EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Heart retransplant is a treatment option for some patients with graft failure. With heart donor short-age, it is important to assess candidates carefully for cardiac retransplant. An adult patient had a successful urgent heart retransplant due to severe toxic cardiomyopathy (anthracycline-induced) after posttransplant lymphoproliferative disease that was a diffuse large B-cell lymphoma.

Key words : Adverse effects, Cardiology, Immuno-suppression, Lymphoproliferative disorders

Heart transplant is the best treatment for end-stage heart failure. There are around 5000 heart transplants performed each year worldwide. Heart retransplant accounts for 2.6% of all heart transplant cases.¹ Posttransplant lymphoproliferative disease (PTLD) is a serious and potentially fatal complication of solid-organ transplant. In this article we present a rare case of an adult patient who underwent urgent cardiac retransplant due to severe toxic cardio-myopathy (anthracycline-induced) after treatment for large B-cell lymphoma.

A 14-year-old male patient underwent heart transplant in our hospital due to severe heart failure after viral myocarditis. He developed cytomegalovirus pneumonitis in the first month after surgery, but otherwise he led a normal, medically uneventful life and attended his medical follow-up regularly. At 6 years after heart transplant, he started to experience strong, dull, and intermittent pain in the upper back radiating caudally and to the lateral abdominal wall. The pain did not decrease despite analgesics. He had some relief when applying warm bandages. However, after 2 weeks, he began to experience abdominal discomfort and heaviness in the stomach, and he sought medical help.

Physical examination showed only mild spleno-megaly. Laboratory results indicated mild anemia (hemoglobin level, 122 g/L), increased sedimentation rate (32 mm/h) and slightly elevated liver enzyme levels (aspartate aminotransferase [AST], 56 U/L; alanine aminotransferase [ALT], 73 U/L). Abdominal ultrasound revealed multiple hypoechogenic lesions (diameter ≤ 3 cm) in the liver with clear borders and splenomegaly (14 cm). Positron emission tomography-computed tomography scan was performed and showed numerous hypodense lesions in the liver (≤ 3 × 2.5 cm) with enlarged lymph nodes in the retroperitoneum and along the hepatic artery (Figure 1). Histopathology of the focal liver lesion showed diffuse large monoclonal B-cell lymphoma (DLBCL). Echocardiography confirmed good allograft function, and myocardial biopsy showed no signs of graft rejection.

The patient's immunosuppressive therapy included cyclosporine (220 mg/d), mycophenolate mofetil (3000 mg/d), and prednisone (2.5 mg/d). After the diagnosis of PTLD was confirmed, the patient's cyclosporine daily dose was reduced by 50%, mycophenolate mofetil was reduced by 66%, and prednisone dose was increased to 10 mg/d. The patient received 8 cycles R-CHOP protocol (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) in 5 months, and he had no major adverse events or evidence of significant rejection on heart biopsy (International Society for Heart and Lung Transplantation grade 0 or 1R). Serial echo-
cardiographic studies showed normal heart function, and complete lymphoma remission was achieved.

Several months later, the patient was hospitalized for a sudden onset of dry cough, nausea, and malaise. Clinical examination showed mild hepatomegaly and mild perimalleolar edema. Laboratory results indicated liver and kidney dysfunction (prothrombin time [PT], 0.59; creatinine level, 145 μmol/L; potassium, 5.5 mmol/L; bilirubin, 38 μmol/L; AST, 66 U/L; ALT, 92 U/L). Echocardiography revealed dilation and severe systolic dysfunction of both ventricles (left ventricular ejection fraction, 25%; tricuspid annular plane systolic excursion, 12 mm) with severe mitral regurgitation and intermediate tricuspid regurgitation. The patient was treated with a diuretic, but his condition deteriorated rapidly, and dobutamine was added. Swan-Ganz catheterization showed severely reduced cardiac index (1.55 L/min/m²). Lactate level was elevated, and mixed venous oxygen saturation was 45%.

The patient showed no clinical response to medical treatment that included levosimendan, and his condition deteriorated progressively. The panel reactive antibody level was 6%, and the decision was made to enlist him for urgent heart transplant. He underwent the transplant 14 days later. This was complicated by an ischemic cerebrovascular accident and transient left limb paresis. The histopathology report of the explanted allograft excluded coronary allograft vasculopathy, graft rejection, and pericardial constriction as causes of heart failure. After heart retransplant he received prednisone and mycophenolate mofetil, and was switched to tacrolimus. After follow-up (22 mo), the patient's condition was uneventful.

Repeat cardiac transplant is considered in some heart transplant recipients. Although survival after repeat cardiac transplant has improved in the past decade, retransplant has an important ethical question due to chronic donor shortage and increased number of primary heart transplant candidates. The main causes of repeat heart transplant are allograft rejection, primary graft dysfunction, and coronary allograft vasculopathy.^2-5

The PTLD is a serious and potentially fatal complication of solid-organ transplant. The patho-genesis of PTLD in most patients (> 90%) is related to B-cell proliferation induced by infection with Epstein-Barr virus (EBV) in patients who have chronic immunosuppression and decreased T-cell immune surveillance.^6,7 The blood level of EBV replication for our patient was unavailable at the time of PTLD development, but he previously had positive EBV Epstein-Barr nuclear antigen 1 and EBV immunoglobulin G antibodies.

The PTLD may occur at any time after transplant, and systematic analysis showed that PTLD occurs in 1% to 20% solid-organ transplant patients.⁸ The incidence of PTLD is much greater in heart transplant recipients in whom a greater degree of immunosuppression is required.⁹ The most common form of PTLD is monomorphic B-cell PTLD, and most cases are DLBCL. There are no randomized studies that evaluated different treatment options for these patients, but the reduction of immuno-suppression can lead to regression of PTLD due to restoration of cytotoxic T-cell function.^10,11 Although reduction of immunosuppressive medications remains the first-line therapy for PTLD, many patients do not respond to this treatment alone, especially monomorphic or more aggressive cases of lymphoma. Guidelines for treating PTLD in heart and lung transplant patients include the recommendation of maximum reduction of immunosuppressive therapy to 50% to 75% baseline.¹² Trappe and coworkers showed good efficacy of immunochemotherapy with R-CHOP for PTLD.¹³

The onset of anthracycline-induced heart failure can occur at any time after anthracycline therapy. This heart failure is strongly correlated with the cumulative dose but has substantial interindividual variability which is not fully understood. The reported incidence of doxorubicin-induced cardiac dysfunction varies from 0.14% in patients who received < 400 mg/m², 4% to 7% patients who received 550 mg/m², and 18% to 36% patients who received ≥ 600 mg/m².^14,15 The prognosis of anthracycline-induced cardiotoxicity is poor, possibly even worse than the prognosis of ischemic or idiopathic cardiomyopathy.¹⁶ Our patient received doxorubicin (cumulative dose, 405.2 mg/m² in 5 months). A series of echocardiographic examinations during that period showed no myocardial dysfunction until clinical signs and symptoms of heart failure appeared. Time from chemotherapy introduction to heart failure symptoms and diagnosis was 9.5 months. Furthermore, N-terminal of the prohormone brain natriuretic peptide (NTproBNP) as a marker of heart failure had a slight increase during 5 months of chemotherapy but did not exceed 350 pg/mL until the clinical deterioration of the patient's condition. The patient had a previous history of cytomegalovirus infection after the first heart transplant, and polymerase chain reaction analysis for cytomegalovirus was performed when admitted due to heart failure and showed no detectable copies of cytomegalovirus DNA. Khan and associates reported a case of a 29-year-old patient with chronic anthracycline-induced cardiomyopathy that was treated successfully and reversed after treatment for 17 months with a left ventricular assist device.¹⁷ In one review, Johnson and coworkers reported 6 children who had heart retransplant after PTLD; the median time from first transplant to PTLD diagnosis was 5.8 years, median time from first transplant to retransplant was 7.33 years, and median patient survival after retransplant was 750 days (range, 15-2137 d).¹⁸ When performing retransplant after PTLD, it is advised to wait ≥ 12 months after achieving total remission except when dealing with critically ill and unstable patients, as was the situation with our patient who achieved total remission only 3 months earlier.¹²

In summary, to our knowledge, this case is the first report of a successful urgent heart retransplant in an adult patient who had PTLD and anthracycline-induced cardiomyopathy.

Volume: 13 Issue: 6 December 2015

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