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follicular lymphoma ( fl ) cases comprise approximately 35 and 22% of all adult non - hodgkin lymphomas in the usa and worldwide , respectively .
fl has a chronic relapsing - remitting disease course , and there are several treatment options ranging from watchful waiting to chemoimmunotherapy using rituximab in combination with cyclophosphamide , doxorubicin , vincristine , and prednisolone ( r - chop ) .
a recent report showed that bendamustine and rituximab ( br ) therapy was more efficacious and less toxic when compared with r - chop therapy .
although bendamustine has a favorable tolerability , the most frequent hematologic adverse events associated with its use are leukocytopenia , lymphocytopenia , and neutropenia [ 4 , 5 , 6 , 7 , 8 , 9 ] .
common nonhematologic adverse events include nausea , fatigue , and anorexia , and are mainly grade 1 or 2 in severity [ 4 , 5 , 6 , 7 , 8 , 9 ] . here ,
we report an informative fl case with severe liver dysfunction and nonallergic bronchitis accompanied by eosinophilia that developed following br therapy .
in july 2013 , a 66-year - old female was diagnosed with fl ( grade 2 ) using lymph node biopsy of the right supraclavicular lymph node . based on the follicular lymphoma international prognostic index score criteria , she had stage iiia disease ( cervical , axillar , abdominal para - aortic , mesenteric , iliac , and inguinal lymph node involvement ) and was at high risk ( 3 points based on age , stage , and the number of involved nodal sites ) .
the patient refused further r - chop therapy mainly because of finger numbness , hair loss , and general malaise . therefore , br therapy was administered during the second chemotherapy cycle .
the patient received 1 cycle of rituximab ( 375 mg / m on day 1 ) in combination with bendamustine ( 75 mg / m on days 2 and 3 ) . on day 16 of the br therapy , the patient developed liver dysfunction with aspartate aminotransferase ( ast ) and alanine aminotransferase ( alt ) levels of 133 and 93 iu / l , respectively .
she also developed a severe cough , which resulted in insomnia ( grade 3 ) , and was admitted to our hospital for further assessment . as summarized ( table 1 ) , her hepatic function had deteriorated further ( total bilirubin , 3.1 mg / dl ; ast , 800 iu / l ; alt , 557 iu / l ; alkaline phosphatase , 932 u / l ; gamma - glutamyltransferase , 422 u / l ; lactate dehydrogenase , 641 u / l ) . hepatitis b surface antigen , anti - hepatitis c virus , anti - hepatitis b virus surface antigen , anti - hepatitis b core antigen , and anti - hepatitis a igm antibodies were all negative . a computed tomography ( ct ) examination
did not show any liver abnormalities ( data not shown ) . with regard to the severe coughing exhibited by the patient ,
a ct examination revealed no significant lung abnormalities , demonstrating that she had not been suffering from bacterial pneumonia ( data not shown ) .
the nonspecific ige level was within normal limits and no specific ige was detected against 11 antigens that were tested ( cocksfoot , japanese cedar , cat dander , dog dander , egg white , wheat , buckwheat , soy bean , shrimp , candida albicans , and derematophagoides farinae ) ( table 2 ) .
the c - reactive protein level was not elevated throughout the course of the patient 's illness ( table 1 ) .
these data indicated that bacterial , fungal or cytomegalovirus infection , and allergic reactions might not have been the cause of the severe coughing .
however , an increase in the eosinophil level was observed around 4 weeks after the beginning of the br therapy , and the eosinophilia was progressive ( table 1 , fig .
1 ) . considering these results together , the patient 's severe cough was thought to be a result of nonallergic bronchitis due to eosinophilia .
the patient was referred to the department of respiratory medicine , and was diagnosed as having bronchitis with eosinophilia .
methylprednisolone sodium succinate ( 1,000 mg ) was administered intravenously for 3 consecutive days . on day 47 of the br therapy ,
50 mg of oral prednisolone was administered for 7 days , and the amount of prednisolone was gradually decreased to 0 mg ( fig .
the severe coughing greatly improved after steroid pulse therapy and diminished very rapidly , and both liver dysfunction and eosinophilia resolved .
bendamustine , consisting of a nitrogen mustard moiety bound to a purine - like ring , is an agent with unique alkylating properties .
bendamustine induces dna damage , apoptosis , and mitotic catastrophe , and shows only a low level or absence of cross - resistance with other alkylating agents [ 10 , 11 , 12 , 13 ] .
the administration of bendamustine in combination with rituximab in the treatment of fl demonstrated a significantly improved progression - free survival compared with r - chop therapy , but with a distinct toxicity profile .
significantly fewer hematological toxic effects were noted in patients treated with br than in those treated with r - chop .
no alopecia was observed in br - treated patients , but a drug - associated erythematous skin reaction was more common than in r - chop - treated patients .
side effects such as liver damage , bronchitis , and eosinophilia were seldom reported in br - treated patients . in this case , the patient was admitted to our hospital for examination because of liver damage and severe coughing .
the laboratory data and a ct examination did not indicate that hepatitis viruses or lymphoma cell infiltration into the liver was the cause of the liver damage .
negative laboratory data including a microbiological examination suggested that bacterial and fungal pneumonia , and cytomegalovirus pneumonitis , were also not responsible for the damage ( table 2 ) .
there was no neutropenia , but lymphocytopenia ( up to grade 3 ) was observed ( table 1 ) ; therefore , the possibility of viral infectious disease could not be excluded .
however , no significant abnormalities were observed in the bilateral lung ct scan examination ( data not shown ) . as eosinophilia was present ,
therefore , nonspecific ige and specific ige for 11 antigens were examined , but no positive results were observed , suggesting that nonallergic bronchitis with eosinophilia caused the severe coughing ( table 2 ) .
we speculated that the patient 's severe liver damage and nonallergic bronchitis were the results of eosinophilia , and that steroids would be an effective treatment . as expected , the administration of steroid pulse therapy and prednisolone resulted in the complete resolution of the pathology ( fig .
br is generally a well - tolerated therapy , and eosinophilia seldom occurs as a side effect of the treatment .
reported a bendamustine - induced skin rash with eosinophil infiltration , but malipatil et al .   reported that no eosinophilia was noted in patients with a skin rash
at present , the relationship between br therapy side effects and eosinophilia is not clear .
in summary , we reported a case of br - induced severe liver damage and nonallergic bronchitis with eosinophilia
. the efficacy of steroid treatment in this patient indicated that eosinophilia resulting from br therapy might have caused severe liver dysfunction and nonallergic bronchitis .
abstracta 66-year - old female with follicular lymphoma developed severe liver dysfunction and nonallergic bronchitis after 1 cycle of treatment with bendamustine and rituximab ( br ) therapy . 
 simultaneously , eosinophilia was observed . 
 further examination revealed negative results for both hepatitis virus - induced liver damage and lymphoma cell invasion into the liver . 
 no bacterial , fungal , or cytomegaloviral infections of the respiratory tract were observed . 
 the patient was treated with steroid pulse therapy followed by prednisolone with complete resolution of her symptoms . 
 this suggests that eosinophilia induced by the treatment with br may result in liver dysfunction and nonallergic bronchitis .