Novel Approaches Challenge Toxicity Restraints in Classical Hodgkin Lymphoma

David S. Morgan, MD

The ability to increase the efficacy and decrease the toxicity of treatment regimens in classical Hodgkin lymphoma (cHL) had stood at odds until the introduction of response-adapted treatment approaches, antibody-drug conjugates (ADCs), and checkpoint inhibitors to the paradigm, explained David S. Morgan, MD.

In a presentation¹ during the 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Morgan, an associate professor of medicine at Vanderbilt University Medical Center, provided insight into the efforts that have been made to advance treatment outcomes and reduce toxicity in patients with cHL.

ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)has been the standard treatment for patients with stage III or IV Hodgkin lymphoma for the past 40 years, said Morgan. Typically given for 6 cycles in 12 treatments, once every 2 weeks, ABVD has a complete response (CR) rate of approximately 80%, a 5-year progression-free survival (PFS) rate of approximately 71%, and a grade 3 or 4 infection rate of 2%.

Although ABVD is a highly effective regimen, the rate of lung toxicity with bleomycin can occur in up to 53% of patients. Moreover, the drug carries a 4% to 5% mortality rate, and a 1996 study published in the Journal of Clinical Oncology demonstrated that long-term pulmonary symptoms can be found in 18% of patients who had received ABVD in the past.

“We’re told that we can do frequent [pulmonary function tests and omit bleomycin if the [diffusing lung capacity for carbon monoxide]goes down by 10%. In practice, this is rarely done, and it doesn’t account for the sudden pulmonary toxicity we’ve all seen in the clinic,” said Morgan.

BEACOPP had been initially positioned as an alternative option to ABVD, explained Morgan. The regimen demonstrated a 5% to 10% improvement in PFS compared with ABVD in comparative trials and meta-analyses. However, the PFS benefit was negated by severe hematologic toxicity and infections, increased risk of myelodysplastic syndrome, and infertility.

“BEACOPP as an effort to improve on ABVD, while widely used in Europe, is not widely adopted or used selectively in North America,” said Morgan.

Response-adapted treatment, which bases subsequent therapy after 2 cycles of ABVD on PET scan, is another approach that had been put forth as a way to improve on ABVD.

In the phase 3 RATHL trial, investigators put this approach to the test by randomizing patients with a negative PET scan after 2 cycles of treatment (PET2) with ABVD to another 4 cycles of ABVD or AVD (ABVD minus bleomycin). At a median follow-up of 41 months, the 3-year PFSrate was 85.7% with ABVD vs 84.4% with AVD.²

“The [PFS] was not significantly different in the 2 groups, and therefore it has become accepted standard treatment to omit the bleomycin if the PET scan is negative after 2 cycles. It’s expected that this will decrease the rate of pulmonary toxicity long term,” said Morgan.

In the trial, patients with a positive PET scan after 2 cycles of treatment with ABVD were escalated to BEACOPP, and the 3-year PFS rate was 68%, suggesting that the approach could be used to decrease the rate of pulmonary toxicity and improve outcomes among patients who were expected to have inferior outcomes with ABVD.

The addition of the CD30-directed ADC brentuximab vedotin (Adcetris) to AVD (A+AVD) represents another approach that can be used in the frontline setting, explained Morgan. The regimen was evaluated in the phase 3 ECHELON-1 trial and was compared with ABVD.

The results demonstrated a 2-year PFS rate of 82.1% with A+AVD vs 77.2% with ABVD (HR, 0.77; 95% CI, 0.60-0.98; P = .04).³ The 4-yearPFS rates were 75.1% and 81.7%, respectively, mirroring those from the previously reported primary analysis at 2 years.⁴

“Almost every prespecified subgroup that was looked at benefitted [from A+AVD], particularly patients who had high [International Prognostic Score (IPS)] score of 4 to 7, a high ECOG score of 2 or greater, and more than 1 extranodal site,” said Morgan.

Though, the benefit was offset slightly by some toxicity, said Morgan. The rate of serious adverse effects (AEs) was 25% in the ABVD arm vs 43% in the A+AVD arm. Additionally, the rates of neutropenia and peripheral sensory neuropathy were higher in the A+AVD arm vs the ABVD arm, although manageable with the use of pegfilgrastim. Conversely, the rate of pulmonary toxicity was lower in the A+AVD arm vs the ABVD arm, at 2% and 7%, respectively.

“The current standard practice is to adapt ABVD per the PET2 results. That was not done on the control arm of ECHELON-1 which potentially increased the rate of pulmonary toxicity on the control arm. [Therefore, the design] doesn’t really reflect how ABVD is optimally used today,” said Morgan.

Moreover, the approximate wholesale price of 6 cycles of A+AVD plus filgrastim, which is recommended to offset the hematologic toxicity, is more than $360,000, vs approximately $8000 with ABVD.

“For me, A+AVD is useful in selected patients, especially in patients with an IPS score of 4 to 7, or in patients who have preexisting pulmonary disease or pulmonary risks such as smoking,” said Morgan.

Before brentuximab vedotin had been evaluated in the first-line setting, it had been a staple treatment in the relapsed/refractory setting, explained Morgan, reflecting a 38% response rate. However, in 2019, a study published in Blood demonstrated that salvage therapy with pembrolizumab (Keytruda) led to an ORR of 72%.

Investigators subsequently launched the phase 3 KEYNOTE-204 study, which randomized patients with relapsed/refractory cHL to pembrolizumab or brentuximab vedotin. With 2 years of follow-up, the ORRs were 65.6% and 54.2% with pembrolizumab and brentuximab vedotin, respectively. Although the CR rates were approximately the same, at 24.5% vs 24.2%, respectively, the PFS was significantly longer with pembrolizumab, at 13.2 months vs 8.3 months with brentuximab vedotin.⁵

Moreover, the 1-year PFS rates were 53.9% vs 35.6%, respectively. Notably, the duration of response was longer with pembrolizumab, at 20.7 months vs 13.8 months with brentuximab vedotin, which could be an important distinction between the 2 regimens in the context of bridging therapy for transplant, said Morgan.

“The hazard ratio [HR] reflected an advantage for pembrolizumab in a number of subgroups, including patients who had never had an autologous stem cell transplant [HR, 0.61], patients who were primary refractory [HR, 0.52], patients who had prior brentuximab vedotin [HR, 0.34], and patients who were brentuximab vedotin-naïve [HR, 0.67],” said Morgan.

Regarding toxicity, the rate of grade 3 to 5 treatment-related AEs was 19.6% with pembrolizumab vs 25.0% with brentuximab vedotin.

In July 2020, the FDA granted a priority review designation to a supplemental biologics license application for pembrolizumab for the treatment of patients with relapsed/refractory cHL based on findings from the KEYNOTE-204 trial.

“Pembrolizumab is a very effective regimen and can be considered a standard of care in relapsed/refractory Hodgkin lymphoma,” concluded Morgan.

References

1. Morgan D. Institutional perspectives in cancer webinar on hematologic malignancies: Update in Hodgkin lymphoma. October 1, 2020. Accessed November 11, 2020.
2. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med. 2016;374:2419-2429. doi:10.1056/NEJMoa1510093
3. Connors JM, Jurczak W, Straus DJ, et al. 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.
4. 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 Echeleon-1 study. Blood. 2019;134(supp 1):4026. doi:10.1182/blood-2019-124116
5. Kuruvilla J, Ramchandren R, Santoro A, et al. KEYNOTE-204: randomized, open-label, phase III study of pembrolizumab (pembro) versus brentuximab vedotin (BV) in relapsed or refractory classic Hodkin lymphoma (R/R cHL). J Clin Oncol. 2020;38(suppl 15):8005. doi:10.1200/JCO.2020.38.15_suppl.8005