Should we be treating lower risk myelofibrosis patients with a JAK2 inhibitor?

1. Introduction

Myelofibrosis (MF) is a clonal hematopoietic stem cell malig- nancy classified by the World Health Organization as a Philadelphia chromosome-negative (Ph−) myeloproliferative neoplasm (MPN) [1]. MF typically presents in patients in their fifth to sixth decade of life as primary myelofibrosis or as a sequela of polycythemia vera (PV) or essential thrombocythe- mia (ET) denoted as PPVMF/PETMF [1–3]. Clinical disease is variable, ranging from asymptomatic to debilitating constitu- tional symptoms, progressive splenomegaly, and clinically sig- nificant cytopenias. The most dreaded complication is evolution to acute myeloid leukemia, which occurs in 10–20% of patients with MF and carries a dismal prognosis [4]. Prognosis in MF varies widely based on risk stratification. Currently, the International Prognostic Scoring System (IPSS) is used at diagnosis to classify patients as low, intermediate-1, intermediate-2, and high risk, with reported median survivals of 135, 95, 48, and 27 months, respectively [5]. The IPSS was the first robust prognostic model developed for MF and accounts for five clinical and laboratory variables that predict worse survival: age > 65 years, presence of constitutional symptoms, Hgb < 10 g/dL, leukocyte count > 25 × 109/L, and circulating blasts ≥ 1%. The Dynamic IPSS (DIPSS) can be used at any time in the disease course and has been further refined to the DIPSS-plus, which includes thrombocytopenia (<100 × 109/L), red blood cell transfusion dependence, and unfavorable karyotype [6,7]. These models do not yet include emerging knowledge about the molecular underpinnings of MF. Driver mutations involving JAK2, MPL, and CALR are noted in 90% of patients with MF and are associated with hyperactive Janus-associated kinase-signal transducer and activator of transcription (JAK-STAT) signaling [8–10]. Subclonal mutations involving ASXL1, EZH2, IDH1/2, and SRSF2 have also been documented in patients with MF and appear to have independent prognostic influence [11]. A recent multivariate analysis of prognostic factors in MF found that presence of mutated JAK2 or MPL, ASXL1, and SRSF2 held prognostic significance and could be integrated in a new prognostic model, the Mutation-Enhanced IPSS (MIPSS) [12]. As a result, patients previously thought to be at lower risk by former clinico-hematologic scoring systems may harbor dele- terious mutations that actually put them at an increased risk for poor survival. The benefit of refined risk stratification is in the optimization of therapeutic decision-making, particularly the appropriate application of definitive therapy with hema- topoietic stem cell transplantation (HSCT). However, HSCT carries a substantial risk of morbidity and mortality, and given the patient population in MF, many are not appropriate candidates. In addition, HSCT is rarely pursued in low and intermediate-1 risk patients as they are generally considered to have reasonably long-term prognosis and the risks of aggressive intervention are not felt to be justified. In a recent retrospective analysis, patients classified as low risk based on DIPSS who received a HSCT had a significantly elevated rela- tive risk of death of 5.6 (95% confidence interval [CI]: 1.7–19) compared with those who received non-transplant therapy, while intermediate-1 risk patients had a relative risk of 1.6 (95% CI: 0.79–3.2) [13]. The focus of pharmacologic interven- tion in patients not eligible for HSCT has been centered on the JAK-STAT pathway. JAK-STAT is a tyrosine kinase signal transduction pathway that has been shown to play a key role in a number of vital physiological processes, including hema- topoietic cell proliferation, inflammatory response, and immu- nity [8]. JAK2V617F is the most common mutation found in MPNs, seen in approximately 95% of PV, 55% of ET, and 60% of MF [14]. Even in MF patients lacking JAK2V617F, there is evidence of significant dysregulation of the JAK-STAT pathway [15]. This has provided an attractive target for the treatment of MF and has spurred the development of JAK inhibitors, a new class of small molecule therapy. 1.1. Data for JAK inhibitors Ruxolitinib (Jakafi, Incyte), a selective JAK1/2 inhibitor, is cur- rently the only drug in its class approved by the US FDA for the treatment of MF. Its use is indicated specifically for the treatment of intermediate and high-risk MF based on results from two pivotal phase III clinical trials, COMFORT-I and COMFORT-II, which demonstrated clinically significant reduc- tion in splenomegaly and constitutional symptoms [16,17]. Subsequent analyses have also demonstrated a potential sur- vival benefit [18,19], although this is difficult to interpret as the original trials were not powered for survival, study treatment crossover was allowed, and analysis was based on the inten- tion to treat principle. Of note, these trials did not include patients categorized in the low and intermediate-1 risk groups. However, there are nonrandomized studies that provide supportive data for the use of ruxolitinib in the lower risk patients. In the expanded-access open-label JUMP study, inter- mediate-1 risk patients were included if they had a palpable spleen length ≥ 5 cm from the left costal margin [20]. This group achieved a ≥50% reduction in palpable splenomegaly in 63.8% and 60.5% of patients at 24 and 48 weeks, respectively, with an additional 19.6% and 21.0% of patients achieving a 25% to <50% reduction. Improvements in symptoms as mea- sured by various Function Assessment in Cancer Therapy scales were noted in approximately 30–40% of patients. Adverse events leading to discontinuation occurred in 11% of patients; hematologic toxicity was common with 54% of patients experiencing anemia (grade 3/4, 24.5%) and 40.5% experiencing thrombocytopenia (grade 3/4, 11.0%). In the ROBUST trial, an open-label phase II trial in the UK evaluating the safety and efficacy of ruxolitinib in intermediate-1, inter- mediate-2, and high-risk MF, 8 (57.1%) of 14 patients classified as intermediate-1 had a ≥50% reduction in palpable splenomegaly at both 24 and 48 weeks, and 3 (21.4%) of 14 patients achieved a >50% reduction in their symptoms based on the Myelofibrosis Symptom Assessment Form Total Symptom Score [21]. Adverse events were not reported by subgroup but were overall similar to those seen in the COMFORT-I and COMFORT-II trials. Additionally, a retrospective analysis of rux- olitinib use in 108 lower risk MF patients reported consistent decrease in splenomegaly and decreased severity, but not frequency, of most MF symptoms, though this study has sub- stantial limitations [22]. A summary of available data of rux- olitinib therapy in lower risk MF patients is presented in Table 1.

Although ruxolitinib is the only FDA-approved JAK inhibitor for MF, there are other JAK inhibitors in late stages of devel- opment, including momelotinib (Gilead) and pacritinib (CTI Biopharma). Momelotinib is a JAK1/2 inhibitor currently being evaluated in two large phase III trials (SIMPLIFY-1 and 2). SIMPLIFY-1 compares momelotinib head-to-head with rux- olitinib in lntermediate-1 (associated with symptomatic sple- nomegaly, hepatomegaly, anemia [hemoglobin < 10.0 g/dL], and/or unresponsive to available therapy) and higher risk MF patients that are JAK inhibitor naïve, while SIMPLIFY-2 com- pares momelotinib with best available therapy for intermedi- ate-1 (associated with symptomatic splenomegaly, and/or hepatomegaly) or higher risk MF patients with anemia or thrombocytopenia. In the initial phase II trial, momelotinib showed surprising durable improvements in anemia, with 23/33 (70%) of transfusion-dependent patients achieving inde- pendence from red blood cell transfusions after a median of 9.6 months, and 1/8 (13%) non-transfusion-dependent patients with anemia showing a sustained increase in hemo- globin of 2 g/dL. However, there was significant grade 3/4 thrombocytopenia (32%) and grade 1/2 peripheral neuropathy (27%), consisting of hypoesthesia, paresthesia, formication, and neuropathic pain, which were often irreversible [23]. Pacritinib is a JAK2/FLT3 inhibitor that demonstrated favorable results in the PERSIST-1 phase III trial with 25% of red blood cell transfusion-dependent patients at baseline achieving independence [24]. Unfortunately, pacritinib was placed on a full clinical hold by the FDA in early 2016 due to concern over increased deaths related to intracranial hemorrhage, cardiac arrest, and cardiac failure in the PERSIST-2 trial dedicated to patients with baseline platelet count <100 × 109/L. Fedratinib (Sanofi Aventis) was also discontinued late in development due to emergence of significant treatment-related adverse events, particularly Wernicke’s encephalopathy [25]. A number of other JAK inhibitors with differing JAK2 selectivity remain in phase I/II trials [26]. 2. Rationale for earlier use of JAK2 inhibition in MF 2.1. Overall survival Despite the majority of prospective data assessing the effect of ruxolitinib therapy in higher risk patients with MF, there exists rationale for initiating treatment with ruxolitinib in lower risk patients. The emergence of a possible survival ben- efit from the COMFORT trials, while not directly applicable to lower risk patients, indicates that ruxolitinib may delay the progression of clinical disease when started earlier in the clinical course [27]. In a pooled analysis from COMFORT-I and COMFORT-II, the Kaplan–Meier survival curves comparing the ruxolitinib randomized arm to placebo (CI) or best available therapy (CII) are in fact comparing early versus late JAK2 inhibitor therapy in the intention to treat analysis and favor a survival advantage in the ruxolitinib arm (hazard ratio = 0.65; 95% CI: 0.46–0.90) [28]. This modest survival benefit associated with the ruxolitinib arm could potentially be the result of delaying the onset of disease signs and symptoms that are associated with significant morbidity and clinical decline. In a retrospective comparison of trial participants at MD Anderson Cancer Center with matched historical controls, there was a significant survival advantage among high-risk but not inter- mediate-risk patients receiving ruxolitinib therapy compared to matched historical controls [29]. However, patients in the ruxolitinib cohort were younger, had higher initial hemoglobin levels, and had larger spleen size at baseline. As of now, there are little data that JAK inhibition substan- tially alters the disease course at the molecular level, although this has been reported in a minority of long-term treated patients from prospective studies, including reversal of bone marrow fibrosis and JAK2 V617F allele burden [30–33]. Nevertheless, given the survival benefit that has been described from the COMFORT trials, it is possible that ruxolitinib therapy initiated earlier in the disease course may indeed result in alteration of the clinical course indirectly through improvements in disease-related inflammation that contributes to high symp- tom burden, reduced quality of life, and poor functional status. 2.2. High-risk mutations One area of emerging importance is the discovery of muta- tions that appear to play a role in the pathogenesis and influence prognosis of MF, including CALR, MPL, ASXL1, and SRSF2, in addition to the well-studied and described JAK2V617F [11]. A new prognostic model noted above, MIPSS, has incorporated these mutations into a clinico-hema- tologic risk stratification system in order to refine prognostica- tion [12]. While not yet validated and ready for clinical use, it is a strong indicator of the future of molecular-based risk-strati- fication in MF. The MIPSS and other mutation-based scoring systems may eventually help better discriminate between IPSS low and intermediate-1 risk patients who will have a largely indolent course not requiring treatment and those who are actually at higher risk for an aggressive clinical course and may benefit from earlier interventions. 2.3. Quality of life Specific patient groups that may benefit from earlier therapy are those with splenomegaly or significant symptoms that impact on quality of life. The IPSS accounts for the presence of constitutional symptoms (fever, night sweats, >10% weight loss) but not for their severity, nor does it address splenome- galy related symptoms (early satiety, abdominal discomfort, subcostal pain) or pruritus. MF-related symptoms can be debil- itating and negatively impact patients’ quality of life [34]. Furthermore, this debility can lead to a decrease in activity and overall conditioning that may adversely affect long-term outcomes. Ruxolitinib was originally approved in MF precisely for its ability to reduce splenomegaly and constitutional symp- toms that led to improvements in quality of life. Given the significant impact of MF on quality of life, even in lower risk patients [34], earlier therapy with ruxolitinib may be beneficial in this regard.

2.4. Adverse effects

Of course, any benefits of therapy with ruxolitinib must be weighed against the potential risks involved, which are not insubstantial. The most common adverse events reported in the COMFORT-I and COMFORT-II trials were anemia (96.1% and 96.6% overall; 45.2% and 42.5% grade 3/4) and thrombo- cytopenia (69.7% and 67.8% overall; 12.9% and 8.2% grade 3/ 4), which can necessitate dose reduction and even disconti- nuation of the therapy [16,17]. The most common grade 3/4 non-hematologic adverse effects were diarrhea, fatigue, pyr- exia, abdominal pain, back pain, and arthralgia. Sudden dis- continuation of ruxolitinib can lead to a potentially fatal septic shock-like picture, likely mediated by an acute rebound of inflammatory cytokines [35]. Follow-up data from the COMFORT-II study indicate that infections may be more com- mon with ruxolitinib therapy, particularly urinary-tract infec- tions (24.6%), pneumonia (13.1%), and herpes zoster (11.5%) [36]. Tuberculosis was seen in 1% of patients. In addition, 25 patients (17.1%) in the ruxolitinib arm had newly diagnosed nonmelanoma skin cancer, compared with 2 patients (2.7%) in the BAT arm from COMFORT-II [36]. There was no other increase in the rate of treatment-related adverse events or the emergence of unknown late term toxicity seen in longer term follow-up of the COMFORT trials [18,19,36]. Nevertheless, further follow-up is needed, particularly as the lower risk population would be expected to remain on this oral medica- tion for many years. Careful patient monitoring of clinical status and laboratory data and appropriate patient selection are essential to mitigating risk and ensuring success of ther- apy. Further data on adverse events, especially long term, would be helpful in deciding the most appropriate timing to institute treatment in this population of MF patients.

3. Expert commentary

The question of whether to treat lower risk MF patients with a JAK2 inhibitor is a complex one and is constantly evolving. The prevailing strategy for many years has been ‘watch and wait’ given the long survival times and relatively slow progression in low-risk patients. However, these risk groups are derived solely from clinical and laboratory data and do not factor in the molecular characteristics of their disease. As our under- standing of this complex disease progresses, more focus will be placed on the underlying molecular events. This will ideally allow early identification of patients with an anticipated aggressive disease course who otherwise would have been classified as lower risk. The question of whether this popula- tion will benefit from early JAK inhibition remains open and will be examined in an ongoing Novartis sponsored, rando- mized, double-blind, placebo-controlled, multicenter, phase III trial, specifically looking at the clinical benefit of ruxolitinib intervention in classically defined lower risk patients who harbor high-molecular risk mutations (HMR). HMR is defined as having mutations in at least one of ASXL1, EZH2, SRSF2, and IDH1/IDH2 (NCT02598297). The ReTHINK trial will enroll 320 non-symptomatic MF patients that are JAK inhibitor naïve with a primary objective to evaluate clinical benefit of ruxolitinib therapy in delaying progression to more advanced disease stages [37].

While we await data from this important trial, there is existing rationale for treating MF patients earlier in the disease course which may impart clinical benefit. Encouraging survival data originating from the COMFORT-1 and COMFORT-2 stu- dies provide an indication that ruxolitinib therapy does indir- ectly affect the clinical course of MF even in the absence of bone marrow pathologic and molecular response. It is possible that despite not having a clear direct impact on the malignant hematopoietic stem/progenitor cell burden, JAK2 inhibition leads to a decrease in release of inflammatory cytokines within the bone marrow niche thereby indirectly limiting or delaying clonal progression [38]. In patients with a high symptom burden and lower risk status, this logic is readily applied, as improvement in quality of life remains an important target in treatment of MF, even independent of survival benefit. Intermediate-1 risk patients have consistently seen impressive reductions in splenomegaly and symptoms in several nonran- domized studies reported to date [20–22].
In considering JAK inhibition with ruxolitinib in this MF population, each case must be assessed individually, with careful thought given to how aggressively the patient should be treated, how likely they are to derive benefit, and the potential treatment-related risks. At present, this entails a holistic view factoring in eligibility for HSCT, the presence of HMR mutations, the clinical symptom burden, presence of splenomegaly, and the risks of treatment emergent cytope- nias, infections, secondary skin cancers, and potentially fatal discontinuation syndrome. In a highly compliant patient who can be carefully monitored, substantial benefit may be derived from early initiation of ruxolitinib with acceptable risk. However, prospective clinical trial evidence is required before this approach is adopted in the community setting.

4. Five-year view

The landscape for treatment of MF is promising and rapidly evolving. Ruxolitinib remains the only FDA-approved drug for intermediate and high-risk MF patients and may soon find applications within the lower risk populations as well. An ongoing phase III clinical trial evaluating the safety and effi- cacy of ruxolitinib in early MF with HMR mutations will hope- fully answer many of the questions centered around low-risk patients and provide further therapeutic guidance. Additionally, further study of the specific HMR mutations will help to delineate their individual impact on disease progres- sion and possibly identify new treatment targets.

At present, there are several ongoing trials assessing agents outside of the JAK-STAT pathway, either alone or in combina- tion with ruxolitinib. Imetelstat is a first-in-class telomerase inhibitor that has shown the ability to induce complete responses, including molecular response and reversal of bone marrow fibrosis, in select patients [39]. Other classes of drugs under active investigation include PI3K inhibitors, hedgehog inhibitors, anti-fibrotics (PRM-151), histone deace- tylase inhibitors, and interferon-alpha [40]. Most of these agents are being studied in higher risk patients and are in early stages of development. In the next 5 years, ruxolitinib will likely remain the mainstay of initial treatment in higher risk patients. Several other JAK inhibitors (momelotinib, pacri- tinib) may also gain approval and differentiate themselves from ruxolitinib in terms of anemia response and less therapy-related thrombocytopenia, although it should be noted that pacritinib has recently been placed on full clinical hold by the FDA due to concerns of increased risk of bleeding and cardiovascular events. Ruxolitinib will potentially find expanding indications in the treatment of lower risk MF patients once ongoing trials provide prospective evidence of clinically meaningful benefit.

Key issues

● MF is associated with debilitating constitutional symptoms, splenomegaly, and cytopenias, and has a negative effect on overall survival
● Ruxolitinib is the only drug approved for MF in intermedi- ate and high-risk patients. Presently, no randomized con- trolled trials including lower risk patients have resulted.
● As our understanding of the pathogenetic and prognostic contribution of molecular alterations evolves, refinement of MF risk stratification may improve therapeutic decision making.
● Lower risk patients either harboring high risk mutations, significant symptom burden or splenomegaly may derive clinical benefit from immediate rather than delayed ruxoli- tinib therapy.
● Survival data from the COMFORT studies also provides
rationale for earlier initiation of ruxolitinib therapy.
● Long-term risk of therapy is not fully understood yet, and cumulative risk of therapy related adverse events must be considered in deciding to implement JAK2 inhibitor therapy earlier in the clinical course.
● An ongoing global phase III clinical trial of ruxolitinib treatment in lower risk STAT5-IN-1 MF patients will provide further evidence-based guidance for clinicians.