“The important thing is not to stop questioning. Curiosity has its own reason for existing.” —Albert Einstein

Syed A. Abutalib, MD

James O. Armitage, MD, FASCO

The phase III international ECHELON-1 study, designed to evaluate brentuximab vedotin (Adcetris) as part of a front-line chemotherapy regimen for previously untreated advanced classic Hodgkin lymphoma, met its primary endpoint of “modified progression-free survival,” according to a plenary session abstract presentation during the 2017 American Society of Hematology Annual Meeting & Expostion¹ and simultaneous publication in The New England Journal of Medicine.² As reported in the December 25 issue of The ASCO Post, the investigators of the study concluded: “Compared with standard ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine], A+AVD [brentuximab vedotin, doxorubicin, vinblastine, dacarbazine] as front-line therapy improves outcome for patients with advanced [Hodgkin lymphoma], including a 23% risk reduction in progression, death, or need for additional anticancer therapy. This establishes A+AVD as a new front-line option for patients with advanced-stage [Hodgkin lymphoma].”^1,2 

It is commendable that 218 clinical sites in 21 countries participated in this global effort comparing the widely accepted standard of ABVD (n = 670) to the experimental regimen of A+AVD (n = 664) in patients with stage III and IV newly diagnosed classic Hodgkin lymphoma. Herein, we attempt to examine the most up-to-date data from the ECHELON-1 study.^1,2 Additionally, we will highlight some of the important questions that are raised with its presentation and publication. 

Why Was It Important to Conduct Such a Study?

Although front-line ABVD has superb clinical activity and mostly manageable side effects, approximately 30% of patients with advanced-stage classic Hodgkin lymphoma eventually relapse or have refractory disease.³ In addition, bleomycin is associated with sometimes fatal pulmonary toxicity; however, when bleomycin is omitted from the ABVD regimen, treatment efficacy is somewhat compromised.³ 

Brentuximab vedotin has shown remarkable activity in classic Hodgkin lymphoma and certain other CD30-positive lymphoid malignancies. It is an attractive candidate in combination with AVD in the front-line setting.⁵ The ECHELON-1 study tested brentuximab vedotin in the experimental arm in combination with AVD with a very optimistic goal of replacing the ABVD regimen for patients with stage III and IV classic Hodgkin lymphoma.^1,2

Modified Progression-Free Survival: Definition and Controversy

To capture all events that reflect a failure of front-line chemotherapy in advanced classic Hodgkin lymphoma, the ECHELON-1 study primary endpoint of modified progression-free survival included “modified progression events,” defined as a less-than-complete remission to front-line therapy (an end-of-treatment positron-emission tomography [PET] scan score of Deauville 3, 4, or 5—although in most studies, a score of Deauville 3 post treatment is considered a complete remission) and the delivery of subsequent treatment. Both conditions had to be present for the patient to be considered as having experienced a modified progression event. 

We believe that at present, it is too early to confidently recommend A+AVD over ABVD in patients with newly diagnosed stage III and IV classic Hodgkin lymphoma—even in specific subsets of that population.

— Syed A. Abutalib, MD and James O. Armitage, MD, FASCO

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Furthermore, potential investigator bias for the modified endpoint was minimized by the use of a blinded independent review facility to read the end-of-treatment PET scans. Results from the independent review facility readings were not available to investigators. 

Nevertheless, there has been debate over why and how the study investigators defined all primary endpoint outcomes as modified progression events. The definition included deaths from causes other than disease progression (eg, regimen toxicity). Hence, there would have been less confusion in the medical community if the ECHELON-1 authors had used the term “event-free survival” rather than modified progression-free survival.

How Should We Interpret These Results After Publication of the RATHL Trial?

The ECHELON-1 study showed that the addition of brentuximab vedotin and the elimination of bleomycin from front-line therapy in the A+AVD regimen lowered the incidence of pulmonary toxicity. However, encouraging results from the RATHL trial⁴ established that bleomycin can be omitted after two cycles of ABVD in patients with a “negative” PET scan. This approach reduces the incidence of pulmonary toxicity but, in all fairness, does not favor AVD over A+AVD with regard to efficacy in the clinical context of the ECHELON-1 study. 

Also, it should be noted that treatment with brentuximab vedotin is not completely free of pulmonary toxicity. 

Why the Higher Mortality and Hospitalization in the ABVD Arm?

The New England Journal of Medicine article and accompanying supplemental appendix do not venture to explain why mortality and hospitalization events were unusually high in the ABVD arm of ECHELON-1. These findings are puzzling, especially given that patients were being carefully monitored on the trial. 

During treatment, there were 13 deaths in the ABVD arm; 11 deaths were due to or associated with pulmonary toxicity. The natural question is, were these patients being monitored closely? Our experience is that monitoring of carbon monoxide–diffusing capacity (DLCO) before and periodically during treatments with bleomycin essentially eliminates clinical pulmonary toxicity. 

It is worth mentioning that the omission of bleomycin toxicity (and the costs associated with its infusion and, in selected cases, its toxicity) would have favored ABVD followed by AVD over the A+AVD arm in the context of modified progression-free survival, as defined in ECHELON-1. Still, it is unclear why, among 659 patients in the ABVD group, 186 were hospitalized—a quite unusual occurrence with the administration of ABVD. 

Why the Hazard Ratio Discrepancy by Geographic Region?

It is also unclear why patients treated in the regions identified as “Americas” and North America obtained a greater benefit from A+AVD compared to patients treated in Europe and Asia. The hazard ratio (HR) is 0.65 (95% confidence interval [CI] = 0.44–0.97) and 0.60 (95% CI = 0.39–0.90) in cohorts of patients treated in the Americas and North America, respectively, compared with 0.83 (95% CI = 0.59–1.17) and 0.91 (95% CI = 0.43–1.93) in cohorts treated in Europe and Asia. 

This is an important question, provided investigators are sure that correct doses of drugs were infused and at scheduled times. According to the supplementary appendix to the study publication, there were approximately 323 to 315 dose delays, but no doses of brentuximab vedotin were missed in the A+AVD arm. The geographic locations of such delays, even in the ABVD arm (219 to 211) were not reported.

New Set of Toxicities With A+AVD 

The majority of the deaths (7 of 9) during treatment in the A+AVD arm were associated with febrile neutropenia, although they are unusual events, especially in a carefully monitored trial. However, primary prophylaxis with granulocyte colony-stimulating factor appeared to mitigate the increased risk of febrile neutropenia and its sequelae in the subgroup of 83 patients who received primary prophylaxis, resulting in reduced rates of neutropenia, febrile neutropenia, and serious infection. Among 662 patients in the A+AVD group, 242 were hospitalized during the trial—also unusual and unexplained.

Peripheral neuropathy occurred more frequently in patients in the A+AVD group (442 of 662 patients). The incidence of peripheral neuropathy of grade 3 or higher was increased by 9 percentage points in this group (vs the ABVD group), resulting in discontinuation of the trial drug in 44 of 442 patients, and peripheral neuropathy was “largely” (but not always) reversible, either resolving or abating in 67% of the patients in whom the condition had developed.

Two-thirds of patients in the A+AVD group (295 of 442) who developed peripheral neuropathy had resolution (43%, 191 of 442) or improvement by at least 1 grade (24%, 104 of 442) in terms of events at the time of the last follow-up visit. At that time, 92% of ongoing events related to peripheral neuropathy were grade 1 (64%) or grade 2 (29%) in the A+AVD group. Longer follow-up data evaluating quality of life will be important.

Which Regimen Is Optimal for Older Adults?

Older patients with advanced classic Hodgkin lymphoma represent a special group, considering the incidence of disease (approximately 20% of all cases), lower rates of treatment efficacy, and typically higher rates of severe toxicity, particularly the pulmonary toxicity associated with bleomycin. According to the study investigators, “The results of the ECHELON-1 trial are particularly important considering the opportunity A+AVD provides to administer a treatment to older patients that is at least equivalent in its effectiveness to ABVD and to do so safely.” 

Here, it is important to highlight a few observations from the ECHELON-1 study. To begin, patients older than 60 years benefited equally from A+AVD and ABVD, with a hazard ratio of 1.01 (95% CI = 0.59–1.73). Additionally, with the encouraging results of the RATHL trial,⁴ bleomycin can be safely omitted after two cycles of ABVD if an interim PET scan is negative, thereby decreasing the incidence and risk of pulmonary toxicity, especially in older high-risk individuals with classic Hodgkin lymphoma. 

What Is the Incidence of Infertility With A+AVD vs ABVD? 

Fertility was not formally assessed in the ECHELON-1 study; however, similar numbers of pregnancies were reported in each treatment group, which suggests there was no significant difference in the effect on fertility. At the time of the study’s publication, a total of 78 pregnancies were reported among trial participants and their partners (42 in the A+AVD group and 36 in the ABVD group). According to the investigators, all patients are being followed carefully by the safety monitoring committee for long-term side effects.

Should the Economic Burden of A+AVD With Growth Factors Be Considered? 

Yes. The data require a longer follow-up period to assess any overall survival difference between the two arms, but at this time, it is reasonable to debate the cost difference between the two approaches (Table 1). A+AVD is more than 100 times as costly—ie, we could treat approximately 108 patients with ABVD with what it would cost to treat 1 patient with A+AVD. In addition to the added cost incurred from A+AVD plus growth factors for a total of six cycles, proper guidance on how best to administer growth factors with an every-2-week schedule should be discussed and remains challenging. 

Concluding Remarks

We believe that at present, it is too early to confidently recommend A+AVD over ABVD in patients with newly diagnosed stage III and IV classic Hodgkin lymphoma—even in specific subsets of that population. Again, we applaud the effort underlying the ECHELON-1 study and look forward to long-term data, especially with regard to overall survival. ■

Dr. Abutalib is Assistant Director, Hematology and Hematopoietic Cell Transplantation, Director, Hematopoietic Cell Transplant Apheresis Program, Cancer Treatment Centers of America, Zion, Illinois. Dr. Armitage is The Joe Shapiro Professor of Medicine, Division of Oncology & Hematology, University of Nebraska Medical Center, Omaha.

DISCLOSURE: Dr. Armitage reported serving in a consulting or advisory role with Tesaro, ZIOPHARM Oncology, Conatus, and Asentage Pharma. Dr. Abutalib reported no conflicts of interest.

REFERENCES

1. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma. 2017 ASH Annual Meeting. Abstract 6. Presented -December 10, 2017. 

2. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. December 10, 2017 (early release online); supplementary appendix available at www.nejm.org/doi/suppl/10.1056/NEJMoa1708984/suppl_file/nejmoa1708984_appendix.pdf. Accessed January 5, 2018.

3. Behringer K, Goergen H, Sasse S, et al: Omission of dacarbazine or bleomyccin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin’s lymphoma (GHSG HD13). Lancet 385:1418-1427, 2015.

4. 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 374:2419–229, 2016.

5. Connors JM, Ansell SM, Fanale M, et al: Five-year follow-up of brentuximab vedotin combined with ABVD or AVD for advanced-stage classical Hodgkin lymphoma. Blood 130:1375-1377, 2017.