Frontline Brentuximab Vedotin Leads to High Response Rate for Older Hodgkin Lymphoma Patients

Older patients with Hodgkin lymphoma (HL) tend to have worse outcomes than younger patients when treated with conventional chemotherapy regimens, likely due to a different biology and a higher comorbidity burden. In addition, this patient population tolerates conventional initial therapy poorly – resulting in under-treatment and making evaluation of novel, less-toxic treatment strategies necessary.

Previous studies of brentuximab vedotin have reported promising results in older patient populations with relapsed/refractory HL, leading Andres Forero-Torres, MD, from the University of Alabama at Birmingham, and colleagues to evaluate the efficacy and safety of brentuximab vedotin, a CD30-directed antibody drug conjugate, as frontline therapy in patients 60 years or older with classic HL.

“Although the incidence of Hodgkin lymphoma is elevated in individuals ≥65 years old relative to younger patients and is expected to increase by 70 percent by 2030,” Dr. Forero-Torres and authors observed, “few clinical trials specifically enroll older adults.”

Twenty-seven patients from 16 clinical sites in the United States were included in the phase II, open-label study, with 74 percent (20 patients) coming from community-based sites. The median age of patients was 78 years (range, 64-92 years); 17 patients were 75 years of age or older, and five patients were 85 years or older. Most patients had stage three or four HL. Data were collected on patients from October 2012 to March 2015; some patients are still receiving follow-up care.

All patients were treatment-naïve and either ineligible for frontline conventional chemotherapy or had declined chemotherapy after being informed of the potential benefits and risks of treatment.

“Since chronologic age alone does not capture the heterogeneity present within an elderly population, baseline geriatric assessment was conducted to more fully characterize the patients,” the authors added, which included an evaluation of physical function, comorbidities, nutritional status, cognition, psychological state, and social activity/support.

The study’s primary objective was to assess the overall response rate (ORR). Secondary objectives included duration of response, complete remission (CR), progression-free survival (PFS), resolution of B symptoms, safety and tolerability, and pharmacokinetics.

“Eighty-one percent of patients were impaired in at least one aspect including physical performance problems,” the authors noted, “[illustrating] the relatively fragile condition of the patients enrolled on this study.”

Patients received 1.8 mg/kg of brentuximab vedotin intravenously every three weeks for up to 16 doses. Patients who demonstrated clinical benefit could continue treatment beyond 16 cycles until disease progression, unacceptable toxicity, or study closure. If toxicity occurred, dose reductions to 1.2 mg/kg and treatment delay of up to three weeks were allowed depending on the type and severity of toxicity.

Patients received a median of eight cycles of treatment, with four patients completing 16 cycles and one completing 23 cycles.

Computed tomography and PET scans were conducted at baseline, at cycles 2 and 8, and again at the end of treatment.

Of the 26 evaluable patients, the ORR was 92 percent (n=24), exceeding the 25 percent ORR considered to represent a threshold for clinical benefit in this patient population. In addition, 73 percent of patients (n=17) achieved CR and 19 percent (n=5) achieved partial remission. The remaining two patients achieved stable disease (TABLE).

At the time of analysis, the median duration of objective response was 9.1 months (range = 2.8-20.9 months), 4.1 months for partial remission (range = 3.9-10.3 months), and 9.2 months for CR (range = 2.8-20.9 months). Median PFS was 10.5 months (range = 2.6-22.3), while median OS had not been reached.

Most patients (89%) experienced treatment-emergent peripheral neuropathy events. Other commonly reported treatment-related adverse events included fatigue (44%) and nausea (44%), both of which were generally consistent with the known safety profile of brentuximab vedotin. However, the incidence of grade three neuropathy events was “relatively high,” at 30 percent overall – particularly among patients with the known risk factors of diabetes and/or hypothyroidism.

“Brentuximab vedotin monotherapy may provide a frontline treatment option for older patients who are unable to tolerate conventional multi-agent chemotherapy,” the authors concluded. There were some limitations to note, though, including the single-arm and open-label (rather than randomized and blinded) design, the relatively small number of patients in the evaluable population.

“An attempt to improve response duration is currently being tested in additional treatment arms in this ongoing study, in which elderly Hodgkin lymphoma patients receive a combination of brentuximab vedotin with either bendamustine or dacarbazine,” they added.


Reference

Forero-Torres A, Holkova B, Goldschmidt J, et al. Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older. Blood. 2015. [Epub ahead of print]

TABLE. Best Clinical Response to Frontline Brentuximab Vedotin Monotherapy
 

Number of patients (N=26)

Percentage

95% Confidence Interval

Objective response rate (complete remission + partial remission)

24

92%

74.9-99.1

Best clinical response
Complete remission

19

73%

52.2-88.4

Partial remission

5

19%

N/A

Stable disease

2

8%

N/A

Disease control rate 26 100% 86.9-100

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