Recommendations on the use of ruxolitinib for the treatment of myelofibrosis

ABSTRACT

Objectives: Myelofibrosis (MF) is a severe disease, with decreased life expectancy and heavy symptom burden. Ruxolitinib is the only approved pharmacotherapy for the treatment of MF patients. In Belgium, ruxolitinib is only reimbursed for MF patients with splenomegaly for whom the disease is categorized as intermediate-2 or high risk. The improvement of symptoms without spleen volume reduction is not considered sufficient to continue treatment. The aim of this manuscript is to provide guidance for the safe and effective administration of ruxolitinib, considering the particularities of the Belgian reimbursement criteria.

Methods: Our recommendations are based on a consensus reached during two meetings, where available data and observations derived from clinical experience were discussed.

Results and discussion: We recommend changing the current Belgian reimbursement conditions to include the evaluation of disease-related symptoms along with splenomegaly to decide whether ruxolitinib treatment should be continued or not. Indeed, the decrease in disease-related symptoms seems to be an equally important parameter as the decrease in splenic volume in the evaluation of the response to ruxolitinib. We also advocate for the treatment with ruxolitinib of MF patients in lower-risk categories with severe disease-related symptoms, as this drug could greatly improve their quality of life. Optimization of the ruxolitinib dose is recommended to avoid an unnecessary decrease in platelet count or hemoglobin that may jeopardize treatment continuation.

Conclusion: With the aim to optimize the treatment of MF patients, the Belgian regulation for ruxolitinib should be revised in terms of reimbursement criteria, dose titration, stopping rules, and patient follow-up.

KEYWORDS:

• Ruxolitinib
• myelofibrosis
• myeloid neoplasm
• splenomegaly
• dosing
• reimbursement
• Belgium

Introduction

Myelofibrosis (MF) is a rare, but serious myeloproliferative neoplasm affecting mainly individuals over 50 years [1]. MF has a heavy symptom burden, which severely impacts patients’ quality of life and overall survival [2]. Clinical manifestations are bone marrow fibrosis and related progressive anemia, and extramedullary hematopoiesis with splenomegaly [3]. MF is also characterized by disease-related symptoms, including fatigue, night sweats, fever, pruritus, early satiety and abdominal pain or discomfort related to splenomegaly, unintentional weight loss, cachexia, bleeding related to cytopenia, and bone pain [4]. Mutations of Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) genes, inducing the activation of JAK/signal transducer and activator of transcription (STAT) signaling, are associated with MF, and strategies in MF treatment development mainly target JAK inhibition [5,6].

Clinical MF phenotypes are recognized de novo as primary MF (PMF) or may evolve from fibrotic states of essential thrombocythemia (post-ET) and polycythemia vera (post-PV) [7]. PMF diagnosis is based on the presence of major and minor criteria, recently revised by the World Health Organization [8]. MF patients are classified into four risk groups: low risk, intermediate-1, intermediate-2, and high risk, according to a scoring system estimating survival from the time of diagnosis (international prognostic scoring system [IPSS]) [9], or from any point in the disease course (dynamic IPSS) [10]. Both systems are based on the evaluation of five risk factors: age >65 years, hemoglobin (Hb) <10 g/dL, leukocyte count >25 × 10⁹/L, circulating blasts ≥1%, and constitutional symptoms [9,10].

In Belgium, a cross-sectional scientific survey captured the disease characteristics of 250 MF patients in 2011 [11]. Most cases in the whole population (60%) and patients over 65 years (73%) were classified as intermediate-2 or high risk by IPSS. In this survey, up to 66% of patients were diagnosed with PMF, around 23% with post-ET MF, and 11% with post-PV MF [11].

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative MF treatment [12]. However, patients over 65 years are usually not considered for HSCT because of the risks involved [13]. The only pharmacotherapy with approved indications for MF treatment is ruxolitinib (Jakavi^™, Novartis International AG), an orally bioavailable JAK1 and JAK2 inhibitor [14,15]. Two pivotal randomized Phase III clinical trials showed that ruxolitinib is efficacious when compared with placebo (COMFORT-I) or best available treatment (COMFORT-II) and has a clinically acceptable safety profile [16–18]. A recent pooled analysis of both studies after five years showed that ruxolitinib-treated patients gained about three years in median overall survival compared to placebo or best available treatment (Figure 1) [19].

Figure 1. Overall survival after 5 years of follow-up in a pooled analysis of COMFORT-I and COMFORT-II trials, corrected by censoring at crossover [19].

This manuscript provides guidance for the safe and effective administration of ruxolitinib, considering the particularities of the Belgian reimbursement criteria. Our recommendations are based on a consensus reached during two face-to-face meetings, where available data and observations derived from clinical experience were discussed by four Belgian hematologists.

Which patients may benefit from ruxolitinib?

While HSCT is not recommended in elderly patients or patients with poor performance status or prohibitive comorbidities [13], all intermediate-2 or high-risk MF patients younger than 70 years and intermediate-1-risk MF patients younger than 65 years with refractory and transfusion-dependent anemia, circulating blasts >2%, or adverse cytogenetics are candidates for HSCT [20].

Current reimbursement conditions in Belgium limit ruxolitinib use to intermediate-2 and high-risk MF patients, who often present splenomegaly and constitutional symptoms [11,21]. Recent studies showed that in intermediate-1 risk patients and in patients with constitutional symptoms without splenomegaly, ruxolitinib has a safety and efficacy profile consistent with that observed in higher-risk categories [22–24]. In the JUMP study, >60% of patients with intermediate-1 risk MF had ≥50% reduction from baseline in palpable spleen length after 24 weeks of treatment, and meaningful symptom improvements were seen within four weeks [22,23]. In the ROBUST study, 50.0% of patients with intermediate-1 risk MF achieved ≥50% reduction in palpable spleen length after 48 weeks of treatment and 21.4% had ≥50% reduction in symptoms [22,24]. Also, recent international guidelines include ruxolitinib as a treatment option for symptomatic MF patients from low-risk and intermediate-1-risk groups [25]. Thus, an extension of the ruxolitinib reimbursement criteria to include patients from lower-risk groups would be desirable. In our opinion, intermediate-1-risk MF patients with severe disease-related symptoms, even those without palpable splenomegaly, could benefit from ruxolitinib. Severe symptoms are defined as heavy night sweats, anorexia and weight loss, unbearable itching, and bone pains. To measure the symptom burden, the MPN10 score can be used, and we agree with the recent recommendations of the Italian Society of Haematology and the European LeukemiaNet for the selection of MF patients in whom ruxolitinib therapy should be initiated to decrease symptoms [26].

Currently, symptom improvement without spleen volume reduction is not considered sufficient to continue treatment, although it leads to improved quality of life and may translate into prolongation of survival. Again, we recommend the use of the MPN10 symptom tracking tool to give an objective measure of symptom burden in MF patients [27].

According to our experience and in line with clinical trials, patients without JAK2 mutation may also respond to ruxolitinib [3,16,17,28]. The overall mutation profile characterization is important for the diagnosis of MF patients, but also has a significant impact on prognosis and likelihood of treatment success, which appears to diminish with the presence of multiple mutations [29]. The most frequently detected molecular abnormalities in MF patients (JAK2 V617F, CALR exon 9, and MPL exon 10 mutations) are implicated in the JAK-STAT signaling activation and are called driver mutations in MF [4,18,30]. About 5–10% of MF patients are negative for the three driver mutations and have poor clinical outcome [31]. In these patients, clinicians should search for accompanying epigenetic mutations (e.g. ASXL1, EZH2, TET2, IDH1/2, SRSF2, and SF3B1) if next generation sequencing techniques are available [31]. The presence of these epigenetic mutations can be decisive in the decision to perform transplant. ASXL1, EZH2, SRSF2, or IDH1/2 mutations were identified in PMF patients at increased risk for premature death or leukemic transformation and represent unfavorable prognostic factors [31–33].

Dose optimization and monitoring of patient under ruxolitinib

Regardless of Hb levels, starting doses of ruxolitinib should be 15 mg twice daily for MF patients with baseline platelet counts between 100–200 × 10⁹/L and 20 mg twice daily for patients with platelet counts >200 × 10⁹/L (Table 1) [28]. For patients with low-baseline platelet counts (50–100 × 10⁹/L), studies suggested that 5 mg starting doses with gradual increase up to 10 mg twice daily may be the best approach [34]. However, Belgian reimbursement criteria limit ruxolitinib use to patients with baseline platelet counts >100 × 10⁹/L [21].

Table 1. Dose of ruxolitinib according to platelet count.

Platelet count	Starting dose
50–100 × 10^9/L	5 mg BID
100–200 × 10^9/L	15 mg BID
> 200 × 10^9/L	20 mg BID

BID, bis in die (twice daily).

Besides platelet count evaluation, a complete blood cell count and assessment of diverse clinical parameters are also necessary before reaching a decision on the optimal dosage, and ruxolitinib doses should be adapted on a case-by-case basis [35]. Ruxolitinib tablets are available in strengths of 5, 10, 15, and 20 mg, allowing for individualized dosing regimens [36].

In MF patients with severe renal impairment (creatinine clearance <30 mL/min), starting doses should be reduced by approximately 50% and subsequent doses should be adjusted based on careful monitoring of safety and efficacy [18,37]. For patients on hemodialysis, a single daily dose should be administered after the dialysis session. In case of hepatic impairment (any severity; there is no correlation between ruxolitinib exposure and hepatic impairment degree), the dose should be reduced by half, and titrated based on liver function and blood counts [37,38]. As ruxolitinib is metabolized by CYP3A4 and CYP2C9, reductions in starting and maintenance doses are recommended for patients taking potent CYP3A4 inhibitors, such as fluconazole [39].

Clinical trials have shown that higher ruxolitinib doses lead to better reductions in splenomegaly; optimal doses should depend on the evolution of spleen volume and patients’ symptoms [15,40].

MF patients should be closely monitored during initial phases of ruxolitinib treatment. Based on our experience, the best practice includes a visit every two weeks during the first month to ensure that ruxolitinib is well tolerated and to check blood cell counts. We do not think that there is a need to differentiate the monitoring of patients with baseline platelet counts between 100–200 × 10⁹/L or >200 × 10⁹/L. In case of insufficient response and after dose reductions due to adverse events (AEs), doses may be increased by 5 mg twice daily to the maximum of 25 mg twice daily to ensure maximum efficacy. Doses should not be increased within the first four weeks following treatment initiation; subsequently, each dose should be maintained at least two weeks before a further increase [37]. For optimal management, monthly visits are sufficient during two or three months after the initial month. Once patients are on stable doses, complete blood cell counts should be performed at least every three months.

Imaging technologies are not strictly indicated to monitor MF patients during ruxolitinib treatment. Monitoring spleen length by ultrasound (craniocaudal diameter) could be indicated in two situations: first, in patients in whom the spleen length is difficult to evaluate by clinical examination (e.g. obese patients), and second, when spleen imaging is required by the national authorities for the reimbursement of ruxolitinib. Magnetic resonance scans of the spleen are performed in clinical trials to obtain standardized spleen volume measurements, but are not necessary for routine clinical use. Molecular monitoring (quantitative polymerase chain reaction) of the mutational load of driver mutations (e.g. V617F JAK2) is not indicated in MF patients during treatment with ruxolitinib.

Management of AEs related to ruxolitinib treatment

Hematologic AEs

Anemia and thrombocytopenia are the most frequent ruxolitinib-associated AEs, as expected from its mechanism of action [35]. Both events are dose related and close monitoring of blood cell counts and judicious changes in ruxolitinib doses are usually effective in the control of these events in MF patients [35]. Neutropenia was less common in the COMFORT-I study, but treatment should be interrupted in patients with absolute neutrophil count <0.5 × 10⁹/L [41].

Anemia

Anemia, which is one of the MF diagnostic criteria and a known adverse prognostic factor, was reported as AE in 82.4% of patients in clinical studies assessing ruxolitinib safety [37]. Anemia can strongly affect performance scores of some patients. A drop in Hb levels may occur in the first weeks of ruxolitinib treatment to reach the nadir after 8–12 weeks; then, Hb levels gradually return to near baseline values by week 24 [14]. Although no dose adjustment is needed if anemia occurs after treatment initiation, a close follow-up during the first three months is important, at intervals of maximum two weeks, until Hb levels remain constant. Although anemic (Hb levels <8 g/dL) and transfusion-dependent patients before treatment initiation should be monitored more closely, we do not recommend excluding these patients from ruxolitinib treatment. The right ruxolitinib dose in anemic MF patients is investigated in the REALISE study (NCT02966353).

Importantly, ruxolitinib-related anemia, as opposed to disease-related anemia, was not associated with shortened survival in MF patients [14,42]. Therefore, the presence of anemia should not be the sole basis of treatment discontinuation as it can be managed with blood transfusions or administration of erythropoietin-stimulating agents (ESAs) and possibly with dose adjustments [14,42,43]. In the pivotal clinical trials COMFORT-I and COMFORT-II, anemia was successfully managed by careful titration of ruxolitinib doses, ESAs [43], and red blood cell transfusions if needed [16,17].

There is increasing literature suggesting that lower starting doses of ruxolitinib should be used, with up-titrations depending on safety and efficacy in anemic patients [44–47]. In our opinion, temporary decreases in Hb levels should be treated with transfusion in young patients with Hb levels <7.5 g/dL and older patients with Hb levels <8 g/dL.

A post hoc analysis of the COMFORT-II study suggested that ESAs administration to increase Hb levels was well tolerated and had no impact on ruxolitinib efficacy [43]. However, the study was limited by the small number of patients. Therefore, no definitive recommendations could be made regarding ESAs use in the management of anemia in ruxolitinib-treated patients and further investigations are needed to guide clinical decisions [43]. Since ESAs administration may increase the risk of thromboembolic complications, our recommendation is to stop ESA therapy when Hb levels reach >12.0 g/dL.

Thrombocytopenia

In the two COMFORT studies, approximately 70% of ruxolitinib-treated patients reported thrombocytopenia as AE [16,17,37]. Decreases in platelet levels are expected in the first 4–12 weeks of treatment, but levels remain stable afterward [23,35]. A recent analysis conducted on 2,233 patients from the JUMP study showed that, although reported by 16.3% of participants, grade 3–4 thrombocytopenia led to treatment discontinuation in only 2.7% of cases [48]. Management of thrombocytopenia in ruxolitinib-treated patients involves dose optimization (Table 1) and careful monitoring to ensure that platelet counts do not decrease drastically [3]. Dose reductions are recommended for patients with platelet count <100 × 10⁹/L and treatment interruption is required in patients with platelet count <50 × 10⁹/L [37].

Non-hematologic AEs

In general, there is no need to stop ruxolitinib treatment for non-hematologic AEs. The most common non-hematologic AEs include fatigue, diarrhea, ecchymosis, peripheral edema, dizziness, and headache [16,23,49,50]. Another important AE is arterial hypertension (personal experience). Previous reports have suggested that ruxolitinib could exert an immunosuppressive activity and be associated with reactivation or acquisition of infections, such as urinary tract infections and herpes zoster [18,51]. Increased vigilance for opportunistic infections is recommended in ruxolitinib-treated MF patients, and physicians should advise patients to seek medical attention as soon as signs of infection develop. IPSS intermediate-2 and high-risk MF patients with large spleens (≥10 cm below left costal margin) are at higher risk of infections [52]. Before starting the drug, a systematic evaluation of the patient should be performed to exclude any active infection. We recommend vaccination of ruxolitinib-treated MF patients against pneumococcal diseases [51,52]. Although there is no need for systematic prophylactic treatment against herpes zoster, patients should receive prophylactic treatment after a first episode (after treating the acute episode). Two infection markers are also important because of their therapeutic consequences. First, hepatitis B serology should be performed before starting ruxolitinib, and lamivudine (100 mg daily) should be started together with monthly hepatitis B DNA testing in positive patients. If any suspicion of tuberculosis exists, screening should be performed with the interferon-gamma release assay. In case of latent tuberculosis, isoniazid 300 mg daily will be prescribed [51].

Interruption, failure, and stopping rules

Our recommendations are to continue ruxolitinib treatment as long as there is a clinical benefit. If there is no decrease in spleen volume and no symptom improvement within six months, treatment is usually discontinued [37,53]. In the COMFORT-II study, treatment was discontinued within three years after initiation in approximately 55% of MF patients [54]. Potential causes of treatment failure include resistance (worsening of symptoms, not achieving or loss of spleen response), treatment-related toxicities (hematological and non-hematological AEs), disease progression (including leukemic transformation), and early mortality [49].

Dose tapering when stopping ruxolitinib treatment has been suggested [28], as sudden discontinuation may induce symptoms reactivation within one week [17] and serious AEs [37]. Our recommendation is to stop the treatment by reducing the dose by 5 mg twice daily every week.

Conclusion

Ruxolitinib seems to be the best currently available drug for the treatment of MF patients. Although approved indications of ruxolitinib in MF patients are the treatment of splenomegaly as well as disease-related symptoms, current reimbursement policies in Belgium limit its use to the treatment of splenomegaly for patients in intermediate-2 and high-risk groups. Regulations should be revised to allow its reimbursement for MF patients in intermediate-1 risk categories with severe symptoms, as they would greatly benefit from an improvement in symptoms. Evaluation of ruxolitinib efficacy in MF patients should not only be based on spleen volume but also on an improvement of symptoms. The MPN10 score can be used to measure the symptom burden.

Close monitoring of blood cell counts and careful dose titration, particularly during the first 8–12 weeks of treatment, are critical in the management of cytopenia. Optimization of the ruxolitinib dose is recommended to avoid decreases in platelet counts that may jeopardize treatment continuation. In the patient with transfusion-dependent anemia, the right starting dose of ruxolitinib is still under investigation.

In case of insufficient response and after dose reductions, careful up-titration of ruxolitinib doses is recommended to maximize its efficacy, while carefully monitoring the safety. An individualized dosing approach is key to long-term treatment success.

Trademark statement

Jakavi is a registered trademark of Novartis AG in countries outside the U.S.A.

Acknowledgements

The authors would like to thank Julie Todoroff, Claire Verbelen, and Petronela M. Petrar (XPE Pharma & Science, on behalf of Novartis) who provided editorial and writing support based on direction from the authors. The authors had full editorial control of the paper and provided their final approval of all content.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Devos Timothy is a hematologist specialized in myeloproliferative neoplasms and a member of the Belgian Hematology Society. He is currently working at the University Hospitals Leuven (UZ Leuven) and the Catholic University Leuven (KU Leuven), Leuven, Belgium.

Selleslag Dominik is a hematologist specialized in myeloproliferative neoplasms and a member of the Belgian Hematology Society. He is currently working at the Algemeen Ziekenhuis Sint-Jan, Bruges, Belgium.

Zachée Pierre is a hematologist specialized in myeloproliferative neoplasms and a member of the Belgian Hematology Society. He is currently working at the Ziekenhuis Netwerk Antwerpen Stuivenberg, Antwerp, Belgium.

Fleur Samantha Benghiat is a hematologist specialized in myeloproliferative neoplasms and a member of the Belgian Hematology Society. She is currently working at the Hôpital Erasme, Brussels, Belgium.

Additional information

Funding

This work was logistically supported by Novartis Pharma.