Abstract
Neurologic complications (NCs) may be a significant source of morbidity and mortality after hematopoietic cell transplantation (HCT). We performed a retrospective study of 263 consecutive patients undergoing allogeneic HCT for hematological malignancies to determine the incidence, risk factors and clinical impact of NCs in the first 5 years after HCT. We determined the incidence of central nervous system (CNS) infection, intracranial hemorrhage, ischemic stroke, metabolic encephalopathy, posterior reversal encephalopathy syndrome, seizure and peripheral neuropathy. In all, 50 patients experienced 63 NCs—37 early (⩽day +100), 21 late (day +101 to 2 years) and 5 very late (2 to 5 years). The 1- and 5-year cumulative incidences of all NCs were 15.6% and 19.2%, respectively, and of CNS complication (CNSC; all of the above complications except peripheral neuropathy) were 12.2 and 14.5%. Risk factors for CNSC were age (hazard ratio (HR)=1.06 per year, P=0.0034), development of acute GvHD grade III–IV (HR=2.78, P=0.041), transfusion-dependent thrombocytopenia (HR=3.07, P=0.025) and delayed platelet engraftment (>90th centile; HR=2.77, P=0.043). CNSCs negatively impacted progression-free survival (HR=2.29, P=0.0001), overall survival (HR=2.63, P<0.0001) and non-relapse mortality (HR=8.51, P<0.0001). NCs after HCT are associated with poor outcomes, and usually occur early after HCT.
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References
Horan JT, Logan BR, Agovi-Johnson MA, Lazarus HM, Bacigalupo AA, Ballen KK et al. Reducing the risk for transplantation-related mortality after allogeneic hematopoietic cell transplantation: how much progress has been made? J Clin Oncol 2011; 29: 805–813.
Saiz A, Graus F . Neurological complications of hematopoietic cell transplantation. Semin Neurol 2004; 24: 427–434.
Pruitt AA, Graus F, Rosenfeld MR . Neurological complications of transplantation: part I: hematopoietic cell transplantation. Neurohospitalist 2013; 3: 24–38.
Maffini E, Festuccia M, Brunello L, Boccadoro M, Giaccone L, Bruno B . Neurologic Complications after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2017; 23: 388–397.
Pruitt AA . Neurologic complications of transplantation. Continuum (Mineapp Minn) 2017; 23: 802–821.
Reece DE, Frei-Lahr DA, Shepherd JD, Dorovini-Zis K, Gascoyne RD, Graeb DA et al. Neurologic complications in allogeneic bone marrow transplant patients receiving cyclosporin. Bone Marrow Transplant 1991; 8: 393–401.
Eidelman BH, Abu-Elmagd K, Wilson J, Fung JJ, Alessiani M, Jain A et al. Neurologic complications of FK 506. Transplant Proc 1991; 23: 3175–3178.
Woo M, Przepiorka D, Ippoliti C, Warkentin D, Khouri I, Fritsche H et al. Toxicities of tacrolimus and cyclosporin A after allogeneic blood stem cell transplantation. Bone Marrow Transplant 1997; 20: 1095–1098.
Shah AK . Cyclosporine A neurotoxicity among bone marrow transplant recipients. Clin Neuropharmacol 1999; 22: 67–73.
Cordonnier C, Feuilhade F, Vernant JP, Marsault C, Rodet M, Rochant H . Cytomegalovirus encephalitis occurring after bone marrow transplantation. Scand J Haematol 1983; 31: 248–252.
Guppy KH, Thomas C, Thomas K, Anderson D . Cerebral fungal infections in the immunocompromised host: a literature review and a new pathogen—Chaetomium atrobrunneum: case report. Neurosurgery 1998; 43: 1463–1469.
Steer CB, Szer J, Sasadeusz J, Matthews JP, Beresford JA, Grigg A . Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir. Bone Marrow Transplant 2000; 25: 657–664.
Wainwright MS, Martin PL, Morse RP, Lacaze M, Provenzale JM, Coleman RE et al. Human herpesvirus 6 limbic encephalitis after stem cell transplantation. Ann Neurol 2001; 50: 612–619.
Mele A, Paterson PJ, Prentice HG, Leoni P, Kibbler CC . Toxoplasmosis in bone marrow transplantation: a report of two cases and systematic review of the literature. Bone Marrow Transplant 2002; 29: 691–698.
Jantunen E, Volin L, Salonen O, Piilonen A, Parkkali T, Anttila VJ et al. Central nervous system aspergillosis in allogeneic stem cell transplant recipients. Bone Marrow Transplant 2003; 31: 191–196.
Kharfan-Dabaja MA, Ayala E, Greene J, Rojiani A, Murtagh FR, Anasetti C . Two cases of progressive multifocal leukoencephalopathy after allogeneic hematopoietic cell transplantation and a review of the literature. Bone Marrow Transplant 2007; 39: 101–107.
Schmidt-Hieber M, Schwender J, Heinz WJ, Zabelina T, Kuhl JS, Mousset S et al. Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents. Haematologica 2011; 96: 142–149.
Hill JA, Koo S, Guzman Suarez BB, Ho VT, Cutler C, Koreth J et al. Cord-blood hematopoietic stem cell transplant confers an increased risk for human herpesvirus-6-associated acute limbic encephalitis: a cohort analysis. Biol Blood Marrow Transplant 2012; 18: 1638–1648.
Kaufman GP, Aksamit AJ, Klein CJ, Yi ES, Delone DR, Litzow MR . Progressive multifocal leukoencephalopathy: a rare infectious complication following allogeneic hematopoietic cell transplantation (HCT). Eur J Haematol 2014; 92: 83–87.
Pomeranz S, Naparstek E, Ashkenazi E, Nagler A, Lossos A, Slavin S et al. Intracranial haematomas following bone marrow transplantation. J Neurol 1994; 241: 252–256.
Coplin WM, Cochran MS, Levine SR, Crawford SW . Stroke after bone marrow transplantation: frequency, aetiology and outcome. Brain 2001; 124 (Pt 5): 1043–1051.
Zhang XH, Wang QM, Chen H, Chen YH, Han W, Wang FR et al. Clinical characteristics and risk factors of Intracranial hemorrhage in patients following allogeneic hematopoietic stem cell transplantation. Ann Hematol 2016; 95: 1637–1643.
Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A et al. A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996; 334: 494–500.
Wong R, Beguelin GZ, de Lima M, Giralt SA, Hosing C, Ippoliti C et al. Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation. Br J Haematol 2003; 122: 128–134.
Aisa Y, Mori T, Shimizu T, Tsukada Y, Kato J, Suzuki S et al. Retrospective analysis of posterior reversible encephalopathy syndrome after allogeneic stem cell transplantation. Rinsho Ketsueki 2009; 50: 9–15.
Hammerstrom AE, Howell J, Gulbis A, Rondon G, Champlin RE, Popat U . Tacrolimus-associated posterior reversible encephalopathy syndrome in hematopoietic allogeneic stem cell transplantation. Am J Hematol 2013; 88: 301–305.
Singer S, Grommes C, Reiner AS, Rosenblum MK, DeAngelis LM . Posterior reversible encephalopathy syndrome in patients with cancer. Oncologist 2015; 20: 806–811.
Fugate JE, Rabinstein AA . Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol 2015; 14: 914–925.
Davis JM, Rowley SD, Braine HG, Piantadosi S, Santos GW . Clinical toxicity of cryopreserved bone marrow graft infusion. Blood 1990; 75: 781–786.
Ferrucci PF, Martinoni A, Cocorocchio E, Civelli M, Cinieri S, Cardinale D et al. Evaluation of acute toxicities associated with autologous peripheral blood progenitor cell reinfusion in patients undergoing high-dose chemotherapy. Bone Marrow Transplant 2000; 25: 173–177.
Hoyt R, Szer J, Grigg A . Neurological events associated with the infusion of cryopreserved bone marrow and/or peripheral blood progenitor cells. Bone Marrow Transplant 2000; 25: 1285–1287.
Hequet O, Dumontet C, El Jaafari-Corbin A, Salles G, Espinouse D, Arnaud P et al. Epileptic seizures after autologous peripheral blood progenitor infusion in a patient treated with high-dose chemotherapy for myeloma. Bone Marrow Transplant 2002; 29: 544.
Windrum P, Morris TC . Severe neurotoxicity because of dimethyl sulphoxide following peripheral blood stem cell transplantation. Bone Marrow Transplant 2003; 31: 315.
Wiznitzer M, Packer RJ, August CS, Burkey ED . Neurological complications of bone marrow transplantation in childhood. Ann Neurol 1984; 16: 569–576.
Davis DG, Patchell RA . Neurologic complications of bone marrow transplantation. Neurol Clin 1988; 6: 377–387.
Graus F, Saiz A, Sierra J, Arbaiza D, Rovira M, Carreras E et al. Neurologic complications of autologous and allogeneic bone marrow transplantation in patients with leukemia: a comparative study. Neurology 1996; 46: 1004–1009.
Antonini G, Ceschin V, Morino S, Fiorelli M, Gragnani F, Mengarelli A et al. Early neurologic complications following allogeneic bone marrow transplant for leukemia: a prospective study. Neurology 1998; 50: 1441–1445.
Iguchi A, Kobayashi R, Yoshida M, Kaneda M, Watanabe N, Cho Y et al. Neurological complications after stem cell transplantation in childhood. Bone Marrow Transplant 1999; 24: 647–652.
Sostak P, Padovan CS, Yousry TA, Ledderose G, Kolb HJ, Straube A . Prospective evaluation of neurological complications after allogeneic bone marrow transplantation. Neurology 2003; 60: 842–848.
Kishi Y, Miyakoshi S, Kami M, Ikeda M, Katayama Y, Murashige N et al. Early central nervous system complications after reduced-intensity stem cell transplantation. Biol Blood Marrow Transplant 2004; 10: 561–568.
Uckan D, Cetin M, Yigitkanli I, Tezcan I, Tuncer M, Karasimav D et al. Life-threatening neurological complications after bone marrow transplantation in children. Bone Marrow Transplant 2005; 35: 71–76.
Denier C, Bourhis JH, Lacroix C, Koscielny S, Bosq J, Sigal R et al. Spectrum and prognosis of neurologic complications after hematopoietic transplantation. Neurology 2006; 67: 1990–1997.
Siegal D, Keller A, Xu W, Bhuta S, Kim DH, Kuruvilla J et al. Central nervous system complications after allogeneic hematopoietic stem cell transplantation: incidence, manifestations, and clinical significance. Biol Blood Marrow Transplant 2007; 13: 1369–1379.
Barba P, Pinana JL, Valcarcel D, Querol L, Martino R, Sureda A et al. Early and late neurological complications after reduced-intensity conditioning allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2009; 15: 1439–1446.
Narimatsu H, Miyamura K, Iida H, Hamaguchi M, Uchida T, Morishita Y et al. Early central nervous complications after umbilical cord blood transplantation for adults. Biol Blood Marrow Transplant 2009; 15: 92–100.
Cao XY, Wu T, Lu Y, Wang JB, Yin YM, Lu DP . A study of the central nervous system complications after hematopoietic stem cell transplantation. Zhonghua Nei Ke Za Zhi 2010; 49: 42–44.
Azik F, Yazal Erdem A, Tavil B, Bayram C, Tunc B, Uckan D . Neurological complications after allogeneic hematopoietic stem cell transplantation in children, a single center experience. Pediatr Transplant 2014; 18: 405–411.
Kang JM, Kim YJ, Kim JY, Cho EJ, Lee JH, Lee MH et al. Neurologic complications after allogeneic hematopoietic stem cell transplantation in children: analysis of prognostic factors. Biol Blood Marrow Transplant 2015; 21: 1091–1098.
Patchell RA, White CL 3rd, Clark AW, Beschorner WE, Santos GW . Neurologic complications of bone marrow transplantation. Neurology 1985; 35: 300–306.
Mohrmann RL, Mah V, Vinters HV . Neuropathologic findings after bone marrow transplantation: an autopsy study. Hum Pathol 1990; 21: 630–639.
Bleggi-Torres LF, de Medeiros BC, Werner B, Neto JZ, Loddo G, Pasquini R et al. Neuropathological findings after bone marrow transplantation: an autopsy study of 180 cases. Bone Marrow Transplant 2000; 25: 301–307.
Ballen KK, Spitzer TR, Yeap BY, McAfee S, Dey BR, Attar E et al. Double unrelated reduced-intensity umbilical cord blood transplantation in adults. Biol Blood Marrow Transplant 2007; 13: 82–89.
Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 2009; 15: 1628–1633.
Cutler C, Stevenson K, Kim HT, Brown J, McDonough S, Herrera M et al. Double umbilical cord blood transplantation with reduced intensity conditioning and sirolimus-based GVHD prophylaxis. Bone Marrow Transplant 2011; 46: 659–667.
Nikiforow S, Li S, Snow K, Liney D, Kao GS, Haspel R et al. Lack of impact of umbilical cord blood unit processing techniques on clinical outcomes in adult double cord blood transplant recipients. Cytotherapy 2017; 19: 272–284.
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.
Cahn JY, Klein JP, Lee SJ, Milpied N, Blaise D, Antin JH et al. Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood 2005; 106: 1495–1500.
Bartynski WS . Posterior reversible encephalopathy syndrome, part 1: fundamental imaging and clinical features. AJNR Am J Neuroradiol 2008; 29: 1036–1042.
Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.
Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.
Putter H, Fiocco M, Geskus RB . Tutorial in biostatistics: competing risks and multi-state models. Stat Med 2007; 26: 2389–2430.
Iacobelli S, Committee ES. Suggestions on the use of statistical methodologies in studies of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2013; 48 (Suppl 1): S1–37.
Fox J . An R and S-Plus Companion to Applied Regression. Sage, Thousand Oaks, CA, USA, 2002.
Gooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363: 2091–2101.
Qin W, Tan CY, Huang X, Huang Z, Tao Y, Fu P . Rapamycin-induced posterior reversible encephalopathy in a kidney transplantation patient. Int Urol Nephrol 2011; 43: 913–916.
Barbas AS, Rege AS, Castleberry AW, Gommer J, Ellis MJ, Brennan TV et al. Posterior reversible encephalopathy syndrome independently associated with tacrolimus and sirolimus after multivisceral transplantation. Am J Transplant 2013; 13: 808–810.
Acknowledgements
MRD acknowledges support from a National Health and Medical Research Council (NHMRC) Fellowship and a Medical Insurance Group Australia (MIGA) doctors-in-training grant.
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Dowling, M., Li, S., Dey, B. et al. Neurologic complications after allogeneic hematopoietic stem cell transplantation: risk factors and impact. Bone Marrow Transplant 53, 199–206 (2018). https://doi.org/10.1038/bmt.2017.239
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DOI: https://doi.org/10.1038/bmt.2017.239
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