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Alessandro M. Vannucchi

CRIMM- Center of Research and Innovation of MPN

Hematology Department

University & Azienda Ospedaliera Universitaria Careggi

Florence, Italy

Current and Emerging Treatment Options of Myeloproliferative Neoplasms

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Barbui T, et al. Leukemia 2018;32:1057–69

Mesa RA, et al. J Natl Compr Canc Net 2017;15:1193–207

A. Tefferi et al., BJH 2020; 189:291-302mod

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How to Risk-Stratify Patients with Polycythemia Vera

and Essential Thrombocythemia

  • Conventional ‘’Thrombosis Score’’ for PV
  • Different ‘’Thrombosis Risk Scores’’ for ET

Barbui T et al, Blood 2012; 120: 5128-5133.

Barbui T et al, BCJ 2015; 5: e369.

Guglielmeli P et al, BCJ 2020; 10: 21.

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Current Treatment Approach in Polycythemia Vera

@

(CYTO-PV trial) (Marchioli R, NEJM 2013; 368:22-33)

(ECLAP trial) (Landolfi R, NEJM 2004;350:114-24))

@

A. Tefferi & T. Barbui, AJH 2024; 98:1465-87

ELN 2021 Recommendations for Cytoreductive Therapy in PV

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RECOMMENDED to shift therapy

Intolerance

Inefficacy

Marchetti M et al, Lancet Haematol 2022; 9:e301

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CONSIDER to shift therapy

Inefficacy

Marchetti M et al, Lancet Haematol 2022; 9:e301

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How to Manage Interferon Therapy in Polycythemia Vera

Kiladjian JJ, Hematology 2024; 535-540.

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Long-term PROUD/CONTI : Impact on EFS & JAK2V617F Allele Burden

Alvarez-Larrán et al., 2014 Am J Hematol. 2014 May;89(5):517-23

Passamonti et al., 2010. Leukemia. 2010 Sep;24(9):1574-9

Gisslinger H et al. Leukemia 2023; 10:2129-2132.

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Harrison CN, et al. J Clin Oncol. 2023;41:3534-3544

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JAK2V617F Molecular Response and Event Free Survival

  • EFS (major hemorrhage, thrombosis, transformation or death) was superior for both ruxolitinib & for attaining a CR within 1 yr (HR 0.41; p=0.01)

Guglielmelli P et al, AJH, 2024; 99:1550-9.

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Kremyanskaya, M. et al. NEJM 2024; 390:723-735.

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Current Treatment Approach in Essential Thrombocythemia

Tefferi A et al, AJH 2024; 99:697-718 .

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One Thousand (x2) Patients with Essential Thrombocythemia

Mayo, Rochester

CRIMM, Florence

Gangat N et al, BCJ 20214;11:11. Loscocco G et al, BCJ 2024; 11:10.

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Ongoing Trials for Essential Thrombocythemia

Agent

​

Phase

Comparator

Patients’ criteria

Ropeg-IFN

Interferon

3 (SURPASS)

Anagrelide

Refractory/intolerant to HU. n= 160

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3 (ROP-ET)

Single arm

Refractory/intolerant to HU and other BAT. n=117

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2 (EXCEED-ET)

Single arm

Naive or refractory/ intolerant to HU. n= 64

Bomedestat

LSD1 inhibitor

2

Single arm

Refractory/intolerant to HU. n= 73

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3 (MK-3543-006)

Best available therapy

Refractory/intolerant to HU. n= 300

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Pelabresib

BET inhibitor

2 (arm 4 MANIFEST)

Single arm

Refractory/intolerant to HU.

INCA033989

Anti-CALR Ab

Phase 1-2

Single arm

Refractory/intolerant to HU.

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Interpreting Patients’ Prognostic Heterogeneity in MF

A. Tefferi & A.M. Vannucchi, AJH, 2024; NCCN 2024, V1

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NCCN Guidelines for Myelofibrosis: High Risk category

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Drug (MoA)

FDA approval and indication

EU approval and indication

Approved

Ruxolitinib3,4

(JAK1/JAK2 inhibitor)

2011

Intermediate- or high-risk primary or secondary MF

2012

Disease-related splenomegaly or symptoms in primary or secondary MF

Platelet count ≥50 /mm3) recommended starting dose and dose adjustment of ruxolitinib are based on the platelet count

Fedratinib5,6

(JAK2/FLT3 inhibitor)

2019

Intermediate-2 or high-risk primary or secondary MF

2021

Disease-related splenomegaly or symptoms in primary or secondary MF (JAK inhibitor naïve or previously treated with ruxolitinib)

Platelet count ≥50 /mm3

Pacritinib7

(JAK2/FLT3/IRAK1/ACVR1 inhibitor)8

2022

Intermediate or high-risk primary or secondary MF with a platelet count <50×109/L

–

Platelet count ≥25 /mm3

Momelotinib9

(JAK1/JAK2/ACVR1 inhibitor)

2023

Intermediate or high-risk primary or secondary MF in adults with anemia

2023

disease-related splenomegaly or symptoms with moderate to severe anemia who have PMF and sMF either JAKi naïve or have been treated with ruxo

�Irrespective of platelet count

JAK Inhibitors Approved for Patients with Myelofibrosis

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Cytopenias in MF, at Diagnosis and at Follow-up

TefferI A. Mayo Clin Proc. 2012;87(1):25-33

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Bose P, et al. Expert Opin Pharmacother. 2023;24(9):1091-1100

Pacritinib and Momelotinib are Relatively Non-Myelosuppressive

for Cytopenic Patients

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Novel Drugs for Myelofibrosis with Different Trial Designs

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Setting

Modalities

Druga

JAKi naive

JAKi R/R/I

Monotherapy

Add-on

Combo RUX

Pelabresib

✓

✓

✓

✓

✓

INCB057643 LIMBER103

​

✓

✓

✓

​

BMS-986158

✓

✓

✓

​

✓ & FED

Navitoclax

✓

✓

​

✓

✓

Imetelstat

​

✓

✓

​

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Parsaclisib

​

✓

​

✓

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Luspatercept

​

✓

​

✓

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Navtemadlin (KRT-232)

​

✓

✓

​

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Selinexor

​

✓

​

✓

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MANIFEST-2: More Patients Have Both SVR35 and TSS50

Mascarenhas J, ASH 2024.

  • 2-fold increase in patients achieving both SVR35 and TSS50 with pela+ruxo vs ruxo alone
  • Adverse Side effects were similar between the 2 arms: BP are under scrutiny.

SVR at w48: 57% vs 37.5%

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EBMT/ELN 2024 Recommendations for HSCT in MF

Kroger N. et al, Lancet Haematol 2024; 11:e62-64

  • Pre-transplantation management
  • Donor selection criteria
  • Stem-cell source and dose
  • Conditioning regimen
  • Prophylaxis for GVHD
  • Post-transplantation managemet

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  • In patients with myelofibrosis, clearance of driver mutations at day 30 after transplantation appeared to influence relapse and survival, irrespective of the underlying driver mutation.

Gagelman N et al. NEJM2025; 392:150-160.

Clearance of Driver Mutations after Transplantation for Myelofibrosis

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Thank you for your attention.