- Email: [email protected]
Fludarabine-associated autoimmune hemolytic anemia occurring in B-cell chronic lymphocytic leukemia
Letters to the Editor / Leukemia Research 30 (2006) 1585–1595
[6]
[7]
[8]
[9]
[10]
cohort of patients with no evidence for an association with Chlamydia psittaci. Blood 2006;107:467–72. Vargas RL, Fallone E, Felgar RE, Friedberg JW, Arbini AA, Andersen AA, et al. Is there an association between ocular adnexal lymphoma and infection with Chlamydia psittaci? The University of Rochester experience. Leuk Res 2006;30:547–51. Mulder MMS, Heddema ER, Pannekoek Y, Faridpooya K, Oud MECM, Shilder-Tol E, et al. No evidence for an association of ocular adnexal lymphoma with Chlamydia psittaci in a cohort of patients from the Netherlands. Leuk Res 2006;30:1305–7. Nakata M, Matsuno Y, Katsumata N, Takenaka T, Kobayashi Y, Narabayashi M, et al. Histology according to the Revised EuropeanAmerican Lymphoma Classification significantly predicts the prognosis of ocular adnexal lymphoma. Leuk Lymphoma 1999;32:533– 43. Madico G, Quinn TC, Boman J, Gaydos CA. Touchdown enzyme time release-PCR for detection and identification of Chlamydia trachomatis, C. pneumoniae, and C. psittaci using the 16S and 16S–23S spacer rRNA genes. J Clin Microbiol 2000;38:1085–93. Peeling RW, Brunham RC. Chlamydia as pathogens: new species and new issue. Emerg Infect 1996;2:307–19.
Yi-Chang Liu a,e Junko H. Ohyashiki b Yoshikazu Ito a Kei-ichi Iwaya c Hiromi Serizawa c Kiyoshi Mukai c Hiroshi Goto d Masahiko Usui d Kazuma Ohyashiki a,∗
a
1589
The First Department of Internal Medicine, Hematology and Oncology Division, Tokyo Medical University, Tokyo, Japan
b Intractable
Immune System Research Center, Tokyo Medical University, Tokyo, Japan c Department of Diagnostic Pathology, Tokyo Medical University, Tokyo, Japan d
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan e Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ROC ∗ Corresponding
author at: The First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Tel.: +81 3 3342 1510; fax: +81 3 5381 6651. E-mail address: [email protected] (K. Ohyashiki) 28 January 2006 Available online 9 March 2006
doi:10.1016/j.leukres.2006.01.015
Fludarabine-associated autoimmune hemolytic anemia occurring in B-cell chronic lymphocytic leukemia Abstract Autoimmune phenomena are reported to occur frequently in B-cell chronic leukemia (B-CLL). Fludarabine, one of the most effective chemotherapeutic agents for CLL, may increase the risk of these phenomena and may be life-threatening. Here we present a case of an 80-year-old man with B-CLL who developed autoimmune hemolytic anemia (AIHA), associated with one cycle of fludarabine treatment, and who was successfully treated with rituximab and prednisolone. © 2006 Elsevier Ltd. All rights reserved. Keywords: B-CLL; Fludarabine; AIHA; Rituximab; Prednisolone
An 80-year-old male at the National Tokyo Medical Center Hospital, Tokyo, Japan had a history of B-cell chronic leukaemia (B-CLL) diagnosis since July 1994, and chronic hepatitis due to type C hepatitis virus. Chemotherapy was not started until September 1997, when leukocytosis and hepatosplenomegaly had progressed (Rai stage III). He was treated with monthly cyclophosphamide, and his disease responded to the treatment. In October 2004, he was admitted to the hospital because of progressive leukocytosis and liver dysfunction. Physical examination showed hepatomegaly (3 cm) and splenomegaly (5 cm). Laboratory findings showed a leukocyte count of 46.7 × 109 l−1 , with 87% of leukocytes being mature small lymphocytes,
The hemoglobin was 10.0 g/dl, and platelet count was 59 × 109 l−1 . The Coombs’ test was negative. One cycle of intravenous fludarabine (25 mg/m2 × 5 days) treatment was given. His leukocyte count decreased to 4.6 × 109 l−1 and hepatosplenomegaly was improved in 2 weeks following treatment. He was discharged from the hospital. In April, 2005, 6 months after the one cycle of fludarabine treatment, anemia gradually progressed. In June, hemoglobin decreased to 7.5 g/dl and haptoglobin decreased to less than 10mg/dl. The reticulocyte count was 10.84%, total/indirect bilirubin was 6.74/4.87 mg/dl and lactate dehydrogenase (LDH) was 378IU l−1 . A peripheral blood smear showed anisopoikilocytosis, compatible with hemolysis. The Coombs’ test
1590
Letters to the Editor / Leukemia Research 30 (2006) 1585–1595
mune events [5]. We added prednisolne treatment for the persistent anemia, and a dramatic improvement of AIHA was attained.
Acknowledgement We thank the doctors and nurses at the hematology ward of National Tokyo Medical Center Hospital for providing their excellent patient care.
References Fig. 1. Hemoglobin and reticulocyte counts after fludarabine treatment.
became positive and a diagnosis of autoimmune hemolytic anemia (AIHA) was made. The leukocyte count became also moderately elevated (15.6 × 109 l−1 ), due to moderate disease progression, so we tried one cycle of rituximab treatment (375 mg/m2 × 1 day). In July, 2005, the leukocyte count decreased to 5.2 × 109 l−1 , and reticulocyte count also decreased to 5.84%. For the persistent anemia, prednisolone therapy (0.5 mg/kg) was given. As a result, not only the reticulocyte count but also the hemoglobin, LDH and total bilirubin levels dramatically improved. One month after this treatment, hemoglobin was 9.8 g/dl, and the leukocyte count was 7.8 × 109 l−1 , with 69% of the leukocytes being mature small lymphocytes. The platelet count was 77 × 109 l−1 , LDH 170 IU l−1 and total/indirect bilirubin 3.96/2.58 mg/dl. He is in follow-up in the outpatient clinic 6 months after the start of prednisolone treatment without reappearance of AIHA (Fig. 1). Fludarabine is one of the most effcective chemotherapeutic agents for CLL, whether used as a first-line or secondline therapy. The most common fludarabine toxicities are myelosuppression and immunosuppression with opportunistic infections [1–3]. AIHA is a rare but potentially lifethreatening toxic response to fludarabine treatment. In general, it is difficult to determine how common AIHA events related to fludarabine treatment might be. In our case, before fludarabine treatment, there were no signs to suspect hemolysis. No autoimmune phenomena, well-known as complications of CLL, were detected. Fludarabine may predispose a patient to AIHA by inducing a remarkable lymphocytopenia, particularly of CD4+ lymphocytes with CD8+ subset imbalance, which may favor the emergence of autoreactive T cells [1,2,4]. In our case, rituximab treatment for disease control was also effective for some time and improved hemolysis before the start of prednisolone treatment. Rituximab is a genetically engineered chimeric monoclonal antibody to target the CD20 antigen on B-cells. It also depletes circulating B-cells with the first few doses and remains effective for 6–9 months. Thus, it is valuable for the treatment of autoim-
[1] Mauro FR, Cerretti FR, Giannarelli D, Coluzzi S, Mandelli F, Girelli G. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 2000;95: 2786–92. [2] Weiss RB, Freiman J, Kweder SL, Diehl KL, Byrd JC. Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia. J Clin Oncol 1998;16(5):1885–9. [3] Wells T, Kovacs MJ. Autoimmune thrombocytopenia due to chronic lymphocytic leukemia treated with fludarabine. Ann Pharmacother 2003;37:671–4. [4] Vick DJ, Byrd JC, Beal CL, Chaffin DJ. Mixed-type autoimmune hemolytic anemia following fludarabine treatment in a patient with chronic lymphocytic leukemia/small cell lymphoma. Vox Sang 1998;74:12–26. [5] Paytas S. Fludarabine-induced hemolytic anemia: successful treatment by rituximab. Hematol J 2004;5:81–3.
Hiroko Nishida a,b,∗ Tadashi Murase b,c Hironori Ueno a,b Jae Wong Park b Takahiro Yano b Yasuo Ikeda a a Division of Hematology, Department of Internal Medicine, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan b Division
of Hematology, Department of Internal Medicine, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan c Department
of Internal medicine, Fuji Xerox Health Promotion Center, Tokyo, Japan
∗ Corresponding
author. Tel.: +81 3 5363 3785; fax: +81 3 3353 3515. E-mail address: [email protected] (H. Nishida) 7 February 2006 Available online 20 March 2006
doi:10.1016/j.leukres.2006.02.011
[6]
[7]
[8]
[9]
[10]
cohort of patients with no evidence for an association with Chlamydia psittaci. Blood 2006;107:467–72. Vargas RL, Fallone E, Felgar RE, Friedberg JW, Arbini AA, Andersen AA, et al. Is there an association between ocular adnexal lymphoma and infection with Chlamydia psittaci? The University of Rochester experience. Leuk Res 2006;30:547–51. Mulder MMS, Heddema ER, Pannekoek Y, Faridpooya K, Oud MECM, Shilder-Tol E, et al. No evidence for an association of ocular adnexal lymphoma with Chlamydia psittaci in a cohort of patients from the Netherlands. Leuk Res 2006;30:1305–7. Nakata M, Matsuno Y, Katsumata N, Takenaka T, Kobayashi Y, Narabayashi M, et al. Histology according to the Revised EuropeanAmerican Lymphoma Classification significantly predicts the prognosis of ocular adnexal lymphoma. Leuk Lymphoma 1999;32:533– 43. Madico G, Quinn TC, Boman J, Gaydos CA. Touchdown enzyme time release-PCR for detection and identification of Chlamydia trachomatis, C. pneumoniae, and C. psittaci using the 16S and 16S–23S spacer rRNA genes. J Clin Microbiol 2000;38:1085–93. Peeling RW, Brunham RC. Chlamydia as pathogens: new species and new issue. Emerg Infect 1996;2:307–19.
Yi-Chang Liu a,e Junko H. Ohyashiki b Yoshikazu Ito a Kei-ichi Iwaya c Hiromi Serizawa c Kiyoshi Mukai c Hiroshi Goto d Masahiko Usui d Kazuma Ohyashiki a,∗
a
1589
The First Department of Internal Medicine, Hematology and Oncology Division, Tokyo Medical University, Tokyo, Japan
b Intractable
Immune System Research Center, Tokyo Medical University, Tokyo, Japan c Department of Diagnostic Pathology, Tokyo Medical University, Tokyo, Japan d
Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan e Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ROC ∗ Corresponding
author at: The First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishi-shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Tel.: +81 3 3342 1510; fax: +81 3 5381 6651. E-mail address: [email protected] (K. Ohyashiki) 28 January 2006 Available online 9 March 2006
doi:10.1016/j.leukres.2006.01.015
Fludarabine-associated autoimmune hemolytic anemia occurring in B-cell chronic lymphocytic leukemia Abstract Autoimmune phenomena are reported to occur frequently in B-cell chronic leukemia (B-CLL). Fludarabine, one of the most effective chemotherapeutic agents for CLL, may increase the risk of these phenomena and may be life-threatening. Here we present a case of an 80-year-old man with B-CLL who developed autoimmune hemolytic anemia (AIHA), associated with one cycle of fludarabine treatment, and who was successfully treated with rituximab and prednisolone. © 2006 Elsevier Ltd. All rights reserved. Keywords: B-CLL; Fludarabine; AIHA; Rituximab; Prednisolone
An 80-year-old male at the National Tokyo Medical Center Hospital, Tokyo, Japan had a history of B-cell chronic leukaemia (B-CLL) diagnosis since July 1994, and chronic hepatitis due to type C hepatitis virus. Chemotherapy was not started until September 1997, when leukocytosis and hepatosplenomegaly had progressed (Rai stage III). He was treated with monthly cyclophosphamide, and his disease responded to the treatment. In October 2004, he was admitted to the hospital because of progressive leukocytosis and liver dysfunction. Physical examination showed hepatomegaly (3 cm) and splenomegaly (5 cm). Laboratory findings showed a leukocyte count of 46.7 × 109 l−1 , with 87% of leukocytes being mature small lymphocytes,
The hemoglobin was 10.0 g/dl, and platelet count was 59 × 109 l−1 . The Coombs’ test was negative. One cycle of intravenous fludarabine (25 mg/m2 × 5 days) treatment was given. His leukocyte count decreased to 4.6 × 109 l−1 and hepatosplenomegaly was improved in 2 weeks following treatment. He was discharged from the hospital. In April, 2005, 6 months after the one cycle of fludarabine treatment, anemia gradually progressed. In June, hemoglobin decreased to 7.5 g/dl and haptoglobin decreased to less than 10mg/dl. The reticulocyte count was 10.84%, total/indirect bilirubin was 6.74/4.87 mg/dl and lactate dehydrogenase (LDH) was 378IU l−1 . A peripheral blood smear showed anisopoikilocytosis, compatible with hemolysis. The Coombs’ test
1590
Letters to the Editor / Leukemia Research 30 (2006) 1585–1595
mune events [5]. We added prednisolne treatment for the persistent anemia, and a dramatic improvement of AIHA was attained.
Acknowledgement We thank the doctors and nurses at the hematology ward of National Tokyo Medical Center Hospital for providing their excellent patient care.
References Fig. 1. Hemoglobin and reticulocyte counts after fludarabine treatment.
became positive and a diagnosis of autoimmune hemolytic anemia (AIHA) was made. The leukocyte count became also moderately elevated (15.6 × 109 l−1 ), due to moderate disease progression, so we tried one cycle of rituximab treatment (375 mg/m2 × 1 day). In July, 2005, the leukocyte count decreased to 5.2 × 109 l−1 , and reticulocyte count also decreased to 5.84%. For the persistent anemia, prednisolone therapy (0.5 mg/kg) was given. As a result, not only the reticulocyte count but also the hemoglobin, LDH and total bilirubin levels dramatically improved. One month after this treatment, hemoglobin was 9.8 g/dl, and the leukocyte count was 7.8 × 109 l−1 , with 69% of the leukocytes being mature small lymphocytes. The platelet count was 77 × 109 l−1 , LDH 170 IU l−1 and total/indirect bilirubin 3.96/2.58 mg/dl. He is in follow-up in the outpatient clinic 6 months after the start of prednisolone treatment without reappearance of AIHA (Fig. 1). Fludarabine is one of the most effcective chemotherapeutic agents for CLL, whether used as a first-line or secondline therapy. The most common fludarabine toxicities are myelosuppression and immunosuppression with opportunistic infections [1–3]. AIHA is a rare but potentially lifethreatening toxic response to fludarabine treatment. In general, it is difficult to determine how common AIHA events related to fludarabine treatment might be. In our case, before fludarabine treatment, there were no signs to suspect hemolysis. No autoimmune phenomena, well-known as complications of CLL, were detected. Fludarabine may predispose a patient to AIHA by inducing a remarkable lymphocytopenia, particularly of CD4+ lymphocytes with CD8+ subset imbalance, which may favor the emergence of autoreactive T cells [1,2,4]. In our case, rituximab treatment for disease control was also effective for some time and improved hemolysis before the start of prednisolone treatment. Rituximab is a genetically engineered chimeric monoclonal antibody to target the CD20 antigen on B-cells. It also depletes circulating B-cells with the first few doses and remains effective for 6–9 months. Thus, it is valuable for the treatment of autoim-
[1] Mauro FR, Cerretti FR, Giannarelli D, Coluzzi S, Mandelli F, Girelli G. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 2000;95: 2786–92. [2] Weiss RB, Freiman J, Kweder SL, Diehl KL, Byrd JC. Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia. J Clin Oncol 1998;16(5):1885–9. [3] Wells T, Kovacs MJ. Autoimmune thrombocytopenia due to chronic lymphocytic leukemia treated with fludarabine. Ann Pharmacother 2003;37:671–4. [4] Vick DJ, Byrd JC, Beal CL, Chaffin DJ. Mixed-type autoimmune hemolytic anemia following fludarabine treatment in a patient with chronic lymphocytic leukemia/small cell lymphoma. Vox Sang 1998;74:12–26. [5] Paytas S. Fludarabine-induced hemolytic anemia: successful treatment by rituximab. Hematol J 2004;5:81–3.
Hiroko Nishida a,b,∗ Tadashi Murase b,c Hironori Ueno a,b Jae Wong Park b Takahiro Yano b Yasuo Ikeda a a Division of Hematology, Department of Internal Medicine, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan b Division
of Hematology, Department of Internal Medicine, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan c Department
of Internal medicine, Fuji Xerox Health Promotion Center, Tokyo, Japan
∗ Corresponding
author. Tel.: +81 3 5363 3785; fax: +81 3 3353 3515. E-mail address: [email protected] (H. Nishida) 7 February 2006 Available online 20 March 2006
doi:10.1016/j.leukres.2006.02.011