The classical Philadelphia-negative myeloproliferative neoplasms (MPNs) , namely essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF), lack a therapeutic strategy aimed at efficiently targeting the molecular hallmark leading to malignancy. Thus, therapies are addressed to prevent the inherent propensity to incur clinically relevant events, such as thrombosis and hemorrhage in polycythemia vera and essential thrombocythemia, or to alleviate the symptoms that most influence the patient's quality of life, such as microvascular disturbances in polycythemia vera and essential thrombocythemia, or anemia and splenomegaly in PMF. Resolutive treatments, such as stem cell transplantation, are limited to a minority of patients, and the risk of transplant-related mortality renders the appropriate selection of patients problematic, considering the chronic and often indolent nature of the diseases.
The present review highlights recent developments in therapeutic strategies for patients with MPNs and critically evaluates the chance they have in resolving the unmet clinical needs and in targeting the newly discovered molecular abnormalities, first of all the Janus kinase 2 (JAK2) V617F gain of function mutation.
Resolving unmet clinical needs in myeloproliferative neoplasms
A number of unmet clinical needs, that is, strategies whose nonperformance is a leading cause of reduced survival and increased morbidity, have emerged in the last few years, challenging the traditional therapeutic strategies in MPNs.
Treating low-risk patients with essential thrombocythemia or polycythemia vera
Clinical guidelines and expert opinions recommend to approach an individual patient with essential thrombocythemia or polycythemia vera by first identifying their potential risk of developing major thrombotic complications [2–5]. Risk stratification today is based on well established risk factors, according to which the incidence of cardiovascular complications is higher in patients aged more than 60 years or with a history of thrombosis. Recommendations for treatment in polycythemia vera and essential thrombocythemia include chemotherapy in high-risk disease, whereas asymptomatic low-risk patents, that is, with an age lower than 60 years and no prior thrombosis, can be safely observed. These recommendations are based on prospective trials showing that low-risk patients have a thrombotic risk comparable with that of the control population [6,7]. None of these trials, however, has a statistical power adequate to derive conclusive incidence figures for thrombosis. Thus, concern has been raised about the possibility that the population at low risk could include a subset of patients for whom the currently used risk stratification is not completely fitting. The continuous search for new prognostic factors has brought up the hypothesis that two other factors could be taken into consideration in risk stratification, that is, JAK2 V617F mutational status and leukocytosis.
Two systematic literature reviews and meta-analyses [8•,9•] were carried out to compare the frequency of clinically significant outcomes between JAK2 V617F-positive and wild-type patients with essential thrombocythemia. Both analyses included 17 studies up to February 2008. In the first analysis [8•], incidence figures for thrombosis varied from 17 to 43%, and JAK2 V617F positivity varied from 37 to 71%. A significant association of JAK2 mutation with thrombosis was evident in half of these studies, whereas no such correlation was documented in the remaining. A meta-analysis of 2905 patients with essential thrombocythemia and 778 patients with thrombosis showed that JAK2 V617F patients have a two-fold risk of developing thrombosis [odds ratio (OR) 1.84, 95% confidence interval (CI) 1.40–2.43], with significant heterogeneity between studies. JAK2 V617F patients were older at diagnosis, had higher hemoglobin levels, higher leukocyte counts, and lower platelet counts. Given the exaggerating effect of smaller studies, larger series (>100 patients) were analyzed separately (eight studies, 2394 patients, 627 of them with thrombosis) and the effect remained significant (OR 1.77, 95% CI 1.46–2.15).
The second meta-analysis [9•] reported on 2436 patients of whom 56% were found to be positive to JAK2 mutation. JAK2 V617F positivity was associated with clear increase in the odds of thrombosis (OR 1.83, 95% CI 1.32–2.53) and much higher odds of transformation to polycythemia vera (OR 7.67, 95% CI 2.04–28.87). The mean difference of the white blood cell (WBC) count between JAK2-positive and negative patients was associated with an increased OR for thrombosis.
These analyses represent the cumulative evidence on JAK2 association with thrombosis in essential thrombocythemia with all its inherent biases and weaknesses. Therefore, these studies cannot prove direct causality. The effect on JAK2 mutation is probably mediated through a distinct prothrombotic phenotype that includes leukocytosis, older age, and thrombosis at presentation, features that are well established risk factors of thrombosis even in the pre-JAK2 era.
Recent ad-hoc studies have added new evidence for leukocytosis bing an independent risk factor for thrombosis in polycythemia vera and essential thrombocythemia. Gangat et al.  showed that leukocyte count higher than 15 × 109/l was an independent predictor of inferior survival, leukemic transformation, and venous thrombosis in patients with polycythemia vera. Three large cohort studies [11–13] reported similar results in essential thrombocythemia. In addition, Carobbio et al. [14••] demonstrated that ‘low-risk’ essential thrombocythemia patients with leukocytosis have the same probability of developing a vascular event in the follow-up as ‘high-risk’ patients without leukocytosis. This paper deserves high consideration as it documented that using a prognostic score that included leukocytosis had more discrimination accuracy over the previous one, that is, the new score better differentiated between individual survivors and nonsurvivors.
Prospective thorough validation is now needed before leukocytosis could be confidently applied to clinical practice as a criterion for selecting low-risk essential thrombocythemia and polycythemia vera patients in need for cytoreductive treatment.
Pursuing clonal remission in polycythemia vera
Hydroxyurea, the most commonly used agent to treat polycythemia vera and essential thrombocythemia patients requiring cytoreductive therapy, is unable to eradicate the disease malignant clone. This goal has been recently approached in polycythemia vera patients, placing high expectation on the therapeutic efficacy of interferon (IFN). IFNα has for a long time been considered for the treatment of patients with MPNs because this agent suppresses the proliferation of hematopoietic progenitors. In addition, IFNα has proven to induce reversion from monoclonal to polyclonal patterns of hematopoiesis in some cases [15–17]. IFNα also, however, may have immunological properties by inducing immune responses to candidate tumor antigens, among which the recently identified polycythemia vera-associated tumor antigens may represent targets for immune effectors .
In a multicenter phase II trial of pegylated IFNα2a in 27 polycythemia vera patients, Kiladjian et al. [19••] showed a decrease of JAK2 mutant expression in 24 cases (89%) and in one patient mutant JAK2 was no longer detectable after 12 months of therapy. A profound and sustained molecular response with a JAK2 V617F allele burden below 1.0% was further reported in two patients with polycythemia vera treated with IFNα2b. Discontinuation of the drug in one of the patients was followed by a sustained long-lasting (12 months of follow-up) major molecular response .
These results open new perspectives in the management of polycythemia vera and questions the therapeutic strategy of limiting cytoreductive therapy to patients at high risk of vascular events.
Reducing the risk and discomfort of unnecessary hematocrit-lowering strategies in polycythemia vera
Only the elevated hematocrit (Hct) in polycythemia vera is a mandatory therapy target among the primary consequences of the myeloproliferative process of MPNs. This derives from scientific evidence testifying a relationship between the increased Hct values and the risk of thrombosis [21,22], whereas the same is not documented for elevated platelet count in essential thrombocythemia. This prompted general recommendation to keep polycythemia vera patients at a Hct level below 45% in men and 42% in women by phlebotomies or cytoreductive therapy [3,23]. However, in the European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study , a randomized controlled study comparing aspirin versus placebo in polycythemia vera, only 48% of patients had Hct values below the recommended threshold, whereas 39 and 13% of patients remained between 45 and 50%, and higher than 50%, respectively. Moreover, a multivariate analysis considering all the confounders failed to show any correlation between these Hct values and thrombosis. The uncertainty described above has raised concern about the unnecessary over exposure of patients to phlebotomy or cytoreductive drugs, and on the logistic, economic, and medical consequences of such intensive strategy such as severe iron deficiency or risk of chemotherapy-induced late malignancy. The recognition of this unmet clinical need has prompted Italian Investigators to launch a prospective, randomized clinical study (CYTOreductive therapy to prevent cardiovascular events in patients with Polycythemia Vera, CYTO-PV).
Molecularly targeted therapies for myeloproliferative neoplasms
The era of molecularly targeted therapy, that implies use of drugs that target molecular hallmarks for which a direct influence on tumorigenesis is proven, has received a drive in light of the efficacy of imatinib and second-generation Abelson (abl) kinase inhibitors in the treatment of chronic myeloid leukemia. In the classical Philadelphia-negative MPNs, the lack of clear documentation that malignancy depends on a well defined molecular mechanism, and that JAK2 mutations only marginally impact on disease progression and outcome, has empirically extended the paradigm of targeted therapy to potential targets not specifically engaged in the malignancy.
Therapies against nonspecific molecular targets
In the past 2 years, a number of nonspecific molecular hallmarks of malignancy have been the target of experimental therapies for MPNs.
The farnesyltransferase inhibitor tipifarnib inhibits in-vitro proliferation of myeloid progenitors from patients with MPNs. In a phase II clinical trial, single-agent oral tipifarnib (300 mg twice daily × 21 of 28 days) was given to 34 symptomatic patients with either PMF or postpolycythemia vera/essential thrombocythemia myelofibrosis [25•]. Response rate was 33% for hepatosplenomegaly and 38% for transfusion-requiring anemia. No favorable changes occurred in bone marrow fibrosis, angiogenesis, or cytogenetic status. Clinical response did not correlate with either degree of colony growth or measurable decrease in quantitative JAK2 V617F levels seen in pretreatment samples.
Hematopoietic cells from patients with PMF have been identified as having activation of the nuclear factor-kappa B (NF-κB) pathway, which in turn activates the production of transforming growth factor-beta (TGF-β), a stimulator of fibrogenesis and osteogenesis . On the basis of these observations and results obtained in a murine model , clinical trials have been launched to test the efficacy and safety of bortezomib, a proteasome inhibitor with anti-TGF-β properties, in patients with PMF. In a phase II clinical study [28•] on 11 patients, therapy with bortezomib was found substantially ineffective and according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria , no patient achieved even a clinical improvement. In another phase I–II study  performed by the Myeloproliferative Disorders Research Consortium (MPDRC), 12 patients with PMF, refractory to or not suitable for first-line chemotherapy, were treated with bortezomib given at day 1, 4, 8, and 11 at a dose of 0.8–1.3 mg/m2, every 21 days × 6 cycles. The maximum tolerated dose was 1.3 mg/m2 for 4 days every 3 weeks. No complete, major, or moderate responses according to the European Myelofibrosis Network (EUMNET) response criteria  were documented.
In patients with PMF, hypermethylation in the p15INK4b, p16INK4a, calcitonin, retinoic acid receptor B2 (RARβ2), and chemokine (C–X–C motif) receptor 4 (CXCR4) gene has been demonstrated [32,33,34••]. Shi et al.  documented that exposure of CD34+ cells derived from PMF patients to a DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5-Aza), in combination with histone deacetylase inhibitor, trichostatin A (TSA), resulted in a significant reduction of both JAK2 V617F-positive hematopoietic colonies and the number of colonies that contained chromosomal abnormalities in two JAK2 V617F-negative PMF patients. Bogani et al. [34••] documented that following incubation with 5-Aza, the percentage of PMF CD34+ cells expressing CXCR4 increased 3–10 times, whereas CXCR4 mRNA level increased approximately four times. 5-Aza-treated PMF CD34+ cells displayed almost complete reversal of CpG1 island 1 hypermethylation and showed enhanced migration in vitro in response to stromal cell-derived factor (SDF-1). These data provided a rationale for therapy with chromatin-modifying agents for patients with PMF.
In a phase II trial, 34 patients with either relapsed/refractory or newly diagnosed PMF with poor prognosis were treated with 5-Aza at a dose of 75 mg/m2 subcutaneously daily for 7 days, every 4 weeks [36•]. The median duration of 5-Aza therapy was 5.5 months and a clinical response was observed in eight (24%) patients. Only one patient met all the criteria for complete remission except for the achievement of bone marrow histological remission. Responses were observed in patients both with and without JAK2 V617F mutation. Therapy with 5-Aza resulted in gradual and significant decline of the methylation from the baseline but the degree of global DNA hypomethylation achieved during treatment was not different between responders and nonresponders. The outcome of 10 other patients treated with an abbreviated 5-day course of 5-Aza reaffirmed the limited benefit of this agent in PMF [37•].
Fifteen patients treated with low-dose thalidomide were audited and the responses evaluated according to the EUMNET criteria [38•]. Three of seven transfusion-dependent patients had a fall in transfusion requirement (43%), two patients becoming transfusion independent.
In three consecutive patients with del(5q)-associated PMF or postpolycythemia vera myelofibrosis (all three patients were JAK2 V617F-positive), lenalidomide, an immunomodulatory, antiangiogenic, and antineoplastic drug structurally related to thalidomide, produced clinical and hematological complete response [39•]. On the basis of this limited experience, the authors encouraged screening for del(5q) in all patients with PMF or postpolycythemia vera myelofibrosis; whenever found, lenalidomide therapy should be offered and continued indefinitely, if tolerated.
In summary, trials with new nonspecific-targeted therapies have confirmed that their use in PMF is of modest clinical activity. Tipifarnib may be added to conventional therapeutic instruments for symptomatic PMF. Lenalidomide has a role in the del(5q) variant of PMF.
Anti-Janus kinase 2-targeted therapy
At present, several groups are developing small molecules that selectively target JAK2 kinase, including JAK2 V617F, or agents which were previously used for non-MPN, but considered to have significant therapeutic potential in MPNs due to their ‘off-target’ JAK2 inhibitory activity (Table 1). These drugs demonstrated the in-vitro ability to significantly inhibit JAK2 V617F-positive cell lines or hematopoietic progenitor cells from JAK2 V617F-positive MPN patients [40–50].
A number of such JAK2 inhibitors have been tested in in-vivo animal models of JAK2 V617F-induced hematopoietic diseases. In a mouse xenograft model with Ba/F3-V617F cells, administration of TG-101207 rescued the animals from a fully penetrant fatal hematopoietic malignancy . In a murine bone marrow transplant assay of established polycythemia vera, animals treated with TG-101348 showed a dose-dependent reduction in the degree of splenomegaly, extramedullary hematopoiesis, and reduction of bone marrow reticulin with survival advantage .
Currently, the following agents are being studied in patients with MPNs: MK-0456, CEP-701, INCBO1842, XL 019, and AT 9283. In a phase I/II trial with INCB018424, a potent and selective inhibitor of JAK1 and JAK2, a dose of 25 or 50 mg postoperatively twice daily resulted in a rapid and marked reduction in splenomegaly, marked and durable improvement in constitutional symptoms, and striking reduction in systemic cytokine levels. However, minor reduction of V617F: WT JAK2 ratio was noted in both peripheral blood and bone marrow. Reversible thrombocytopenia was the dose-limiting toxicity . The results of anti-JAK2-targeted therapies are encouraging as regards symptoms reduction but not disease clonal remission.
To face unmet clinical needs in MPNs, the scientific community has reacted by engaging an extensive experimental approach. However, neither the concern of leaving untreated low-risk essential thrombocythemia and polycythemia vera patients presenting with leukocytosis or JAK2 V617F mutation, nor pursuing clonal remission in polycythemia vera by IFNα or reducing the risk and discomfort of unnecessary Hct-lowering strategies in polycythemia vera, have enough evidence to be translated into strategies for clinical practice. The preliminary results with anti-JAK2 agents reinforce the concept that clinical development of these agents requires a new set of skills and a higher degree of complexity when compared with conventionally developed chemotherapeutic agents, such as incorporation of novel endpoints of clinical benefit and precise selection of patients.
This study was supported in part by the National Cancer Institute grant number P01CA108671 to G.B.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 149–150).
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