The addition of interferon or high dose cyclophosphamide to standard chemotherapy in the treatment of patients with multiple myeloma: phase III Eastern Cooperative Oncology Group Clinical Trial EST 9486.

BACKGROUND: Interferon (IFN) has demonstrated activity in the treatment of patients with multiple myeloma. A previous Eastern Cooperative Oncology Group (ECOG) study suggested that the rates of complete response (CR) and survival were increased with a regimen that alternated IFN with chemotherapy. The current study was designed to evaluate the effect of adding alternating cycles of IFN or early intensification with high dose cyclophosphamide (HiCy) to the VBMCP regimen for the treatment of multiple myeloma patients. METHODS: From February 1988 to May 1992, the ECOG entered previously untreated patients with active multiple myeloma on a study in which they were randomized to VBMCP (vincristine 1.2 mg/m(2) administered intravenously [i.v.] on Day 1, BCNU 20 mg/m(2) i.v. on Day 1, melphalan 8 mg/m(2) administered orally [p.o.] on Days 1-4, cyclophosphamide 400 mg/m(2) i.v. on Day 1, and prednisone 40 mg/m(2) p.o. on Days 1-7; 5-week cycles) or VBMCP + rIFN(alpha2), the latter given at 5 Mu/m(2) 3 times a week starting on Day 22 of each 6-week cycle after 2 initial cycles of VBMCP. Patients younger than 70 years were also randomized to a third treatment that substituted cyclophosphamide 600 mg/m(2) i.v. on Days 1-4 and prednisone 100 mg/m(2) p.o. on Days 1-4 for cycles 3 and 5 of VBMCP (VBMCP + HiCy). Treatment was continued for 2 years. RESULTS: Of the 653 patients entered, 628 were eligible for the study. All were evaluated for response. With median follow-up for surviving patients of 54 months, the median survival duration was 42 months-1 year longer than usually reported for melphalan combined with prednisone. A comparison of the three regimens revealed no significant difference in the rates of survival or objective response (OR). However, CRs were increased among patients treated with VBMCP + rIFN(alpha2) compared with VBMCP alone (18% vs. 10%, P = 0.03). Patients treated with VBMCP + rIFN(alpha2) had a longer response duration than patients treated with VBMCP alone (30 vs. 25 months, P = 0.035). There was a greater response rate with the IFN regimen among elderly patients (OR and CR = 67% and 31%, respectively) and patients with immunoglobulin A (IgA) myeloma (OR and CR = 83% and 29%, respectively). Severe infections were seen as often with VBMCP as with VBMCP + rIFN(alpha2) (13% vs. 15%), but they were more frequent with VBMCP + HiCy (25%). CONCLUSIONS: VBMCP + rIFN(alpha2) yields a higher rate of CR and a longer response duration than VBMCP alone but appears to make no difference in the rates of overall response or survival compared with VBMCP or VBMCP + HiCy. The superior ability of VBMCP + rIFN(alpha2) induction therapy to produce CR and more durable responses, as well as its activity in older patients and in those with IgA myeloma, suggest that this therapy has important biologic activity in myeloma and merits further clinical investigation.

Dementia improvement with cytotoxic chemotherapy. A case of Alzheimer disease and multiple myeloma.

OBJECTIVES: To describe a patient with Alzheimer disease and multiple myeloma (with Bence Jones proteinuria) with improvement of both conditions following cytotoxic chemotherapy, and to present issues related to the pathogenesis and management of Alzheimer disease. DESIGN: Report of a case. SETTING: Progressive dementia and myeloma developed in a 64-year-old man. Cytotoxic chemotherapy for the myeloma resulted in maintained improvement of the dementia. Clinical, neuropsychological, pathological, and laboratory data are presented. MAIN OUTCOME AND RESULTS: For 2 years, vincristine sulfate, carmustine, melphalan, cyclophosphamide, and prednisone were administered cyclically, and the patient's dementia and lambda light chain production improved. Severe dementia recurred before death and cessation of therapy, although light chain production remained decreased. CONCLUSION: Dementia improvement with cytotoxic (ie, immunosuppressive, anti-inflammatory) therapy may offer insight into the pathogenesis and management of Alzheimer disease.

Transdermal modification of platelet function: an aspirin patch system results in marked suppression of platelet cyclooxygenase.

Aspirin inhibits platelet cyclooxygenase and prevents thromboxane A2 (TXA2) production. Although it is an effective antithrombotic, even at a low doses aspirin may induce gastrointestinal toxicity. We examined the feasibility of delivering aspirin transdermally using two patch systems, one without (type A) and one with (type B) the permeation enhancer limonene. Daily application of two type A patches that had a total surface area of 100 cm2 and contained 84 mg/patch resulted in 85% +/- 6% reduction in serum TXB2 in six male subjects by day 14. Suppression of serum TXB2 was less marked in females (32% +/- 16%). Analysis of the residual drug in the patch showed that each patch delivered 18 +/- 3 mg on day 1 and 17 +/- 4 mg on day 14, with no difference between males and females. Daily application of a single patch B that had a surface area of 50 cm2 and contained 120 mg aspirin resulted in 60% +/- 11% suppression of serum TXB2 by day 14 in nine male subjects and 84% +/- 9% suppression by day 21. Analysis of the applied patches showed that patch B delivered 33 +/- 3 mg of aspirin daily. Plasma aspirin and salicylate were determined by gas chromatography, mass spectrometry. No aspirin was detected, whereas plasma salicylate was 157 +/- 38 ng/ml and 133 +/- 20 ng/ml by day 14 with patch A and patch B, respectively. Analysis of aspirin applied by patch to the skin in three subjects showed marked hydrolysis to the inactive product, salicylic acid. Aspirin can be delivered transdermally by patch in a dose that suppresses platelet cyclooxygenase. The delivery rate is low reflecting hydrolysis of the drug in the skin. Delivery is improved by the permeation enhancer limonene. This novel route of delivery may be applicable to other antithrombotics and may limit the risk of gastrointestinal toxicity.

Transdermal modification of platelet function. A dermal aspirin preparation selectively inhibits platelet cyclooxygenase and preserves prostacyclin biosynthesis.

BACKGROUND: Even low doses of oral aspirin inhibit prostacyclin (prostaglandin [PG] I2) formation and cause gastrointestinal toxicity. We examined the skin as a novel route for continuous low-dose aspirin administration and selective inhibition of platelet cyclooxygenase in humans. METHODS AND RESULTS: Aspirin 250 or 750 mg/d for 10 days induced a dose-dependent inhibition of serum thromboxane (TX) B2. At the highest dose, five of six subjects responded, with a mean reduction in serum TXB2 of 95 +/- 3% (P = .003). Urinary 2,3-dinor TXB2, an index of in vivo TXA2 formation, decreased by 68 +/- 7% and recovered slowly, consistent with inhibition of platelet cyclooxygenase in vivo. In contrast, PGI2 biosynthesis, determined as excretion of 2,3-dinor-6-keto PGF1 alpha, was 81 +/- 5% of baseline at 10 days. Intravenous bradykinin increased PGI2 biosynthesis 5.1 +/- 1.6-fold (n = 4) before aspirin treatment. Oral aspirin 75 mg/d for 14 days abolished bradykinin-induced PGI2 formation, whereas dermal aspirin 750 mg/d had no effect despite similar inhibition of TXA2 biosynthesis. In five subjects, plasma aspirin and salicylate were determined after a single application of 750 mg. Aspirin was absorbed slowly, with peak levels of 0.24 +/- 0.11 micrograms/mL at 3 hours. Salicylate levels peaked at 6 to 12 hours, with plasma levels of 0.79 +/- 0.14 micrograms/mL. CONCLUSIONS: Thus, it is possible to achieve selective inhibition of platelet cyclooxygenase by aspirin applied to the skin. This approach may be applicable to other antiplatelet agents and be useful in patients at risk for gastrointestinal bleeding or toxicity.

Post-transfusion purpura associated with alloimmunization against the platelet-specific antigen, Baka.

Post-transfusion purpura (PTP) with severe thrombocytopenia occurred eight days after transfusion in a 28-year-old woman and responded to treatment with prednisone and plasma exchange. In contrast to nearly all previously studied cases of PTP, the patient's platelets were PlA1-positive and anti-PlA1 antibody could not be detected in serum obtained during the thrombocytopenic episode. Her serum was found to contain an antibody specific for a recently described platelet-specific alloantigen, Baka, in addition to multiple HLA-specific antibodies. The patient's platelets, typed following recovery, were Baka-negative. These findings indicate that post-transfusion purpura can occur in association with alloimmunization to platelet-specific antigens other than PlA1. In performing the serologic studies, a close relationship and possible identity between Baka and another recently reported platelet antigen, Leka, was observed. A method for analyzing mixtures of cytotoxic platelet-reactive antibodies without separating the individual antibodies is described.

Age and treatment response in acute nonlymphoblastic leukemia.

Treatment of older acute leukemia patients has been the subject of recent debate. We treated 101 acute leukemia patients in a prospective randomized trial. Fifty-seven per cent of the population was over 50. Half were treated with a mild induction program (VAMP) and half with a vigorous program (CAT). The older patients who received vigorous treatment did better than those who received mild treatment. We suggest that patients over 50 should be regarded as a separate category in design of treatment protocols in order to further maximize the benefits of therapy.