How can Janus kinase (JAK) inhibitors be used to treat myeloproliferative neoplasms (MPNs) associated with JAK2 mutations in patients with a history of cancer, given their potential to cause secondary malignancies?

JAK Inhibitors in Myeloproliferative Neoplasms: Reconciling Cancer Risk with Therapeutic Use

JAK inhibitors are used to treat myeloproliferative neoplasms (MPNs) associated with JAK2 mutations because these conditions themselves ARE hematologic malignancies—the JAK inhibitors target the dysregulated JAK-STAT signaling pathway that drives the disease, not the mutation itself, which explains both their therapeutic benefit and their cancer risk profile. 1

Understanding the Paradox: Why JAK Inhibitors Work in MPNs Despite Cancer Warnings

The Mechanism Clarifies the Paradox

• JAK inhibitors are non-selective inhibitors that block both wild-type and mutated JAK2 equally, targeting the dysregulated JAK-STAT signaling present in all MF patients regardless of mutation status 1, 2
• The drugs work by inhibiting the pathologic signaling pathway rather than selectively eliminating the malignant clone, which is why they provide symptom control but limited disease modification 1, 2
• Ruxolitinib (JAK1/JAK2 inhibitor) demonstrates only modest effects on JAK2V617F allele burden reduction, confirming it acts primarily through anti-inflammatory mechanisms rather than clone eradication 1

MPNs Are Already Malignancies

• Myeloproliferative neoplasms are themselves hematologic cancers—polycythemia vera, essential thrombocythemia, and primary myelofibrosis are WHO-classified neoplasms with inherent risk of transformation to acute leukemia 1
• The JAK2V617F mutation is present in >90% of PV patients and ~60% of ET/PMF patients, representing the oncogenic driver 1
• These patients already carry malignancy; the question is managing their existing cancer, not preventing a new one 1

The Cancer Risk Profile: Context Matters

Risk in Inflammatory Diseases vs. MPNs

• The boxed warning for malignancy risk primarily derives from studies in rheumatoid arthritis patients, where a randomized trial of tofacitinib showed hazard ratio 1.48 (95% CI 1.04–2.09) for cancer versus TNF inhibitors, with lung cancer most common in patients ≥65 years 1
• In atopic dermatitis trials, baricitinib showed incidence rate of malignancies (except NMSC) of 0.22/100 patient-years versus 0.66/100 patient-years in placebo, suggesting the risk may be disease-context dependent 1
• The risk-benefit calculation differs fundamentally when treating an inflammatory condition versus treating an existing hematologic malignancy with median survival <5 years in high-risk myelofibrosis 1

Survival Benefit Outweighs Theoretical Risk

• Extended follow-up of COMFORT-I and COMFORT-II trials demonstrated survival advantage for ruxolitinib-treated myelofibrosis patients compared to placebo or best available therapy 1
• Historical comparisons with matched MF populations confirmed improved survival with ruxolitinib treatment 1
• Allogeneic stem cell transplantation—the only curative option—is justified when median survival is expected to be <5 years, establishing the threshold where aggressive intervention is warranted 1

Clinical Application: When to Use JAK Inhibitors in MPN Patients

Indications for JAK Inhibitor Therapy

For Myelofibrosis:

• Ruxolitinib is approved for intermediate-2 and high-risk myelofibrosis based on International Prognostic Scoring System (IPSS) 1
• Primary indication is splenomegaly ≥5 cm below left costal margin with constitutional symptoms 1
• Both JAK2-mutated and JAK2-unmutated patients benefit equally, as dysregulated JAK-STAT signaling is universal in MF 1

For Polycythemia Vera:

• Ruxolitinib is indicated for hydroxyurea-resistant or -intolerant PV 1, 2
• High-risk PV patients (age >60 years or prior thrombosis) should receive phlebotomy, low-dose aspirin, and cytoreduction with hydroxyurea or interferon first-line 1

Contraindications Related to Malignancy History

• There is no absolute contraindication to using JAK inhibitors in MPN patients with prior cancer history, as the MPN itself is a malignancy requiring treatment 1
• The decision requires weighing the immediate mortality risk from untreated MF (median survival 19.8 years for PV/ET but significantly shorter for high-risk MF) against theoretical secondary malignancy risk 1
• For patients with active solid tumor malignancies, coordinate care with oncology to assess whether the MPN or the solid tumor poses greater immediate mortality risk 1

Monitoring and Risk Mitigation

Enhanced Surveillance for Secondary Malignancies

• Baseline evaluation should include complete blood count, liver enzymes, creatinine, and assessment for lymphadenopathy 1, 3
• Monitor at 1 month, 3 months, then every 3 months with complete blood count and clinical examination for new masses or lymphadenopathy 1, 3
• Patients ≥65 years require heightened vigilance as malignancy risk was concentrated in older patients in RA trials 1
• Non-melanoma skin cancer surveillance is particularly important, as NMSC was analyzed separately in most trials 1

Dose Adjustments for Comorbidities

• For severe renal impairment (eGFR <30 mL/min), reduce fedratinib dose per FDA labeling 4
• Patients with moderate renal impairment require more intensive safety monitoring due to increased drug exposure 4
• Avoid JAK inhibitors in severe hepatic disease (Child-Pugh C); no adjustment needed for Child-Pugh A/B 1

Key Clinical Pitfalls

Common Misconceptions to Avoid

• Do not withhold JAK inhibitors from MPN patients solely based on prior cancer history—the MPN is itself a malignancy requiring treatment, and survival benefit is established 1
• Do not abruptly discontinue ruxolitinib—sudden withdrawal can provoke shock-like syndrome from re-emergence of suppressed inflammatory cytokines; taper the drug if discontinuation is necessary 1
• Do not expect disease modification or cure—JAK inhibitors provide symptom control and survival benefit but have minimal effect on clone burden or disease biology 1, 2
• Do not assume JAK2 mutation status determines treatment eligibility—JAK inhibitors work equally well in JAK2-mutated and unmutated patients because they target the pathway, not the mutation 1, 2

Managing Competing Risks

• In patients with both active solid tumor and symptomatic MF, prioritize the condition with shorter expected survival if untreated 1
• For patients with remote cancer history (>5 years disease-free), the MPN typically takes precedence as the active malignancy requiring immediate management 1
• Thrombocytopenia is the dose-limiting toxicity for JAK inhibitors, not malignancy risk—adjust dosing based on platelet counts per FDA labeling 1, 4