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