Leukemia & Lymphoma, 2014; Early Online: 1–2 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.964701
LETTER TO THE EDITOR
Toxic encephalopathy after exposure to azacitidine Ken Watanabe1, Noriko Doki1, Yoshiharu Miura2, Takeshi Hagino1, Shuhei Kurosawa1, Yutaro Hino1, Naoki Shingai1, Kosuke Yoshioka1, Shinya Ishida1, Aiko Igarashi1, Yuho Najima1, Takeshi Kobayashi1, Kazuhiko Kakihana1, Hisashi Sakamaki1 & Kazuteru Ohashi1 1Hematology Division and 2Department of Neurology, Tokyo Metropolitan Cancer and Infectious Diseases Center,
Leuk Lymphoma Downloaded from informahealthcare.com by UMEA University Library on 04/06/15 For personal use only.
Komagome Hospital, Tokyo, Japan
The patient was administered AZA intravenously for 7 days (75 mg/m2/day). Body surface area was 2.065 m2 based on a height of 172.2 cm and a body weight of 93.4 kg. The dose of AZA administered (154 mg) was based on actual body weight. Adverse events were grade 1 nausea on day 1, and grade 1 rash on day 7 after administration of AZA. Nausea improved with administration of granisetron. The rash disappeared without medication. On day 8 after administration of AZA, vital signs and neurological examination appeared normal, but disturbance of orientation developed (Glasgow Coma Sale [GCS], E4V4M6). On day 9, the level of consciousness became depressed (GCS, E3V3M6). No hypothyroidism or symptoms of hypoadrenalism were identified. Blood work-up, including electrolytes, kidney and liver function, blood ammonium, blood glucose and arterial oxygen tests, yielded normal results. Computed tomography and magnetic resonance imaging of the brain showed no significant abnormalities. Lumbar puncture was performed, and the total cell count in the cerebrospinal fluid (CSF) was 4 cells/μL, without malignant cells. Analysis of the CSF showed the following: protein, 63.0 mg/dL (normal, 8.0–43.0 mg/dL); glucose, 126 mg/dL (normal, 50–75 mg/dL); and immunoglobulin (Ig) G index, 0.286 (normal, ⬍ 0.6). Human herpesvirus 6 DNA, herpes simplex virus DNA and cytomegalovirus DNA were not detected in the CSF using polymerase chain reaction. Electroencephalography (EEG) on day 10 showed a diffuse abnormality, i.e. dominant theta activity with some delta slow waves associated with slow background activity. No new medications had been introduced other than AZA and granisetron. No medications had recently been discontinued to cause a withdrawal syndrome. These results suggested that acute toxic encephalopathy (TE) might have developed after exposure to AZA. The level of consciousness and disorientation began to recover from day 12, and normalized by day 16. EEG showed no abnormalities on day 17. The second course of AZA was not administered to the patient. He has received chemotherapy
Azacitidine (AZA) is a pyrimidine nucleoside analog of cytidine that has been shown to improve survival, reduce the risk of leukemic transformation and delay progression to acute myeloid leukemia (AML) in higher-risk myelodysplastic syndrome (MDS) [1,2]. AZA has become the standard of care for higher-risk MDS [3], and is generally well tolerated in patients, including the elderly [4]. The most common serious adverse events resulting in hospitalization are thrombocytopenia, febrile neutropenia, fever and pneumonia [5]. Aside from hepatic coma, severe central nervous system (CNS) complications have not been reported [6]. We report the case of a patient who showed disorientation and a depressed level of consciousness after AZA administration. A 59-year-old man was admitted with leukocytosis. His medical history consisted of mild diabetes mellitus (DM) without treatment, paroxysmal atrial fibrillation and sleep apnea syndrome (SAS) being treated using a bilevel positive airway pressure mask. On examination, he showed slight splenomegaly without lymphadenopathy. He was fully conscious, and neurological examination on admission showed normal results. Liver, kidney and heart functions were normal. Laboratory studies showed a hemoglobin level of 7.6 g/dL, and a white blood cell (WBC) count of 9.9 ⫻ 103/μL with 9% myeloblasts, 60.0% monocytes, 11% neutrophils and 18% mature lymphocytes. The platelet count was 12.5 ⫻ 104/μL. Lactate dehydrogenase (LDH) was 519 U/L (normal range, 115–245 U/L). A bone marrow (BM) aspirate showed hypercellular marrow with 14.7% myeloblasts, 29.2% promonocytes and 38.4% monocytes. Myeloblasts showed the following immunophenotype: CD13 (40%); CD33 (99%); CD11b (95.4%); CD14 (86.9%); CD38 (99.4%); and human leukocyte antigen (HLA)-DR (99.6%). Cytogenetic study revealed a normal karyotype. AML with myelodysplasiarelated changes was diagnosed based on the World Health Organization classification [7]. These results suggested that leukemia would develop from chronic myelomonocytic leukemia.
Correspondence: Noriko Doki, MD, PhD, Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3–18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. Tel: 81-3-3823-2101. Fax: 81-3-3824-1552. E-mail: [email protected] Received 24 August 2014; revised 1 September 2014; accepted 7 September 2014
1
Leuk Lymphoma Downloaded from informahealthcare.com by UMEA University Library on 04/06/15 For personal use only.
2
K. Watanabe et al.
(cytarabine and aclacinon) and will undergo allogeneic hematopoietic stem cell transplant in the near future. Acute TE is an acute condition of global cerebral dysfunction in the absence of primary structural brain disease. A diagnosis of TE can be made after documentation of the following: (1) sufficiently intense or prolonged exposure to a neurotoxin; (2) a neurological syndrome appropriate for the putative neurotoxins; (3) evolution of symptoms and signs over a compatible temporal course; and (4) exclusion of other neurological disorders that may account for a similar syndrome [8]. According to one approach to the diagnosis of TE, our patient was diagnosed with TE after exposure to AZA. The toxic effects on the CNS would result from the dose to which the patient was exposed [8,9]. That is, the higher is the level of exposure, the more severe are the symptoms [8,9]. However, other factors such as genetic polymorphisms, chronicity of exposure and pharmacokinetics of a particular agent have been reported as being associated with the development of CNS toxicity [9]. Peak plasma concentration (Cmax) following intravenous administration was approximately 3.7-fold higher than that following subcutaneous administration [10]. AZA and its metabolites (85% of the dose after intravenous administration and 50% of the dose after subcutaneous administration) are primarily eliminated by urinary excretion, with fecal excretion contributing less than 1% [4,11]. In this case, liver function was normal, and creatinine clearance was 81 mL/ min. This clinical course indicated that intravenous administration could increase the concentration of AZA to within a toxic range, and other factors such as obesity and genetic polymorphisms might influence the pharmacokinetics. However, the effects of intrinsic factors such as age, sex, race, obesity or in vivo drug–drug interaction in relation to the pharmacokinetics of AZA have not been studied [11], and thus there was no empirical evidence. AZA is an important agent for use in the treatment of patients with MDS/AML. To the best of our knowledge, this represents the first report of TE resulting from AZA. When patients treated with AZA demonstrate disorientation or
a depressed level of consciousness, we should consider the possibility of TE due to AZA among the differential diagnoses. This case also emphasizes the need for clinical awareness when administering AZA.
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] Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002;20:2429–2440. [2] Gore SD, Fenaux P, Santini V, et al. A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial. Haematologica 2013;98:1067–1072. [3] Garcia-Manero G. Myelodysplastic syndromes: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 2014;89:97–108. [4] Keating GM. Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. Drugs 2012;72:1111–1136. [5] Kaminskas E, Farrell AT, Wang YC, et al. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist 2005;10:176–182. [6] Von Hoff DD, Slavik M, Muggia FM. 5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Ann Intern Med 1976;85:237–245. [7] Vardiman JW, Thiele J, Arber DA , et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114:937–951. [8] Kim Y, Kim JW. Toxic encephalopathy. Saf Health Work 2012;3: 243–256. [9] Ruha AM, Levine M. Central nervous system toxicity. Emerg Med Clin North Am 2014;32:205–221. [10] Uchida T, Ogawa Y, Kobayashi Y, et al. Phase I and II study of azacitidine in Japanese patients with myelodysplastic syndromes. Cancer Sci 2011;102:1680–1686. [11] Kaminskas E, Farrell A , Abraham S, et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 2005;11:3604–3608.
LETTER TO THE EDITOR
Toxic encephalopathy after exposure to azacitidine Ken Watanabe1, Noriko Doki1, Yoshiharu Miura2, Takeshi Hagino1, Shuhei Kurosawa1, Yutaro Hino1, Naoki Shingai1, Kosuke Yoshioka1, Shinya Ishida1, Aiko Igarashi1, Yuho Najima1, Takeshi Kobayashi1, Kazuhiko Kakihana1, Hisashi Sakamaki1 & Kazuteru Ohashi1 1Hematology Division and 2Department of Neurology, Tokyo Metropolitan Cancer and Infectious Diseases Center,
Leuk Lymphoma Downloaded from informahealthcare.com by UMEA University Library on 04/06/15 For personal use only.
Komagome Hospital, Tokyo, Japan
The patient was administered AZA intravenously for 7 days (75 mg/m2/day). Body surface area was 2.065 m2 based on a height of 172.2 cm and a body weight of 93.4 kg. The dose of AZA administered (154 mg) was based on actual body weight. Adverse events were grade 1 nausea on day 1, and grade 1 rash on day 7 after administration of AZA. Nausea improved with administration of granisetron. The rash disappeared without medication. On day 8 after administration of AZA, vital signs and neurological examination appeared normal, but disturbance of orientation developed (Glasgow Coma Sale [GCS], E4V4M6). On day 9, the level of consciousness became depressed (GCS, E3V3M6). No hypothyroidism or symptoms of hypoadrenalism were identified. Blood work-up, including electrolytes, kidney and liver function, blood ammonium, blood glucose and arterial oxygen tests, yielded normal results. Computed tomography and magnetic resonance imaging of the brain showed no significant abnormalities. Lumbar puncture was performed, and the total cell count in the cerebrospinal fluid (CSF) was 4 cells/μL, without malignant cells. Analysis of the CSF showed the following: protein, 63.0 mg/dL (normal, 8.0–43.0 mg/dL); glucose, 126 mg/dL (normal, 50–75 mg/dL); and immunoglobulin (Ig) G index, 0.286 (normal, ⬍ 0.6). Human herpesvirus 6 DNA, herpes simplex virus DNA and cytomegalovirus DNA were not detected in the CSF using polymerase chain reaction. Electroencephalography (EEG) on day 10 showed a diffuse abnormality, i.e. dominant theta activity with some delta slow waves associated with slow background activity. No new medications had been introduced other than AZA and granisetron. No medications had recently been discontinued to cause a withdrawal syndrome. These results suggested that acute toxic encephalopathy (TE) might have developed after exposure to AZA. The level of consciousness and disorientation began to recover from day 12, and normalized by day 16. EEG showed no abnormalities on day 17. The second course of AZA was not administered to the patient. He has received chemotherapy
Azacitidine (AZA) is a pyrimidine nucleoside analog of cytidine that has been shown to improve survival, reduce the risk of leukemic transformation and delay progression to acute myeloid leukemia (AML) in higher-risk myelodysplastic syndrome (MDS) [1,2]. AZA has become the standard of care for higher-risk MDS [3], and is generally well tolerated in patients, including the elderly [4]. The most common serious adverse events resulting in hospitalization are thrombocytopenia, febrile neutropenia, fever and pneumonia [5]. Aside from hepatic coma, severe central nervous system (CNS) complications have not been reported [6]. We report the case of a patient who showed disorientation and a depressed level of consciousness after AZA administration. A 59-year-old man was admitted with leukocytosis. His medical history consisted of mild diabetes mellitus (DM) without treatment, paroxysmal atrial fibrillation and sleep apnea syndrome (SAS) being treated using a bilevel positive airway pressure mask. On examination, he showed slight splenomegaly without lymphadenopathy. He was fully conscious, and neurological examination on admission showed normal results. Liver, kidney and heart functions were normal. Laboratory studies showed a hemoglobin level of 7.6 g/dL, and a white blood cell (WBC) count of 9.9 ⫻ 103/μL with 9% myeloblasts, 60.0% monocytes, 11% neutrophils and 18% mature lymphocytes. The platelet count was 12.5 ⫻ 104/μL. Lactate dehydrogenase (LDH) was 519 U/L (normal range, 115–245 U/L). A bone marrow (BM) aspirate showed hypercellular marrow with 14.7% myeloblasts, 29.2% promonocytes and 38.4% monocytes. Myeloblasts showed the following immunophenotype: CD13 (40%); CD33 (99%); CD11b (95.4%); CD14 (86.9%); CD38 (99.4%); and human leukocyte antigen (HLA)-DR (99.6%). Cytogenetic study revealed a normal karyotype. AML with myelodysplasiarelated changes was diagnosed based on the World Health Organization classification [7]. These results suggested that leukemia would develop from chronic myelomonocytic leukemia.
Correspondence: Noriko Doki, MD, PhD, Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, 3–18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan. Tel: 81-3-3823-2101. Fax: 81-3-3824-1552. E-mail: [email protected] Received 24 August 2014; revised 1 September 2014; accepted 7 September 2014
1
Leuk Lymphoma Downloaded from informahealthcare.com by UMEA University Library on 04/06/15 For personal use only.
2
K. Watanabe et al.
(cytarabine and aclacinon) and will undergo allogeneic hematopoietic stem cell transplant in the near future. Acute TE is an acute condition of global cerebral dysfunction in the absence of primary structural brain disease. A diagnosis of TE can be made after documentation of the following: (1) sufficiently intense or prolonged exposure to a neurotoxin; (2) a neurological syndrome appropriate for the putative neurotoxins; (3) evolution of symptoms and signs over a compatible temporal course; and (4) exclusion of other neurological disorders that may account for a similar syndrome [8]. According to one approach to the diagnosis of TE, our patient was diagnosed with TE after exposure to AZA. The toxic effects on the CNS would result from the dose to which the patient was exposed [8,9]. That is, the higher is the level of exposure, the more severe are the symptoms [8,9]. However, other factors such as genetic polymorphisms, chronicity of exposure and pharmacokinetics of a particular agent have been reported as being associated with the development of CNS toxicity [9]. Peak plasma concentration (Cmax) following intravenous administration was approximately 3.7-fold higher than that following subcutaneous administration [10]. AZA and its metabolites (85% of the dose after intravenous administration and 50% of the dose after subcutaneous administration) are primarily eliminated by urinary excretion, with fecal excretion contributing less than 1% [4,11]. In this case, liver function was normal, and creatinine clearance was 81 mL/ min. This clinical course indicated that intravenous administration could increase the concentration of AZA to within a toxic range, and other factors such as obesity and genetic polymorphisms might influence the pharmacokinetics. However, the effects of intrinsic factors such as age, sex, race, obesity or in vivo drug–drug interaction in relation to the pharmacokinetics of AZA have not been studied [11], and thus there was no empirical evidence. AZA is an important agent for use in the treatment of patients with MDS/AML. To the best of our knowledge, this represents the first report of TE resulting from AZA. When patients treated with AZA demonstrate disorientation or
a depressed level of consciousness, we should consider the possibility of TE due to AZA among the differential diagnoses. This case also emphasizes the need for clinical awareness when administering AZA.
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] Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002;20:2429–2440. [2] Gore SD, Fenaux P, Santini V, et al. A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial. Haematologica 2013;98:1067–1072. [3] Garcia-Manero G. Myelodysplastic syndromes: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 2014;89:97–108. [4] Keating GM. Azacitidine: a review of its use in the management of myelodysplastic syndromes/acute myeloid leukaemia. Drugs 2012;72:1111–1136. [5] Kaminskas E, Farrell AT, Wang YC, et al. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist 2005;10:176–182. [6] Von Hoff DD, Slavik M, Muggia FM. 5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Ann Intern Med 1976;85:237–245. [7] Vardiman JW, Thiele J, Arber DA , et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114:937–951. [8] Kim Y, Kim JW. Toxic encephalopathy. Saf Health Work 2012;3: 243–256. [9] Ruha AM, Levine M. Central nervous system toxicity. Emerg Med Clin North Am 2014;32:205–221. [10] Uchida T, Ogawa Y, Kobayashi Y, et al. Phase I and II study of azacitidine in Japanese patients with myelodysplastic syndromes. Cancer Sci 2011;102:1680–1686. [11] Kaminskas E, Farrell A , Abraham S, et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 2005;11:3604–3608.
