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2. Ozer H, Armitage JO, Bennett CL, Crawford J, Demetri GD, Pizzo PA, et al. Update of recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol 2000;18:3558 – 3585. 3. Crawford J, Althaus B, Armitage J, Blayney DW, Cataland S, Dale C. Myeloid growth factors clinical practice guidelines in oncology. J Natl Compr Cancer Network 2005;3:540 – 555. 4. Rabinowitz AP, Weiner NJ, Tronic BS, Fridman M, Liberman RF, Delgado DJ. Severe neutropenia in CHOP occurs most frequently in cycle 1: a predictive model. Leuk Lymphoma 2006;47:853 – 858. 5. Morrison VA, Weller EA, Habermann TM, Li S, Horning SJ, Fisher RI, et al. Patterns of growth factor (GF) usage and febrile neutropenia (FN) among older patients (pts) with diffuse large B-cell lymphoma (DLBCL) treated with CHOP or R-CHOP: An intergroup experience (CALGB 9793, ECOG-SWOG 4494). Blood 2004;104:904a (Abstract # 3309). 6. Go´mez H, Mas L, Casanova L, Pen DL, Santillana S, Valdivia S, et al. Elderly patients with aggressive non-Hodgkin’s lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor: Identification of two age subgroups with differing hematologic toxicity. J Clin Oncol 1998;16:2352 – 2358. 7. Zinzani PL, Pavone E, Storti S, Moretti L, Fattori PP, Guardigni L, et al. Randomized trial with or without granulocyte colony-stimulating factor as adjunct to induction VNCOP-B treatment of elderly high-grade non-Hodgkin’s lymphoma. Blood 1997;89:3974 – 3979. 8. Zagonel V, Babare R, Merola MC, Talamini R, Lazzarini R, Tirelli U, et al. Cost-benefit of granulocyte colony-stimulating factor administration in older patients with non-Hodgkin’s lymphoma treated with combination chemotherapy. Ann Oncol 1994;2(Suppl):127 – 132. 9. Bertini M, Freilone R, Vitolo U, Botto B, Pizzuti M, Gavarotti P, et al. P-VEBEC: A new 8-weekly schedule with or without rG-CSF for elderly patients with aggressive non-Hodgkin’s lymphoma (NHL). Ann Oncol 1994;5:895 – 900. 10. Balducci L, Lyman GH. Patients aged 70 are at high risk for neutropenic infection and should receive hemopoietic growth factors when treated with moderately toxic chemotherapy. J Clin Oncol 2001;19:1583 – 1585.
11. Rolston KVI. New trends in patient management: risk-based therapy for febrile patients with neutropenia. Clin Infect Dis 1999;29:515 – 521. 12. Klastersky J, Paesmans M, Rubenstein EB, Boyer M, Elting L, Feld R, et al. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038 – 3051. 13. Lyman GH. Balancing the benefits and costs of colonystimulating factors: A current perspective. Semin Oncol 2003;30:10 – 17. 14. Cosler LE, Sivasubramaniam V, Agboola O, Crawford J, Dale D, Lyman GH. Effect of outpatient treatment of febrile neutropenia on the risk threshold for the use of CSF in patients with cancer treated with chemotherapy. Value in Health 2005;8:47 – 52. 15. Kwak LW, Halpern J, Olshen RA, Horning SJ. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: Results of a tree-structured survival analysis. J Clin Oncol 1990;8:963 – 977. 16. Epelbaum R, Haim N, Ben-Shahar M, Roy Y, Cohen Y. Dose-intensity analysis for CHOP chemotherapy in diffuse aggressive large cell lymphoma. Isr J Med Sci 1988;24:533 – 538. 17. Dixon DO, Neilan B, Jones SE, Lipschitz DA, Miller TP, Grozea PN, Wilson HE. Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol 1986;4:295 – 305. 18. Doorduijn JK, van der Holt B, van Imhoff GW, van der Hem KG, Kramer MH, van Oers MH, et al. CHOP compared with CHOP plus granulocyte colony-stimulating factor in elderly patients with aggressive non-Hodgkin’s lymphoma. J Clin Oncol 2003;21:3041 – 3050. ¨ sby E, Hagberg H, Kvaløy S, Teerenhovi L, Andersson H, 19. O Cavallin-Stahl E, et al. CHOP is superior to CNOP in elderly patients with aggressive lymphoma while outcome is unaffected by filgrastim treatment: Results of a Nordic Lymphoma Group randomized trial. Blood 2003;101:3840 – 3848.
DOI: 10.1080/10428190600648713
Pitfalls in predicting tumor lysis syndrome Commentary on: Mato et al. A predictive model for the detection of tumor lysis syndrome during AML induction therapy. Leuk Lymphoma 2006;47:877 – 883.
SCOTT C. HOWARD1,2 & CHING-HON PUI1,2,3 1
Department of Hematology-Oncology and the International Outreach Program, St. Jude Children’s Research Hospital, Memphis, TN, USA, 2Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA, and 3 American Cancer Society-F.M. Kirby Clinical Research Professor
Importance of predicting tumor lysis syndrome Tumor lysis syndrome (TLS) is a constellation of metabolic abnormalities that includes hyperurice-
mia, azotemia, hyperkalemia, hyperphosphatemia, and hypocalcemia (Figure 1) [1]. It is common in patients with lymphoma and leukemia, who often present with bulky disease and have a rapid
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Figure 1. Risk factors for development of laboratory and clinical tumor lysis syndrome. TLS, tumor lysis syndrome; PO4, phosphate; IVF, intravenous fluids. Treatments are indicated in italics. Figure used with permission of St. Jude Children’s Research Hospital (originally posted on www.Cure4Kids.org).
response to chemotherapy. During tumor lysis, crystallization of uric acid and calcium phosphate in the renal tubules can cause nephrotoxicity and renal failure, hyperkalemia, and hypocalcemia, which can cause life-threatening cardiac arrhythmias. In severe cases, TLS can be fatal. Accurate identification of patients who will develop tumor lysis syndrome and nephrotoxicity is important, since it would allow selection of those who need more aggressive monitoring and therapy. This is the goal of the study by Mato and colleagues in this issue of Leukemia and Lymphoma [2].
Risk factors for tumor lysis syndrome Known risk factors for TLS (Figure 1) include cancer factors (highly proliferative or bulky tumor), patient factors (pre-existing renal insufficiency or gout, presentation with dehydration or acute renal insufficiency), and treatment factors (adequacy of hydration, use of phosphate binders,
choice of anti-uricemic agent). An elevated lactate dehydrogenase (LDH) is a surrogate for tumor bulk and high proliferative rate, and has been consistently associated with increased risk for TLS.
Treatment and prevention of tumor lysis syndrome The frequency of acute renal failure in high-risk patients, especially those with advanced-stage Burkitt leukemia or lymphoma, can be as high as 30% [3 – 5]. Therefore, all patients with these features should receive hydration with at least 3000 mL/m2/ day of intravenous fluids that contain no potassium, provided that they have good cardiac function, and close monitoring of urine output and electrolytes. Hyperhydration maintains urine output, flushes micro-crystals from the renal tubules, and prevents metabolic acidosis, which worsens renal function and increases uric acid precipitation. In patients at high risk to develop TLS, treatment with allopurinol or rasburicase is warranted [1,6].
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Allopurinol inhibits xanthine oxidase and thus reduces the formation of new uric acid [7]. It is moderately effective and well-tolerated, but requires one to two days to achieve peak effect (even when given intravenously), does not remove existing uric acid, and leads to accumulation of the upstream products of purine catabolism (hypoxanthine and xanthine), which can also precipitate in the kidneys [7]. In fact, xanthine is less soluble than uric acid [8]. Oral allopurinol has a bioavailability of 80% and is given at a dose of 600 – 800 mg/day (300 mg/ m2/day in children) [7]. Rasburicase oxidizes uric acid into allantoin, which is soluble regardless of urine pH and is readily excreted in urine. It is administered intravenously at a dose of 0.05 mg/kg to 0.2 mg/kg (rounded to the nearest 1.5 mg vial to reduce waste), depending on the level of uric acid and the risk of TLS. Rasburicase achieves peak effect within hours of administration, removes existing uric acid, and does not induce accumulation of xanthine [8]. It is more effective than allopurinol in reducing uric acid levels [8] and is associated with a lower incidence of acute renal insufficiency in uncontrolled studies of adults and children with hematologic malignancies [1,9 – 11]. Although indicated for daily use for 5 days, one to three doses of rasburicase are usually sufficient to control TLS [1,9,11]. To reduce cost, allopurinol can be administered after initial rasburicase treatment. Concomitant or preceding use of allopurinol is not recommended because rasburicase cannot breakdown the precursors of uric acid. Rasburicase should not be given to patients with a deficiency in glucose-6-phosphate dehydrogenase because one of the by-products of uric acid breakdown is hydrogen peroxide, which can induce hemolytic anemia in them [8]. Definition of tumor lysis syndrome Mato and colleagues defined TLS as either: (i) a doubling of baseline serum creatinine in association with at least one of the following measures: PO4 4 1.6 mmol/l (5 mg/dl), uric acid 4 416 mmol/l (7 mg/dl) or Kþ 4 5 mmol/l (5 mEq/l) or (ii) elevations of two of these measures, regardless of serum creatinine. This definition differs from that of Cairo and Bishop: the thresholds for abnormal PO4, uric acid, and Kþ differ; a 25% increase from baseline is not considered; and hypocalcemia is not included [2]. Further, in the Cairo-Bishop system a rise in creatinine to 1.5 times the upper limit of normal indicates clinical TLS; whereas, the predictive model in the current study does not distinguish between laboratory and clinical TLS.
Development and application of a predictive model A predictive model must be based on a well-defined patient population (adults with acute myeloid leukemia, in this case) who were treated uniformly. To be useful, the model must predict a clinically relevant outcome. Although development of renal failure is the outcome of most interest to clinicians, it occurred in only one case (0.5%) in this study cohort. Although most patients in the study had laboratory evidence of TLS, it can be argued that successful treatment of laboratory TLS will prevent the occurrence of clinical TLS. Of the 194 evaluable adults with acute myeloid leukemia in this study, 19 (9.8%) developed TLS. One patient (0.5%) required hemodialysis and none died of TLS. The white blood cell count, LDH, uric acid, and creatinine were reported for the patients who developed TLS, but not for the others. Multivariate analysis confirmed previously reported TLS risk factors (elevated LDH, elevated uric acid) and male gender. These three factors were then used to construct a predictive model, with each of the three variables contributing to a TLS score, ranging from 0 to 10. Patients with a score of 0 or more have a 9.8% probability of TLS; whereas, those with a score of 10 have a 78% probability. If a score of 5 or greater is used as a cutoff to define ‘‘high-risk’’ for TLS, then the TLS score has a sensitivity of 0.95 and specificity of 0.49. Extension of the predictive model The next step for TLS prevention should include validation of the model in a separate population of adults with acute myeloid leukemia, those with other cancers, and children. If the model performs adequately in these settings, it could be used to guide clinicians as to which patients require closer monitoring and rasburicase treatment, and could be used to identify cohorts of patients at high enough risk for TLS to be good candidates for clinical trials of TLS prevention. Additional model development should focus on prediction of clinical TLS, and should include information about baseline renal function; comorbid illness; the quantity of intravenous fluids administered; urine output; use of diuretics, phosphate binders, supplemental calcium, kayexalate; and choice of antiuricemic agent (none, allopurinol, rasburicase). Acknowledgements Supported in part by Cancer Center Support (CORE) grant CA-21765 from the National Cancer Institute, by a Center of Excellence grant from the State of Tennessee, by an American Cancer Society F.M. Kirby Clinical Research Professorship, and by
Commentaries the American Lebanese Syrian Associated Charities (ALSAC). Scott C. Howard, MD, MS Department of Hematology-Oncology and International Outreach Program St. Jude Children’s Research Hospital 332 N. Lauderdale, Memphis, TN 38105-2794 Tel: (901) 495-2972 Fax: (901) 495-5319 E-mail:
[email protected]
References 1. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004; 127:3 – 11. 2. Mato AR, Riccio BE, Qin L, Heitjan DF, Carroll M, Loren A, et al. A predictive model for the detection of tumor lysis syndrome during AML induction therapy. Leuk Lymphoma 2006;47:877 – 883. 3. Cohen LF, Balow JE, Magrath IT, Poplack DG, Ziegler JL. Acute tumor lysis syndrome. A review of 37 patients with Burkitt’s lymphoma. Am J Med 1980;68:486 – 491.
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4. Wibe E, Kvaloy S, Nome O, Abrahamsen AF, Bjorgo S. Tumor lysis syndrome. A life-threatening complication during cytostatic treatment of chemosensitive types of cancer. Tidsskr Nor Laegeforen 1991;111:2435 – 2437. 5. Jones DP, Stapleton FB, Kalwinsky D, McKay CP, Kellie SJ, Pui CH. Renal dysfunction and hyperuricemia at presentation and relapse of acute lymphoblastic leukemia. Med Pediatr Oncol 1990;18:283 – 286. 6. Pui CH, Mahmoud HH, Wiley JM, Woods GM, Leverger G, Camitta B, 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. 7. DeConti RC, Calabresi P. Use of allopurinol for control of hyperuricemia in leukemia and lymphoma. Conn Med 1967;30:430 – 436. 8. Pui CH. Rasburicase: a potent uricolytic agent. Expert Opin Pharmacother 2002;3:433 – 442. 9. Jeha S, Kantarjian H, Irwin D, Shen V, Shenoy S, Blaney S, et al. Efficacy and safety of rasburicase, a recombinant urate oxidase (Elitek), in the management of malignancy-associated hyperuricemia in pediatric and adult patients: final results of a multicenter compassionate use trial. Leukemia 2005;19:34 – 38. 10. Goldman SC. Rasburicase: potential role in managing tumor lysis in patients with hematological malignancies. Expert Rev Anticancer Ther 2003;3:429 – 433. 11. Lee AC, Li CH, So KT, Chan R. Treatment of impending tumor lysis with single-dose rasburicase. Ann Pharmacother 2003;37:1614 – 1617.
DOI: 10.1080/10428190600765798
Managing monoclonal gammopathy-associated neuropathy Commentary on: Kilidireas et al. Rituximab therapy in monoclonal IgM-related neuropathies. Leuk Lymphoma 2006;47:859 – 864.
MORIE A. GERTZ Division of Hematology, Mayo Clinic, College of Medicine, Rochester, MN, USA
When a hematologist sees a patient with a peripheral neuropathy and a monoclonal gammopathy, the endeavor is often an exercise in frustration for both the patient and the physician. Because the prevalence of monoclonal proteins in the population rises with age and reaches 4% at the age of 70 years, there is always the question of whether the presence of a monoclonal gammopathy in a patient with a peripheral neuropathy is pathogenic or coincidental. In addition, the differential diagnosis of peripheral neuropathy with a monoclonal protein requires an extensive diagnostic evaluation. The differential diagnosis includes type II cryoglobulinemia, immunoglobulin (Ig) light chain amyloidosis and the POEMS syndrome (osteosclerotic myeloma) [1].
Each of the former requires a specific diagnostic evaluation which may include biopsy of the sural nerve to exclude the immune complex vasculitis of cryoglobulinemia or amyloid deposition. However, the most common is monoclonal gammopathy-associated peripheral neuropathy (MGUS neuropathy). The pathogenesis in most of these patients is not well understood, with the exception of those patients who have an IgM monoclonal protein. The likelihood that an IgM monoclonal protein is related to a patient’s neuropathy is greater than that associated with an IgG or IgA protein. IgM antibodies have been demonstrated to have antimyelinassociated glycoprotein activity (anti-MAG) [2]. Anti-MAG or other anti-ganglioside antibodies are
