Is the Era of Traditional Chemotherapy for Hodgkin Lymphoma Over?

Treatment of Hodgkin lymphoma (HL) has been one of the greatest success stories in oncology, with the invention of radiation therapy and combination chemotherapy (like the standard regimen of doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD]), leading to a cure for most patients. However, improved staging techniques and novel drugs are now challenging the role of a standard chemotherapy approach for all patients diagnosed with HL. In an education session at the 2018 ASH Annual Meeting, presenters discussed moving beyond the approach of “ABVD for everyone” with HL.

Maximizing Cure, Minimizing Toxicity

Recent advances in the staging and treatment of HL have had a “dramatic impact on the outcome of our patients,” presenter Alison Moskowitz, MD, from the lymphoma inpatient unit at Memorial Sloan Kettering Cancer Center in New York, said. “Now, our challenges are deciding how we best select patients for more or less intense therapy, finding the optimal time to use newer agents for HL, and determining the appropriate predictors of response and outcome in HL.”

In the first presentation, Ranjana Advani, MD, physician leader of the Lymphoma Clinical Care Program at Stanford Medicine in Palo Alto, California, tackled the question of when to escalate or de-escalate therapy.

“ABVD has been the gold standard of care, but this was in the CT era, when patients were not staged using a PET-CT,” she said, before outlining alternative approaches that take advantage of more intense upfront therapy. In Europe, for instance, intense chemotherapy with BEACOPP (bleomycin sulfate, etoposide phosphate, doxorubicin hydrochloride, cyclophosphamide, vincristine sulfate, procarbazine hydrochloride, prednisone) is a standard of care. While it is associated with a progression-free survival (PFS) of more than 80 percent, it also is associated with substantial toxicity (including hematologic events and sterility) that preclude its adoption in the U.S. Concerns about long-term toxicity also are warranted, particularly given the increased risk of secondary cancers observed after BEACOPP treatment.

“This is the dilemma of therapy,” Dr. Advani said. “Do you accept a slightly lower cure rate with an ABVD-like regimen, or do you go with the ‘big gun’ of BEACOPP and accept a slightly higher toxicity rate, but with higher efficacy?”

To help answer that question, interim PET imaging has emerged as a tool to distinguish “good vs bad” disease, she explained. Recent research evaluating whether patients can safely de-escalate treatment if they achieve PET-negative disease or whether they would have better outcomes with more intense therapy if they have PET-positive disease has shown favorable results.

Omitting bleomycin from the ABVD regimen after patients achieve PET negativity also allowed clinicians to minimize the pulmonary toxicity associated with this agent, without affecting clinical efficacy – a chief concern of therapy.

Given these results, Dr. Advani said, it seems clear that a “positive PET scan after two cycles of ABVD might warrant a change in treatment regimen, but prognostic factors other than PET might affect outcomes.” For example, patients with stage IV disease or an International Prognostic Score (IPS) between 4 and 7 are less likely to achieve PET-negative disease. Generally, however, “overall survival (OS) irrespective of approach has been excellent,” she concluded.

“This is the dilemma of therapy: Do you accept a slightly lower cure rate with an ABVD-like regimen, or do you go with the ‘big gun’ of BEACOPP and accept a slightly higher toxicity rate, but with higher efficacy?”

—Ranjana Advani, MD

Brentuximab Vedotin

The recent approval of brentuximab vedotin (BV) for the frontline treatment of stage III or IV classic HL also has changed the landscape, and its availability is one of the “building blocks for individualized therapy,” according to Dr. Moskowitz, who reviewed the potential impact of BV on the treatment of HL.

BV initially was approved for the secondline treatment of HL, “which is mainly where we use it at our institution, and where I think it has the potential to improve the PET-negative rate for patients going to transplant,” Dr. Moskowitz said. However, recent clinical trials data suggest that BV may have a role outside of advanced-stage disease, with the potential to reduce or eliminate the need for radiation therapy in early-stage disease and to offer a less toxic treatment regimen for older patients with HL.

Although her review of recent studies led her to believe that “we are not quite ready to use [frontline BV in early-stage HL] outside of a clinical trial,” Dr. Moskowitz said that it is a reasonable option for patients with high-risk disease who cannot receive bleomycin, including older patients with HL. Sequential BV+AVD – an approach that eliminates bleomycin and its associated pulmonary toxicity, as well as minimizes the toxicity seen with combined BV+AVD – is a promising option. Single-agent BV has been evaluated in this setting as well, but with disappointing PFS results.

Ongoing studies also are evaluating BV as a single agent or in combination with agents like bendamustine and the PD1 inhibitor nivolumab in patients with relapsed/refractory HL, and these approaches are starting to show durability of responses. For patients in remission following AHCT, BV maintenance is being evaluated, with data showing that it significantly reduced risk of relapse, but the effect was strongest in patients with certain high-risk characteristics. Longer follow-up is needed to determine which patients are the best candidates for this approach.

Of course, “[BV-containing combinations] may not be for everyone,” Dr. Moskowitz said. In the pivotal ECHELON trial, adding BV to ABVD conferred a 5-percent improvement in modified PFS; however, the results were difficult to interpret, given the observation that ABVD appeared to have performed worse in the trial’s North American population than other sites. As expected, the BV+ABVD regimen was associated with higher toxicity, specifically neuropathy and febrile neutropenia.

The trials’ experience with BV points to the need for improved risk-stratification techniques to optimize its use across disease settings. “Risk stratification now is based upon historical series and may not be optimal for today,” Dr. Moskowitz said. Bulky disease and interim PET scans have proven to be reliable prognostic indicators of patient outcome, but definitions of bulky disease are changing, as are methods for interpreting PET scans. Newer techniques, like metabolic tumor burden or circulating tumor DNA (ctDNA) levels, give clinicians a more sophisticated method for measuring tumor burden and “may represent a better way to risk-stratify patients,” she concluded.

Checkpoint Inhibition

In his presentation, Alex Herrera, MD, assistant professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California, also highlighted the challenges of using PET scans to guide treatment decisions in an era of novel treatment, particularly with the use of checkpoint inhibitors like nivolumab or pembrolizumab.

“What we’ve come to understand over many years is that there is extensive crosstalk between Reed Sternberg cells and nearby immune cells, which results in a niche that’s favorable for these Reed Sternberg cells,” he said, explaining the development of checkpoint inhibitors for HL. “PD1 normally serves to dampen immune response, but tumor cells can highjack this … and basically shut down the immune response against them.”

This interaction makes HL a “ripe target for PD1 blockade,” he continued, and agents like nivolumab and pembrolizumab are designed to interrupt PD1 signaling and restore an effective immune response.

In clinical trials, nivolumab and pembrolizumab have been associated with overall response rates ranging between 66 and 69 percent, with similar responses seen across BV- or AHCT-exposure groups. However, “after PD1 blockade, it is common to have new FDG lesions or growth of non-target lesions [on the scan], even though the overall tumor burden has reduced,” Dr. Herrera noted. This can complicate the treatment decision-making process, he added because, although survival was associated with depth of response, the OS curves in trials of these agents overlapped whether a patient had a complete response, partial response, or stable disease. “[These findings] suggest that PD1 blockade may persist after patients stop receiving therapy, and patients may benefit from treatment beyond progression,” he explained.

He cautioned careful interpretation of PET scans because patients might benefit from ongoing therapy.

For the future of PD1 blockade in the treatment of HL, Dr. Herrera stated that a main goal of research should be “trying to increase the proportion of patients who have a complete response to these drugs.” Immune checkpoint inhibitors have represented a major advance in HL therapy, he added, but “when we look at PFS curves, there appears to be an ongoing risk of relapse” that also needs to be addressed.

Given the low curative potential of checkpoint inhibitor monotherapy observed in clinical trials, Dr. Herrera believes that the optimal role of checkpoint inhibitors is as part of a combination therapy and that incorporating checkpoint blockade earlier might improve depth of responses.

Of course, with so many new options available, and some data suggesting a benefit with prolonged treatment of nivolumab, members of the audience questioned whether it is advisable to replace ABVD, a therapy with known efficacy and toxicity profiles, with approaches that have unknown toxicities – including significant financial toxicity.

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