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Journal of Clinical Oncology, Vol 25, No 9 (March 20), 2007: pp. 1054-1060 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.3484 Phase II Study on the Effect of Disease Sites, Age, and Prior Therapy on Response to Iodine-131-Metaiodobenzylguanidine Therapy in Refractory Neuroblastoma
From the Departments of Pediatrics, Nuclear Medicine, and Biostatistics and Epidemiology, University of California at San Francisco and UCSF Children's Hospital, San Francisco, CA; Department of Pediatrics, University of Michigan and Mott Children's Hospital, Ann Arbor, MI; Department of Pediatrics, Children's Hospital of Philadelphia; University of Pennsylvania; and the Abramson Family Cancer Research Institute, Philadelphia, PA Address reprint requests to Katherine K. Matthay, MD, Department of Pediatrics, University of California at San Francisco, 505 Parnassus, M647, San Francisco, CA 94143-0106; e-mail: matthayk{at}peds.ucsf.edu
Purpose To evaluate the effect of disease sites and prior therapy on response and toxicity after iodine-131-metaiodobenzylguanidine (131I-MIBG) treatment of patients with resistant neuroblastoma. Patients and Methods One hundred sixty-four patients with progressive, refractory or relapsed high-risk neuroblastoma, age 2 to 30 years, were treated in a limited institution phase II study. Patients with cryopreserved hematopoietic stem cells (n = 148) were treated with 18 mCi/kg of 131I-MIBG. Those without hematopoietic stem cells (n = 16) received 12 mCi/kg. Patients were stratified according to prior myeloablative therapy and whether they had measurable soft tissue involvement or only bone and/or bone marrow disease. Results Hematologic toxicity was common, with 33% of patients receiving autologous hematopoietic stem cell support. Nonhematologic grade 3 or 4 toxicity was rare, with 5% of patients experiencing hepatic, 3.6% pulmonary, 10.9% infectious toxicity, and 9.7% with febrile neutropenia. The overall complete plus partial response rate was 36%. The response rate was significantly higher for patients with disease limited either to bone and bone marrow, or to soft tissue (compared with patients with both) for patients with fewer than three prior treatment regimens and for patients older than 12 years. The event-free survival (EFS) and overall survival (OS) times were significantly longer for patients achieving response, for those older than 12 years and with fewer than three prior treatment regimens. The OS was 49% at 1 year and 29% at 2 years; EFS was 18% at 1 year. Conclusion The high response rate and low nonhematologic toxicity with 131I-MIBG suggest incorporation of this agent into initial multimodal therapy of neuroblastoma.
Neuroblastoma is a malignant tumor derived from the sympathetic nervous system. It is the most common extracranial solid tumor in children, with metastatic disease at diagnosis in half of the cases.1 Despite improvement in outcome with intensification of therapy and treatment of minimal residual disease, more than 50% of patients will relapse and die from their malignancy.2 Metaiodobenzylguanidine (MIBG) is a guanethidine derivative with specificity for neural crest tissues.3 MIBG labeled with iodine-131 (131I-MIBG) has shown activity against neuroblastoma, with response rates for relapsed disease from less than 10% to 50%.4-10 Some groups have used 131I-MIBG alone earlier in treatment11 or combined with chemotherapy.12-16 Understanding the optimal use of 131I-MIBG with regard to patient variables and dose has become increasingly important with this expanding role. Despite regular use and commercialization in Europe of this targeted radionuclide, progress in the United States has been slowed by the orphan drug status due to restricted tumor applications and the radiation safety requirements. In a phase I trial of 131I-MIBG for relapsed neuroblastoma, the primary toxicity of 131I-MIBG was myelosuppression, particularly thrombocytopenia. At doses of 15 mCi/kg or higher, though response rates were apparently greater, almost half of the patients required autologous hematopoietic cell transfusion (HCT) with bone marrow or peripheral blood stem cell support for prolonged myelosuppression.4,17 Due to the limited number of centers offering this therapy, and the requirement for HCT, prospective studies are lacking to examine optimal dose, toxicity, and whether prior therapy, age, and disease sites affect response rate. We performed a phase II study for patients with refractory or relapsed neuroblastoma with the aims of determining (1) response rate with 131I-MIBG therapy (18 mCi/kg); (2) acute and late toxicity of high-dose 131I-MIBG; (3) impact of disease sites and prior myeloablative therapy on response and toxicity; and (4) toxicity and safety of moderate-dose 131I-MIBG therapy (12 mCi/kg) for patients without an autologous hematopoietic cell product.
Study Design This was a phase II study to evaluate the response rate to 18 mCi/kg of 131I-MIBG supported by autologous HCT, if required. A second cohort of patients, for whom hematopoietic stem cells were not available, was treated with 12 mCi/kg of 131I-MIBG, the highest tolerated dose not requiring HCT.4 Patients were recruited into four strata, divided first by whether or not previous myeloablative therapy had been given, and second by the presence or absence of volumetric measurable disease by computed tomography or magnetic resonance imaging scan (Table 1). Planned accrual was 40 patients per stratum in the 18 mCi/kg cohort. Since so few patients were recruited without prior transplantation, Strata 3 and 4 did not reach accrual goals. Strata 1 and 2 were permitted to continue to accrue patients to achieve a minimum target of 20 patients surviving greater than 1 to 2 years to assess late toxicity.
Patients received intravenous 131I-MIBG over 2 hours with hydration, thyroid protection with potassium iodide and potassium perchlorate, and a Foley catheter for bladder protection. 131I-MIBG was supplied either by the Michigan Memorial Phoenix Laboratory at the University of Michigan (investigational new drug 17,239; Ann Arbor, MI) or synthesized at the University of California at San Francisco (investigational new drug 32,147; San Francisco, CA), with free iodide content of less than 5%. Patients remained in radiation-protected isolation for 2 to 7 days, until radiation emissions met institutional regulations.4 The dose of radiation to the whole body from 131I-MIBG was calculated using multiple measurements from a handheld or ceiling-mounted Geiger counter.18 Granulocyte colony-stimulating factor was administered for absolute neutrophil count (ANC) less than 500/µL. Patients were eligible for a second infusion 6 weeks after the first infusion if they had tumor response, ANC more than 750, and did not meet criteria for HCT. Thirty-five patients had multiple infusions, including 20 who were previously reported in a separate publication.19 Patients were monitored each week for 6 weeks or until recovery from toxicity. Response evaluation, reported here for the first course only, used International Neuroblastoma Response Criteria20 and was performed at 6 to 8 weeks post-therapy, including bilateral bone marrow aspirate and biopsy, urine catecholamines, appropriate imaging studies for soft tissue lesions, and a diagnostic MIBG scan. A central review of all scan and pathology reports was performed; all pre- and post-therapy scans were read by radiologists at the three treating institutions, and central radiological MIBG scan scoring was done in 49 cases.21 Tumor response evaluations and hematologic, hepatic, renal, and endocrine toxicity evaluations were required at 3-month intervals for 1 year, then every 6 months, or until the patient died or went on to other therapy. Toxicity was graded according to Common Toxicity Criteria version 2.0. Criteria for HCT were ANC less than 200/µL for more than 2 weeks despite the use of hematopoietic growth factors or platelet transfusions more frequently than twice weekly for 3 consecutive weeks.
Patient Population
Statistical Analyses
Patients Characteristics of the 164 eligible patients are shown in Table 1. Twenty-six patients had either refractory disease or progression during induction before any myeloablative therapy. The remainder had relapsed disease, either with (N = 128) or without (N = 10) prior to transplantation. Most patients (n = 148) had stem cell product and were entered into the 18-mCi/kg stratum. Sixteen patients without stem cell product were assigned the 12-mCi/kg stratum. Sixteen other patients assigned to the 18-mCi/kg stratum received a range of 131I-MIBG activity from 8.6 to 16.0 mCi/kg, either because of weight that would have resulted in exceeding radiation safety limits or because of technical factors in MIBG preparation. Patient characteristics were similar among the strata, with the usual features of high-risk neuroblastoma, including young age, male predominance, 37% with MYCN amplification, and 86% with bone and/or bone marrow involvement. Sites of involvement were usually multiple, including 82 patients with combined soft tissue and bone and/or bone marrow tumors, 33 patients with combined bone and bone marrow tumor, 26 patients with bone tumors only, 22 patients with soft tissue tumors only, and a single patient with bone marrow only. The patients with only soft tissue tumors had high-risk stage 3 or 4 neuroblastoma at diagnosis, and included metastatic nodal recurrences, lung metastases, and large retroperitoneal or mediastinal tumors. Their prior therapy included surgery and chemotherapy in all, radiation in 19 of 22 patients, and myeloablative therapy in 12 of 22 patients. The vast majority of all patients were heavily pretreated, with a median of three prior regimens, and more than 90% with prior radiation therapy and surgery. Six patients had only one prior therapy because of primary refractory disease or progression during induction, and they were treated with MIBG as their first attempt at salvage. The cohort without prior HCT had a shorter time from diagnosis to MIBG therapy, and a higher proportion with soft tissue disease (86% v 57%). Shortly after opening this study, myeloablative therapy became standard treatment for high-risk neuroblastoma,2 so fewer patients accrued to the strata without prior transplantation.
Response
In a multivariable analysis with variables from Table 3 of age, site, time from diagnosis, and number of prior regimens, the variables with increased likelihood of achieving CR/PR were less than 3 prior regimens (P = .001), longer time from diagnosis (P = .009), site (P = .058), and age (P = .23). Age lost significance in the multivariable analysis because of close association with time from diagnosis. As in the univariate analysis, the effects of sex, prior HCT, MYCN, and dose on the response rate were not significant in the multivariable analysis. Urine vanillylmandelic acid and homovanillic acid were excluded from the multivariable analysis because there were too many missing data when combined with MYCN. The final multivariable analysis included only age, site, time from diagnosis, and number of regimens.
Event-Free Survival and Overall Survival
Toxicity and Deaths The chief toxicity on this study was hematologic. Forty-nine of 148 patients (33%) treated at the 18-mCi/kg level required HCT due to either ANC less than 200/µL for more than 2 weeks or prolonged dependence on platelet transfusions. Eighty-eight percent of all 164 patients required platelet transfusions, and 65% had an ANC nadir of less than 500/µL. Despite myelosuppression, only 21% of patients had infectious episodes, including 18 proven infections and 16 cases of febrile neutropenia. None of the 16 patients treated at 12 mCi/kg had an ANC nadir of less than 200/µL, although the majority (n = 12) required platelet transfusions, and one patient was admitted for febrile neutropenia. The presence or absence of bone marrow involvement, treatment stratum, and number of prior regimens did not significantly predict the proportion of patients receiving HCT. Four heavily pretreated patients developed myelodysplasia (MDS) and acute myeloblastic leukemia (AML), of whom two were previously reported.25 The cytogenetic abnormalities included monosomy 7 in two, 11q23 in one, and trisomy12 with monosomy 11 in one patient. Grade 3 and 4 nonhematologic toxicities are shown in Table 4 and were similar for both dose levels. Thirty-six patients (22%) had at least one grade 3 nonhematologic toxicity as their highest grade, and 15 patients (9.1%) had a grade 4 toxicity (excluding the five second malignancies). The secondary malignancies included four patients with MDS/AML and one patient, still alive, who developed a retroperitoneal mesothelioma 38 months after MIBG treatment. Other late toxicities attributable to the MIBG therapy, except for asymptomatic grade 1 hypothyroidism, were not observed.
By March 1, 2006, 116 patients died, including 106 from progressive disease. Three toxic deaths occurred less than 3 months after MIBG without intervening therapy—one from Pneumocystis carinii pneumonia at 2.6 months, one from capillary leak syndrome at 2.8 months in close proximity to HCT, and one with progressive disease and fungal sepsis (secondary cause) at 1.8 months. Four patients died later from MDS/AML, possibly attributable to the 131I-MIBG, at 11, 23, 39, and 41 months after MIBG treatment. Four patients died more than 10 months later from toxicity of subsequent treatments for their neuroblastoma, including two with sepsis and two with multiorgan failure.
This is the largest reported phase II study to date of single-agent 131I-MIBG radiotherapy at a uniform and maximum feasible dose. It shows that this targeted radionuclide is highly active with an objective response rate of 36% in patients with heavily pretreated neuroblastoma in a multi-institutional setting with central review of response and semiquantitative scoring.21 An additional 34% of patients were without progression for a median of 6.2 months after treatment, and they had frequent palliation of pain. The patients in this study had a median of three prior regimens, with some as many as 13 different prior therapies, and 128 (78%) of all patients had recurrent disease after myeloablative therapy. These data unequivocally demonstrate the activity of 131I-MIBG in the relapse setting and strongly suggest that its incorporation earlier in the course of the disease would be beneficial. The effect of different variables on response rate was examined. First, older patients had a significantly higher likelihood of response and longer EFS than younger patients, including both cohorts age 6 to 12 years, and older than 12 years at diagnosis. This may be related to a lower incidence of MYCN amplification and more indolent disease in these groups,26 although MYCN itself was not prognostic. The better response and EFS cannot be due to the more limited extent of disease because all three age groups had a similar proportion of patients with soft tissue only: nine (13%) of 67 patients younger than 6 years of age, eight (12%) of 65 patients age 6 to12 years, and five (16%) of 31 patients older than 12 years. The significance of age was confounded by the close association with time from diagnosis, also a favorable factor for response, in the multivariable analysis. This may be due partly to the fact that older patients have a more indolent course and thus longer time from diagnosis to MIBG therapy, or because patients with a longer time from diagnosis to MIBG have more responsive disease. The other variables found to be significantly favorable for response in univariate and multivariable analyses were disease limited to either soft tissue or to bone and bone marrow only, and less prior treatment. This is compatible with the frequent observations that therapy resistance is generally less common in patients with less extensive disease and less prior therapy. The seemingly contradictory observation that response rate was apparently higher (P = .12) in patients with prior myeloablative therapy and HCT compared with those who had not had HCT, may reflect the fact that the majority of patients entering the MIBG protocol without prior HCT were patients who had primary therapy resistance and had never achieved a significant response to extended induction regimen, although the smaller number of patients without prior HCT suggests caution in this interpretation. Another nearly significant (P = .06) favorable factor for response in univariate analysis was the absence of measurable vanillylmandelic acid and homovanillic acid in the urine, which may be a reflection of less extensive disease. The effect of dose was not assessable, due to the small number of patients in the 12-mCi/kg cohort, and the fact that patients in this category may have differed from patients for whom hematopoietic stem cells could be collected. A randomized trial of higher versus lower dose would be required to determine a dose-response relationship. The toxicity of the 131I-MIBG was chiefly myelosuppression, abrogated by HCT. Despite myelosuppression, the incidence of grade 3 to 4 proven infection was low (11%) and the acute toxic death rate only 1%. Other acute nonhematologic grade 3 and 4 toxicities were infrequent and reversible. Myelodysplasia with AML occurred in four patients. This complication was previously reported, and causality is hard to separate from heavy prior therapy with alkylating agents, anthracyclines, radiotherapy, and etoposide.25,27-29 Other late toxicities are still under investigation, but thus far consist only of occasional asymptomatic hypothyroidism, and no late hepatic or cardiac toxicity. Toxicity limited to myelosuppression together with the high response rate suggests that 131I-MIBG should be used in combination with other therapies earlier in the course of the disease, with appropriate hematopoietic support. Several studies of 131I-MIBG alone or combined with conventional chemotherapy have shown responsiveness in newly diagnosed patients.11,12 A recent phase I dose escalation study of 131I-MIBG with myeloablative carboplatin, etoposide, and melphalan with HCT showed good feasibility and a significant response rate of 25% in patients with primary refractory disease.15 Currently, a phase II study of this regimen is under way in the New Approaches to Neuroblastoma Therapy (Los Angeles, CA) consortium. The excellent response rate in relapsed patients with 131I-MIBG as a single agent and the feasibility of the combination regimen demonstrated in phase I and ongoing phase II studies argue strongly for use in patients in first response with MIBG-positive disease at diagnosis.
The authors indicated no potential conflicts of interest.
Conception and design: Katherine K. Matthay, Su-Chun Cheng, Janet Veatch, John M. Maris Administrative support: Katherine K. Matthay, Julia Messina, Alekist Quach, Janet Veatch, Randall A. Hawkins Provision of study materials or patients: Katherine K. Matthay, Gregory Yanik, John Huberty, Patricia Brophy, Leslie S. Kersun, Randall A. Hawkins, John M. Maris Collection and assembly of data: Katherine K. Matthay, Gregory Yanik, Julia Messina, Alekist Quach, John Huberty, Janet Veatch, Patricia Brophy Data analysis and interpretation: Katherine K. Matthay, Gregory Yanik, Alekist Quach, Su-Chun Cheng, Robert Goldsby, John M. Maris Manuscript writing: Katherine K. Matthay, Gregory Yanik, Janet Veatch, Robert Goldsby, John M. Maris Final approval of manuscript: Katherine K. Matthay, Gregory Yanik, Julia Messina, Alekist Quach, John Huberty, Su-Chun Cheng, Janet Veatch, Robert Goldsby, Patricia Brophy, Leslie S. Kersun, Randall A. Hawkins, John M. Maris
Supported by the National Institute of Health Grants No. PO1 CA81403, 2MO1 RR0127, and M01-RR00240, as well by donations from the Campini Foundation, Conner Research Fund, Katie Dougherty Foundation, Kasle and Tkalcevik Neuroblastoma Research Fund, Thrasher Research Fund, Alex's Lemonade Stand Foundation, and the Evan T.J. Dunbar Neuroblastoma Foundation. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Matthay KK, Yamashiro D: Neuroblastoma, in Bast RC, Kufe DW, Pollock RE, et al (eds): Cancer Medicine. London, BC Decker, 2000, pp 2185-2197 2. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 341:1165-1173, 1999 3. Wieland DM, Wu JL, Brown LE, et al: Radiolabeled adrenergic neuron-labeling agents: Adrenomedullary imaging with 131-I-iodobenzylguanidine. J Nucl Med 21:349-353, 1980 4. Matthay KK, DeSantes K, Hasegawa B, et al: Phase I dose escalation of 131I-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma. J Clin Oncol 16:229-236, 1998 5. Garaventa A, Bellagamba O, Lo Piccolo MS, et al: 131I-metaiodobenzylguanidine (131I-MIBG) therapy for residual neuroblastoma: A mono-institutional experience with 43 patients. Br J Cancer 81:1378-1384, 1999[CrossRef][Medline] 6. Klingebiel T, Berthold F, Treuner J, et al: Metaiodobenzylguanidine (mIBG) in treatment of 47 patients with neuroblastoma: Results of the German Neuroblastoma Trial. Med Pediatr Oncol 19:84-88, 1991[Medline] 7. Hutchinson RJ, Sisson JC, Miser JS, et al: Long-term results of [131I]metaiodobenzylguanidine treatment of refractory advanced neuroblastoma. J Nucl Biol Med 35:237-240, 1991[Medline] 8. Voute PA, Hoefnagel CA, de Kraker J, et al: Results of treatment with 131 I-metaiodobenzylguanidine (131 I-MIBG) in patients with neuroblastoma. Future prospects of zetotherapy. Prog Clin Biol Res 366:439-445, 1991[Medline] 9. Lashford LS, Lewis IJ, Fielding SL, et al: Phase I/II study of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: A United Kingdom Children's Cancer Study Group investigation. J Clin Oncol 10:1889-1896, 1992[Abstract] 10. Lumbroso J, Hartmann O, Schlumberger M: Therapeutic use of [131I]metaiodobenzylguanidine in neuroblastoma: A phase II study in 26 patients. Societe Francaise d'Oncologie Pediatrique and Nuclear Medicine Co-investigators. J Nucl Biol Med 35:220-223, 1991[Medline] 11. Hoefnagel CA, De Kraker J, Valdes Olmos RA, et al: 131I-MIBG as a first-line treatment in high-risk neuroblastoma patients. Nucl Med Commun 15:712-717, 1994[Medline] 12. Mastrangelo S, Tornesello A, Diociaiuti L, et al: Treatment of advanced neuroblastoma: Feasibility and therapeutic potential of a novel approach combining 131-I-MIBG and multiple drug chemotherapy. Br J Cancer 84:460-464, 2001[CrossRef][Medline] 13. Klingebiel T, Bader P, Bares R, et al: Treatment of neuroblastoma stage 4 with 131I-meta-iodo-benzylguanidine, high-dose chemotherapy and immunotherapy: A pilot study. Eur J Cancer 34:1398-1402, 1998[CrossRef][Medline] 14. Yanik GA, Levine JE, Matthay KK, et al: Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma. J Clin Oncol 20:2142-2149, 2002 15. Matthay KK, Tan JC, Villablanca JG, et al: Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: A New Approaches to Neuroblastoma Therapy Consortium Study. J Clin Oncol 24:500-506, 2006 16. Gaze MN, Chang YC, Flux GD, et al: Feasibility of dosimetry-based high-dose 131I-meta-iodobenzylguanidine with topotecan as a radiosensitizer in children with metastatic neuroblastoma. Cancer Biother Radiopharm 20:195-199, 2005[CrossRef][Medline] 17. Dubois SG, Messina J, Maris JM, et al: Hematologic toxicity of high-dose iodine-131-metaiodobenzylguanidine therapy for advanced neuroblastoma. J Clin Oncol 22:2452-2460, 2004 18. Matthay KK, Panina C, Huberty J, et al: Correlation of tumor and whole-body dosimetry with tumor response and toxicity in refractory neuroblastoma treated with (131)I-MIBG. J Nucl Med 42:1713-1721, 2001 19. Howard JP, Maris JM, Kersun LS, et al: Tumor response and toxicity with multiple infusions of high dose (131)I-MIBG for refractory neuroblastoma. Pediatr Blood Cancer 44:232-239, 2005[CrossRef][Medline] 20. Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11:1466-1477, 1993 21. Messina JA, Cheng SC, Franc BL, et al: Evaluation of semi-quantitative scoring system for metaiodobenzylguanidine (mIBG) scans in patients with relapsed neuroblastoma. Pediatr Blood Cancer 47:865-874, 2006[CrossRef][Medline] 22. Seeger RC, Reynolds CP, Gallego R, et al: Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: A Children's Cancer Group Study. J Clin Oncol 18:4067-4076, 2000 23. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 24. Cox DRB: Regression models and life tables. J R Stat Soc B 34:187-220, 1972 25. Weiss B, Vora A, Huberty J, et al: Secondary myelodysplastic syndrome and leukemia following 131I-metaiodobenzylguanidine therapy for relapsed neuroblastoma. J Pediatr Hematol Oncol 25:543-547, 2003[CrossRef][Medline] 26. Franks LM, Bollen A, Seeger RC, et al: Neuroblastoma in adults and adolescents: An indolent course with poor survival. Cancer 79:2028-2035, 1997[CrossRef][Medline] 27. Robison LL, Mertens A: Second tumors after treatment of childhood malignancies. Hematol Oncol Clin North Am 7:401-415, 1993[Medline] 28. Kushner BH, Meyers PA: How effective is dose-intensive/myeloablative therapy against Ewing's sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 19:870-880, 2001 29. Le Deley MC, Leblanc T, Shamsaldin A, et al: Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: A case-control study by the Societe Francaise d'Oncologie Pediatrique. J Clin Oncol 21:1074-1081, 2003 Submitted September 29, 2006; accepted December 13, 2006.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
750/µL and platelets 
