Hoo G. Chun

Incidence and Treatment of Tumor Lysis Syndrome in Patients with Acute Leukemia

Tumor lysis syndrome (TLS) is a complication associated with electrolyte abnormalities that is observed in patients with acute leukemia who are receiving intense doses of chemotherapy. Forty-one patients with acute leukemia were treated with high-dose combination chemotherapy and were evaluated for TLS. A grading system developed for the evaluation of these patients was applied. Grade I tumor lysis was observed in 22 patients, grade II TLS in 2 patients and grade III in 1 patient. All patients were treated with intravenous fluids, mannitol, allopurinol and in some patients, aluminum-based antacids. Treatment for TLS prior to intensive chemotherapy reduced morbidity and mortality associated with high-dose chemotherapy for acute leukemias.

Merbarone: an antitumor agent entering clinical trials.

SummaryMerbarone was developed to clinical trial stage on the basis of its ‘curative’ activity against P388 and L1210 leukemias and moderate activity against B16 melanoma and M5076 sarcoma. Its activity appears to be schedule-dependent favoring a longer duration of administration. The mechanism of action of merbarone is not yet established but it does induce single strand breaks in DNA apparently without binding to DNA.The pharmacokinetic data in the dog indicate that clearance mechanisms may be saturable. Merbarone is hydroxylated at the 4′ position in the rat, mouse and dog, and glucuronidated in the dog. Parent drug and the hydroxy metabolite are excreted in the urine. If saturable clearance mechanisms also pertain to man, this will mean that infusion rate (and therefore steady state concentrations reached) may be a significant factor in determining acute toxicity.Preclinical toxicology studies revealed that major target tissues are in the lymphoid organs, bone marrow, gastrointestinal tract and kidney. Some behavioral signs of reversible central nervous system toxicity were observed.Phase I trials have commenced using only a 5-day continuous intravenous infusion schedule based on the preclinical data. The pharmacokinetic information from these trials will be crucial for further clinical development of the compound, including selection of the optimal schedule(s) for phase II/III evaluation.

Phase II Clinical Trial of Didemnin B in Patients with Recurrent or Refractory Anaplastic Astrocytoma or Glioblastoma Multiforme (NSC 325319)

The activity of didemnin B, a natural product derived from the Caribbean Tunic was assessed in 16 patients with Glioblastoma multiforme. Didemnin B was administered intravenously by a short infusion at a dose of 4.3 mg/m2 and subsequently escalated to 6.3 mg/m2. No anti-tumor activity was observed. Toxicity consisted of fatigue, weakness, stomatitis, mild blood count changes, nausea and vomiting and occasional fever. Based on these results further studies with didemnin B in patients with Glioblastoma multiforme are not recommended.

Amsacrine is safe and effective therapy for patients with myocardial dysfunction and acute leukemia

The role of amsacrine in inducing remission in patients with cardiac disease and acute leukemia was evaluated. There were 17 patients with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL), and one with biphenotypic leukemia. In this series of 24 patients whose disease had relapsed and who had reduced left ventricular ejection fraction, nine had a complete remission, seven with AML and two with ALL. In addition, four of six with newly diagnosed acute leukemia and reduced left ventricular ejection fraction also responded. Among nine patients who underwent endomyocardial biopsy, none had morphologic changes of sufficient degree to account for drug‐induced heart failure. Patients with preexisting arrhythmias received amsacrine without incident if their serum potassium level was higher than 4.0 mEq/1 at the time of drug administration. Amsacrine is safe and effective therapy for patients with acute leukemia and cardiac disease.

Chloroquinoxaline sulfonamide: A sulfanilamide antitumor agent entering clinical trials

SummaryChloroquinoxaline sulfonamide (CQS) has been developed to the clinical trial stage based on its activity in the Human Tumor Colony Forming Assay (HTCFA). In the HTCFA, CQS demonstrated inhibition of colony formation against breast, lung, melanoma and ovarian carcinomas. The mechanism of action of CQS is unknown. It does not appear to inhibit folate metabolism as does the structurally similar sulfaquinoxaline. Preclinical toxicology studies in dogs and rats have shown that CQS is toxic to lymphoid organs, bone marrow, gastrointestinal tract, pancreas, CNS, adrenal glands and testes. Toxicity was generally reversible with the exception of testicular atrophy in dogs and rats which occurred late and was not reversible within the study time frame.The pharmacokinetic data indicate that CQS binds to serum proteins in a dose and species specific manner. Terminal half-lives appear to vary between species from 60 hours in mice, 15 hours in rats, and 45–132 hours in dogs. Preliminary data indicate a longer terminal half-life in humans.Two phase I trials are ongoing using a 60 min infusion schedule once every 28 days. The starting dose for each trial was 18 mg/m2.

Phase II Trial of Fludarabine Phosphate in Multiple Myeloma Using a Loading Dose and Continuous Infusion Schedule

A phase II trial of fludarabine phosphate using a bolus and continuous infusion regimen in previously treated multiple myeloma was performed. No responses were observed in eleven patients. There was no significant non-hematologic toxicity noted. Fludarabine phosphate is inactive in multiple myeloma using this schedule.

Phase II trial of fludarabine phosphate (F-ara-AMP) in patients with advanced head and neck cancer

SummaryThirteen patients with advanced head and neck cancer were entered into a phase II study of fludarabine phosphate. Fludarabine phosphate was given by continuous infusion for 5 days, at a starting dose of 20 mg/m2 per day for patients previously treated with one regimen and 25 mg/m2 per day for previously untreated patients; therapy was repeated every 3–4 weeks. Of the 13 patients, 3 had undergone one prior regimen and 10 patients were previously untreated by chemotherapy. No responses were observed. Myelosuppression was the most common toxicity observed. Four patients developed mild nausea, vomiting and seven developed bleeding stomatitis that resolved in one week. In addition, four patients developed headaches which resolved spontaneously. No renal, hepatic, or neurotoxicity was observed. Our study demonstrates that in previously treated and untreated patients, fludarabine phosphate given on this schedule has little activity in patients with advanced head and neck cancer.

A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer.

492 Background: Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Oxaliplatin-based treatment (FOLFOX, CapeOX) combined with bevacizumab is one of the standard chemotherapies for metastatic CRC. However, several clinical studies performed using S-1 plus oxaliplatin (SOX) indicate that SOX is a treatment option for metastatic CRC. TSU-68 (orantinib) is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor and has promising efficacy and high safety. The recommended phase II dose of TSU-68 plus SOX has been determined in a phase I study. This trial aimed to evaluate the efficacy of TSU-68 in combination with SOX. Methods: We performed an open-label multicenter randomized phase II trial in Korea. Treatment-naive metastatic CRC patients with a performance status 0 or 1 were randomized in a ratio of 1:1 to receive either TSU-68 plus SOX (group A) or SOX (group B). The primary endpoint was progression-free surv...

Higher cure rates in acute leukemia: now more probable with increasingly effective induction therapy.

SummaryTraditional therapy of acute myelogenous leukemia has not cured more than 10% of patients and, of acute lymphoblastic leukemia not more than 30% of adults. In part, this is due to the lack of agents effective enough to induce remissions of such quality that cure is possible. The introduction of mitoxantrone and its use in high dose with high-dose cytarabine for induction therapy, raises the possibility of an increased cure rate of acute myelogenous leukemia and acute lymphoblastic leukemia.

Improving the Remission Quality in Acute Myelogenous Leukemia (AML) by Increasing Cytoreduction During Induction Therapy

Induction of remission in AML has, for many years, been achieved by the administration of daunorubicin with cytarabine [1]. With traditional doses of these drugs, approximately two-thirds of the patients treated have gone into remission. Roughly two-thirds of these have achieved their remission after the first cycle of therapy and one-third required additional treatment. Although physicians have consistently tried to increase the cure rate of patients with AML achieving CR by the administration of subsequent therapy, the “quality” of CR has never been thought to be vital, since post-induction chemotherapy was considered the most important aspect of treatment. Because of this, consolidation therapy has gone from gentle to very intense and has been given for as little as 1–2 months to as long as 1 year or more. Death, associated with delivery of this therapy, has varied between 0% and 40% [2, 3]. The therapy reported here is based on the presumption that, at the time of diagnosis or at relapse, with fully evident disease, the normal stem cells are asleep and somewhat protected from the chemotherapy that is administered. Therefore, induction treatment with high-dose cytarabine, mitoxantrone, and etoposide can be administered with less risk than previously expected. Indeed, it may be that, in most protocols, what is accomplished during “induction” therapy may be the most important element of treatment.