Post on 21-Mar-2020
Dott.ssa M. Bergamaschi
Mielofibrosi idiopatica:
update diagnostico-
terapeutico
Policlinico S. Martino-IST
Clinica EmatologicaClinica Ematologica
criteri Diagnostici WHO2016 per la PMF Criteri PREFIBROTIC /EARLY PMF OVERT PMF
Criteri maggiori 1.Proliferazione della linea megacariocitaria e
atipia associata SENZA fibrosi reticolinica di
grado > 1 associato a un incremento della
cellularità midollare, con proliferazione dei
granulociti e spesso ridotta eritropoiesi (fase di
malattia cellulare, pre-fibrotica)
2.Assenza di criteri WHO per PV, LMC, MDS o
altre neoplasie mieloidi
3.Presenza della mutazione JAK2V617F, CALR o
MPL o di altre anomalie clonali oppure, nessuna
evidenza di fibrosi midollare reattiva
1.Proliferazione della linea megacariocitaria e atipia associata
alla presenza di fibrosi reticolinica e/o fibrosi collagene di
grado ≥ 2 o 3
2.Assenza di criteri WHO per PV, LMC, MDS o altre neoplasie
mieloidi
3.Presenza della mutazione JAK2V617F, CALR o MPL o di
altre anomalie clonali oppure, nessuna evidenza di fibrosi
midollare reattiva
evidenza di fibrosi midollare reattiva
Criteri minori 1. Leucocitosi ≥ 11 x 10 9
2. Aumento dei livelli sierici di LDH
3. Anemia
4. Splenomegalia palpabile
1. Leucocitosi ≥ 11 x 10 9
2. Leucoeritroblastosi
3. Aumento dei livelli sierici di LDH
4. Anemia
5. Splenomegalia palpabile
Combinazioni
diagnostiche
Tutti e 3 i criteri maggiori + 1 criterio minori Tutti e 3 i criteri maggiori + 1 criterio minori
Klampfl T, et al. NEJM 2013 Dec 19;369(25):2379-90; Nangalia J, et al. NEJM 2013 2013 Dec 19;369(25):2391-405
Stratificazione del rischio nella MF1
MIPSS70: Mutation Enhanced Prognostic
Score System for Transplant-Age Patients
With MFVariables
Hb < 100 g/L
WBC > 25 × 109/L
PLT < 100 × 109/L
PB blasts ≥ 2%
Constitutional symptoms
Grade ≥ 2 BM fibrosis
Absence CALR Type 1
Weighted value
1
2
2
1
1
1
1
Low
Pro
bab
ility
(%
)
1.0
0.8
0.6
0.4
P < .001
Absence CALR Type 1
HMR categorya
≥ 2 HMR mutations
1
1
2
Intermediate
High
Survival (years)
0.2
05 105 15 20 25 30
Risk category Score OS (y) HR
Low 0-1 27.7 1
Intermediate 2-4 7.1 5.5 (3.8-8.0)
High ≥ 5 2.3 16.0 (10.2-25.1)
http://www.mipss70score.it/
Guglielmelli P, et al. J Clin Oncol. 2018;36(4):310-318. Reprinted with permission. © 2018 American Society of Clinical Oncology. All rights reserved.
• The MIPSS70-plus score also includes unfavorable karyotype, defined as any abnormal karyotype other than normal karyotype or sole abnormalities of 20q-, 13q-, +9, chromosome 1 translocation/duplication, -Y, or sex chromosome abnormality other than -Y
a HMR category was defined as having any mutation in ASXL1, EZH2, SRSF2, IDH1/2.
Covariate HR (95% CI) P value Points
Age at MF diagnosisa 1.07 (1.05-1.09) < .0001 0.15
Hb < 11 g/dL 2.3 (1.6-3.3 < .0001 2
PLT < 150 × 109/L 1.7 (1.2-2.5) .006 1
PB blasts ≥ 3% 2.9 (1.8-4.8 < .0001 2
CALR wild-type 2.6 (1.2-5.3) .001 2
Constitutional symptoms 1.5 (1.0-2.0) .03 1
a Continuous, 0.15 point/year.
Low(NR)
Int-19.3 y (8.1-NR)
Overall Survival in Patients With SMF
a Continuous, 0.15 point/year.
Passamonti F, et al. Leukemia. 2017;31(12):2726-2731.MYSEC-PM Calculator: http://www.mysec-pm.eu
Hb, hemoglobin; MYSEC-PM, Myelofibrosis Secondary to PV and ET-Prognostic Model; NR, not reached; PLT, platelet count; PB, peripheral blood; SMF, secondary MF.
Int-24.4 y (3.2-7.9)
High2.0 y (1.7-3.9)
2018 ELN Recommendations for
the Treatment of MF
Splenomegaly
Low
Hydroxyurea
Highly symptomatic?a
Int-1Int-2/high
Ruxolitinib
Second line
Ruxolitinib
First line
Low/Int-1
Leukocytosisor
thrombocytosis
Asymptomatic, and Hb ≥ 10 g/dL,
Spleen ≤ 10 cm, WBC ≤ 25 × 109/L, PLT ≤ 1000 × 109/L
a Presence of local symptoms or impairment of food intake.b Refractory, transfusion-dependent anemia, blasts > 2% in ≥2 repeated measurements, adverse cytogenetics, or high-risk mutations.
Ruxolitinib
Yes No
Hydroxyurea
Second line
First line
Ruxolitinib
Drug-refractory symptomatic splenomegaly
Splenectomy
RuxolitinibObservation Hydroxyurea
AlloSCT
Transplant candidate
Int-2/high
Int-1b
AlloSCT (controlled settings)
Anemia (Hb < 10 g/dL)
Patient-based, depending on overall toxicity
and risk
Barbui T, et al. Leukemia. 2018 Feb 27. [Epub ahead of print].
Studi COMFORT – Follow up a 5 anniDati di sopravvivenza
COMFORT I – Ruxolitinib vs placeboCOMFORT II – Ruxolitinib vs BAT
Srdan Verstovsek et al. EHA 2016, abstract 452
Rischio di morte è ridotto 33% vs BAT
(ITT: HR, 0.67 (95% CI, 0.44-1.02); P = .06)
Harrison, C. ASH 2015. Abstract 59.
Ruxolitinib per basso rischio MF:
Esperienze
Two studies have evaluated the use of ruxolitinib in patients with
lower-risk MF
– In the UK ROBUST study (N = 48), similar improvements in
splenomegaly and symptoms were observed across risk groups,
including for patients with intermediate-1 risk MF (n = 14)1
– The global JUMP study showed that reductions in spleen length – The global JUMP study showed that reductions in spleen length
and symptom burden for patients with intermediate-1 risk MF
(n = 163) were within the range observed in the overall JUMP
population (N = 2233)2
• Findings from these studies suggest that patients with lower-risk
MF derive clinical benefit from treatment and that ruxolitinib is an
effective treatment option for these patients
19
1. Mead AJ, et al. Br J Haematol. 2015;170(1):29-39.
2. Al –Ali HK, et al Haematologica 2016, Vol. 101(9):1065-1073 .
Ruxolitinib e infezioni
• Infezione da Herpes Zoster molto comune secondaria a linfocitopenia ( vaccino inattivato in arrivò)
• HbcAb pos e HbsAg pos: profilassi con lamivudinalamivudina
• Polmoniti infettive batteriche e cistiti ricorrenti
• Consigliate: vaccinazione antipneumococcica e anti-influenza inattivato
• PRIMA di iniziare terapia: eseguire RX torace in 2 proiezioni e dosaggio quantiferon� rischio ri-attivazione TBC
GRAZIE PER L’ATTENZIONE
mica.bergamaschi@gmail.com