Transformed lymphoma: biology and treatment

Transcription

1 Transformed lymphoma: biology and treatment Silvia Montoto Centre for Haemato-Oncology Barts Cancer Institute

2 N = Years %Viability Concentration (um) Observation Experiments Treatment

3 Problem Information Solution

4 The problem Histological transformation (HT) Frequent event Change in histology Change in clinical course Poor prognosis

5 The problem Impact of HT on outcome Survival from HT Overall Survivalsurvival from HT according vs survival to HTfrom 1 st relapse in de novo DLBCL Not p= transformed 0.3 = Transformed Transformed = 88 follicular 0.00 de novo DLBCL Years

6 The problem How to improve the outcome of tfl Reduce the risk of HT What patients are at high risk of HT? Does the initial management impact on the risk of HT? Improve the response at the time of HT Does initial management impact on the outcome after HT? What is the best treatment at the time of HT?

7 The problem Treatment of tfl Heterogeneous population: Number of previous treatment lines Type of previous treatment Investigational trials: Excluded from FL studies Excluded from DLBCL studies Data extrapolated from DLBCL studies

8 The information tfl and DLBCL Davies A et al, Br J Haematol, 2006

9 The information Impact of initial management on the risk of HT Series Hubbard (1982) Acker (1983) RT risk of HT No impact Risk of HT Horning (1984) No impact of expectant management Giné (2006) No impact of CB-CVP vs CHOP Montoto (2007) Expectant management risk of HT

10 The information Impact of initial therapy on the risk of HT Prospective randomised study: PCOP vs PACOP The addition of doxorubicin does NOT influence the risk of HT Lepage et al, Hematological Oncology, 1990 Al-Tourah et al, JCO, 2008

11 The information Impact of W&W on the risk of HT Chlorambucil vs W&W Ardeshna et al, Lancet, 2003 No data Prednimustine vs IFN- 2 vs W&W Brice et al, JCO, 1997 No diffs risk HT ProMACE-MOPP vs W&W Young et al, Semin Hematol, 1988 Chemo risk HT

12 The information Treatment for HT = treatment for DLBCL (in most cases) CHOP-R BUT CHOP-R already given at the time of HT AND outcome of tfl DLBCL at relapse 2 nd line chemotherapy for DLBCL?

13 The information Treatment for HT Series Treatment at HT SFT (median) Hubbard (1982) 63% combination chemotherapy 11 mo Yuen (1995) 60% doxo-containing chemo 22 mo Bastion (1997) 58% CHOP-like 7 mo Giné (2006) 23% CHOP 57% VIA, MINE/ESHAP 1.2 yrs Montoto (2007) 73% doxo-containing chemo 1.2 yrs

14 The information Treatment for HT: CHOP-R 1.0 CHOP-R (N= 23) 5yr OS: 61%.8.6 CHOP-like (N= 85) 5yr OS: 33%.4.2 p= Courtesy of Joseph M Connors and Abdul Al-Tourah, unpublished data

15 The information Improvement over time Chemoterapy-naïve patients Rituximab at HT Tam et al, ICML-10 Lugano 2008

16 The information Non-CHOP-R treatments for HT Treatment Series MINE/ESHAP N (tfl/total) Previous rituximab RR HDT EFS/TTF Rodriguez 14/ % (HT) No Median TTF: 8 mo (HT) Mini-BEAM Girouard /104-50% (HT) 37% - R-EPOCH Jermann /50 8/50 68% 61% Median EFS: 12 mo (HT) No detailed data on results with ICE/R-ICE in patients with HT

17 The information Non-CHOP-R treatments for HT: RIT Series N (tfl/total) RR CR PFS (median) OS Kaminsky /59 79% 50% 14 mo 4yrs: 62% Vose /47 60% 50% RD: 12 mo Median: 36 mo Davies /41 71% 28% RD: 41 mo NS

18 The information Non-CHOP-R treatments for HT: RIT Kaminsky et al, Blood, 2000

19 The information Non-CHOP-R treatments for HT: lenalidomide Patients N RR CR/CRu PFS (median) All patients 33 45% 21% 5 mo tfl 23 56% 26% 8 mo tcll/sll mo Czuczman et al, BJH, 2011

20 The information Treatment for HT: autologous SCT Williams et al, JCO, 2001

21 The information Treatment for HT: autologous SCT Probability FL (N: 50) 0.50 tfl (N: 30) 0.25 p: NS Time (years) Montoto et al, ICML-2011

22 The information Treatment for HT: autologous SCT Series N RD/PFS for tnhl (median) 5-yr PFS Williams (JCO 2001) mo 30% Sabloff (BBMT 2007) 23/ mo 25% Montoto (ICML-11) 30/80 7 mo* 45% mo** 32% Eide (BJH 2011) * 16 relapse: 15 Bx (5 FL, 8 DLBCL, 2 NK); ** 13 relapse: 7 Bx (4 FL, 3 DLBCL)

23 The information Treatment for HT: allotransplant Rezvani et al, JCO, 2008 Thomson et al, JCO, 2009

24 The information Open questions in the treatment of HT Do doxo-containing regimens decrease the risk of HT? Do patients NEED doxo-containing regimens at the time of HT? Is HDT necessary for all patients with HT? Can something different be done?

25 The solution Answers : how to get them Risk of HT as an end-point in randomised trials Include HT in trials for aggressive lymphomas Search for specific molecular therapeutic targets

26 N = %Viability Years Concentration (um) Observation Experiments Treatment

27 What we do at Barts: Treat as DLBCL: R-CHOP (if no prior doxo) 2nd line chemo for DLBCL HDT unless: little prior treatment localised disease (?)

28 The information Maintenance rituximab for HT? HT is an exclusion criteria in: Studies of maintenance after first-line: Ghielmini, Blood 2004 Hochster, JCO 2009 Salles, Lancet 2011 Studies of maintenance at relapse: Ghielmini, Blood 2004 Van Oers, Blood 2006

29 The information Maintenance rituximab for HT: maintenance rituximab in DLBCL? After CHOP-R Haberman et al, JCO, 2006 After HDT in first-line Haioun et al, Annals of Oncology, 2009