International Randomized Study of Interferon Versus STI571 (IRIS) 7-Year Follow-up: Sustained Survival, Low Rate of Transformation and Increased Rate of Major Molecular Response (MMR) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CMLCP) Treated with Imatinib (IM)

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) n >10% > 1.0–≤10% > 0.1–≤1.0% ≤0.1% (MMR) n ≤0.1% (MMR) 3 174 25% 39% 24% 13% 87 8% 6 258 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.