Early Treatment Intensification in Advanced-Stage High-Risk Hodgkin Lymphoma (HL) Patients, with a Positive FDG-PET Scan After Two ABVD Courses – First Interim Analysis of the GITIL/FIL HD0607 Clinical Trial

Abstract

550 Background: Interim FDG-PET performed after 2 chemotherapy courses (PET-2) is the most powerful predictor of treatment outcome in advanced-stage, ABVD-treated HL (AAHL) patients (pts). Whether early therapy intensification in PET-2 positive HL pts improves overall treatment efficacy for all AAHL pts compared to standard ABVD is still unproven. Patients and study design: In the HD 0607 clinical trial (ClinicalTRial.gov identifier 00795613), AHL (stage IIB-IVB) pts prospectively enrolled by 26 Italian and one Israelian institution are treated with 2 ABVD courses and a PET-2 performed afterwards. PET-2+ pts are randomized to either BEACOPP escalated (Be) plus BEACOPP baseline (Bb) (4+4 courses) or Be+Bb (4+4) and Rituximab (R). PET-2 negative pts are treated with 4 additional ABVD and, upon CR achievement, randomized to either consolidation radiotherapy (Rxt) on the sites of initial bulky disease or no further treatment. Primary endpoint is the efficacy and feasibility of the overall therapeutic strategy. All the non-negative PET-2 (nnPET-2), defined as scans without any residual FDG uptake in any site outside the physiological areas of the tracer concentration, are uploaded in a website for blinded independent central review (BICR) by 6 nuclear medicine experts. Scans are interpreted by visual assessment according to the Deauville 5-point scale (5PS). Results: Starting from 07/2008 till 07/2012, 497 AHL pts were consecutively enrolled and 446 scanned with PET-2. 189/446 (42%) PET-2scans, judged as nnPET-2 by the local PET center, underwent review: 92 were adjudged as positive (62 score 4, 30 score 5) and 97 as negative (score 1–3). Altogether, of 446 pts scanned with a PET-2, 92 (20%) resulted positive and 354 (80%) negative. Age, sex, stage III-IV, bulky, extranodal sites or IPS class where equally distributed among PET-2 positive and negative pts.(p>.05). The median time from PET uploading in the website to review was 45.38 hours, (1–119). The BICR yielded a binary concordance rate among pair of reviewers “very good”, ranging from 0.77 to 0.83 (Cohen's k coefficient) and a overall concordance rate of 0.77 (Krippendorf's alpha). In 92 PET-2+ pts, 60 showed a single site of residual uptake in mediastinal (48), laterocervical (4), supraclavear (2), abdominal (3), axillary (1) nodes and in lung (2).In 32 there were ≥ 2 sites of persistent FDG uptake. In 38/40 pts with a positive PET-2 and bulky disease at baseline the residual FDG uptake (singe or multifocal) was seen within the bulky lesion. Overall response to treatment could be assessed in a cohort of 263 pts who had been fully restaged after lymphoma treatment. Forty-one (15%) had a positive and 222 (84%) a negative PET-2 scan. The relative dose intensity (RDI) for Be+Bb ± R and ABVD ± RxT treated pts. was 94.7% and 97.8%, respectively. Among 41 PET-2+ pts CR was achieved in 30 (73%), PR in 1 (2%) Progression or Relapse (Pro/Rel) in 8 (19%) and not evaluable (NE) in 2(5%). Among 222 PET-2- pts. CR was achieved in 212 (95.5%), PR in 2 (1%), Pro/Rel in 6 (3%), NE in 1 (0,5%). Treatment efficacy could be assessed in a cohort of 187 pts. with a complete treatment and a minimum follow-up of 12 months from treatment completion: 27 (15%) with a positive PET-2, treated with Be+Bb ± R and 160 (85%) with a negative PET-2, treated with ABVD ± RxT. The median follow-up from diagnosis was 845 days (101–1345). Among 27 PET-2+ pts, CCR (Continuous CR) was recorded in 22 (81%) Pro/Rel in 5 (18%). Three patients died in CR: 2 for septic shock and one for pneumonia. Among 160 PET-2- pts. CCR was recorded in 146 (91%), Pro/Rel in 9 (5%), Lost of FU (in CR) in 5 (3%). The 1-y PFS was 80.5%, 97.3% and 94.7% for PET-2+, PET-2- p, and for the entire population, respectively. Overall, treatment was well tolerated: 512 Adverse effects were reported: WHO grade 0+1: 453, grade 2: 45. Grade 3 were observed in 12 pts: anemia (2), neutropenia (6), pancytopenia (1), sepsis (1), diverticulitis (1), Vomiting (1). Grade 4 in 2 pts: pneumonia and neutropenia. Conclusions: These preliminary findings suggest that 1) an early switch from ABVD to escalated BEACOPP can be done safely in PET-2 positive pts, with CR achievement in the majority of cases; 2) a centralized online PET scan review system is feasible and allows a real time decision making process, without significant reduction in the RDI administered; 3) 5PS is a reliable interpretation criteria for interim PET scan, with a very good concordance rate among reviewers. Disclosures: No relevant conflicts of interest to declare.

Guidelines for the first line management of classical Hodgkin lymphoma

“…uk/search/StudyDetail.aspx?StudyID=4488) chose to intensify therapy with either 49 escalated BEACOPP or 4 9 BEA-COPP-14 with no RT requirement, while the Italian approach has been to use 8 cycles of BEACOPP (49 escalated and 49 standard) and RT to sites of initial bulk disease. Initial reports from the Italian group appear encouraging (Gallamini et al, , 2012.…”

“…A positive PET/CT scan after two cycles of ABVD, interim PET (iPET), has been shown to be strongly predictive of treatment failure for patients who continue with ABVD therapy (Gallamini et al, 2007). A number of recently closed and ongoing therapeutic trials are assessing whether, in comparison with historical controls, treatment intensification for iPET2 positive patients with escalated BEACOPP can improve patient outcomes (Gallamini et al, , 2012. The UK RATHL trial (http://public.ukcrn.org.…”

Evaluación del tratamiento de linfoma de Hodgkin con esquema ABVD en Chile

“…A su vez, en pacientes con etapa avanzada, un PET negativo después de dos a cuatro ciclos de ABVD, predice una evolución favorable. En cambio un PET positivo, se beneficiaría de un tratamiento intensificado [25][26][27] .…”

In Vivo Treatment Sensitivity Testing With Positron Emission Tomography/Computed Tomography After One Cycle of Chemotherapy for Hodgkin Lymphoma

“…Considering patients with advanced-stage HL, Gallamini et al 28 presented an interim analysis of the Gruppo Italiano Terapie Innovative nei Linfomi HD0607 trial where ABVD-treated, PET2-positive patients were switched to BEACOPPesc therapy, whereas PET2negative patients continued with ABVD. The interim analysis of 187 patients was performed after a minimum follow-up of 12 months.…”

“…Twenty-two of the 27 early PET-positive patients achieved continued CR after switching to BEACOPPesc, and the early PET-positive patients had a 1-year PFS of 80.5%. 28 In available observational studies, PET2-positive patients had only an approximately 30% chance of long-term PFS with continued ABVD. 3,[29][30][31] A recently opened trial for patients with advanced-stage HL is investigating an experimental approach where the results of PET/CT after one cycle of ABVD determine if patients continue with ABVD treatment (if PET negative) or are offered intensification to BEACOPPesc.…”