Initial Molecular Response at 3 Months May Predict Both Response and Event-Free Survival at 24 Months in Imatinib-Resistant or -Intolerant Patients With Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase Treated With Nilotinib

• Published in: Journal of clinical oncology Vol. 30; no. 35; pp. 4323 - 4329
• Main Authors: Branford, Susan, Kim, Dong-Wook, Soverini, Simona, Haque, Ariful, Shou, Yaping, Woodman, Richard C., Kantarjian, Hagop M., Martinelli, Giovanni, Radich, Jerald P., Saglio, Giuseppe, Hochhaus, Andreas, Hughes, Timothy P., Müller, Martin C.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 10.12.2012
• Subjects: Adolescent; Adult; Antineoplastic Agents - therapeutic use; Benzamides - therapeutic use; Biological and medical sciences; Disease-Free Survival; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl - biosynthesis; Fusion Proteins, bcr-abl - genetics; Hematologic and hematopoietic diseases; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mutation; ORIGINAL REPORTS; Piperazines - therapeutic use; Pyrimidines - therapeutic use; Remission Induction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Survival Rate; Treatment Outcome; Tumors; Young Adult; Antineoplastic agent; Human; Nilotinib; Imatinib; Enzyme; Tyrosine kinase inhibitor; Transferases; Enzyme inhibitor; Chronic myelogenous leukemia; Malignant hemopathy; Philadelphia positive leukemia; Survival; Resistance; Myeloproliferative syndrome; Cancerology; Treatment; Predictive factor; Protein-tyrosine kinase; Cancer
• ISSN: 0732-183X; 1527-7755; 1527-7755
• DOI: 10.1200/JCO.2011.40.5217

The association between initial molecular response and longer-term outcomes with nilotinib was examined. Patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase from the phase II nilotinib registration study with available postbaseline BCR-ABL1 transcript assessments were included (N = 237). BCR-ABL1 transcript levels (International Scale [IS]) at 3 months correlated with complete cytogenetic response (CCyR) by 24 months. Patients with BCR-ABL1 (IS) of > 1% to ≤ 10% at 3 months with nilotinib had higher cumulative incidence of CCyR by 24 months than patients with BCR-ABL1 (IS) of > 10% (53% v 16%). BCR-ABL1 (IS) at 3 months predicted major molecular response (MMR) by 24 months. Cumulative incidence of MMR by 24 months for patients with BCR-ABL1 (IS) of > 0.1% to ≤ 1%, > 1% to ≤ 10%, and > 10% was 65%, 27%, and 9%, respectively. These differences were observed for patients with or without baseline BCR-ABL1 mutations and for those with imatinib resistance or intolerance. Estimated event-free survival (EFS) rates at 24 months decreased with higher transcript levels at 3 months; patients with BCR-ABL1 (IS) of ≤ 1% had an estimated 24-month EFS rate of 82%, compared with 70% for patients with BCR-ABL1 (IS) of > 1% to ≤ 10% and 48% for patients with BCR-ABL1 (IS) of > 10%. Patients with BCR-ABL1 (IS) of > 10% at 3 months had a lower cumulative incidence of CCyR and MMR and lower rates of EFS versus patients with BCR-ABL1 (IS) of ≤ 10%. Prospective studies may determine whether close monitoring or alternative therapies are warranted for patients with minimal initial molecular response.