Faculty Bibliography

Interleukin-2 (IL-2) has been shown to produce durable complete remission in patients with renal cell carcinoma (RCC). A phase 2 study was conducted to evaluate the potential therapeutic synergy as well as the toxic side effects of the concurrent administration of IL-2 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced stage disease. Twenty-one patients with unresectable or metastatic RCC having an Eastern Oncology Cooperative Group performance status of 0 or 1 were enrolled. Six patients had received prior immunotherapy with interferon (IFN)-alpha, IFN-gamma, and IL-12, whereas the remaining 15 subjects were previously untreated. Thirteen patients were assigned to a moderate-dose bolus of IL-2 at 72,000 IU/kg every 8 hours on days 1 through 5 and days 15 through 19, whereas 8 patients were given IL-2 as an intravenous continuous infusion at a dose of 5 MU/m2/d on days 1 through 5 and days 15 through 19. Subcutaneous GM-CSF at 125 microg/d on days 1 through 21 was administered concomitantly with IL-2. The median number of IL-2 bolus doses was 23 of a scheduled 28 (85%), whereas with the continuous infusion, 93% of planned IL-2 was given. All patients received 100% of GM-CSF doses. There were no complete or partial responses in this study. Of 13 patients treated in the bolus IL-2 arm, 10 had systemic progression of disease at 4 to 8 weeks, 1 developed metastasis in the brain at 4 weeks, and 2 had stable disease for 4 and 17 months. Among the 8 subjects treated with continuous infusion IL-2, 3 progressed with brain lesions at 3 to 8 weeks and 5 had stable disease at 6+, 7, 8+, 15+, and 17+ months. The median survival for the whole group was 10 months, with a range of 0.5 to 40+ months. There were no regimen-related deaths, and most of the observed toxicities were grade 1 and 2. Serious toxicities (grade 3 and 4) included anemia, atrial fibrillation, oliguria, abnormal liver function, and neurologic events like agitation or confusion. The combination of recombinant IL-2 and GM-CSF administered in the designed schedule and doses was not effective in patients with metastatic RCC and may even interfere with the therapeutic potential of moderate-dose IL-2 and increase its adverse events

BACKGROUND: Drug resistance and early disease recurrence were major contributing factors in the limited survival of patients with acute lymphocytic leukemia (ALL). New chemotherapeutic agents and drug combinations were employed in refractory patients to overcome drug resistance. METHODS: The current study evaluated the efficacy of a regimen comprising intravenous bolus injections of idarubicin, 12 mg/m2 daily x 3, and a continuous 7-day infusion of cytosine arabinoside (ara-C), 100 mg/m2 daily, in adults with refractory or recurrent ALL. Twenty patients aged 14-75 years were treated. RESULTS: Six patients (30%) achieved complete remission (CR), 5 (25%) had a partial response (PR), and 9 (45%) did not respond. Recovery of blood counts occurred at a median of 20 days. One patient who achieved CR and one who achieved PR survived 1.5 and 2 years, respectively, after receiving this treatment. The median response and overall survival periods were 2.75 and 6.3 months, respectively. There was no relation between remission duration and previous chemotherapy. Neither leukocyte count at study entry nor patient karyotype was associated with attainment of CR. All patients experienced profound myelosuppression. Gastrointestinal toxicity was mild to moderate, with the exception of one case of World Health Organization Grade 3 mucositis. CONCLUSIONS: The regimen of idarubicin and ara-C achieved a 55% overall response rate in patients with recurrent or refractory ALL. This response rate compared favorably with other regimens and was achieved with acceptable toxicity. Response duration was disappointing, however

Patients with metastatic cancers occasionally present with microangiopathic hemolysis and thrombocytopenia. A patient with metastatic adenocarcinoma of the colon and microangiopathic hemolysis was treated with plasma exchange for a presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP). However, her condition continued to deteriorate and a determination of ADAMTS13 activity revealed that she did not have TTP. Despite similarity in clinical manifestation, microangiopathic hemolysis in patients with metastatic cancers may not be caused by ADAMTS13 deficiency and the role of plasma exchange in such patients should be reevaluated

Ongoing research in cancer therapy has led to the development of antineoplastic agents which target specific components of the cell cycle. In Part II of this series, we discuss agents which target the mitotic mechanism by inhibiting microtubules. Although many of these agents are being shown to have multiple effects, the Vinca alkaloids and the taxanes are known as antimitotic drugs. They are among the most important anticancer agents currently available, and because of their unique mechanisms, can be combined with a wide variety of other antineoplastic agents in a spectrum of diseases. In addition, in part II, we are discussing agents that target DNA and prevent replication and thus cell growth by inhibiting the enzymes which protect DNA during replication, the topoisomerases. These drugs, too, have unique mechanisms of action and have become major components of combination regimens. The topoisomerase I inhibitors are new drugs derived from an older parent drug, and their full possibilities are still being explored

The study was a Phase II randomized study to evaluate the efficacy of new agents for the treatment of advanced gastric carcinoma. Patients were randomized to receive single agent chemotherapy with mitoxantrone, etoposide, aclacinomycin-A or spirogermanium. The patients were stratified by prior use of chemotherapy, prior doxorubicin use and ECOG performance status. Patients with a history of cardiac disease or prior doxorubicin exceeding a dose of 400 mg/m2 were restrictively randomized to sopirogermanium or etoposide only. One hundred and fourteen patients were registered for the study. Among 98 evaluable patients there were only two partial responses (both in the etoposide arm), and one complete response in the mitoxantrone arm. The median survival on the study was 3.3 months. One hundred and six patients were analyzable for toxicity. There were four treatment-related deaths and four life-threatening toxicities. Because of low response rates and relatively high toxicities the studied compounds were not deemed worth further investigation for advanced gastric cancer

Theophylline, a methylxanthine commonly used as a treatment for asthma, has been shown to induce apoptosis in chronic lymphocytic leukemia (CLL) cells both in vitro and in vivo. We have treated three advanced CLL patients with theophylline, and seen responses in two. The clinical courses of the responders are presented, and the literature concerning theophylline as therapy for CLL is reviewed

A family with erythroleukemia is presented, in which father and son were diagnosed at the same age, but 20 years apart, with almost identical clinical and morphological features of the disease. No environmental factors were identified. The karyotypic abnormalities of the bone marrow blasts in the son demonstrated 2 major clones, involving chromosomes 5 and 7, as well as 8, 13, 16 and 21. Both patients demonstrated a poor response to chemotherapy. Previously described families with erythroleukemia are reviewed with available specific karyotypic aberrations