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Sunday, October 25, 2015

Hodgkin Lymphoma: Frontline Brentuximab Monotherapy Promising for Elderly Patients (Online First)


Older patients with Hodgkin lymphoma (HL) tend to do poorly when compared with their younger counterparts due to significant comorbidities and treatment-related toxicity from conventional chemotherapy regimens. Since up to 20 percent of newly diagnosed patients are estimated to be age 60 or older, the lack of safe yet effective treatment options for this population is a growing issue.

However, a small prospective, Phase II open-label study has found that brentuximab vedotin may be able to help older patients with HL who have trouble tolerating more harsh chemotherapy drugs. The study, now online ahead of print in Blood (doi 10.1182/blood-2015-06-644336) used the antibody-drug conjugate as frontline monotherapy in 27 elderly HL patients located at 16 clinical sites in the U.S. in order to evaluate the drug's efficacy and safety.

 The team, led by Andres Forero-Torres, MD, Professor of Hematology and Oncology and Senior Scientist in the Comprehensive Cancer Center at the University of Alabama at Birmingham School of Medicine, reported that the objective response rate was 92 percent, with 19 patients achieving a complete response (73%) and five attaining a partial remission (19%).


While patients were able to tolerate a median of eight cycles of brentuximab vendotin, all experienced at least one adverse event. The most commonly reported adverse events were neuropathy, fatigue, and nausea, but most were mild or moderate in severity. The authors concluded that brentuximab vendotin should be investigated further as a safe option for elderly HL patients, either as a single agent or in combination with other chemotherapy drugs.

“We took patients who were older than 60 and not candidates for chemotherapy due to comorbidities or who did not want to receive chemotherapy, and we treated them with brentuximab vedotin as a single agent,” Forero-Torres said. “We were able to show in this small but significant population of patients that older patients tolerated brentuximab vendotin very nicely. We found very high rates of response--almost everybody had a response, and a very good percentage had a complete remission.”


Brentuximab vendotin was granted accelerated approval by the U.S. Food and Drug Administration in 2011 for treatment of HL patients after failure of either autologous stem cell transplantation or at least two prior chemotherapy regimens for those who were not candidates for transplant. Earlier this year, it was also approved as a consolidation therapy following autologous stem cell transplantation in HL patients at risk of relapse or disease progression (OT 9/10/15 issue).

Now, brentuximab vendotin is being explored as an alternative drug for elderly patients, who typically have more comorbidities and are more susceptible to chemotherapy toxicities. Forero-Torres and his colleagues had previously performed a retrospective evaluation of brentuximab vendotin monotherapy in a similarly aged group of patients with relapsed/refractory HL. That study showed an objective response rate of 56 percent with a complete response rate of 38 percent and median overall survival time of 12.4 months.

Comments from John Leonard

 “The issue is that the standard therapies in elderly and frail patients do have significant toxicity, so trying to come up with something that has less toxicity, if it can also be effective, is valuable,” said John P. Leonard, MD, the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medical College. “Brentuximab vedotin has less toxicity against the lungs, which is an issue with bleomycin, and less in the way of low blood count which you have in standard chemotherapy. It also avoids the cardiac toxicity of standard treatment as well.”

Study Details

After their initial retrospective analysis, the researchers decided to investigate further with the first-ever prospective study of brentuximab vedotin therapy in older patients with HL. Subjects were age 60 or older with classical HL, were previously untreated, and were either deemed ineligible for or decided against having frontline conventional combination treatment (e.g., ABVD, BEACOPP).


Each patient received 1.8 mg/kg of brentuximab vedotin intravenously every three weeks for up to 16 doses. Data including imaging scans (e.g., CT and PET scans) and safety evaluations were collected from October 2012 to March 2015 at 16 centers in the U.S.

The median age of the patients in the study was 78 (range of 64 to 72), although one patient was excluded from efficacy analysis due to a history of having nodular lymphocyte-predominant HL. Among the remaining patients, the objective response rate was 92 percent--19 patients (73%) had a complete remission, five (19%) had a partial remission, and the remainder had stable disease.

Toxicity Profile

After an average of eight cycles of brentuximab monotherapy, the most common adverse events leading to dose modifications were those due to peripheral neuropathy. Fourteen subjects required dose delays, and 11 needed permanent dose reductions to 1.2 mg/kg. Eight patients had treatment-related Grade 3 neuropathy events. Other commonly reported adverse events were fatigue (12 patients), nausea (12 patients), and peripheral edema (10 patients). However, most of these events were Grade 1 or 2 in severity.

“The toxicity profile for brentuximab vedotin monotherapy was not as bad as that for traditional chemotherapy,” Forero-Torres said. “If you have a patient with all these medical comorbidities, and you know the patient cannot be treated with traditional chemotherapy--ABVD can be a toxic combination--brentuximab vedotin can be a good alternative as a single agent for those cases.”

The median duration of objective response was 9.1 months for all responders, 4.1 months for partial responders, and 9.2 months for those who had a complete response. Overall survival for this group ranged from 4.6+ to 24.9+ months, with the median not yet reached.

Prolonging Response

“The only limitation of the trial is that some of these responses didn't last for a long time,” he said. “So the idea is, what else can we do to improve the chances that the remission with stay and not disappear? That's exactly what we're trying to do now. But the responses are still very significant, and brentuximab vedotin may open the door for treatment of older patients if the patient is not eligible for conventional chemotherapy.”

Forero-Torres noted that the researchers are currently looking for a partner drug for brentuximab vedotin--most likely from the ABVD combination (doxorubicin, bleomycin, vinblastine, vacarbazine)--that will prolong responses so that patients can stay in remission longer.


Leonard agreed about the need to strengthen the durability of responses with the addition of another agent: “I think brentuximab vedotin will be combined with some component of ABVD, but not all of them, in trying to reduce toxicity while still trying to maintain or increase efficacy. Most patients in this study progressed within roughly a year's time, so something more beyond just using this as a single agent is going to be necessary.”