Treatment-free remission as a new goal for patients with PV

Polycythemia vera (PV) treatment goals vary according to clinical scenario.¹ For patients diagnosed with low-risk PV, treatment is often aimed at normalizing blood counts and reducing the risk of thrombotic events. While improvement of symptoms and quality of life is a universal aim, particular emphasis is placed on this in patients who are pregnant or trying to conceive in order to reduce the risk of late transformation, especially for younger patients. In clinical trials, the induction of a molecular response and restoration of normal hematopoiesis may be the primary focus.¹

During the European School of Hematology (ESH) 3rd How to Diagnose and Treat: CML/MPN meeting, Palandri¹ gave a presentation on the overall treatment goals for patients with PV, as well as discussing whether treatment-free remission is attainable and whether it should be a future focus. We summarize the key points from the presentation in the article below.

Goal 1: Prevention of vascular complications and reduce symptoms

• Prevention of complications through the control of associated risk factors is key
  • Lower risk of thromboembolism and higher overall survival
• Low-dose aspirin is recommended for all patients
• Hematocrit kept at <45% in order to lower mortality rates and risk of thrombotic events
• Hydroxyurea (HU) and interferon (IFN) treatment are both current first-line treatment options
  • International treatment guidelines do not yet provide rationale on how to select between either therapy
• HU is the most common choice for first-line therapy
  • Overall response rate is ~90%
  • Complete response rate is only ~20%
  • Rate of resistance is 11%
  • Reduces the risk of fatal/non-fatal cardiovascular events
  • Reduces recurrence of arterial and venous thrombosis
• The recent approval of IFN treatment was based on the PROUD (NCT01949805)/CONTINUATION (NCT02218047) studies
  • IFN was superior compared with HU in achieving a complete hematologic response
  • Patients were also more likely to achieve phlebotomy-free status
  • The Low-PV study (NCT03003325) also showed IFN to be superior compared with stringent phlebotomy alone
  • Treatment provided better control of leukocyte levels, platelet count, and splenomegaly

Goal 2: Prevention of disease progression

• For patients who are pregnant at the time of diagnosis, IFN is the only therapy considered safe for use
  • Potential benefits outweigh the risks when compared with HU and ruxolitinib treatment
  • Important for younger patients to reduce the risk of disease progression
• Bone marrow fibrosis at diagnosis is also a potential predictor of myelofibrosis evolution
• The presence of JAK2 mutation increases the risk of high leukocyte levels and platelet counts, inflammation, thrombosis, and genomic instability
  • High allele burden is associated with an increased risk of myelofibrosis transformation

Goal 3: Achieving a molecular response

• The MAJIC-PV trial (ISRCTN61925716) showed response rates of 56% in patients treated with ruxolitinib compared with 23% for patients treated with best available therapy
  • The median time to response was 36 months
  • 50% reduction in JAK2 allele burden leading to improved overall survival and clearance of myeloproliferative stem cells
  • Highlights potential disease modification effects
• The PROUD-PV/CONTINUATION-PV study (NCT01949805/NCT02218047) also showed significantly higher molecular responses with IFN when compared with HU
  • After 60 months of treatment, 53% of patients treated with IFN had <10% JAK2 variant allele frequency

Goal 4: Treatment-free remission

• Patients are considered to be in treatment-free remission when therapy is discontinued and the following occur:
  • Complete hematologic response
  • Deep molecular response
  • Reversion of bone marrow picture
  • Absence of vascular events and disease evolution
  • No treatment restart
• Treatment discontinuation with IFN is feasible
  • Prolonged complete hematologic response and <10% variant allele frequency at time of treatment stop is required

Conclusion

Treatment goals for patients with PV remain varied according to the clinical scenario. Treatment-free remission is currently only considered viable with IFN treatment. However, HU and ruxolitinib remain adequate options for first-line therapy through the control of disease-associated symptoms and reducing the risk of disease progression, which is especially important in younger patients. Overall, a thorough review of current treatment rationale may be important in optimizing clinical outcomes and fully exploring the potential for treatment-free remission.