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7/12/2016

1

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New Directions in Aplastic Anemia:

What's on the Horizon?

Amy E. DeZern, MD; MHS

Assistant Professor

Hematologic Malignancies

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, MD

Objectives

To provide information on new concepts

emerging in AA in somatic molecular

testing

To review updates on markers of

response to therapy in AA

To review newer data on emerging

therapies in aplastic anemia (AA)

TESTING

July 12, 2016 3

Better way to evaluate clonal

evolution?

As survival is improving, we may see

more late development of MDS/AML in

15% of patients clonal evolution

Extrapolation from MDS field somatic

mutational testing

Goal: to use this testing to ID group of

AA pts more likely to get MDS

(treatment would be modified)

Kulasekararaj et al. Blood 2014

Yoshizato et al. NEJM 2015

4

The Dawn of the Molecular Era of

the Myelodysplastic Syndromes 51% of patients 1 mutation (including ~50% with

normal karyotype)

FIVE genes (in ~30% of pts) independent

prognostic significance and predicted poor overall

survival

EZH2 ETV6 RUNX1 ASXL1 P53

Bejar et al NEJM

2011

RUNX1

ETV6

WT1 PHF6

GATA2

DNMT3AEZH2

ASXL1

IDH1 & 2

UTX

TP53

Transcription FactorsTyrosine Kinase Pathway

Epigenetic Dysregulation

SF3B1

Splicing Factors

JAK2

NRAS

BRAFKRAS

RTKs

PTPN11

NOTCH?MAML?

ZSWIM4?UMODL1?

CBL

NPM1

ATRX

Others

SRSF2

U2AF1ZRSF2

SETBP1

SF1SF3A1

PRPF40BU2AF2

PRPF8

BCOR

TET2

Genes Recurrently Mutated in MDS

Courtesy of Bejar R.

7/12/2016

2

Retrospective from the UK

From UK: looked at 150 pts with no

evidence (by microscope) of MDS

Screen for mutations

ASXL1, DNMT3A, BCOR, TET2, MPL at least

19% AA pts had mutations

Pts with mutations had a longer disease

duration (37 vs. 8 months, p 6 mos

AND mutation40% risk of transformation to

MDS (p 2

Number mutations

per SAA patient

65%

23%

7%

5%

0%

25%

50%

75%

100%

EpigenesisTranscription

factorSignal

transductionOthers

DNA

repair Receptor

Ribosomal

protein

AEBP2 ATM BRAF CDAN1 FANCA FLT3 RPL11ASXL1 BCOR CSMD1 CDH23 FANCC KIT RPL35aATRX BCORL1 GNAS DIS3 FANCD1 GCSFR RPL5DNMT3A CEBPA GPRC5A DKC1 FANCD2 MPL RPS10EED CTCF JAK1 ELANE FANCE RPS19EZH1 CUX1 JAK2 ETNK1 FANCG RPS26EZH2 DAXX JAK3 LAMB4IDH1 Dido1 KRAS LUC7L2 Telomere Splicing CohesinIDH2 ETV6 LNK PEG3 NHP2 DDX41 RAD21JARID2 GATA1 MAP3K4 PIGA NOP10 PRPF8 SMC1AKDM6A GATA2 NF1 PRF1 POT1 SF3B1 SMC3RBBP4 IRF1 NRAS SBDS RAP1 SRSF2 STAG2RBBP7 NCOR2 PTPN11 SETBP1 RTEL1 U2AF1SUZ12 NPM1 RIT1 UMODL1 TERC U2AF2 UbiquitinTET2 PHF6 SRP72 ZSWIM4 TERF1 ZRSR2 BRCC3

Rb STAT3 TERF2 CBLRUNX1 TERT FBXW7TP53 TINF2WT1 TPP1

Targeted gene panel

ACQUIRED MUTATIONS IN SAA NIH COHORT (n=256)

0.0%4.0%8.0%12.0%

PIGA

BCOR/BCORL1

DNMT3A

ASXL1

Splicing

cohesin

JAKs

RUNX1

TP53

TET2

SETBP1

GNAS

PRC2

CSMD1

LAMB4

WT1

TERF1/TERT

ATRX

PHF6

ATM

RIT1

CDAN1

IDH2

CUX1

RBBP4

CBL

PRPF8

KRAS

MPL

NF1

POT1

RAP1A

STAT3

PEG3

DIS3

SH2B3

77%% of patients

multiplemissense

nonsense

frameshiftsplicing

PIGA

BCOR/BCORL1

DNMT3A

ASXL1

ACQUIRED MUTATIONS IN SAA STRONG AGE BIAS

7/12/2016

3

Odds ratio (95% CI) p value

ARC

7/12/2016

4

Telomeres

Telomeres: regions of repetitive nucleotides at the ends of chromosomes that are there to protect the chromosomes from damage and breakdown.

Telomere length testing very helpful in inherited AA DKC (very short)

Reports suggest that telomeres are shorter (not very short) in up to one-third of patients with acquired SAA

At NIH, telomere lengths measured in the white blood cells of 183 patients treated with IST

Shorter telomeres not found to predict who would have improved blood counts at 6 months after IST

Shorter lengths may be associated with late effects such as relapse or clonal evolution to MDS

Scheinberg et al. JAMA, 304 (2010), 1358-64.July 12, 2016

DeZern and Armanios (unpublished)

PNH clones and telomeres predict

response to IST in Pediatric AA

Prospective study of 113 children (Ages 0-16)

All had PNH clones and telomeres done in CLIA certified

way before IST

Response assessed based on PNH clone presence and

telomere length

If PNH clone + and telomeres long- ~70% response

If PNH clone neg and telomeres short- ~19%

response

Suggestion for upfront HSCT if in this group

Narita et al. Haematolgica 201521

TREATMENTS

July 12, 2016 22

Severe Aplastic Anemia 2015 Treatment Paradigm

Bone Marrow

Transplantation

Immunosuppressive

Therapy

No Response

~30%

~40% Relapse or

Clonal Evolution TRANSPLANTClinicalfollow up

Response

Rate ~70%

Age < 40 years with

HLA matched sibling

Age > 40 years OR

No HLA matched sib

Diagnosis of Severe

Aplastic AnemiaTreatment based upon age and

donor availability

Alternative Donor transplants in

SAA

Reserve for relapsed or refractory SAA After failing ATG

Should be done in a specialist center with major experience in hematopoietic SCT procedures

Perform in setting of clinic trial designed specifically to address the prevention of graft rejection and GVHD

Ciceri et al BMT 2013

7/12/2016

5

Unrelated Donor or Alternative donor

BMT

The sooner, the better after relapse/ refractoriness noted

Bone marrow still the best source

Similar conditioning regimens

Often in setting of clinical trial

Unrelated donor (NMDP- MUDs)

Haplo-identical donor (half match)

Umbilical cord donor

New Trial

July 12, 2016 26

Primary Objective

Assess overall survival in 2 cohorts

(unrelated cord blood and haplo-

identical) at 1 year post-hematopoietic

stem cell transplantation in patients with

severe aplastic anemia

Hypothesisboth cohorts >75% 1yr OS27

Hopkins Haplo BMT for Acquired and

inherited SAA

28

Age/

Sex59

Pre-BMT

Therapy

Degree of

HLA

match

Day of

engraftm

ent

(ANC

>1000)

Donor

chimerism

at day 100

aGVHD cGHVD ResponseFollow-

Up (mos)

35M ATG/ CsA 5/10 30 100 none none CR 50

52M ATG/ CsA 5/10 24 100 none none CR 27

45F ATG/ CsA 5/10 27 100 Gr 2 skin Gr 2 skin CR 22

27F ATG 5/10 24 100 none none CR 15

33M HiCY 5/10 16 100 none none CR 17

17M HiCY 5/10 17 100 none none CR 9

54M ATG/ CsA 5/10 15 100 none None CR 9

26F

ATG/

CsA/TPO 5/10 17 100 none None CR 6

59

ATG/

CsA/TPO 5/10 24

100 (Day

60 none None CR 3

21 Steroids 5/10 18 100 none none CR 33

38 Danazol 9/10 17 100 none Gr 2 skin CR 20

Mini-BMT for Refractory SAA

Treatment schema

Adult URD

Survival now >75%

Similar conditioning regimens- may add

TBI

Bacigalupo and Marsh BMT 2013

7/12/2016

6

Kaplan-Meier survival rate estimates (and 95%

confidence intervals) for recipients of an HLA-matched

sibling or unrelated donor HCT for SAA registered with

CIBMTR from 1990 through 2011, by donor type, age

group, and graft source HLA-Matched Sibling Donor Unrelated Donor

Age < 40y Age 40y Age < 40y Age 40y Survival rate (95% CI), Graft Source: BM and PB 1 year 84 (82 85) 68 (64 72) -- -- 3 years 80 (79 82) 61 (57 65) -- -- 5 years 80 (78 81) 57 (52 62) -- -- 10 years 77 (75 79) 50 (45 56) -- -- Survival rate (95% CI), Graft Source: CB 1 year 79 (56 94) -- 52 (44 59) Not estimated* 3 years 72 (48 90) -- 44 (36 51) Not estimated* 5 years 72 (48 90) -- 40 (32 49) Not estimated* * CIBMTR requires a sample size of at least 20 for KM survival-rate estimations

The data presented here are preliminary and were obtained from the Statistical Center of the Center for International Blood and

Marrow Transplant Research. The analysis has not been reviewed or approved by the Advisory or Scientific Committee of the

CIBMTR.

Umbilicord Transplants

Survival is still lower ~40%

Conditing regimens more varied

CY/Flu/ TBI

Melphalan/Flu/ TBI

Japanese study

12 adult patients, 11/12 engrafted, survival

10/12 median 36 mos

Yamamoto et al B

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