Shopping Cart

TREATMENT: LOWER RISK

Management of lower risk disease is dependent on patient symptom burden. The Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) scoring system is a useful tool to parse out severity of symptomatic patients.²⁰ Clinicians should complete this assessment upon diagnosis for all and throughout the treatment period for those who initiate therapy to help determine its effectiveness. The MPN-SAF TSS is a patient self-reported assessment that requires the documentation of symptom severity on a scale from 0 to 10 of 10 different MF symptoms (e.g., fatigue, abdominal discomfort, night sweats). The individual scores are added together for a total score of 0 to 100 with 0 being no symptoms present and 100 being the worst imaginable symptom burden.

Patients who are lower risk and asymptomatic are observed only for signs of disease progression every 3 to 6 months. There is no data to recommend initiating treatment in these patients. Symptomatic patients, however, are treated with a variety of modalities based on presenting symptom(s).

Anemia Management

The primary mechanism of anemia due to MF is the displacement of medullary erythropoietic tissue by fibrosis, which results in inadequate erythropoiesis.²¹ Other mechanisms include destruction of circulating RBCs due to splenomegaly, a dilutional anemia effect due to plasma volume increases, and interestingly, genetic factors may play a role. Patients who have triple negative disease (the absence of CALR, MPL, and JAK mutations) are less likely to develop anemia than those with CALR or MPL mutations.²²

Fatigue resulting from anemia is 1 of the most debilitating symptoms for a patient with MF. In 2016, the MPN Landmark survey found that 80% of the 207 MF patients surveyed experienced fatigue that reduced their quality of life (QoL).²³ Furthermore, a large cohort of 1000 MF patients revealed that 24% were RBC transfusion-dependent at the time of diagnosis and more had Hgb levels of less than 10 g/dL.¹⁰ Over the course of the disease, nearly all untreated MF patients will become transfusion-dependent. The definition of transfusion-dependence per the International Working Group-Myeloproliferative Neoplasm Research and Treatment (IWG-MRT) consensus report is greater than 6 RBC units in a 12 week period for a Hgb of less than 8.5 g/dL.²⁴ Because transfusion-dependence is a poor predictor of survival, many trials of therapeutic agents for MF have transfusion-independence as an endpoint. In addition, iron overload is a risk of chronic RBC transfusions, and there is no clear data that chelation improves outcomes in MF specifically.²⁵ Given anemia’s significance on affecting patient outcomes, clinicians should be aware of how to manage it and strive to achieve their patient’s transfusion-independence. Table 4 describes current therapies for MF-associated anemia.

Androgens were at 1 time considered the treatment of choice for MF-induced anemia. Androgens are theorized to work via a direct stimulating effect on erythropoietin production.²⁶ Small trials of testosterone derivatives have produced response rates of anywhere from 30% to 60%.²⁷ These trials, however, lacked robustness and a standard definition of response as per the IWG-MRT criteria. Danazol is a unique semisynthetic androgen that has become the standard go-to medication in its class given its studied efficacy and favorable safety profile. Though no direct comparative trials have been performed, Cervantes et al. studied danazol at a starting dose of 600 mg orally daily in 50 patients.²⁸ After a median follow-up of 36 months, response was seen in 30% of patients. Of those who were transfusion-dependent, 18.5% had a response which endured for a median of 14 months. Toxicity was moderate with the most frequent adverse drug reaction of a grade 1 or 2 transaminitis. Because of the pro-stimulatory effects of androgens on prostate cancer cells, researchers monitored prostate specific antigen (PSA) for all patients. Clinicians should be aware of danazol-related hepatoxicity, as it is metabolized almost exclusively via the liver and its use is contraindicated in patients with markedly impaired hepatic function. Clinicians need to monitor liver function tests (LFTs) and PSA. Lastly, for patients responding to therapy, providers can lower the dose to the minimum necessary to maintain efficacy.

Erythropoiesis stimulating agents (ESAs) are attractive because of their ability to induce maturation and differentiation of erythroid progenitor cells. Researchers have studies erythropoietin and darbepoetin for MF-associated anemia. In a study of 20 patients, erythropoietin 10,000 units given subcutaneously 3 times per week allowed for a cessation of transfusion requirements and a normalization of Hgb values for 8 weeks in 20% of patients.²⁹ Darbepoetin 150 mcg subcutaneously weekly (increased to 300 mcg if no response was observed after 4 to 8 weeks) was found to be similarly effective with 40% of patients achieving a response throughout the treatment period.³⁰ In both studies, patients who were transfusion-dependent or had serum erythropoietin (S-EPO) levels of less than 125 U/L at baseline did not respond to therapy. Therefore, ESAs should not be used for those patients meeting these criteria. In addition, clinicians should be aware that ESAs can exacerbate splenomegaly.³¹

Immunomodulatory inhibitors (IMiDs) are used for a variety of hematologic disorders including MF-associated anemia due to their anti-angiogenic, anti-tumor necrosis factor-alfa, and anti-inflammatory properties. All 3 current IMiDs (lenalidomide, pomalidomide, and thalidomide) have been studied to ameliorate MF-associated symptoms, including anemia. The earliest trials of thalidomide for MF-associated anemia studied doses of 100 to 200 mg orally daily. In a pooled analysis of trials at this dose, 29% of patients with moderate or severe anemia had an increase in Hgb levels or reduced RBC transfusions.³² Unfortunately, many patients discontinued the drug within 6 months due to an inability to tolerate adverse drug reactions. This led to investigators study lower doses of 50 mg daily with the addition of prednisone in an attempt to mitigate toxicity. There was some success to this strategy, as 95% of patients were able to finish 3 months of therapy with 62% achieving an objective complete response in anemia improvement and 40% becoming transfusion-independent.³³ Prednisone is dosed at 0.5 mg/kg/day by mouth and then tapered when given concurrently with thalidomide. Prohibitive toxicities of thalidomide include fatigue, constipation, and neuropathy.

Lenalidomide 10 mg orally daily can also be combined with prednisone to help prevent toxicity while also decreasing incidence of neuropathy. Responses with this combination are as modest as thalidomide plus prednisone with 23% of patients having a response in their anemia in a phase II trial. This does come at the cost of myelosuppression, however, as 88% of patients had a grade 3 or greater hematologic toxicity.³⁴ Though the incidence of a del 5q is rare in MF, these patients may benefit the most from lenalidomide therapy, as remissions have been reported.³⁵ The authors conclude that lenalidomide should be the drug of choice in this patient population.

The second-generation IMiD, pomalidomide, showed promise in early phase trials. Unfortunately, the phase III randomized placebo-controlled RESUME trial—which studied pomalidomide 0.5 mg orally daily in transfusion-dependent MF patients—produced disappointing results with transfusion-independence only occurring in 16% of patients in both arms.³⁶ Given this, pomalidomide is not recommended for MF-associated anemia.

Overall, IMiDs have a relatively modest benefit in MF-associated anemia, and their best use yet may be in combination therapy with other MF-active drugs. Multiple trials are ongoing using IMiDs with ruxolitinib to capitalize on targeting multiple pathways.^37,38 Although, this strategy has not always paid off. Because of single agent lenalidomide’s prominent myelosuppression, the combination with ruxolitinib led to early discontinuation rates due to the augmentation of hematologic toxicity.³⁹

A recently-developed agent that clinicians have in their armamentarium treats MF-associated anemia in a novel way. Luspatercept is a activin receptor ligand trap that the United States Food and Drug Administration (FDA) approved in April 2020 for use in beta thalassemia and anemia in myelodysplastic syndromes failing to respond to ESAs.^40,41 This agent is able to stop the blockade of the end stages of erythropoiesis by sequestering bone marrow stroma-derived ligands that belong to the transforming growth factor-beta superfamily to prevent them from binding to activin IIB receptors. Clinicians administer luspatercept subcutaneously every 3 weeks at a starting dose of 1 mg/kg and then titrate to response defined as a reduction in RBC transfusion burden. Providers should assess Hgb prior to each dose and blood pressure throughout therapy, as there is a risk of hypertension. For MF, researchers are currently studying luspatercept in a phase III randomized, placebo-controlled trial in transfusion-dependent patients who are receiving concomitant Janus kinase (JAK) inhibitors.⁴²

Finally, JAK inhibition is another attractive modality to combat MF-associated anemia. Although the 2 FDA-approved JAK inhibitors are traditionally used to primarily decrease spleen size, momelotinib—an investigational drug currently in clinical trials—has the unique added property of alleviating anemia. This is paradoxical, as JAK inhibition can cause myelosuppression as an adverse drug reaction. However, momelotinib also inhibits ACVR1/ALK2, which in turn upregulates hepcidin synthesis leading to the amelioration of anemia.⁴³ Phase III trial data of momelotinib showed it was not able to improve total symptom scores in MF patients over ruxolitinib; however, there was a noted benefit in transfusion-independence at 24 weeks in the momelotinib arms. Because of this, the MOMENTUM study is evaluating momelotinib versus danazol in symptomatic and anemic patients with MF.⁴⁴ The ability of momelotinib to improve anemia may allow its best use for those patients who experience cytopenias with the other JAK inhibitors or who have marked anemia upon presentation.