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Total Lymphoid Irradiation in Heart Transplantation: Long-Term Efficacy and Survival—An 18-Year Experience

Tallaj, José A.1,2,4; Pamboukian, Salpy V.1; George, James F.3; Brown, Robert N.3; Pajaro, Octavio E.3; Bourge, Robert C.1; Cadeiras, Martin1; Smallfield, Melissa1; Kirklin, James K.3; McGiffin, David C.3

doi: 10.1097/TP.0b013e318231e9d3
Clinical and Translational Research
Free
SDC

Background. Total lymphoid irradiation (TLI) has been used in transplantation for over 20 years and is currently used in a number of major heart transplant centers as a secondary therapy for recalcitrant recurrent rejection or rejection with hemodynamic compromise. The purpose of this study is to evaluate the long-term risks and efficacy of TLI in the treatment of rejection.

Methods. Between 1990 and 1996, 73 adult patients (from 211 adult transplant recipients) received TLI for recurrent rejection (71%), rejection with hemodynamic compromise (25%), and rejection with vasculitis (4%). The treatment consisted of 80 cGy twice per week for 5 weeks. Fifty-five patients received at least 80% of the full dose (>640 cGy). Follow-up ended December 31, 2007, comprising a total 18 year experience.

Results. Patients treated with TLI exhibited a short-term decrease in hazard for rejection in the first 12 months posttransplantation (relative risk, 0.36) but exhibited increased cumulative rejection over the long term. There were no differences in the rates of infection, allograft coronary disease, or malignancy, but seven patients developed myelodysplasia or acute myelogenous leukemia, four of those being the rare but uniformly fatal acute megakaryocytic leukemia type 7.

Conclusions. Patients treated with TLI seemed to experience a reduction in the early hazard for rejection, but long-term outcomes indicate that such patients continued to accumulate more rejection and rejection-death events, likely because these patients were overall at much higher risk for rejection than the other patient groups. We observed minimal long-term complications, except for the unique occurrence of myelodysplasia and acute megakaryocytic leukemia type 7.

1 Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.

2 Department of Medicine, Birmingham VA Medical Center, Birmingham, AL.

3 Division of Cardiothoracic Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL.

The authors declare no funding or conflicts of interest.

4 Address correspondence to: José A. Tallaj, M.D., University of Alabama at Birmingham, THT 331, 1900 University Boulevard, Birmingham, AL 35294.

E-mail: jtallaj@uab.edu

J.A.T. and S.V.P. performed overall supervision of the project and analyzed the data in cooperation with R.N.B., J.F.G., R.N.B., and O.E.P. participated directly in the data analyses. J.F.G. and R.N.B. coordinated clinical data collection. M.C., M.S., J.K.K., R.C.B., and D.C.M. collected data over a period of years. J.K.K. and D.C.M. also supervised the databases in which the clinical data were stored.

Received 16 May 2011. Revision requested 1 June 2011.

Accepted 1 August 2011.

Total lymphoid irradiation (TLI) was initially used for the treatment of Hodgkin's lymphoma (1). Study of the immune response in TLI-treated patients showed significant alterations of T lymphocyte-mediated responses (2), suggesting a potential for the use of TLI to moderate immune responses. With this rationale, TLI has been used as salvage therapy for patients experiencing recurrent rejection or rejection with hemodynamic compromise (HC), which are associated with significant morbidity and mortality in heart transplant patients (2, 3). Treatment of severe or recurrent rejection usually involves aggressive augmentation of immunosuppression, which in turn is associated with increased morbidity and mortality. In addition, some rejection episodes seem to be refractory to augmentation of immunosuppression, resulting in death or graft loss. Therefore, TLI is in use by a number of centers for clinical situations in which other options are limited (4–12). Twenty-one percent of major centers use it as a secondary treatment for antibody-mediated rejection and in other clinical contexts including renal and lung transplantation (4, 6–9, 13).

Objective evidence of the effectiveness of TLI for treatment of recurrent rejection has been elusive, because demonstration of a clear benefit of TLI has been complicated by its use as a secondary treatment, so the number of treated patients at most institutions has been low and TLI is nearly always administered concomitantly with other antirejection treatments. Because of the limited experience, there are few long-term outcome and safety data for TLI in cardiac transplant recipients. In this study, we analyzed outcomes over 18 years in a large cohort of TLI-treated patients to study the long-term effects of TLI and to test the hypothesis that TLI results in a long-term decrease in recurrent rejection and death due to rejection in cardiac transplant recipients.

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RESULTS

Indications for TLI and Treatment Profiles

Of 73 patients treated with TLI, recalcitrant/recurrent rejection was the indication for TLI in 71% (n=52), HC rejection in 25% (n=18), and rejection with vasculitis in the remaining 4.1% (n=3). Fifty-nine of 73 patients completed a full course of TLI, defined as receiving at least 80% (640 cGy) of the intended 800 cGy radiation dose. Treatment was terminated before receiving 80% of the intended radiation dose in the remaining 14 patients because of leukopenia (n=5, 6.8%), leukopenia with thrombocytopenia (n=5, 6.8%), intervening treatment for rejection with HC (n=1, 1.4%), and death before completion of TLI (n=3, 4.1%).

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Rejection and Rejection With HC

Figure 1 depicts a parametric model using multiphase hazard analysis in which the instantaneous risk for rejection was estimated as a function of time posttransplantation. All 73 patients were included in this analysis. The plot shows that, among all patients in which the decision was made to treat with TLI (n=73), the hazard for a rejection episode was markedly elevated before the initiation of TLI. As previously observed by us and others (14–17), the hazard model consisted of two phases in which there was an early phase with a marked peak early posttransplantation followed by a steady tapering of risk over time. TLI was administered at less than 6 months posttransplantation in all but two patients. Hazard analysis of rejection frequency after treatment with TLI suggests a marked reduction in the short-term (<12 months) risk for rejection. At 1 year posttransplantation, the hazard for rejection decreased from approximately 16 to 6 episodes/year (relative risk=0.36).

FIGURE 1.

FIGURE 1.

For further analyses, patients who completed TLI within 6 months after transplant and survived were included. Patients who died less than 6 months posttransplant were excluded because the goal of this analysis was to examine long-term effect of TLI. Two patients who received TLI greater than 2 years posttransplant were also excluded. The following four groups were compared: (1) patients who received a complete course of TLI (n=55); (2) patients who received a partial course of TLI (n=11); (3) a comparison group of patients who did not receive TLI but were at higher risk for subsequent rejection because they experienced greater than or equal to one rejection episode in the first 3 months (n=100); and (4) a comparison group of patients who did not receive TLI and were at lower risk for rejection as demonstrated by no rejection episodes in the first 3 months posttransplantation (n=22). Time 0 (i.e., the start of the analysis) was 6 months posttransplant.

To analyze the effect of TLI, we plotted actuarial data showing cumulative rejections (number of rejections/patient) as a function of time posttransplantation for the four groups. Figure 2 shows a comparison of cumulative HC rejection between the groups. Among patients that completed TLI, the accumulation of HC rejections was lower between the first and fifth years posttransplantation. After the fifth year posttransplantation, HC rejection episodes accumulated much more rapidly among the patients receiving complete TLI in comparison with other groups (P<0.0001, Fig. 2). Figure 3 shows that cumulative cellular rejection episodes (i.e., non-HC rejections) among TLI-treated patients were increased starting at time 0 (6 months posttransplantation) until the end of follow-up. As expected, the patients who did not receive TLI did not accumulate as many rejection episodes over time.

FIGURE 2.

FIGURE 2.

FIGURE 3.

FIGURE 3.

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Association of TLI and Long-Term Survival

To determine whether the association of TLI with HC rejection was reflected in patient survival, we analyzed survival among the same patients compared in Figures 2 and 3. Long-term survival of patients receiving partial or full treatment with TLI was significantly decreased (Fig. 4, P=0.02), suggesting that patients treated with TLI experience a higher risk for death. To determine whether this observation was a function of death due to rejection (rejection death), we determined the percent freedom from rejection death among the patient groups as a function time posttransplantation and noted similar results in that those that completed TLI (i.e., those at high risk for rejection) also suffered a significantly greater frequency of rejection death (P=0.03, Fig. 5). There were too few events in the patients receiving partial TLI to make a determination for them (dashed line, Fig. 5). There were no differences in deaths from other causes including malignancy, allograft vasculopathy, or infection (P=nonsignificant for all groups).

FIGURE 4.

FIGURE 4.

FIGURE 5.

FIGURE 5.

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TLI and Blood Dyscrasias

No difference was observed in the rate of malignancy or death due to malignancy among the different patient groups. However, among TLI-treated patients (n=73), seven developed a blood dyscrasia 3 to 9 years after completion of therapy. Six of these patients received a full course of at least 640 cGY, and showed complex karyotypic abnormalities, including p53 mutations. Four patients aged 52, 55, 15, and 49 years developed acute megakaryocytic leukemia (acute myelogenous leukemia type 7; AML-7). These four patients developed AML at 51.4, 48.8, 55.6, and 45.6 months after TLI. All died within a few months of the diagnosis, despite institution of therapy.

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DISCUSSION

TLI has been in use by a number of centers for secondary treatment of recurrent rejection, HC rejection, and antibody-mediated rejection (6–9, 11–13, 18–22). Because TLI is used primarily as a secondary treatment, patients treated with TLI usually received augmented immunosuppression. In most clinical heart transplant settings in which patients are treated for recurrent rejection, the augmented immunosuppression successfully mitigates acute rejection episodes in the short term. TLI is administered with the expectation that it will reduce the probability of subsequent rejection episodes rather than as a treatment for a specific rejection episode. Because of the clinical milieu in which TLI is usually administered, and the relative infrequency of its use at a given center, larger datasets on the long-term efficacy and risks of TLI have been unavailable. Most information in the current literature addresses the short-term effects of TLI with one recent study reporting an intermediate-term follow-up (median, 7 years) in seven patients (11). This study describes the largest experience to date on the use of TLI for treatment of recurrent rejection and HC rejection in heart transplantation with long-term follow-up data extending over 18 years.

Any analysis of the efficacy of TLI is problematic because of the unique group of patients to which it is applied and because changes in background immunosuppression are made concurrently, making it difficult to isolate the effect of TLI. These patients are at extraordinarily high risk for rejection, which also tends to confound the ability to determine causality with respect to TLI and changes in the accumulation of rejection episodes or death. It is notable that our study demonstrated a relative decrease, or blunting, of the hazard slope for rejection after TLI for at least 12 months, indicating that the observed effect cannot be fully attributed to a normal decrease in the hazard for rejection observed as a function of time posttransplantation. Over the long term, however, the actuarial analysis showed that TLI patients continued to be at high risk for rejection. The hazard analysis suggests that it is possible that cumulative rejection might have been even higher in the TLI-treated group had they not received TLI. However, in the absence of a comparable group of patients with similar risk, not treated with TLI, this cannot be definitively determined. In our study, we attempted to formulate two comparison groups who did not receive TLI: patients with one or more rejections within the first 3 months posttransplantation representing a “higher risk” group and patients without rejection representing a “lower risk” group. Neither one of these groups accumulated as many rejection episodes over the 18-year follow-up period. Even our “higher risk” control group was not really comparable with respect to rejection risk to the TLI-treated patients. The ongoing high risk for rejection was further reflected in patient survival and death attributed directly to rejection among TLI-treated patients.

TLI seemed to be well tolerated. Most patients received a dose of at least 640 cGY or 80% of the goal considered as completed therapy. Leukopenia, with or without thrombocytopenia, was the main reason for early discontinuation of TLI. As previously reported, TLI therapy did not result in an increased incidence of infection, in the short or long term (22). Therefore, TLI seemed to be relatively safe, with the important exception of the development of blood dyscrasias. Seven patients developed some form of hematological condition, with four patients (5.5% of the TLI-treated group population) developing AML, a rare and highly resistant form of acute myeloid leukemia (23). All four patients died from this malignancy within months of diagnosis. To our knowledge, this type of leukemia has not been previously described in transplant patients. All four patients received OKT3 induction at the time of transplantation, but the absence of AML in any patients not treated with TLI regardless of OKT3 use does not support a relationship between the development of this hematologic malignancy and OKT3. After the occurrence of the blood dyscrasias, we discontinued the use of TLI at our center. Since then, we have not observed another case of AML.

Because of the nature of the patient group in which TLI was applied, there are a number of limitations that must be considered in the interpretation of the data presented here. Because we evaluated long-term follow-up, the patients included in the present study were treated with TLI between 1990 and 1996, an era in which the usual immunosuppressive regimen consisted of cyclosporine, steroids, and azathioprine. The incidence of rejection during this era was higher than is commonly observed in the present era, in which immunosuppressive regimens are better optimized with newer calcineurin inhibitors, alternative proliferation signal inhibitors, and humanized monoclonal antibodies (24, 25). Most patients included in this study experienced recurrent rejection early posttransplantation, which has been associated with a poor prognosis (17, 26) and therefore the vast majority were treated within the first 6 months posttransplantation as part of a comprehensive regime that included augmented and alternative immunosuppression. Therefore, data demonstrating the efficacy of TLI may be confounded by these concomitant therapies.

The mechanisms of the immunosuppressive effect of TLI in solid organ transplantation is largely unknown. TLI results in a decrease in peripheral T cells (18, 27) and causes an increase in the proportion of natural killer T cells which favor polarization of alloreactive T cells toward secretion of anti-inflammatory cytokines such as IL-4 (18, 28), which could inhibit graft rejection. Our study does not suggest that TLI-induced tolerance, because the patients treated with TLI experienced a higher incidence of rejection overall.

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CONCLUSION

Patients treated with TLI for recurrent rejection, rejection with HC or vasculitis exhibited a short-term decrease in the hazard for rejection. In this long-term study, this effect seemed to last 3.5 years after completion of TLI, with a late rebound in the incidence of rejection and rejection death. Survival after TLI is acceptable, with minimal long-term complications, except for unique occurrence of blood dyscrasias, particularly uniformly fatal AML. Given these results, we suggest that TLI may be an appropriate secondary therapy for the treatment of recalcitrant recurrent or severe rejection, but should be applied cautiously only in high-risk patients in which the risk for blood dyscrasias seems to be preferable in comparison to the potential risk for fatal rejection events.

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MATERIALS AND METHODS

Patient Population

Between 1990 and 1996, 211 adult patients (≥18 years of age) received primary heart transplants at the University of Alabama at Birmingham. Eighty-five percent were treated with induction therapy at the time of transplantation. Only patients receiving TLI within the first 6 months posttransplant and surviving greater than 6 months posttransplantation were included in the study. The study analysis extended to December 31, 2007, a total of 18 years. Seventy-three of 211 patients were treated with TLI, with a mean follow-up of 8.3 years (median, 6.9 years). Of 73 patients, 59 received a full course of TLI. Of these, two died less than 6 months posttransplantation and two did not receive TLI until greater than 2 years posttransplantation. These four patients were excluded from analysis. The remaining 55 patients were included. There were 14 patients who received a partial dose of TLI. Of these 14, three died before 6 months posttransplantation and were excluded, leaving 11 patients who were included in the analyses.

Two comparison groups were derived from the 138 patients who did not receive TLI. Thirty-one among this group experienced no rejection episodes during the first 3 months posttransplantation, indicating a “lower risk” for subsequent rejection. Of these 31, 22 survived greater than 6 months posttransplantation. These 22 (mean follow-up 9.6 years, median 10.2 years) served as a comparison group of “lower risk” patients who did not receive TLI (no rejection—no TLI group). Among the 138 patients who did not receive TLI, 107 experienced at least one rejection episode during the first 3 months posttransplantation indicating a “higher risk” for subsequent rejection. Of these 107, 100 patients (mean follow-up 9.7 years, median 10.2 years) survived greater than 6 months posttransplantation and were included in the analysis. This group served as a comparison group of “higher risk” patients that did not receive TLI (rejection—no TLI).

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Definitions

Rejection Episodes

Because biopsy frequency and clinical protocols related to biopsy results change over time, it was necessary to implement a definition of rejection that has previously been described to be relatively independent of these variables (24, 26, 29). Throughout the experience, treatment for rejection was initiated based on a number of clinical indications, including a biopsy grade 3A or higher (30). However, if grade 1B or grade 2 biopsies were found in the early transplant period (first month) rejection treatment could be initiated. A rejection episode was considered ended if the next biopsy, performed 10 or more days later, did not result in further augmentation of immunosuppression. If the next biopsy resulted in a continuation of rejection treatment or further augmentation of immunosuppression, then it was considered part of the same rejection episode. Other than evidence of cellular rejection on endomyocardial biopsy, rejection was also defined as acute left or right ventricular dysfunction on transthoracic echocardiogram, abnormal hemodynamics on right heart catheterization, or clinical symptoms indicative of acute rejection as determined by the treating physician.

Recalcitrant/recurrent rejection was defined as more than or equal to two episodes of cellular rejection within a 3-month period despite augmentation of immunosuppression. Rejection with HC was defined as a decline in ejection fraction to less than or equal to 45% as measured by echocardiography, with previous documentation of a normal ejection fraction of more than or equal to 55%. Rejection with vasculitis was defined as rejection without evidence of cellular rejection (ISHLT grade ≤2) but with evidence of endothelial damage and antibody deposition in the endomyocardial biopsy. In the groups defined earlier, 55% of the no rejection—no TLI group, 39% of the rejection—no TLI group, and 85% of patients receiving TLI were treated with induction therapy.

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Radiation Therapy

The method used to provide radiotherapy has been described elsewhere (20). Briefly, three separate fields were used to encompass all node-bearing areas and the spleen: a supradiaphragmatic mantle field extending from the base of the skull to the T8-T9 areas with lateral extension to treat the axillary nodes, a periaortic and splenic field extending down to the L4-L5 level, and a pelvic field encompassed all pelvic and inguinal lymph node areas. The goal for TLI was for a total of 800 cGY given at 80 cGY per session twice weekly. Treatment was delayed if hematologic toxicity was detected. In general, TLI was withheld when WBC counts rapidly declined or when total WBC dropped to less than 2000/mm or platelet counts were reduced to less than l00,000/mm or both.

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Statistical Analysis

Time-dependent outcomes were parametrically modeled using multiphase hazard analysis in which the instantaneous risk for a specific event (e.g., rejection diagnosis) was estimated as a function of time (15). The effects of risk factors were estimated by proportional hazards regression within each phase of hazard. Variables associated with increased risk over a specified period of time were identified using parametric survival regression in the hazard function domain. Data were analyzed using an array of parametric methods and a hazard function analysis of the instantaneous risk for a given event across time (15). Risk factors were identified using multivariate analyses. All statistics were performed using SAS software (SAS Institute, Inc., Cary, NC) in conjunction with custom software used for hazard analysis (for additional details, see http://www.clevelandclinic.org/heartcenter/hazard). This study was approved by the Institutional Review Board of the University of Alabama at Birmingham.

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Keywords:

Total lymphoid irradiation; Outcomes; Heart transplantation

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