　Azacitidine, which has the capacity to induce DNA hypomethylation in vitro, is currently available for treatment of myelodysplastic syndrome (MDS). As a result of some trials, azacitidine has been recently recommended as a frontline therapy for elderly patients with high-risk and very high-risk MDS1), 2). The commonly encountered side effects of azacitidine are manageable1), 2). However, potentially serious complications have been recently reported3). We now describe fatal bone marrow necrosis following azacitidine and granulocyte colony-stimulating factor administration in a patient with high-risk MDS

加藤  丈夫

加藤  裕一

塩野  洋介

山田  茜

鈴木  郁子

Yamagata University Academic Repository

Bone marrow necrosis induced azacitidine and granulocyte colony-stimulating factor
－ 29 －
Case report
　Azacitidine has been recently recommended as a 
frontline therapy for intermediate-2 and high-risk 
myelodysplastic syndrome (MDS)1), 2). Generaly, most 
hematologists consider that azacitidine is used safely 
and easily as compared with other anticancer 
drugs1), 2). However, potentialy serious complications 
have been reported recently3). Here, we report a case 
of high-risk MDS that developed fatal bone marrow 
necrosis after granulocyte colony-stimulating factor 
(G-CSF) and azacitidine combination therapy.
　A 78-year-old woman developed pancytopenia 
during treatment for nontuberculous mycobacteria. 
Laboratory findings on the first visit showed platelets 
of 5.7 × 109/L, white blood cels of 1,700 × 109/L 
(blasts: 0%), and hemoglobin of 6.8 g/dL. Bone 
marrow aspiration (BMA) showed trilineage dysplasia 
and 13% blasts. There was no evidence of bone 
marrow necrosis at this time. The patient was 
diagnosed as refractory anemia with excess blasts-2 
and high risk according to IPSS. Azacitidine was 
administered for 7 days via intravenous injection 
folowing the manufacturer’s usage instructions after 
administration of G-CSF 75 μg/day for 4 days. Two 
days after the third course, she had a high fever (40
℃) and intolerable generalized bone pain. Laboratory 
findings showed platelets of 9 × 109/L, white blood 
cels of 2.17 × 109/L (blasts: 2.5%), hemoglobin of 6.6 
g/dL, lactate dehydrogenase (LDH) of 2,391 U/L, and 
alkaline phosphatase of 1,280 U/L (Table 1). Her bone 
marrow demonstrated difuse necrosis with sheets of 
ghost cels; these cultures were negative. She died 13 
days after the third course.
　In postmortem examination, her bone marrow 
demonstrated widespread necrosis in the lumbar 
vertebrae and sternum. Wel-preserved areas of bone 
marrow alternated with patchy foci containing 
eosinophilic ghost cels (Figure 1). No granulomas or 
thrombi were distinguishable in her bone marrow. 
These findings were consistent with a diagnosis 
of bone marrow necrosis (BMN) by leukemic 
transformation. 
Fatal Bone marrow necrosis folowing azacitidine and
granulocyte colony-stimulating factor administration
in a patient with high-risk myelodysplastic syndrome
Yamagata Med J 2015；33(1)：29-31
Yuichi Kato, Akane Yamada, Yosuke Shiono, Ikuko Suzuki, Takeo Kato
Third Department of Internal Medicine, Yamagata University Faculty of Medicine
（Accepted October 6, 2014）
　Azacitidine, which has the capacity to induce DNA hypomethylation in vitro, is currently available for 
treatment of myelodysplastic syndrome (MDS). As a result of some trials, azacitidine has been recently 
recommended as a frontline therapy for elderly patients with high-risk and very high-risk MDS1), 2). The 
commonly encountered side efects of azacitidine are manageable1), 2). However, potentialy serious 
complications have been recently reported3). We now describe fatal bone marrow necrosis folowing 
azacitidine and granulocyte colony-stimulating factor administration in a patient with high-risk MDS.
Key words : azacitidine, granulocyte colony-stimulating factor, myelodysplastic syndrome, bone marrow 
necrosis
ABSTRACT
Kato, Yamada, Shiono, Suzuki, Kato
－ 30 －
Discussion
　BMN is reportedly associated with anticancer drugs 
and some cytokines (e.g., high-dose G-CSF) as a 
background to disease progression4)－9). In our patient, 
G-CSF, with a dosage lower for her than in cases 
reported thus far, and azacitidine combination 
therapies were performed safely until the second 
course. However, leukemic cels increased silently and 
suddenly in her bone marrow, even though we 
carefuly administered azacitidine according to the 
manufacturer’s usage instructions. BMN does not 
develop in al high-risk MDS patients. In ours, the 
rapid leukemia cel growth may reflect a synergistic 
efect of G-CSF and azacitidine because both agents 
have the efect of inducing cel diferentiation. In 
addition, it has the efect of up-regulating the 
expression of the c-abl gene and IL-6 to bone marrow 
stromal  cels  directly;  azacitidine　 might  have 
an adverse efect on the bone marrow microen-
vironment10).
　Azacitidine, with the potential to cause serious side 
efects, may be used in combination with other drugs, 
as there is an unknown part of the mechanism of 
action of this agent. We think BMA is the only way 
to confirm the transformation to leukemia with 
azacitidine. To perform azacitidine therapy safely, we 
suggest performing BMA during each course of 
azacitidine, with or without change of state.
　Conflict of interest: The authors report no conflict 
of interest.
　
References
 1 . Fenaux P, Mufti GJ, Helstrom-Lindberg E, Valeria 
Santini, Carlo Fineli, Aristoteles Giagounidis, et al.: 
Efficacy of azacitidine compared with that of 
conventional care regimens in the treatment of higher-
risk myelodysplastic syndromes: a randomised, open-
label, phase III study. Lancet Oncol 2009; 10: 223-232
 2 . Garcia-Manero G, Fenaux P.: Hypomethylating 
agents and other novel strategies in myelodysplastic 
syndromes. J Clin Oncol 2011; 29: 516-523
 3 . Hueser CN1, Patel AJ.: Azacitidine-associated 
hyperthermia and interstitial pneumonitis in a patient 
with myelodysplastic syndrome. Pharmacotherapy 
2007 Dec; 27(12): 1759-1762
 4 . Wade LJ, Stevenson LD.: Necrosis of the bone 
marrow with fat embolism in sickle cel anemia. Am J 
Pathol 1941; 17: 47-54
 5 . Dreosti LM, Bezwoda W, Gunter K.: Bone marrow 
Table 1.
The clinical course of the patient. A high fever, bone pain, LDH and 
high ALP appeared after the start of the third course of azacitidine.
Figure 1.
Bone marrow examination 11 days 
after the third course of azacitidine 
therapy showing necrotic and eosino-
philic cel ghosts at antemortem (May-
Giemsa stain x 200).
Bone marrow necrosis induced azacitidine and granulocyte colony-stimulating factor
－ 31 －
necrosis folowing ALL-trans retinoic acid therapy for 
acute promyelocytic leukaemia. Leuk Lymphoma 
1994; 13: 353-356
 6 . Limentani SA, Pretel JO, Potter D, DuBois JS, 
Daoust PR, Spieler PS., et al.: Bone marrow necrosis 
in two patients with acute promyelocytic leukemia 
during treatment with al-trans retinoic acid. Am J 
Hematol 1994; 47: 50-55
 7 . Ishitsuka K, Shirahashi A, Iwao Y, Shishime M, 
Takamatsu Y, Takatsuka Y., et al.: Bone marrow 
necrosis in a patient with acute promyelocytic 
leukemia during re-induction therapy with arsenic 
trioxide. Eur J Haematol 2004; 72: 280-284
 8 . Aboulafia DM, Demirer T.: Fatal bone marrow 
necrosis folowing fludarabine administration in a 
patient with indolent lymphoma. Leuk Lymphoma 
1995; 19: 181-184
 9 . Katayama Y, Deguchi S, Shinagawa K, Teshima T, 
Notohara K, Taguchi K., et al.: Bone marrow necrosis 
in a patient with acute myeloblastic leukemia during 
administration of G-CSF and rapid hematologic 
recovery after alotransplantation of peripheral blood 
stem cels. Am J Hematol 1998; 57: 238-240
10. Andrews DF 3rd, Nemunaitis J, Tompkins C, Singer 
JW.: Effect of 5-azacytidine on gene expression in 
marrow stromal cels. Mol Cel Biol. 1989; 9(6): 2748-
2751


Fatal Bone marrow necrosis following azacitidine and granulocyte colony-stimulating factor administration in a patient with high-risk myelodysplastic syndrome

論文(Article)Azacitidine, which has the capacity to induce DNA hypomethylation in vitro, is currently available for treatment of myelodysplastic syndrome (MDS). As a result of some trials, azacitidine has been recently recommended as a frontline therapy for elderly patients with high-risk and very high-risk MDS1), 2). The commonly encountered side effects of azacitidine are manageable1), 2). However, potentially serious complications have been recently reported3). We now describe fatal bone marrow necrosis following azacitidine and granulocyte colony-stimulating factor administration in a patient with high-risk MDS.departmental bulletin pape

加藤,  裕一

山田,  茜

塩野,  洋介

鈴木,  郁子

加藤,  丈夫

Bone marrow necrosis induced azacitidine and granulocyte colony-stimulating factor－ 29 －Case report　Azacitidine has been recently recommended as a frontline therapy for intermediate-2 and high-risk myelodysplastic syndrome (MDS)1), 2). Generaly, most hematologists consider that azacitidine is used safely and easily as compared with other anticancer drugs1), 2). However, potentialy serious complications have been reported recently3). Here, we report a case of high-risk MDS that developed fatal bone marrow necrosis after granulocyte colony-stimulating factor (G-CSF) and azacitidine combination therapy.　A 78-year-old woman developed pancytopenia during treatment for nontuberculous mycobacteria. Laboratory findings on the first visit showed platelets of 5.7 × 109/L, white blood cels of 1,700 × 109/L (blasts: 0%), and hemoglobin of 6.8 g/dL. Bone marrow aspiration (BMA) showed trilineage dysplasia and 13% blasts. There was no evidence of bone marrow necrosis at this time. The patient was diagnosed as refractory anemia with excess blasts-2 and high risk according to IPSS. Azacitidine was administered for 7 days via intravenous injection folowing the manufacturer’s usage instructions after administration of G-CSF 75 μg/day for 4 days. Two days after the third course, she had a high fever (40℃) and intolerable generalized bone pain. Laboratory findings showed platelets of 9 × 109/L, white blood cels of 2.17 × 109/L (blasts: 2.5%), hemoglobin of 6.6 g/dL, lactate dehydrogenase (LDH) of 2,391 U/L, and alkaline phosphatase of 1,280 U/L (Table 1). Her bone marrow demonstrated difuse necrosis with sheets of ghost cels; these cultures were negative. She died 13 days after the third course.　In postmortem examination, her bone marrow demonstrated widespread necrosis in the lumbar vertebrae and sternum. Wel-preserved areas of bone marrow alternated with patchy foci containing eosinophilic ghost cels (Figure 1). No granulomas or thrombi were distinguishable in her bone marrow. These findings were consistent with a diagnosis of bone marrow necrosis (BMN) by leukemic transformation. Fatal Bone marrow necrosis folowing azacitidine andgranulocyte colony-stimulating factor administrationin a patient with high-risk myelodysplastic syndromeYamagata Med J 2015；33(1)：29-31Yuichi Kato, Akane Yamada, Yosuke Shiono, Ikuko Suzuki, Takeo KatoThird Department of Internal Medicine, Yamagata University Faculty of Medicine（Accepted October 6, 2014）　Azacitidine, which has the capacity to induce DNA hypomethylation in vitro, is currently available for treatment of myelodysplastic syndrome (MDS). As a result of some trials, azacitidine has been recently recommended as a frontline therapy for elderly patients with high-risk and very high-risk MDS1), 2). The commonly encountered side efects of azacitidine are manageable1), 2). However, potentialy serious complications have been recently reported3). We now describe fatal bone marrow necrosis folowing azacitidine and granulocyte colony-stimulating factor administration in a patient with high-risk MDS.Key words : azacitidine, granulocyte colony-stimulating factor, myelodysplastic syndrome, bone marrow necrosisABSTRACTKato, Yamada, Shiono, Suzuki, Kato－ 30 －Discussion　BMN is reportedly associated with anticancer drugs and some cytokines (e.g., high-dose G-CSF) as a background to disease progression4)－9). In our patient, G-CSF, with a dosage lower for her than in cases reported thus far, and azacitidine combination therapies were performed safely until the second course. However, leukemic cels increased silently and suddenly in her bone marrow, even though we carefuly administered azacitidine according to the manufacturer’s usage instructions. BMN does not develop in al high-risk MDS patients. In ours, the rapid leukemia cel growth may reflect a synergistic efect of G-CSF and azacitidine because both agents have the efect of inducing cel diferentiation. In addition, it has the efect of up-regulating the expression of the c-abl gene and IL-6 to bone marrow stromal  cels  directly;  azacitidine　 might  have an adverse efect on the bone marrow microen-vironment10).　Azacitidine, with the potential to cause serious side efects, may be used in combination with other drugs, as there is an unknown part of the mechanism of action of this agent. We think BMA is the only way to confirm the transformation to leukemia with azacitidine. To perform azacitidine therapy safely, we suggest performing BMA during each course of azacitidine, with or without change of state.　Conflict of interest: The authors report no conflict of interest.　References 1 . Fenaux P, Mufti GJ, Helstrom-Lindberg E, Valeria Santini, Carlo Fineli, Aristoteles Giagounidis, et al.: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223-232 2 . Garcia-Manero G, Fenaux P.: Hypomethylating agents and other novel strategies in myelodysplastic syndromes. J Clin Oncol 2011; 29: 516-523 3 . Hueser CN1, Patel AJ.: Azacitidine-associated hyperthermia and interstitial pneumonitis in a patient with myelodysplastic syndrome. Pharmacotherapy 2007 Dec; 27(12): 1759-1762 4 . Wade LJ, Stevenson LD.: Necrosis of the bone marrow with fat embolism in sickle cel anemia. Am J Pathol 1941; 17: 47-54 5 . Dreosti LM, Bezwoda W, Gunter K.: Bone marrow Table 1.The clinical course of the patient. A high fever, bone pain, LDH and high ALP appeared after the start of the third course of azacitidine.Figure 1.Bone marrow examination 11 days after the third course of azacitidine therapy showing necrotic and eosino-philic cel ghosts at antemortem (May-Giemsa stain x 200).Bone marrow necrosis induced azacitidine and granulocyte colony-stimulating factor－ 31 －necrosis folowing ALL-trans retinoic acid therapy for acute promyelocytic leukaemia. Leuk Lymphoma 1994; 13: 353-356 6 . Limentani SA, Pretel JO, Potter D, DuBois JS, Daoust PR, Spieler PS., et al.: Bone marrow necrosis in two patients with acute promyelocytic leukemia during treatment with al-trans retinoic acid. Am J Hematol 1994; 47: 50-55 7 . Ishitsuka K, Shirahashi A, Iwao Y, Shishime M, Takamatsu Y, Takatsuka Y., et al.: Bone marrow necrosis in a patient with acute promyelocytic leukemia during re-induction therapy with arsenic trioxide. Eur J Haematol 2004; 72: 280-284 8 . Aboulafia DM, Demirer T.: Fatal bone marrow necrosis folowing fludarabine administration in a patient with indolent lymphoma. Leuk Lymphoma 1995; 19: 181-184 9 . Katayama Y, Deguchi S, Shinagawa K, Teshima T, Notohara K, Taguchi K., et al.: Bone marrow necrosis in a patient with acute myeloblastic leukemia during administration of G-CSF and rapid hematologic recovery after alotransplantation of peripheral blood stem cels. Am J Hematol 1998; 57: 238-24010. Andrews DF 3rd, Nemunaitis J, Tompkins C, Singer JW.: Effect of 5-azacytidine on gene expression in marrow stromal cels. Mol Cel Biol. 1989; 9(6): 2748-2751

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Fatal Bone marrow necrosis following azacitidine and granulocyte colony-stimulating factor administration in a patient with high-risk myelodysplastic syndrome

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