Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes.

Relapse of chronic myeloid leukemia (CML) in chronic phase after allogeneic stem cell transplantation (SCT) can be successfully treated by donor lymphocyte infusion (DLI). However, relapse of accelerated phase CML, blast crisis, or acute leukemia after allogeneic SCT are resistant to DLI in the majority of cases. In vitro-selected and expanded leukemia-reactive T-cell lines may be more effective in inducing an antileukemic response in vivo. To treat a patient with accelerated phase CML after allogeneic SCT, leukemia-reactive cytotoxic T-lymphocyte (CTL) lines were generated from her HLA-identical donor. Using a modification of a limiting dilution assay, T cells were isolated from the donor, selected based on their ability to inhibit the in vitro growth of CML progenitor cells, and subsequently expanded in vitro to generate CTL lines. Three CTL lines were generated that lysed the leukemic cells from the patient and inhibited the growth of leukemic progenitor cells. The CTL did not react with lymphocytes from donor or recipient and did not affect donor hematopoietic progenitor cells. The 3 leukemia-reactive CTL lines were infused at 5-week intervals at a cumulative dose of 3.2 x 10(9) CTL. Shortly after the third infusion, complete eradication of the leukemic cells was observed, as shown by cytogenetic analysis, fluorescence in situ hybridization, molecular analysis of BCR/ABL-mRNA, and chimerism studies. These results show that in vitro cultured leukemia-reactive CTL lines selected on their ability to inhibit the proliferation of leukemic progenitor cells in vitro can be successfully applied to treat accelerated phase CML after allogeneic SCT.

Renal excretion of iodine-131 labelled meta-iodobenzylguanidine and metabolites after therapeutic doses in patients suffering from different neural crest-derived tumours.

Iodine-131 labelled meta-iodobenzylguanidine ([131I]MIBG) is used for diagnostic scintigraphy and radionuclide therapy of neural crest-derived tumours. After administration of therapeutic doses of [131I]MIBG (3.1-7.5 GBq) to 17 patients (n=32 courses), aged 2-73 years, 56%+/-10%, 73%+/-11%, 80%+/-10% and 83%+/-10% of the dose was cumulatively excreted as total radioactivity in urine at t=24 h, 48 h, 72 h and 96 h, respectively. Except for two adult patients, who showed excretion of 14%-18% of [131I]meta-iodohippuric acid ([131I]MIHA), the cumulatively excreted radioactivity consisted of >85% [131I]MIBG, with 6% of the dose excreted as free [131I]iodide, 4% as [131I]MIHA and 2.5% as an unknown iodine-131 labelled metabolite. Cumulative renal excretion rates of total radioactivity and of [131I]MIBG appeared to be higher in neuroblastoma and phaeochromocytoma patients than in carcinoid patients. Based on the excretion of small amounts of [131I]meta-iodobenzoic acid in two patients, a possible metabolic pathway for [131I]MIBG is suggested. The degree of metabolism was not related to the extent of liver uptake of radioactivity.

Radiochemical purity, at expiry, and radiochemical stability of iodine-131 labelled meta-iodobenzylguanidine concentrates for intravenous infusion.

AIM: The determination of the amount of free [131I]iodide in [131I]metaiodobenzylguanidine ([131I]MIBG) concentrates for intravenous infusion under different storage conditions derived from daily practice. METHOD: The percentage of free [131I]iodide was determined in [131I]MIBG concentrates (1.6-3.9 GBq in 7.5 ml), kept on dry ice (up to expiry, 3 days after production) or, after thawing, at room temperature (up to 24 h). A validated solid phase extraction (SPE) assay was used. RESULTS: Free [131I]iodide increased from 1.9% +/- 0.34% at production to 4.4% +/- 0.67% (mean +/- SD; n = 5) at expiry in 3.7 GBq per 7.5 ml [131I]MIBG infusion concentrates stored on dry ice (-78 degrees C). At room temperature, formation of free [131I]iodide was found to be dependent on the radioactive concentration of the fluid. [131I]iodide levels increased from 3.1%, immediately after thawing, to 6.6% and 16.6% at t = 5 and 24 h, respectively, for a 3.9 GBq per 7.5 ml concentrate. CONCLUSION: The investigated formulation of [131I]MIBG concentrates, stored in its original packing containing dry ice, can generally be used up to expiry. After thawing, the undiluted concentrates should be administered to a patient within 3.5 h.

Renal excretion of meta-iodobenzylguanidine after therapeutic doses in cancer patients and its relation to dose and creatinine clearance.

Iodine-131 radioiodinated meta-iodobenzylguanidine (131I-MIBG) is used for diagnostic scintigraphy and radionuclide therapy of neural crest-derived tumours. In higher doses (up to 80 mg), non-radioactive MIBG is now evaluated for palliation in carcinoid patients. After administration of therapeutic doses of 131I-MIBG (3.7-7.4 GBq, 1.7-5.8 mg MIBG) to patients aged 2-73 years, 53 +/- 8.8%, 69 +/- 7.8% and 83 +/- 7.0% of the dose was cumulatively excreted as MIBG in the urine after 24, 48 and 72 h, respectively. Within the MIBG dose range of 1.7-80.0 mg, a linear relationship was found between the excretion rate over the first 24 h (mg per 24 h) and the dose. In adults, the MIBG excretion rate over the first 24 h (% of dose per 24 h) was shown to be only partially related to the glomerular filtration rate (GFR).

Synthesis, radiolabelling and stability of radioiodinated m-iodobenzylguanidine, a review.

Since the introduction of radioiodinated m-iodobenzylguanidine in 1980, much research has been performed, both in the chemical field as well as in medical sciences. This paper reviews the synthesis, radiolabelling and stability of radioiodinated m-iodobenzylguanidine. Regarding the many radiolabelling procedures for m-iodobenzylguanidine, the Cu(1+)-assisted nucleophilic exchange radioiodination can be considered as the method of first choice. Quality control of the radiopharmaceutical product is discussed and attention is paid to recent studies regarding the radiochemical stability of iodine-131 labelled m-iodobenzylguanidine.

High-performance liquid chromatographic determination of metaiodobenzylguanidine in whole blood and plasma of cancer patients.

An accurate and simple high-performance liquid chromatographic (HPLC) assay is presented for the quantitative determination of metaiodobenzylguanidine (MIBG) in human whole blood and plasma. The sample pretreatment involves a solid-phase extraction on Bakerbond SPE cyano columns. The HPLC system comprises a microBondapak C18 column and ammonium phosphate (pH4.0; 25 mM)-acetonitrile (80:20, v/v) as the mobile phase. Detection is performed by UV absorbance measurements at 254 nm. Linear regression with weighting factor l/chi 2 yielded the smallest sum of per cent relative concentration residuals over the concentration range of the assay (0.1-10 micrograms ml-1). MIBG levels, at the end of a 3-h infusion, in whole blood and plasma of carcinoid patients were measured and compared with the results obtained with radiodetection after addition of iodine-131-labelled MIBG.

Radioiodinated metaiodobenzylguanidine: a review of its biodistribution and pharmacokinetics, drug interactions, cytotoxicity and dosimetry.

Since the introduction of radioiodinated metaiodobenzylguanidine in 1980, considerable research has been performed, both in the chemical field and in medical sciences. However, despite the wide use of radioiodinated metaiodobenzylguanidine, knowledge about its pharmacology is still limited. This paper reviews the biodistribution and pharmacokinetics, drug interactions, cytotoxicity and dosimetry of radioiodinated metaiodobenzylguanidine. Iodine-131 metaiodobenzylguanidine therapy is in general well tolerated, but its effectiveness needs improvement. Also whole-body dosimetry as part of treatment planning needs to be improved. Future prospects on these items are included in this review.

High-performance liquid chromatographic determination of m-iodobenzylguanidine in urine of cancer patients.

An accurate, sensitive, reproducible and selective HPLC assay is presented for the quantitative determination of m-iodobenzylguanidine (MIBG) in human urine. The sample pretreatment involves a solid-phase extraction on Bakerbond SPE cyano columns. The HPLC systems consists of a muBondapak C18 column and 25 mM ammonium phosphate (pH 3.0)-acetonitrile (75:25, v/v) as the mobile phase. Detection is performed by UV absorbance at 254 nm. Log y vs. log x is the response function that yielded the smallest sum of percent relative concentration residuals over the whole concentration range of the assay (0.2-100 micrograms/ml). The excretion profile of MIBG in urine of a three-year old patient is shown.

Radiochemical stability during infusion of 131I-labelled metaiodobenzylguanidine for therapeutic use.

131I-labelled metaiodobenzylguanidine ([131I]MIBG) is used both for diagnostic scintigraphy and for radionuclide therapy of neural crest derived tumours in particular neuroblastoma, malignant phaeochromocytoma and paraganglioma. This paper presents data on radiochemical stability during the infusion of 3.8, 5.7 and 7.7 GBq [131I]MIBG in 100 ml infusion fluids for therapy. The period of investigation started at the moment of dilution of the thawed infusion concentrates (t = 0), which arrived in a frozen condition from the manufacturer, and ended at the termination of infusion (t = 7 h). In 7 h the percentage of free [131I]iodide increased from 3.74 to 5.82, from 3.52 to 6.02 and from 3.72 to 6.40% in the 3.8, 5.7 and 7.7 GBq [131I]MIBG infusion fluids, respectively. The 0-7 h increases of the different radioactive concentrations did not differ significantly. All the infusion fluids contained less than 7% free [131I]iodide at the end of infusion (t = 7 h).

Radiochemical purity of iodine-131 labelled metaiodobenzylguanidine infusion fluids: a report from clinical practice.

Iodine-131 labelled metaiodobenzylguanidine ([131I]MIBG) has a diagnostic and therapeutic role in the management of neural crest tumours, particularly neuroblastoma, malignant phaeochromocytoma and paraganglioma. With therapeutic amounts of [131I]MIBG it is essential that the amount of free [131I]iodide, the most important impurity, is known. In clinical practice the percentage of free [131I]iodide seen in a [131I]MIBG infusion concentrate increased from 2.2% +/- 0.67% to 3.6% +/- 0.39% (mean +/- SD; n = 23) 1 day after production. At the time of use the percentage of free [131I]iodide was always below our upper limit of acceptance of 5%. Since 5% of free [131I]iodide is within practical reach in our environment, a higher percentage at the time of preadministration quality control is not accepted in the Netherlands Cancer Institute.