Richter syndrome: pathogenesis and management. Clemens Wendtner Professor of Medicine Chief Physician Klinikum Schwabing University of Munich

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1 Richter syndrome: pathogenesis and management Clemens Wendtner Professor of Medicine Chief Physician Klinikum Schwabing University of Munich

2 Conflict of Interest Disclosure I hereby declare the following potential conflicts of interest concerning my presentation: Consultancy: Hoffmann-La Roche, Celgene, Janssen, Gilead, Morphosys, Abbvie Research Funding: Hoffmann-La Roche, Celgene, Janssen, Gilead, Morphosys, Abbvie Honoraria: Hoffmann-La Roche, Celgene, Janssen, Gilead, Morphosys, Abbvie Patents and Royalties: none Membership on an Entity s Board of Directors or Advisory Committees: none Discussion of off-label drug use: ibrutinib, pembrolizumab, venetoclax

3 Cumulative incidence of RS 0.5% per year of observation Parikh et al Br J Haematol 2013

4 Diagnosis of RT When to suspect RT? Rapid growth of lymph nodes Rapid clinical deterioration Fever in the absence of infection Rising LDH Diagnostic test PET scan

5 Survival by SUV max Total Died p<.0001

6 FNA is Inferior to Tissue Biopsy in Diagnosis of RT RT (N= 95) Biopsy FNA FNA + biopsy In those with concurrent FNA and biopsy, FNA was non-diagnostic in 53% patients

7 Differential diagnosis: prolymphocytoid evolution CLL Prolymphocytoid evolution Ginè et al, Haematologica 2010 RS After pathology revision, 20% of RS are downgraded to CLL in prolymphocytoid evolution Soilleux et al, Histopathology 2016

8 Richter syndrome 95-99% DLBCL LN BM PB CLL 1-5% LN HL LN CD15 CD30 Swerdlow SH. WHO classification of tumours of haematopoietic and lymphoid tissues 2008

9 Clonally related vs unrelated Richter syndrome 50/63 (80%) Clonally related RS V4-39 D6 J4 13/63 (20%) CLL V4-39 D6 J4 Rossi et al, Blood 2011 Clonally unrelated RS V4-34 D2-2 J3

10 The genetic lesions of Richter syndrome can be detectable at subclonal levels in the initial CLL clone NOTCH 1 EX34: c.7544_7545delct p.p2515fs*4 (heterozygous) TP53 EX7: c.716a>c p.n239t (heterozygous) 5.6% 58% 0.39% 43% CLL CLL 62 months 30 months RS precursor CLL diagnosis CLL progression RS transformation Fabbri G, et al, J Exp Med 2011; 208: ; Rossi D, et al. Blood 2012; 119: 521-9

11 HL variant of Richter syndrome HL variant Clonally related Clonally unrelated EBV+ EBV- Median OS: 4 y DLBCL variant Clonally related Clonally unrelated 40% 80% EBV+ EBV- 70% 5% Median OS: <1 y Abruzzo et al, Am J Surg Pathol 2002; 26: O Brien et al, Cancer 2003; 98: Thornton et al, Leuk Res 2005; 29: Ammatuna et al, Leuk Lymphoma 2009; 50:; Kanzler et al, Blood 2000; 95: Tsimberidou et al, Cancer 2006; 107: Rossi D, et al, Clin Cancer Res 2009; 115: , Xiao et al, Hum Pathol 2016;55:108-16

12 The genetic profile of clonally unrelated RS differs from that of clonally related RS p=.018 p=.009 Clonally unrelated Clonally related p=.017 Rossi et al, Blood 2011

13 The genetic profile of Richter sydrome (RS) differs from that of de novo DLBCL Frequency 100% RS de novo DLBCL 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Lesions of TP53, NOTCH1, MYC and CDKN2A recapitulates 90% RS TP53 CDKN2A/B MYC NOTCH1 Rossi D, et al. Blood 2011; 117: Fabbri G, et al. J Exp Med 2011; 208: Fabbri G, et al. J Exp Med 2013; 210: Chirginova et al. Blood 2013; 122: Monti, et al. Hematol Oncol 2014; 32: 155-7

14 TP53 abnormalities in Richter syndrome No TP53 disruption TP53 disruption cdc2 p21 cyclin B Cell cycle arrest p21 cyclin B p53 P Caspase 9 BAX p53 P P p<.001 Apoptosis DNA damage Frequency 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% N=1/63 (1.5%) MBL TP53 M del17p13 TP53 M/del17p13 N=13/268 (4.8%) Early stage CLL N=30/318 (9.4%) CLL requiring treatment N=44/99 (44.4%) F-refactory CLL N=25/38 (65.7%) Richter syndrome Döhner H, et al. New Engl J Med 2000;343:1910 6;Rasi S, et al. Haematologica 2012;97:153 4; Zainuddin N, et al. Leuk Res 2011;35:272 4; Zenz T, et al J Clin Oncol 2010;28:4473 9; Rossi D, et al. Blood 2011;117: ; Stilgenbauer S, et al. Blood 2014;123: ; Fabbri G, et al. J Exp Med 2013;210:

15 CDKN2A/B abnormalities in Richter syndrome Rinaldi A, et al, Br J Haematol 2011; 154: Edelmann J et al, Blood 2012; 120: Fabbri G et al, J Exp Med 2013; 210: Chirginova et al, Blood 2013; 122: % 40% Frequency (%) 30% 20% N=14/59 (24%) 10% 0% N=0/305 (0%) CLL diagnosis N=0/144 (0%) CLL requiring treatment Richter syndrome

16 MYC abnormalities in Richter syndrome Mutation Missense MYC Translocation IgH MYC Aberrant cell proliferation Metabolic reprogramming Genomic instability 50% 40% Amplification CASC11 MYC MYC MYC Frequency (%) 30% 20% 10% N=6/161 (3%) N=7/27 (26%) 0% CLL diagnosis Richter syndrome Rossi D, et al. Blood 2011;117: ; Brown J, et al. Clin Cancer Res 2012;18: ; Fabbri G, et al. J Exp Med 2013;210: ; Monti S, et al. Hematol Oncol 2014;32:155-7

17 NOTCH1 mutations in Richter syndrome S3 γ-secretase NOTCH1 wt NOTCH1 M DSL NOTCH1 ICN Pro-NOTCH Ubiquitination Degradation ER-Golgi ICN DTX1 S2 Metalloprotease SPEN p<.001 Degradation RPBJ Other Co-Activators MAML RPBJ gene expression Arruga, et al. Leukemia % *** Frequency (%) 40% 30% 20% 10% 0% P<0.001 *** P<0.05 ** N=2/134 (1%) de novo DLBCL N=2/63 (3%) MBL ** N=60/539 (11%) CLL diagnosis ** *** N=10/48 (20%) F-ref CLL N=18/58 (31%) Richter syndrome Fabbri G, et al, J Exp Med 2011; 208: Puente X, et al. Nature 2011; 475: Rossi D, et al. Blood 2012; 119: Rasi S, et al. Haematologica 2012; 97: Fabbri G et al, J Exp Med 2013; 210:

18 Richter syndrome show biased usage of the BCR in the subset 8 (IGHV4-39) configuration 100% 80% +12 del17p13 del BIRC3 Subset 2 Subset 8 Subset 8 usage 60% 40% 20% 0% 14/753 CLL p<.001 6/69 RS del13q14 del11q22 Normal BIRC3 M SF3B1M NOTCH1 M TP53 M Subset 1 Subset 3 Subset 4 Subset 5 Subset 6 Subset 7B BCR from subset 8 CLL display extreme antigen polyreactivity Subset 8 IGHV4-39/no stereotyped HCDR3 No IGHV4-39/stereotyped HCDR3 No IGHV4-39/no stereotyped HCDR3 Subset 8 CLL clones respond avidly to stimulation by multiple antigens Rossi D, et al, Clin Cancer Res 2009; 15: Chu, et al, Blood 2011; 117: Rossi D, et al, Blood 2013; 121: Gounari M, et al, Blood 2015; 125:

19 Proliferation and apoptosis are the master cellular programs deregulated in Richter syndrome CLL DLBCL BCR (subset 8) MYC TP53 Trasnformation Chemoresistance Rapid disease kinetics Driving forces NOTCH1 CDKN2A/B

20 Type of prior treatment as risk factor for Richter s transformation?

21 Risk of 2 nd malignancies for FCR-based vs nongenotoxic regimens as initial therapy for CLL in patients >65 years Malignancy* FCR-based (n=120) Nongenotoxic* (n=170) Solid tumors 13 (11%) 18 (11%) Richter s transformation 8 (7%) 2 (1%) p=.02 AL/MDS 10 (8%) 7 (4%) *Antibody regimens(n=53), Lenalidomide regimens (n=68), BCR antagonist regimens (n=49)

22 Incidence of RS in various studies of Ibrutinib STUDY PATIENTS PROG _ CLL PROG17 _ RS RESONATE-17 (DEL 17P/ TP53 MUTATED) RESONATE PHASE 3 (VS OFATUMUMAB) OSU (MADDOCKS) PRIOR RX (97%) (15%) 17 (12%) (6%) 1 (1%) (4%) 18 (6%)

23 Ibrutinib : Patterns of Relapse, and Subsequent Survival Cumulative Incidence Richter Transformation mos 3.5 months Richter's Months Other Event CLL Progression CLL with Mutations mos 18 months Maddocks, JAMA Oncology 2015, 1:80 Jain, Blood 2015, 125:2062

24 Richter syndrome after ibrutinib 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 4/4 4/4 2/4* 0/4 0/4 0/4 0/4 * Not acquired at transformation

25 Richter s Transformation under Treatment with Venetoclax (M Trial)

26 BAG Trial: Venetoclax plus Obinutuzumab before after 3 weeks after 3 months

27 Venetoclax and Richter s transformation 70 patients with relapsed / refractory CLL enrolled in venetoclax studies at Melbourne Health and Peter MacCallum Cancer Center ( ) M : Venetoclax Monotherapy (Phase I) M : Venetoclax + Rituximab (Phase I) M : Venetoclax Monotherapy (Phase II, del(17p) CLL) 28 patients discontinued venetoclax treatment: 16 (57%) Richter Transformation 7 (25%) CLL progression 5 (18%) other reasons* Median 12 months (0 34) follow-up after discontinuation *lung CA, oesophageal CA, strangulated hernia, poor ECOG status, personal choice

28 Survival After Discontinuation of Venetoclax CLL (n=7), 1yOS 69% RS (n=16), 1yOS 48% Median OS 1 year CLL vs RS, p=0.88 Others (n=5) Months

29 Treatment options for patients with Richter s transformation

30 Therapeutic Regimens in RT Patient characteristics OFAR1 OFAR2 Hyper CVAD+R R-CHOP p No. of patients Age 60 yrs, % PS > 1, % PLT >= 100 x 10 9 /L, % Prior therapies >1, % Overall response, % Median survival, mos Median FFS, mos Tsimberidou AM et al. Clin Lymphoma Myeloma Leuk

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32 Stem Cell Transplant in RT 20 pts with RT underwent SCT (17 allo, 3 auto) Only 10% of pts with RT SCT Tsimberidou AM et al. JCO 2006

33 Biol Blood Marrow Transplant 2016 Sept 19 [Epub ahead of print]

34 Targeting the molecular programs that are altered in RS TP53 independent cell death: venetoclax BCR signaling: BTKi, PI3Ki MYC: bromodomain inhibitors NOTCH signaling: anti NNR antibodies Oncogene deregulation: XPO1 inhibitors

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40 PNAS 2011; 108:

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42 Selinexor = Selective inhibitor of nuclear export (SINE) BLOOD, 14 MAY 2015 VOLUME 125, NUMBER 20

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48 Faitschuk et al., BLOOD 2016

49 Does immune escape has any role in RS development? Allo SCT is effective in RS Pembrolizumab signaled activity in RS RS lacks immune escape genes mutations (no selective pressure) No info on the immune status of RS patients

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53 A Phase 1/2, open label, multicenter study to assess the safety and tolerability of durvalumab (anti-pd-l1 antibody) as monotherapy and in combination therapy in subjects with lymphoma or chronic lymphocytic leukemia

54 SUMMARY RS occurs in 5% of chemo-immunotherapy frontline patients in 5 years. Especially common in del17p patients and salvage patients. Appears to be less common in targeted therapies but too early Essential to get biopsies not FNA of PET positive nodes for accurate diagnosis, genomic studies with concurrent CLL cells Standard treatment is an anthracycline-based induction chemo, followed by allogeneic transplantation, if possible. Potential new therapeutic approaches include venetoclax, ibrutinib, BET inhibitors, NOTCH receptor inhibitors, XPO inhibitors and immune approaches (CAR T cells, PD-1/PD-L1inhibitors, etc.).

55 Thanks for your attention!