German Hodgkin Study Group Deutsche Hodgkin Studiengruppe Avoiding Relapse of Hodgkin Lymphoma: Have We Moved The Needle? Andreas Engert, MD Chairman, German Hodgkin Study Group University Hospital of Cologne Cologne, Germany
Have We Moved the Needle in HL? Overview Background First line New approaches Summary HL, Hodgkin lymphoma
Hodgkin Lymphoma Cumulative relative survival (Sweden) Sjöberg J, et al. Blood. 2090;114: Abstract 1553.
Estimated Mortality Rates Hodgkin lymphoma Courtesy of Lena Specht 2012
Have We Moved the Needle in HL? Overview Background First line New approaches Summary
Freedom From Treatment Failure Freedom from Treatment Failure (FFTF) GHSG HD10 Study Weakest vs strongest arm (FFTF) HD10, arms A v s. D (ITT) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 At 5 years: 4 x ABVD + 30 Gy IFRT: 92.8% 2 x ABVD + 20Gy IFRT: 91.2% Difference -1,6%; 95% CI [-6,3%; 3,1%] 0.1 0.0 A D 0 12 24 36 48 60 72 84 96 108 120 Pts. at Risk Time [months] Time, Months A 298 277 264 255 239 217 167 121 74 35 3 D ABVD, doxorubicin, 299 bleomycin, 275 265 vinblastine, 252and dacarbazine; 239 199 IFRT, involved-field 151 110 radiotherapy 66 28 4 Engert A, et al. N Engl J Med. 2010;363(7):640-652.
Question For a 55-year-old patient with stage II HL, all of the following are considered unfavorable risk factors except which of the following? 1. Elevated ESR (>50) 2. Presence of B symptoms 3. Elevated LDH (>2x ULN) 4. MMR >.35
Unfavorable Risk Factors for Stage I-II chl Risk Factor GHSG EORTC NCCN Age 50 Histology ESR and B symptoms >50 if A; >30 if B >50 if A; >30 if B >50 or any B symptoms Mediastinal mass MMR >.33 MMR >.35 MMR >.33 # Nodal sites >2 >3 >3 E lesion any Bulky >10 cm EORTC, European Organisation for the Research and Treatment for Cancer; ESR, erythrocyte sedimentation rate; GHSG, German Hodgkin Study Group; MMR, mediastinal mass ratio; MTR, mediastinal thoracic ratio; NCCN, National Comprehensive Cancer Network National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Renal cell carcinoma. V3.2016. Available online at: http://www.nccn.org/professionals/physician_gls/ f_guidelines.asp. Accessed October 18, 2016.
Early-Stage Hodgkin Lymphoma Current approaches Further reduction of chemo in early favorable failed (HD13) 1 PET-driven approaches in PET-negative failed (RAPID, H10) 2,3 PET-driven approaches in PET-positive were successful, new SOC? (H10) 3 Can new drugs such as BV and/or immune checkpoint inhibitors replace chemo/radiotherapy? BV, brentuximab vedotin; PET, positron-emission tomography; SOC, standard of care 1. Behringer K, et al. Lancet. 2015;385(9976):1418-1427. 2. Radford J, et al. N Engl J Med. 2015;372(17):1598-1607. 3. Raemaekers JM, et al. Haematol Oncol. 2015;33(S1): Abstract 20051.
Long-Term Results of HL Patients in advanced stages FFTF OS Years After Study Entry Canellos GP, et al. N Engl J Med. 2002;346(18):1417-1418.
Prognostic Factors for Advanced Hodgkin Lymphoma International Prognostic Score (IPS) Albumin <4 g/dl Hemaglobin <10.5 g/dl Male Age 45 years Stage IV disease Leukocytosis (white blood cell count at least 15,000/mm 3 ) Lymphocytopenia (lymphocyte count less than 8% of white blood cell count, and/or lymphocyte count less than 600/mm 3 Number of factors 5 years freedom from progression (%) 0 84 89 1 77 90 2 67 81 3 60 78 4 51 61 4 42 56 Hasenclever D, et al. N Engl J Med. 1998;339(21):1506-1514. 5 years overall survival (%)
Freedom From Treatment Failure HD15 in Advanced HL Freedom from treatment failure 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 P value 60 months difference A vs B:.009 4.9% 97.5%-CI: [ 0.5%, 9.3%] A vs C:.5 1.1% 97.5% CI: [-3.7%, 5.8%] C vs B:.04 (ns) 3.9% 97.5% CI: [-0.5%, 8.2%] 5-yr freedom from treatment failure: A: 84.4% B: 89.3% C: 85.4% 0.0 0 12 24 36 48 60 72 Time [months] A, 8 cycles of BEACOPP escalated B, 6 cycles of BEACOPP escalated C, 8 cycles of BEACOPP 14 Engert A, et al, Lancet. 2012;379(9828):1791-1799.
Have We Moved the Needle in HL? Overview Background First line New approaches Summary
Brentuximab Vedotin (SGN-35) Mechanism of action Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), potent antitubulin agent protease-cleavable linker anti-cd30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex traffics to lysosome MMAE is released MMAE disrupts Microtubule network G2/M cell cycle arrest Apoptosis
AETHERA: Study Design Cross over design, patients with POD on placebo could receive BV free of charge on a companion study Moskowitz CH, et al. Lancet. 2015;385(9980):1853-1862.
ECHELON-1: Phase III Trial BV + AVD vs ABVD in front-line advanced chl R A N D O M I Z E Brentuximab Vedotin 1.2 mg/kg q2w + AVD 28-day cycles ABVD 28-day cycles * Assessment based on Revised Response Criteria for Malignant Lymphoma E V A L U A T I O N Younes A, et al, J Clin Oncol. 2013;31(suppl): Abstract #TPS8612. National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/nct01712490. Accessed: September 21, 2016.
HD21: GHSG Perspective BV in advanced-stage HL 2 x BEACOPP esc 2 x BrECADD Centrally reviewed PET 4x BEACOPP esc 4x BrECADD End of therapy and residual nodes >2.5 cm: PET positive: Rx PET negative: Follow up GHSG, German Hodgkin Study Group; BEACOPPesc, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; BrECADD, brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone; PET, positron emission tomography; RX, radiotherapy National Institutes of Health. Available at: http://clinicaltrials.gov/ct2/show/nct02661503. Accessed: September 21, 2016.
Treatment of HL in Pts >60 Yrs BV + dacarbazine or bendamustine Treatment-naïve patients Age 60 years ECOG 3 Ineligible for conventional treatment BV alone BV + dacarbazine BV + bendamustine Patients with clinical benefit received additional cycles of BV Response assessed after cycles 2, 4, 8, 12, 16 Primary endpoint ORR N = 70 Yasenchak et al. Blood. 2015;126: Abstract 587.
Have We Moved the Needle in HL? Overview Background First line New approaches Summary
Have We Moved the Needle in Front-Line HL? Summary Hodgkin lymphoma has become one of the most curable cancers Combined modality therapy in early stages; ABVD and BEACOPP escalated in advanced stages High-dose chemotherapy (HDCT) and ASCT in R/R chl BV effective in RR chl; currently studied in combination Future trials will challenge chemotherapy and radiotherapy with less-toxic drugs ASCT, autologous stem cell transplantation; chl, classical Hodgkin lymphoma; R/R, relapsed/refractory