PET-Adapted Therapy Effective in Hodgkin Lymphoma

Alessandro Rambaldi, MD

Investigators successfully used PET/CT scanning to determine whether patients with stage IIB to IVB Hodgkin lymphoma should switch from ABVD to BEACOPP, according to updated results from the international GITIL/FIL HD 0607 trial published in the Journal of Clinical Oncology.

In previous studies, ABVD (doxorubicin, vinblastine, vincristine, and dacarbazine) has been associated with a 3- to 5-year progression-free survival (PFS) ranging from 61% to 76%. The more intensive BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen has shown superior disease control, with a 5-year freedom from treatment failure of up to 90%, but at the cost of increased toxicity. BEACOPP has been associated with increased hematologic toxicity, a high incidence of sterility, and severe late complications/long-term toxicities including a 5-year cumulative risk for myelodysplastic syndrome or acute leukemia of 2.2% compared with 0.4% for ABVD.

Therefore, physicians have been looking for a risk-adapted treatment strategy to avoid such adverse events (AEs). Investigators initiated this prospective, multicenter phase II trial to identify the patients at highest risk for chemotherapy resistance, as defined by a positive early interim PET scan, and direct them to the more intensive regimen. The primary endpoint was 3-year PFS.

From June 2008 to June 2014, patients (N = 780) received 2 cycles of ABVD, then underwent a PET2 scan. Most patients (81%) had a negative result. Those with a positive PET2 result (n = 150) were randomly assigned to the escalated BEACOPP program, with 76 patients allocated to receive only chemotherapy and 72 to receive the rituximab supplement.

Of the 630 patients with PET2-negative results, 629 continued with 4 additional ABVD cycles and 86% of those achieved a durable complete response (CR). Eighty-one (13%) experienced treatment failure, and 4 withdrew consent. Of patients with a large nodal mass at baseline and a negative final PET scan (n = 296), 148 were randomly assigned to consolidation radiation therapy on the initial nodal site of disease and 148 to no further treatment.

Patients with PET2-positive results were more likely to be male (57% vs 47%; P = .036), had a higher International Prognostic Score (P <.001), and had a larger nodal mass (P <.001). Median age among the patient population was 31 years (range, 14-60), 51% were women, and 36% had stage IIB, 32% stage III, and 32% stage IV Hodgkin lymphoma. More than 4 in 5 displayed B symptoms.

The largest diameter of systemic adenopathy was <5 cm in 328 patients, 5 to 7 cm in 140, 8 to 10 cm in 159, and >10 cm in 155 patients.

In the intent-to-treat population, 80.4% of patients remained in first CR, with a 3-year PFS rate of 82% (95% CI, 79-84) and a 3-year overall survival (OS) rate of 97% (95% CI, 95-98).

For patients with PET2-positive results, the 3-year PFS rate was 60% (95% CI, 51-68) and the 3-year OS rate was 89% (95% CI, 82-93). In the PET2-negative patients, 3-year PFS rate was 87% (95% CI, 84-89) and 3-year OS was 99% (95% CI, 97-99). The 3-year event-free survival was identical to PFS results in both groups because no secondary cancers have been reported so far, and only 1 late pulmonary toxicity was observed in a patient treated with ABVD.

There was no difference in CR for patients allocated to rituximab-supplemented BEACOPP compared with BEACOPP. Outcomes with BEACOPP were significantly different when investigators analyzed PET2-positive scans by the Deauville five-point scale (DS). In patients with a DS score of 4, the 3-year PFS rate was 73% (95% CI, 62-81) compared with 35% (95% CI, 22-49) in patients with a DS score of 5 (P <.001). The 3-year OS rate was 92% (95% CI, 84-96) in patients with a DS score of 4 versus 83% (95% CI, 67-92) for those with a score of 5 (P <.001).

During the first 2 ABVD cycles, 41% of patients experienced grade 3/4 neutropenia. Other toxicities—including grade 3 nausea/vomiting, pulmonary infection, and ALT/AST increase—occurred in <1% of patients.

Three in 4 patients who switched to BEACOPP experienced grade 3/4 hematologic toxicities and 10% experienced grade 3/4 infections. Roughly one-third of patients who continued with ABVD experienced a grade 3/4 hematologic toxicity and 2% experienced a grade 3 pulmonary toxicity.

Overall, 30 patients (3.8%) died as a result of disease progression and cardiac failure (n = 2), resistant or progressive disease (n = 18), transplant-related toxicity (n = 5), infections (n = 4), or pulmonary fibrosis (n = 1). Sixteen patients (11%) with PET2-positive scans and 2% of those with negative scans died.

“In this study, we showed that a PET-driven switch from ABVD to escalated BEACOPP can be safely done in advanced-stage Hodgkin lymphoma. With an adequate prolonged follow-up, the final results of this trial showed a 3-year PFS of 82%, three points lower than hypothesized (85%) by the study design,” corresponding author Alessandro Rambaldi, MD, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Italy, and coauthors concluded.

Gallamini A, Tarella C, Viviani S, et al. Early chemotherapy intensification with escalated BEACOPP in patients with advanced-stage Hodgkin lymphoma with a positive interim positron emission tomography/computed tomography scan after two ABVD cycles: long-term results of the GITIL/FIL HD 0607 trial [published online January 23, 2018]. J Clin Oncol. doi: 10.1200/JCO.2017.75.2543.