Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies.
OBJECTIVE
To document the toxicity and activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with pretreated hematologic malignancies.


METHODS
Two formulations of SAHA (intravenous [IV] and oral) have been assessed in two consecutive phase I trials. In both trials, dose escalation was performed in parallel and independently in patients with solid tumors and hematologic malignancies. Eligible patients were required to have adequate hepatic and renal function, an absolute neutrophil count > or = 500/microL and a platelet count more than 25,000/mL. All patients provided informed consent for study inclusion.


RESULTS
A total of 39 patients with hematologic malignancy were enrolled (14 on IV SAHA and 25 on oral SAHA), of whom 35 were treated. The spectrum of diseases included patients with diffuse large B-cell lymphoma (n = 12), Hodgkin's disease (HD; n = 12), multiple myeloma (n = 2), T-cell lymphoma (n = 3), mantle cell lymphoma (n = 2), small lymphocytic lymphoma (n = 2), and myeloid leukemia (n = 2). Major adverse events with the oral formulation included fatigue, diarrhea, anorexia, and dehydration, whereas myelosuppression and thrombocytopenia were more prominent with the IV formulation. Typically, the hematologic toxicities resolved shortly after SAHA was stopped. There was no neutropenic fever or neutropenic sepsis. Reduction in measurable tumor was observed in five patients. One patient with transformed small lymphocytic lymphoma met criteria for complete response, whereas another met the criteria for partial response (PR). One patient with refractory HD had a PR, whereas three patients had stable disease for up to 9 months.


CONCLUSIONS
These results suggest that SAHA has activity in hematologic malignancies including HD and select subtypes of non-Hodgkin's lymphoma.
O'Connor
Owen A
OA
Department of Medicine, Division of Hematologic Oncology, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, NY 10021, USA. oconnoro@mskcc.org
Heaney
Mark L
ML
Schwartz
Lawrence
L
Richardson
Stacie
S
Willim
Robert
R
MacGregor-Cortelli
Barbara
B
Curly
Tracey
T
Moskowitz
Craig
C
Portlock
Carol
C
Horwitz
Steven
S
Zelenetz
Andrew D
AD
Frankel
Stanley
S
Richon
Victoria
V
Marks
Paul
P
Kelly
William K
WK
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D000077337:Vorinostat
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat