systemic anaplastic large cell lymphoma. As Carson et al reported the diagnosis of PML after therapy with a monoclonal antibody-based drug, herein our group also reports another case of PML in a patient with a lymphoid malignancy after combination chemotherapy with a similar drug, namely rituximab. A 52-year-old man was diagnosed with stage IVB diffuse large B-cell non-Hodgkin lymphoma. The patient received 6 cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP regimen), the standard of care for patients with advanced nonHodgkin lymphoma,2 but did not respond and the disease progressed. Rituximab was added, as suggested by Sehn et al for patients with therapy-refractory diffuse large B-cell nonHodgkin lymphoma.3 After the administration of rituximab, the patient presented with acute neurological symptoms that included photophobia, derailment, loss of speech, and dizziness, as well as convergent strabismus of the left eye, bradylalia, myoclonic movements of the upper limbs, marked hypotonia of the lower limbs, and fecal incontinence. The computed tomography scan showed no metastatic spread of the lymphoma and analysis of the cerebrospinal fluid demonstrated the absence of malignant infiltration of the central nervous system. Nevertheless, magnetic resonance imaging of the brain revealed multiple infiltrative lesions of the deep white matter, the periventricular area, the corpus callosum, and the thalamus. Subependymal extension was noted, along with perilesional edema. PML is a rare side effect of chemotherapy for nonHodgkin lymphoma,4,5 with severe consequences for the patient if not diagnosed early. Our report demonstrates the importance of a magnetic resonance imaging-based diagnosis of this disease after monoclonal antibody-based chemotherapy regimens for lymphoid malignancies, a key aspect in the clinical management of these patients because the immune reconstitution may lower their morbidity and mortality.
advanced non-Hodgkin’s lymphoma. N Engl J Med. 1993;328:10021006. 3. Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23:5027-5033. 4. Sikkema T, Schuiling WJ, Hoogendoorn M. Progressive multifocal leukoencephalopathy during treatment with rituximab and CHOP chemotherapy in a patient with a diffuse large B-cell lymphoma. BMJ Case Rep. 2013 Jan 25;2013. 5. Khoury S, Shapira S, Zilberman T, Mekori YA, Hershko AY. Progressive multifocal leukoencephalopathy in an HIV-negative patient following treatment with rituximab. Isr Med Assoc J. 2013;15:321322.
Delia Dima, MD Department of Hematology Ion Chiricuta Oncology Institute Cluj-Napoca, Romania
Ciprian Tomuleasa, MD, PhD Department of Hematology Ion Chiricuta Oncology Institute; Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania
Alexandru Irimie, MD, PhD Department of Surgery Ion Chiricuta Oncology Institute; Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania
Ioan-Stefan Florian, MD, PhD Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania
Bobe Petrushev, MD Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania
Ioana Berindan-Neagoe, PhD Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania
Andrei Cucuianu, MD, PhD Department of Hematology Ion Chiricuta Oncology Institute; Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania DOI: 10.1002/cncr.28948, Published online August 13, 2014 in Wiley Online Library (wileyonlinelibrary.com)
Reply to Magnetic Resonance Imaging-Based Diagnosis of Progressive Multifocal Leukoencephalopathy in a Patient With Non-Hodgkin Lymphoma After Therapy With Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, and Rituximab
1. Carson KR, Newsome SD, Kim EJ, et al. Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project. Cancer. 2014;120:2464-2471. 2. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for
Disseminating timely information concerning serious adverse drug reactions is difficult. This is the mission of the Southern Network on Adverse Reactions (SONAR).
FUNDING SUPPORT No specific funding was disclosed. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures.
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Dima et al from Romania described a patient with nonHodgkin lymphoma who was treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R regimen) who developed speech and motor dysfunction. Magnetic resonance imaging identified white matter defects. Cerebrospinal fluid (CSF) analysis did not identify JC virus (John Cunningham virus). An empirical diagnosis of rituximab-associated progressive multifocal leukoencephalopathy (PML) was made. Recently proposed PML diagnostic criteria from the Neuro-infectious Disease Section of the American Academy of Neurology require evidence of clinical disease progression, imaging, and JC virus (histopathologically or in the CSF).1 If full criteria are not met, then alternative diagnoses need to be investigated. Access to relevant publications may not have been available in Romania, including our case series and review of PML.2,3 The product label also does not report this information.4 Although >300 individuals with rituximab-associated PML have been reported to regulatory authorities, the label does not report this. The label also does not describe that in the setting of a suggestive magnetic resonance imaging scan and a negative CSF evaluation for JC virus, a second lumbar puncture or a brain biopsy should be considered. Finally, emerging data have identified a low baseline PML rate in patients with lymphoma, but a 5-fold increased rate in patients treated with rituximab and chemotherapy.5 We thank Dima et al for reporting this case, thereby reinforcing the observation that the most available source of safety information is the product label. FUNDING SUPPORT Supported in part by: the National Cancer Institute (1R01CA165609-01A1), the South Carolina SmartState Program, and the Doris Levkoff Meddin Medication Safety Center.
CONFLICT OF INTEREST DISCLOSURES Dr. Newsome participated in scientific advisory boards for Biogen Idec and Genzyme, and received research support from Biogen Idec and Novartis that was paid directly to his institution for work performed outside of the current study. Dr. Carson received fees for consulting and participation in a Speakers Bureau from Genentech for work performed outside of the current study.
REFERENCES 1. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 2013;80:1430-1438. 2. Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113:4834-4840. 3. Carson KR, Focosi D, Major EO, et al. Monoclonal antibodyassociated progressive multifocal leucoencephalopathy in patients
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treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol. 2009;10:816-824. 4. US Food and Drug Administration. Package Insert for Rituximab. accessdata.fda.gov/drugsatfda_docs/label/2010/103705s5311lbl.pdf. Accessed July 3, 2014. 5. Norris LB, Georgantopoulos P, Rao GA, et al. Association between rituximab use and progressive multifocal leukoencephalopathy among non-HIV, non-Hodgkin lymphoma Veteran’s Administration patients. Presented at 2014 American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2014; Chicago, IL. meetinglibrary.asco.org/ content/132159-144. Accessed July 3, 2014.
Charles L. Bennett, MD, PhD, MPP Southern Network on Adverse Reactions (SONAR) Program South Carolina College of Pharmacy Columbia, South Carolina
Scott D. Newsome, DO Division of Neuroimmunology and Neuroinfectious Diseases Johns Hopkins School of Medicine Baltimore, Maryland Oliver Sartor, MD Department of Urology Tulane University School of Medicine New Orleans, Louisiana
Kenneth R. Carson, MD Division of Medical Oncology Washington University School of Medicine St Louis, Missouri DOI: 10.1002/cncr.28947, Published online August 13, 2014 in Wiley Online Library (wileyonlinelibrary.com)
Poverty and Lung Cancer Incidence Boscoe et al reported a socioeconomic component of cancer incidence.1 In Figure 2 of their article, they demonstrated a highly significant correlation between area poverty rate, race, and age-adjusted lung cancer incidence. However, they did not control for smoking because smoking data are not included in the central cancer registry data they used. We have examined age-adjusted lung cancer incidence in men in 50 US states and the District of Columbia. We can confirm that there is a significant negative correlation between lung cancer incidence in men and median income level. However, we found that this significant correlation disappears when multivariate analysis is performed to control for smoking, age, and race. The lung cancer incidence data we used were obtained from the American Cancer Society.2 Tobacco use for 2012 (percent of smokers) was obtained from the Centers for Disease Control and Prevention (apps.nccd.cdc.gov/brfss/list. asp?cat5TU&yr52012&qkey58161&state5All). Household income by state using the 3-year average medians was 4007
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