Jak-2 Positive Myeloproliferative Neoplasms

Current Treatment Options in OncologyDOI 10.1007/s11864-014-0279-3

Leukemia (JP Dutcher, Section Editor)

Jak-2 PositiveMyeloproliferative NeoplasmsPablo J. Muxı́, MD*

Ana Carolina Oliver, MD

Address*Department of Haematology, British Hospital, Av. Italia 2420, Montevideo,UruguayEmail: [email protected]

* Springer Science+Business Media New York 2014

Keywords Myeloproliferative neoplasms I Chronic myelogenous meukemia (CML) I Chronic neutrophilic leukemia(CNL) I Polycythemia vera (PV) I Primary myelofibrosis (PMF) I Essential thromobocythemia I JAK2 I JAK2inhibitors I Ruxolitinib

Opinion statement

Originally described by Dameshek in 1951, myeloproliferative disorders are today clas-sified as myeloproliferative Neoplasms (MPNs) in WHO’s Classification of Tumors of He-matopoietic and Lymphoid Tissues. The term includes a range of conditions, [ie, BCR-ABL-positive chronic myelogenous leukemia (CML), chronic neutrophilic leukemia(CNL), polycythemia vera (PV), pr imary myelof ibrosis (PMF), essentialthromobocythemia (ET), chronic eosinophilic leukemia not otherwise specified (CEL-NOS), mastocytosis, and unclassifiable myeloproliferative neoplasm]. In the specificcase of CML, a better understanding of the pathogenesis and pathophysiology of thedisease has led to a targeted therapy. The presence of chromosome Philadelphia,t(9;22)(q34;11) results in the oncogene BCR-ABL, which characterizes the disease; thismolecular rearrangement gives rise to a tyrosine-kinase, which in turn triggers the pro-liferation of the myeloid line through the activation of the signaling pathways down-stream. Tyrosine-kinase inhibitors (TKIs) have altered the therapy and monitoring ofCML patients and improved both their prognosis and quality of life. In 2005, variousgroups of investigators described a new point mutation of the gene JAK2 associatedto MPNs. Although the presence of this mutation has led to a modification in the di-agnostic criteria of these conditions, the impact of the use of JAK2 inhibitors on theprognosis and course of the disease continues to be controversial.

IntroductionMPNs are a number of conditions characterized by aclonal derangement of stem cells that causes the exces-sive proliferation of the various myeloid lines. In 1951Dameshek published an editorial, in which he pooled

these conditions together, and introduced novel con-cepts on MPNs, including the fact that “erythroblasts,granulocytes and megakaryocytes often proliferate enmasse or as a unit, rather than as single elements,” this

first observation of the overlap of the clinical andlaboratory findings in PV, ET, and MF continuesto be valid [1]. The entities currently grouped asmyeloproliferative disorders are well defined. In2008 the WHO Classification of Tumors of Hema-topoietic and Lymphoid Tissues calls them myelo-proliferative neoplasms, and includes conditions

such as BCR-ABL positive chronic myelogenous leu-kemia (CML), chronic neutrophilic leukemia, poly-cythemia vera (PV), primary myelofibrosis (PMF),essential thromobocytemia (ET), chronic eosino-ph i l i c l e uk emi a no t o th e rw i s e sp e c i f i e d ,mastocytosis and unclassifiable myeloproliferativeneoplasm [2].

Myeloproliferative Neoplasms

In MPNs, clonal changes of the hematopoietic stem cells result in bonemarrow hypercellularity, with a myeloid proliferation characterized by thepredominance of one of the lines, either granulocytes, erythrocytes, orplatelets; further on patients may potentially develop bone marrow fibrosisor acute leukemia. The annual incidence of MPNs ranges from 6 to 10/100,000 [2–5].

During the course of the disease MPNs share some common clinical man-ifestations, initial proliferation of the myeloid lines, general symptoms in-cluding fatigue, itching, sweating, fever, bone pain, and weight loss, bleedingor thrombotic complications, symptomatic spleen enlargement and cytope-nias, and eventually the clones may evolve toward a myelodisplasia or ablastic phase.

In a study conducted by Mesa et al, fatigue (80.7 %) was the symptommost frequently reported by patients with MPN, followed by pruritus(52.2 %), night sweats (49.2 %), and bone pain (43.9 %) [6]. Validated in 11languages, the Myeloproliferative Neoplasm Symptom Assessment Form(MPN-SAF) is a 10-item questionnaire used to evaluate fatigue, concentra-tion, early satiety, inactivity, night sweats, itching, bone pain, abdominaldiscomfort, weight loss, and fever, intended to assess the quality of life inMPN patients. In 1408 MPN patients, the mean score was 21.2–18.7 in ET,21.8 in PV and 25.3 in PMF. This symptom’s evaluation system correlateswith the MPN patients’ quality of life. The relevance of evaluating thesesymptoms is evidenced by the fact that they are currently considered whendefining the patient’s remission, and they must be taken into accountwhenever new drugs are assessed [7•, 8, 9•].

Mutations in PV, ET, and PMF

In CML, Chromosome Philadelphia t(9;22) determines a molecular re-ar-rangement that forms the chimeric gene BCR-ABL, disregulating the activityof tyrosine kinase and leading to myeloid proliferation and the developmentof the disease. Multiple studies in cell cultures have shown a direct rela-tionship with the occurrence of oncogene BCR-ABL and the development ofCML [10–15]. The therapy and prognosis of CML has significantly changedwith the use of tyrosine kinase inhibitors that curb myeloid proliferation byblocking the BCR-ABL oncogene. The IRIS trial showed an 89 % 60-monthoverall survival in chronic phase patients treated with imatinib [16–19]. In


the pre-TKI era, the mean survival of patients with CML reached 7 years withinterferon, and the only chance for a prolonged survival was with the allo-geneic transplant of hematopoietic stem cells.

In 2005 4 independent groups of researchers described the mutationof the JAK2 gene and its relation with MPNs. This articler will firstdiscuss the mutation, its incidence in the various MPNs, and its prog-nostic value, and then it will address the development of drugs thattarget this mutation [20–24].

JAK2 mutation

The thyrosine kinase JAK2 plays an essential role in the signaling pathway ofthe homodimeric receptors of cytokines, such as erythropoietin (EPO),thrombopoietin (Tpo), and the granulocyte colony stimulating factor(GCSF); all the appropriate receptors are critical for normal myelopoiesis.Thyrosine kinase plays a key role in hematopoiesis; studies with JAK2knockout mice showed they died on day 13 of gestation due to a flaweddevelopment of their definitive final hematopoiesis [25, 26] JAK2V617F isthe product of a mutation that takes place in the domain of JAK2pseudokinase, and causes a valine in position 617 to be replaced for aphenylalanin. Physiologically, the pseudokinase domain lacks the residuesthat are key for the catalytic action of the kinase domain, causing its down-regulation [21–24]. It is believed that the V617F mutation either releases theinhibitory function of the pseudokinase domain of JAK2’s catalytic domain,or it induces a conformational change in the pseudokinase domain, which inturn activates the kinase domain. The activation of the JAK2V617F kinasedomain causes the constitutive activation of proteins STAT5 and STAT3 [27].There is evidence suggesting that the activation of STAT5 is essential for aJAK2V617F-mediated cell transformation. This is supported by the fact thatthe constitutive expression of STAT5 in human stem cells suffices to inducethe growth of endogenous erythroid colonies [28]. The absence of this mu-tation in the germ line indicates it is an acquired mutation.

The JAK2V617F mutation is present in 95 % of the PVs and in 50 %–60 %of the patients with ET and PMF [29, 30]. Likewise, it has been found in othermyeloid diseases: in 60 % of the refractory anemias with ring sideroblastsassociated with thrombocytosis (RARS-T), in 8 % of the chronicmyelomonocytic leukemias, and to a lesser extent in primary acute myelo-blastic leukemias (AML), myelodysplastic syndromes (MDS), and CML. Thismutation has not been detected in lymphoid malignancies [31–33].

Some patients with PV, TE, and PMF fail to show the JAK2V617F muta-tion, even if sought with specific allele testing. As the clinical differences ofpatients with and without the mutation are scarce, it has been hypothesizedthat JAK2V617F-negative NMPCs are the result of a somatic mutation thatactivates the JAK2 signaling pathway in a manner analogous to that of theJAK2V617F mutation. Several studies have been conducted in search of thesemutations. Since 2007 it is known that 2 %–5 % of the PVs have a mutationin JAK2, at the level of exon 12; this mutation has not been found inJAK2V617F-positive PVs or in either ETs or PMF [34, 35]. This mutationcauses the hematopoietic cells to proliferate regardless of the presence of

Jak-2 Positive Myeloproliferative Neoplasms Muxí and Oliver

cytokines, and activates the JAK2 signaling pathway, resulting in the gener-ation of a PV phenotype similar to that observed in the JAK2V617F mutation[34]. Some patients with ET and PMF (5 %–10 %) present a mutation incodon 515 of gene MPL. In vitro studies have shown that the MPLW515Lmutation constitutively activates the JAK2 signaling pathway, and in vivostudies reveal that it generates a phenotype characterized by a markedthrombocytosis and myelofibrosis [36, 37]. These studies support the notionthat the constitutive activation of the JAK2 signaling pathway is a pathogenicevent shared by the 3 conditions, ie, PV, ET, and PMF.

The JAK2V617F mutation assay has acquired a key role in the clinicalmanagement of MPNs, including PV, ET, and MFP, since it is part of thediagnostic criteria included in the WHO classification. In PV and PMF it isone of the major diagnostic criteria and in TE it is 1 of the 4 criteria includedin the score [2].

The presence of the same mutation in 3 clinically distinct diseases led tothe idea that it is not the only important factor; the mutant allele burdenwould also be of relevance. This has been shown in mouse models, where thepresence of JAK2V617F homozygosity was found more frequently in PV andheterozygotes or low allele burden was seen in ET [38]. A patient is usuallyreferred to as being mutant JAK2 homozygote if the mutation is present inover 50 % and heterozygote if it is in less than 50 %. The allele burdennormally increases from ET, PV, to PMF, with the highest levels being seen inthe fibrotic transformation.

Within the same condition, there are clinical differences between carrierswith a high and a low allelic burden. A high burden of JAK2V617F in PV isassociated with an increased incidence of pruritus, a greater degree ofsplenomegaly, higher serum hemoglobin levels, and development of mye-lofibrosis; in ET it is associated with: older age, higher levels of hemoglobinand leukocyte counts, but lower platelet counts; in PMF it associates with ahigher hemoglobin level and leukocytosis [39].

There is contradictory information with regard to the significance ofJAK2V617F in predicting the risk of thrombosis in MPN. Nine papers,which include both PV and ET, have proposed an association between themutational status and the risk for thrombosis, and 4 papers reject the hy-pothesis through which they would be related. Hence, at present, it cannot beclaimed that the JAK2V617F mutation per se may result in an increased riskfor thrombotic events [40].

In PV, the odds of shifting to a postpolycythemic myelofibrosis rangesfrom 15 % at 10 years to 35 % at 15 years. A high JAK2V617F allele bur-den is considered to be a major risk factor. The risk of turning into MDS andAML is 2 %–3 % in patients not treated with cytotoxic agents and 10 % inthose treated with busulphan or pipobroman [41–43]. In ET, the risk ofdeveloping a myelofibrosis is very low, and the odds of turning into AML orMDS is G5 %, in general associated with the use of cytotoxic drugs [2, 44]. InPMF, the risk of developing AML is 20 % at 10 years [45]. Although a highallele burden has been associated with a higher risk of developing a PMF,there is no clear evidence suggesting that it entails a higher risk of developingAML/MDS as well. It is to be noted that JAK2V617F produces genomic in-stability; it has an impact on gene expression and reduces the apoptosissecondary to DNA damage, elements that may increase the risk of accumu-


lation of gene lesions that lead to leukemic transformation [46]. The impactof the JAK2V617F mutation on overall survival of MPN patients is still underdebate [39].

JAK2 inhibitors

So far, the current therapy of MPNs includes ASA to prevent thromboticevents, cytoreducing drugs such as hydroxyurea, pipobroman, busulfan,anagrelide, and interferon, cytopenic drugs such as erythropoietin, andro-gens, thalidomide, and lenalidomide, correction of vascular risk factors andhematopoietic stem cell transplantation for some cases of PMF. Except forthe latter choice, the rest of the approaches are typically considered supporttherapies, as they do not alter the MPN patients’ survival.

The example of what happened with CML, where TKIs dramaticallychanged the course of the disease, led to think that the use of JAK2 couldimprove the therapy of BCR-ABL-negative MPNs.

The JAK2V617F mutation activates the JAK2-STAT pathway, and in MPNsit leads to the proliferation of myeloid lines; owing to that, this JAK2 mu-tation would be an ideal target for the therapy of MPN. However, it seemsobvious that the existence of MPNs with wild type JAK2 is indicative of al-ternative stimulation pathways.

In recent years, several molecules have been developed to inhibit theJAK2 pathway; they do not target the JAK2V617F mutation specifically,but inhibit the entire family.

This nonselective inhibition accounts for the side effects related to thedownregulation of the hematopoiesis observed with its usage, and ex-plains why these drugs succeed in inhibiting the JAK2-STAT pathway,whatever the MPN patient’s JAK2V617F status [47].

Although there are several molecules in the pipeline that would inhibitthe JAK family members, the only one approved by the FDA so far isruxolitinib.

RuxolitinibRuxolitinib is an oral JAK1 and JAK2 inhibitor. The first clinical benefitsproven with this molecule were shown in a phase I–II study that enrolled153 patients with PMF, postessential thrombocythemia myelofibrosis, orpostpolycythemia vera myelofibrosis. The use of ruxolitinib was associatedwith a reduction of the spleen size, improvement of constitutional symp-toms, weight gain, and improvement of the patient’s physical performance,regardless of the JAK2V617F status. This showed that in patients with thewild type there need to be alternative ways for activating the JAK2-STATpathway [48••].

In November 2011 the FDA approved the use of ruxolitinib in the interme-diate or high riskmyelofibrosis, be it primary or during the course of an ETor PV.This decision was made on the basis of phase III studies COMFORT I and II.

COMFORT I and COMFORT II were double-blind, placebo-controlledstudies that included patients with intermediate or high risk myelofibrosis;COMFORT I compared ruxolitinib (15–20 mg bid) vs placebo and COM-


FORT II compared ruxolitinib (15–20 mg bid) vs the best available therapy.The primary end point was a 35 % reduction of the splenomegaly measuredby MRI on week 24 for COMFORT I and on week 48 for study COMFORT II.On week 24, COMFORT I showed a reduction of the spleen size in41.9 % of the patients that received ruxolitinib vs 0.7 % of the patientsthat were kept on placebo (PG0.001). In COMFORT II, the reduction ofthe splenomegaly at week 48 was achieved in 28 % of the patients withruxolitinib and in none of the patients in the group that received thebest available treatment (PG0.001). Both studies achieved a significantreduction (50 % reduction) of the constitutional symptoms, showingimprovement in 49.5 % of the patients treated with ruxolitinib, vs 5.3 %of those treated with placebo in COMFORT I (PG0.001). The mostcommon adverse effects were anemia and thrombocytopenia. In COM-FORT I, grade III/IV anemia and thrombocytopenia were documented in45.2 % and in 12.9 % of the patients with ruxolitinib, respectively; thenumber of patients on the JAK1-2 inhibitor that required a red bloodcell transfusion was 60 % vs 38 % in the placebo group. In COMFORT IIthe incidence of anemia and thrombocytopenia were 40.4 % and 44.5 %in the group on ruxolitinib vs 12.3 % and 9.6 % in the group on thebest available treatment [49••, 50••].

In a quality of life analysis conducted with patients enrolled in the COM-FORT I study, ruxolitinib showed a significant improvement of the consti-tutional symptoms and in the quality of life. This improvement was moreimportant in the group of patients in which the size of the spleen was re-duced [51•].

An analysis of the COMFORT I patients, with a median follow-up of2 years, showed preservation of the response in terms of an enhancedquality of life and spleen reduction, and that there was a tendency toward animproved survival. There were 27 deaths among the group of patients withruxolitinib, and 41 deaths in the placebo group (hazard ratio=0.58; 95 % CI:0.36, 0.95; P=.03] [52].

The COMFORT II study was analyzed with a 3-year mean follow-up; withthis follow-up time the mean duration of the response of the spleen sizereduction has not been reached. The deaths reported in this period were19.9 % in the ruxolitinib arm and 30.1 % in the arm that received the bestavailable treatment; these results would yield a tendency to a better survivalwith the use of ruxolitinib [53]. The quality of life analysis performed to thepatients in COMFORT II also showed benefits of ruxolitinib in terms ofquality of life [54].

In a study conducted to assess the degree of bone marrow fibrosis and itscourse under hydroxyurea or ruxolitinib therapy, there was a greater per-centage of patients with stabilization or improvement of fibrosis in the groupthat was receiving ruxolitinib [55].

Reductions in the JAK2V617F allele burden with ruxolitinib treatmentwere demonstrated in the COMFORT-II study, where that approach wascompared with the best available treatment [56].

The above-mentioned work show benefits with the use of ruxolitinib inthe intermediate 2 and high risk patients, with objective and lasting re-sponses in the size of the spleen and quality of life; its impact on survival,however, is yet to be confirmed. There are studies currently under way


combining ruxolitinib with danazol, or with lenalidomide or withazacitidine.

The use of ruxolitinib in ET and PV is currently under research. A Phase IIstudy with ET patients reported a reduction of the platelet count, while phaseII studies that enrolled PV patients achieved a reduction of the number ofphlebotomies and improvement of the constitutional symptoms [57].

Other JAK1-2 inhibitorsThere are several molecules in the pipeline, but none of them have beenapproved by the FDA yet for the management of MPNs.

Phase II studies with fedratinib (SAR302503)—a selective oral JAK2inhibitor—have shown a reduction in the size of splenomegaly and im-provement of constitutional symptoms regardless of the presence or absenceof a JAK2V617F mutation. There was a decrease in the JAK2V617F alleleburden. The most frequent side effects were nausea and diarrhea, observed inmost patients, followed by red blood cell transfusion-dependent anemia in38 % of the patients, liver enzyme elevation (27 %), and pancreatic lipase(27 %) [58, 59]. The JAKARTA study has been closed and its results arepending; it is a phase III study comparing fedratinib 400 or 500 mg day withplacebo in PMF or secondary to PV or ET. The ongoing study JAKARTA2includes Ruxolitnib-refractory patients.

Fedratinib is also being studied in PV and ET with intolerance or resis-tance to hydroxyurea; the dosages in the study were 100, 200, or400 mg day. The primary endpoint for PV is the proportion of patientsmaintaining a hematocrit below 45 % without phlebotomy for at least3 months; for ET, the proportion of patients with a platelet count lower than400×109/L for at least 3 months.

Pacritinib (SB1518) is a potent mutant JAK2 and JAK2 oral inhibitor.Thirty-3 patients with MF were enrolled in a phase II study. Of those, 29of the 30 patients that were assessed with MRI had a reduction of theirspleen volume; in 17 (57 %) that reduction was≥25 %. There was also areduction of the symptoms related to myelofibrosis, being diarrhea(81 %) and nausea (41 %) the most frequent adverse effects. No cases ofgrades III/IV anemia or thrombocytopenia were reported [60].

Momelotinib (CYT387) is a JAK 1-2 inhibitor. In an expanded phase IIstudy in patients with myelofibrosis it led to improvements in splenomeg-aly, constitutional symptoms, and anemia. The most frequent grade III/IVadverse effects were thrombocytopenia (16 %), and hyperlipasemia (3 %),with almost no reports of anemia [61, 62].

LY2784544 is a selective JAK2 V617F/STAT5 signaling and mutant cellproliferation inhibitor. Nineteen patients with MPN were treated, including17 patients with myelofibrosis, 1 PV, and 1 post-ET myelofibrosis. A 35 %spleen size reduction was observed in 13 of 17 patients. Moreover, 59 % ofthe patients reported an improvement of constitutional symptoms over50 %. The most frequent adverse effects were an elevation of serum creati-nine and uric acid levels related to a tumoral lysis syndrome, anemia (21 %),diarrhea (42 %), and nausea [63].

Overall, JAK1-2 inhibitors have proven to be effective in reducing the size ofthe spleen and in improving the constitutional symptoms; furthermore, they


could also have an impact on survival, but they have not been successful ineliminating the mutant clone in MPN patients.

Compliance with Ethics Guidelines

Conflict of InterestPablo J. Muxí had travel/accommodations expenses covered or reimbursed by Novartis. Ana Carolina Oliverdeclares that she has no conflict of interest.

Human and Animal Rights and Informed ConsentThis article does not contain any studies with human or animal subjects performed by any of the authors.

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Jak-2 Positive Myeloproliferative Neoplasms