Danon disease is a rare X-linked lysosomal storage disease (LSD) characterized by an early onset of muscle weakness and severe cardiomyopathy sometimes, necessitating heart transplantation.[1,2] The underlying defect is poorly understood, but is associated with a mutation in the lysosome-associated membrane protein-2 (LAMP2) gene and modulations in autophagy. Elevated serum creatinine kinase (CK) levels are sometimes observed.
Posttransplant lymphoproliferative disorders (PTLDs) occur in up to 10% of organ transplant recipients with heterogeneous clinical manifestations ranging from indolent polyclonal proliferations of lymphocytes to aggressive lymphomas.[4,5] Current treatment strategies recommend a sequential therapy including reduction of immunosuppression, use of rituximab (R), combination chemotherapy, and radiation.[4–8] If chemotherapy is needed, anthracycline-based chemotherapy, that is the CHOP protocol (cyclophosphamide, doxorubicin, vincristine, prednisone) in combination with R, is generally considered to be the most effective treatment especially in B-cell-derived PTLDs.[6,7]
As far as our knowledge is concerned, the co-occurrence of Danon disease and PTLD has not been reported yet.
2 Case report
We report a unique case of Danon disease with PTLDs after heart transplantation.
In March 2015, a 22-year-old Caucasian male student who had undergone heart transplantation at the age of 12 due to hypertrophic cardiomyopathy associated with LAMP2-positive Danon disease was diagnosed with a non-Epstein–Barr virus (EBV)-associated PTLD. Histopathological examination showed diffuse large B-cell lymphoma (DLBCL) of centroblastic and germinal center type highly positive for BCL6, weakly for v-myc avian myelocytomatosis viral oncogene homolog, but negative for BCL2 protein (double hit score 0), with a proliferation index of 95%. Clinical manifestations included extranodal lymphoma of the jejunum, mesentery, rectus abdominis muscle, and multiple lymph nodes (clinical stage III with bulky disease) (Fig. 1A). Physical examination revealed a large (5 × 6 cm) tumor in the abdominal wall. Lactate dehydrogenase levels (LDHs) had been elevated since childhood (range 450–1885 U/L) and was assumed to be associated with Danon disease. The patient's family history did not include Danon disease, and was negative for malignant diseases. The patient's medical history revealed chronic rhabdomyolysis, with CK levels around 1100 U/L, a retinopathy/myopia, and a human cytomegalovirus (HCMV) reactivation in 2007.
Initially, immunosuppression was modified (treatment with mycophenolic acid 900 mg/d was discontinued, whereas treatment with tacrolimus 2.5 mg/d was unchanged), and the patient received a total of 4 doses of rituximab weekly without sufficient response.[4,6,10] Immunochemotherapy was therefore planned.[4,6,10] Since we were concerned for an exacerbation of the rhabdomyolysis with short-term infusion of R-CHOP, we initiated treatment with reduced-dose EPOCH-R (1 m2 instead of 1.68 m2; etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone with rituximab).[11,12] This was intended to reduce peak concentrations of doxorubucin, which can be associated with muscle damage and carry a higher risk for cardiotoxicity[13,14]; and to enable immediate interruption of doxorubicin administration in case of severe myolysis. EPOCH-R was well-tolerated and CK levels even decreased during treatment (Fig. 2).
After the second cycle, the patient developed febrile neutropenia and reported abdominal pain, and was affected by enduring vomiting. A computed tomography (CT) scan showed distended intestinal loops, and also partial remission of the lymphoma. Our interdisciplinary team decided to use a conservative approach and to continue chemotherapy with EPOCH-R.
After the third cycle, a positron emission tomography–magnetic resonance imaging revealed complete metabolic remission (CR) of the lymphoma, but intestinal loops were still distended (Fig. 1B). A few days later, the patient developed clinical signs of a mechanical ileus due to adhesions that required surgical treatment. Histologically, no signs of malignancy were detected. After surgery, the patient received additional 3 cycles of EPOCH-R, which he tolerated well without any side-effects, and has been in CR since. Both the systolic function monitored by echocardiography and pro-B-type natriuretic peptide (pro-BNP) remained unaffected before, during, and after treatment.
The LSDs are a heterogeneous group of rare inherited disorders with trafficking dysfunctions within the lysosome–endosome system leading to substrate accumulation in different organs. Long-term complications include prolonged local inflammation, activation of cell-death signaling, and dysregulation of autophagy. These pathologic conditions often induce irreversible organ dysfunction that require organ transplantation. Recently, LSDs were reported to be at increased risk for malignancies, including multiple myeloma and aberrant myelopoiesis, but further studies are urgent.[16,17] Due to the rare co-occurrence of LSDs and malignancies, and since drug metabolism and side-effects may differ, there is an urgent need to report cases like ours to improve management of these patients. Therapeutic approaches in LSDs are currently being investigated in preclinical and clinical trials. Evidence for administration of immunomodulating agents such as R has been reported in cases in which patients developed IgG antibodies after treatment with enzyme replacement therapy (ERT).
Initially, the reduction of immunosuppression and treatment with R alone—according to the international recommendations and to our local standard operating procedures for patients with PTLD—seemed to be a safe option for our patient.[4,6,7] Although CK and LDH levels began to decrease upon treatment initiation, the lymphoma did not sufficiently respond to therapy. Complicating circumstances were: the underlying Danon disease that had already affected the heart requiring heart transplantation; cardiac toxicity as a well-known side-effect of anthracyclines, particularly when administered with high peak concentrations; lack of literature and local experience with respect to administration of chemotherapy in patients with pre-existent chronic rhabdomyolysis and considerable muscle infiltration.
In nontransplant-associated DLBCL, continuous administration of EPOCH-R showed high efficiency in high-risk cases such as double-hit (DH) lymphomas, and treatment with EPOCH has been reported in a few PTLD cases.[18,19]
Given that this form of anthracycline infusion might be less cardiotoxic and might have other advantages, especially the presented, we decided to start therapy with reduced dose (1 m2) EPOCH-R.[11,13] Treatment was generally well-tolerated with rapid response and without severe side-effects, and left ventricular systolic function remained unaffected.
We conclude that the EPOCH-R protocol might have an advantage over R-CHOP, especially in more complex cases with higher risk of therapy-induced complications, and also shows high efficacy in PTLDs.
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