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Nilotinib first-line therapy in patients with Philadelphia chromosome-negative/BCR-ABL-positive chronic myeloid leukemia in chronic phase: ENEST1st sub-analysis.

ABSTRACT: The ENEST1st sub-analysis presents data based on Philadelphia chromosome (Ph) status, i.e., Ph+ and Ph-/BCR-ABL1?+?chronic myeloid leukemia.Patients received nilotinib 300 mg twice daily, up to 24 months.At screening, 983 patients were identified as Ph+ and 30 patients as Ph-/BCR-ABL?+?based on cytogenetic and RT-PCR assessment; 76 patients had unknown karyotype (excluded from this sub-analysis). In the Ph-/BCR-ABL1?+?subgroup, no additional chromosomal aberrations were reported. In the Ph+ subgroup, 952 patients had safety and molecular assessments. In the Ph-/BCR-ABL1?+?subgroup, 30 patients had safety assessments and 28 were followed up for molecular assessments. At 18 months, the molecular response (MR) 4 rate [MR4; BCR-ABL1 ?0.01% on International Scale (IS)] was similar in the Ph-/BCR-ABL1+ (39.3%) and Ph+ subgroups (38.1%). By 24 months, the cumulative rates of major molecular response (BCR-ABL1IS ?0.1%;), MR4, and MR4.5 (BCR-ABL1IS ?0.0032%) were 85.7, 60.7, and 50.0%, respectively, in the Ph-/BCR-ABL1?+?subgroup, and 80.3, 54.7, and 38.3%, respectively, in the Ph+ subgroup. In both Ph-/BCR-ABL1?+?and Ph+ subgroups, rash (20 and 22%), pruritus (16.7 and 16.7%), nasopharyngitis (13.3 and 10.4%), fatigue (10 and 14.2%), headache (10 and 15.8%), and nausea (6.7 vs 11.4%) were frequent non-hematologic adverse events, whereas hypophosphatemia (23.3 and 6.8%), anemia (10 and 6.5%), and thrombocytopenia (3.3 and 10.2%) were the common hematologic/biochemical laboratory events.Based on similar molecular response and safety results in both subgroups, we conclude that Ph-/BCR-ABL1?+?patients benefit from nilotinib in the same way as Ph+ patients.

SUBMITTER: Hochhaus A

PROVIDER: S-EPMC5486575 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Nilotinib first-line therapy in patients with Philadelphia chromosome-negative/BCR-ABL-positive chronic myeloid leukemia in chronic phase: ENEST1st sub-analysis.

Hochhaus Andreas A Mahon Franҫois-Xavier FX le Coutre Philipp P Petrov Ljubomir L Janssen Jeroen J W M JJWM Cross Nicholas C P NCP Rea Delphine D Castagnetti Fausto F Hellmann Andrzej A Rosti Gianantonio G Gattermann Norbert N Coronel Maria Liz Paciello MLP Gutierrez Maria Asuncion Echeveste MAE Garcia-Gutierrez Valentin V Vincenzi Beatrice B Dezzani Luca L Giles Francis J FJ

Journal of cancer research and clinical oncology 20170221 7

<h4>Purpose</h4>The ENEST1st sub-analysis presents data based on Philadelphia chromosome (Ph) status, i.e., Ph+ and Ph-/BCR-ABL1 + chronic myeloid leukemia.<h4>Methods</h4>Patients received nilotinib 300 mg twice daily, up to 24 months.<h4>Results</h4>At screening, 983 patients were identified as Ph+ and 30 patients as Ph-/BCR-ABL + based on cytogenetic and RT-PCR assessment; 76 patients had unknown karyotype (excluded from this sub-analysis). In the Ph-/BCR-ABL1 + subgroup, no additional chromo ...[more]

PMID: 28224300

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Project description:Additional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are non-random and strongly associated with disease progression, but their prognostic impact and effect on treatment response is not clear. Point mutations in the BCR-ABL kinase domain are probably the most common mechanisms of imatinib resistance.We assessed the influence of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to the second-generation tyrosine kinase inhibitor nilotinib after imatinib-failure. Standard cytogenetic analysis of metaphases was performed to detect additional chromosomal aberrations and the BCR-ABL kinase domain was sequenced to detect point mutations.Among 53 patients with a median follow-up of 16 months, of whom 38, 5 and 10 were in chronic phase, accelerated phase and blast crisis, respectively, 19 (36%) had additional chromosomal aberrations and 20 (38%) had BCR-ABL kinase domain mutations. The 2-year overall survival rate of all patients with-out additional chromosomal aberrations (89%) was higher than that of patients with such aberrations (54%) (P=0.0025). Among patients with chronic phase disease, overall survival at 2 years was 100% and 62% for patients without or with additional chromosomal aberrations, respectively (P=0.0024). BCR-ABL kinase domain mutations were associated with lower remission rates in response to nilotinib, with 9 of 20 (45%) of these patients achieving a major cytogenetic remission as compared to 26 of 33 (79%) patients without mutations (P<0.05). However, overall survival was not affected by BCR-ABL kinase domain mutations.Whereas BCR-ABL kinase domain mutations may confer more specific resistance to nilotinib, which will predominantly affect response rates, the presence of additional chromosomal aberrations may reflect genetic instability and, therefore, intrinsic aggressiveness of the disease which will be less amenable to subsequent alternative treatments and thus negatively affect overall survival. Conventional cytogenetic analyses remain mandatory during follow-up of patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy.

Dataset Information

Nilotinib first-line therapy in patients with Philadelphia chromosome-negative/BCR-ABL-positive chronic myeloid leukemia in chronic phase: ENEST1st sub-analysis.

Publications

Nilotinib first-line therapy in patients with Philadelphia chromosome-negative/BCR-ABL-positive chronic myeloid leukemia in chronic phase: ENEST1st sub-analysis.

Similar Datasets

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