Expired activity
Please go to the PowerPak homepage and select a course.

Updates in the Treatment of Myelofibrosis: Pharmacist Focus on Improving Outcomes

CLASSIFICATION OF MYELOFIBROSIS

Myelofibrosis (MF) is an oncologic disease that is considered a myeloproliferative neoplasm (MPN). In the most recent World Health Organization (WHO) classification of MPNs, MF encompasses 3 different modalities: primary myelofibrosis (PMF), post-essential thrombocythemia, and post-polycythemia vera.1 As the names imply, PMF arises de novo, whereas the latter 2 arise as part of the disease course of essential thrombocythemia (ET) and polycythemia vera (PV). Unlike in previous WHO classifications of MPNs, PMF is now separated into pre-fibrotic early stage and primary fibrotic stage. This separation was added to avoid misdiagnosis with ET, mainly differentiating the presence of palpable splenomegaly, which is found in PMF but not ET.

Epidemiology

MF is the rarest of MPNs, with an estimated annual incidence of 1.5 per 100,000 in the United States and from 0.1 to 1 per 100,000 in the European Union. It is a disease of older adults: the median age of presentation is 67 years and only approximately 5% of patients are diagnosed prior to the age of 40 years.2-4 The disease occurs in both men and women.5

DISEASE COURSE OF MF

MF has a progressive nature, characterized by worsening constitutional symptoms such as fever, fatigue, night sweats, hepatosplenomegaly, and anemia. The disease burden and quality of life (QOL) issues from these symptoms mostly stem from anemia and resulting fatigue. In the MPN Landmark survey, which included 207 MF patients, fatigue was the most commonly reported symptom, affecting 80% of patients and resulting in a reduced QOL.6 Coupled with this characterization, MF is the most aggressive MPN and has the least favorable prognosis, as MF patients are most likely to have leukemic transformation. Roughly 20% of patients will progress to acute myelogenous leukemia (AML) at 10 years; however, the median overall survival is approximately 6 years, with death mostly due to AML, infections, or bleeding.7,8

Pathogenesis

The pathogenesis of MF is highly dependent on driver mutations, which activate the JAK2-STAT signaling pathway and lead to cell proliferation and survival. These mutations are JAK2, CALR, and MPL, which account for 90% of PMF patients’ diagnoses. The other 10% of cases are considered “triple negative,” meaning that none of these mutations are present. More than 50% of patients with MF have a somatic acquisition of JAK2V617F mutation leading to JAK2-STAT–mediated cell transcription.9 Historically, patients who were negative for JAK2 spurred investigation into other MF drivers, leading to MPL being found upstream in the signaling pathway and CALR being found in the endoplasmic reticulin.10,11 All 3 of these driver mutations are implicated in the prognosis of the disease, with the presence of CALR being associated with the best outcomes and triple-negative disease being associated with the worst outcomes.12

DIAGNOSTIC CRITERIA FOR MF

The diagnosis of MF consists of a combination of criteria that are separated into major and minor categories.1 The 3 major criteria include bone marrow result findings, as well as the presence of novel molecular mutations. All 3 major criteria must be present for the diagnosis of MF. First, the presence of a proliferation of atypical megakaryocytes accompanied by a grade 2 or 3 fibrosis in the bone marrow is needed. Second, a JAK2, CALR, or MPL mutation or, in their absence, another MF clonal marker must be present. These mutations are analyzed via a blood sample in which next-generation sequencing can determine clonality. The last major criterion is a diagnosis of exclusion, meaning the disease must not meet the WHO criteria for chronic myelogenous leukemia, PV, or myelodysplastic syndrome. Additionally, 5 minor criteria exist: for a diagnosis of MF, only 1 minor criterion needs to be present with the 3 major criteria. The criteria involve laboratory findings of red blood cells (RBCs), leukocytes, serum lactate dehydrogenase, and leukoerythroblastosis and the physical finding of palpable splenomegaly (Table 1).1

Table 1: WHO Diagnostic Criteria for Myelofibrosis1

Major criteria (all 3 must be present)

1. Megakaryocyte proliferation and atypia accompanied by either reticulin and/or collagen fibrosis (grade 2 or 3)
2. Presence of JAK2, CALR, or MPL mutation or, in their absence, the presence of another clonal marker or absence of evidence for reactive bone marrow fibrosis
3. Not meeting the WHO criteria for CML, PV, ET, MDS, or other myeloid neoplasm

Minor criteria (only 1 must be present, in addition to all 3 major criteria)

1. Anemia not attributed to a comorbid condition
2. Leukocytosis ≥ 11 x 109/L
3. Palpable splenomegaly
4. LDH level above the upper limit of the institutional reference range
5. Leukoerythroblastosis
CML, chronic myelogenous leukemia; ET, essential thrombocythemia; LDH, lactate dehydrogenase; MDS, myelodysplastic syndrome; PV, polycythemia vera; WHO, World Health Organization.

Risk stratification

Stratifying MF patients into risk categories on the basis of disease characteristics has evolved with the understanding of the disease. There are 3 commonly used scoring systems; all stratify patients into 4 different risk groups on the basis of the number of risk factors present: low risk, intermediate risk 1 (INT-1), intermediate risk 2 (INT-2), and high risk. The first stratification tool was the International Prognostic Scoring System (IPSS) developed by Cervantes and colleagues in 2009.13 This tool is to be used at the time of diagnosis. The authors showed that inferior survival is predicted with older age, constitutional symptoms, low hemoglobin level, high leukocyte count, and high circulating blast cells.

In contrast to the IPSS, the Dynamic International Prognostic Scoring System (DIPSS) can be used at any point during the disease course.14 This newer system modified the IPSS and assigned more weight to the hemoglobin level. The third system, named the DIPSS-Plus, can also be used at any time during the disease course and incorporates platelet counts, cytogenetics, and the patient’s need for RBC transfusions. The negative impact of 1 or more of these additional prognostic factors in the DIPSS-Plus is associated with a decrease in overall survival time of nearly 1.5 years compared to the DIPSS alone in high-risk patients.15

Additional scoring systems that incorporate genetic data for MF are being utilized more frequently in clinical care, as these models can further distinguish risk groups. The first systems to be validated were the Mutation-Enhanced International Prognostic Scoring System (MIPSS70) and the MIPSS70-Plus, which incorporate clinical, cytogenetic, and molecular data.16,17 The Genetically Inspired Prognostic Scoring System (GIPSS)18 streamlines prognostic information to only include genetic markers of MF and has incorporated very high risk mutations, including ASXL1,19SRSF2,20 and U2AF1Q157,21with the driver mutations of JAK2, CALR, and MPL. Incorporating genetic data into the scoring systems is a more recent endeavor and poses a clinical conundrum on how best to stratify patients when there are other validated systems that do not include this information. Efforts have been made to validate the GIPSS with positive results, though, overall, there is currently no consensus on which prognostic model to use.22 Lastly, genetic information can be used to determine thrombosis risk, since JAK2 and MPL mutations lead to a higher risk of thrombosis than CALR.23

All the aforementioned scoring systems are validated only for PMF. The Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) was developed to provide risk categories and prognostics for post-ET and post-PV MF.24 This model was developed by incorporating both clinical and molecular features of 685 patients with MF resulting from PV or ET and was compared directly to the IPSS with superior predictive accuracy.

MF TREATMENT

PMF is treated via a risk-adapted approach based most frequently on the IPSS, DIPSS, and DIPSS-Plus scoring systems, and post-PV/ET MF treatment is based mostly on the MYSEC-PM system. For all 3 manifestations of MF, the National Comprehensive Cancer Network guidelines utilize these scoring systems to divide treatment according to categories, with low-risk and INT-1 disease treated as separate pathways, and INT-2 and high-risk disease being treated in a similar fashion.25 The goals of therapy are to reduce bone marrow fibrosis, symptom burden, transfusion dependence, and the rate of transformation to AML.

Low risk: asymptomatic

Low-risk patients are assessed for symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), which contains questions regarding constitutional symptoms and activity level scored on a 0-to-10 scale.26 Patients deemed asymptomatic can be managed by monitoring for progression every 3 to 6 months, as there are no data to support treatment in the absence of symptoms.

Low risk: symptomatic

Patients who are symptomatic need to be managed to alleviate symptom burden. Treatment options that are used for splenomegaly symptoms include oral hydroxyurea, intravenous interferons, and the oral JAK1/2 inhibitor ruxolitinib. Hydroxyurea is particularly effective for symptoms relating to cellular hyperproliferation and can reduce spleen size by 50%.27 Interferons have been studied in a retrospective report with the resolution of constitutional symptoms occurring in nearly 80% of patients and in a prospective trial resulting in 40% of patients halving their initial spleen size.28,29 Though ruxolitinib is only approved by the United States Food and Drug Administration (FDA) for INT-2 and high-risk MF, its use in symptomatic low-risk disease is based on a non-randomized retrospective report that demonstrated a decrease in splenomegaly and fatigue.30

As referenced in the MPN Landmark study, fatigue resulting from anemia is one of the most reported complications of MF. Patients with only anemia can be spared systemic therapy with hydroxyurea or ruxolitinib and can be managed with RBC infusions. In addition, administration of erythropoiesis-stimulating agents (ESAs) can be considered for patients with a low serum erythropoietin (EPO) level of less than 500 mU/mL. Patients are most likely to respond to ESAs if no transfusion dependence exists and they have a hemoglobin level of greater than 8.5 g/dL at the start of treatment. However, there is a risk of exacerbating splenomegaly if EPO is initiated in these patients.31 For patients with EPO levels of 500 mU/mL or higher and anemia, danazol is an oral androgen option for palliative care that has been shown to decrease transfusion dependence and increase hemoglobin levels at doses of 600 mg daily.32 Testosterone and fluoxymesterone are additional androgen options. Because of these drugs’ androgenic properties, clinicians should screen patients for prostate cancer prior to initiation.

Immunomodulating drugs (IMiD) and steroids have been used with success in patients with anemia, especially if they also exhibit thrombocytopenia. These are recommended when the serum EPO level is 500 mU/mL or greater.25 Thalidomide has shown improvement in cytopenias as a single-agent, low-dose therapy of 50 mg orally daily; it may also be combined with oral prednisone starting at 0.5 mg/kg/day with subsequent taper.33,34 Lenalidomide dosed at 10 mg orally daily as monotherapy or combined with prednisone is also able to produce sustained responses, particularly in patients with a 5q deletion.35,36 Pomalidomide is the third and most recent IMiD to be studied in MF patients with anemia.37 The phase III RESUME trial evaluated pomalidomide doses of 0.5 mg orally daily compared to placebo and showed no difference in transfusion independence response rates, leading to its omission as a recommendation for MF-associated anemia in national guidelines.25

If using IMiDs for MF therapy, the clinician needs to monitor for neuropathies. The risk for thrombosis also exists when using IMiD therapy, as is evident from its use in multiple myeloma (MM). In MF, a comparison of lenalidomide and prednisone with thalidomide therapy showed that the lenalidomide and prednisone combination does not have a higher risk of thrombosis than thalidomide, unlike in MM.38 These patients were not given thromboprophylaxis and, indeed, thromboprophylaxis is not usually recommended in MF, as thrombocytopenia can be a disease manifestation.39

Novel agents are also being studied for MF-associated anemia. Sotatercept is a first-in-class activin receptor IIA “ligand trap,” which sequesters ligands of transforming growth factor beta. The lack of circulating ligand promotes RBC maturation. A phase II trial evaluating the endpoints of transfusion independence and an increase in hemoglobin of at least 1.5 g/dL from baseline is currently ongoing.40

Lastly, symptomatic splenomegaly that is refractory to drug therapy can be managed surgically with splenectomy. Splenectomy ultimately reduces transfusion dependence and resolves thrombocytopenia; however, it is associated with high morbidity and mortality.41

INT-1 risk

The treatment options for INT-1 patients range widely. An evaluation of symptoms and cytogenetics can help guide therapy. Observation is an option for asymptomatic patients with adequate platelet counts and low-risk cytogenetic disease. On the opposite end of the treatment spectrum, allogeneic hematopoietic stem cell transplantation (HSCT) can be appropriate for patients with transfusion dependence, circulating blasts, and poor-risk cytogenetics.42 Unfavorable karyotypes, including complex karyotype or a trisomy 8, del 7q, del 5q, and inv(3), for example, would dictate more aggressive therapy. Lastly, ruxolitinib has been shown effective in the phase II ROBUST trial and the phase III JUMP trial. In ROBUST, 52% and 21% of INT-1 patients experienced a reduction of at least 50% in spleen size or a decrease of at least 50% in the Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF TSS) at 48 weeks of therapy, respectively.43 The JUMP trial produced similar results, with ruxolitinib reducing palpable spleen size by at least 50% in 61% of patients at 48 weeks.44

INT-2 and high risk

Because of the poor outcomes and aggressive nature of INT-2 and high-risk disease, all patients with these classifications should be evaluated for allogeneic HSCT. Transplantation is the only treatment modality to offer a cure, but this benefit needs to be weighed against the risk of transplant-related mortality (TRM). Therefore, a thorough patient evaluation for eligibility is necessary. Eligibility consideration includes an evaluation of age, performance status, and comorbid conditions. Recently, it was discovered that an important factor in the decision for a patient to undergo HSCT or not rests on the impact of genetic alterations, as CALR-negative and ASXL1-positive disease are more aggressive than other types. Thus, consideration for transplant in these patients should be made sooner rather than later.45 Once a patient is deemed eligible for transplantation, subsequent considerations include donor source and the use of myeloablative versus non-myeloablative conditioning regimens. Studies have shown that a matched-related donor stem cell source increases long-term survival rates compared with an unrelated donor stem cell source due to the lower incidence of graft-versus-host disease.46-48 Non-myeloablative conditioning regimens have also made it possible to treat an older subset of patients, since TRM has decreased with this approach.49

JAK inhibitor therapy

Patients who are deemed ineligible for transplant and who have platelet counts of at least 50 x 109/L receive therapy with JAK inhibition. Currently, 2 JAK inhibitors are FDA-approved for use in MF: ruxolitinib and fedratinib. Ruxolitinib was the first to be developed based on the discovery that JAK2V617F was the most common molecular mutation in MPNs. The COMFORT Trials were landmark trials of ruxolitinib that led to its FDA approval in MF. COMFORT-I was a randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of ruxolitinib in patients with IPSS INT-2 or high-risk MF. Patients needed to have a platelet count of at least 100 x 109/L to be included, and they received 15 mg ruxolitinib twice daily for platelets of 100 to 200 x 109/L and 20 mg twice daily for platelets greater than 200 x 109/L. Patients randomized to the placebo arm were allowed to cross over to the treatment arm. The primary endpoint was the proportion of patients achieving a spleen volume reduction (SVR) of at least 35% at week 24, as assessed by magnetic resonance imaging (MRI): this was achieved in nearly 42% of ruxolitinib patients and 0.7% placebo patients.50

The COMFORT-II study was similarly designed to COMFORT-I, except ruxolitinib was compared to best available therapy (BAT) rather than placebo. Entry criteria mirrored those of COMFORT-I, and the primary endpoint of an SVR of at least 35% by blinded MRI at week 48 was achieved by 28.5% in the ruxolitinib arm and 0% in the BAT arm.51 The effect on spleen volume translates nicely into a reduction of symptoms and QOL score. In a study that evaluated this relationship, patients who had an SVR of at least 10% had better QOL scores, with those whose spleens were reduced by at least 35% achieving the greatest impact on QOL.52 

Toxicities in the COMFORT trials included myelosuppression of all hematopoietic cell lines. Anemia was most pronounced, with grade 3 and 4 toxicity occurring in 34.2% and 11% of patients, respectively. Toxicities occurred in the first 8 to 12 weeks of treatment, with anemia and thrombocytopenia resolving in about 6 months. Discontinuation of treatment because of anemia or thrombocytopenia was rare, which suggests that, while myelosuppression is a concern with ruxolitinib, it is not a cause for stopping therapy. Fatigue, diarrhea, and peripheral edema were the most frequent non-hematologic adverse effects.

The sustained efficacy of ruxolitinib in this setting has been evaluated in 3- and 5-year follow-ups of the COMFORT trials.53-56 The analyses at 3 years suggested an overall survival advantage in the ruxolitinib arms; however, the true difference may have been underestimated due to the crossover designs. The 5-year pooled analysis, however, confirmed the risk of death was reduced by 30% among patients randomized to the ruxolitinib arms. After correcting for the crossover, the overall survival was 5.3 versus 2.3 years for those originally randomized to ruxolitinib compared to those who crossed over. Ruxolitinib also showed consistency with no worsening of severe anemia or thrombocytopenia with long-term use. These results suggest that ruxolitinib should be started early in the disease course and cytopenias be managed with dose modifications rather than discontinuations to keep the patient on therapy as long as possible. Additionally, there is also evidence that ruxolitinib may possess disease-modifying properties, as another follow-up study showed that ruxolitinib patients had improved bone marrow fibrosis at 5 years compared to those randomized to BAT.57 Despite this, patients may not be able to receive long-term ruxolitinib therapy. Discontinuation rates at years 1, 2, and 3 were reported to be 49%, 71%, and 86%, respectively, due to lack of response or cytopenias.58 Discontinuation is linked to poor survival and, therefore, post-ruxolitinib treatment is warranted.59

Fedratinib is a second-generation JAK2-selective kinase inhibitor and, therefore, has more inhibitory activity against JAK2 than JAK1 or JAK3, so it has the potential to be a potent option in MF. Fedratinib was approved for IPSS INT-2 and high-risk MF in the phase III randomized JAKARTA trial.60 Patients were randomized to 1 of 2 doses of fedratinib (400 mg or 500 mg daily) or placebo as first-line therapy for at least 6 consecutive 4-week cycles. Patients were required to have a platelet count of at least 50 x 109/L and the primary endpoint was the proportion of patients with an SVR of at least 35% by MRI or computed tomography at week 24. A reduction of at least 50% in total symptom score was also evaluated. After 24 weeks of treatment, patients could cross over to the treatment arms from the placebo arm. The primary endpoint was reached in 36%, 40%, and 1% of patients in the 400 mg, 500 mg, and placebo arms, respectively. Additionally, in the same groups, 36%, 34%, and 7% of patients, respectively, met the symptom-reduction endpoint.60

The JAKARTA-2 trial evaluated the 400-mg dose of fedratinib. This phase II, single-arm trial was designed to answer the question of efficacy, which was determined by an SVR of at least 35% in patients who were refractory or intolerant to ruxolitinib according to investigators. Efficacy in this problematic patient population occurred in 55% of patients.61 Duration of spleen reduction was not able to be evaluated due to the study’s early termination. The trial was burdened by safety reviews of other fedratinib trials showing neurologic toxicity, notably Wernicke’s encephalopathy (WE), and trials were placed on clinical hold by the FDA in 2013. After review of suspected WE cases, the FDA lifted the hold in 2017, determining that many suspected cases were confounded.62 Notably, in JAKARTA-2, there was 1 incident of encephalopathy, but it was deemed inconsistent with WE.

Other toxicities in the JAKARTA trials were similar to those of ruxolitinib. Myelosuppression was common, as well as gastrointestinal toxicities and fatigue. Hepatoxicity and elevated pancreatic enzymes were also noted. These data from JAKARTA-2 secured fedratinib’s role as a second-line treatment option for patients who are refractory or intolerant to ruxolitinib, and fedratinib is now FDA approved for this indication. Recently, an updated analysis of QOL and other outcome data in JAKARTA-2 that more stringently defined ruxolitinib-refractory or ruxolitinib-intolerant disease was published, which confirmed fedratinib’s efficacy in this patient population.63 Lastly, the ongoing phase III, randomized, FREEDOM-2 trial will compare fedratinib to BAT in ruxolitinib-refractory and ruxolitinib-intolerant populations.64

Other JAK inhibition strategies

The novel JAK2/fms-like tyrosine kinase 3 (FLT3) inhibitor pacritinib was also developed to fulfill a therapeutic need for patients who discontinue ruxolitinib. Additionally, patients with platelet counts less than 50 x 109/L do not have JAK inhibitor options, as neither ruxolitinib nor fedratinib is approved in this population. Pacritinib was studied in 2 phase III trials: PERSIST-1 and -2.65,66 PERSIST-1 randomized patients to 400 mg daily of pacritinib versus BAT with no baseline platelet count requirement and no previous JAK inhibitor treatment.65 Results were encouraging: more pacritinib-treated patients than BAT patients achieved at least 35% SVR, regardless of baseline platelet count. PERSIST-2 compared pacritinib 400 mg daily, pacritinib 200 mg twice daily, and BAT in patients previously treated with a JAK2 inhibitor. Like PERSIST-1, there was no platelet count requirement.66 Additionally, BAT could include ruxolitinib. Interim analysis of PERSIST-2 led to a clinical hold by the FDA due to concerns of deaths from intracranial hemorrhage, arrythmias, and cardiac failure. Pacritinib has since been taken off this hold and the PACIFICA trial has been resurrected in order to study a lower pacritinib dose of 200 mg daily compared to physician’s choice in the first-line setting for MF patients with platelet counts less than 50 x 109/L.

Momelotinib is a JAK1/2 inhibitor that was studied in the phase III SIMPLIFY-1 and -2 trials.67,68 SIMPLIFY-1 was designed as a non-inferiority trial of momelotinib versus ruxolitinib in JAK inhibitor-naïve patients. In SIMPLIFY-2, momelotinib was compared to BAT in a superiority design in which patients were allowed previous ruxolitinib therapy. In these trials, momelotinib met non-inferiority, but not superiority, criteria in SVR and superiority, but not non-inferiority, criteria in symptom score. A small portion of patients also experienced irreversible peripheral neuropathy. Because of these mixed results, momelotinib was shelved. However, it was noted that patients in these studies had an improvement in anemia and transfusion dependency. Therefore, the FDA has since fast-tracked momelotinib to be studied in the MOMENTUM trial, which will compare momelotinib to danazol for symptomatic and anemic MF patients.69

Lastly, trials are currently underway studying JAK inhibitors in combination with other agents in MF. Ruxolitinib is being studied with hypomethylating agents, IMiDs, PI3K inhibitors, and histone deacetylase inhibitors: all are trying to capitalize on the one-two punch of concomitant cessation of both JAK and non-JAK activation pathways.70

PHARMACIST IMPLICATIONS IN THE MANAGEMENT OF MF

For MF patients, JAK inhibitors have provided symptom relief, and ruxolitinib, specifically, may provide an overall survival benefit. However, it is important that these agents are managed correctly to maximize their therapeutic effects and minimize toxicities. The dosing of these medications is complex, since the clinician must consider platelet counts, organ function, and drug interactions. Unique toxicities, such as withdrawal syndrome, infection risk, and lipid abnormalities with ruxolitinib and WE with fedratinib, must be given special consideration. Pharmacists play a key role for the MF patient on JAK inhibition therapy to ensure safe and efficacious medication management.

Ruxolitinib

Ruxolitinib inhibits both JAK1 and JAK2, which leads to the risk of trilineage cytopenias. For this reason, ruxolitinib is initiated on the basis of a patient’s platelet level: for platelet counts of 50 to less than 100 x 109/L, patients receive 5 mg twice daily; for 100 to less than 200 x 109/L, 15 mg twice daily; and for 200 x 109/L or higher, 20 mg twice daily. A patient’s renal and hepatic function must also be considered when starting therapy, with patients having platelet counts of 100 to 150 x 109/L or 50 to less than 100 x 109/L with a creatinine clearance of 15 to 59 mL/min initially receiving 10 mg twice daily or 5 mg twice daily, respectively. No dose adjustments are necessary with a creatinine clearance of greater than 59 mL/min. Patients with end-stage renal disease on dialysis should receive a dose of either 15 mg or 20 mg according to platelet counts after dialysis. For mild or severe hepatic impairment, the initial doses are 5 mg or 10 mg and are based on platelet counts of 50 to less than 100 x 109/L and 100 to 150 x 109/L, respectively.71

Ruxolitinib is metabolized by the cytochrome P450 (CYP) 3A4 enzyme, and, therefore, dose modifications are needed to minimize drug interactions. Doses are reduced by 50% for concomitant strong CYP3A4 inhibitors, as well as fluconazole doses of up to 200 mg daily. Any fluconazole dose above 200 mg daily should be avoided. There are no clear guidelines for concomitant administration with strong CYP3A4 inducers. In instances where this cannot be avoided, more frequent complete blood count (CBC) monitoring should be performed for any necessary increases in dosing. For other pharmacokinetic considerations, the dose can be taken without regard to food, as there are no significant differences in pharmacokinetic parameters when given with or without a high-fat meal.71

During therapy, any dose adjustments need to be tailored to each patient’s individual response. This should be done by diligent monitoring of both clinical manifestations of the disease and the presence of cytopenias. CBCs must be monitored every 2 to 4 weeks initially, modifying the dose up or down by 5 mg twice daily until the dose has stabilized and then as clinically indicated. For patients who initiate ruxolitinib with a platelet count of 100 x 109/L or greater, discontinuation of ruxolitinib should occur for platelets less than 50 x 109/L or an absolute neutrophil count (ANC) of less than 0.5 x 109/L. These values change to less than 25 x 109/L or an ANC of less than 0.5 x 109/L if the starting platelet level was 50 to less than 100 x 109/L. Upon count recovery, a low dose of 5 mg once or twice daily may be restarted. If the patient has an insufficient response, the dose can be increased by 5 mg twice daily. However, due to the platelet stability needed initially, dose increases should not occur within the first 4 weeks of therapy and no more frequently than every 2 weeks. Finally, ruxolitinib should be discontinued if there is no spleen reduction or symptom improvement after 6 months.71

Discontinuation of ruxolitinib comes with its own precautions. Withdrawal syndrome is a risk of dose interruption or discontinuation of ruxolitinib caused by a rapid rebound of inflammatory cytokines and is described in many case reports.72-74 This syndrome can occur within less than 24 hours of discontinuation but may not appear until a few days after discontinuation. It is characterized by a recurrence of MF symptoms, acute respiratory distress, disseminated intravascular coagulation, or a tumor lysis syndrome-like picture. The risk of withdrawal syndrome is higher if interrupting or discontinuing higher ruxolitinib doses and with the presence of comorbid conditions, such as pulmonary hypertension. To prevent its occurrence, a slow taper should be done with re-initiation of ruxolitinib, if it was abruptly stopped. Successful management of withdrawal syndrome is dependent on rapid recognition and intervention with close monitoring of CBC, the presence of recurrent splenomegaly, and the risk of respiratory distress. Management strategies have included systemic glucocorticoid therapy with methylprednisolone or prednisone with subsequent taper and myelosuppressive therapy with hydroxyurea, especially if uncontrolled myeloproliferation is present.

Another concern related to ruxolitinib that needs special consideration is the risk of infection. JAK inhibition impairs dendritic and natural killer cell function and downregulates T-regulatory cells, which can lead to opportunistic infections.75 In the COMFORT trials, pneumonia, sepsis, urinary tract infections, cellulitis, and upper respiratory tract infections were seen. A particular risk is herpes zoster reactivation, which a meta-analysis has determined is a significant risk when utilizing ruxolitinib for PV.76 In case reports, tuberculosis, hepatitis B reactivation, and Pneumocystis jirovecii pneumonia infection have all been documented. Even though infection has been reported in the data and seen in real-world experience, there are no standard recommendations for prophylaxis and prophylaxis is not required. A retrospective analysis sought to determine if prophylaxis may be warranted in a certain subgroup of patients receiving ruxolitinib who were at increased risk of infection, but the analysis determined that there were no patient characteristics or disease factors that led patients to be more likely to develop an infection.77 The infection risk does, however, mandate that clinicians assess patients carefully prior to ruxolitinib initiation. Tuberculosis risk factors should be examined and high-risk patients should be tested for latent infection. Patients with existing hepatitis B infection should be treated and hepatitis B viral load should be monitored. Because of the risk of herpes zoster, the inactivated shingles vaccine can be considered.

Finally, ruxolitinib patients are presented with concerns of lipid abnormalities and the rare development of non-melanoma skin cancer. Patients should have their total cholesterol, low-density lipoprotein, and triglycerides tested every 2 to 3 months, and any hyperlipidemia should be managed according to current guidelines. Skin exams should be performed periodically to screen for skin cancer.71

Fedratinib

Like ruxolitinib, fedratinib therapy is also initiated according to platelet counts. The starting dose is 400 mg daily if platelets are at least 50 x 109/L. The starting dose should be decreased to 200 mg if the patient’s creatinine clearance is less than 30 mL/min, since, in this population, there is a nearly 2-fold increase in the area under the curve compared to patients with a creatinine clearance of 90 mL/min or higher.

Like ruxolitinib, fedratinib is a major substrate of CYP3A4. Concurrent administration with strong CYP3A4 inhibitors or inducers should be avoided. However, if administration with a strong inhibitor cannot be avoided, fedratinib should be dosed at 200 mg daily. Fedratinib is also a moderate inhibitor of CYP2D6 and, therefore, medications that are substrates of this enzyme should be avoided or the doses of those medications should be reduced accordingly.

Fedratinib can be taken with or without food, as pharmacokinetic studies have shown no significant difference when it is administered with high-fat or low-fat meals. Taking the medication with food, however, may increase tolerability by reducing nausea. Before initiating therapy, a CBC and renal and hepatic function evaluations should be obtained; amylase, lipase, and thiamine levels should also be obtained before initiation and periodically thereafter. During treatment, gastrointestinal toxicity and bleeding should be monitored. If a patient experiences a grade 3 or 4 thrombocytopenia with bleeding or a grade 4 neutropenia, the drug must be held until resolution of counts, after which fedratinib can be restarted at 100 mg lower than the last given dose. The same dosing strategy holds true for non-hematologic grade 3 or 4 toxicities. Additionally, antiemetics or antidiarrheals can be initiated prophylactically for gastrointestinal toxicities.78

One of the most concerning adverse effects with fedratinib is the possibility of WE, which has earned it a Black Box warning. Because of this fatal effect, patients must have thiamine levels assessed prior to initiation of fedratinib and repleted if found deficient. Thiamine levels, as well as any signs of encephalopathy, need to be assessed periodically during treatment. If patients are found to have changes in mental status or confusion, a full neurologic workup should be performed and fedratinib must be stopped and intravenous thiamine given.78

Currently, there are no reports of fedratinib withdrawal syndrome, and, as the half-life of fedratinib is longer than that of ruxolitinib, this may be less of a concern, theoretically. However, careful monitoring should still occur if discontinuing fedratinib. The same pharmacokinetic considerations should be kept in mind when switching from one JAK inhibitor to another. Since both ruxolitinib and fedratinib are available for different lines of MF therapy, switching between the agents requires careful consideration. Any transition strategy needs to maintain JAK inhibition efficacy, as well as mitigate toxicity. There are no standard strategies recommended for switching from one to another and each patient scenario needs to be evaluated individually. Clinicians must keep a careful watch of the patient and keep in mind the pharmacokinetic parameters of both drugs to guide transition.79

Other pharmacy considerations with MF therapy

Pharmacists who sit on their institutions’ Pharmacy and Therapeutic committees need to consider a variety of clinical and non-clinical factors when implementing MF treatment pathways. Formulary addition decisions should consist of an evidenced-based evaluation, as well as a financial analysis. While the COMFORT and JAKARTA trials with ruxolitinib and fedratinib, respectively, had endpoints of SVR and not overall survival, the dearth of data outside of HSCT for any other effective therapy for higher-risk MF would favor a formulary inclusion decision of these agents. There is also unlikely to be a head-to-head trial of ruxolitinib versus fedratinib. Though caution should be used when comparing agents in a cross-trial manner, the responses of both appear to be similar, although with different toxicities. Both are FDA approved for front-line therapy and fedratinib is approved for second-line therapy. For these reasons, there is room for multiple JAK inhibitors on MF treatment pathways.

Addition to institutional formularies is moot if the patient does not have access to the drug or is limited by financial burdens. Procurement and insurance reimbursement are issues that may delay medication initiation. As new oral chemotherapies, both ruxolitinib and fedratinib need to be dispensed by specialty pharmacies. The actual wholesale price of both agents is updated by Medi-Span monthly. Pharmacists, whether they work in oncology clinics or in specialty pharmacies, are key individuals who can perform prior authorizations, if needed. Procedures should be established to incorporate this need into the workflow to efficiently procure drug for the MF patient. Pharmacists should also assist in identifying financial assistance programs. Ruxolitinib can be procured through the IncyteCARES program, which will help with co-pay assistance, provide the drug for free in some instances if a patient is uninsured, or give temporary access to the medication for patients with insurance delays.80 Fedratinib has a similar assistance program.81

Hospitals should also establish standard operating procedures for initiating oral chemotherapies in different settings. Institutions should consider a pathway if the drug is initiated in the inpatient or outpatient settings or if the patient brings in his or her own JAK inhibitor when being admitted for a complication or disease management. For example, does initiating a JAK inhibitor as an inpatient require approval from a pharmacy director or designee? And, should JAK inhibitor ordering be restricted to certain services or areas?

In the outpatient setting, pharmacists are in a perfect position to monitor and educate patients about the importance of adherence to MF therapies. Many studies have shown the impact pharmacists can have in increasing compliance with oral chemotherapies.82,83 An Italian observational study highlighted issues with ruxolitinib adherence in MF patients: it showed that nearly one-third of ruxolitinib patients had low or intermediate adherence over a 24-week period, which could lead to suboptimal outcomes.84 Though fedratinib is given daily and ruxolitinib is given twice daily, there are currently no data that fedratinib is better adhered to than ruxolitinib. Pharmacists should, however, keep this in mind when assessing a patient’s pill burden.

CONCLUSIONS

MF is a rare MPN disease characterized by the presence of constitutional symptoms that arises most frequently from genomic mutations in the JAK-STAT pathway, including JAK2, CALR, and MPL. Patients most frequently report fatigue resulting from anemia as the biggest detriment to their QOL. To determine treatment, patients are scored on 1 of 3 classic prognostic scoring systems or a system that incorporates genetic data. Therapy selection can range from symptomatic anemia treatment in low-risk patients to transplantation and oral oncolytic therapy with JAK inhibitors for higher-risk disease. Pharmacists, at minimum, should be familiar with the management strategies of the 2 FDA-approved JAK inhibitors in order to optimize patient tolerance of these medications. Both ruxolitinib and fedratinib have dosing intricacies associated with platelet counts, organ function, and toxicities. Pharmacists should also be patient advocates by procuring drug, eliminating barriers to access, and ensuring adherence.

Update: January 23, 2021

  • No new drug approvals, indications, black box or safety warnings, or significant practice-changing clinical trial results

Update: October 22, 2020

  • No new drug approvals, indications, black box or safety warnings
  • On October 13, 2020, a rolling new drug application for JAK2/FLT3 inhibitor pacritinib has been filed for patients with myelofibrosis and severe thrombocytopenia defined as platelet counts of < 50,000/mm3 based on phase III PERSIST-1 and PERSIST-2 studies as well as data from the phase II PAC203 trial.

Update: July 25, 2020

  • No new drug approvals, indications, black box or safety warnings
  • Results of the JUMP trial were recently reported. JUMP was a global, phase 3b, expanded-access, open-label study of ruxolitinib for treatment of high, intermediate-2 or intermediate-1 risk myelofibrosis was conducted in countries without access to a clinical trial. Thus patients with low platelet counts and splenomegaly were included. Dosing of ruxolitinib was based on baseline platelet count (5-20 mg po BID). Meaningful reductions in spleen length and symptoms and no new safety concerns were identified. This study confirms results of the COMFORT studies, supporting use of ruxolitinib in patients with thrombocytopenia (platelet counts 50-100 x 109/L). Al-ali HK, et al. Br J Hematol. 2020;189:888-903.

REFERENCES

  1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-405.
  2. Visani G, Finelli C, Castelli U, et al. Myelofibrosis with myeloid metaplasia: clinical and haematological parameters predicting survival in a series of 133 patients. Br J Haematol. 1990;75(1):4-9.
  3. Mesa RA, Silverstein MN, Jacobsen SJ, et al. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995. Am J Hematol. 1999;61(1):10-5.
  4. Moulard O, Mehta J, Fryzek J, et al. Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol. 2014;92(4):289-97.
  5. The Leukemia & Lymphoma Society. Myelofibrosis facts: No. 14; 2012. https://www.lls.org/sites/default/files/file_assets/FS14_Myelofibrosis_Fact%20Sheet_Final9.12.pdf. Accessed March 20, 2020.
  6. Mesa R, Miller CB, Thyne M, et al. Myeloproliferative neoplasms (MPNs) have a significant impact on patients’ overall health and productivity: the MPN Landmark survey. BMC Cancer. 2016;16:167.
  7. Rampal R, Mascarenhas J. Pathogenesis and management of acute myeloid leukemia that has evolved from a myeloproliferative neoplasm. Curr Opin Hematol. 2014;21(2):65-71.
  8. Tefferi A, Mudireddy M, Mannelli F, et al. Blast phase myeloproliferative neoplasm: Mayo-AGIMM study of 410 patients from two separate cohorts. Leukemia. 2018;32(5):1200-10.
  9. Griesshammer M, Sadjadian P. The BCR-ABL1-negative myeloproliferative neoplasms: a review of JAK inhibitors in the therapeutic armamentarium. Expert Opin Pharmacother. 2017;18(18):1929-38.
  10. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3(7):e270.
  11. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-90.
  12. Tefferi A, Nicolosi M, Mudireddy M, et al. Revised cytogenetic risk stratification in primary myelofibrosis: analysis based on 1002 informative patients. Leukemia. 2018;32(5):1189-99.
  13. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895-901.
  14. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115(9):1703-8.
  15. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392-7.
  16. Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018;36(4):310-8.
  17. Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for primary myelofibrosis. J Clin Oncol. 2018;36(17):1769-70.
  18. Tefferi A, Guglielmelli P, Nicolosi M, et al. GIPSS: Genetically Inspired Prognostic Scoring System for primary myelofibrosis. Leukemia. 2018;32(7):1631-42.
  19. Tefferi A, Lasho TL, Finke C, et al. Prognostic significance of ASXL1 mutation types and allele burden in myelofibrosis. Leukemia. 2018;32(3):837-9.
  20. Tefferi A, Lasho TL, Hanson CA, et al. Screening for ASXL1 and SRSF2 mutations is imperative for treatment decision-making in otherwise low or intermediate-1 risk patients with myelofibrosis. Br J Haematol. 2018;183(4):678-81.
  21. Tefferi A, Finke CM, Lasho TL, et al. U2AF1 mutation types in primary myelofibrosis: phenotypic and prognostic distinctions. Leukemia. 2018;32(10):2274-8.
  22. Kuykendall AT, Talati C, Padron E, et al. Genetically Inspired Prognostic Scoring System (GIPSS) outperforms Dynamic International Prognostic Scoring System (DIPSS) in myelofibrosis patients. Am J Hematol. 2019;94(1):87-92.
  23. Rumi E, Pietra D, Pascutto C, et al; Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood. 2014;124(7):1062-9.
  24. Passamonti F, Giorgino T, Mora B, et al. A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia. 2017;31(12):2726-31.
  25. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative neoplasms. Version 3.2019. Published September 27, 2019.
  26. Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012;30(33):4098-103.
  27. Martinez-Trillos A, Gaya A, Maffioli M, et al. Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients. Ann Hematol. 2010;89(12):1233-7.
  28. Ianotto J-C, Boyer-Perrard F, Gyan E, et al. Efficacy and safety of pegylated-interferon α-2a in myelofibrosis: a study by the FIM and GEM French Cooperative Groups. Br J Haematol. 2013;162(6):783-91.
  29. Silver RT, Barel AC, Lascu E, et al. The effect of initial molecular profile on response to recombinant interferon-a (rIFN-a) treatment in early myelofibrosis. Cancer. 2017;123(14):2680-7.
  30. Davis KL, Cote I, Kaye JA, et al. Real-world assessment of clinical outcomes in patients with lower-risk myelofibrosis receiving treatment with ruxolitinib. Adv Hematol. 2015;2015:848473.
  31. Cervantes F, Alvarez-Larrán A, Hernández-Boluda J-C, et al. Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature. Br J Haematol. 2004;127(4):399-403.
  32. Cervantes F, Alvarez-Larrán A, Domingo A, et al. Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients. Br J Haematol. 2005;129(6):771-5.
  33. Marchetti M, Barosi G, Balestri F, et al. Low-dose thalidomide ameliorates cytopenias and splenomegaly in myelofibrosis with myeloid metaplasia: a phase II trial. J Clin Oncol. 2004;22(3):424-31.
  34. Mesa RA, Steensma DP, Pardanani A, et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood. 2003;101(7):2534-41.
  35. Tefferi A, Cortes J, Verstovsek S, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood. 2006;108(4):1158-64.
  36. Quintas-Cardama A, Kantarjian HM, Manshouri T, et al. Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis. J Clin Oncol. 2009;27(28):4760-6.
  37. Tefferi A, Al-Ali HK, Barosi G, et al. A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence. Leukemia. 2017;31(4):896-902.
  38. Jabbour E, Thomas D, Kantarjian H, et al. Comparison of thalidomide and lenalidomide as therapy for myelofibrosis. Blood. 2011;118(4):899-902.
  39. Sekhar M. Prevention and management of thrombosis in myeloproliferative neoplasms. Clin Adv Hematol Oncol. 2017;15(3):178-81.
  40. Sotatercept in Treating Patients With Myeloproliferative Neoplasm-Associated Myelofibrosis or Anemia. NLM identifier: NCT01712308. https://clinicaltrials.gov/ct2/show/study/NCT01712308. Accessed February 2020.
  41. Cervantes F. How I treat splenomegaly in myelofibrosis. Blood Cancer J. 2011;1(1):e37.
  42. Kröger N, Giorgino T, Scott BL, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood. 2015;125(21):3347-50.
  43. Mead AJ, Milojkovic D, Knapper S, et al. Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST Trial. Br J Haematol. 2015;170(1):29-39.
  44. Al-Ali HK, Griesshammer M, le Coutre P, et al. Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP Trial. Haematologica. 2016;101(9):1065-73.
  45. Tefferi A, Guglielmelli P, Lasho TL, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia. 2014;28(7):1494-500.
  46. Gupta V, Malone AK, Hari PN, et al. Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplan. 2014;20(1):89-97.
  47. Lussana F, Rambaldi A, Finazzi MC, et al. Allogeneic hematopoietic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia: a report from the MPN Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2014;99(5):916-21.
  48. Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2010;16(3):358-67.
  49. Alchalby H, Kröger N. Reduced-intensity conditioning followed by allogeneic hematopoietic stem cell transplantation in myelofibrosis. Curr Hematol Malig Rep. 2010;5(2):53-61.
  50. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807.
  51. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-98.
  52. Mesa RA, Gotlib J, Gupta V, et al. Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2013;31(10):1285-92.
  53. Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013;122(25):4047-53.
  54. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156.
  55. Verstovsek S, Mesa RA, Gotlib J, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55.
  56. Verstovsek S, Mesa RA, Gotlib J, et al; COMFORT-I investigators. Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica. 2015;100(4):479-88.
  57. Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis. J Hematol Oncol. 2018;11(1):42.
  58. Abdelrahman RA, Begna KH, Al-Kali A, et al. Revised assessment of response and long-term discontinuation rates among 111 patients with myelofibrosis treated with momelotinib or ruxolitinib. Leukemia. 2015;29(2):498-500.
  59. Newberry KJ, Patel K, Masarova L, et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017;130(9):1125-31.
  60. Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643-51.
  61. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4(7):e317-24.
  62. Center for Drug Evaluation and Research. Application Number: 212327Orig1s000. Risk Assessment and Risk Mitigation Review(s). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212327Orig1s000RiskR.pdf. Review completed August 7, 2019. Accessed March 20, 2020.
  63. Harrison C, Schaap N, Vannucchi A, et al. Fedratinib induces spleen responses in patients with myeloproliferative neoplasm (MPN)-associated intermediate- or high-risk myelofibrosis (MF) resistant or intolerant to ruxolitinib: an updated analysis of the phase II JAKARTA2 Study. Clin Lymphoma Myeloma Leuk. 2019;19(Suppl 1):S356.
  64. An Efficacy and Safety Study of Fedratinib Compared to Best Available Therapy in Subjects With DIPSS-intermediate or High-risk Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis and Previously Treated With Ruxolitinib (FREEDOM2). NLM identifier: NCT03952039. https://clinicaltrials.gov/ct2/show/NCT03952039. Accessed February 2020.
  65. Mesa RA, Vannucchi AM, Mead A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol. 2017;4(5):e225-36.
  66. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-9.
  67. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-50.
  68. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5(2):e73-81.
  69. A Study of Momelotinib Versus Danazol in Symptomatic and Anemic Myelofibrosis Patients (MOMENTUM). NLM identifier: NCT04173494. https://clinicaltrials.gov/ct2/show/NCT04173494. Accessed February 2020.
  70. Schieber M, Crispino JD, Stein B. Myelofibrosis in 2019: moving beyond JAK2 inhibition. Blood Cancer J. 2019;9(9):74.
  71. Jakafi (ruxolitinib) [package insert]. Wilmington, DE: Incyte Corporation; 2020.
  72. Coltro G, Mannelli F, Guglielmelli P, et al. A life-threatening ruxolitinib discontinuation syndrome. Am J Hematol. 2017;92(8):833-8.
  73. Dai T, Friedman EW, Barta SK. Ruxolitinib withdrawal syndrome leading to tumor lysis. J Clin Oncol. 2013;31(29):e430-2.
  74. Beauverd Y, Samii K. Acute respiratory distress syndrome in a patient with primary myelofibrosis after ruxolitinib treatment discontinuation. Int J Hematol. 2014;100(5):498-501.
  75. Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013;122(7):1192-202.
  76. Lussana F, Cattaneo M, Rambaldi A, Squizzato A. Ruxolitinib-associated infections: a systematic review and meta-analysis. Am J Hematol. 2018;93(3):339-47.
  77. King AC, Hsu M, Mauro MJ, Rampal RK. Treatment-related infections and risk factors in patients with myeloproliferative neoplasms treated with ruxolitinib. Blood. 2016;128(22):1930.
  78. Inrebic (fedratinib) [package insert]. Summit, NJ: Celgene Corporation; 2019.
  79. Ragheb M, Harrison CN, McLornan DP. Current and future role of fedratinib in the treatment of myelofibrosis. Future Oncol. 2020;16(6):175-86.
  80. Incyte Corporation. IncyteCARES. https://www.incytecares.com. March 2020.
  81. Celgene Corporation. Celgene Patient Support. https://celgenepatientsupport.com/inrebic-patient/. Accessed March 2020.
  82. Muluneh B, Schneider M, Faso A, et al. Improved adherence rates and clinical outcomes of an integrated, closed-loop, pharmacist-led oral chemotherapy management program. J Oncol Pract. 2018;14(6):e324-34.
  83. Mackler E, Segal EM, Muluneh B, et al. 2018 Hematology/Oncology Pharmacist Association best practices for the management of oral oncolytic therapy: pharmacy practice standard. J Oncol Pract. 2019;15(4):e346-55.
  84. Guglielmelli P, Palandri F, Selleri C, et al. Adherence to treatment in myelofibrosis patients: preliminary results from Italian Romei Observational Study. Blood. 2019;134(Supplement_1):4179.

Back to Top