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Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by ineffective hematopoiesis, bone marrow fibrosis and splenomegaly which carries the risk of transforming to acute myeloid leukemia (AML).1 In approximately 95% of patients the underlying MF etiology involve mutations affecting the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling pathway. These include driver mutations in the JAK2, calreticulin (CALR) or the thrombopoietin receptor (MPL) genes.2
The JAK inhibitor, ruxolitinib, has long provided a licensed treatment option for patients with MF improving disease-related symptoms like splenomegaly and inducing hematological responses.1,2 Nevertheless, ruxolitinib is not a curative therapy and is also associated with significant treatment-limiting side effects, including anemia, thrombocytopenia, infections and weight gain. However, there is currently limited agreement on how to define ruxolitinib failure or intolerance. These current challenges along with more management recommendations have been further discussed in our article here.
For this, the Canadian MPN Group published in the Journal of Clinical Oncology a consensus for the early recognition and management of ruxolitinib failure in MF.2 We hereby summarize the key definitions and points raised in this consensus.
Table 1. Canadian MPN Group criteria for defining ruxolitinib failure in MF2
AP, accelerated phase; BP, blast phase; Hb, hemoglobin; JAK, Janus kinase; MF, myelofibrosis; MPN, myeloproliferative neoplasm *If dose optimization does not resolve the issue consider additional treatment strategy per the management algorithms shown below |
|||
Pattern of ruxolitinib failure |
Definition by the Canadian MPN Group |
Expected survival |
Optimization strategy for ruxolitinib* |
---|---|---|---|
Suboptimal spleen response |
< 25% reduction in palpable spleen length after at least 3 months of optimally dosed JAK inhibitor therapy |
14-18 |
Increase JAK inhibitor dose depending on Hb and platelet counts |
Loss of spleen response |
³ 50% increase in spleen length from best response |
14-18 |
Increase JAK inhibitor dose depending on Hb and platelet counts |
Transfusion-dependent anemia
|
³ 4 units of RBC transfusions in 8 weeks occurring ³ 6 months from ruxolitinib therapy |
8 |
Decrease JAK inhibitor dose |
Severe thrombocytopenia |
Unable to maintain unsupported platelet count > 35-50×109/L in patients receiving anticoagulation medication; and > 25×109/L in patients without coagulation |
8 |
Decrease JAK inhibitor dose |
Transformation to AP/BP |
|
4-6 |
Continue JAK inhibitor if required for splenomegaly and symptoms, dose adjustment dependent on Hb and platelet counts |
Second cancers |
|
variable |
Case-by-case discussion for JAK inhibitor discontinuation |
Infectious complications |
|
variable |
Consider potential benefit from adding prophylactic treatment to prevent recurrent infections |
2. Suboptimal Spleen or symptom response or loss of response
Figure 1. Management algorithm for ruxolitinib failure with suboptimal or loss of spleen response2
HCT, hematopoietic cell transplantation
a) Anemia
Figure 2. Management algorithm for ruxolitinib failure with a new onset transfusion-dependent anemia2
EPO, erythropoietin; ESA, erythropoietin-stimulating agent; HCT, hematopoietic cell transplantation
Figure 3. Management algorithm for the ruxolitinib failure with severe thrombocytopenia2
HCT, hematopoietic cell transplantation
Figure 4. Management algorithm for the ruxolitinib failure with severe thrombocytopenia2
AP, accelerated phase; AML, acute myeloid leukemia; BP, blast phase; HCT, hematopoietic cell transplantation
The Canadian MPN group have provided useful guidelines and management algorithms for the identification of MF patients with ruxolitinib failure. Recognition of the exact pattern of failure following ruxolitinib treatment is crucial for the management and outcomes of patients. A summary of the key recommendations discussed above are presented as useful practice points in Table 2 below.
Table 2. Useful practice points by the Canadian MPN Group for the management of MF patient with ruxolitinib failure2
DIPSS, Dynamic International Prognostic Stratification System; HCT, hematopoietic cell transplantation; MF, myelofibrosis; RBC, red blood cell |
|
1 |
Ruxolitinib dose optimization should be attempted in MF patients with suboptimal response or those who develop severe cytopenias |
---|---|
2 |
Patient survival after ruxolitinib failure is poor and variable depending on the cause (see Table 1). Patients should be clinically evaluated by experts if ruxolitinib failure is suspected |
3 |
HCT should be considered in eligible patients who failed ruxolitinib treatment. Consider earlier HCT referral in high-risk patients for ruxolitinib failure (i.e. high-risk DIPSS, RBC transfusion-dependent prior ruxolitinib, high-risk mutations like ASXL1 and EZH2) |
4 |
Patients not eligible for transplant should be offered enrolment in clinical trials |
5 |
When switching patients from ruxolitinib to alternative therapy, gradual taper should be considered, as sudden discontinuation can lead to withdrawal symptoms |
6 |
For symptomatic refractory splenomegaly, transfusion-dependent anemia and severe thrombocytopenia, symptom control such as splenectomy is a useful option |
Schieber M,Crispino J, Stein S et al. Myelofibrosis in 2019: moving beyond JAK2 inhibition.Blood Cancer Journal. 2019 ;9(9):74. DOI: 10.1038/s41408-019-0236-2
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