US Versus European Opinions on Upfront Therapy in Hodgkin Lymphoma

Ranjana Advani, MD

United States’ versus European perspectives on the inclusion or exclusion of bleomycin in chemotherapy combinations for advanced Hodgkin lymphoma (HL), along with the value of interim positron emission tomography (PET), were discussed in a dual presentation at the 2018 Pan Pacific Lymphoma Conference (PPLC).¹

Ranjana Advani, MD, of Stanford University School of Medicine, and Andreas Engert, MD, of the University Hospital of Cologne, Germany, discussed contrasting views on the success of treatment, relative toxicities, and costs, basing their opinions on recent and ongoing investigations.

Comparing trials and results, Advani generalized that, “If you just look at patients with an interim PET, you can expect about 80% to 85% progression-free survival [PFS], and overall survival [OS] in excess of 90%, irrespective of what you do. Advani reviewed a core set of interim PET trials—the US Intergroup Trial, RATHL, and GITIL/FIL HD 0607. These tested PET-driven therapy adjustments following 2 cycles of ABVD, or doxorubicin, bleomycin, vinblastine, dacarbazine.

“If they’re PET-positive [for disease] at the interim scan and you escalate therapy or you transplant or they’re continued on BV-AVD [brentuximab vedotin plus doxorubicin, vinblastine and dacarbazine], I think the results are also strikingly similar [across trials], where the PFS is in the 60% to 65% range and the overall survival, again, is in excess of 85%,” Advani said.

She said the results of these trials favor de-escalation of dosage upon negative interim PET scans, whereas a positive scan following 2 cycles of ABVD might warrant a regimen change. She concluded that omitting bleomycin after a negative PET minimizes toxicity without affecting clinical efficacy.

“This is now reflected in the current version of the NCCN guidelines, where the PET-adapted approach is the preferred approach, where you’re starting with ABVD and adding brentuximab with AVD,” she said. Engert agreed that standard of care in Europe is now PET-driven “and it allows us to make a smarter choice of treatment for these patients [with HL].”

Engert discussed the BEACOPPesc regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), which was developed by the German Hodgkin Study Group (GHSG) to deliver a stronger chemotherapy dose compared with ABVD in advanced-stage HL.

He expressed disappointment with the utility of findings from the phase III ECHELON-1 trial, which investigated brentuximab vedotin (BV, Adcetris) as a less-toxic substitute for bleomycin. The “modified PFS [mPFS]” used in ECHELON-1 defined a Deauville score of 3 as a less-than-complete remission, in a change from standard that has mystified some physicians. “It’s not something we can compare with all of the trials that have been done, both in the United States and Europe,” Engert said.

Advani remarked that although a Deauville 3 was considered positive for progression in ECHELON-1, the BV-AVD combination in that study was associated with a roughly 5% improvement in mPFS over standard of care.

In addition, Engert said, BV “is not what most countries in Europe would use because it’s much more expensive.”

Huntington et al presented a poster at the 2018 ASCO Annual Meeting evaluating the relative cost of adding BV to stage III/IV HL treatment, as a replacement for bleomycin in the ABVD combination. The group found that adding BV to first-line therapy boosted lifetime treatment costs to $334,863 from $193,780, which they said would not be cost-effective under current drug pricing. However, they said that implementation of indication-specific pricing for BV could move prices downward by 40% to 60%, within an acceptable range.²

However, Advani remarked that the poster did not fully explain the cost effectiveness of dropping bleomycin and substituting it with BV. “It raises the question of whether alternative treatment schedules or combinations could minimize toxicities while achieving the same or better results. Similarly, identifying the patient population most likely to benefit from BV may lessen the cost of the toxicity burden,” she said.

Even so, the systemic toxicities of bleomycin, which is strongly linked to pulmonary disorders, are not to be discounted, a physician audience member stated at the PPLC event. “In all of the things I do on a day-to-day basis, I find that to be one of the most nightmarish parts of practicing oncology,” he said, noting the unpredictable nature of bleomycin adverse events that can result in very rapid death, not to mention serious legal entanglements, which he said have befallen some of his peers.

Advani responded that an interim PET-adapted approach would enable physicians to discontinue bleomycin in at least 80% of PET-negative cases, “so that would mean pulmonary events are substantially lower in that subset, but for patients who are PET positive, that’s the subgroup where if you escalate to BEACOPP you’re giving them more bleomycin. I think identifying the group of patients who would maximally benefit makes sense. If you’re in a situation where you cannot do an interim PET scan or you have concerns about lung toxicities, then it could be the right choice to give them BV-AVD right from the get-go and not worry about it.”

Engert responded that he did not see a place for bleomycin if it could be avoided. “I think actually bleomycin should not be given at all. From the trials we’ve seen so far, it does not really add anything, just toxicity.” The catch is that BV adds toxicity, too. “That’s why we [in Europe] are a little more hesitant. The most important issue, certainly, is efficacy, and here BEACOPP is certainly much more effective than AVD or [BV-AVD],” he said.

Ultimately, Engert said, “the use of checkpoint inhibition might help us to detoxify these treatments so that less chemotherapy is needed, but we need more trials to really demonstrate that. But I’m convinced that in the future these antibodies will increasingly replace chemotherapy and/or radiotherapy in Hodgkin lymphoma.”

References

1. Advani R, Engert A. Hodgkin lymphoma: upfront therapy in Germany/advanced Hodgkin lymphoma: upfront therapy in the US. In: Proceedings from the 2018 Pan Pacific Lymphoma Conference; July 16-20, 2018; Maui, Hawaii.
2. Huntington SF, Von Keudell GR, Davidoff AJ, et al. Cost-effectiveness analysis of brentuximab vedotin with chemotherapy in newly diagnosed stage III/IV Hodgkin lymphoma. J Clin Oncol. 2018;36 (suppl; abstr 6609).