Farnesyl transferase inhibitor (lonafarnib) in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia: a phase II study.

Although an activating mutation of Ras is commonly observed in myelodysplastic syndrome (MDS), the role of Ras in the natural history of MDS remains largely unknown. We prospectively studied efficiency and tolerance of lonafarnib, a compound able to inhibit Ras signalling pathway through an inhibition of farnesyl transferase, in patients with MDS or secondary acute myeloid leukaemia (sAML). Lonafarnib was administered orally at a dose of 200 mg twice daily for three courses of 4 weeks (separated by 1 to 4 weeks without treatment). Sixteen patients were included: FAB/RAEB (n = 10), RAEB-T (n = 2), sAML (n = 2) and chronic myelomonocytic leukaemia (CMML; n = 2); WHO/RAEB-1 (n = 4), RAEB-2 (n = 5), AML (n = 5), CMML (n = 2). Median age was 70 (53-77) years. The karyotype was complex or intermediate in 11 patients, and the International Prognostic Scoring Systems (IPSS) risk groups were low in two patients, INT-1 in one patient, INT-2 in four patients and high in six patients (unknown or not applicable in three patients). Among the 14 patients tested, five had Ras mutations in codons 12, 13 or 61 of N-Ras, K-Ras or H-Ras. One patient was excluded of the analysis for protocol violation, and 15 patients were assessable for tolerance. Gastrointestinal toxicities (diarrhoea, nausea and anorexia) and myelosuppression were the major side effects. Other toxicities included infections, fatigue, increase of liver enzymes, arrhythmia and skin rash. One patient died of infection, and the treatment was stopped in one other who developed atrial fibrillation. Doses were reduced in all but one patient treated with more than one course of farnesyl transferase inhibitor. Responses were assessable in 12 patients. A partial response in one sAML patient and a very transient decrease of blast cell count with normalisation of karyotype in one MDS patient were observed. No relation between improvement of marrow parameters and detected Ras mutations was observed. Lonafarnib alone, administered following our schedule, has shown limited activity in patients with MDS or secondary AML. Gastrointestinal and haematological toxicities appear the limiting toxicity in this population of patients.

Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study.

OBJECTIVES/METHODS: This 1-yr prospective phase II trial evaluated the efficacy of deferasirox in regularly transfused patients aged 3-81 yrs with myelodysplastic syndromes (MDS; n = 47), Diamond-Blackfan anaemia (DBA; n = 30), other rare anaemias (n = 22) or beta-thalassaemia (n = 85). Dosage was determined by baseline liver iron concentration (LIC). RESULTS: In patients with baseline LIC > or = 7 mg Fe/g dry weight, deferasirox initiated at 20 or 30 mg/kg/d produced statistically significant decreases in LIC (P < 0.001); these decreases were greatest in MDS and least in DBA. As chelation efficiency and iron excretion did not differ significantly between disease groups, the differences in LIC changes are consistent with mean transfusional iron intake (least in MDS: 0.28 +/- 0.14 mg/kg/d; greatest in DBA: 0.4 +/- 0.11 mg/kg/d). Overall, LIC changes were dependent on dose (P < 0.001) and transfusional iron intake (P < 0.01), but not statistically different between disease groups. Changes in serum ferritin and LIC were correlated irrespective of disease group (r = 0.59), supporting the potential use of serum ferritin for monitoring deferasirox therapy. Deferasirox had a safety profile compatible with long-term use. There were no disease-specific safety/tolerability effects: the most common adverse events were gastrointestinal disturbances, skin rash and non-progressive serum creatinine increases. CONCLUSIONS: Deferasirox is effective for reducing iron burden with a defined, clinically manageable safety profile in patients with various transfusion-dependent anaemias. There were no disease-specific adverse events. Once differences in transfusional iron intake are accounted for, dose-dependent changes in LIC or serum ferritin are similar in MDS and other disease groups.

De novo CD5-positive diffuse large B-cell lymphoma of the skin arising in chronic limb lymphedema.

We report the case of a 79-year-old woman with a longstanding lymphedema of the right arm who developed a skin lymphoma involving the right wrist area. Microscopically, the lesion was composed of numerous centroblasts infiltrating both the dermis and the subcutaneous tissue. Phenotypic investigations showed expression of CD20, CD79a, and bcl-2 protein by neoplastic cells. In addition, these cells were CD5 positive. No expression of anaplastic large cell lymphoma kinase (ALK), CD10, CD23, CD30, CD43, bcl-6, cyclin D1, p53 or p16INK4a could be seen. Polymerase chain reaction (PCR) analysis demonstrated a clonal rearrangement of the genes coding for the kappa light chain of the immunoglobulin (Ig). No rearrangement of the genes coding for the Ig heavy chain, t(14;18) or t(11;14) chromosome translocations, or Epstein-Barr virus (EBV) genomic sequences could be found. The tumor was classified as stage IE and was first cured by complete surgical excision. Nineteen months later, a recurrence was noted in the right elbow area. This study further illustrates that lymphoma of the skin may complicate chronic limb lymphedema. Like most of the previously reported cases, this neoplasm belonged to the category of diffuse large B-cell lymphoma. However, it showed CD5 expression as a singular feature.

Endogenous factor V synthesis in megakaryocytes contributes negligibly to the platelet factor V pool.

BACKGROUND AND OBJECTIVES: Coagulation factor V (FV) is distributed between two pools: 80% circulates in plasma and 20% is stored in platelets. The aim of the study was to determine the origin of platelet FV. DESIGN AND METHODS: We investigated a FV Leiden heterozygous patient who had received an allogeneic bone marrow transplant from a normal donor. The patient had been referred to our laboratory for his marked activated protein C (APC) resistance in the apparent absence of FV Leiden. Analysis of the DNA from a buccal swab showed that the patient was indeed a heterozygous carrier of FV Leiden. The difference in FV genotype between the hepatocytes (heterozygous FV Leiden) and the blood cells (homozygous normal) of the patient provided a good model to investigate the origin of platelet FV. Platelets were isolated from the patient and the bone marrow donor and activated with thrombin and ionomycin to release and activate FV. APC was then added and the inactivation of platelet FVa was followed over time with a highly sensitive prothrombinase-based assay. RESULTS: While the donor's platelet FVa showed a normal inactivation time course, the patient's platelet FVa was considerably resistant to APC. The kinetic pattern of APC-catalyzed inactivation of the patient's platelet FVa was indistinguishable from that of plasma FVa from a FV Leiden heterozygote. INTERPRETATION AND CONCLUSIONS: These data indicate that platelet FV is derived from plasma and that endogenous FV synthesis by megakaryocytes contributes negligibly to the platelet FV pool.