Policitemia Vera Qual o manejo ideal · Passamonti F et al Leukemia 2010; Barbui T, N Engl J Med...
Transcript of 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