In the management of myelofibrosis (MF), Janus kinase (JAK) inhibition as first-line treatment has been shown to play a crucial role in the reduction of symptom burden and spleen size, as well as the preservation of blood count in patients. A JAK1/2 inhibitor, ruxolitinib, has been part of the treatment algorithm for almost a decade in treating intermediate or high-risk MF based on results from the COMFORT phase III trials. However, patients with MF are still likely to experience disease that becomes unresponsive to JAK inhibitors (JAKi). At that point, the disease may become more aggressive, and its management more challenging, with an approximated survival in the range of 14 months.1
In our first article of the new editorial theme series, we will focus on the challenges to define ruxolitinib failure and on the accompanying symptoms and clinical features that come with a more advanced disease. Our next article will provide an overview of novel drugs that are currently being tested either as monotherapy or in combination with ruxolitinib to treat relapsed/refractory (R/R) MF.
Before going in depth on treating R/R MF, we would like to indicate that the MPN Hub has also published a summary article on the biology, diagnosis, and treatment of MF here.
Ruxolitinib, the first approved JAK 1/2 inhibitor, has commonly been used for the treatment of primary or secondary, intermediate or high-risk MF for almost a decade following its approval by the U.S. Food and Drug Administration (FDA) in 2011 and the European Medicines Agency (EMA) in 2012. Ruxolitinib was shown to be superior to placebo and best available therapy, i.e., hydroxyurea, no medication, or prednisone/prednisolone, in COMFORT-I and COMFORT-II phase III trials, which also led to regulatory approvals. Ruxolitinib demonstrated a ≥35% reduction in spleen volume and >50% reduction in symptoms in more than half of the study population. Re-evaluation of the COMFORT trial data indicated that ruxolitinib may stabilize bone marrow fibrosis and improve overall survival (median of 30 months vs 22 months with alternatives).1
However, it is not uncommon for patients to have disease that loses response to JAK inhibition over time (>50% of patients within 3 years of JAKi therapy). Another challenge is that JAKi are associated with severe anemia or thrombocytopenia, which may be dose limiting. Furthermore, they induce immunosuppression with the risk of developing atypical infections. Although it is not confirmed, there is also a concern that patients receiving ruxolitinib could develop lymphoma.
Fedratinib is another JAK and FLT3 inhibitor that is currently approved by the FDA and EMA as first- and second-line therapy for the treatment of patients with primary or secondary MF. A detailed summary on fedratinib’s activity as a single agent for the treatment of R/R MF will be provided in an upcoming overview article.
What is JAK inhibition failure?
Robyn M. Scherber and Ruben A. Mesa1 define failure to JAKi when patients who are on treatment for ≥28 days demonstrate the following outcomes:
- An inadequate or loss of symptom response of >10% and unmet symptom needs.
- A need for dose adjustment to a subtherapeutic dose due to Grade ≥3 anemia, thrombocytopenia, or bleeding.
- A need for continuous red blood cell or platelet transfusion despite all efforts to manage cytopenias.
The Canadian Myeloproliferative Neoplasms (MPN) Group consensus, while acknowledging the difficulty to define ruxolitinib failure, agreed on the following seven criteria2:
- Suboptimal spleen response: a <25% reduction in palpable spleen length after ≥3 months of optimal JAK inhibitor therapy.
- Loss of spleen response: a 50% increase in spleen length from best response.
- Transfusion-dependent anemia: four units of red blood cell transfusion in 8 weeks within 6 months of ruxolitinib therapy.
- Severe thrombocytopenia: unable to maintain an unsupported platelet count >35–50 × 109/L in patients receiving anticoagulants and >25 × 109/L in patients not receiving anticoagulants.
- Transformation to accelerated phase/blast phase.
- The presence of second cancers.
- Occurrence of infectious complications.
In the JAKARTA trials investigating fedratinib in treating primary or secondary MF in JAKi-naïve patients or those who failed JAKi therapy, the following definitions were made:
- Refractoriness or loss of response was defined as ≥3 months administration of ruxolitinib with an initial response followed by either regrowth of the spleen or an insignificant response (defined as <10% reduction of spleen volume or <30% reduction in spleen size from baseline).
- Intolerance was defined as ≥28 days ruxolitinib therapy that led to the need of transfusion (≥2 units per month for 2 months) or the development of Grade ≥3 thrombocytopenia, anemia, hematoma, and/or hemorrhage during ruxolitinib treatment.
When JAK inhibition fails, allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be considered if the patient has high-risk disease, and is eligible for and willing to undergo allo-HSCT. However, considering the median age is ~60 years at the time of diagnosis, most patients are unlikely to be fit for this option.1
Challenges in managing R/R MF
In the case of ruxolitinib failure, treatment challenges arise from cytopenias, including anemia and thrombocytopenia, as well as loss of response in the spleen and symptoms.
Anemia represents an important characteristic of the disease, presenting in ~35% of patients at the time of diagnosis and occurring in almost all patients over the course of MF. Anemia is also considered as a risk factor in all prognostic scoring systems and is a known side effect of JAKi therapy that occurs mostly during early therapy. However, a post hoc analysis of the COMFORT phase III trials did not find that ruxolitinib-associated anemia led to shorter survival.2 The possible approaches for managing anemia include dose titration to lower JAK inhibitor doses, erythropoietin supplementation, a variety of combinations, including ruxolitinib + danazol, ruxolitinib + thalidomide, and ruxolitinib + pomalidomide, and hypomethylating agents.
Thrombocytopenia is another prognostic marker that is present in ≤25% of patients with MF. It can occur as a result of ineffective megakaryocytopoiesis, splenomegaly, abnormal spleen function, and mutational status. The progressive nature of MF may increase the rates of thrombocytopenia,3 while JAK inhibition is also known to be a contributing factor; in the COMFORT studies, patients experienced a platelet reduction of 15–20 × 109/L. 1 Another therapeutic option in treating MF is hydroxyurea, which is also known to induce thrombocytopenia.4
The management of thrombocytopenia may include the combination of ruxolitinib + danazol, ruxolitinib + thalidomide, lenalidomide monotherapy, or hypomethylating agents.3
More information on the management of thrombocytopenia in MF can be found here.
Loss of response
MF is characterized by constitutional symptoms, including fatigue, night sweats, weight loss, or cachexia. When response is lost, these disease-related symptoms recur. There are a variety options to manage individual symptoms. Low-dose aspirin can be considered for erythromelalgia and headaches. Pruritus may be resolved with H1 and H2 blockers, low-dose aspirin, topical steroids, or hydroxyzine, as well as UV-light treatment.1 The most common symptom, fatigue, may be managed with exercise, such as yoga or physical therapy. A recent survey-based study revealed that integrative medicine may be helpful to improve the symptoms and quality of life for patients with MPN. The MPN Hub has summarized this study in detail here.
Apart from these options, a drug holiday was found to have potential to reacquire response; however, the risk of abrupt discontinuation of JAK inhibitor should be considered.
A short drug holiday or optimizing/increasing the JAK inhibitor dosing, considering hemoglobin and platelet counts, may be typical approaches to reinduce spleen response if clinical trials are not available. Splenectomy or splenic radiation may be considered if the treatment options are limited or clinical trials are not available.
There is an unmet need for the treatment of R/R MF and investigators are putting a lot of effort into overcoming this challenge. A large number of clinical trials are under way to evaluate novel approaches of single agents or combinations with other targeted therapies, such as using ruxolitinib to improve outcomes and survival in patients with MF. In the next article, we will summarize the emerging single agents, including the JAKi fedratinib, pacritinib, and momelotinib, a telomerase inhibitor imetelstat, a lysine-specific demethylase-1 inhibitor bomedemstat, a second mitochondrial-derived activator of caspases mimetic LCL161, and a mouse double minute 2 inhibitor KRT-232, as well as allo-HSCT.