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5-Azacytidine partially restores CD20 expression in follicular lymphoma that lost CD20 expression after rituximab treatment: a case report
© Tsutsumi et al. 2016
Received: 21 April 2015
Accepted: 14 January 2016
Published: 2 February 2016
The loss of CD20 protein expression after a rituximab-containing regimen is one of the resistance mechanisms in non-Hodgkin's lymphoma. Recently, it was reported that 5-azacitidine administration upregulates the expression of CD20 in CD20-negative B-cell acute lymphoblastic leukemia. Here we report a similar upregulation in a patient with follicular lymphoma who was treated with 5-azacitidine against secondary myelodysplastic syndrome.
A 69-year-old Japanese woman with follicular lymphoma with treatment-related myelodysplastic syndrome was negative for the CD20 antibody at the time of her relapse. After treatment of 5-azacytidine for her myelodysplastic syndrome, CD20 expression was upregulated in the follicular lymphoma cells in her peripheral blood. We also observed follicular lymphoma cell stimulation in her peripheral blood due to 5-azacytidine.
Although partial, CD20 expression was upregulated after treatment with 5-azacitidine. However, CD20 expression was not re-upregulated after a second administration of 5-azacitidine and we also observed the risk of lymphoma cell stimulation due to 5-azacitidine.
Rituximab is a standard drug for the treatment of CD20-positive B-cell non-Hodgkin's lymphoma (NHL). The loss of CD20 protein expression after a rituximab-containing regimen is one of the resistance mechanisms in NHL [1, 2]. Recently, it was reported that 5-azacitidine (5-AZA) administration upregulates the expression of CD20 in CD20-negative B-cell acute lymphoblastic leukemia . Here we report the case of a patient who was treated with 5-AZA against secondary myelodysplastic syndrome (MDS) that was caused by the treatment of B-cell follicular lymphoma (FL). CD20 expression was upregulated in CD20-negative FL cells after 5-AZA treatment.
The loss of CD20 expression is often observed after rituximab treatment in CD20-positive NHL [1, 2]. In the present case, the expression of CD20 protein gradually lost negative after bendamustine and rituximab treatments. Although a loss of CD20 expression is often associated with transformation in the FL to diffuse large B-cell lymphoma (DLBCL) [1, 2], the histology remained FL at the time of the loss of the CD20-negative transformation. This suggests that the phenomenon of CD20 expression does not necessarily indicate a transformation from FL to DLBCL.
Our patient’s FL was complicated by therapy-related MDS, and 5-AZA was administered for MDS. Following the first cycle of 5-AZA treatment, a small proportion of the CD20-negative cells exhibited CD20 expression. We also observed the risk of lymphoma cell stimulation due to 5-AZA. However, CD20 expression was not restored in the FL cells in her peripheral blood after the second course of 5-AZA. One possibility was that GDP-rituximab might have eliminated the FL clone, which restored the CD20 protein by 5-AZA. Another possibility was that the FL cells might have obtained a new chromosomal abnormality.
Recent studies demonstrated that CD20 protein and its messenger ribonucleic acid (mRNA) expression were enhanced in a CD20-negative transformed cell line RRBL1 in a culture with 5-AZA in vitro [1, 4]. 5-AZA upregulated CD20 due to the stimulation of transcription factors that stimulate MS4A1 by the regulation of the CpG methylation of gene promoters. This phenomenon restored the sensitivity of the FL cells to rituximab [1, 3, 4]. Our case further proved these in vitro findings in vivo. However, the effects of 5-AZA on CD20 induction were partial. In vitro studies demonstrated that the maximal effect of 5-AZA for the expression of the CD20 protein was observed 3 days after 5-AZA treatment [1, 4]. Therefore, a much earlier evaluation of CD20 expression after 5-AZA and earlier administration of rituximab following 5-AZA therapy may be required.
Although there was partial upregulation of CD20 expression after 5-AZA treatment, it was not observed after a second administration of 5-AZA; we also observed lymphoma cell stimulation due to 5-AZA. Further studies must address these issues.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The authors thank all of the physicians and staff at the hospital in this study.
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