1. DIAGNOSIS AND MANAGEMENT
OF MYELOPROLIFERATIVE
NEOPLASMS (MPN)
Dr. Natalia Curto Garcia
Haematology Consultant
Royal Free London NHS
April 2016

2. Index
• Introduction
• Diagnosis MPN
• Management MPN
• Future
• Summary

3. INTRODUCTION (I)
• MPN- rare disorders of the bone marrow that
cause an increase in the number of blood
cells.
• Median age 60y, also in young, rare in children
• Incidence varied: ET 0.6-2.3/105,MF 0.5-1/105
PV is more prevalent in Europe 1.05/100000.G J.
Titmarsh et al. American Journal of Hematology, 2014
• Progression to acute leukaemia .

4. The history of myeloproliferative disorders: before and after Dameshek
A Tefferi Leukemia 2008.
1845:
Bennett- CML
1879:
Heuck- PMF
1892:
Vaquez- PV
1934:
Estein &
Goedel-
ET
1951:Dameshek- MPD
1953: DNA structure
1960: Nowel- Crom.Ph
1967: PVGS. Stem cell
origin
1982-1990
Molecular and oncogenic
characterization of
BCR-ABL
1996: Imatinib
2005:
JAK2 V617F exon 14.
2006: MPL
2007: JAK2 exon12.
2013: CALR
Present:
Molecular therapy
INTRODUCTION (II):a little of history

5. INTRODUCTION (III): WHO classification

6. INTRODUCTION (IV): Aetiology
• Genetic mutation, familiar predisposition, exposure to toxins.
R.Jager et al. Haematologica 2010
• Increase
proliferation
and survival
• Cytokine
activation
• Signalling
immune
system

7. Mutations affecting
the JAK-STAT
signalling
• MPL
• LNK
• c-CBL
• SOCS1-3
Mutations affecting
the epigenetic
regulation
• TET2
• EZH2
• ASXL1
• IDH1/2
• DNMT3A
Mutations associated
with Leukemic
transformation
• IDH1/2
• IKZF1
• TP53
• NF1
• RUNX1
• NRAS
• KRAS
• DNMT3A
INTRODUCTION (V): Aetiology
• Other mutations beyond JAK2
Image modified from Genetic and epigenetic complexity in MPD. Nicholas C.P. Cross, Hematology 2011.

8. INTRODUCTION (VI): Aetiology
Charles G Mullighan, Nature Genetics 2009

9. INTRODUCTION (VII): Aetiology
Kazuhiko Ikeda, Fukushima J Med Sci. 2012

10. INTRODUCTION (VIII): Aetiology
• Dec ´13: CALR Exon 9 mutation described in: ET, PMF, MDS/MPN
overlap disorder, and RARS-T.
• Mutually exclusive of JAK2 and MPL. Longest survival in MF.
• Triple negative patients identified.

11. DIAGNOSIS: when suspect MPN?
• Erythrocytosis or thrombocytosis without
other causes---- think in PV & ET.
• Unusual thrombosis ( portal or hepatic vein
thrombosis)--- think in PV.
• Leucoerythroblastic blood film, splenomegaly,
anemia--- think in MF.
• Aquagenic pruritus, extramedullar
haematopoiesis and bone marrow fibrosis---
think in MPN.

12. Polycythaemia Vera –PV
• Raised Htc >0.52 M, > 0.48 F for> 2 months*
• Incidence 0.2-28/106, median age 60y, youngest
(5% < 50yo**)
• Median survival >10y
• RF survival: advanced age, leucocytosis,
thrombosis and abnormal karyotype.
• Leukaemia progression 10% in 20y. Fibrotic
transformation is slightly higher.
• JAK2 V617F presents over 95%, exon 12
mutation ~ 3%, exon14 mutation ~ 3%.
*BSH guidelines , **Passamonti et al. Haematologica

13. PV Diagnosis (I)
• Clinical presentation:
– Recurrent headaches, blurred vision- hyperviscosity
– Dyspnoea, gout
– Aquagenic pruritus, Erythromelalgia, Plethoric
appearances,
– Splenomegaly- 70%
– Haemorrhage or thrombosis ( arterial or venous):
• first manifestation (MI, stroke, DVT)
• 20%,
• unusual places: mesenteric, portal or splenic
• causes of dead
– Asymptomatic

14. Guidelines for the diagnosis, investigation and management of PV/erythocytois, BSH,
2005
PV Diagnosis (II)
ABSOLUTE
Congenital :
• High oxygen affinity Hb,
• 2,3- BPG deficiency,
• EPO receptor mediated,
• Chuvash erythrocytosis (VHL mutation).
Acquired:
• EPO mediated
 Hypoxia- driven: chronic lung diseases,
cardiopulmonary shunts, smoking,
hypoventilation syndromes
 Local renal hypoxia: renal artery stenosis,
renal cysts, etc.
 Pathological EPO production: tumours (
hepatocellular, renal cancer, parathyroid
carcinoma, etc)
• Exogenous EPO : androgen, postrenal
transplant erythrocytois, idiopathic.
RELATIVE
Haemoconcentration ( dehydration, smoking)
SECONDARYERYTHROCYTOSIS
Congenital :
• Congenital
erythropoietin
receptor mutation-
EPOR exon 8
Acquired:
• PV – JAK2 mutation
PRIMARYERYTHROCYTOSIS

15. FBC • Raised Hb, htc, red cell count and red cell volume
• Thrombocytosis 50% , neutrophilia 2/3 patients –
smokers have neutrophilia ( upper limit
12.5x109/L).
Ferritin & Vit B12 • Low serum ferritin
• Absence iron stores in BM
• Elevated B12 ( transcobalamin release from
increased granulocytic mass)
Red cell mass • Increased ( >25% for age, sex and weight- less usage now)
U&E, LFT´s and Ca profile • Essential to exclude secondary causes.
Sat O2 • Indicator of tissue hypoxia
• Measure can be misleading in high affinity Hb,
SAS, carbon monoxide poisoning---- measure
COHb, p50
• Consider respiratory tests
EPO • Reduce, also in idiopathic erythrocytosis
Adapted for the Guidelines for the diagnosis, investigation and management of PV/ erythrocytosis, BSH, 2005
PV Diagnosis (III): laboratory findings

16. BM Aspirate • Dense particles and cellular trials
• Marked erythroid hyperplasia with moderate
hyperplasia of granulopoiesis and
megakaryopoesis.
• Wide MK size ( large with hyperlobated nuclei)
• Iron stores absent.
BM trephine • Hypercellular for age and panmyelosis ( trilineage
proliferation)
• Erythroid maturation maintained and
normoblastic
• Erythroid nests abnormally located trabeculae
• Granulocyte maturation maintained
• Increased MK, large size , reduce lobulation
• Clusters MK pleomorphic
• Mild to moderate stromal reticulin ( gr 2-3)
PV Diagnosis (IV): laboratory findings
Adapted for the Guidelines for the diagnosis, investigation and management of PV/ erythrocytosis, BSH, 2005

17. BM Aspirate BM Trephine
PostPV-MF
PV Diagnosis (V): laboratory findings

18. PV Diagnosis (VI): laboratory findings
Molecular studies • JAK2 V617F, Exon 12 and exon 14
• Less frequency MPL, CALR
Karyotype • 10-20% pat: trisomy in chr8 and 9, del (20q), del
(13q) and del (1p).
Culture studies of BFU-E • Not usually found in normal individuals
• Expensive not standardised
EPO receptor, VHL gene
mutation analysis, PRV-1
& other genes
• Unexplained erythrocytosis and low serum EPO
levels
• VHL gene mutation related Chuvash disorder
• PRV-1 ( novel cell surface receptor)- overexpressed
in granulocytes in PV
• c-MPL protein found in platelets of PV
Adapted from the Guidelines for the diagnosis, investigation and management of PV/erythrocytosis, BSH, 2005

19. PV diagnosis (VII) Masked PV
• JAK2+ with PV-characteristic BM morphology
despite lower Hb levels ( <16-18.5g/l men and
15-16.5g/l women).
• Distinguish to ET– Hb optimal cutoff level:
16.5g/L and htc 49% for men and Hb 16g/L and
htc 48% women.
• Therapeutic implication- risk of thrombotic
complications associated with borderline
increased Htc
• ? Modified WHO criteria diagnosis
A.Tefferi and T.Barbui, AJH 2015.

20. 2008 WHO criteria 2014 Proposed revision
Either both major criteria and one minor
criterion or the first major criterion and
two minor criteria.
Requires meeting either all three major
criteria or the first two major criteria and
one minor criterion.
Major criteria Major criteria
• Hb ＞18.5 g/dL (men), ＞16.5
g/dL (women)
• Presence of JAK2V617F or JAK2
exon 12 mutation .
• Hb ＞16.5 g/dL (men), ＞16 g/dL
(women) or Hct ＞49% (men), ＞
48% (women)
• BM trilineage myeloproliferation
with pleomorphic MK
• Presence of JAK2 mutation.
Minor criteria Minor criteria
• BM trilineage myeloproliferation
• Subnormal serum EPO level
• Endogenous erythroid colony
growth
• Subnormal serum EPO
Table adapted from Bhee-Jin Kim et al, Blood Research 2014
PV criteria diagnosis

21. Essential Thrombocythaemia- ET
• Raised platelets > 450x109/L
• Discard secondary causes.
• Median survival ~ 20y, pat >60 y increases to 33 y.
• RF survival: advanced age, leucocytosis and
thrombosis.
• Causes of dead: haemorrhage and/or thrombosis
• Leukaemia progression 5% in 20y, higher rates for
fibrotic transformation
• JAK2 V617F presents over 60%, CALR 20%, MPL
3%, triple negative 20%

22. ET diagnosis (I)
• Clinical presentation:
– Thrombosis ( venous and arterial)
– Haemorrhage event: nosebleeding, mucosa bleeds,
blood stool, bruising.
– Asymptomatic – 25-33%
– Mild splenomegaly ( 50%) and hepatomegaly 15-
20%. Splenic atrophy due to infarction.
– Erythromelalgia , microvascular occlusion,
numbness and tingling in hands/feet, headache,
dizziness, weakness, vision changes.
– Pregnancy complications: spontaneous abortions,
placental infarctions,

23. ET diagnosis (II)
THROMBOCYTOSIS
Iron deficiency,
Haemolysis.
Infection/inflammation
Haemorrhage
Trauma
Post surgery,
Splenectomy,
Connective tissue diseases
Solid cancer,
Other MPN or MDS
Guidelines for the diagnosis, investigation and management of PV/erythocytois, BSH,
2005
ASH imagebank

24. FBC • Raised plat.
• Marked anisocytosis in platelets and atypical
granulation, occ MK fragments ,
• Features of iron deficiency ( haemorrhage
episodes)
• WBC can be elevated. Leucoerythroblastic film
and tear drops are unusual.
Clotting screening and
platelets aggregation
study
• Usually normal
• Bleeding time may or may not be prolonged.
• Abnormal platelets aggregation, acquired Von-
Willebrand
Ferritin and vit b12 • Low serum ferritin if iron deficiency associated.
• Increased vitamin b12 -25%
U&E, LFT´s, CRP,ESR
LDH
• Essential to exclude secondary causes.
• Elevated LDH correlation with fibrotic
transformation
Adapted from the Guidelines for diagnosis and management of thrombocytosis , BSH, 2010 and P.Beer Blood, 2011
ET Diagnosis (III): laboratory findings

25. BM Aspirate • Normocellular for age or mildly hypercellular.
• MK increased in number, spectrum morphology:
large or giants with hyperlobulated ( staghorn),
occ small forms and normal MK.
• No significant hyperplasia in erythroid and
myeloid series.
• Iron stores may be reduced. Siderotic granulation
is normal,
BM trephine • MK similar description as in aspirate.
• MK distribution is disperse, may occur in loose
clusters within the interstitium.
• Reticulin generally no increased ( gr 0-2/4 or 0/3).
• Proliferation of erythroid is haemorrhages.
ET Diagnosis (IV): laboratory findings
Adapted from the Guidelines for diagnosis and management of thrombocytosis , BSH, 2010 and P.Beer Blood, 2011

26. ET diagnosis (V)morphology features
Blood film
Hyperlobulated MK in BM
Hypercellular BM
Clusters MK in BM
ASH imagebank

27. ET Diagnosis (VI): laboratory and radiology
findings
Molecular studies • JAK2 V617F, CALR, MPL.
• Triple negative 20%
• BCR-ABL
Karyotype • No required in routine test, useful as marker of
disease progression.
Radiology tests • Splenomegaly and/or hepatomegaly
• Thrombosis
• To discard other causes of thrombocytosis
Adapted from the Guidelines for diagnosis and management of thrombocytosis , BSH, 2010 and P.Beer Blood, 2011

28. 2008 WHO criteria 2014 Proposed revision
Meeting all four major criteria. Meeting all four major criteria or first three
major criteria and one minor criterion.
Major criteria Major criteria
• Platelet count ≥450×109/L
• MK proliferation with large and
mature morphology.
• Not meeting WHO criteria for CML,
PV, PMF, MDS or other myeloid
neoplasm
• Demonstration of JAK2V617F or other
clonal marker or no evidence of
reactive thrombocytosis
• Platelet count ≥450×109/L
• MK proliferation with large and mature
morphology.
• Not meeting WHO criteria for CML, PV, PMF,
MDS or other Myeloid neoplasm
• Presence of JAK2, CALR or MPL mutation
Minor criteria Minor criteria
No minor criteria. • Presence of a clonal marker (e.g. abnormal
karyotype) or absence of evidence for
reactive thrombocytosis.
ET Criteria diagnosis
Table adapted from Bhee-Jin Kim et al, Blood Research 2014

29. Myelofibrosis (MF)
• Characterized by marked reticulin fibrosis and
osteosclerosis with extramedullary hematopoiesis
and organomegaly.
• Primary MF or secondary to PV ( PPV-MF) and ET (
PET-MF).
• Median age 65y, incidence 0.5-1.5 /100,000 per
year.
• Median survival in pat<60y is 15y. Leukaemia
transformation 10-20%.
• JAK2 +60%, CALR 25% ( superior survival) and MPL
7%

30. MF diagnosis (I)
• Clinical presentation:
– Anemia
– Constitutional symptoms
– Symptomatic splenomegaly ( palpable up 90%)
– hemorrhage and thrombosis events
– Infections,
– Bone pain
– Extramedullar haematopoiesis,
– 30% Asymptomatic

31. MF diagnosis (II)
MYELOFIBROSIS
Splenomegaly
• Haematology diseases:
• Lymphoma, leukaemia, myeloma
• Portal hypertension
• Autoimmune disorders:
• SLE, RA
• Infections
Leucoerithrobalastic film
• Bone marrow infiltration
• AL, Lymphoma, MPN, MDS
• Solid cancer
• Hematopathologies
• Sepsis
• Massive haemolysis
Fatigue
Weight loss

32. FBC • Anemia, WBC and plat higher at initial diagnosis
and pancytopenia is common at advance stages.
• Leucoerythroblastic film and tear drops.
LDH • Elevated
Radiology tests(US, CT) • Splenomegaly and other organomegalies.
Molecular and
cytogenetic studies
• JAK2 V617F, CALR, MPL.
• Triple negative~ 10%
• BCR-ABL
• ASXL1 ( associated to inferior survival)
• Abnormal karyotype 50-60% : +8, -7/7q, inv (3),
etc.
Adapted from the Guidelines for diagnosis and management of myelofibrosis , BSH, 2012 and Cervantes F, Blood, 2014
MF Diagnosis (III): laboratory and radiology
findings

33. BM Aspirate • Dry ( 50%)
• Hypocellular
BM trephine • Prefibrotic phase:
- hypercellular with increased neutrophils and
atypical MK( enlarged). Erythroid is reduced.
- MK dense clusters of variable size and
adjacent to vascular sinuses and bone
trabecule.
- Reticulin fibrosis is reduce.
• Fibrotic phase:
- Normo or hypocelluar with patches of active
haematopoiesis.
- Atypical MK large clusters.
- Dense reticulin or collagen fibrosis.
- 10-19% blasts detected by cytometry.
MF Diagnosis (IV): laboratory findings
Adapted from the Guidelines for diagnosis and management of myelofibrosis , BSH, 2012 and Cervantes F, Blood, 2014

34. MF diagnosis (V) morphology features
Hypercelular BM
Clusters MK Reduce reticulin
Increase
neutrophilis
MK clusters
Marked reticulin

35. 2008 WHO criteria 2014 Proposed revision
Meeting all three major criteria and two minor
criteria.
Meeting all three major criteria or the first
two major criteria and all three minor criteria
Major criteria Major criteria
• MK proliferation and atypia, accompanied
by either reticulin and/or collagen fibrosis.
• Not meeting WHO criteria for CML, PV, MDS
or other myeloid neoplasm.
• Demonstration of JAK2V617F or other
clonal marker or no evidence of reactive BM
fibrosis.
• MK proliferation and atypia, accompanied
by either reticulin and/or collagen fibrosis.
• Not meeting WHO criteria for CML, PV,
MDS or other myeloid neoplasm
• Presence of JAK2, CALR or MPL mutation
Minor criteria Minor criteria
• Leukoerythroblastosis
• Increased serum LDH level
• Anemia
• Palpable splenomegaly
• Presence of a clonal marker (e.g.
abnormal karyotype) or absence of
evidence for reactive BM fibrosis
• Presence of anemia or palpable
splenomegaly
• Presence of leukoerythroblastosis or
increased LDH level.
MF Criteria diagnosis
Table adapted from Bhee-Jin Kim et al, Blood Research 2014

36. Practical Algorithm for Diagnosis of MPN
JAMA Oncol. 2015;1(1):97-105. doi:10.1001/jamaoncol.2015.89

37. MK IN MPN
PV ET MF
• Mk varied size ( mostly
large ) and hypolobulated
• Loose clusters or adjacent
to endosteum
• MK large to giants and
deep lobulated – staghorn
like nuclei
• Loose clusters or
dispersed
Prefibrotic phase:
• Atypical MK –cloud like
or hyperchromatic nuclei
• Dense clusters adjacent
to endosteum or sinosids
Fibrotic phase:
• Atypical MK mostly small
MK
• Large clusters or sheets
No reticulin increased No reticulin increased Reticulin increased

38. MANAGEMENT OF MPN: OBJECTIVES
• Reduce the risk of thrombosis and haemorrhage.
• Reduce the risk of transformation to MF and/or
AL.
• Manage constitutional symptoms and
complications associated ( thrombosis,
haemorrhage, pruritus, infections).
• Manage cardiovascular risk factors
• Manage MPN in special situations like pregnancy

39. Conventional risk stratification International polycythemia vera study
stratification.1
High risk PV - ANY ONE of the following: Risk factors (weight)
• Age >60 years
• Previous documented thrombosis,
• Erythromelagia (if refractory to aspirin)
Platelets > 1000x109/L*
• Diabetes or hypertension requiring
pharmacological therapy*
• Significant (i.e. >5 cm below costal margin
on palpation) or symptomatic (pain, early
satiety) splenomegaly
• Age ≥67 years (5 points)
• Age 57-66 years (2 points)
• Leukocyte count ≥15x109/L (1 point)
• Venous thrombosis (1 point),
• Abnormal karyotype (identified but no
weight)
Low-risk PV Risk categories
• Patients not having any of the above risk
factors.
• Low-risk (sum of scores 0 points)
• Intermediate-risk (sum of scores 1 or 2
points)
• High-risk (sum of scores ≥3 points
Table adapted from C.Harrison EHA 2014
Risk stratification in MPN: PV

40. Risk stratification in MPN: ET
Conventional risk stratification2 Intermediate
risk ET**
International Prognostic Score for
ET – ( IPSET A novel risk stratification
based upon histopathologically defined
ET3)
High risk ET- ANY ONE of the following: • Patients 40-60
years lacking
any of the
above markers
of high risk
disease
Risk factors (weight)
• Age ≥60 years (2 points)
• Leukocyte count ≥11x109/L (1 point)
• Prior thrombosis (1 point)
• Age >60 years
• Platelet count >1500x109/L
• Previous thrombosis,
• Erythromelagia (if refractory to
aspirin)
• Previous hemorrhage related to ET
• Diabetes or hypertension requiring
pharmacological therapy*
Low-risk ET** Risk categories
• Patients under 40 years lacking any of
the above markers of high-risk
disease
• Low-risk (sum of scores 0 points)
• Intermediate-risk (sum of scores 1 or
2 points)
• High-risk (sum of scores ≥3 points
Table adapted from C.Harrison EHA 2014

41. Risk stratification in MPN: MF (I)
IPSS prognostic score DIPSS
Prognostic variables 0 1 Prognostic variables 0 1 2
• Age in years <65 >65 • Age in years <65 >65
• WBC count
x109/L
<25 >25• WBC count x109/L <25 >25
• Hemoglobin g/l - <10 • Hemoglobin g/l - - <10
• Peripheral blasts% <1 >1 • Peripheral blood
%
<1 >1
• Constitutional
symptoms
No Yes • Constitutional
symptoms
No Yes
Risk assignment: Low = 0, Intermediate
1 = 1, Intermediate 2 = 2 High = 3+.
Median survivals are 135, 95, 48 and
27 months, respectively.
Risk assignment: Low = 0; Intermediate 1 = 1 or 2;
Intermediate 2 = 3 or 4; High = 5 or 6.
Median survival: not reached, 14.2, 4, and 1.5
years, respectively
Table adapted from C.Harrison EHA 2014

42. DIPSS plus prognostic score
Points for DIPPS 0 1 2 3
DIPSS prognositic group points Low risk 0 Intermidate-1 Intermidate-2 High risk
To the DIPSS prognostic group add one point for:
• Platelets count x109/L • - • <100 • - • -
• Red cell trasnfusion required • No • Yes • - • -
• Unfavorable karyotype (includes
+8, -7/7q-, i(17q), inv(3), -5/5q-,
12p-. 11q23 rearrangements and
complex karyotypes. )
• No • yes
Risk assignment number of points Low = 0; Intermediate 1 = 1; Intermediate 2 = 2 or 3;
High = 4 to 6. Corresponding median survival
estimates: 185, 78, 35 and 16m.
Risk stratification in MPN: MF (II)
Table adapted from C.Harrison EHA 2014

43. Risk stratification in MPN: MF (III)
Tefferi A. et al, JAMA network, 2015
• CALR mutations associated favourable survival
(10.4y), ASXL1 unfavourable survival (2.3y)
independent of DIPSS-plus risk
• New prognostic models:
– MIPSS- mutation enhanced international prognostic
scoring system.
– GPSS- genetics based prognostic system.

44. Recommendation of Treatment in PV (I)
ALL PATIENTS HIGH RISK ( age>60y and/or
presence thrombosis)
PV in pregnacy
• Assess and manage CV risk • Assess and manage CV risk • Low risk: Aspirin low dose
and Phlebotomy
• Cytoreductive treatment no
recommended in low risk
patients
• >60y:
• Hydroxyurea,
• Second line: Ruxolitinib,
Interferon , Busulfan (
>75y), clinical trial.
• <60y :
• Interferon, Anagrelide,
clinical trial
• Cytoreduction therapy if High
risk : Interferon and
phlebotomy
• Aspirin low dose, unless CI,
• If Jak2+ and CV risk:
Aspirin bd.
• Determinate ristocetin
cofactor activity >30% if
high platetets
• Monitor closely pat with
abnormal bleeding
diathesis.
• Low dose of aspirin
• Phlebotomy hto target<0.45 • Phlebotomy hto target<0.45
Table adapted from C.Harrison EHA 2014 and A.Tefferi AJH 2015

45. Recommendation of Treatment in PV (II)
• Ruxolitinib- Indicate in patients inadequate response to or are
intolerant of hydroxyurea.
• Approved in Europe in 2015.
• Control hematocrit and PV-related symptoms
• Reduce spleen volume
Verstovsek s et all. ASCO meeting 2011

46. Recommendation of Treatment in ET
ALL PATIENTS HIGH RISK ( age>60y and/or presence
thrombosis)
ET in pregnacy
• Assess and manage CV risk • Assess and manage CV risk • Low risk: Aspirin
low dose
• Cytoreductive treatment no
recommended in low risk
patients
• >60y:
• Hydroxyurea,
• Second line: Interferon, anagrelide
, Busulfan ( >65y), clinical trial.
• <60y :
• Hydroxyurea or Interferon,
• Second line: clinical trial,
interferon, Anagrelide,
combination
• Cytoreduction
therapy if High risk
: Interferon
• Observation or
• Aspirin low dose unless CI,
• If Jak2+ and CV risk:
Aspirin bd.
• Determinate ristocetin
cofactor activity >30% if
high platetets
• Monitor closely pat with
abnormal bleeding
diathesis.
• Low dose of aspirin
Table adapted from C.Harrison EHA 2014 and A.Tefferi AJH 2015

47. Recommendation of Treatment in MF (I)
Intermediate 2 and high-risk patients
• AlloHSCT  DIPSS-plus high or int-2 risk pat.
 High mort-morb ( 50%pat)
 5y survival 37% SCTmatched
 Graft-vs-host 43% SCT matched
 ? Cord blood transplatation
• Cytoreductive agents  Hydroxiurea
 Interferon (early phase)
• Mangement of anemia  Transfusion if symptomatic anaemia
 Erythropoiesis-stimulating agents
 Androgens
 Immunomodulatory agents
 Prednisolone
 Danazol
• Splenomegaly  Splenectomy
 Radiotherapy
 HU
 Ruxolitinib
Table adapted from Guidelines BSH 2012, C.Harrison EHA 2014 and A.Tefferi AJH 2015

48. Recommendation of Treatment in MF (II)
Ruxolitinib  High risk and/or int-2 risk pat.
 COMFORT studies:
• reduced splenomegaly
• increased in volume spleen in 5dl, increase risk of death
9%,
• improve constitutional symptoms and QOL
• Survival benefit- response maintaned after 3yFU (hazard
ratio, 0.48; 95% CI, 0.28-0.85; log-rank test, P = .009)
 Heam toxicities: anemia and thrombocytopenia.
 Increase risk of infections
Other JAK inhibitors
& combination
therapies
 Fedratinib – halted due to Wernicke´s encephalopathy
 Pacrinitib- JAK2 and FTL3 inh.
 Momelotinib- ph3, improve in anaemia, symptoms and
splenomegaly.
 Imetelstat- telomerase inhibitor
 Pomalidomide & Rux
 LDE225 & Rux
 Panobinostat & Rux
 Buparlisib, Everolimus, PRM-151….
Table adapted from Guidelines BSH 2012, C.Harrison EHA 2014 and A.Tefferi AJH 2015

49. JAMA Oncol. 2015;1(1):97-105. doi:10.1001/jamaoncol.2015.89
Treatment algorithm for PV and ET
Copyright © 2016 American Medical
Association. All rights reserved.

50. Copyright © 2016 American Medical
Association. All rights reserved.
Treatment algorithm for MF
JAMA Oncol. 2015;1(1):97-105. doi:10.1001/jamaoncol.2015.89

51. SUMMARY
• Knowledge of MPN pathogenesis has rapidly changed in
last decade and continues evolving.
• New molecular markers to be included in criteria diagnosis
and risk factor prognosis.
• ? WHO criteria diagnosis to be reviewed.
• Consider ongoing clinical trials as option for high risk pat
or resistance/intolerance to previous conventional
therapies.
• Future target therapies focus on new molecular pathways.
• Further clinical trials are required for promising agents to
clarify adverse events and molecular and histopathology
response.

52. What is past is prologue. The best is yet to be...
Thanks