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.

Morphologically defined myeloid cell compartments, lymphocyte subpopulations, and histological findings of bone marrow in patients with nonimmune chronic idiopathic neutropenia of adults.

This report describes the morphologically defined myeloid cell compartments, lymphocyte subpopulations, and histological findings of bone marrow in 38 patients with nonimmune chronic idiopathic neutropenia of adults (NI-CINA) and in 14 controls. We found that patients had a striking shift to the left of the granulocytic series due to both an increased proportion of proliferating cells and a reduced proportion of maturating cells compared with controls (P<0.001 and P<0.001, respectively). Individual proportions of these cells strongly correlated with the number of circulating neutrophils (r = -0.462, P < 0.01 and r = 0.495, P<0.01, respectively). However, in the great majority of patients (78.9%), no significant changes in marrow cellularity or the myeloid to erythroid cell ratio could be demonstrated. Patients also had increased proportions of CD19+B cells, CD20+B cells, and plasma cells with polytypic expression relative to controls (P < 0.02, P< 0.01, and P< 0.001, respectively). Individual values of plasma cells were inversely correlated with the number of blood neutrophils (r=-0.414, P<0.01). Dispersed bcl-2+lymphocytic aggregates without germinal centers were seen in about one-third of the patients. T cells and natural killer (NK) cells did not show any significant change. Patients had increased proportions of CD57+, CD16+, and HLA-DR+ cells and, in a few cases, increased proportions of histiocytes and eosinophils. CD45RO+ cells were reduced only in patients with pronounced neutropenia. Expression of p53 protein has not been detected in any cell population. With the exception of some megaloblastoid features of erythroid lineage seen in two patients and the presence of some micromegacaryocytes seen in two others, no significant morphological abnormalities were noted. All of these findings are consistent with our previously reported suggestion for the possible existence of an underlying low-grade chronic inflammatory process in NI-CINA patients, which may be involved in the pathogenesis of neutropenia in the affected subjects.

Defective natural killer cell activity of peripheral blood lymphocytes correlates with the degree of neutropenia in patients with chronic idiopathic neutropenia of adults.

Natural killer cell activity (Nka) of peripheral blood mononuclear cells (PBMCs) against K562 cell targets was assessed in 66 patients with chronic idiopathic neutropenia of adults (CINA) using the 16-h 51Cr-release assay. It was found that CINA patients exhibited significantly lower Nkr than normal subjects, which strongly correlated with the degree of neutropenia and the numbers of circulating neutrophils. Patients' NKa was increased by recombinant human interleukin-2 (rhIL-2) or recombinant human interferon-alpha (rhIFN-alpha), but the values obtained did not reach the respective NKa values found in normals. However, percentages of cytokine-induced rises of NKa did not differ statistically between patients and normal subjects. No serum inhibitors of NKa were demonstrated in our patients. CINA patients had low numbers of circulating NK cells as defined by the expression of NK-cell-related surface markers CD16, CD56, and CD57. CD16+ and CD56+, but not CD57+, cells correlated with the values of baseline NKa. The numbers of all these cell subsets correlated with the degree of neutropenia and the numbers of circulating neutrophils. Using CD56+-enriched PBL suspensions, it was shown that patients' NK cells displayed normal tumor cell binding capacity and produced in vitro normal amounts of natural killer cytotoxic factor(s) against K562 cell targets upon activation with rhIFN-alpha. Finally, percentages of perforin-expressing and granzyme B-expressing CD16+ cells did not differ statistically between patients and normal controls. Based on all these observations, we concluded that CINA patients display low NKa probably because they have low numbers of circulating NK cells. No functional abnormalities of NK cells were demonstrated. The cause and the underlying mechanisms leading to NK-cell depletion in these patients remain to be clarified.

Inhibition of mitogen-induced cellular cytotoxicity by serum from patients with multiple myeloma.

Mitogen-induced cellular cytotoxicity (MICC) of peripheral blood mononuclear cells (PBMCs) against K562 cell targets was assessed in 24 patients with multiple myeloma (MM) using the 24 hours 51Cr-release assay. We found that PBMCs from MM patients exhibited normal MICC values when cells were isolated, washed and cultured in vitro in the absence of patients' serum. Patients' serum inhibited MICC of normal PBMCs stimulated by PHA. A strong positive correlation was found between percentages of inhibition and the amount of serum paraprotein in the patients studied, suggesting that paraprotein should be the main inhibitory component in this model of cytotoxicity. The possible inhibitory effect of serum paraprotein of MM patients on other types of cellular immunity remains to be elucidated.