Incidence and Predictors of Late-Occurring Central Nervous System Complications in Allogeneic Hematopoietic Cell Transplant Survivors

Introduction: Advances in treatment strategies and supportive care have resulted in a growing number of survivors of allogeneic hematopoietic cell transplantation (allo-HCT). In this population, central nervous system (CNS) complications represent a major cause of morbidity and mortality in the immediate post-HCT setting. However, there is a paucity of knowledge regarding the incidence and risk factors for CNS complications developing years after HCT. Potential mediators of late-occurring CNS toxicity could include previous exposure to radiation or drugs (e.g. fludarabine, Busulfan, and calcineurin inhibitors), infections resulting from immunodeficiency or tissue barrier breakthrough, bleeding due to thrombocytopenia, or CNS recurrence of primary malignancy. The current report addresses the existing gap in literature by comprehensively evaluating the role of demographic, HCT-related therapeutic exposures, graft versus host disease (GVHD) and its management, as well as post-HCT comorbidities in the development of late-occurring (>1 year) CNS complications after allo-HCT. Methods: A retrospective cohort study design was used to describe the cumulative incidence of CNS complications (Common Terminology of Adverse Events Grade 3-5: seizure disorder, stroke, encephalopathy), and to examine the role of demographic, disease-related and conditioning factors in 1,543 one-year survivors who underwent allo-HCT at City of Hope between 1995 and 2010. Next, a nested case-control approach (1:2 match: age at HCT, sex, length of follow-up) was used to evaluate the role of post-HCT exposures and comorbidities on long term risk. Cumulative incidence was calculated taking into consideration the competing risk of death. Multivariable regression analysis was used to calculate hazard ratios (HR) and odds ratios (OR), as well as 95% confidence intervals (CI), adjusted for relevant covariates. Results: Median follow-up for the entire cohort was 5.2 years (range: 1-18.9 years), representing 9,850 person-years of follow-up. Fifty-five survivors developed 83 CNS complications at a median of 2.5 years (range: 1-14.4 years) from allo-HCT; 53% were female; underlying diagnoses at allo-HCT: ALL (29%), AML (20%), Lymphoma (15%), CML (12%), other (24%); HCT conditioning: busulfan/cytoxan (11%), total body irradiation/etoposide (25%), fludarabine/melphalan (36%), other (29%). Ten-year cumulative incidence of CNS complications was highest (9.9%) for females who underwent allo-HCT for ALL (Figure). Diagnosis of ALL (HR: 2.3 [CI 1.1-4.7]), and conditioning with fludarabine/melphalan (HR: 5.3 [CI 1.2-23.6]) were significant predictors of CNS complications, independent of age. Post-HCT risk factors: Multivariable regression analysis adjusting for disease relapse and GVHD status revealed a significantly higher risk of CNS complications in survivors who were on mycophenolate mofetil or sirolimus (OR: 4.5 [CI 1.4-15.1]), who developed hypertension (OR: 3.5 [CI 1.3-9.3]), or thrombocytopenia (OR: 3.1 [CI 1.2-8.1]) in the years following allo-HCT. Five-year overall survival was significantly worse in patients who developed CNS complications when compared to those who did not (53.8% vs. 73.6%, p<0.001). Conclusions: Patients undergoing allo-HCT for ALL or those receiving conditioning with fludarabine/melphalan as part of reduced-intensity conditioning had a significantly higher risk of late CNS complications; females with ALL had the highest risk over time. Post-HCT hypertension, thrombocytopenia, and use of mycophenolate mofetil or sirolimus are important risk factors for late-occurring CNS toxicity. Taken together these data form the basis for identifying high-risk individuals for targeted surveillance, as well as vigilant management of post-HCT risk factors.

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