Progress in the Treatment of Hodgkin’s Lymphoma
Mené sur 1 334 patients atteints d'un lymphome hodgkinien de stade III ou IV, cet essai de phase III compare l'efficacité, du point de vue de la survie sans progression, et la toxicité de deux protocoles thérapeutiques, une chimiothérapie standard combinant doxorubicine, bléomycine, vinblastine et dacarbazine, et un traitement à base de brentuximab védotin en combinaison avec une chimiothérapie à base de doxorubicine, vinblastine et dacarbazine
Although there has been considerable research activity in the treatment of Hodgkin’s lymphoma since advanced stages of the disease became curable with combination chemotherapy in the 1960s, the most significant advances have involved the maintenance of a particular level of antitumor efficacy while acute and late toxic side effects and their attendant mortality are reduced. These advances include the preservation of high response rates at reduced levels of toxicity with the current standard regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); the demonstration that various forms of radiation therapy were associated with unacceptably high levels of long-term toxicity; the application of high-dose salvage chemotherapy; and the tailoring of treatment to the evidence of response revealed on midterm positron-emission tomography (PET). Little progress has been made in improving overall survival.
Two notable exceptions to this general lack of progress in the development of newer approaches to treatment are the application of the CD30 immunotoxin brentuximab vedotin1 and the programmed death 1–inhibitor nivolumab2 to the treatment of patients with Hodgkin’s lymphoma that has not been cured with the primary approach to treatment. The incorporation of these new active agents into frontline therapy has been eagerly anticipated, and the wait is over for brentuximab vedotin.
In this issue of the Journal, Connors and colleagues3 report the results of a phase 3 randomized trial in which standard ABVD was compared with a regimen in which brentuximab vedotin replaces bleomycin but is otherwise the same. Although the toxic effects of ABVD are generally modest, with none of the leukemia, risk of a second cancer, or infertility associated with regimens that use alkylating agents alone or with radiation therapy, the bleomycin in ABVD can cause serious acute and chronic pulmonary toxicity. Although the incidence of clinically relevant pulmonary toxicity associated with ABVD is low, clinicians have the impression that it is unpredictable. In practice, bleomycin toxicity could be diminished if measurements of the diffusing capacity of the lung for carbon monoxide (DLco) were made during treatment and decreases of 10% or more were used to withhold further exposure to bleomycin. However, DLco is rarely followed in patients receiving treatment with ABVD.
The value of bleomycin as a component of the ABVD regimen has been challenged. Johnson and colleagues4 found that in 84% of their patients with advanced-stage Hodgkin’s lymphoma, PET scans were negative after two cycles of ABVD. Randomly assigning patients whose PET scans were negative to complete six cycles of ABVD or to switch to AVD without bleomycin resulted in an adjusted reduction in the rate of 3-year progression-free survival of only 1.6 percentage points (85.7% with ABVD vs. 84.4% with AVD). In contrast, when Behringer and colleagues5 examined the use of ABVD versus AVD in early-stage disease, the difference in the rates of 5-year freedom from treatment failure was approximately 4 percentage points (93% with ABVD vs. 89% with AVD), a margin that statistically failed to confirm noninferiority.
Regardless of the value of bleomycin in ABVD, replacing it with brentuximab vedotin, an agent with substantial single-agent activity,6 had the potential to improve on ABVD. And it did.
Investigators randomly assigned 670 patients to receive ABVD and 664 to receive AVD plus brentuximab vedotin (A+AVD). PET was used to monitor disease activity. For the primary outcome, the authors used a modified version of progression-free survival in which responses that were judged by an independent committee as being less than complete were considered to have disease progression. In most instances, objective disease progression must be documented by a measure such as radiography, computed tomography, or biopsy of palpable nodes in order to be counted as a progression-free survival event. Because the need for additional therapy can be a subjective judgment, such measures can skew the outcome. In this study, objective criteria for the interpretation of the PET scans were applied by independent reviewers after the completion of six planned cycles of therapy. Progression was determined on the basis of the Deauville score, which accounts for the level of tracer uptake relative to the background blood pool, with higher numbers indicating greater uptake. Deauville scores of 3, 4, or 5 indicated a progression event if such an event was detected and a different therapy not specified in the protocol was initiated. There remains some controversy as to whether uptake that is assigned a Deauville score of 3 defines residual disease, but only a small number of the patients in this study were counted as having modified progression events on the basis of a Deauville score of 3.
After a median follow-up of approximately 25 months, the projected 2-year modified progression-free survival rate was 82% in the A+AVD group and 77% in the ABVD group (P=0.03). The side effects of neutropenia and neuropathy were higher in the A+AVD group, and pulmonary toxicity was lower. The neutropenia was addressed by incorporating prophylaxis with granulocyte colony-stimulating factor (G-CSF) routinely between doses. In the A+AVD group the neuropathy was mainly of low grade (67% overall; 11% grade 3 or higher) and completely resolved in most patients. Fertility was not formally assessed, but similar numbers of pregnancies occurred in the two groups. A total of 9 deaths in the A+AVD group were attributed to treatment toxicity (7 from the effects of myelotoxicity), as compared with 13 related deaths in the ABVD group, 11 of which were associated with pulmonary toxicity.
Although it is too early to rule out unanticipated late side effects, it appears that the addition of brentuximab vedotin to AVD combination chemotherapy (supported with G-CSF to alleviate myelotoxicity) merits consideration as first-line treatment for advanced Hodgkin’s lymphoma. Although the follow-up time has been relatively short, A+AVD appears to be more effective than ABVD (and is unlikely to be less effective) and is associated with fewer, more treatable toxicities
New England Journal of Medicine , éditorial en libre accès, 2016