Wil B. Nelp

Radiolabeled-Antibody Therapy of B-Cell Lymphoma with Autologous Bone Marrow Support

BACKGROUND Radiolabeled monoclonal antibodies recognizing B-lymphocyte surface antigens represent a potentially effective new therapy for lymphomas. We assessed the biodistribution, toxicity, and efficacy of anti-CD20 (B1 and 1F5) and anti-CD37 (MB-1) antibodies labeled with iodine-131 in 43 patients with B-cell lymphoma in relapse. METHODS Sequential biodistribution studies were performed with escalating doses of antibody (0.5, 2.5, and 10 mg per kilogram of body weight) trace-labeled with 5 to 10 mCi of 131I. The doses of radiation absorbed by tumors and normal organs were estimated by serial gamma-camera imaging and tumor biopsies. Patients whose tumors were estimated to receive greater doses of radiation than the liver, lungs, or kidneys (i.e., patients with a favorable biodistribution) were eligible for therapeutic infusion of 131I-labeled antibodies according to a phase 1 dose-escalation protocol. RESULTS Twenty-four patients had a favorable biodistribution, and 19 received therapeutic infusions of 234 to 777 mCi of 131I-labeled antibodies (58 to 1168 mg) followed by autologous marrow reinfusion, resulting in complete remission in 16, a partial response in 2, and a minor response (25 to 50 percent regression of tumor) in 1. Nine patients have remained in continuous complete remission for 3 to 53 months. Toxic effects included myelosuppression, nausea, infections, and two episodes of cardiopulmonary toxicity, and were moderate in patients treated with doses of 131I-labeled antibodies that delivered less than 27.25 Gy to normal organs. CONCLUSIONS High-dose radioimmunotherapy with 131I-labeled antibodies is associated with a high response rate in patients with B-cell lymphoma in whom antibody biodistribution is favorable.

Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas.

25 patients with relapsed B-cell lymphomas were evaluated with trace labelled doses (2.5 mg/kg, 185-370 MBq [5-10 mCi]) of 131I-labelled anti-CD20 (B1) antibody in a phase II trial. 22 patients achieved 131I-B1 biodistributions delivering higher doses of radiation to tumour sites than to normal organs and 21 of these were treated with therapeutic infusions of 131I-B1 (12.765-29.045 GBq) followed by autologous haemopoietic stem cell reinfusion. 18 of the 21 treated patients had objective responses, including 16 complete remissions. One patient died of progressive lymphoma and one died of sepsis. Analysis of our phase I and II trials with 131I-labelled B1 reveal a progression-free survival of 62% and an overall survival of 93% with a median follow-up of 2 years. 131I-anti-CD20 (B1) antibody therapy produces complete responses of long duration in most patients with relapsed B-cell lymphomas when given at maximally tolerated doses with autologous stem cell rescue.

Treatment of refractory non-Hodgkin's lymphoma with radiolabeled MB-1 (anti-CD37) antibody.

The biodistribution, toxicity, and therapeutic potential of anti-CD37 monoclonal antibody (MoAb) MB-1 labeled with iodine 131 (131I) was evaluated in ten patients with advanced-, low- or intermediate-grade non-Hodgkins lymphomas who failed conventional treatment. Sequential dosimetric studies were performed with escalating amounts of antibody MB-1 (0.5, 2.5, 10 mg/kg) trace-labeled with 5 to 10 mCi 131I. Serial tumor biopsies and gamma camera imaging showed that the 10 mg/kg MoAb dose yielded the best MoAb biodistribution in the ten patients studied. Biodistribution studies in the five patients with splenomegaly and tumor burdens greater than 1 kg indicated that not all tumor sites would receive more radiation than normal organs, and these patients were therefore not treated with high-dose radioimmunotherapy. The other five patients did not have splenomegaly and had tumor burdens less than 0.5 kg; all five patients in this group showed preferential localization and retention of MoAb at tumor sites. Four of these patients have been treated with 131I (232 to 608 mCi) conjugated to anti-CD37 MoAb MB-1, delivering 850 to 4,260 Gy to tumor sites. Each of these four patients attained a complete tumor remission (lasting 4, 6, 11+, and 8+ months). A fifth patient, whose tumor did not express the CD37 antigen, was treated with 131I-labeled anti-CD20 MoAb 1F5 and achieved a partial response. Myelosuppression occurred 3 to 5 weeks after treatment in all cases, but there were no other significant acute toxicities. Normal B cells were transiently depleted from the bloodstream, but immunoglobulin (Ig) levels were not affected, and no serious infections occurred. Two patients required reinfusion of previously stored autologous, purged bone marrow. Two patients developed asymptomatic hypothyroidism 1 year after therapy. The tolerable toxicity and encouraging efficacy warrant further dose escalation in this phase I trial.

Long-term calcitonin therapy in postmenopausal osteoporosis

Results are presented from a 2-year controlled study evaluating the efficacy of 100 units synthetic salmon calcitonin/d in the treatment of postmenopausal osteoporosis. All patients received 400 units D2 po qd and 1200 mg CaCO3 po qd. The 21 control and 24 treated patients (mean age 65) were not statistically different at baseline. Although mean total body calcium (TBCa) was not significantly different between treated and control patients throughout the study, mean differences in the change in TBCa from baseline (treated minus control) were significant at 12, 18, and 26 months. The mean slope of TBCa for treated patients, but not for controls, was significantly positive through 18 months. Iliac crest bone biopsies showed (1) a significantly greater percent total bone area in treated compared to control patients at 2 years, and (2) a significantly decreased percent resorbing surface in treated patients when evaluated by paired difference from baseline. At 4 months, serum calcium values were significantly lower in treated patients than in controls (mean difference, treated minus controls), but were not statistically different from controls at study completion. Urine calcium increased significantly for the first 4 months in treated subjects and then declined to baseline levels. Since urinary calcium increased, the increase in TBCa was probably associated with an increase in net intestinal calcium absorption.

Stanozolol in postmenopausal osteoporosis: Therapeutic efficacy and possible mechanisms of action

To assess the efficacy of the anabolic steroid stanozolol in the treatment of osteoporosis, a 29-month double-blind study was performed with 23 treated and 23 control postmenopausal osteoporotic women. Drug efficacy was assessed by serial determinations of total body calcium (TBC--total bone mass) by neutron activation analysis, regional bone mass (RBM) by single-photon absorptiometry, and by spinal roentgenograms. Total body calcium increased 4.4% from baseline values (P less than 0.01) in the treated group and remained unchanged in the control group; the difference in the change in TBC between the treated and control groups was significant (P less than 0.03). The effect of the drug on TBC persisted throughout the 29-month period. In contrast to TBC, measurements of RBM indicated no significant differences between the treated and placebo groups, suggesting a possible differential response to therapy at various skeletal sites. No new spinal compression fractures were noted in the treated group (compared with three new fractures in the control group). Assessment of serum and urine values indicated a decrease in the level of urinary calcium and an increase in the level of total urinary cyclic AMP in the treated group. These changes were observed even though the level of serum iPTH was significantly decreased during the study. An analysis of changes in bone biopsy specimens revealed no significant differences between the treated and control groups. Seventy-six percent of the treated subjects developed SGOT elevations or other side effects from the stanozolol therapy; at no time were these effects sufficiently severe to cause termination of medication. The data suggest that long-term use of stanozolol increases the net total bone mass above pretreatment levels.

Relationship between local and total bone mass in osteoporosis

The relationship between total body calcium (TBC) and local bone calcium mass (BCM) was studied in a group of osteoporotic patients (12 females and two males) with a wide range of body size. Two methods were used to estimate BCM: photon absorptiometry and radiographic morphometry. TBC was estimated by total-body neutron-activation analysis. Since 99 percent of TBC is located in the skeleton, it was assumed that TBC was essentially a measure of total skeletal (calcium) mass. TBC ranged from 482 to 1076 g. High correlations with r values from 0.84 to 0.94, p less than 0.001, were found between TBC and BCM measured by absorptiometry at six different sites of radius, ulna, and humerus. Additionally, high correlations with r values from 0.89 to 0.95, p less than 0.001, were found between BCM at the distal tenth of the radius and BCM at the five other sites. A high correlation was also found between body height and TBC, but partial correlations indicated that this accounted for very little of the correlation between TBC and BCM. In contrast to the above, correlations between BCM determined by radiographic morphometry and TBC were weak or nonsignificant. When TBC and BCM were expressed as percent of their mean value, the slopes of the estimating equations, describing the relationships between TBC and BCM, were essentially the same, but significantly less than one, which is the value of the slope expected if TBC and BCM had changed at the same relative rate. From these relationships, we conclude (1) that the rate of change in BCM was similar in the six sites examined, and (2) that the rate of change in these six sites was relatively more rapid than the change in total body calcium. Whether the change in rate of BCM was related to rate of increase during attainment of maximum BCM or subsequent rate of loss of BCM or both remains to be determined.

Comparison of serum PSMA, PSA levels with results of cytogen-356 ProstaScint® scanning in prostatic cancer patients

Stored serum from clinical trial cases undergoing ProstaScint® (CYT‐356) scanning were available for Prostate Specific Membrane Antigen (PSMA) assay. Prostate Specific Antigen (PSA) levels had already been determined. This provided an opportunity to see what correlations existed between the serum markers and the ProstaScint® scan. A group of patients had the studies preprostatectomy, whereas another group had the studies postprostatectomy.

Effect of methandrostenolone on postmenopausal bone wasting as assessed by changes in total bone mineral mass

To assess the efficacy of methandrostenolone in the treatment of osteoporosis a 26-mo double-blind study was performed with 13 treated and 13 control (placebo) postmenopausal osteoporotic females. Drug effect was assessed primarily by determinations of total body calcium (TBC) by neutron activation analysis, essentially a measurement of total bone mineral mass. Results in the 16 patients completing the study (10 treated and 6 placebo), as well as in all 26 patients participating in the study, showed significant (p less than 0.01) differences in the change in TBC between treated and control groups. In patients dropping out, TBC changes through the time of dropout were similar to those in patients completing the study. In those patients completing the study, TBC increased 2% in the treated group and decreased 3% in the placebo group. An approximate sixfold difference in extraskeletal calcium balance would be required to explain the magnitude of the observed intergroup TBC difference. The drug effect appeared to persist throughout the 26-mo observation period. Thus these data strongly suggest that long-term use of methandrostenolone in postmenopausal osteoporosis prevented bone loss; the possibility that it increased bone mass above initial values is less certain.

Basal Plasma Immunoreactive Calcitonin in Postmenopausal Osteoporosis

Calcitonin (CT) deficiency has been suggested as an etiologic factor in postmenopausal osteoporosis (PM-OP). Basal immunoreactive calcitonin (iCT) was measured with a sensitive radioimmunoassay (RIA) in 62 PM-OP women with compression fractures (CF) and in 28 normal age-matched women. Mean iCT values in the two groups were not significantly different (43.5 and 45.1 pg/ml, p greater than 0.10). In the 62 PM-OP females, no significant correlation was noted between basal plasma iCT levels and (1) age; (2) severity of disease as assessed by number of CF; (3) serum calcium, phosphorus, alkaline phosphatase, and immunoreactive parathyroid hormone; and (4) total bone mass as assessed by neutron activation analysis determinations of total body calcium (TBC). In 20 PM-OP patients treated for 24 mo with 100 Medical Research Council (MRC) units daily of synthetic salmon CT, no correlation was observed between basal plasma iCT and response of bone mass (TBC) to therapy. These data suggest that basal CT is not decreased in women with PM-OP, and that the level of circulating CT does not influence therapeutic changes in bone mass during CT therapy. CT is probably not a major etiologic or pathogenetic factor in PM-OP.

Measurement of left ventricular volume using single-photon emission computed tomography

A count-based method for measuring left ventricular (LV) volume using technetium-99m-labeled red cells and ungated single-photon emission computed tomography is described. The tomographic slices were used to determine the counts per milliliter in the center of the left ventricle and total LV counts, which were used to derive mean LV volume. End-diastolic and end-systolic volumes were calculated from the mean volume using the LV time-activity curve from planar gated blood pool images. Phantom evaluation with simulated LV volumes (50 to 400 ml) in air, in a phantom filled with water, with 10% background, and with a simulated right ventricle, showed excellent accuracy. For clinical validation, 30 patients underwent electrocardiographically gated planar and nongated tomographic acquisition of the cardiac blood pool followed by single-plane cineangiography. For end-diastolic and end-systolic volumes combined, the correlation with cineangiography showed a standard error of the estimate (SEE) of 24 ml and 14 ml, respectively. Mean intra- and interobserver deviation was 12 ml and 14 ml (SEE 13 ml and 16 ml), respectively. It is concluded that this noninvasive count-based technique, requiring no assumptions regarding LV geometry, is an accurate and reproducible way to measure LV volume.