Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: Updated results from a campus CML real-life study.

TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.

Expression of c-myb and B-myb oncogenes on myelofibrotic marrow fibroblasts.

The term IMF (Idiopathic Myelofibrosis) refers to a primary bone marrow disease in which the normal haematopoietic bone marrow cells are for unknown reasons replaced by connective tissue. The pathogenesis of the disease has not been clarified yet. We have speculated that the increment of proliferation of bone marrow fibroblasts in IMF may be the consequence of the over-expression of some oncogenes, leading or contributing to the fibrosis via a cell amplification. Thus, we investigated the possible role of the c-myb and B-myb genes in IMF and control bone marrow fibroblasts in different culture conditions to evaluate proliferation parameters in the absence or presence of serum. Using the reverse transcriptase polymerase chain reaction technique, we demonstrated that the kinetics of induction was similar for both c-myb and B-myb during the proliferation of normal bone marrow fibroblasts. When compared to normal controls, cultured IMF fibroblasts showed more elevated values of c-myb and B-myb RNA; furthermore, after a 72 hours stimulation with serum, c-myb and B-myb messages remained relatively high in myelofibrotic fibroblasts. Finally, after serum starvation, c-myb and to a lesser extent B-myb RNA levels remained unusually high in IMF fibroblasts, while under the same experimental conditions c-myb and B-myb messages became virtually undetectable in normal bone marrow fibroblasts. To our knowledge this work represents the first description of an abnormal behavior of these genes in IMF fibroblasts.

[Biologic aspects and clinical use of granulocyte growth factor]. / Aspetti biologici e impiego clinico del fattore di crescita granulocitario.

Granulocyte colony stimulating factors (G-CSF) has a wide spectrum of action: it stimulates proliferation and differentiation of granulocyte-macrophage progenitors, it promotes the chemotactic activity of monocytes and granulocytes and it develops the antibody-dependent cytotoxicity of neutrophils. In vivo G-CSF induces leucocytosis and it hastens the granulocyte recovery after chemio-radiotherapy. So it has been used in many pathologies: aplastic anaemia, AIDS in treatment with antiviral drugs, myelodysplastic syndromes, acute leukemias and solid tumors. If G-CSF is administered after chemotherapy, both in acute leukemias and in solid tumors, it reduces the duration of neutropenia and the number of febrile episodes so that it is possible to give the whole therapy at the planned dosage with no delay. However G-CSF does not modify the incidence of complete remissions and the overall survival. G-CSF allowed the increase of dose-intensity in chemoresistent neoplasms even if this therapy is always complicated by a heavy extrahaematological toxicity. Moreover G-CSF shortens the total duration of neutropenia after autologous or allogenic bone marrow and peripheral stem cell transplantation even if the appearance of the first neutrophil is not accelerated.

[Idiopathic myelofibrosis. Main pathogenetic, prognostic and therapeutic aspects]. / Mielofibrosi idiopatica. Principali aspetti patogenetici, prognostici e terapeutici.

Primary myelofibrosis is a complex disorder characterized by bone marrow fibrosis with no apparent cause. It is known in literature under a wide number of terms, reflecting the variety of clinical features and the different pathogenetic hypotheses. In most cases it is plain that marrow fibrosis is secondary to a clonal myeloproliferative disorder and, in particular, to the presence of abnormal megakaryocytes secreting (MKDGF/PDGF); but probably some other growth factors synthesized by megakaryocytes and contained in platelet alpha-granules are involved. The molecular event that determines the advantage of the clonal growth is, at present, unknown, and the pathogenetic importance of some chromosome anomalies is still under discussion. Over the last years, besides megakaryocyte dysplasia, several fibrogenetic mechanisms such as a bone marrow immune damage have been taken into consideration. Studies on prognostic factors regarding the main clinical, hematological and histological parameters have given conflicting results, because of low incidence of the disease, different criteria used for the diagnosis, and different terms of the clinic presentation of the pathology. Although a great deal of progress has been made in terms of pathogenetic mechanisms, a lot of questions must be still definitively settled, further in depth studies still have to go into many matters.