Leukemia & Lymphoma, February 2015; 56(2): 536–538 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.926348

LETTER TO THE EDITOR

Toxoplasmosis in patients with hematologic malignancies Ashish Chintakuntlawar1,2*, Michael Kidd1,2*, Aref Al-Kali1, Walter Wilson3 & Carrie A. Thompson1 1Division of Hematology/Department of Internal Medicine, 2Department of Oncology and 3Division of Infectious

Diseases/Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

Toxoplasmosis is one of the most common parasitic infections [1] and is caused by a protozoan, Toxoplasma gondii. Clinically significant toxoplasmosis is a well-recognized opportunistic infection usually due to reactivation of a latent infection [2]. Adults with intact immunity usually have a self-limited infection; however, in immunocompromised patients, it can cause a life-threatening central nervous system (CNS) or disseminated infection. The frequency of this opportunistic infection in patients treated with antineoplastic chemotherapy in the modern era is unknown, as most series were published in patients with bone marrow transplant, and before the widespread use of trimethoprim–sulfamethoxazole prophylaxis or the advent of immunotherapy, including rituximab (R) [3–5]. Here we report a case of CNS toxoplasmosis after treatment with R and bendamustine (B) in a patient with Waldenström macroglobulinemia (WM), and describe three other cases of toxoplasmosis in patients with hematologic malignancies treated at our institution from 2000 to 2013. A 79-year-old female presented with progressive fatigue and dyspnea on exertion for the past year. She noted easy bruising and several episodes of epistaxis over the preceding 2 months. Physical examination revealed palpable lymphadenopathy. Excisional lymph node biopsy demonstrated that the lymph node architecture was partially effaced by an infiltrate of neoplastic lymphoplasmacytoid cells that were positive for CD20, bcl-2 and immunoglobulin kappa light chains, suggesting a diagnosis of lymphoplasmacytic lymphoma. Laboratory studies showed hemoglobin 7.7 g/dL (12.0–15.5 g/dL), M-spike 4.6 g/dL, immunoglobulin M (IgM) 6910 mg/dL (37–286 mg/dL) and viscosity of 3.2 cP (⬍ 1.5 cP). Bone marrow biopsy showed a hypercellular marrow with 60% involvement by lymphoplasmacytic lymphoma; monoclonal kappa light chain-restricted B-cell lymphocytes were present. The diagnosis of WM with hyperviscosity syndrome was made. After initial therapeutic apheresis, she was treated with B and R (BR) at 90 mg/m2/day (day 1 and 2) and 375 mg/m2 (day 1) of body surface area, respectively, every 4 weeks. Following the completion of four cycles of BR, hemoglo-

bin was 10.9 g/dL, M-spike was 1.9 g/dL and IgM was 2690 mg/dL, and observation was recommended. At that time, she was able to perform all activities of daily living independently and had a steady improvement in energy levels. Eight weeks after her last chemotherapy cycle, her family noted intermittent episodes of mild cognitive dysfunction which progressed to frank confusion and visual hallucinations. There were no reported falls, seizures or symptoms suggestive of infection, including fevers and chills. She was admitted to our institution for further work-up. On initial examination, vital signs were normal. Mucous membranes were dry. Lymph nodes, heart, lung, abdomen and extremities were unremarkable. Her pupils were equal, round and reactive to light. She was restless and only partially oriented to person (only able to say her first name), but not oriented to time or place. Strength, sensation, coordination and gait could not be evaluated, but reflexes were brisk throughout, with Babinski flexor bilaterally. Laboratory examination revealed hemoglobin of 12.5 g/ dL, leukocyte count 6.4 ⫻ 109/L, with normal absolute neutrophil and lymphocyte counts. Serum viscosity and IgM levels were 1.2 cP and 2760 mg/dL, respectively. Fungal, human immunodeficiency virus (HIV) and syphilis serologies were negative. Magnetic resonance imaging (MRI) showed innumerable peripherally enhancing lesions of variable size, many at the gray–white junction. A mild to moderate mass effect was noted on the right frontal horn (Figure 1). Cerebrospinal fluid (CSF) analysis showed glucose of 51 mg/dL (blood sugar 93 mg/dL), total protein of 239 mg/dL (0–35 mg/dL) and a cell count of 239 cells/μL (94% lymphocytes). Cytology was negative for malignancy, and flow cytometry showed no monotypic B-cells. CSF cultures were negative for bacteria, fungi and mycobacteria. CSF polymerase chain reaction (PCR) was positive for T. gondii. Therapy with both intravenous trimethoprim– sulfamethoxazole and oral pyrimethamine with folinic acid was initiated due to concerns about erratic oral intake. Intravenous trimethoprim–sulfamethoxazole was later changed to sulfadiazine when oral therapy could be given reliably. Follow-up examination and MRI 6 weeks later

*Contributed equally to this work. Correspondence: Carrie A. Thompson, Division of Hematology/Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: 507-284-2511. Fax: 507-266-4972. E-mail: [email protected] Received 18 March 2014; revised 9 May 2014; accepted 12 May 2014

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Letter to the Editor 537

Figure 1. A T2-weighted fluid attenuated inversion recovery image of the brain showed multiple ring-enhancing lesions at the gray–white matter junction with mild–moderate mass effect.

showed improvement; therefore, she was transitioned to maintenance therapy with sulfadiazine, pyrimethamine and folinic acid. MRI of the brain 7 months following the start of initial treatment for toxoplasmosis continued to show improvement, with a reduction in size of all lesions. However, after repeated hospitalizations for aspiration pneumonia she expired 1 year after her initial diagnosis of toxoplasmosis. We further searched the clinical databases at Mayo Clinic, Rochester, for patients with a diagnosis of hematologic malignancy (search terms “leukemia,” “myeloma,” “amyloidosis” and “lymphoma”) and “toxoplasmosis” from January 2000 to December 2013, with approval by the institutional review board. Patients ⬎ 18 years of age, with confirmed hematologic malignancy by pathology or laboratory criteria, and HIV-negative status were included. A total of 34 701 patients evaluated over that time interval had a diagnosis of leukemia, myeloma, amyloidosis or lymphoma; only 339 patients

over that same time frame were diagnosed with toxoplasmosis, although the majority of patients with toxoplasmosis were HIV-positive and therefore excluded. One of the cases had undergone allogenic stem cell transplant and hence was excluded. Four patients had a concurrent diagnosis of toxoplasmosis and hematologic malignancy, including the case above (Table I). The median age was 76 years and 75% were male. Hematological diagnoses included two cases of chronic lymphocytic leukemia (CLL), one of multiple myeloma and the patient with WM described above. One patient with CLL was diagnosed with toxoplasmosis prior to any treatment and without any other significant risk factors (i.e. steroids, or other immunosuppressive treatments), and in the remaining three cases toxoplasmosis developed after cytotoxic chemotherapy. In terms of risk factors, at the time of toxoplasmosis diagnosis none of the patients were neutropenic (absolute neutrophil count ⬍ 1500 ⫻ 109/L), but two had a history of long-term oral steroid use (⬎ 8 weeks). Two patients developed toxoplasmosis of the CNS and two in the lungs. The diagnosis was obtained based on the clinical picture and positive serology (Table I, cases 1 and 2) or the presence of positive CSF PCR (Table I, case 3) or surgical pathology (Table I, case 4). Treatment in three included antimicrobial treatment with sulfadiazine, pyrimethamine and folinic acid, with one patient undergoing surgical resection prior to therapy. In all cases the toxoplasmosis resolved, except for the present case, where improvement was noted clinically and on imaging, although she did not fully recover. In this report we present four cases at our institution who developed toxoplasmosis in association with hematologic malignancies. Considering the number of patients treated at our institution, the paucity of this number was surprising. Since the discovery of toxoplasmosis, it has been reported in patients with hematologic malignancies, especially those with Hodgkin lymphoma, although uncommonly [3,4,6]. It is even rarer in patients with solid malignancies [3]. However, based on some reports, it is possible that this infection is more common than thought, due to underdiagnosis [7–9]. A Brazilian prospective autopsy study reported that toxoplasma was present in about 4.5% of brains studied [8]. Another study from India prospectively analyzed 125 patients with hematologic malignancy during a febrile episode and found that 14% had toxoplasmosis positive serum PCR [7]. However, not all developed clinical disease. This is the first reported case of toxoplasmosis after treatment with B or the combination of BR. Interestingly,

Table I. Diagnosis, treatment and outcome results for toxoplasmosis. Date of diagnosis

Disease

1

2013

CLL

R-CVP

2

2002

CLL

3 4*

2012 2013

WM MM

R-CVP; chemotherapy started after diagnosis of toxoplasmosis BR VRD; pomalidomide and dexamethasone

Case

Treatment for hematologic disorder

Organ involvement

Serum IgG

Serum IgM

CSF PCR

Treatment for toxoplasmosis

Lung and lymph node Lung

ND



ND





ND

CNS CNS

⫹ ND

⫺ ND

⫹ ND

Pyr/Sulfa/Fol changed to Atov Resolved without treatment Pyr/Sulfa/Fol Pyr/Sulfa/Fol and surgery

CLL, chronic lymphocytic leukemia; WM, Waldenström macroglobulinemia; MM, multiple myeloma; R-CVP, rituximab, cyclophosphamide, vincristine, prednisone; BR, bendamustine, rituximab; VRD, bortezomib, lenalidomide, dexamethasone; CNS, central nervous system; ND, not done; Pyr, pyrimethamine; Sulfa, sulfadiazine; Fol, folinic acid; Atov, atovaquone. *Toxoplasmosis was diagnosed via surgical resection.

538 A. Chintakuntlawar et al. two of the other cases also received R with combination chemotherapy prior to developing toxoplasmosis. It is not known whether the cytotoxic chemotherapy or R alone is responsible for this opportunistic infection, and the numbers are too small to make any definitive conclusions. There have been case reports of possible R associated toxoplasmosis, although in both cases, patients received R in combination with another immunosuppressive therapy [10,11]. B can impair T-cell activity [12], and has been implicated in Pneumocystis jiroveci infections [13]. In the case presented here, the patient received both B and R in the setting of hypogammaglobinemia at diagnosis. Therefore, like other cases, it is difficult to ascertain which agent, or whether perhaps the combination, was responsible for this opportunistic infection. In addition, one patient with CLL developed toxoplasmosis before any cytotoxic chemotherapy was given and in the absence of any other risk factors. At this time there is no prospective evidence to suggest that patients receiving cytotoxic chemotherapy with or without immunotherapy (i.e. R) should be treated with antimicrobial prophylaxis, although this decision needs to be individualized based on the patient’s risk profile. It can be difficult to differentiate between lymphomatous processes and infectious processes such as toxoplasmosis [14]. However, in our patient, the laboratory studies showed continued improvement in IgM levels and cytopenias. CNS involvement by WM (“Bing–Neel syndrome”) was ruled out. In patients who present with cognitive or neurological deficits after chemotherapy, infectious CNS processes, including toxoplasmosis, should be considered, along with the other entities, such as progressive multifocal leukoencephalopathy. In conclusion, we have presented a case of toxoplasmosis in a patient treated with BR for WM in addition to three other cases of toxoplasmosis in patients with a hematologic malignancy. Despite the immunosuppressive state of many patients with hematologic disorders with or without treatment, our search of 34 701 patients with a hematologic malignancy yielded only five cases of toxoplasmosis (one excluded from this report), indicating that this is a rare association. This is perhaps due to the frequent use of prophylactic antibiotics including trimethoprim–sulfamethoxazole. In this

series, the prognosis for toxoplasmosis was generally favorable. Toxoplasmosis should be in the differential diagnosis for patients with a hematological malignancy and infectious complication, particularly if CNS symptoms are present. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

References [1] Feldman HA . Toxoplasmosis. N Engl J Med 1968;279:1431–1437. [2] Ruskin J, Remington JS. Toxoplasmosis in the compromised host. Ann Intern Med 1976;84:193–199. [3] Israelski DM, Remington JS. Toxoplasmosis in patients with cancer. Clin Infect Dis 1993;17(Suppl. 2): S423–S435. [4] Carey RM, Kimball AC, Armstrong D, et al. Toxoplasmosis. Clinical experiences in a cancer hospital. Am J Med 1973;54:30–38. [5] Roemer E, Blau IW, Basara N, et al. Toxoplasmosis, a severe complication in allogeneic hematopoietic stem cell transplantation: successful treatment strategies during a 5-year single-center experience. Clin Infect Dis 2001;32: E1–E8. [6] Vietzke WM, Gelderman AH, Grimley PM, et al. Toxoplasmosis complicating malignancy. Experience at the National Cancer Institute. Cancer 1968;21:816–827. [7] Adurthi S, Sahoo T, Chakka K, et al. Acute toxoplasmosis in nonstem cell transplant patients with haematological malignancies: a study from a regional cancer institute in South India. Hematol Oncol 2008;26:229–233. [8] Bleggi-Torres LF, de Medeiros BC, Werner B, et al. Neuropathological findings after bone marrow transplantation: an autopsy study of 180 cases. Bone Marrow Transplant 2000;25:301–307. [9] de Medeiros BC, de Medeiros CR, Werner B, et al. Disseminated toxoplasmosis after bone marrow transplantation: report of 9 cases. Transpl Infect Dis 2001;3:24–28. [10] Safa G, Darrieux L. Cerebral toxoplasmosis after rituximab therapy. JAMA Intern Med 2013;173:924–926. [11] Desmond R, Lynch K , Gleeson M, et al. Progressive multifocal leukencephalopathy and cerebral toxoplasmosis in a patient with CLL. Am J Hematol 2010;85:607. [12] Hosoda T, Yokoyama A , Yoneda M, et al. Bendamustine can severely impair T-cell immunity against cytomegalovirus. Leuk Lymphoma 2013;54:1327–1328. [13] Carter SJ, Bernstein SH, Friedberg JW, et al. Pneumocystis jirovecii pneumonia as a complication of bendamustine in a patient receiving bendamustine plus rituximab for marginal zone lymphoma. Leuk Res 2011;35:e223–e224. [14] Mighell A , Carton A , Carey P, et al. Toxoplasmosis masking non-Hodgkin’s lymphoma: a case report. Br J Oral Maxillofac Surg 1995;33:388–390.

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Toxoplasmosis in patients with hematologic malignancies.

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