Original Study

Central Nervous System Complications and Outcomes After Allogeneic Hematopoietic Stem Cell Transplantation Vijaya Raj Bhatt,1 Vamshi Balasetti,2 Jagar J. Abduall,3 Smith Giri,4 James O. Armitage,1 Fausto R. Loberiza, Jr,1 R. Gregory Bociek,1 Philip J. Bierman,1 Lori J. Maness,1 Julie M. Vose,1 Pierre Fayad,2 Mojtaba Akhtari1 Abstract This retrospective study of 351 patients who underwent allogeneic hematopoietic stem cell transplantation between 2002 and 2011 at the University of Nebraska Medical Center demonstrated 12% incidence of central nervous system complications (CNSC). The most common complications included posterior reversible encephalopathy syndrome (40%), stroke or transient ischemic attack (24%), seizures (20%), and infection (9%). The 5-year overall survival was significantly lower among patients with versus without CNSC (14% vs. 44%, P [ .0004). Background: Central nervous system complications (CNSC) can be the cause of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to determine the incidence of CNSC and its impact on survival. Patients and Methods: This retrospective cohort study included patients with hematologic disorders who received allo-HSCT between 2002 and 2011 at the University of Nebraska Medical Center. Results: Of the 351 patients identified, 45 developed CNSC (12.8%). The 100-day cumulative incidence of CNSC was 8% (95% confidence interval, 8-15). The most common CNSC included posterior reversible encephalopathy syndrome (40%), stroke or transient ischemic attack (24%), seizures (20%), and infection (9%). The 5-year overall survival was significantly lower among patients with versus without CNSC (14% vs. 44%, P ¼ .0004). In multivariate analysis, the risk of mortality for patients with versus without CNSC was significantly higher (hazard ratio, 1.56; 95% confidence interval, 1.03-2.36; P ¼ .04). Conclusion: The occurrence of CNSC after allo-HSCT was associated with reduced survival. Identifying patients at risk, monitoring, early detection, and management of CNSC after allo-HSCT are needed to improve outcomes. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Allogeneic hematopoietic stem cell transplantation, Central nervous system complications, Posterior reversible encephalopathy syndrome, Seizure, Stroke, Survival

Introduction 1

Department of Internal Medicine, Division of Hematology-Oncology, University of Nebraska Medical Center 2 Department of Neurology University of Nebraska Medical Center Omaha, NE 3 Department of Neurology, Ohio State University, Columbus, OH 4 Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN Submitted: Nov 18, 2014; Revised: Jun 9, 2015; Accepted: Jun 12, 2015 Address for correspondence: Mojtaba Akhtari, MD, University of Nebraska Medical Center, Department of Internal Medicine, Division of Hematology-Oncology, 987680 Nebraska Medical Center, Omaha, NE 68198 Fax: (402) 559-6520; e-mail contact: [email protected]

2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.06.004

The techniques of allogeneic hematopoietic stem cell transplantation (allo-HSCT) have advanced tremendously in the last few decades. Such advancements include the development of highresolution donorerecipient human leukocyte antigen (HLA) matching,1 progress in conditioning regimen including the use of reduced-intensity conditioning regimens, improved prophylaxis and treatment of graft-versus-host disease (GVHD), as well as opportunistic infections, better overall supportive care, use of umbilical cord allo-HSCT, and establishment of the National Marrow Donor Program. Consequently, allo-HSCT has been increasingly used in last few decades with improved success in offering cure for patients with several diseases, including leukemias, lymphomas, and other

Clinical Lymphoma, Myeloma & Leukemia Month 2015

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CNS Complications of Allotransplant benign and malignant hematologic disorders.2,3 With the increasing use of allo-HSCT, and with transplanted patients living longer, it is possible that the complications from allo-HSCT will continue to rise. Allo-HSCT patients are at a heightened risk of central nervous system complications (CNSC) in addition to several other organ toxicities.4,5 The potential risk factors for CNSC include the toxicities of total body irradiation (TBI) used in conditioning regimen6,7 as well as the use of immunosuppressants such as cyclosporine8 and tacrolimus,9 immunocompromised status leading to increased susceptibility to central nervous system infections,10-13 and GVHD.7,14 Furthermore, CNSC can contribute to the increased mortality and thus compromise long-term outcome of allo-HSCT.6,7,15-20 There is a relative paucity of literature on CNSC of allo-HSCT, and importantly, previous studies differ in terms of the definition of CNSC, age group of study population, and other characteristics.6,7,15-20 In this retrospective analysis of allo-HSCT done at University of Nebraska Medical Center (UNMC), we studied the incidence of CNSC, its identifiable risk factors, and its impact on survival.

Patients and Methods Patients We conducted a retrospective cohort study to evaluate the CNSC among 351 patients who underwent allo-HSCT for malignant and benign hematologic conditions at UNMC from January 2002 to December 2011. All allo-HSCT patients were included, irrespective of the conditioning regimen or type of graft and whether they were matched or mismatched and related or unrelated. CNSC were defined as occurrence of seizure (without other CNSC), transient ischemic attack or stroke, meningitis, posterior reversible encephalopathy syndrome (PRES), and others. The diagnosis was made on the basis of established criteria by neurologists who are routinely consulted for CNSC per standard practice. In each case, diagnosis of CNSC was made using clinical, radiologic, and/or microbiologic data. Diagnosis of stroke was made with history, clinical examination, and neuroimaging, including computed tomography or magnetic resonance imaging. Areas of low attenuation on computed tomographic scan and areas of T1-weighted hypointensity or T2weighted hyperintensity on magnetic resonance imaging were defined as abnormalities suggestive of ischemic stroke. Diagnosis of PRES required demonstration of focal vasogenic edema on neuroimaging as well as clinical or radiologic proof of reversibility. Diagnosis of meningitis required the presence of characteristic cerebrospinal fluid results. Similar definitions have been utilized in prior studies.15,16 Any regimen that included a cytarabine dose of 2000 mg/m2 or more was considered as high-dose cytarabine (HDAC); this included regimens such as hyper-CVAD. Electronic medical records including neurology consult records and final progress notes as well as transplant database were reviewed to evaluate for the presence of CNSC and for patients’ characteristics. The study was performed after approval by the institutional review board at UNMC.

Conditioning Regimen, GVHD, and Infection Prophylaxis

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Conditioning regimens for myeloablative allo-HSCT included cyclophosphamide (60 mg/kg/day on days 5 and 4) and TBI

Clinical Lymphoma, Myeloma & Leukemia Month 2015

(200 cGy twice daily on days 3 to 1), or intravenous busulfan (0.8 mg/kg every 6 hours from days 5 to 2, dose adjusted based on pharmacokinetics performed after the first dose; patients who received busulfan were also started on antiseizure prophylaxis with lorazepam) and fludarabine (40 mg/m2 daily from days 5 to 2). For HLA-identical sibling donor allo-HSCT for severe aplastic anemia, the conditioning regimen included cyclophosphamide (50 mg/kg/day on days 5 and 4) and antithymocyte globulin (30 mg/kg daily from days 5 to 3). Conditioning regimens for nonmyeloablative allo-HSCT included fludarabine (40 mg/m2 daily from days 5 to 2) and TBI (2 Gy on day 1), or busulfan (0.8 mg/kg every 6 hours from days 5 to 4) and fludarabine (40 mg/m2 daily from days 5 to 2). GVHD prophylaxis included tacrolimus (target level, 8-12 ng/mL) and mycophenolate for myeloablative and nonmyeloablative matched related donor allo-HSCT. For nonmyeloablative matched unrelated donor alloHSCT, GVHD prophylaxis incorporated tacrolimus and methotrexate, whereas myeloablative matched unrelated donor allo-HSCT additionally had antithymocyte globulin. Infection prophylaxis included pretransplantation screening of donors and recipients with viral serology, routine use of antibiotics (fluoroquinolones during the period of neutropenia, and sulfamethoxazole and trimethoprim subsequently for Pneumocystis jiroveci pneumonia prophylaxis), antifungal (fluconazole for at least day þ100), and antiviral agents (acyclovir for at least 6 months after transplantation), as well as surveillance for cytomegalovirus antigenemia after allo-HSCT.

Statistical Analyses Outcomes evaluated include cumulative incidence of CNSC, length of hospital stay and overall survival (OS). The following covariates were adjusted in the analysis: age, sex, disease type, disease stage at transplantation, donorerecipient sex match, time interval from diagnosis to transplant, type of graft, type of transplant, number of antigen mismatched, cytomegalovirus seropositivity status of donor and recipient, use of TBI as a part of conditioning regimen, use of reduced-intensity conditioning, use of cranial irradiation, prior use of HDAC, and year of transplantation. Univariate comparison of patient-, disease-, and transplant-related variables between patients with or without CNSC were performed by the Wilcoxon or chi-square tests. Cumulative incidence was used to estimate incidence of CNSC after allo-HSCT with death as a competing risk.21 Using the Fine and Gray model for competing risk analysis, we also determined the cumulative incidence of nonrelapse mortality (NRM) among patients with versus without CNSC; deaths and relapses were considered as competing events. Multivariate analysis used Cox proportional hazard regression analysis to compare risk of mortality between patients with or without CNSC while adjusting for significant baseline prognostic covariates. The main effect term for the presence or absence of CNSC was handled in a time-varying manner22 and was forced in all model building. The assumption of proportionality was tested before and after model building. All other baseline prognostic covariates were selected in a stepwise manner, and only those with an a value of  0.05 were included in the final model. All analyses were performed by SAS 9.3 for Windows (SAS Institute).

Vijaya Raj Bhatt et al Table 1 Characteristics of Patients With Allogeneic Stem Cell Transplantation Variable Number Age (years), median (range) Male sex

Without CNSC 306 46 (1-74) 184 (60)

With CNSC

P

45

Table 1 Continued Variable

Without CNSC

With CNSC

Use of TBI as Part of Conditioning

52 (7-70)

.07

No

120 (39)

21 (47)

31 (69)

.26

Yes

186 (61)

24 (53)

Disease Type

.93

History of High-dose ARA-C

.76

AML

109 (36)

15 (33)

ALL

49 (16)

5 (11)

CML

13 (4)

2 (4)

MDS

40 (13)

7 (15)

NHL

74 (24)

12 (27)

No

301 (98)

44 (98)

HD

12 (4)

3 (7)

Yes

5 (2)

1 (2)

2002 to 2005

127 (42)

18 (40)

2006 to 2008

99 (32)

7 (16)

2009 to 2011

80 (26)

20 (44)

2 (