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.
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.
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.
MATERIALS AND METHODS
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).
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.
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.
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.
1. Kaplan HS, Rosenberg SA. Extended-field radical radiotherapy in advanced Hodgkin's disease: Short-term results of 2 randomized clinical trials. Cancer Res
1966; 26: 1268.
2. Fuks Z, Strober S, Bobrove AM, et al. Long term effects of radiation on T and B lymphocytes in peripheral blood of patients with Hodgkin's disease. J Clin Invest
1976; 58: 803.
3. Kirklin JK, Naftel DC, McGiffin DC, et al. Analysis of morbid events and risk factors for death after cardiac transplantation. J Am Coll Cardiol
1988; 11: 917.
4. Villar RC, Chocair PR, Nadalin W, et al. Total lymphoid irradiation
for pretransplant immunosuppression and recurrence of focal segmental glomerulosclerosis. Transpl Int
2008; 21: 286.
5. Lim TS, O'Driscoll G, Freund J, et al. Short-course total lymphoid irradiation
for refractory cardiac transplantation rejection. J Heart Lung Transplant
2007; 26: 1249.
6. Trivedi HL, Kaneku H, Terasaki PI, et al. Clonal deletion using total lymphoid irradiation
with no maintenance immunosuppression in renal allograft recipients. Clin Transpl
7. Bhorade SM, Stern E. Immunosuppression for lung transplantation. Proc Am Thorac Soc
2009; 6: 47.
8. Verleden GM, Lievens Y, Dupont LJ, et al. Efficacy of total lymphoid irradiation
in azithromycin nonresponsive chronic allograft rejection after lung transplantation. Transplant Proc
2009; 41: 1816.
9. Comerci GD Jr, Williams TM, Kellie S. Immune tolerance after total lymphoid irradiation
for heart transplantation
: Immunosuppressant-free survival for 8 years. J Heart Lung Transplant
2009; 28: 743.
10. Neurohr C, Behr J. [Immunosuppression and infection prophylaxis after lung transplantation.] Pneumologie
2011; 65: 94.
11. Ghadjar P, Joos D, Martinelli M, et al. Tailored total lymphoid irradiation
in heart transplant patients: 10-years experience of one center. Radiat Oncol
2010; 5: 3.
12. Chin C, Hunt S, Robbins R, et al. Long-term follow-up after total lymphoid irradiation
in pediatric heart transplant recipients. J Heart Lung Transplant
2002; 21: 667.
13. Kobashigawa J, Crespo-Leiro MG, Ensminger SM, et al. Report from a consensus conference on antibody-mediated rejection in heart transplantation
. J Heart Lung Transplant
2011; 30: 252.
14. Kirklin JK, Naftel DC, Kirklin JW, et al. Risk factors for death and related events after cardiac transplantation. Adv Cardiol
1988; 36: 278.
15. Blackstone EH, Naftel DC, Turner ME. The decomposition of time-varying hazard into phases, each incorporating a separate stream of concomitant information. J Am Stat Assoc
1986; 81: 615.
16. Chin C, Naftel DC, Singh TP, et al. Risk factors for recurrent rejection in pediatric heart transplantation
: A multicenter experience. J Heart Lung Transplant
2004; 23: 178.
17. Kirklin JK, Young J, McGiffin DC. Survival after heart transplantation
. In: Heart transplantation
. New York, Churchill Livingstone 2003, p 587.
18. Rigby SM, Rouse T, Field EH. Total lymphoid irradiation
nonmyeloablative preconditioning enriches for IL-4-producing CD4+-TNK cells and skews differentiation of immunocompetent donor CD4+ cells. Blood
2003; 101: 2024.
19. Evans MA, Schomberg PJ, Rodeheffer RJ, et al. Total lymphoid irradiation
: A novel and successful therapy for resistant cardiac allograft rejection. Mayo Clin Proc
1992; 67: 785.
20. Salter MM, Kirklin JK, Bourge RC, et al. Total lymphoid irradiation
in the treatment of early or recurrent heart rejection. J Heart Lung Transplant
1992; 11: 902.
21. Kirklin JK, George JF, McGiffin DC, et al. Total lymphoid irradiation
: Is there a role in pediatric heart transplantation
? J Heart Lung Transplant
1993; 12(6 Pt 2): S293.
22. Salter SP, Salter MM, Kirklin JK, et al. Total lymphoid irradiation
in the treatment of early or recurrent heart transplant rejection. Int J Radiat Oncol Biol Phys
1995; 33: 83.
23. Krause JR. Morphology and classification of acute myeloid leukemias. Clin Lab Med
2000; 20: 1.
24. George JF, Taylor DO, Blume ED, et al. Minimizing infection and rejection death: Clues acquired from 19 years of multi-institutional cardiac transplantation data. J Heart Lung Transplant
2011; 30: 151.
25. George JF, Pamboukian SV, Tallaj JA, et al. Balancing rejection and infection with respect to age, race, and gender: Clues acquired from 17 years of cardiac transplantation data. J Heart Lung Transplant
2010; 29: 966.
26. Kubo SH, Naftel DC, Mills RM Jr, et al. Risk factors for late recurrent rejection after heart transplantation
: A multiinstitutional, multivariable analysis. Cardiac Transplant Research Database Group. J Heart Lung Transplant
1995; 14: 409.
27. Halperin EC, Haas G, Dosoretz DE, et al. 1982 resident's essay award: The immunologic effects of lymphoid irradiation in human and non-human primates: Cellular changes and the potential for renal transplantation. Int J Radiat Oncol Biol Phys
1983; 9: 1083.
28. Bourge RC, Naftel DC, Costanzo-Nordin MR, et al. Pretransplantation risk factors for death after heart transplantation
: A multiinstitutional study. The Transplant Cardiologists Research Database Group. J Heart Lung Transplant
1993; 12: 549.
29. Mills RM, Naftel DC, Kirklin JK, et al. Heart transplant rejection with hemodynamic compromise: A multiinstitutional study of the role of endomyocardial cellular infiltrate. Cardiac Transplant Research Database. J Heart Lung Transplant
1997; 16: 813.
30. Billingham ME, Cary NR, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation
. J Heart Transplant
1990; 9: 587.
Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
Total lymphoid irradiation; Outcomes; Heart transplantation