The treatment of DLBCL Michele Ghielmini Medical Oncology Dept Oncology Institute of Southern Switzerland Bellinzona
NHL frequency at the IOSI Mantle Cell Lymphoma 6.5 % Diffuse Large B-cell Lymphoma 37% CLL/SLL 15 % MALT lymphoma 7% Follicular Lymphoma 20 %
DLBCL: either cured or dead IOSI Database Ghielmini and Zucca, Blood 2009
1993: CHOP is the best 100% 80% OVERALL SURVIVAL 60% 40% 20% 0 Regimen pts deaths 3-yr OS Pro-MACE-CytaBOM 225 88 54% MACOP-B 223 93 52% m-bacod 233 97 50% CHOP 218 93 50% P = 0.90 0 2 4 6 years Fisher et al, NEJM, 1993
Strategies to improve on CHOP 1. Adding more drugs 2. Dose-intensification 3. Myeloablative consolidation 4. Addition of rituximab 5. Adding radiotherapy
1.- More drugs improve survival? ACVBP better than CHOP CHOP + Vindesine Bleomycine Ifosfamide Etoposide AraC
LNH03-2B study R-ACVBP is superior to R-CHOP R-ACVBP vs R-CHOP, patients <60, aaipi=1 Recher et al., Lancet 2011;378(9806):1858-67
2.- Shorter intervals improve survival? CHOP 14 >CHOP 21 CHOP-14 vs. CHOP-21 p < 0.001 Pfreundschuh et al, Blood 2004
Dose-dense not better R-CHOP 21 vs R-CHOP 14 if rituximab is added PFS OS Cunningham D et al.lancet 2013;381:1817-26. Delarue R et al. Lancet Oncol. 2013;14:525-33
3.- is HDCT mandatory? Milpied et al, NEJM 2006
Meta-analysis of HDCT trials Greb et al., 2007, Cancer Treat Rev
Consolidation by HDT and ASCT In the R-era EFS OS Stiff PJ et al. N Engl J Med 2013. Vitolo U et al. ICML 2011.
4.- Rituximab improves survival Elderly population, Can not be rescued by HDCT at relapse Feugier et al, JCO, 2005
Overall survival by treatment era All Patients in British Columbia: N=294 Mixed population, Half could be rescued by HDCT at relapse Sehn, L. H. et al. J Clin Oncol; 2005
5.- Can Radiotherapy improve on systemic treatment? Retrospective study of patients with DLBCL reciving chemo +/- consolidation radiotherapy in the R-era in the NCCN centres (n=841) Failure Free Survival Overall Survival P=0.06 P=0.01 48% had stage I-II 23% had bulky disease 35% of cohort received RT 119 deaths: 88 in CHOP-R and 31 CHOP-R+RT Dabaja at al, Abstr 121, 12-ICML, Lugano 2013
Survival curves according to PET positivity and performed RT 1.0.8 PROGRESSION-FREE SURVIVAL Positive- XRT (n=60) OVERALL SURVIVAL 1.0.8 Positive- XRT (n=60) Percent Survival.6.4.2 0.0 0 Negative (n=167) Positive- No XRT (n=22) 2 4 Time (years) 6 8 Percent Survival.6.4.2 0.0 0 2 Negative (n=167) Positive- No XRT (n=22) 4 Time (years) Sehn at al, Abstr 123, 12-ICML, Lugano 2013 6 8
1st-line treatment guidelines: ESMO 60 years > 60 years IPI low risk, no bulk Low risk with bulk or low intermediate risk R-CHOP21 6 R-ACVBP R-CHOP21 6 + RT Fit R-CHOP21 6 > 80 years R-miniCHOP21 6 High intermediate or high risk R-CHOP21 8 R-CHOP14 6 + 8 R or intensify Unfit or cardiac dysfunction Substitute doxorubicin with etoposide, liposomal doxorubicin or others
Treatment of relapse: Parma trial HDCT better than standard CT Event-free survival Overall survival 100 80 100 80 Transplantation Conventional chemotherapy EFS (%) 60 40 OS (%) 60 40 20 0 p = 0.001 0 15 30 45 60 75 90 20 0 p = 0.038 0 15 30 45 60 75 90 Months after randomisation Months after randomisation Philip et al. N Engl J Med 1995;333:1540.
Is there a better induction therapy? ICE/R-ICE vs DHAP/R-DHAP Gisselbrecht at al, JCO, 2010 Gisselbrecht et al. J Clin Oncol 2010; 28:4184.
Canadian study: GDP vs DHAP (+ R since 2005) EFS OS QoL Crump at al, Abstr 85, 12-ICML, Lugano 2013
Auto vs allo -transplant EBMT database, 1992-2010 OS 6 700 Autologous 132 Myeloablative allo 98 RIC allo All as first transplant Robinson et al, BMT 2016
Treatment of relapse: ESMO 1st relapse 2nd relapse Eligible for transplant Platinum-based induction If response: HDT + PBSCT Allogeneic transplant Not eligible for transplant Platinum- and/or gemcitabine-based regimens Clinical trials BSC Ghielmini et al. Ann Oncol 2013;24:561. Tilly et al. Ann Oncol 2012;23(Suppl 7):vii78.
Risk of secondary CNS relapse: DSHNHL (n=2164) and BCCA (n=1597) 0.40 Risk factors Proportion 0.35 0.30 0.25 0.20 0.15 0.10 Median time to CNS relapse - DSHNHL 7.2 months - BCCA 6.7 months Age > 60 LDH > N PS > 1 E > 1 Stage > II Renal or adrenal Number of factors: IPI 0.05 0-1 0.00 0 1 2 3 4 5 6 7 8 Years 2-3 4-6 Savage et al, ASH 2014, abstr. 394
Older patients are often not treated Retrospective SEER Db: 9333 DLBCL patients > 66 years enrolled Medicare A/B 2000-2007 Hamlin P et al, The Oncologist, 2014
Overall survival of advanced-stage DLBCL aged > 70 by therapy group S. A. M. van de Schans et al. Ann Oncol 2012;23:1280-1286
TRM and Toxicity is greatest in initial cycles of therapy: prephaseimpact Vincristine 1 mg + Prednisone 100 mg x 7 days in DSHNHL NHL-B2 Trial Therapy associated mortality before and after institution of Pre-Phase NHL-B2 Courtesy M. Pfreundschuh
Cardiac comorbidity: gemcytabine or etoposide instead of doxo n=62 Median age 76.5 (52-90) Adv Stage: 69% Case-control study of R-CEOP (n=81) or R-CHOP (n=162) in DLBCL Disease Specific survival IPI 3-5: 71% All with cardiac disease 1.0.9.8.7.6.5.4.3.2 R-CHOP R-CEOP.1 0.0 0 2 4 6 8 Fields P A et al. JCO 2014;32:282-287 Moccia et al, ASH 2000
DH lymphomas have a bad prognosis BL DHL DLBCL Snuderl et al, Am J Surg Pathol, 2010
Bcl-2 +/ Myc + Gene translocation vs protein expression FISH IHC DHL = 11 DEL = 54 Green et al, JCO, 2012 10% cases Well reproducible Consistent data 30% cases Not well reproducible Less consistent data
High grade B-cell Lymphomas Diagnostic approach MYC+ MYC+ DH+ DH+ DH+ DH+ Swerdlow et al, Blood 2016, in press
23 US CCC: retrospective analysis Induction treatment N = 311 previously untreated DHL Intensive = DA-EPOCH, Hyper CVAD, CODOX-M-IVAC PFS OS Petrich et al., Blood, 2014
23 US CCC: retrospective analysis Consolidation treatment N = 151/311 DHL in CR Petrich et al., Blood, 2014
Meta-analysis of 11 DHL studies N = 394 R-CHOP = 180 R-EPOCH = 91 Dose-intensive = 123 (R-HyperCVAD/R-MC or R-CODOX-M/R-IVAC) Howlett et al., BJH, 2015
Conclusions R-CHOP is the standard treatment for DLBCL Different types of intensification might obtain slightly better results, at the cost of higher toxicity For relapsed patients, HDT is the only curative option For DH lymphomas the best treatment is unknown: inducing with DA-R-EPOCH and consolidating with HDCT is a possible option Try to treat elderly in a curative manner Dont forget the risk of CNS relapse