Double hit lymphoma Clinical perspectives

Transcription

1 Double hit lymphoma Clinical perspectives Peter Johnson

2 Some definitions, for clarity Double-hit lymphoma (5% of DLBL) Rearranged MYC (8q24) by FISH Plus either rearranged BCL2 (18q21) or BCL6 (3q27) Double-expression (by IHC) is different and much more common: about 1 / 3 of DLBL

3 Immunohistochemical detection of MYC in representative Primary DLBCLs. Kluk MJ, Chapuy B, Sinha P, Roy A, et al. (2012) PLoS ONE 7(4): e33813.

4 FISH or IHC for Detecting Double Hit DLBL 193 DLBL treated with R-CHOP Incidence of BCL2 and MYC positive: FISH: 6% (n=11) IHC: 29% (>40% + MYC, >70% + BCL2) Clinical Outcomes: DH by FISH DH by IHC Green T M et al. JCO 2012;30:

5 The Importance of Being MYC A transcription factor controlling: Cell cycle, promoting G0 to S transition Metabolism, stress response DNA repair Protein synthesis Apoptosis Amplification of transcriptionally active genes Central activator of many other genes by reprogramming mirna transcriptome Key to formation and maintenance of germinal centres Abnormal MYC expression can be driven by Translocations Mutations within the gene sequence Copy number increase

6 BCL6 and BCL2 at the heart of germinal centre dynamics Memory B-Cell Plasma Cell Differentiation BCL6 on BCL2 off BCL6 off BCL2 on T/B cognate interaction Competition for Antigen Select DZ Re-entry Proliferation BCL6 off BCL2 on Divide Mutate BCL6 on BCL2 off Pre-GC activated B-cell Germinal Centre DZ Cell proliferation

7 Biology of BCL2+/MYC+ versus BCL6+/MYC+ DHL Comparison of gene expression profiles. 80 MYC-translocated lymphomas: 47 double, 31 single hit by FISH Few biological differences (SHL have other translocations or mutations) 83% DHL GCB type 52% SHL GCB, 29% ABC BCL2- and BCL6-type DHL: Similar IG partners, genome complexity, mutation frequencies BCL2-type more often GCB (96 vs 50%) Differentially expressed genes between BCL2- and BCL6-type enriched for cell-oforigin tags Aukema S M et al. Haematologica 2014;99:

8 TP53 mutations may also cooperate with MYC rearrangements Du et al., J Pathol., in press

9 Relationship between COO and MYC/BCL2 expression t(8;14), t(14;18) usually GC type More protein overexpression in non-gc type GC Non-GC patients with primary DLBCL All treated with R-CHOP Stained for MYC, BCL2 Double-hit score: Above median (40% MYC, 70% BCL2) scores 1. Green T M et al. JCO 2012;30: Hu S et al. Blood 2013;121:

10 MYC/BCL2 effect seems to cut across cell of origin 466 cases assigned to GC/non-GC by GEP (411) or IHC (55) Subset of MYC+/BCL2+ by IHC (157) analysed separately, suggest GC/ABC equally bad Other mechanisms may also account for poor outcomes in non-gc lymphoma MYC+ in the absence of t(8;14) is likely different to MYC+ with t(8;14) Hu S et al. Blood 2013;121:

11 MYC deregulation: regulatory element invasion and super-enhancers Aukema et al. Haematologica 2013 IHC expression Double Hit Lymphoma Hu et al. Blood 2013 MYC tx BLC2 tx GCB-DLBCL (Also Triple Hit) Differen al gene expression GCB-like BLC6 tx Mixed COO MYC+/BCL2+ ABC > GCB 2:1 Differen al gene expression ABC-like MYC-/BCL2GCB > ABC 2:1 Differen al gene expression GCB-like

12 MYC+ and Double-Hit NHL Translocations involving MYC, with or without BCL2 rearrangements, are associated with shortened PFS and OS in aggressive NHL1,2 DLBL over-expressing MYC and BCL2 or BCL6 also have a worse outlook3-6 1 Savage et al. Blood (2009) Johnson et al. Blood (2009) 3 Visco et al. Haematologica (2013) 4 Green et al. J Clin Oncol (2012) 5 Johnson et al. J Clin Oncol (2012) 6 Horn et al. Blood (2013) 2

13 Summary FISH vs IHC for Detecting Double Hit DLBCL MYC (FISH or IHC) alone without BCL2 did not appear to predict inferior outcome (but others have found that it does) BCL2 alone appear slightly inferior to non-mutated. BCL2 + MYC by IHC or FISH have worst outlook. Assessment of MYC and BCL2 expression by IHC represents a robust, rapid, and inexpensive approach to risk-stratify patients with DLBCL at diagnosis. MYC by FISH +/- BCL2 MYC by IHC +/- BCL2 Johnson N, et al. JCO (28): Outcomes: FISH vs IHC

14 EFS and OS in R-CHOP-treated elderly DLBCL patients. FISH IHC MYC BCL2 BCL6 Among MYC-rearranged cases, 18/26 (69%) were positive by IHC using a cut-off of 40% Horn H et al. Blood 2013;121:

15 Clinical Features of MYC/BCL2 and MYC/BCL6 DH NHLs Study # DH % Prev Ind NHL Med Age % Stage III/IV % High LDH % Pos BM % Pos CNS Bertrand NA NA NA Johnson NA Kanugo 14 None 55 NA LeGouill Macpherson NA Niitsu 19 None Snuderl Tomita Oki Petrich

16 Historic outcomes of Therapy for DH NHLs Study DH/Total Therapy % ORR Med OS (Yr) Bertrand 10/17 NA 5/10 <1 Johnson 54/54 R-CHOP-11; SCT-6 NA Kanugo 14/14 CTNOS-11 NA <1 LeGouill 16/16 SCT Macpherson 15/39 SCT-3 NA 0.21 Niitsu 19/19 CHOP Snuderl 20/20 Most R-CHOPlike Tomita 27/27 R-CHOP, HCVAD, CODOXM

17 Initial therapy for Double Hit Lymphoma Petrich A M et al. Blood 2014;124: Retrospective study of outcomes in 23 US centres over 12 years: 311 patients with newly-diagnosed DLBL(154), BCLU(150), FL(7) MYC-R and BCL2 (87%) or BCL6 (5%) by FISH/cytogenetics 76% raised LDH, 33% 3x normal 65% stage IV, 41% BM+ve, 7% CNS+ve

18 Response rates by induction regimen Treatment regimens: R-CHOP 32% R-Hyper-CVAD 21% DA-EPOCH-R 21% R-CODOX-M/IVAC 14% CNS prophylaxis 56% SCT in 1st remission 17% Petrich A M et al. Blood 2014;124:

19 Survival outcomes by initial therapy Median PFS 10.9 mo Median OS 21.9 mo Petrich A M et al. Blood 2014;124:

20 Novel prognostic score, IPI, and R-IPI. Novel score: OS in multivariate analysis: WBC ( 103 cells/ml) LDH (3x ULN) Stage (3-4) CNS involved Petrich A M et al. Blood 2014;124:

21 High dose therapy? Non-significant trends Petrich et al. Blood 2014;124: Oki et al B J Haem, 2014, 166,

22 CNS prophylaxis 13% cumulative risk of CNS progression in MDACC series Petrich et al. Blood 2014;124: Oki et al B J Haem, 2014, 166,

23 Second line therapy: new ideas needed Petrich A M et al. Blood 2014;124: Oki et al B J Haem, 2014, 166,

24 Novel targets Drug Action Effect Response rate Ref Selinexor (KPT-330) XPO1 binding Inhibits nuclear export Phase 1 7/28 Gutierrez ASCO 2014 JQ1 GSK CPI-0610 Bromodomain inhibitors Mute aberrant gene transcription by binding BRD4 Phase I ABT-199 BH3 mimetic Restores apoptotic programme Phase I/II 19/44 Davids ASCO 2014

25 Conclusions Double-hit outcomes are inferior Double-expression outcomes are also inferior IHC will identify more, but FISH identifies the worst Stain all for MYC: FISH if >30% positive, BCLU, immunoblastic, transformed Intensified therapy improves response rate and PFS, but with less certain effect on OS CNS prophylaxis is indicated for double-hit lymphoma High dose therapy in first remission is of uncertain benefit Results of conventional salvage are poor: recurrent disease requires different approaches