Intensified Frontline ABVD Improves PFS in Advanced Classical Hodgkin Lymphoma

Dose-dense and dose-intense doxorubicin, bleomycin, vinblastine, dacarbazine, and granulocyte colony–stimulating factor (G-CSF; ABVD DD-DI) generated an improvement in progression-free survival (PFS) and other efficacy end points compared with PET-adapted ABVD in previously untreated patients with advanced classical Hodgkin lymphoma, according to data from the phase 3 FIL-Rouge trial (NCT03159897).

Findings presented at the 17th Annual International Conference on Malignant Lymphoma showed that patients treated with ABVD DD-DI (n = 251) experienced a 56% reduction in the relative risk of 3-year progression, relapse, or death compared with those treated with PET-adapted ABVD (n = 252; HR, 0.44; 95% CI, 0.28-0.67; P < .0002). At a median follow-up of 35 months, the PFS rates were 86.7% for ABVD DD-DI vs 73.2% for PET-adapted ABVD.

“What we are doing now, in collaboration with several other groups, is trying to identify true biomarkers. During the study, samples were collected to understand if there is a way to make it clear which types of patients would really benefit with this from this version of ABVD,” lead study author Antonio Pinto, MD, of Istituto Nazionale Tumori IRCCS Fondazione G. Pascale in Naples, Italy, said in a presentation of the data.

The randomized, open-label, 2-arm FIL-Rouge trial enrolled patients between 18 and 60 years of age with untreated classical Hodgkin lymphoma who had stage IIB disease with extranodal sites and/or bulky disease, or stage III/IV disease.

Patients were randomly assigned 1:1. Those in the ABVD DD-DI arm received 35 mg/m² of doxorubicin, 10,000 units/m² of bleomycin, 6 mg/m² of vinblastine, and 375 mg/m² of dacarbazine on days 1 and 11, plus 263 µg of G-CSF on days 6 to 8 and days 17 to 19, during the first 4, 21-day cycles. Patients received the same regimen in cycles 5 and 6, with the exception of a lower dose of doxorubicin at 25 mg/m² on days 1 and 11. Additionally, 30 Gy of involved site radiation therapy (ISRT) was given to patients who had a partial response (PR), or those with a complete response (CR) and a Deauville score of 3 with residual tumors of at least 2.5 cm. Notably, patients in this arm with no response or progressive disease underwent an interim PET scan that was not decisional.

In the PET-adapted ABVD arm, patients received 2 cycles of standard ABVD before undergoing a decisional interim PET scan. Those with a negative PET scan with a Deauville score of 1 to 3 received 4 more cycles of standard ABVD, and those with a positive scan and a Deauville score of 4 or 5 underwent escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for 4 cycles or chemotherapy plus autologous stem cell transplant (ASCT). Patients who had a PR, CR with a Deauville score of 3 with residual tumors of at least 2.5 cm, or a CR with a Deauville score of 1 to 3 with initial bulky disease also received 30 Gy of ISRT.

Patients were stratified by age (<45 vs ≥45), International Prognostic Score (IPS; 0-2 vs ≥3), bulky disease (nodal, <10 cm vs >10 cm; mediastinum, M/T <0.35 vs >0.35), and clinical stage (II vs III/IV).

Three-year PFS served as the trial’s primary end point. Secondary end points included complete metabolic response rate at the end of treatment, event-free survival (EFS), disease-free survival (DFS), overall survival (OS), and safety.

Pinto noted that baseline characteristics were well balanced between the 2 study arms. Among all enrolled patients, the median age was 33.6 years (interquartile range, 26.2-43.0), 20% of patients were at least 45 years old, and 54% were male. Twenty-one percent had Ann Arbor stage II disease, 33% had stage III disease, and 46% had stage IV disease. Bulky mediastinal disease was reported in 24% of patients, and bulky nodal disease was observed in 14% of patients. Forty-four percent of patients had no sites of extranodal involvement, 30% had 1 site, and 24% had more than 1 site. IPS risk factors included 0 or 1 (28%), 2 (30%), 3 (25%), or at least 4 (17%). Notably, 12% of patients had bone marrow involvement.

Among the 251 patients randomly assigned to AVBD DD-DI, 4 patients did not receive an interim PET scan due to withdrawal of consent (n = 3) or adverse effect (AE; n = 1). Interim PET scan showed 213 of 247 experienced a CR. Four patients then withdrew due to AEs after 4 cycles (n = 1), 5 cycles (n = 2), and 5 cycles plus consent withdrawal (n = 1). Treatment was completed by 243 patients, and 25 received radiotherapy. At the end of treatment, 231 of 246 patients had a CR, 7 had a PR, and 9 had progressive disease.

In the PET-adapted AVBD arm, prior to the interim pet scan, 1 patient withdrew consent, and 1 patient received ABVD DD-DI despite being randomly assigned to the control arm. Among 209 patients who had a negative interim PET scan, 8 were deemed positive upon central revision. In this group, 4 patients stopped treatment due to progressive disease, 2 stopped due to AEs, 2 stopped after completing 5 cycles, and 2 patients changed treatment centers. Among 200 patients who completed 6 cycles of standard ABVD, 186 had a CR, and 64 underwent radiation.

Among 42 patients who had a positive interim PET scan, 28 received subsequent escalated BEACOPP, and 14 underwent chemotherapy plus ASCT. Thirty-seven of these patients completed treatment, 21 had a CR (BEACOPP, n = 12; ASCT, n = 9), and 17 underwent radiation (BEACOPP, n = 14; ASCT, n = 3). Overall, in the control arm, 237 patients completed treatment, and 81 received radiation; 208 of 245 patients had a CR, 20 had a PR, and 17 had progressive disease.

Additional data showed that ABVD DD-DI led to an improvement in EFS (HR, 0.54; 95% CI, 0.37-0.78; P <.001) and DFS (HR, 0.49; 95% CI, 0.26-0.85; P = .018).

The 2-month CR rates were 85.5% for the ABVD DD-DI arm and 80.5% for the PET-adapted ABVD arm (P = .15). The CR rates at the end of treatment were 93.8% and 84.5%, respectively (P = .002). At the end of treatment, 2.8% of patients in the ABVD DD-DI arm vs 8.1% in the PET-adapted ABVD arm had a PR (P = .01). Lower rates were also observed for ABVD DD-DI regarding progressive disease (3.6% vs 6.9%; P = .11), patients with primary refractory disease less than 3 months from the end of treatment (4.2% vs 11.6%; P = .006), and those with early recurrence between 3 and 12 months after end of treatment (6.0% vs 10.3%; P = .09).

At the March 7, 2023, data cutoff, 4 patients in the ABVD DD-DI arm had died due to lymphoma (n = 2), infection (COVID-19 at month 24; n = 1), or graft-vs-host disease following allogeneic stem cell transplant (n = 1). Five patients in the PET-adapted ABVD arm had died due to lymphoma (n = 4) or infection (H1N1 at month 7; n = 1). “We'll see what happens with the OS, but we are very happy that there was no excess death,” Pinto said.

ABVD DD-DI also elicited an improvement in 3-year PFS among patients with mediastinal bulk (87% [95% CI, 75%-93%] vs 72% (95% CI, 57%-82%) for PET-adapted ABVD] and those with stage IV disease (86% [95% CI, 78%-90%] vs 70% [95% CI, 59%-78%]). In patients who had a negative interim PET scan, ABVD DD-DI produced a 3-year PFS rate of 90% (95% CI, 85%-93%) compared with 80% (95% CI, 73%-85%) for PET-adapted ABVD. In those who had positive PET scans, the 3-year PFS rates were 72% (95% CI, 53%-84%) and 46% (95% CI, 30%-59%) for ABVD DD-DI and PET-adapted ABVD, respectively.

Regarding safety, 70% of patients in the ABVD DD-DI arm experienced grade 3/4 AEs compared with 57% of those in the PET-adapted ABVD arm. No grade 5 AEs occurred in the experimental arm vs 1 in the control arm. The rates of serious AEs were 24.7% and 15.9%, respectively. The rates of treatment discontinuation due to AEs were 2% and 1.6%, respectively.

In the ABVD DD-DI arm, treatment was delayed by more than 2 days in 6.06% of patients due to an AE, and 11.45% of patients had treatment delayed within a cycle due to AEs. Those rates were 3.20% and 5.63%, respectively, in the PET-adapted ABVD arm.

Higher rates of anemia, neutropenia, febrile neutropenia, and thrombocytopenia were reported with standard ABVD.

Disclosures: Dr Pinto reported receiving honoraria from F. Hoffmann-La Roche AG, Incyte – Italy, Merck Sharp and Dohme, Servier Affaires Medicales, and BMS-Celgene; personal fees for consultancy and advisory board participation from F. Hoffmann-La Roche AG, Incyte – Italy, Merck Sharp and Dohme, and BMS-Celgene; and reimbursement/payment for travel/accommodations from F. Hoffmann-La Roche AG.

Reference

Pinto A, Corazzelli G, Evangelista A, et al. Frontline intensified ABVD demonstrates superior efficacy than PET-adapted ABVD in advanced Hodgkin lymphoma: the FIL-Rouge phase 3 trial by the Fondazione Italiana Linfomi. Hematol Oncol. 2023;41(suppl 2):31-33. doi:10.1002/hon.3163_4