MYELOPROLIFERATIVE DISORDERS (JJ KILADJIAN, SECTION EDITOR)

The New Landscape of Therapy for Myelofibrosis

Krisstina Gowin & Robyn Emanuel & Holly Geyer &

Ruben A. Mesa

# Springer Science+Business Media New York 2013

Abstract The landscape of therapy for myelofibrosis (MF) isevolving at a pace not previously seen for this clonal myelo-proliferative neoplasm. The discovery of the JAK2 V617Fmutation in 2005 has led to the rapid development of therapyspecifically developed for afflicted MF patients. Indeed, thesuccessful phase III studies of ruxolitinib demonstrating im-proved symptomatic burden, splenomegaly and survival led tothe first approved myelofibrosis drug in the United States andEurope. Multiple additional JAK2 inhibitors are currently in ornearing phase III testing, including SAR302503 (fedratinib),SB1518 (pacritinib) and CYT387 (momelotinib), seeking tooffer incremental benefits to ruxolitinib in regards tocytopenias or other disease features. In parallel, phase IIItesting of pomalidomide is ongoing, with the goal of solidify-ing the role of immunomodulatory therapy in MF-associatedanemia. Multiple single agents strategies are ongoing withhistone deacetylase inhibitors, hedgehog inhibitors and hypo-methylation agents. Incremental advances are further sought,either in additive or synergistic fashion, from combinationstrategies of ruxolitinib with multiple different approachesranging from allogeneic stem cell transplant to current thera-pies mitigating anemia and further impacting the bone marrowmicroenvironment or histology. Transitioning from a pre-2011era devoid of approved MF therapies to one of multiple agentsthat target not only disease course but symptomatic burden has

indeed changed the platform from which MF providers areable to launch individualized treatment plans. In this article, wediscuss the diagnostic and therapeutic milestones achievedthrough MF research and review the emerging pharmacologicagents on the treatment horizon.

Keywords Myelofibrosis . JAK2 inhibitors . Ruxolitinib .

Myeloproliferative neoplasms . Hematologic malignancy

Introduction

Myelofibrosis (MF) (primary myelofibrosis [PMF], post-essential thrombocythemia myelofibrosis [post-ET MF], andpost-polycythemia vera myelofibrosis [post-PV MF]) is aclonal myeloproliferative neoplasm (MPN) [1]. In 2013, ourunderstanding of the molecular pathogenesis of MF remainsincomplete, but many more layers of understanding continueto be elucidated. The 2005 the discovery of the JAK2 V617F[2••, 3, 4] mutation marked a watershed moment in the dis-covery of molecular mutations associated with the disease.Since 2005, multiple additional molecular abnormalities havebeen identified at varying frequencies in patients with myelo-fibrosis. These include mutations in MPL, ASXL1, TET2,IDH1/2 and EZH2, amongst others [4–11]. This advancingera of further elucidating potential molecular targets and im-proving our understanding of disease pathophysiology hassparked an age of increasing targeted drug development forpatients with the disease.

Myelofibrosis Disease Burden and Assessment of Risk

Patients with MF may come to such a diagnosis either at theinitial time of presenting to the hematologist or havingprogressed from earlier phases of myeloid neoplasia, specifi-cally ET, PV or those that we recognize now that have early

K. Gowin : R. A. Mesa (*)Division of Hematology andMedical Oncology,MayoClinic CancerCenter, Mayo Clinic, 13400 East Shea BoulevardScottsdale, AZ 85259, USAe-mail: mesa.ruben@mayo.edu

R. EmanuelInternal Medicine Residency Program, Mayo Clinic,Scottsdale, AZ, USA

H. GeyerDivision of Hospital Internal Medicine, Mayo Clinic,Scottsdale, AZ, USA

Curr Hematol Malig RepDOI 10.1007/s11899-013-0178-x

myelofibrosis in a prefibrotic form [12]. We currently recog-nize the underlying therapeutic target in MF to be the clonalmyeloid neoplasm. MF displays phenotypic variabilitythat includes a variety of comorbid complications, spe-cifically the potential to develop splenomegaly, myelofi-brosis associated symptomatology, anemia and thrombocyto-penia (Fig. 1a) [13]. Though not unique to the disease, avariety of histologic changes are observed within the bonemarrow microenvironment. These include fibrosis ofeither a reticulin or collagen nature, hypercellularityand other dysfunction. Finally, myelofibrosis is associ-ated with a clear decrease in survival. Mortality may bepotentiated from the disease itself through exacerbation ofcomorbidities, or with events such as thrombosis, bleeding orinfections. Transformation to acute myeloid leukemia (AML)may be observed in the minority (20–30 %) of patients [14].

The symptom burden inherent to MF has been a topic ofongoing interest to MF researchers. In regards to cytopenias,studies have identified that anemia remains the most prevalent

hematological aberrancy with 75 % of patients maintaining ahemoglobin of less than normal, 25% of individuals being redcell transfusion dependent and the other 50 % of patientsresiding somewhere between these two benchmarks [14,15]. Thrombocytopenia occurs in one-third of individualswith 20 % of individuals having a platelet count of less than100×109/L and 9 % of patients less than 50×109/L [14, 15].Leukopenia is quite uncommon with less than 10 % ofindividuals having a leukocyte count under 10 %. Overtneutropenia, defined as a value of less than 0.5×109/L neu-trophils, is rare in the absence of transformation to blast phaseor significant myelosuppression from therapy [14, 15].

As is evident, the burden of cytopenias is important inmyelofibrosis. We recognize that anemia, the most prevalentcytopenias, can contribute to fatigue, dyspnea and organ dys-function. It is important to note that MF-associated fatiguemay demonstrate some improvement upon increasing hemo-globin levels in the setting of anemia, but does not completelynormalize despite red cell transfusions, given its multifactorialnature (Fig. 1b). The prevalence of splenomegaly ranges from64 to 89 % [14, 15], depending upon the series chosen, with amedian spleen size of 7–8 cm below the costal margin in thebroad cross-section of patients with myelofibrosis. Individualclinical trials that self-select for patients with more advanceddisease will typically have larger spleens. Splenomegaly playsa central role in MF symptom development by contributing tomechanical discomfort through organ compression and splenicinfarctions. It may also cause early satiety which perpetuatesdisease-related cachexia and leads to exacerbation of under-lying cytopenias through splenic sequestration. Of significantconcern is its capability to delay engraftment, particularly inthe setting of allogeneic stem cell transplantation, by seques-tration of the infused CD34 cells at the time of allotransplant.Complicating the MF disease burden is the potential forvascular and thrombotic events in an estimated 10 % ofpatients, including myocardial infarction, stroke, venousthromboembolism, and splenic vein thrombosis [16].

Significant effort has been expended over the past severalyears to recognize and capture theMF disease burden. Utilizingthe myeloproliferative neoplasm symptom assessment form(MPN-SAF) [17] and the subset Total Symptom Score(MPN-SAF TSS) [15], our group has reported that over 90 %of patients with myelofibrosis experience significant fatigueand roughly 50% experience night sweats, itching, weight loss,and fever (20 %). Additionally, we have reported that spleen-related symptomatology, including early satiety, abdominaldiscomfort and abdominal pain, is prevalent and severe withinthese patients [15, 17]. It has been identified that patientswith myelofibrosis may experience a series of end-organ–related symptomatology including challenges with sexuality(both sexual desire and function), inactivity, insomnia, de-creased concentration, issues of mood, bone pain, dizziness,cough, and headache. In aggregate, these symptoms impair

Fig. 1 Impact of myelofibrosis. Panel A: Overlapping morbidity andmortality of myelofibrosis. Panel B: Cytopenias and their impact inmyelofibrosis

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health-related quality of life [15, 17]. Recently, utilizing ahierarchical cluster analysis of patients with myelofibrosis,we reported to the American Society of Hematology Meetingin 2012 that four different clusters of increasing symptomaticburden exist amongst patients with myelofibrosis [18]. Uponanalyzing the placebo arm of the COMFORT-I study [13], weidentified that global health status/quality of life, fatigue,dyspnea, insomnia and appetite loss in the placebo patientswere all inferior to published data on individuals with recur-rent or metastatic cancers. Notably, this study utilized theEORTC QLQ-C30 as a benchmark.

Given the spectrum of difficultiesMF patients experience, itremains imperative that these difficulties be accurately strati-fied from the perspective of disease burden and risk. Aspreviously mentioned, the spectrum of symptomatic burdenis relevant and should be assessed using the MPN SAF TSS[17]. Overall prognosis may be estimated in a dynamic mannerwith the Dynamic International Prognostic Scoring Scale(DIPSS) [19] or DIPSS-PLUS[20], which utilize the factorsof age (above or below age 65), leukocytosis (above or below25×109/L), anemia (above or below a hemoglobin of 10 g/dL),constitutional symptoms (defined as greater than 10 % weightloss over 6 months, night sweats or unexplained fever) andblasts in the peripheral blood (greater or less than 1%). DIPSS-PLUS additionally incorporates negative karyotypes, throm-bocytopenia (greater or less than 100×109/L) and red celltransfusion dependence. Utilizing these factors, it has beendetermined that individuals who have zero factors (low-riskdisease) have survival similar to age-matched controls through5 years. If they have one factor (intermediate-1), their survivalis similar to age-matched control for 3 years. With two or morefactors (intermediate-2 to high-risk), patients have an estimatedsurvival less than age-matched controls from the moment ofdiagnosis and median survivals are typically less than 3 years.

Therapy of Myelofibrosis Before the JAK2 Inhibitor Era

The therapeutic choices formyelofibrosis fall into three potentialgroups on a spectrum of risk and benefit [21]. Low-risk, low-benefit patients may be observed and high-risk, high-benefitpatients are may be considered for allogeneic stem cell trans-plantation. Individuals between these two disease spectrumsmay be considered for medical therapy and JAK2 inhibition.Decisions regarding if and when to utilize allogeneic stem celltransplantation in MF requires comprehensive patient assess-ment. Allogeneic stem cell transplant can be successful in thisgroup of patients, but there is not insignificant morbidity andmortality [22], and the decision is dependent uponmany factors,including the physiologic age of the patient, donor availability,match status and overall MF prognosis. Comorbidities, patientperformance status, the presence of massive splenomegaly, theimpact of medical therapy, current patient quality of life and

impact of survival should also be taken into account [23].Patients for whom transplant is feasible, either in the immediatefuture or in the distant future, should undergo a transplantconsult and be HLA-typed. The disease may have rapid, unex-pected progression and delay in time to transplantation (if notpreviously typed) can be problematic for these individuals.

Prior to the development of JAK2 inhibitors, medical ther-apies for myelofibrosis were limited (Fig. 2). Numerous ther-apies have been employed in attempts to address the anemiaassociated with myelofibrosis, with the greatest benefit havingbeen achieved with androgens [24], erythropoietin stimulatingagents (in individuals with inadequate baseline erythropoietinlevels [25, 26]), and the use of immunomodulatory drugs(specifically thalidomide with corticosteroid taper orlenalidomide [27]). Medications used to reduce splenomegaly,such as hydroxyurea, have offered modest benefits at best[28]. The spleen-reducing effects of hydroxyurea are likelyrelated to its myelosuppressive effects, resulting in reducedthrombocytosis rather than direct splenic suppression [29••].Similar results have been observed with cladribine [30]. Sple-nectomy and/or splenic radiation have been used both withsignificant limitations; splenectomy with significant morbidi-ty and mortality risk attributable to surgery [31] and splenicradiation to limited efficacy [32]. Myelofibrosis symptomshave historically been exceptionally difficult to treat and untilthe advent of JAK2 inhibitors, lacked any specific therapy.

JAK2 Inhibitors: Impact for Patients and Strategy of Use

Ruxolitinib

Necessity being the nidus for invention, the first JAK2 inhib-itor, ruxolitinib, began phase I–II testing in August of 2007 atMD Anderson and Mayo Clinic, roughly 2 years after thediscovery of the JAK2 mutation. With over 150 patients

Fig. 2 Medical approaches for managing myelofibrosis prior to approvalof JAK2 inhibitors

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accrued, it was noted that patients had a rapid improvement inthe symptomatic burden related with the disease, typicallyeven within 2–4 weeks [33]. There was also durable and rapidimprovement in splenomegaly with improvement in the base-line elevated inflammatory cytokines. Of particular interest wasthe improvement in performance status and reversal of theweight loss and cachexia associated with the disease. It hasbeen recently demonstrated in long-term follow-up of theseindividuals that ruxolitinib treatment may incur a survival ad-vantage [34]. Additionally, a recent analysis presented at theAmerican Society of Clinical Oncology suggested long-termuse of ruxolitinib may stabilize or regress marrow fibrosis [35].

The success of the initial phase I/II trials led to the first twophase III studies, COMFORT I [36••] and COMFORT II[29••], evaluating ruxolitinib vs. placebo and ruxolitinib vs.best available therapy, respectively (Fig. 3). In both studies, asignificant difference in reduction of splenomegaly (as objec-tified by MRI) was identified (COMFORT-I, p <0.001;COMFORT-II, p <0.001). Additionally, significant improve-ment was noted in the overall patient symptomatic burden asassessed by the Myelofibrosis Symptom Assessment Score(MFSAF 2.0) [37]. For both studies, control arms (placeboand best alternative therapy) were equally non-efficacious interms of splenomegaly and symptoms reduction [37, 38]. Sub-group analysis of COMFORT-I study patients identified thatthere were similar responses seen with the ruxolitinib-treatedgroup independent of the type of myelofibrosis, IPSS risk, age,

V617F mutation status, baseline spleen size or baselinehemoglobin levels [39]. Of significant interest is the surviv-al advantage observe in both COMFORT-I COMFORT-II[40]. The mechanisms incurring this survival advantageremain obscure. Recognizing the roles portal hypertension,bleeding, infection, thrombosis, and other progression andexacerbations of comorbidities play [14], it is reasonablethat performance status improvements and the drug’s pro-found impact on MF-related morbidities may in part beresponsible.

Additional JAK2 Inhibitors

Three other JAK2 inhibitors are either currently within orforthcoming to phase III trials in MF (Fig. 3). SAR302503(fedratinib) has recently completed accrual and reached itsprimary endpoint (press release 2013) [41, 42]. This JAK2and FLT3 inhibitor has demonstrated improvements in spleno-megaly and constitutional symptoms. Select individuals havenoted improvements in anemia, mild decreases in the JAK2allele burden, and changes in bone marrow histology. Thisdrug is actively being investigated in a placebo-controlledstudy (JAKARTA), and the results of this study are eagerlyanticipated. Additionally, this agent is being examined at aspotential second-line therapy for individuals who havebeen previously treated with ruxolitinib (JAKARTA II).Finally, there are ongoing phase II studies evaluating this

Fig. 3 JAK2 inhibitors inmyelofibrosis. Efficacy colorcoded by target, phase of datapublished cited (PI, PII, PIII)

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therapy in patients with earlier disease, such as essentialthrombocythemia and polycythemia vera.

Pacritinib (SB1518), a JAK2 and FLT3 inhibitor, has un-dergone two phase II studies that demonstrated improvementin splenomegaly and constitutional symptoms with a favor-able toxicity profile. Anemia and thrombocytopenia havebeen particularly less burdensome than those observed withother JAK2 inhibitors under investigation [43, 44]. The PER-SIST I study is currently accruing and evaluates pacritinib vs.best alternative therapy for MF patients, particularly thosewith marked thrombocytopenia.

CYT387 (momelotinib), a JAK2 and JAK1 inhibitor, hasrecently completed phase II testing and demonstrated signif-icant efficacy in improving anemia and transfusion depen-dence, as well as splenomegaly and constitutional symptomsin MF patients [45]. Dose-limiting toxicities, including eleva-tion in lipase levels and neurological effects, continue to beinvestigated.

Several other JAK2 inhibitors are currently undergoingclinical testing with limited data in the public domain. Theseinclude LY2784544, NS018 and BMS-911543. The results ofthese phase I–II studies are anticipated with great interest.Three JAK2 inhibitors have ceased further development forMF, including XL019, which was tested in 2007 and 2008 butnot pursued as a result of neurologic toxicities. Similarly,testing for CEP701 and AZD1480 was halted for a varietyof reasons including lack of efficacy.

In evaluating JAK2 inhibitors as a cohort, the significantoverlap in efficacy they share becomes apparent. Discrepan-cies in drug phase testing format and lack of randomized databetween individual agents further complicates our abilities toaccurately inter-compare efficacy and safety profiles. At thepoint phase III data is available for all therapies, more discrim-inant comparisons may be made, though this remains a diffi-cult undertaking without true randomization. Anemia andthrombocytopenia have manifested in variable degrees of tox-icity between agents, and appear to provide a more transparentplatform for comparative analysis than drug landmarks follow-ed to assess benefits. Notably, drug efficacy and toxicity re-main closely related to dose intensity and the specific popula-tion treated. Gastrointestinal toxicities can be particularly prev-alent and, though in general are manageable, have remained aconcern in with SAR302503 and pacritinib. Leukopenia to anysignificant degree is rare with all of these drugs.

Other Agents in Single Agent Drug Trial Testing

Evolving therapies not particularly targeting JAK2 are cur-rently in clinical testing, the most mature of which is theimmunomodulatory agent (IMiD), pomalidomide. It was not-ed earlier in this discussion that thalidomide and lenalidomidehave both demonstrated efficacy in improving anemia and

thrombocytopenia within MF [27]. It was on this basis thatpomalidomide, recently approved for multiple myeloma, hasbeen of great interest in this disease. The first trial conductedwith pomalidomide inMF patients was a randomized Phase IIstudy [46] comparing two different doses of pomalidomide,2 mg vs. 0.5, ± the addition of prednisone with a prednisone-only control arm. Amongst 84 MF patients, pomalidomidedemonstrated response rates from 16 to 36 % and moresignificant and durable responses than treatment with steroidsalone. Subsequent studies attempting to dose escalatepomalidomide have been unsuccessful [47]. On the basis ofthese studies, pomalidomide has recently undergone Phase IIItesting in the RESUME trial. This trial will be evaluatingpomalidomide vs. placebo in transfusion-dependent patients.Other single agent trials have recently been conducted.Panobinostat has demonstrated efficacy in reducing anemia,splenomegaly and improving marrow histology in MF pa-tients at the expense of dose-limiting thrombocytopenia [48].Givinostat (ITF2357) has offered some modest single agentresponses in MF patients [49]. The mTOR inhibitor, everoli-mus, was evaluated in a Phase I–II study in MF patients withten patients tolerating the maximum dose [50]. Improvementsin symptoms and spleen size have made this drug worthy ofongoing investigation.

Combination Studies: Rationale and Candidates

Historically, combination strategies have been the norm fortreating MPN’s hematological counterparts such as lympho-ma, myeloma, acute myeloid leukemia and even solid tumordisease. Single agent therapy has been reserved for the minor-ity of patients with specific disorders such as chronic myeloidleukemia or hairy cell leukemia. Akin to its counterparts,rationale can be made for combination therapy in myelofibro-sis (Fig. 4). An obvious combination strategy would be that of

Fig. 4 Clinical trials ongoing (partial list) for myelofibrosis

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applying pharmacological agents to non-medicinal therapies.An example of this would be the use of JAK2 inhibition priorto stem cell transplantation. This treatment approach wouldoffer the potential benefits of improving performance statusand decreasing splenic size that may secondarily reduce thesequestration of infused stem cells. Indeed, on this basis, theMyeloproliferative Disorders Research Consortium (MPD-RC) currently has a clinical trial beginning with ruxolitinibas a run-in prior to allogeneic stem cell transplantation. An-other example may include JAK2 inhibition in individualswho have already had a therapeutic splenectomy. Althoughthe primary endpoint of most of the JAK2 inhibitor trials up tothis point in time has been reduction of splenomegaly, thepotential for significant improvements in constitutional symp-toms, weight loss and survival are all relevant reasons toconsider combination therapy.

The next group of combination studies to consider involvesutilizing ruxolitinib in parallel with other concurrent therapies.Ruxolitinib-associated anemia, either pre-existing or resultantfrom the drug itself, provides a potential target for interven-tion. Clinical trials, planned or ongoing, include ruxolitinibplus danazol, ruxolitinib plus IMiD therapy (lenalidomide orpomalidomide) and ruxolitinib in individuals receivingerythropoietin-stimulating agents. Ruxolitinib may also beconsidered in combination with other available therapiesthat have shown single agent activity. This would includehypomethylating agents, including azacytidine and/ordecitabine. These therapies in parallel host potential to decreaseblasts, provide a more enhanced response and potentially ad-dress therapeutic gaps in overlap syndromes. Potential limiterswould be the additive myelosuppression. An area of particularinterest has been combination strategies with agents targetingthe marrow microenvironment. These include the LOXL2antibody GS-6624, a theoretical anti-fibrosing agent thatis now being used in a Phase II clinical trial in combi-nation with ruxolitinib. Additionally, two Hedgehog in-hibitors (including IPI926) are undergoing Phase II clinicaltesting. Finally, combination studies with experimental agentsinvolving other pathways linked with myeloproliferation posean excellent opportunity for intervention. Histone deacetylaseinhibitors, such as panobinostat, are currently being eval-uated in two Phase II dose-seeking studies (one in theU.S. and one in Europe). The mTOR inhibitor, everolimus,has also been of particular interest. Potential future combina-tions may additionally include MAP kinase inhibition and PI3kinase inhibition [51].

The Landscape forMyelofibrosis for the Next ThreeYears

The landscape for myelofibrosis is rapidly evolving. Itincludes recognition that myelofibrosis is a heterogeneous

disease, and that despite forging significant advances, therecontinue to be unanswered questions that require investiga-tion. Questions addressing how we can further improvecytopenias, impact the bone marrow microenvironment andextend the survival beyond what has been observed withruxolitinib will be of particular importance as we enter thisnew decade. The next 3 years will likely offer significantexpansion of public literature data regarding the single agentefficacy of JAK2 inhibition, particularly with the emergingagents, SAR302503, pacritinib and CYT387; as well as ad-dress the benefits of combination therapy. Knowledge regard-ing the safety and efficacy of JAK2 inhibition, both pre-allogeneic and post-allogeneic transplant, as well as in thesetting of graft vs. host disease and relapse, is anxiouslyanticipated. We additionally expect to advance our un-derstanding of JAK2 inhibition effects in low-risk andintermediate-1–risk myelofibrosis patients, particularlythose with heightened symptomatic burden. The impactof such inhibition on the natural disease course is atopic of ongoing interest. Concomitant to treatment ad-vances are expected improvements in our understandingof disease progression, and potential interventions thatmay impede life-threatening complications. We addition-ally hope to see Food and Drug Administration (FDA)approval of other therapeutic agents, particularly thefirst IMiD specifically licensed for myelofibrosis withcytopenias. Finally, the next 3 years will provide an enhancedunderstanding of the role of JAK2 inhibitors play in polycy-themia vera. Still undergoing investigation, much has yetto be learned regarding the effect of JAK2 inhibition ondisease and its ability to postpone progression to overtpost-PV myelofibrosis.

In conclusion, the future of MPNs is one of significantpotential scientific advances, rapid knowledge acquisitionand apposite application of current therapeutic armaments.Extension of this era that so confidently embraced scientificadvancement while syndicating it with investigational coop-eration will assuredly offer an optimistic future for MPNpatients, and serve as a propitious beacon to other hematolog-ical disorders.

Compliance with Ethics Guidelines

Conflict of Interest Krisstina Gowin, Robyn Emanuel, and HollyGeyer declare that they have no conflict of interest.

Ruben A. Mesa has received payment for consulting from Novartis,and research support from Sanofi, Incyte, Genentech, Lilly, Gilead, CTI,and Celgene.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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