Induction immunotherapy in pediatric heart transplant recipients: a multicenter study

Induction immunotherapy in pediatric heart transplant recipients: a multicenter study

PEDIATRICS Induction Immunotherapy in Pediatric Heart Transplant Recipients: A Multicenter Study Robert J. Boucek, Jr., MD,a David Naftel, PhD,b Mark...

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PEDIATRICS

Induction Immunotherapy in Pediatric Heart Transplant Recipients: A Multicenter Study Robert J. Boucek, Jr., MD,a David Naftel, PhD,b Mark M. Boucek, MD,c Richard Chinnock, MD,d Robert W. Morrow, MD,e Elfriede Pahl, MD,f Sharon DiSano, RN,g and the Pediatric Heart Transplant Study Group Background: The efficacy and safety of induction immunotherapy with antithymocyte antibody preparations (IND) in pediatric heart transplantation is controversial. Experimentally, recipient age is an important determinant of immune responses. The effects on induction immunotherapy were determined by an analysis of outcomes of 465 pediatric (age , 18 years) heart recipients that either did or did not receive IND in the first week post-transplant. Methods: The outcomes of 2 groups who received either OKT3 (n 5 101) or rabbit polyclonal antithymocyte serum (N/R-ATS, n 5 105) were compared with 255 recipients who did not receive antithymocyte antibodies. The study population were all heart recipients enrolled in the Pediatric Heart Transplant Study Group (PHTS) between January 1993 and December 1995 and followed up to 36 months. Results: Overall mortality and death due to rejection were lowest with N/R-ATS IND (8/105 and 1/105, respectively) compared with the no-induction group (58/255 and 8/ 255, respectively) or the OKT3 group (22/101 and 7/101, respectively) with significance of p 5 0.001 and 0.06 respectively. Late mortality beyond 30 days after transplant was lowest with N/R-ATS IND compared with the OKT3 and no IND (p 5 0.01). Induction did not affect cumulative infections, deaths due to infection, or the frequency of malignancies. Patients excluded from N/R-ATS induction had the highest mortality (18/ 43), suggesting that the protocol’s exclusion criteria identified a high-risk group. To minimize potential effect(s) of exclusion bias, patients transplanted at centers participating in the N/R-ATS induction trial were reanalyzed with a post hoc intent-totreat analysis assigning patients by center (IND or no IND) irrespective of actual treatment. With this analysis overall mortality was 18% for N/R-ATS centers, 21% for OKT3 centers, and 26% for centers not using IND (p 5 0.3). The mortalities of recipients , 6 months old at transplant were lowest at centers using N/R-ATS and OKT3 IND compared to centers not using IND (p 5 0.04). Cumulative rejection (0.8 vs 1.2 rejection/pt/year, p 5 0.01) and freedom from rejection death (99% vs 93% at From the University of South Florida/All Children’s Hospital, St. Petersburg, Florida;a University of Alabama, Birmingham, Alabama;b University of Colorado/The Children’s Hospital, Denver, Colorado;c Loma Linda University Medical Center, Loma Linda, California;d University of Arkansas/Arkansas Children’s Hospital, Little Rock, Arkansas;e Children’s Memorial Hospital, Chicago, Illinois;f and All Children’s Hospital, St. Petersburg, Floridaa,g Corresponding author: Robert J. Boucek, Jr., MD, Professor of Pediatrics, Cardiology, Director, Pediatric Heart Transplant

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Program, University of South Florida/All Children’s Hospital, 880 Sixth Street South, Suite 260, St. Petersburg, Florida 33701-4827. Telephone: 813-892-8984. Fax: 813-897-4803. Email: [email protected] Submitted June 30, 1998; accepted Dec. 7, 1998. Copyright © 1999 by the International Society for Heart and Lung Transplantation. 1053-2498/99/$–see front matter PII S1053-2498(98)00076-X

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year 1, p 5 0.02) of the N/R-ATS centers were lower compared to OKT3 centers but were not different from centers not using IND. Conclusion: Following orthotopic transplantation, induction immunotherapy can exert the enduring benefit of reducing late deaths, a possible surrogate for rejection severity, in recipients less than 6 months of age, while not being associated with higher rates of infectious or malignant complications. Since polyclonal anti-T cell antibody preparations appears superior to OKT3 induction in pediatric recipients, the efficacy of ATS induction should be further evaluated in a randomized prospective study in pediatric heart recipients. J Heart Lung Transplant 1999;18:460–469.

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ediatric heart transplantation is an effective therapeutic modality for children with end-stage or inoperable cardiac disease.1,2 Acute rejection can lead to graft dysfunction, graft failure, and death.3,4 As many as one-quarter of the pediatric transplant recipients will have acute rejection that is either recurrent or does not resolve despite standard immunosuppressive agents. Thus, reducing the overall incidence and/or severity of rejection remains an important therapeutic goal in pediatric cardiac transplant recipients. One strategy to reduce the incidence and/or severity of rejection is induction therapy. Prophylactic use of cytolytic antibodies in the immediate posttransplant period has been effective in animal models.5 Clinical trials in adult cardiac transplant recipients have been reported with prophylactic administration of polyclonal antithymocyte preparations such as N/R-ATS, ATGAM, antilymphocyte globulin (ALG), and monoclonal antithymocyte preparations such as OKT3. The effects observed have been mainly to delay the onset of rejection6,7 without demonstrating any enduring benefit. The efficacy of induction immunotherapy in pediatric heart transplantation has not been resolved. Preliminary reports have suggested that induction

immunotherapy with N/R-ATS reduced the rate of rejection8-10 and overall mortality in recipients, the majority of which were less than 6 years old.11 Induction immunotherapy with OKT3, however, did not appear to affect the rate of rejection in older pediatric heart recipients.12 These observations suggest that recipient age can affect the efficacy of induction immunotherapy. In the initial experimental animal models in which induction immunotherapy had achieved tolerance, the recipients were developmentally immature.13 Immaturity of the immune system is not an intrinsic property of the newborn immune system, but the immature nature of the antigen presenting cells can determine whether the outcome of antigen exposure is tolerance or immune response.14 Recent analyses of rejection from PHTS preliminarily indicated that age at transplant less than 6 months reduced posttransplant mortality from rejection.15 To date, the interaction of recipient age on induction immunotherapy in man has not been reported. The primary aim of this study was to determine if anti-T cell induction immunotherapy in infants and children had an effect on patient and graft survival, and the frequency and severity of rejection. Corollary aims were to determine the effect of recipient age on the efficacy of anti-T cell induction therapy,

TABLE I Patient profiles grouped by induction treatment status Induction therapy

TABLE II Mortality of recipients by induction Patients Centers

Age (yrs) at Tx mean 6 SD

ATS OKT3 ATGam None (ATS center)* None (non-ATS center)

105 101 4 43 212

4 9 3 4 14

3.3 6 4.9 7.6 6 6.7 2.5 6 4.7 1.7 6 3.8 6.3 6 6.3

Total

465

21

5.5 6 6.3

p , .0001 *Excluded per protocol.

treatment status Deaths Induction therapy

n

No.

%

ATS OKT3 None (ATS center) None (non-ATS center)

105 101 43 212

8 22 18 54

8% 22% 42% 25%

Total

461

102

22%

p , .0001

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FIGURE 1 The effects of induction immunotherapy on overall survival (%) are presented

as a Kaplan-Meier actuarial with log-rank testing. The 2 groups were identified as receiving either N/R-ATS (ATS) or OKT3 induction immunotherapy. Two groups were identified as not receiving induction immunotherapy based on whether the patients were or were not at a center where N/R-ATS induction was also used. The number of patients in each of the 4 groups is shown in parentheses.

and to compare the safety and efficacy of OKT3 and N/R-ATS. The results were preliminarily reported.11

apy. Induction immunotherapy was defined as cytolytic therapy given in the immediate post-transplant period in the absence of rejection. Three cytolytic therapies were used: N/R-ATS (Applied Medical Research, Nashville, TN), OKT3 (Ortho Biotech, Raritan, NJ), and ATGAM (Upjohn, Kalamazoo, MI). The outcomes of 2 of the induction therapies used, N/R-ATS (n 5 105) and OKT3 (n 5 101) were retrospectively reviewed and compared with 255

METHODS A total of 465 recipients of orthotopic cardiac transplants under the age of 18 years of age were enrolled and followed in the PHTS between January 1, 1993 and December 31, 1995. Of these, 210 pediatric patients received induction immunother-

TABLE III Cause of death by induction treatment status Induction therapy ATS

None

OKT3

ATS center

non-ATS center

Cause of death

N

n

% of 8

n

% of 22

n

% of 18

n

% of 54

Early graft failure Rejection Infection Sudden Non-specific graft failure CAD Other

27 19 20 12 6 3 15

2 1 3 1 0 0 1

25% 12% 38% 12% — — 12%

2 6 6 3 1 0 4

9% 27% 27% 14% 5% — 18%

8 3 3 1 1 0 2

44% 17% 17% 6% 6% — 11%

15 8 8 7 4 3 9

28% 15% 15% 13% 7% 6% 17%

102

8

100%

22

100%

18

100%

54

100%

Total

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pediatric recipients who did not receive induction therapy (Table I). Only 4 recipients were given ATGAM IND, and this group was not considered in the analysis because of the small number of patients. All patients received immunosuppression regimens with anti-inflammatory corticosteroids, calcinurin inhibitor (cyclosporine A, Sandimmune), and antiproliferative therapy (azathioprine) at the discretion of each recipient’s physician. N/R-ATS was administered at a dose of 0.5 mL/kg intravenously daily for a total of 5 consecutive days. Forty-three of the 252 pediatric recipients did not receive induction at institutions participating in a phase 1 trial of N/R-ATS. Ten recipients were excluded based on study exclusion criteria: positive skin test (n 5 1), active infection at the time for induction (n 5 4), or open sternotomy (n 5 5). Eight patients died prior to receipt of the first dose. The remainder of the 43 were not given N/R-ATS, either because the drug was not available in the pharmacy at the time of induction (n 5 6) or because informed consent was not obtained or it was refused (n 5 20). Because of the potential for selection bias, the results of all 43 patients were considered separately. In addition, selected analyses were performed as intent to treat, combining patients receiving, and excluded from, induction therapies.

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Statistical Analysis The data was initially examined with simple contingency tables, chi-square tests for comparing proportions, t tests, and cumulative frequency distributions. The Nelson method for estimating cumulative events in the presence of censoring was used for rejection episodes. Kaplan-Meier actuarial techniques were combined with the log-rank test for analysis of death.

RESULTS The mean follow-up time of all survivors was 17 months (range, 1 to 36 months). The age at transplant was different between the 4 groups (p , 0.0001; Table I). There was a small difference in the duration of follow-up among survivors. The durations of follow-up were: 17.7 6 1 month in the group that received N/R-ATS induction, 14.2 6 2.3 months for the group that did not receive induction at N/R-ATS centers, 19.4 6 1.18 months for the group that received OKT3 induction, and 15.6 6 0.85 months for the group that did not receive induction (p 5 0.03).

Survival Overall survival of the 4 groups was significantly different (p , 0.0001, see Table II, chi-square test) with the highest survival in the group receiving

FIGURE 2 The effects of induction immunotherapy on overall survival (%) of patients in the 4 groups who survived at least 30 days are presented as a Kaplan-Meier actuarial with log-rank testing.

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FIGURE 3 The effects of induction immunotherapy on rejection mortality (% free from

rejection death) are presented as a Kaplan-Meier actuarial. The number of patients whose death was directly attributed to rejection and the patient number for each of the 4 groups are shown in parentheses. Log-rank testing was performed for all 4 groups, designated as overall, and for ATS vs other groups.

N/R-ATS induction therapy. Of the 102 (102/465) pediatric patients who died, only 8 of 105 (8%) patients receiving N/R-ATS induction died compared with 54 of 212 (25%) patients who did not receive induction (Table II). Induction with OKT3 did not improve overall survival compared with patients at institutions who did not routinely use induction (Table II). At those institutions where induction therapy was administered, the group that

TABLE IV Number of recipients rejection free by

was excluded and did not receive induction had the highest mortality. Eighteen of the 43 patients excluded from receipt of N/R-ATS per protocol died, a 42 % mortality (Table II), and 1 of 4 patients excluded from OKT3 died, a 25% mortality. When survival rates were estimated over the follow-up period by actuarial survival analysis (Figure 1), N/R-ATS induction had the highest survival compared to the other groups. Multivariate analysis confirmed that no N/R-ATS induction both at N/RATS centers (p 5 0.004) and at all other centers

induction treatment status Patients with at least one rejection episode

TABLE V Number of malignancies by induction treatment status Malignancies

Induction therapy

n

No.

%

Induction therapy

n

No.

%

ATS OKT3 None (ATS center) None (non-ATS center)

105 101 43 212

66 64 26 118

63% 63% 60% 56%

ATS OKT3 None (ATS center) None (non-ATS center)

105 101 43 212

2 3 0 5

2% 3% 0% 2%

Total

461

274

59%

Total

461

10

2%

p 5 .5

p 5 .7

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FIGURE 4 The effect of induction immunotherapy on the number of rejection episodes

per patient are presented for the 4 groups. Log-rank testing was performed comparing ATS vs other groups.

(p 5 0.003) are early risk factors of death after transplant. Previous surgical intervention was a constant risk factor for death after transplant. The timing of the deaths was analyzed for the 4 groups. The largest number of deaths were attributed to early graft failure (27/102) not related to rejection or infection (Table III). In the group excluded from N/R-ATS, mortality was largely early, with 12 of the 18 deaths in the first 30 days posttransplant and 10 in the first 24 hours post-transplant, as might be anticipated by the exclusion criteria. The early mortalities of the other groups were not different. Induction immunotherapy did affect the outcome of recipients who survived greater than 30 days. Mortality rates for recipients who survived greater than 30 days were as follows: 4 of 96 recipients (; 4%) who received N/R-ATS induction died; 13 of 89 recipients (; 15%) who received OKT3 died; and 49 of 175 recipients (; 28%) who did not receive induction at non-ATS centers died; 6 of 31 recipients who did not receive induction at the ATS centers died (p 5 0.01; Figure 2). Causes of death other than early graft failure that were identified in this study were rejection (n 5 19), infection (n 5 20), non-specific graft failure (n 5 6), sudden (n 5 12), and coronary artery disease (n 5

3). Only 16 deaths could not be classified into these groups.

Rejection A total of 483 rejection episodes— defined as intensified immunosuppression associated with diagnostic biopsy (334, ; 70%) and/or echocardiogram (124, ; 26%)—were diagnosed in 277 pediatric patients. Death due to rejection was low but was less for the group receiving N/R-ATS (1/105) compared to the other groups (p 5 0.05) when analyzed by freedom from death due to rejection (Figure 3). The mortality of rejection (rejection deaths/number of rejection episodes) was the highest in the group receiving OKT3 (6/123; Table V) and lowest in the group receiving N/R-ATS (1/114). The group excluded from N/R-ATS had 3 deaths due to rejection (17% of deaths in this group) and the highest mortality from rejection (6 rejection deaths per rejection episode, Table III). The mortality of rejection in the other groups were not different (Table III). Freedom from rejection death with intent-totreat analysis was significantly less for N/R-ATS than OKT3 induction (99% vs 93% at year 1; p 5 0.02). Induction therapy did not appear to affect the incidence and frequency of rejection when com-

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pared with no induction. The number of recipients free from rejection was not different between the groups (Table IV). In an analysis that censors for death, the cumulative number of rejection episodes for the 4 patient groups was not different (Figure 4). However, when compared with OKT3, N/R-ATS did reduce rejection frequency (0.8 vs 1.2 rejection/ pt/year, p 5 0.01, intent-to-treat analysis).

Infection A total of 439 episodes of infection— defined as life threatening and/or requiring IV therapy—were diagnosed and reported. Induction therapy did not affect the incidence or frequency of infections. Cumulative infection rates at 24 months were not different, 1.2 and 1.5 for N/R-ATS and OKT3 induction groups, respectively, and 1.4 and 1.1 for groups not receiving induction at N/R-ATS and other institutions, respectively. Overall mortality due to infection and cumulative infection frequency was not significantly increased by induction therapy (Figure 5). CMV infection were not different (p 5 0.23) between induction and no induction groups with CMV infections reported in 21 of 206 recipients receiving induction and 24 of 255 recipients not receiving induction.

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Malignancy A total of 10 malignancies were reported over the follow-up period with no significant differences between the 4 groups (Table V). In specific, induction immunotherapy did not increase the frequency of malignancies over the interval of follow-up. However, both the short duration of follow-up and the small number of malignancies limit the power of the comparison.

DISCUSSION This study has shown that pediatric cardiac recipients who received induction immunotherapy with N/R-ATS had significantly lower mortality compared to recipients who did not receive any induction protocol (Figure 1). The effect of N/R-ATS induction appeared to be enduring, as N/R-ATS induction reduced “late” deaths (Figure 2, survival . 30 days). This study suggests that N/R-ATS and OKT3 induction were not comparable. Induction protocols using OKT3 did not improve survival compared to the patient group who receive N/RATS induction (Figure 1). With an intent-to-treat analysis, freedom from rejection and death from rejection were significantly less for N/R-ATS than OKT3 induction.

FIGURE 5 The effects of induction immunotherapy on infection mortality (% free from infection death) are presented as a Kaplan-Meier actuarial. Log-rank testing was performed comparing all 4 groups, designated as overall, and ATS vs other groups.

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FIGURE 6 The effects of induction immunotherapy on overall mortality (% survival) are

presented as a Kaplan-Meier actuarial. Patients transplanted at centers participating in the N/R-ATS induction trial were analyzed with a post hoc intent-to-treat analysis assigning patients by center irrespective of actual treatment. Patients (n 5 148) from centers using N/R-ATS were assigned to the ATS group. Patients (n 5 107) from centers using OKT3 were assigned to the OKT3 group. Patients from institutions not using either N/R-ATS or OKT3 induction were assigned to the group designated in this figure as none. Log-rank testing was performed for all 4 groups.

The mechanism for the apparent reduction in mortality with induction therapy (Figure 1) is not known, but one possible mechanism is immunomodulation, as there is a reduction in mortality due to rejection (p 5 0.06; Figure 3). Both monoclonal and polyclonal anti-T cell antibodies result in immediate lymphocytopenia and can have long-term immunomodulatory effects.5 Recently, CD4 T cell numbers have been reported to be reduced for up to 60 months following polyclonal anti-T cell antibody administration to renal recipients (adult).16 These long-lasting (3-year) immunomodulatory effects could be related to the development of “tolerance.” That cumulative rejection (Figure 4) and the number of recipients who were rejection free (Table IV) were not different raises questions about an enduring immunologic benefit of induction immunotherapy in this study. The most immature recipients—those less than 6 month of age— had the largest mortality difference between induction (24 deaths in 121 infants, 19%) and no induction (19 deaths in 52 infants, 37%). Induction immunotherapy reduced overall mortality

for recipients under 6 months old (p 5 0.04, Figure 7). In preliminary phase 1 and 2 trials in pediatric cardiac recipients, N/R-ATS induction immunotherapy appears to be efficacious. In a randomized, placebo-controlled trial with pediatric heart recipients (n 5 59), N/R-ATS, when used in an induction protocol, decreased overall rejection frequency by ; 50% (1.72 vs 0.85 rejection episodes/pt in year 1).8,12 N/R-ATS significantly decreased the number of patients with at least 1 episode of rejection from 68% (17/25) in the placebo group to only 38% (13/34).8,12 The monoclonal anti-T cell antibody OKT3 appears to have little enduring benefit and possibly unacceptable risks when used for induction in pediatric12 and adult cardiac transplant recipients.17 Polyclonal anti-T cell antibodies such as N/R-ATS have been reported to be either no different than,6 or superior to,18 OKT3 for induction-prophylactic immunotherapy in adult cardiac transplant. Differences in the immunomodulatory effects of monoclonal OKT3, which is a potent T-cell activator, and polyclonal anti-T cell antibodies, which also contain

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“blocking” antibodies such as anti-CD4, may account for these differences.5 This study did not identify a significant increase in either infectious (Figure 5) or malignant (Table IV) complications of induction immunotherapy in pediatric heart recipients. This study does forward new evidence that polyclonal anti-T cell antibody preparations may be superior to OKT3 induction in pediatric recipients in reducing rejection frequency.

Limitations of the Study The power of the multicenter design used in this analysis must be balanced with its limitations. In specific, the maintenance immunosuppression and the treatment of rejection episodes were not standardized between participating institutions. Since induction tended to be an institutional decision, some of the observed differences between induction and no induction may be attributed to institutional differences (Figure 6). Initial analysis of the data indicated that highest mortality (; 42%) following cardiac transplantation was in recipients who were excluded from participating in N/R-ATS or OKT3 trials (Figure 1).

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Because this group’s mortality was so different, a possible interpretation of results shown in Figure 1 is that the N/R-ATS protocol’s exclusion criteria introduced an inadvertent exclusion bias. This interpretation is supported by the post hoc center-based intent-to-treat analysis of mortality which was not significantly affected by induction (Figure 6). However, late mortality also was reduced by induction (Figure 2) and it would be more difficult to “select” for late mortality. Furthermore, approximately half of the group of 43 infants who did not receive induction would not be considered at high risk and would not a priori contribute to selection bias favoring N/R-ATS induction. Thus, while this post hoc center-based intent-to-treat analysis reduces the likelihood of a type 1 error, it can increase the likelihood of a type 2 error and magnify center differences. Despite these limitations, we believe that from these analyses a prospective randomized trial of induction immunotherapy with polyclonal anti-T cell antibodies vs placebo is justified in children. In addition, a direction identified for future study is the hypothesis that immunologic immaturity is a clini-

FIGURE 7 The effects of induction immunotherapy on overall mortality (% survival) for

recipients that are less than 6 months at the time of transplant are presented in a KaplanMeier actuarial format. The number of patients whose death was directly attributed to rejection and the patient number for each of the 4 groups are shown in parentheses. Patients transplanted at centers in the N/R-ATS induction trial (n 5 89) and in centers using OKT3 induction (n 5 32) were compared with centers not using induction (n 5 52).

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cally significant determinant of efficacy of polyclonal anti-T cell induction protocol. The authors express their sincere appreciation for the efforts of all of the transplant coordinators at the participating centers. All of them should be cited for their contributions to the collection of the factual base for this study. The editorial assistance of Terra Sroka is gratefully acknowledged.

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10.

11.

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