Randomized Double-Blind Study of Standard Versus Low-Dose OKT3 Induction Therapy in Renal Allograft Recipients

Randomized Double-Blind Study of Standard Versus Low-Dose OKT3 Induction Therapy in Renal Allograft Recipients R. Alloway, PharmD, M. Kotb, PhD, O.K. Hathaway, PhD, L.W. Gaber, MD, S.R. Vera, MD, and A.D. Gaber, MD • A double-blind, randomized, prospective study was undenaken to determine if the dose of OKT3 used for induction immunosuppression following kidney and kidney-pancreas transplantation affected clinical outcomes. Twenty-five patients were randomized in each group. Five patients in each group received a combined kidney/pancreas transplant. All patients received sequential quadruple immune suppression (azathioprine and methylprednisolone, followed by oral prednisone and cyclosporine A), regardless of randomization to the standard (5 mg) or low-dose (2 mg) OKT3 group. OKT3 was administered for 7 to 14 days. The dose of OKT3 was adjusted to ascenain the clearance of peripheral positive CD3 lymphocytes. The mean cumulative OKT3 dose for the standard dose group was 52.0 mg versus 23.4 mg for the low-dose group (P < 0.00001). Dosage increases were necessary for 29% of the standard dose and 32% of the low-dose patients. The side effect score for the standard versus low-dose group was not statistically different (0.79 ± 0.58 v 0.84 ± 0.68), except for chills, which occurred more frequently in the low-dose-treated patients (P = 0.003). Anti-OKT3 antibodies developed with similar frequency in both dosage groups, with 8% exhibiting titers of 1:500 or greater at the end of treatment. Kidney graft survival was 96% for the standard dose and 92% for the lowdose group. The overall incidence of rejection was similar in both groups; however the low-dose group did experience an increase in early rejection episodes. The incidence of major and minor viral and bacterial infections was also similar for both dosage groups. The mean creatinine levels for the standard versus low-dose groups at 1 month (1.8 v 2.03 mg/dL) and 6 months (1.48 v 1.62 mg/dL) were not significantly different between groups. This study demonstrates that low-dose OKT3 therapy, when administered in conjunction with sensitive immunologic monitoring, is successful in achieving adequate induction therapy.

© 1993 by the National Kidney Foundation, Inc. INDEX WORDS: OKT3, induction, immunosuppression, renal, transplants.

T

HE SUCCESSFUL reversal of acute rejection episodes with the anti-CD3 monoclonal antibody OKT3 has led to its increasing use in sequential induction immunosuppressive protocols.! The use of OKT3 as a rejection prophylaxis has been shown to be particularly advantageous for recipients with delayed graft function who can benefit from the delayed initiation of cyclosporine? Since the use of OKT3 in a prophylactic manner constitutes a different application than that used for acute rejection, questions have arisen regarding the optimal dosing regimen necessary for therapeutic results. Norman et al 3 reported an early experience with lowdose induction immune suppression that successfully maintained graft survival results when compared with the standard 5-mg daily dose. We conducted a nonrandomized pilot study which From the Department of Surgery. Division of Transplantation, and the Departments ofPathology and Pharmacy, The University of Tennessee, Memphis, TN. Received August 21, 1992; accepted in revised form February 23, 1993. Address reprint requests to A. O. Gaber, MD, Coleman College ofMedicine Bldg, Department ofSurgery, 956 Court Ave, Suite A202, Memphis, TN 38163. © 1993 by the National Kidney Foundation, Inc. 0272-6386/93/2201-0006$3.00;0 36

confirmed that low-dose induction therapy with 2 mg ofOKT3 per day could achieve a graft survival rate and incidence of early rejection similar to that seen in higher-dose protocols. 4 Results of the pilot study also highlighted the importance of immune monitoring during treatment with OKT3 as a basis for determining dosage adjustments required to prevent breakthrough rejections. 5 To validate the results of our pilot study, we embarked on a double-blind, randomized, prospective study comparing the lower and standard dose of OKT3 as induction therapies. This prospective study was designed to eliminate clinical bias during treatment and to validate the usefulness of various immune monitoring techniques. METHODS

Patient Population and Randomization Following approval of study procedures and informed consent by the Institutional Review Board, 50 recipients of a first renal cadaveric allograft, whether alone or in association with a pancreas, were enrolled in the study. Study patients were randomized in a double-blind fashion to receive either the standard (5 mg) or low (2 mg) dose of OKT3 as part of their immunosuppressive induction therapy. On notification of signed informed consent, randomization was performed by the pharmacy, which dispensed all OKT3 doses in a total

American Journal of Kidney Diseases, Vol 22, No 1 (July), 1993: pp 36-43

37

STANDARD V LOW-DOSE OKT3 INDUCTION volume of 15 mL. This volume expansion was achieved with normal saline in addition to the inherent volume of the OKT3 dose. These doses were sent to the operating room or to the transplant unit marked only by the patient randomization number. The randomization code was broken only on completion of data collection at 6 months posttransplant, or if the patient was withdrawn from the study due to complications (one patient).

Immunosuppressive Protocol The same quadruple, sequential, immunosuppressive protocol using OKT3, high-dose steroids, azathioprine, and cyclosporine was used for both study groups. Induction immunosuppression began in the operating room with the first doses of methylprednisolone (500 mg) and azathioprine (5 mg/kg) administered as the patient was anesthetized. The initial dose of OKT3 (5 or 2 mg) was also given in the operating room intravenously, pushed over 2 minutes following revascularization of the renal allograft. Following surgery, methylprednisolone was decreased to 250 mg on the first postoperative day and to 125 mg on the second postoperative day. Prednisone was initiated on the third postoperative day at a daily dose of 0.5 mg/kg and tapered to 0.2 mg/kg daily at approximately 3 months posttransplant. Azathioprine was given at a dose of 25 mg/d on the first postoperative day and increased to a daily dose of 2 mg/kg on initiation of cyclosporine. Cyclosporine was initiated in all patients on the seventh postoperative day or when the serum creatinine dropped to below 3 mg/dL. Cyclosporine was begun at a daily dose of 4 to 8 mg/kg and was adjusted to maintain a whole blood trough level of approximately 200 ng/dL (TDX). All patients received cefazolin for surgical prophylaxis for 24 to 72 hours and were converted to an oral agent if continued prophylactic therapy was indicated. Cytomegalovirus prophylaxis therapy included acyclovir (200 mg) orally three times daily for 6 weeks, and fungal prophylaxis was accomplished with nystatin or oral ketoconazole. Ketoconazole was continued indefinitely in some patients to reduce the dose of cyclosporine necessary to maintain therapeutic levels.

OKTJ Dosing Postoperative changes in OKT3 doses were preset by protocol to maintain peripheral CD3 lymphocytes at less than lO/mm 3 or 5% of the total CD3-positive lymphocytes. If cell counts exceeded this level on 2 consecutive days, doses for patients randomized to the standard dose (5 mg) group were increased to 10 mg and then to 15 mg if necessary. Similarly, doses for patients randomized to the low-dose (2 mg) group were increased to 5 mg and then to 10 mg if necessary. OKT3 was continued daily for a period of 7 to 14 days, depending on the achievement of therapeutic cyclosporine trough levels.

Monitoring of Adverse Effects Adverse effects secondary to OKT3 therapy were assessed on a daily basis by patient interview and chart review. The adverse effects assessed included fever (> 10 1.5°F), chills, tremor, dyspnea, myalgia, chest pain, wheezing, nausea, vomiting, diarrhea, thrombocytopenia «4,000 mm 3 ), leukopenia «4,000), hypertension (diastolic blood pressure > 100 mm Hg), hypotension (diastolic blood pressure < 60

mm Hg), joint pain, rash, mental status changes, pulmonary edema, aseptic meningitis, and photophobia. The adverse effects were collapsed into a clinical side effect score (SES) to provide a more comprehensive view of the side effect severity experienced by the patients. The SES was assigned by the physician to each patient at the end of OKT3 therapy, while the physician was still blinded to the OKT3 dose administered for induction. The SES assessed the severity of side effects as follows: 0, no side effects; 1, mild side effects that required close patient monitoring; 2, moderate side effects that required other pharmaceutical intervention; and 3, severe side effects that required admission to an intensive care unit or withdrawal of OKT3. This score provides a clinical tool for comparing the severity of the side effect secondary to OKT3 in the individual patient.

Laboratory Monitoring Anti-OKT3 antibodies were determined at the end oftherapy and at 30 days. Levels of the antimurine anti-OKT3 antibody were determined using an enzyme-linked immunosorbent assay.4 OKT3 was coated to the bottom of a 96-well microtiter plate overnight at 4°C and was then washed three times in a wash buffer. Patients' samples, a negative control of commercially bought AB serum, and a known positive sample were diluted to 1:100, 1:500, and 1:1,000, respectively, and 100 mL was added to the appropriate well and incubated at 37°C for 1 hour. The plate was washed three times, then 50 mL of horseradish peroxidase-conjugated goat anti-human immunoglobulin G was added to each well; the plate was again incubated for 1 hour at 37°C. After washing the plate, 100 iLL of chromagen was added to each well and incubated at room temperature. Absorbance at 415 nm was measured at 15 and 20 minutes. An absorbance value at each dilution of greater than twice the absorbance of the negative control was considered positive. In our clinical experience, patients with titers greater than 1:500 cannot be effectively treated as evidenced by continued appearance of peripheral CD3-positive cells despite dosage adjustments. During OKT3 therapy, daily flow cytometry T-cell subset analysis was performed and the number ofCD3-positive lymphocytes was used to adjust OKT3 dosages as previously described in the OKT3 dosing section. T-lymphocyte subsets were measured by flow cytometry. Briefly, 100 iLL of whole blood was incubated with the appropriate antibody for 10 minutes at room temperature. Each sample was then processed on a Coulter Q-Prep (Coulter Corp., Hialeah, FL) and analyzed on a Coulter Profile II. Dual color analysis measured CD2positive cells using Coulter Tl1-RD and a Coulter T3-FITC for measuring CD3-positive cells. The flow cytometer gate was set on the lymphocyte population and cells that fell within this gated region were analyzed. A quad stat histogram was analyzed and percentages of positive cells were derived from the dual positive region ofCD2- and CD3-positive cells.

Clinical Evaluation Rejection episodes were diagnosed clinically and confirmed by biopsy. All grafts with delayed graft function were biopsied on a weekly basis to assure that any rejection episode would be detected. Rejection was initially treated with high-dose steroids, consisting of 500-mg intravenous boluses of methylprednisolone for 3 consecutive days. Steroid-resistant rejections

ALLOWAY ET AL

38 Table 1. Characteristics of the Standard and LowDose OKT3 Treatment Groups Standard Dose (Smg) (n = 2S)

Patients

Kidney alone Kidney/pancreas Mean age (yr) Race White Black Gender Male Female Original disease Diabetes Hypertension Glomerular disease Other No. of months on dialysis CMV + recipients CMV + donors ATN episodes

Low Dose (2 mg) = 2S)

(n

20 5 39.6

20 5 39.2

18 7

17 8

14 11

12 13

12 6 2 5 19.8 20 15 4

7 6 5 7 19.3 15 15 5

Abbreviations: CMV, Cytomegalovirus; ATN, acute tabular necrosis.

were treated with 5-mg daily doses ofOKT3 for 7 to 14 days. Patients exhibiting anti-OKT3 antibody sensitization were treated with 10 to 20 mg/kg of ATGAM (Kirkegaard and Perry Labs, Gaithersburg, MD) for 7 to 14 days. Patient records were reviewed at 6 months after transplantation , and all episodes of renal dysfunction (creatinine increase of 0.3 mg/dL) were identified. Renal dysfunction episodes were classified at that time by the clinician, who was still blinded to patient randomization, based on biopsy findings , clinical response to antirejection treatment, cyclosporine adjustments, or other treatment maneuvers. Infections were identified and classified into major and minor episodes. Major infections were those that resulted in hospitalization, while minor infections were those treated on an outpatient basis with oral agents.

Immunosuppressive Managem ent The total mean OKT3 dose was significantly greater for the standard dose group even though the immunosuppressive protocol provided a mechanism for dosage adjustments (52.0 v 23.4 mg, P < 0.0001). Aside from the total dose administered, there were no significant differences in the therapeutic regimen between study groups (Table 2). Specifically, both groups were similar with regard to the total number of doses administered, the number of original doses administered prior to a change or discontinuation in treatment, and the number of increased doses administered. A single increase in OKT3 dose was required by seven patients in the standard dose group and eight patients in the low-dose group. Only one patient in the low-dose group required a second dosage adjustment. This implies that the dosage adjustments necessary were successful in reducing peripheral CD3-positive cells to target range in all but this patient. All dosage adjustments in both groups occurred late in therapy, as evidenced by the mean number of increased doses administered (1.3 ± 0.5 standard v 1.2 ± 0.5 low). Seven patients in the standard dose group and 12 patients in the low-dose group received ketoconazole in combination with cyclosporine for maintenance of therapeutic levels at a lower dose of cyclosporine. Despite the use of ketoconazole in some patients, trough cyclosporine A levels were similar in the standard versus low-dose groups throughout the study period: at I month, 179 versus 157 ng/dL; at 3 months, 175 versus 141 ng/dL; and at 6 months, 159 versus 175 ng/ dL, respectively. The average cost ofOKT3 therapy per standard dose patient was $5,252 ($3,535 to $8,585) compared with $2,363 ($1,414 to

RESULTS

Twenty-five patients were enrolled into each dosage group. Five patients receiving a pancreas in association with the kidney transplant were randomized to each group. Demographic characteristics were not different for the standard and low-dose groups (Table 1). The original disease for most patients was either diabetes (48% standard dose, 28% low dose) or hypertension (24% in each group). Pretransplant donor and recipient cytomegalovirus status, HLA mismatches, and pretransplant sensitization were also similar in both groups.

Table 2. Dosing Data of the Standard and Low-Dose OKT3 Treatment Groups Standard Dose

Total milligrams dosed Total doses administered No. of original doses given No. of increased doses given

(S mg) (n = 2S)

Low Dose (2mg) (n = 2S)

52.0 ± 3.0 9.3 ± 0.6 8.0 ± 0.6

23.4 ± 3.3" 8.0 ± 0.6 6.8 ± 0.6

1.3 ± 0.5

1.2 ± 0.5

NOTE. Data are presented as mean values ± SEM. "P < 0.0001 .

STANDARD V LOW-DOSE OKT3 INDUCTION

39

Table 3. Occurrence of Adverse Effects in the Standard and Low-Dose OKT3 Groups

Adverse Effect Fever (> 101.5°F) Hypertension Nausea/vomiting Thrombocytopenia Chills· Diarrhea Wheezing Dyspnea Tremor Myalgia Leukopenia Rash Hypotension Pulmonary edema Mental status changes Joint pain Photophobia Chest pain Aseptic meningitis

79% 83% 38% 40% 4% 25% 21% 12% 8% 4% 8% 8% 17% 8% 20% 4% 0% 0% 0% 0.79

SES

•P

Standard Dose (5 mg) (n ~ 25)

~

Low Dose (2 mg) (n ~ 25) 72% 52% 56% 48% 40% 32% 28% 24% 20% 12% 12% 12% 8% 8% 4% 4% 4% 4% 0% 0.84

0.003.

severity of side effects, as measured by the SES, was also found to be not statistically different between study groups (0.79 ± 0.58 standard v 0.84 ± 0.68 low). Because of the prevalence of side effects in both treatment groups we were unable to correlate immunomonitoring parameters or dosage increases to specific side effects. Laboratory Findings

The rate of sensitization to OKT3 was similar for the two study groups at the end of treatment and also at 60 days following the conclusion of therapy (Table 4). Both dosage groups, however, experienced an increased incidence of sensitization at the 30-day measurement compared with the immediate posttreatment values. Development of anti-OKT3 sensitization could not alone explain the need for dosage increase, since less than half the patients requiring a dosage increase (six of 15 patients) developed sensitization. The frequency of sensitization in relation to dosage increase was similar in both groups (three of seven patients in the standard dose group and three of eight patients in the low-dose group) . Clinical Outcomes

$6,868) per low-dose patient. The cost of daily immunomonitoring with two markers, CD2 and CD3, is $250 per day. Based on the average length of therapy, the cost per patient for immunomonitoring was $2,325 for the standard dose group and $2,000 for the low-dose group. Adverse Effects

The occurrence of side effects related to OKT3 administration was not statistically different between study groups, with the sole exception of chills (Table 3). A significant increase in the incidence of chills was associated with treatment in the low-dose group, in which 10 patients experienced chills. Only one patient in the standard dose group experienced chills (P = 0.003). The

Clinical outcomes, including renal function (as reflected by 1-,3-, and 6-month serum creatinine) and renal dysfunction episodes were found to be no different between study groups (Table 5). During the 6-month follow-up period, 19 renal dysfunction episodes occurred in the standard dose group while 24 episodes occurred in the lowdose group. In the standard dose group, these episodes were related to rejection (n = 4), cyclosporine toxicity (n = 5), delayed graft function (n = 4), dehydration (n = 4), and interstitial nephritis (n = 2). Patients in the low-dose group displayed a similar pattern with dysfunctional episodes related to rejection (seven episodes, five patients), cyclosporine toxicity (n = 5), delayed graft function (n = 5), dehydration (n = 4), in-

Table 4. Number of Patients Developing Anti-OKT3 Antibodies According to Dosing Group

Standard Dose (5 mg)

At end of treatment 30 days after treatment

Low Dose (2 mg)

>1:100

>1:500

>1:1,000

>1:100

>1:500

>1:1,000

6 8

2 6

2

4 7

2 6

3

40

ALLOW A Y ET AL

Table 5. Clinical Outcomes Associated With Standard and Low-Dose OKT3 Induction

Outcome

Mean serum creatinine at 1 mo Mean serum creatinine at 3 mo Mean serum creatinine at 6 mo Rejection episodes within 1 mo Rejection episodes between 1 and 6 mo Patients with steroid-resistant rejection Patients experiencing a major infection Patients experiencing a minor infection Graft survival at 1 yr Patient survival at 1 yr

Standard Dose (5 mg) (n = 25)

Low Dose (2 mg) (n = 25)

1.80 1.50 1.48

2.03 1.56 1.62

2

6

2 3

3

9

10

30 21 24

22 22 23

NOTE. No significant differences existed between groups.

terstitial nephritis (n = 1), and urinary obstruction (n = 2). All rejection episodes were treated initially with high-dose steroids. Three patients in each study group were resistant to this therapy and had biopsy-proven rejection. These patients were subsequently treated with either OKT3 (one standard dose patient, two low-dose patients) or ATGAM (two standard dose patients, one lowdose patient). The total number of infectious episodes was also similar for study groups with slightly fewer patients in the low-dose group experiencing an infection (Table 5). The distribution of bacterial and viral infections was similar for both study groups, with bacterial infections responsible for 23 of 30 minor infections in the standard dose group and 20 of 22 infections in the low-dose group. A smaller number of minor infections was the result of viral infections, with seven reported in the standard group and two in the low-dose group. Most of these infections were of urinary tract origin for both study groups (83% in the standard dose group and 77% in the low-dose group). Major infections developed in nine standard dose patients (seven bacterial, two viral) and 10 low-dose patients (eight bacterial, two viral). The only graft loss in the standard dose group was secondary to primary nonfunction in a pa-

tient who experienced a severe postoperative perirenal infection. Multiple biopsies did not reveal evidence of acute rejection, and the kidney was removed 6 months later without ever functioning. Graft losses in the low-dose group were secondary to two patient deaths. One death, due to pulmonary edema, occurred in a patient withdrawn from the study after receiving one dose of OKT3. Despite excellent graft function, this patient developed reactivation of lupus with pneumonitis and cerebritis. The patient died 8 weeks following transplantation. At the 6-month followup, a second death had occurred in the low-dose group in a patient with sepsis who had undergone multiple antirejection treatments. Despite these early differences the i-year patient and graft survival rates were similar in both groups. The standard dose group had 100% patient survival and 84% graft survival at 1 year, while the low-dose group had 96% patient survival and 88% graft survival. DISCUSSION

The results of this randomized, double-blind study confirm the findings of our previous pilot study5 by demonstrating that a lower dose of OKT3 is as effective as a standard dosing regimen for induction of immune suppression. Both dose regimens produced similar outcomes with regard to CD3-positive T lymphocytes, subsequent therapy failures, and the incidence of sensitization with anti-OKT3 antibodies. Similar findings have been reported by Norman et aI, who found that CD3 modulation on the lower doses of OKT3 was similar to that of the higher dose and that doses as low as 1 mg ofOKT3 were able to deplete T cells from the peripheral circulation. 3 Consistent with the similar immunologic outcomes, both dose regimens were also found to have similar clinical results with regard to rejection, graft survival, patient survival, and infectious complications.

Rejection and Infection The total incidence of rejection using low-dose therapy is not different from that using high-dose therapy. However, this current study demonstrated the increased incidence of early rejection in the low-dose group. This is in agreement with the report of Norman et al. 3 The majority of the increase in the incidence of early rejection for the

STANDARD V LOW-DOSE OKT3 INDUCTION

low-dose group in this randomized study can be attributed to one highly sensitized kidney-pancreas recipient who experienced repeated early rejection episodes. However, the success of both regimens in providing rejection prophylaxis is reflected in the good graft function present at 1, 3, and 6 months posttransplant (Table 5). Furthermore, the incidence of rejection episodes beyond the first month is similar for both groups, as is the incidence of steroid-resistant rejection. It remains to be seen if this slight increase in early rejection episodes will be reflected in longer-term graft surviva1. 6 The overall incidence of infections was similar for both groups in this study. The risk for serious infectious complications was apparent mainly in patients requiring repeated anti-rejection treatment in both groups and was most evident by the lethal infection in the one patient who received multiple treatments for recurrent rejection episodes. Dosing Data

The dosing data indicates a statistically significant reduction in the total milligrams of drug used during the treatment course. This difference existed even though the total number of doses administered was similar for both groups. A reduction in OKT3 dosage can have a significant impact on the cost of therapy, which translates into a significant savings in the cost of induction therapy. In this study, however, the cost of daily immunomonitoring diluted the savings afforded by the dose reduction of OKT3. These data support the necessity of immunomonitoring to maintain effective OKT3 therapy regardless of the OKT3 dose. This was evidenced by the equal need for dosage adjustments in both dosage groups. As immunomonitoring becomes an integral part of OKT3 administration, as with monitoring other drugs, the savings will once again be related to the cost of the drug required to achieve the desired therapeutic outcome. In addition to cost savings, lower OKT3 doses may also reduce the risk associated with antilymphocyte immunosuppressant therapy by decreasing the total lifetime dosage exposure, which has been linked to the development of lymphomas. 7 By instituting a low dose regimen, lifetime dosage can be reduced and repeated treatment provided without approaching the threshold

41

dose associated with the development of lymphomas. Dosage increases were required in approximately one third of all patients in both treatment groups due to an elevation in CD3-positive Tlymphocyte levels. Characteristically, the dosage increase occurred toward the end of therapy, resulting in a similar number of dose increases per patient for the two groups. This reappearance of CD3-positive cells seemed to be unrelated to the OKT3 dose being administered. The number of patients requiring dosage adjustment in both arms of the study may be related, at least in part, to the use of extremely sensitive immunologic parameters. The 10 cells per cubic millimeter cutoff value used for dose increases in this study is lower than that commonly used by other centers. Dosage adjustment is often determined by a higher cutoff value of CD3-positive8 ,9 T lymphocytes per cubic millimeter or by measuring the CD3 receptor density of the T lymphocytes. 3 Another cause for the apparent resistance to OKT3 effect during treatment may be related to the development of anti-OKT3 antibodies. 10 Low-titer anti-OKT3 antibodies appeared in a frequency parallel to the need for a dosage increase near the end of the treatment regimen. Significantly, this antibody appearance and the appearance of CD3-positive cells occurred with equal frequency in both treatment arms, indicating that the OKT3 dose was not an important determinant for sensitization. Since the number of increased doses administered to both treatment groups was quite small, it appears that this late anti-OKT3 resistance has not affected the success of therapy and would have probably been unnoticed in other protocols that do not use such exhaustive immunologic monitoring. It is important to emphasize, however, that with two patients in whom CD3 elevations occurred early in therapy, rejection was demonstrated on biopsy, indicating that monitoring is vital for assurance of treatment success. A third important factor influencing the rate of sensitization in this population is the withholding of other immunosuppressants during the OKT3 therapy. It has been shown recently that the concomitant administration of cyc1osporine significantly reduces the risk of anti-OKT3 sensitization. II The withholding of cyc1osporine in our study may have contributed to the observed rate of sensitization.

ALLOWAY ET AL

42

Adverse Effects

OKT3 administration stimulates the production of cytokines, particularly tumor necrosis factor and gamma interferon, which are believed to be primarily responsible for most of the adverse effects associated with OKT3 therapy.12 We attempted to prevent the cytokine release syndrome by administering methylprednisolone in the operating room prior to the first dose of OKT3. In spite of this, three fourths of the patients in both groups developed side effects, especially fever. The SES indicated that, overall, the severity of clinical side effects was similar in both treatment groups. There was, however, a significant difference (P < 0.003) in the incidence of chills between dosage groups, and there was an increased tendency for the development of nausea, vomiting, and diarrhea in the lower-dose group. An explanation for the side effects in the lower-dosage group may be related to the inability of the smaller doses of OKT3 to clear all CD3-positive T lymphocytes following first injection. Thus, subsequent injections continued to produce activation of the remaining nonmodulated T cells and resulted in a more prolonged cytokine release syndrome. Norman et aI, using a different lowdose protocol, found that although lower doses ofOKT3 cleared CD3-positive cells in a manner equivalent to high doses, CD3 antigen density was not completely modulated from the surface of the T cell until 3 to 4 days after therapy.3 With increasing success of other anti-tumor necrosis factor preparations in avoiding OKT3 side effects, these problems appear to be quite surmountable in the near future. 13 The ability to limit OKT3 sensitization is of particular interest since in our experience, 50% to 60% of all rejections are steroid resistant and will therefore require the administration of alternative antirejection treatment. The incidence of high-titer sensitization that would prevent retreatment with OKT3 was also similar in both study groups. This indicates that the use oflowerdose OKT3 also does not prevent the development of high-titer antibodies, thus offering no particular advantage in terms of reduced sensitization and the ability to retreat. As indicated previously, withholding immunosuppressants may have contributed to the high-titer sensitization. The administration of cyclosporine may

result in a significant reduction in the level of anti-OKT3 sensitization. I I CONCLUSION

The data generated by this study demonstrate that low-dose OKT3 can effectively be used in induction immune suppression and that standard and low doses are similar in immunologic and clinical outcomes measured. Because the number of patients studied is small, the data have to be interpreted with caution. However, both dosage regimens were equally successful in eliminating CD3-positive T lymphocytes from the circulation in patients with negative OKT3 antibodies. These data also demonstrate that a systematic approach to therapeutic monitoring of OKT3 be incorporated with the use ofOKT3 at any dosage level. The smaller cumulative dose incurred by using a low-dose induction may reduce the incidence of long-term complications, particularly lymphomas, and may add to cost containment. The success of low-dose OKT3 therapy in this setting may justify a trial of low-dose therapy for the treatment of rejection episodes to further reduce the cumulative dose of the monoclonal antibody. REFERENCES I. Ackerman JR, leFor WM , Kahana L Weinstein S Shires OL: Prophylactic use ofOKT3 in renal t~ansplantation; Part of a prospective randomized multicenter trial. Transplant Proc 20:242-244, 1988 (suppl I) 2. Cohen OJ, Bonvenisty AI, Cianci J, Hardy MA: OKT3 prophylaxis in cadaveric kidney transplant recipients with delayed graft function. Am J Kidney Dis 14:19-27, 1989 (suppI5) 3. Norman DJ, Barry JM, Bennett WM, Munson JL, Meyer M, Henell K, Kimball J, Hubert B: OKT3 for induction immunosuppression in renal transplantation: A comparative study of high versus low doses. Transplant Proc 23: 1052-1054, 1991 4. Goldstein G, Fuccello AJ , Norman OJ: OKT3 monoclonal antibody plasma levels during therapy and subsequent development of host antibodies to OKT3. Transplantation 42:507-511 , 1986 5. Alloway RR, Kotb M, Gaber LW, Vera S, Gaber AO: Standard versus low dose OKT3 induction therapy of cadaveric renal transplants: Comparison of outcome data and serum levels. Clin Transplant 46:468-472, 1992 6. Basadonna G, Matas AJ , Gillingham KJ, Payne WD, Dunn DL, Sutherland DER, Najarian JS: Early versus late rejection. Impact on graft loss to chronic rejection in kidney transplantation. Am Soc Transplant Phys I I th Annual Meeting, Chicago, IL, May 1992, p 193 7. Swinnen LJ, Costanzo-Nordin MR, O'Sullivan EJ, Johnson MR, Heroux AL, Dizikes GJ , Pifarre R , Fisher RI: Increased incidence of Iymphoproliferative disorders after immunosuppression with the monoclonal antibody OKT3 in

STANDARD V LOW-DOSE OKT3 INDUCTION cardiac transplant recipients. N Engl J Med 323(25): 17231728, 1990 8. Schroeder TJ, First MR, Hurtubise PE, Marmer DJ, Martin DM, Mansour ME, Melvin DB: Immunologic monitoring with orthoclone OKT3 therapy. J Heart Transplant 8: 371-380, 1989 9. Gebel HM, Lebeck LK, Jensik SC, Webster K, Bray RA: T cells from patients successfully treated with OKT3. Hum ImmunoI26:123-129, 1989 10. Jaffers GJ , Fuller TC, Cosimi AB, Russell PS, Winn HJ , Colvin RB: Monoclonal antibody therapy: Anti-idiotypic and non-anti-idiotypic antibodies to OKT3 arising despite intense immunosuppression. Transplantation 5:572-578, 1986

43 II . Hricik OE, Mayes JT, Schulak JA: Inhibition or antiOKT3 antibody generation by cyclosporine-Results of a prospective randomized trial. Transplantation 50:237-240, 1990 12. Chatenoud L, Ferran C, Legendre C, Thouard I, Merite S, Reuter A, Gevaert Y, Kreis H, Franchimont P, Bach JF: In vivo cell activation following OKT3 administration. Transplantation 49:697-702, 1990 13. Alegre ML, Gastaldello K, Abramowicz D, Kinnaert P, Vereerstraeten P, De Pauw L, Vandenabeele P, Moser M, Leo 0, Goldman M: Evidence that pentoxifylline reduces antiCD3 monoclonal antibody-induced cytokine release syndrome. Transplantation 52:674-6 79, 199 1