Efficacy of Frontline Nilotinib Therapy in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP)

In 2005, we initiated a phase II study of nilotinib as 1^st line therapy in pts with newly diagnosed CML-CP to investigate the efficacy and safety of nilotinib as frontline therapy for pts with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP within 6 mo from diagnosis were eligible and received nilotinib 400 mg twice daily. Results: 100 pts (41% female) have received for a median of 24 mo (range 1 to 72mos). Median age was 49 years (range 17–86). Median WBC, PB blasts, PB basophils, hemoglobin, and platelet count was 42.6, 0%, 2.5%, 12.3, 307, respectively. Five pts (5%) had a variant Philadelphia chromosome and 1 (1%) had deletion of derivative chromosome 9. Seventy-two (72%), 20 (20%), and 8 (8%) pts had low, intermediate, and high Sokal risk score. Among the 102 CP pts who were not in CHR at the start, 100 (98%) achieved CHR (one discontinued after 2 weeks without adverse events). Among 73 CP pts followed for at least 12 mo, 69 (95%) achieved a complete cytogenetic response (CCyR). MMR at 18 mo has been achieved in 51 (89%) pts, including 30 (52%) with a complete molecular response (CMR)(Table 1). The median time to achieve CCyR, MMR was 6 mo each.

Grade 3–4 thrombocytopenia, neutropenia, and anemia occurred in 9%, 12%, and 6% pts. The most frequent non-hematologic toxicities were rash (62%), pain (57%), and elevated transaminases (45%) and bilirubin (42%). However, grade 3–4 non-hematologic adverse events (possible, probable or suspected relationship only) were rare, including: pain and increased bilirubin (4% each), elevated lipase, fatigue, and elevated transaminases (2% each), and hyperglycemia (1%). One (1%) pt experienced QTc prolongation (grade 2; QTc prolonged from 444msec to 483msec), not associated with arrhythmias and resolved after a brief treatment interruption. Forty-five (45%) pts had transient treatment interruptions (median days off-nilotinib 7 [range 1–68]) and 27 (27%) had dose reductions. Of the patients that were dose reduced, their current or last known dose was either 200mg daily (n=7), 200mg twice daily (n=14), or 400mg daily (n=6). Nineteen (19%) pts terminated nilotinib therapy due to toxicity (n=7), personal reasons or loss to follow-up (n=7), loss of MCyR (n=2), progression to BP (n=2), or death (n=1). Of the pts who discontinued therapy, 3 were tested for BCR-ABL1 mutations; 2 were found to have mutations (F359C and Y253H). The 48 mo probability of EFS (event= loss of CHR, loss of MCyR, AP/BP, or death) is 88%. The annual rate of events during the first 48 mo of follow-up was 4%, 0%, 2%, 5%, and 0% and the rate of transformation 2%, 0%, 0%, and 0%, respectively. The best response achieved on nilotinib by the 2 pts that transformed to BP was CCyR and PCyR, respectively. The overall survival at 48 mos is 96%. One pt died due to stroke, unrelated to nilotinib. No other vascular events have been observed to date. Conclusion: Nilotinib 400 mg twice daily induces CCyR in 78% of pts as early as 3 mo and MMR in 86% at 12 mo after the start of therapy, with very low rates of progression to AP/BP and a mild toxicity profile.

No relevant conflicts of interest to declare.