Immediate Effects of Dasatinib on the Migration and Redistribution of Naïve and Memory Lymphocytes Associated With Lymphocytosis in Chronic Myeloid Leukemia Patients.

Introduction: Dasatinib is a dual SRC/ABL tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML) that is known to have unique immunomodulatory effects. In particular, dasatinib intake typically causes lymphocytosis, which has been linked to better clinical response. Since the underlying mechanisms are unknown and SRC family kinases are involved in many cell motility processes, we hypothesized that the movement and migration of lymphocytes is modulated by dasatinib. Patients, Materials and Methods: Peripheral blood samples from CML patients treated with second-line dasatinib were collected before and 2 h after the first dasatinib intake, and follow-up samples from the same patients 3 and 6 months after the start of therapy. The migratory capacity and phenotype of lymphocytes and differential blood counts before and after drug intake were compared for all study time-points. Results: We report here for the first time that dasatinib intake is associated with inhibition of peripheral blood T-cell migration toward the homeostatic chemokines CCL19 and CCL21, which control the trafficking toward secondary lymphoid organs, mainly the lymph nodes. Accordingly, the proportion of lymphocytes in blood expressing CCR7, the chemokine receptor for both CCL19 and CCL21, decreased after the intake including both naïve CD45RA+ and central memory CD45RO+ T-cells. Similarly, naïve B-cells diminished with dasatinib. Finally, such changes in the migratory patterns did not occur in those patients whose lymphocyte counts remained unchanged after taking the drug. Discussion: We, therefore, conclude that lymphocytosis induced by dasatinib reflects a pronounced redistribution of naïve and memory populations of all lymphocyte subsets including CD4+ and CD8+ T-cells and B-cells.

Frecuencia de mutaciones del gen ABL en pacientes con leucemia mieloide crónica resistentes a imatinib y resultado del cambio de tratamiento a inhibidores de tirosín-cinasa de segunda generación / Frequency of ABL gene mutations in chronic myeloid leukemia patients resistant to imatinib and results of treatment switch to second-generation tyrosine kinase inhibitors

Background and objectives: Tyrosine kinase inhibitors (TKI) have improved the management of patients with chronic myeloid leukemia (CML). However, a significant proportion of patients do not achieve the optimal response or are resistant to TKI. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Treatment with second-generation TKI has produced high rates of hematologic and cytogenetic responses in mutated ABL patients. The aim of this study was to determine the type and frequency of ABL mutations in patients who were resistant to imatinib or had lost the : response, and to analyze the effect of second-generation TKI on their outcome. Patients and methods: The presence of ABL mutations in 45 CML patients resistant to imatinib was evaluated by direct sequencing and was correlated with the results of the cytogenetic study (performed in 39 cases). The outcome of these patients after therapy with nilotinib or dasatinib was analyzed. Results: ABL mutations were detected in 14 out of 45 resistant patients. Patients with clonal cytogenetic evolution tended to develop mutations more frequently than those without clonal evolution. Nine out of the 15 patients with ABL mutation responded to a treatment switch to nilotinib (n = 4), dasatinib (n = 2), interferon (n = 1) or hematopoietic stem cell transplantation (n = 2). Conclusion: The frequency of ABL mutations in CML patients resistant to imatinib is high and is more frequent among those with clonal cytogenetic evolution. The change to second-generation TKI can overcome imatinib resistance in most of the mutated patients (AU)

Fundamento y objetivos: La mayoría de los pacientes con leucemia mieloide crónica (LMC) obtienen respuesta clínica bajo tratamiento con imatinib. Sin embargo, una proporción significativa de ellos no alcanza dicha respuesta o son resistentes al tratamiento, implicándose en ello mutaciones del gen ABL. El desarrollo de inhibidores de tirosín-cinasa (ITK) de segunda generación ha permitido superar la resistencia al tratamiento con imatinib en muchos casos. El objetivo de este estudio fue analizar el tipo y frecuencia de mutaciones del gen ABL en pacientes resistentes a imatinib o que han perdido la respuesta y determinar el efecto de los ITK de segunda generación, nilotinib y dasatinib. Sujetos y métodos: Se analizó la presencia de mutaciones en el gen ABL en 45 pacientes con LMC resistentes a imatinib y se correlacionó con el estudio citogenético (realizado en 39 pacientes). También se evaluó la respuesta al tratamiento con ITK de segunda generación. Resultados: Se detectó mutación del gen ABL en 14 de los 45 casos analizados, y fue más frecuente en aquellos pacientes con evolución clonal. Nueve de los 15 pacientes portadores de una mutación en el gen ABL respondieron al cambio de tratamiento con nilotinib (n = 3), dasatinib (n = 2), interferón (n = 1) o trasplante de progenitores hematopoyéticos (n = 2) (AU)

Frequency of ABL gene mutations in chronic myeloid leukemia patients resistant to imatinib and results of treatment switch to second-generation tyrosine kinase inhibitors.

BACKGROUND AND OBJECTIVES: Tyrosine kinase inhibitors (TKI) have improved the management of patients with chronic myeloid leukemia (CML). However, a significant proportion of patients do not achieve the optimal response or are resistant to TKI. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Treatment with second-generation TKI has produced high rates of hematologic and cytogenetic responses in mutated ABL patients. The aim of this study was to determine the type and frequency of ABL mutations in patients who were resistant to imatinib or had lost the response, and to analyze the effect of second-generation TKI on their outcome. PATIENTS AND METHODS: The presence of ABL mutations in 45 CML patients resistant to imatinib was evaluated by direct sequencing and was correlated with the results of the cytogenetic study (performed in 39 cases). The outcome of these patients after therapy with nilotinib or dasatinib was analyzed. RESULTS: ABL mutations were detected in 14 out of 45 resistant patients. Patients with clonal cytogenetic evolution tended to develop mutations more frequently than those without clonal evolution. Nine out of the 15 patients with ABL mutation responded to a treatment switch to nilotinib (n=4), dasatinib (n=2), interferon (n=1) or hematopoietic stem cell transplantation (n=2). CONCLUSION: The frequency of ABL mutations in CML patients resistant to imatinib is high and is more frequent among those with clonal cytogenetic evolution. The change to second-generation TKI can overcome imatinib resistance in most of the mutated patients.

Polyethylene glycol interferon-alpha2b alone or in combination with low-dose Ara-C in patients newly diagnosed with chronic myeloid leukemia.

Thirty-five patients newly diagnosed with chronic myeloid leukemia received pegylated interferon alpha-2b (PEG-IFN) alone or combined with intermittent Ara-C for a median of 6.5 months (range: 1.4-19.2). The median weekly PEG-IFN dose was 4.0 microg/kg. Complete hematologic, major and complete cytogenetic responses were observed in 73%, 32% and 14%, respectively. Extra-hematologic side-effects were frequent and 20% of patients had grade III-IV hematologic toxicity.

The post-transplant cytogenetic response to interferon is a major determinant of survival after autologous stem cell transplantation for chronic myeloid leukaemia in chronic phase.

We have analysed the outcome of 581 autologous stem cell transplants (SCT) for chronic myeloid leukaemia (CML) in first chronic phase reported to the European Group for Blood and Marrow Transplantation between 1983 and 1998. Out off 207 patients evaluable for cytogenetics within 6 months of SCT, 36 patients (17%) were in complete cytogenetic remission (CCR), 34 (16%) in major remission (MCR), 74 (36%) in minor remission (mCR) and 63 (31%) had no cytogenetic response (NR). Interferon (IFN) was given post SCT to 267 patients. Results of the cytogenetic analysis within 1-2 years from SCT were available for 117 patients, the majority of whom (n = 101) received IFN post SCT: 17 (15%) were in CCR, 18 (15%) in MCR, 24 (20%) in mCR and 58 (50%) NR. The median survival in this series was 96 months (71-125) from SCT. There was no difference in survival according to cytogenetic status pre- and immediately post SCT. However, patients in CCR or MCR at 1-2 years post SCT had a 10-year survival of 66% compared with 36% for patients in mCR or NR (P = 0.003). The 5-year survival for patients receiving IFN post SCT was 72% compared with 61% for patients not treated with IFN (P = 0.01). Out of 155 patients refractory to IFN pre SCT, 70% achieved a cytogenetic response post SCT, which was complete or major in 31%. IFN refractory patients who sustained a CCR or MCR for 1-2 years after SCT had an excellent outcome.

Novel dic(16;18)(q11;p11) in two cases of Philadelphia chromosome positive acute B-cell lymphoblastic leukemia.

We report two adult patients with Philadelphia chromosome positive (Ph+) B-cell acute lymphoblastic leukemia (ALL) who presented an additional dic(16;18)(q11;p11) that, to the best of our knowledge, has never been previously reported. Fluorescence in situ hybridization analysis confirmed the translocation and showed it to be dicentric. Both patients were treated for the ALL, but showed refractory disease and died despite aggressive treatment. Similarly to what has been reported with other additional chromosome abnormalities, our cases suggest that the presence of this novel translocation confers an adverse effect to the already poor prognosis of Ph+ ALL.