post-eha 2017 myeloid malignancies...relapsing polychondritis 14% (mds in 40% of relapsing...

Post-EHA 2017

Myeloid malignancies(except AML)

EHA 2017: it was hot!!

Part 1:

Myelodysplastic syndromes

New WHO classification

Mutational landscape of MDS

Haferlach T, Leukemia 2014

Clonal evolution

Driver vs passenger mutations

1 driver mutation = CHIP (clonal hematopoesis of

indetermined potential)

• >10% of

individuals over

age of 70 years

• CHIP: 10-fold

increased risk of

hematological

disease

Jaiswal, NEJM 2014

Acquisition of driver mutations

Some synergistic, some no added value

Order of mutations

Linear and branching evolution

Clonal evolution

NGS-based classification?

Transcriptome sequencing -> clustering of gene

expression data in class I and class II

Ogawa, oral 123

Class I Class II

Blast count Lower Higher

Genomic lesions SFB31, TET2 NRAS, TP53, del(7q)

Up-regulated pathways Signaling pathways

Up-regulated lineages Erythroid Progenitors

Class II:

Shorter survival

High frequency of leukemic transformation

Overall survival Leukemic transformation

Mutational profile and

prediction of response to HMA?

MDACC Texas – 222 patients with MDS and CMML

Overall response rate to HMA 61%

ASXL1: lower likelihood of response and CR

RUNX1: lower likelihood of repsonse

TP53 with VAF ≥0,31%: lower likelihood of reponse

and longer time to response and shorter duration of

response

3 or more mutations: shorter duration of response

Montalban-Bravo, oral 489

MDS and the immune system

Kordasti, Educational

In MDS augmented

levels of pro-

inflammatory cytokines

(TNFα, IFNγ, IL1β)

Low risk MDS: pro-

inflammatory state with

adequate immune respons

High risk MDS:

inhibitory cytokines

and upregulation of

suppressive Treg

Role of MDSC!

MDSC: myeloid derived

suppressor cells

Chen, J Clin Invest 2013

• Suppress T-cell respons

• Promote development of

FOXP3+ T regulatory cells

MDS and auto-immune disease

Previous AID: 2,1x higher risk for MDS

Chronic inflammation

Treatment of AID with hematotoxic agents

More frequent in low-risk MDS (pro-inflammatory state)

Manifestations:

Vasculitis 32%

Arthritis 23%

Relapsing polychondritis 14% (MDS in 40% of relapsing

polychondritis)

Neutrophilic dermatosis (Sweet’s syndrome) 10% (NLRP3-

inflammasome mediated chronic inflammation)

MDS and auto-immune disease

Prognosis: contradictory data

Treatment:

corticosteroids high dose, Rituximab

Treatment underlying MDS, even if no hematologicalneed

French retrospective study:

No difference

Moffitt Cancer Center and

King’s College: 1408 pts

Increased overall survival

Due to protective adaptive

immune response?

vs

Treatment of low risk MDS

Not a whole lot of news

Treatment of high risk MDS

Real-life results of HMAFondazione Italiana Sindromi Mielodisplastiche

Jan 2009-June 2014: 418 pt treated with Aza

21% RA(RS)-RCMD, 60% ≥IPSS Int-2 (13% unknown)

Response rate

Median overall survival 23 months

At median follow up after 16 months only 9% still on Azacitidine

Discontinuation mainly because of loss of response or progression to AML

Median overall survival after stop 8 months

CR 13%

PR 22%

SD 25%

NR 40%

Clavio, poster 667

HMA and the immune system

Viral mimicryUpregulation of TAA (tumor

associated antigen, pe CTA)

attraction of T-cells

Upregulation of PD-L1

Treatment of MDS

Ipilimumab

Pembrolizumab

Nivolumab

Checkpoint inhibition after

HMA failurePatients after HMA failure

Nivo (n = 15) Ipi (n = 9)

Age 78 71

Overall

respons

0 (0%) 2 (22%)

CR 0 (0%) 0 (0%)

SD 3 (23%) 4 (57%)

Garcia-Manero, ASH 2016

No clinical efficacy

Poster presentation: Atezolizumab (humanized IgG

against PD-L1) – stable disease in 60-70%, but no ORRGerds, poster 662

Combination of HMA and

checkpoint inhibition

Garcia-Manero, oral 487

Toxicity: most grade 1-2 – grade 3

pneumonia/febrile neutropenia and hepatitis

Immune toxicity (pneumonitis, hepatitis, myositis,

hypophysitis,…) – no mortality

Untreated

Global respons

(n = 32)

Aza + Nivo

(n = 20)

Aza + Ipi (n

= 12)

Overall

respons

23 (70%) 15 (75%) 8 (67%)

CR 13 (39%) 9 (45%) 4 (35%)

mCT 6 (18%) 5 (25%) 1 (8%)

HI 6 (18%) 3 (15%) 3 (25%)

SD 3 (9%) 0 (0%) 3 (23%)

PD 5 (16%) 4 (20%) 1 (8%)

NR 1 (3%) 0 (0%) 1 (8%)

Conclusion:

Active in presence of high risk features, in p53 mutation

Safe, but close monitoring for immune reactions

Warrants future randomized trials

Rigosertib + Azacitidine

Treatment naïve and R/R – phase I/II

Interferes with RAS-binding domain of RAF kinases

and inhibits RAS-RAF-MEK and PI3kinase pathway

Navada, oral 488

Treatment schedule

Week 1: Rigosertib PO (560 mg AM, 280 mg PM)

Week 2: Rigosertib PO + Azacitidine 75 mg/m2 SC

Week 3: Rigosertib PO

Week 4: no treatment

40 patients; IPSS int-1, int-2 or high

Side effects: diarrhea, nausea, hematuria/dysuria

Evaluable patients 33

Overall respons rate 25 (76%)

Treatment naïve 85%

R/R 62%

CR 8 (25%)

mCR + HI 10 (30%)

PR 0

SD 8 (24%)

PD 0

Median time to respons 2 cycles

Median duration of CR 8 months

Duration of overall response

Vit C?

Vit C is essential for

demethylation by TET

Vit C + HMA: higher ERV

expression, higher 5hmC

Vit C + HMA: more

apoptosisLiu, PNAS 2016

Vit C

Patients with hematological malignancies: strikingly

high percentage with vit C levels below normal

Association of vit C may increase efficacy of HMA:

EVITA-trial (epigenetics, vit C and abnormal

hematopoeisis) – Gronbaek, Denmark

Liu, PNAS 2016

AlloSCT and MDS

Who? Depending on disease risk and comorbidity

IPSS-R based decision making:2 years gain in life expectancy vs IPSS-based

• Timing?• IPSS-R very low/low:

postpone transplant

until progression

• IPSS-R int or higher:

immediate

Della Porta, Leuk 2017

Part 2:

Chronic myeloid leukemia

How to treat CML in 2017

Hochhaus

Choice 1st line?

No difference in OS between 1st and 2nd gen

Difference in early and deep molecular respons and

progression (MR4.5 42-54% vs 32%)

5 year OS

Dasatinib vs Imatinib 91% vs 90%

Nilotinib vs Imatinib 94% vs 92%

Dasision

ENESTnd

Cortes, JCO 2016

Hochhaus, Leuk 2016

Individual therapy based on

comorbidities

interactions

vascular risk

chance to achieve treatment free remission

cost

…

High leukocytosis at diagnosis: start withHydroxyurea 40 mg/kg until confirmation of BCR-ABL

No Allopurinol: risk of xanthine accumulation – useNaHCO3

A new kid on the block?

BFORE trial:

Bosutinib vs Imatinib first line

Chronic phase CML – ECOG 0-1

Well balanced groups

Bosutinib 400 mg 1x/d – Imatinib 400 mg 1x/d

BFORE trial

Bosutinib

(n = 246)

Imatinib

(n = 241)

<10% at 3 months 75% 57% p <0,0001

MMR 12 months 47% 37% P = 0,02

progression 1,6% (4) 2,5% (6)

Cortes, JCO 2017

BFOREBosutinib Imatinib

% all grades ≥grade 3 all grades ≥grade 3

diarrhea 70 8 34 1

musculoskeletal 30 2 59 2

liver function 40 24 14 4

periorbital edema 1 0 14 0

hematological 46 16 43 20

vascular events 4 1 2 <1

Discontinuation of Bosutinib in 22% - mostly because of

adverse events (14%) – also more dose reductions

Discontinuation of Imatinib in 27% - mostly because of

suboptimal respons (6%) of physician’s choice (5%)

Start with 100 mg Bosutinib and augment dose to prevent

diarrhea Brümmendorf, oral 425

PACE trial 5y follow-up – phase II

Ponatinib in heavily pretreated or T315I

Ponatinib in heavily pretreated or T315I CP-CML

267 patients (for 5y efficacy results)

Early cytogenetic response en deep reduction of BCR-ABL correlates with better OS

BCR>ABL <0,1% at 12 months: 4y OS 97%

Arterial occlusive events 29% - dose reduction to 15 mg

CCyR 54%

MMR 40%

MR4.5 24%

Cortes, poster 603

Succesful TKI discontinuation

Succesful stop in +/- 45%

Relapse mostly in first 6

months

If stop is attempted: monitor

BCR-ABL PCR monthly for first

6 months, thereafter every 2

months for another 6 months

and 3 monthly thereafterTwister trial

No ELN guidelines yet

Succesful TKI discontinuation:

some data

Definition of relapse: loss of MMR

No impact of age or gender

• STIM-trial: loss of

CMR (>1log rise)

• A-STIM: loss of MMR

Lower relapse rate

Etienne, JCO 2017

Higher Sokal score: succesful stop less likely

Longer duration of TKI therapy

Longer duration of DMRMahon, Blood 2016Euroski

High succes rate if still in MR4.5 3 months after stop

Stop possible if 2nd line therapy?

If switch because of

intolerance, not if

suboptimal response or

resistance

STOP 2G-TKI, Rea, Blood 2017

STOP 2G-TKI, Rea, Blood 2017

Some prudent guidelines

Hughes, Blood 2016

Stop-trials

ENESTfreedom – 96 weeks

1st line Nilotinib – 190 patients

Succesful TFR 46,3% (93 pt)

After week 48 recurrence in only 3 extra patients

ENESTop – 96 weeks

2nd line Nilotinib – 126 patients

Succesful TFR 53,2% (67 pt)

After week 48 recurrence in only 4 extra patients

DADI – 3 years

2nd line Dasatinib – 63 patients

Succesful TFR 44,’% (28 pt)

After 1 year recurrence in only 2 extra patients

Ross/Nakamae/Hughes, poster 601/263/257

DESTINYDe-escalation and Stopping of Therapy of Imatinib, Nilotinib and sprYcel

Inclusion:

Chronic phase CML

TKI therapy ≥3 years

At least MMR for ≥ 1 year

No TKI resistance (switch only for intolerance)

De-escalation: ½ dose of TKI for 12 months before

stopping

174 patients – 125 ≥ MR4.0 and 49 MMR but no MR 4.0

Destiny MR4.0

EuroSKI

Destiny MMR

De-escalation:

Recurrence

MMR: 9/49 (18.4%)

MR4.0: 3/125 (2,4%)

Stop:

Recurrence

MMR: 20/36 – RFS 39%

MR4.0: 26/117 – RFS 77%

Clark, oral 423

Targeting the leukemic stem cell

Anti-IL1RAP-Ab

Gliptin

Venetoclax

PPARΥ agonist

Part 3:

Myeloproliferative neoplasms

New WHO classification

Driver mutations

All mutations leading to pathological activation of JAK-STAT pathway

All mutations capable of inducing MPN on their own

Driver mutations

PV ET PMF

JAK2 >95% 60% 60%

JAKexon12 3%

CALR 20-25% 20-25%

MPL 3-8% 3-8%

Influence of driver mutations on

survival

PMF: triple negative fare worse

Rumi, Blood 2014

JAK2 mutation and metabolism

Reduced body

weight and atrophy

of adipose tissue

Resistant to high

fat diet

Warburg effect: malignant cells predominantly

produce energy by high rate of glycolysis, even in

the presence of abundant oxygen

Inhibition of fatty

acid oxidation

induces lethality in

MPN mice

Etomoxir = fatty acid oxidation inhibitor

Triple negative ET and MF

ET:

15% non-canonical

activation of MPL or JAK2

30% other clonal

55% polyclonal

MF: only small percentage

non-canonical mutations

Additional, non-driver mutations

Grinfeld, Haematologica 2017

Comparable to mutations in other

myeloid disease

Often low variant allele frequency

subclonal and meaning in disease

initiation is unclear (CHIP?)

Accumulation of mutations at

progression to MF

High molecular risk mutation in MF:

ASXL1, EZH2, SRSF2, IDH1/2

Impact on OS and blast transform

Vannuchi, Leuk 2013

Prospective monitoring of VAF-

evolution not recommended

Detection of non-

driver mutations

useful

In int-1 pts

presence of ASXL1

consider alloSCT

Targeting driver mutations

First in class: Ruxolitinib

Non-selective JAK1/2 inhibitor --> also inhibits

normal JAK-STAT activation causing

myelosuppression

Same efficacy and tolerability in elderly (Raanani, poster 702)

Also active on non-JAK mutated MPN

Guglielmelli, Br J H 2016

Overcoming problems of

Ruxolitinib

Pacritinib: JAK2/FLT3 inhibitor

Reducing splenomegaly but no worsening of trombocytopenia

Temporary hold because of safety concerns was liftedin Jan 2017

Momelotinib: JAK1/2 inhibitor

Reducing splenomegaly and improving anemia

Improving efficacy of JAK inhibitor monotherapy: new strategies

New strategies

JAK2 is chaperone

client of HSP90 – trial

closed gastro-intestinal

toxicity, but all PR

Combination with

inhibitors downstream

in JAK/STAT pathway

Type II JAKi: stabilizes

inactivated

unphosphorylated

conformation of JAK

New strategies

All different mutant

CALR have the same

tumorspecific C-

terminal peptide

with immunogenic

properties target

for immunotherapy

Treating ET

R-IPSET thrombosis risk score based on JAK2+,

age > 60 years and previous VTE

• Very low risk: no risk

• Low risk: JAK2+

• Int ris: age >60

• High risk: previous

VTE or age >60 and

JAK+

Gugliotta, poster 358

Does treatment with Hydroxyureum or Anagrelide alter

outcomes associated with molecular status?

Unpublished Nangalia EHA 2016

Venous thrombosisMyelofibrosis

Treating PV

RESPONSE 2 – 80 weeks follow-up

PV – Hydrea intolerant or resistant – no splenomegaly

Ruxolinitib 10 mg 2x/d vs best available therapy –

crossover after 28 weeks

At week 80:

Durable Hct controle in 47% (vs 3% BAT)

>50% reduction in symptom score (MPN-SAF-TSS)

Minor reduction in JAK2 allele burden (-9,7% vs +0,3%)

Low grade toxicities (anemia, weight gain) with >90% of

patients still on therapy at week 80

Greishammer, oral 784

PROUD/CONTI-PV

At 12 months Ropeginterferon Hydroxyureum

CHR 50/113 (44,3%) 53/114 (46,5%)

Non-inferiority was demonstrated

Hydrea

IFN

Evolution %JAK2

Substudy in 13 French patients to

evaluate effect on JAK2-allele buren

Kiladjian, oral 787

Treating MF: Momelotinib

SIMPLIFY-1: JAKi naïve

Momelotinib 200 mg 1x/d vs Ruxolitinib 20 mg 2x/d

(1:1)

Inclusion:

DIPSS high, int2 or symptomatic int1

Palpable spleen

Trombocyte count >50000/µl

End point at 24 weeks

Gotlib, oral 785

Spleen reduction Symptom score

Transfusion inde-

pendence rate

MMB not inferior to RUX MMB inferior to RUX

MMB superior to RUX

MMB RUX

Trombopenia 7% 5%

Anemia 6% 23%

PNP 10% 5%

SIMPLIFY-2: previously treated with Ruxolitinib

Momelotinib 200 mg 1x/d vs BAT (2:1)

Inclusion:

DIPSS high, int2 or symptomatic int1

Palpable spleen

Ruxolitinib but rbc transfusion or grade 3 cytopenia

No >grade 2 neuropathy

BAT: included mostly Ruxolitinib (88%)

End point at 24 weeks

Verstovsek, oral 786

Spleen reduction

No superiority for Momelotinib

But better response on

anemia (transfusion

independency, reduction in

transfusion)

• Toxicities: diarrhea, asthenia and

nausea – similar in both groups

• Specific for MMB: peripheral

neuropathy in 11% (1% grade 3)

Part 4:

Peculiarities in MDS-MPN

Peculiarities in MDS-MPN: CMML

CMML or reactive monocytosis?

• MO1: CD14+/CD16-

= classical monocyte

• MO2: CD14+/CD16+

= intermediate

monocyte

• MO3: CD14zw/CD16+

= non-classical

monocyte

CMML: high number of

classical monocytes (cut-off

94%) at the expense of non-

classical monocytes

Reactive: higher numer of

classical monocytes (both less

than in CMML) and non-

classicalSelimoglu-Buet, Blood 2015

Prognosis?: different prognostic score

CPSS-Mol: incorporates new NGS results

cytogen ASXL1 NRAS RUNX1 SETBP1

0 low umut unmut unmut unmut

1 int mut mut - mut

2 high - - mut -

Spaanse cytogenetica

risico:

- laag: normaal, -Y

- int: andere

- hoog: +8, afwijkingen

chrom 7 en complex

0 1 2 3

CPSS gen low int-1 int-2 high

BM blasts <5% ≥5% - -

leukocytes <13000/µl ≥13000/µl - -

transf dep no yes - -

Risk factors 0 1 2-3 ≥4

Med OS (months) NR 68 30 17

Therapy

HMA: Useful in

treating cytopenia

Little effect on

symptoms

GM-CSF hypersensitivity

KB003 NCT02546284:

Ruxolitinib

Anti GM-CSF antibody

Ruxolitinib supresses GM-CSF dependent

pSTAT5-activation

Phase I trial 20 mg 2x/d:

• Reduced spleen volume (5/9 pt)

• Better symptom control (10/11 pt)

• Hematological improvement (5/20)

But… no cyoptenias!

Peculiarities in MDS-MPN:

Mastocytosis

Midostaurin: multitargeted kinase inhibitor thatblocks both wild type and D816Vmutated KIT

Pooled analysis of 2 phase II studies vs registry

Advanced mastocytosis: aggressive SM, SM-AHN and mast cell leukemia

Studygroup 89 pts on Midostaurin (100 mg 2x/d) vs German registry 46 pts not on Midostaurin

Well balanced except for age (more pts >65 years in registry)

Follow-up median 54 months

Midostaurin studies: 60-69% partial or complete

remission of SM-related organ damage

Survival advantage for Midostaurin-group:

Med OS 42,6 mo vs 24 mo

Reiter, oral 788

Thank you for your

attention

Smouldering inflammation

Augmented levels of pro-inflammatory cytokines

(TNFα, IFNγ, IL1β)

bone marrow apoptosis with impaired clearance

of apoptotic cells TLR4 mediated cytokine

production inflammation –> proliferation

pressure on progenitor cells genetic instability

and somatic mutations

overexpression of immunoinhibitory molecule

B7H1 growth advantage of MDS clone

Treatment of low risk MDS

Immunosuppressive therapyParikh, Semin Hemat 2012

Patient’s age (years) + duration of red

cell transfusion dependency (months)

Predicted

probability of

responsDR15- DR15+

>57 >71 Low (0-40%)

≤57 ≤71 High (41-100%)

Saunthararajah, Blood 2003

Stadler, Leukemia 2004

No difference in horse or

rabbit ATG

Response ±30%

Sloand, JCO 2010

Promising results for

Alemtuzumab, but

selection for predicted

high response

Passweg, JCO 2011

No OS difference

ATG+CsA vs BSC

Better response rate

Luspatercept – phase II

Low or int-1 MDS, with or without RS, all EPO-levels

Baseline

EPO

RS status HI-E

N = 88

RBC-TI

N = 60

<200 IU/L RS+ 23/35 (66%) 13/21 (62%)

RS- 4/8 (50%) 1/4 (25%)

200-500

IU/L

RS+ 7/12 (58%) 3/8 (38%)

RS- 4/8 (50%) 3/5 (60%)

>500 IU/L RS+ 5/9 (56%) 2/9 (22%)

RS- 1/13 (8%) 1/11 (9%)

= Binds TGFβ

superfamily ligands

Giagounidis, poster 665

Vitamin C is an essential co-factor for ten-eleven translocation(TET) enzymes, which initiate DNA demethylation throughoxidation of 5-methylcytosine (mC) to 5-hydroxy-methylcytosine (hmC). In-vitro studies show that vitamin C at physiological doses added to DNA methyltransferase inhibitors (DNMTis), induce a synergistic inhibition of cell proliferation and enhanced apoptosis. These effects are mediated via a viral mimicry response recentlyassociated with cancer stem-like cell death and enhanced immune signals including increased expression of bi-directionallytranscribed endogenous retrovirus (ERV) transcripts, increasedpresence of cytosolic double stranded RNAs, and activation of aninterferon inducing cellular response to these transcripts. Data suggest that correction of vitamin C deficiency may improveresponses to epigenetic therapy with DNMTis. In the EVITA pilot study, the investigators include MDS/AML patients and explorethe potential role of restoring vitamin C within the normalphysiological range in treatment of hematological cancer withDNMTis.

• Overexpression IL-1R pathway

• IL-1R antagonist

• Antibody against IL1RAP

(IL1R accessory protein)

• Overexpression of

CD26 (dipeptidyl

peptidase-4)

• Inhibition by gliptin

Upregulation of Notch to reduce

self-renewal capacity

Peroxisome proliferator-activator

(PPAR)γ agonist: render quiescents

cells into cell cycle making them

sensitive to TKI

Actim-study: Actos + Imatinib

MR 4.5 in combination 56% vs

Imatinib alone 23%

Overexpression of BCL-2 in

advanced phase: Venetoclax?

AlloSCT and CML

AlloSCT and CML

Donor vs no-donor:

OS similar

Relapse rate lower

Biggest advantage if transplant risk low

Gratwohl, Leuk 2016

<1j HLA-id

<1j mismatched or >1j HLA-id

>1j mismatched

If bad response at 6 months: proceed to alloSCT

Driver mutations

JAK2

Chr 9p24.1

MPL

Chr 1p34.2

CALR

Chr 19p13.13

Combination of HMA and

checkpoint inhibition

Untreated Patients after HMA

failure

Aza + Nivo

(n = 13)

Nivo (n =

15)

Ipi (n = 9)

Age 70 78 71

Overall

respons

9 (70%) 0 (0%) 2 (22%)

CR 2 (18%) 0 (0%) 0 (0%)

SD 1 (9%) 3 (23%) 4 (57%)

Garcia-Manero, ASH 2016

Clinical efficacy and tolerable safety