Central nervous system is a sanctuary site for chronic myelogenous leukaemia treated with imatinib mesylate

Imatinib mesylate (IM) is currently used as the first therapeutic choice against chronic myelogenous leukaemia (CML). Because IM poorly penetrates the blood-brain barrier, IM-treated CML patients may have a potential risk of central nervous system (CNS) involvement. Here we report a case with lymphoid blast crisis isolated only in CNS after bacterial meningitis, although the patient achieved and maintained complete cytogenetic response by IM therapy. It is important to consider isolated CNS blast crisis as a possible event in IM-treated CML patients.     

Sustained cytogenetic response after discontinuation of imatinib mesylate in a patient with chronic myeloid leukaemia

A 58-yr-old woman was diagnosed with Ph(+) chronic myeloid leukaemia in May 2001. She was initially treated with hydroxyurea and subsequently with interferon-alpha (IFN-alpha). Imatinib mesylate was started in April 2002 after failure of IFN-alpha to induce a cytogenetic response. The patient remained on treatment with imatinib mesylate for 3 months during which she suffered daily fever resulting in discontinuation of the treatment. Response evaluation performed shortly after discontinuing imatinib mesylate revealed a complete cytogenetic remission and a substantial molecular response. Fifteen months later, she was still enjoying a major cytogenetic response. This case illustrates that a short course of imatinib mesylate may result in a sustained haematological and cytogenetic response.     

Secondary T-acute lymphoblastic leukaemia mimicking blast crisis in chronic myeloid leukaemia

A 34-year-old man with chronic myeloid leukaemia (CML) firstly developed a lymphoid blast crisis of B-cell type. After a second chronic phase which lasted for > 4 years with maintenance chemotherapy of hydroxyurea, 6-mercaptopurine and methotrexate, he developed a T-cell acute lymphoblastic leukaemia of TcR-gammadelta+ type. Cytogenetic analysis revealed disappearance of the t(9;22) translocation and appearance of new abnormalities consistent with the diagnosis secondary acute leukaemia. To our knowledge, secondary leukaemia in CML has not previously been reported.     

Early and tardive skin adverse events in chronic myeloid leukaemia patients treated with imatinib

Imatinib related non-haematological side-effects are reported in <10% of chronic myeloid leukaemia patients and include oedema, weight gain, nausea, vomiting and muscle cramps. Cutaneous reactions are well-recognized events occurring mostly in patients treated at doses of 600 mg/d and higher, either in stable or progressive disease. We report on our experience relating to dermatological toxicities in imatinib treated CML patients showing a spectrum of skin reactions ranging from rashes to cutaneous carcinoma.     

Blood outgrowth endothelial cells from chronic myeloid leukaemia patients are BCR/ABL1 negative

The existence of adult haemangioblasts with dual haematopoietic and endothelial developmental potential was confirmed after detection of Ph⁺ vascular endothelial cells in chronic myeloid leukaemia (CML) patients. Blood outgrowth endothelial cells (OECs) from CML patients were found not to harbour the Philadelphia translocation and were thus not clonally related to BRC/ABL1 ⁺ hematopoietic progenitors, but comprised a distinct subfraction of endothelial cells. Remarkably, the frequency of CML-derived OECs was 9-fold higher as compared to healthy donors ( n  = 19 and n  = 300, respectively; P  <   0·0001) and these cells showed increased proliferative potential, possibly reflecting the mobilisation of OEC progenitors by pro-angiogenic cytokines.     

Cardiac morbidity in advanced chronic myelogenous leukaemia patients treated by successive allogeneic stem cell transplantation with busulphan/cyclophosphamide conditioning after imatinib mesylate administration

Imatinib mesylate is useful for facilitating allogeneic stem cell transplantation (allo-SCT) in advanced-phase chronic myelogenous leukaemia (AP-CML) patients. However, although the side-effects of imatinib are usually minor, cardiac morbidity can develop as a latent adverse effect post SCT when a myeloablative SCT is given to patients taking imatinib. Two AP-CML patients who were treated with imatinib manifested severe cardiac dysfunction after an allo-SCT, whereas cardiac morbidity was not observed in 45 other patients who had not received imatinib. It would appear that exposure to imatinib may have an adverse impact on the heart in AP-CML patients who receive an allo-SCT conditioned with busulphan/cyclophosphamide.     

Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome

Five to 10 per cent of patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukaemia (CML) have variant translocations involving chromosomes other than 9 and 22. We investigated the characteristics and outcome of patients with variant translocations treated with imatinib. Among 721 patients, 44 (6%) had variant translocations, involving one (n = 39) or two (n = 4) additional chromosomes. Nineteen patients (44%) were in chronic (12 previously untreated), 24 (55%) in accelerated and one (2%) in blastic phase. A major cytogenetic response was achieved in 14 (74%) patients treated in chronic phase and in 14 (58%) treated in accelerated phase. Six of 13 (46%) evaluable patients had deletion of derivative chromosome 9, and there was a trend for a lower response rate in these patients. We compared the 43 patients in chronic or accelerated phase to 678 patients with classic Ph treated with imatinib. The only significant difference in clinical characteristics was a higher frequency of accelerated phase among those with variant translocations (56%) compared with those with classic translocations (38%). No differences in outcome were evident. In a multivariate analysis, variant Ph translocations had no impact in response rate, overall survival or duration of response. We conclude that patients with variant Ph translocations have a similar prognosis to those with classic Ph translocations when treated with imatinib.     

BCR-ABL1 tyrosine kinase sustained MECOM expression in chronic myeloid leukaemia

MECOM oncogene expression correlates with chronic myeloid leukaemia (CML) progression. Here we show that the knockdown of MECOM (E) and MECOM (ME) isoforms reduces cell division at low cell density, inhibits colony-forming cells by 34% and moderately reduces BCR-ABL1 mRNA and protein expression but not tyrosine kinase catalytic activity in K562 cells. We also show that both E and ME are expressed in CD34(+) selected cells of both CML chronic phase (CML-CP), and non-CML (normal) origin. Furthermore, MECOM mRNA and protein expression were repressed by imatinib mesylate treatment of CML-CP CD34(+) cells, K562 and KY01 cell lines whereas imatinib had no effect in non-CML BCR-ABL1 -ve CD34(+) cells. Together these results suggest that BCR-ABL1 tyrosine kinase catalytic activity regulates MECOM gene expression in CML-CP progenitor cells and that the BCR-ABL1 oncoprotein partially mediates its biological activity through MECOM. MECOM gene expression in CML-CP progenitor cells would provide an in vivo selective advantage, contributing to CML pathogenesis.     

Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia

The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukaemia (CP‐CML) is 400 mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematological and cytogenetic response to IM400 vs. imatinib 400 mg twice daily (IM800) in 153 adult patients with CP‐CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4‐log reduction of BCR‐ABL1 mRNA: 25% vs. 10% of patients, P = 0·038; 3‐log reduction: 53% vs. 35%, P = 0·049). During the first 12 months BCR‐ABL1 levels in the IM800 arm were an average 2·9–fold lower than in the IM400 arm (P = 0·010). Complete haematological response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P = 0·040). Grade 3–4 toxicities were more common for IM800 (58% vs. 31%, P = 0·0007), and were most commonly haematological. Few patients have relapsed, progressed or died, but both progression‐free (P = 0·048) and relapse‐free (P = 0·031) survival were superior for IM800. In newly diagnosed CP‐CML patients, IM800 induced deeper MRs than IM400, with a trend for improved progression‐free and overall survival, but was associated with more severe toxicity.     

Long‐term results of high‐dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: the Italian experience

Imatinib mesylate (IM) is used for the management of childhood chronic myeloid leukaemia (CML). The most effective dosage of IM and its long‐term efficacy in children are not well defined. The purpose of this multicentre study is to report on the long‐term results of high‐dose IM (340 mg/m²/d) in CML patients in chronic phase (CP‐CML) aged <18 years at diagnosis. A total of 47 CP‐CML patients with a median age at diagnosis of 11 years 9 months were enrolled in nine Italian centres. Complete cytogenetic response was achieved in 91·5% of the evaluable patients at a median time of 6 months. BCR‐ABL1 International Scale ≤ 0·1% (major molecular response; MMR) and ≤0·01% (molecular response; MR) at 12 months were 66·6% and 33%, respectively. During follow‐up, MMR and MR were achieved in 78·6% and 61% of children, respectively. IM was safely discontinued in 3 long‐term treated children with a durable MR. Twelve patients (eight cytogenetic/molecular responders) underwent stem cell transplantation. The progression‐free survival probabilities at 96 months for responding patients who continued IM and for those transplanted were 60% and 50%, respectively. After a median follow‐up of 52 months (range 3–146), all patients are alive . High‐dose IM is a long‐term effective therapy in children and adolescents with CP‐CML.