Abstract

Background: Based on results from the IRIS trial, IM is the standard of care for pts with newly diagnosed CML-CP. This report presents the 7 yr data update of IRIS to assess long term outcome, response rate, and safety in pts on primary IM therapy.

Methods: 553 pts were randomly assigned to IM and evaluated for hematologic, cytogenetic and molecular responses, discontinuations/cross-over reasons, event-free survival (EFS), progression to accelerated-phase (AP) or blast crisis (BC) and OS. Events for EFS were defined as the first occurrence of any of the following during treatment: death from any cause, progression to AP/BC, loss of a complete hematologic response or major cytogenetic response (MCyR), or an increasing white blood cell count to > 20 × 109/L. After discontinuation of study treatment, pts were followed only for OS.

Results: At 7 yrs, the estimated EFS was 81%, freedom from progression (FFP) to AP/ BC was 93%, and the estimated OS was 86%. The best observed rates for MCyR and complete cytogenetic response (CCyR) were 89% and 82%, respectively. A total of 317 (57%) of all randomized pts remained on IM per protocol and were in CCyR. The estimated rates of progression to AP/BC from yrs 1 through 7 are 1.5, 2.8, 1.6, 0.9, 0.5, 0, and 0.4%, respectively, with one pt progressing to AP/BC between yrs 6 and 7. Yearly event rates are 3.3%, 7.5%, 4.8%, 1.7%, 0.8%, 0.3% and 2% (5 events occurred in the 7th yr: 3 unconfirmed loss of MCyR, 2 deaths). Of the 456 pts who achieved CCyR, 79 (17%) subsequently lost CCyR; 25 remained on IM (19 pts regained CCyR, of whom 6 responded to an increase in IM dose; 6 pts remained in MCyR without dose escalation). A total of 15 pts (3%) who achieved CCyR on IM progressed to AP/BC during study treatment, typically during the 1st year after achievement of CCyR; 3 CCyR pts progressed to AP/BC after the 2nd year. A total of 332 (60%) pts remain on IM on protocol at the 7-yr data cut-off. Reasons for discontinuation or crossover include: 5% adverse events/ safety, 15% lack of efficacy/progression, 3% bone marrow transplant, 2% death, and 15% other (protocol violation, withdrawal of consent or lack of renewal of consent, lost to follow-up, administrative) reasons. Between yrs 6 and 7, 17 pts (3%) discontinued IM for the following reasons: adverse events (n=3), death (n=2; 1 CML-related), unsatisfactory therapeutic effect (n=7; 1 progression to AP/BC, 4 unconfirmed loss of MCyR, 2 unconfirmed loss of CCyR), protocol violation (n=1), and withdrawal of consent (n=4). Molecular response (MR) assessment was required per the IRIS protocol only in pts who had achieved CCyR. However, MR was measured routinely in 98 pts treated in Australia/ New Zealand and Germany (sub-study) at baseline and every 3 mo through 72 mo, and other sites contributed assessments if available. Of the total IRIS IM cohort, 476 pts had at least one PCR measurement. MMR was defined as a ratio of BCR-ABL/control transcripts of ≤ 0.1% according to the International Scale.

Table 1: MR over time: BCR-ABL/control gene transcript levels (as % of available samples)

 All available samples Sub-study samples 
Time-points (mo) >10% > 1.0–≤10% > 0.1–≤1.0% ≤0.1% (MMR) ≤0.1% (MMR) 
174 25% 39% 24% 13% 87 8% 
258 15% 17% 35% 33% 86 28% 
12 305 9% 12% 30% 50% 81 47% 
18 253 6% 10% 19% 65% 70 63% 
48 238 6% 9% 10% 75% 66 82% 
60 273 3% 4% 8% 85% 71 90% 
72 210 2% 3% 9% 86% 57 88% 
 All available samples Sub-study samples 
Time-points (mo) >10% > 1.0–≤10% > 0.1–≤1.0% ≤0.1% (MMR) ≤0.1% (MMR) 
174 25% 39% 24% 13% 87 8% 
258 15% 17% 35% 33% 86 28% 
12 305 9% 12% 30% 50% 81 47% 
18 253 6% 10% 19% 65% 70 63% 
48 238 6% 9% 10% 75% 66 82% 
60 273 3% 4% 8% 85% 71 90% 
72 210 2% 3% 9% 86% 57 88% 

The MMR rates at 12 and 48 mo for all available samples are consistent with the reported rates of 53% and 80%, respectively, noted in a subset of pts with CCyR (Druker et al, NEJM, 2006) and similar to the unselected sub-study data. Additionally, MMR responses at 12 mo are similar to the recently reported TOPS trial (Cortes et al, EHA 2008). Between yr 6 and 7, serious adverse events suspected to be related to IM were reported in 9 pts, resulting in treatment discontinuation in 3 pts. No new safety issues were identified.

Conclusions: Responses with IM therapy remain durable with estimated 7 yr rates of FFP to AP/BC 93%, EFS 81%, and OS 86%. Only 1 patient progressed between yrs 6 and 7. The safety profile is unchanged and confirms a favorable risk-benefit ratio in CML-CP. Long-term follow-up of pts who continue to respond to IM demonstrate an MMR rate of 85–90% at 5–6 years. These results demonstrate increasing suppression of CML over time in patients who continue to receive imatinib.

Disclosures: O’Brien:Novartis Pharmaceuticals: Research Funding. Hochhaus:Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Innovive: Research Funding; Wyeth: Research Funding; Merck: Research Funding. Hughes:Novartis Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Radich:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Rudoltz:Novartis Pharmaceuticals: Employment, Equity Ownership. Filian:Novartis Pharmaceuticals: Employment. Gathmann:Novartis Pharmaceuticals: Employment. Druker:Novartis Pharmaceutical: Research Funding; MolecularMD: Scientific founder. OHSU/Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. Potential COI has been reviewed/managed by the OHSU COI in Research Comm. & Integrity Program Oversight Comm; BMS: Research Funding. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding.

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