Primary myelofibrosis
Description
- MPN with clonal megakaryocyte + granulocyte proliferation -> reactive marrow fibrosis -> marrow failure + extramedullary haematopoiesis
- The fibrosis is polyclonal and reactive - fibroblasts responding to cytokines from the clone. Not part of the malignant clone, which is why it can regress on effective therapy
Forms
| Prefibrotic PMF (pre-PMF) | Grade 0-1 fibrosis, thrombocytosis, near-normal counts. *Mistaken for ET* - but worse survival and higher transformation |
| Overt PMF | Grade 2-3 fibrosis, cytopenias, splenomegaly, constitutional symptoms |
| Secondary MF | Post-PV MF, post-ET MF. Same phenotype, different prognostic score (MYSEC-PM) |
The clinical triad
- Constitutional symptoms - weight loss, drenching night sweats, fever, fatigue, bone pain, pruritus
- Massive splenomegaly - early satiety, LUQ pain, splenic infarct
- Cytopenias - anaemia is near-universal and dominates management
Epidemiology
- Incidence ~0.5-1.5 per 100,000/yr - the rarest of the classic MPNs
- Median age at diagnosis ~65-70; <10% under 45
- M slightly > F
- Shortest survival of any MPN
Aetiopathogenesis
Driver mutations - all converge on constitutive JAK-STAT activation
| Frequency | Prognosis | |
|---|---|---|
| JAK2 V617F | ~50-60% | Intermediate |
| CALR | ~25-35% | *Type 1 (52-bp deletion) is the most favourable driver* |
| MPL (W515) | ~5-8% | Intermediate |
| Triple negative | ~10% | Worst |
- High molecular risk (HMR) mutations - added on NGS, and they change the score, not the diagnosis
- *ASXL1, EZH2, SRSF2, IDH1/2, U2AF1 Q157 - >=2 HMR mutations is the highest-risk molecular group*
From clone to fibrosis
- Clonal, dysplastic megakaryocytes release TGF-beta, PDGF, bFGF, VEGF
- -> polyclonal fibroblast activation -> reticulin then collagen deposition
- -> osteosclerosis, neoangiogenesis
- Marrow architecture destroyed -> haematopoiesis relocates to spleen and liver = extramedullary haematopoiesis
- -> massive splenomegaly, hepatomegaly, leucoerythroblastic blood film
- Can occur anywhere: paraspinal (cord compression), pleura, peritoneum, lymph node, skin
- Inflammatory cytokines (TNF-alpha, IL-6, IL-8) -> constitutional symptoms and cachexia
- These, not the fibrosis, are what JAK inhibitors relieve within weeks
- Aberrant CD34+ progenitor mobilisation into blood
Diagnosis
WHO criteria - overt PMF: all 3 major + >=1 minor
Major
1. Megakaryocyte proliferation and atypia, with grade 2-3 reticulin and/or collagen fibrosis
2. Exclusion of ET, PV, CML (BCR::ABL1 negative) and MDS
3. JAK2, CALR or MPL mutation - or another clonal marker, or exclusion of reactive fibrosis
Minor (confirmed on 2 consecutive determinations)
- Anaemia not otherwise explained
- Leucocytosis >=11 x10^9/L
- Palpable splenomegaly
- LDH above the ULN
- Leucoerythroblastic blood film
- Prefibrotic PMF: identical except grade 0-1 fibrosis with age-adjusted hypercellularity and granulocytic proliferation
Blood film - the giveaway
- Teardrop cells (dacrocytes) - deformed squeezing past fibrotic sinusoids
- Leucoerythroblastic picture: nucleated red cells + immature granulocytes (myelocytes, metamyelocytes)
- Giant platelets, circulating megakaryocyte fragments, circulating blasts
Marrow
- Aspirate is a dry tap - trephine is mandatory
- Reticulin/collagen grading (0-3, WHO), megakaryocyte clustering with dense, bulbous, hyperchromatic nuclei, dilated sinusoids with intraluminal haematopoiesis, osteosclerosis
- Cytogenetics + NGS myeloid panel (driver + HMR mutations) - both prognostic
Other findings
- inc LDH, inc urate, inc ALP; anaemia, then pancytopenia
- *Always exclude CML - massive splenomegaly + leucocytosis. BCR::ABL1 on every patient*
- Differential for a leucoerythroblastic film: marrow infiltration by carcinoma or lymphoma, miliary TB, severe sepsis, massive haemorrhage, myelophthisis
- Secondary myelofibrosis: MDS, AML with fibrosis, hairy cell leukaemia, systemic mastocytosis, lymphoma, metastatic carcinoma, SLE, HIV, TB, vitamin D deficiency/hyperparathyroidism
Prognostic scores - pick the score for the decision being made
| Use | |
|---|---|
| IPSS | At diagnosis: age >65, constitutional symptoms, Hb <100 g/L, WCC >25 x10^9/L, blasts >=1% |
| DIPSS / DIPSS-plus | Dynamic, any time. DIPSS-plus adds platelets <100, transfusion dependence, unfavourable karyotype |
| MIPSS70 / MIPSS70+ v2.0 | Transplant-age patients (<=70) - adds HMR mutations and absence of type 1 CALR |
| GIPSS | Genetics only - karyotype + mutations |
| MYSEC-PM | Post-PV and post-ET MF - do not use DIPSS in secondary MF |
Management
Axis: risk score decides transplant; the dominant clinical problem decides everything else.
Step 1 - Is this patient a transplant candidate?
- Allogeneic SCT is the only curative therapy
- Consider in intermediate-2 or high risk, and in intermediate-1 with high-risk molecular features (>=2 HMR, ASXL1, triple-negative) or transfusion dependence
- Broadly age <70 and fit - biological rather than chronological age
- Refer early and in parallel with starting a JAK inhibitor - JAK inhibition shrinks the spleen and improves performance status before transplant, and should be tapered rather than stopped abruptly at conditioning
- TRM 10-30%; graft failure higher with massive splenomegaly
Step 2 - Dominant problem = symptomatic splenomegaly / constitutional symptoms
Choose the JAK inhibitor by the platelet count and the haemoglobin
| Agent | Choose it when | Watch |
|---|---|---|
| Ruxolitinib (JAK1/2) | Default. Platelets >50 | Anaemia and thrombocytopenia (dose-limiting), reactivation: HZV, HBV, TB, non-melanoma skin cancer |
| Fedratinib (JAK2/FLT3) | After ruxolitinib failure or intolerance | *Wernicke encephalopathy - check and replace thiamine before and during*; GI toxicity |
| Pacritinib (JAK2/IRAK1) | Platelets <50 - the reason it exists. No dose reduction needed | GI toxicity, bleeding |
| Momelotinib (JAK1/2 + ACVR1/ALK2) | Anaemic or transfusion-dependent | Peripheral neuropathy. ALK2 inhibition -> dec hepcidin -> improves anaemia while also reducing spleen and symptoms |
- Ruxolitinib: spleen and symptom response in weeks, survival benefit vs placebo/best available therapy (COMFORT-I/II), and reduces transfusion need in responders
- *Never stop a JAK inhibitor abruptly - cytokine rebound / withdrawal syndrome*: fever, rapid splenic re-enlargement, haemodynamic collapse. Taper
- Emerging combinations (BET inhibitors, BCL-xL inhibitors, MDM2 inhibitors added to ruxolitinib) remain trial-based
Step 3 - Dominant problem = anaemia
- Momelotinib if a JAK inhibitor is also indicated
- ESA if erythropoietin <500 IU/L and not transfusion-dependent (ineffective, and may enlarge the spleen, if EPO is already high)
- Danazol 600 mg/day - monitor LFTs, PSA
- Luspatercept for transfusion-dependent anaemia, particularly on a JAK inhibitor
- Immunomodulators (thalidomide/lenalidomide + prednisolone) - especially with del(5q)
- Transfusion + iron chelation once heavily transfused
Step 4 - Lower-risk, minimally symptomatic
- Observation is correct - no therapy alters natural history except transplant
- Hydroxyurea for symptomatic proliferative disease (leucocytosis, thrombocytosis, painful splenomegaly) but it worsens anaemia
- Aspirin in prefibrotic PMF with thrombocytosis or vascular risk, as in ET
- Allopurinol for hyperuricaemia
Refractory splenomegaly
- Splenectomy - high morbidity: portal vein thrombosis, post-splenectomy hepatomegaly, accelerated blastic transformation. Last resort
- Splenic irradiation - short-lived benefit, severe cytopenias
- TIPS for symptomatic portal hypertension
Associations
- Post-polycythaemia vera and post-essential thrombocythaemia MF - the same disease arrived at differently
- Portal hypertension - inc splenic blood flow + intrahepatic obstruction by extramedullary haematopoiesis; variceal bleeding, ascites
- Budd-Chiari and splanchnic vein thrombosis - check JAK2 V617F in any unexplained abdominal vein thrombosis
- Pulmonary hypertension from pulmonary extramedullary haematopoiesis
- Gout and urate nephropathy
- Acquired von Willebrand disease with extreme thrombocytosis
- Osteosclerosis, periostitis, bone pain
- Cachexia, malnutrition
- Prior benzene or ionising radiation exposure
Natural history & complications
- Median survival ~5-7 years overall, but the range across risk groups is enormous: >15 years (low risk) to ~1.5-2 years (high risk)
- Leukaemic transformation ~10-20% at 10 years - blast phase, median survival <6 months, rarely salvageable except by transplant
- Higher with prior cytotoxic therapy, >=2 HMR mutations, ASXL1, unfavourable karyotype, circulating blasts
Causes of death
- Leukaemic transformation, infection, bleeding, thrombosis, portal hypertension, cardiac failure, cachexia
Adverse prognostic markers
- Age >65, constitutional symptoms
- Hb <100 g/L, transfusion dependence, platelets <100, WCC >25, circulating blasts >=1-2%
- Unfavourable karyotype (complex, +8, -7/7q-, i(17q), 12p-, 11q23)
- >=2 HMR mutations; triple-negative genotype
- Type 1 CALR is protective
Monitor
- FBE + film, LDH, urate; spleen size clinically
- Symptom burden with MPN-SAF TSS - drives the decision to start or switch a JAK inhibitor
- Repeat marrow/NGS if counts shift or blasts appear - transformation
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