Brentuximab Vedotin and Panobinostat: New Drugs for Hodgkin's Lymphoma—Can They Make One of Medical Oncology's Chemotherapy Success Stories More Successful?
Authors: George P. Canellos
Journal: Journal of Clinical Oncology (2012)

The chemotherapy of Hodgkin’s lymphoma (HL) is indeed an early success story in medical oncology. The pioneering effort by the National Cancer Institute to develop the MOPP regimen (nitrogen mustard, vincristine, procarbazine, prednisone) was the model for combination chemotherapy for cancer. This was followed by the Milan-inspired regimen, ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) which, because of its lower degree of toxicity, has emerged as a current standard. However, patients who relapse after ABVD motivated the German Hodgkin Study Group to develop the more intensive regimen of escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), which has shown an even higher response rate and progression-free survival in the range of 85% to 87% compared with approximately 75% with ABVD. Because of effective salvage, overall survival among these regimens has been variable and, in some cases, equivalent. Although there have been several other regimens containing known active agents, those mentioned are the more widely used and studied. How then could new active agents best be incorporated into the management of HL to increase an already high cure rate? Brentuximab vedotin was recently approved by the US Food and Drug Administration for the treatment of HL relapsing from salvage autologous stemcell transplantation (ASCT) or failure of two multiagent regimens in patients not candidates for ASCT. The approval was based on the results of a phase II trial of Younes et al. It is an immunotoxin of antiCD30 linked to an antitubulin toxin, monomethyl auristatin E directed to CD30-bearing lymphomas, which include HL as well as anaplastic large T-cell lymphoma (ALCL). In contrast to the action of the unlinked antibody rituximab, which is active in CD20-positive non-Hodgkin’s lymphoma, the unlinked antiCD30 antibody is inactive in HL. The linkage of cytotoxic chemicals or radioisotopes to specific monoclonal antibodies is not new in the field of lymphoma therapy. Their impact on the disease has been variable and difficult to place in the management of especially the non-Hodgkin’s lymphomas. The high order of activity and the absence of significant myelosuppression have the potential to incorporate brentuximab vedotin in several therapeutic settings for HL and, by extension, ALCL. The data for tumor response presented in the current trial of Younes et al is remarkably high and may be the most active salvage agent ever tested in relapsed and/or refractory HL. The reported response of 75% with 34% complete remissions in that population bespeaks quite an active agent. The previously introduced new active agent for HL was gemcitabine, introduced in 2000 with less singledrug activity than brentuximab vedotin. In the initial two trials, there was a 37% response rate with 8.5% complete remissions. However, the question and challenge for clinical research remains: how can these agents best be combined with known active chemotherapeutic agents to improve initial response rate and durability, especially in patients with advanced-stage disease. Ultimately, the question is can these added agents result in an improved overall survival? These are expensive new drugs, and the justification for their use will ideally be evidence-based derived from randomized clinical trials. The other new agent, panobinostat, is representative of a new family of drugs, histone deacetylase inhibitors. Several of these agents are in early clinical trials. One, vorinostat, has already received US Food and Drug Administration approval for the treatment of cutaneous T-cell lymphoma. In contrast to brentuximab vendotin, panobinostat is an oral drug that was administered three times a week in 21-day cycles. The exact mechanism of action in HL is not known, but alteration of histone proteins and their effect on proliferation and survival pathways are assumed. There was notable activity with a response rate of 21.7% by independent central review and 27% by investigator assessment. However, there was some reduction in tumor size in 74% of patients. The median response duration was 6.1 months with a wide range of 0 to 17.2 months. The most striking toxic effect was grade 3 to 4 thrombocytopenia in 79% of patients with some neutropenia (21%) and anemia (21%). This order of myelotoxicity would certainly limit the ability to combine panobinostat with other myelotoxic drugs. The relatively low response rate and its toxicity will diminish the enthusiasm for this drug. It does not suggest, however, that other histone deacetylase inhibitors in the future may be more active and less toxic. But at the present time, this editorialist sees a lesser role for panobinostat compared with brentuximab vedotin in the treatment of HL. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 18 JUNE 2