Síndromes

mieloproliferativos

crónicos

Alberto Alvarez Larrán Hospital del Mar

PV: intensidad del tratamiento (Abstract #4)

MFP: impacto pronóstico de mutaciones (#431)

Actualización COMFORT I y II (#800 y #801)

Ruxolitinib en pacientes con MF y trombocitopenia (#176 y #177)

CYT387 en mielofibrosis (#178)

Ruxolitinib en PV (#804)

Resumen ASH 2012

TE: antiagregantes en pacientes de alto riesgo (#2848)

Thrombosis in PV: role of hematocrit

0.0

2.5

5.0

7.5

10.0

40-44 45-49 50-54 55-59 > 60

Hematocrit (%)

Nº

of

thro

mb

os

is in

10

ye

ars

Pearson and Wetherley-Mein, 1978

Reduction in blood flow

Increase of peripheral vascular

resistance

Elevated blood viscosity

Effect on platelets and leukocytes

Increased movement in a direction

perpendicular to blood flow

Higher interaction with endotelium

Objetivo del Hto < 45% cuestionado en estudio ECLAP

Abstract #4 A Large-Scale Trial Testing the Intensity of Cytoreductive Therapy to Prevent Cardiovascular Events in Polycythemia Vera Barbui T. et al

Objetivo del tratamiento en PV: mantener el Hto < 45%

PV n = 365 Flebotomías n= 248 (68%) Hidroxiurea n= 192 (53%)

ALEATORIZACIÓN

Hto < 45% Hto 45-50%

Objetivo principal: tiempo hasta muerte por causa cardiovascular o hasta la aparición de trombosis mayor Seguimiento mediano: 31 meses

0

10

20

30

40

Ble

ed

ing

per

1000

pers

on

-years

Cytoreduction plus aspirin

Cytoreductionalone

13.7

2.1

p=0.04

0

10

20

30

40

Cytoreduction plus aspirin

Cytoreductionalone

8.6

29.2p= 0.02

Th

rom

bo

sis

per

1000

pers

on

-years

Abstract #2828 Cytoreduction plus low-dose aspirin versus cytoreduction in monotherapy as primary prophylaxis of thrombosis in essential thrombocythemia Alvarez-Larrán A. et al

La adición de AAS al tratamiento citorreductor beneficia a pacientes

con TE mayores de 60 años sin antecedente de trombosis

TE alto riesgo No historia de trombosis

Estudio retrospectivo Edad > 60 años (n = 193)

Cyto + AAS: 763 años/paciente Cyto: 685 años/paciente

Abstract #431

Prognostic impact of mutations in a large series of patients with myelofibrosis Guglielmelli P et al

• Diagnosis of PMF according to the WHO 2008 criteria

• Availability of a sample of DNA from granulocytes (n= 415) or whole blood

(n= 68) collected at, or within 6 months from, diagnosis in the absence of

cytotoxic treatment

• A minimum set of clinical information and adequate follow-up

• Mutations were genotyped using allele specific RTQ-PCR, HRM and direct

sequencing (Sanger)

Study inclusion criteria

JAK2

(V617F)

MPL

(W515) EZH2

ASXL1

TET2

IDH1 DNMT3A

SRSF2 CBL

IDH2

CBL

Mutational Profile

382 (79.1%) of patients presented at least one somatic mutation

• 154 pts (32.5%) had >2 mutations

• 31 pts (6.4%) had >3 mutations

0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bili

ty0 5 10 15 20 25 30

Years from diagnosis

Wildtype Mutated

Adjusted for IPSS category

Survival by ASXL1 mutational status

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ility

0 5 10 15 20 25 30Years from diagnosis

Unmutated Mutated

IPSS risk categories Low and Intermediate-1

Survival according to ASXL1 mutational status

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ility

0 5 10 15 20 25 30Years from diagnosis

Unmutated Mutated

IPSS risk categories High and Intermediate-2

Survival according to ASXL1 mutational status

ASXL1 Mutations Have an IPSS-Independent Prognostic Value for Survival

P<0.0001

P=0.07 P=0.0004

WT

WT WT

Mut

Mut

Mut

IPSS (LOW-INT1) IPSS (INT2-HIGH)

Median Follow-up: 3.7y

157 patients died (32%)

Median Overall Survival: 9.7 y

0.0

0.2

0.4

0.6

0.8

1.0

Cum

ula

tive In

cid

ence

0 5 10 15 20 25 30Years

ASXL1 wildtype ASXL1 mutated

IDH1/2 wildtype IDH1/2 mutated

Adjusted cumulative incidence of AMLaccording to ASXL1 and IDH1/2 mutational status

ASXL1 and IDHs Mutations IPSS-Independently Predict for Leukemia

ASXL1-WT

ASXL1-Mut

P<0.0001

IDHs-WT

IDHs-Mut

Abstract #800

Long-Term Outcome of Ruxolitinib Treatment in Patients With Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I

Verstovsek S et al

Background

• Placebo-controlled, randomized, double-blind, phase III study

• Ruxolitinib starting doses:

– Baseline platelet count 100–200×109/L: 15 mg BID

– Baseline platelet count >200×109/L: 20 mg BID

• Doses individually titrated based on safety and efficacy

• Ruxolitinib treatment significantly reduced spleen size and improved MF-related symptoms and QoL and was also associated with a survival advantage relative to placebo1

Objective

• To describe long-term efficacy and safety of ruxolitinib with 1 year of additional follow-up beyond previously published data (median follow-up ~24 months) Data cutoff for current analysis: March 1, 2012.

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

Patient Disposition at Current Analysis

Patients, n (%) Ruxolitinib (n = 155)

Placebo (n = 151)

Placebo Ruxolitinib

(n=111)

Still on treatment 100 (64.5) 0 73 (65.8)

Discontinued 55 (35.5) 40 (26.5) 38 (34.2)

Crossed over 111 (73.5)

Primary reasons for discontinuation

Death 13 (8.4) 10 (6.6) 11 (9.9)

Adverse event 11 (7.1) 9 (6.0) 7 (6.3)

Consent withdrawn 9 (5.8) 6 (4.0) 9 (8.1)

Disease progression 12 (7.7) 12 (7.9) 5 (4.5)

Other 10 (6.5) 3 (2.0) 5 (4.5)

Noncompliance with study medication 1 (0.9)

• All patients receiving placebo at the primary analysis crossed over or discontinued

within 3 months of the primary analysis

• Median time to crossover: 41.1 weeks

Mean Daily Dose of Ruxolitinib Over Time

• 70% of patients had dose

adjustments during the first 12 weeks

• Patients achieved a stable dose with

longer-term use

25

20

15

10

0

BL 24 64 72 80 88 96

Da

ily D

os

e (

mg

BID

)

Weeks

32 40 48 56 8 16

5

All Ruxolitinib (n=155)

15 mg BID starting dose (n=55)

20 mg BID starting dose (n=100)

• 90/155 (58%) had a 35%

reduction in spleen volume

• 64% probability of maintaining a

≥35% reduction at 2 years

Incidence of New Onset Grade 3 or 4 Anemia and Thrombocytopenia Over Time

Ruxolitinib Grade 4 Ruxolitinib Grade 3

• Mean hemoglobin nadirs after 8–12 weeks of therapy and recovers to a new steady state which

remains stable with longer-term therapy

• Platelet count remain stable with longer-term therapy.

Median platelet count at baseline:

262×109/L

Mean percentage change from

baseline –40%

Median Hb at baseline: 105 g/L

Mean percentage change from

baseline –11% at 12 weeks

Overall Survival: ITT Population

Note: For this unplanned analysis, P-values are descriptive and nominally significant. *Age was the only baseline characteristic that differed significantly between treatment groups as reported in Verstovsek S, et al. N Engl J Med

2012;366:799-807 (median age: ruxolitinib, 66 years; placebo, 70 years; P<0.05).

Placebo

Ruxolitinib

1.0

0.8

0.6

0.4

0.2

0

0 12 24 36 48 60 72 84 96 108 120 132

Su

rviv

al P

rob

ab

ilit

y

Weeks

148 142 133 117 111 102 95 74 32 7 Placebo

154 148 145 136 125 121 113 96 44 6 Ruxolitinib

No. at risk

154

155

Unadjusted P=0.028

Age adjusted HR*=0.61 (95% CI: 0.37, 0.99); P=0.040

No. of deaths: Ruxolitinib=27; Placebo=41

Median follow up: 102 weeks

111 patients receiving placebo crossed over to ruxolitinib

Median time to crossover: 41.1 weeks

Ruxolitinib 15 or 20 mg oral bid

n = 146

Best available therapy (BAT) n = 73

Randomize

Patients with

PMF, PPV-MF, or

PET-MF with ≥ 2

IPSS risk factors2

N = 219 2:1

Ruxolitinib crossover and extension phase

1. Harrison C, et al. N Engl J Med. 2012;366(9):787-798.

2. Cervantes F, et al. Blood. 2009;113(13):2895-2901.

• Progression events that qualified for the crossover and extension phase:

– Splenectomy

– Progressive splenomegaly as defined by a 25% increase in spleen volume compared with the on-study nadir (including baseline)

Abstract #801 Long-Term Safety, Efficacy, and Survival Findings from Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treament of Myelofibrosis (MF) Cervantes F et al

n (%) Ruxolitinib (n = 146)

BAT (n = 73)

Ruxolitinib After Crossover From

BAT (n = 45)

Still on treatment 81 (55.5) 0 26 (57.8)

Discontinued 65 (44.5) 73 (100.0) 19 (42.2)

Crossed over -- 45 (61.6) --

Primary reasons for discontinuation

Adverse event 20 (13.7) 5 (6.8) 5 (11.1)

Consent withdrawn 8 (5.5) 9 (12.3) 0

Protocol deviation 2 (1.4) 0 5 (11.1)

Disease progression 16 (11.0) 4 (5.5) 5 (11.1)

Noncompliance with study medication 3 (2.1) 0 1 (2.2)

Noncompliance with study procedures 0 1 (1.4) 0

Unsatisfactory therapeutic effect 2 (1.4) 0 1 (2.2)

Other 14 (9.6) 9 (12.3) 2 (4.4)

Patient Disposition

• The majority of patients randomized to ruxolitinib remained on treatment after more than 2 years on study

Reduction in spleen volumen >35% at 48 weeks

0

25

50

75

100

% o

f p

ati

en

ts

Ruxolitinib n=144

BATn=72

40 (28%)

0%

Reduction in spleen volume> 35% at any time

0

25

50

75

100

% o

f p

ati

en

ts

70 (49%)

1 (0,1%)

Ruxolitinib N=144

BATN=72

Primary end-point: proportion of patients achieving >

35% reduction in spleen volume by MRI at 48 weeks

Median time to response: 12 weeks (11-49)

Harrison et al, NEJM 2012

• Patients have a 58% probability of maintaining their response for 84 weeks

• The median duration of spleen response has not yet been reached

Duration of Spleen Response

1.0

Pro

ba

bil

ity o

f M

ain

tain

ing

Sp

lee

n R

es

po

ns

e

Weeks0 12 24 36 48 60 72 84 96

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Ruxolitinib

No. of Patients

Events

Censored

70

18 (25.7%)

52 (74.3%)

1

0

1 (100%)

Ruxolitinib BAT

1.0

Pro

ba

bil

ity o

f M

ain

tain

ing

Sp

lee

n R

es

po

ns

e

Weeks0 12 24 36 48 60 72 84 96

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Ruxolitinib

No. of Patients

Events

Censored

70

18 (25.7%)

52 (74.3%)

1

0

1 (100%)

Ruxolitinib BAT

Hemoglobin Levels Over Time

19

146 127 127 121 101

73 50 59 53 37 31

101

29

89 Ruxolitinib n =

BAT n =

71 63

19 6 1

96 78

10

61

• Mean hemoglobin levels in the ruxolitinib arm reached a nadir at week 12, then

increased to levels similar to those in the BAT arm from week 24 onward

0

Red Blood Cell Transfusions

20 Transfusion data is from the randomized treatment phase only.

146 143 139 136 128 121 Ruxolitinib n = 105 96 25 105 121 136

73 68 66 53 45 BAT n = 37 24 4 24 37 53 0

Survival

P=0.04

Abstract #176 Efficacy, Hematologic Effects, and Dose of Ruxolitinib in Myelofibrosis Patients with Low Starting Platelet Counts (50–100×109/L): A Comparison to Patients With Normal or High Starting Platelet Counts Talpaz M et al

• N= 41

• Starting at a dose of 5 mg BID and titrating to 10 mg BID or greater resulted in spleen volume reductions and improvements in symptoms and QoL that were consistent with COMFORT-I

• Decreases in mean Hb were of lesser magnitude compared with ruxolitinib-treated patients in COMFORT-I

• Changes in mean platelet count were similar to patients receiving placebo in COMFORT-I

En pacientes con MF y trombocitopenia (50-100x109/L): Ruxolitinib

dosis inicial 5 mg/12 h y mantenimiento 10 mg/12h

Abstract #178

Phase I/II Study of CYT387, a JAK1/JAK2

Inhibitor for the Treatment of Myelofibrosis Pardanani A et al

– Highly specific, small molecule, ATP-competitive, JAK1/JAK2 inhibitor

– Orally active

– Key entry criteria: PMF or post-PV/ET MF, Platelets > 50x109/L

– Response criteria: IWG-MRT

– N=166 (150 mg/24h, 300 mg/24h, 150 mg/12)

– Median follow-up: 17 m (0.8-34)

– Discontinuation n= 42 (25%)

Maximum Duration of Transfusion-Free Period De 68 pacientes que requerían transfusiones, 46 no se transfundieron

en un periodo de al menos 12 semanas

*ongoing †data collection ongoing

Response by Dose (Core Study) 150 mg QD

(n=52) 300 mg QD

(n=60) 150 mg BID

(n=42) Total1

(n=166)

Spleen evaluable (n) 47 51 37 145

Spleen response (IWG-MRT) 32% 39% 38% 37%

Median spleen decrease at six months2 -36% -38% -46% -38%

Response in spleen and constitutional symptoms

Hematologic Adverse Event *(n=166) Grade 1 Grade 2 Grade 3 Grade 4

Anemia 2% 2% 2% 0%

Leukopenia 2% <1% 0% <1%

Neutropenia <1% 2% 1% 2%

Thrombocytopenia 14% 8% 17% 7%

Non-hematologic Adverse Event Incidence ≥ 10% Grade 1 Grade 2 Grade 3 Grade 4

Diarrhea 18% 4% 0% 0%

Dizziness1 22% 1% 0% 0%

Headache 14% 0% 1% 0%

Nausea 20% <1% 0% 0%

Neuropathy peripheral 25% 2% 0% 0%

300mg QD is a safe dosing regimen providing compelling efficacy and has

been selected for use in the Phase III clinical development program

Abstract #804 Long-term Efficacy and Safety Results From a Phase II Study of Ruxolitinib in Patients with Polycythemia Vera

Verstovsek S et al

• 59% (20/34) achieved a CR as their best response

• 38% (13/34) achieved a PR as their best response

• 3 patients required phlebotomies during study

• Deep vein thrombosis in 1 patient

• No treatment discontinuation for cytopenias

34 patients with PV enrolled

• Median follow-up duration: 3 years (range: 35 to 179 weeks)

• 26 (76%) remain on study, 8 discontinued

Ruxolitinib es eficaz en pacientes con PV resistentes o

intolerantes a HU, por lo que podría ser una buena opción de

tratamiento en segunda línea