Prof. Dr. brahim C. Haznedarolu Hacettepe niversitesi Tp Fakltesi

Hastalklar Anabilim Dal Hematoloji Bilim Dal, Ankara

MYELOPROLFERATF HASTALIKLAR:

Klinik Hematologlar Patologlardan ne bekler?

Hasta

Genel Analiz

FM

leri lab

nvazif giriim AYIRICI TANI

TANI

N TANI

TEDAV & ZLEM

HASTALIK BLGLER (KLNK BLMLER)

B L M S E L T E M E L (TEMEL BLMLER)

HASTAYA KLNK YAKLAIM

Genel Analiz

Myelofibrozis kk hcreleri

Primer myelofibrozis patogenezinde defektif stem hcre ni

ASEM

PTO

MAT

K

TRO

MBO

ZLAR

LA L

GL

SEM

PTO

MLA

R

ANEM

SEM

PTO

MAL

ARI

SPLE

NO

MEG

AL S

EMPT

OM

LARI

KON

STT

SY

ON

EL S

EMPT

OM

LAR:

AT

E, T

ERLE

ME,

ZAY

IFLA

MA

LK

YET

MEZ

L

SEM

PTO

MLA

RI

PORT

AL H

PER

TAN

SYO

N il

e L

GL

SEM

PTO

MAL

R

KEM

K A

RI

LARI

KAI

NTI

D

ER E

M H

EMAT

OPO

EZ il

e L

GL

SEM

PTO

LAR

PM

PV ET HU ihtiyacnn kaybolmas, dalak , LDH , konstitsyonel semptomlar, dakrositler ve lkoeritroblastozis

HASTALIK EVRELER LSEMye DNM YAKLAIK %10. BATA GELEN LM NEDEN DELDR. HASTALIIN DOAL SEYR (VE ONU DETRMEK) NE DEMEKTR?

Priorities for MPN treatment, perceptions of physicians and patients.

Alessandro M. Vannucchi, and Claire N. Harrison Blood 2017;129:693-703

2017 by American Society of Hematology

Thiele J, Best Pract Res Clin Haematol 2006; 19:413.

Original Article Ruxolitinib versus Standard Therapy for the

Treatment of Polycythemia Vera

Alessandro M. Vannucchi, M.D., Jean Jacques Kiladjian, M.D., Ph.D., Martin Griesshammer, M.D., Tamas Masszi, M.D., Ph.D., Simon Durrant, M.D., Francesco

Passamonti, M.D., Claire N. Harrison, D.M., Fabrizio Pane, M.D., Pierre Zachee, M.D., Ph.D., Ruben Mesa, M.D., Shui He, Ph.D., Mark M. Jones, M.D.,

William Garrett, M.B.A., Jingjin Li, Ph.D., Ulrich Pirron, Ph.D., Dany Habr, M.D., and Srdan Verstovsek, M.D., Ph.D.

N Engl J Med Volume 372(5):426-435

January 29, 2015

Primary Response and Duration of Response.

Vannucchi AM et al. N Engl J Med 2015;372:426-435

Symptom Assessments.

Vannucchi AM et al. N Engl J Med 2015;372:426-435

Ruxolitinib in PV has been evaluated in 3 phase 3 studies, RESPONSE, RESPONSE2, and RELIEF, showing that in the second line after HC failure/intolerance, ruxolitinib effectively controls blood count, spleen size, and symptoms, and interestingly, there may be molecular responses in some patients. In RESPONSE, there was a reduction in thrombotic events (6 vs 1), although not a preplanned endpoint, which thus cannot be overinterpreted; transformation to PPV-MF and AML occurred on both arms of the study. Selection of patients resistant to HC is important because those patients with cytopenias in particular have an increased risk for death (hazard ratio, 3.5; 95% confidence interval, 1.5-8.3; P = .003). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukemia (hazard ratio, 20.3; 95% confidence interval, 5.4-76.5; P < .001). Problems with these studies is the selection of the endpoints: control of hematocrit, reduction of spleen size, and as a result of restricted alternative therapies, the comparison of ruxolitinib against drugs the patient already failed. Nonetheless, ruxolitinib presents a valuable treatment of PV resistant and/or intolerant of HC and could be tested earlier in disease to assess the effect on major manifestations and disease course. No new safety signals emerged here, but an excess of herpes zoster reactivation and nonmelanoma skin cancers were observed.

JAK2(+) PV 64y fenale Splenectomised due to gastric cancer surgery Hyperproliferative BM with hyperleukocytosis Failure of hydrea and interferon Controlling the cellular proliferation with PEG-intron+Ruxolutinib

TYPICAL MPN CASE FOR HYPOTHESES

Real-life MPN patient

PM TEDAV YNTEMLER BEKLE-ZLE YAKLAIMI

LA TEDAVLER

SPLENEKTOM

RADYOTERAP

ALLOJENEK TRANSPLANT

Tek kratif tedavidir. Az hastaya uygulanabilir.

PALYATF YAKLAIMLAR

SEMPTOMATK SPLENOMEGAL

SPLENEKTOM* * Eer splenektomi uygun deilse z. infarkt gibi acil hallerde radyoterapi dnlebilir. Hidroksire

Ruxolitinib ve/veya

Int-2 ve yksek riskli hastalkta sakalm avantaj Daha kalc yant Daha yksek dalak/ semptom yant oran??

SEMPTOM YNETM: SPLENOMEGAL

Ortanca ya: 64,8 Endikasyonlar: Transfzyon baml anemi % 45,3 Symptomatik splenomegali % 39 Portal hipertansiyon % 10,8 Ar trombositopeni % 4,9 Kalc dzelme olaslklar: Konstitsyonel semptomlar % 67 Portal HT % 50 Anemi % 23 Trombositopeni % 0

Subklinik DK (D-dimer ykseklii dier lab bozukluklar) varsa splenektomi ertele (artm periop kanama riski) Postop tromboz riskine kar proflaksi unutma! Postop hepatik ekstramedller hematopoez ve sitozlar iin sitoredktif tedavi

KME NAKL YAPALIM? AZALTILMI YOUNLUKTA HAZIRLAMA REJM ALIMASI

In MF, MPN disease-propagating stem cells aberrantly mobilize from the bone marrow to the spleen.

Lane S W , and Mullally A Blood 2014;124:2898-2900

2014 by American Society of Hematology

MYELOFIBROSIS 1. Shortened survival

2. Poor quality of life Thrombosis/bleeding

Cachexia Constitutional symptoms

Pruritus

Anemia

Splenomegaly

Leukemic transformation

Fibrotic transformation

http://gateway.ut.ovid.com/gw1/ovidweb.cgi?View+Image=00043426-200703000-00006|FF1&S=IDNJHKOAFCMHEL00D&WebLinkReturn=Full+Text=L|S.sh.15.16|0|00043426-200703000-00006http://images.google.com/imgres?imgurl=http://sfghed.ucsf.edu/ClinicImages/Clin%20anemia%205.1.jpg&imgrefurl=http://health.on-topic.net/health/Anemia&h=634&w=845&sz=90&hl=en&start=9&tbnid=Rp5xkYYwckrAdM:&tbnh=109&tbnw=145&prev=/images?q=Anemia&svnum=10&hl=en&lr=http://images.google.com/imgres?imgurl=http://www.path.utah.edu/casepath/PM%20Cases/PMCase3/PMCase3Image12.jpg&imgrefurl=http://www.path.utah.edu/casepath/PM%20Cases/PMCase3/PMCase3Part4.htm&h=1200&w=1600&sz=565&hl=en&start=49&tbnid=jqx5p1IUez7dIM:&tbnh=113&tbnw=150&prev=/images?q=cachexia+picture&start=40&ndsp=20&svnum=10&hl=en&lr=&sa=N

Survival and prognosis in primary myelofibrosis: A Mayo Clinic study of 884 patients

Based on 8 risk factors: Karyotype, Transfusion-dependency, Hgb 65

DIPSS-plus intermediate-1 risk; n=128 median survival ~ 94 months; 2-year mortality 11%

DIPSS-plus low risk; n=84 median survival ~ 200 months; 2-year mortality 3%

DIPSS-plus high risk; n=298 median survival ~ 23 months; 2-year mortality 53%

DIPSS-plus intermediate-2 risk; n=322 median survival ~ 44 months; 2-year mortality 26%

Surv

ival

Months

1

.8

.6

.4

.2

0 0 50 100 150 200 250 300 350 400

P40k, circulating blasts >9%, unfavorable karyotype

ASXL1 tested 279: mutated 85 (30.5%) SRSF2 tested 358: mutated 52 (14.5%) EZH2 tested 270: mutated 15 (5.6%) IDH2 tested 374: mutated 10 (2.7%) IDH1 tested 374: mutated 7 (1.9%)

At time of:

Diagnosis (n=483)

Referral (n=396)

European study: Vannucchi et al.

Mayo Clinic study: Tefferi et al.

879 PMF patients

Myelofibrosis Extramedullary hematopoiesis Spleen enlergement

Study 251 Spleen Size Reduction in Patient Treated with INC424

MF Patient Pre-Therapy Patient After 2 Months of Therapy

Photos used with permission from M. D. Anderson Cancer Center.

COMFORT trials

Verstovsek S, et al. N Engl J Med. 2012;366:799-807; Harrison C, et al. N Engl J Med. 2012;366:787-798.

Patients with MF

N = 309

Patients with MF

N = 219

COMFORT-I

COMFORT-II

Randomized 1:1

Randomized 2:1

Ruxolitinib 15 or 20 mg BID

Placebo BID

Ruxolitinib 15 or 20 mg BID

BAT

Primary endpoint Proportion of patients achieving 35%

reduction in spleen volume from baseline to Week 24 measured by MRI or CT

Secondary endpoints Duration of the reduction in spleen volume Proportion of patients with a reduction in

the total symptom score of 50% or more from baseline to Week 24, as assessed with MS-SAF (v2.0)

Overall survival

Primary endpoints Proportion of patients with 35% reduction

in spleen volume from baseline at Week 48, measured by MRI or CT

Secondary endpoints Key: Achievement of 35% reduction in

spleen volume from baseline at Week 24 Duration 35% reduction in spleen volume Time to achieve 35% reduction in spleen

volume Progression-free survival Leukemia-free survival Overall survival Change in bone marrow histomorphology

BAT, best available therapy.

Design and dosing

Verstovsek S, et al. N Engl J Med. 2012;366:799-807.

COMFORT-I

Patients with MF (N=309)

Ruxolitinib (n=155) 15 mg bid if platelets 100-200x109/L 20 mg bid if platelets >200x109/L

Placebo (n=154) Oral bid

1:1 randomization

The dose was adjusted for lack of efficacy or excess toxicity as specified in the protocol

Crossover Criteria Unblinding of the study-drug assignments and crossover from placebo to ruxolitinib were

permitted for protocol defined worsening splenomegaly

Ruxolitinib was associated with a greater reduction in splenomegaly vs placebo

Verstovsek S, et al. N Engl J Med. 2012;366:799-807.

COMFORT-I

Spleen volume was reduced by 35% in a significantly greater

proportion of patients in the ruxolitinib compared with the placebo group

at Week 24

41.9%

0.7% 0

10

20

30

40

50

Patie

nts

with

35

% s

plee

n vo

lum

e re

duct

ion

(%)

Patients who discontinued prior to week 24 or crossed over prior to week 24 were counted as nonresponders

p

Reduction in spleen volume from baseline

At Week 24, spleen volume had decreased in most patients treated with ruxolitinib, whereas it increased in most patients treated with placebo

Ruxolitinib-treated patients had a median 33.0% decrease in spleen volume; in contrast, placebo-treated patients had a median 8.5% increase

Verstovsek S, et al. N Engl J Med. 2012;366:799-807.

Cha

nge

in s

plee

n vo

lum

e fr

om b

asel

ine

(%)

80

60

40

20

0

-20

-40

-60

-80

Corresponding to 50% reduction

in palpable spleen length

35% reduction (primary endpoint)

Ruxolitinib (n = 155)

Placebo (n = 153) =

106)

COMFORT-I

Design and dosing

Harrison C, et al. N Engl J Med. 2012;366:787-798.

COMFORT-II

Patients with MF (N=219)

Ruxolitinib (n=146) 15 mg bid if platelets 200x109/L 20 mg bid if platelets >200x109/L

Best available therapy* (n=73)

2:1 randomization

Dose regimen could be adjusted based on safety and efficacy so that each patient was titrated to their most appropriate dose; doses were not to exceed 25 mg bid

Crossover Criteria At any time, patients who met protocol-specified criteria (underwent splenectomy or had an increase in spleen volume of

>25% from the nadir during the study period, which could include the baseline volume) discontinued the randomized treatment phase of the study and could enter an extension phase. In the extension phase, patients who had been randomly assigned to the best available therapy could receive ruxolitinib if they met protocol-specified safety criteria, and patients who had been randomly assigned to ruxolitinib could continue to receive ruxolitinib if they were still deriving a clinical benefit. Patients who had leukemic transformation or underwent splenic irradiation were withdrawn from the study.

*Any commercially available agents (as monotherapy or in combination) or no therapy at all and which could be changed during the treatment phase.

Ruxolitinib was associated with a greater reduction in splenomegaly vs BAT

Harrison C, et al. N Engl J Med. 2012;366:787-798.

COMFORT-II

28% of patients achieved 35% reduction in spleen

volume at Week 48 compared with 0% of

patients receiving BAT (p

Reduction in spleen volume from baseline

The mean percentage change in spleen volume from baseline in ruxolitinib vs. BAT was 29.2% vs. 2.7% (p

Best percentage change in spleen volume on 5 year follow-up

Harrison CN, et al. ASH 2015; abstract 59.

97.1% of patients (132/136) experienced some degree of spleen volume reduction 78 patients (53.4%) in the ruxolitinib arm achieved a 35% reduction in spleen volume at any time on treatment 75.6% (34/45) of patients who crossed over experienced spleen volume reductions from the time of crossover, and

42.2% (19/45) had a 35% reduction At 5 years, 88% of patients (45/51) who remained on treatment had improvements from baseline in spleen

volume, and 67% (34/51) achieved 35% reductions a Only patients with baseline and postbaseline spleen volume assessments are included; for crossover patients, the spleen volume at the time of crossover was used as the new baseline value.

-100

-80

-60

-40

-20

0

20

40

60

35% decrease

Bes

t Cha

nge

From

Bas

elin

e

in S

plee

n Vo

lum

e, %

Ruxolitinib randomizeda (n = 136)

After crossovera (n = 39)

COMFORT-II

Median duration of response: ruxolitinib, 3.2 years The Kaplan-Meier estimated probability of maintaining response

3 years, 0.51 (95% CI, 0.38-0.62) 5 years, 0.48 (95% CI, 0.35-0.60)

Duration of spleen response on 5 year follow-up

Harrison CN, et al. ASH 2015; abstract 59.

Loss of response: no longer a 35% reduction that is also a >25% increase over nadir

a For patients who achieved a 35% reduction at any time during randomized treatment; crossover patients are not summarized.

Ruxolitiniba n = 78

BATa n = 1

Events Censored

34 (43.6%) 44 (56.4%)

0 1 (100%)

78 59 47 42 39 30 23 18 15 12 Ruxolitinib, n = 1 1 0 BAT, n =

0

COMFORT-II

Overall survival on 5 year follow-up

Harrison CN, et al. ASH 2015; abstract 59.

Median OS was not yet reached in the ruxolitinib arm (ie, > 5 years) ITT: HR, 0.67 (95% CI, 0.44-1.02); P = .06 RPSFT: HR, 0.44 (95% CI, 0.18-1.04) in favor of ruxolitinib vs BAT

HR, hazard ratio; ITT, intent-to-treat; RPSFT, Rank-Preserving Structural Failure Time.

1.0

0.8

0.6

0.4

0.2

0.0 0 1 2 3 4 5 6

146 130 109 100 88 61 0 73 58 48 35 30 22 0

Ruxolitinib

BAT (ITT) BAT (RPSFT) P

roba

bilit

y

Time, years

n =

Median Overall Survival Ruxolitinib (ITT) = not reached BAT (ITT) = 4.1 years BAT (RPSFT) = 2.7 years

COMFORT-II

Ruxolitinib may modify the natural history of PMF

Passamonti F, et al. Blood. 2014;123:1833-1835.

COMFORT-II

Survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-II was compared with that of 350 matched patients of the DIPSS study

Data showed that the risk of death might be reduced by 40% to 50% by introducing ruxolitinib into the treatment of PMF patients

Patients receiving ruxolitinib had longer

survival (5 years, 95% CI: 2.9-7.8 vs 3.5 years, 95% CI: 3.0-3.9) with a hazard ratio of 0.61 (95% CI: 0.41-0.91; p=0.0148)

Ruxolutinib, Anti-sitokin etkiler, MPN kk hcreleri

Klonal miyeloproliferasyon % 60 JAK2V617F, % 3-8 MPL ve kalanlarn yarsnda

CALR mutasyonlar Disregle kinaz sinyalizasyonu Anormal sitokin salnm

Salnan sitokin ve byme faktrlerine bal ilikte fibrozis ve stroma deiiklikleri

Anormal hcrelerin ekstramedller dokulara yerlemeleri Salnan sitokinlere bal sistemik semptomlar ve

performans bozukluu

PM PATOBYOLOJS: STOKNLERN ROLLERNE DKKAT!

PMde STOKNEM KONTROL SEMPTOMLARI ve SAKALIMI DZELTR IL-6 MYELOM, POEMS ve CASTLEMAN PATOBYOLOJLERNDE NEMLDR HEMOFAGOSTK SENDROM KONTROLSZ STOKNEMYE BALIDIR LENFOMADA B SEMPTOMLARININ OLMASI DAHA KT PROGNOZLA LGL

OLABLR. B SEMPTOMLARI STOKNLERLE LGLDR PERFORMANS SKORU BTN NEOPLAZLERDE EN NEML PROGNOSTK

BELRTE PERFORMANS SKORU NEDEN BOZULUR?

SADECE LK YETMEZL/ ORGAN BOZUKLUU/ KOMPLKASYONLAR? STOKNEMNN ROL?

HEMATOLOJK NEOPLAZLERDE STOKNLERN PATOGENEZ/SEMPTOMATOLOJ ile LKS?

T ya da NK lenfosit

Makrofaj

EBV

MULTORGAN YETMEZLK SENDROMU

HEMOFAGOSTK SENDROM

According to WHO-defined 4-point scoring system (0-3)1

Grading of BM Fibrosis

Grade-0

Grade-2

Grade-1

Grade-3

1 Thiele J, Kvasnicka HM, et al. Haematologica. 2005;90:1128-1132.

Changes at 24 and 48 mo (vs BL) were characterized as Improvement, Stabilization, and Worsening.

Patients

Phase I/II*, single-arm, open-label study of ruxolitinib, a JAK1/JAK2 inhibitor.1,2

158 patients with PMF, Post-PV MF and Post-ET MF; median study follow-up period 32 mo.

107 of the 158 study patients were enrolled at a single center (MDACC).

Inclusion criteria: PMF, Post-ET MF or Post-PV MF requiring therapy Intermediate or high-risk status (Lille scoring) Splenomegaly

1 Verstovsek S, et al. N Engl J Med. 2010;363:1117-1127. 2 Verstovsek S, et al. Blood. 2012;120:1202-1209. * Study INCB18424-251; NCT00509899.

Baseline Characteristics of Patients Characteristic Value 95% CI

Age (yrs), mean 66.8 65.1 68.5 Gender (F/M), % 44% / 56% IPSS risk status, % high risk intermediate-2 intermediate-1

59% 28% 13%

Spleen size* (cm), mean 18.8 17.1 20.6 Hemoglobin (g/dL), mean 10.8 10.4 11.3 Platelets (x109/L), mean 401.9 341.0 462.9 WBC (x109/L), mean 17.7 14.2 21.3 Peripheral blasts (%), mean 0.8 0.5 1.1 Total Symptom Score, mean 9.8 7.4 12.2

* Palpable spleen length below costal margin

Change in WHO-Defined BM Fibrosis Grade at 24 and 48 mo Following Ruxolitinib

24 mo 48 mo

Perc

enta

ge o

f pat

ient

s

Perc

enta

ge o

f pat

ient

s

10/68

39/68

19/51*

4/18

10/18

4/16*

Distribution of Direction of Changes Versus Baseline

15% 57% 37% 22% 56% 25%

* Excludes patients with Grade-3 WHO-defined BM fibrosis at baseline (since progression cannot be demonstrated)

Diagramm1

Improvement

Stabilization

Worsening

Column1

14.9

56.7

38

Sheet1

Column1

Improvement14.9

Stabilization56.7

Worsening38

Diagramm1

Improvement

Stabilization

Worsening

Column1

23.5

52.9

26.7

Sheet1

Column1

Improvement23.5

Stabilization52.9

Worsening26.7

Baseline biopsy Grade-3

24 mo post Rux Grade-2

48 mo post Rux Grade-0

Ruxolitinib: Approved Indications of Use

FDA (Jakafi): Treatment of patients with intermediate or high-risk myelofibrosis (November 16, 2011)

EMA (Jakavi): Treatment of disease- related splenomegaly or symptoms in adult patients with myelofibrosis (August 28, 2012)

A PHARMACOBIOLOGICAL APPROACH FOR THE CLINICAL DEVELOPMENT OF RUXOLUTINIB, IN MPN

Ruxolutinib is a JAK-STAT signaling patway inhibitor drug The function of JAK-STAT signaling patway is cellular proliferation in health and disease Ruxolutinib is an anti-proliferative drug in health and disease Ruxolutinib has the potential to inhibit neoplastic cellular proliferation of MPN Ruxolutinib can cause cytopenias due to its anti-proliferative effects at any lineage (good in disease; bad in health)

CURRENT CLINICAL CHALLENGES FOR RUXOLUTINIB IN MPN

(VERY) LOW-RISK MPN (VERY) HIGH-RISK MPN Survival is long and may even not different from the healthy population in some in low-risk MPNs like ET and PV.

Profound deep (pan)cytopenias already in the high-risk MPN could become worse after the addition of Ruxolutinib-induced cytopenias.

Competitors of Ruxolutinib is observation only, low-dose aspirin, phlebotomy, hydroxyurea, anagrelide. All of them are cheaper and safer in most cases.

Inability of Ruxolutinib administration in optimal dosage and duration due to cytopenias of high-risk MPN. Interruption and discontinuation of the drug. (Ruxolutinib cessation syndrome)

There is no data that long-term Ruxolutinib may affect disease course via the prevention of BM fibrosis in low-risk MPN.

Ruxolutinib may not improve already very shortened survival, morbidity, and comorbidities due to advanced/terminal MPN.

Ruxolutinib may not improve irreversible severe organ damage due to advanced/terminal MPN (hepatic failure, portal hypertension bone marrow failure, huge spleen, etc.)

What is the ideal subpopulation of MPN for the long-term Ruxolutinib administration at the proper therapeutic dosage and duration to let the drug modifying the MPN disease course and/or bone marrow architecture?

Slayt Numaras 1Slayt Numaras 2Slayt Numaras 3Myelofibrozis kk hcreleriSlayt Numaras 5Slayt Numaras 6Slayt Numaras 7Slayt Numaras 8Slayt Numaras 9Slayt Numaras 10Slayt Numaras 11Slayt Numaras 12Slayt Numaras 13Slayt Numaras 14Slayt Numaras 15Slayt Numaras 16Slayt Numaras 17Slayt Numaras 18Slayt Numaras 19Slayt Numaras 20Slayt Numaras 21Slayt Numaras 22Slayt Numaras 23Slayt Numaras 24Slayt Numaras 25Slayt Numaras 26Slayt Numaras 27Slayt Numaras 28Slayt Numaras 29PM TEDAV YNTEMLERSlayt Numaras 31Slayt Numaras 32Slayt Numaras 33Slayt Numaras 34Slayt Numaras 35Slayt Numaras 36Slayt Numaras 37Slayt Numaras 38Slayt Numaras 39Slayt Numaras 40Slayt Numaras 41Slayt Numaras 42Slayt Numaras 43Slayt Numaras 44Slayt Numaras 45Slayt Numaras 46Slayt Numaras 47Study 251Spleen Size Reduction in Patient Treated with INC424COMFORT trialsDesign and dosingRuxolitinib was associated with a greater reduction in splenomegaly vs placeboReduction in spleen volume from baselineDesign and dosingRuxolitinib was associated with a greater reduction in splenomegaly vs BATReduction in spleen volume from baselineBest percentage change in spleen volume on 5 year follow-upDuration of spleen response on 5 year follow-upOverall survival on 5 year follow-upRuxolitinib may modify the natural history of PMFSlayt Numaras 60Slayt Numaras 61Slayt Numaras 62Slayt Numaras 63Grading of BM FibrosisPatientsBaseline Characteristics of PatientsChange in WHO-Defined BM Fibrosis Grade at 24 and 48 mo Following RuxolitinibSlayt Numaras 68Slayt Numaras 69Slayt Numaras 70A PHARMACOBIOLOGICAL APPROACH FOR THE CLINICAL DEVELOPMENT OF RUXOLUTINIB, IN MPNCURRENT CLINICAL CHALLENGES FOR RUXOLUTINIB IN MPN Slayt Numaras 73