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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