Myelofibrosis and chronic myeloid leukemia (CML) are myeloproliferative disorders (MPD) of hematopoietic stem cell and characterized by clonal neoplastic proliferation of one or more of the myeloid lineage in the bone marrow. The reciprocal translocation t (9; 22) of the bcr-abl fusion gene is a key genetic marker for CML. Until recently, a point mutation at codon 617 (V617F) of the Janus kinase 2 gene (JAK2) was considered absent in CML patients with Philadelphia positive chromosome (Ph+) [1]. However, current findings have identified the coexistence of both genetic defects in patients with MPD [2, 3]. Here we present a myelofibrosis patient with CML in whom a coexistence of JAK2 V617F mutation was detectable at the initial diagnosis and despite the excessive accumulation of CML clone.In June 2007, a 52-year-old white female presented with pronounced splenomegaly. At admission, she complained of 15 kg sudden weight loss. Initial laboratory tests showed hemoglobin 100 g/L, platelets 689 9 10 9 /L and white cell count 193 9 10 9 /L with a differential revealing 3% myeloblasts, 9% promyelocytes, 8% myelocytes, 3% metamyelocytes, 10% band cells, 63% neutrophils, 7% eosinophils, 8% basophils, 2% lymphocytes and 7% monocytes. A bone marrow biopsy disclosed megakaryocytic hyperplasia and marked marrow reticulin fibrosis (grade 3). Based on this result, a search for JAK2 V617F mutation by restriction and DNA sequence analysis in a blood sample taken at that time confirmed the presence of the homozygote mutation (Fig. 1b). Cytogenetic analysis revealed 100% Ph+ in each of 20 metaphase cells examined (Fig. 2). This was further confirmed by quantitative RT-PCR technique, which showed 130% of BCR-ABL/ BCR mRNA b2a2 transcript. The patient was initially given hydroxyurea (25 mg/kg/day) which permitted a rapid reduction of leucocytes and platelets to 37 9 10 9 and 398 9 10 9 /L, respectively. As a result, hydroxyurea was substituted with imatinib at a dose of 400 mg/day and was followed. Fifteen days after initiation of imatinib, the patient achieved complete hematological response. By the end of 30 days, the leucocytes count had remained normal, but platelets count had a marked increase and rose steadily for 4-6 weeks during treatment until reached a value of 936 9 10 9 /L. Consequently, we aimed to evaluate the molecular events underlying imatinib effect by quantifying BCR-ABL/BCR transcript. The results showed a 2-log decrease (3.7%) in mRNA transcript and suggested a gradual reduction of residual leukemic burden. Given this, the patient was placed on combinational therapy with hydroxyurea. His platelet count returned to normal levels within 10 days after treatment. The DNA sequence from blood sample collected at that time confirmed the existence of JAK2 V617F mutation and indicated approximately 50% reduction of the T peak at position 1849 (Fig. 1c). At the latest follow-up in December 2007, she remained well and evaluated as being in cytological remission.It has been suggested that the perturbation of JAK2 signaling by g...

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Tyrosine kinase inhibitors (TKIs) have dramatically changed the survival of chronic myeloid leukemia (CML) patients, and treatment-free remission (TFR) has recently emerged as a new goal of CML treatment. The aim of this work was to develop recommendations for TKI discontinuation in Latin America (LA), outside of clinical trials. A working group of CML experts from LA discussed 22 questions regarding TFR and reached a consensus for TFR recommendations in the region. TFR is indicated in patients in first chronic phase, with typical BCR-ABL transcripts, under TKI treatment of a minimum of 5 years, in sustained deep molecular response (DMR; molecular response 4.5 [MR4.5]) for 2 years. Sustained DMR must be demonstrated on at least 4 international reporting scale quantitative polymerase chain reaction (PCR) tests, separated by at least 3 months, in the immediate prior 2 years. After second-line therapy, TFR is indicated in previously intolerant, not resistant, patients. Molecular monitoring is recommended monthly for the first 6 months, every 2 to 3 months from months 7 to 12, and every 3 months during the second year, indefinitely. Treatment should be reintroduced if major molecular response is lost. Monitoring of withdrawal syndrome, glucose levels, and lipid profile is recommended after discontinuation. After TKI reintroduction, molecular monitoring is indicated every 2 to 3 months until MR4.0 achievement; later, every 3 to 6 months. For the TFR attempt, having standardized and reliable BCR-ABL PCR tests is mandatory. These recommendations will be useful for safe discontinuation in daily practice and will benefit patients who wish to stop treatment in emergent regions, in particular, with TKI-related chronic adverse events.

O imatinibe tem sido confirmado como terapia de primeira linha para a Leucemia Mielóide Crônica (LMC) por apresentar respostas duradouras na maior parte dos pacientes, principalmente nos que se encontram em fase precoce da doença. Entretanto, resistência ou intolerância ao imatinibe podem ocorrer. A resistência ao imatinibe ocorre com muito mais freqüência em fases mais avançadas da doença, sendo a causa mais comum o desenvolvimento de mutações no sítio BCR-ABL. Em face deste problema, novos inibidores de tirosino quinase têm sido desenvolvidos, com maior potência, diminuindo assim a chance de desenvolvimento de resistência ao tratamento. O nilotinibe e o dasatinibe são dois exemplos de inibidores de segunda geração de tirosino quinase recentemente aprovados. Ambos têm demonstrado excelentes resultados em pacientes que desenvolvem resistência ou são intolerantes ao imatinibe. Rev. bras. hematol.

We report our experience in 4 patients with chronic myeloid leukemia (CML) who had discontinued imatinib as a result of adverse events and had switched to dasatinib. The chronic phase (n 2) and accelerated phase (n 2) CML patients received dasatinib at starting dose of 100 and 140 mg once daily, respectively. Reappearance of hematological toxicity was observed in 3 patients and pancreatitis in one patient. Treatment was given at a lower dose and patients were followed. The median follow-up was 13 months and the median dose of dasatinib until achievement of complete cytogenetic remission (CCyR) was 60 mg daily (range = 20 to 120 mg). All four patients had achieved CCyR at a median of 4 months (range = 3 to 5 months) and among them, three had also achieved major molecular remission. We conclude that low-dose dasatinib therapy in intolerant patients appears safe and efficacious and may be tried before drug discontinuation.