Defining ruxolitinib failure and transition to next-line therapy in MF

Ruxolitinib is a Janus kinase 1/2 (JAK1/JAK2) inhibitor commonly used as a first-line therapy for the treatment of myelofibrosis.¹ However, 50–72% of patients experience a loss of response or intolerability to ruxolitinib within 3–5 years of treatment, and discontinuation is complicated by serious adverse events risks and poor outcomes. There is currently a lack of consensus on the definition of ruxolitinib failure and guidance on the transition to next-line therapy.¹

A group of myelofibrosis experts, including steering committee member John Mascarenhas, formed a Delphi panel to lay out the criteria and guidance for the management of these patients.¹ The MPN Hub is pleased to summarize this consensus here.

Determining therapy failure¹

Ruxolitinib failure can be considered in three scenarios:

1. Non-response/primary refractory status
2. A loss of response
3. Progressive disease status

Primary refractory consensus

A 3-month period of a maximum tolerated dose of ruxolitinib is required before primary refractory status can be determined. Following this period, spleen and symptom response can be taken for comparison with baseline. Figure 1 outlines the consensus criteria for primary refractory status.

Figure 1. Consensus criteria for primary refractory status* 

LCM, Left costal margin; MF, myelofibrosis; MPN-SAF, Myeloproliferative Neoplasm Symptom Assessment Form; MRI, magnetic resonance imaging.
*Data from Mascarenhas, et al.¹

Loss of response consensus

A loss of response to ruxolitinib after an initial clinical response can be established by measuring changes in the same two clinical features; spleen and symptom response. These measures are considered in comparison with either baseline or best achieved response during the initial response period. Symptom changes can be measured using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) or using the patient-reported experiences. Criteria and assessments for a loss of response are outlined in Figure 2.

Figure 2. Consensus criteria for loss of response to ruxolitinib* 

MPN-SAF, Myeloproliferative Neoplasm Symptom Assessment Form.
*Data from Mascarenhas, et al.¹

Progressive disease consensus

Ruxolitinib failure is also considered in patients with characteristics of progressive disease. These characteristics are outlined in Figure 3. Progression of splenomegaly requires treatment adaption due to its links with splenic extramedullary hematopoiesis, hypertension, and increased cytopenia.

Figure 3. Consensus criteria for progressive disease status* 

BC, blast count; BM, bone marrow; LCM, Left costal margin.
*Data from Mascarenhas, et al.¹

Transition to next-line therapy¹

The transition to next-line therapy presents challenges, namely the risk of ruxolitinib discontinuation syndrome (RDS); characterized by relapse of symptoms, accelerated splenomegaly, and worsening of cytopenias. Figure 4 lists strategies for the transition to next-line therapy to mitigate the risk of RDS.

Figure 4. Strategies for next-line therapy transition* 

*Data from Mascarenhas, et al.¹

Conclusion

The lack of clear clinical guidelines on the definition of first-line ruxolitinib failure presents a challenge to transitioning patients to further lines of therapy. This Delphi panel reached a consensus on determining ruxolitinib failure based on non-response, loss of response, and characteristics of progressive disease. These criteria may serve to inform clinical decision making in the absence of evidence-based guidance. Strategies to limit the risk of adverse events and RDS are also defined to guide the transition of therapy based on individual risk factors and comorbidities.