Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia

Abstract

BackgroundSecond-generation tyrosine kinase inhibitors induce cytogenetic responses in approximately 50% of patients with chronic myeloid leukemia in chronic phase in whom imatinib treatment has failed. However, it has not yet been established which of the patients in whom imatinib treatment fails are likely to benefit from therapy with second-generation tyrosine kinase inhibitors. Design and MethodsWe analyzed a cohort of 80 patients with chronic myeloid leukemia who were resistant to imatinib and who were treated with dasatinib or nilotinib while still in first chronic phase. We devised a scoring system to predict the probability of these patients achieving complete cytogenetic response when treated with second-generation tyrosine kinase inhibitors. ResultsThe system was based on three factors: cytogenetic response to imatinib, Sokal score and recurrent neutropenia during imatinib treatment. We validated the score in an independent group of 28 Scottish patients. We also studied the relationship between cytogenetic responses at 3, 6 and 12 months and subsequent outcome. We classified the 80 patients into three categories, those with good risk (n=24), intermediate risk (n=27) and poor risk (n=29) with 2.5-year cumulative incidences of complete cytogenetic response of 100%, 52.2% and 13.8%, respectively (P<0.0001). Moreover, patients who had less than 95% Philadelphia chromosome-positive metaphases at 3 months, those with 35% or less Philadelphia chromosome-positive metaphases at 6 months and patients in complete cytogenetic response at 12 months all had significantly better outcomes than patients with lesser degrees of cytogenetic response. ConclusionsFactors measurable before starting treatment can accurately predict response to secondgeneration tyrosine kinase inhibitors. Cytogenetic responses at 3, 6 and 12 months may influence the decision to continue treatment with second-generation tyrosine kinase inhibitors.Key words: early prediction, tyrosine kinase inhibitors, chronic myeloid leukemia.Citation: Milojkovic D, Nicholson E, Apperley JF, Holyoake TL, Shepherd P, Drummond MW, Szydlo R, Bua M, Foroni L, Reid A, Khorashad JS, de Lavallade H, Rezvani K, Paliompeis C, Goldman JM, and Marin D. Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Haematologica. 2010; 95:224-231. doi:10.3324/haematol.2009 This is an open-access paper.

Efficacy of tyrosine kinase inhibitors (TKIs) as third-line therapy in patients with chronic myeloid leukemia in chronic phase who have failed 2 prior lines of TKI therapy

“…Probabilities of overall survival (OS), progression-free survival (PFS), and event-free survival (EFS), all as defined previously, 10 were calculated using the Kaplan-Meier method. The probabilities of cytogenetic and molecular responses were calculated as previously described.…”

“…We have previously reported the association between hematologic toxicity and lack of cytogenetic response in CP patients treated with imatinib as first-line therapy, 11 in patients treated with imatinib after interferon-␣ failure, 12 and in patients treated with nilotinib or dasatinib after imatinib failure. 10 In these cases, the poor prognosis associated with hematologic toxicity may in part explained by the lack of an expandable population of Philadelphia chromosomenegative cells. 12 We report here the largest series of CML patients in CP treated with a third-line TKI after failing both imatinib and another TKI.…”

“…Dasatinib and nilotinib were administered at standard doses as described by others. 4,5,[8][9][10] CP, complete hematologic responses (CHR), CCyR major cytogenetic response (MCyR), and major molecular response (MMR) were defined by conventional criteria. 11…”

Mexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

“… Chronic phase with high Sokal;  Low Sokal with therapeutic failure to the first-line TKIs;  Identify the patients with therapeutic failure to TKIs to take them to second-line treatment and who have poor risk, according to the Hammersmith index [78];  Patients who reach accelerated and blastic phase.…”

Advanced Phase Chronic Myeloid Leukemia Treatment and Transplantation

“…[1][2][3] Patients refractory to IM treatment compose 35% of CML patients and half of these patients are also refractory second generation TKIs. [3][4][5][6] The mortality risk of the allogeneic transplant has decreased continuous-ly during the last 20 years.…”