Antithymocyte Globulin Group Research Articles

In vivo T cell depletion with pretransplant anti-thymocyte globulin reduces graft-versus-host disease without increasing relapse in good risk myeloid leukemia patients after stem cell transplantation from matched related donors.

One-hundred and two patients with good risk myeloid leukemia (CML first chronic phase or AML first CR) were transplanted from HLA-related donors after conditioning with (n = 45) or without anti-thymocyte globulin (ATG) (n = 57). One graft failure was observed in the non-ATG and none in the ATG group. The median time to leukocyte engraftment (> 1 x 10(9)/l) was 16 (range 12-33) in the ATG group and 17 days (range 11-29) in the non-ATG group (NS) and for platelet engraftment (> 20 x 10(9)/l) 24 and 19 days (P = 0.002), respectively. Acute GVHD grade II-IV was observed in 47% of the non-ATG and in 20% of the ATG group (P = 0.004). Grade III/IV GVHD occurred in 7% of the ATG and in 32% of the non-ATG group (P = 0.002). Chronic GVHD was seen in 36% and 67% (P = 0.005), respectively. After a median follow-up of 48 months (range 2-128), the 5-year estimated OS is 66% (95% KI: 51-81%) for the ATG group and 59% (95% KI: 46-72%) for the non-ATG group (NS). The 5-year estimated DFS is 64% (95% KI: 50-78%) for ATG and 55% (95% KI: 43-67%) for the non-ATG regimen (NS). The 5-year probability of relapse was 5% in the ATG and 15% in the non-ATG group (NS). ATG as part of the conditioning regimen leads to a significant reduction in GVHD without increase of relapse in patients with myeloid leukemia after stem cell transplantation from HLA-related donors.

ASSOCIATION OF NATURAL KILLER CELL DEPLETION AND INDUCTION OF MIXED CHIMERISM AND ALLOGRAFT TOLERANCE IN NON-HUMAN PRIMATES

58 Introduction: Nonmyeloablative T cell depletion followed by donor bone marrow infusion has proved to be an effective approach to induction of mixed chimerism and tolerance to organ allografts in non-human primates. To help define the conditions required for marrow engraftment, we compared the effects of two different regimens on T-cell depletion and NK cell functions. Method: The non-myeloablative regimen included low dose total body irradiation (1.5GyX2), thymic irradiation (7Gy), anti-T cell antibody, splenectomy and kidney and donor bone marrow transplantation followed by a 4-week post transplant course of cyclosporine. Anti-thymocyte globulin (ATG) was used in 13 monkeys and anti-CD2 monoclonal antibody (Lo-CD2) was used in 10 monkeys for more selective anti-T cell activity. Results: In the ATG group, 12 of 13 monkeys developed multilineage chimerism and 9 monkeys survived more than 100 days without kidney allograft rejection. In contrast, no monkeys in the Lo-CD2 group developed chimerism, 5 died of infection and 5 suffered progressive rejection with only one recipient surviving beyond 100 days (Table 1, *rejection).Table 1In the Lo-CD2 group, despite better T cell (CD3+) depletion, NK cell numbers (CD16+CD3−) were less depressed and NK function quickly recovered by day 5. In contrast, in the ATG group, NK cell numbers were more significantly depleted and NK function remained significantly abrogated for 3 weeks following transplant (Table 2, *p<0.05).Table 2[Conclusion] There appears to be an association between NK function and induction of mixed chimerism and allograft tolerance by the non-myeloablative regimen in MHC mismatched non-human primates.

Dacluzimab is Comparable to Antithymocyte Globulin (ATG) Induction in Preventing Acute Rejection (AR) Episodes in High Risk Renal Transplant Recipients

577 Dacluzimab has been shown to significantly reduce the incidence of AR in primary cadaveric renal transplants as compared to placebo [cyclosporine (CSA) and prednisone, or CSA, prednisone and azathioprine]. Its role in high risk renal transplant recipients has not been evaluated. Prior to the availability of Dacluzimab, we used ATG induction in these patients. Methods: In this pilot study we used variable doses of Dacluzimab (1-5 doses depending upon the status of graft function) in conjunction with CSA or FK 506, mycophenolate mofetil (MMF) and prednisone in 17 high risk renal transplant recipients. The indications for Dacluzimab induction included primary graft dysfunction in 5, post- transplant graft dysfunction in 4, prolonged cold ischemia time (>24 hours) in 4, and retransplants with high panel reactive antibodies (PRA) in 4. One patient had a combined liver kidney transplant. The number of AR episodes, need for OKT3 treatment, patient and graft survival and serum creatinines at 3 months were compared to 16 retrospective controls who received ATG induction along with CSA or FK 506, MMF and prednisone. The indications for ATG included primary graft dysfunction in 13 and post-transplant graft dysfunction in 3. Results: Both groups were comparable for age, sex, race, HLA mismatches, PRA, primary versus retransplants, cadaver versus living related transplants, number of patients receiving CSA or FK 506, dialysis and duration of dialysis. One patient died in each group (pseudomonas sepsis in the Dacluzimab group and myocardial infarction in the ATG group). The remaining patients are alive with functioning grafts. One patient in ATG group developed cytomegalovirus (CMV) infection. Three patients (17.6%) had AR in the Dacluzimab group. Of these, one had acute vascular rejection on day 3 after transplant and required treatment with OKT3. Four patients (25%) had AR in ATG group. None required treatment with OKT3. The number of Dacluzimab doses ranged from 1-5 (1.8 ± 1.3). The number of ATG doses ranged from 2-14 (8.9 ± 3.5). The length of stay in the hospital was longer in Dacluzimab group 12.6 ± 8.1 versus 8.4 ± 2.8. The difference was due to pseudomonas sepsis, pulmonary hemorrhage, and liver transplant related complications in three patients respectively. Serum creatinines at 3 months were comparable (1.9 ± 1.4 in Dacluzimab group versus 1.7 ± 1.7 in ATG group). The long term data is not yet available. Conclusions: 1) In this pilot study we show that Dacluzimab induction is comparable to ATG in high risk renal transplant recipients in preventing AR. 2) Patient and graft survival, incidence of CMV infections and serum creatinine at 3 months are comparable in both groups. 3) Since the cost of ATG per dose is equivalent to Dacluzimab dose, it is cost effective to use Dacluzimab (2 doses versus 9 doses of ATG). 4) Dacluzimab is also more convenient to administer avoiding a central line essential for ATG. These results need to be validated in a larger multicenter trial.

Randomized comparison of triple therapy and antithymocyte globulin induction treatment after simultaneous pancreas-kidney transplantation

The incidence of acute rejection is considered to be higher after simultaneous pancreas-kidney (SPK) transplantation as compared to renal transplant alone. Therefore, the majority of SPK transplant recipients commonly receive a combination of cyclosporine (CsA) or tracolimus, and azathioprine or mycophenolic mofetyl, corticosteroids and/or antilymphocyte preparations. This study was designed to compare two immunosuppressive protocols for the prevention of acute rejection in patients undergoing SPK transplantation. The primary end-point was the incidence of acute rejection during the first 12 months after transplantation Fifty patients with type-I insulin-dependent diabetes and chronic renal failure were randomized to receive a triple drug immunosuppressive regimen including CsA, azathioprine and corticosteroids (N = 25), or the quadruple sequential combination of rabbit antithymocyte globulin (ATG) given for 10 days, azathioprine, corticosteroids and delayed CsA (N = 25). Maintenance immunosuppression (CsA and azathioprine, without corticosteroids) was similar in both arms. The average follow-up was 36 months in both groups (range 9 to 60 months). No patient was excluded from the study. Although the percentage of patients with adverse events was higher in the ATG group (80 vs. 40%, P < 0.01), none of them resulted in premature discontinuation of the drug. Patients receiving ATG experienced a lower incidence (36% vs. 76%, P < 0.01) and number (13 vs. 29, P < 0.05) of acute renal rejection episodes. However, no difference was observed in patient, pancreas and kidney survival rates between groups. No case of isolated pancreas rejection was observed. The quadruple sequential combination ATG, azathioprine, corticosteroid and CsA significantly reduced the one year incidence of acute renal rejection after SPK transplantation, compared to a triple immunosuppressive regimen.

An increased HLA DR2 frequency is seen in aplastic anemia patients

The underlying etiology of aplastic anemia is unknown in the majority of patients, although medications, chemical exposure, or viral infections can be implicated in some. Genetic susceptibility to a variety of diseases has been shown and it has recently been suggested that aplastic anemia is more common in individuals who are HLA DR2+ than in the general population. To examine this question, we retrospectively analyzed the results of HLA-DR typing in 75 aplastic anemia patients who received antithymocyte globulin (ATG) therapy or an HLA-matched sibling bone marrow transplant at UCLA between 1978 and 1989. Thirty-one patients were DR2+, a 1.9-fold higher incidence than the expected number of 16.6 patients (P &lt;.0005). Of the 37 patients who received ATG, 33 were evaluable for a response; 14 patients had either a complete (4 patients) or partial (10 patients) response, for an overall response rate of 42.4%. Of the 14 DR2+ patients who received ATG, 7 responded, for a 50% response rate, which is not significantly higher than the response rate for the DR2- patients (7 of 19 [36.8%]; P = .50). The median survival of patients who are DR2+ was slightly, but not significantly, longer than that of the DR2- patients in the ATG group (P = .19). Although the incidence of HLA DR2 was clearly increased in these patients with aplastic anemia, response rates to ATG were not significantly different in the DR2+ and DR2- patients.

An Increased HLA DR2 Frequency Is Seen in Aplastic Anemia Patients

The underlying etiology of aplastic anemia is unknown in the majority of patients, although medications, chemical exposure, or viral infections can be implicated in some. Genetic susceptibility to a variety of diseases has been shown and it has recently been suggested that aplastic anemia is more common in individuals who are HLA DR2+ than in the general population. To examine this question, we retrospectively analyzed the results of HLA-DR typing in 75 aplastic anemia patients who received antithymocyte globulin (ATG) therapy or an HLA-matched sibling bone marrow transplant at UCLA between 1978 and 1989. Thirty-one patients were DR2+, a 1.9-fold higher incidence than the expected number of 16.6 patients (P < .0005). Of the 37 patients who received ATG, 33 were evaluable for a response; 14 patients had either a complete (4 patients) or partial (10 patients) response, for an overall response rate of 42.4%. Of the 14 DR2+ patients who received ATG, 7 responded, for a 50% response rate, which is not significantly higher than the response rate for the DR2- patients (7 of 19 [36.8%]; P = .50). The median survival of patients who are DR2+ was slightly, but not significantly, longer than that of the DR2- patients in the ATG group (P = .19). Although the incidence of HLA DR2 was clearly increased in these patients with aplastic anemia, response rates to ATG were not significantly different in the DR2+ and DR2- patients.

Acute rejection of lung allografts with various immunosuppressive protocols

Between February 1990 and December 1991, 69 patients who survived for a minimum of 5 days after single-lung (27), double-lung (32), or heart-lung transplantation (10) were studied to learn the incidence and severity of acute rejection and the possible effects of various immunosuppressive protocols on this rejection. Acute rejection was less common (2.1 versus 3.1 episodes/patient) after transplantation in those 30 candidates who received rabbit antithymocyte globulin for the first 5 postoperative days versus the 28 who were maintained on cyclosporine, azathioprine, and prednisone alone ( p < 0.05), but no patient escaped at least one episode. Patients given cyclosporine received more 3-day courses of methylprednisolone ( p < 0.02) than those given rabbit antithymocyte globulin (2.5 versus 1.7 courses). Although no disadvantage in terms of infectious morbidity was noted in the rabbit antithymocyte globulin group, no obvious intermediate advantage was noted in survival (85% at 12 months) or grade of rejection or airway flows. The most common histopathologic grades were mild (A2) and moderate (A3); the average grade was A2.3. FK 506 was tested in 11 patients, and early results are promising relative to low early and likely fewer late episodes of rejection. No differences were noted in the likelihood of rejection for any procedures.

Multicenter Randomized Study Comparing Cyclosporine-A Alone and Antithymocyte Globulin With Prednisone for Treatment of Severe Aplastic Anemia

Abstract We report the results of a randomized multicenter study comparing the efficacy of antithymocyte globulin (ATG) with that of cyclosporin A (CsA) as first-line therapy for severe aplastic anemia (SAA). Patients were randomized to receive ATG and prednisone (PDN) or CsA; hematologic response and toxicity were compared. At 3-month evaluation, patients who had no or minimal response received the alternative therapy to assess the value of a sequential immunosuppressive therapy for treatment of severe aplastic anemia. One hundred nineteen patients were randomized; 25 were excluded, of whom 3 were misdiagnosed and 22 did not follow the cross-over protocol. Ninety-four patients were analyzed; 46 received CsA, and 48 received ATG-PDN. The actuarial survival was 66.7%, with a median follow-up time of 19 months. There was no significant difference in survival between the groups with, at 3 months, an actuarial survival of 88% in the CsA group and 75% in the ATG group (NS); at 12 months, it was 70% in the CsA group and 64% in the ATG group (NS). The percentage of complete and partial response was 11.6% and 16%, respectively, at 3 months, and 31.6% and 30%, respectively, at 12 months (NS). The main prognostic factor was the absolute neutrophil count (ANC) at entry: Patients with ANC less than 0.2 x 10(9)/L had a significantly lower survival as compared with patients with more than 0.2 x 10(9)/L ANC (P = .0001). At 12 months, 62 evaluable patients were alive, with a complete or partial response in 36 patients. Patients who had responded to the first treatment had a better recovery of bone marrow failure than those who had sequential immunosuppression. The main complication was infection, which was more often observed and more often lethal during ATG and PDN therapy. In this study, initial treatment of SAA with either CsA or ATG-PDN followed by cross-over therapy for nonresponders produced comparable response and survival rates.

Multicenter randomized study comparing cyclosporine-A alone and antithymocyte globulin with prednisone for treatment of severe aplastic anemia

We report the results of a randomized multicenter study comparing the efficacy of antithymocyte globulin (ATG) with that of cyclosporin A (CsA) as first-line therapy for severe aplastic anemia (SAA). Patients were randomized to receive ATG and prednisone (PDN) or CsA; hematologic response and toxicity were compared. At 3-month evaluation, patients who had no or minimal response received the alternative therapy to assess the value of a sequential immunosuppressive therapy for treatment of severe aplastic anemia. One hundred nineteen patients were randomized; 25 were excluded, of whom 3 were misdiagnosed and 22 did not follow the cross-over protocol. Ninety-four patients were analyzed; 46 received CsA, and 48 received ATG-PDN. The actuarial survival was 66.7%, with a median follow-up time of 19 months. There was no significant difference in survival between the groups with, at 3 months, an actuarial survival of 88% in the CsA group and 75% in the ATG group (NS); at 12 months, it was 70% in the CsA group and 64% in the ATG group (NS). The percentage of complete and partial response was 11.6% and 16%, respectively, at 3 months, and 31.6% and 30%, respectively, at 12 months (NS). The main prognostic factor was the absolute neutrophil count (ANC) at entry: Patients with ANC less than 0.2 x 10(9)/L had a significantly lower survival as compared with patients with more than 0.2 x 10(9)/L ANC (P = .0001). At 12 months, 62 evaluable patients were alive, with a complete or partial response in 36 patients. Patients who had responded to the first treatment had a better recovery of bone marrow failure than those who had sequential immunosuppression. The main complication was infection, which was more often observed and more often lethal during ATG and PDN therapy. In this study, initial treatment of SAA with either CsA or ATG-PDN followed by cross-over therapy for nonresponders produced comparable response and survival rates.

Prophylactic therapy for rejection after cardiac transplantation: A comparison of rabbit antithymocyte globulin and OKT3

The value of prophylactic monoclonal or polyclonal antibody therapy early after cardiac transplantation is controversial. Between Jan. 1, 1987, and July 1, 1988, 32 consecutive patients underwent cardiac transplantation (cyclosporine, azathioprine, and prednisone maintenance therapy) with either early prophylactic rabbit antithymocyte globulin (n = 17) or monoclonal OKT3 (Ortho Diagnostic Systems, Inc., Raritan, N.J.) (10 days) (n = 15). Follow-up was through Sept. 1, 1988, for morbid events and through Jan. 1, 1989, for survival. All patients (100%) survived the study period (follow-up of 6 to 24 months). The efficacy of rabbit antithymocyte globulin and OKT3 prophylaxis was similar regarding median time (days) to first rejection (16 versus 21 days, p = 0.5), number of rejection episodes during first 2 months (1.5 versus 1.3 days, p = 0.8), and freedom from rejection at 2 months (18% versus 27%, p = 0.8). Early infections were slightly less common in the rabbit antithymocyte globulin group than the OKT3 group (median time to first infection: 318 versus 250 days, p = 0.5; freedom from rejection at 2 months: 82% versus 64%, p = 0.21), although differences were likely due to chance. Cytomegalovirus syndrome was common, with one case of cytomegalovirus pneumonia. T-cell markers during OKT3 treatment did not predict subsequent rejection (within 2 weeks after OKT3) as assessed by mean T3-lymphocyte count during OKT3 use (p = 0.3) or T3-lymphocyte count during the last 3 days of OKT3 use (p = 0.4). Inferences: (1) Prophylactic rabbit antithymocyte globulin or OKT3 with triple-drug immunosuppression yields excellent intermediate survival after heart transplantation. (2) These protocols for rabbit antithymocyte globulin and OKT3 provide similar protection against early rejection with a relatively low risk of early infection. (3) T-cell markers do not predict early rejection after OKT3.

Do androgens enhance the response to antithymocyte globulin in patients with aplastic anemia? A prospective randomized trial

We analyzed the effect of antithymocyte globulin (ATG) with or without androgens in 121 patients with aplastic anemia. Fifty-three patients with moderate to severe aplastic anemia were prospectively randomized to receive ATG with or without oral androgens. Eleven of 26 patients (42%) receiving ATG plus androgen responded, including three complete and eight partial responses. Twelve of 27 patients (44%) receiving ATG plus placebo responded, including five complete and seven partial responses. The difference in response rates was not significant (P greater than .9). Survival was also comparable in the two groups; for patients with severe aplastic anemia, actuarial survival at two years was 55% +/- 24% (95% confidence interval) in patients receiving ATG plus androgen compared with 50% +/- 24% in the ATG plus placebo group (P = .65). Furthermore, results in both groups were indistinguishable from those obtained in 68 historical controls receiving ATG without androgens. These data indicate that androgens are not required in order to respond to antithymocyte globulin and the addition of androgens, as used in this trial, did not significantly improve response rates to ATG treatment.

Do Androgens Enhance the Response to Antithymocyte Globulin in Patients With Aplastic Anemia? A Prospective Randomized Trial

We analyzed the effect of antithymocyte globulin (ATG) with or without androgens in 121 patients with aplastic anemia. Fifty-three patients with moderate to severe aplastic anemia were prospectively randomized to receive ATG with or without oral androgens. Eleven of 26 patients (42%) receiving ATG plus androgen responded, including three complete and eight partial responses. Twelve of 27 patients (44%) receiving ATG plus placebo responded, including five complete and seven partial responses. The difference in response rates was not significant (P greater than .9). Survival was also comparable in the two groups; for patients with severe aplastic anemia, actuarial survival at two years was 55% +/- 24% (95% confidence interval) in patients receiving ATG plus androgen compared with 50% +/- 24% in the ATG plus placebo group (P = .65). Furthermore, results in both groups were indistinguishable from those obtained in 68 historical controls receiving ATG without androgens. These data indicate that androgens are not required in order to respond to antithymocyte globulin and the addition of androgens, as used in this trial, did not significantly improve response rates to ATG treatment.