mielofibrosis: manejo del paciente convencional...anemia response - transfusion dependency -...
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Mielofibrosis: Manejo del paciente “convencional”
Valentín García Gutiérrez
Servicio de Hematología
Hospital Universitario Ramón y Cajal
Antecedentes Personales
• Varón de 69 años de edad remitido a nuestras consultas de hematología (mayo 2014) por cuadro de anemia y astenia:
HEMOGRAMA: Hb 9.7g/dl, Plaquetas 198.000, Leucocitos 8900 x109/L BIOQUIMICA: Creat 1.1, LDH 989, GOT 32; GPT 23 FSP: Cuadro leucoeritroblastico, 0% blastos, 3% mielocitos, 2% metamielocitos, displasia trilineal EXP FISICA: Sin hallazgos patologicos, no esplenomegalia
Diagnóstico ANAT PATOLOGICA: Mielofibrosis Primaria ESTUDIO MUTACIONES: CALR positivo CARIOTIPO: Sin alteraciones
¿Cuál es el pronóstico de nuestro paciente?
¿Qué clasificación pronóstica debemos usar y como cambia?
Mutaciones “driver” en MF
Modelo pronóstico para la MFP < 70 años MIPSS70
Guglielmelli P et al, JCO 2018;36(4):310-8
Factor de riesgo Puntos
Sínt. constitucionales 1
Hb < 10 g/dL 1
Blastos SP ≥ 2% 1
Fibrosis MO > 2 1
Ausencia CALR tipo 1 1
Mutación alto riesgo* 1
WBC > 25 x 109/L 2
Plaq < 100 x 109/L 2
Mut. alto riesgo* ≥ 2 2
*ASXL1, EZH2, SRSF2, IDH1/2
Risk Score No. cases (%) Median SRV (yr)
Low 0-1 238 (49%) 27.7
Interm 2-4 198 (40%) 7.1
High ≥ 5 54 (11%) 2.3
N= 490
Edad al Dx: 55 a.
MF inicial: 46%
http://www.mipss70score.it/
Diagnóstico Final
• Mielofibrosis primaria
• Riesgo: IPSS: intermedio-2 vs alto?? • Blastos >1%: no
• Edad >65 años: si
• Anemia Hb<10g/dl: si
• Sintomatología ???
¿Son útiles las escalas de calidad de vida?
¿Cuál es su recomendación terapéutica?
• 1. Ruxolitinib
• 2. Hidroxiurea
• 3. EPO
• 4. Lenalidomida
• 5. Abstención terapéutica
Evolución mayo 2014-enero2016
• Abstención terapéutica: • No sintomatología relacionada con la enfermedad
• HEMOGRAMA: Hb 8.4g/dl, plaquetas 143.000 x109/L, leucos 4300 x109/L
• FSP: 3% eritroblastos, 2% blastos, displasia trilineal.
• EXP FISICA: No esplenomegalia
¿Cuál es su recomendación terapéutica?
• 1. Ruxolitinib
• 2. Hidroxiurea
• 3. EPO
• 4. Lenalidomida
• 5. Abstención terapéutica
Algoritmo para el manejo de la anemia
Anemia not due to reversible
causes
EPO levels
Inadequate
Adequeate Danazol
ESA 3 months response?
6 months response?
ESA Yes
No
Yes Danazol
Inmunomodulators
Modified from Cervantes F. Expert Review of Hematology, 9:5, 489-496
Algoritmo para el manejo de la anemia
Anemia not due to reversible
causes
EPO levels
Inadequate
Adequeate Danazol
ESA 3 months response?
6 months response?
ESA Yes
No
Yes Danazol
Inmunomodulators
Modified from Cervantes F. Expert Review of Hematology, 9:5, 489-496
Anemia not due to reversible
causes
EPO levels
Inadequate
Adequeate Danazol
ESA 3 months response?
6 months response?
ESA Yes
No
Yes Danazol
Inmunomodulators
Modified from Cervantes F. Expert Review of Hematology, 9:5, 489-496
Algoritmo para el manejo de la anemia
Anemia not due to reversible
causes
EPO levels
Inadequate
Adequeate Danazol
ESA 3 months response
?
6 months response
?
ESA Yes
No
Yes Danazol
Inmunomodulators
Modified from Cervantes F. Expert Review of Hematology, 9:5, 489-496
Algoritmo para el manejo de la anemia
Experiencia estimulantes eritropoyéticos Agent N Low EPO levels Responses Remarks
rHuEPO1 20 16/20 Favorable response 45% (9/20) Complete Response 20% (5/20)
7/20 had previously received other therapies
α-darbepoetin2 20 - Treatment response 40% (8/20): - Complete response 6/20 - Partial response 2/20
Older age was the only factor associated with a favorable response to treatment (P = 0.006). None of the patients with appropriate serum erythropoietin levels responded.
ESA3 43 Median 34 U⁄L Overall responses 23%: - 0/16 in transfusion-dependent - 10/27 in transfusion-independent
ESA response was not correlated with baseline serum Epo level
1. Cervantes F. British Journal of Haematology, 127, 399–403 2. Cervantes F. Br J Haematol. 2006 Jul;134(2):184-6 3. Huang J. European Journal of Haematology 83 (154–155)
RESULTS
Anemia Responses -Transf Dependency -Transf Independency
56% (86/163) 29% (7/24) 57% (79/139)
Pretreatment Clinical Factors associated with Response:
-Female sex OR 2.7/ p 0.003
-Ferritin levels <200ng/ml OR 3.63/p0.001
-Grade 1-2 bone fibrosis OR2.1/p0.038
-Leukocyte counts>10 0R2.73/p0.003
-Serum EPO levels<125U/L OR 4.62/p0.023
-No prior transfusion support 0R 3.61/p0.009
No correlation with Response
Patients baseline characteristics (n 163)
Age 72
Transfusion dependency 15%
Median Hb 9.3
EPO levels <125 85%
Treatment: - Hydroxicarbamida - JAK inhibitors - Danazol - Immunomodulators
110 32 11 2
Initial choise of ESA - Erythropoietin - Darbepoetin
55 108
Anemia not due to reversible
causes
EPO levels
Inadequate
Adequeate Danazol
ESA 3 months response
?
6 months response?
ESA Yes
No
Yes Danazol
Inmunomodulators
Modified from Cervantes F. Expert Review of Hematology, 9:5, 489-496
Algoritmo para el manejo de la anemia
Danazol 600mg 400mg
6 months
200mg
Results (n 50)
Anemia response - Transfusion dependency - Transfusion independency
30% (15/50) 18% (5/27) 43% (10/23)
Median time to response 3 months
Median dose on responders 200mg
Median duration of response 14 months
Thrombocytopenia - Increase >50x109
23% (3/13)
Toxicities
Discontinued due to adverse events while on response
18% (5/50)
Increase liver enzymes 16% (8/50)
Severe cholestasic hepatitis
2
Prostate adenocarcinoma 1
Liver peliosis
Cervantes F. Ann Hematol (2015) 94:1791–1796
Anemia not due to reversible
causes
EPO levels
Inadequate
Adequeate Danazol
ESA 3 months response?
6 months response?
ESA Yes
No
Yes Danazol
Inmunomodulators
Modified from Cervantes F. Expert Review of Hematology, 9:5, 489-496
Algoritmo para el manejo de la anemia
Lenalidomide: MDACC and Mayo Clinic experience
Mayo Clinic (27 patients) MDACC (41 patients)
Treatment schedule 3 cycles for all patients Responders complete 6 cycles
3-4 months all patients 24 months complete responders
One cycle treatment Lenalidomide 10mg/day x28 days
Lenadidomide 10mg/day x28 days (5 mg if platelets cound <100.000)
Elegibility criteria PMF/PV-MF/ET-MF Hb <10g/dl Neutrophils >100x109/L
PMF/PV-MF/ET-MF Platelets count at least 100x109/L No Hb or neuthrophil requirement
% patientes required dose modifications
22% 24%
Anemia Response criteria: - MAJOR indicates normalization of hemoglobin - MINOR means either becoming transfusion independent or having an increase of at least 20 g/L in hemoglobin
Tefferi A. BLOOD, 15 AUGUST 2006 ! VOLUME 108, NUMBER 4
Results (n 40)
Overall response rate Major Hb response - Partial Response - Clinical improvement
30% (12/40) 30% (7/23) 3 4
Splenomegaly improvement 42% (10/24)
- Partial response - Clinical improvement
2 8
None of the patients with baselineneutropenia (n 2) or thrombocytopenia (n 6) attained clinicali mprovement.
Esteroides en el manejo de las citopenias
30 patients out of 511 MF patients recorded in GEMFIN data base (6%)
All response occurred in first 4 months Median anemia response 12.3 months No variables were correlated with outcomes
Hernandez Boluda JC Leukemia & Lymphoma, January 2016; 57(1): 120–124 .
Evolución de su enfermedad
• Inicia tratamiento con EPO
Empeoramiento de la astenia, fatiga, pérdida de
peso y sudoración
Cuál su actitud terapéutica
• Ruxolitinib
• Danazol
• Lenalidomida
• Esteroides
• Abstención terapéutica
Beneficio Ruxolitinib: Esplenomegalia
Beneficio Ruxolitinib: calidad de vida
n (%)
Ruxolitinib
(n = 146)
BAT
(n = 73) Ruxolitinib After Crossover From BAT
(n = 45)
Completed 5 years of treatment/follow-upa 39 (26.7) 0 11 (24.4)
Discontinued 107 (73.3) 28 (38.4) —
Crossed over — 45 (61.6) —
After qualifying progression event — 27 (37.0) —
After protocol amendment 5 — 12 (16.4) —
Otherb — 6 (8.2) —
Discontinued after crossover — — 34 (75.6)
Primary reason for discontinuation
Adverse event 35 (24.0) 5 (6.8) 10 (22.2)
Consent withdrawn 10 (6.8) 9 (12.3) 0
Protocol deviation 2 (1.4) 0 5 (11.1)
Disease progression (per investigator) 32 (21.9) 4 (5.5) 7 (15.6)
Nonadherence with study medication 4 (2.7) 0 1 (2.2)
Nonadherence with study procedures 0 1 (1.4) 0
Unsatisfactory therapeutic effect 8 (5.5) 0 5 (11.1)
Other reasons (including stem cell transplant) 16 (11.0) 9 (12.3) 6 (13.3)
Proportion of patients that benefit from Ruxolitinib
Beneficio ruxolitinib: Supervivencia Global
31
• Median OS was not yet reached in the ruxolitinib arm (ie, > 5 years)
— RPSFT: HR, 0.44 (95% CI, 0.18-1.04) in favor of ruxolitinib vs BAT
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
73 59 42 6 5 4 0
Ruxolitinib
BAT (RPSFT) Pro
ba
bili
ty
Time, years
n =
Median Overall Survival
Ruxolitinib = not reached
BAT (RPSFT) = 2.7 years
HR, hazard ratio; ITT, intent-to-treat; RPSFT, Rank-Preserving Structural Failure Time.
Modified form Abstract #59
Presented at the 57th American Society of Hematology Annual Meeting
Orlando, Florida, USA, Dec 05−08, 2015
POOLED COMFORT-I AND –II: 5-YEAR OVERALL SURVIVAL (3)
Verstovsek et al. Poster presentation at ASH 2016. Session 634. Abstract 3110. CI, confidence interval; HR, hazard ratio; NE, not evaluable.
OVERALL SURVIVAL IN THE ITT POPULATION
Indicaciones de Ruxolitinib en MF • EMA therapeutic indication: Jakavi is indicated for the treatment of disease-
related splenomegaly o symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis.
• British guidelines: Symptomatic splenomegaly (1ª) Myelofibrosis-related symptoms that are impinging upon QoL (1B) Hepatomegaly and portal Hypertension due to myelofibrosis are reduced by ruxolitinib and it can be considered for these indicacionts (2B) Whilst treatment with ruxolitinib is suggested to confer a survival advantage treatment with this agent in asymptomatic patients and/or those who lack bothersome splenomegaly is not currently recommended.
• FDA therapeutic indication: Jakafi is a kinase inhibitor indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis
https://ec.europa.eu/health/documents/community-register/2017/20170424137360/anx
Reilly J. British Journal of Haematology, 158, 453–471
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202192lbl.pdf
35
•¿Aplica el beneficio para todos los pacientes con mielofibrosis? • Independientemente del riesgo? • Independientemente del estado mutacional? • Puede utilizarse en pacientes con citopenias • Se benefician los pacientes de inicio de tratamiento precoz?
Población Int-II/alto riesgo
Población int-II/alto riesgo
¿Condiciona la clasificación pronóstica?
¿Es importante el estado mutacional?
Harrison C. Expert Rev. Hematol. 6(5), 511–523 (2013)
Impacto de Ruxolitinib en anemia y trombopenia
• OS in the ruxolitinib group was not significantly affected by patients’ transfusion independence vs nonindependence (P=0.132), whereas it was in the control group (P=0.0004)
• Median OS was significantly longer in the ruxolitinib group compared with the control group, even for patients who were transfusion-nonindependent at Week 24 (P=0.002)
Evolución
Sintomatologia: Mejora de sudoración, ganancia de peso (6kg), mejora significativa de la astenia Anemia: Transfusión dependiente ocasional Plaquetas: Disminución progresiva ( 80.000x109/L)
Evolución
Sintomatologia: Empeoramiento astenia, pérdida de peso, sudoración… Anemia: Transfusión dependiente (bisemanal) Plaquetas: Disminución progresiva ( 60.000x109/L)
¿Hasta cuándo mantener el tratamiento? Ficha técnica y Guías internacionales
Manera de suspender el tratamiento
Los síntomas y la esplenomegalia regresarán tras la retirada del fármaco, a veces rápidamente. Se recomienda una reducción gradual de la dosis en 7-10 días y el evitar interrupciones bruscas. La combinación con esteroides a dosis bajas (se sugiere prednisona 20-30 mg) se ha utilizado en este contexto clínico (evidencia grado 1A).
Guías UK1:
Ficha técnica2:
1.Reilly et al., Br J Haematol. 2014 Jun 25. doi: 10.1111/bjh.12985. [Epub ahead of print] 2.Ficha técnica. Agencia Europea del Medicamento www.ema.europa.eu
Reflexiones sobre el manejo de segunda línea • La gran mayoría de pacientes responden a ruxolitinib, sin embargo una
amplia mayoría perderán la respuesta tras 2-3 años de tratamiento
• Significa la evolución de la esplenomegalia que el paciente no se beneficia del tratamiento?
• Es fundamental diferenciar entre la intolerancia (efectos secundarios atribuidos al tratamiento) o falta de eficacia
• La decisión de suspensión de tratamiento estará influenciada por la posibilidad de tratamientos alternativos
• Aún en pacientes con pérdida de respuesta, existe un beneficio claro de tratamiento con ruxolitinib
Opciones actuales en el manejo de pacientes resistentes a ruxolitinib • Trasplante: Pocos pacientes candidatos, alta mortalidad
• Otros inhibidores de JAK (presumiblemente mayor eficacia inhJAK2)
• Combinaciones: inhJAK ->imids/TKIs/hipometilantes/IFN,,,,,
Ruxolitinib-Azacitidina
Masarova M. Blood. 2018 Oct 18; 132(16
Momelotinib
Mesa R. www.thelancet.com/haematology
Platelets change in patients with baseline platelets <50,000/μL.
Mean hemoglobin levels (±SEM) in patients with baseline hemoglobin <10 g/dL, including patients who received red blood cell transfusions.
Pacritinib
56
EOC3 EOC6
Insufficient
response (n=19) 8 (42%) 10 (53%)
Disease
progression (n=13) 5 (38%) 5 (38%)
Loss of
response (n=23) 12 (52%) 14 (61%)
≥35% spleen volume reduction from baseline by reason for ruxolitinib
discontinuation*
≥35% spleen volume reduction from baseline
39/83 46/83 14/27 17/27 25/55 29/55
Spleen response by subtype of
ruxolitinib resistance
FEDRATINIB JAKARTA-2: fedratinib in patients with myelofibrosis previously treated with Ruxolitinib – Spleen response
• Due to the early termination, 35/83 patients had an end of cycle 3, but no end of cycle 6, spleen measurement; the last observation carried forward (LOCF) method was used to impute missing end of cycle 6 data with the end of cycle 3 data (except for patients who discontinued before end of cycle 6 due to disease progression)
*One patient discontinued due to other reasons (not definable), and was therefore not classified as resistant or intolerant
EOC, end of cycle; JAK2, Janus kinase-2; LOCF, last observation carried forward
Harrison et al. Lancet Haematol 2017;4:e317–24.
JAKARTA-2: fedratinib in patients with myelofibrosis previously treated with Ruxolitinib – adverse events
57
Harrison et al. Lancet Haematol 2017;4:e317–24.
Adverse Events, n (%) Grade 1-2 Grade 3-4 Grade 5
Hematological adverse events*
Anemia 10 (10) 37 (38) 0
Thrombocytopenia 5 (5) 21 (22) 0
Lymphopenia 1 (1) 3 (3) 0
Nonhematological adverse events
Diarrhea 56 (58) 4 (4) 0
Nausea 54 (56) 0 0
Vomiting 40 (41) 0 0
Constipation 19 (20) 1 (1) 0
Pruritis 16 (16) 0 0
Fatigue 13 (13) 2 (2) 0
Headache 12 (12) 1 (1) 0
Cough 13 (13) 0 0
Urinary tract infection 12 (12) 0 0
Dyspnea 11 (11) 1 (1) 0
Dizziness 11 (11) 0 0
Abdominal pain 7 (7) 2 (2) 0
Alanine aminotransferase increased 3 (3) 3 (3) 0
Pneumonia 3 (3) 2 (2) 1 (1)
Hyperlipasemia 1 (1) 3 (3) 0
Hyperuricemia 2 (2) 2 (2) 0
Dehydration 1 (1) 2 (2) 0
Tumor lysis syndrome 0 2 (2) 0
Cardiac failure 1 (1) 2 (2) 0
Amylase increased 1 (1) 2 (2) 0
Blood bilirubin increased 0 2 (2) 0
Respiratory failure 0 0 1 (1)
Splenic rupture 0 0 1 (1) Data are n (%). Shown are any grade event occurring in more than 10% of patients, grade 3–4 events occurring in more than one patient, and all deaths (excluding four deaths due to
disease progression).
*Laboratory measurements
Posicionamiento de “nuevos” inhibidores de JAK en pts resistentes a ruxolitinib
• Pacientes con dosis inadecuadas de ruxolitinib por: • Anemia: EPO-Momelotinib?, Pacritinib?Luspatercept?
• Trombopenia: Pacritinib?
• Pacientes resistentes/pérdida de respuesta: • Fedratinib
• Combinaciones: Agentes hipometilantes?
Conclusiones
• La anemia y trombopenia son complicaciones frecuentes en la mielofibrosis
• El “algoritmo terapéutico” de la anemia obtiene respuestas “modestas”
• La anemia en pacientes con indicación no debe limitar la indicación ni el manejo de ruxolitinib
• La pérdida de respuesta a ruxolitinib no debe implicar la suspensión si no tenemos alternativas terapéuticas
• Combinaciones de ruxolitinib con “otros agentes” no han demostrado beneficio
• Nuevos inhibidores JAK presumiblemente tendrán un hueco en función de la respuesta previa a ruxolitinib
