BRENDUXIMAB FOR HODGKIN LYMPHOMA

In patients with relapsed or refractory Hodgkin's lymphoma, brentuximab vedotin (Adcetris, Seattle Genetics) might be an effective first salvage therapy.

The product, a novel agent that targets CD30, is currently approved for use in patients with Hodgkin's lymphoma after the failure of autologous stem cell transplantation (ASCT) or the failure of at least two multiagent chemotherapy regimens in patients not candidates for ASCT.

A phase 2 trial, published online February 13 in the Lancet Oncology, highlights the importance of a negative PET scan.

"The findings imply that attaining PET-negative status is the most important action item for relapsed/refractory patients before transplant," said investigator Alison J. Moskowitz, MD, from the Memorial Sloan Kettering Cancer Center in New York City.

"It does not matter whether we use one or two salvage regimens to achieve that goal," she told Medscape Medical News.

"This is arguably the ideal setting in which the drug could be used because it has been shown to have substantial activity as a monotherapy," write Umberto Tirelli, MD, and Michele Spina, MD, from the Department of Medical Oncology at the National Cancer Institute of Aviano in Pordenone, Italy, in an accompanying comment. They note that there are no data on the use of brentuximab vedotin in this patient population.

"We do not need to use a toxic second-line regimen. This is a new effective and safe regimen for salvage/relapsed Hodgkin's lymphoma, and has the potential to improve cure rates for patients with Hodgkin's lymphoma, in particular, if used in the first-line setting," Dr Tirelli told Medscape Medical News.

Importance of Negative PET Scan

In their study, Dr Moskowitz and her colleagues evaluated 45 patients with relapsed or refractory Hodgkin's lymphoma. All were treated with weekly brentuximab vedotin alone for 3 weeks of every 28-day cycle for two cycles. The results of an interim PET scan determined the next step.

Patients scoring 1 or 2 on the 5-point Deauville criteria, indicating a negative PET scan, proceeded to high-dose therapy followed by ASCT.

The other patients went on to receive an augmented regimen of ifosfamide, carboplatin, and etoposide (augICE).

The primary end point of the study was the PET-negativity rate after brentuximab vedotin alone or brentuximab vedotin followed by augICE. Secondary end points included overall survival, event-free survival, and toxicity.

After two cycles of brentuximab vedotin, PET results were negative for 12 (27%) of the 45 patients. After augICE therapy, PET results were negative for 22 (69%) of the remaining 32 patients (one patient withdrew from the study).

Overall, 76% of patients achieved PET-negativity before transplantation.

This is a significant achievement, noted Dr Tirelli. "PET-negativity after induction chemotherapy is the main prognostic factor for survival in these patients."

At a median follow-up of 20.1 months, the overall event-free survival rate was 80%. For patients who achieved PET-negativity, there was no difference in event-free survival between patients treated with brentuximab vedotin alone and those treated with augICE (92% vs 91%).

For patients who underwent ASCT after a positive PET result, the event-free survival rate was 46%.

Adverse events related to brentuximab vedotin were typically grade 1 or 2 fatigue, hyperglycemia, rash, or sensory neuropathy.

Brentuximab vedotin was associated with serious adverse events, including one hospitalization due to hyperglycemia, hypocalcemia, and hypomagnesemia. Twenty-six serious adverse events occurred in patients with brentuximab vedotin and augICE. These included neutropenic fever, vomiting, anorectal infection, and skin infection. One patient died after high-dose therapy followed by ASCT due to multifocal leukoencephalopathy.

"Most therapies that prepare patients for transplantation are toxic regimens. Brentuximab vedotin seems to be less toxic than the standard salvage therapies that are currently used, and enables patients to proceed to transplantation," Dr Tirelli explained.

He noted, however, that the patient numbers are small and that some patients with early-stage disease might have been effectively rescued with radiation alone.

Dr Moskowitz and her colleagues agree, and say that their sample size did not enable them to tease out factors that could have predicted response to brentuximab vedotin.

However, Dr Moskowitz indicated that their results are supported by similar observations reported at the 2014 American Society of Hematology meeting (abstract 501).

She said that brentuximab vedotin in combination with bendamustine has also been shown to be successful as salvage therapy for patients with relapsed or refractory Hodgkin's lymphoma.

Clinical Significance

The study established that PET-negativity before transplantation is associated with significantly better clinical outcomes, and that brentuximab vedotin is a better first salvage therapy than other more toxic regimens.

Although only 27% of patients achieved PET-negativity after treatment with brentuximab alone, Hodgkin's lymphoma was sensitive to brentuximab vedotin alone in 96% of patients, the investigators report.

"Brentuximab vedotin is a suitable agent for inclusion in novel combinations to further improve the proportion of patients who are PET-negative at an interim PET scan and enable more patients to avoid ICE or other more toxic regimens," the investigators write.

In fact, "PET-negativity can be used as a surrogate to test new promising regimens," Dr Moskowitz told Medscape Medical News.

If patients do not achieve PET-negativity with less toxic therapy, subsequent chemotherapy remains a good option to achieve PET-negativity, she said.

A more exciting prospect is the potential for brentuximab vedotin to elicit a cure in patients with relapsed or refractory Hodgkin's lymphoma. The investigators seem to think it might just do that.

"We postulate that a select group of relapsed patients who originally present with early-stage Hodgkin's lymphoma and receive short-course chemotherapy alone are potential candidates for such an approach, provided they achieve PET-negative status after salvage chemotherapy and the site can be irradiated," Dr Moskowitz and colleagues explain.

But they concede that "in view of the high proportion of patients who achieved PET-negative status with sequential PET-adapted salvage therapy, randomized trials are warranted" to determine whether high-dose therapy followed by ASCT can be avoided in favorable subsets of PET-negative patients.

Dr Tirelli said he agrees that brentuximab vedotin can improve cure rates for patients with Hodgkin's lymphoma. For all disease stages, the cure rate is 70%, he told Medscape Medical News. "With brentuximab vedotin, we have an opportunity to improve this by another 15%."

Currently, brentuximab vedotin is not approved for salvage therapy in either the United States or Europe. Dr Tirelli said he is hopeful that studies such as this one and others ongoing in the first-line setting for patients with newly diagnosed Hodgkin's lymphoma will eventually lead to the replacement of the standard doxorubicin, bleomycin, vinblastine, and dacarbazine regimen with brentuximab vedotin.

Dr Moskowitz said she hopes that evidence from this and other studies will prompt the National Comprehensive Cancer Network to recommend brentuximab vedotin as salvage therapy for relapsed on refractory Hodgkin's lymphoma in its next update.

The study was supported by Seattle Genetics. Dr Moskowitz and some of her coauthors report financial relationships with pharmaceutical companies. Dr Tirelli has disclosed no relevant financial relationships.

Lancet Oncol. Published online February 13, 2015. Abstract, Comment