[en] Older classical Hodgkin lymphoma (cHL) patients require more effective and less toxic therapies. In this multicenter, prospective, phase 2 study, we investigated a new first-line therapy regimen comprising 6 cycles of prednisone (40 mg/m2 Day 1-5), vinblastine (6 mg/m2, Day 1), doxorubicin (40 mg/m2, Day 1), bendamustine (120 mg/m2, Day 1) (PVAB regimen) every 21 days for newly diagnosed classical HL patients aged 61 years or older with an advanced Ann Arbor stage. A Mini Nutritional Assessment (MNA) score ≥ 17 was the cutoff value for including patients ≥70 years old. The primary endpoint was the complete metabolic response (CMR) rate after 6 cycles. The median age of the 89 included patients was 68 years (range, 61-88), with 35 patients aged ≥70 years old (39%). Seventy-eight patients (88%) completed the 6 cycles. The toxicity rate was acceptable, with a 20% rate of related serious adverse events. CMR was achieved by 69 patients (77.5%; 95% CI, 67-86). After a median follow-up of 42 months, 31 patients progressed or relapsed (35%), and 24 died (27%) from HL (n=11), toxicity during treatment (n=4), secondary cancers (n=6), or other causes (n=3). The 4-year progression-free survival (PFS) and overall survival rates were 50% and 69%, respectively. Multivariate analysis showed that liver involvement (P =0.001), lymphopenia (P =0.001), CRP (P =0.0005), comedications (P =0.003) were independently associated with PFS. The PVAB regimen yielded a high CMR rate with acceptable toxicity. Over long-term follow-up, survival endpoints were influenced by unrelated lymphoma events. Registration at www.clinicaltrials.gov was NCT02414568.
Disciplines :
Hematology
Author, co-author :
Ghesquieres, Herve; Hopital Lyon Sud, Claude Bernard Lyon 1 University, Pierre-Benite, France
Krzisch, Daphné ; APHP, Hopital Saint Louis, Paris, France
Nicolas Virelizier, Emmanuelle; Centre Leon Berard, Claude Bernard Lyon 1 University, Lyon, France
Kanoun, Salim ; Cancer Research Center of Toulouse, Team 9, INSERM UMR 1037, Toulouse, France
Gac, Anne Claire; Institut d'Hematologie de Basse Normandie, France
Guidez, Stéphanie; CHU de Poitiers
Touati, Mohamed; CHU LIMOGES, Limoges, France
Laribi, Kamel; Department of Hematology, Centre Hospitalier Le Mans, Le Mans, France, Le Mans, France
Morschhauser, Franck ; CHU Lille, ULR 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France
The authors acknowledge the Lymphoma Study Association Clinical Research PVAB team and every research team and nurse in the participating centers. Mundipharma provided bendamustine and funded the trial in part. The funder had no role in trial design, data collection, data analysis, data interpretation, or the writing of the report. Lymphoma Study Association Clinical Research is the sponsor of the PVAB trial. Contribution: H.G. designed the trial in collaboration with F. Morand; H.G. D.K. E.N.-V. A.C.G. S.G. M.T. K.L. F. Morschhauser, C.B. A.W.-R. F.O.-P. M.A. P.Q. and O.C. enrolled and treated patients; M.F. performed the statistical analysis; A.T.-G. D.D. and B.B. performed the pathology review; S.K. and A.B.-R. performed the PET review; H.G. S.K. M.F. F. Morand, A.B.-R. B.B. D.D. A.T.-G. and O.C. analyzed the results; H.G. wrote the first draft of the manuscript; and all authors approved the final version of the manuscript and are accountable for all aspects of the work.
Hjalgrim, H, On the aetiology of Hodgkin lymphoma. Dan Med J, 59(7), 2012, B4485.
Björkholm, M, Weibull, CE, Eloranta, S, Smedby, KE, Glimelius, I, Dickman, PW, Greater attention should be paid to developing therapies for elderly patients with Hodgkin lymphoma-a population-based study from Sweden. Eur J Haematol 101:1 (2018), 106–114.
Böll, B, Görgen, H, The treatment of older Hodgkin lymphoma patients. Br J Haematol 184:1 (2019), 82–92.
Evens, AM, Helenowski, I, Ramsdale, E, et al. A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era. Blood 119:3 (2012), 692–695.
Stamatoullas, A, Brice, P, Bouabdallah, R, et al. Outcome of patients older than 60 years with classical Hodgkin lymphoma treated with front line ABVD chemotherapy: frequent pulmonary events suggest limiting the use of bleomycin in the elderly. Br J Haematol 170:2 (2015), 179–184.
Böll, B, Bredenfeld, H, Görgen, H, et al. Phase 2 study of PVAG (prednisone, vinblastine, doxorubicin, gemcitabine) in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma. Blood 118:24 (2011), 6292–6298.
Proctor, SJ, Wilkinson, J, Jones, G, et al. Evaluation of treatment outcome in 175 patients with Hodgkin lymphoma aged 60 years or over: the SHIELD study. Blood 119:25 (2012), 6005–6015.
Moskowitz, AJ, Hamlin, PA Jr., Perales, MA, et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol 31:4 (2013), 456–460.
Santoro, A, Mazza, R, Pulsoni, A, et al. Five-year results of the BEGEV salvage regimen in relapsed/refractory classical Hodgkin lymphoma. Blood Adv 4:1 (2020), 136–140.
LaCasce, AS, Bociek, RG, Sawas, A, et al. Three-year outcomes with brentuximab vedotin plus bendamustine as first salvage therapy in relapsed or refractory Hodgkin lymphoma. Br J Haematol 189:3 (2020), e86–e90.
Vellas, B, Guigoz, Y, Garry, PJ, et al. The Mini Nutritional Assessment (MNA) and its use in grading the nutritional state of elderly patients. Nutrition 15:2 (1999), 116–122.
Soubeyran, P, Fonck, M, Blanc-Bisson, C, et al. Predictors of early death risk in older patients treated with first-line chemotherapy for cancer. J Clin Oncol 30:15 (2012), 1829–1834.
Cheson, BD, Fisher, RI, Barrington, SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32:27 (2014), 3059–3068.
Linn, BS, Linn, MW, Gurel, L, Cumulative illness rating scale. J Am Geriatr Soc 16:5 (1968), 622–626.
Lawton, MP, Brody, EM, Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 9:3 (1969), 179–186.
Katz, S, Ford, AB, Moskowitz, RW, JACKSON, BA, JAFFE, MW, Studies of illness in the aged: the index of ADL—a standardized measure of biological and psychosocial function. JAMA 185 (1963), 914–919.
Bellera, CA, Rainfray, M, Mathoulin-Pélissier, S, et al. Screening older cancer patients: first evaluation of the G-8 geriatric screening tool. Ann Oncol 23:8 (2012), 2166–2172.
Casasnovas, RO, Kanoun, S, Tal, I, et al. Baseline total metabolic volume (TMTV) to predict the outcome of patients with advanced Hodgkin lymphoma (HL) enrolled in the AHL2011 LYSA trial. J Clin Oncol, 34(15 suppl), 2016 Abstract 7509.
Evens, AM, Hong, F, Gordon, LI, et al. The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496. Br J Haematol 161:1 (2013), 76–86.
Simon, R, Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1 (1989), 1–10.
Halinski, RS, Feldt, LS, The selection of variables in multiple regression analysis. J Educ Meas 7:3 (1970), 151–157.
Tucci, A, Martelli, M, Rigacci, L, et al. Comprehensive geriatric assessment is an essential tool to support treatment decisions in elderly patients with diffuse large B-cell lymphoma: a prospective multicenter evaluation in 173 patients by the Lymphoma Italian Foundation (FIL). Leuk Lymphoma 56:4 (2015), 921–926.
Evens, AM, Advani, RH, Helenowski, IB, et al. Multicenter phase II study of sequential brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine chemotherapy for older patients with untreated classical Hodgkin lymphoma. J Clin Oncol 36:30 (2018), 3015–3022.
Gray, RJ, A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:3 (1988), 1141–1154.
Camp, RL, Dolled-Filhart, M, Rimm, DL, X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10:21 (2004), 7252–7259.
Prentice, RL, Kalbfleisch, JD, Peterson, AV, Flournoy, N, Farewell, VT, Breslow, NE, The analysis of failure times in the presence of competing risks. Biometrics 34:4 (1978), 541–554.
Putter, H, Fiocco, M, Geskus, RB, Tutorial in biostatistics: competing risks and multi-state models. Stat Med 26:11 (2007), 2389–2430.
Evens, AM, Connors, JM, Younes, A, et al. Older patients (aged 60 years) with previously untreated advanced-stage classical Hodgkin lymphoma: a detailed analysis from the phase III ECHELON-1 study. Haematologica 107:5 (2022), 1086–1094.
Böll, B, Fosså, A, Goergen, H, et al. B-CAP (brentuximab vedotin, cyclophosphamide, doxorubicin and predniso(lo)Ne) in older patients with advanced-stage Hodgkin lymphoma: results of a phase II intergroup trial by the German Hodgkin Study Group (GHSG) and the Nordic Lymphoma Group (NLG). Blood, 132(suppl 1), 2018 Abstract 926.
Orellana-Noia, VM, Isaac, K, Malecek, MK, et al. Multicenter analysis of geriatric fitness and real-world outcomes in older patients with classical Hodgkin lymphoma. Blood Adv 5:18 (2021), 3623–3632.
Cheng, PTM, Villa, D, Gerrie, AS, et al. The outcome of older adults with classic Hodgkin lymphoma in British Columbia. Blood Adv 6:22 (2022), 5924–5932.
Övergaard, N, Lia, K, Asdahl, P, et al. AVD - a possible golden standard in the first-line treatment of older classical Hodgkin lymphoma patients. HemaSphere 6 (2022), 37–38 Abstract 082.
Hasenclever, D, Diehl, V, A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 339:21 (1998), 1506–1514.
Klimm, B, Goergen, H, Fuchs, M, et al. Impact of risk factors on outcomes in early-stage Hodgkin's lymphoma: an analysis of international staging definitions. Ann Oncol 24:12 (2013), 3070–3076.
Cottereau, AS, Versari, A, Loft, A, et al. Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial. Blood 131:13 (2018), 1456–1463.
Engert, A, Ballova, V, Haverkamp, H, et al. Hodgkin's lymphoma in elderly patients: a comprehensive retrospective analysis from the German Hodgkin's Study Group. J Clin Oncol 23:22 (2005), 5052–5060.
Moccia, AA, Aeppli, S, Güsewell, S, et al. Clinical characteristics and outcome of patients over 60 years with Hodgkin lymphoma treated in Switzerland. Hematol Oncol 39:2 (2021), 196–204.
Weekes, CD, Vose, JM, Lynch, JC, et al. Hodgkin's disease in the elderly: improved treatment outcome with a doxorubicin-containing regimen. J Clin Oncol 20:4 (2002), 1087–1093.
Goh, Z, Latimer, M, Lewis, KL, et al. Characteristics and outcomes of older patients with classical Hodgkin lymphoma: an Australasian Lymphoma Alliance, and Lymphoma and Related Diseases Registry study. Clin Lymphoma Myeloma Leuk 23:5 (2023), 370–378.
Wahlin, BE, Övergaard, N, Peterson, S, et al. Real-world data on treatment concepts in classical Hodgkin lymphoma in Sweden 2000-2014, focusing on patients aged >60 years. EJHaem 2:3 (2021), 400–412.
Torka, P, Feldman, T, Savage, K, et al. Phase 2 trial of Nivolumab plus Adriamycin, vinblastine, dacarbazine (N-AVD) as frontline therapy in older adults with Hodgkin lymphoma. Hematol Oncol 41:S2 (2023), 161–162.
Herrera, AF, LeBlanc, M, Castellino, SM, et al. Nivolumab (N)-AVD improves progression-free survival compared to brentuximab vedotin (BV)-AVD in advanced stage (AS) classical Hodgkin lymphoma (HL): results of SWOG S1826. Hematol Oncol 41:S2 (2023), 33–35.
