Valproic acid monotherapy leads to CR in a patient with refractory diffuse large B cell lymphoma

The rapidly growing understanding of the mechanism underlying transcriptional regulation at the histone level, has already led to FDA approval for three drugs in this class. Azacytidine and deoxycytidine, believed to operate as methyltransferase inhibitors, have been FDA approved for use in myelodysplastic syndrome, with activity also shown in acute leukemias [1]. The third drug, vorinostat (SAHA, Zolinza), a histone deacetylase inhibitor (HDACi), has been FDA approved for use in CTCL, the first approved indication for a drug designed as a histone deacetylase inhibitor [2]. Several other HDACi are in trials for CTCL, which seems to respond quite dramatically to this class of agents both in vivo and in vitro [3]. Preclinical data suggests that HDACi may be effective against many lymphoma types other than CTCL. HDACi treatment leads to decreased levels of bcl-2 in mantle cell lines [4] and leads to accumulation of acetylated BCL-6, which causes cell cycle arrest and apoptosis in B cell lymphoma lines [5]. In the broader picture, HDACi treatment has shown effect upon expression of many targets which could have an impact upon lymphoma survival, including numerous DNA damage response and proapoptotic proteins [6]. There are several classes of HDACi, including cyclic peptides, hydroxamic acids, benzamides, and short chain fatty acids. Among the latter, is valproic acid, which has been used for many years to treat seizure disorders, but was recently demonstrated to have histone deacetylase inhibitor activity [7]. The addition of valproic acid to hypomethylating agents has shown beneficial activity in myelodysplastic syndrome and AML [8], but has not been studied clinically in B cell lymphoma. We present a dramatic response in a patient with refractory diffuse large B cell lymphoma to valproic acid as monotherapy. MB is a 64-year-old woman with a history of recurrent diffuse large B cell lymphoma who has been followed at City of Hope since January of 2005. She was diagnosed with stage I left sided breast cancer in 1995 and underwent lumpectomy, lymph node dissection, and local radiation; remission was achieved and there has been no evidence of recurrence. In early 2002, she complained of progressive lower back pain radiating down her left leg; an MRI of the lumbosacral spine in June 2003 revealed a large retroperitoneal mass measuring 86 46 5 cm along with abnormal signal in several vertebrae. CT guided biopsy confirmed a diagnosis of diffuse large B-cell lymphoma. Immunophenotyping was consistent with a follicular center cell origin, bcl-2þ, bcl-6þ; blocks were recently reanalyzed and now classified as being of germinal center origin, staining CD10þ, bcl-6þ, and MUM-17[9]. Staging was consistent with stage IV disease with several bony areas of involvement in the spine and ribs. Bone marrow was involved with B cell lymphoma with a mixture of small and large cells and significant fibrosis. She had normal blood counts and LDH and no B symptoms. She received six cycles of CHOP and rituximab with repeat staging, which showed that her retroperitoneal mass had decreased