Bortezomib and gemcitabine in relapsed or refractory Hodgkin's lymphoma

Mendler, Jason H.; Kelly, Jennifer L.; Voci, Susan; Marquis, Diana; Rich, Lynn; Rossi, Randy; Bernstein, Steven H.; Jordan, Craig T.; Liesveld, Jane L.; Fisher, Richard I.; Friedberg, Jonathan W.

doi:10.1093/annonc/mdn365

Cited by 40 publications

(24 citation statements)

References 28 publications

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“…No clinical benefit was observed as single agent or in combination with gemcitabine or dexamethasone. [15][16][17] The trial combining bortezomib and dexamethasone was prematurely closed after 12 patients due to lack of response. Serum was available from three patients who received treatment according to the protocol until the end of study.…”

Section: Resultsmentioning

confidence: 99%

TNF-α-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species

Vahdat¹,

Reiners²,

Simhadri³

et al. 2009

Leukemia

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Combinations with proteasome inhibitors are currently being investigated to improve the therapy of hematological malignancies. We previously found that proteasome inhibition by bortezomib failed to sensitize anti-CD30 antibody (Ab)-based lymphoma cell killing. In this study, we demonstrate in L540 Hodgkin's lymphoma cells that proteasome inhibition not only communicates apoptosis but also more rapidly causes a loss of CD30 antigen from cell membrane and a simultaneous release of soluble CD30, a targeting competitor. This shedding was catalyzed by the tumor necrosis factor (TNF)-a-converting enzyme (TACE, ADAM17) and blocked by the ADAM17-selective inhibitor, Ro32-7315. In parallel with CD30 shedding, bortezomib caused the generation of reactive oxygen species (ROS). As apoptosis and shedding were inhibited by the radical scavenger, N-acetyl-L-cysteine, ROS might have a pivotal function in both effects. In contrast, the pan-caspase inhibitor, zVAD-fmk, blocked bortezomib-induced apoptosis but not CD30 shedding, and Ro32-7315 blocked shedding but allowed apoptosis. This suggests independent terminal signaling pathways that are conflicting in Ab-based immunotherapy. Consequently, shedding inhibition substantially improved the synergistic antitumor efficacy of the human anti-CD30 Ab, MDX-060, and bortezomib. As proteasome inhibition also stimulated loss of TNF receptors, interleukin-6 receptor and syndecan-1 in different leukemia and lymphoma cell lines, we concluded that proteasome inhibition might impede targeted therapy against antigens susceptible to shedding.

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Section: Resultsmentioning

confidence: 99%

TNF-α-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species

Vahdat¹,

Reiners²,

Simhadri³

et al. 2009

Leukemia

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“…The association of bortezomib and gemcitabine is less active and has higher toxicity in relapsed HL as against other current regimens. It can produce severe liver toxicity: a grade III transaminase increasing was showed in 3 of 18 patients [50].…”

Section: Findings Of Evidence-based Medicinementioning

confidence: 99%

Liver Involvement in Hodgkin's Lymphoma: Types of Injuries and Therapeutic Implications

Mihăilă

2017

IJPPE

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Abstract. The hepatocytolysis raises questions on following therapeutic conduct when it occurs during chemotherapy for Hodgkin's lymphoma, expression of its liver toxicity. But the onset of primary liver Hodgkin's lymphoma, including the form manifested by acute liver failure, poses even greater problems, as in the case of occurrence of vanishing bile duct syndrome -expression of a paraneoplastic syndrome, hemophagocytic lymphohistiocytosis, peliosis hepatis or association of lymphoma with infection with hepatitis viruses or human immunodeficiency virus or different autoimmune diseases. This review summarizes the clinical experience acquired on the relationship between Hodgkin's lymphoma and liver, from the point of view of clinical manifestations, used treatments and clinical evolution. Suggestions on the course of treatment in patients with Hodgkin's lymphoma and liver damage have been formulated starting from the metabolism and elimination of chemotherapy drugs and taking into account the clinical experience of published clinical trials and cases. This review is a synthesis of knowledge obtained in this field, during the time, of therapeutic possibilities and limits, and formulates potential future milestones for research.

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“…The ORR for all patients was only 22%, with significant grade 3 transaminase elevations; based on these results, this regimen was deemed to be less active and more toxic than other currently available treatments. 35 Heat shock proteins (HSPs) are cellular chaperone proteins that perform essential functions, such as protein folding, assembly, and transportation. They are overexpressed by HRS cells and are known to promote HRS cell survival via ERK, Akt, and NF-κB.…”

Section: Intracellular Survival Pathway Targetsmentioning

confidence: 99%

Targeted Therapy in Relapsed Classical Hodgkin Lymphoma

Dinner

Advani

2013

J Natl Compr Canc Netw

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Although frontline treatment of advanced Hodgkin lymphoma (HL) produces high cure rates, disease either will not respond to or will relapse after initial therapy in approximately a quarter of patients. Many patients with disease relapse can be successfully salvaged with second-line chemotherapy followed by autologous stem cell transplantation (ASCT). Patients whose disease relapses after ASCT are rarely cured. A unique pathophysiologic feature of HL is that the malignant Reed-Sternberg (HRS) cell is rare and resides within a microenvironment of inflammatory and immunerelated cells. The recent FDA approval of the anti-CD30 antibodydrug conjugate brentuximab vedotin (BV) for patients with either primary refractory HL or those whose disease relapses after ASCT represents a major advance in therapy. This article focuses on BV and other novel agents that target the HRS cell surface, intracellular signaling pathways, and tumor microenvironment. (JNCCN 2013;11:968-976) NCCN: Continuing Education Accreditation StatementThis activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center`s Commission on Accreditation.This activity is accredited for 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/ node/26206; and 4) view/print certificate. Learning ObjectivesUpon completion of this activity, participants will be able to:• Describe the rationale for targeted therapy in patients with relapsed classical HL• Discuss novel agents that target the rare malignant ReedSternberg (HRS) cell surface, a unique pathophysiologic feature of HL

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Bortezomib and gemcitabine in relapsed or refractory Hodgkin's lymphoma

Abstract: The combination of gemcitabine and bortezomib is a less active and more toxic regimen in relapsed HL than other currently available treatments. It poses a risk of severe liver toxicity and should be pursued with caution in other types of cancer.

Cited by 40 publications

References 28 publications

TNF-α-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species

TNF-α-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species

Liver Involvement in Hodgkin's Lymphoma: Types of Injuries and Therapeutic Implications

Targeted Therapy in Relapsed Classical Hodgkin Lymphoma

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