World Lymphoma Day: Advances in Therapy Signal A New Standard of Care for Patients with Hodgkin or Non-Hodgkin Lymphoma

The field of hematology has never had more changes than in recent years. This year alone brought several new studies that may significantly alter the lives of patients with Hodgkin disease and non-Hodgkin lymphoma (NHL).

The most recent report from the ECHELON-1 study (NCT01712490), which was first published in the New England Journal of Medicine in 2018, confirmed for the first time that we now should have a new standard of care for patients with advanced Hodgkin lymphoma.¹ This international study compared the unchallenged standard we have used since the 1970s of ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) with A+AVD (brentuximab vedotin [Adcetris], doxorubicin, vinblastine, and dacarbazine).

This was a large international phase 3 study of 1334 patients who early on clearly showed a progression-free survival (PFS) advantage over patients who received A+AVD when initially reported at 82.1% (95% CI, 78.9%-85%) vs 77.2% (95% CI, 73.7%-80.4%), respectively (HR, 0.77; 95% CI, 0.60-0.98; P = .04).

When the study was first reported, however, there was significant discussion of the chosen end point, which was a modified PFS, and the fact that there was no survival advantage observed. In addition, patients clearly had an increased risk of neutropenia at 58% in the A+AVD group vs 45% of the patients receiving ABVD, and with febrile neutropenia at 19% and 8%, respectively. Moreover, the costs to the system were a major concern.

As such, this treatment was not widely adopted at this stage. Despite the PFS improvements being confirmed during the 5-year follow-up study, many continued to consider ABVD the standard of care.² But now, the 6-year overall survival (OS) follow-up data presented by Stephen M. Ansell, MD, PhD, and his collaborators should settle the argument as to whether there should be a new standard of care in town.

The latest results demonstrate an OS advantage for patients who receive AAVD, with an improvement of 4.5 percentage points with A+AVD over ABVD at 93.9% (95% CI, 91.6%-95.5%) vs 89.4% (95% CI, 86.6%-91.7%), respectively.³ Two other key findings showed that there was no excess in secondary cancers and that pregnancies were still possible for patients on this treatment, which will help relieve these potential concerns.

Some questions remain. For instance, the costs of adding brentuximab vedotin are not insignificant, and neurotoxicity and neutropenia are real issues in using this regimen. Brentuximab vedotin should remain part of the initial therapy for most patients with advanced stage Hodgkin lymphoma, and I suspect that future studies will investigate whether there are ways to incorporate this in a less toxic manner. For now, it should be considered a new standard of care.

For patients with NHL, many profound changes are also occurring. One cannot turn around without a new CAR T-cell trial and it seems obvious that immune effector cells, like CAR T or bispecific T-cell engagers (BITE), will change how we treat patients with disease relapse. There are new trials that suggest patients who relapse within a year of initial therapy benefit more from CAR T cells than a standard autologous transplant.⁴ Although exciting, it is not surprising in some ways because patients with relatively refractory disease have never done well with autologous transplants.

However, what I think has the better potential to make a difference is changes to the upfront treatment of patients with diffuse large B-cell lymphoma (DLBCL). We now have a true challenger to R-CHOP (rituximab, cyclophosphamide, hydroxydaunomycin, vincristine sulfate [Oncovin], prednisone), which has held the mantle of standard of care since the 1990s.

The phase 3 POLARIX trial (NCT03274492) incorporated polatuzumab vedotin into up-front therapy and has many analogies to the brentuximab data.⁵ It too introduces an antibody-drug conjugate (ADC) therapy to the backbone of chemotherapy, and data published in the New England Journal of Medicine compared results of 879 patients with intermediate and high DLBCL on either polatuzumab combined with R-CHP (n=440) vs R-CHOP (n=439) alone.

After a median follow-up of 28.2 months, PFS favored patients in the combination arm compared with R-CHOP alone at 76.7% (95% CI, 72.7%-80.8%) vs 70.2% (95% CI, 65.8%-74.6%), respectively (HR, 0.73; 95% CI, 0.57-0.95, P=.02). As with the ECHELON data, there was no difference in OS at this point. Importantly, unlike the ECHELON data, in this study the toxicity profile was similar between the 2 groups.

As noted, there was a slow adaptation of brentuximab as up-front therapy, so will we see the same delays because there is only a noted PFS advantage without OS data available? Or will we use this experience and our knowledge that the vast majority of relapses occur in the first 2 years post therapy and add polatuzumab?

At what point will we be convinced that this benefit is real, or do we need to wait for an OS advantage to be shown? How do we measure the value of jumping on early and helping those patients ready for treatment now vs waiting for further data? Can we learn from prior studies? Can we select patients who might benefit most? Or we could go to the old standard of how would we want our loved ones treated if we had the option? Of course, it is possible that the addition may not cure more patients but just shift them to relapse later, but the current benefits are hard to ignore.

As of now, the biggest fundamental difference between the trials was that there were no new toxicities noted in the experimental arm. I believe we may follow some of our multiple myeloma colleagues who are starting to utilize a quadruplet regimen over the standard triplet for patients with newly diagnosed myeloma based on PFS data, and with good evidence of a better achievement of minimal residual disease.

As much of an advance that CAR T and BITE cells are, what if we can shrink the pool of patients who ultimately fail treatment? The addition of ADCs like polatuzumab to CHOP seems to offer that potential. The FDA has yet to approve this combination, so it is perhaps premature to celebrate, but to challenge the status quo is no small chore.

What is important about both trials is that for the first time in many years we may have new standards for up-front therapy for patients with Hodgkin disease and NHL. As exciting as new salvage options are, having fewer patients fail up front would benefit far more patients.

There is still much to be learned in both settings. Are there groups who benefit more, and are there patients who do not require the extra therapy? Can we limit the dosing and minimize toxicity? Can we find ways to reduce costs of therapy? Regardless of these questions, it appears we are entering the era of more targeted therapies, which include ADCs in combination with chemotherapy. This is a huge potential shift and a boon for all of our patients that should not go unnoticed.

_References

_{1. Connors JM, Jurczak W, Straus DJ, et al; ECHELON-1 Study Group. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331-344. doi:10.1056/NEJMoa1708984}

_{2. Straus DJ, Długosz-Danecka M, Connors JM, et al. Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. Lancet Haematol. 2021;8(6):e410-e421. doi:10.1016/S2352-3026(21)00102-2}

_{3. Ansell SM, Radford J, Connors JM, et al; ECHELON-1 Study Group. Overall survival with brentuximab vedotin in stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2022;387(4):310-320. doi:10.1056/NEJMoa2206125}

_{4. Should CAR T cells be used earlier in people with non-Hodgkin lymphoma? National Cancer Institute. January 13, 2022. Accessed September 15, 2022. https://bit.ly/3d8fQZ3}

_{5. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304}