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Diagnosis and Treatment of Rituximab-Induced Acute Tumor Lysis Syndrome in Patients With Diffuse Large B-Cell Lymphoma
CASE REPORT
Diagnosis and Treatment of Rituximab-Induced Acute Tumor Lysis Syndrome in Patients With Diffuse Large B-Cell Lymphoma Bo Yang, PhD, Xue-Chun Lu, PhD, Rui-Li Yu, PhD, Xiao-Hua Chi, MD, Wen-Ying Zhang, MS, Hong-Li Zhu, PhD, Jing Yuan, MS and Po Zhao, PhD
Abstract: Acute tumor lysis syndrome (ATLS) is a recognized complication of the treatment of malignant lymphomas and is associated with significant morbidity and mortality. However, there have been few reports of the occurrence of ATLS in patients treated with rituximab. This study reports 2 patients with high-grade diffuse large B-cell non-Hodgkin’s lymphoma who presented high tumor load, were sensitive to treatment and had multiple risk factors for ATLS. Both patients developed ATLS after treatment with rituximab and, despite aggressive supportive therapy, died of multiple organ failure. These cases illustrate that ATLS can occur after treatment with rituximab and that a high index of suspicion is necessary for the prompt diagnosis of ATLS. Key Indexing Terms: Acute tumor lysis symptom; Non-Hodgkin’s lymphoma; Diffuse large B-cell lymphoma; Diagnosis; Treatment. [Am J Med Sci 2012;343(4):337–341.]
A
cute tumor lysis syndrome (ATLS) is a series of lifethreatening complications after the lysis of tumor cells in patients undergoing treatment for malignancies.1,2 The main pathophysiology mechanism of ATLS is the massive lysis of tumor cells and rapid release of intracellular toxic metabolites that overwhelm the metabolic and excretory capacity of the liver and kidneys.1,2 The primary clinical manifestations include hyperkalemia, hyperphosphatemia, hypocalcemia, refractory metabolic acidosis and acute renal insufficiency.2 NonHodgkin’s diffuse large B-cell lymphoma (DLBCL-NHL) is a common hematologic malignancy, and Hande and Garrow3 reported that the incidence of ATLS in high-grade NHL was about 42%, but only a few (6%) present with obvious clinical features. Because of the significant morbidity associated with ATLS, early recognition in patients with lymphoma is critical for good outcomes.4 Rituximab, an anti-CD20 monoclonal antibody that mediates the destruction of CD20⫹ B-lymphocytes, is used as an alternative to chemotherapy for the treatment of CD20⫹ lymphomas.5 Although up to 50% of patients may experience symptoms such as fever and chills immediately after administration,6,7 there have been few reports of ATLS associated with rituximab. We review the clinical characteristics and laboratory features of ATLS in 2 patients with DLBCL-NHL treated with rituximab.
From the Departments of Geriatric Hematology (BY, X-CL, R-LY, W-YZ, and Pathology (JY, PZ), Chinese PLA General Hospital; and Department of Pharmacy (X-HC), the Second Artillery General Hospital, Beijing, China. Submitted June 28, 2011; accepted in revised form October 19, 2011. Correspondence: Xue-Chun Lu, PhD, Department of Geriatric Hematology, Chinese PLA General Hospital, Fuxing Road 28, Handian District, Beijing 100853, China (E-mail: [email protected]). H-LZ)
CASE REPORTS Case 1 A 71-year-old man was admitted because of a decrease of hemoglobin over 6 months and malaise with weight loss for 1 month. Positron emission tomography-computed tomography (PET-CT) revealed multiple areas of tracer accumulation, and intestinal malignancy was suspected (Figure 1A). Pathologic examination of tissues collected with gastroenterologic endoscopy showed abnormal lymphocytes diffusely infiltrating the lamina propria of the junction between gastric antrum and body, which were positive for CD2 and CD792. The proportion of Ki-67–positive cells was ⬎75%, and the diagnosis was DLBCL-NHL with involvement of whole gastrointestinal tract. Bone marrow aspiration and biopsy revealed a normal profile, with evidence of active proliferation. The distribution of cell types was granulocytes (64.4%), erythrocytes (16.0%) and lymphocytes with normal morphology (10.6%); megakaryocytes of all types were present, and platelets were banking up. There was no evidence of infiltration of abnormal lymphocytes. Two days after the biopsy, the patient began the first of 7 courses of chemotherapy: the first regimen was COP (cyclophosphamide, vindesine, prednisone), and the remaining 6 were R-CHOP (rituximab, cyclophosphamide, vindesine, pirarubicin, dexamethasone). Allopurinol (300 mg/d) was administered for 3 days before the first R-CHOP regimen. After completion of chemotherapy, gastroenterologic endoscopy and biopsy showed no evidence of lymphoma, and chest and abdominal CT and double-contrast barium studies were normal, suggesting complete remission. PET-CT was not performed at this time to limit the extent of radiation injury. Approximately 50 days after completion of chemotherapy, the patient complained of pain in the right lower quadrant (RLQ) and exhibited symptoms of intestinal obstruction. CT revealed solid masses in the abdominal RLQ (9.1 ⫻ 5.4 ⫻ 6.8 cm3) and the rectal fossa (9.5 ⫻ 8.7 ⫻ 7.2 cm3), and PET-CT showed tracer accumulation in the RLQ and vesicorectal space (Figure 1B). Pathologic examination of gastrointestinal biopsy specimens indicated recurrence of gastrointestinal lymphoma. Two courses R-EPOCH (rituximab, cyclophosphamide, doxorubicin liposomes, vindesine, dexamethasone, etoposide) were administered, and CT indicated the masses were reduced in size. However, 1 week later, CT revealed enlargement of the masses, and a right hemicolectomy and fistulization of the ileum and transverse colon were performed. The surgery revealed extensive cancerous invasion of pelvic tissues. The tumor involved the entire pelvis and was unresectable, and a colostomy was performed to relieve the intestinal obstruction. Approximately 1 month later, the patient’s white blood cell (WBC) count was 22 ⫻ 109/L, and 10 days later, it increased to 40.59 ⫻ 109/L. Bone marrow aspiration and
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FIGURE 1. Case 1. (A) Initial positron emission tomography-computed tomography (PET-CT) revealed multiple areas of tracer accumulation representing multiple metabolically active lesions in the abdominal cavity. (B) Approximately 50 days after completion of chemotherapy, PET-CT revealed 2 bulky metabolically active lesions in the pelvic cavity.
biopsy showed that the proportion of lymphocytes was 3.2%, with naive lymphocytes accounting for 0.4%. Immunophenotyping, however, revealed no abnormalities. There was no indication of involvement of lymphoma cells in bone marrow and peripheral blood, ruling out blastic transformation of DLBCL. Therefore, we speculated the increase of WBC count was due to a leukemoid reaction. This patient was treated twice with 600 mg rituximab (285.7 mg/m2), with 14 days between doses. Hydration and alkalization were performed for the prevention of ATLS. However, 1 day after administration of the second dose of rituximab, the patient developed abdominal distention, nausea, vomiting, palpitations and labored breathing. Laboratory studies revealed the following blood levels: potassium, 2.49 mmol/L; phosphorous, 1.20 mmol/L; calcium, 1.98 mmol/L; lactate dehydrogenase (LDH), 9422 U/L; and uric acid, 3.50 mg/dL. Blood gas analysis revealed a pH of 7.03; PO2, 90.2 mm Hg; PCO2, 15.3 mm Hg; HCO3, ⫺6.5 mmol/L; base excess, ⫺17.9 mmol/L; and SO2, 94.3%. The patient was diagnosed with ATLS. The dose of allopurinol was increased to 600 mg/d, sodium bicarbonate was administered, and hydration was performed. However, LDH and uric acid continued to increase, and the patient developed hepatic insufficiency, renal insufficiency and type I respiratory failure. The patient was placed on mechanical ventilation and hemodialysis. Despite supportive measures, the acidosis persisted, and 12 days after the second dose of rituximab, the patient died of multiple organ failure. Case 2 An 89-year-old man was admitted because of abdominal distention and pain and nausea and vomiting for 10 days, in combination with jaundice and tea-colored urine for 2 days. Ultrasonography revealed lesions in the pancreas, and histopathologic examination of a biopsy specimen revealed negative labeled streptavidin-biotin (LSAB) staining for CD3, CD10 and CD30, but strong positive staining for CD20 (Figure 2A–D), indicating DLBCL-NHL. Hematoxylin and eosin staining
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showed destructive infiltration of pancreatic tissue by moderate-to-large heteromorphic lymphocytes, large deeply stained nuclei and 1 to 3 nucleoli, widespread mitosis and enlarged cytoplasm in the residual structure of the pancreas (Figure 3). Because of the patient’s advanced age and comorbidities, including hypertension, coronary heart disease, diabetes mellitus and Parkinson’s disease, he was treated once with 600 mg rituximab (272.7 mg/m2) alone. His symptoms improved, and ultrasonography revealed a decrease in the size of the lesion. Five days later, he developed tachypnea and dyspnea, and his oxygen saturation decreased to 80%. Laboratory studies revealed a potassium of 5.51 mmol/L; uric acid, 8.34 mg/dL; LDH, 812 U/L; calcium, 1.62 mmol/L; and phosphorous, 4.67 mmol/L and increased blood urea nitrogen and creatinine levels. A diagnosis of ATLS was made. The patient was placed on mechanical ventilation and treated with allopurinol, diuresis, hydration, alkalization and nutritional support. The patient rapidly developed oliguria, and blood urea nitrogen and creatinine levels progressively increased. His physical status continued to deteriorate, and 10 days after rituximab administration, he died of multiple organ failure.
DISCUSSION The incidence of ATLS in all patients with malignancies ranges from 5% to 20%.1,4,8 Mild consequences of ATLS may delay treatment, and severe consequence may result in death; thus, identification of risk factors and prevention are of paramount importance.1,2,8 Risk factors for the development of ATLS include tumor type (Burkitt’s lymphoma, lymphoblastic lymphoma, acute lymphoblastic leukemia), solid tumors with rapid proliferation and sensitivity to treatment, large tumor load, LDH ⬎2 times upper normal limit, WBC count ⬎25,000 /L, preexisting renal failure or oliguria, uric acid level ⬎450 mol/L and effective or prompt cytoreductive therapy.1,2,8 The risk factors of ATLS in these patients are summarized in Table 1. Volume 343, Number 4, April 2012
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FIGURE 2. The immunohistochemistry findings of case 2. (A) The staining of CD3 with LSAB method is negative in tumor cells. (B) The staining of CD10 with LSAB method is negative in tumor cells. (C) The staining of CD20 with LSAB method is strongly positive in cytoplasm and membrane of tumor cells. (D) The staining of CD30 with LSAB method is negative in tumor cells. Magnification ⫻100.
FIGURE 3. Pancreatic tissue was infiltrated and destroyed by moderate-to-large diffuse heteromorphic lymphocytes in case 2. The nucleus is large and deeply stained with 1 to 3 nucleoli, mitosis is commonly seen and cytoplasm is abundant; residual structure of the pancreas gland is visible (HE staining, ⫻400). © 2012 Lippincott Williams & Wilkins
Cairo and Bishop8 divided ATLS into laboratory tumor lysis syndrome (LTLS) and clinical tumor lysis syndrome. The criteria for LTLS include uric acid ⱖ476 mol/L, potassium ⱖ6.0 mmol/L, phosphorous ⱖ2.1 mmol/L for children and ⱖ1.45 mmol/L for adults or each parameter increased by 25%, and calcium ⱕ1.75mmol/L or decreased by 25%. The occurrence of at least 2 laboratory abnormalities within 3 to 7 days after cytotoxic therapy is considered evidence of LTLS. Clinical tumor lysis syndrome is diagnosed when one of the following symptoms occur when LTLS criteria are met: renal impairment, arrhythmia, sudden death or seizures. Although ATLS can occur as a result of chemotherapy and radiotherapy, there have been only 7 reports of ATLS occurring after rituximab treatment.9 –14 Of the cases in which ATLS was associated with rituximab, 2 patients had DLBCL-NHL11,14 (Table 2). The other 5 reported cases of ATLS occurring after rituximab treatment include Burkitt’s lymphoma,12 B-cell chronic lymphocytic leukemia,9 high-grade non-Hodgkin’s lymphoma,13 chronic lymphocytic leukemia13 and posttransplant lymphoproliferative disorder,10 and of these 5 cases, 1 patient died despite aggressive treatment. In the current report, both patients had DLBCL-NHL and received treatment with rituximab before ATLS occurred. Of interest, all patients in the previous reports developed ATLS after the first treatment with rituximab. These
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TABLE 1. Risk factors of ATLS in the 2 patients Risk factor
Case 1
Case 2
Solid tumor with rapid proliferation and sensitive to treatment Large mass (⬎10 cm) LDH ⬎2 times of upper normal limit White blood cell count ⬎25 ⫻ 109/L Preexisting renal failure or oliguria Uric acid ⬎450 mol/L Effective treatment or type of cancer
Present
Present
Present Absent Present Absent Absent Present
Present Present Absent Present Present Present
ATLS, acute tumor lysis syndrome; LDH, lactate dehydrogenase.
patients were tolerant to a second treatment with rituximab, and no ATLS was observed after the second treatment. In the current report, the patient in case 1 was treated with 8 courses of chemotherapy (6 with R-CHOP regimen and 2 with REPOCH regimen), but he did not develop ATLS. After a second dose of monotherapy with rituximab, ATLS developed and may have been associated with the high tumor load and renal insufficiency. ATLS-induced renal impairment is cause by the deposition of uric acid crystals in the renal tubules.1,15,16 The traditional treatment of ATLS includes oral administration of allopurinol (300 – 600 mg/d) until the uric acid level returns to normal.1,8 When hyperkalemia occurs, calcium gluconate (100 –200 mg/kg) and insulin in 10% glucose can be administered intravenously to promote the entry of potassium into the cells. For improvement of renal blood flow, a low dose of dopamine is given. Diuresis may be performed to increase urine volume and the excretion of metabolites. Hypocalcemia is difficult to correct and may be caused by hypomagnesemia. Therefore, magnesium sulfate (25–100 mg/kg) may be administered intravenously. Of note, all treatments should be performed in combination with hydration. When acidosis is difficult to correct and concomitant renal failure is present, hemodialysis is recommended.1,8
TABLE 2. Summary of reported cases of rituximab-induced ATLS in patients with DLBCL-NHL Case
Age (yr)/ LDH gender (U/L)
Jabr12
60/F
Abou Mourad et al14
67/F
Case 1
71/M
Case 2
89/M
Treatment
3430 Dexamethasone (16 mg); rituximab (50 mg) 7130 Dexamethasone (16 mg); rituximab (50 mg) 1402 Rituximab (600 mg) 712 Rituximab (600 mg)
Hemodialysis Outcome
REFERENCES
Yes
Death
1. Abu-Alfa AK, Younes A. Tumor lysis syndrome and acute kidney injury: evaluation, prevention, and management. Am J Kidney Dis 2010;55:S1–3; quiz S14 –9.
Yes
Remission
2. Mughal TI, Ejaz AA, Foringer JR, et al. An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome. Cancer Treat Rev 2010;36:164 –76.
Yes
Deatha
Yes
Deathb
a Patient died 12 days after receiving the second dose of single agent rituximab. b Patient died 10 days after receiving a single dose of single agent rituximab. ATLS, acute tumor lysis syndrome; DLBCL-NHL, non-Hodgkin’s diffuse large B-cell lymphoma; LDH, lactate dehydrogenase.
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Hemodialysis is an important strategy in the treatment of ATLS. Hemodialysis should be considered when continuous hyperkalemia, significant metabolic acidosis, volume overload, nonresponse to diuretics or obvious symptoms of uremia are present. When significant hyperphosphatemia (⬎6 mg/dL) and hypocalcemia are present, prophylactic hemodialysis is recommended even in the absence of uremia.1,4,8 In recent years, several studies have indicated that recombinant urate oxidases, such as rasburicase, are more effective than allopurinol in reducing the level of uric acid and can be used for the prevention of purine crystal-induced renal failure.17,18 Rasburicase catalyzes the conversion of uric acid to the highly water-soluble compound allantoin, which is easily eliminated in urine. This reduces plasma uric acid and prevents the development of uric acid nephritis.19 In a randomized controlled trial, children with hematologic malignancies (acute lymphoblastic leukemia or type III/IV NHL) were stratified and then randomly assigned to receive rasburicase or allopurinol. Children treated with rasburicase had significantly lower uric acid levels and smaller areas under curve compared with patients treated with allopurinol.20 Recombinant urate oxidases are not appropriate for all patients, however. For example, rasburicase is contraindicated for patients with methemoglobinemia, glucose-6-phosphate dehydrogenase deficiency and other metabolic diseases that can cause hemolytic anemia. For these individuals, oral allopurinol treatment, hydration and urinary alkalinization are recommended. In addition, controversy remains regarding the benefits of urine alkalization in patients receiving urate oxidases. Urinary alkalinization may promote the calcium salt deposition resulting in calcium phosphate nephritis and should be discontinued when phosphate level increases.21 Urinary alkalinization is gradually being abolished in clinical practice, especially when a urate oxidase is used.4,22 Finally, the high cost of rasburicase treatment significantly limits its wide application in developing countries. In summary, ATLS is one of the causes of death in patients with malignant lymphomas. The clinical manifestations of ATLS are not typical, and its diagnosis is based on laboratory examination. Although uncommon, ATLS can occur with rituximab administration. It may be possible to prevent ATLS or reduce ATLS-related mortality by identifying patients at high risk for ATLS and making preparations (such as hospitalization, hydration, starting allopurinol, collecting electrolytes) before starting treatment.21,23
3. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. Am J Med 1993;94:133–9. 4. Tosi P, Barosi G, Lazzaro C, et al. Consensus conference on the management of tumor lysis syndrome. Haematologica 2008;93: 1877– 85. 5. Maloney DG, Smith B, Rose A. Rituximab: mechanism of action and resistance. Semin Oncol 2002;29:2–9. 6. Bienvenu J, Chvetzoff R, Salles G, et al. Tumor necrosis factor alpha release is a major biological event associated with rituximab treatment. Hematol J 2001;2:378 – 84. 7. Dillman RO. Infusion reactions associated with the therapeutic use of
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monoclonal antibodies in the treatment of malignancy. Cancer Metastasis Rev 1999;18:465–71. 8. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004;127:3–11.
16. Kunkel L, Wong A, Maneatis T, et al. Optimizing the use of rituximab for treatment of B-cell non-Hodgkin’s lymphoma: a benefitrisk update. Semin Oncol 2000;27:53– 61.
9. 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 (IDEC-C2B8, rituximab). Ann Hematol 1998;77:89 –91.
17. Cortes J, Moore JO, Maziarz RT, et al. Control of plasma uric acid in adults at risk for tumor lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone—results of a multicenter phase III study. J Clin Oncol 2010;28:4207–13.
10. Francescone SA, Murphy B, Fallon JT, et al. Tumor lysis syndrome occurring after the administration of rituximab for posttransplant lymphoproliferative disorder. Transplant Proc 2009;41:1946 – 8.
18. Pui CH, Mahmoud HH, Wiley JM, et al. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol 2001;19:697–704.
11. Jabr FI. Acute tumor lysis syndrome induced by rituximab in diffuse large B-cell lymphoma. Int J Hematol 2005;82:312– 4.
19. Senbanjo IO. Tumor lysis and acute renal failure in Burkitt’s lymphoma: a review on pathophysiology and management. Indian J Nephrol 2009;19:83– 6.
12. Otrock ZK, Hatoum HA, Salem ZM. Acute tumor lysis syndrome after rituximab administration in Burkitt’s lymphoma. Intern Emerg Med 2008;3:161–3. 13. Yang H, Rosove MH, Figlin RA. Tumor lysis syndrome occurring after the administration of rituximab in lymphoproliferative disorders: high-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Am J Hematol 1999;62:247–50. 14. 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 2003;4:222– 4. 15. Cohen LF, Balow JE, Magrath IT, et al. Acute tumor lysis syndrome. A review of 37 patients with Burkitt’s lymphoma. Am J Med 1980;68: 486 –91.
© 2012 Lippincott Williams & Wilkins
20. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 2001;97:2998 – 3003. 21. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med 2011;364:1844 –54. 22. van den Berg H, Reintsema AM. Renal tubular damage in rasburicase: risks of alkalinisation. Ann Oncol 2004;15:175– 6. 23. Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol 2010;149:578 – 86.
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Diagnosis and Treatment of Rituximab-Induced Acute Tumor Lysis Syndrome in Patients With Diffuse Large B-Cell Lymphoma Bo Yang, PhD, Xue-Chun Lu, PhD, Rui-Li Yu, PhD, Xiao-Hua Chi, MD, Wen-Ying Zhang, MS, Hong-Li Zhu, PhD, Jing Yuan, MS and Po Zhao, PhD
Abstract: Acute tumor lysis syndrome (ATLS) is a recognized complication of the treatment of malignant lymphomas and is associated with significant morbidity and mortality. However, there have been few reports of the occurrence of ATLS in patients treated with rituximab. This study reports 2 patients with high-grade diffuse large B-cell non-Hodgkin’s lymphoma who presented high tumor load, were sensitive to treatment and had multiple risk factors for ATLS. Both patients developed ATLS after treatment with rituximab and, despite aggressive supportive therapy, died of multiple organ failure. These cases illustrate that ATLS can occur after treatment with rituximab and that a high index of suspicion is necessary for the prompt diagnosis of ATLS. Key Indexing Terms: Acute tumor lysis symptom; Non-Hodgkin’s lymphoma; Diffuse large B-cell lymphoma; Diagnosis; Treatment. [Am J Med Sci 2012;343(4):337–341.]
A
cute tumor lysis syndrome (ATLS) is a series of lifethreatening complications after the lysis of tumor cells in patients undergoing treatment for malignancies.1,2 The main pathophysiology mechanism of ATLS is the massive lysis of tumor cells and rapid release of intracellular toxic metabolites that overwhelm the metabolic and excretory capacity of the liver and kidneys.1,2 The primary clinical manifestations include hyperkalemia, hyperphosphatemia, hypocalcemia, refractory metabolic acidosis and acute renal insufficiency.2 NonHodgkin’s diffuse large B-cell lymphoma (DLBCL-NHL) is a common hematologic malignancy, and Hande and Garrow3 reported that the incidence of ATLS in high-grade NHL was about 42%, but only a few (6%) present with obvious clinical features. Because of the significant morbidity associated with ATLS, early recognition in patients with lymphoma is critical for good outcomes.4 Rituximab, an anti-CD20 monoclonal antibody that mediates the destruction of CD20⫹ B-lymphocytes, is used as an alternative to chemotherapy for the treatment of CD20⫹ lymphomas.5 Although up to 50% of patients may experience symptoms such as fever and chills immediately after administration,6,7 there have been few reports of ATLS associated with rituximab. We review the clinical characteristics and laboratory features of ATLS in 2 patients with DLBCL-NHL treated with rituximab.
From the Departments of Geriatric Hematology (BY, X-CL, R-LY, W-YZ, and Pathology (JY, PZ), Chinese PLA General Hospital; and Department of Pharmacy (X-HC), the Second Artillery General Hospital, Beijing, China. Submitted June 28, 2011; accepted in revised form October 19, 2011. Correspondence: Xue-Chun Lu, PhD, Department of Geriatric Hematology, Chinese PLA General Hospital, Fuxing Road 28, Handian District, Beijing 100853, China (E-mail: [email protected]). H-LZ)
CASE REPORTS Case 1 A 71-year-old man was admitted because of a decrease of hemoglobin over 6 months and malaise with weight loss for 1 month. Positron emission tomography-computed tomography (PET-CT) revealed multiple areas of tracer accumulation, and intestinal malignancy was suspected (Figure 1A). Pathologic examination of tissues collected with gastroenterologic endoscopy showed abnormal lymphocytes diffusely infiltrating the lamina propria of the junction between gastric antrum and body, which were positive for CD2 and CD792. The proportion of Ki-67–positive cells was ⬎75%, and the diagnosis was DLBCL-NHL with involvement of whole gastrointestinal tract. Bone marrow aspiration and biopsy revealed a normal profile, with evidence of active proliferation. The distribution of cell types was granulocytes (64.4%), erythrocytes (16.0%) and lymphocytes with normal morphology (10.6%); megakaryocytes of all types were present, and platelets were banking up. There was no evidence of infiltration of abnormal lymphocytes. Two days after the biopsy, the patient began the first of 7 courses of chemotherapy: the first regimen was COP (cyclophosphamide, vindesine, prednisone), and the remaining 6 were R-CHOP (rituximab, cyclophosphamide, vindesine, pirarubicin, dexamethasone). Allopurinol (300 mg/d) was administered for 3 days before the first R-CHOP regimen. After completion of chemotherapy, gastroenterologic endoscopy and biopsy showed no evidence of lymphoma, and chest and abdominal CT and double-contrast barium studies were normal, suggesting complete remission. PET-CT was not performed at this time to limit the extent of radiation injury. Approximately 50 days after completion of chemotherapy, the patient complained of pain in the right lower quadrant (RLQ) and exhibited symptoms of intestinal obstruction. CT revealed solid masses in the abdominal RLQ (9.1 ⫻ 5.4 ⫻ 6.8 cm3) and the rectal fossa (9.5 ⫻ 8.7 ⫻ 7.2 cm3), and PET-CT showed tracer accumulation in the RLQ and vesicorectal space (Figure 1B). Pathologic examination of gastrointestinal biopsy specimens indicated recurrence of gastrointestinal lymphoma. Two courses R-EPOCH (rituximab, cyclophosphamide, doxorubicin liposomes, vindesine, dexamethasone, etoposide) were administered, and CT indicated the masses were reduced in size. However, 1 week later, CT revealed enlargement of the masses, and a right hemicolectomy and fistulization of the ileum and transverse colon were performed. The surgery revealed extensive cancerous invasion of pelvic tissues. The tumor involved the entire pelvis and was unresectable, and a colostomy was performed to relieve the intestinal obstruction. Approximately 1 month later, the patient’s white blood cell (WBC) count was 22 ⫻ 109/L, and 10 days later, it increased to 40.59 ⫻ 109/L. Bone marrow aspiration and
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FIGURE 1. Case 1. (A) Initial positron emission tomography-computed tomography (PET-CT) revealed multiple areas of tracer accumulation representing multiple metabolically active lesions in the abdominal cavity. (B) Approximately 50 days after completion of chemotherapy, PET-CT revealed 2 bulky metabolically active lesions in the pelvic cavity.
biopsy showed that the proportion of lymphocytes was 3.2%, with naive lymphocytes accounting for 0.4%. Immunophenotyping, however, revealed no abnormalities. There was no indication of involvement of lymphoma cells in bone marrow and peripheral blood, ruling out blastic transformation of DLBCL. Therefore, we speculated the increase of WBC count was due to a leukemoid reaction. This patient was treated twice with 600 mg rituximab (285.7 mg/m2), with 14 days between doses. Hydration and alkalization were performed for the prevention of ATLS. However, 1 day after administration of the second dose of rituximab, the patient developed abdominal distention, nausea, vomiting, palpitations and labored breathing. Laboratory studies revealed the following blood levels: potassium, 2.49 mmol/L; phosphorous, 1.20 mmol/L; calcium, 1.98 mmol/L; lactate dehydrogenase (LDH), 9422 U/L; and uric acid, 3.50 mg/dL. Blood gas analysis revealed a pH of 7.03; PO2, 90.2 mm Hg; PCO2, 15.3 mm Hg; HCO3, ⫺6.5 mmol/L; base excess, ⫺17.9 mmol/L; and SO2, 94.3%. The patient was diagnosed with ATLS. The dose of allopurinol was increased to 600 mg/d, sodium bicarbonate was administered, and hydration was performed. However, LDH and uric acid continued to increase, and the patient developed hepatic insufficiency, renal insufficiency and type I respiratory failure. The patient was placed on mechanical ventilation and hemodialysis. Despite supportive measures, the acidosis persisted, and 12 days after the second dose of rituximab, the patient died of multiple organ failure. Case 2 An 89-year-old man was admitted because of abdominal distention and pain and nausea and vomiting for 10 days, in combination with jaundice and tea-colored urine for 2 days. Ultrasonography revealed lesions in the pancreas, and histopathologic examination of a biopsy specimen revealed negative labeled streptavidin-biotin (LSAB) staining for CD3, CD10 and CD30, but strong positive staining for CD20 (Figure 2A–D), indicating DLBCL-NHL. Hematoxylin and eosin staining
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showed destructive infiltration of pancreatic tissue by moderate-to-large heteromorphic lymphocytes, large deeply stained nuclei and 1 to 3 nucleoli, widespread mitosis and enlarged cytoplasm in the residual structure of the pancreas (Figure 3). Because of the patient’s advanced age and comorbidities, including hypertension, coronary heart disease, diabetes mellitus and Parkinson’s disease, he was treated once with 600 mg rituximab (272.7 mg/m2) alone. His symptoms improved, and ultrasonography revealed a decrease in the size of the lesion. Five days later, he developed tachypnea and dyspnea, and his oxygen saturation decreased to 80%. Laboratory studies revealed a potassium of 5.51 mmol/L; uric acid, 8.34 mg/dL; LDH, 812 U/L; calcium, 1.62 mmol/L; and phosphorous, 4.67 mmol/L and increased blood urea nitrogen and creatinine levels. A diagnosis of ATLS was made. The patient was placed on mechanical ventilation and treated with allopurinol, diuresis, hydration, alkalization and nutritional support. The patient rapidly developed oliguria, and blood urea nitrogen and creatinine levels progressively increased. His physical status continued to deteriorate, and 10 days after rituximab administration, he died of multiple organ failure.
DISCUSSION The incidence of ATLS in all patients with malignancies ranges from 5% to 20%.1,4,8 Mild consequences of ATLS may delay treatment, and severe consequence may result in death; thus, identification of risk factors and prevention are of paramount importance.1,2,8 Risk factors for the development of ATLS include tumor type (Burkitt’s lymphoma, lymphoblastic lymphoma, acute lymphoblastic leukemia), solid tumors with rapid proliferation and sensitivity to treatment, large tumor load, LDH ⬎2 times upper normal limit, WBC count ⬎25,000 /L, preexisting renal failure or oliguria, uric acid level ⬎450 mol/L and effective or prompt cytoreductive therapy.1,2,8 The risk factors of ATLS in these patients are summarized in Table 1. Volume 343, Number 4, April 2012
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FIGURE 2. The immunohistochemistry findings of case 2. (A) The staining of CD3 with LSAB method is negative in tumor cells. (B) The staining of CD10 with LSAB method is negative in tumor cells. (C) The staining of CD20 with LSAB method is strongly positive in cytoplasm and membrane of tumor cells. (D) The staining of CD30 with LSAB method is negative in tumor cells. Magnification ⫻100.
FIGURE 3. Pancreatic tissue was infiltrated and destroyed by moderate-to-large diffuse heteromorphic lymphocytes in case 2. The nucleus is large and deeply stained with 1 to 3 nucleoli, mitosis is commonly seen and cytoplasm is abundant; residual structure of the pancreas gland is visible (HE staining, ⫻400). © 2012 Lippincott Williams & Wilkins
Cairo and Bishop8 divided ATLS into laboratory tumor lysis syndrome (LTLS) and clinical tumor lysis syndrome. The criteria for LTLS include uric acid ⱖ476 mol/L, potassium ⱖ6.0 mmol/L, phosphorous ⱖ2.1 mmol/L for children and ⱖ1.45 mmol/L for adults or each parameter increased by 25%, and calcium ⱕ1.75mmol/L or decreased by 25%. The occurrence of at least 2 laboratory abnormalities within 3 to 7 days after cytotoxic therapy is considered evidence of LTLS. Clinical tumor lysis syndrome is diagnosed when one of the following symptoms occur when LTLS criteria are met: renal impairment, arrhythmia, sudden death or seizures. Although ATLS can occur as a result of chemotherapy and radiotherapy, there have been only 7 reports of ATLS occurring after rituximab treatment.9 –14 Of the cases in which ATLS was associated with rituximab, 2 patients had DLBCL-NHL11,14 (Table 2). The other 5 reported cases of ATLS occurring after rituximab treatment include Burkitt’s lymphoma,12 B-cell chronic lymphocytic leukemia,9 high-grade non-Hodgkin’s lymphoma,13 chronic lymphocytic leukemia13 and posttransplant lymphoproliferative disorder,10 and of these 5 cases, 1 patient died despite aggressive treatment. In the current report, both patients had DLBCL-NHL and received treatment with rituximab before ATLS occurred. Of interest, all patients in the previous reports developed ATLS after the first treatment with rituximab. These
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TABLE 1. Risk factors of ATLS in the 2 patients Risk factor
Case 1
Case 2
Solid tumor with rapid proliferation and sensitive to treatment Large mass (⬎10 cm) LDH ⬎2 times of upper normal limit White blood cell count ⬎25 ⫻ 109/L Preexisting renal failure or oliguria Uric acid ⬎450 mol/L Effective treatment or type of cancer
Present
Present
Present Absent Present Absent Absent Present
Present Present Absent Present Present Present
ATLS, acute tumor lysis syndrome; LDH, lactate dehydrogenase.
patients were tolerant to a second treatment with rituximab, and no ATLS was observed after the second treatment. In the current report, the patient in case 1 was treated with 8 courses of chemotherapy (6 with R-CHOP regimen and 2 with REPOCH regimen), but he did not develop ATLS. After a second dose of monotherapy with rituximab, ATLS developed and may have been associated with the high tumor load and renal insufficiency. ATLS-induced renal impairment is cause by the deposition of uric acid crystals in the renal tubules.1,15,16 The traditional treatment of ATLS includes oral administration of allopurinol (300 – 600 mg/d) until the uric acid level returns to normal.1,8 When hyperkalemia occurs, calcium gluconate (100 –200 mg/kg) and insulin in 10% glucose can be administered intravenously to promote the entry of potassium into the cells. For improvement of renal blood flow, a low dose of dopamine is given. Diuresis may be performed to increase urine volume and the excretion of metabolites. Hypocalcemia is difficult to correct and may be caused by hypomagnesemia. Therefore, magnesium sulfate (25–100 mg/kg) may be administered intravenously. Of note, all treatments should be performed in combination with hydration. When acidosis is difficult to correct and concomitant renal failure is present, hemodialysis is recommended.1,8
TABLE 2. Summary of reported cases of rituximab-induced ATLS in patients with DLBCL-NHL Case
Age (yr)/ LDH gender (U/L)
Jabr12
60/F
Abou Mourad et al14
67/F
Case 1
71/M
Case 2
89/M
Treatment
3430 Dexamethasone (16 mg); rituximab (50 mg) 7130 Dexamethasone (16 mg); rituximab (50 mg) 1402 Rituximab (600 mg) 712 Rituximab (600 mg)
Hemodialysis Outcome
REFERENCES
Yes
Death
1. Abu-Alfa AK, Younes A. Tumor lysis syndrome and acute kidney injury: evaluation, prevention, and management. Am J Kidney Dis 2010;55:S1–3; quiz S14 –9.
Yes
Remission
2. Mughal TI, Ejaz AA, Foringer JR, et al. An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome. Cancer Treat Rev 2010;36:164 –76.
Yes
Deatha
Yes
Deathb
a Patient died 12 days after receiving the second dose of single agent rituximab. b Patient died 10 days after receiving a single dose of single agent rituximab. ATLS, acute tumor lysis syndrome; DLBCL-NHL, non-Hodgkin’s diffuse large B-cell lymphoma; LDH, lactate dehydrogenase.
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Hemodialysis is an important strategy in the treatment of ATLS. Hemodialysis should be considered when continuous hyperkalemia, significant metabolic acidosis, volume overload, nonresponse to diuretics or obvious symptoms of uremia are present. When significant hyperphosphatemia (⬎6 mg/dL) and hypocalcemia are present, prophylactic hemodialysis is recommended even in the absence of uremia.1,4,8 In recent years, several studies have indicated that recombinant urate oxidases, such as rasburicase, are more effective than allopurinol in reducing the level of uric acid and can be used for the prevention of purine crystal-induced renal failure.17,18 Rasburicase catalyzes the conversion of uric acid to the highly water-soluble compound allantoin, which is easily eliminated in urine. This reduces plasma uric acid and prevents the development of uric acid nephritis.19 In a randomized controlled trial, children with hematologic malignancies (acute lymphoblastic leukemia or type III/IV NHL) were stratified and then randomly assigned to receive rasburicase or allopurinol. Children treated with rasburicase had significantly lower uric acid levels and smaller areas under curve compared with patients treated with allopurinol.20 Recombinant urate oxidases are not appropriate for all patients, however. For example, rasburicase is contraindicated for patients with methemoglobinemia, glucose-6-phosphate dehydrogenase deficiency and other metabolic diseases that can cause hemolytic anemia. For these individuals, oral allopurinol treatment, hydration and urinary alkalinization are recommended. In addition, controversy remains regarding the benefits of urine alkalization in patients receiving urate oxidases. Urinary alkalinization may promote the calcium salt deposition resulting in calcium phosphate nephritis and should be discontinued when phosphate level increases.21 Urinary alkalinization is gradually being abolished in clinical practice, especially when a urate oxidase is used.4,22 Finally, the high cost of rasburicase treatment significantly limits its wide application in developing countries. In summary, ATLS is one of the causes of death in patients with malignant lymphomas. The clinical manifestations of ATLS are not typical, and its diagnosis is based on laboratory examination. Although uncommon, ATLS can occur with rituximab administration. It may be possible to prevent ATLS or reduce ATLS-related mortality by identifying patients at high risk for ATLS and making preparations (such as hospitalization, hydration, starting allopurinol, collecting electrolytes) before starting treatment.21,23
3. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma. Am J Med 1993;94:133–9. 4. Tosi P, Barosi G, Lazzaro C, et al. Consensus conference on the management of tumor lysis syndrome. Haematologica 2008;93: 1877– 85. 5. Maloney DG, Smith B, Rose A. Rituximab: mechanism of action and resistance. Semin Oncol 2002;29:2–9. 6. Bienvenu J, Chvetzoff R, Salles G, et al. Tumor necrosis factor alpha release is a major biological event associated with rituximab treatment. Hematol J 2001;2:378 – 84. 7. Dillman RO. Infusion reactions associated with the therapeutic use of
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monoclonal antibodies in the treatment of malignancy. Cancer Metastasis Rev 1999;18:465–71. 8. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004;127:3–11.
16. Kunkel L, Wong A, Maneatis T, et al. Optimizing the use of rituximab for treatment of B-cell non-Hodgkin’s lymphoma: a benefitrisk update. Semin Oncol 2000;27:53– 61.
9. 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 (IDEC-C2B8, rituximab). Ann Hematol 1998;77:89 –91.
17. Cortes J, Moore JO, Maziarz RT, et al. Control of plasma uric acid in adults at risk for tumor lysis syndrome: efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone—results of a multicenter phase III study. J Clin Oncol 2010;28:4207–13.
10. Francescone SA, Murphy B, Fallon JT, et al. Tumor lysis syndrome occurring after the administration of rituximab for posttransplant lymphoproliferative disorder. Transplant Proc 2009;41:1946 – 8.
18. Pui CH, Mahmoud HH, Wiley JM, et al. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol 2001;19:697–704.
11. Jabr FI. Acute tumor lysis syndrome induced by rituximab in diffuse large B-cell lymphoma. Int J Hematol 2005;82:312– 4.
19. Senbanjo IO. Tumor lysis and acute renal failure in Burkitt’s lymphoma: a review on pathophysiology and management. Indian J Nephrol 2009;19:83– 6.
12. Otrock ZK, Hatoum HA, Salem ZM. Acute tumor lysis syndrome after rituximab administration in Burkitt’s lymphoma. Intern Emerg Med 2008;3:161–3. 13. Yang H, Rosove MH, Figlin RA. Tumor lysis syndrome occurring after the administration of rituximab in lymphoproliferative disorders: high-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Am J Hematol 1999;62:247–50. 14. 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 2003;4:222– 4. 15. Cohen LF, Balow JE, Magrath IT, et al. Acute tumor lysis syndrome. A review of 37 patients with Burkitt’s lymphoma. Am J Med 1980;68: 486 –91.
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20. Goldman SC, Holcenberg JS, Finklestein JZ, et al. A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 2001;97:2998 – 3003. 21. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med 2011;364:1844 –54. 22. van den Berg H, Reintsema AM. Renal tubular damage in rasburicase: risks of alkalinisation. Ann Oncol 2004;15:175– 6. 23. Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol 2010;149:578 – 86.
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