PET Scans and Novel Therapies Propel Progress in Hodgkin Lymphoma

The introduction of PET scans was a major advancement in the Hodgkin lymphoma treatment paradigm; however, some questions cannot be answered with that test, such as identifying which patients with PET-negative disease will relapse, according to Tatyana Feldman, MD, who added that research with novel combinations has also propelled the field forward.

One of the most pivotal trials in the space that has read out in recent years is ECHELON-1, according to Feldman. In the multicenter, open-label study, patients with newly diagnosed stage III or IV classical Hodgkin lymphoma were treated with either brentuximab vedotin (Adcetris) and doxorubicin, vinblastine, and dacarbazine (A + AVD) or ABVD (AVD plus vincristine). Data from a 4-year follow-up of the trial showed that A + AVD resulted in a 31% reduction in the risk of disease progression or death versus ABVD. At a median follow-up of 43.3 months, the progression-free survival (PFS) rates per investigator assessment were 81.7% versus 75.1% in the A + AVD and ABVD arms, respectively (HR, 0.69; 95% CI, 0.54-0.89).

Brentuximab vedotin was initially approved by the FDA in 2011 for the treatment of patients with Hodgkin lymphoma and systemic anaplastic large cell lymphoma. In March 2018, the FDA approved its use in combination with chemotherapy as a first-line treatment for adult patients with stage III/IV classical Hodgkin lymphoma, based on earlier data from ECHELON-1.

“The major advantage is that after 2 cycles of ABVD, 80% of patients with negative PET-2 are cured, regardless of whether there is a residual mass or not,” said Feldman. “The disadvantage is that we do not know how to identify the 20% who are PET negative [and] relapse. Although that is not exactly a disadvantage, it is a shortcoming, because [it indicates that the] PET scan is not 100%.”

In an interview with OncLive, Feldman, hematologist and medical oncologist and director of the T-cell Program at John Theurer Cancer Center, Hackensack Meridian Health, discussed the significance of PET-adapted strategies in Hodgkin lymphoma, novel therapies that have emerged in the pipeline, and where future research is headed.

OncLive: What have we learned from the PET-adapted approaches?

Feldman: The PET scan was one of the major advances in Hodgkin lymphoma. Patients with Hodgkin lymphoma very frequently would have residual masses, particularly in the mediastinum, which made it very difficult to determine whether disease was still active or it just scar tissue. In the old days, patients were overtreated and radiation was very commonly used. Splenic disease, for example, was not detected on CT scans. When studies were done, it was realized that a negative PET scan after 2 cycles of chemotherapy basically means that the majority of patients were cured. Based on those findings, the field began to develop tremendously.

Multiple trial designs in Europe and the United States set out to understand whether radiation could be omitted in [the treatment of patients with] bulky disease or early-stage disease. Investigators were also playing around with chemotherapy to determine whether it could be de-escalated or escalated, based on PET results. The majority of those large trials came to fruition and have long-term follow up, so we do have [more] information [now]. We also realized that the PET scan is not perfect, and some questions cannot be answered with that test. Now, new technology is developing, such a circulating tumor DNA; this will probably be the next best thing in terms of evaluating complete responses and progressive disease [in these patients].

Another major development was the emergence of novel agents. Two major drug [classes have generated excitement] in Hodgkin lymphoma. One of them is brentuximab vedotin, which is an antibody-drug conjugate. The second class of drugs are the PD-1 inhibitors, such as nivolumab (Opdivo) or pembrolizumab (Keytruda), which have significant activity. All those drugs are now being studied in the frontline setting; that is where the field is headed. Within the next 10 years, the whole field of Hodgkin lymphoma will be very different.

What are the advantages and disadvantages of PET scans?

For patients with positive PET-2, most of the trials started to escalate bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), for example. Interesting data showed that, on average, approximately 60% to 65% of patients are cured. However, the recent ECHELON-1 trial, which studied A + AVD versus ABVD, had very similar results. Even [with] ABVD, about 45% of patients are cured.

We are overtreating some patients and we still do not have good results for patients who are truly progressive and that is what we need to work toward, to identify the patient population who truly have residual disease and probably do not benefit much from chemotherapy; that is where novel therapy will come in. The patients who, despite being PET positive, are probably in remission, which we also cannot identify with a PET scan only.

Is there any ongoing research to help overcome these shortcomings?

Valeria Spina, of the Institute of Oncology Research, and colleagues, reported their work on detecting mutations within Reed–Sternberg cells, and this is much more difficult, particularly in the old days, because Reed–Sternberg cells do not circulate and are surrounded by inflammatory infiltrates. To understand whether you are picking up mutations from Reed–Sternberg cells or not was difficult; however, with modern technology, investigators analyzed blood and tissue samples. They confirmed that Hodgkin lymphoma has a high rate of mutations, as high as [that seen in] diffuse large B-cell lymphoma (DLBCL).

Secondly, the correlation between mutations that were detected in peripheral blood and in Reed–Sternberg cells was very high. As such, the picture in the blood really reflects a true Hodgkin lymphoma. They’re very particular mutations; it’s not like in DLBCL because each disease has its own mutations. Hodgkin lymphoma has a very stable set of mutations. Notably, if you give 2 cycles of ABVD and check the mutational profile in the peripheral blood, if it goes down by 2 logs, this patient has excellent survival—regardless of what the PET scan shows. If a patient has a positive PET scan, but the mutational burden goes down by 2 logs, they are cured. Patients who have PET-negative disease, but their mutational burden does not go down by 2 logs, relapse. This field is actively developing. This was a retrospective analysis, so the majority of new therapeutic protocols incorporate correlative studies to analyze these topics. Hopefully, we will have more knowledge and we will be able to identify the 20% of patients with PET-negative disease who relapse.

What are the data we see with the novel therapies in the pipeline?

One important trial, which was reported a few years ago, is the ECHELON-1 trial; this was a large, randomized, multi-institutional study comparing the standard-of-care ABVD versus A + AVD, so bleomycin was removed. It was not double-blinded, and the primary end point was modified PFS, which was slightly better in the A + AVD arm, at 82% percent versus 77%. You can say that [improvement] is pretty small, but in this field, any improvement is welcome, considering that the toxicity is also very manageable. All patients had advanced-stage disease. Interestingly, the 4-year update is holding up. The PFS at 4 years continues to be 82% in the A +AVD arm, and it is slowly drifting down in the ABVD arm. This is kind of similar to the SWOG data, where investigators reported 5-year results of patients treated with ABVD, [in which the trend] slowly drifted down, which was disappointing.

Another interesting finding in ECHELON-1 was that it was not a PET-adaptive study. Everyone would receive 6 cycles, regardless of what the PET-2 was, unless the investigator decided to change it. They retrospectively analyzed the outcomes in patients with PET-2 positive disease and PET-2 negative disease, and they discovered that the PFS at 4 years for those PET-2 positive disease is about 60%, which is very similar to the escalated BEACOPP trial. It looks like we may continue with A + AVD and achieve similar results when [therapy is escalated], and that is very promising. We need to look into this further, because again, the numbers are very small. The number of patients with PET-positive disease was very low.

What are the key takeaways?

ECHELON-1 was a positive study and we need to build upon that work. To this end, groups are working on designing a trial incorporating novel therapies, such as brentuximab vedotin plus PD-1 inhibitors, into the backbone of chemotherapy in early-stage diseases. For example, about 1 year ago, studies of a large cooperative group study incorporating novel agents in advanced Hodgkin lymphoma were reported by Lisa Abramson, MD, of Mount Sinai. The field is evolving, and we will get more answers in a few years.

Reference

Bartlett NL, Straus DJ, Dlugosz-Danecka M, et al. Brentuximab vedotin with chemotherapy for stage 3/4 classical Hodgkin lymphoma (cHL): 4-year update of the Echelon-1 study. Blood. 2019;134 (suppl 1):4026. doi:10.1182/blood-2019-124116