Late effects of Hodgkin lymphoma treatment: We can still do better
In more than 6 years as a chief medical editor for HemOnc Today, only a few subjects have prompted me to write more than one editorial.
Minimizing late effects in Hodgkin lymphoma and the use of CAR T-cell therapy for hematologic malignancies are two of them.
I’m returning to the Hodgkin lymphoma theme and (briefly) CAR T cells based on new data that show continued excess mortality of Hodgkin lymphoma survivors — even in the “modern” therapy era — and potential strategies for reducing the risks.
Established elevated risks
There are extensive data documenting the late effects of Hodgkin lymphoma therapy, mostly derived from long-term follow-up of survivors of classic Hodgkin lymphoma (cHL) treated with alkylating agent-based chemotherapy, with and without extensive radiation therapy. These data have demonstrated elevated risks for second malignancies and heart disease as important causes of excess mortality.
Based on these data, anthracycline-based chemotherapy — most commonly ABVD, which consists of doxorubicin, bleomycin, vinblastine and dacarbazine — has become the standard backbone front-line regimen in the United States, with other more intensive regimens used in a risk-stratified approach, directed by early interim functional imaging.
Similarly, carefully conducted clinical trials have demonstrated that functional imaging can identify patients for whom radiation therapy can be omitted safely without affecting OS.
Even before the advent of functional imaging, the use of radiation therapy was declining. It’s now estimated that fewer than 10% of patients receive radiation as a component of first-line therapy, a trend affecting patients with both advanced and localized disease.
Although there is a strong rationale for these changes and an expectation that they will have modified the long-term outlook for the increasing proportion of patients with Hodgkin lymphoma who achieve long-term survival, few data have been available for ABVD-treated patients.
‘Important and concerning data’
A new population-based study that included SEER data of more than 20,000 patients with cHL treated from 2000 through 2015 provides important and concerning data regarding the persistent excess mortality associated with cHL and its treatment, despite remarkable therapeutic advances.
The study included adults (age range, 20 to 74 years) regardless of disease stage.
After 12 years of follow-up, 3,380 deaths occurred, of which 59% were due to lymphoma, 9% to other cancers, 31% to causes other than cancer and 2% to unknown causes.
The cumulative mortality for patients with cHL was higher than the general population for all groups studied, but the degree of risk was related to age at diagnosis, as well as disease stage.
For patients aged 20 to 44 years at the time of treatment, for all stages of disease, deaths related to cHL were higher than noncancer deaths. In the older age group, those with advanced-stage disease were more likely to die of cHL, whereas deaths due to cHL and noncancer causes were similar among those with early-stage disease.
A more detailed look at the noncancer deaths shows that — for patients with advanced cHL — heart disease, infections and interstitial lung disease were leading causes. Among those with early-stage cHL, heart disease and infections were the leading causes.
Not surprisingly, deaths due to infections and interstitial lung disease were early events — usually within the first year. Patients aged 60 to 74 years were at higher risk for death due to these causes, as well as heart disease and second solid tumors.
Because this study was based on SEER data, we need to be cautious about how much we read into it.
For example, SEER does not collect robust treatment data, so we can only assume that most of these patients were treated with ABVD. We have no specific details about first-line or subsequent treatment.
That said, it does represent a real-world perspective on the current landscape of cHL mortality and demonstrates that there still are substantial opportunities to improve the already good outcomes. Continued evolution of treatment regimens to reduce short- and long-term toxicities will be the key intervention.
This study emphasizes the impact of interstitial lung disease and confirms the importance of studies that have changed practice regarding bleomycin. This drug is now avoided for older patients, and its use by younger patients is modified by early withdrawal among those who achieve compete metabolic response after interim functional imaging.
Awareness and vigilance
The increased awareness of cardiac effects of lymphoma therapy in general has placed growing emphasis on the importance of cardio-oncology. Heart disease remains a significant long-term problem for patients with cHL, and survivorship efforts still need to be directed toward reducing cardiac risks in general.
The cardiac effects of cHL therapy are attributable to anthracyclines, as well as the use of mediastinal radiation. Recent studies successively identified patients — on the basis of presenting characteristics, radiologic response or metabolic response — for whom radiation can be omitted safely, without an effect on long-term outcomes.
For the most part, these studies have been conducted in early-stage disease. However, a report from the GITL/FIL HD0607 trial in Italy showed that — among patients with advanced-stage cHL (stages IIB through IVB) with bulky disease at presentation — consolidative radiation therapy can be omitted safely if functional imaging shows a complete metabolic response at the completion of therapy, irrespective of the size or site of the original nodal mass. Of note, more than 80% of patients in this study had the mediastinum as the site of their bulky disease.
This population-based study shows that, even after the early excess noncancer deaths — most of which likely are treatment-related — and even with newer cHL treatment regimens, these patients are not out of the woods once they complete therapy. They remain at elevated risk for multiple complications in subsequent years.
Awareness of these complications, coupled with vigilant survivorship care, hopefully will improve their outcomes, but the ultimate solution will be even further refinement of front-line and subsequent treatment.
Still many unknowns
There is no doubt that new modalities are emerging for the treatment of cHL.
Agents such as brentuximab vedotin (Adcetris, Seattle Genetics) and checkpoint inhibitors such as pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol Myers Squibb) have substantial activity in relapsed and refractory cHL and are being moved into front-line therapy.
Whether combinations of these or other drugs will result in chemotherapy-free therapy for Hodgkin lymphoma is not yet clear, but they undoubtedly will change the front-line approach.
Early results of anti-CD30 CAR T-cell therapy also offer promise of a new treatment modality that likely will modify the posttreatment survivorship landscape for these patients.
Whatever the future for these newer therapies, this recent study shows that — despite all of the advances in the past 20 years — this patient population still has major long-term challenges, the full extent of which we still don’t know.
Follow-up in this study is not yet long enough to understand the true second malignancy risk, and the late consequences of the newer approaches are unknown.
Dores GM, et al. J Cliin Oncol. 2020;doi:10.1200/JCO.20.00264.
Gallamini A, et al. J Clin Oncol. 2020;doi:10.1200/JCO.20.00935.
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