen licensed to MolecularMD. Potential COI has been reviewed/managedby the OHSU COI in Research Comm & Integrity Program OversightComm.; Novartis Pharmaceuticals: Research Funding; BMS: ResearchFunding. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria,Research Funding. OBrien:Novartis Pharmaceuticals: ResearchFunding. Waltzman:Novartis Pharmaceuticals: Employment, EquityOwnership. Mone:Novartis Pharmaceuticals: Employment. Wehrle:novartis Pharmaceuticals: Employment. Radich:novarits Pharmaceuticals:Consultancy, Honoraria, Research Funding; BMS: Consultancy,Honoraria, Research Funding.
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April 7, 2011;
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