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

Abstract

PurposeThe ENEST1st sub-analysis presents data based on Philadelphia chromosome (Ph) status, i.e., Ph+ and Ph−/BCR-ABL1 + chronic myeloid leukemia.MethodsPatients received nilotinib 300 mg twice daily, up to 24 months.ResultsAt 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.ConclusionBased 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.

Prognostic significance of a normal karyotype in adult patients with BCR-ABL1-positive acute lymphoblastic leukemia in the tyrosine kinase inhibitor era

“…In this study, we found that the NK/BCR-ABL1 + group was similar to the isolated Ph + group, which corroborated the findings obtained in case of CML ( 12 , 15 - 17 ). With regard to the efficacy of TKIs and prognosis, there are only relevant studies for CML patients.…”

“…They concluded that the clinical benefit of TKIs in patients with NK/BCR-ABL1 + is similar to that in patients with Ph + , and this view is also recognized by Bennour et al (13). A study published by Hochhaus et al also found that like Ph + patients, CML patients with an NK benefit from nilotinib, as these patients show similar molecular responses (12). On the contrary, three cases of CML with cryptic Ph chromosome reported by Haigh et al failed to show a major cytogenetic response after imatinib therapy for at least three years, and two of them were shown to have an NK at the initial diagnosis via cytogenetic analysis (4).…”

“…At the time of disease diagnosis, cytogenetic analysis showed that the cryptic Ph chromosome translocation could present with a normal karyotype (NK) in approximately 3.0%-7.7% of CML patients, as well as a relatively small proportion of BCR-ABL1 + ALL patients (5)(6)(7)(8)(9)(10). The prognosis of NK in CML patients has been reported, and the results in the tyrosine kinase inhibitor (TKI) era were controversial (4,(11)(12)(13). However, its role has not been systematically elucidated in adult patients with BCR-ABL1-positive ALL.…”

Cryptic BCR-ABL fusion gene as variant rearrangement in chronic myeloid leukemia: molecular cytogenetic characterization and influence on TKIs therapy

“…As the latter [18], Ph-neg rearrangement does not influence the response to TKIs therapy. We confirm that Ph-neg CML patients do not constitute a “warning” category in imatinib era, in according to ELN 2013 recommendations [19, 20]. …”

Recommendations from a Portuguese Expert Group for Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Patients in Clinical Practice

“…The main factors associated with a sustained TFR are TKI treatment duration and depth of DMR. 1,11,13,25,27,29,[40][41][42] These factors have been taken into consideration for the practical recommendations detailed below. The discontinuation of TKI treatment in CML should only be considered in individual patients with ensured access to certified molecular monitoring.…”