Intensification with 2 cycles of BEACOPPesc + INRT is effective in stage I and II Hodgkin Lymphoma patients who are early PET-positive after 2 cycles of ABVD – results of the phase III H10 trial

This month, in the Journal of Clinical Oncology, Marc P.E. André from the Université Catholique de Louvain, Yvoir, Belgium, and colleagues published the final results of the EORTC/LYSA/FIL H10 trial (NCT00433433).

Between November 2006 and June 2011, this multicenter, phase III trial enrolled 1,950 previously untreated Favorable (F; n=754) and Unfavorable (U; n=1,196) stage I and II Hodgkin Lymphoma (HL) patients with the aim of assessing treatment adaptation based on early Positron Emission Tomography (ePET) after 2 cycles of ABVD.

The primary objective was to assess if removal of Involved Node Radiotherapy (INRT) results in decreased efficacy of 2 cycles of ABVD in ePET-negative patients:

• Standard arm (n=371): ePET-negative pts, 1 (F) or 2 (U) additional ABVD cycles + INRT
• Experimental arm (n=376): ePET-negative pts, 2 (F) or 4 (U) additional ABVD cycles; no INRT

The secondary objective was to determine if intensification with escalated doses of BEACOPPesc after 2 cycles of ABVD improves outcome in ePET-positive patients:

• Standard arm (n=583): ePET-positive pts, 1 (F) or 2 (U) additional ABVD cycles + INRT
• Experimental arm (n=595): ePET-positive pts, (both F & U) switch to 2 cycles of BEACOPPesc + INRT

Key Highlights

Patients

• Did not start, completed <2 cycles of ABVD, or no PET scan = 25 pts
• Baseline recommended PET carried out in 96% of pts
• ePET positivity: overall = 18.8% of pts; F = 13.0% of pts; U = 22.4% of pts

Outcome of ePET-positive patients

• ePET-positive group (n=361), median follow-up = 4.5 years
• ITT 5-yr PFS rates: ABVD+INRT arm = 77.4% (95% CI, 70.4–82.9); BEACOPPesc+INRT arm = 90.6% (95% CI, 84.7–94.3); HR = 0.42 (95% CI, 0.23–0.74; P = 0.002) in favor of BEACOPPesc+INRT
• In ABVD+INRT arm vs. BEACOPPesc+INRT arm: relapse exclusively in previously involved nodes = 23 vs. 7; previously uninvolved nodes = 8 vs. 4; both = 2 vs. 2
• 5-year OS rates: ABVD+INRT arm = 89.3%; BEACOPPesc+INRT arm = 96.0%; HR = 0.45 (95% CI, 0.19–1.07; P = 0.062)

Outcome of ePET-negative patients

• F group (n = 465), median follow-up = 5.0 years
  • ITT 5-year PFS rates: ABVD+INRT arm = 99.0% (95% CI, 95.9–99.7); ABVD only arm = 87.1% (95% CI, 82.1–90.8); HR = 15.8 (95% CI, 3.8–66.1) in favor of ABVD+INRT
  • In ABVD+INRT arm vs. ABVD alone arm: relapse exclusively in previously involved nodes = 0 vs. 22; previously uninvolved nodes = 1 vs. 5; both = 1 vs. 3
  • 5-year OS rates: ABVD+INRT arm = 100.0%; ABVD alone arm = 99.6%
• U group (n=595), median follow-up = 5.1 years
  • ITT 5-year PFS rates: ABVD+INRT arm = 92.1% (95% CI, 88.0–94.8); ABVD only arm = 89.6% (95% CI, 85.5–92.6); HR = 1.45 (95% CI, 0.8–2.5) in favor of ABVD+INRT
  • In ABVD+INRT arm vs. ABVD alone arm: relapse exclusively in previously involved nodes = 5 vs. 20; previously uninvolved nodes = 4 vs. 4; both = 6 vs. 6
  • 5-year OS rates: ABVD+INRT arm = 96.7%; ABVD alone arm = 98.3%

Treatment compliance and toxicity

• ePET-negative pts:
  • No unexpected toxicities reported in ePET-negative pts in either arm
• ePET-positive pts:
  • 6% did not start the allocated chemotherapy after ePET; 4 pts in the ABVD+INRT arm; 27 pts in the BEACOPPesc+INRT arm (18 of these due to patient and/or investigator decision)
  • 11% of pts in the ABVD+INRT arm did not receive INRT, mainly because of progression
  • 8% of pts in the BEACOPPesc arm did not receive INRT
  • Grade 3–4 hematologic toxicities in the BEACOPPesc+INRT vs. the ABVD+INRT arm: neutropenia (53.5% vs. 30.3%), anemia (4.9% vs. 0.0%), and thrombocytopenia (19.7% vs. 0.0%)
  • Grade 3–4 febrile neutropenia occurred in 23.9% of BEACOPPesc+INRT pts vs. 1.1% of ABVD+INRT pts
  • Infections without neutropenia were reported in 5.6% of BEACOPPesc+INRT pts vs. 1.1% of ABVD+INRT pts

The authors concluded that the H10 trial demonstrates that in patients who are ePET-positive after 2 cycles of ABVD, intensification with 2 cycles of BEACOPPesc + INRT should be considered. In ePET-negative patients, “overall outcome is excellent”.

However, statistically non-inferiority of omitting INRT from treatment could not be confirmed; nonetheless, negative ePET presents as an ideal tool to identify patients who do not require radiotherapy.

Lastly, in F patients, combined modality treatment achieved better immediate disease control; although in U patients, this benefit appeared to be less clinically relevant. 

Abstract

Purpose: Patients who receive combined modality treatment for stage I and II Hodgkin lymphoma (HL) have an excellent outcome. Early response evaluation with positron emission tomography (PET) scan may improve selection of patients who need reduced or more intensive treatments.

Methods: We performed a randomized trial to evaluate treatment adaptation on the basis of early PET (ePET) after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in previously untreated-according to European Organisation for Research and Treatment of Cancer criteria favorable (F) and unfavorable (U)-stage I and II HL. The standard arm consisted of ABVD followed by involved-node radiotherapy (INRT), regardless of ePET result. In the experimental arm, ePET-negative patients received ABVD only (noninferiority design), whereas ePET-positive patients switched to two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) and INRT (superiority design). Primary end point was progression-free survival (PFS).

Results: Of 1,950 randomly assigned patients, 1,925 received an ePET-361 patients (18.8%) were positive. In ePET-positive patients, 5-year PFS improved from 77.4% for standard ABVD + INRT to 90.6% for intensification to BEACOPPesc + INRT (hazard ratio [HR], 0.42; 95% CI, 0.23 to 0.74; P = .002). In ePET-negative patients, 5-year PFS rates in the F group were 99.0% versus 87.1% (HR, 15.8; 95% CI, 3.8 to 66.1) in favor of ABVD + INRT; the U group, 92.1% versus 89.6% (HR, 1.45; 95% CI, 0.8 to 2.5) in favor of ABVD + INRT. For both F and U groups, noninferiority of ABVD only compared with combined modality treatment could not be demonstrated.

Conclusion: In stage I and II HL, PET response after two cycles of ABVD allows for early treatment adaptation. When ePET is positive after two cycles of ABVD, switching to BEACOPPesc + INRT significantly improved 5-year PFS. In ePET-negative patients, noninferiority of ABVD only could not be demonstrated: risk of relapse is increased when INRT is omitted, especially in patients in the F group.