http://www.jhltonline.org
Single-center experience with extracorporeal photopheresis in pediatric heart transplantation Waldemar F. Carlo, MD,a F. Bennett Pearce, MD,a James F. George, PhD,b Jose A. Tallaj, MD,c David C. McGiffin, MD,b Marisa B. Marques, MD,d Jill Adamski, MD, PhD,e and James K. Kirklin, MDb From the aDivisions of Pediatric Cardiology, The University of Alabama at Birmingham, Birmingham, Alabama; bDivisions of Cardiothoracic Surgery, The University of Alabama at Birmingham, Birmingham, Alabama; cDivisions of Cardiovascular Diseases, The University of Alabama at Birmingham, Birmingham, Alabama; dDivisions of Laboratory Medicine, The University of Alabama at Birmingham, Birmingham, Alabama; and eDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Arizona.
KEYWORDS: extracorporeal photopheresis; pediatric heart transplant; rejection; hemodynamic compromise
BACKGROUND: The pediatric heart transplant literature contains little information regarding extracorporeal photopheresis (ECP), despite International Society for Heart and Lung Transplantation guidelines recommending it for recurrent/recalcitrant rejection. We report our experience with ECP in pediatric heart transplantation. METHODS: Data were obtained on heart transplant patients who were aged r 18 years at the time of transplantation and received ECP between 1990 and 2012 at our institution. RESULTS: Twenty heart transplant patients underwent 22 courses of ECP. Median ages were 12.7 years (range, 0.3–18.5 years) at transplant and 15.3 years (range, 7.3–31 years) at initial ECP. Median time from transplant to ECP was 1.4 years (range, 0.1–12.6 years). The median ECP duration was 5.8 months (range, 1.9–16.1 months). Indications for ECP included rejection with hemodynamic compromise (HC) in 4 patients, rejection without HC in 12, and prophylaxis in 2. Eleven patients died at a median time of 3.1 years after the start of ECP. Survival after ECP was 84% at 1 year and 53% at 3 years. Eleven patients were considered non-compliant and had a trend toward lower survival of 75% at 1 year and 18% at 3 years (p ¼ 0.06 compared with compliant patients). One patient developed Pneumocystis carinii pneumonia during ECP and post-transplant lymphoproliferative disease 21 months after finishing ECP. No other adverse effects or infectious complications associated with ECP were noted. CONCLUSIONS: This case series represents the largest reported experience with ECP in pediatric heart transplantation. ECP can be safely applied in this patient group. Despite EPC, non-compliant patients showed a trend toward lower survival than compliant patients. J Heart Lung Transplant 2014;33:624–628 r 2014 International Society for Heart and Lung Transplantation. All rights reserved.
Allograft rejection remains an important cause of morbidity and the leading cause of death in the first 5 years after heart transplant in children.1 Medical immunosuppression Reprint requests: Waldemar F. Carlo, MD, University of Alabama at Birmingham, 619 19th St S, 176F Ste 9100, Birmingham, AL 35249-6852. Telephone: 205-934-3460. Fax: 205-975-6291. E-mail address: [email protected]
represents the primary means of rejection prophylaxis and treatment. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has documented effectiveness in transplantation and other pediatric disorders such as graft versus host disease and cutaneous T-cell lymphoma. The most recent American Society for Apheresis (ASFA) guidelines for the clinical applications of apheresis considers ECP for rejection prophylaxis or treatment of cellular or
1053-2498/$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.01.863
Carlo et al.
ECP in Pediatric Heart Transplantation
625
recurrent rejection as category II indications: “second-line therapy, either as a standalone treatment or in conjunction with other modes of treatment.” ECP for treatment of rejection received a grade of 1B (“strong recommendation, moderate quality evidence”), and rejection prophylaxis, grade 2A (“weak recommendation, high quality evidence”).2 The 2010 International Society of Heart Lung Transplantation (ISHLT) Guidelines for the Care of Heart Transplant Recipients suggest ECP as a class IIb therapy for recurrent or recalcitrant rejection.3 Despite these recommendations, the pediatric heart transplant literature contains very little information related to ECP, which may be a reflection of the technical difficulties of performing ECP in small patients, its unfamiliarity, and/or its unavailability, particularly in freestanding children’s hospitals. Furthermore, query of the Pediatric Heart Transplant Study database reveals that most instances of ECP use occurred at our institution (personal communication). Our objective is to report our unique experience with ECP in pediatric heart transplant patients.
volumes of red blood cells and albumin according to the patient’s total blood volume and hematocrit. To prevent fluid overload, the same volume given during ECP was removed from the patient at the end of the procedure. Other ECP pediatric modifications have been further described previously.6 In addition, the duration of the protocol changed during the study period. One course of ECP originally consisted of 15 series of 2 treatments on consecutive days, separated by 3 to 6 weeks, over 18 months. After 2000, the protocol was modified, such that 1 course of ECP now consists of 10 series of 2 treatments on consecutive days initially weekly but spacing out to monthly and finishing approximately within 6 total months. For purposes of this analysis, patients who received more than 1 ECP course separated by less than 6 months were not considered to have received distinct courses. Basic statistical analysis included a chi-square analysis using a Pearson test for significance. Kaplan-Meier curves were generated for the entire cohort and were also stratified by medical compliance vs non-compliance. Log-rank analysis was used to analyze survival differences.
Methods
Twenty heart transplant patients underwent 22 courses of ECP. Table 1 summarizes the characteristics of our ECP cohort. These patients received transplants at a mean age of 12.9 years (range, 0.3–18.5 years). Indications for transplantation included dilated cardiomyopathy in 14 patients, congenital heart disease in 4, restrictive cardiomyopathy in 1, and myocarditis in 1. ECP use has been relatively stable since 2001, averaging approximately 1.5 patients per year in the pediatric/young adult cohort (Figure 1). Median age at the time of the initial ECP was 15.7 years (range, 7.3–31 years). Only 1 patient was older than 19 years at the initial ECP. Median time from transplant to ECP was 1.4 years (range, 0.1–12.6 years). Nine patients underwent ECP within the first year after transplant. Indications for ECP varied and are listed in Table 1. The indication could not be ascertained in 2 patients. There were no important procedural complications related to ECP. Typically, immunosuppression was augmented before ECP (Table 1). Data were unavailable for 3 patients. All patients received steroid pulses after rejection. The following were also used depending on the rejection characteristics and era of transplantation: TPE in 6 patients, intravenous immunoglobulin in 2, rituximab in 2, Thymoglobulin (Genzyme Corp, Cambridge, MA) in 5, OKT3 in 2, and the addition of sirolimus in 2. Seven patients received more than 1 of these therapies. Two patients underwent a second course of ECP. Patient 17 had rejection with HC (felt to be mixed cellular and antibodymediated) 7 years after her initial ECP and underwent a second course of ECP but died 1 month after completing the ECP course of terminal rejection with HC. Non-compliance was not a concern. Patient 7 had recurrent rejection episodes beginning 2 years after the initial ECP; he received nearly 1.5 years of monthly ECP before dying of rejection. Non-compliance was a chronic concern in this patient. Thirteen patients died at a median of 3.1 years (range, 0.3 -13.8 years) from the start of ECP. Cause of death was
After obtaining approval from the Institutional Review Board, data were obtained from medical records of heart transplant patients aged 18 years or younger at the time of transplant who received ECP between 1990 and 2012. Heart–lung transplant recipients were excluded. Basic demographic and peri-transplant variables were collected. The transplant team defined medical noncompliance at the time clinical care was administered based partly on evidence of non-compliance with immunosuppression medication that compromised the patient’s clinical course. The primary outcome of interest was death. Secondary outcomes studied were ECP complications, infections, rejection episodes, and coronary artery vasculopathy (CAV). Immunosuppression protocols evolved during the study interval and have been summarized previously.4 Rejection episodes were routinely treated with intravenous pulse methylprednisolone or oral prednisone for 3 days. Patients with persistent or recurrent rejection additionally received lytic therapy (OKT3 or anti-thymocyte globulin) and conversion to tacrolimus and mycophenolate mofetil if not already receiving them. Patients with rejection with hemodynamic compromise (HC) additionally received 3 or more therapeutic plasma exchanges (TPE). ECP was generally used after these therapies at the discretion of the clinical care team. The presence of non-compliance was considered in the ECP decision making with the assumption that ECP would provide additional background immunosuppression that might reduce the likelihood of rejection if further noncompliance occurred. Occasionally, ECP was used prophylactically, and indications evolved during the study period. The standard adult ECP protocol, as previously published, was used.5 Most commonly, ECP was performed through a subcutaneous port accessing a subclavian vein. With this protocol, the total extracorporeal volume should be limited to 15% of the patient’s blood volume. The standard adult protocol was typically used for most patients in this series, including a 36-kg 17-year-old and a 38-kg 10-year-old. The modified pediatric protocol was used for Patient 3, a 24-kg 8-year-ol. The modification included priming the ECP circuit with crossmatched leukocyte-reduced packed red blood cells and giving an albumin bolus to the patient at the beginning of ECP. The apheresis team individualized the exact
Results
626 Table 1
The Journal of Heart and Lung Transplantation, Vol 33, No 6, June 2014 Details of Pediatric Heart Transplant Recipients Undergoing Extracorporeal Photopheresis Rejectionb
Age at Tx Pt Sex (year)
Etiology
Age at ECP (year)
Wt (kg) at ECP Indications for ↑Immuno prePost(kg) ECP ECPa Pre-ECP ECP
NC Outcome
1 F
0.3
CHD
10.2
55
Mixed HC
R, T
3A/HC
None
0
2 F
3.6
DCM
14.5
50
HC, AMR
P, R, T
AMR/HC None
0
3 M
4.3
RCM
7.3
24
Rec Rej
None
3A, 3A
None
0
4 F
9.3
DCM
10.7
47
Rec Rej
None
0
5 F
9.6
DCM
14.2
NA
NA
2R, 2R, None 2R NA NA
6 F
9.7
DCM
11.4
79
Pers Rej
None
3A/HC
3A
1
7 M
10.1
DCM
10.5
38
Pers Rej
NA
3A
3A
1
8 F
12.9
DCM
13.7
63
Pers Rej
T, S
3A
3A
1
9 M
14.2
Myocarditis
15.1
79
HC
P, T
HC, HC
None
1
10 M
15
CHD
16.4
45
Rec Rej
S
3A, 3A
3A
0
11 M
15
DCM
17.4
68
Pers Rej
None
3A
None
1
12 F
15.1
DCM
15.3
65
Rej
P, O
3B
None
1
13 M
15.6
DCM
17.9
69
Pers & Rec Rej None
3A, 3A
None
1
14 M
16
DCM
16.1
59
Prophylaxis
þXM
HC
1
15 M
17
CHD
17.2
36
Mixed, Pers Rej P, IVIG, T
2R/AMR 2R
0
16 F
17.4
DCM
19.3
61
Rej
O
3B
None
1
17 F
17.7
CHD
17.8
86
Prophylaxis
P, IVIG
þXM
None
0
18 M
18.2
DCM
18.6
71
NA
NA
NA
None
1
19 M
18.3
DCM
30.9
78
HC
P
HC, HC
HC
1
20 M
18.5
DCM
19
86
Rec Rej
None
3A, 2R
2R, 2R, 0 2R
None
1
Alive, 2.8 years Alive, 3.7 years Alive, 13.8 years Alive, 1.3 years Dead, 6.9 years Dead, 3.1 years Dead, 4.9 years Dead, 3.1 years Alive, 10.5 years Dead, 2.3 years Dead, 1.8 years Dead, 1.3 years Dead, 7.8 years Dead, 0.7 years Alive, 1.5 years Dead, 3.8 years Dead, 7.6 years Dead, 0.6 years Dead, 0.3 years Alive, 2 years
AMR, antibody-mediated rejection; CHD, congenital heart disease; DCM, dilated cardiomyopathy; HC, hemodynamic compromise; IVIG, intravenous immunoglobulin; NA, not available; NC, noncompliance; O, OKT3; P, plasmapheresis; Per, persistant; þXM, positive crossmatch; R, rituximab; RCM, restrictive cardiomyopathy; Rec, recurrent; Rej, rejection; S, sirolimus, T, Thymoglobulin (Genzyme Corp, Cambridge, MA); Tx, transplant. a Indicates administration of additional agents, excluding standard maintenance immunosuppression and steroid pulses, r 6 months of initiating ECP. All patients received intravenous steroid pulses after rejection. b Rejection definitions: Rec Rej (recurrent rejection) indicates Z 2 episodes of rejection (at least 3A or 2R) r 3-month period. Pers Rej (persistent rejection) indicates Z 2 biopsy specimens with at least 3A or 2R grade without an intervening improved biopsy specimen. Mixed indicates cellular and humoral rejection. HC indicates a rejection episode with hemodynamic compromise. Rejection pre-ECP or post-ECP indicates rejection episodes occurring in the 6 months before or after the start of ECP. A comma separates rejection episodes and a slash separates rejection episodes with multiple features.
related to rejection in 7 patients, infection in 1, sudden death with severe coronary allograft vasculopathy in 2, and sudden death of unclear etiology in 1. Cause of death could not be ascertained in 1 patient. Survival was not affected by era of transplantation (pre-2003) and ECP use during or after the first year post-transplant. Figure 2 depicts the survival curve for all patients starting at the time of ECP.
Twelve patients were considered non-compliant and died more frequently during the follow-up period than patients without documented non-compliance (92% vs 25%). These results represent worse survival over time (p ¼ 0.04) as determined by log-rank analysis. Figure 3 depicts the survival curve of all patients stratified by noncompliance.
Carlo et al.
ECP in Pediatric Heart Transplantation
Figure 1 Extracorporeal photopheresis use in pediatric heart transplant recipients is shown by year.
Rejection data were available for 18 patients. The number of rejection episodes in the 6 months preceding ECP was higher than in the 6 months after ECP (1.5 ⫾ 0.7 vs 0.6 ⫾ 0.8, p ¼ 0.002; Figure 4). Only 1 serious infection occurred during ECP. Patient 10 developed Pneumocystis carinii pneumonia that resulted in a prolonged hospitalization and cessation of ECP after 1.9 months. This same patient developed post-transplant lymphoproliferative disorder 3 years after heart transplantation, 18 months after ECP, and 4 months after renal transplantation. Of the 7 patients who received ECP within the first 3 years after transplant and lived longer than 5 years after transplant, 4 had angiographic evidence of CAV at 5.7, 6, 9.4, and 11.5 years after transplant, whereas 3 had no CAV at 5, 7.7, and 16.8 years after transplant.
Discussion Our objective was to review our unique experience with pediatric ECP after cardiac transplantation. We demonstrated that ECP could be applied to the pediatric population
Figure 2 Survival curve is shown for the entire extracorporeal photopheresis (ECP) cohort. Time 0 begins at ECP initiation.
627
Figure 3 Survival curve for the extracorporeal photopheresis (ECP) cohort is shown stratified by patients who were and were not compliant. Time 0 begins at ECP initiation. Non-compliant patients had a trend toward lower survival (p ¼ 0.063).
safely, down to an age and size of 8 years and 24 kg, respectively, by modifying the ECP method. We furthermore demonstrated that non-compliant patients demonstrated lower survival than compliant patients despite ECP. Finally, acute rejection episodes were less frequent after ECP than before. Our survival curve and median survival time of 3.1 years after ECP are comparable to the 2-year survival of 65% for high-risk recurrent rejectors as reported by the Pediatric Heart Transplant Study.7 This mortality rate confirms that we used ECP in a high-risk sub-set. The poor outcomes of the non-compliant patients should not be considered as evidence against ECP. Rather, this supports ECP use as an adjunct to standard medical immunosuppression. In animal studies, transplanted mice not provided with medical immunosuppression live longer when treated with ECP products.8
Figure 4 Shown are the number of rejection episodes in the 6 months preceding extracorporeal photopheresis (ECP; 1.5 ⫾ 0.7) and in the 6 months after ECP (0.5 ⫾ 0.9; p ¼ 0.002 by paired Student’s t-test). The horizontal line in the middle of each box indicates the median; the top and bottom borders of the box mark the 75th and 25th percentiles, respectively; and the whiskers mark the 90th and 10th percentiles.
628
The Journal of Heart and Lung Transplantation, Vol 33, No 6, June 2014
Our study serves as the largest series of ECP in pediatric heart transplantation. Larger pediatric experiences with ECP exist in other conditions, however, such as graft-versus-host disease.9,10 Clinical application of ECP in heart transplant patients has been better studied in adults. Prospective studies have demonstrated beneficial effects of prophylactic ECP on acute rejection11,12 and graft intimal hyperplasia.13 In a retrospective review from our institution’s adult transplant program, Kirklin et al4 demonstrated a reduction in the incidence of rejection down to a level comparable to the control transplant group when ECP was used as secondary prophylaxis in patients with HC rejection. From the results of these studies and other data, ASFA has endorsed ECP as an important second-line therapy for prophylaxis against rejection and treatment of acute rejection.2 Our study has important limitations. First, this study was by design a small retrospective case series, and any statistical analysis is limited. A large enough comparison cohort of at-risk patients not treated with ECP at our institution could not be identified. Next, indications for ECP varied between patients and were based on the clinical decision making of numerous physicians. Although intended to be a pediatric study, we included patients who received allografts at age 18 years or younger but who were older than 18 when they received ECP. These young adults, along with adolescents, have a higher risk of death from rejection in the first 5 years after transplant than other age groups.14 Importantly, we are unable to draw any conclusions regarding the effectiveness of ECP independent of other immunosuppressive modalities given the multiple methods of augmented immunosuppression prior to ECP in many of these patients. Finally, analysis of ECP effect on acute rejection is limited by the expected decreasing hazard of rejection over time, although this has been addressed in a prior adult study.4 In conclusion, despite its limitations, this study is important because it represents the largest series of ECP in pediatric heart transplantation. We have shown that ECP can be applied safely in this population. Because ECP is used more commonly in other pediatric disorders as well as in adult transplant centers, ECP may be available to pediatric heart transplant programs that have not previously used it. Factors favoring ECP use in our current practice include appropriate patient age and weight, recurrent/persistent rejection despite a course of anti-thymocyte therapy, rejection
with HC, medication non-compliance, and concerns related to donor-specific antibodies. We encourage consideration of ECP as a safe immunomodulatory tool in combatting pediatric allograft rejection.
Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Dodd DA, Cabo J, Dipchand AI. Acute rejection: natural history, risk factors, surveillance, and treatment. In: Canter CE, Kirklin JK, editors. Pediatric transplantation. Philadelphia: Elsevier; 2007. p. 139-56. 2. Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the writing committee of the American Society for Apheresis: the sixth special issue. J Clin Apher 2013;28:145-284. 3. Costanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010;29:914-56. 4. Kirklin JK, Brown RN, Huang ST, et al. Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis. J Heart Lung Transplant 2006;25:283-8. 5. Marques MB, Tuncer HH. Photopheresis in Solid Organ Transplant Rejection. J Clin Apher 2006;21:72-7. 6. Chan KW. Extracorporeal photopheresis in children with graft-versushost disease. J Clin Apher 2006;21:60-4. 7. 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;23:178-85. 8. George JF, Gooden CW, Guo L, Kirklin JK. Role for CD4(þ)CD25 (þ) T cells in inhibition of graft rejection by extracorporeal photopheresis. J Heart Lung Transplant 2008;27:616-22. 9. Kanold J, Paillard C, Halle P, D'Incan M, Bordigoni P, Deméocq F. Extracorporeal photochemotherapy for graft versus host disease in pediatric patients. Transfus Apher Sci 2003;28:71-80. 10. Messina C, Locatelli F, Lanino E, et al. Extracorporeal photochemotherapy for pediatric patients with graft-versus-host disease after hematopoietic stem cell transplantation. Br J Haematol 2003;122: 118-27. 11. Barr ML, Meiser BM, Eisen HJ, et al. Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. N Engl J Med 1998;339:1744-51. 12. Meiser BM, Kur F, Reichenspurner H, et al. Reduction of the incidence of rejection by adjunct immunosuppression with photochemotherapy after heart transplantation. Transplantation 1994;57:563-8. 13. Barr ML, Baker CJ, Schenkel FA, et al. Prophylactic photopheresis and chronic rejection: effects on graft intimal hyperplasia in cardiac transplantation. Clin Transplant 2000;14:162-6. 14. 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;30:151-7.
Single-center experience with extracorporeal photopheresis in pediatric heart transplantation Waldemar F. Carlo, MD,a F. Bennett Pearce, MD,a James F. George, PhD,b Jose A. Tallaj, MD,c David C. McGiffin, MD,b Marisa B. Marques, MD,d Jill Adamski, MD, PhD,e and James K. Kirklin, MDb From the aDivisions of Pediatric Cardiology, The University of Alabama at Birmingham, Birmingham, Alabama; bDivisions of Cardiothoracic Surgery, The University of Alabama at Birmingham, Birmingham, Alabama; cDivisions of Cardiovascular Diseases, The University of Alabama at Birmingham, Birmingham, Alabama; dDivisions of Laboratory Medicine, The University of Alabama at Birmingham, Birmingham, Alabama; and eDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Arizona.
KEYWORDS: extracorporeal photopheresis; pediatric heart transplant; rejection; hemodynamic compromise
BACKGROUND: The pediatric heart transplant literature contains little information regarding extracorporeal photopheresis (ECP), despite International Society for Heart and Lung Transplantation guidelines recommending it for recurrent/recalcitrant rejection. We report our experience with ECP in pediatric heart transplantation. METHODS: Data were obtained on heart transplant patients who were aged r 18 years at the time of transplantation and received ECP between 1990 and 2012 at our institution. RESULTS: Twenty heart transplant patients underwent 22 courses of ECP. Median ages were 12.7 years (range, 0.3–18.5 years) at transplant and 15.3 years (range, 7.3–31 years) at initial ECP. Median time from transplant to ECP was 1.4 years (range, 0.1–12.6 years). The median ECP duration was 5.8 months (range, 1.9–16.1 months). Indications for ECP included rejection with hemodynamic compromise (HC) in 4 patients, rejection without HC in 12, and prophylaxis in 2. Eleven patients died at a median time of 3.1 years after the start of ECP. Survival after ECP was 84% at 1 year and 53% at 3 years. Eleven patients were considered non-compliant and had a trend toward lower survival of 75% at 1 year and 18% at 3 years (p ¼ 0.06 compared with compliant patients). One patient developed Pneumocystis carinii pneumonia during ECP and post-transplant lymphoproliferative disease 21 months after finishing ECP. No other adverse effects or infectious complications associated with ECP were noted. CONCLUSIONS: This case series represents the largest reported experience with ECP in pediatric heart transplantation. ECP can be safely applied in this patient group. Despite EPC, non-compliant patients showed a trend toward lower survival than compliant patients. J Heart Lung Transplant 2014;33:624–628 r 2014 International Society for Heart and Lung Transplantation. All rights reserved.
Allograft rejection remains an important cause of morbidity and the leading cause of death in the first 5 years after heart transplant in children.1 Medical immunosuppression Reprint requests: Waldemar F. Carlo, MD, University of Alabama at Birmingham, 619 19th St S, 176F Ste 9100, Birmingham, AL 35249-6852. Telephone: 205-934-3460. Fax: 205-975-6291. E-mail address: [email protected]
represents the primary means of rejection prophylaxis and treatment. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has documented effectiveness in transplantation and other pediatric disorders such as graft versus host disease and cutaneous T-cell lymphoma. The most recent American Society for Apheresis (ASFA) guidelines for the clinical applications of apheresis considers ECP for rejection prophylaxis or treatment of cellular or
1053-2498/$ - see front matter r 2014 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.01.863
Carlo et al.
ECP in Pediatric Heart Transplantation
625
recurrent rejection as category II indications: “second-line therapy, either as a standalone treatment or in conjunction with other modes of treatment.” ECP for treatment of rejection received a grade of 1B (“strong recommendation, moderate quality evidence”), and rejection prophylaxis, grade 2A (“weak recommendation, high quality evidence”).2 The 2010 International Society of Heart Lung Transplantation (ISHLT) Guidelines for the Care of Heart Transplant Recipients suggest ECP as a class IIb therapy for recurrent or recalcitrant rejection.3 Despite these recommendations, the pediatric heart transplant literature contains very little information related to ECP, which may be a reflection of the technical difficulties of performing ECP in small patients, its unfamiliarity, and/or its unavailability, particularly in freestanding children’s hospitals. Furthermore, query of the Pediatric Heart Transplant Study database reveals that most instances of ECP use occurred at our institution (personal communication). Our objective is to report our unique experience with ECP in pediatric heart transplant patients.
volumes of red blood cells and albumin according to the patient’s total blood volume and hematocrit. To prevent fluid overload, the same volume given during ECP was removed from the patient at the end of the procedure. Other ECP pediatric modifications have been further described previously.6 In addition, the duration of the protocol changed during the study period. One course of ECP originally consisted of 15 series of 2 treatments on consecutive days, separated by 3 to 6 weeks, over 18 months. After 2000, the protocol was modified, such that 1 course of ECP now consists of 10 series of 2 treatments on consecutive days initially weekly but spacing out to monthly and finishing approximately within 6 total months. For purposes of this analysis, patients who received more than 1 ECP course separated by less than 6 months were not considered to have received distinct courses. Basic statistical analysis included a chi-square analysis using a Pearson test for significance. Kaplan-Meier curves were generated for the entire cohort and were also stratified by medical compliance vs non-compliance. Log-rank analysis was used to analyze survival differences.
Methods
Twenty heart transplant patients underwent 22 courses of ECP. Table 1 summarizes the characteristics of our ECP cohort. These patients received transplants at a mean age of 12.9 years (range, 0.3–18.5 years). Indications for transplantation included dilated cardiomyopathy in 14 patients, congenital heart disease in 4, restrictive cardiomyopathy in 1, and myocarditis in 1. ECP use has been relatively stable since 2001, averaging approximately 1.5 patients per year in the pediatric/young adult cohort (Figure 1). Median age at the time of the initial ECP was 15.7 years (range, 7.3–31 years). Only 1 patient was older than 19 years at the initial ECP. Median time from transplant to ECP was 1.4 years (range, 0.1–12.6 years). Nine patients underwent ECP within the first year after transplant. Indications for ECP varied and are listed in Table 1. The indication could not be ascertained in 2 patients. There were no important procedural complications related to ECP. Typically, immunosuppression was augmented before ECP (Table 1). Data were unavailable for 3 patients. All patients received steroid pulses after rejection. The following were also used depending on the rejection characteristics and era of transplantation: TPE in 6 patients, intravenous immunoglobulin in 2, rituximab in 2, Thymoglobulin (Genzyme Corp, Cambridge, MA) in 5, OKT3 in 2, and the addition of sirolimus in 2. Seven patients received more than 1 of these therapies. Two patients underwent a second course of ECP. Patient 17 had rejection with HC (felt to be mixed cellular and antibodymediated) 7 years after her initial ECP and underwent a second course of ECP but died 1 month after completing the ECP course of terminal rejection with HC. Non-compliance was not a concern. Patient 7 had recurrent rejection episodes beginning 2 years after the initial ECP; he received nearly 1.5 years of monthly ECP before dying of rejection. Non-compliance was a chronic concern in this patient. Thirteen patients died at a median of 3.1 years (range, 0.3 -13.8 years) from the start of ECP. Cause of death was
After obtaining approval from the Institutional Review Board, data were obtained from medical records of heart transplant patients aged 18 years or younger at the time of transplant who received ECP between 1990 and 2012. Heart–lung transplant recipients were excluded. Basic demographic and peri-transplant variables were collected. The transplant team defined medical noncompliance at the time clinical care was administered based partly on evidence of non-compliance with immunosuppression medication that compromised the patient’s clinical course. The primary outcome of interest was death. Secondary outcomes studied were ECP complications, infections, rejection episodes, and coronary artery vasculopathy (CAV). Immunosuppression protocols evolved during the study interval and have been summarized previously.4 Rejection episodes were routinely treated with intravenous pulse methylprednisolone or oral prednisone for 3 days. Patients with persistent or recurrent rejection additionally received lytic therapy (OKT3 or anti-thymocyte globulin) and conversion to tacrolimus and mycophenolate mofetil if not already receiving them. Patients with rejection with hemodynamic compromise (HC) additionally received 3 or more therapeutic plasma exchanges (TPE). ECP was generally used after these therapies at the discretion of the clinical care team. The presence of non-compliance was considered in the ECP decision making with the assumption that ECP would provide additional background immunosuppression that might reduce the likelihood of rejection if further noncompliance occurred. Occasionally, ECP was used prophylactically, and indications evolved during the study period. The standard adult ECP protocol, as previously published, was used.5 Most commonly, ECP was performed through a subcutaneous port accessing a subclavian vein. With this protocol, the total extracorporeal volume should be limited to 15% of the patient’s blood volume. The standard adult protocol was typically used for most patients in this series, including a 36-kg 17-year-old and a 38-kg 10-year-old. The modified pediatric protocol was used for Patient 3, a 24-kg 8-year-ol. The modification included priming the ECP circuit with crossmatched leukocyte-reduced packed red blood cells and giving an albumin bolus to the patient at the beginning of ECP. The apheresis team individualized the exact
Results
626 Table 1
The Journal of Heart and Lung Transplantation, Vol 33, No 6, June 2014 Details of Pediatric Heart Transplant Recipients Undergoing Extracorporeal Photopheresis Rejectionb
Age at Tx Pt Sex (year)
Etiology
Age at ECP (year)
Wt (kg) at ECP Indications for ↑Immuno prePost(kg) ECP ECPa Pre-ECP ECP
NC Outcome
1 F
0.3
CHD
10.2
55
Mixed HC
R, T
3A/HC
None
0
2 F
3.6
DCM
14.5
50
HC, AMR
P, R, T
AMR/HC None
0
3 M
4.3
RCM
7.3
24
Rec Rej
None
3A, 3A
None
0
4 F
9.3
DCM
10.7
47
Rec Rej
None
0
5 F
9.6
DCM
14.2
NA
NA
2R, 2R, None 2R NA NA
6 F
9.7
DCM
11.4
79
Pers Rej
None
3A/HC
3A
1
7 M
10.1
DCM
10.5
38
Pers Rej
NA
3A
3A
1
8 F
12.9
DCM
13.7
63
Pers Rej
T, S
3A
3A
1
9 M
14.2
Myocarditis
15.1
79
HC
P, T
HC, HC
None
1
10 M
15
CHD
16.4
45
Rec Rej
S
3A, 3A
3A
0
11 M
15
DCM
17.4
68
Pers Rej
None
3A
None
1
12 F
15.1
DCM
15.3
65
Rej
P, O
3B
None
1
13 M
15.6
DCM
17.9
69
Pers & Rec Rej None
3A, 3A
None
1
14 M
16
DCM
16.1
59
Prophylaxis
þXM
HC
1
15 M
17
CHD
17.2
36
Mixed, Pers Rej P, IVIG, T
2R/AMR 2R
0
16 F
17.4
DCM
19.3
61
Rej
O
3B
None
1
17 F
17.7
CHD
17.8
86
Prophylaxis
P, IVIG
þXM
None
0
18 M
18.2
DCM
18.6
71
NA
NA
NA
None
1
19 M
18.3
DCM
30.9
78
HC
P
HC, HC
HC
1
20 M
18.5
DCM
19
86
Rec Rej
None
3A, 2R
2R, 2R, 0 2R
None
1
Alive, 2.8 years Alive, 3.7 years Alive, 13.8 years Alive, 1.3 years Dead, 6.9 years Dead, 3.1 years Dead, 4.9 years Dead, 3.1 years Alive, 10.5 years Dead, 2.3 years Dead, 1.8 years Dead, 1.3 years Dead, 7.8 years Dead, 0.7 years Alive, 1.5 years Dead, 3.8 years Dead, 7.6 years Dead, 0.6 years Dead, 0.3 years Alive, 2 years
AMR, antibody-mediated rejection; CHD, congenital heart disease; DCM, dilated cardiomyopathy; HC, hemodynamic compromise; IVIG, intravenous immunoglobulin; NA, not available; NC, noncompliance; O, OKT3; P, plasmapheresis; Per, persistant; þXM, positive crossmatch; R, rituximab; RCM, restrictive cardiomyopathy; Rec, recurrent; Rej, rejection; S, sirolimus, T, Thymoglobulin (Genzyme Corp, Cambridge, MA); Tx, transplant. a Indicates administration of additional agents, excluding standard maintenance immunosuppression and steroid pulses, r 6 months of initiating ECP. All patients received intravenous steroid pulses after rejection. b Rejection definitions: Rec Rej (recurrent rejection) indicates Z 2 episodes of rejection (at least 3A or 2R) r 3-month period. Pers Rej (persistent rejection) indicates Z 2 biopsy specimens with at least 3A or 2R grade without an intervening improved biopsy specimen. Mixed indicates cellular and humoral rejection. HC indicates a rejection episode with hemodynamic compromise. Rejection pre-ECP or post-ECP indicates rejection episodes occurring in the 6 months before or after the start of ECP. A comma separates rejection episodes and a slash separates rejection episodes with multiple features.
related to rejection in 7 patients, infection in 1, sudden death with severe coronary allograft vasculopathy in 2, and sudden death of unclear etiology in 1. Cause of death could not be ascertained in 1 patient. Survival was not affected by era of transplantation (pre-2003) and ECP use during or after the first year post-transplant. Figure 2 depicts the survival curve for all patients starting at the time of ECP.
Twelve patients were considered non-compliant and died more frequently during the follow-up period than patients without documented non-compliance (92% vs 25%). These results represent worse survival over time (p ¼ 0.04) as determined by log-rank analysis. Figure 3 depicts the survival curve of all patients stratified by noncompliance.
Carlo et al.
ECP in Pediatric Heart Transplantation
Figure 1 Extracorporeal photopheresis use in pediatric heart transplant recipients is shown by year.
Rejection data were available for 18 patients. The number of rejection episodes in the 6 months preceding ECP was higher than in the 6 months after ECP (1.5 ⫾ 0.7 vs 0.6 ⫾ 0.8, p ¼ 0.002; Figure 4). Only 1 serious infection occurred during ECP. Patient 10 developed Pneumocystis carinii pneumonia that resulted in a prolonged hospitalization and cessation of ECP after 1.9 months. This same patient developed post-transplant lymphoproliferative disorder 3 years after heart transplantation, 18 months after ECP, and 4 months after renal transplantation. Of the 7 patients who received ECP within the first 3 years after transplant and lived longer than 5 years after transplant, 4 had angiographic evidence of CAV at 5.7, 6, 9.4, and 11.5 years after transplant, whereas 3 had no CAV at 5, 7.7, and 16.8 years after transplant.
Discussion Our objective was to review our unique experience with pediatric ECP after cardiac transplantation. We demonstrated that ECP could be applied to the pediatric population
Figure 2 Survival curve is shown for the entire extracorporeal photopheresis (ECP) cohort. Time 0 begins at ECP initiation.
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Figure 3 Survival curve for the extracorporeal photopheresis (ECP) cohort is shown stratified by patients who were and were not compliant. Time 0 begins at ECP initiation. Non-compliant patients had a trend toward lower survival (p ¼ 0.063).
safely, down to an age and size of 8 years and 24 kg, respectively, by modifying the ECP method. We furthermore demonstrated that non-compliant patients demonstrated lower survival than compliant patients despite ECP. Finally, acute rejection episodes were less frequent after ECP than before. Our survival curve and median survival time of 3.1 years after ECP are comparable to the 2-year survival of 65% for high-risk recurrent rejectors as reported by the Pediatric Heart Transplant Study.7 This mortality rate confirms that we used ECP in a high-risk sub-set. The poor outcomes of the non-compliant patients should not be considered as evidence against ECP. Rather, this supports ECP use as an adjunct to standard medical immunosuppression. In animal studies, transplanted mice not provided with medical immunosuppression live longer when treated with ECP products.8
Figure 4 Shown are the number of rejection episodes in the 6 months preceding extracorporeal photopheresis (ECP; 1.5 ⫾ 0.7) and in the 6 months after ECP (0.5 ⫾ 0.9; p ¼ 0.002 by paired Student’s t-test). The horizontal line in the middle of each box indicates the median; the top and bottom borders of the box mark the 75th and 25th percentiles, respectively; and the whiskers mark the 90th and 10th percentiles.
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The Journal of Heart and Lung Transplantation, Vol 33, No 6, June 2014
Our study serves as the largest series of ECP in pediatric heart transplantation. Larger pediatric experiences with ECP exist in other conditions, however, such as graft-versus-host disease.9,10 Clinical application of ECP in heart transplant patients has been better studied in adults. Prospective studies have demonstrated beneficial effects of prophylactic ECP on acute rejection11,12 and graft intimal hyperplasia.13 In a retrospective review from our institution’s adult transplant program, Kirklin et al4 demonstrated a reduction in the incidence of rejection down to a level comparable to the control transplant group when ECP was used as secondary prophylaxis in patients with HC rejection. From the results of these studies and other data, ASFA has endorsed ECP as an important second-line therapy for prophylaxis against rejection and treatment of acute rejection.2 Our study has important limitations. First, this study was by design a small retrospective case series, and any statistical analysis is limited. A large enough comparison cohort of at-risk patients not treated with ECP at our institution could not be identified. Next, indications for ECP varied between patients and were based on the clinical decision making of numerous physicians. Although intended to be a pediatric study, we included patients who received allografts at age 18 years or younger but who were older than 18 when they received ECP. These young adults, along with adolescents, have a higher risk of death from rejection in the first 5 years after transplant than other age groups.14 Importantly, we are unable to draw any conclusions regarding the effectiveness of ECP independent of other immunosuppressive modalities given the multiple methods of augmented immunosuppression prior to ECP in many of these patients. Finally, analysis of ECP effect on acute rejection is limited by the expected decreasing hazard of rejection over time, although this has been addressed in a prior adult study.4 In conclusion, despite its limitations, this study is important because it represents the largest series of ECP in pediatric heart transplantation. We have shown that ECP can be applied safely in this population. Because ECP is used more commonly in other pediatric disorders as well as in adult transplant centers, ECP may be available to pediatric heart transplant programs that have not previously used it. Factors favoring ECP use in our current practice include appropriate patient age and weight, recurrent/persistent rejection despite a course of anti-thymocyte therapy, rejection
with HC, medication non-compliance, and concerns related to donor-specific antibodies. We encourage consideration of ECP as a safe immunomodulatory tool in combatting pediatric allograft rejection.
Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
References 1. Dodd DA, Cabo J, Dipchand AI. Acute rejection: natural history, risk factors, surveillance, and treatment. In: Canter CE, Kirklin JK, editors. Pediatric transplantation. Philadelphia: Elsevier; 2007. p. 139-56. 2. Schwartz J, Winters JL, Padmanabhan A, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the writing committee of the American Society for Apheresis: the sixth special issue. J Clin Apher 2013;28:145-284. 3. Costanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010;29:914-56. 4. Kirklin JK, Brown RN, Huang ST, et al. Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis. J Heart Lung Transplant 2006;25:283-8. 5. Marques MB, Tuncer HH. Photopheresis in Solid Organ Transplant Rejection. J Clin Apher 2006;21:72-7. 6. Chan KW. Extracorporeal photopheresis in children with graft-versushost disease. J Clin Apher 2006;21:60-4. 7. 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;23:178-85. 8. George JF, Gooden CW, Guo L, Kirklin JK. Role for CD4(þ)CD25 (þ) T cells in inhibition of graft rejection by extracorporeal photopheresis. J Heart Lung Transplant 2008;27:616-22. 9. Kanold J, Paillard C, Halle P, D'Incan M, Bordigoni P, Deméocq F. Extracorporeal photochemotherapy for graft versus host disease in pediatric patients. Transfus Apher Sci 2003;28:71-80. 10. Messina C, Locatelli F, Lanino E, et al. Extracorporeal photochemotherapy for pediatric patients with graft-versus-host disease after hematopoietic stem cell transplantation. Br J Haematol 2003;122: 118-27. 11. Barr ML, Meiser BM, Eisen HJ, et al. Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. N Engl J Med 1998;339:1744-51. 12. Meiser BM, Kur F, Reichenspurner H, et al. Reduction of the incidence of rejection by adjunct immunosuppression with photochemotherapy after heart transplantation. Transplantation 1994;57:563-8. 13. Barr ML, Baker CJ, Schenkel FA, et al. Prophylactic photopheresis and chronic rejection: effects on graft intimal hyperplasia in cardiac transplantation. Clin Transplant 2000;14:162-6. 14. 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;30:151-7.
