Blood & Lymphoreticular

Primary myelofibrosis: management overview

Clinical Overview and When to Suspect Primary Myelofibrosis

— JAK2 V617F (~50–60%)

— CALR exon 9 (~20–25%) — best prognosis

— MPL W515 (~5–10%)

— "Triple negative" (~10%) — worst prognosis, higher leukemic risk

— Older adult with fatigue, weight loss, drenching night sweats, early satiety, left upper quadrant fullness

— Massive splenomegaly on exam, often crossing the midline

— Anemia + abnormal CBC with teardrop RBCs (dacrocytes) and a leukoerythroblastic smear (nucleated RBCs + immature myeloid forms)

— Unexplained elevated LDH, hyperuricemia, or marrow aspirate yielding a "dry tap"

— Prefibrotic/early PMF — thrombocytosis, mild anemia; often misdiagnosed as essential thrombocythemia (ET)

— Overt fibrotic PMF — cytopenias, marked splenomegaly, constitutional symptoms

Board pearl: The triad of leukoerythroblastic smear + teardrop cells + splenomegaly in an older adult is PMF until proven otherwise — order a JAK2 mutation panel and refer to hematology before pursuing marrow biopsy yourself.

Primary myelofibrosis (PMF) is a BCR-ABL–negative myeloproliferative neoplasm (MPN) characterized by clonal stem cell proliferation, bone marrow fibrosis, extramedullary hematopoiesis, and a leukoerythroblastic blood picture.

Driver mutations (mutually exclusive in ~90%):

Median age at diagnosis ~65; uncommon under 50. Median survival ranges from <2 years (high risk) to >10 years (low risk).

When to suspect on Step 3:

Disease spectrum:

Common Step 3 framing: chronic ambulatory workup of macrocytic or normocytic anemia + splenomegaly in an older patient, often discovered after a routine CBC during a Medicare wellness visit.

Secondary (post-PV, post-ET) myelofibrosis is managed similarly but staged differently (MYSEC-PM score).

Presentation Patterns and Key History

— Constitutional/cytokine-driven: fatigue (most common), night sweats, low-grade fever, unintentional weight loss >10%, pruritus (especially post-bath aquagenic if post-PV MF), bone pain

— Splenomegaly-driven: LUQ discomfort, early satiety, postprandial bloating, weight loss from reduced intake, referred left shoulder pain (splenic infarct)

— Cytopenia-driven: dyspnea on exertion and pallor (anemia), mucocutaneous bleeding (thrombocytopenia), recurrent infections (neutropenia or dysfunctional granulocytes)

— Thrombohemorrhagic: DVT/PE, portal/splenic/hepatic vein thrombosis, stroke, MI; paradoxically also bleeding from acquired von Willebrand syndrome with extreme thrombocytosis

— Duration and trajectory of fatigue, weight loss, sweats

— Bleeding/bruising, prior thrombosis, pregnancy losses

— Bone pain (sternum, long bones) — fibrosis and marrow expansion

— Prior CBCs — look for years of unexplained thrombocytosis or erythrocytosis (suggests prior ET/PV)

— Family history of MPN, lymphoma, or unexplained thrombosis

— Medication history — rule out drug-induced cytopenias and prior cytotoxic exposure (post-therapy MDS mimic)

Step 3 management: When a patient with suspected PMF reports a new unilateral leg swelling or RUQ pain, immediately evaluate for DVT and splanchnic vein thrombosis (Budd-Chiari, portal vein thrombosis) — these are the classic Step 3 vignettes that "unmask" an underlying MPN, so check JAK2 V617F even when imaging is your first move.

Up to 30% are asymptomatic at diagnosis, found on incidental CBC abnormalities during outpatient screening or preoperative labs.

Symptomatic presentations cluster into four buckets:

Key history elements to elicit (Step 3 ambulatory style):

MPN-10 (MPN Symptom Assessment Form Total Symptom Score) — a validated 10-item PRO tool quantifying symptom burden; used at every follow-up visit to guide JAK inhibitor initiation and dose adjustment.

Physical Exam Findings (and Hemodynamic Assessment)

— Cachexia, temporal wasting in advanced disease

— Pallor (anemia), occasional jaundice (hemolysis or extramedullary hematopoiesis in liver)

— Petechiae, ecchymoses if thrombocytopenic or qualitatively dysfunctional platelets

— Splenomegaly in 80–90%; often massive (palpable >10 cm below costal margin, sometimes crossing midline to right iliac fossa)

— Splenic rub if recent infarct; tenderness suggests infarct or perisplenitis

— Hepatomegaly in ~40–70% from extramedullary hematopoiesis

— Ascites and dilated abdominal veins if portal hypertension from splanchnic thrombosis or sinusoidal infiltration

— Resting tachycardia from anemia or cytokine storm

— Wide pulse pressure with severe anemia

— Signs of high-output heart failure in chronically transfusion-dependent patients (S3, JVD, lower extremity edema)

— Pulmonary hypertension (loud P2, RV heave) — under-recognized PMF complication from extramedullary hematopoiesis in lung and chronic inflammation

— Paraspinal masses → cord compression (neurologic deficits, urgent MRI)

— Pleural/pericardial effusions

— Skin nodules ("leukemia cutis" mimic)

Key distinction: Massive splenomegaly narrows the differential dramatically — PMF, CML, hairy cell leukemia, splenic marginal zone lymphoma, Gaucher disease, visceral leishmaniasis. Absence of lymphadenopathy and presence of teardrop cells favor PMF; a high WBC with basophilia and the Philadelphia chromosome would point to CML instead.

General appearance:

Abdominal exam — the centerpiece:

Lymphadenopathy is uncommon — its presence should prompt consideration of lymphoma or transformation; pursue biopsy.

Hemodynamic and cardiopulmonary assessment:

Extramedullary hematopoiesis (EMH) findings:

Functional/frailty assessment — ECOG performance status drives transplant eligibility and ruxolitinib dosing tolerance.

Diagnostic Workup — Initial Labs, Imaging, and Biomarkers

— Anemia (normocytic to macrocytic) in most; can be severe

— WBC variable — leukocytosis early, leukopenia late

— Platelets variable — thrombocytosis early (prefibrotic), thrombocytopenia in advanced disease (poor prognosis if <100k)

— Smear: teardrop RBCs (dacrocytes), nucleated RBCs, immature granulocytes (myelocytes, metamyelocytes) = leukoerythroblastic picture; giant/dysmorphic platelets

— LDH elevated (ineffective hematopoiesis, cell turnover)

— Uric acid elevated, hyperkalemia possible

— Alkaline phosphatase elevated if hepatic EMH

— Low haptoglobin, indirect hyperbilirubinemia if hemolytic component

— Erythropoietin (EPO) level — informs anemia therapy (low EPO <500 → ESA candidate)

— Abdominal ultrasound or CT to quantify spleen length and rule out splanchnic vein thrombosis

— Baseline chest imaging if pulmonary symptoms (rule out EMH, pulmonary hypertension)

— Echocardiogram if dyspnea — assess RV pressure and ejection fraction baseline before ruxolitinib

Board pearl: A "dry tap" on bone marrow aspiration is a classic clue — order a marrow core biopsy with reticulin and trichrome stains to grade fibrosis (MF-0 through MF-3) rather than re-attempting aspirate.

CBC with differential and peripheral smear — the highest-yield initial test:

Chemistries and biomarkers:

Iron studies, B12, folate, TSH, reticulocyte count, DAT — rule out reversible anemia contributors before attributing to PMF.

HIV, hepatitis B/C panel — required before immunosuppressive or JAK inhibitor therapy.

Coagulation: PT/PTT, fibrinogen; consider VWF activity/antigen ratio if extreme thrombocytosis (acquired VWD).

Imaging:

ECG baseline — many MPN patients are older with CAD comorbidity; QT baseline matters for future antifungal/antiemetic use.

Diagnostic Workup — Advanced and Confirmatory Studies

— Hypercellular early, then progressively fibrotic with reticulin/collagen fibrosis (MF-2 or MF-3)

— Atypical megakaryocytic proliferation with clustering, hyperchromatic and bulbous nuclei — pathognomonic feature

— Increased CD34+ cells, dilated sinusoids with intrasinusoidal hematopoiesis

— Osteosclerosis in advanced disease

— JAK2 V617F PCR/allele-specific assay

— If negative → CALR exon 9, MPL W515 mutation analysis

— BCR-ABL1 RT-PCR — must exclude CML (mandatory per WHO criteria)

— Next-generation sequencing (NGS) myeloid panel for high-molecular-risk (HMR) mutations: ASXL1, EZH2, SRSF2, IDH1/2, U2AF1 Q157 — drive MIPSS70/MIPSS70+ v2.0 scores

— Major: megakaryocytic proliferation/atypia with reticulin and/or collagen fibrosis (grade 2–3); exclusion of other MPNs, MDS, and reactive causes; demonstration of JAK2/CALR/MPL — or another clonal marker, or absence of reactive fibrosis

— Minor: anemia, leukocytosis ≥11k, palpable splenomegaly, LDH elevation, leukoerythroblastosis

Step 3 management: Once PMF is confirmed, immediately calculate DIPSS-Plus or MIPSS70+ v2.0 — these scores determine whether to observe, start ruxolitinib, or refer for transplant evaluation. Don't simply "treat the spleen" without staging.

Bone marrow biopsy is mandatory for diagnosis and risk stratification:

Molecular testing (order on peripheral blood):

Cytogenetics on marrow — unfavorable karyotypes (complex, +8, −7/7q−, i(17q), inv(3), −5/5q−, 12p−, 11q23) worsen prognosis (MIPSS70+).

WHO 2022 diagnostic criteria (must meet all 3 major + ≥1 minor):

HLA typing early in fit candidates (<70, good performance status) — allogeneic HSCT is the only curative therapy.

Risk Stratification and First-Line Management Logic

— IPSS — at diagnosis only; 5 variables (age >65, constitutional symptoms, Hb <10, WBC >25k, blasts ≥1%)

— DIPSS — dynamic, applied any time during disease course

— DIPSS-Plus — adds platelets <100k, RBC transfusion dependence, unfavorable karyotype

— MIPSS70 / MIPSS70+ v2.0 — incorporates HMR mutations and CALR type 1 status; preferred in transplant-eligible patients

— Low / asymptomatic intermediate-1: observation with serial CBCs every 3–6 months; treat thrombosis risk and anemia as they arise

— Symptomatic intermediate-1 (splenomegaly, constitutional symptoms): ruxolitinib (JAK1/2 inhibitor) first-line

— Intermediate-2 / high risk in transplant-eligible patients (<70, ECOG 0–1, adequate organ function): evaluate for allogeneic HSCT — the only curative option

— Intermediate-2 / high risk, transplant ineligible: JAK inhibitor (ruxolitinib, fedratinib, pacritinib, momelotinib depending on cytopenias)

— Spleen >5 cm below costal margin or symptomatic

— MPN-10 total symptom score ≥20

— Constitutional symptoms refractory to supportive care

Board pearl: Transplant is the only curative therapy — every newly diagnosed PMF patient under 70 with intermediate-2 or high risk should be referred for HLA typing and transplant consultation early, before performance status declines.

Risk stratification tools (know at least one for boards):

Four risk categories: low, intermediate-1, intermediate-2, high. Median survival ranges from >15 years (low) to <2 years (high).

Management algorithm based on risk and symptoms:

Symptom-driven triggers for JAK inhibitor initiation:

Anemia-predominant disease: consider momelotinib (also inhibits ACVR1 → reduces hepcidin → improves anemia) or anemia-directed therapy (ESA if EPO <500, danazol, luspatercept, lenalidomide ± prednisone if del(5q)).

Pharmacotherapy — First-Line Drug Regimens

— Dose by baseline platelet count: 20 mg BID if plt >200k; 15 mg BID if 100–200k; 5 mg BID if 50–100k

— Reduces spleen volume ≥35% in ~40% (COMFORT-I/II), improves symptoms, prolongs survival

— Adverse effects: dose-dependent anemia and thrombocytopenia (early, often improves), opportunistic infections (HSV, VZV reactivation, TB, PML, cryptococcus, hepatitis B reactivation), nonmelanoma skin cancers, weight gain, lipid changes

— Never stop abruptly — risk of ruxolitinib withdrawal syndrome (cytokine rebound, SIRS-like presentation); taper over 1–2 weeks with steroid coverage

— Black box warning: Wernicke encephalopathy — check and supplement thiamine before and during therapy

— Anemia: ESA if EPO <500 mU/mL; danazol 600 mg/day (monitor LFTs, virilization); luspatercept; transfusion with iron chelation if dependent

— Symptomatic thrombocytosis or extreme leukocytosis: hydroxyurea (also for splenomegaly in low-risk patients)

— Hyperuricemia: allopurinol prophylaxis when starting cytoreduction

— Pruritus: antihistamines, SSRIs, ruxolitinib itself effective

Step 3 management: Before starting ruxolitinib, screen for latent TB (IGRA), HBV (HBsAg, anti-HBc), HCV, and HIV, vaccinate against zoster (recombinant), pneumococcus, and influenza, and counsel on infection precautions — this is a frequent Step 3 ambulatory safety checkpoint.

Ruxolitinib (JAK1/2 inhibitor) — first-line for symptomatic splenomegaly and constitutional symptoms:

Fedratinib (JAK2/FLT3 inhibitor) — second-line after ruxolitinib failure or intolerance; 400 mg daily

Pacritinib (JAK2/IRAK1 inhibitor) — preferred when platelets <50k; 200 mg BID; doesn't worsen thrombocytopenia

Momelotinib (JAK1/2/ACVR1 inhibitor) — preferred when anemia is dominant; 200 mg daily; reduces transfusion burden

Adjunctive supportive therapy:

Allogeneic HSCT and Splenic Procedures

— Candidates: intermediate-2/high-risk by DIPSS-Plus or MIPSS70+, age typically <70, ECOG 0–1, adequate cardiac/pulmonary/hepatic/renal function, available HLA-matched donor

— Pre-transplant optimization: ruxolitinib for 2–3 months to reduce spleen size (improves engraftment); taper but don't abruptly stop pre-conditioning

— Conditioning: reduced-intensity (RIC) preferred in older fit patients (fludarabine/busulfan or fludarabine/melphalan)

— 5-year overall survival: 30–65% depending on risk and donor match

— Complications: graft failure (higher with massive splenomegaly), acute/chronic GVHD, infection, relapse, transplant-related mortality 10–30%

— Symptomatic massive splenomegaly refractory to JAK inhibitors

— Transfusion-dependent anemia attributed to splenic sequestration

— Symptomatic portal hypertension

— Mortality 5–10%, morbidity 30–50% (bleeding, thrombosis, infection, post-splenectomy hepatomegaly)

— Pre-op: vaccinate against encapsulated organisms (pneumococcus, meningococcus ACWY and B, Hib) at least 2 weeks prior; lifelong penicillin prophylaxis often recommended

CCS pearl: For a Step 3 CCS case of PMF with new ascites and abdominal pain, order abdominal Doppler ultrasound first to evaluate for Budd-Chiari syndrome or portal vein thrombosis, then anticoagulate and consult hepatology/hematology.

Allogeneic hematopoietic stem cell transplant (allo-HSCT) — the only curative therapy:

Splenectomy — considered when:

Splenic irradiation — palliative; transient response (3–6 months); risk of severe pancytopenia

Transjugular intrahepatic portosystemic shunt (TIPS) — for portal hypertension from splanchnic thrombosis with refractory variceal bleeding or ascites

Anticoagulation for splanchnic vein thrombosis — indefinite, typically warfarin or DOAC after acute LMWH bridge; lifelong if underlying MPN persists.

Special Populations — Elderly and Renal/Hepatic Impairment

— Comprise the majority of PMF patients; assess frailty (e.g., Karnofsky, geriatric assessment) before any cytoreduction

— Transplant rarely offered above 75; focus on symptom control and quality of life

— Higher risk of ruxolitinib-related infections — emphasize zoster vaccination (recombinant only — never live vaccines on JAK inhibitor), pneumococcal series

— Polypharmacy review for CYP3A4 interactions (ruxolitinib metabolized by CYP3A4)

— Falls risk from anemia and orthostasis — careful titration

— Ruxolitinib: if CrCl 15–60 mL/min and platelets 50–150k, start at lower dose (5 mg BID); avoid in ESRD on dialysis unless platelets >200k (then 10 mg post-dialysis only)

— Fedratinib: reduce to 200 mg daily if CrCl 15–29 mL/min

— Pacritinib: no dose adjustment for mild-moderate renal impairment

— Allopurinol dose-adjust; avoid NSAIDs given bleeding and renal risks

— Ruxolitinib: any hepatic impairment → start at 5 mg BID and titrate carefully

— Fedratinib: avoid in severe hepatic impairment (Child-Pugh C)

— Hepatic EMH and portal hypertension complicate dosing — frequent LFT monitoring

— Strong CYP3A4 inhibitors (clarithromycin, ketoconazole, ritonavir) → reduce ruxolitinib to 10 mg BID

— Strong CYP3A4 inducers (rifampin, phenytoin) → consider alternative

— Concomitant fluconazole moderate/strong: dose modify

Step 3 management: Before adding any new antimicrobial or antifungal to a PMF patient on ruxolitinib, explicitly screen for CYP3A4 interactions — this is exactly the kind of medication reconciliation Step 3 tests at care transitions (e.g., hospital discharge to PCP).

Elderly (>75) considerations:

Renal impairment:

Hepatic impairment:

Drug interactions of clinical importance:

Special Populations — Pregnancy and Younger Patients

— First-trimester loss (25–40%), IUGR, preeclampsia, placental abruption, preterm delivery

— Maternal thrombosis (DVT, splanchnic, stroke) — peripartum highest risk

— Postpartum hemorrhage if thrombocytopenic or acquired VWD

— Discontinue ruxolitinib, fedratinib, hydroxyurea preconception (teratogenic/embryotoxic)

— Interferon alfa (peg-IFN-α-2a) is the preferred cytoreductive in pregnancy — not teratogenic, crosses placenta minimally

— Aspirin 81 mg daily throughout pregnancy (especially JAK2-positive) for thrombosis prevention

— LMWH prophylaxis during pregnancy and 6 weeks postpartum in high-risk women (prior thrombosis, severe thrombocytosis, JAK2 mutation)

— Avoid combined oral contraceptives postpartum (thrombosis risk)

— Aggressively pursue transplant eligibility — best long-term outcomes

— Fertility preservation counseling before alkylator exposure or conditioning

— Genetic counseling — most PMF is sporadic but family clustering of MPNs exists (germline JAK2 46/1 haplotype, RBBP6, others)

Board pearl: A pregnant patient with JAK2-positive PMF on hydroxyurea presents at 8 weeks — stop hydroxyurea immediately, start aspirin 81 mg, and if cytoreduction needed, transition to pegylated interferon-α. This swap is a recurring Step 3 stem.

PMF in reproductive-age women is uncommon (<10% of cases) but does occur — more often the prefibrotic form or post-ET MF.

Pregnancy risks:

Pregnancy management (multidisciplinary: hematology + MFM):

Younger PMF patients (<50):

Pediatric PMF is rare — consider germline predisposition, GATA2 deficiency, or familial MPN syndromes; refer to pediatric hematology.

Complications and Adverse Outcomes

— Progressive pancytopenia with transfusion dependence and iron overload

— Leukemic transformation (blast phase, ≥20% blasts) — occurs in 10–20%; median survival 3–6 months; outcomes poor even with induction chemotherapy

— Severe bleeding from thrombocytopenia or acquired VWD

— Arterial (stroke, MI, peripheral arterial) and venous (DVT/PE)

— Splanchnic vein thrombosis (portal, splenic, hepatic/Budd-Chiari) — sometimes presenting feature

— Risk drivers: JAK2 V617F, age >60, prior thrombosis, leukocytosis >11k

— Spinal cord compression (paraspinal EMH) — neurosurgical emergency

— Pleural/pericardial effusions

— Renal/ureteral obstruction

Key distinction: Sudden worsening of cytopenias with new circulating blasts and rising LDH in a known PMF patient = leukemic transformation — recheck peripheral blood blasts, repeat marrow biopsy, and arrange urgent hematology referral; this is not "disease progression" to be observed.

Hematologic complications:

Thrombotic complications:

Infections — neutropenia, dysfunctional immunity, JAK inhibitor immunosuppression; HSV/VZV reactivation, TB, fungal, HBV reactivation

Portal hypertension — from splanchnic thrombosis or sinusoidal hepatic EMH → ascites, varices, hepatic encephalopathy

Pulmonary hypertension — under-recognized; consider with progressive dyspnea

Extramedullary hematopoiesis (EMH) complications:

Cachexia and protein-calorie malnutrition — high cytokine burden

Iron overload from chronic transfusion (>20 units RBCs) — start chelation (deferasirox) when ferritin >1000 ng/mL in long-life-expectancy patients

Secondary malignancies: nonmelanoma skin cancer (especially on ruxolitinib) — annual dermatologic exam recommended.

Treatment-related complications: ruxolitinib withdrawal syndrome, fedratinib Wernicke encephalopathy, transplant-related GVHD/infections, post-splenectomy sepsis.

When to Escalate Care — ICU, Consult, and Inpatient Triage

— Suspected splanchnic vein thrombosis (acute abdominal pain, ascites, new LFT derangement)

— New focal neurologic deficits — stroke or paraspinal EMH cord compression

— Hemodynamic instability from GI bleed in setting of varices or thrombocytopenia

— Splenic infarct or rupture — severe LUQ pain, hypotension, free fluid on FAST

— Febrile neutropenia — ANC <500 with T ≥38.3°C or sustained ≥38°C

— Suspected leukemic transformation with circulating blasts and metabolic derangement

— Tumor lysis syndrome after cytoreduction initiation (rare but described)

— Septic shock — common with post-splenectomy patients and JAK inhibitor users

— Massive bleeding requiring massive transfusion protocol

— Acute respiratory failure from pulmonary EMH, hemorrhage, or pneumonia

— Ruxolitinib withdrawal syndrome with multi-organ failure (cytokine storm-like)

— Hematology — at diagnosis and at every major decision point (risk reassessment, transplant timing, transformation)

— Transplant team — for any intermediate-2/high-risk patient under 70

— Interventional radiology — TIPS for portal hypertension complications

— Hepatology — for splanchnic thrombosis, portal hypertension management

— Palliative care — early integration in high-risk disease, transplant-ineligible patients

— Pulmonology/cardiology — pulmonary hypertension workup

CCS pearl: For a PMF patient admitted with febrile neutropenia, immediately obtain blood cultures × 2, lactate, CXR, UA, then start empiric cefepime (or pip-tazo); hold ruxolitinib until source controlled to avoid cytokine rebound — but plan to resume to prevent withdrawal syndrome.

Immediate ED/inpatient triage triggers:

ICU criteria:

Specialty consultations:

Step 3 transitions: at hospital discharge, ensure clear handoff regarding JAK inhibitor continuation, taper plans, vaccination status, anticoagulation duration, and next hematology appointment within 1–2 weeks.

Key Differentials — Same-Category MPNs and Marrow Disorders

— Massive splenomegaly, leukocytosis with left shift and basophilia/eosinophilia

— BCR-ABL1 (Philadelphia chromosome) positive — definitional

— Treat with TKI (imatinib, dasatinib, nilotinib); BCR-ABL testing mandatory in PMF workup to exclude

— Erythrocytosis, often pruritus and erythromelalgia, JAK2 V617F+ in 95%

— Can progress to post-PV myelofibrosis (treated like PMF; staged by MYSEC-PM)

— Low EPO, increased RCM

— Persistent thrombocytosis >450k, mild splenomegaly

— Prefibrotic PMF often mistaken for ET — distinguished by megakaryocyte morphology and reticulin grade on biopsy

— JAK2/CALR/MPL mutations overlap

— Cytopenias with dysplasia in ≥2 lineages, ring sideroblasts, blast counts variable

— Cytogenetics: del(5q), −7, complex

— Less megakaryocytic atypia; consider in older patients with cytopenias and modest fibrosis

— CMML — monocytosis >1000/µL, splenomegaly, often elderly

— MDS/MPN-RS-T (refractory anemia with ring sideroblasts and thrombocytosis) — SF3B1 + JAK2

— Atypical CML (BCR-ABL negative) — leukocytosis with dysgranulopoiesis

— Blasts ≥20%; rapid clinical decline; cytopenias

— Distinguish AML arising from PMF (worse prognosis) from de novo AML

Key distinction: JAK2 V617F alone doesn't distinguish PMF, PV, or ET — the diagnosis hinges on bone marrow morphology (megakaryocytic atypia + reticulin/collagen fibrosis grade) plus clinical context. Don't anchor on the molecular result.

Chronic myeloid leukemia (CML):

Polycythemia vera (PV):

Essential thrombocythemia (ET):

Myelodysplastic syndrome (MDS) with fibrosis:

MDS/MPN overlap syndromes:

Acute leukemias (AML, including post-PMF blast phase):

Key Differentials — Non-MPN Causes of Marrow Fibrosis and Splenomegaly

— Metastatic carcinoma (breast, prostate, gastric) infiltrating marrow with desmoplastic reaction

— Lymphomas — hairy cell leukemia (classic massive splenomegaly with dry tap and TRAP+/BRAF V600E+), splenic marginal zone lymphoma

— Multiple myeloma and plasma cell disorders

— Hodgkin lymphoma with marrow involvement

— Granulomatous disease: TB, histoplasmosis, sarcoidosis

— Associated with SLE, autoimmune cytopenias; ANA+, more lymphoid infiltrate, less megakaryocytic atypia

— Often responds to corticosteroids — important reversible mimic

— Benzene, ionizing radiation

— Thrombopoietin receptor agonists (romiplostim, eltrombopag) can cause reversible reticulin fibrosis

— Vitamin D deficiency-related osteomalacia (rare)

— Renal osteodystrophy / secondary hyperparathyroidism — osteosclerosis pattern

— Gray platelet syndrome — congenital, with thrombocytopenia

— PMF, CML, hairy cell leukemia, splenic marginal zone lymphoma, Gaucher disease (lysosomal storage, glucocerebrosidase deficiency), visceral leishmaniasis (kala-azar), chronic malaria, schistosomiasis with portal hypertension, thalassemia major

— Gaucher — bone pain, splenomegaly, thrombocytopenia, "crinkled paper" macrophages on marrow; treat with enzyme replacement

Board pearl: A patient with marrow fibrosis, autoimmune features (positive ANA, Coombs+), and steroid-responsive cytopenias likely has autoimmune myelofibrosis, not PMF — don't commit to JAK inhibitors before excluding this reversible mimic.

Secondary (reactive) myelofibrosis — fibrosis without clonal MPN:

Autoimmune myelofibrosis:

Toxin and drug exposures:

Nutritional/metabolic causes of marrow fibrosis:

Massive splenomegaly differential refresher:

Storage diseases:

Long-Term Plan, Maintenance, and Secondary Prevention

— Disease-modifying therapy (JAK inhibitor, transplant)

— Symptom and complication management

— Thrombosis and infection prevention

— Low-dose aspirin (81 mg daily) for JAK2-positive PMF or any cardiovascular risk factor — unless contraindicated by thrombocytopenia <50k or acquired VWD

— Cytoreduction (hydroxyurea or JAK inhibitor) if leukocytosis >25k or symptomatic thrombocytosis

— Aggressive risk factor modification — BP, lipids, smoking cessation, diabetes control, weight management

— Vaccinations (all inactivated): annual influenza, PCV20 or PCV15→PPSV23, recombinant zoster (especially before/during ruxolitinib), Tdap, COVID-19, RSV in eligible age groups

— Avoid live vaccines (MMR, varicella, yellow fever, live zoster, oral typhoid) while on JAK inhibitor

— Post-splenectomy: lifelong daily penicillin or amoxicillin prophylaxis; emergency antibiotics on hand for febrile illness

— Annual skin exam (nonmelanoma skin cancer risk increased with ruxolitinib)

— Age-appropriate USPSTF screening — colon, breast, cervical, lung

— DEXA periodically (especially if on long-term steroids for symptom control)

— Iron chelation (deferasirox or deferoxamine) when ferritin >1000 ng/mL in patients with reasonable life expectancy

Step 3 management: At every PMF follow-up, run a structured "thrombosis-infection-screening-symptom" checklist: aspirin appropriate? vaccines current? skin exam done? MPN-10 score trend? This systematizes the longitudinal Step 3 ambulatory mindset.

Long-term care framework — three pillars:

Thrombosis prevention:

Infection prevention:

Cancer screening:

Bone health and iron overload:

Anticoagulation duration: indefinite for splanchnic vein thrombosis in PMF; lifelong aspirin for arterial event prevention.

Lifestyle counseling: smoking cessation (huge thrombosis multiplier), moderate exercise, balanced nutrition, hydration, alcohol moderation.

Follow-Up, Monitoring, and Counseling

— Low-risk asymptomatic: every 3–6 months — CBC, smear, symptom assessment, exam

— On JAK inhibitor: CBC weekly × 4, then every 2 weeks × 1 month, then every 4–8 weeks once stable; LFTs and lipids every 3 months

— Pre-transplant: monthly hematology, weekly during conditioning

— Post-transplant: intensive monitoring per transplant center protocol — graft function, GVHD, CMV/EBV PCR, immunosuppression levels

— CBC with differential, peripheral smear review

— Spleen size (palpation and periodic imaging)

— MPN-10 symptom score

— LDH, uric acid, LFTs, renal function

— Transfusion requirement trend, ferritin (every 3 months if transfused)

— Annual marrow biopsy is not routine — repeat only if transformation suspected (new cytopenias, rising blasts, refractory symptoms) or to confirm transplant readiness

— Disease trajectory and prognosis — frank but hopeful, anchored in risk score

— Symptom diary — bleeding, fevers, new pain, weight loss

— Medication adherence — never abruptly stop ruxolitinib; how to handle missed doses

— When to call: fever ≥38°C, new bleeding/bruising, severe abdominal pain, focal neurologic deficits, dyspnea

— Fatigue management — graded exercise, sleep hygiene, nutritional optimization

— Mental health — depression and anxiety prevalent; screen with PHQ-2/GAD-2

— Advance care planning — appropriate in high-risk and transplant-ineligible patients

Board pearl: Increasing transfusion frequency, rising peripheral blasts, or worsening cytopenias on stable JAK inhibitor dose = trigger for repeat bone marrow biopsy to assess for transformation or progression — not a reason to simply increase the JAK inhibitor dose.

Follow-up cadence:

Monitoring parameters at each visit:

Counseling topics:

Rehabilitation/supportive: PT for deconditioning, dietitian for cachexia, social work for transplant logistics and insurance navigation.

Ethical, Legal, and Patient Safety Considerations

— Allogeneic HSCT requires detailed informed consent — TRM 10–30%, GVHD, infertility, secondary malignancies, indefinite immunosuppression; document understanding of curative intent vs. mortality risk

— Ruxolitinib withdrawal syndrome — patients and any covering clinician (hospitalist, surgeon, ED physician) must understand the drug cannot be abruptly stopped; place prominent EHR alerts

— Clinical trial enrollment — many PMF patients are candidates for novel JAK combinations (e.g., navitoclax, pelabresib, selinexor add-ons); ensure non-coercive enrollment

— Hospital discharge: medication reconciliation must include JAK inhibitor dose, anticoagulation, prophylactic antimicrobials, taper schedules

— Perioperative: communicate cytopenia status, bleeding risk, splenomegaly to surgical/anesthesia team; hold/adjust JAK inhibitor per multidisciplinary plan; bridge anticoagulation thoughtfully

— PCP-hematology shared care: clear delineation of who manages CBC trending, vaccinations, and acute symptom escalation

— Medication errors: ruxolitinib dosing varies by platelets — verify at each refill

— Vaccine errors: never administer live vaccines on JAK inhibitor — flag in EHR

— Transfusion safety: leukoreduced, irradiated products in transplant candidates to prevent alloimmunization and TA-GVHD

— Reportable infections (TB reactivation on JAK inhibitor) — notify health department

— Cancer registry reporting per state requirements

— Resource allocation for expensive therapies (ruxolitinib, allogeneic HSCT) — financial toxicity counseling, social work referral

— Goals-of-care discussions in advanced disease — early palliative care integration improves QOL and may extend survival

— Fertility preservation conversations before transplant in young patients — time-sensitive and ethically obligatory

Step 3 management: When a PMF patient on ruxolitinib is admitted for an unrelated reason (e.g., cholecystectomy), the single most important safety step is ensuring ruxolitinib is continued or carefully tapered, never abruptly held — this is a tested patient-safety transition-of-care pitfall.

Informed consent edge cases:

Transitions of care — high-risk handoff points:

Patient safety:

Mandatory reporting and public health:

Ethical issues:

High-Yield Associations and Rapid-Fire Facts

Board pearl: If a stem mentions a 65-year-old with fatigue, massive splenomegaly, teardrop cells, dry tap, JAK2-positive — PMF is the answer; the next-best-step question almost always centers on risk stratification (DIPSS/MIPSS70+) and transplant referral consideration.

Driver mutations and prognosis (best → worst): CALR type 1 > JAK2 V617F > MPL > triple-negative.

High-molecular-risk (HMR) mutations: ASXL1, EZH2, SRSF2, IDH1/2, U2AF1 Q157 → worse OS, higher leukemic risk.

Pathognomonic smear finding: teardrop RBCs (dacrocytes) + leukoerythroblastic picture.

Marrow finding: atypical megakaryocyte clusters with bulbous/hyperchromatic nuclei + reticulin/collagen fibrosis.

Dry tap on aspirate → reflexively order core biopsy with reticulin stain.

Risk scores: IPSS (at dx) → DIPSS (dynamic) → DIPSS-Plus → MIPSS70/MIPSS70+ v2.0 (molecular).

Only curative therapy: allogeneic HSCT.

First-line drug for symptomatic splenomegaly: ruxolitinib.

JAK inhibitor for plt <50k: pacritinib.

JAK inhibitor for anemia-predominant: momelotinib (ACVR1/hepcidin).

Fedratinib black box: Wernicke encephalopathy → supplement thiamine.

Ruxolitinib infections to know: VZV/HSV reactivation, TB, HBV, cryptococcus, PML.

Ruxolitinib withdrawal syndrome: cytokine rebound; never stop abruptly; taper with steroid bridge.

Pregnancy cytoreductive of choice: pegylated interferon-α.

Aspirin 81 mg for JAK2-positive disease (thrombosis prevention).

Splenectomy mortality: 5–10%; complications 30–50%.

Splanchnic vein thrombosis in young patient → screen for JAK2 V617F even if CBC normal.

WHO criterion: must exclude BCR-ABL1 (CML) before diagnosing PMF.

Leukemic transformation: ≥20% blasts; median survival 3–6 months.

MYSEC-PM score for secondary (post-PV/post-ET) myelofibrosis.

Vaccines on JAK inhibitor: all inactivated allowed; no live vaccines.

Iron chelation threshold: ferritin >1000 ng/mL in transfusion-dependent patients with reasonable prognosis.

Acquired von Willebrand syndrome: consider with extreme thrombocytosis + bleeding.

Board Question Stem Patterns

— 67-year-old with fatigue, 15-lb weight loss, drenching night sweats, early satiety; exam shows spleen palpable 10 cm below costal margin; CBC shows Hb 9.2, WBC 14k with myelocytes and metamyelocytes, platelets 380k; smear shows teardrop RBCs and nucleated RBCs; LDH elevated. Marrow aspirate is a dry tap. Answer: primary myelofibrosis; next step → JAK2/CALR/MPL testing + core biopsy with reticulin stain + BCR-ABL to exclude CML.

— Newly diagnosed PMF, intermediate-2 by DIPSS-Plus, age 58, ECOG 1. Answer: refer for allogeneic HSCT evaluation and HLA typing; bridge with ruxolitinib if symptomatic.

— Patient on ruxolitinib develops pneumonia and is started on clarithromycin — what do you do? Reduce ruxolitinib dose (CYP3A4 inhibition) or switch to azithromycin.

— Fedratinib starting — what do you supplement? Thiamine (Wernicke prevention).

— Pregnant PMF patient on hydroxyurea. Stop hydroxyurea, start aspirin 81 mg, transition to peg-IFN-α if cytoreduction needed.

— PMF patient with new ascites and abdominal pain → Doppler ultrasound for portal/hepatic vein thrombosis (Budd-Chiari) → anticoagulate.

— PMF on ruxolitinib admitted ICU for sepsis — held abruptly, becomes hemodynamically unstable with high fevers. Diagnosis: ruxolitinib withdrawal syndrome; resume drug, give steroids.

— PMF patient discharged after pneumonia; ruxolitinib was held. Next step: resume ruxolitinib at prior dose with close CBC monitoring; arrange hematology follow-up within 1–2 weeks.

— Don't pick "imatinib" — that's for CML (BCR-ABL+)

— Don't pick "phlebotomy" — that's for PV

— Don't pick "splenectomy first" — reserved for refractory cases

— Don't pick "live zoster vaccine" — contraindicated on JAK inhibitor

Key distinction: Stems describing massive splenomegaly + dry tap + teardrop cells + leukoerythroblastic smear point to PMF; stems with massive splenomegaly + pancytopenia + TRAP+ lymphocytes + BRAF V600E point to hairy cell leukemia — read the cell-line details carefully.

Classic "what's the diagnosis" stem:

"Next best step in management" stem:

Pharmacology stems:

Special population stem:

Complication stems:

Transition-of-care stem:

Distractors to avoid:

One-Line Recap

Primary myelofibrosis is a clonal myeloproliferative neoplasm (JAK2/CALR/MPL-driven) producing marrow fibrosis, splenomegaly, leukoerythroblastosis, and constitutional symptoms — managed by risk-stratifying with DIPSS-Plus/MIPSS70+, treating symptomatic disease with JAK inhibitors (ruxolitinib first-line; pacritinib if plt <50k; momelotinib if anemia dominant), and referring all intermediate-2/high-risk fit patients <70 for allogeneic HSCT — the only curative therapy.

Board pearl: When in doubt on a PMF Step 3 stem, the right answer almost always involves risk stratification before drug selection, transplant referral while the patient is still fit, and respecting the JAK inhibitor's pharmacologic boundaries (taper, interactions, infection screening).

Diagnosis hinges on bone marrow biopsy with reticulin/collagen fibrosis grading + megakaryocytic atypia + driver mutation + exclusion of BCR-ABL1; teardrop RBCs and a dry tap are clinical fingerprints.

Risk stratification drives management: observation for low-risk; ruxolitinib for symptomatic intermediate-1; transplant evaluation for intermediate-2/high-risk fit patients; choice of JAK inhibitor tailored to platelets and anemia.

Never stop ruxolitinib abruptly — withdrawal syndrome is a tested patient-safety pitfall at every care transition; vaccinate (no live vaccines), screen TB/HBV/HIV before initiation, and watch for VZV reactivation and CYP3A4 interactions.

Longitudinal care = thrombosis prevention (aspirin in JAK2+), infection prevention (vaccines, post-splenectomy prophylaxis), symptom tracking (MPN-10), transfusion/iron management, dermatologic surveillance, early palliative integration, and vigilance for leukemic transformation (≥20% blasts → poor prognosis, urgent hematology).