Clinical Significance of Dose Reductions of Dasatanib and Nilotinib When Used As Frontline Therapy for Chronic Phase -Chronic Myeloid Leukemia (CML-CP) Does Not Affect Outcome,

Dasatinib and nilotinib are now standard frontline therapy for patients (pts) with CML-CP. Transient treatment interruptions and dose reductions occur frequently in pts treated with these agents, most frequently due to adverse events (AE). (Cortes et al. JCO 2010). The impact that such interruptions may have over the clinical outcome is not known.

To determine the causes, frequency, and time to dose reductions of 2nd generation tyrosine kinase inhibitors (TKI), dasatinib and nilotinib when used as initial therapy for CML-CP and to investigate the impact that dose reduction has over outcome.

We analyzed 204 pts with CML-CP treated with frontline dasatinib (n=99) at an initial dose of 100mg QD (n=66) or 50mg BID (n=33) or nilotinib at a starting dose of 400mg BID (n=105) in parallel trials. Data on dosing, treatment interruptions and reasons for dose adjustment were collected prospectively. The protocols included guidelines for treatment interruptions and dose reductions for drug-related grade 3–4 AEs, or persistent grade 2 AEs.

The median age for the 204 pts was 47 years (range, 17 to 86), 58% were males. A complete hematological response was achieved by 99%, complete cytogenetic response (CCyR) by 95%, major molecular response (MMR) by 87%, and complete molecular response (CMR; BCR-ABL/ABL ≤0.0032% IS) by 62%. A total of 71 pts (35%) required a dose reduction due to an AE, including 39/99 (39%) treated with dasatinib (23/66 -35%- at 100mg QD, 16/33 -48%- at 50mg BID) and 32/105 (30%) with nilotinib. Thirty-one pts (44%) required a second or subsequent dose reduction. The first dose reduction occurred within 3 months from start of therapy in 21 (54%) of pts treated with dasatinib while 18 (46%) (n=18) required it after 3 months. For pts treated with nilotinib 21 (66%) required a dose reduction within 3 months and 11 (34%) after 3 months of start of treatment. The most common AEs grade 2–4 leading to dose reductions on dasatanib included pleural effusion (n=24), headache (n=11), peripheral neuropathy (n=6), myelosuppression (n=6) (5 thrombocytopenia, 1 neutropenia), cough (n= 5), dizziness (n=4), generalized body pain (n=3), fatigue (n=3), rash (n=3), chest pain (n=2), anxiety/mood alteration(n=2), memory impairment (n=2), A.fib (n=2), and pneumonia, bradycardia, MI, CHF and depression (1 each) (>1 AE could be coded as reason for dose reduction if concomitant). For nilotinib causes were increased bilirubin (n=6), increased LFT's (n=6), myelosuppression (n=5) (2 thrombocytopenia, 3 neutropenia), rash (n=5), head ache (n=3), chest pain (n=3), lipase (n=2), bone pain (n=2), fatigue (n=2), nausea/vomiting (n=2), and bradycardia, pericarditis, PVC's, and abdominal pain (1 each). Only 3 pts had a re-escalation of dose after their dose reduction. Median dose for pts requiring a dose reduction on nilotinib was 400 mg/day (range was 200–400) and the median dose for dasatinib was 80mg/d (range 20–80mg/d). The outcome of patients with or without dose reduction is presented in Table 1.

Although dose reductions are frequently required for pts with CML treated with dasatinib or nilotinib, dose reductions did not lead to adverse outcome. Dose adjustments can be used when required to manage AEs. This approach allows in most instances continuation of these highly effective therapies.

Kantarjian:BMS: Research Funding; Novartis: Research Funding. Quintas-Cardama:Novartis: Consultancy; BMS: Consultancy. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Jabbour:BMS: Honoraria; Novartis: Honoraria. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.