ABSTRACT
Only a minority of patients with high risk lymphoma will be cured with autologous transplant, so maintenance with vorinostat, an oral agent with activity in relapsed lymphoma, was studied starting day + 60 for 21 consecutive days followed by a week off for up to 11 cycles. Twenty-three patients with lymphoma were treated. Ten patients completed the full 11-cycle treatment plan per protocol, four patients were removed due to progressive disease and seven withdrew or were removed from the study due to toxicities. Despite Prevnar vaccine administration every 2 months for three injections, the mean antibody concentration never reached protective levels (> 0.35 µg/mL). Fatigue and functional well-being measured by Brief Fatigue Inventory and Functional Assessment of Cancer Therapy-General improved significantly from cycle 1 to cycle 7, but depression scores from the Center for Epidemiologic Studies Depression scale did not change. Given the toxicities observed, this broad-spectrum deacetylase inhibitor at this schedule is not optimal for prolonged maintenance therapy.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Hydroxamic Acids/therapeutic use , Lymphoma/therapy , Administration, Oral , Adult , Aged , Child , Combined Modality Therapy , Diarrhea/chemically induced , Disease-Free Survival , Dose-Response Relationship, Drug , Drug Administration Schedule , Fatigue/chemically induced , Heptavalent Pneumococcal Conjugate Vaccine/administration & dosage , Heptavalent Pneumococcal Conjugate Vaccine/immunology , Histone Deacetylase Inhibitors/adverse effects , Histone Deacetylase Inhibitors/therapeutic use , Humans , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/adverse effects , Lymphoma/immunology , Lymphoma/pathology , Lymphopenia/chemically induced , Middle Aged , Nausea/chemically induced , Quality of Life , Recurrence , Transplantation, Autologous , Treatment Outcome , Vaccination/methods , VorinostatABSTRACT
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a short median survival despite multimodal therapy. FTY720, an immunosuppressive drug approved for the treatment of multiple sclerosis, promotes MCL cell death concurrent with down-modulation of phospho-Akt and cyclin D1 and subsequent cell-cycle arrest. However, the mechanism of FTY720-mediated MCL cell death remains to be fully clarified. In the present study, we show features of autophagy blockage by FTY720 treatment, including accumulation of autolysosomes and increased LC3-II and p62 levels. We also show that FTY720-induced cell death is mediated by lysosomal membrane permeabilization with subsequent translocation of lysosomal hydrolases to the cytosol. FTY720-mediated disruption of the autophagic-lysosomal pathway led to increased levels of CD74, a potential therapeutic target in MCL that is degraded in the lysosomal compartment. This finding provided rationale for examining combination therapy with FTY720 and milatuzumab, an anti-CD74 mAb. Treatment of MCL cell lines and primary tumor cells with FTY720 and milatuzumab resulted in statistically significant enhanced cell death, which was synergistic in blastic variant MCL cell lines. Significant in vivo therapeutic activity of combination treatment was also demonstrated in a preclinical, in vivo model of MCL. These findings support clinical evaluation of this combination in patients with MCL.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antigens, Differentiation, B-Lymphocyte/metabolism , Histocompatibility Antigens Class II/metabolism , Lymphoma, Mantle-Cell/drug therapy , Propylene Glycols/pharmacology , Sphingosine/analogs & derivatives , Animals , Antibodies, Monoclonal, Humanized/administration & dosage , Antigens, Differentiation, B-Lymphocyte/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Autophagy/drug effects , Cell Death/drug effects , Cell Line, Tumor , Drug Synergism , Female , Fingolimod Hydrochloride , Gene Expression Regulation, Neoplastic/drug effects , Histocompatibility Antigens Class II/genetics , Humans , Immunoblotting , Immunosuppressive Agents/pharmacology , Lymphoma, Mantle-Cell/metabolism , Lymphoma, Mantle-Cell/pathology , Lysosomes/metabolism , Mice , Mice, SCID , Microscopy, Confocal , Microtubule-Associated Proteins/metabolism , Propylene Glycols/administration & dosage , Protein Transport/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Sphingosine/administration & dosage , Sphingosine/pharmacology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Mantle cell lymphoma (MCL) is a distinct histologic subtype of B cell non-Hodgkins lymphoma (NHL) associated with an aggressive clinical course. Inhibition of the ubiquitin-proteasome pathway modulates survival and proliferation signals in MCL and has shown clinical benefit in this disease. This has provided rationale for exploring combination regimens with B-cell selective immunotherapies such as rituximab. In this study, we examined the effects of combined treatment with bortezomib and rituximab on patient-derived MCL cell lines (Jeko, Mino, SP53) and tumor samples from patients with MCL where we validate reversible proteasome inhibition concurrent with cell cycle arrest and additive induction of apoptosis. When MCL cells were exposed to single agent bortezomib or combination bortezomib/rituximab, caspase dependent and independent apoptosis was observed. Single agent bortezomib or rituximab treatment of Mino and Jeko cell lines and patient samples resulted in decreased levels of nuclear NFkappaB complex(es) capable of binding p65 consensus oligonucleotides, and this decrease was enhanced by the combination. Constitutive activation of the Akt pathway was also diminished with bortezomib alone or in combination with rituximab. On the basis of in vitro data demonstrating additive apoptosis and enhanced NFkappaB and phosphorylated Akt depletion in MCL with combination bortezomib plus rituximab, a phase II trial of bortezomib-rituximab in patients with relapsed/refractory MCL is underway.
