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Policitemia vera: resistencia/intolerancia
a hidroxiurea
Madrid, 6 junio 2019
Alberto Alvarez Larrán
Servicio de Hematología, Hospital Clínic, Barcelona
Meet the Expert, GEMFIN
Caso clínico
Mujer de 34 años, fumadora, ingresada en Hepatología para
estudio y tratamiento de síndrome de Budd-Chiari. Al
diagnóstico presentaba:
• Hb 16.6 g/dL, Hto 0.52 L/L, leucocitos 12x109/L, plaquetas
594x109/L
• Eritropoyetina sérica normal
• Masa eritrocitaria aumentada
• JAK2V617F mutado
• Crecimiento endógeno de colonias eritroides
Se inició tratamiento anticoagulante, se colocó un TIPS y tras
establecerse el diagnóstico de policitemia vera se remitió a
Hemoterapia para la realización de flebotomías periódicas con
el objetivo de mantener el Hto < 45%
30
35
40
45
50
55
60
IFN Hidroxiurea
Anticoagulación
Retrombosis
Retrombosis Retrombosis
IFN Hidroxiurea
1 2 3 4 5 6 7
Años tras el diagnóstico
Hem
ato
crito
, %
Embarazo
AAS
Flebotomías
Caso clínico
Durante el último año se mantuvo con hidroxiurea 1000 mg/día
ya que no toleraba el incremento de dosis por aparición de
sintomatología digestiva.
Se remitió de nuevo a Hemoterapia donde se realizaron 3
flebotomías en 1 mes. La última analítica mostraba:
Hematies 5.76 x1012/L, Hb 125 g/L, Hto 43L/L, VCM 78fL,
leucocitos 10.1 x109/L, plaquetas 396 x109/L.
¿Cumple los criterios de resistencia/intolerancia
a la hidroxiurea definidos por la ELN?
Resistencia/Intolerancia a HU
Barosi et al, BJH 2010
Citopenias
Esplenomegalia masiva
Necesidad de flebotomías
Mieloproliferación
incontrolada
Toxicidad extra-
hematológica
2 g/día > 3 meses
A la mínima dosis
para mantener la
respuesta
A cualquier dosis
Frequency of resistance/intolerance to hydroxyurea in 890 patients with PV
Patients
(%
)
Alvarez-Larrán et al, BJH
Resistance / Intolerance n=137 (15,4%)
3,3 1,6 0,8
1,7
9
0
5
10
15
20
25
30
Phlebotomies Myeloproliferation Splenomegaly Cytopenia Extrahematological toxicity
Median follow up: 4.6 years
Extra-hematological toxicity: Spanish Registry of PV (n=890)
6
3
0,1 0
5
10
15
20
25
30
Leg ulcers Mucocutaneous Fever
Unacceptable toxicity n=79 (9%)
4,4
1,6 0,1 0,1 0,7
0
5
10
15
20
25
30
Manageable toxicity n= 62 (7%)
Patients
, %
Patients
(%
)
Alvarez-Larrán et al, BJH 2016
Resistance/Intolerance to HU: modified criteria
McMullin et al, BJH 2015
Cytopenia
Massive splenomegaly
Need of phlebotomies
Uncontrolled
myeloproliferation
Extrahematological toxicity
After 3 months at
MTD of HU
At the lowest dose
of HU to achieve
response
At any HU dose
Disease-related thrombosis
or bleeding
Disease-related symptoms At any HU dose
New
New
New
Resistance/Intolerance to HU: modified criteria
McMullin et al, BJH 2015
Cytopenia
Massive splenomegaly
Need of phlebotomies
Uncontrolled
myeloproliferation
Extrahematological toxicity
After 3 months at
MTD of HU
At the lowest dose
of HU to achieve
response
At any HU dose
Disease-related thrombosis
or bleeding
Disease-related symptoms At any HU dose
Case 1!!!
Case 1!!!
Case 1!!!
Clinical characteristics of patients requiring frequent phlebotomies*
• Younger age (65 vs 70 years, p=0.02)
• Higher Htc before HU start (55% vs 51%, p<0.0001)
• Similar frequency of cardiovascular risk factors and history of thrombosis,
• No differences regarding leukocyte and platelet counts
• Similar JAK2V617F allele burden
• Higher doses of HU
• Higher frequency of intolerance to HU
Inadequate dose of HU according to disease proliferation
*In comparison with those not requiring frequent phlebotomies
Alvarez-Larrán et al, Haematologica 2017
Hematocrit control according to need of phlebotomies under HU therapy
55
48 46,5 47
48 47
51
48
35
40
45
50
55
60
Pre-HU 6 12 18 24 36 48 60
> 3 phlebotomies/year n= 85 (16%)
< 3 phlebotomies/year n= 448 (84%)
Month of HU therapy
Alvarez-Larrán et al, Haematologica 2017
0
<3 phlebotomies/year
≥3 phlebotomies/year
P < .0001
Th
ro
mb
os
is,
%
0
20
40
60
80
100
12 24 36
Months of Therapy
48 60
P < .0001
Alvarez-Larrán et al, Haematologica 2017
Multivariate analysis of risk factors predicting thrombosis in 533 patients treated with HU
Clinical feature HR (95%CI) P value
Male sex 0.5 (0.25-1.1) 0.08
Thrombosis at PV diagnosis 4.7 (2.3-9.8) <0.0001
Cardiovascular risk factors 2.2 (0.8-5.6) 0.1
Three or more PHL per year 3.3 (1.5-6.9) 0.002
Clinical meaning of phlebotomies under HU
Case 2
Phlebotomies
Antiplatelet therapy
Hydroxyurea
2003 2016
• Progressive
splenomegaly
• Night sweats
• Massive spleen
• Hb 174 g/L, Leukocytes
30x109/L, platelets 281x109/L
• Leukoeryhthroblastic picture
• JAK2V617F: 93%
• Bone marrow: intermediate
between PV and MF
2018
• Male
• 43 years
• Ischemic stroke
Ruxolitinib
Myelofibrotic transformation
0
Any criteria of HU intolerance/resistance
No HU intolerance/resistance
Tra
ns
form
ati
on
, %
0
20
40
60
80
100
5 10 15
Years
20 25 30 0
Development of cytopenia
No development of cytopenia
Tra
ns
form
ati
on
, %
0
20
40
60
80
100
5 10 15
Years
Myelofibrosis Acute Myeloid Leukemia
20 25 30
p= 0,026
Alvarez-Larran et al., Br J Haematol. 2016 Mar;172(5):786-93
Myelofibrosis
HR (95%CI) P
Need for phlebotomies 1.2(0.2-9.2) 0.8
Uncontrolled myeloproliferation
0.2(0.02-2.2) 0.2
Splenomegaly* 9.1(2.3-35.9) 0.002
Cytopenia 5.1(1.9-13.7) 0.001
Extrahematological toxicity 1.6(0.7-3.6) 0.2
* Failure to reduce massive splenomegaly (>10 cm from the costal margin) by >50% by palpation OR resolve splenomegaly-related symptoms HR: hazard ratio.
Clinical meaning of resistance/intolerance to HU
0
100
200
300
400
30
35
40
45
50
55
Pla
tele
ts x
10
9/L
H
em
ato
cri
t, %
Phlebotomies
Hu dose
Myelofibrosis
Case 3: 65 years-old male with JAK2V617F-positive
PV presenting with pulmonary embolism
1 y 2 y
Oral anticoagulation
Progression to acute leukemia
0
Any criteria of HU intolerance/resistance
No HU intolerance/resistance
Tran
sfo
rm
ati
on
, %
0
20
40
60
80
100
5 10 15
Years
20 25 30 0
Development of cytopenia
No development of cytopenia
Tran
sfo
rm
ati
on
, %
0
20
40
60
80
100
5 10 15
Years
Myelofibrosis Acute Myeloid Leukemia
20 25 30
HR: 20,3 (95%CI: 5.4-76.5) p=0,001*
* Corrected for age, leukocytosis at diagnosis and
sequential treatment with busulphan, P32,
pipobroman or melphalan Alvarez-Larran et al., Br J Haematol. 2016 Mar;172(5):786-93
Senín et al, Annals Hematol 2018
Patients developing cytopenia
under HU have a high genomic
instability as demonstrated by a
higher frequency of mutations in
DNMT3A, SRSF2, TP53,
RUNX1 enes
Clinical meaning of cytopenia under HU
Probability of progression to myelodysplstic
syndrome/acute myeloid leukemia in patients with
resistance/intolerance to HU
Patients with TP53 disruption/aneuploidy or with chromatine/spliceosome mutations
Patients belonging to other genomic subgroups
p <0.0001
Díaz et al, EHA 2019
Second line therapy in PV: ELN 2018 recommendations
Barbui T, et al. Leukemia 2018
• Ruxolitinib
• Interferon in young patients
• Hydroxyurea if not previously used
• Busulfan in the elderly
Ruxolitinib in PV: Response study
Primary composite endpoint: hematocrit control in the absence of phlebotomy
and ≥35% reduction in spleen volume at Week 32
Secondary endpoints: Complete hematologic remission at Week 32; % of
subjects who maintain primary endpoint response for ≥48 weeks
BAT: hydroxyurea, IFN/peg-IFN, anagrelide, pipobroman, IMIDS or observation
Kiladjian et al, EHA 2015
n = 91 (83%)
n = 98
n = 0
Ruxolitinib n=110
Vannucchi et al, NEJM 2015
Starting dose: 10 mg/ 12h
Treatment modalities in Response Trial
59% 12%
15%
Response: primary objective week 32
20,9
38,2
60,0
0,9 0,9
19,6
0
10
20
30
40
50
60
70
Composite Primary End Point
> 35% Reduction in Spleen Volume
Hematocrit Control
Ruxolitinib Standard Therapy
Vannucchi et al NEJM 2015
P < 0.001
Durability of primary response week 208
Kiladjian et al, ASH 2017, abstract 322
• 6 of 25 primary responders have progressed.
• K-M estimates of duration of hematocrit control: 73%
• K-M estimates of duration of spleen response: 86%
100
80
60
40
20
0
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 6 18 30 42 54 66 78 90 102 114 126 138 150 162 174 186 198 210 222
0 0 0 0 0 0 1 2 2 2 2 2 2 2 3 3 3 4 4 4 4 4 4 4 4 4 4 5 5 5 5 5 6 6 6 6 6 6 6
8 8 7 0 22 22 22 21 21 21 20 20 20 20 19 19 19 18 18 18 17 17 17 14 14 13 12 12 25 25 25 25 25 25 24 22 22 22 22
No. of responders/events/censor: 25/6/19
Kaplan-Meier median: Not reached
Duration of response (Weeks)
Pro
bab
ilit
y (
%)
Events
At Risk
Censoring times
Ruxolitinib
+
Durability of Hct control with ruxolitinib
Verstovsek et al, Haematologica 2016
24
49
9
5
0
10
20
30
40
50
60
CHR MPN-SAF
Ruxolitinib BAT
Patients
,%
Efficacy of ruxolitinib in polycythemia vera: RESPONSE TRIAL
• CHR: Hematocrit control, platelets < 400x109/L and WBC < 10x109
• MPN-SAF: percentage of patients with > 50% improvement in MPN-SAF symptom score
Vannucchi et al NEJM 2015
RESPONSE: Adverse Events of Interest
Ruxo BAT-CO
Rate* Rate*
Thrombotic events 1.2 2.9
Nonmelanoma skin cancer 6.6 2.5
Herpes-Zoster 4.9 4.2
Myelofibrosis 2.2 1.9
AML 0.2 0.3
Kiladjian et al, ASH 2017, abstract 322,
* eventsx100 person-years (Follow-up: 409 and 310 patient-years for Ruxo and BAT-CO,
respectively)
RESPONSE-2 Study Design
• Ruxolitinib-randomized patients had their doses individually titrated for efficacy and safety (to a maximum of 25 mg bid)
• Investigator-selected BAT as monotherapy included HU (at a tolerated dose if the patient were likely to receive benefit), interferon (IFN)/peg-IFN, anagrelide, pipobroman, immunomodulatory drugs, or no medication
• All patients received low-dose aspirin unless medically contraindicated
• Data cutoff date: 29 September 2015
BAT
Week 28 (primary analysis)
Week 80
n = 74
n = 75
Crossover to ruxolitinib
• Resistance to or intolerance of HU (modified ELN criteria)
• Phlebotomy requirement
• Nonpalpable spleen
• ECOG PS ≤ 2
Prerandomization (day −35)
Hct, 40%-45%
Ra
nd
om
ize
d (
1:1
)
Extended treatment
phase Ruxolitinib 10 mg bid
Week 260
Week 260
Final analysis
bid, twice daily; ECOG, Eastern Cooperative Oncology Group; ELN, European LeukemiaNet; PS, performance status. 26
Response-2: ruxolitinib in resistant/intolerant patients without splenomegaly
Endpoint Ruxolitinib BAT
Hct control 62%
(P < .0001) 19%
CHR 23%
(P = .0019) 5%
≥50% improvement in MPN-SAF TSS 45% 23%
Griesshammer et al, EHA 2017
Eficacia de ruxolitinib en la práctica clínica real: análisis de 68 pacientes
procedentes del Registro Español de Policitemia Vera (SEHH2019)
Basal 6 meses 12 meses
Prurito 57% 31% 6%
S. microvascular 36% 8% 0%
S. constitucional 15% 15% 12%
Esplenomegalia palpable 35% 16% 6%
Hematocrito > 45% 53% 42% 29%
Leucocitos > 10x109/L 51% 46% 47%
Plaquetas > 400x109/L 58% 58% 53%
Leucocitosis y
trombocitosis
37% 31% 23%
Respuesta hematológica
completa
18% 21% 18%
Busulfan
• Second-line: patients resistant/intolerant to HU (> 65 years)
• Schedule: 2 mg/day. Close monitoring and stop when normalization of
blood counts
• CHR 83%. Median time to response 203 days.
• Median duration of response: 45 months
• Rate of thrombosis: 5.1 events x 100 person-years
• Hematological toxicity 22%
• Acute myeloid leukemia in JAK2V617F-negative clone carrying aditional
mutations
EORTC, BJC 1981
Messinezy et al, BJH 1985
Alvarez-Larrán et al, Anals of Hematol 2014
Evolución clonal en paciente tratado con Busulfán
JAK2V617F DNMT3A
ASXL1
SETBP1
Dx 2005
STOP por PRURITO
STOP por PANCITOPENIA
Flebotomías AAS
RHC Hb 7,9 NF 0,75 Plq 47
Hb 12,7 Leuc 12 Plq 277
HU BUSULFÁN AAS
2005 2008 2011 2012 2015 2018
PV
Cortesía Dra A. Senín
Selección del paciente candidato a busulfán en segunda línea
• Edad > 70 años
• Toxicidad extra-hematológica por hidroxiurea
• Buena disposición para realizar controles
frecuentes
• Adecuada adherencia al tratamiento
• Tratamiento combinado si trombocitosis extrema
(anagrelide)
Resistencia a Hidroxiurea
Ruxolitinib Ensayo clínico
Ruxolitinib Busulfán Interferón
1. Descartar transformación de la enfermedad
2. Adecuar el tratamiento al perfil del paciente: edad,
comorbilidades y tipo de resistencia/intolerancia
Sintomatología
constitucional
Esplenomegalia
Citopenias
Toxicidad extra-
hematológica
Altas dosis de Hu
para control Hto Trombocitosis
aislada
Anagrelide Ruxolitinib Interferón
Conclusiones
• Los pacientes con resistencia/intolerancia a la hidroxiurea se
caracterizan por una mayor complejidad molecular especialmente
aquellos que desarrollan citopenias
• La necesidad de flebotomías frecuentes traduce un mal control del
hematocrito y mayor riesgo de trombosis
• La elección del tratamiento de segunda línea tiene que adaptarse
a las características del paciente
• El interferón podría ser una opción para pacientes jóvenes
• El busulfán requiere experiencia en el manejo y una adecuada
selección del paciente
• Ruxolitinib constituye una nueva alternativa para pacientes con
respuesta inadecuada o intolerancia a hidroxiurea con un
adecuado perfil de eficacia y seguridad
GEMFIN: MPN Spanish Group
Muchas gracias!!!