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Biomedical subjects

C Hurvitz

Publications and source records attributed to C Hurvitz.

9 recordsLinked to original sources
PubMed1999

Clinical pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in patients with B-lineage lymphoid malignancies.

The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.

Adolescent↗
PubMed1999

Treatment of therapy-refractory B-lineage acute lymphoblastic leukemia with an apoptosis-inducing CD19-directed tyrosine kinase inhibitor.

Seven children and eight adults with CD19+ B-lineage acute lymphoblastic leukemia, as well as one adult with chronic lymphocytic leukemia, were treated with the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein. All patients had failed previous chemotherapy regimens, and six patients had relapsed after bone marrow transplantation. B43-Genistein was administered as a 1-hour i.v. infusion at 0.1-0.32 mg/kg/day dose levels for 10 consecutive days or 3 consecutive days weekly for a total of nine doses. B43-Genistein was well tolerated by all patients with no life-threatening side effects. There were six episodes of grade 2-3 fever, two of which were clearly drug related, one episode each of grade 3 myalgia, grade 2 sinus tachycardia, and grade 2 vascular leak syndrome. There was one durable complete remission and two transient responses. Pharmacokinetic analyses in 12 patients revealed a plasma half-life of 20 +/- 5 h, mean residence time of 24 +/- 5 h, and a systemic clearance rate of 20 +/- 3 ml/h/kg. Moderate levels of human antimouse antibody (HAMA) ranging from 20-87 ng/ml were detected in the day 28 blood samples from three of nine cases examined. Treatment of these three HAMA-positive patients with a second course of B43-Genistein did not yield measurable immunoconjugate levels in the plasma, indicating that the administered B43-Genistein molecules were rapidly cleared from circulation due to the HAMA. On the basis of its acceptable toxicity profile and its ability to elicit objective responses at nontoxic dose levels, B43-Genistein may provide the basis for an effective treatment strategy for B-lineage acute lymphoblastic leukemia patients who have failed standard therapy.

Adolescent↗
PubMed1994

Clonogenicity of circulating neuroblastoma cells: implications regarding peripheral blood stem cell transplantation.

Peripheral blood stem cells (PBSCs) are being used as an alternative to autologous marrow rescue for hematopoietic reconstitution after high-dose chemotherapy in patients with neuroblastoma and other solid malignancies. Use of PBSCs is preferred by some because of the belief that there is less risk of tumor contamination. Because tumor stem cell contamination is thought to be one contributing cause of relapse after myeloablative therapy and autologous reconstitution, we examined the potential risk of reinfusing circulating neuroblastoma cells by in vitro evaluation of their clonogenicity. Immunocytologic and tumor cell clonogenic analyses were performed on 74 blood samples obtained from 56 children with advanced-stage neuroblastoma. Concurrently drawn bone marrow specimens were evaluated in 30 instances. Circulating neoplastic cells were detected in 19 of 74 (26%) for all specimens and by immunologic techniques (26%). Using a clonogenic assay, 13 grew identifiable tumor colonies. Comparing results with the two techniques showed tumor colony growth in 10 of the 19 positive specimens by immunocytology. However, 3 of 53 samples (6%) that were negative by immunocytology were positive by the clonogenic assay. Of the 11 positive blood samples, 9 concurrent marrows contained neuroblastoma cells; of the 19 negative blood specimens, 3 concurrent marrows had metastatic disease. We conclude that circulating neuroblastoma cells are present in peripheral blood and have clonogenic properties in vitro. This supports the view that tumor cell contamination may well be one cause of relapse after autologous reconstitution. Consequently, PBSC collections should also undergo meticulous monitoring for tumor contamination before autologous reinfusion.

Child↗
PubMed1993

Quality control of immunocytologic testing. Prolonged preservation of cell surface antigen reactivity with magnesium chloride-sucrose solution.

A sucrose-magnesium chloride-glycerol storage solution (sucrose-magnesium chloride) can preserve antigenicity of cytologic preparations for prolonged periods of time. This storage method was evaluated relative to our immunocytologic technology with the specific aim of exploring its use as a quality control measure. Neuroblastoma and leukemia cell lines, patient bone marrow, and blood specimens were serially tested during a 15-week period to evaluate preservation of immunoreactivity and cell morphological features. Slides that had been air dried and stored at 4 degrees C were compared with those that had been fixed with methanol and paraformaldehyde and stored in sucrose-magnesium chloride at -20 degrees C. The sucrose-magnesium chloride method proved to be superior, and antigen-antibody binding and cell morphology were preserved even after 15 weeks of storage. This method, now in use as a quality control measure in our laboratory, constitutes a practical assurance program for immunocytologic analysis.

Antigens, Surface↗
PubMed1991

Scintigraphic findings mimicking focal nodular hyperplasia in a case of hepatoblastoma.

Hepatoblastoma is a primary liver neoplasm in which prompt diagnosis and resection are critical to long-term survival. Liver scintigraphy using Tc-99m sulfur colloid and Tc-99m iminodiacetic acid (IDA) derivatives has been used in the evaluation of hepatic masses. Most space-occupying lesions of the liver appear as photopenic regions following either Tc-99m SC or IDA agents. Two exceptions have been reported. Focal nodular hyperplasia (FNH) has been shown to have variable colloid uptake, which is dependent upon the number of Kupffer cells per given volume. Many patients with FNH will demonstrate activity within the FNH to be greater or equal to the normal liver. In addition, two cases of hepatoblastoma have been reported to show colloid activity within the tumor, and in one patient slight uptake of Tc-99m IDA was noted in the tumor 15 minutes postinjection. The current case demonstrates a hepatoblastoma in which the scintigraphic findings with Tc-99m SC and Tc-99m IDA were similar to those reported, with retention of IDA far greater than the previously reported case.

Carcinoma, Hepatocellular↗
PubMed1989

Mature T-lineage leukemia with growth factor-induced multilineage differentiation.

We report an acute T-lymphoblastic leukemia with a predominantly mature CD3+ CD7+ WT31+ phenotype that was induced to differentiate into different cell lineages by various recombinant human growth factors. In the presence of IL-3 or GM-CSF, the leukemic cells gave rise to myeloid and monocytic cells including terminally differentiated, partially functional, segmented neutrophilic granulocytes as assessed by morphologic, cytochemical, immunophenotypic, and functional criteria. In the presence of IL-2, leukemic granulated lymphoid cells exhibiting MHC-unrestricted cytotoxicity and expressing a CD2+ CD3+ CD5+ CD7+ CD8+ CD33+ WT31+ Leu19+ phenotype arose. Leukemic cell cultures initiated with IL-3 yielded growth factor-independent cells with a mixed lineage phenotype and morphologic and cytochemical evidence of immature blasts. These were T lymphocyte and myeloid surface antigen (CD2,CD3,CD5,CD7,CD13,CD33,WT31) positive. Identical rearrangements of the constant region of the TCR-delta gene and of the joining regions of the TCR-beta, -gamma, and -delta genes were observed in the fresh and all cultured leukemic cells, indicating that they were derived from the same malignant clone. Consistent with the molecular genetic data, the cytogenetic analyses of the GM-CSF-, IL-3-cultured and the growth factor-independent leukemic cells showed the presence of multiple, closely related abnormal clones, all of which had an interstitial deletion of part of the long arm of chromosome 6 and a complex 1;10;12 translocation. In conclusion, these data demonstrate the involvement of a multipotent leukemic precursor cell in this predominantly mature CD2+ CD3+ CD5+ CD7+ WT31+ T-ALL. This multipotent leukemic precursor may be susceptible to various growth factors and respond with ordered differentiation and maturation.

Adult↗
PubMedDate not supplied

Exchange red blood cell pheresis in a pediatric patient with severe complications of sickle cell anemia.

Exchange transfusion is a well-established procedure for the treatment of severe complications of sickle cell anemia. However, large-volume exchange is a difficult, time-consuming technique, and therefore rarely used. Exchange red blood cell pheresis, using automated equipment, can accomplish red blood cell exchange more rapidly and efficiently, and can be easily performed by a skilled team of nursing personnel. The recent introduction of a pediatric centrifuge bowl allows this technique to be applied to pediatric patients. This procedure was used in a 13-year-old male with sickle cell anemia, who presented with bilateral pulmonary infiltrates, respiratory distress, and hypoxemia, unresponsive to antibiotics and other means of conservative therapy. A one and one-half volume red blood cell exchange reduced the hemoglobin S concentration to 13 per cent. The patient experienced dramatic improvement within 24 hours, progressing to complete recovery within a few days.

Adolescent↗