24 Months Update of the TOPS Study: a Phase III, Randomized, Open-Label Study of 400mg/d (SD-IM) Versus 800mg/d (HD-IM) of Imatinib Mesylate (IM) in Patients (Pts) with Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase (CML-CP).

12-month results from TOPS showed an advantage for the high dose (800mg/day, HD-IM) arm for: (1) time to achievement of major molecular response (MMR); MMR rates at 3 and 6 months (mos); and (2) complete cytogenetic response (CCyR) at 6 mos (Guilhot et al. [TOPS] ASH 2008). There was no significant difference in the MMR rates at 12 mos, the primary endpoint, and results support 400 mg/day as the standard initial dose for imatinib (SD-IM) in CML-CP pts. The purpose of this update is to assess the outcome of the two arms at 24 mos, as well as the impact of dose intensity (DI) and dose interruption on pts outcome.

476 pts with newly diagnosed CML-CP were randomized 2:1 to receive HD-IM (n = 319) or SD-IM (n = 157) at 103 sites in 19 countries. The endpoints assessed at 24 mos were: rates of CCyR and MMR, event-free (EFS), progression-free (PFS), and overall survival (OS). CCyR and MMR rates were calculated based on pts with available assessments at specified timepoints. Adverse events (AE) and laboratory results were also monitored. Additional analyses were performed using DI (< 600 mg/d and ≥ 600 mg/d) and number of dose interruptions (periods of zero dose of > 5 days) as variables. In the trial dose interruptions were specified as an AE management strategy prior to dose reduction.

At 24 mos, 129/157 (82%) of SD-IM and 247/319 (77%) of HD-IM pts remained on study treatment. There was no significant difference in rates of MMR at 12 mos (SD-IM: 40% vs. HD-IM: 46%), 18 mos (52% vs 47%) or 24 mos (54% vs 51%) (intention to treat analysis). There was no significant difference in the cumulative rates of CCyR at 24 mos (76% in each arm). Overall, 9 (6%) pts on SD-IM and 15 (5%) pts on HD-IM had experienced an event (loss of complete hematologic response, loss of major cytogenetic response, progression to accelerated phase and blast crisis, or death due to any cause). There were no significant differences in estimated EFS (SD-IM: 95% vs. HD-IM: 95%), PFS (97% vs. 98%), or OS (97% vs. 98%) at 24 mos. The most common grade 3/4 hematologic AEs were neutropenia (17.8% vs. 28.2%) and thrombocytopenia (8.9% vs. 19.9%), and for the most part occurred during the first 12 mos. The most common grade 3/4 nonhematologic toxicities for SD-IM and HD-IM were rash (2.5% vs 5.7%), diarrhea (1.3% vs 6.0%) and myalgia (0.6% vs 3.5%), respectively. The most common reasons for discontinuation in both arms were AEs (4.5% vs. 10.7%) and unsatisfactory therapeutic effect (7.0% vs 7.2%). Median DI was 400 mg/d in the SD-IM arm and 728 mg/d in the HD-IM arm. Dose interruptions for > 5 days occurred more frequently in the HD-IM arm (71% vs. 44%). Pts in both arms combined who had ≤ 1 dose interruption during the first 12 mos achieved higher MMR rates at 12 (57.1% vs 33.3% for ≤ 1 vs > 1 interruption; P < 0.0001) and 18 mos (72.6 vs. 46.8; P < 0.0001), faster time to MMR (P = 0.0002), and higher CCyR rates at 12 mos (88.8 vs 63.8; P < 0.0001), compared with pts who had > 1 dose interruption during the same period. On the SD-IM arm pts with ≤ 1 (vs > 1) dose interruption also had higher MMR rates at 12 and 18 mos (12 mos: 49.6% vs 22.2%, P = 0.04; 18 mos: 70.9% vs 50%, P = NS). Comparing pts in the HD-IM arm with DI ≥ 600mg/d for the first 12 mos vs DI < 600 mg/d, the MMR rates at 12 mos (62.4% vs 34.1%, P < 0.0001) and 18 mos (75.2% vs 40.3%, P < 0.0001) were higher, the time to MMR was faster (P < 0.0001), duration of MMR was longer (P = 0.0141) and CCyR rates at 12 mos (89.6% vs 70.3%, P < 0.0001) were higher for pts with DI ≥ 600mg/d.

TOPS continues to confirm the safety and efficacy of 400 mg/day IM for newly diagnosed pts with CML-CP, with very similar results to IRIS. HD-IM was also safe and generally well tolerated, but overall did not result in better outcomes at milestones up to 24 months. Frequent or prolonged dosage interruptions on IM adversely affect patient outcomes and should be avoided. These data emphasize the importance of maintaining dose intensity in CML-CP pts treated with imatinib. The TOPS study will continue to assess the impact of dose intensity on long-term outcomes.

Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pane:Novartis: Research Funding; Ministero dell'Università/PRIN: Research Funding; Regione Campania: Research Funding; Ministero della Salute/Progetto integrato Oncologia: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Jin:Novartis: Employment. Krahnke:Novartis: Employment, Equity Ownership. Rudoltz:Novartis: Employment, Equity Ownership. Radich:Novartis: Consultancy, Honoraria, Research Funding. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria.