Abstract
Abstract 3698
Follicular, marginal zone and mantle cell lymphomas are indolent lymphomas that tend to recur with decreasing intervals of remissions. Vorinostat (SAHA) is an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deacetylases. Single agent vorinostat has an overall response rate of 29% in all indolent lymphomas (47% in follicular lymphoma) with prolonged disease free survival. (Kirschbaum, JCO 2009) Preclinical data suggests enhanced activity for the combination of vorinostat plus rituximab. We report the clinical results of a phase II study of the combination of vorinostat plus rituximab.
These are the updated results of our two-stage phase II study in patients with newly diagnosed, relapsed or refractory follicular, marginal zone, or mantle cell lymphoma. Vorinostat is given at 200 mg PO twice daily for 14 consecutive days on a 21 day cycle. Rituximab is given on day 1 of each cycle. CT scanning and/or FDG-PET are performed after every three cycles. Patients may have received up to four prior chemotherapy regimens including tositumomab or ibritumomab; previous autologous transplant is allowed. The primary endpoint was the overall response rate according to Revised Response Criteria for Malignant Lymphoma (Cheson 2007).
26 eligible patients were accrued thus far. See Table 1 for baseline characteristics. Outcomes are available on 23 patients: the overall response (CR+PR) rate thus far is 35% (8/23) The CR rate for all patients is 30% (7/23). The response rate for untreated patients (5 FL, 1 MZL) is 66.6% (4/6, all CR). The other two patients remain on study with prolonged stable disease. The formal response rate thus far for relapsed/refractory patients is 23.5% (4/17). By histology, the response rate is 35% (7/19) for FL, 0/2 for mantle cell, 1/1 for MZL, and 0/1 for lymphoplasmacytic lymphoma. The median time to achieve CR is 12 months. Of the 7 patients who achieved CR, 3 have relapsed while off treatment and were retreated with vorinostat plus rituximab. 1 achieved CR and is 13 months into treatment, 1 achieved PR and is 23 months into treatment, while 1 transformed both to Hodgkin lymphoma and diffuse large B cell lymphoma (biopsy proven). The median time to treatment failure for patients achieving CR is 38 months, with 6 ongoing, including the two retreated patients (14, 27, 29, 29, 31, and 35 months). Of non-responders, 8 patients achieved stable disease for at least 9 cycles with one SD for 63+ cycles. The disease control rate for > 9 cycles (CR+PR+SD) is 69.6% (16/23). Five patients were taken off study for reasons other than progression (2 patients choice, 1 to transplant, 1 for concomitant medication violation, and 1 physician choice). The median time to treatment failure for all patients was 9 months (95% CI, 6 months, NR). Treatment was well tolerated. Grade 4 toxicities possibly attributable to study drug include neutropenia (n=1), asymptomatic thrombosis (n=4), and thrombocytopenia (n=2). Grade 3 possibly related toxicities include fatigue (n=7), hyperglycemia (n=3), dehydration (n=2), and one each of thrombocytopenia, neutropenia, anemia, hypophosphatemia, hypotension, pneumonia, diarrhea, diverticulitis, and syncope. The thromboses were nonclinical pulmonary embolism discovered incidentally on CT scan, and resulted in amending the study to include 40 mg enoxaparin as prophylaxis, resulting in no further thromboses identified.
The combination of vorinostat with rituximab is well tolerated, and shows encouraging activity against newly diagnosed, as well as relapsed/refractory indolent lymphoma. Durable responses can be achieved. Extended treatment with this combination is feasible and well tolerated, and retreatment with this regimen is efficacious in previous responders who relapsed.
Characteristics . | N (%) or median (range) . |
---|---|
Median age | 62 (44–89) |
Male | 14 |
Female | 12 |
Histology | |
Follicular | 20 |
Mantle cell | 2 |
Marginal zone | 3 |
Lymphoplasmacytic | 1 |
Relapsed/Refractory | 21 |
Untreated | 5 |
Median number of prior regimen (relapsed/refractory) | 2 (1–4) |
Prior rituximab (relapsed/refractory) | 21 |
Prior R-CVP | 5 |
Prior R-CHOP | 11 |
Prior R-Bendamustine | 5 |
Prior RICE | 3 |
Prior FCR | 2 |
Prior bortezomib containing regimen | 4 |
Characteristics . | N (%) or median (range) . |
---|---|
Median age | 62 (44–89) |
Male | 14 |
Female | 12 |
Histology | |
Follicular | 20 |
Mantle cell | 2 |
Marginal zone | 3 |
Lymphoplasmacytic | 1 |
Relapsed/Refractory | 21 |
Untreated | 5 |
Median number of prior regimen (relapsed/refractory) | 2 (1–4) |
Prior rituximab (relapsed/refractory) | 21 |
Prior R-CVP | 5 |
Prior R-CHOP | 11 |
Prior R-Bendamustine | 5 |
Prior RICE | 3 |
Prior FCR | 2 |
Prior bortezomib containing regimen | 4 |
Off Label Use: Use of vorinostat in combination with rituxan for indolent B cell lymphomas.
Author notes
Asterisk with author names denotes non-ASH members.
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