policitemia vera qual o manejo ideal · passamonti f et al leukemia 2010; barbui t, n engl j med...

Fábio Pires de Souza Santos

Médico Hematologista do Hospital BP

Policitemia Vera – Qual o manejo

ideal ?

Neoplasia mieloproliferativa Ph-negativo

Quadro Clínico

• Hematócrito elevado; alta carga de sintomas

• Mutações no exon 14 (V617F; 96%) e exon 12 (3%) do

gene da tirosino-quinase JAK2

• Risco aumentado de trombose venosa e/ou arterial

• Pode evoluir para mielofibrose (MF) e/ou leucemia

mielóide aguda (LMA)

Policitemia Vera (PV)

WHO 2008 Classification of Neoplasms from Hematopoietic and Lymphoid Tissues

Características Clínicas de

Policitemia Vera

Passamonti F et al Leukemia 2010; Barbui T, N Engl J Med 2012; Tefferi A et al, Leukemia 2013; Vaidya R et al, Am J Hematol 2012; Alvarez-Larran A et al, Br J Haematol 2016

Variável Passamonti Barbui Tefferi Vaidya Larran

Idade, anos NI 64.5 61 61 68

Sexo Masculino, % 42 62.2 49 55 51

Hb, g/dL 17.9 15.3 18.4 18.5 NI

Ht, % NI 47.4 55 56 56/53

Plaquetas,

x109/mm3

NI 406 466 408 506

Trombocitose, % 72 NI 53 43 57

Leuco, x109/mm3 NI 9.3 10.4 11.4 10.8

Leucocitose, % 37 NI 49 38 58

Esplenomegalia,

%

25 NI 36 38 18

JAK2V617F, % 100 97.3 98 98 96

1. Scherber R, et al. Blood. 2011;118:401-408. 2. Johannson P, et al. Leuk Lymphoma. 2012;53:441-444.

THE VAST MAJORITY OF PV PATIENTS EXPERIENCE

SYMPTOMS1

4

• Symptoms may be constitutional (weight loss, fever, night sweats) or related to

splenomegaly (eg, early satiety, abdominal pain)1

Symptoms can occur

independently of blood

values, disease duration,

and myelosuppressive

treatment.2

WHO 2016-Critérios Diagnósticos

Arber DA et al, Blood 2016

Critério Maior

1. Hb > 16.5 g/dL (homem)/ >16.0 g/dL (mulher) ou hematócrito >49%

(homem)/>48%(mulher) ou aumento de massa eritrocitária

2. Presença de mutação JAK2V617F ou Mutações JAK2 Exon 12

3. Biopsia de MO mostrando hipercelularidade para a idade com

crescimento trilinhagem (panmielose)*

Critério Menor

1. Nivel de EPO sérico diminuido

Diagnostico de PV requer os 3 critérios maiores ou maior 1 e 3 e o critério menor

*-critério no. 3 não é necessário na presença de poliglobulia absoluta (Hb >18.5(H)/16.5(M) ou Ht>55.5%(H)/49.5%(M)) se critério

no. 2 e critério menor estão presentes

Policitemia Vera - Mutações

95%

3%

1% 1%

JAK2V617F

JAK2 Exon12

CALR Exon 9

Desconhecido

Estratificação de Risco e

Principios de Tratamento

Causas de Morte em PV

Marchioli R et al, J Clin Oncol 2005; Kiladijian J-J et al, J Clin Oncol 2011

15%

54%

12%

19%

Mediana Seguimento 16.3a

45%

13%

20%

22%

Mediana Seguimento 2.8 a

Cardiovascular

EvoluçãoMF/LMA

Tumor Solido

Outros

Fatores de Risco p/ Trombose

Marchioli R et al, J Clin Oncol 2005; Barbui T et al, J Clin Oncol 2011

European

LeukemiaNet

1. História prévia

de trombose

2. Idade ≥ 60 anos

LEUKOCYTOSIS IS AN INDEPENDENT RISK FACTOR

FOR THROMBOSIS IN PV

10

In a retrospective chart review of 1080 patients currently receiving HU, 58.2% had elevated

leukocyte counts >10 × 109/L

1. Parasuraman S, et al. Exp Hematol Oncol. 2016;5(3):1-10. doi:10.1186/s40164-016-0031-8.

HU=hydroxyurea; PV=polycythemia vera.

RISK FACTOR POINTS ASSIGNED

Age, years

≥67 5

57-66 2

Leukocyte count

≥15109/L 1

Venous thrombosis 1

A stratification system incorporating leukocytosis in addition to advanced age and

venous thrombosis effectively predicts increased risk1

Intermediate risk (1-2 points)

High risk (≥3 points)

Low risk (0 points)

Reprinted by permission from Macmillan Publishers Ltd:

Tefferi A. Leukemia. 2013;27(9):1874-1881, ©2013.

LEUKOCYTOSIS IS NOW RECOGNIZED AS A KEY

COMPONENT OF RISK STRATIFICATION1

11 1. Tefferi A, et al. Leukemia. 2013;27:1874-1881.

Tratamento de PV: European

Leukemia Net 2018

Barbui T et al, Leukemia 2018

Baixo

Risco

Alto

Risco

Aspirina Dose Baixa

Flebotomia

Citorredução:

• Hidroxiurea

• Interferon-a

• Busulfan

Flebotomia em PV – Valor de

Ht

Marchioli R et al, N Engl J Med 2012

AAS dose Baixa em PV

Landolfi R et al, N Engl J Med 2004

Sobrevida Livre de Trombose

Hidroxiureia vs. Pipobroman em

PV

Desfecho 1ario: EFS

Hidroxiuréia

Indução 25 mg/Kg/dia

Manutenção 10-15 mg/Kg/dia

(N=136)

Pipobroman

Indução 1.25 mg/Kg/dia

Manutenção 0.4-0.7 mg/Kg/dia

(N=149)

Pacientes <65 anos

com Policitemia Vera

(N = 285)

Randomização

Kiladjian J-J et al, J Clin Oncol 2012

Hidroxiurea vs. Pipobroman

em PV

Kiladjian J-J et al, J Clin Oncol 2012

Peg-IFN-a2a em PV

80%

100%

70%

95%

0%

20%

40%

60%

80%

100%

120%

MDACC French

Resposta Global

Resposta Completa

Quintas-Cardama A et al, J Clin Oncol 2009; Kiladjian J-J et al, Blood 2008

Peg-IFN-a2a em PV – 7 anos

Seguimento

Masarova L et al, ASH 2015

Parâmetro 1a avaliação Ultima avaliação

RCH 62 25

RPH 4 1

RGH 66 26

RCM 10 9

RGM 35 16

83 pacientes - após 7 anos

• 32 (39%) ainda recebendo o medicamento

• 51 (61%) interromperam o medicamento 27(35%) devido a toxicidade

• Mediana duração resposta hematologica 66 meses

• Mediana duração resposta molecular 53 meses

After 3 months of at least 2 g/day of Hydroxyurea

• Need for phlebotomy to keep hematocrit <45%

• Platelet >400x109/L or white blood cell count >10x109/L

• <50% reduction of massive splenomegaly; no relief of

spleen-related symptoms

• Myelosuppression at the lowest effective doses of

hydroxyurea

• Presence of leg ulcers or other unacceptable non-

hematological toxicities related to hydroxyurea

Resistance/Intolerance to Hydroxyurea

WHO 2008 Classification of Neoplasms from Hematopoietic and Lymphoid Tissues

261 PV patients; 30 (11.5%) with criteria for hydroxyurea

resistance

Hydroxyurea resistance and survival in

PV

Alvarez-Larran A et al, Blood 2012

ClinicalTrials.gov.

Verstovsek S, et al. Cancer. 2014;120:513-520.

STUDY DESIGN

21

Dose ranging 2 cycles (56 days) Dose expansion

Patients

with PV

(N=34)

Ruxolitinib

10 mg BID

(oral)

Ruxolitinib

25 mg BID

(oral)

Ruxolitinib

50 mg QD

(oral)

Ruxolitinib

10 mg BID

(oral)

R

A

N

D

O

M

I

S

A

T

I

O

N

Study 256 enrolled a total of 73 patients, including 39 patients with ET and 34 patients with PV.

Only results for PV will be discussed in this module.

BID=twice a day; ET=essential thrombocythaemia; PV=polycythemia vera; QD=once a day.

Verstovsek S, et al. Cancer. 2014;120:513-520.

• Response was achieved in 97% of patients by Week 24– 59% achieved a complete response as their best response

– 38% achieved a partial response as their best response

PRIMARY ENDPOINT

EFFICACY RESULTS

22

Images from Verstovsek S, et al. Cancer. 2014;120(4):513-520. © 2013 The authors, published by Wiley Periodicals, Inc. on behalf of the American

Cancer Society.

BAT 1o

En

dp

oin

t F

ail

ure

Dis

ea

se P

rog

res

sio

n

Week

32

Week

80

N = 100

N = 100

Cross over

I. Resistance to or

intolerance of HU

(ELN-based criteria)

II. Phlebotomy

requirement

III. Splenomegaly with

MRI-confirmed

volume of ≥ 450 cm3

HCT

40% to 45%

inclusive

Ran

do

miz

ed

Ruxolitinib 10 mg BID

R 1:1

Verstovsek S et al. Abstract 7026; 2014 ASCO Annual Meeting . Oral and Poster Presentation. Chicago, Illinois, USA.

RESPONSE STUDY (PHASE III)- STUDY DESIGN

23

SIGNIFICANT IMPROVEMENT IN PRIMARY ENDPOINT

24

Ruxolitinib demonstrated results

superior to BAT1,2

• Among patients who achieved a

primary response, 91% had a

durable response at Week 481,2

– Durability of primary response at

Week 48 was a key secondary

endpoint1,2

1. Vannucchi AM, et al. N Engl J Med. 2015;372(5):426-435.

2. Scossa D, Melko G. JAKAVI (ruxolitinib) Core Data Sheet: Version 1.5. Novartis Pharma AG; May 2015.

BAT=best available therapy; CI=confidence interval; CT=computed tomography; MRI=magnetic resonance imaging.

RUXOLITINIB

N=110

Primary response at week 32 1,2

1. Vannucchi AM, et al. N Engl J Med. 2015;372(5):426-435.

2. Ruxolitinib® (ruxolitinib) tablets: EU Summary of Product Characteristics. Novartis; April 2015.

RUXOLITINIB DEMONSTRATED COMPREHENSIVE

HAEMATOLOGIC REMISSION

Significantly more patients receiving Ruxolitinib achieved complete haematologic remission

compared with those in the BAT arm1,2

CHR was secondary endpoint in the RESPONSE-I trial1

25

BAT=best available therapy; CHR=complete haematologic remission.

RUXOLITINIB

N=110

CHR at week 32 1,2

Ruxolitinib

(n=110)

1. Vannucchi AM, et al. N Engl J Med. 2015;372(5):426-435.

2. Scossa D, Melko G. JAKAVI (ruxolitinib) Core Data Sheet: Version 1.5. Novartis Pharma AG; May 2015.

RUXOLITINIB RELIEVED BURDENSOME SYMPTOMS

OF PV

26

Consistent, clinically meaningful

improvement of the most commonly

reported PV symptoms1,2

BAT=best available therapy; MPN-SAF=The Myeloproliferative Neoplasm Symptom Assessment Form; PV=polycythemia vera.

RUXOLITINIB N=110

1. Vannucchi AM, et al. N Engl J Med. 2015;372(5):426-435.

SAFETY RESULTS: HAEMATOLOGIC EVENTS

27BAT=best available therapy.

RUXOLITINIB N=110

1. Vannucchi AM, et al. N Engl J Med. 2015;372(5):426-435.

SAFETY RESULTS: NONHAEMATOLOGIC EVENTS

28

BAT=best available therapy.

The majority of nonhaematologic adverse reactions were Grade 1/21

RUXOLITINIB N=110

• Estratificar risco de trombose

• Flebotomia alvo hematócrito <45%

• Profilaxia anti-trombótica (AAS)

• Evitar QT risco transformação LMA

• Citorredução em alto risco Hidroxiuréia

é 1a linha (Interferon p/ pcts jovens)

Tratamento de PV – Conclusão I

• Crucial identificar pacientes com PV não

controlada WBC, Ht, Sintomas, Res/Into a

Hydrea

• Tratamento com Inibidor de JAK2 Ruxolitinib

melhora sintomas, esplenomegalia e controla

hematócrito

• Melhor escolha para esse subgrupo de

pacientes

• Futuro: determiner impacto na sobrevida e

risco de transformação

Tratamento de PV – Conclusão II