Early heart transplant in a child withadvanced lymphoma

Advanced stage large cell lymphoma in childrenis often curable using modern chemotherapy withoverall disease-free survival in excess of 70% (1).

The most common complications of therapyare immediate and reversible. Anthracycline-induced cardiomyopathy occurs less frequently,but may be life-threatening (2). For patients withsevere cardiomyopathy who fail medical man-agement, heart transplantation can be life saving(3).

We report a child with B-cell large cell StageIII lymphoma who developed overwhelminganthracycline cardiotoxicity early in the courseof her planned treatment protocol when theoutcome of her primary malignancy was stilluncertain. She required ventilation, dialysis andintensive inotropic support. This child received aheart transplant after lengthy and difficult dis-cussions concerning the medical and ethicalissues inherent in the situation.

Case report

A 6-yr-old Caucasian female presented inDecember 1996 with a 10-day history of scleralicterus, dark urine, jaundice and clay coloredstools. She had been previously well with nonausea, vomiting, diarrhea, abdominal pain,anorexia, weight loss, fever, diaphoresis or bonepain. Her physical examination was remarkablefor jaundice, abdominal distention and a firm

mass in the upper abdomen. Initial laboratorystudies revealed a normal CBC, BUN and creat-inine, electrolytes and uric acid; ALT-305 IU,AST-294 IU, total bilirubin 13.9 mg/dL, directbilirubin-11.1 mg/dL, lipase-390 mg/dL. CT ofthe abdomen and chest revealed soft tissuedensities anterior to the left lobe of the liverand right ventricle, multiple lymph nodes in theporta hepatis, a large soft tissue mass in theregion of the head of the pancreas, and biliaryduct dilatation. A bone scan, bone marrow, andcerebrospinal fluid evaluation were normal. Anopen biopsy of the epigastric mass was consistentwith a diagnosis of large cell lymphoma (T-cellrich B-cell type Stage III).

The patient was treated with prednisone,cyclophosphamide and prophylactic intrathecalmedications every 3 weeks for two courses.Adriamycin and vincristine were then addedafter resolution of hyperbilirubinemia. After6 weeks of initial therapy, a CT scan confirmedthe remission of the lymphoma. Therapy wascontinued following a standard pediatricprotocol. At week 22, one week following acourse of medication (total anthracycline dose ¼240 mg/m2) she was admitted to the intensivecare unit with hypotension, liver and renal failureand marked cardiac dysfunction. Her cognitiveand neurologic function were normal. Echocar-diographic findings revealed a left ventricularshortening fraction of 9.2% on intravenousinotropes. An endomyocardial biopsy was con-sistent with severe anthracycline cardiotoxicity.There was no evidence of viral infection. During1 month in intensive care, the patient’s statuscontinued to worsen, requiring hemodialysis and

Morgan E, Pahl E. Early heart transplant in a child with advancedlymphoma.Pediatr Transplantation 2002: 6: 509–512.� 2002 Blackwell Munksgaard

Abstract: A child with advanced stage large cell lymphoma in remissiondeveloped overwhelming, irreversible anthracycline cardiac toxicityincompatible with life early in her treatment course. The medicalcomplexities and ethical issues concerning a decision to proceed withorthotopic heart transplantation are discussed.

Elaine Morgan and Elfriede PahlChildren's Memorial Hospital, NorthwesternUniversity Medical School, Chicago, Illinois, USA

Key words: cardiomyopathy – lymphoma – hearttransplantation – ethics

Correspondence: Elaine R. Morgan, MD, Division ofHematology/Oncology, Children's Memorial Hospital,2300 Children's Plaza, Chicago, IL 60614, USA

Accepted for publication 10 June 2002

Abbreviations: CT, computerized tomography; EBV,Epstein–Barr virus; CNS, central nervous system; ICU,intensive care unit; PTLD, post-transplant lymphoprolifer-ative disease.

Pediatr Transplantation 2002: 6: 509–512

Printed in UK. All rights reservedCopyright � 2002 Blackwell Munksgaard

Pediatric TransplantationISSN 1397-3142

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mechanical ventilation with neuromuscularblockade for optimal control of her cardiorespi-ratory function. Based on the lack of underlyingrenal disease, as evidenced by renal ultrasound,the urinalysis lacking evidence for intrinsic renalpathology and initial improvements in urineoutput related to improved blood pressure, aswell as experience with other patients with severemyocardial dysfunction, the nephrologists wereconvinced that her kidney function would recov-er if her cardiac output could be improved.

At this time, intensive discussions with in-volved caregivers and the parents were underta-ken concerning the possibility of hearttransplantation as the only potential treatmentwhich would permit survival. Although therewere uncertainties regarding renal function andeventual cancer outcome, it was decided that thechance for survival justified proceeding withtransplantation.

The patient received an orthotopic hearttransplant 5 weeks following her initial ICUadmission and subsequently recovered com-pletely. Immunosuppression included cyclospo-rin (CSA) 5 mg/kg and imuran 0.5 mg/kg pre-operatively and post-operatively beginning atdays 4 and 21, respectively, at standard dosing.She did not receive induction lympholytics.Routine steroids were administered for6 months. One episode of rejection at day 25necessitated an increased steroid dose. Subse-quent tumor surveillance consisted of physicalexamination, CBC, hepatic chemistries and ab-dominal ultrasound performed during the first2 yr. Currently, 5 yr later, she continues to dowell with normal hematologic, renal and liverfunction and no evidence of tumor recurrence.Current immunosuppression consists of CSAand imuran. Her clinical course has been unre-markable and cardiac graft function remainsexcellent; she has no physical activity restrictionsand attends school full-time. EBV titers havebeen consistently negative since the date of initialdiagnosis.

Discussion

Our patient, who developed idiosyncratic over-whelming anthracycline cardiotoxicity early inthe course of treatment of lymphoma, presentedcomplex medical and ethical challenges. Herunstable ICU course and uncertainty aboutorgan function (renal and CNS) raised concernabout probability of immediate survival follow-ing the proposed cardiac transplantation. Therewas also concern about the outcome of hermalignancy, which had been in remission for

only 5 months with administration of less thanone-half of the initially planned courses ofchemotherapy. Children with Stage III large celllymphomas of the B-cell immunophenotype havedemonstrated a disease-free survival of 60–80%(4, 5) with the majority of relapses occurringwithin 2 yr of diagnosis (6). For this child,further treatment and/or observation prior totransplantation was contra-indicated by hermedical status. Likewise, there was the theoret-ical risk of reactivation of this child’s tumorfollowing immunosuppression. Since her lym-phoma was not EBV related, as evidenced byconsistently negative EBV titers in this previouslyimmunocompetent host, the risk of secondaryPTLD in this child was not felt to be significantlyhigher than that for other patients (7). Howeverthe extent to which immune recovery afterchemotherapy is necessary for control of minimalresidual cancer has not been ascertained.

Anthracycline induced cardiac toxicity rarelyoccurs in children and is generally, but notpredictably, dose related (8). For patients withsevere cardiac decompensation, which is notmedically reversible, heart transplantation is theonly option for the preservation of organ func-tion and life (3). Fortunately, in children treatedfor malignancy, the majority of such events occurafter the completion of treatment (9), and at atime when the risk of relapse of the underlyingcancer is sufficiently low that the transplant canbe ethically performed without undue concernabout death from cancer (2). In a recent guidelinestatement, 5 yr has been considered the routineperiod of waiting.

Organ transplantation has been performed inadults with malignancy soon after treatment (10,11), in children and adults who are long-termsurvivors (7, 12) and in selected children as aprimary management of embryonal liver orkidney tumors (13).

Heart transplantation in children is performedin approximately 300 patients each year in theUSA (14), with immediate survival rates atexperienced centers greater than 90% and 5-yearsurvival rates after listing for transplant rangingfrom 65% to 75% (15). The quality of life inchildren receiving heart transplants is excellentdespite limitations to late survival.

The decision to transplant a child must bemade carefully because of the long-term impli-cations for the child and family. Discussionsmust involve the entire multidisciplinary medicalcare team, as well as the family and wheneverappropriate, the child. The primary factorsinfluencing the decision include life expectancy

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and quality of life with or without transplant.Relative contra-indications to transplant arestated in a recent consensus report, and includeactive or recent malignancy, as well as evidenceof irreversible end organ damage to kidney, liveror CNS (16). There is no clear consensus onwhen it might be safe in a patient with malig-nancy, as regards tumor recurrence, to offer hearttransplant. The majority of pediatric tumorsdestined to relapse will do so within 2 yr ofdiagnosis, calling into question the traditional5 yr waiting time. Absolute contra-indications toheart transplantation at our center are rare, butinclude: (i) Sepsis, (ii) active malignancy, (iii)irreversible multiorgan failure, (iv) severe CNSinsult with poor prognosis neuro-clinically and(v) systemic disease affecting non-cardiac organswith poor prognosis.

Regulations regarding the allocation of cada-ver organs have been developed by UNOS andare not uniform among kidney, heart, lung andliver donations. Rules governing patient priori-tization for heart transplant impact time totransplant after the initial assessment of appro-priateness of an individual patient based on thefactors listed above. These rules consider geo-graphic proximity, organ size and disease severity(17, 18). Furthermore, there are allocation issuesrelated to the procurement of organ donor heartsappropriate for pediatric use (19).

Decisions concerning the transplantation ofscarce organs are ethical dilemmas regardingresource allocation that are currently decidedindividually at the bedside. It requires the moraland ethical commitment of physicians requestingorgans to honestly evaluate the chance of survi-val of the patient, given all the variables involvedin the case.

This minimizes the likelihood of use of anorgan when transplantation could be predicted tohave minimal chance of success, thereby denyingthe organ to another patient who may then alsonot survive.

The principle of justice requires that suchdecisions be based on need and outcome, and noton social or economic considerations or on somearbitrary and biased evaluation of the �worth� ofa life.

When there is a �rational� chance of successdespite a degree of uncertainty, it seems reason-able for the patient’s physician to act as thepatient’s advocate and to proceed with listing fortransplantation, assuming the patient, if compet-ent, or the surrogate is fully informed of the risk,burdens of further care and potential short andlong-term complications of the treatment. Themeaning of what constitutes a �rational chance

for success� must at this time be determined on acase-by-case basis and cannot be assigned astatistical probability of survival.

While guidelines concerning the allocation ofscarce resources (e.g. transplantable cadavericorgans) are important for the just care ofpotential recipients, cases such as this maychallenge the guidelines. Rigid rules about prog-nosis and survival from pre-existent illness basedon statistical probabilities may unfairly excludesome potentially salvageable recipients. This isespecially true in situations such as ours, whereconsiderable medical uncertainty exists. By itsvery nature transplant medicine is often associ-ated with risk of failure.

Transplant should only be undertaken wherethere is clearly a good chance for benefit to thepatient. However, weighing the risks of failureand chance of success is at best an inexactscience. Furthermore, the assessment of ethicallyacceptable chance for success is a question ofphilosophy rather than science and will undoub-tedly be impacted by situational and personalfactors. These must be combined with generallyaccepted guidelines governing organ allocation.A team approach to controversial and difficultdecisions including patient, family, medical care-givers and if necessary, external medical reviewand ethical consultation may help to preservebasic ethical principles of beneficence, non-maleficence, autonomy and justice (20).

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