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Bortezomib with vorinostat safe, active in lymphoma subtypes
The combination of bortezomib and vorinostat appeared safe and showed moderate activity among patients with diffuse large B-cell lymphoma and mantle cell lymphoma, according to a nonrandomized multicenter phase 2 trial.
“Although many patients with diffuse large B-cell lymphoma will be cured with R-CHOP (rituximab [Rituxan; Genentech, Biogen], cyclophosphamide, doxorubicin, vincristine, prednisone), a significant number of patients will develop a relapse or refractory disease, both associated with a poor prognosis,” Victor Yazbeck, MD, assistant professor in the department of internal medicine at Virginia Commonwealth University School of Medicine, and colleagues wrote. “For mantle cell lymphoma, an increasing number of therapeutic options have become available; however, the disease has remained incurable, with relapse inevitable for most patients. Consequently, additional therapies are needed to improve the outcomes of patients with mantle cell lymphoma and DLBCL.”
The analysis included 22 patients with mantle cell lymphoma with no previous bortezomib treatment, four patients with mantle cell lymphoma with previous bortezomib and 39 patients with relapsed/refractory DLBCL with no previous bortezomib.
Patients received 400 mg oral vorinostat (Zolinza, Merck) — a histone deacetylase inhibitor — on days 1 to 5 and 8 to 12 and 1.3 mg/m2 IV bortezomib, a proteasome inhibitor, on days 1, 4, 8 and 11 of each 21-day cycle. Patients received treatment until disease progression, unacceptable toxicity, investigator decision to discontinue or withdrawal of consent.
Among patients with DLBCL, researchers observed an overall response rate of 7.7% (95% CI, 2.7-20.3). Median PFS was 1.8 months (95% CI, 1.4-2.3). Three patients had a partial response and eight had stable disease.
Among patients with mantle cell lymphoma, the ORR was 31.8% (95% CI, 16.3-52.7) among those who were bortezomib naive and 0% among those previously treated with bortezomib. Median PFS was 7.6 months (95% CI, 2.2-not reached) among bortezomib-naive patients with mantle cell lymphoma, which included seven patients with partial response and five with stable disease.
The combination appeared well tolerated across the subgroups. The most common grade 3 or grade 4 hematologic toxicities included thrombocytopenia (bortezomib-naive mantle cell lymphoma, n = 8; mantle cell lymphoma with previous bortezomib, n = 1; DLBCL, n = 15), lymphopenia (n = 1; n = 0; n = 6) and neutropenia (n = 0; n = 0; n = 6). The most common nonhematologic grade 3 or grade 4 event was diarrhea (n = 3; n = 0; n = 3).
bortezomib-naive patients with mantle cell lymphoma, the most common grade 2 toxicities were decreased platelet count (31.8%), fatigue (31.8%), decreased lymphocyte count (22.7%), decreased white blood cell count (22.7%) and nausea (22.7%).
The most common grade 2 toxicities among patients with mantle cell lymphoma with previous bortezomib were decreased platelet count (50%), abdominal pain (25%), arthralgia (25%), back pain (25%), fatigue (25%) and a prolonged QT (corrected) interval on electrocardiography (25%). Among those with DLBCL, the most common grade 2 toxicities were anemia (28.2%) and fatigue (25.6%).
One patient with DLBCL died. The patient had relapsed/refractory DLBCL that had progressed after two cycles, and researchers withdrew the patient from study.
“Despite the significant single-agent activity of the Bruton tyrosine kinase inhibitor ibrutinib [Imbruvica; Pharmacyclics, Janssen] in ABC-subtype DLBCL and mantle cell lymphoma, patients develop resistance and ultimately relapse, with very poor outcomes,” the researchers wrote. “However, the modest response rates observed in the present study argue against pursuing this regimen for relapsed DLBCL or mantle cell lymphoma.” – by Cassie Homer
Disclosures: Yazbeck reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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Yazbeck V, et al. Clin Lymphoma Myeloma Leuk. 2018;doi:10.116/j.clml.2018.05.023.
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