Primary Myelofibrosis

Table of Contents

1. What is Primary Myelofibrosis?
2. Pathophysiology and Driver Mutations
3. WHO 2022 Diagnostic Criteria
4. Symptoms and Clinical Presentation
5. Diagnosis: Blood and Bone Marrow Findings
6. DIPSS-Plus Prognostic Scoring
7. Treatment: Symptom Management and JAK Inhibitors
8. Allogeneic Stem Cell Transplantation
9. Research Papers
10. Connections
11. Featured Videos

What is Primary Myelofibrosis?

Primary Myelofibrosis (PMF) is the most aggressive of the classic Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs), a group that also includes Polycythemia Vera (PV) and Essential Thrombocythemia (ET). PMF is characterized by clonal hematopoiesis that drives progressive bone marrow fibrosis, ultimately causing failure of normal blood cell production and forcing the spleen and liver to take over blood-making — a process called extramedullary hematopoiesis (EMH).

The disease occurs at an incidence of approximately 0.5–1.5 per 100,000 people per year, with a median age at diagnosis of 65 years. It can arise de novo (primary) or transform from prior PV (post-PV MF) or ET (post-ET MF). Massive splenomegaly — a spleen that may extend deep into the pelvis — is one of its most defining clinical features, causing crushing abdominal fullness and pain in many patients.

Prognosis depends heavily on risk stratification: median survival ranges from over 15 years for low-risk patients to just 1–2 years for high-risk disease. The only potentially curative treatment is allogeneic stem cell transplantation (SCT), though most patients are not candidates due to age and comorbidities. JAK inhibitors have transformed symptom management and improved quality of life dramatically over the past decade.

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Pathophysiology and Driver Mutations

PMF is driven by somatic mutations that constitutively activate the JAK-STAT signaling pathway, producing autonomous proliferation of megakaryocytes and other myeloid progenitors. Three canonical driver mutations account for approximately 90% of cases:

• JAK2 V617F (~60%): A point mutation in Janus kinase 2 that creates constitutive, erythropoietin-independent JAK-STAT signaling. Found across all three MPNs, but in PMF it is associated with older age and higher risk of thrombosis.
• CALR exon 9 mutations (~25%): Insertions or deletions in the calreticulin gene. Type 1 (52-bp deletion) confers a better prognosis than Type 2 (5-bp insertion). CALR-mutant PMF tends to occur in younger patients with higher platelet counts and lower thrombotic risk than JAK2-mutant disease.
• MPL W515L/K (~6%): Activating mutations in the thrombopoietin receptor, producing constitutive megakaryocyte and platelet stimulation.
• Triple-negative (~10%): No JAK2, CALR, or MPL mutation detected; generally carries an intermediate to adverse prognosis.

High-Molecular-Risk (HMR) Mutations

Beyond the driver mutations, the presence of additional somatic mutations in epigenetic and splicing regulator genes — designated "high-molecular-risk" (HMR) — dramatically worsens prognosis. The most clinically important HMR mutations are:

• ASXL1 — most common HMR mutation; associated with shortened survival and increased leukemic transformation risk.
• SRSF2 — splicing factor; independently associated with inferior outcomes.
• EZH2 — histone methyltransferase; marks aggressive disease biology.
• IDH1/IDH2 — isocitrate dehydrogenase mutations; associated with blastic transformation.

The presence of two or more HMR mutations identifies a "very high-risk molecular" group with markedly poor outcomes, now incorporated into the MIPSS70-Plus v2.0 prognostic model.

Fibrosis Mechanism

Clonal megakaryocytes in PMF are morphologically abnormal (atypical, with cloud-like nuclei and naked nuclei clusters) and release excess TGF-β, platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) into the marrow microenvironment. These cytokines stimulate stromal fibroblasts and osteoblasts to lay down reticulin and collagen fibrils, progressively replacing the normal marrow space with scar tissue. Neoangiogenesis from VEGF contributes to the hypervascularity. The resulting cytokine storm also drives constitutional symptoms (night sweats, fever, weight loss, profound fatigue). In advanced disease, bone remodeling leads to osteosclerosis. The hallmark peripheral blood picture — called leukoerythroblastic — shows teardrop red blood cells (dacryocytes), nucleated red blood cells (NRBCs), circulating immature granulocytes, giant platelets, and circulating blasts.

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WHO 2022 Diagnostic Criteria

The 2022 WHO Classification of Haematolymphoid Tumours divides PMF into two stages based on bone marrow fibrosis grade, with distinct clinical courses:

Pre-fibrotic / Early PMF (Pre-PMF)

Pre-PMF is defined by the following major criterion plus all three major criteria being met, and at least one minor criterion:

• Major criteria (all required):
  1. Megakaryocyte proliferation and atypia without significant reticulin fibrosis (>MF-1), accompanied by increased age-adjusted bone marrow cellularity.
  2. Not meeting WHO criteria for any other myeloid neoplasm (ET, PV, BCR-ABL1+ CML, MDS, or other myeloid neoplasm).
  3. Presence of JAK2, CALR, or MPL mutation, or in their absence, another clonal marker (e.g., ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1 mutation), or absence of reactive bone marrow reticulin fibrosis.
• Minor criteria (at least 1 required): anemia not attributable to a comorbid condition; leukocytosis ≥11×10&sup9;/L; palpable splenomegaly; elevated LDH above upper limit of normal.

Overt Fibrotic PMF

Overt PMF meets the same major criteria as pre-PMF but is distinguished by a reticulin and/or collagen fibrosis grade of MF-2 or MF-3 on bone marrow biopsy. The fibrosis grade on bone marrow trephine biopsy (MF-0 through MF-3) is the critical pathological differentiator between pre-PMF and overt PMF, with significant implications for prognosis and treatment intensity.

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Symptoms and Clinical Presentation

PMF can be strikingly symptomatic at diagnosis, unlike the earlier MPNs. The symptom burden is quantified using validated tools — the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) and the MPN-10 — which assess 10 key domains:

Constitutional (B) Symptoms

• Profound fatigue: The most debilitating and most common symptom; present in over 80% of patients. Driven by cytokine excess (TNF-α, IL-6), anemia, and splenic sequestration. Often disproportionate to hemoglobin levels.
• Night sweats: Drenching, requiring clothing or linen changes; present in approximately 50% of patients.
• Fever: Low-grade, without obvious infectious source; reflects cytokine storm.
• Weight loss: Involuntary loss of >10% body weight over 6 months; a major DIPSS constitutional symptom criterion. Cachexia is prominent in advanced disease.

Splenomegaly and Hepatomegaly

• Massive splenomegaly: The spleen becomes the primary site of extramedullary hematopoiesis and can extend from the left upper quadrant into the pelvis. Causes early satiety, abdominal fullness, left upper quadrant pain, and occasional splenic infarcts (acute, severe left-sided pain).
• Hepatomegaly: The liver also becomes a site of EMH, causing hepatomegaly and, in severe cases, portal hypertension with ascites and esophageal varices.

Hematologic Symptoms

• Anemia: Progressive and often transfusion-dependent; causes dyspnea on exertion, pallor, and worsening fatigue. Transfusion dependence is a major adverse prognostic factor.
• Thrombosis and bleeding: Thrombotic events (DVT, PE, splanchnic vein thrombosis) reflect the underlying myeloproliferative state; bleeding risk increases with thrombocytopenia and platelet dysfunction.
• Pruritus: Especially aquagenic (triggered by warm water), related to basophil degranulation and histamine release.

Other Manifestations

• Bone pain: From osteosclerosis in advanced disease; may affect hips, spine, and long bones.
• Extramedullary hematopoiesis: Beyond spleen and liver, EMH can occur in lymph nodes, pleura (pleural effusion), lungs, and epidural space (spinal cord compression, rare but serious).

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Diagnosis: Blood and Bone Marrow Findings

Diagnosing PMF requires integrating peripheral blood morphology, bone marrow biopsy, molecular mutation testing, and cytogenetics. No single test is sufficient.

Peripheral Blood Smear

The leukoerythroblastic smear is the hallmark of overt PMF and is highly suggestive of marrow fibrosis or infiltration:

• Teardrop red blood cells (dacryocytes): RBCs deformed as they squeeze past marrow fibrosis; the most characteristic finding.
• Nucleated red blood cells (NRBCs): Immature erythroid precursors released prematurely from EMH sites.
• Left-shifted granulocytes: Myelocytes, metamyelocytes, and band forms in circulation.
• Circulating blasts: Even small percentages (≥1%) are prognostically significant (DIPSS criterion).
• Giant platelets and megakaryocyte fragments: Reflect dysmegakaryopoiesis.

Bone Marrow Biopsy

Trephine biopsy (not aspiration alone) is essential. Key findings:

• Reticulin / collagen fibrosis: Graded MF-0 (absent) to MF-3 (dense collagen + osteosclerosis). MF-2 or MF-3 = overt PMF. Grading uses the European Consensus Grading system.
• Megakaryocyte atypia: Clusters of abnormal megakaryocytes with cloud-like nuclei, hyperchromatic nuclei, and naked (denuded) nuclei are pathognomonic.
• Hypercellularity (early): Pre-PMF shows hypercellular marrow with megakaryocytic and granulocytic proliferation.
• "Dry tap": Aspiration failure due to dense fibrosis is characteristic of overt PMF and should prompt biopsy and consideration of PMF diagnosis.
• Osteosclerosis: Thickened, irregular bony trabeculae in advanced (MF-3) disease.

Laboratory Studies

• CBC: Progressive anemia (often Hgb <10 g/dL at presentation); WBC variable (elevated, normal, or suppressed); platelets variable (may be high early, then drop as disease progresses).
• LDH: Elevated, reflecting high cell turnover; included as a DIPSS minor criterion marker.
• Uric acid: Elevated from cell turnover; gout can complicate treatment.
• Alkaline phosphatase: Often elevated; reflects osteosclerosis and liver EMH.
• Serum EPO: Low relative to degree of anemia in most patients.
• Cytogenetics (karyotype): Abnormal in ~30% of PMF. Common abnormalities include del(13q), +8, del(20q). Unfavorable karyotype (included in DIPSS-Plus) = +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, 11q23 rearrangement.
• NGS mutation panel: JAK2 V617F allele burden, CALR type, MPL; plus HMR mutations (ASXL1, SRSF2, EZH2, IDH1/2). JAK2 V617F allele burden has prognostic significance — high allele burden correlates with more symptomatic disease.

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DIPSS-Plus Prognostic Scoring

Risk stratification in PMF uses a series of progressively refined prognostic models. The Dynamic International Prognostic Scoring System (DIPSS) and DIPSS-Plus are the most widely used in clinical practice.

DIPSS Adverse Factors (1 point each, except anemia and blasts = 2 points)

• Age >65 years — 1 point
• Hemoglobin <10 g/dL — 2 points
• WBC >25×10&sup9;/L — 1 point
• Circulating blasts ≥1% — 2 points
• Constitutional symptoms (night sweats, fever, or >10% weight loss) — 1 point

DIPSS Risk Groups

• Low (0 points): Median OS ~15 years
• Intermediate-1 (1–2 points): Median OS ~6.5 years
• Intermediate-2 (3–4 points): Median OS ~2.9 years
• High (5–6 points): Median OS ~1.3 years

DIPSS-Plus Additional Adverse Factors

DIPSS-Plus (Gangat et al., 2011) adds three independent adverse prognostic variables to the DIPSS score:

• Platelet count <100×10&sup9;/L
• Transfusion dependence (requiring ≥1 RBC transfusion)
• Unfavorable karyotype: +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement

MIPSS70 and MIPSS70-Plus v2.0

The Mutation-Enhanced International Prognostic Score System for Transplant-Age Patients (MIPSS70, 2018) and its updated version (MIPSS70-Plus v2.0) incorporate HMR mutation status, fibrosis grade, sex, and karyotype alongside clinical variables, providing the most refined prognostic discrimination for transplant-eligible patients. Two or more HMR mutations identify the highest-risk molecular group, where early referral for allogeneic SCT is strongly recommended.

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Treatment: Symptom Management and JAK Inhibitors

Treatment of PMF is stratified by risk and symptom burden. For intermediate-2 or high-risk patients, or symptomatic intermediate-1 patients, JAK inhibitor therapy is the current standard. Four JAK inhibitors are now FDA-approved for PMF, each occupying a distinct clinical niche.

Ruxolitinib (Jakafi) — JAK1/2 Inhibitor

Ruxolitinib was FDA-approved in 2011 following the landmark COMFORT-I (vs. placebo) and COMFORT-II (vs. best available therapy) trials. It remains the first-line JAK inhibitor for most patients:

• Efficacy: ≥35% spleen volume reduction achieved in ~42% of patients; symptom response (MPN-SAF TSS reduction ≥50%) in ~46%; improved overall survival in COMFORT-I and COMFORT-II.
• Dosing: 15–20 mg twice daily based on platelet count; reduce for thrombocytopenia.
• Side effects: Anemia (most common; usually manageable, often improves over 12 weeks), thrombocytopenia, opportunistic infections (PCP prophylaxis with trimethoprim-sulfamethoxazole is recommended), increased cholesterol, reactivation of herpes zoster. Abrupt discontinuation causes "ruxolitinib withdrawal syndrome" — rapid return of symptoms and splenomegaly.
• Limitations: Disease-modifying but not curative; responses typically plateau or wane after 2–3 years.

Fedratinib (Inrebic) — Selective JAK2 Inhibitor

Fedratinib was FDA-approved in 2019 for intermediate-2 or high-risk PMF, including for patients after ruxolitinib failure (second-line). The JAKARTA trial demonstrated significant spleen volume reduction and symptom improvement. A critical safety concern is Wernicke's encephalopathy — a serious neurological complication caused by thiamine (B1) deficiency. Thiamine levels must be assessed before starting treatment and repleted if low; symptoms of encephalopathy require immediate drug discontinuation.

Pacritinib (Vonjo) — JAK2/IRAK1 Inhibitor

Pacritinib received FDA approval in February 2022 specifically for patients with PMF and severe thrombocytopenia (platelet count <50×10&sup9;/L) — a population excluded from or poorly served by other JAK inhibitors. The PERSIST-2 trial demonstrated superior spleen and symptom responses compared with best available therapy (including low-dose ruxolitinib) in this high-risk, hard-to-treat group. Dose: 200 mg twice daily; no dose modification required for thrombocytopenia.

Momelotinib (Ojjaara) — JAK1/2/ACVR1 Inhibitor

Momelotinib, FDA-approved in September 2023, is unique among JAK inhibitors because it also inhibits ACVR1 (Activin A Receptor Type 1), which normally upregulates hepcidin — the master regulator of iron absorption. By suppressing hepcidin, momelotinib allows more iron to be available for erythropoiesis, which:

• Improves anemia independently of its JAK inhibition
• Reduces transfusion dependence
• Addresses a symptom dimension that ruxolitinib worsens

The MOMENTUM trial demonstrated superiority of momelotinib over danazol in previously JAK-inhibitor-treated, symptomatic, anemic PMF patients — with improvements in symptoms, spleen volume, and transfusion independence. Approved for symptomatic, anemic PMF patients (Hgb <10 g/dL), including those previously treated with ruxolitinib.

Supportive and Additional Therapies

• Red blood cell transfusions: For symptomatic anemia; threshold typically Hgb <7–8 g/dL. Chronic transfusion leads to iron overload requiring chelation.
• Erythropoiesis-stimulating agents (ESAs): Modest benefit in early-stage, non-transfusion-dependent patients with low serum EPO levels.
• Luspatercept: Being studied for MF-related anemia; not yet standard of care for PMF.
• Hydroxyurea: For leukocytosis or splenomegaly when JAK inhibitors are unavailable; cytoreductive but not a JAK pathway agent.
• Splenic irradiation: Rare; reserved for patients who cannot tolerate surgery or JAK inhibitors; responses are short-lived and marrow suppression is significant.
• Splenectomy: Considered in selected patients with refractory massive splenomegaly, severe cytopenias, or portal hypertension; carries significant surgical risk (30-day mortality 5–10%) in this patient population.
• Clinical trials: Navitoclax (BCL-XL/BCL-2 inhibitor) in combination with ruxolitinib has shown promising responses in ruxolitinib-refractory PMF (TRANSFORM-1 trial); imetelstat (telomerase inhibitor) showed disease-modifying activity in the IMbark and IMpactMF trials.

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Allogeneic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the only treatment with curative potential in PMF. However, it carries significant risks and is reserved for patients with intermediate-2 or high-risk disease (or intermediate-1 with adverse features) who are fit enough to tolerate the procedure.

Outcomes and Efficacy

• 5-year overall survival: Approximately 35–40% with reduced-intensity conditioning (RIC) regimens in modern series; higher with favorable donor match and lower disease burden at transplant.
• Non-relapse mortality (NRM): 15–25% at 1 year; driven by graft-versus-host disease (GvHD), infections, and organ toxicity.
• Relapse rate: ~20–30% at 5 years; chronic GvHD has a graft-versus-myelofibrosis effect that reduces relapse risk.

Patient Selection and Timing

• Indications: DIPSS intermediate-2 or high-risk; DIPSS intermediate-1 with HMR mutations (≥2), rapid spleen progression, transfusion dependence, or adverse karyotype; blast phase PMF (accelerated/blastic transformation).
• Optimal timing: Before blast transformation (>10% blasts), which dramatically worsens post-transplant outcomes. Early referral for transplant evaluation is critical for eligible patients.
• Age: RIC regimens have extended eligibility to patients up to age 70–75 with good performance status; myeloablative conditioning (MAC) is preferred for younger, fit patients with high-risk disease.

Transplant Procedure Considerations

• Graft source: Matched sibling donor (MSD) is preferred; 10/10 HLA-matched unrelated donor (MUD) is equivalent; haploidentical transplant is an option when no fully matched donor is available.
• Pre-transplant cytoreduction: Ruxolitinib therapy for 3–6 months before transplant reduces spleen size and constitutional symptoms, improving engraftment conditions and reducing the risk of splenic complications during conditioning. However, ruxolitinib must be tapered carefully before conditioning to avoid withdrawal syndrome.
• Graft failure: Higher rates than in other hematologic malignancies due to marrow fibrosis impairing engraftment; close monitoring of chimerism in the early post-transplant period is essential.
• Post-transplant monitoring: JAK inhibitor use post-transplant for relapse prevention is being actively studied in clinical trials but is not yet established practice. Ruxolitinib has been used in some centers for post-transplant relapse.

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Research Papers

The following PubMed links point to key peer-reviewed publications on primary myelofibrosis. Each link opens the specific article record.

• Verstovsek et al. (2012) COMFORT-I ruxolitinib vs. placebo — PMID 22236222
• Harrison et al. (2012) COMFORT-II ruxolitinib vs. BAT — PMID 22739776
• Guglielmelli et al. (2014) HMR mutations and MIPSS in PMF — PMID 24981197
• Klampfl et al. (2013) CALR mutations in MPNs — PMID 24325356
• Tefferi et al. (2014) CALR vs. JAK2 PMF outcomes — PMID 24369076
• Passamonti et al. (2010) Dynamic IPSS (DIPSS) for MF — PMID 20813947
• Gangat et al. (2011) DIPSS-Plus prognostic model — PMID 21109498
• Pardanani et al. (2022) Pacritinib PERSIST-2 thrombocytopenic MF — PMID 35050273
• Verstovsek et al. (2023) Momelotinib MOMENTUM trial — PMID 36881073
• Gupta et al. (2019) Fedratinib JAKARTA trial — PMID 31167593
• Kröger et al. (2015) Allogeneic SCT in myelofibrosis — PMID 25721093
• Tefferi & Barbui (2019) ELN recommendations for ET, PV, MF — PMID 31067882

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Connections

• Polycythemia Vera
• Essential Thrombocythemia
• Myelodysplastic Syndrome
• Acute Myeloid Leukemia
• Anemia
• Thrombocytopenia
• Hemochromatosis
• Deep Vein Thrombosis
• Disseminated Intravascular Coagulation
• Complete Blood Count
• Fatigue
• Iron

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