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M J Ratain

Publications and source records attributed to M J Ratain.

At least 145 records · Page 8Linked to original sources
PubMed1992

The treatment of hairy cell leukemia: an update.

The treatment of hairy cell leukemia (HCL) requires continuing update. The role for splenectomy is extremely limited. Alfa-interferon therapy has been available and utilized for five years; there have been few complete remissions. The experience with Pentostatin has resulted in a majority of clinical complete remissions after several months of therapy, but persistence of a small percentage of hairy cells in the bone marrow. The most recent therapeutic agent, 2-chloro-deoxyadenosine (2-CDA) is given for seven days and results in a complete remission in the great majority of patients with no evidence of persistent bone marrow disease. If this trend persists, 2-CDA will become first line therapy for HCL as it may cure the disease.

2-Chloroadenosine↗
PubMed1992

Interferon treatment for hairy cell leukemia: an update on a cohort of 69 patients treated from 1983-1986.

This report documents the follow-up information on 69 hairy cell leukemia (HCL) patients treated with interferon alpha-2b (IFN) as primary treatment from 1983-86. Follow-up through October 1991 shows only 11 patients have died. Forty-one of the 57 patients completing the intended 12 or more months of initial IFN treatment were eventually considered IFN failures. Thirty-nine required retreatment (38 received a second course of IFN and one received pentostatin). Two patients died without further therapy for HCL. The median time to interferon failure was 33 months. Sixteen patients are alive and have not required further treatment after completing their initial 12 or more months of interferon. Eight patients underwent a third course of interferon therapy at a median time after completion of a second course of IFN of 1.3 years. Seven patients developed a second malignancy; three of these patients developed a high-grade lymphoma between 3.5 and 6.5 years after initiation of interferon therapy. We conclude that although interferon provides excellent palliation, most patients will eventually require further treatment with interferon or chemotherapy. Future trials in HCL must be aware of second malignancies as a common cause of death.

Adult↗
PubMed1992

New perspectives on the toxicity of etoposide.

Etoposide has been used in the treatment of a wide variety of neoplasms, including small cell lung cancer. Kaposi's sarcoma, testicular cancer, acute leukemia, and lymphoma. Its current therapeutic use is limited by myelosuppression, particularly neutropenia. Pharmacodynamic studies of etoposide show that this toxicity can be modeled using a modified Hill equation, and that the dose intensity of etoposide can be successfully increased by adaptive control using this model. Significant influences on the degree of myelosuppression include pretreatment leukocyte count, performance status, extent of prior erythrocyte transfusions, and serum albumin level. In the past 5 years, interest has developed in a distinct subset of acute nonlymphocytic leukemia that is associated with prior exposure to etoposide. This syndrome has been described in several studies, and is characterized by the lack of a preleukemic phase, M4 or M5 morphology, and distinct translocations involving the chromosome 11q23 region.

Bone Marrow Diseases↗
PubMed1992

Therapeutic relevance of pharmacokinetics and pharmacodynamics.

Most antineoplastic drugs have a narrow therapeutic index. The medical world's incomplete understanding of the variability of pharmacokinetics and pharmacodynamics has led to dosing problems with these agents. Basic understanding of linear and nonlinear pharmacokinetic models as well as interpatient and intrapatient variability is necessary to optimize dosing. Pharmacodynamic information relates pharmacokinetic information to clinical outcome.

Animals↗
PubMed1992

Laboratory and clinical studies of biochemical modulation by hydroxyurea.

Hydroxyurea is a potent inhibitor of the enzyme ribonucleotide reductase. Due to its effects on cellular deoxyribonucleotide pools, hydroxyurea can modulate the activity of several pyrimidine and purine antimetabolites. As an inhibitor of DNA repair, it can potentially interact with DNA-damaging agents such as alkylating agents or inhibitors of topoisomerase II. Both cytokinetic and biochemical interactions occur between hydroxyurea and cytarabine (ara-C), which account for their synergistic cytotoxicity. Inhibition of ribonucleotide reductase by hydroxyurea depletes cellular deoxycytidine triphosphate pools, thereby enhancing ara-C uptake and phosphorylation to ara-C triphosphate. In a phase II clinical trial, the combination of hydroxyurea and ara-C produced a 43% response rate in patients with refractory malignant lymphoma. Studies in murine leukemia models have demonstrated therapeutic synergy when hydroxyurea is combined with fluoropyrimidines. High levels of deoxyuridine monophosphate that have been associated with resistance to 5-fluorouracil can be suppressed by hydroxyurea, leading to greater inhibition of thymidylate synthase. Despite the strong biochemical rationale for the use of hydroxyurea and 5-fluorouracil in combination, few clinical trials have been conducted thus far. Antimetabolites and topoisomerase II inhibitors have also been shown to be synergistic in vitro. Hydroxyurea has been shown to enhance the formation of DNA strand breaks produced by amsacrine and to produce synergistic cytotoxicity with etoposide. A phase I clinical trial of these drugs has demonstrated bone marrow suppression to be the major toxicity of the combination. In summary, hydroxyurea has been shown to undergo cytokinetic and biochemical interactions with a number of established antitumor agents. Clinical trials of hydroxyurea in combination with these agents have identified doses and schedules of administration that produce acceptable levels of clinical toxicity and appear feasible for further testing.

Animals↗
PubMed1991

Modeling interpatient pharmacodynamic variability of etoposide.

This report describes approaches to modeling interpatient pharmacodynamic variability of etoposide effect as measured by white blood cell count nadir. Such models may be utilized in adaptive control dosing to individualize the dose administered to a patient with the aim of lessening the risk of severe myelosuppression. We have successfully employed adaptive control dosing of etoposide administered by 72-hour continuous infusion based on our prior pharmacodynamic model for white blood cell count nadir. Data from our most recent series of 41 patients were used to investigate new linear and nonlinear pharmacodynamic models. We then cross-validated our best models on data from an independent series of 27 similarly treated patients. We identified an unbiased model that exhibited high precision in both data sets (root mean square errors of 1.11 x 10(3) and 1.20 x 10(3) cells/microL, respectively). The optimal model was a nonlinear Hill model defined by 24-hour etoposide concentration, pretreatment white blood cell count, and pretreatment serum albumin level. The level of albumin was found to be both a component of kinetic (protein binding) and dynamic (patient health) variability. Patients with lower pretreatment albumin levels are at higher risk of severe myelosuppression during etoposide therapy.

Bias↗
PubMed1991

Five-day infusion of fluorodeoxyuridine with high-dose oral leucovorin: a phase I study.

Fluorodeoxyuridine (FUdR) interferes with cellular metabolism by inhibiting thymidylate synthase. Therefore, we sought to modulate its activity with leucovorin (LV) and to identify the maximally tolerated dose given as a 5-day continuous intravenous infusion in combination with oral administration of LV at a dose of 100 mg every hour for four doses immediately preceding the start of the FUdR infusion and then every 4 h for the entire duration of FUdR treatment. Patients were evaluated at six FUdR dose levels ranging from 0.1 to 0.375 mg/kg per day. Severe or life-threatening mucositis was first observed in two of six patients treated at 0.25 mg/kg daily. Further escalation of the dose to 0.3 mg/kg per day resulted in grade 2 mucositis in four of six patients and in grade 3 mucositis in two cases. A dose of 0.375 mg/kg daily resulted in grade 3 toxicity in all three patients treated. Other types of toxicities included skin rash and hand-foot syndrome, but no hematologic toxicities were observed. Stable disease was observed in 11 of 24 evaluable patients, including 3 subjects with renal cell carcinoma. Our recommended dose for phase II trials is 0.3 mg/kg FUdR per day.

Aged↗
PubMed1991

Hairy cell leukaemia: the role of alpha interferon.

Hairy cell leukaemia (HCL) is a chronic progressive disease of predominantly middle-aged men. Alpha interferon has been shown to induce significant responses in HCL patients. With interferon treatment the platelet count normalizes first, followed by the haemoglobin and neutrophil counts. The number of hairy cells in the bone marrow decreases and granulocytic, erythroid and megakaryocytic cells increase. Interferon is well tolerated with the most common side effect being a flu-like syndrome. A number of HCL patients will develop neutralizing antibodies and in these cases the chemotherapeutic agents pentostatin and 2-chlorodeoxyadenosine should be considered. Preliminary results with these agents are promising and further trials are ongoing to confirm their clinical promise.

Antibody Formation↗
PubMed1991

Paradoxical relationship between acetylator phenotype and amonafide toxicity.

Patients receiving the investigational antineoplastic agent amonafide underwent prospective determination of acetylator phenotype with use of caffeine as a test drug. Fast acetylators of caffeine had significantly greater toxicity (myelosuppression) after amonafide treatment than slow acetylators, presumably because of greater conversion of amonafide to the active acetylated metabolite. Furthermore, the estimated area under the plasma concentration-time curve of amonafide was significantly greater in the fast acetylators, indicating that the total plasma clearance was paradoxically lower in this group. It is hypothesized that this paradox is attributable to competition for oxidation of amonafide by its acetylated metabolite (parallel pathway interaction). Pretreatment white blood count and patient age were also independent predictors of leukopenia. In addition, it was noted that the ratio of actual to ideal body weight was significantly higher in the fast acetylators. Studies are in progress to determine the optimal amonafide dose in both acetylator subgroups.

Acetylation↗
PubMed1991

Treatment of chemotherapy-induced anemia with recombinant human erythropoietin in cancer patients.

Thirty patients with chemotherapy-induced anemia were treated with recombinant human erythropoietin for 4 weeks. In this dose-escalation study, cohorts of five to eight patients were treated per dose level. The doses of erythropoietin were 25, 50, 100, 200, or 300 IU/kg/d given intravenously for 5 days each week. Of 30 patients, 15 (50%) had a greater than 10% increase of their hemoglobin (Hb) values and were considered responders. At the two highest dose levels, 11 of 13 patients (85%) responded. In the 15 responding patients, the mean Hb level increased by 1.7 g/dL from baseline compared with an average decrease of 1.5 g/dL in the previous cycles of chemotherapy without erythropoietin administration. Recombinant human erythropoietin is effective in ameliorating chemotherapy-induced anemia when administered in adequate doses.

Adult↗
PubMed1991

Limited sampling models for doxorubicin pharmacokinetics.

Although doxorubicin is one of the most commonly used antineoplastics, no studies to date have clearly related the area under the concentration-time curve (AUC) to toxicity or response. The limited sampling model has recently been shown to be a feasible method for estimating the AUC to facilitate pharmacodynamic studies. Data from two previous studies of doxorubicin pharmacokinetics were used, including 26 patients with sarcoma and five patients with breast cancer or unknown primary. The former were divided into a training data set of 15 patients and a test datum set of 11 patients, and the latter patients formed a second test data set. The model was developed by stepwise multiple regression on the training data set: AUC (nanogram hour per milliliter) = 17.39 C2 + 163 C48-111.0 [dose/(50 mg/m2)], where C2 and C48 are the concentrations at 2 and 48 hours after bolus dose. The model was subsequently validated on both test data sets: first test data set--mean predictive error (MPE), 4.7%; root mean square error (RMSE), 12.4%; second test data set--MPE, 4.5%, RMSE, 9.2%. An additional model was also generated using a simulated time point to estimate the total AUC for a daily x 3-day schedule: AUC (nanogram hour per milliliter) = 44.79 C2 + 175.65 C48 + 47.25 [dose/(25 mg/m2/d)], where the C48 is obtained just prior to the third dose. We conclude that the AUC of doxorubicin after bolus administration can be adequately estimated from two timed plasma concentrations.

Doxorubicin↗
PubMed1991

Pharmacologically based dosing of etoposide: a means of safely increasing dose intensity.

We have previously demonstrated that individualized dosing of etoposide (VP16) by 72-hour infusion is feasible and that the extent of leukopenia is a function of plasma concentration, pretreatment WBC (WBCp), albumin (ALB), performance status (PS), and bone marrow function (based on transfusion requirements). In the current study, 45 patients were randomized between a fixed dose of VP16 (125 mg/m2/d) versus individualized dosing to a target WBC nadir (WBCN) of 1,700/microL. The total dose was increased by an average of 22% in the latter patients (459 +/- 130 mg/m2 v 375 mg/m2, P = .002). This was associated with a decrease in both the mean WBCN (1,510 +/- 950 v 2,500 +/- 1,420/microL, P = .013) and in the variability of the WBCN (P = .039). The VP16 clearance (mL/min) was not correlated with body surface area. Partial responses were observed in one patient each with hepatoma and non-Hodgkin's lymphoma. We conclude that pharmacologically based dosing may be a means of increasing dose intensity without increasing the incidence of life-threatening toxicity due to a decrease in variability around a target WBC.

Aged↗
PubMed1990

Serum soluble interleukin-2 receptor is associated with clinical and pathologic disease status in hairy cell leukemia.

Hairy cell leukemia is a chronic lymphoproliferative disorder of B-cell lineage, whose malignant cells express the interleukin-2 (IL-2) receptor. A soluble form of the IL-2 receptor is released by these cells in culture, and the sera of patients with hairy cell leukemia contain elevated levels of this soluble receptor. Four hundred twenty-seven serum samples from 101 patients were analyzed for soluble IL-2 receptor (sIL-2R). The clinical status of patients appeared to be associated with the serum level of sIL-2R. The hairy cell index (a measure of tumor cell burden) was correlated with the square root of the serum sIL-2R level (r = .77). Improved clinical status was associated with decreasing serum sIL-2R levels, whereas disease relapse was associated with increasing levels. Notably, every patient who responded to therapy had a decline in serum sIL-2R level, and every patient with disease progression had an increase in serum sIL-2R level. This phenomenon was observed for several different treatments, including standard-dose interferon, low-dose interferon, and deoxycoformycin. The predictive reliability of this test is currently being prospectively evaluated.

Dose-Response Relationship, Drug↗