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Tumor Lysis Syndrome Occurring After the Administration of Rituximab for Posttransplant Lymphoproliferative Disorder
Tumor Lysis Syndrome Occurring After the Administration of Rituximab for Posttransplant Lymphoproliferative Disorder S.A. Francescone, B. Murphy, J.T. Fallon, K. Hammond, and S. Pinney ABSTRACT Tumor lysis syndrome (TLS) may occur after the administration of rituximab for lymphoproliferative disorders. We describe the case of a heart transplant recipient who developed TLS after a single dose of rituximab for the treatment of posttransplant lymphoproliferative disorder. Because rituximab is being used more frequently, it is important for transplant physicians to be aware of this potential complication particularly after administering the first dose. ITUXIMAB IS AN engineered, chimeric, monoclonal antibody targeting the CD20 antigen found on the surface of B lympocytes.1 Rituximab has been used to treat low-grade non-Hodgkins lymphoma (NHL), chronic lymphocytic leukemia (CLL), and posttransplant lymphoproliferative disorder (PTLD).2,3 The binding of the engineered antibody to CD20 antigen ultimately results in B-cell lysis through antibody-dependent as well as complementmediated cytotoxicity.4 The low incidence of adverse events has made it an attractive alternative to the anthracyclines.3 There are, however, 5 reported cases of tumor lysis syndrome (TLS) occurring after the administration of rituximab for lymphoproliferative disorders.1,2,5,6 We describe a heart transplant recipient who developed TLS after receiving rituximab for treatment of B-cell PTLD.
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CASE REPORT A 47-year-old man with a history of psoriasis and hypertension underwent orthotopic heart transplantation at age 35 for treatment of a dilated cardiomyopathy. His posttransplant course was unremarkable for rejection or opportunistic infection. Twelve years later, he developed dyspnea and near syncope while climbing a flight of stairs. Angiography revealed diffuse allograft vasculopathy. The first diagonal branch of the left anterior descending artery was stented with a bare metal stent to relieve a 95% stenosis. Echocardiography revealed moderate biventricular dysfunction. Azathioprine was discontinued and rapamycin prescribed. Other medicines included cyclosporine (Sandimmune), simvastatin, amlodipine, aspirin, and clopidogrel. An implantable cardioverter defibrillator was implanted for prevention of sudden cardiac death. He was evaluated for a second heart transplant and simultaneous renal transplant because his glomerular filtration rate was less than 40 mL/min. A renal biopsy showed arterial and arteriolar nephrosclerosis, focal segmental glomerular sclerosis, and no evidence of calcineurin inhibitor toxicity. Four months after starting rapamycin, he developed a nonproductive cough. Computed tomography (CT) of the chest showed
subcentimeter mediastinal adenopathy and innumerable nodular opacities in both lungs with ground glass opacities at both lung bases. In addition, there were focal areas of consolidation with air bronchograms in both bases. Repeat CT 4 weeks later showed resolution of the ground glass opacities with the new development of nodular densities in the superior segment of the right upper lobe, including a 1.3-cm nodule and a reticular nodular infiltrate in the right middle lobe. He was readmitted with acute on chronic renal failure. He was pancytopenic with a white blood count (WBC) 2.2 ⫻ 103/L, hematocrit 26%, and platelets 103 ⫻ 103/L. Lactate dehydrogenase (LDH) was 669 /L. Rapamycin was discontinued. Polymerase chain reaction for Ebstein-Barr virus (EBV) was positive with 8731 copies. A bone marrow biopsy showed a mildly hypercellular marrow. No evidence of tumor or infiltrative disease was seen. Flow cytometry revealed no abnormal phenotypes. A video-assisted thoracoscopy was performed along with right lower and right middle lobe biopsy and mediastinal lymph node sampling. All wedge biopsies showed organizing pneumonia without identification of infectious organisms. The lymph nodes were benign. An atypical lymphoid aggregate was seen in one of the wedge biopsies from the right upper lobe. Immunoperoxidase stains showed positive staining of lymphoid aggregates for both CD3 and CD20. An in situ hybridization test with Epstein-Barr virus-encoded small RNA (EBER) showed strong nuclear staining of cells diffusely throughout the aggregates (Fig 1). These findings were consistent with EBV-positive plasma cell hyperplasia or early phase PTLD. After the diagnosis of B-cell PTLD was confirmed, he received a single infusion of rituximab 375 mg/m2. Four days later he was brought by ambulance to a local hospital in respiratory distress and placed on mechanical ventilation. He was anuric with severe From the Mount Sinai Medical Center, New York, New York. Address reprint requests to Dr Sean Pinney, Mount Sinai Medical Center, Department of Cardiology, One Gustav Levy Place, Box 1030, New York, NY 10029. E-mail: sean.pinney@ mssm.edu
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.03.060
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1946
Transplantation Proceedings, 41, 1946 –1948 (2009)
RITUXIMAB AND TUMOR LYSIS SYNDROME
1947
Fig 1. Photomicrographs of mononuclear cell infiltrate in 1 lung wedge biopsy. A. H&E stain of the polymorphic infiltrate with occasional large blast like cells. B. CD20 immunoperoxidase stain of same area as in A revealing that most of the cells in the infiltrate are B-cells. C. In situ hybridization for EBV showing that the majority of the cell nuclei are positive for EBV. (Original magnifications: A ⫻20; B ⫻40; C ⫻40.) metabolic acidosis. The arterial blood gas was pH, 7.19; PCO2, 32 mmHg, PO2, 219 mmHg; HCO3, 12 mEq/L arterial lactate, 7.4 mmol/L; and ionized calcium, 0.74 mmol/L. The serum calcium was 6.0 mg/dL; potassium, 6.5 mEq/L; phosphorous, 12.7 mg/dL; blood urea nitrogen, 149 mg/dL; creatinine 6.4, mg/dL; LDH, 22,300 /L; uric acid, 11 mg/dL; and cyclosporine level, 107 ng/mL. Complete blood count showed WBC, 20 ⫻ 103/L; hematocrit, 30.9%; and platelets, 168 ⫻ 103/L. Hemodialysis was performed and broad-spectrum antibiotics were administered. Blood cultures remained negative for microorganisms. He experienced pulseless electrical activity, but was not resuscitated as per his family’s wishes. A postmortem examination was not obtained.
DISCUSSION
PTLD occurs in approximately 2% of all solid organ transplant recipients. The patient we present had an EBVassociated B-cell PTLD and developed TLS after a single dose of rituximab. The diagnosis of TLS was based on the presence of hypocalcemia, hyperphosphatemia, increased
uric acid, acute renal failure, and the markedly elevated LDH. TLS has been reported with the use of rituximab in cases of NHL and CLL including in immunocompromised hosts.1 We believe this to be the first reported case of TLS from rituximab occurring in a heart transplant recipient. This case raises several important concerns regarding the use of rituximab. First, it adds to the reports of TLS encountered with rituximab in treating other malignancies. Second, it raises awareness about a potentially fatal complication of treating PTLD in organ transplant recipients. Finally, it strengthens the view that TLS usually occurs after administering the first dose of rituximab.1,2,5,6 Transplant physicians who may be less familiar with treating hematologic malignancies should be aware of the need to monitor patients closely after administering rituximab, and consider extending hospitalization to ensure an adequate period of observation. The development of TLS is not always fatal; in fact, the majority of patients in prior case reports survived and went
1948
on to receive further cycles of therapy. Our patient received the standard dose of 375 mg/m2, but some have recommended treatment with an initially reduced “predose” for patients considered high risk for TLS on the basis of either bulky nodal disease or significantly elevated WBC counts.2 Pretreatment with a reduced rituximab dose or aggressive hydration followed by several days of close observation seem to be prudent steps to take to reduce the risks of TLS.
REFERENCES 1. Yang H, Rosove MH, Figlin RA: Tumor lysis syndrome occurring after the administration of rituximab in lymphoprolifera-
FRANCESCONE, MURPHY, FALLON ET AL tive disorders: high-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Am J Hematol 62:247, 1999 2. Jensen M, Winkler U, Manzke O, et al: Rapid tumor lysis in a patient with B-cell chronic lymphocytic leukemia and lymphocytosis treated with an anti-CD20 monoclonal antibody (IDECC2B8, rituximab). Ann Hematol 77:89, 1998 3. Scott SD: Rituximab: a new therapeutic monoclonal antibody for non-Hodgkin’s lymphoma. Cancer Pract 6:195, 1998 4. Reff ME, Carner K, Chambers KS, et al: Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435, 1994 5. Jabr FI: Acute tumor lysis syndrome induced by rituximab in diffuse large B-cell lymphoma. Int J Hematol 82:312, 2005 6. Abou Mourad Y, Taher A, Shamseddine A: Acute tumor lysis syndrome in large B-cell non- Hodgkin lymphoma induced by steroids and anti-CD 20. Hematol J 4:222, 2003
R
CASE REPORT A 47-year-old man with a history of psoriasis and hypertension underwent orthotopic heart transplantation at age 35 for treatment of a dilated cardiomyopathy. His posttransplant course was unremarkable for rejection or opportunistic infection. Twelve years later, he developed dyspnea and near syncope while climbing a flight of stairs. Angiography revealed diffuse allograft vasculopathy. The first diagonal branch of the left anterior descending artery was stented with a bare metal stent to relieve a 95% stenosis. Echocardiography revealed moderate biventricular dysfunction. Azathioprine was discontinued and rapamycin prescribed. Other medicines included cyclosporine (Sandimmune), simvastatin, amlodipine, aspirin, and clopidogrel. An implantable cardioverter defibrillator was implanted for prevention of sudden cardiac death. He was evaluated for a second heart transplant and simultaneous renal transplant because his glomerular filtration rate was less than 40 mL/min. A renal biopsy showed arterial and arteriolar nephrosclerosis, focal segmental glomerular sclerosis, and no evidence of calcineurin inhibitor toxicity. Four months after starting rapamycin, he developed a nonproductive cough. Computed tomography (CT) of the chest showed
subcentimeter mediastinal adenopathy and innumerable nodular opacities in both lungs with ground glass opacities at both lung bases. In addition, there were focal areas of consolidation with air bronchograms in both bases. Repeat CT 4 weeks later showed resolution of the ground glass opacities with the new development of nodular densities in the superior segment of the right upper lobe, including a 1.3-cm nodule and a reticular nodular infiltrate in the right middle lobe. He was readmitted with acute on chronic renal failure. He was pancytopenic with a white blood count (WBC) 2.2 ⫻ 103/L, hematocrit 26%, and platelets 103 ⫻ 103/L. Lactate dehydrogenase (LDH) was 669 /L. Rapamycin was discontinued. Polymerase chain reaction for Ebstein-Barr virus (EBV) was positive with 8731 copies. A bone marrow biopsy showed a mildly hypercellular marrow. No evidence of tumor or infiltrative disease was seen. Flow cytometry revealed no abnormal phenotypes. A video-assisted thoracoscopy was performed along with right lower and right middle lobe biopsy and mediastinal lymph node sampling. All wedge biopsies showed organizing pneumonia without identification of infectious organisms. The lymph nodes were benign. An atypical lymphoid aggregate was seen in one of the wedge biopsies from the right upper lobe. Immunoperoxidase stains showed positive staining of lymphoid aggregates for both CD3 and CD20. An in situ hybridization test with Epstein-Barr virus-encoded small RNA (EBER) showed strong nuclear staining of cells diffusely throughout the aggregates (Fig 1). These findings were consistent with EBV-positive plasma cell hyperplasia or early phase PTLD. After the diagnosis of B-cell PTLD was confirmed, he received a single infusion of rituximab 375 mg/m2. Four days later he was brought by ambulance to a local hospital in respiratory distress and placed on mechanical ventilation. He was anuric with severe From the Mount Sinai Medical Center, New York, New York. Address reprint requests to Dr Sean Pinney, Mount Sinai Medical Center, Department of Cardiology, One Gustav Levy Place, Box 1030, New York, NY 10029. E-mail: sean.pinney@ mssm.edu
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.03.060
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1946
Transplantation Proceedings, 41, 1946 –1948 (2009)
RITUXIMAB AND TUMOR LYSIS SYNDROME
1947
Fig 1. Photomicrographs of mononuclear cell infiltrate in 1 lung wedge biopsy. A. H&E stain of the polymorphic infiltrate with occasional large blast like cells. B. CD20 immunoperoxidase stain of same area as in A revealing that most of the cells in the infiltrate are B-cells. C. In situ hybridization for EBV showing that the majority of the cell nuclei are positive for EBV. (Original magnifications: A ⫻20; B ⫻40; C ⫻40.) metabolic acidosis. The arterial blood gas was pH, 7.19; PCO2, 32 mmHg, PO2, 219 mmHg; HCO3, 12 mEq/L arterial lactate, 7.4 mmol/L; and ionized calcium, 0.74 mmol/L. The serum calcium was 6.0 mg/dL; potassium, 6.5 mEq/L; phosphorous, 12.7 mg/dL; blood urea nitrogen, 149 mg/dL; creatinine 6.4, mg/dL; LDH, 22,300 /L; uric acid, 11 mg/dL; and cyclosporine level, 107 ng/mL. Complete blood count showed WBC, 20 ⫻ 103/L; hematocrit, 30.9%; and platelets, 168 ⫻ 103/L. Hemodialysis was performed and broad-spectrum antibiotics were administered. Blood cultures remained negative for microorganisms. He experienced pulseless electrical activity, but was not resuscitated as per his family’s wishes. A postmortem examination was not obtained.
DISCUSSION
PTLD occurs in approximately 2% of all solid organ transplant recipients. The patient we present had an EBVassociated B-cell PTLD and developed TLS after a single dose of rituximab. The diagnosis of TLS was based on the presence of hypocalcemia, hyperphosphatemia, increased
uric acid, acute renal failure, and the markedly elevated LDH. TLS has been reported with the use of rituximab in cases of NHL and CLL including in immunocompromised hosts.1 We believe this to be the first reported case of TLS from rituximab occurring in a heart transplant recipient. This case raises several important concerns regarding the use of rituximab. First, it adds to the reports of TLS encountered with rituximab in treating other malignancies. Second, it raises awareness about a potentially fatal complication of treating PTLD in organ transplant recipients. Finally, it strengthens the view that TLS usually occurs after administering the first dose of rituximab.1,2,5,6 Transplant physicians who may be less familiar with treating hematologic malignancies should be aware of the need to monitor patients closely after administering rituximab, and consider extending hospitalization to ensure an adequate period of observation. The development of TLS is not always fatal; in fact, the majority of patients in prior case reports survived and went
1948
on to receive further cycles of therapy. Our patient received the standard dose of 375 mg/m2, but some have recommended treatment with an initially reduced “predose” for patients considered high risk for TLS on the basis of either bulky nodal disease or significantly elevated WBC counts.2 Pretreatment with a reduced rituximab dose or aggressive hydration followed by several days of close observation seem to be prudent steps to take to reduce the risks of TLS.
REFERENCES 1. Yang H, Rosove MH, Figlin RA: Tumor lysis syndrome occurring after the administration of rituximab in lymphoprolifera-
FRANCESCONE, MURPHY, FALLON ET AL tive disorders: high-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Am J Hematol 62:247, 1999 2. Jensen M, Winkler U, Manzke O, et al: Rapid tumor lysis in a patient with B-cell chronic lymphocytic leukemia and lymphocytosis treated with an anti-CD20 monoclonal antibody (IDECC2B8, rituximab). Ann Hematol 77:89, 1998 3. Scott SD: Rituximab: a new therapeutic monoclonal antibody for non-Hodgkin’s lymphoma. Cancer Pract 6:195, 1998 4. Reff ME, Carner K, Chambers KS, et al: Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435, 1994 5. Jabr FI: Acute tumor lysis syndrome induced by rituximab in diffuse large B-cell lymphoma. Int J Hematol 82:312, 2005 6. Abou Mourad Y, Taher A, Shamseddine A: Acute tumor lysis syndrome in large B-cell non- Hodgkin lymphoma induced by steroids and anti-CD 20. Hematol J 4:222, 2003