Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms
Simple Summary
Abstract
1. Introduction
2. Clinical Features, Diagnosis, and Classification
2.1. Chronic Myeloid Leukemia (CML)
2.2. Ph-Negative MPN: PV, ET, PMF
2.2.1. Polycythemia Vera (PV)
2.2.2. Essential Thrombocythemia (ET)
2.2.3. Primary Myelofibrosis (PMF)
- Very high risk: single or multiple abnormalities of −7, i(17q), inv(3)/3q21, 12p−/12p11.2, 11q−/11q23, or other autosomal trisomies not including +8/+9 (eg, +21, +19).
- Favorable: normal karyotype or sole abnormalities of +9, 13q−, 20q−, chromosome 1 translocation/duplication, or sex chromosome abnormality including −Y.
- Unfavorable: all other abnormalities.
- High risk: GIPSS > 2; MIPSS70+ > 4.
- Intermediate risk: GIPSS 1–2.
- Low risk: GIPSS = 0; MIPSS70+ 1–4.
3. Molecular Characteristics of Ph-Negative MPN
3.1. Driver Mutations
3.1.1. JAK (Janus Kinase)
3.1.2. CALR (Calreticulin)
3.1.3. MPL (Myeloproliferative Leukemia Virus Oncogene)
3.2. Passenger Mutations
3.3. Genomic Variation and Epigenetic Modification
3.4. Genetic Inheritance and Germline Predisposition
4. Pivotal Clinical Trials and Therapeutic Update
4.1. Chronic Myeloid Leukemia (CML)
4.1.1. FDA Approved TKIs (Table 5)
Trial | MMR (%) (Cumulative) | MR 4/4.5 (%) (Cumulative) | PFS (%) (at the End of Study) | OS (%) (at the End of Study) | Activity Against T315I Mut | Follow-Up |
---|---|---|---|---|---|---|
IRIS (IM vs. IFN) | 93.1 vs. NA | 63.2 vs. NA | 79.6 vs. 56.6 | 82.3 vs. NA (HR 0.74) | No | 11 years [96] |
DASISION (DAS vs. IM) | 76 vs. 64 | 42 vs. 33 | 85 vs. 86 | 91 vs. 90 | No | 5 years [97] |
ENESTnd (NIL 300 vs. IM) | 77.7 vs. 62.5 | 61 vs. 39.2 | 86.2 vs. 87.2 | 87.6 vs. 88.3 | No | 10 years [98] |
BEFORE (BOS vs. IM) | 74.4 vs. 63.3 | 58.2 vs. 48.1 (MR4) 47.4 vs. 36.6 (MR 4.5) | NA | 94.5 vs. 94.6 | No | 5 years [99] |
PACE (phase II) (Ponatinib) | Not yet approved for newly diagnosed CML. | yes | ||||
ASC4FIRST (Asciminib vs. 2G TKI) | 74.1 vs. 52.8 | NA | NA | NA | yes | 2 years [100] |
4.1.2. Novel Agents: Olverembatinib and Vodobatinib
4.1.3. Impact of Cancer Gene Variants on Treatment Response
4.1.4. Evolving Strategies for CML Treatment: Balancing Efficacy and Safety
4.2. Therapeutic Updates for PV, ET, and PMF
4.2.1. Polycythemia Vera (PV)
4.2.2. Essential Thrombocythemia (ET)
4.2.3. Primary Myelofibrosis (PMF) (Table 6)
JAK Inhibitor (Brand Name) | Targets | Clinical Trial | SVR35 at 24 Weeks | TSS50 at 24 Weeks | OS | Common Side Effect |
---|---|---|---|---|---|---|
Ruxolitinib (Jakafi) | JAK1, JAK2 | COMFORT-I 1st line: Ruxolitinib vs. Placebo COMFORT-II 1st line: Ruxolitinib vs. BAT | 41.9% vs. 0.7% 31.9% vs. 0% | 45.9% vs. 5.3% | 91.6% vs. 84.4% (HR = 0.5) NR vs. 4.1 yrs (0.52) | Thrombocytopenia, anemia, infections |
Fedratinib (Inrebic) | JAK2 | JAKARTA 1st line: Fedratinib vs. BAT FREEDOM2: 2nd line after ruxolitinib | 47% vs. 1% 35% vs. 6% | 40% vs. 9% 34.1% vs. 16.9% | NA NA | Dizziness, diarrhea, nausea, low platelet counts |
Pacritinib (Vonjo) | JAK2, FLT3, IRAK1, CSF1R | PERSIST-1 1st line, Pacritinib vs. BAT PERSIST (prior ruxolitinib) 2nd line, Pacritinib vs. BAT | 19% vs. 5% 22% vs. 3% 15% vs. 2% (once daily) 22% vs. 2% (twice daily) | 32% vs. 14% 33% vs. 15% (prior ruxolitinib) | NA OS benefit in subgroup patient with spleen response | Bleeding, cardiac events |
Momelotinib (Ojjaara) | JAK1, JAK2, ACVR1 | SIMPLIFY-1 1st line: momelotinib vs. ruxolitinib SIMPLIFY-2 (prior ruxolitinib) 2nd line: momelotinib vs. BAT | 26.5% vs. 29% 6% vs. 7% | 28.4% vs. 42.2% 26% vs. 6% | 65.8% vs. 61.2% at 2 yrs | Dizziness, fatigue, diarrhea, liver problems |
4.2.4. JAK Inhibitors (Table 6)
4.2.5. Emerging Therapies Beyond Frontline JAK Inhibitors
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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WHO 5th Edition: High Risk CP-CML | 2022 ICC: AP-CML | |
---|---|---|
At diagnosis | High ELTS score | |
10–19% blasts in the PB and/or BM | 10–19% blasts in the PB and/or BM | |
≥20% basophils in the PB | ≥20% basophils in the PB | |
Additional clonal chromosomal abnormalities in Ph+ cells * | Additional clonal chromosomal abnormalities in Ph+ cells at diagnosis * | |
Clusters of small megakaryocytes associated with significant reticulin and/or collagen fibrosis in biopsy | ||
Emerging on treatment | Resistance to TKI, including loss of prior responses, emergence of ACA and BCR::ABL1 kinase domain mutations |
Disease | Diagnostic Criteria |
---|---|
PV | 3 major or the first 2 major + 1 minor 3 Major criteria PB: ↑ Hb (>16.5 g/dL in men; >16.0 g/dL in women) or ↑ Hct (>49% in men; >48% in women) BM: age-adjusted hypercellularity with panmyelosis with pleomorphic mature megakaryocytes (differences in size) Presence of JAK2 V617F or JAK2 exon 12 mutation 1 minor criterion Subnormal serum EPO level |
Post-PV MF | All required criteria + at least 2 additional criteria Required criteria Documentation of a previous Dx of WHO-defined PV Bone marrow fibrosis of grade 2–3 on a 0–3 scale Additional criteria (2 are required) Anemia or sustained loss of requirement of either phlebotomy or cytoreductive treatment for erythrocytosis Leukoerythroblastosis Increasing splenomegaly in palpable splenomegaly of >5 cm from baseline or the development of a newly palpable splenomegaly Development of any 2 (or all 3) of the following constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5 °C) |
ET | All major criteria or the first 3 major + minor criterion Major criteria PB: Platelet count ≥ 450 × 109/L BM: showing proliferation mainly of the megakaryocytic lineage, with increased numbers of enlarged, mature megakaryocytes with hyperlobated nuclei; no significant increase or left shift in neutrophil granulopoiesis or erythropoiesis; very rarely a minor (grade 1) increase in reticulin fibers WHO criteria for BCR-ABL1-positive CML, PV, PMF, or other myeloid neoplasms are not met Minor criterion: Presence of a clonal marker or absence of evidence of reactive thrombocytosis |
Post ET MF | All required criteria + at least 2 additional criteria Required criteria Documentation of a previous Dx of WHO-defined ET Bone marrow fibrosis of grade 2–3 on a 0–3 scale Additional criteria (2 are required) Anemia and a >2 g/dL decrease from baseline Hb Leukoerythroblastosis Increasing splenomegaly: ↑ in palpable splenomegaly of >5 cm from baseline or the development of a newly palpable splenomegaly ↑ LDH (above reference range) Development of any 2 (or all 3) of the following constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained fever (>37.5 °C) |
Prefibrotic PMF | All 3 major criteria + at least 1 minor Major criteria Megakaryocytic proliferation and atypia, without reticulin fibrosis grade > 1, accompanied by ↑ age-adjusted BM cellularity, granulocytic proliferation, and (often) ↓ erythropoiesis WHO criteria for BCR-ABL1-positive CML, PV, ET, MDS, or other myeloid neoplasms are not met JAK2, CALR, or MPL mutation; or presence of another clonal marker (e.g., ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 mutations); or absence of minor reactive bone marrow reticulin fibrosis * Minor criteria (at least 1, confirmed in 2 consecutive determinations) Anemia not attributed to a comorbid condition Leukocytosis ≥ 11 × 109/L Palpable splenomegaly ↑ LDH (above reference range) |
Fibrotic PMF | All 3 major criteria + at least 1 minor Major criteria Megakaryocytic proliferation and atypia, accompanied by reticulin and/or collagen fibrosis grades 2 or 3 WHO criteria for BCR-ABL1-positive CML, PV, ET, MDS, or other myeloid neoplasms * are not met JAK2, CALR, or MPL mutation; or presence of another clonal marker (e.g., ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 mutations); or absence of reactive fibrosis Minor criteria (at least 1, confirmed in 2 consecutive determinations) Anemia not attributed to a comorbid condition Leukocytosis ≥ 11 × 109/L Palpable splenomegaly ↑ LDH (above reference range) Leukoerythroblastosis |
Clinical | Karyotype | Driver Mutation | HMR Mutations | |
---|---|---|---|---|
GIPSS | Not included |
|
|
|
MIPSS70+v2.0 |
|
|
|
|
Driver Mutations | PV | ET | PMF |
---|---|---|---|
JAK2 | Increased risk of thrombosis and disease progression | Increased thrombosis risk | An intermediate prognosis and an elevated risk of thrombosis compared to patients with CALR mutation |
CALR (frameshift in exon 9) | Lower risk of thrombosis compared to JAK2 mutated | CALR type 1 are associated with improved survival compared to JAK2 V617F and triple-negative cases, with better outcomes following SCT. CALR type 2 mutations lower OS compared to CALR type 1 [65] | |
MPL (exon10) | Intermediate prognosis and increased thrombosis risk compared to CALR mutation patients |
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Wang, L.; Li, J.; Arbitman, L.; Zhang, H.; Shao, H.; Martin, M.; Moscinski, L.; Song, J. Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms. Cancers 2025, 17, 1834. https://doi.org/10.3390/cancers17111834
Wang L, Li J, Arbitman L, Zhang H, Shao H, Martin M, Moscinski L, Song J. Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms. Cancers. 2025; 17(11):1834. https://doi.org/10.3390/cancers17111834
Chicago/Turabian StyleWang, Le, Julie Li, Leah Arbitman, Hailing Zhang, Haipeng Shao, Michael Martin, Lynn Moscinski, and Jinming Song. 2025. "Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms" Cancers 17, no. 11: 1834. https://doi.org/10.3390/cancers17111834
APA StyleWang, L., Li, J., Arbitman, L., Zhang, H., Shao, H., Martin, M., Moscinski, L., & Song, J. (2025). Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms. Cancers, 17(11), 1834. https://doi.org/10.3390/cancers17111834