Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma.

BACKGROUND: The combination of vincristine and doxorubicin administered as a continuous infusion via an indwelling catheter together with intermittent high-dose dexamethasone (VAD) is an effective primary treatment for patients with symptomatic multiple myeloma. In order to avoid the need for an indwelling catheter, which imposes logistic problems for outpatient administration, several phase II studies have explored the feasibility and efficacy of VAD-like outpatient regimens. We designed a prospective randomized study to compare the objective response rates of two VAD-like outpatient regimens as primary treatment for symptomatic patients with multiple myeloma. PATIENTS AND METHODS: Patients were entered in a randomized study regardless of age, performance status and renal function. One hundred and twenty-seven patients received VAD bolus, which consisted of vincristine 0.4 mg i.v., doxorubicin 9 mg/m(2) i.v. and dexamethasone 40 mg p.o. daily for four consecutive days and 132 patients received VAD doxil, which consisted of vincristine 2 mg i.v. and liposomal doxorubicin 40 mg/m(2) i.v. on day 1 and dexamethasone 40 mg p.o. daily for 4 days. The two regimens were administered every 28 days for four courses and in courses 1 and 3, in both arms, dexamethasone was also given on days 9-12 and 17-20. RESULTS: An objective response was documented in 61.4% and 61.3% of patients treated with VAD bolus and VAD doxil, respectively. Hematological and non-hematological toxicities were mild or moderate and equally distributed between the two treatment arms with the exception of alopecia, which was more common after VAD bolus, and of palmar-plantar erythrodysesthesia, which was more common after VAD doxil. CONCLUSIONS: Our multicenter trial, which included an unselected patient population, indicated that both VAD bolus and VAD doxil can be administered to outpatients and can provide an equal opportunity of rapid response in many patients with multiple myeloma.

Treatment of anemia in low-risk myelodysplastic syndromes with amifostine. In vitro testing of response.

Amifostine (AMF) promotes in vitro growth and survival of hematopoietic progenitors. In this study we evaluated the efficacy of AMF in the treatment of anemia in patients with low-risk myelodysplastic syndromes (MDS) and the possible predicting value for response to AMF therapy of two types of in vitro clonogenic assays. Two different doses of AMF, 300 mg/m2 (group A, 11 patients) or 400 mg/m2 (group B, 16 patients), were studied. AMF was given three times weekly for 3 weeks, i.v., followed by 2 weeks off therapy. Patients were evaluated after two cycles of treatment. Partially or nonresponding patients of group A received 400 mg/m2 AMF and were reevaluated. An increase of hemoglobin (Hb) values of more than 2 g/dl and a 100% decrease in transfusion requirements for at least 6 weeks were defined as a complete response (CR) while an increase of Hb values of 1-2 g/dl or a 50% decrease in transfusion requirements was considered as a partial response (PR). In group A, two out of 11 (18.1%) patients achieved a CR with the initial dose and one of the nine that received 400 mg/m2 AMF achieved a PR. In group B, three out of 16 (18.7%) patients achieved a PR; the overall response rate in both groups was 22.2%. In group A, bone marrow progenitor assay was performed pre- and post-amifostine treatment. Erythroid burst-forming units (BFU-E) were increased in six out of 11 (54.5%) patients, and this increase preceded the rise in Hb levels in three of them. In group B, a clonogenic assay was performed in 11 out of 16 patients before AMF treatment. In vitro results after pretreatment with 500 microM amifostine confirmed the response of two MDS patients that achieved a PR. No response in vitro was observed in all eight nonresponding patients and in one PR patient. The lack of response in the clonogenic assays predicted for nonresponse to treatment with a predictive power of 91.8%. We conclude that 300 mg/m2 is an adequate initial treatment for low-risk MDS patients and both clonogenic assays have a strong predicting value for response to treatment.

Hodgkin's disease in a patient with common variable immunodeficiency.

A 61 year old man with long standing common variable immunodeficiency presented with pyrexia, anaemia and leucopenia. A diagnoses of Hodgkin's disease of the bone marrow was made. The typical histopathological and immunophenotypic appearances were clearly distinct from those of T cell lymphoma with Reed-Sternberg-like cells which, in contrast to Hodgkin's disease, is a known complication of common variable immunodeficiency. Complete clinical and histological remission was achieved with combination chemotherapy. The latter was complicated by severe myelosuppression, unusually severe erosive mucositis and viral retinitis.

Cold agglutinin syndrome and hemophagocytosis in systemic leishmaniasis.

A 3-year-old male child with high fever, hepatosplenomegaly, pancytopenia, haemolysis, striking histiocytosis and hemophagocytosis in bone marrow aspiration and high titre of cold agglutinin is described. Cold agglutinins were defined as polyclonal IgM with anti-I specificity. Diagnosis of visceral leishmaniasis was made on the basis of typical Leishman-Donovan bodies found in the patient's bone marrow, high titre of anti-leishmania antibodies and excellent response to treatment. Visceral leishmaniasis must be considered in the differential diagnosis of diseases with histiocytosis. Cold agglutinin syndrome may contribute to the haemolytic process which exists in leishmania-donovani infection.

Transient hemophagocytosis in Brucella melitensis infection.

Bone marrow phagocytic activity was studied in 40 patients with Brucella melitensis infection and 35 patients with a variety of medical conditions. Evidence of erythrophagocytosis was found in 14 of the 40 patients with B melitensis infection and in 15 of the 35 control cases; this was taken as baseline bone marrow phagocytic activity. Considerably increased erythrophagocytosis or phagocytosis of all blood elements by increased number of histiocytes was found in one and seven patients, respectively, in the brucellosis group. All but one patient with increased phagocytic activity had splenomegaly. These findings may reflect an intense host response in some patients with B melitensis infection.

Sideroblastic anaemia associated with lincomycin therapy.

Sideroblastic anaemia developed after lincomycin therapy in a 58-year-old woman. The anaemia proved completely reversible after termination of lincomycin therapy and the introduction of pyridoxine. The patient also had pseudomembranous enterocolitis, a well-known side effect of lincomycin.

Asymptomatic diffuse fasciitis with eosinophilia.

The case of a 70-year-old woman with asymptomatic diffuse fasciitis with eosinophilia, confirmed by biopsy, is presented.

Modification of hemoglobin by ninhydrin.

The Strecker degradation reaction was evaluated as a means of modifying hemoglobin in vitro, utilizing ninhydrin as a model compound. Ninhydrin led to modification of hemoglobin (when incubated with hemoglobin or red cells) at physiologic temperature and pH. Isoelectric focusing documented the formation of new hemoglobin bands, all with decreased (more negative) isoelectric points that hemoglobin A. Both alpha and beta chains were modified to an equal degree, although electrophoretic studies documented two modified species of alpha-chains and three modified species of beta-chains. Amino acid analysis of modified hemolysate following NaB3H4 reduction revealed peaks that coeluted with deaminated valine, epsilon-deaminated lysine, and a product with the guanidino group of arginine. The oxygen affinity of hemoglobin increased following its incubation with increasing concentrations of ninhydrin. These studies suggest that ninhydrin is representative of a class of carbonyl compounds that could be utilized to specifically modify that structure and function of hemoglobin variants.

Rhodotorulic acid--investigation of its potential as an iron-chelating drug.

The use of rhodotorulic acid (RA) as an iron-chelating drug was suggested by experiments in hypertransfused rats in which urinary and fecal iron excretion were significantly enhanced in response to RA. The toxicity of the drug appears to be minimal at a parenteral dose less than 250 mg/kg. An increased excretion of zinc was the only notable side effect of the drug at the doses used. When administered i.v. to humans, RA was only 16% more effective than desferrioxamine (DF). Pharmacokinetic studies showed that RA persisted in the bloodstream of dogs 6 times longer than desferrioxamine after an intravenous injection. Accordingly RA was evaluated as a potential repository drug. While animal experiments were encouraging, human subjects experienced a painful local reaction to RA administered either i.m. or s.c. as a suspension in physiological saline. Accordingly it appears that RA is best looked at as a second line drug, unless a means can be found to obviate local inflammatory reactions.