RESUMO
Patients with myelofibrosis (MF) who discontinue ruxolitinib due to progression/resistance have poor prognoses. JAK inhibitors control symptoms and reduce spleen volumes with limited impact on underlying disease pathophysiology. Murine double minute 2 (MDM2), a negative regulator of p53, is overexpressed in circulating malignant CD34+ MF cells. The oral MDM2 inhibitor navtemadlin (KRT-232) restores p53 activity to drive apoptosis of wild-type TP53 tumor cells by inducing expression of pro-apoptotic Bcl-2 family proteins. Navtemadlin demonstrated promising clinical and disease-modifying activity and acceptable safety in a phase II study in patients with relapsed/refractory MF. The randomized phase III BOREAS study compares the efficacy and safety of navtemadlin to best available therapy in patients with MF that is relapsed/refractory to JAK inhibitor treatment.
Myelofibrosis (MF) is a rare blood cancer that disrupts normal blood cell production and causes fibrosis (tissue thickening/scarring) in bone marrow, reduced red blood cells in the circulation, and an enlarged spleen. Although currently approved treatments can help relieve some effects, they have limited impact on the underlying cause of the disease. Navtemadlin is a new therapy that inhibits a protein frequently overexpressed in cancer cells found in MF patients called murine double minute 2 (MDM2), which regulates a common tumor suppressor protein called p53. By inhibiting MDM2, navtemadlin restores normal p53 function and its ability to kill MF cancer cells. BOREAS is a large clinical study of navtemadlin for MF patients whose disease is not responding to current therapy.
RESUMO
Chronic neutrophilic leukemia is an uncommon hematological entity. According to the WHO classification it is recognized as part of the family of myeloproliferative disorders. In the last 20 years seven patients have been diagnosed with chronic neutrophilic leukemia at our department. All but one had splenomegaly, two patients developed severe anaemia and in one case thrombocytosis was present at the time of diagnosis. White blood cell count ranged between 39 x 10(9)/1-71 x 10(9)/l with 80% of neutrophils and striking myeloid hyperplasia were present in the bone marrow without evidence of any dysplasia resembling chronic myelocytic leukemia. Granulocyte alkaline phosphatase scores were increased except one case and both cytogenetics (Philadelphia chromosome) and molecular biologic analysis (bcr/abl) revealed no alteration of any. Four patients have been followed up. Three of them died due to progression of chronic neutrophilic leukemia. One patient, initially receiving hydroxyurea + interferon therapy and showing progression, developed complete hematological remission with an eight week imatinib mesylate (Glivec) treatment. Beside of their own experiences the authors review the current literature and discuss differential diagnostic and therapeutic challenges, as well.
