Jerry P. Lewis

Maximum-tolerated dose, toxicity, and efficacy of (131)I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin's lymphoma.

PURPOSE Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced remissions in patients with non-Hodgkins lymphoma (NHL) when labeled with iodine 131 ((131)I). Based on the strategy of fractionating the total dose, this study was designed to define the maximum-tolerated dose (MTD) and efficacy of the first two, of a maximum of four, doses of (131)I-Lym-1 given 4 weeks apart. Additionally, toxicity and radiation dosimetry were assessed. MATERIALS AND METHODS Twenty patients with advanced NHL entered the study a total of 21 times. Thirteen (62%) of the 21 entries had diffuse large-cell histologies. All patients had disease resistant to standard therapy and had received a mean of four chemotherapy regimens. (131)I-Lym-1 was given after Lym-1 and (131)I was escalated in cohorts of patients from 40 to 100 mCi (1.5 to 3.7 GBq)/m2 body surface area. RESULTS Mean radiation dose to the bone marrow from body and blood (131)I was 0.34 (range, 0. 1 6 to 0.63) rad/mCi (0.09 mGy/MBq; range, 0.04 to 0.17 mGy/ MBq). Dose-limiting toxicity was grade 3 to 4 thrombocytopenia with an MTD of 100 mCi/m2 (3.7 GBq/m2) for each of the first two doses of (131)I-Lym-1 given 4 weeks apart. Nonhematologic toxicities did not exceed grade 2 except for one instance of grade 3 hypotension. Ten (71 %) of 14 entries who received at least two doses of (131)I-Lym-1 therapy and 11 (52%) of 21 total entries responded. Seven of the responses were complete, with a mean duration of 14 months. All three entries in the 100 mCi/m2 (3.7 MBq/m2) cohort had complete remissions (CRs). All responders had at least a partial remission (PR) after the first therapy dose of (131)I-Lym-1. CONCLUSION (131)I-Lym-1 induced durable remissions in patients with NHL resistant to chemotherapy and was associated with acceptable toxicity. The nonmyeloablative MTD for each of the first two doses of (131)I-Lym-1 was 100 mCi/m2 (total, 200 mCi/m2) (3.7 GBq/m2; total, 7.4 GBq/m2).

Myxoid chondrosarcoma with a translocation involving chromosomes 9 and 22

Myxoid chondrosarcoma is an uncommon neoplasm thought to be derived from mesenchymal chondrocytic cells. Although cytogenetic abnormalities have been reported in sarcomas, too few cases have been studied to determine the frequency of nonrandom chromosomal changes in mesenchymal tumors. In this article, we describe a chondrosarcoma with a nonrandom reciprocal translocation t(9;22)(q22;q11). The cellular homologue to the retrovirus transforming gene of simian sarcoma virus is located on chromosome #22, and its possible significance in this case is discussed.

Infusion Carboplatin Treatment of Relapsed and Refractory Acute Leukemia: Evidence of Efficacy With Minimal Extramedullary Toxicity at Intermediate Doses

Carboplatin (CBDCA) is a second-generation platinum analog with prominent myelotoxicity and modest extramedullary toxicity. We performed a phase I study of CBDCA in adult patients with relapsed acute leukemia. Therapy was administered as a five-day continuous infusion. The initial dose of 875 mg/m2 over five days was escalated in 15% increments to a final dose of 2,100 mg/m2 over five days. Twenty-eight patients received 35 induction courses of CBDCA, including two patients who achieved a complete remission (CR) following the first course, and received a second induction course at the time of relapse. Therapy was well tolerated. No grade 3 or 4 extramedullary toxicity was seen. Myelosuppression was regularly observed, with prolonged myelosuppression at 2,100 mg/m2 over five days being the indication to cease dose escalation. Eight of 28 patients (28.5%) responded to CBDCA therapy (six CR, two partial remission [PR]) or ten of 30 initial induction courses (33.3%). Continuous-infusion CBDCA has an advantage over other therapy for acute leukemia because of its highly selective myelotoxicity and minimal gastrointestinal and renal toxicity. A standard phase II study should be undertaken to establish a more accurate response rate.

Effect of lym‐1 radioimmunoconjugate on refractory chronic lymphocytic leukemia

Background. Although chronic lymphocytic leukemia is usually indolent and responsive to treatment early in its course, later stages are characterized by inexorable progression despite standard treatment so that new therapies are needed. Because malignant lymphocytes have characteristic surface antigens, the role of monoclonal antibodies is worthy of intensive investigation.

Diagnostic and prognostic significance of t(1;3)(p36;q21) in the disorders of hematopoiesis

We describe a cytogenetic abnormality with important diagnostic and prognostic implications. The translocation t(1;3)(p36;q21) is an acquired chromosomal rearrangement associated with myelodysplastic syndromes, which have a high propensity for conversion to refractory acute nonlymphocytic leukemia.

Mast cell disease followed by leukemia with clonal evolution

A 29-yr old woman developed urticaria pigmentosa which subsequently progressed through systemic mastocytosis to Philadelphia chromosome negative (Ph neg) chronic myelogenous leukemia (CML) with t(8;17). Further cytogenetic evolution occurred at the time of transformation to the aggressive phase of the disease. Unlike Ph-positive CML, chromosome number 9 was not involved, nor was the breakpoint cluster region located at band 22q11. This clearly separates this case from other Ph-negative CML patients who do have involvement of 9q34 or the breakpoint cluster region. Since this is the first case of its type to be reported with cytogenetic abnormalities, the clinical relevance of the unique chromosomal rearrangement t(8;17)(p11;q25) in the setting of systemic mastocytosis is unclear. Additional cases need to be reported to determine if this genetic rearrangement is a nonrandom marker of leukemia evolving in a setting of malignant mast cell disease.

Analysis of mosaic states in amniotic fluid using the in-situ colony technique

Appropriate counselling and clinical management of the pregnant woman with a mosaic amniotic fluid cell karyotype are difficult. The majority of the data on mosaicism and pseudomosaicism are derived from studies employing the flask technique for the analysis of amniotic fluid cell cultures. Since the majority of laboratories now utilize the in‐situ technique, such data may not be relevant when analyzing results from the in‐situ colony technique. We reviewed the incidence of mosaicism in 6339 amniotic fluid samples using the in‐situ technique. Data are presented on the types of aberrations and clinical outcomes. A classification of mosaicism is presented that distinguishes mosaicism of clinical importance from that which is obviously of extrafetal origin or artifactual. This approach clarifies the significance of mosaic states detected by the in‐situ colony technique and provides a rational foundation for genetic counselling and for planning clinical interventions.

Randomized clinical trial of cystosine arabinoside and 6-thioguanine in remission induction and consolidation of adult nonlymphocytic acute leukemia

One hundred and forty‐seven adults with acute nonlymphocytic leukemia were randomized to one of two treatment regimens utilizing cytosine arabinoside and 6‐thioguanine. In regimen A the drugs were administered every 12 hours until marrow cellularity was reduced by at least 50%. In regimen B the drugs were administered every 12 hours for 5 days with five to 7 days rest intervals between courses. Decisions to continue or reinstitute therapy were based solely on marrow cellularity and marrow ratings. The overall response in refereeverified cases in both groups was similar (41%); regimen B proved to be the easier protocol to administer but required greater support. Younger patients or those with an initial high hemoglobin count responded best to these drug regimens. Only 36% of our patients experienced severe marrow hypoplasia (i.e., a 75% or greater reduction in marrow cellularity) prior to complete remission, suggesting that cytosine arabinoside and 6‐thioguanine in combination may selectively suppress leukemic cells while sparing normal hematopoietic elements.

Bone Marrow and Bone Mineral Scintigraphic Studies in Sickle Cell Disease

Summary. Using discriminating radioisotopic techniques, a consistent pattern of abnormalities of both bone marrow and mineral was demonstrated in a series of patients with acute bone pain of sickle cell disease in which no roentgenographic evidence of infarction or infection was present. Bone scans utilizing reticulo‐endothelial uptake of 99mTc sulphur colloid showed discrete lesions of decreased radioisotopic localization in regions of acute pain suggesting decreased marrow blood flow. In these same areas, 85Sr bone scans showed markedly increased uptake whereas 18F bone scans showed little or no alteration. The strontium findings are consistent with accelerated calcium turnover while the fluorine studies suggest that bone blood flow, in contrast to marrow blood flow, remains nearly normal. In one patient, 52Fe positron scans confirmed an absence of effective erythropoiesis in those areas of involvement demonstrated by 99mTc and 85Sr. Marrow aspiration from one such area demonstrated sterile necrotic bone. These studies demonstrate that acute bone pain of sickle cell disease is associated with bone marrow death and increased bone mineral turnover.

Daunomycin administered by continuous intravenous infusion is effective in the treatment of acute nonlymphocytic leukaemia

Summary. Anthracyclines given by continuous infusion, as opposed to bolus administration, are associated with a reduced incidence of cardiac and gastrointestinal toxicity. Our study was developed to test the antileukaemic effect of anthracyclines given as a continuous infusion. Nineteen sequential patients admitted for treatment of acute nonlymphocytic leukaemia (ANLL) were managed with a regimen utilizing a 3 d continuous intravenous infusion of daunomycin (DNM), and the complete response rate was similar to this institutions past experience with antileukaemic regimens employing 3 d bolus DNM. In our studies, infusion DNM was at least as myelotoxic and antileukaemic as bolus DNM; thus this method of administration should be explored further in remission‐induction regimens for ANLL.