A Research Guide for
Facing Myelofibrosis

Recent Breakthroughs in Myelofibrosis

Momelotinib: Rewriting the Anemia Story (2023)

For decades, one of the most frustrating aspects of myelofibrosis treatment was a cruel paradox: the drugs that best controlled the disease — particularly ruxolitinib — often worsened anemia, sometimes severely enough that patients needed frequent blood transfusions. That changed in September 2023 when the FDA approved momelotinib (Ojjaara, GSK) for adults with intermediate- or high-risk myelofibrosis who also have anemia.

Momelotinib works differently from other JAK inhibitors because it blocks not only JAK1 and JAK2 but also a protein called ACVR1 (also known as ALK2). This third target turns out to be critical for anemia. ACVR1 drives the liver to produce hepcidin, a hormone that restricts the body's ability to use iron and suppresses red blood cell production. By blocking ACVR1, momelotinib lowers hepcidin levels, which frees up iron stores and allows the bone marrow — and sites of extramedullary blood production like the spleen — to produce more red blood cells.

The MOMENTUM trial (NCT04173494), which enrolled patients who had already received ruxolitinib or fedratinib, showed that momelotinib achieved transfusion independence in 31% of patients compared with 20% on danazol, while also controlling symptoms and reducing spleen size. Importantly, 25% of momelotinib-treated patients achieved a 50% or greater reduction in symptom burden (TSS50) compared with only 9% on danazol. These results, published in The Lancet (PMID 36709073), established momelotinib as the preferred choice when anemia is a dominant concern. The 200mg once-daily dosing is also simpler than twice-daily schedules.

Pacritinib: A Lifeline for Severe Thrombocytopenia (2022)

Before February 2022, patients with myelofibrosis and platelet counts below 50,000 per microliter had no approved systemic therapy. Ruxolitinib's label required a platelet count of at least 50,000, and the drug commonly caused further platelet drops, making it unsafe in this population. These patients — often the sickest, with the most advanced marrow failure — were left with supportive care only.

Pacritinib (Vonjo, CTI BioPharma), approved by the FDA in February 2022, changed that. Unlike ruxolitinib, pacritinib targets JAK2 along with IRAK1, ACVR1, and FLT3, and its clinical trials were specifically designed to include patients with counts below 50,000. The PERSIST-2 trial (NCT02055781) showed a spleen volume reduction of 35% or more in 29% of pacritinib patients versus 3% on best available therapy, and the benefit held even in the most thrombocytopenic subgroups (PMID 29522138). The approved dose of 200mg twice daily was established through the PAC203 dose-finding study.

Pacritinib carries important cardiovascular warnings — including QTc prolongation and risk of atrial fibrillation, major bleeding, and intracranial hemorrhage — so patients require a baseline ECG and careful monitoring. But for patients who previously had no options, having any effective disease-directed therapy is a significant step forward.

The Combination Frontier: Pelabresib Plus Ruxolitinib

One of the most anticipated developments in myelofibrosis is the potential FDA approval of pelabresib (Constellation Pharmaceuticals, now MorphoSys/Novartis) combined with ruxolitinib for frontline treatment. Pelabresib is a BET bromodomain inhibitor that suppresses inflammatory gene expression at the level of chromatin, including the cytokine storm that drives many myelofibrosis symptoms.

The MANIFEST-2 trial (NCT04603495) was a Phase 3 randomized study comparing pelabresib plus ruxolitinib against ruxolitinib plus placebo in JAK-inhibitor-naive patients. The results, presented at ASH 2023, were striking: 66% of combination patients achieved a spleen volume reduction of 35% or more (SVR35) at week 24, compared with 35% in the ruxolitinib-alone arm — nearly doubling the benchmark response rate. However, the symptom co-primary endpoint (TSS50) was not statistically significant overall and an imbalance in leukemic transformation was observed; Novartis did not pursue a US filing on the MANIFEST-2 data and is running a confirmatory trial, MANIFEST-3 (NCT07357727). Pelabresib is not FDA-approved. If a future trial succeeds, the combination could still become a frontline option.

Selinexor, Navtemadlin, and the Post-Ruxolitinib Challenge

One of the most pressing unmet needs in myelofibrosis is what to do after ruxolitinib fails or stops working. Most patients eventually lose response over two to three years, and options afterward are limited. Several trials are tackling this problem with novel mechanisms. Selinexor (Karyopharm) is an XPO1 inhibitor being evaluated in the SENTRY trial (NCT04562389) in frontline myelofibrosis. Navtemadlin (Kartos Therapeutics) is an MDM2 inhibitor evaluated in the BOREAS trial (NCT03662126) in patients who have progressed on or are ineligible for JAK inhibitors. Navitoclax (AbbVie), a BCL-2/BCL-XL inhibitor, is being evaluated with ruxolitinib in the TRANSFORM-1 trial (NCT04472598).

Generic Ruxolitinib: Access Expanding

The availability of generic ruxolitinib (manufacturers including Teva and Sun Pharmaceuticals) following patent expiration has significantly improved access for patients who faced affordability barriers to Jakafi. For a disease requiring indefinite daily treatment, the cost reduction can be life-changing.

Molecular Prognostication: MIPSS70 and Beyond

Risk stratification in myelofibrosis has become dramatically more precise. The MIPSS70 and MIPSS70+ version 2.0 systems now incorporate molecular mutation data — specifically high-molecular-risk (HMR) mutations including ASXL1, EZH2, IDH1, IDH2, SRSF2, and U2AF1 — along with cytogenetics. Patients with two or more HMR mutations have significantly worse outcomes and may be considered for early allogeneic transplant regardless of their clinical risk score.

Understanding Myelofibrosis

What Goes Wrong in the Bone Marrow

Bone marrow manufactures all three types of blood cells. This process is regulated by molecular signals — erythropoietin and thrombopoietin bind to receptors on stem cells and activate JAK2, which switches on genes driving blood cell production. When the job is done, JAK2 turns off. The system is self-limiting by design.

In myelofibrosis, this off-switch is broken. The most common culprit is a single-letter change in the JAK2 gene — the JAK2 V617F mutation — which keeps JAK2 permanently switched on regardless of whether the body needs more blood cells. The result is continuous, uncontrolled proliferation of megakaryocytes (platelet-making cells). These abnormal megakaryocytes cluster in the marrow, release fibrosis-promoting signals (TGF-beta and PDGF), and trigger bone marrow stromal cells to lay down scar tissue (reticulin and eventually collagen). Over time, the scar tissue crowds out functional marrow and the body's ability to make blood cells in the bone marrow collapses.

The Three Driver Mutations

JAK2 V617F accounts for approximately 55-65% of myelofibrosis cases. It is a single amino acid substitution that bypasses normal regulatory mechanisms. Patients can have varying allele burdens — the percentage of cells carrying the mutation — which can affect disease severity and treatment response. JAK2 V617F is also found in polycythemia vera (PV) and essential thrombocythemia (ET), which can transform into post-PV or post-ET myelofibrosis.

CALR mutations affect the calreticulin gene. Type 1 CALR mutations (52 base pair deletions) are associated with a more favorable disease course, lower rate of transformation, and better overall survival compared with Type 2 mutations (5 base pair insertions). CALR mutations are found in approximately 25% of myelofibrosis patients.

MPL mutations (most commonly W515L or W515K) directly activate the thrombopoietin receptor and account for approximately 5% of cases. Approximately 10% of patients are "triple negative" — carrying none of the three canonical driver mutations — and require comprehensive NGS panel testing.

The Downstream Cascade: From Mutation to Symptoms

Regardless of which driver mutation initiates the process, the downstream consequences are similar. Constitutive JAK-STAT signaling drives megakaryocyte overproduction and dysplasia. Abnormal megakaryocytes release TGF-beta, PDGF, and VEGF, which stimulate fibroblasts to produce reticulin and collagen. At the same time, an inflammatory cytokine storm — driven by IL-6, IL-8, TNF-alpha, and other signals — produces the constitutional symptoms that are often most debilitating for patients: drenching night sweats, profound fatigue, unintentional weight loss, low-grade fevers, and diffuse bone pain.

Why the Spleen Enlarges — and Why It Matters

As bone marrow fibrosis progresses, hematopoietic stem cells migrate to alternative sites — primarily the spleen and liver — a process called extramedullary hematopoiesis. The spleen can become massively enlarged, sometimes extending all the way to the pelvis and weighing more than 5 kilograms. This splenomegaly causes early satiety, left-sided abdominal pain, a visible or palpable mass, and — when splenic blood flow is compromised — painful splenic infarcts. Massive splenomegaly can also cause portal hypertension, increasing pressure in the portal vein system with risk of esophageal varices and ascites.

Anemia: Multiple Mechanisms

Anemia in myelofibrosis is multifactorial. The bone marrow cannot produce enough red blood cells as fibrosis advances. An enlarged spleen sequesters and destroys red blood cells faster than normal. And critically, the JAK-STAT pathway drives the liver to produce hepcidin, a hormone that blocks iron absorption from the gut and prevents iron recycling from macrophages. This hepcidin-mediated pathway is specifically targeted by momelotinib's ACVR1 inhibition, explaining why it is uniquely effective for anemia while other JAK inhibitors may worsen it.

High-Molecular-Risk Mutations

Beyond the three driver mutations, myelofibrosis cells frequently acquire additional mutations in genes involved in chromatin remodeling, RNA splicing, and cell cycle regulation. Six mutations — in ASXL1, EZH2, IDH1, IDH2, SRSF2, and U2AF1 — are collectively called high-molecular-risk (HMR) mutations because patients carrying one or more have significantly shorter survival and higher rates of blast-phase transformation. IDH1 and IDH2 mutations carry particular importance because targeted IDH inhibitors (ivosidenib for IDH1, enasidenib for IDH2) may offer treatment options if blast phase transformation occurs. Patients with two or more HMR mutations may warrant early referral for transplant evaluation regardless of their clinical risk score.

Blast Phase Transformation

Approximately 10-20% of myelofibrosis patients transform to accelerated phase or blast-phase AML. This carries a very poor prognosis, with median survival measured in months without transplant. Patients with HMR mutations, complex cytogenetics, or rapidly rising blast percentages require close surveillance and early discussion about transplant planning and clinical trial eligibility.

Diagnosis and Workup

Blood Tests: What the Numbers Show

The complete blood count (CBC) in myelofibrosis typically shows a characteristic pattern. Anemia is present in the majority of patients at diagnosis — usually normocytic or macrocytic — reflecting ineffective hematopoiesis and bone marrow failure. Platelet counts may be elevated early in the disease course (particularly in post-ET MF or prefibrotic MF) but fall as fibrosis advances. White blood cell counts are often elevated, with a left shift (immature white cells appearing in the peripheral blood). Leukoerythroblastosis — the presence of both immature white cells and nucleated red blood cells in the peripheral circulation — is a hallmark finding indicating severe marrow distress. LDH is typically elevated. Alkaline phosphatase (ALP) is often high from hepatic involvement. A comprehensive metabolic panel assesses hepatic and renal function, both relevant to drug dosing and transplant planning.

The Peripheral Blood Smear: Pathognomonic Findings

The peripheral blood smear reviewed by an experienced hematopathologist remains essential in myelofibrosis. The classic leukoerythroblastic picture — combination of immature granulocytes and nucleated red blood cells alongside mature cells — indicates that the bone marrow is under severe stress and hematopoiesis has shifted to extramedullary sites. Most characteristic are dacrocytes, also called teardrop cells — red blood cells squeezed into a teardrop shape as they are forced through fibrotic marrow. Their presence on peripheral smear in the context of splenomegaly, constitutional symptoms, and cytopenia should immediately prompt consideration of myelofibrosis.

Molecular Testing: The Diagnostic Hierarchy

Molecular testing in myelofibrosis follows a stepwise diagnostic hierarchy aligned with WHO 2022 criteria. The first test ordered is quantitative JAK2 V617F testing by PCR or droplet digital PCR (ddPCR). If JAK2 V617F is negative, CALR exon 9 sequencing is performed — the specific type (Type 1 or Type 2) is reported because of its prognostic significance. If CALR testing is also negative, MPL codon 515 testing follows. If all three are negative (triple-negative), a comprehensive myeloid next-generation sequencing (NGS) panel is performed.

Comprehensive myeloid NGS panels — typically covering 40 to 80 genes — should be ordered for all newly diagnosed myelofibrosis patients regardless of driver mutation status. Beyond identifying triple-negative cases, NGS detects HMR mutations (ASXL1, EZH2, IDH1, IDH2, SRSF2, U2AF1) that critically inform prognosis and treatment planning. Other clinically actionable mutations include RUNX1 (associated with blast-phase risk), TP53 (poor prognosis), TET2, DNMT3A, and CBL. For patients being considered for transplant, cytogenetics (conventional karyotype and FISH) is mandatory.

Bone Marrow Biopsy: Grading the Fibrosis

A bone marrow biopsy (core biopsy plus aspirate attempt) is required for diagnosis. The WHO 2022 grading system classifies marrow fibrosis on a four-tier scale: MF-0 is no fibrosis (scattered linear reticulin with no intersections); MF-1 is loose network of reticulin with many intersections, especially in perivascular areas; MF-2 is diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of collagen; and MF-3 is diffuse and dense reticulin with extensive intersections and coarse bundles of collagen, often associated with significant osteosclerosis.

MF-0 and MF-1 fibrosis defines prefibrotic MF, which has a more indolent natural history and different clinical presentation (often presenting with thrombocytosis rather than anemia) compared with overt MF (MF-2 and MF-3). Prefibrotic MF may initially be mistaken for essential thrombocythemia on clinical grounds — bone marrow biopsy is the only way to reliably distinguish them. The aspirate portion of the biopsy often yields a "dry tap" in overt myelofibrosis — the dense fibrosis prevents aspiration of marrow cells. Megakaryocyte morphology in myelofibrosis shows large, hyperlobated cells tightly clustered in dense sheets.

Cytogenetics and FISH

Conventional cytogenetics (karyotype) may show abnormalities in approximately 30-40% of primary MF patients. Recurrent abnormalities include del(20q), del(13q), trisomy 8, trisomy 9, and complex karyotype. Complex karyotype and specific high-risk cytogenetic lesions — including monosomy 7, inv(3), and i(17q) — are incorporated into the MIPSS70+v2 risk score and are associated with significantly worse outcomes.

Imaging

Abdominal ultrasound is the standard initial imaging for spleen and liver evaluation. For clinical trials, magnetic resonance imaging (MRI) spleen volumetry provides more precise measurement of spleen volume — the endpoint used in pivotal JAK inhibitor trials (SVR35 = spleen volume reduction of 35% or more from baseline). CT scanning of the chest, abdomen, and pelvis is appropriate when extramedullary hematopoiesis outside the spleen and liver is suspected.

Risk Stratification: Choosing the Right Score

At the time of initial diagnosis, the International Prognostic Scoring System (IPSS) is applied. IPSS assigns one point each for five adverse features: age over 65 years, hemoglobin below 10 g/dL, white blood cell count above 25,000/mcL, circulating blast cells of 1% or more, and the presence of constitutional symptoms. Patients are categorized as Low (0 points, median OS approximately 11 years), Intermediate-1 (1 point, approximately 8 years), Intermediate-2 (2 points, approximately 4 years), or High (3 or more points, approximately 2 years).

The Dynamic IPSS (DIPSS) can be applied at any point during follow-up and weights hemoglobin below 10 more heavily (2 points instead of 1). DIPSS-Plus adds platelet count below 100,000, transfusion dependence, and unfavorable cytogenetics. MIPSS70 incorporates HMR mutations, sex-based gene expression, fibrosis grade, and clinical variables. MIPSS70+v2 further adds cytogenetic risk categories. GIPSS relies entirely on genetic/molecular data, making it useful when clinical parameters are confounded by prior treatment.

Differential Diagnosis

Not every patient with bone marrow fibrosis has myelofibrosis. Secondary causes must be excluded, including metastatic carcinoma to the marrow (especially breast, prostate, lung), systemic mastocytosis (with KIT D816V mutation), hairy cell leukemia (with BRAF V600E mutation), autoimmune myelofibrosis, and granulomatous infections (tuberculosis, fungal). Chronic myelogenous leukemia (CML) can present with marked leukocytosis and organomegaly mimicking MF — BCR-ABL1 testing is mandatory to exclude CML.

Risk Scoring and Prognosis

IPSS — International Prognostic Scoring System

The IPSS was the first validated prognostic model for MF and can only be applied at the time of initial diagnosis. Five adverse prognostic variables, each worth 1 point: age > 65, hemoglobin < 10 g/dL, WBC > 25 × 10&sup9;/L, circulating blasts ≥ 1%, and constitutional symptoms. Risk categories: Low (0 points, median OS 11.3 years), Intermediate-1 (1 point, 7.9 years), Intermediate-2 (2 points, 4.0 years), High (≥3 points, 2.3 years). Important limitation: IPSS does not incorporate mutational data, cytogenetics, or transfusion dependence.

DIPSS — Dynamic International Prognostic Scoring System

DIPSS uses the same five clinical variables as IPSS but assigns 2 points to hemoglobin < 10 g/dL, giving anemia greater prognostic weight. The critical advantage is that it can be applied at any time during the disease course — at diagnosis, at a follow-up visit, or when reassessing after treatment — allowing dynamic risk reclassification as the disease evolves.

DIPSS-Plus

DIPSS-Plus builds on DIPSS by adding three additional adverse prognostic factors: platelet count < 100,000/µL, red blood cell transfusion dependence (≥2 units in prior 8 weeks), and unfavorable karyotype (complex karyotype, inv(3), i(17q), -7/7q-, or +21). It remains widely used in clinical practice because it integrates practical clinical parameters routinely assessed.

MIPSS70 and MIPSS70+v2.0

MIPSS70 represented a significant advance by incorporating molecular mutation data into risk stratification. It includes DIPSS clinical factors plus HMR mutations (ASXL1, EZH2, IDH1, IDH2, SRSF2, or U2AF1 Q157 variant), absence of driver mutation (triple-negative status is adverse), and CALR type 1 mutation (favorable — the only protective molecular marker). Five risk categories from Very Low to Very High. MIPSS70+v2.0 is the most molecularly refined system, adding cytogenetic risk categories. Its primary practical role is identifying patients who should be referred promptly for transplant evaluation, even if they appear clinically stable by older scoring systems.

GIPSS — Genotypically Inspired Prognostic Scoring System

GIPSS uses only karyotype and mutation data — no clinical parameters at all. This makes it particularly useful at the time of initial diagnosis before any therapy has altered the clinical picture, and when clinical parameters are confounded by prior therapy. It is based on four molecular variables: unfavorable karyotype, absence of CALR type 1 mutation, and presence of ASXL1 and/or SRSF2 mutations.

High-Molecular-Risk (HMR) Mutations: What They Mean

• ASXL1 (approximately 35% of MF): The most common HMR mutation. Truncating mutations disrupt polycomb repressor complex 2 (PRC2), altering histone methylation. ASXL1 mutation alone upgrades prognosis and is associated with worse overall survival, higher rate of leukemic transformation, and poorer response to JAK inhibitors. ASXL1-mutated patients should have transplant eligibility discussed early.
• EZH2: Also a PRC2 component; loss-of-function mutations associated with worse OS and accelerated blast-phase transformation.
• IDH1 / IDH2: Mutations produce the oncometabolite 2-hydroxyglutarate (2-HG), causing DNA hypermethylation and blocked differentiation. IDH1 and IDH2 mutations are targetable: ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) are FDA-approved in AML for these mutations and are being investigated in IDH-mutated MF and blast-phase MF.
• SRSF2: RNA splicing factor mutation; associated with worst prognosis among HMR mutations and very high risk of blast-phase transformation.
• U2AF1 Q157: The Q157 variant (not the P34 variant, which is lower risk) is HMR. Sequencing reports must specify the exact codon — Q157 vs P34 — as clinical management differs.

Blast-Phase MF: Leukemic Transformation

Myelofibrosis carries a 10-20% lifetime risk of transformation to blast-phase (BP-MF), defined as ≥10% circulating or bone marrow blasts (accelerated phase) or ≥20% blasts (overt AML-like transformation). HMR mutations substantially increase this risk. Median overall survival after blast-phase transformation is approximately 6 months without treatment. Management options include hypomethylating agents (azacitidine, decitabine) as bridging therapy toward transplant, IDH1/2 inhibitors for IDH-mutated BP-MF, venetoclax-based combinations (investigational), and allogeneic SCT as the only potentially curative option. Referral to a transplant center should occur at the first sign of blast-phase MF (bone marrow blasts ≥10%) — not after the patient has progressed to ≥20%.

Using Risk Scores in Practice

In a comprehensive MPN specialist consultation, expect molecular risk assessment to follow this sequence: (1) bone marrow biopsy with fibrosis grading, cytogenetics, and NGS panel; (2) calculate DIPSS from current clinical parameters; (3) calculate MIPSS70+v2.0 and GIPSS incorporating molecular and cytogenetic data; (4) integrate risk category into treatment decision. Free online risk calculators are available through the MPN Research Foundation at mpnresearchfoundation.org and through QxMD (Calculate app, searchable as "MIPSS70").

JAK Inhibitor Therapy

Ruxolitinib (Jakafi / Jakavi — Incyte)

Mechanism of Action

Ruxolitinib is a potent, competitive inhibitor of both JAK1 and JAK2 kinases. In myelofibrosis, constitutive JAK-STAT pathway activation drives an inflammatory cytokine storm: IL-6, TNF-alpha, IL-8, and TGF-beta are chronically elevated. Ruxolitinib blocks phosphorylation of downstream STATs 1, 3, and 5, suppressing this cytokine cascade. This mechanism explains why ruxolitinib reduces constitutional symptoms and splenomegaly across all molecular subtypes — JAK2V617F, CALR type 1, CALR type 2, MPL, and triple-negative — because it targets the shared downstream signaling node rather than the upstream mutation itself. It does not selectively target mutant over wild-type JAK2, which is why cytopenias (anemia, thrombocytopenia) are on-target pharmacologic effects rather than off-target toxicities.

FDA Approval and Landmark Clinical Trials

Ruxolitinib received FDA approval in November 2011 for intermediate- or high-risk myelofibrosis — the first JAK inhibitor approved for any indication.

COMFORT-I (NCT00952289): A US-based, randomized, double-blind, placebo-controlled trial enrolling 309 patients with intermediate-2 or high-risk MF. SVR35 at week 24: 41.9% ruxolitinib vs 0.7% placebo. TSS50 at week 24: 45.9% vs 5.3%. Two-year landmark overall survival was superior in the ruxolitinib arm. PMID 22375971.

COMFORT-II (NCT00934544): A European, randomized, open-label trial comparing ruxolitinib to best available therapy in 219 patients. SVR35 at week 48: 28% ruxolitinib vs 0% BAT. Long-term 5-year follow-up confirmed a sustained overall survival benefit. PMID 22375970.

Dosing by Platelet Count

After starting, obtain a CBC every 2–4 weeks until the dose is stable. Dose increases may be considered if platelets remain adequate and response is insufficient (increase by 5 mg BID at minimum 2-week intervals, up to 25 mg BID maximum). Dose reductions are required for cytopenias: reduce by 5 mg BID for grade 2 thrombocytopenia (platelets 50,000–75,000/µL); hold for platelets < 50,000/µL or ANC < 750/µL, then restart at a dose 5 mg BID lower than the dose at which hold occurred.

Critical Safety Warning: Never Abruptly Discontinue

Infectious Risks and Pre-Treatment Screening

Drug Interactions

Ruxolitinib is primarily metabolized by CYP3A4. Strong CYP3A4 inhibitors (ketoconazole, itraconazole, voriconazole, clarithromycin, ritonavir) approximately double ruxolitinib exposure — reduce the ruxolitinib dose by approximately 50%. Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's Wort) reduce ruxolitinib exposure and may compromise efficacy. Fluconazole (moderate CYP3A4/CYP2C9 inhibitor): reduce ruxolitinib dose by approximately 50% with fluconazole doses > 200 mg/day.

Dyslipidemia

Ruxolitinib can cause clinically significant elevations in total cholesterol, LDL, and triglycerides, typically emerging within the first 8–12 weeks. Obtain a fasting lipid panel at baseline and repeat at 8–12 weeks. Initiate or adjust statin therapy as appropriate per standard cardiovascular guidelines.

Generic Availability

Multiple generic formulations of ruxolitinib are now available from manufacturers including Teva, Sun Pharmaceutical, Aurobindo, and others, providing substantially reduced cost. Jakavi is the brand name used in the European Union. For patients requiring brand-name Jakafi, Incyte Cares provides patient assistance and co-pay support: 1-855-463-3463 or InkyteCares.com.

Fedratinib (Inrebic — Bristol Myers Squibb)

Mechanism of Action

Fedratinib is a JAK2-selective oral kinase inhibitor with additional activity against FLT3 and RET. Its relative selectivity for JAK2 over JAK1 distinguishes it pharmacologically from ruxolitinib. Fedratinib also inhibits BRD4. The critical safety distinction is fedratinib's interference with thiamine (vitamin B1) cellular transport, creating a unique and serious encephalopathy risk that requires active monitoring and supplementation.

FDA Approval and Clinical Trials

Fedratinib received FDA approval in August 2019 for adults with intermediate-2 or high-risk primary or secondary MF. A clinical hold from 2013–2017 related to Wernicke's encephalopathy cases was lifted after the FDA and sponsor agreed on risk mitigation measures including mandatory thiamine monitoring.

JAKARTA (NCT01437787): Randomized, double-blind, placebo-controlled Phase 3 trial in 289 patients. SVR35 at cycle 6: 36.1% (400 mg) vs 1.1% placebo. TSS50: 40.2% (400 mg) vs 9.2% placebo. PMID 26181658. The 400 mg dose was selected for approval.

JAKARTA-2: Single-arm Phase 2 study in 97 patients with prior ruxolitinib exposure (≥14 days). SVR35 at cycle 6: 27% (intent-to-treat population). This established fedratinib as a viable second-line option after ruxolitinib failure.

Dosing

Fedratinib 400 mg orally once daily, taken with food. Taking with food significantly reduces nausea and GI adverse effects. Co-administration with a meal of at least 300–400 calories is recommended.

Critical Boxed Warning: Wernicke's Encephalopathy

Gastrointestinal Toxicity Management

Nausea, vomiting, and diarrhea occur in greater than 60% of fedratinib-treated patients. Proactive antiemetic therapy: administer ondansetron 8 mg 30 minutes before each fedratinib dose. Prochlorperazine or metoclopramide as rescue. For diarrhea: loperamide 4 mg at first episode, then 2 mg after each loose stool (maximum 16 mg/day). For grade 3 GI toxicity: hold fedratinib until resolved to grade ≤1, then reduce dose to 300 mg/day. Patient assistance for Inrebic: Bristol Myers Squibb Access Support 1-800-861-0048.

Pacritinib (Vonjo — CTI BioPharma)

Mechanism of Action

Pacritinib inhibits JAK2, IRAK1, ACVR1, and FLT3. IRAK1 inhibition contributes to suppression of NF-κB-driven inflammatory signaling. ACVR1 inhibition reduces hepcidin production. Critically, pacritinib's kinase selectivity profile results in substantially less myelosuppression than ruxolitinib — particularly less thrombocytopenia — which is the pharmacologic basis for its unique role in patients with severe thrombocytopenia.

FDA Approval and Clinical Trials

PERSIST-2 (NCT02055781): Randomized, open-label Phase 3 trial in 311 patients with MF and platelet counts < 100,000/µL. In the primary efficacy population with PLT < 50,000/µL, SVR35 at week 24: 29% pacritinib (200 mg BID) vs 3% BAT. PMID 29522138. Pacritinib received FDA accelerated approval in February 2022, specifically for adults with MF with a platelet count below 50,000/µL — the only approved therapy for this population.

Dosing: Mandatory 200 mg BID

Cardiovascular Warnings and Monitoring

• QTc prolongation: Obtain a 12-lead ECG at baseline. Repeat at 4–6 weeks. Avoid co-administration of other QTc-prolonging agents. If QTc > 500 ms or increases by > 60 ms from baseline, hold pacritinib and investigate.
• Atrial fibrillation and flutter: Monitor for palpitations, dyspnea, or irregular pulse. Manage per cardiology guidelines.
• Intracranial hemorrhage: New-onset or worsening headache, focal neurological symptoms, or altered consciousness requires urgent brain imaging.
• Major bleeding: Grade 4 hemorrhagic events require permanent discontinuation of pacritinib.

Patient assistance for Vonjo: CTI BioPharma Patient Assistance 1-877-557-2676.

Momelotinib (Ojjaara — GSK)

Mechanism of Action: The ACVR1 Advantage

Momelotinib inhibits JAK1, JAK2, and, critically, ACVR1 (activin A receptor type 1, also called ALK2). This third target is the mechanistic basis for momelotinib's unique anemia benefit. In the bone morphogenetic protein (BMP) signaling pathway, ACVR1 activation drives transcription of hepcidin in hepatocytes. Hepcidin binds ferroportin on intestinal enterocytes, splenic macrophages, and hepatocytes, causing internalization and degradation, thereby blocking iron export into the bloodstream. In MF, hepcidin is chronically elevated, creating functional iron deficiency. By inhibiting ACVR1, momelotinib suppresses hepcidin production, restoring functional iron availability for erythropoiesis — a mechanism not replicated by ruxolitinib or fedratinib.

FDA Approval and Clinical Trials

Momelotinib received FDA approval in September 2023 for intermediate- or high-risk primary or secondary MF with anemia.

MOMENTUM (NCT04173494): Randomized, double-blind, active-controlled Phase 3 trial comparing momelotinib 200 mg/day versus danazol in 195 patients with prior JAK inhibitor therapy. TI rate at week 24: 31% vs 20% (p = 0.023). TSS50: 24.6% vs 9.2% (p = 0.0095). PMID 36709073.

SIMPLIFY-1 (NCT01969838): Randomized, double-blind Phase 3 trial comparing momelotinib 200 mg/day to ruxolitinib in 432 JAK inhibitor-naive patients. Primary endpoint: SVR35 at week 24: 26.5% momelotinib vs 29% ruxolitinib (non-inferiority margin met). TI rate at week 24 significantly higher with momelotinib: 66.5% vs 49.3% (p < 0.001). This supports momelotinib as a frontline option for anemia-dominant MF.

Dosing

Momelotinib 200 mg orally once daily, with or without food. The once-daily dosing schedule provides a convenience advantage. No dose adjustment is required based on platelet count at initiation.

Peripheral Neuropathy Warning

When to Choose Momelotinib vs Other JAK Inhibitors

Patient assistance for Ojjaara: GSK Oncology Patient Access Program 1-888-825-5249 or GSKForYou.com.

Anemia Management in Myelofibrosis

Understanding the Multiple Causes of MF Anemia

• Bone marrow failure from fibrosis: As reticulin and collagen fibrosis replace normal marrow architecture, the space available for red blood cell precursors is progressively lost. This is the foundational cause and worsens as the disease progresses through MF-1 to MF-3 fibrosis grades.
• Ineffective erythropoiesis: Even where erythroid precursors persist, they fail to mature normally due to the disordered marrow microenvironment, abnormal cytokine signaling (excess TNF-alpha, IL-6, TGF-beta), and clonal competition.
• The ACVR1/hepcidin inflammatory pathway: In MF, the chronic inflammatory state drives massive upregulation of hepcidin. Elevated hepcidin blocks iron release from stores into the plasma, creating functional iron deficiency: iron is abundant in macrophage stores (serum ferritin often elevated) but unavailable for erythropoiesis. Momelotinib's ACVR1 inhibition directly breaks this cycle.
• JAK inhibitor-induced worsening (weeks 4–12): Ruxolitinib and other JAK inhibitors reduce EPO-driven erythropoiesis as a class effect. In the first 1–3 months of ruxolitinib therapy, hemoglobin commonly drops 1–2 g/dL before stabilizing. Do not discontinue ruxolitinib for this expected early decline without giving it time to stabilize.
• Hypersplenism-mediated RBC destruction: The massively enlarged spleen sequesters and destroys RBCs at an accelerated rate — the spleen can hold up to 40% of total RBC mass. Effective spleen reduction often improves hemoglobin as a secondary benefit.
• Autoimmune hemolytic anemia: Occurs in a minority of MF patients. Coombs test should be checked in patients with disproportionate anemia, elevated LDH, low haptoglobin, or reticulocytosis.
• Nutritional and iatrogenic factors: B12, folate, and iron deficiency should be excluded before attributing anemia entirely to MF.

Momelotinib (Ojjaara, GSK) — First JAK Inhibitor with a Dedicated Anemia Indication

Momelotinib received FDA approval in September 2023 for adult patients with intermediate- or high-risk myelofibrosis with anemia. Its ACVR1 inhibition suppresses hepcidin production in the liver, releasing the iron blockade and allowing effective erythropoiesis to resume — a fundamentally different mechanism from simple EPO stimulation.

MOMENTUM trial (NCT04173494): Enrolled 195 previously JAK inhibitor-treated MF patients with anemia (Hgb <10 g/dL or transfusion-dependent). Momelotinib 200 mg once daily vs danazol. TI rate at week 24: 31% vs 20% (PMID 36709073). TSS50: 25% vs 9%. SVR35: 24% vs 18%. Key safety considerations: peripheral neuropathy (monitor for tingling, numbness, weakness in extremities); hemolytic anemia monitoring (check Coombs if hemoglobin drops unexpectedly); embryo-fetal toxicity (contraception required).

Danazol — Attenuated Androgen for MF Anemia

Danazol is a synthetic attenuated androgen that reduces transfusion requirements in approximately 30–40% of patients. Particularly useful in patients who are not candidates for, or who have failed, JAK inhibitors, and in the palliative setting. Dosing: 200 mg orally three times daily (600 mg/day total). Assess at 3–6 months; continue if hemoglobin has risen ≥1 g/dL or transfusion frequency has decreased.

Critical safety monitoring: Hepatotoxicity (monitor LFTs every 3 months; danazol is associated with peliosis hepatis and, with long-term use >2 years, hepatocellular carcinoma — discontinue if LFTs exceed 3× ULN); virilization in women (acne, hirsutism, voice deepening potentially irreversible, clitoral enlargement, menstrual irregularities); thromboembolism; PSA elevation in men; warfarin potentiation.

Erythropoiesis-Stimulating Agents (ESAs)

ESAs (epoetin alfa, darbepoetin alfa) have limited but real efficacy in a subset of MF patients. Consider ESAs in non-transfusion-dependent patients with symptomatic anemia (Hgb 8–10 g/dL) and serum EPO <500 mU/mL. Check endogenous EPO level before prescribing. Dosing options: darbepoetin alfa 150–300 mcg subcutaneously every 3 weeks, or epoetin alfa 40,000 units subcutaneously weekly. Assess at 4–6 weeks; discontinue if hemoglobin has not risen ≥1 g/dL after 8–12 weeks. Response rates in MF are typically 15–30%.

Luspatercept (Reblozyl) — Emerging Role in MF Anemia

Luspatercept is a TGF-beta superfamily ligand trap that promotes late-stage erythroid maturation by inhibiting aberrant SMAD2/3 signaling. It is FDA-approved for MDS-associated anemia and beta-thalassemia-associated anemia. The INDEPENDENCE trial (NCT04717414) evaluated luspatercept plus ruxolitinib vs placebo plus ruxolitinib in MF patients with anemia already on stable ruxolitinib. In topline results (2025) it did not meet its primary endpoint of red-blood-cell transfusion independence (p=0.0674); however, several secondary endpoints — including a ≥50% reduction in transfusion burden and a hemoglobin rise of ≥1 g/dL — showed clinically meaningful benefit. The sponsor (Bristol Myers Squibb) has said it will discuss possible submissions with the FDA and EMA. Luspatercept is not FDA-approved for myelofibrosis.

Immunomodulatory Agents

Lenalidomide: Has modest activity in MF anemia, most likely to benefit patients with del(20q) cytogenetics (response rates approximately 30% in small series). Typically dosed at 10 mg daily for 21 of every 28 days. Thromboembolic prophylaxis (aspirin or LMWH) is mandatory. Myelosuppression is common; monitor CBC weekly for the first 8 weeks. Thalidomide: Low-dose thalidomide (50 mg nightly) has shown anemia responses in small Phase 2 trials, often with prednisone. Responses are modest and not durable. Strict REMS program required. Pomalidomide: Phase 2 data in MF anemia have shown responses in approximately 16–36% of selected patients; not FDA-approved for MF but used off-label in relapsed/refractory settings.

Transfusion Management

Red blood cell transfusions are often required every 2–4 weeks in transfusion-dependent MF patients. Target hemoglobin typically ≥7–8 g/dL for most patients, or higher (≥9–10 g/dL) for patients with significant cardiovascular disease. For transplant-eligible patients: all transfusions should be leukoreduced and irradiated. Monitor type and screen with antibody identification before each transfusion episode. Alloimmunization occurs in 5–10% of chronically transfused patients and can complicate future transplant crossmatching.

Iron Overload and Chelation

Chronically transfused MF patients accumulate iron at approximately 200–250 mg per unit of packed RBCs. Organ damage from iron overload (liver fibrosis, cardiac arrhythmias) becomes clinically relevant after approximately 20–30 units of lifetime transfusions. Monitor serum ferritin every 3 months. MRI T2* cardiac and hepatic iron quantification annually once ferritin exceeds 1,000–2,500 mcg/L.

Deferasirox (Jadenu/Exjade): Jadenu (film-coated tablet) 7–14 mg/kg/day orally once daily. Exjade (dispersible tablet) 20–40 mg/kg/day in water or juice, taken on empty stomach. Monitor serum creatinine monthly; dose reduce or hold if creatinine rises >33% above baseline on two consecutive measurements. GI side effects common; Jadenu formulation preferred for GI tolerance. Goal: ferritin <500–1000 mcg/L.

Deferoxamine: Subcutaneous infusion via pump over 8–12 hours, 5–7 nights per week. Reserved for patients who cannot tolerate deferasirox. Eye and hearing examinations annually.

Splenomegaly as a Driver of Anemia — Surgical and Radiation Options

In patients with truly massive splenomegaly (>20 cm or >3,000 cm³ by imaging) where systemic therapy has failed, invasive spleen-directed therapies may be considered.

Splenectomy: Can reduce transfusion requirements and increase platelet counts, but carries significant risks: post-splenectomy sepsis (vaccinate against encapsulated organisms at least 2 weeks before surgery); accelerated hepatomegaly; perioperative mortality 5–10% at less specialized centers; thrombocytosis after surgery (aspirin mandatory post-operatively). Not a first-line or routine option in the JAK inhibitor era.

Splenic irradiation: Reserved for transplant-ineligible patients with symptomatic splenomegaly. Doses of 100–200 cGy in 5–10 fractions can reduce spleen size temporarily (months). Cytopenia worsening is common after radiation. Palliative and temporary only.

Allogeneic Stem Cell Transplantation

Who Should Be Referred for Transplant Evaluation

• IPSS/DIPSS Intermediate-2 or High-risk: Strong recommendation for transplant consultation at diagnosis. Median survival without transplant is 2–4 years in this group.
• IPSS/DIPSS Intermediate-1 with high-molecular-risk (HMR) mutations: ASXL1, EZH2, IDH1, IDH2, SRSF2, or U2AF1 mutations confer a significantly worse prognosis even in intermediate-1 disease. Two or more HMR mutations further compound risk.
• IPSS/DIPSS Intermediate-1 with adverse cytogenetics: Complex karyotype, monosomy 7, inv(3) — early referral warranted.
• Blast-phase transformation (>10% blasts): Urgently refer for transplant after achieving blast control with HMA-based therapy or venetoclax-based regimens.
• Age and comorbidities: Age alone is not a disqualifier. With reduced-intensity conditioning (RIC), patients up to age 70–75 who are functionally fit have been successfully transplanted. The HCT Comorbidity Index (HCT-CI) is more informative than age alone.

Donor Selection

• HLA-matched sibling donor (MSD, 8/8): The gold standard. Best outcomes across all studies — lowest TRM, best disease control. Only approximately 25–30% of patients will have a matched sibling.
• Matched unrelated donor (MUD, 8/8 at high resolution): Outcomes at experienced centers are now comparable to MSD. The National Marrow Donor Program (NMDP/Be the Match) registry contains over 40 million volunteer donors and cord blood units. Search time is typically 4–8 weeks.
• Mismatched unrelated donor (MMUD, 7/8): A single antigen or allele mismatch is associated with higher GvHD and modestly higher TRM. Used when no 8/8 match is available.
• Haploidentical donor (half-match): Any first-degree relative who shares exactly one HLA haplotype. Post-transplant cyclophosphamide (PT-Cy) protocols have dramatically improved haploidentical transplant outcomes, making it a viable option when no matched donor is available. Expanding access particularly for patients of non-European ancestry.

Timing and Bridging to Transplant

JAK inhibitor bridging — the standard of care: Continue ruxolitinib (or the patient's current JAK inhibitor) up to and including the start of conditioning. Never abruptly stop ruxolitinib before transplant — abrupt discontinuation can trigger a severe cytokine rebound syndrome. The standard approach is to continue ruxolitinib through the first day of conditioning and then taper over 5–7 days during the conditioning regimen, or simply use the conditioning chemotherapy itself as the taper.

Spleen reduction before transplant: Massive splenomegaly at the time of transplant is associated with delayed engraftment, higher TRM, and worse survival. Successful JAK inhibitor therapy that reduces spleen volume by >50% before transplant is associated with meaningfully improved outcomes.

HMA bridging for blast-phase MF: Patients with MF transformed to accelerated or blast phase need blast control before transplant. Azacitidine (75 mg/m² × 7 days per 28-day cycle) or decitabine (20 mg/m² × 5–10 days per 28-day cycle) can reduce blast percentage sufficiently to proceed to transplant. Venetoclax in combination with azacitidine is being used increasingly in this setting; IDH1/2 inhibitors for IDH-mutant blast-phase MF represent an emerging approach.

Conditioning Regimens

Myeloablative conditioning (MAC): Busulfan + cyclophosphamide (BuCy) or busulfan + fludarabine (BuFlu). Completely ablates native hematopoiesis before infusing donor stem cells. Strongest anti-tumor effect; appropriate for younger (<55), fit patients with low comorbidity burden. TRM 15–25%.

Reduced-intensity conditioning (RIC): Fludarabine + low-dose busulfan (FluBu2) or fludarabine + melphalan (FluMel). Does not fully ablate native hematopoiesis; relies on graft-versus-myelofibrosis (GvMF) effect for disease eradication. TRM 10–15% in fit elderly patients at experienced centers; applicable to patients age 55–70. Higher relapse rate than MAC.

Transplant Outcomes in Myelofibrosis

• 3-year overall survival: 30–60% depending on risk score, age, donor type, conditioning regimen, and center experience
• Treatment-related mortality (TRM): 10–20% at experienced centers with RIC; higher with MAC in older patients
• Relapse: 20–30% at 3–5 years; molecular relapse (JAK2V617F or CALR allele burden rising) can precede clinical relapse by months
• Fibrosis resolution: In patients who engraft successfully, bone marrow fibrosis typically resolves over 6–18 months post-transplant. MF-3 at transplant can become MF-0 by 1 year in a responder.
• Molecular monitoring post-transplant: JAK2V617F allele burden by quantitative PCR at day 30, 60, 90, 180, 365 post-transplant. Rising allele burden warrants donor lymphocyte infusion (DLI) consideration before overt morphologic relapse occurs.

Graft-versus-Host Disease (GvHD)

Acute GvHD (aGvHD): Occurs within the first 100 days. Targets skin (maculopapular rash), liver (cholestasis), and GI tract (profuse watery diarrhea, nausea, abdominal pain). Grade 1–2: managed with topical steroids and systemic methylprednisolone 1–2 mg/kg/day. Grade 3–4: escalation to second-line agents including ruxolitinib (FDA-approved for steroid-refractory aGvHD 2021, REACH2 trial CR rate approximately 34%).

Chronic GvHD (cGvHD): Onset typically after day 100; can affect virtually every organ system. Belumosudil (Rezurock), ibrutinib (Imbruvica), and ruxolitinib are FDA-approved for steroid-refractory cGvHD.

Transplant Centers Serving Utah and the Mountain West

• Huntsman Cancer Institute, University of Utah — Salt Lake City, UT: 801-585-0303 — BMT program with MPN specialty
• University of Utah Hematology: 801-581-2121
• Intermountain Health — Salt Lake City, UT: 801-442-2000
• VA Salt Lake City Health Care System (Wahlen VA): 801-582-1565
• MD Anderson Cancer Center — Houston, TX: 713-792-2121 — one of the highest-volume MPN transplant programs globally
• Mayo Clinic — Rochester, MN: 507-284-2511 — Dr. Kebede Begna; Dr. Mrinal Bhave; internationally recognized MPN program
• Memorial Sloan Kettering Cancer Center — New York, NY: 212-639-2000
• Cleveland Clinic — Cleveland, OH: 216-444-6833
• Fred Hutchinson Cancer Center — Seattle, WA: 206-667-5000 (approximately 840 miles from Salt Lake City)
• Stanford Medicine — Palo Alto, CA: 650-723-6111 (approximately 740 miles from Salt Lake City)

Investigational Therapies and the MF Pipeline

Pelabresib (CPI-0610) — BET Bromodomain Inhibitor

Developer: Constellation Pharmaceuticals (acquired by MorphoSys/Novartis). Mechanism: Pelabresib inhibits BET proteins — specifically BRD2, BRD3, and BRD4 — which are epigenetic readers that regulate transcription of oncogenes including MYC, as well as inflammatory cytokines that drive MF pathobiology. By silencing BET-driven transcription, pelabresib reduces MYC-dependent proliferation and decreases inflammatory cytokine output. It does not directly inhibit JAK signaling, making it a mechanistically complementary partner to ruxolitinib.

MANIFEST-2 trial (NCT04603495): Randomized, double-blind, placebo-controlled Phase 3 trial comparing pelabresib 125 mg once daily plus ruxolitinib vs placebo plus ruxolitinib in approximately 249 JAK inhibitor-naive patients with intermediate-2 or high-risk MF. SVR35 at week 24: 65.9% (pelabresib arm) vs 35.2% (placebo arm). On mature (48-week) analysis the symptom co-primary TSS50 was not statistically significant overall (~52% vs 46%, p=0.216), and an imbalance in leukemic transformation was noted. Novartis did not pursue a US filing on these data; a confirmatory Phase 3 (MANIFEST-3, NCT07357727) is ongoing. Pelabresib is not FDA-approved.

Navitoclax (BCL-2/BCL-XL Inhibitor, AbbVie)

Mechanism: Navitoclax inhibits anti-apoptotic BCL-2 family proteins — BCL-2, BCL-XL, and BCL-w — restoring programmed cell death in malignant cells that have upregulated these survival proteins. BCL-XL inhibition also reduces platelet survival, which limits navitoclax dosing due to thrombocytopenia.

TRANSFORM-1 trial (NCT04472598): Phase 3 randomized trial of navitoclax 200 mg daily plus ruxolitinib vs placebo plus ruxolitinib in JAK inhibitor-naive patients. SVR35 at week 24: 63% (navitoclax arm) vs 31% (placebo arm); however, the symptom co-primary was not met. After regulatory feedback, AbbVie discontinued the navitoclax myelofibrosis program (the TRANSFORM-2 study was halted in April 2024); navitoclax is not FDA-approved for MF. Dose-limiting thrombocytopenia: platelet count <75,000 requires dose hold/reduction.

Navtemadlin (KRT-232) — MDM2 Inhibitor

Developer: Kartos Therapeutics. Mechanism: The MDM2 protein is upregulated by the malignant clone to ubiquitinate and degrade p53, neutralizing its tumor-suppressor function. Navtemadlin blocks the MDM2-p53 interaction, allowing p53 to accumulate and trigger apoptosis. This mechanism is TP53-dependent — patients must have wild-type TP53 to benefit; mutant TP53 tumors are intrinsically resistant.

BOREAS trial (NCT03662126): Phase 3 randomized trial of navtemadlin versus best available therapy (BAT) in previously JAK inhibitor-treated MF patients who are TP53 wild-type. This addresses the urgent unmet need in the second-line post-JAKi setting. Navtemadlin carries FDA Breakthrough Therapy Designation. BOREAS reported at ASH 2024: navtemadlin improved SVR35 (15% vs 5%) and TSS50 (24% vs 12%) versus BAT.

Selinexor (Xpovio) — XPO1/Exportin-1 Inhibitor

Developer: Karyopharm Therapeutics. Mechanism: XPO1 (exportin-1) shuttles tumor suppressor proteins (p53, FOXO, pRb) from the nucleus to the cytoplasm, inactivating them. Selinexor blocks XPO1, forcing these tumor suppressors to remain in the nucleus. Already FDA-approved for multiple myeloma and DLBCL. SENTRY trial (NCT04562389): Phase 3 randomized trial of selinexor 60 mg once weekly plus ruxolitinib vs placebo plus ruxolitinib in JAK inhibitor-naive MF. Results pending.

Imetelstat (Rytelo) — Telomerase Inhibitor

Developer: Geron Corporation. Mechanism: Imetelstat is a first-in-class telomerase inhibitor — a lipid-conjugated 13-mer oligonucleotide that competitively inhibits telomerase (hTERT) enzymatic activity. Malignant hematopoietic stem cells are critically dependent on telomerase to maintain telomere length and replicate indefinitely; imetelstat preferentially shortens telomeres in MPN clone cells. IMbark Phase 2 trial (NCT02426086): Post-JAK inhibitor MF patients; the 9.4 mg/kg cohort demonstrated median overall survival of 29.9 months compared to a historical control of approximately 14 months in comparable post-JAKi MF patients. Imetelstat received FDA approval in June 2024 for myelodysplastic syndrome (MDS). Phase 3 trial development for MF is ongoing.

Luspatercept — INDEPENDENCE Trial for MF Anemia

As described in the Anemia Management section, luspatercept's INDEPENDENCE trial (NCT04717414) did not meet its primary endpoint of transfusion independence (p=0.0674), though secondary anemia endpoints showed clinically meaningful benefit. It is not FDA-approved for MF; the sponsor is in regulatory discussions.

IDH1/IDH2 Inhibitors for Mutant Blast-Phase MF

Approximately 3–5% of MF patients harbor IDH1 or IDH2 mutations, which increase substantially in blast-phase transformation. FDA-approved IDH inhibitors from the AML setting are being used off-label and in trials for IDH-mutant accelerated/blast-phase MF: ivosidenib (Tibsovo) for IDH1-mutant disease; enasidenib (Idhifa) for IDH2-mutant disease. These agents can reduce blast counts and serve as bridges to transplant. Differentiation syndrome is a class toxicity to monitor.

Emerging Anemia-Directed Biologics and Future Directions

KER-050 (Keros Therapeutics): A modified activin receptor type IIA-Fc fusion protein designed to improve anemia and thrombocytopenia in MF by inhibiting multiple TGF-beta ligands including GDF11, activin A, and activin B. Phase 2 trial data in MF with anemia are emerging. CALR-targeting strategies: Mutant CALR generates a neoantigen specific to the malignant clone, making it an ideal immunotherapy target. Early-phase trials of CALR mutant-specific vaccines and T-cell therapies are underway. JAK2V617F peptide vaccines: Phase 1/2 trials evaluating safety and immunogenicity; combination with checkpoint inhibitors is being explored. Anti-ALK2/ACVR1 antibodies: A class of monoclonal antibodies directly targeting ACVR1 to reduce hepcidin production are in early development — the next generation of hepcidin-pathway modulation beyond momelotinib's kinase inhibition approach.

How to Find and Enroll in a Clinical Trial

• MPN Research Foundation Clinical Trial Finder: mpnresearchfoundation.org — disease-specific, curated trial listings with patient-friendly descriptions
• ClinicalTrials.gov: Search "myelofibrosis" as condition; filter by status (recruiting), age, proximity (ZIP code radius), and phase
• Huntsman Cancer Institute — Salt Lake City, UT: 801-585-0303 — ask for the clinical trials office or MPN coordinator
• University of Colorado Cancer Center — Aurora, CO: 720-848-0300 (approximately 550 miles from Salt Lake City)
• Mayo Clinic Arizona — Scottsdale, AZ: 480-301-8000 (approximately 600 miles from Salt Lake City)
• MD Anderson — Houston, TX: 713-792-2121 — leading MPN trials site; telehealth consultation available for trial eligibility screening

Clinical Trials

Completed Pivotal Trials

• COMFORT-I (NCT00952289): Double-blind, placebo-controlled trial of ruxolitinib in 309 patients with intermediate-2 or high-risk MF. SVR35 at week 24: 41.9% ruxolitinib vs 0.7% placebo. Published New England Journal of Medicine 2012, PMID 22375971. Led directly to the first FDA approval of any drug for myelofibrosis in November 2011.
• COMFORT-II (NCT00934544): Open-label trial comparing ruxolitinib to best available therapy in 219 European patients. SVR35 at week 48: 28% vs 0%. Durable responses and overall survival advantage confirmed. Published New England Journal of Medicine 2012, PMID 22375970. Supported EMA approval of Jakavi in 2012.
• JAKARTA (NCT01437787): Randomized, double-blind, placebo-controlled trial of fedratinib 400 mg daily in 289 patients. SVR35 at week 24: 36% fedratinib vs 1% placebo. TSS50: 40% vs 9%. Published JAMA Oncology 2015;1(5):643-651, PMID 26181658. Supported FDA approval of fedratinib (Inrebic) in August 2019.
• JAKARTA-2: Single-arm Phase 2 trial of fedratinib in patients previously treated with ruxolitinib. SVR35 achieved in 27% of patients. Established fedratinib as the standard second-line option after ruxolitinib.
• PERSIST-2 (NCT02055781): Randomized trial of pacritinib 200 mg BID or 400 mg QD versus best available therapy in patients with platelet counts below 100,000/µL. Among patients with platelet counts under 50,000: SVR35 29% on pacritinib 200 mg BID vs 3% on BAT. Published JAMA Oncology 2018, PMID 29522138. FDA approved pacritinib in February 2022 specifically for patients with platelet counts below 50,000/µL.
• SIMPLIFY-1 (NCT01969838): Randomized, double-blind, active-controlled trial of momelotinib versus ruxolitinib in 432 JAK-inhibitor-naive patients. Momelotinib non-inferior to ruxolitinib for SVR35 (26.5% vs 29%). Transfusion independence rates significantly higher with momelotinib: 66.5% vs 49.3%. Published Journal of Clinical Oncology 2017, PMID 28930494.
• MOMENTUM (NCT04173494): Randomized, double-blind, active-controlled trial of momelotinib versus danazol in 195 patients with prior JAK inhibitor treatment and anemia. TI rate: 30.6% vs 19.6%. TSS50: 24.6% vs 9.2%. Published Lancet 2023;401(10373):269-280, PMID 36709073. Led to FDA approval of momelotinib (Ojjaara) in September 2023 with an explicit anemia indication — the first JAK inhibitor with this label.

Active and Recently Reported Trials

• MANIFEST-2 (NCT04603495) — Pelabresib + Ruxolitinib vs Placebo + Ruxolitinib: Phase 3, randomized, double-blind trial of the BET bromodomain inhibitor pelabresib combined with ruxolitinib as frontline therapy. Reported at ASH 2023: SVR35 at week 24 was 65.9% in the combination arm versus 35.2% in the ruxolitinib plus placebo arm. TSS50 was not statistically significant overall on mature analysis (~52% vs 46%, p=0.216), with a leukemic-transformation imbalance; no US filing was pursued on these data. MANIFEST-3 (NCT07357727) is ongoing.
• BOREAS (NCT03662126) — Navtemadlin (MDM2 inhibitor, Kartos Therapeutics): Phase 3, randomized trial of navtemadlin versus best available therapy (BAT) in patients with TP53 wild-type MF previously treated with a JAK inhibitor. Reported at ASH 2024 (SVR35 15% vs 5%; TSS50 24% vs 12%). FDA Breakthrough Therapy Designation.
• SENTRY (NCT04562389) — Selinexor + Ruxolitinib vs Placebo + Ruxolitinib: Phase 3, randomized, double-blind trial of the XPO1 inhibitor selinexor combined with ruxolitinib as frontline therapy. Results expected 2025–2026.
• TRANSFORM-1 (NCT04472598) — Navitoclax + Ruxolitinib vs Placebo + Ruxolitinib: Phase 3, randomized, double-blind trial of the BCL-2/BCL-XL inhibitor navitoclax combined with ruxolitinib in JAK-inhibitor-naive patients. SVR35 at week 24: 63% (navitoclax arm) vs 31% (placebo arm); symptom co-primary not met. AbbVie discontinued the navitoclax MF program in 2024 (TRANSFORM-2 halted); not FDA-approved.
• INDEPENDENCE (NCT04717414) — Luspatercept + Ruxolitinib: Phase 3, randomized, double-blind trial of luspatercept added to ongoing ruxolitinib in MF patients with transfusion-dependent anemia. Did NOT meet its primary transfusion-independence endpoint (p=0.0674); secondary anemia endpoints favorable. Not FDA-approved for MF.
• IMbark (NCT02426086) — Imetelstat (Geron): Phase 2 trial of the telomerase inhibitor imetelstat in patients with intermediate-2 or high-risk MF relapsed or refractory to JAK inhibitor therapy. Median OS 29.9 months in the 9.4 mg/kg cohort vs approximately 14 months historical control. Further Phase 3 development ongoing.

How to Find Open Trials

• MPN Research Foundation: mpnresearchfoundation.org — disease-specific trial finder curated for MPN patients; patient navigators available
• ClinicalTrials.gov: Search "myelofibrosis" + "recruiting" — filter by distance from your ZIP code; updated daily
• MPN Advocacy and Education International: mpnadvocacy.com — patient community with trial discussion forums
• Leukemia & Lymphoma Society Clinical Trial Finder: 1-800-955-4572 — free one-on-one navigation with a specialist
• Your treatment center: Huntsman Cancer Institute 801-585-0303; MD Anderson 713-792-2121; Mayo Clinic 507-284-2511; Cleveland Clinic 216-444-6833; Memorial Sloan Kettering 212-639-2000

International Access

United States

The US FDA has approved four JAK inhibitors for myelofibrosis — more than any other regulatory agency worldwide:

• Ruxolitinib (Jakafi, Incyte): FDA approved November 2011. Generic ruxolitinib became available in the US in 2024 from multiple manufacturers (Teva, Sun Pharma, others). Medicare Part D covers both brand and generic. VA formulary: available at VA medical centers nationally with hematology consultation.
• Fedratinib (Inrebic, Bristol-Myers Squibb): FDA approved August 2019. Covered under most Medicare Part D and commercial plans; prior authorization typically required.
• Pacritinib (Vonjo, CTI BioPharma/Swedish Orphan Biovitrum): FDA approved February 2022 specifically for adults with MF and platelet counts below 50,000 per microliter. This is the only agent approved for severe thrombocytopenia; no equivalent approval exists in the EU or most other jurisdictions as of 2024.
• Momelotinib (Ojjaara, GSK): FDA approved September 2023 for intermediate or high-risk MF in adults with anemia. The first JAK inhibitor with a dedicated anemia indication on its label.

Financial assistance (US): Incyte Cares Program 1-855-463-3463 (Jakafi); BMS patient assistance (Inrebic); GSK Oncology Access (Ojjaara); CTI BioPharma assistance (Vonjo) 1-877-557-2676; LLS copay assistance 1-800-955-4572; NeedyMeds.org for all four agents.

European Union

The European Medicines Agency (EMA) has approved three of the four US-approved agents. Pacritinib does not hold EMA approval as of 2024.

• Ruxolitinib (Jakavi, Novartis): EMA approved August 2012. Available in all EU member states; national reimbursement varies. Germany (GKV/AMNOG process), France (ATU/AAP process), Netherlands (ZIN assessment), Belgium (NIHDI), and Spain (AEMPS) each have their own coverage pathways.
• Fedratinib (Inrebic, BMS): EMA approved April 2021. Indicated for intermediate-2 and high-risk MF in adults who have been previously treated with ruxolitinib or are naive to JAK inhibitor treatment. National reimbursement roll-out ongoing across EU member states.
• Momelotinib (Ojjaara, GSK): EMA approved 2024. Reimbursement assessments proceeding through national HTA bodies. Patients in countries where reimbursement is not yet secured may apply for compassionate use (named patient program) through their treating center.
• Pacritinib: Not EMA approved as of 2024. EU patients with severe thrombocytopenia (platelets under 50,000) should discuss compassionate use or enrollment in clinical trials with their hematologist. CRIMM Florence and Aachen have experience accessing investigational agents for this population.

EURORDIS (Rare Diseases Europe, eurordis.org) provides cross-border access guidance and patient advocacy support across EU member states for rare hematologic conditions including myelofibrosis.

United Kingdom

NICE (National Institute for Health and Care Excellence) assesses drugs for NHS England commissioning:

• Ruxolitinib: NICE Technology Appraisal TA386, approved August 2016 for treatment of disease-related splenomegaly or symptoms in adults with primary, post-PV, or post-ET MF. NHS England specialist commissioning; available via haematology centres with MPN expertise.
• Fedratinib: NICE Technology Appraisal TA784, approved December 2022 for adults with intermediate-2 or high-risk MF who have been treated with ruxolitinib.
• Momelotinib: NICE appraisal in progress as of 2024–2025. Ask your haematologist about Managed Access Agreement or early access programs.
• Key UK centre: Guy's and St Thomas' NHS Foundation Trust, London — Professor Claire Harrison (Reader in Haematology and international MPN thought leader); King's College Hospital; Christie Hospital Manchester; Edinburgh Cancer Centre.

Canada

• Ruxolitinib: Health Canada approved 2012; pan-Canadian Oncology Drug Review (pCODR) recommendation for reimbursement through provincial drug programs. Available through all provincial cancer programs.
• Fedratinib: Health Canada approved 2020; reimbursement through provincial exceptional access programs.
• Momelotinib: Health Canada approved 2024; pCODR reimbursement assessment pending in most provinces. GSK compassionate access program available.
• Key Canadian centre: Princess Margaret Cancer Centre, Toronto (610 University Ave, Toronto, ON; 416-946-2220) — Dr. Vikas Gupta (leading Canadian MPN specialist). BC Cancer Vancouver; Juravinski Cancer Centre Hamilton; Cross Cancer Institute Edmonton.

Australia

• Ruxolitinib: TGA approved 2013; listed on the Pharmaceutical Benefits Scheme (PBS) for MF — substantially subsidised for eligible patients.
• Momelotinib: TGA approved 2024; PBS listing assessment underway.
• Key Australian centre: Peter MacCallum Cancer Centre, Melbourne (305 Grattan St; 03 8559 5000); Royal Prince Alfred, Sydney; Princess Alexandra, Brisbane.

Japan

• Ruxolitinib: PMDA approved 2014. Reimbursed under National Health Insurance; available at major university hospitals and designated cancer centers.
• Fedratinib: PMDA approved 2022.
• Momelotinib: PMDA approved 2024.
• Key Japanese centres include the National Cancer Center Hospital (Tokyo) and Kyoto University Hospital.

Named International MPN Specialists

• CRIMM, Florence, Italy: Professor Alessandro Vannucchi and Dr. Paola Guglielmelli — among the world's foremost MF research groups; leaders of ELN MPN working group; AOU Careggi, Largo Giovanni Alessandro Brambilla 3, Florence.
• RWTH Aachen University Hospital, Germany: Professor Steffen Koschmieder — extensive MPN translational research program; Wilhelm-Johnen-Str., 52074 Aachen; +49 241 80-89805.
• Guy's Hospital, London, UK: Professor Claire Harrison — Chair of the UK MPN Forum.
• Princess Margaret Cancer Centre, Toronto, Canada: Dr. Vikas Gupta — Canada's leading MPN specialist.
• Peter MacCallum Cancer Centre, Melbourne, Australia: Contact MPN clinic via 03 8559 5000.

Global Patient Resources

• MPN Research Foundation: mpnresearchfoundation.org — global community, international trial finder
• MPN Advocacy and Education International: mpnadvocacy.com
• MPN World: mpn-world.org
• EURORDIS (EU patients): eurordis.org
• LLS International contacts: 1-800-955-4572

Treatments That Have Not Worked

Abandoned or Superseded Systemic Therapies

• Thalidomide: Investigated in early MPN trials based on its anti-angiogenic and immunomodulatory properties. Some patients showed modest hematologic responses, particularly improvement in anemia. However, tolerability was consistently poor — peripheral neuropathy (sometimes irreversible), somnolence, severe constipation, and venous thromboembolism limited dosing and duration. With the advent of JAK inhibitors, thalidomide has been largely abandoned in MF clinical practice and is not recommended in current NCCN or ELN guidelines.
• Pomalidomide: A more potent immunomodulatory agent (IMiD) evaluated specifically for MF-associated anemia and thrombocytopenia in Phase 2 trials. Modest hematologic responses in a minority of patients; no improvement in splenomegaly or constitutional symptoms. Not approved for MF. Remains an option in specific situations (del5q myeloid disease) but not for standard MF management.
• Panobinostat (HDAC inhibitor): Explored in Phase 2 combinations with ruxolitinib based on synergistic epigenetic rationale. Early combination data suggested additive activity in patients with residual splenomegaly on ruxolitinib. However, dose-limiting toxicities (thrombocytopenia, fatigue, gastrointestinal effects) complicated the combination, and no Phase 3 trial demonstrated superiority over ruxolitinib alone. Phase 3 development was not pursued. Panobinostat is approved for multiple myeloma but not for MF.
• Interferon alfa (non-pegylated): Conventional interferon alfa can reduce JAK2V617F allele burden and is cytoreductive. However, tolerability in MF is substantially worse than in polycythemia vera due to the cytopenias and constitutional symptom burden at baseline. Not approved for MF; not recommended in symptomatic intermediate or high-risk disease. Ropeginterferon alfa-2b (BESREMi) is FDA approved for PV but its role in MF remains investigational.
• Pelabresib (CPI-0610) as monotherapy: The MANIFEST Phase 2 trial included a monotherapy arm of pelabresib alone in patients with prior JAK inhibitor exposure. Single-agent activity was minimal — very few patients achieved SVR35 or meaningful TSS improvement. The positive signal that drove MANIFEST-2 came entirely from the combination arm (pelabresib plus ruxolitinib), not from monotherapy. BET inhibition appears to work through synergistic mechanisms with JAK inhibition rather than as a standalone strategy.
• Momelotinib: initial non-approval and the path to MOMENTUM: After SIMPLIFY-1 failed to show superiority over ruxolitinib on its primary SVR35 endpoint, and SIMPLIFY-2 did not meet its primary endpoint, the FDA did not approve momelotinib based on those data alone. A new trial specifically designed around the anemia endpoint (MOMENTUM vs danazol in anemia-predominant patients) was required before approval was granted in September 2023. This regulatory history illustrates how a drug's failure in one endpoint framework does not necessarily mean clinical irrelevance — trial design matters enormously.

Procedural Approaches with Limited Ongoing Role

• Splenectomy: Surgical removal of the spleen can dramatically reduce the mechanical burden of massive splenomegaly. However, it carries substantial operative mortality (5–10% at major centers), major perioperative risks (thrombosis, bleeding, hepatic enlargement with compensatory extramedullary hematopoiesis), and lifelong risk of overwhelming post-splenectomy infection (OPSI) requiring vaccination against encapsulated bacteria at least 2–4 weeks pre-operatively. Splenectomy does not address the underlying marrow disease, does not reduce constitutional symptoms, and may complicate or preclude allogeneic transplant conditioning. In the JAK inhibitor era, splenectomy is reserved for highly selected patients failing all medical therapies who are not transplant candidates and whose spleen-related morbidity is otherwise unmanageable.
• Splenic radiation: External beam radiation to the spleen provides temporary palliation of splenomegaly-related symptoms in patients who are not surgical candidates and have failed or are ineligible for medical therapy. Responses are modest (partial) and short-lived, typically lasting 4–6 months. Worsening cytopenias are a consistent toxicity. Radiation also compromises future transplant conditioning options. It is used only in the palliative setting for symptom management, not as disease-modifying therapy.
• Hydroxyurea: A cytoreductive agent useful in early or low-risk prefibrotic MF where JAK inhibitors may not yet be indicated. In intermediate-2 and high-risk MF, hydroxyurea does not meaningfully reduce splenomegaly, does not address constitutional symptoms, worsens anemia and thrombocytopenia, and does not alter the fibrotic process. It is not a substitute for JAK inhibitor therapy in symptomatic disease.

Specialist Centers

Mountain West and Utah

• Huntsman Cancer Institute (HCI) at the University of Utah
  2000 Circle of Hope Drive, Salt Lake City, UT 84112
  Phone: 801-585-0303
  NCI-designated Comprehensive Cancer Center. Full allogeneic stem cell transplant program. Dedicated hematologic malignancy and MPN clinic. Molecular profiling through ARUP Laboratories (on-site). Clinical trial participation in national cooperative group studies. Bone marrow biopsy with fibrosis grading and NGS mutation panel available.
• University of Utah Hematology Clinic
  50 N Medical Drive, Salt Lake City, UT 84132
  Phone: 801-581-2121
  Outpatient hematology referrals for MPN evaluation, CBC monitoring, and JAK inhibitor management.
• Intermountain Health Oncology
  5121 S Cottonwood St, Murray, UT 84107
  Phone: 801-442-2000
  Multiple Intermountain oncology locations across the Wasatch Front. Hematology/oncology consultation for MPN patients in the community setting; complex cases referred to HCI or regional transplant centers.
• George E. Wahlen VA Medical Center
  500 Foothill Drive, Salt Lake City, UT 84148
  Phone: 801-582-1565
  Hematology/oncology clinic for eligible veterans. Ruxolitinib available on VA formulary. Complex cases requiring transplant evaluation coordinated through community care network referral.

Nearest MPN Specialists (Outside Utah)

• University of Colorado Cancer Center
  13001 E 17th Place, Aurora, CO 80045
  Phone: 720-848-0300
  Approximately 525 miles from Salt Lake City. NCI-designated; hematologic malignancy and transplant program with MPN experience.
• Mayo Clinic Arizona
  13400 E Shea Blvd, Scottsdale, AZ 85259
  Phone: 480-301-8000
  Approximately 600 miles from Salt Lake City. Affiliated with Mayo Clinic Rochester MPN program; can provide second opinion consultations coordinated through the Mayo network.

US National Centers of Excellence

• MD Anderson Cancer Center — Leukemia/MPN Program
  1515 Holcombe Blvd, Houston, TX 77030
  Phone: 713-792-2121
  Drs. Prithviraj Bose and Srdan Verstovsek — among the world's most cited MPN investigators; extensive MF clinical trials portfolio; dedicated MPN clinic within leukemia department.
• Cleveland Clinic Taussig Cancer Institute
  9500 Euclid Ave, Cleveland, OH 44195
  Phone: 216-444-6833
  Dr. Jaroslaw Maciejewski — international expert in clonal hematopoiesis and myeloid malignancies; dedicated MPN and bone marrow failure program.
• Mayo Clinic Rochester — Hematology
  200 First St SW, Rochester, MN 55905
  Phone: 507-284-2511
  Drs. Mrinal Bhave and Kebede Begna — dedicated MPN specialists; Mayo multidisciplinary MPN board; bone marrow transplant program.
• Memorial Sloan Kettering Cancer Center
  1275 York Ave, New York, NY 10065
  Phone: 212-639-2000
  Dr. Raajit Rampal — leading translational MPN investigator; MSK MPN program; international clinical trial sites for novel combinations.
• Stanford Cancer Institute
  875 Blake Wilbur Drive, Stanford, CA 94305
  Phone: 650-725-8600
  Dr. Jason Gotlib — Director of the MPN Program; COMFORT, MOMENTUM, and MANIFEST-2 site investigator.
• University of Pennsylvania Abramson Cancer Center
  3400 Spruce St, Philadelphia, PA 19104
  Phone: 215-662-6364
  MPN program within hematologic malignancies division; access to Penn allogeneic transplant program.
• Fred Hutchinson Cancer Center
  1100 Fairview Ave N, Seattle, WA 98109
  Phone: 206-667-5000
  One of the world's leading allogeneic transplant centers; extensive experience with RIC conditioning for older MF patients; closest Pacific Northwest option for transplant-eligible Utah patients (approximately 840 miles).
• Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
  401 N Broadway, Baltimore, MD 21231
  Phone: 410-955-5000
  MPN and hematologic malignancy program; allogeneic transplant for MF.

Veterans Affairs

Veterans with MF should contact the hematology/oncology clinic at their nearest VA medical center. Ruxolitinib is available on the VA national formulary. For complex decisions (transplant evaluation, access to newer agents, clinical trials), ask your VA hematologist about a Community Care Network referral to an affiliated academic center.

Canada

• Princess Margaret Cancer Centre
  610 University Ave, Toronto, ON M5G 2M9
  Phone: 416-946-2220
  Dr. Vikas Gupta — Canada's leading MPN specialist and clinical trialist; access to Canadian clinical trials for MF; allogeneic transplant program on site.
• Vancouver BC Cancer (600 W 10th Ave, Vancouver; 604-877-6000)
• Juravinski Cancer Centre, Hamilton (699 Concession St; 905-521-2100)

International

• CRIMM, AOU Careggi, Florence, Italy: Prof. Alessandro Vannucchi and Dr. Paola Guglielmelli — reference centre for the European LeukemiaNet MPN working group.
• RWTH Aachen University Hospital, Germany: Prof. Steffen Koschmieder; Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation; +49 241 80-89805.
• Guy's and St Thomas' NHS Foundation Trust, London, UK: Prof. Claire Harrison; NHS England specialist commissioning for MPN.
• Peter MacCallum Cancer Centre, Melbourne, Australia: 305 Grattan St, Melbourne VIC 3000; 03 8559 5000.

For Patients and Caregivers

Managing Symptoms Day to Day

Drenching night sweats directly reflect the inflammatory cytokine burden driving the disease. Practical measures: cooling blankets or gel-filled mattress pads; moisture-wicking pajamas and bedding; a small fan directed at the bed; keeping the bedroom temperature at or below 68°F. Ruxolitinib is highly effective at reducing night sweats — if they persist on therapy, discuss dose optimization or a switch with your hematologist. Always report new or worsening night sweats promptly, as they can signal concurrent infection, which is a critical concern on JAK inhibitor therapy.

Aquagenic pruritus — intense itching triggered by contact with water — is a hallmark MPN symptom caused by abnormal mast cell activation and histamine release. Practical measures: cool or lukewarm showers (never hot); pat dry rather than rub; apply unscented moisturizer immediately after bathing. Pharmacological options: paroxetine (10–20 mg daily), non-sedating antihistamines for mild cases, colestipol, or narrowband UVB phototherapy for refractory cases. Ruxolitinib is the most effective single intervention for MPN pruritus and often resolves it substantially within the first few weeks of treatment.

Massive splenomegaly causes early satiety, left upper quadrant heaviness or aching, and occasionally acute, severe pain from splenic infarction. Daily management: eat small, frequent, soft meals; avoid large portions; avoid vigorous physical activity that compresses the abdomen; a warm compress can ease mild dull pain. Call your hematologist or go to the emergency department immediately for sudden, severe left-sided or left shoulder-tip pain — this may indicate splenic infarction, which requires urgent evaluation.

Fatigue in MF is multifactorial — driven by anemia, elevated inflammatory cytokines, disrupted sleep from night sweats, and the emotional weight of a serious diagnosis. Counterintuitively, moderate structured exercise — walking, swimming, cycling at a comfortable pace for 20–30 minutes most days — reduces MF-related fatigue more than rest does. Treat anemia aggressively (optimize JAK inhibitor, discuss momelotinib if anemia-dominant, consider transfusion support for symptomatic anemia). Share your fatigue level at every clinic visit using a 0–10 scale so it is formally documented and managed.

Bone pain in MF — particularly in the lower back, hips, and pelvis — reflects hematopoiesis in the marrow space under abnormal pressure from fibrosis. Management: acetaminophen as first-line for mild pain; NSAIDs (ibuprofen, naproxen) if platelets are adequate (typically above 100,000 — confirm with your hematologist); gabapentin or pregabalin if the pain has a neuropathic character; low-dose opioids for severe refractory pain managed by a palliative care or pain specialist. Do not self-medicate severe or worsening bone pain — it may signal blast phase transformation and requires urgent evaluation.

Infection Prevention on JAK Inhibitor Therapy

JAK inhibitors — particularly ruxolitinib — suppress immunologic surveillance needed to control latent and opportunistic infections. The risk of herpes zoster is increased 2–5 fold; tuberculosis reactivation, cryptococcal meningitis, PML, and hepatitis B reactivation have all been reported. Practical steps:

• Fever of 100.4°F (38°C) or higher: call your hematologist the same day. Do not wait until the next appointment.
• Wash hands thoroughly and frequently. Hand hygiene is the single most effective daily infection prevention measure.
• Avoid close contact with people known to have active infections, particularly shingles, chickenpox, or respiratory illnesses.
• Wear an N95 mask in crowded indoor spaces during respiratory virus seasons.
• Receive all recommended vaccinations before JAK inhibitor-induced immune responses blunt them further.

Vaccinations on JAK Inhibitor Therapy

• Shingrix (recombinant zoster vaccine, RZV): 2 doses, 2–6 months apart. This is the recombinant (non-live) shingles vaccine — it IS safe to receive while on a JAK inhibitor. Strongly recommended given the 2–5x increased shingles risk.
• Influenza: Annual inactivated or recombinant flu vaccine (not live attenuated nasal spray).
• Pneumococcal: PCV20 (Prevnar 20) once, plus PPSV23 if not previously received — per CDC schedule for immunocompromised adults.
• COVID-19: Annual updated COVID vaccine; additional doses may be recommended for immunocompromised patients.
• Meningococcal (MenACWY + MenB): Required if you have had or plan to have a splenectomy.
• Avoid all live attenuated vaccines: This includes MMR, varicella (chickenpox), yellow fever, and live attenuated influenza nasal spray.

Medication Safety

• Never abruptly stop ruxolitinib. Sudden discontinuation causes cytokine rebound syndrome — rapid return of fever, spleen pain, hypotension, and systemic inflammatory response that can be life-threatening. Taper over 1–2 weeks in coordination with your hematologist. If hospitalized, ensure your inpatient team knows to continue ruxolitinib unless there is a specific contraindication.
• Carry a full supply when traveling. Request a physician letter explaining your diagnosis and medication for airport security and international travel.
• Review all drug interactions with your pharmacist at every medication change. Ruxolitinib and fedratinib are CYP3A4 substrates — strong inhibitors can double drug levels; strong inducers can halve them.
• Thiamine supplementation (fedratinib patients): Your team should monitor thiamine (vitamin B1) levels. Report any confusion, unsteady gait, or double vision immediately — these are symptoms of Wernicke's encephalopathy, which requires stopping fedratinib and receiving intravenous thiamine urgently.

Financial Assistance Resources

• Incyte Cares Program (Jakafi/ruxolitinib): 1-855-463-3463 — copay assistance, free drug for uninsured or underinsured patients; incytecares.com
• BMS Patient Assistance (Inrebic/fedratinib): BMS Access Support 1-800-861-0048
• GSK Oncology Access (Ojjaara/momelotinib): 1-888-825-5249
• CTI BioPharma/SOBI (Vonjo/pacritinib): 1-877-557-2676
• Leukemia & Lymphoma Society (LLS): 1-800-955-4572 — copay assistance, travel grants, free patient navigation; lls.org
• NeedyMeds: needymeds.org — searchable database of all patient assistance programs by drug name
• FMLA documentation: Your hematologist can complete Family and Medical Leave Act paperwork to protect your employment during treatment, hospitalizations, or transplant recovery.
• Social Security Disability: High-risk MF with significant functional limitation may qualify. Ask your social worker at HCI or your treatment center for a referral.

Emotional Support and Community

• MPN Research Foundation: mpnresearchfoundation.org — patient support community, peer mentors who have lived with MF, annual MPN patient forum
• MPN Forum (MPN Advocacy and Education International): mpnforum.com — active online patient discussion community
• LLS Patient Navigation: Free one-on-one support from a blood cancer specialist; 1-800-955-4572
• Mental health integration: Anxiety and depression are common in MF given the uncertain prognosis and treatment burden. Ask your care team for a referral to an oncology psychologist or social worker. Many cancer centers offer integrated behavioral health at no additional cost.

Advance Care Planning

For patients with intermediate-2 or high-risk myelofibrosis — particularly those considering allogeneic transplant or those who have progressed through multiple JAK inhibitors — advance care planning is an important part of comprehensive care, not a sign of giving up. In Utah: complete a POLST (Physician Orders for Life-Sustaining Treatment) form, designate a healthcare proxy (durable power of attorney for healthcare), and document your wishes in an advance directive. Your social worker at HCI or your hematologist's office can provide the appropriate Utah forms.

Monitoring at Home

When starting or adjusting a JAK inhibitor, CBC monitoring is typically every 4 weeks until counts stabilize. Know your key numbers: hemoglobin (anemia threshold for transfusion typically below 8 g/dL), platelet count (dose adjustment thresholds for each JAK inhibitor differ — know yours), and white cell count (persistent elevation may signal disease progression). Keep a log of your counts and bring it to every appointment.

Fertility Preservation & Pregnancy with Myelofibrosis

Myelofibrosis can affect younger adults. Most targeted MF treatments are not safe during pregnancy, so careful planning is essential if you are of reproductive age.

Before starting treatment: fertility preservation

• Women — ask about egg or embryo freezing before starting any JAK inhibitor or chemotherapy. Discuss timing with your hematologist.
• Men — sperm banking is quick (a few days) and recommended before starting any MF treatment, especially hydroxyurea or JAK inhibitors.

MF medications and pregnancy

• Hydroxyurea — teratogenic; must be stopped before trying to conceive. Both men and women should stop hydroxyurea and use contraception. Men should stop at least 3 months before attempting conception; women should stop before conception.
• Ruxolitinib (Jakafi) — limited human pregnancy data; animal studies show harm. Avoid during pregnancy. Effective contraception is required. Do not breastfeed while taking ruxolitinib.
• Fedratinib (Inrebic) — animal data show fetal harm; avoid in pregnancy. Effective contraception required.
• Pacritinib (Vonjo) — limited data; avoid in pregnancy.
• Interferon alpha (Roferon-A, Intron A, Pegasys) — interferons have been used in MF and related blood disorders during pregnancy, particularly when JAK inhibitors or hydroxyurea are not safe. They are generally considered the most acceptable option for MF management during pregnancy, though they are not without risks. Discuss with your hematologist.

Pregnancy risks with myelofibrosis

Myelofibrosis during pregnancy is high-risk. Possible complications include thrombosis, bleeding (especially if platelet counts are very high or very low), worsening anemia, and progression of the disease itself. Close monitoring throughout pregnancy by both your hematologist and maternal-fetal medicine specialist is essential.

Glossary

Key References and Resources

Landmark Clinical Trial Publications

• Verstovsek S et al. "A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis." New England Journal of Medicine 2012;366(9):799-807. PMID: 22375971. (COMFORT-I)
• Harrison C et al. "JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis." New England Journal of Medicine 2012;366(9):787-798. PMID: 22375970. (COMFORT-II)
• Pardanani A et al. "Safety and Efficacy of Fedratinib in Patients with Primary or Secondary Myelofibrosis." JAMA Oncology 2015;1(5):643-651. PMID: 26181658. (JAKARTA)
• Mascarenhas J et al. "Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis (PERSIST-2)." JAMA Oncology 2018;4(5):652-659. PMID: 29522138. (PERSIST-2)
• Verstovsek S et al. "Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM)." Lancet 2023;401(10373):269-280. PMID: 36709073. (MOMENTUM)
• Mesa RA et al. "SIMPLIFY-1: Momelotinib versus ruxolitinib in JAK inhibitor-naive patients with myelofibrosis." Journal of Clinical Oncology 2017;35(34):3844-3850. PMID: 28930494. (SIMPLIFY-1)
• Pemmaraju N et al. "Pelabresib in Combination with Ruxolitinib for Myelofibrosis." ASH Annual Meeting Abstracts 2023. (MANIFEST-2 primary results)

Clinical Practice Guidelines

• National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms. Version 1.2026. Available at nccn.org/guidelines (free registration required).
• Vannucchi AM et al. "Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet." Leukemia 2018;32(5):1057-1069. (ELN/IWG-MRT consensus guidelines)
• Verstovsek S et al. "Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes." Oncologist 2014;19(1):97-108.

Regulatory Databases

• Drugs@FDA: accessdata.fda.gov/scripts/cder/daf/ — full prescribing information for ruxolitinib, fedratinib, pacritinib, momelotinib including Boxed Warnings
• ClinicalTrials.gov: clinicaltrials.gov — NCT00952289 (COMFORT-I), NCT00934544 (COMFORT-II), NCT01437787 (JAKARTA), NCT02055781 (PERSIST-2), NCT04173494 (MOMENTUM), NCT01969838 (SIMPLIFY-1), NCT04603495 (MANIFEST-2), NCT03662126 (BOREAS), NCT04562389 (SENTRY), NCT04472598 (TRANSFORM-1), NCT04717414 (INDEPENDENCE), NCT02426086 (IMbark)
• EMA European Public Assessment Reports (EPARs): ema.europa.eu/en/medicines

Patient and Caregiver Resources

• MPN Research Foundation: mpnresearchfoundation.org — patient support, trial finder, annual patient forum
• MPN Advocacy and Education International: mpnadvocacy.com
• MPN Forum: mpnforum.com
• Leukemia & Lymphoma Society: lls.org | 1-800-955-4572 — free patient navigation, financial assistance, clinical trial support
• MedlinePlus — Myelofibrosis: medlineplus.gov — plain-language overview from the US National Library of Medicine
• NeedyMeds: needymeds.org — patient assistance program database

Utah and Regional Resources

• Huntsman Cancer Institute, Salt Lake City: 801-585-0303 | healthcare.utah.edu/huntsmancancerinstitute/
• University of Utah Hematology Clinic: 801-581-2121
• Intermountain Health Oncology: 801-442-2000
• George E. Wahlen VA Medical Center: 801-582-1565

Based on: COMFORT-I NEJM 2012 (PMID 22375971); COMFORT-II NEJM 2012 (PMID 22375970); JAKARTA JAMA Oncol 2015 (PMID 26181658); PERSIST-2 JAMA Oncol 2017 (PMID 29522138); MOMENTUM Lancet 2023 (PMID 36709073); SIMPLIFY-1 JCO 2017 (PMID 28930494); NCCN MPNs v1.2026; ELN/IWG-MRT MPN Guidelines 2018; Drugs@FDA (ruxolitinib, fedratinib, pacritinib, momelotinib prescribing information); ClinicalTrials.gov; MPN Research Foundation; Leukemia and Lymphoma Society.

Quality of Life and Living Well with Myelofibrosis

Myelofibrosis places a substantial burden on daily life that goes far beyond lab values and spleen measurements. Fatigue, itching, night sweats, abdominal discomfort, bone pain, anxiety about the future, and financial strain are not minor inconveniences — for most patients they are the defining experience of this disease. Addressing them directly, with the same rigor applied to cytoreduction and transplant planning, is essential to living as fully as possible with MF.

Caregiver note: Living with myelofibrosis is a marathon, not a sprint — and so is caring for someone with MF. As a caregiver, watch honestly for signs of your own burnout: persistent exhaustion, withdrawal from your own social connections, resentment, or difficulty finding meaning in caregiving activities. These are signals to seek support, not signs of failure. Respite care — temporary relief from caregiving duties — is available through local senior services and community organizations. Caregiver support groups (separate from the patient's support group) are offered through the LLS (1-800-955-4572) and the MPN Research Foundation. HCI social work (801-585-0303) can connect you with community resources specific to the Salt Lake City area. You cannot sustain excellent caregiving from an empty reserve — your own well-being is not a luxury.