What is new in HR-MDS. Valeria Santini MDS UNIT Ematologia, Università di Firenze

Transcription

1 What is new in HR-MDS Valeria Santini MDS UNIT Ematologia, Università di Firenze

2 Therapeutical options for higher risk MDS Santini V. Hematology Am Soc Hematol Educ Program. 2012;2012:65-73.

3 Myelodysplastic Syndromes, Version , NCCN Clinical Practice Guidelines in Oncology. Higher risk= IPSS INT-2/high IPSS-R High/very High/ intermediate Greenberg PL et al. J Natl Compr Canc Netw Jan;15(1):60-87

4 How to evaluate MDS clinically? How to determine prognosis?

5 Myelodysplastic syndromes are a constellation of diseases with difficult diagnosis Diagnosis in Not based on new parameters An accurate diagnosis is the basis for successful prognostic stratification (and treatment) of MDS Criteria: presence and number of dysplastic lineages, percentage of bone marrow blasts, cytogenetic abnormalities

6 Proportion surviving AML-free proportion IPSS-R: prognostic scores and risk groups * Values for 70-year-old patient (for consideration of age: [age in years 70] x 0.04, add result to sum of other variables). Age, PS, ferritin, and LDH were significant additive features for OS but not for AML transformation. Risk category Score Very low 1.5 Low > Intermediate > High > Very high > OS by IPSS-R n = 7,012 Very good Good Intermediate Poor Very poor Duration, months AML-free survival Duration, months Very good Good Intermediate Poor Very poor Very low Low Intermediat e High Very high Median OS, years AML 25%, years NR NR, not reached. Greenberg PL, et al. Blood. 2012;120: and updated data.

7 Is IPSS-R enough? Molecular variables: somatic mutations and DNA methylation

8 Molecular variables: somatic mutations IPSS-R does not consider somatic mutations Somatic mutations are present in nearly 90% of MDS Several mutated genes have prognostic significance independent of the IPSS-R How to weigh prognostic mutations in clinical practice remains unclear

9 Somatic mutations in MDS: prognostic value possible therapeutic target help refine therapeutic strategy

10 Somatic gene mutations in MDS are independent prognostic indicators none SF3B1 mut >1mut: TP53, CBL, EZH2, RUNX1, U2AF1, ASXL by American Society of Hematology Rafael Bejar et al. Blood 2015;126:907

11 LFS Leukaemia-free survival in MDS inversely correlates with number of driver mutations Mutations, n (p < ) 0.2 p < Duration, months Papaemmanuil E, et al. Blood. 2012;120:abstract 5.

12 IPSS-R integrated model with molecular variables (83 pts) Montalban-Bravo G et Al,, Oncotarget 2018, Vol. 9, (No. 11), pp:

13 IPSS-R integrated model with molecular variables (426 pts) Mutations of CBL, IDH2, ASXL1, DNMT3A, and TP53 Hou HA et al; Blood Cancer J Apr 4;8(4):39.

14 Somatic mutations in MDS: possible therapeutic target

15 IDH1/2 mutations in MDS Present in ~4-12% of patients with MDS Missense mutations: heterozygous; target highly conserved Arginine residues IDH1: R132H mutations IDH2: R172K or R140Q mutations All variants produce 2-hydroxyglutarate (2-HG) Mutations in IDH1/2 are associated with increased 5- methylcytosine Initial reports: Unfavorable prognosis for IDH-mut MDS

16 16 Response to enasidenib AG221 ( IDH2m-inhibitor) in IDH2m MDS Stein EM, et al. Oral Presentation at ASH Abstract 343

17 Mutations in spliceosome genes are frequent in MDS Bejar et al. 2016

18 Spliceosome inhibitors Martines-Montiel et al; BioMed Research International 2016

19 H3B-8800 Phase I clinical trials in MDS, AML and CMML Buonamici et al ; ASH 2016 abs 966

20 Somatic mutations in HR-MDS: help theraputic decision making?

21 Mutation patterns observed in MDS treated with allo-hsct RUNX1 23% SRSF2 17% ASXL1 17% SF3B1 16% KRAS/NRAS 16% DNMT3A 15% TP53 13% TET2 10% JCO doi: /jco

22 Relationship between type of oncogenic mutations and overall survival of MDS receiving allo-hsct Multivariable analysis MDS patients Probability of relapse Overall Survival Variable HR P HR P ASXL RUNX TP Matteo G. Della Porta et al. JCO doi: /jco

23 Prognostic Mutations in Myelodysplastic Syndrome patients treated with HSCT. TP53 mutations are the strongest predictor TP53 RAS pathway JAK2 Lindsley, RC et al. N Engl J Med 2017;376:

24 100% MDS and AML patients with TP53 mutations respond to Decitabine Welch JS et al. N Engl J Med 2016; 375:

25 Clearance of leukemia-specific mutations correlated with morphologic and cytogenetic responses Variants in TP53 mutations Variants in DNMT3A mutations Gene mutations not yet correlated with AML Blast counts Bone marrow blast clearance frequently preceded mutation reduction. D: Rate of clearance of 21 TP53 mutations in 16 patients Mutations in TP53 consistent reductions E: Mutations in only TP53 and SF3B1 consistent, rapid reductions in variant allele frequency Welch JS et al. N Engl J Med 2016; 375:

26 OS according to risk karyotype and TP53 profile with decitabine No differences between unfavourable and favourable risk Welch karyotype et al. NEJM 2016;375: No differences per status of TP53 mutant Welch et al. NEJM 2016;375:

27 Survival after transplant not adversely affect by TP53 status Welch JS et al. N Engl J Med 2016; 375:

28 Mutation allele burden remains unchanged after DAC Merlevede et al Nat Commun Feb 24;7:10767.

29 Somatic mutations in MDS: a warning on interpretation for clinical decision making

30 ICUS idiopathic cytopenia of unknown significanc IDUS idiopathic dysplasia of unknown significanc CHIP/ARCH clonal hemopoiesis of indeterminate potential/ ag related clonal hemopoiesi CCUS clonal cytopenia of unknown significance

31 ICUS ARCH CHIP CCUS Lower Risk MDS Higher Risk MDS Clonality Dysplasia Cytopenia BM Blast % <5% <5% <5% <5% <5% <19% AML Overall Risk Median Num of mutations Very low Very low Very low Low but cardiopathy /intermediat e Low >1<2 >2 >2 Typical VAF % 9-12% (>10) 30-40% (40) >50% >50% High Types of mutations DNMT3A, TET2,ASXL1, JAK2, TP53 DNMT3A, TET2,ASXL1, JAK2, TP53 TET2, DNMT3A,ASXL1, SRSF2, TP53 Later TET2, SRSF2, ASXL1, U2AF1, DNMT3A SF3B1, TET2, ASXL1, SRSF2, DNMT3A and all the less frequent Modified from Steensma et al, Blood 2015 and Bejar R Leukemia, 2017 online

32 Molecular variables: can we predict response to HMAs?

33 Risk stratification in MDS patients treated with hypomethylating agents Response to HMT OS after HMT Traina F et al, Leukemia 2013

34 Response to HMAs does not depend on specific mutations or different mutation VAFs but on number of mutations LFS Montalban Bravo et al, Oncotarget 2018

35 Distinct DNA methylation profiles at diagnosis of CMML is associated with response to decitabine 167 DMRs Meldi, et al. JCI 2015

36 Differentially methylated regions are enriched at distal intergenic regions and enhancers Background All DMRs HYPER HYPO Meldi, et al. JCI 2015

37 CXCL4 and CXCL7 are up-regulated in the bone marrow of non-responders Expression Meldi, et al. JCI 2015

38 CXCL4 and CXCL7 are up-regulated in the bone marrow of non-responders Francesca Buchi CXCL4 CXCL7 R NR Meldi, et al. JCI 2015

39 Response to DAC is associated with reversal of hypermethylation CHROMOSOMES Before DAC After DAC Responders Loss of mc 25% after DAC Gain of mc 25% after DAC Merlevede et al Nat Commun Feb 24;7:10767.

40 Uptake and metabolism of drugs may be impaired genetically and alter outcome

41 RNA RNA/DNA uptake of hypomethylating agents DNA 5-aza-CTP 5-aza-dCTP Phosphatase 5-aza-CDP 5-aza-CMP 5-aza-CR Azacitidine Ribonucleotide Reductase Uridine Cytidine Kinase hcnt3 hent ABC 5-aza-dCDP 5-aza-dCMP Phosphatase decitabine Decitabine dcmp deaminase Deoxycytidine Kinase Attadia V. Leukemia. 1993;7:9-16.

42 UCK1 hyperexpression modulates response to Azacitidine in HR-MDS Ana Valencia et al, Leukemia 2013 UCK1 expression 57 MDS pts P= 0.07 Azacitidine 75mg/m 2 /7 days every 28 gg UCK1/2 Gene expression Promoter methylation Gene sequence < 0.27 OS according UCK1 levels > 0.27 P= 0.05

43 Evaluated expression of DAC metabolizing enzyme genes hent1 hent2 No/low expression RNAseq was performed in 14/38 (8 responders and 6 no responders) CMML cases p > 0.05 p > 0.05 hcnt3 No/low expression DCK DCTD No/low expression p > 0.05 p > 0.05 CNII CDA R and NR cases did not show a difference in expression levels of DAC metabolizing enzymes!!!

44 Are there new options of therapy for HR-MDS? New drug formulations Monoclonal Antibodies Multi Kinase inhibitors

45 Oral decitabine O H Active form X CDA CEDAZURIDINE (E7727) Inactive form ASTX727 (DAC 35 mg/cedazuridine 100 mg) Group A Random 1:1 DAC 20 mg/m 2 ev ASTX727 35/100mg ASTX727 35/100mg cycle 1 Cycle 2 Cycle 3 and on Group B ASTX727 35/100mg DAC 20 mg/m 2 ev ASTX727 35/100mg Garcia-Manero G et al. ASH 2017, abs 4274

46 PATIENT CHARACTERISTICS(n 50) M/F, n 41/9 Median age (range) ECOG PS, n (%): HMA, n (%): No yes IPSS score, n (%): Int-1 Int-2 High LMMoC 71.5 (32 87) 22 (44) 24 (48) 4 (8) 47 (94) 3 (6) 20 (40) 13 (26) 8 (16) 9 (18) THERAPY RISPOSTA TERAPEUTICA ORR, n (%) 31 (62) CR 8 (16) CRm 14 (28) HI 9 (18) NR 19 (38) CR duration, mos (95%IC) AUC i 5 dd (ng*h/ml) range (90% IC) ASTX DAC 20 mg/m ( ) NR (2.8 NR) Garcia-Manero G et al. ASH 2017, abs 4274

47 oral JAK-1 inhibitor INCB Response ORR, n (%) 3 (30) n %): RC RCm RP 3 (30) 0 0 MDS R/R TMO RC MS PD SD, n (%) 4 (40) PR, n (%) 2 (20) De novo MDS TMO TMO Not evaluable, n (%) 1 (10) days Zeidan A et al. ASH 2017, abs 640

48 SGI-110 Background A Second Generation Hypomethylating Agent Decitabine is rapidly eliminated by Cytidine Deaminase, limiting drug exposure time to cancer cells in vivo SGI-110 is a Dinucleotide of Decitabine and Deoxyguanosine that prolongs the in vivo exposure of decitabine by protecting it from deamination Prolonged decitabine in vivo exposure may translate to better efficacy + SGI-110 Deoxyguanosine

49 Long acting Hypomethylating Agent : SGI-110 Major Eligibility Previously Treated MDS/CMML or Treatment Naïve MDS/CMML IPSS Int-1,2 and HR ECOG PS 0-2 Adequate hepatorenal function R A N D O M I Z A T I O N Biologically Effective Dose 60 mg/m 2 daily x 5 Highest Well Tolerated Dose 90 mg/m 2 daily x 5 IWG 2006 MDS Response Criteria Treatment continued until unacceptable toxicity, disease progression Primary Endpoint: Overall Response Rate (CR, PR, mcr, HI) Secondary Endpoints: Transfusion independence, LINE-1 demethylation, time to AML, overall survival Issa et al; Lancet Oncol Sep;16(9): Kantarjian H et al; Lancet Oncol Oct;18(10):

50 Guadecitabine (Clinical Responses in Tx naïve MDS/CMML) 60 and 90 mg/m 2 SC Dailyx5 combined Response Category 1 Tx Naïve (n=49) Response rate n (%) CR 7 (14.3) mcr 3 (6.1) HI 9 (18.4) CR+mCR 10 (20.4) Overall Response Rate 19 (38.8) 1 International Working Group 2006 MDS Response Criteria Garcia-Manero et al American Society of Hematology

51 Response to SGI-110 in HMT relapsed refractory HR-MDS Response 60 mg/m2/d x5 n=26 N (%) 90 mg/m2/d x5 N=27 N (%) Total N=53 N (%) CR 1 (3.8%) 1 (3.7%) 2 (3.8%) mcr 1 4/13 (31%) 11/21 (52%) 15/34 (44%) PR HI 5 (19.2%) 6 (22.2%) 11 (20.8%) 1 Evaluated only for patients with BM blasts > 5%

52 Phase 2 r/r MDS Overall Survival Combined Data Median Survival = 11.7 months

53 Rigosertib a POLO KINASE inhibitor Multicenter International Phase III Trial 180 patients Patients with de novo or secondary MDS who relapse after, progress, are refractory to azacitidine or decitabine Higher risk MDS, or chronic myelomonocytic leukemia (CMML) 90 patients 270 (223 events)

54 ONTIME Rigosertib Trial: Subgroups Correlated with Longer Median OS - ITT p < 0.05 Additional information on the relationship between rigosertib and karyotype mutations is available in Poster #

55 Rigosertib monotherapy in R/R MDS: Primary Efficacy Results - ITT Garcia-Manero G, et al. Lancet Oncol 2016;17:496.

56 Proposed Ideal Patient Population (<9 HMA DoT; <80 yrs; <6 Month from HMA) Garcia-Manero G, et al. Lancet Oncol 2016;17:496.

57 What about HMA combinations?

58 Azacitidine plus lenalidomide /vorinostat 5AC N=92 ORR 38 % Total Sample Size: 282/277 Higher-risk MDS/CMML (IPSS >1.5) 5AC + LEN N=93 ORR 49 % Primary Objective: 20% improvement of ORR based on 2006 IWG Criteria Power 81%, alpha 0.05 for each combo arm vs. AZA 5AC + VORIN N=92 ORR 27 % Sekeres M, et al JCO 2017

59 Eltrombopag plus azacitidine: TRC Support Screening 4 weeks Treatment fo 6 cycles Continue treatment Follow up 5 years Int1,Int2 or high risk MDS PLT<75/Gi /L Random 1:1 N350 Eltrombopag + Azacitidine 75 mg/m 2 7dd /28dd Placebo + Azacitidine 75 mg/m 2 7dd /28dd Survival Follow up Week 58

60 Eltrombopag plus azacitidine: TRC Support On December 16 recommendation from the IDMC to stop the SUPPORT study based on a risk/benefit assessment: Primary reason: due to futility analysis Secondary reason: due to safety The results show that the futility criterion has been met. The observed p-value is >0.9 and the estimated treatment effect favor to placebo. The IDMC noted that while there was no difference in overall deaths that would indicate harm, there is a trend towards disease progression, favoring placebo

61 The Ubiquitin System and the Proteasome Ubiquitination Ub UAE UAE E2 Ub ATP AMP + PPi ATP Ub AMP + PPi Neddylation N8 NAE NAE N8 pevonedistat (TAK-924,MLN4924) Ubc12 N8 E3 ligase E3 ligase N8 mub, K11,29,63 Ub Signaling K48 Ub Dependent Degradation Ub Independent proteasome

62 Evaluating an inhibitor of the NEDD-8 activating enzyme: Pevonedistat Randomization Phase 2, Randomized, Open-label, Global, Multicenter Study Comparing Pevonedistat Plus Azacitidine vs. Azacitidine in Patients with Higher Risk MDS, CMML, or Low-Blast AML N=117 Pevo + Aza Pevo: 20 mg/m 2 on Days 1, 3, 5 Aza: 75 mg/m 2 Days 1-5,8, 9 1:1 Repeat every 28 days Stratification: Low-Blast AML MDS -very high risk -high risk - intermediate risk CMML Evaluated by IPPS-R Aza Aza: 75 mg/m 2 Days 1-5, 8, 9 Primary Endpoint: Event Free Survival For higher risk MDS or CMML, an event is death or transformation to AML. For low-blast AML, an event is death or disease progression.

63 Venetoclax (ABT-199) in MDS

64 Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Tsao T, Shi Y, Kornblau S, Lu H, Konoplev S, Antony A, Ruvolo V, Qiu YH, Zhang N, Coombes KR, Andreeff M, Kojima K, Konopleva M. Ann Hematol Dec;91(12): PubMed PMID: PMCID: BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies. Bogenberger JM, Kornblau SM, Pierceall WE, Lena R, Chow D, Shi CX, Mantei J, Ahmann G, Gonzales IM, Choudhary A, Valdez R, Camoriano J, Fauble V, Tiedemann RE, Qiu YH, Coombes KR, Cardone M, Braggio E, Yin H, Azorsa DO, Mesa RA, Stewart AK, Tibes R. Leukemia Aug;28(8): PubMed PMID: PMCID: Ex vivo activity of BCL-2 family inhibitors ABT- 199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Bogenberger JM, Delman D, Hansen N, Valdez R, Fauble V, Mesa RA, Tibes R. Leuk Lymphoma Jan;56(1): PubMed PMID: PMCID:

65 Garcia Manero G et al, ASH 2016 abs 344.

66

67 And more novel attempts. schedule IBRUTINIB + AZA 1 SIROLIMUS + AZA 2 DOSE ( 28 day-cycles) mg gg mg/m 2 gg mg g 1, 4 mg gg mg/m 2 gg 4-10 N pts Median age (range) IPSS-R, n (%): Intermediate High Very high Previous therapy, n (%): No HMA 77 (55 82) 3 (20) 5 (33) 7 (47) 9 (60) 6 (40) 71 (49 81) / 8 (40) 12 (60) 16 (80) 4 (20)

68 FOLLOW-UP median, mos (range) IBRUTINIB + AZA 1 SIROLIMUS + AZA ( ) NOT REPORTED Evaluable for response 14 (1 cycle) 8 (4cycles) 20 (%) ORR (RC + RP + HI) Type of R, n (%): RC RP HI SD PD/DI OS, mos (range) 7 (50) 5 (62) 7 (35) 4 (29) 1 (7) 2 (14) 7 (50) / 3 (38) 1 (12) 1 (12) 3 (38) / 4 (20) 3 (15) / 6 (30) 7 (35) Not reached 6.9 ( ) 1) Jonas BA et al. ASH 2017, abs ) Palmisano N et al. ASH 2017, abs 4267

69 Bernardino Allione Ana Valencia Erico Masala Alice Brogi Alessandro Sanna Valeria Santini Monia Lunghi Antonella Poloni Emanuele Angelucci Carlo Finelli Alessandro Levis Omar Abdel-Wahab Institute Gustave Roussy, Paris Maria E.Figueroa Tingting Qin Kristen Meldi Eric Solary Nathalie Droin Dorothée Selimoglu-Buet