Post ASH speaker abstracts 2018

Hodgkin’s Lymphoma

Abstracts to support presentations from Wendy Osborne

Brentuximab Vedotin Plus Doxorubicin, Vinblastine, Dacarbazine (A+AVD) As Frontline Therapy Demonstrates Superior Modified Progression-Free Survival Versus ABVD in Patients with Previously Untreated Stage III or IV Hodgkin Lymphoma (HL): The Phase 3 Echelon-1 Study

Number: 6
Program: General Sessions
Session: Plenary Scientific Session

Joseph M Connors, MD1, Wojciech Jurczak, PhD, MD2, David J. Straus, MD3, Stephen M. Ansell, MD, PhD4, Won Seog Kim, M.D., Ph. D.5*, Andrea Gallamini, MD6*, Anas Younes, MD7, Sergei Alekseev, PhD8, Arpad Illes, MD9*, Marco Picardi10*, Ewa Lech-Maranda, MD, PhD11*, Yasuhiro Oki, MD12, Tatyana A Feldman, MD13, Piotr Smolewski, MD, PhD14*, Kerry J Savage, BSc, MD, MSc15, Nancy L. Bartlett, MD16, Jan Walewski, MD, PhD17, Robert W. Chen, MD18, Rod Ramchandren, MD19, Pier Luigi Zinzani, MD, PhD20, David Cunningham, MD, FRCP21*, Dae Seog Heo, MD22*, Andras Rosta, MD23*, Neil Josephson, MD24, Katherine L. Ruffner, MD25, Jessica Sachs26*, Rachael Liu, PhD27*, Hina Jolin, Pharm D27*, Dirk Huebner, MD28 and John A. Radford, MD29*

1Division of Medical Oncology and Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada, Vancouver, BC, Canada
2Department of Hematology, UJ CM, Krakow, Poland
3Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
4Division of Hematology, Mayo Clinic, Rochester, MN
5Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of (South)
6Research Innovation and Statistics, Lacassagne Cancer Centre, Nice, France
7Memorial Sloan Kettering Cancer Center, New York, NY
8Petrov Research Institute of Oncology, St. Petersburg, RUS
9University of Debrecen, Debrecen, HUN
10Hematology – Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy
11Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
12Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, TX
13John Theurer Cancer Center, Hackensack Meridian Health, Hackensack, NJ
14Medical University of Lodz, Lodz, POL
15Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, BC, Canada
16Washington University School of Medicine, St Louis, MO
17Maria Sklodowska-Curie Institute and Oncology Centre, Warsaw, Poland
18City of Hope National Medical Center, Duarte, CA
19Barbara Ann Karmanos Cancer Institute, Detroit, MI
20Institute of Hematology “L. e A. Seràgnoli”, Istituto Di Ematologia, Bologna, Italy
21The Royal Marsden NHS Foundation Trust, London, United Kingdom
22Seoul National University Hospital, Seoul, Korea, Republic of (South)
23Onkoterapia Alapitvany, Budapest, HUN
24Seattle Genetics, Bothell, WA
25Seattle Genetics, Seattle
26Unum Therapeutics, Inc., Cambridge, MA
27Millenium Pharmaceuticals, Inc.a wholly owned subsidiary of Taked, Cambridge, MA
28Millenium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA
29University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom

 

Background: Approximately 30% of advanced-stage HL patients have refractory disease or relapse following frontline treatment with ABVD. Brentuximab vedotin is a CD30‑directed antibody-drug conjugate approved for classical HL after failure of autologous stem cell transplantation (ASCT) or ≥2 prior chemotherapy regimens and as consolidation post‑ASCT for increased risk HL. We report data from ECHELON-1 (NCT01712490), an unblinded, open-label, randomized, multicenter, phase 3 study comparing A+AVD with ABVD as frontline therapy in previously untreated advanced HL.

Methods: Patients were randomized 1:1 to receive A+AVD (brentuximab vedotin 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2) IV on Days 1 and 15 of up to six 28-day cycles. Patients with a PET scan Deauville score of 5 after Cycle 2 could switch to alternative therapy at the treating physician’s discretion. Patients were stratified by region (Americas vs Europe vs Asia) and International Prognostic Score (0–1 vs 2–3 vs 4–7). Towards the end of the study, the IDMC recommended G-CSF primary prophylaxis for newly randomized patients receiving A+AVD based on a higher incidence of febrile neutropenia in that arm. The primary endpoint was modified PFS (defined as time to progression, death, or evidence of incomplete response followed by subsequent anticancer therapy) determined by independent review facility (IRF) assessment.

Results: 1334 patients with Stage III (36%) or IV (64%) HL were randomized (58% male; median age 36 y [range 18–83]; ≥45 y, 34%; ≥60 y, 14%). The primary endpoint of modified PFS (per IRF) was met (HR 0.770 [95% CI 0.603–0.982]; p=0.035), with 117 events in the A+AVD arm and 146 events in the ABVD arm (Fig), and was consistent with investigator (INV)-reported modified PFS (HR 0.725 [95% CI 0.574–0.916]; p=0.007). Modified PFS events per IRF were attributed to disease progression (90 vs 102); death (18 vs 22) or receipt of additional anticancer therapy for incomplete response (9 vs 22) after A+AVD or ABVD, respectively. The 2‑y modified PFS event free survival per IRF was 82.1% (95% CI 78.7–85.0) with A+AVD vs 77.2% (95% CI 73.7–80.4) with ABVD and per INV 81.0% [95% CI 77.6–83.9) with A+AVD vs 74.4% [95% CI 70.7–77.7] with ABVD. Data will be shown describing several pre-specified subgroups for which there was greater benefit with A+AVD vs the overall population. There were 28 deaths in the A+AVD arm and 39 in the ABVD arm (interim overall survival HR 0.721 [95% CI 0.443–1.173]; p=0.186). Other secondary endpoints including complete response (CR) rate, overall response rate at the end of randomization regimen, CR rate at the end of frontline therapy, the rate of PET negativity at the end of Cycle 2, duration of response, duration of CR, and event-free survival, also trended in favor of A+AVD. Median treatment duration and number of completed cycles were similar across treatment arms. Safety profiles were consistent with known toxicities of the single agents. Neutropenia was reported in 58% of patients receiving A+AVD and 45% receiving ABVD (febrile neutropenia in 19% and 8%, respectively). The incidence of discontinuations due to neutropenia or febrile neutropenia was ≤1% in both arms. Grade ≥3 infections were more common in the A+AVD arm (18%) than the ABVD arm (10%). In patients receiving A+AVD, primary prophylaxis with G‑CSF (n=83) reduced febrile neutropenia from 19% to 11% and Grade ≥3 infections and infestations from 18% to 11%. Peripheral neuropathy (PN) occurred in 67% of patients receiving A+AVD and 43% receiving ABVD (Grade ≥3: 11% A+AVD [1 patient with Grade 4] vs 2% ABVD); 67% of patients experiencing PN in the A+AVD arm had resolution or improvement of PN at last follow-up. Pulmonary toxicity was more frequent and more severe with ABVD (Grade ≥3: 3% ABVD vs <1% A+AVD). Of the on-study deaths, 7/9 in the A+AVD arm were associated with neutropenia; these deaths occurred in patients who had not received G-CSF primary prophylaxis. Of 13 on-study deaths in the ABVD arm, 11 were due to, or associated with, pulmonary toxicity. Conclusions: Compared with standard ABVD, A+AVD as frontline therapy improves outcome for patients with advanced HL including a 23% risk reduction in progression, death, or need for additional anticancer therapy. This establishes A+AVD as a new frontline option for patients with advanced-stage HL.

Early Interim PET in Patients with Advanced-Stage Hodgkin’s Lymphoma Treated within the Phase 3 GHSG HD18 Study

Result Type: Paper
Number: 737
Presenter: Peter Borchmann
Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Hodgkin Lymphoma—Chemotherapy and PET Studies

Peter Borchmann, MD1, Helen Goergen2*, Carsten Kobe, MD3*, Andreas Lohri, MD4, Richard Greil, MD5, Dennis A. Eichenauer6*, Josée M Zijlstra, MD, PhD7*, Jana Markova, MD8*, Julia Meissner, MD9*, Michaela Feuring-Buske, PD Dr.10*, Andreas Hüttmann, MD11, Judith Dierlamm, MD12*, Martin Sökler, MD13*, Stefan W. Krause, MD14*, Hans Eich, MD15*, Christian Baues, MD16*, Stefanie Kreissl, MD2*, Michael Fuchs, MD2*, Markus Dietlein, MD3* and Andreas Engert, MD2

1German Hodgkin Study Group and Department of Internal Medicine I, Klinikum Der Universitaet Zu Koeln, Koeln, DEU
2German Hodgkin Study Group and Department of Internal Medicine I, University Hospital Cologne, Cologne, Germany
3Department of Nuclear Medicine, University Hospital Cologne, Cologne, Germany
4Department of Oncology and Hematology, Cantonal Hospital, Liestal, Switzerland
5Paracelsus Medical University Salzburg and Salzburg Cancer Research Institute, Salzburg, Austria
6German Hodgkin Study Group and Department of Internal Medicine I, University of Cologne, Cologne, Germany
7Department of Hematology, VU University Medical Center Amsterdam, Amsterdam, Netherlands
8Department of Clinical Hematology, 3rd Faculty of Medicine, Charles University Prague, Prague, Czech Republic
9Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany
10Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
11Department of Haematology, University Hospital Duisburg-Essen, Essen, Germany
12Universitatskrankenhaus Eppendorf, Hamburg, DEU
13University Hospital, Tuebingen, Germany
14Medizinische Klinik 5, Hämatologie und Internistische Onkologie, Universitätsklinikum Erlangen, Erlangen, Germany
15Department of Radiotherapy, University Hospital of Muenster, Muenster, Germany
16Department of Radiotherapy, University Hospital Cologne, Cologne, Germany

 

Background: In our GHSG HD18 study for patients with newly diagnosed advanced-stage Hodgkin’s lymphoma (HL), we used early interim positron emission tomography after 2 cycles of eBEACOPP (PET-2) to guide further treatment. In contrast to other groups, we defined a Deauville score at interim staging (iDS) ≥ 3 as positive. The prognostic impact of PET-2 in the context of eBEACOPP was and still is unclear, however. We thus investigated its association with baseline characteristics and treatment outcome in patients treated with eBEACOPP in our international phase 3 HD18 trial (NCT00515554).

Methods: We recruited 2101 patients aged 18–60 years between 05/2008 and 07/2014. All patients received 2xeBEACOPP followed by centrally assessed PET-2, determining the iDS ranging from 1 (no FDG uptake) to 4 (FDG uptake above liver). Before 06/2011, patients were randomized 1:1 between 8xeBEACOPP and experimental treatment depending on iDS. After 06/2011, patients with iDS 1-2 were randomized 1:1 between 6xeBEACOPP and 4xeBEACOPP treatment, while all patients with iDS 3-4 received 6xeBEACOPP. Radiotherapy was recommended in case of residual lesions with DS ≥ 3 (until 04/2014)/ DS 4 (after 04/2014) after chemotherapy.

We explored the association of iDS with baseline characteristics, and assessed treatment outcomes according to iDS among patients treated with 6xeBEACOPP within our trial after 06/2011, considering different cutoffs for positivity. We applied means of descriptive statistics, Fisher’s exact test and multivariate logistic regression, and analyzed survival outcomes according to Kaplan-Meier, using Cox regression for comparisons.

Findings: Among 1945 randomized patients, 1005 (52%), 471 (24%) and 469 (24%) had iDS 1-2, 3 and 4, respectively, according to central review of PET-2.

Many clinical risk factors were associated with an unfavorable iDS, including adverse performance status, high international prognostic score (IPS) and the presence of large mediastinal mass (LMM), extranodal disease, 3 or more nodal areas and elevated ESR. Since patients with clinical stage (CS) IIB were only qualified for the trial when presenting with a large mediastinal mass, they had a high iDS more often than patients with CS III or IV or without B symptoms. Accordingly, in a multivariate analysis including all factors with univariate p<0.001, only LMM, extranodal involvement and a high IPS remained significant. After 06/2011, 216 patients with iDS 1-2 and all 506 patients with iDS 3-4 were assigned to receive 6xeBEACOPP. Among those 722 patients, PET after chemotherapy due to the presence of residual lesions was done in 83 (38%), 204 (76%) and 188 (80%) of patients with iDS of 1-2, 3, and 4, respectively, and FDG uptake above the liver (DS4) was observed in 3 (1%), 19 (7%) and 73 (31%), respectively (p<0.0001 each). Radiotherapy was performed in 9 (4%), 89 (33%) and 108 (46%), respectively (p<0.0001). With a median observation time of 37 months, 3-year PFS was 92.2%, 95.9% and 87.6% with iDS 1-2, 3 and 4, respectively (figure 1). The Hazard Ratio (HR) for iDS 3-4 vs. 1-2 was 1.1 (95% CI 0.6-1.9, p=0.8), but for iDS 4 vs. 1-3 it was 2.3 (95% CI 1.3-3.8, p=0.002). When including the associated baseline factors LMM, extranodal involvement and elevated IPS, the effect of iDS 4 remained significant (HR 2.4, 95% CI 1.4-4.1, p=0.002). Overall survival after 3 years was 97.6%, 99.0% and 96.8% with iDS of 1-2, 3 and 4, respectively, with a univariate HR for score 3-4 vs. 1-2 of 0.9 (95% CI 0.3-2.3, p=0.8) and for score 4 vs. 1-3 of 2.6 (95% CI 1.0-6.6, p=0.04). In the multivariate model, the effect of iDS 4 was even more pronounced (HR 3.2, 95% CI 1.3-8.3, p=0.02). Conclusion: The Deauville score after 2xeBEACOPP is associated with many clinical risk factors at baseline. For patients treated with 6xeBEACOPP followed by irradiation of PET-positive residuals, iDS 3 does not indicate an increased risk of treatment failure and is associated with long-term outcomes identical to those after clearly negative PET-2 (iDS 1-2). DS 4 at PET-2 adds some prognostic information to the baseline risk factors, but 3-year outcomes do not suggest a need for treatment intensification beyond standard therapy. Based on these results, the GHSG has decided to adopt the more widely used cutoff of iDS 4 for PET positivity. Thereby, about 75% of patients could take advantage of the abbreviated treatment with only 4 cycles of eBEACOPP in a PET-2-guided approach as defined in the HD18 study.

Advanced-Stage Hodgkin Lymphoma in the East of England Cancer Network: A 10-Year Comparative Analysis of Outcomes for Patients Treated with ABVD or Escalated BEACOPP in the Non-Trial Setting Compared with Age-Matched Patients Treated in the Multinational RATHL Trial

Result Type: Paper
Number: 735
Presenter: James Russell
Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Hodgkin Lymphoma—Chemotherapy and PET Studies

James Russell, MD1, Angela Collins, MD2*, Alexis Fowler, MD3*, Mamatha Karanth, MD4*, Isabel Lentell, MD1*, Chandan Saha, MD5*, Suzanne Docherty, MD2*, Joseph Padayatty, MD1*, Kyaw Maw, MD6*, Lisa Cooke, MD5*, Andrew Hodson, MD7*, Nimish Shah, MD2*, Shalal Sadullah, MD6*, Nicholas Grigoropoulos, MD, PhD1*, Wendi Qian1*, Amy A Kirkwood8*, Benjamin J Uttenthal, MD, PhD1*, Peter Johnson, MD, FRCP9 and George A Follows, MD, PhD1*

1Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
2Haematology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, United Kingdom
3Haematology, Peterborough and Stamford Hospitals NHS Foundation Trust, Peterborough, United Kingdom
4Haematology, West Suffolk NHS Trust, Bury St Edmunds, United Kingdom
5Haematology, The Queen Elizabeth Hospital King’s Lynn NHS Foundation Trust, King’s Lynn, United Kingdom
6Haematology, James Paget University Hospitals NHS Foundation Trust, Great Yarmouth, United Kingdom
7Haematology, Ipswich Hospital NHS Trust, Ipswich, United Kingdom
8Cancer Research UK and University College London Cancer Trials Centre, London, United Kingdom
9Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom

 

Introduction: The majority of young patients presenting with advanced-stage Hodgkin lymphoma (HL) in the UK are managed with ABVD. However, from 2009, escalated BEACOPP (escBEACOPP) was introduced as a treatment option in certain UK cancer centres. Within the East of England Cancer Network (EECN), 6 hospitals introduced escBEACOPP as a treatment option, while 2 hospitals continued to use ABVD as standard first-line therapy for all patients. During this time period, recruitment to the RATHL (Response Adjusted Therapy for Hodgkin Lymphoma) trial was also a first-line treatment option across the UK and 4 of the EECN centres. Analysing data from all patients treated in the EECN centres and the RATHL trial has therefore enabled outcomes of patients treated with either escBEACOPP or ABVD within a non-trial setting to be compared to patients treated with ABVD in a clinical trial.

Methods: We performed a retrospective multicentre analysis of patients treated for advanced-stage HL, aged 16–59 years, diagnosed between 2004–2014 in the EECN and compared outcomes with age and international prognostic score (IPS)-matched patients in the RATHL trial.

Results: Over this 10-year period, 250 patients were diagnosed with advanced-stage HL in the EECN; 202 commenced treatment with ABVD (23 within RATHL), 44 escBEACOPP, 3 other regimens, and 1 died before treatment. Five-year progression-free survival (PFS) for all patients was 82% and overall survival (OS) was 93%. In RATHL, 1088 patients aged 18-59 years commenced treatment with ABVD, with 5-year PFS of 81% and OS of 95%. Within the EECN, there was a clinician–patient preference to treat higher-risk patients (IPS 3+) with more intensive therapy; a higher proportion of escBEACOPP patients were IPS 3+ (IPS 3+: escBEACOPP 75% vs. ABVD 39%, p<0.0001). ABVD-treated EECN patients had highly similar 5-year PFS and OS rates compared with age-matched RATHL patients (PFS 80% vs 81%; HR: 1.1 (95% CI: 0.8–1.5), p=0.60: OS 93% vs 95%; HR: 1.5 (95% CI: 0.8–2.7), p=0.21; Figure 1A-B). Despite being enriched with higher-risk patients, the 5-year PFS for all escBEACOPP-treated EECN patients was superior to ABVD in both the EECN and RATHL cohorts (PFS 95% vs 80% (EECN); HR 0.2 (95% CI: 0.1–0.9), p=0.04; Figure 1C; Table 1), but there was no significant OS advantage (5-year OS 97% vs. 93% (EECN); HR 0.4 (95% CI: 0.0–2.8), p=0.34; Figure 1D; Table 1). However, subgroup analysis of higher-risk (IPS 3+) patients found that escBEACOPP-treated EECN patients had both a 5-year PFS and OS advantage when compared with IPS 3+ ABVD-treated EECN patients (PFS 97% vs 74%; HR 0.1 (95% CI: 0.0–0.8), p=0.03; OS 100% vs 85%; p=0.03). However, when these higher-risk escBEACOPP patients were compared with IPS 3+ patients from RATHL, the significance of the OS advantage was lost (Table 1). Despite similar relapse/refractory rates for IPS 3+ ABVD-treated patients in the EECN and RATHL datasets, the OS for relapsed/refractory patients was inferior in the EECN. One explanation could be the time period over which the EECN data was collected, as the majority (7/9) of higher-risk ABVD-treated EECN patients who died from progressive disease died prior to 2011, when brentuximab vedotin was unavailable to treat relapsed HL in the UK. Conclusion: Our data support recently published European data showing that first-line HL patients treated in the non-trial setting achieve similar outcomes to those treated in contemporary clinical trials. Our data also reflect prospective trial results which show a first-remission PFS, but not OS, advantage for advanced-stage HL patients treated with escBEACOPP compared with ABVD, but suggest that higher-risk patients might benefit disproportionately from more intensive first-line therapy with escBEACOPP. However, improved access to more effective salvage treatments for relapsed/refractory patients may have diminished any OS benefit from the use of first-line escBEACOPP in higher-risk patients.

Nivolumab for Newly Diagnosed Advanced-Stage Classical Hodgkin Lymphoma (cHL): Results from the Phase 2 Checkmate 205 Study

Result Type: Paper
Number: 651
Presenter: Rod Ramchandren
Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Hodgkin Lymphoma Immunotherapy Studies; nodular lymphocyte predominant Hodgkin lymphoma clinical studies

Rod Ramchandren, MD1, Michelle A. Fanale, MD2, Antonio Rueda3*, Philippe Armand, MD, PhD4, Marek Trněný, MD, PhD5, Tatyana A Feldman, MD6, Stephen M. Ansell, MD, PhD7, Mariano Provencio, MD8*, Ulrich Jaeger, MD9*, Jonathon B Cohen, MD, MS10, Kerry J Savage, BSc, MD, MSc11, Wolfgang Willenbacher12, Mariana Sacchi13*, Anne Sumbul13* and Eva Domingo Domenech, MD14*

1Barbara Ann Karmanos Cancer Institute, Detroit, MI
2University of Texas MD Anderson Cancer Center, Houston, TX
3Costa del Sol Hospital, Marbella, Spain
4Dana-Farber Cancer Institute, Boston, MA
5Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic
6Hackensack University Medical Center, Hackensack, NJ
7Mayo Clinic, Rochester, MN
8Hospital Universitario Puerta de Hierro, Madrid, Spain
9Medical University of Vienna, Vienna, Austria
10Department of Hematology and Medical Oncology, Emory University – Winship Cancer Institute, Atlanta, GA
11British Columbia Cancer Agency Center for Lymphoid Cancer, Vancouver, BC, Canada
12Innsbruck University Hospital & OncoTyrol – Center of Personalized Cancer Medicine, Innsbruck, Austria
13Bristol-Myers Squibb, Princeton, NJ
14Institut Català d’Oncologia (ICO), Barcelona, Spain

 

Introduction: Nivolumab (nivo), an immune checkpoint inhibitor targeting the programmed death-1 (PD-1) receptor, augments T-cell activation and restores antitumor T-cell function. In the phase 2 CheckMate 205 study (NCT02181738), nivo demonstrated frequent (65–73%) and durable objective responses across 3 cohorts of patients (pts) with relapsed/refractory (R/R) cHL after failure of autologous hematopoietic cell transplantation (Fanale M et al. ICML 2017 [oral 125]). While most pts with cHL are cured with first-line therapy, those with advanced-stage disease are more likely to relapse or progress. More aggressive regimens (eg, BEACOPPesc., Borchmann P et al. Lancet Oncol 2017) are associated with improved progression-free survival (PFS) but are hampered by excessive toxicities and have limited applicability in elderly pts. PD-1 ligand gene amplification has been linked to poorer outcomes in cHL pts treated with standard induction regimens (Roemer MG et al. J Clin Oncol 2016) but is associated with improved responses to nivo in R/R cHL (Younes A et al. Lancet Oncol 2016), suggesting that PD-1 blockade may benefit pts in the frontline setting. We therefore assessed the safety and efficacy of nivo as a single-agent lead-in treatment followed by nivo in combination with chemotherapy, excluding bleomycin due to potential overlapping pulmonary toxicity, for pts with previously untreated advanced-stage cHL.

Methods: Cohort D of CheckMate 205 enrolled untreated pts (aged ≥18 y) with advanced-stage newly diagnosed cHL (stage III, IV, or II with B symptoms and extranodal or bulky disease) and ECOG score 0–1. Pts received 4 biweekly doses of nivo monotherapy (240 mg IV flat dose) followed by nivo plus chemotherapy (nivo 240 mg IV, doxorubicin, vinblastine, dacarbazine [N-AVD]) for 6 cycles (12 doses). The primary endpoint was safety and tolerability: proportion of pts with ≥1 grade (G) 3–5 treatment-related adverse event (TRAE) ≤30 d after last dose. Additional endpoints included rates of discontinuation and of independent radiologic review committee–assessed complete remission (CR).

Results: At database lock (June 2017), 51 pts had been treated, with a median (range) follow-up of 8 (1–11) mo. Median (range) age was 37 (18–87) y; 29 (57%) pts had stage IV disease, and 41 (80%) had B symptoms. At baseline, 7 (14%) pts had bulky disease and 17 (33%) had extranodal involvement. International prognostic score was ≥3 in 25 (49%) pts. At analysis, 49 (96%) pts had completed nivo monotherapy treatment, receiving all 4 doses; 1 pt discontinued due to disease progression and 1 due to study drug toxicity (G1–2 hyperthyroidism), subsequently receiving AVD only. TRAEs for both treatment phases are shown in the Table. During nivo monotherapy, 2 pts had 1 dose delay each due to an AE; 2 (4%) pts had serious AEs (SAEs; 1 G1–2 hyperthyroidism; 1 G1–2 polyneuropathy); an immune-mediated AE (IMAE), G1–2 hyperthyroidism, was reported in 2 (4%) pts. Fifty pts started combination therapy; at database lock, 35 (70%) had completed therapy, with 34 (69%) receiving 12 N-AVD doses. With N-AVD, 10 (20%) pts had SAEs, 6 G3–4; the most common G3–4 SAE was febrile neutropenia in 2 (4%) pts; IMAEs occurring in >1 pt were hypothyroidism in 8 (16%) pts and increased ALT in 2 (4%). AEs leading to discontinuation of N-AVD occurred in 2 pts: G1–2 hepatic abnormality, and G3–4 febrile neutropenia (FN) and Klebsiella bacteremia. The pt who developed FN and Klebsiella bacteremia died 38 d after the first dose of his fifth cycle of N-AVD due to study drug toxicity of acute respiratory insufficiency. Important primary, secondary, and exploratory endpoints (including CR and objective response rates at end of monotherapy, after 2 combocycles and end of therapy, and PFS) will be presented at the meeting.

Conclusions: Nivo monotherapy followed by N-AVD combination therapy was well-tolerated in pts with newly diagnosed, untreated, advanced-stage cHL. Nearly all pts completed nivo monotherapy treatment and started combination therapy with N-AVD. The safety profile was consistent with historical experience of nivo and AVD separately, with no new safety signals. Nivo followed by N-AVD may provide a tolerable alternative treatment option to standard-of-care multi-agent chemotherapy for pts with newly diagnosed advanced-stage cHL.

Study support:

BMS. Writing support: Matthew Thomas, PhD, Caudex, funded by BMS.

Efficacy of Chemotherapy or Chemo-Anti-PD-1 Combination after Unsatisfactory Response of Anti-PD-1 Therapy for Relapsed and Refractory Hodgkin Lymphoma: A Retrospective Series from Lysa Centers

Result Type: Paper
Number: 652
Presenter: Cédric Rossi
Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Hodgkin Lymphoma Immunotherapy Studies; nodular lymphocyte predominant Hodgkin lymphoma clinical studies

Cédric Rossi, MD1,2*, Julia Gilhodes3*, Marie Maerevoet, MD4*, Charles Herbaux5*, Pauline Brice, MD6, Sylvain Garciaz7*, Cecile Borel, MD8*, Loic Ysebaert, MD, PhD9*, Lucie Oberic, MD10*, Julien Lazarovici, MD11*, Bénédicte Deau-Fisher, MD12*, Jehan Dupuis, MD13*, Adrien Chauchet14*, Julie Abraham, MD15*, Fontanet Bijou16*, Aspasia Stamatoullas-Bastard17*, Jean Valère Malfuson18*, Camille Golfier1*, Camille Laurent, MD, PhD3*, Salim Kanoun, MD3*, Thomas Filleron, PhD19*, Rene-Olivier Casasnovas, MD20* and Hervé Ghesquières, MD, PhD21*

1Hospital, Dijon, France
2Hospital, TOULOUSE, France
3Institut universitaire du cancer Toulouse- Oncopole, Toulouse, France
4Hospital Jules Bordet, Bruxelles, France
5Service des Maladies du Sang, CHRU de Lille, Lille, France
6Hematology Department, AP-HP Hopital Saint-Louis, Paris, France
7Institut Paoli Calmettes, Department of Hematology, Marseille, France
8Hematology Department, IUCT-Oncopole, Toulouse, France
9Departement d’Hematologie, IUCT-Oncopole, Toulouse, France
10IUCT-Oncopole, Department of Hematology, Toulouse, France
11Department of Hematology, Gustave Roussy Cancer Center, Villejuif, France
12Cochin Hospital, Hematology Department, Paris, France
13Hospital intercommunal, Créteil, France

14Hospital, Besancon, France
15Hospital, Limoges, France
16Hospital Bergonié, Bordeaux, France

17Hospital Henri Becquerel, Rouen, France
18Hôpital Percy, Clamart, France

19Biostatistics unit, Institut universitaire du cancer Toulouse- Oncopole, Toulouse, France
20CHU Dijon, Dijon, FRA
21Hospices Civils de Lyon, Université Claude Bernard, Centre Hospitalier Lyon-Sud, Lyon, France

 

Introduction: Hodgkin lymphoma (HL) pts who relapse after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV) therapy have a poor outcome. For these relapsed and refractory (R/R) HL pts, anti-PD-1 therapy gives a high rate of objective responses. However, the rate of complete response (CR) remains modest and in the updated results of anti-PD-1 therapy clinical trials, about 50% of pts are still without progressive disease after one year of treatment. As anti-PD-1 therapy modifies the anticancer immune response, we hypothesize that anti-PD-1 therapy may increase sensitivity to chemotherapy (CT) given after anti-PD-1 therapy (sequential strategy) or in combination with anti-PD-1 therapy after an unsatisfactory response to immunotherapy (concomitant strategy). We retrospectively analyzed these two clinical situations in 30 R/R HL pts from LYSA centers treated with anti-PD-1 therapy.

Methods: We included R/R HL pts from 14 LYSA centers who received anti-PD-1 therapy in the context of clinical trials (N=4) or an authorization for temporary use (ATU) from the French medical drug agency (N=26). Before the anti-PD-1 therapy, pts had received a median of six (range, 2-14) lines of therapy, 69% had HDT+ASCT, 14% had allograft and 93% had been treated with BV. We considered two groups of pts: i. 19 pts (63%) in whom the anti-PD-1 therapy was stopped at the introduction of CT (Group 1); ii. 11 pts (37%) with an unsatisfactory response to anti-PD-1 therapy in whom a combination of CT with immunotherapy was initiated to optimize the response (Group 2). The quality of the response after the introduction of CT was evaluated retrospectively by each treating physicians according to Cheson 2007 or 2014 criteria. We also determined whether new CT treatments after and in combination with anti-PD-1 therapy led to unexpected toxicities and whether new treatment schedules made pts eligible for allograft.

Results: At the start of anti-PD-1, the median age of pts was 37 years old (range, 20-75), 24% had Ann Arbor III/IV stages, 34% had B symptoms and 21% had a performance status (PS) of 2-3. Patients received a median of 10 infusions (range, 2-52) of anti-PD-1 therapy with nivolumab (N=26, 87%) or pembrolizumab (N=4, 13%). The best responses achieved during anti-PD-1 therapy were a complete response (CR) for 5 patients, a partial response (PR) for 17 pts, stable disease (SD) for 2 pts and progression for 6 pts. In group 1, 17 pts were in progression, one pt in PR, and another pt in SD at the end of anti-PD-1 therapy alone. In group 1, after anti-PD-1 therapy, the pts were treated with vinblastine (N=3), gemcitabine (N=2) or bendamustine alone (N=3) or in combination with BV (N=4), GVD (N=1), ICE (N=1), DHAP (N=1), escalated BEACOPP (N=1), vinorelbine (N=1), vepeside (N=1) and caelyx (N=1). In group 2, before the combination, the response status was progression for 7 pts and PR for 4 pts. In group 2, to optimize the response to anti-PD-1, pts received vinblastine (N=7), gemcitabine (N=2) and BV (N=2). In the 28 evaluable pts, 11/18 (61%) in group 1 and 9/10 (90%) in group 2 showed an improved response after chemotherapy alone or combination with anti-PD-1 therapy respectively. In group 1, there were 6 CR (32%), 5 PR (26%), 1 SD (5%) and 6 PD (32%) (Figure 1B). In group 2, there were 5 CR (45%), 5 PR (45%) and 1 SD (10%) (Figure 1A). Of note, among the ten pts treated with vinblastine, 4 were in CR, 3 in RP, 1 in SD and 2 in progression. No unexpected toxicity was observed during the CT. Four pts had an allograft after the sequential CT (N=3) and concomitant CT strategy (N=1). Three pts were in CR 274, 279 and 480 days after the allograft and the fourth has not yet been evaluated. Allografts are now scheduled for 6 pts. With a median follow-up of 9.1 months (95%CI, 6.1-14) following the initiation of chemotherapy (alone or combined) the median PFS and OS were 8.4 and 14.6 months, respectively.

Conclusions: Our retrospective study showed that pts with an unsatisfactory response or PD with anti-PD-1 therapy had a new objective response with CT alone (61%) or CT in combination with anti-PD-1 therapy (90%). This response could make some pts eligible for allograft. Prospective clinical trials are needed to confirm the synergistic effect of CT with anti-PD-1 therapy and to determine which CT provides the best results in combination with these checkpoint inhibitors.

Sequential Brentuximab Vedotin (Bv) before and after Adriamycin, Vinblastine, and Dacarbazine (Bv-AVD) for Older Patients with Untreated Classical Hodgkin Lymphoma (cHL): Final Results from a Multicenter Phase II Study

Result Type: Paper
Number: 733
Presenter: Andrew Evens
Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphoma and T/NK Cell Lymphoma—Clinical Studies: Hodgkin Lymphoma—Chemotherapy and PET Studies

Andrew M. Evens, DO, MSc1, Ranjana H. Advani, MD2, Michelle A. Fanale, MD3, Sonali M. Smith, MD4, Irene Helenowski, PhD5*, Borko Jovanovic, PhD5*, R. Gregory Bociek, MD6, Andreas Klein, MD7, Jane N. Winter, MD8, Leo I. Gordon, MD9 and Paul A. Hamlin, MD10

1Division of Hematology/Oncology, Chief, Tufts University School of Medicine and Cancer Center, Boston, MA
2Stanford University, Stanford, CA
3Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Ctr., Houston, TX
4Section of Hematology/Oncology, University of Chicago, Chicago, IL
5Department of Preventive Medicine, Northwestern University, Chicago, IL
6Univ. of Nebraska Med. Ctr. Section of Hem./Onc., Omaha, NE
7Tufts Medical Center, Boston, MA
8Department of Medicine-Hematology/Oncology, Robert H. Lurie Comp. Cancer Center, Chicago, IL
9Northwestern University, Chicago, IL
10Memorial Sloan-Kettering Cancer Center, New York, NY

 

Background: Standard therapeutic regimens for older HL patients (pts) may confer significantly increased toxicity and inferior survival compared with younger pts. Reported complete remission (CR) rates for older pts are 45-76% with 2-year (yr) progression-free survival (PFS) rates of 50-71% (eg, Evens et al. Blood 2012). With a goal of improving outcomes for older cHL pts, this multicenter phase 2 study tested Bv given sequentially before and after standard AVD chemotherapy.

Methods: Older pts (aged ≥60 yrs) with stage IIB-IV, untreated cHL were eligible. Pts received 2 ‘lead-in’ doses of single-agent Bv 1.8 mg/kg (q 3 weeks) followed by 6 cycles of standard AVD. Supportive antibiotics were encouraged & granulocyte growth factor was allowed. Responding pts proceeded to consolidation (Cx) therapy with 4 Bv cycles. Study design was a Simon 2-stage; the primary endpoint was CR rate after AVD (ie, prior to Bv Cx) using revised Cheson with FDG-PET; pts must have received 2 cycles of AVD to be evaluable for response. The study was considered promising if >70% of evaluable pts demonstrated CR. Univariate & multivariate analyses (MVA) were performed using Cox proportional hazard regression for associations between lab and clinical factors (including co-morbidities assessed by the Cumulative Illness Rating Scale (CIRS)) with survival.

Results: 48 pts enrolled to the study (8/2012-8/2016) with 41 being evaluable for response. Characteristics for all pts included: median age 69 yrs (60-88); 30M:18F; median ECOG PS of 1 (21% PS=2); 82% stage III/IV disease (bone marrow involved 23%); and IPS 3-7 in 60%. No pts had loss of activities of daily living (ADL) at baseline, while 12% had loss of instrumental ADLs. Median CIRS co-morbidity score at baseline was 6 (0-20). 6 pts received <2 cycles of AVD and were non-evaluable for response for the following reasons: toxicity in cycle 1 AVD, wound infection and syncope (n=2); withdrew consent (n=2); hepatic toxicity to BV lead-in (n=1) & grade 5 pancreatitis with Bv lead-in (n=1) (Gandhi et al Blood 2014). Notably, the median pre-treatment CIRS score among pts who received <2 cycles of AVD (due to toxicity and/or consent withdrawal) was 13 (10-19) vs 5 (0-20) for pts who received 2 or more AVD cycles as planned (P=0.001). Collectively, 52% of pts completed all 12 intended cycles and 65% received at least 1 Bv Cx treatment as planned. Median CIRS for pts who completed all cycles of Bv-AVD was 4 vs 8 for pts who did not (P=0.03). The overall response rate (ORR) to the initial 2 doses of Bv ‘lead-in’ was 87% with 30% CR rate. After completion of AVD, the ORR and CR rates for evaluable pts were 95% and 90%, respectively. One pt improved response after consolidation yielding a post-Cx CR rate of 93%. By intent-to-treat (ITT) including all n=48 pts, ORR and CR rates were 88% and 81%, respectively. With median follow-up of 24 months (6-46), 2-yr PFS for evaluable pts was 90%. On ITT of all 48 pts, the 2-yr PFS rate was 85% with corresponding 2-yr OS of 94% (Figure). 42% of all pts experienced a serious adverse event (AE). Grade 3/4 AEs occurring in >1 pt were neutropenia (60%); infection (15%), febrile neutropenia (8%); transaminitis (6%); renal insufficiency (6%); urinary infection (6%); pneumonia (6%); hyponatremia (6%); fatigue (6%); febrile neutropenia (6%); diarrhea (4%); pancreatitis (4%), & peripheral neuropathy (PN) (4%). 33% of all pts experienced grade 2 PN (6% motor/27% sensory); the majority were reversible. Treatment related mortality on study was 2% (n=1 pancreatitis). Reasons for study discontinuation were: completed treatment (52%); toxicity/AEs (33%); withdrew consent/refused additional treatment (9%); & progressive disease or death (6%). Finally, for pt prognostication, increasing age (continuous) (P=0.005), female (P=0.05) & increased CIRS (continuous) (P=0.006) were associated with inferior PFS on univariate analysis; on MVA, only increasing age remained significant (HR 1.19 per yr >60, 95%CI 1.02–1.37, P=0.02).

Conclusions: Bv-AVD incorporating Bv sequentially before and after chemotherapy represents among the best-reported outcomes to date for untreated older cHL pts. Efforts to maintain these robust remission and survival rates, but with less toxicity, should be a focus of ongoing investigation. This should include response-adapted design and integration of other novel agents (eg, checkpoint inhibitors), especially for pts with advanced ages and/or multiple co-morbidities.