CLL treatment algorithm and state of the art

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1 CLL treatment algorithm and state of the art Davide Rossi, M.D., Ph.D. Hematology IOSI - Oncology Institute of Southern Switzerland IOR - Institute of Oncology Research Bellinzona - Switzerland

2 CLL subgroups Newly presented pts First line pts Relapsed pts

3 CLL subgroups Newly presented pts First line pts Relapsed pts

4 Clinical applications of biomarkers in CLL Clinical stage iwcll criteria Asymptomatic Symptomatic W&W Treatment Hallek iwcll 2017

5 Biomarker: variable that associates with disease outcome Host Factors: Age, sex, etc Disease Markers: Stage, lymphocyte count, LDT, etc Ag expression: CD38, Zap70, CD49d, etc Serology: 2M, TK, LDH, scd23, etc Genetics: del17p, TP53 mutation, del11q22, del13q14, trisomy 12, NOTCH1 mutation, SFRB1 mutation, etc Biology Markers: IGVH-sequence, BCR-structure

6 Overall survival CLL-IPI Variable Adverse factor Coeff. HR TP53 (17p) deleted and/or mutated IGHV status Unmutated B2M, mg/l > Grading Overall survival (all patients) Clinical stage Binet B/C or Rai I-IV Age > 65 years Low Prognostic Score 0 10 Risk group Score Patients N (%) 5-year OS, % Low (29) 93.2 HR (95% CI) p value Intermediate Intermediate (39) ( ) < High (27) ( ) < Very high High Very High (5) ( ) < Time (months) International CLL-IPI working group. Lancet Oncol 2016

7 CLL subgroups Newly presented pts First line pts Relapsed pts

8 CLL10 trial: Progression-free survival Eichhorst B, et al. Lancet Oncol Cum survival Key inclusion criteria: CIRS 6, CrCl >70 ml/min, no TP53 abn Median PFS FCR 55.2 months BR 41.7 months 0.2 P < HR = = > Time to event [PFS] (months)

9 FCR is more toxic than BR Adverse event FCR (% of pt) BR (% of pt) p value All <0.001 Hematological AEs <0.001 Neutropenia <0.001 Anemia Thrombocytopenia Infection TRM

10 FCR > BR in fit and untreated CLL patients (CLL10) Patients 65 years: p<0.001 Patients >65 years: p<0.170 FCR=53.6 months BR=38.5 months FCR=not reached BR=48.5 months Eichhorst B, et al. Lancet Oncol. 2016

11 Goede V, et al. NEJM 2014/ Hillmen P. et al, Lancet 2015 Anti CD20-CLB > CLB in less fit and untreated CLL patients CIRS score >6 and/or Cr Cl <70 ml/min CLL11 COMPLEMENT G-Clb (n=336) R-Clb (n=321) O-Clb(n=217) Age 74 (39-88) 73 (40 90) 69 (35 92) ORR 78% 65% 82% CR 21% 7% 14% MRD neg. 20% 3% 8% PFS med. (mo)

12 Goede V, et al. NEJM 2014/ Hillmen P. et al, Lancet 2015 Adverse events in Clb-based chemoimmunotherapy G-Clb (n=336) R-Clb (n=321) O-Clb(n=217) Any AE grade 3 % Infusion-related reaction Neutropenia Anemia Thrombocytopenia Leukopenia 4 <1 - Infection Pneumonia 4 5 -

13 Ibrutinib is superior to chlorambucil as first line treatment in unfit CLL (RESONATE 2) Key inclusion criteria treatment-naive CLL pts 65 yrs of age or older for pts yrs, comorbidity that precludes FCR no warfarin use no del(17p) Outcome Ibrutinib (n = 136) Chlorambucil (n = 133) P Value Median PFS, mos NE 18.9 < mo PFS rate, % Burger J, et al. New Engl J Med 2015

14 90% PFS at 5 years in TN CLL treated with ibrutinib Progression-Free Survival Overall Survival Median PFS 5-year PFS TN (n=31) NR 92% R/R (n=101) 52 mo 43% Median OS 5-year OS TN (n=31) NR 92% R/R (n=101) NR 57%

15 RESONATE-2: Adverse Events Parameter Selected AEs, % Ibrutinib (n = 136) Chlorambucil (n = 133) Hypertension 14 0 Atrial fibrillation 6 1 Major hemorrhage 4 2 Infection 10 6 Tedeschi A, et al. ASH Abstract 495.

16 Outline Predictive biomarkes in the 1 st line setting Pts fitness TP53 IGHV Predictive biomarkes in the relapsed setting Remission duration TP53 Histology

17 Outline Predictive biomarkes in the 1 st line setting Pts fitness TP53 IGHV Predictive biomarkes in the relapsed setting Remission duration TP53 Histology

18 Biomarkers that identify unfit patients MDACC myelosuppression/dose reductions in patients >60 yrs 1 early treatment discontinuations in patients 70 yrs 2 CLL8 hematological toxicity in patients 65 yrs 3 adverse events in pts with increased CIRS 4 CLL10 infections in patients >65 yrs 5 REACH adverse events in patients with decreased CrCl 6 1 Keating et al. J Clin Oncol. 2005; 2 T Ferrajoli A, et al. Leuk Lymphoma. 2005: S86; 3 Hallek et al. Lancet ; 4 Goede et al. Haematologica (EHA meeting abstracts). 2012; 5 Eichhorst et al. Blood (ASH meeting abstracts) ; 6 Robak et al. J Clin Oncol SIOG recommendation for the identification of pts less fit for FCR: Older age (e.g. 65 years) Higher comorbidity burden (e.g. CIRS >6) Impaired renal function (e.g. CrCl <70 ml/min) Stauder R et al. Ann Oncol : CrCl, creatinine clearance CIRS, cumulative illness rating scale

19 Outline Predictive biomarkes in the 1 st line setting Pts fitness TP53 IGHV Predictive biomarkes in the relapsed setting Remission duration TP53 Histology

20 TP53 abnormalities in CLL Frequency Missense Nonsense Frameshift TP EX4 EX9 1 DNA BINDING 393 p arm p53 q arm M P M P M P M P P P Chr17 normal del(17p) p53 wt (rare) p53 wt/mut (rare) del(17p) p53 mut (>80%) LOH p53 mut 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 Caspase 9 Apoptosis cdc2 p21 cyclin B Cell cycle arrest BAX p21 cyclin B p53 P DNA damage p53 P P Dohner et al, New Engl J Med 2000 ; Rasi et al, Haematologica 2012; Zainuddin et al, Leuk Res 2011; Zenz et al J Clin Oncol 2010;Rossi et al Blood 2011; Rossi et al Blood 2014

21 Response rate Chemoimmunotherapy (CIT) vs novel agents in TP53 disrupted CLL 12-months PFS Response rate Relapsed/Refractory CLL PFS 100% 80% CR PR PR-L 83% 78% 79% 100% 80% 80% 79% 72% 60% 60% 40% 20% 35% 7% 40% 20% 18% 22% 0% 0% CIT Novel agents CIT Novel agents Badoux Blood 2011; Fisher J Clin Oncol 2011; O Brien, ASH 2014; Sharman ASH 2014; Byrd ASH 2015; Stilgenbauer, ASH 2015

22 Outline Predictive biomarkes in the 1 st line setting Pts fitness TP53 IGHV Predictive biomarkes in the relapsed setting Remission duration TP53 Histology

23 IGHV mutated patients gain the greatest benefit from FCR PFS (%) PFS (%) PFS (%) 100 MDACC Phase II study (N=300) 1 CLL8 study vs. FC (N=817) IGHV mutated IGHV mutated, FCR IGHV mutated, FC 25 IGHV unmutated 25 IGHV unmutated, FCR 0 p< Time (years) 0 p< Time (years) IGHV unmutated, FC Italian retrospective analysis (N=404) ibrutinib vs ofatumomab ibrutinib vs chrlorambucil Ibrutinib-BR vs placebo-br 4 IGHV mutated, Ibrutinib IGHV unmutated, Ibrutinib IGHV mutated, comparator IGHV unmutated, comparator Time (years) 1. Thompson PA, et al. Blood 2016; 127: Fischer K, et al. Blood 2016; 127: Rossi D et al. Blood 2015; , 4. Kipps T et al. ICML14

24 Can first line treatment be informed by biomarkers? TP53 Mutated and/or deleted Ibrutinib Idelalisib + R a Wild type IGHV Unmutated Ibrutinib Mutated Chemo + anti-cd20 Age; CIRS; Cr clearance BR FCR Chl + anti-cd20 a In patients who are not eligible for any other therapies Chl: chlorambucil; CIRS: Cumulative Illness Rating Scale; Cr: creatinine Personal communication.

25 CLL subgroups Newly presented pts First line pts Relapsed pts

26 PFS (%) BR in relapsed CLL lacking del(17p) (HELIOS) Key inclusion criteria: Relapsed CLL No del(17p) Key exclusion criteria: Resistance to bendamustine N=289 (placebo + BR arm) Placebo + BR arm: ORR: 68% Median PFS: 13.3 months Ibrutinib + BR (mpfs: NR) Placebo + BR 60 Age, years 63 (median) del(17p) 0% Previous lines 2 (mean) F-refractory 26% Time (months) Placebo + BR (mpfs: 13.3 mos) Chanan-Khan A, et al. Lancet Oncol 2016;17:

27 Outline Predictive biomarkes in the 1 st line setting Pts fitness TP53 IGHV Predictive biomarkes in the relapsed setting Remission duration TP53 Histology

28 Outline Predictive biomarkes in the 1 st line setting Pts fitness TP53 IGHV Predictive biomarkes in the relapsed setting Remission duration TP53 Histology

29 Late relapse after first-line chemoimmunotherapy supports maintained sensitivity Cumulative survival Overall survival Survival after first salvage after FCR first-line failure: MDACC data 1 6 years (n=46), 5-year OS: 71% years (n=61), mos: 54 months (n=34), mos: 27 months <1 year (n=15), mos: 13 months Survival after first salvage after FC/FCR first-line failure: CLL8 data 2 PFS >24 months PFS months PFS <12 months Time (months) Time (months) 36-month cutoff 24-month cutoff FC, fludarabine + cyclophosphamide; FCR, FC + rituximab; MDACC, MD Anderson Cancer Center. 1. Tam CS, et al. Blood 2014; 124: ; 2. Stilgenbauer S and Zenz T. Hematology Am Soc Hematol Educ Program 2010;2010:

30 Progression-free survival P ro g re s s io n -fre e S u rv iv a l (% ) Salvage treatment in CLL not suitable for chemoimmunotherapy Ibrutinib (RESONATE) R/R CLL Not suitable for F-based Tx PFS <36 mo del17p Idelalisib-R (116) R/R CLL Not suitable for cytotoxic Tx: PFS <24 mo Venetoclax M R/R CLL Not suitable for cytotoxic Tx: del17p ORR: 63% ORR: 81% ORR: 79% Ibrutinib (n=196) Ofatumumab (n=195) 75% PFS Months Byrd JC et al. New Engl J Med : Idelalisib + R (n=110) Placebo + R (n=110) T im e (m o n th s ) 60% PFS 51% PFS Furman R et al. New Engl J Med : Stilgenbauer S et al. Lancet Oncol 2016;17:768-78

31 Outline Predictive biomarkes in the 1 st line setting Pts fitness TP53 IGHV Predictive biomarkes in the relapsed setting Remission duration TP53 Histology

32 Event-free survival (proportional) Progression-free survival (%) Event-free survival in relapsed TP53 disrupted patients Bendamustine -R del(17p) del(11q) Trisomy 12q del(13q) single Other* Idelalisib-R del(17p) median PFS: 6.8 months Time (months) Ibrutinib 20 0 P=0.94 No del(17p)/tp53mut Del(17p)/TP53mut Time (months) Venetoclax

33 Toxicities and management for novel therapies Ibrutinib 1 Idelalisib 2 Venetoclax 3 Infections History of atrial fibrillation/flutter, cardiac risk factors, hypertension Risk of bleeding-related events (incl. anticoagulant therapy) Mild/moderate liver impairment Cytopenias Interstitial lung disease Tumour lysis syndrome Non-melanoma skin cancer Drug drug interactions Women of childbearing potential Gastrointestinal disorders (consider diarrhoea/colitis risk) Respiratory insufficiency (consider pneumonitis risk) Neutropenia Transaminase elevations Stevens-Johnson syndrome and toxic epidermal necrolysis CYP3A inducers CYP3A substrates Hepatic impairment Chronic hepatitis Women of childbearing potential Tumour lysis syndrome Neutropenia CYP3A inducers Women of childbearing potential 1. Imbruvica SmPC. Available at: (accessed June 2017); 2. Zydelig SmPC. Available at: (accessed June 2017); 3. Venclyxto SmPC. Available at: (accessed June 2017).

34 Redistribution lymphocytosis Blood Lymph node CLL CLL chemokines CLL BCR CLL CLL CLL Kinase Inhibitor Kinase Kinase integrins De Rooij, Blood 2012; Ponader, Blood 2012; Herman, abstract #185

35 New response criteria are required Lymphocytosis + Nodal Reduction with BCR Antagonists

36 Restoration of apoptosis through BCL2 inhibition

37 Venetoclax induces deep remissions Response Classification MRD-negative MRD-positive Not Evaluable CR/CRi (n=25) npr/pr (n=17) a Other (n=7) 0 1 b 6 c Total, n/n (%) 28/49 (57) 14/49 (29) 7/49 (16) Seymour JF, et al. Lancet Oncol Feb; 18(2):

38 TLS risk assessment and prevention Assess risk factors for TLS Tumor burden (blood count and CT scan) Renal function Other co-morbidities All LN <5 cm and ALC <25 G/L Any LN 5 to 10 cm or ALC >25 G/L Creatinine clearance <80 ml/min increases risk Any LN >10 cm or ALC >25 G/L and LN >5 cm Risk might increase with co-morbidities, splenomegaly, abnormal baseline chemistry labs, dehydratation Establish TLS risk Low Medium High

39 TLS prophylaxis TLS risk HYDRATATION ANTI-HYPERURICEMIC AGENTS BLOOD CHEMISTRY MONITORING Low Medium High Ensure adequate hydratation throughout dose-titration, particularly 2 days prior to and the days of dosing at initiation and each subsequent dose increase; IV fluids based on TLS risk who cannot mantain adequate oral hydratation Oral (1.5-2 L) Oral (1.5-2 L) and consider additional IV if tolerated Oral (1.5-2 L) and IV ( ml/h as tolerated) Start anti-hyperuricemic agents 2 to 3 days prior to first dose, which may be continued through the titration phase based on the ongoing risk of TLS. Subjects allergic to allopurinol must use another uric acid reducer Anti-hyperuricemic agents (e.g., allopurinol) Anti-hyperuricemic agents (e.g., allopurinol) Anti-hyperuricemic agents (consider rasburicase if baseline uric acid is high) Correct pre-existing blood chemistry abnormalities prior to initiation of treatment. Monitor blood chemistry in real time (turn around <2h): potassium, uric acid, phosphorus, calcium, creatinine Outpatient monitoring Pre-dose, 6-8, 24 h* (at 1 dose of 20 and 50 mg) Pre-dose at subsequent ramp-up dosease Outpatient monitoring Pre-dose, 6-8, 24 h* (at 1 dose of 20 and 50 mg) Pre-dose at subsequent ramp-up dosease Consider hospitalization if CrCl <80 ml/min at 1 dose of 20 and 50 mg In hospital monitoring (1 dose of 20 and 50 mg) Pre-dose, 4, 8, 12, 24 h* Outpatient monitoring (subsequent ramp-up doses) Pre-dose, 6-8, 24 h* *24 h labs: do not administer the next dose until 24 h chemistry results have been evaluated.

40 Venetoclax in CLL After Failure of Ibrutinib or Idelalisib PFS (%) PR CR 100% 80% PFS % 50 40% 20% 0% Ibrutinib Idelalisib Pts at Risk, n R/R ibrutinib R/R idelalisib All pts Mos Since First Dose Jones J, et al. ASH Abstract 637.

41 Allo-SCT in high-risk CLL (CLL3X) Probability of survival 1 Cumulative incidence Retrospective analysis OS PFS Time after HCT (years) Event-free survival 2 Event-free survival CLL3X trial unknown (18) del(17p) (13) del(11q) (26) Other (21) del(13q) (12) Time from SCT (months) CLL3X trial: TP53 mutations Relapse incidence Non-relapse mortality Time after HCT (years) TP53 mutations (18) TP53 wt (54) 20 TP53 mutations vs wt: 0 HR=0.82 (95% CI: ); p= Time from SCT (months) 1. Schetelig J, et al. J Clin Oncol 2008; 26: ; 2. Dreger P, et al., Blood 2010; 116: ; 3. Dreger P, et al. Blood 2013; 121:

42 Probability Probability Outcome stratification after allosct in CLL (EBMT) Good transplant risk 46-year-old reference patient with high-risk cytogenetics 1.0 Two-year NRM, CIR, and PFS 1.0 Eight-year PFS PFS 0.6 PFS CIR Time since allosct (years) Baseline characteristics that predict outcome after allosct: Remission at the time of allosct Donor patient HLA match Donor patient sex match NRM CIR, cumulative incidence of relapse; EBMT, European Group for Blood and Marrow Transplantation; NRM, non-relapse mortality. Van Gelder M, et al. Blood 2016; 128: Abstract 522 (oral presentation) Time since allosct (years)

43 Outline Predictive biomarkes in the 1 st line setting Pts fitness TP53 IGHV Predictive biomarkes in the relapsed setting Remission duration TP53 Histology

44 Probability Histology of progressed CLL Prolymphocytoid evolution Richter s syndrome DLBCL variant Non-accelerated CLL Accelerated CLL DLBCL-t Survival from biopsy (months) DLBCL-t, diffuse large B-cell lymphoma transformation. Ginè E, et al. Haematologica 2010; 95:

45 WHO 2016 Classification Richter syndrome Clinical suspicion of transformation 1,2 Asymmetric growth of localised lymph nodes Bulky disease B symptoms Sudden excessive rise in LDH level Histological patterns observed in biopsies from patients with CLL 1,3 PET/CT in RT diagnosis 3 RT Sensitivity 91% Specificity 80% Positive predictive value 53% Negative predictive value 97% Max SUV cut-off = 5 DLBCL Prolymphocytoid CLL Second cancer CT: computed tomography; LDH: lactate dehydrogenase; PET: positron emission tomography; SUV: standardised uptake values 1. Giné E, et al. Haematologica 2010; 95: Rossi D, et al. Semin Oncol 2016; 43: Bruzzi JF, et al. J Nucl Med 2006; 47:

46 Post remission SCT is a potentially curative approach for Richter syndrome (EBMT) Overall survival (proportion) Overall survival (proportion) Allo-SCT (n=25) Auto-SCT (n=34) Time (months) Time (months) Prognostic Factors Chemosensitive disease; RIC No prognostic factors identified Cwynarski K, et al. J Clin Oncol 2012; 30:

47 Can treatment of R/R CLL be informed by biomarkers? Histology: CLL Histology: RT TP53 wt Long remission duration TP53 mutated and/or deleted or Short remission duration Previous Tx: R-chemo Previous Tx: R-chemo and BCR inhibitor BR Ibrutinib Idelalisib + R Venetoclax Venetoclax R-CHOP RIC-allo-SCT BCR: B-cell receptor; R-chemo: rituximab chemotherapy; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RIC-allo-SCT: reduced-intensity conditioning allogeneic stem cell transplant; RT: Richter transformation RIC-allo-SCT RIC-allo-SCT Personal communication.