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Does anything work for anaemia in myelofibrosis?
Best Practice & Research Clinical Haematology 27 (2014) 175e185
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Does anything work for anaemia in myelofibrosis? Gunnar Birgegård, MD, Ph.D., Professor * Department of Haematology, Uppsala University, Sweden
Keywords: myelofibrosis anaemia myeloproliferative neoplasm anaemia treatment
Anaemia is a common finding at diagnosis in myelofibrosis, and becomes a symptomatic problem in most patients with time. There are several treatment options for specific anaemia treatment, none of which has been tested in large, randomized, controlled trials. However, as myelofibrosis is not a disease with spontaneous remissions, even non-randomized trials carry weight. In this survey, the existing evidence will be analysed, both for the commonly used treatments like erythropoiesis-stimulating agents, androgens and thalidomide and for the new drugs in the area, and conclusions will be drawn concerning standard clinical anaemia treatment in myelofibrosis, which according to evidence from studies has a 40e50% chance of response in patients with not too advanced disease. © 2014 Elsevier Ltd. All rights reserved.
Introduction Primary myelofibrosis (PMF) is the most serious of the three Ph1-negative myeloproliferative neoplasms, and anaemia is the most common and often the most serious problem of the patients. Thirty % of PMF patients present with anaemia at diagnosis [1,2], and all patients with PMF will eventually develop anaemia. At diagnosis, the bone marrow shows hyperproliferation, but unlike in PV only of the white cell and megakaryocyte compartments. Patients with MF secondary to essential thrombocytemia (ET) or polycythaemia vera (PV) show a similar development as PMF with regard to anaemia, and the management is also similar.
* Institute of Medical Sciences, University Hospital, 75185 Uppsala, Sweden. Tel.: þ46 186114412; Fax: þ46 18509297. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.beha.2014.07.011 1521-6926/© 2014 Elsevier Ltd. All rights reserved.
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The nature of the anaemia has long been presumed to be secondary to the fibrous infiltration of the bone marrow, with fibres reducing the erythropoietic tissue, a more or less mechanic mechanism. Due to recent progress in the mapping of pathophysiological mechanisms in MF, a more varied view of anaemia development has emerged with inflammation as a potential key mechanism. The fibrosis in itself is a phenomenon secondary to the clonal proliferation of a malignant stem cell [3]. As anaemia develops and worsens, there is often a continuous enlargement of the spleen, and extramedullary erythropoiesis develops in an attempt by the organism to compensate for the reduced bone marrow activity. With worsening spleen enlargement, however, destruction of red blood cells (RBC) in the spleen increases. Therefore, anaemia treatment based on stimulation of erythropoiesis has a smaller chance of effect in patients with advanced disease and large spleens. There are several options for specific anaemia treatment in MF, which will be presented here. Although there is a lack of controlled, randomized studies of anaemia treatment, there is evidence enough for a recommendation that all anaemic patients with MF should be considered for specific anaemia treatment. Erythropoiesis-stimulating agents (ESA) Human recombinant erythropoietin (rHuEPO) was first used in the treatment of PMF anaemia in small pilot studies in the beginning of the 1990ies [4e8]. Although results were promising, no larger study was performed until 2004, when Cervantes collected 20 PMF patients with either transfusion dependency (13/20) or Hb level below 9 g/dl(9). 4/20 patients normalized their Hb level, and 9/20 (45%), had either a complete response (CR) or a partial response (PR). In the same paper, the authors added 31 cases from the literature to their own material and found a CR rate of 31%, PR 24%, total responses 55%. Positive factors for response were lack of transfusion dependency and an S-Epo level <125 U/L. In a later study with long-acting rHuEPO the same authors found a similar response rate in 20 patients [10]. The most positive responses published can be found in a prospective study with 20 transfusion-dependent PMF patients, in whom a 60% response rate was found (CR Hb > 12 g/dl or Transfusion independence (40%), PR increase by 2 g/dl or double transfusion interval (20%)) [11]. In contrast, a retrospective study from the Mayo clinic showed no responders among 16 transfusiondependent patients and no responders among 9 patients with Hb levels >10 g/dl [12]. These results have not been supported by any other study. The dose of rHuEPO used has been the standard dose given in other cancer anaemias, 30,000 U weekly, although usually given as 10,000 three times weekly subcutaneously which used to be the standard dosing in the early days of rHuEPO treatment. The efficacy of a dose increase has not been evaluated. No studies have been published with the use of biosimilars or other forms of erythropoiesisstimulating agents (ESA) of more recent development. Conclusion The studies are small (no larger prospective study than N ¼ 20), and the response criteria used are not uniform. However, a response rate of 40e50% within 6e8 weeks can be found in the studies with a minimal response criterion of Hb increase >2 g/dl or a 50% reduction of transfusions. Factors that are predictive of response include limited or no transfusion dependency and a non-severe anaemia. Response correlation to S-Epo levels is inconclusive. [9,12] ESAs were generally very well tolerated. Androgens Androgen therapy has been used for many years for various bone marrow failure syndromes, and early studies in MF showed promising results. In a small 1978 prospective study in 11 patients, 5 of whom were transfusion dependent, long-term oxymetholone treatment resulted in loss of transfusion dependency in all and > 3 g/dl Hb increase in 9 of the 15 courses given [13]. In a 1982 study including 23 PMF patients, a response rate of 57% was found (sustained increase in Hb level or cessation of transfusion need within 3 months), with a significantly better response among patients with normal karyotype (92% response) [14].
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In more recent times, two studies (2000 and 2005) by Cervantes et al. used danazole 600 mg daily for 6 months with tapering thereafter in responders. Response criteria were not the same in both studies, with more strict criteria for PR in the latter study (an Hb increase >/ ¼ 1.5 g/dl with transfusion-independent Hb values >10 g/dl maintained for at least 8 weeks), giving an overall response rate of 57% vs 37% in the 7 and 30 patients, respectively. Median time to response was 5 months. In the 2005 study, four patients stopped responding at 6e24 months, two responders discontinued treatment because of toxicity, and five maintained response at 3.5e42 months [15,16]. In a recent study, danazole was given in combination with intermittent chemotherapy in 18 elderly MPN patients (16 MF, 2 ET), who had failed other therapy, in doses ranging from 200 to 800 mg daily. Chemotherapy was given as needed for spleen reduction and control of blood counts. Eleven patients (61%) responded, three with normalization of blood counts and spleen (“excellent responders”), eight with Hb increase of 7% and 50% spleen reduction (“good responders”). The mean duration of response was 45 months (10e78 months) and 11 months (2e22 months), respectively [17]. In a retrospective study, Shimoda et al. found 55 MF patients who had been treated with androgen steroids, 39 of which were evaluable. A variety of drugs and dosages had been used (danazole, metenolone acetate, stanozolol). The response criteria were defined as “good” (Hb increase 1.5 g/dl, cessation of transfusion dependence and Hb values >10 g/dl, all maintained for at least 8 weeks) or “minimal” (increase in the Hb concentration of 1.5 g/dl and transfusion independence for at least 8 weeks). Both categories were considered “favourable”, and 17 patients (44%) filled the criteria (21% “good”). The median time to response was 3 months, but 3/17 responders required more than 6 months of treatment for response. In contrast to the Cervantez studies, no pretreatment factor predicted response, including cytogenetics and transfusion dependency [18]. The side effects reported in these studies were mainly moderate liver enzyme increase in some patients, that subsided after dose reduction. Occasional cases of muscle mass increase and headache have also been observed. Conclusion Just as for ESAs, studies are small and with varying response criteria. Meaningful Hb responses (Hb increase >2 g/dl, no transfusion need) can in many of the studies be seen in >40% of patients. The time to response varies widely. Most patients respond within 3e6 months, but occasional responses can be seen after more than 6 months. Toxicity is generally mild and dose dependent. Thalidomide Due to its antiangiogenic [19] and immunologic effects, a renewed interest in this drug has resulted in the discovery of antitumour effects in a wide range of malignant states, among them multiple myeloma [20]. Early studies in PMF using standard doses (100 e >400 mg daily) were noted for some positive effects, especially with regard to anaemia, but side effects, especially fatigue, leucocytosis and thrombocytosis, caused a high drop-out rate [21e25]. However, both reports of wanted biologic [26] activity like reduction of microvessel density [27] and the positive effects on anaemia led to studies with reduced thalidomide dosage. The first study using the dose 50 mg daily included 21 MF patients and also used a combination of thalidomide with a 3 months course of prednisone. The results were encouraging: tolerance was improved, and objective clinical response was demonstrated in 13 (62%) patients, all improvements in anaemia. Among 10 patients who were dependent on erythrocyte transfusions, 7 (70%) improved and 4 (40%) became transfusion-independent. Responses observed were mostly durable after discontinuation of the prednisone [28]. Since then, a number of studies have been performed with low dose thalidomide, mostly in combination with prednisone, and Hb response rates ranging from 22% to 100% have been reported. Toxicity is reduced when doses of 50e100 mg daily are used [29e31]. However, one study using these doses still reports cessation of therapy in 12/14 patients due to fatigue, constipation and peripheral neuropathy [32]. Different response criteria and generally low numbers of patients make comparison of efficacy difficult and statistics uncertain. The first study to use the EUMNET response criteria included 15 patients, and overall, 40% of patients
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achieved major or moderate responses by these criteria. All responses began within the first 12 weeks of treatment, and the median duration of response was 16 weeks (4e95 weeks) [31]. Since lenalinomide has also been tried as a treatment for PMF, a comparison between thalidomide and lenalinomide has been performed recently. However, thalidomide was not given as a low dose regimen, and there was no combination of thalidomide with prednisone, whereas one study arm comprised lenalidomide and prednisone. The resulting superiority for lenalidomide is therefore not surprising [33]. Conclusion Low dose thalidomide in combination with prednisone is effective in ~40% of cases in studies of reasonable size and with meaningful response criteria. The time to response is generally less than 12 weeks, whereas the duration of response varies widely in the published studies. Even with doses of 50e100 mg daily, fatigue, constipation and neuropathy may be notable in individual patients. Lenalinomide Lenalidomide is a derivative of thalidomide and shares its antiangiogenic and immunologic effects [34], may be being more potent. It was therefore natural to test its efficacy in MF, and the first two studies to do so were reported in the same paper [35]. Sixty-eight MF patiens in total were included at two separate institutions and given Lenalidomide monotherapy in two rather similar dose regimens. Forty-six of the patients were anaemic, and the response rate for anaemia was similar, 22%, with 17% having a normalization of Hb (major response) and 4% increased >2 g/dl or became transfusion-free (minor response). Just as with thalidomide, combination with prednisone has been studied. Forty MF patients were accrued for a study combining 6 months of lenalidomide in 21 days on/7 days off cycles with prednisone during the first 3 cycles in the doses 30, 15 and 15 mg daily, respectively. Thirty-three of the patients were anaemic at baseline, and the anaemia response rate was 30% in patients with Hb < 10 g/dl. Among these responders, 10 of 11 assessable patients, all with reticulin fibrosis grade 4 at study entry, exhibited reductions to at least grade 2 fibrosis. Similar reductions were also observed in collagen fibrosis in three of five responders [36]. In a later study with added prednisone, the anaemia response rate was 20%. Neither this study was designed to allow identification of the role of prednisone [37]. In an Austrian “real-life” report 22 MF patients treated with lenalidomide were retrospectively reported, 15 of which were anaemic. A much lower response rate of 12.5% was seen (IWG) criteria. Specific anaemia data were not presented [38]. Similar low response rates were reported in a Spanish retrospective study of 32 MF patients [39]. The toxicity of lenalidomide is lower than for the mother substance thalidomide. However, cytopenia, including anaemia, is a problem. Furthermore, in one of the limited studies with 48 patients 3 thrombotic events were recorded [37] and in another a thrombosis of corpora cavernosus was seen [40]. Conclusion Lenalidomide has general effects that seems to make the drug preferable to thalidomide as a treatment for MF. However, the specific anaemia effect is difficult to evaluate from existing studies but seems to confer a response rate around 20e30%, at least in patients with del (5q31). Notable is a few cases with excellent Hb responses and reduction of bone marrow reticulin. It is also to be noted that anaemia is a common side effect of the treatment. Pomalidomide Pomalidomide is another second-generation immunomodulatory drug, derived from thalidomide with the aim to increase efficacy and reduce toxicity. Almost all published data on pomalidomide treatment comes from one group of authors, who since 2009 have published a series of studies, some of
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which are follow-up studies. The first study was a phase 2, four-armed dose-finding study randomized study in 84 MF patients with Hb < 10 g/dl, comparing effects with and without addition of prednisone [41]. Twenty patients had a Hb response, 4 of which to prednisone alone, which is 19% of the patients in that arm. The response rates in the 3 pomalidomide arms were 23% (pomalidomide 2 mg/d), 16% (pomalidomide 2 mg/d þ pred), 36% (pomalidomide 0.5 mg/d þ pred). This means that the response rates were similar in the prednisone alone and 2 of the pomalidomide arms. Fifteen patients were relieved of transfusion dependence, two of which, though, in the prednisone alone arm. Critically regarded, these results indicate a limited effect on anaemia, even though response duration was longer with pomalidomide and the effect on transfusion dependence seemed impressive. A later doseescalation study from the same group in 19 patients with Hb < 8 g/dl indicated that low dose pomalidomide may be more effective [42]. This was tested in 58 MF patients with Hb < 10 g/dl, 46 of whom were transfusion dependent. Anaemia response (17% in total) was only seen in10 JAK2-positive patients [43]. A follow-up study was then performed in 94 of the161 Mayo clinic patients from the previous 3 studies. Median time from drug initiation was 27 months (range 20e52 months). Pomalidomide therapy had been discontinued in 86 (91%) patients at a rate of 68% at 1 year and 89% at 2 years. The overall anaemia response was given as 27%, higher in JAK2-positive patients without marked splenomegaly and with <5% circulating blasts (53%) [44]. A less favourable study was published in 2013, reporting 3/29 patients to get a clinical improvement (Hb increase) as defined by IWG and 2 who became transfusion-independent after continuous low dose pomalidomide, 0.5 mg/d [45]. Finally, at ASH 2013, the Mayo clinic group reported a randomized international collaborative study in 252 transfusion-dependent MF patients receiving pomalidomide 0.5 mg/d or placebo that surprisingly showed response rates to be similar between the treatment and placebo arms (16% [95% CI, 11e23%] vs 16% [8e26%]), as were response durations. (ASH abstract #394, Tefferi, A [80]). Conclusion From the initial studies it could be hoped that this second-generation IMID would be at least as effective as thalidomide and lenalidomide and with fewer side effects. However, response rates are lower, and the two last presented studies have strongly questioned any role for pomalidomide. Interferon Interferon (IFN) was introduced in studies of PMF mainly due to theoretical considerations concerning its possible effect on the production of growth factors from abnormal megakaryocytes [46], with the aim to reduce collagen deposition in the bone marrow. Early anecdotal evidence and small pilot studies showed very limited effects on Hb levels [47e49] but occasional priomising redcutions of bone marrow fibrosist [50,51]. However, negative studies were also published [52], and still no study with more than 10 evaluable PMF patients was published until 2003, when 31 MF patients were part of a phase II study in MPN patients. The response rate for a composite endpoint was very low (3.2%) in MF, and the specific effect on anaemia cannot be evaluated from the paper [53]. In a large study of bone marrow progression in 153 PMF patients on different therapies, no relevant differences in the evolution of myelofibrosis were evident in the various therapy groups,” especially not following interferon treatment” [54]. In an MPN study from 2007, 11 PMF patients were treated with pegylated interferon IFN2a in a dose of 2e3 mg/kg/wk. Only one response was seen with Hb increase to >11 g/dl [55]. In a retrospective French study 18 PMF patiens were found who had been treated with pegylated IFN2a. Among the three transfusion-dependent patients, two became transfusion-independent. In addition, four of the five other anaemic patients increased their haemoglobin level to Hb > 10 g/l [56]. However, 4 of these had a baseline Hb > 9 g/dl, which means that the response criterion was not very strict. In a study aimed at investigating bone marrow effects of IFNa2b on 13 PMF patients, an increase in Hb > 2 g/dl was seen in only 2 patients; on the other hand, a reduction in Hct >15% was seen in 7 patients [57]. In an update of this study with 17 PMF patients, similarly treated, the Hb level was unchanged before and after treatment [58]. In a recent meta-analysis of 13 studies Nguyen and
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Kiladjian reported the overall effects of IFN in PMF and found problems in the evaluation due to great variation in response criteria [59]. However, their conclusion was that IFN may have a role in the early stages of the disease, when there is still residual haematopoiesis, as also suggested by Silver [47]. In contrast, the most recently published, retrospective, study reports high anaemia response rates [60]. Among 62 patients with pegylated IFNa2b, 25 had a Hb level <10 g/dl, and overall the overall response rate was 63.5% according to IWG-MRT criteria (i.e., Hb > 110 g/l). Interestingly, 10 of the patients were treated with a combination of IFN and ESA, and 9/10 were responders. Three patients responded to the combination after failure of initial IFN treatment. The time to achieve the best response was 7.1 months. There was a 38.5% response rate among the 13 patients requiring transfusions. Interestingly, most responses were obtained within the first 6 months of treatment. Of note, the addition of ESA did not affect the results of Peg-IFNa-2a treatment in transfusion-dependent patients. The only prospective study combining IFN and ESA was performed 17 years ago, a small study where 5/5 patients had a Hb response [6]. The toxicity of IFN is well known and consists both of mental effects like fatigue, depression and cognitive disturbances and of bone marrow depression. Dropout rates vary in different studies but are often reported as ~25%. Conclusion A large number of studies with IFN treatment of PMF patients have been performed with low response rates for anaemia. Positive effects on other disease variables than anaemia may give IFN a role, especially in early disease. Whether the two studies reporting combination with ESA and high response rates for anaemia indicate a true difference is too early to say; one was very small, and the other is limited and retrospective. It is also important to remember that IFN may give a general bone marrow depression with anaemia as a consequence. JAK2 inhibitors With regard to the anaemia effect, the JAK2 inhibitors generally have a detrimental rather than enhancing effect on Hb levels. In the 3-year follow up of the COMFORT II Ruxolitinib study, a lowering of Hb and an increase in need of transfusions was noted during the first 12e24 weeks of therapy, after which Hb levels returned to the same as in the “best available treatment” arm [61]. A similar pattern was seen in the COMFORT I study, with a Hb reduction of 10e12% at a nadir around week 12 and an increase in transfusion need, with recovery of Hb to a level around 5% below baseline after 24e36 weeks [62]. An exception seems to be CYT387, an orally available JAK1/2 inhibitor. In a recent phase I-II study, 41 anaemic MF patients with Hb < 10 (n ¼ 8) or transfusion dependency (n ¼ 33) were treated. Sixty-seven % of the transfusion dependent patients became independent with a minimum Hb of 8 g/dl for at least 12 weeks with a median duration of this response of 9.6 months [63]. Surprisingly, only 1/8 non-transfusion dependent patients with Hb < 10 g/dl achieved a response. Conclusion Anaemia and thrombocytopaenia are common side effects of treatment with JAK2 inhibitors. The only such drug with a positive anaemia effect is the oral CYT387, so far reported in one study to be effective in transfusion dependent patients but strangely enough not in other anaemic patients. Further studies are needed to clarify the role of this drug in anaemia. Other new drugs Generally speaking, two principles are the subject of testing for the relief of anaemia in MF: drugs that reduce the proliferative activity or otherwise may change the basic biology of MF, and drugs that may increase erythropoiesis without doing so. The histone deacetylase inhibitor pracrinostat and the mTOR inhibitor everolimus belong to the former category. Both have been tested in phase I-II trials with minimal or uncertain anaemia effects [64,65]. Drugs belonging to the latter category are being
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developed but have not been tested in MPN patients yet. A group of dioxygenases (Eg1N) that are active in the ubiquitination of the hypoxia-inducible factor HIF1a can be reduced by specific inhibitors, mimicking hypoxia and thereby increasing the endogenous EPO production [66]. Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein inhibits activin and was first developed to improve bone disease, i.e., in myeloma, but was also found to stimulate erythropoiesis by a different route than EPO [67]. No studies in MF patients have yet been published. Imetelstat, the first telomerase inhibitor, has been shown to give complete haematologic remissions in ET (Baerlocher GM, EHA 2013, abstract 4398 [81]), and the first study in MF has shown a Hb response (increase>2 g/dl or transfusion independence) in 4/12 patients (33%) (Tefferi A, ASH 2013, abstract 662 [82]). Red cell transfusion As the disease progresses, most MF patients become transfusion dependent. However, in spite of existing guidelines [68] trigger limits for this therapy vary widely, both between countries and between centres. In a large European study in 15,000 cancer patients, a trigger level of 8.1 g/dl was found [69]. For some patients transfusion is necessary for survival, for others it is a matter of quality of life (QoL). Improvements in QoL have been shown [70], but clinical practice is influenced by availability of stored red cells, patient and doctor attitudes, the fear of disease transmission, concern for iron overload, cost deliberations etc. A discussion of these factors is outside the scope of this paper. Iron chelation It has long been known that iron chelation may elicit an improvement in erythropoiesis, both in MDS, chronic renal anaemia and MF [71e74], with deferoxamine and deferiprone. Recently case reports have also emerged with similar anecdotal Hb improvements with deferasirox [75e77]. However, in a retrospective study on 25 iron-overloaded PMF patients where 10/25 were given iron chelation, no positive effect on anaemia was reported [78]. On the other hand, a significantly better survival was seen in the group with iron chelation (p ¼ 0.02). Similar results have been presented in MDS [79]. Conclusion There are two possible effects of iron chelation in MF. One is the anecdotally reported and sometimes dramatic improvement of erythropoiesis. No systematic study has investigated this phenomenon, for which there is no better explanation than that iron chelation may give biologically nonavailable iron a route to the erythroblasts in the bone marrow. The other issue is the toxicity of iron accumulation in transfusion-dependent MF patients and the possibility to improve survival with iron chelation, where evidence supports active iron chelation. Discussion Anaemia treatment in MF is a field with many small studies, mostly non-randomized and uncontrolled. Different selection principles of patients and a variety of response criteria have been used, making evaluation and comparison of result with various drugs difficult. Nonetheless, the treatment results of the most commonly used modalities in studies are better than what is generally believed. The response rates for the most commonly used treatments, ESAs, danazole and low dose thalidomide þ prednisone are in the order of 30e50% (Hb increase 2 g/dl or no need of transfusion). Still, this indicates that there is a need for more efficient treatments, especially in patients with more advanced disease. It is worth noticing that two small studies, one old and one recent, have presented very high response rates with a combination that has not been tested in any other study, namely ESA and IFN [6,60]. Some of the drugs used, like ESAs and androgens, act mainly by stimulating erythropoiesis, others by interfering with the disease activity. Unfortunately, some of the new drugs acting to reduce proliferative disease activity, like the JAK2 inhibitors, by inhibiting unmutated, non-clonal haematological
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stem cell proliferation, also reduce general bone marrow cell production, not least red cell production, thereby cytopenia as a side effect. Since Hb is an important part of the risk scores, anaemic patients often belong to high or intermediate risk categories. However, many of the patients who develop anaemia have years of life expectancy, and there is evidence enough to state that such treatment should be considered in all anaemic MF patients. It is, however, important to remember that an increase in Hb induced by a symptomatic drug like an ESA should not alter the risk classification of the patient (especially important in the consideration of stem cell transplantation) since it does not change the course of the disease. In several studies the patients with the best chance of response are those with a non-severe anaemia. This coincides with clinical practice experience and indicates that anaemia treatment should not wait until the patient is severely anaemic. In which order should the various treatment be tried? There is no “correct” answer to this question. My own choice is to start with a treatment with very little side effects that can be evaluated within a fairly short time, 6e8 weeks, namely ESA. Just as for general cancer anaemia, it has been shown that response is somewhat more likely if the S-Epo level is < 125 U/L. However, even if there is such a correlation on the group level, such a cut-off cannot be used for the individual patient. Patients with SEpo > 125 U/L still have a good chance to respond. If keeping costs down is a high priority, danazole is probably the first drug of choice. The disadvantage is that the median time to response is 3e6 months, and some patients respond much later than 6 months. For most haematologists, low dose thalidomide þ prednisone is the third choice. The evidence for response is as good as for the previously mentioned drugs, and the time to response about 3 months. However, even with low dose thalidomide (50e100 mg/d) some patients develop both central (fatigue) and peripheral neuropathy during prolonged use. Because of this, some advocate lenalidomide as the drug of choice, due to its lower toxicity. This may be true if the general effect on disease is considered, but the evidence for a specific anaemia response is weaker for lenalidomide, and anaemia is a common side effect of the drug. At present, anaemia treatments other than the three here suggested should be restricted to studies. Summary There is good evidence to recommend use of ESAs, androgens and low dose thalidomide þ cortisone for anaemia in MF. For the other drugs analysed here the evidence either shows a minimal effect or an uncertain effect making further studies necessary for evaluation. There is a disturbing lack of solid controlled studies with enough patients within the area of MF and anaemia. This is probably a situation that will prevail, due to the fact that many new drugs are in the pipe-line for clinical trials that are possible disease-modifiers, where the anaemia effect will be just a part of a broader evaluation. Hopefully, some of these new drugs will modify disease without interfering with the wild type haematopoietic proliferation, but until such a drug is found, there will be MF patients who need specific anaemia treatment, based on the existing evidence. Just as in MDS, iron chelation should be given in transfusion-dependent patients.
Practice points There is a lack of large controlled studies with comparable response criteria, making figures for efficacy approximate and uncertain. The three commonly used treatments for anaemia in MF, ESAs, androgens and low dose thalidomide, all have a response rate in studies of 30e50%. ESA or low dose thalidomide þ prednisone should be first line therapy for anaemia in MF. Response is more likely in patients with non-severa anaemia. The new drugs in MPN treatment so far have not been shown to be more effective.
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Combination therapy with recombinant human erythropoietin, interferon-alpha2b and granulocyte-macrophage colony-stimulating factor in idiopathic myelofibrosis. Acta Haematol 1996;96(2):79e82. [7] Rodriguez JN, Martino ML, Muniz R, et al. Recombinant human erythropoietin for the treatment of anemia in myelofibrosis with myeloid metaplasia. Am J Hematol 1995;48(2):135e6. [8] Hasselbalch HC, Clausen NT, Jensen BA. Successful treatment of anemia in idiopathic myelofibrosis with recombinant human erythropoietin. Am J Hematology 2002;70(2):92e9. [9] Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, et al. Erythropoietin treatment of the anaemia of myelofibrosis with myeloid metaplasia: results in 20 patients and review of the literature. Br J Haematol 2004;127(4):399e403. [10] Cervantes F, Alvarez-Larran A, Hernandez-Boluda JC, et al. Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia. Br J Haematol 2006;134(2):184e6. [11] Tsiara SN, Chaidos A, Bourantas LK, et al. Recombinant human erythropoietin for the treatment of anaemia in patients with chronic idiopathic myelofibrosis. Acta Haematol 2007;117(3):156e61. [12] Huang J, Tefferi A. Erythropoiesis stimulating agents have limited therapeutic activity in transfusion-dependent patients with primary myelofibrosis regardless of serum erythropoietin level. Eur J Haematol 2009;83(2):154e5. [13] Hast R, Engstedt L, Jameson S, et al. Oxymetholone treatment in myelofibrosis. Blut 1978;37(1):19e26. [14] Besa EC, Nowell PC, Geller NL, et al. Analysis of the androgen response of 23 patients with agnogenic myeloid metaplasia: the value of chromosomal studies in predicting response and survival. Cancer 1982;49(2):308e13. [15] Cervantes F, Alvarez-Larran A, Domingo A, et al. Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: long-term results in 30 patients. Br J Haematol 2005;129(6):771e5. [16] Cervantes F, Hernandez-Boluda JC, Alvarez A, et al. Treatment of idiopathic myelofibrosis with severe anemia. Haematologica 2000;85(6):595e9. [17] Fontana V, Dudkiewicz P, Ahn ER, et al. Danazol therapy combined with intermittent application of chemotherapy induces lasting remission in myeloproliferative disorder (MPD): an alternative for the elderly with advanced MPD. Hematol Amst Neth 2011;16(2):90e4. [18] Shimoda K, Shide K, Kamezaki K, et al. The effect of anabolic steroids on anemia in myelofibrosis with myeloid metaplasia: retrospective analysis of 39 patients in Japan. Int J Hematol 2007;85(4):338e43. [19] D'Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994;91(9): 4082e5. [20] Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl J Med 1999; 341(21):1565e71. [21] Barosi G, Grossi A, Comotti B, et al. Safety and efficacy of thalidomide in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 2001;114(1):78e83. [22] Barosi G, Elliott M, Canepa L, et al. Thalidomide in myelofibrosis with myeloid metaplasia: a pooled-analysis of individual patient data from five studies. Leuk Lymphoma 2002;43(12):2301e7. [23] Canepa L, Ballerini F, Varaldo R, et al. Thalidomide in agnogenic and secondary myelofibrosis. Br J Haematol 2001;115(2): 313e5. [24] Elliott MA, Mesa RA, Li CY, et al. Thalidomide treatment in myelofibrosis with myeloid metaplasia. Br J Haematol 2002; 117(2):288e96. [25] Strupp C, Germing U, Scherer A, et al. Thalidomide for the treatment of idiopathic myelofibrosis. Eur J Haematol 2004; 72(1):52e7. [26] Berrebi A, Feldberg E, Spivak I, et al. Mini-dose of thalidomide for treatment of primary myelofibrosis. Report of a case with complete reversal of bone marrow fibrosis and splenomegaly. Haematologica 2007;92(2):15e6. [27] Piccaluga PP, Visani G, Pileri SA, et al. Clinical efficacy and antiangiogenic activity of thalidomide in myelofibrosis with myeloid metaplasia. A pilot study. Leukemia 2002;16(9):1609e14. [28] Mesa RA, Steensma DP, Pardanani A, et al. A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia. Blood 2003;101(7):2534e41. [29] Marchetti M, Barosi G, Balestri F, et al. Low-dose thalidomide ameliorates cytopenias and splenomegaly in myelofibrosis with myeloid metaplasia: a phase II trial. J Clin Oncol 2004;22(3):424e31. [30] Benetatos L, Chaidos A, Alymara V, et al. Combined treatment with thalidomide, corticosteroids, and erythropoietin in patients with idiopathic myelofibrosis. Eur J Haematol 2005;74(3):273e4. [31] Weinkove R, Reilly JT, McMullin MF, et al. Low-dose thalidomide in myelofibrosis. Haematologica 2008;93(7):1100e1. [32] Holle N, de Witte T, Mandigers C, et al. Thalidomide and lenalidomide in primary myelofibrosis. Neth J Med 2010;68(1): 293e8.
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[33] Jabbour E, Thomas D, Kantarjian H, et al. Comparison of thalidomide and lenalidomide as therapy for myelofibrosis. Blood 2011;118(4):899e902. [34] Marriott JB, Dredge K, Dalgleish AG. Thalidomide derived immunomodulatory drugs (IMiDs) as potential therapeutic agents. Curr Drug Targets Immune Endocr Metabol Disord 2003;3(3):181e6. [35] Tefferi A, Cortes J, Verstovsek S, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood 2006;108(4): 1158e64. [36] Quintas-Cardama A, Kantarjian HM, Manshouri T, et al. Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis. J Clin Oncol 2009;27(28):4760e6. [37] Mesa RA, Yao X, Cripe LD, et al. Lenalidomide and prednisone for myelofibrosis: Eastern Cooperative Oncology Group (ECOG) phase 2 trial E4903. Blood 2010;116(22):4436e8. [38] Burgstaller S, Fridrik M, Hojas S, et al. Experience with lenalidomide in an Austrian non-study population with advanced myelofibrosis. Wien Klin Wochenschr 2013;125(7e8):196e9. [39] Castillo I, Ojea MA, Boque C, et al. Effectiveness and safety of lenalidomide in myelofibrosis patients: a case series from the Spanish compassionate use program. Farm Hosp 2013;37(2):135e42. [40] El Rassi FA, Tam CS, Carwile J, et al. Thrombosis of the corpora cavernosa complicating lenalidomide therapy of myelofibrosis. Leuk Res 2008;32(5):821e2. [41] Tefferi A, Verstovsek S, Barosi G, et al. Pomalidomide is active in the treatment of anemia associated with myelofibrosis. J Clin Oncol 2009;27(27):4563e9. [42] Mesa RA, Pardanani AD, Hussein K, et al. Phase1/-2 study of Pomalidomide in myelofibrosis. Am J Hematol 2010;85(2): 129e30. [43] Begna KH, Mesa RA, Pardanani A, et al. A phase-2 trial of low-dose pomalidomide in myelofibrosis. Leukemia 2011;25(2): 301e4. [44] Begna KH, Pardanani A, Mesa R, et al. Long-term outcome of pomalidomide therapy in myelofibrosis. Am J Hematol 2012; 87(1):66e8. [45] Daver N, Shastri A, Kadia T, et al. Modest activity of pomalidomide in patients with myelofibrosis and significant anemia. Leuk Res 2013;37(11):1440e4. [46] Hasselbalch H. Hypothesis: a possible role for interferon in the treatment of idiopathic myelofibrosis. Med Hypotheses 1988;27(4):345e7. [47] Barosi G, Liberato LN, Costa A, et al. Cytoreductive effect of recombinant alpha interferon in patients with myelofibrosis with myeloid metaplasia. Blut 1989;58(6):271e4. [48] Barosi G, Liberato LN, Costa A, et al. Induction and maintenance alpha-interferon therapy in myelofibrosis with myeloid metaplasia. Eur J Haematol Suppl 1990;52:12e4. [49] Yataganas X, Meletis J, Plata E, et al. alpha Interferon treatment of essential thrombocythaemia and other myeloproliferative disorders with excessive thrombocytosis. Eur J Cancer 1991;27(Suppl. 4):S69e71. [50] Cervantes F, Alcorta I, Escoda L, et al. Alpha interferon treatment of idiopathic myelofibrosis. Med Clin 1993;101(13):498e500. [51] Domingues MA, Haepers AT, Massaut IH, et al. Reversal of bone marrow fibrosis in idiopathic myelofibrosis after treatment with alpha-interferon. Haematologica 1998;83(12):1124e5. [52] Tefferi A, Elliot MA, Yoon SY, et al. Clinical and bone marrow effects of interferon alfa therapy in myelofibrosis with myeloid metaplasia. Blood 2001;97(6):1896. [53] Radin AI, Kim HT, Grant BW, et al. Phase II study of alpha2 interferon in the treatment of the chronic myeloproliferative disorders (E5487): a trial of the Eastern Cooperative Oncology Group. Cancer 2003;98(1):100e9. [54] Thiele J, Kvasnicka HM, Schmitt-Graff A, et al. Therapy-related changes of the bone marrow in chronic idiopathic myelofibrosis. Histol Histopathol 2004;19(1):239e50. [55] Jabbour E, Kantarjian H, Cortes J, et al. PEG-IFN-alpha-2b therapy in BCR-ABL-negative myeloproliferative disorders: final result of a phase 2 study. Cancer 2007;110(9):2012e8. [56] Ianotto JC, Kiladjian JJ, Demory JL, et al. PEG-IFN-alpha-2a therapy in patients with myelofibrosis: a study of the French Groupe d'Etudes des Myelofibroses (GEM) and France Intergroupe des syndromes Myeloproliferatifs (FIM). Br J Haematol 2009;146(2):223e5. [57] Silver RT, Vandris K. Recombinant interferon alpha (rIFN alpha-2b) may retard progression of early primary myelofibrosis. Leukemia 2009;23(7):1366e9. [58] Silver RT, Vandris K, Goldman JJ. Recombinant interferon-alpha may retard progression of early primary myelofibrosis: a preliminary report. Blood 2011;117(24):6669e72. [59] Nguyen HM, Kiladjian JJ. Is there a role for the use of IFN-alpha in primary myelofibrosis? Hematology Am Soc Hematol Educ Program 2012;2012:567e70. [60] Ianotto JC, Boyer-Perrard F, Gyan E, et al. Efficacy and safety of pegylated-interferon alpha-2a in myelofibrosis: a study by the FIM and GEM French cooperative groups. Br J Haematol 2013;162(6):783e91. [61] Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood 2013;122(25):4047e53. [62] Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012;366(9):799e807. [63] Pardanani A, Laborde RR, Lasho TL, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia 2013;27(6):1322e7. [64] Quintas-Cardama A, Kantarjian H, Estrov Z, et al. Therapy with the histone deacetylase inhibitor pracinostat for patients with myelofibrosis. Leuk Res 2012;36(9):1124e7. [65] Guglielmelli P, Barosi G, Rambaldi A, et al. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/ 2 study in patients with myelofibrosis. Blood 2011;118(8):2069e76. [66] Bernhardt WM, Wiesener MS, Scigalla P, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol 2010;21(12):2151e6. [67] Fields SZ, Parshad S, Anne M, et al. Activin receptor antagonists for cancer-related anemia and bone disease. Expert Opin Investig Drugs 2013;22(1):87e101.
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[68] Gale RP, Barosi G, Barbui T, et al. RBC-transfusion guidelines update. Leuk Res 2012;36(5):659e60. [69] Ludwig H, Van Belle S, Barrett-Lee P, et al. The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 2004;40(15): 2293e306. [70] Lucioni C, Finelli C, Mazzi S, et al. Costs and quality of life in patients with myelodysplastic syndromes. Am J Blood Res 2013;3(3):246e59. [71] Goch J, Birgegard G, Danielson BG, et al. Treatment of erythropoietin-resistant anaemia with desferrioxamine in patients on haemofiltration. Eur J Haematol 1995;55(2):73e7. [72] Jensen PD, Jensen IM, Ellegaard J. Desferrioxamine treatment reduces blood transfusion requirements in patients with myelodysplastic syndrome. Br J Haematol 1992;80(1):121e4. [73] Smeets ME, Vreugdenhil G, Holdrinet RS. Improvement of erythropoiesis during treatment with deferiprone in a patient with myelofibrosis and transfusional hemosiderosis. Am J Hematol 1996;51(3):243e4. [74] Di Tucci AA, Murru R, Alberti D, et al. Correction of anemia in a transfusion-dependent patient with primary myelofibrosis receiving iron chelation therapy with deferasirox (Exjade, ICL670). Eur J Haematol 2007;78(6):540e2. [75] Messa E, Cilloni D, Messa F, et al. Deferasirox treatment improved the hemoglobin level and decreased transfusion requirements in four patients with the myelodysplastic syndrome and primary myelofibrosis. Acta Haematol 2008;120(2): 70e4. [76] Matsuki E, Matsumoto K, Nakaya A, et al. Marked improvement of anemia during treatment with deferasirox in patients with primary myelofibrosis and acute myeloid leukemia with myelodysplasia-related changes. [Rinsho Ketsueki] Jpn J Clin Hematology 2012;53(1):78e82. [77] Tesch H, Ihling C. Loss of transfusion dependency following deferasirox treatment of iron overload in a woman with myelofibrosis and spherocytosis e a case report. Onkologie 2013;36(4):205e8. [78] Leitch HA, Chase JM, Goodman TA, et al. Improved survival in red blood cell transfusion dependent patients with primary myelofibrosis (PMF) receiving iron chelation therapy. Hematol Oncol 2010;28(1):40e8. [79] Neukirchen J, Fox F, Kundgen A, et al. Improved survival in MDS patients receiving iron chelation therapy e a matched pair analysis of 188 patients from the Dusseldorf MDS registry. Leuk Res 2012;36(8):1067e70. [80] Tefferi A, Passamonti F, Barbui T, Barosi G, Begna K, Cazzola M, et al. Phase 3 study of pomalidomide in myeloproliferative neoplasm (MPN)-Associated myelofibrosis with RBC-transfusion-dependence. Blood (ASH Annual Meeting abstracts). Abstract 394. https://ash.confex.com/ash/2013/webprogram/Paper58167.html. €th A, et al. ImetelstAt: a Novel Approach with Robust [81] Baerlocher GM, Leibundgut EO, Spitzer G, Ottmann O, Odenike O, Ro hematologic and molecular responses in a phase 2 study in patients with essential Thrombocythemia (ET) who are refractory or Intolerant to Prior therapy. 2013 Congress of the european Hematology Association. Abstract 4398. http:// www.geron.com/PDFs/Geron-Imetelstat-ETPh2-EHA-2013.pdf. [82] Tefferi A, Begna K, Laborde RR, Patnaik MM, Lasho TL, Zblewski D, et al. Imetelstat, a Telomerase Inhibitor, Induces Morphologic and Molecular Remissions In Myelofibrosis and Reversal Of Bone Marrow Fibrosis. Blood (ASH Annual Meeting abstracts). Abstract 662. https://ash.confex.com/ash/2013/webprogram/Paper60875.html.
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9
Does anything work for anaemia in myelofibrosis? Gunnar Birgegård, MD, Ph.D., Professor * Department of Haematology, Uppsala University, Sweden
Keywords: myelofibrosis anaemia myeloproliferative neoplasm anaemia treatment
Anaemia is a common finding at diagnosis in myelofibrosis, and becomes a symptomatic problem in most patients with time. There are several treatment options for specific anaemia treatment, none of which has been tested in large, randomized, controlled trials. However, as myelofibrosis is not a disease with spontaneous remissions, even non-randomized trials carry weight. In this survey, the existing evidence will be analysed, both for the commonly used treatments like erythropoiesis-stimulating agents, androgens and thalidomide and for the new drugs in the area, and conclusions will be drawn concerning standard clinical anaemia treatment in myelofibrosis, which according to evidence from studies has a 40e50% chance of response in patients with not too advanced disease. © 2014 Elsevier Ltd. All rights reserved.
Introduction Primary myelofibrosis (PMF) is the most serious of the three Ph1-negative myeloproliferative neoplasms, and anaemia is the most common and often the most serious problem of the patients. Thirty % of PMF patients present with anaemia at diagnosis [1,2], and all patients with PMF will eventually develop anaemia. At diagnosis, the bone marrow shows hyperproliferation, but unlike in PV only of the white cell and megakaryocyte compartments. Patients with MF secondary to essential thrombocytemia (ET) or polycythaemia vera (PV) show a similar development as PMF with regard to anaemia, and the management is also similar.
* Institute of Medical Sciences, University Hospital, 75185 Uppsala, Sweden. Tel.: þ46 186114412; Fax: þ46 18509297. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.beha.2014.07.011 1521-6926/© 2014 Elsevier Ltd. All rights reserved.
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The nature of the anaemia has long been presumed to be secondary to the fibrous infiltration of the bone marrow, with fibres reducing the erythropoietic tissue, a more or less mechanic mechanism. Due to recent progress in the mapping of pathophysiological mechanisms in MF, a more varied view of anaemia development has emerged with inflammation as a potential key mechanism. The fibrosis in itself is a phenomenon secondary to the clonal proliferation of a malignant stem cell [3]. As anaemia develops and worsens, there is often a continuous enlargement of the spleen, and extramedullary erythropoiesis develops in an attempt by the organism to compensate for the reduced bone marrow activity. With worsening spleen enlargement, however, destruction of red blood cells (RBC) in the spleen increases. Therefore, anaemia treatment based on stimulation of erythropoiesis has a smaller chance of effect in patients with advanced disease and large spleens. There are several options for specific anaemia treatment in MF, which will be presented here. Although there is a lack of controlled, randomized studies of anaemia treatment, there is evidence enough for a recommendation that all anaemic patients with MF should be considered for specific anaemia treatment. Erythropoiesis-stimulating agents (ESA) Human recombinant erythropoietin (rHuEPO) was first used in the treatment of PMF anaemia in small pilot studies in the beginning of the 1990ies [4e8]. Although results were promising, no larger study was performed until 2004, when Cervantes collected 20 PMF patients with either transfusion dependency (13/20) or Hb level below 9 g/dl(9). 4/20 patients normalized their Hb level, and 9/20 (45%), had either a complete response (CR) or a partial response (PR). In the same paper, the authors added 31 cases from the literature to their own material and found a CR rate of 31%, PR 24%, total responses 55%. Positive factors for response were lack of transfusion dependency and an S-Epo level <125 U/L. In a later study with long-acting rHuEPO the same authors found a similar response rate in 20 patients [10]. The most positive responses published can be found in a prospective study with 20 transfusion-dependent PMF patients, in whom a 60% response rate was found (CR Hb > 12 g/dl or Transfusion independence (40%), PR increase by 2 g/dl or double transfusion interval (20%)) [11]. In contrast, a retrospective study from the Mayo clinic showed no responders among 16 transfusiondependent patients and no responders among 9 patients with Hb levels >10 g/dl [12]. These results have not been supported by any other study. The dose of rHuEPO used has been the standard dose given in other cancer anaemias, 30,000 U weekly, although usually given as 10,000 three times weekly subcutaneously which used to be the standard dosing in the early days of rHuEPO treatment. The efficacy of a dose increase has not been evaluated. No studies have been published with the use of biosimilars or other forms of erythropoiesisstimulating agents (ESA) of more recent development. Conclusion The studies are small (no larger prospective study than N ¼ 20), and the response criteria used are not uniform. However, a response rate of 40e50% within 6e8 weeks can be found in the studies with a minimal response criterion of Hb increase >2 g/dl or a 50% reduction of transfusions. Factors that are predictive of response include limited or no transfusion dependency and a non-severe anaemia. Response correlation to S-Epo levels is inconclusive. [9,12] ESAs were generally very well tolerated. Androgens Androgen therapy has been used for many years for various bone marrow failure syndromes, and early studies in MF showed promising results. In a small 1978 prospective study in 11 patients, 5 of whom were transfusion dependent, long-term oxymetholone treatment resulted in loss of transfusion dependency in all and > 3 g/dl Hb increase in 9 of the 15 courses given [13]. In a 1982 study including 23 PMF patients, a response rate of 57% was found (sustained increase in Hb level or cessation of transfusion need within 3 months), with a significantly better response among patients with normal karyotype (92% response) [14].
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In more recent times, two studies (2000 and 2005) by Cervantes et al. used danazole 600 mg daily for 6 months with tapering thereafter in responders. Response criteria were not the same in both studies, with more strict criteria for PR in the latter study (an Hb increase >/ ¼ 1.5 g/dl with transfusion-independent Hb values >10 g/dl maintained for at least 8 weeks), giving an overall response rate of 57% vs 37% in the 7 and 30 patients, respectively. Median time to response was 5 months. In the 2005 study, four patients stopped responding at 6e24 months, two responders discontinued treatment because of toxicity, and five maintained response at 3.5e42 months [15,16]. In a recent study, danazole was given in combination with intermittent chemotherapy in 18 elderly MPN patients (16 MF, 2 ET), who had failed other therapy, in doses ranging from 200 to 800 mg daily. Chemotherapy was given as needed for spleen reduction and control of blood counts. Eleven patients (61%) responded, three with normalization of blood counts and spleen (“excellent responders”), eight with Hb increase of 7% and 50% spleen reduction (“good responders”). The mean duration of response was 45 months (10e78 months) and 11 months (2e22 months), respectively [17]. In a retrospective study, Shimoda et al. found 55 MF patients who had been treated with androgen steroids, 39 of which were evaluable. A variety of drugs and dosages had been used (danazole, metenolone acetate, stanozolol). The response criteria were defined as “good” (Hb increase 1.5 g/dl, cessation of transfusion dependence and Hb values >10 g/dl, all maintained for at least 8 weeks) or “minimal” (increase in the Hb concentration of 1.5 g/dl and transfusion independence for at least 8 weeks). Both categories were considered “favourable”, and 17 patients (44%) filled the criteria (21% “good”). The median time to response was 3 months, but 3/17 responders required more than 6 months of treatment for response. In contrast to the Cervantez studies, no pretreatment factor predicted response, including cytogenetics and transfusion dependency [18]. The side effects reported in these studies were mainly moderate liver enzyme increase in some patients, that subsided after dose reduction. Occasional cases of muscle mass increase and headache have also been observed. Conclusion Just as for ESAs, studies are small and with varying response criteria. Meaningful Hb responses (Hb increase >2 g/dl, no transfusion need) can in many of the studies be seen in >40% of patients. The time to response varies widely. Most patients respond within 3e6 months, but occasional responses can be seen after more than 6 months. Toxicity is generally mild and dose dependent. Thalidomide Due to its antiangiogenic [19] and immunologic effects, a renewed interest in this drug has resulted in the discovery of antitumour effects in a wide range of malignant states, among them multiple myeloma [20]. Early studies in PMF using standard doses (100 e >400 mg daily) were noted for some positive effects, especially with regard to anaemia, but side effects, especially fatigue, leucocytosis and thrombocytosis, caused a high drop-out rate [21e25]. However, both reports of wanted biologic [26] activity like reduction of microvessel density [27] and the positive effects on anaemia led to studies with reduced thalidomide dosage. The first study using the dose 50 mg daily included 21 MF patients and also used a combination of thalidomide with a 3 months course of prednisone. The results were encouraging: tolerance was improved, and objective clinical response was demonstrated in 13 (62%) patients, all improvements in anaemia. Among 10 patients who were dependent on erythrocyte transfusions, 7 (70%) improved and 4 (40%) became transfusion-independent. Responses observed were mostly durable after discontinuation of the prednisone [28]. Since then, a number of studies have been performed with low dose thalidomide, mostly in combination with prednisone, and Hb response rates ranging from 22% to 100% have been reported. Toxicity is reduced when doses of 50e100 mg daily are used [29e31]. However, one study using these doses still reports cessation of therapy in 12/14 patients due to fatigue, constipation and peripheral neuropathy [32]. Different response criteria and generally low numbers of patients make comparison of efficacy difficult and statistics uncertain. The first study to use the EUMNET response criteria included 15 patients, and overall, 40% of patients
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achieved major or moderate responses by these criteria. All responses began within the first 12 weeks of treatment, and the median duration of response was 16 weeks (4e95 weeks) [31]. Since lenalinomide has also been tried as a treatment for PMF, a comparison between thalidomide and lenalinomide has been performed recently. However, thalidomide was not given as a low dose regimen, and there was no combination of thalidomide with prednisone, whereas one study arm comprised lenalidomide and prednisone. The resulting superiority for lenalidomide is therefore not surprising [33]. Conclusion Low dose thalidomide in combination with prednisone is effective in ~40% of cases in studies of reasonable size and with meaningful response criteria. The time to response is generally less than 12 weeks, whereas the duration of response varies widely in the published studies. Even with doses of 50e100 mg daily, fatigue, constipation and neuropathy may be notable in individual patients. Lenalinomide Lenalidomide is a derivative of thalidomide and shares its antiangiogenic and immunologic effects [34], may be being more potent. It was therefore natural to test its efficacy in MF, and the first two studies to do so were reported in the same paper [35]. Sixty-eight MF patiens in total were included at two separate institutions and given Lenalidomide monotherapy in two rather similar dose regimens. Forty-six of the patients were anaemic, and the response rate for anaemia was similar, 22%, with 17% having a normalization of Hb (major response) and 4% increased >2 g/dl or became transfusion-free (minor response). Just as with thalidomide, combination with prednisone has been studied. Forty MF patients were accrued for a study combining 6 months of lenalidomide in 21 days on/7 days off cycles with prednisone during the first 3 cycles in the doses 30, 15 and 15 mg daily, respectively. Thirty-three of the patients were anaemic at baseline, and the anaemia response rate was 30% in patients with Hb < 10 g/dl. Among these responders, 10 of 11 assessable patients, all with reticulin fibrosis grade 4 at study entry, exhibited reductions to at least grade 2 fibrosis. Similar reductions were also observed in collagen fibrosis in three of five responders [36]. In a later study with added prednisone, the anaemia response rate was 20%. Neither this study was designed to allow identification of the role of prednisone [37]. In an Austrian “real-life” report 22 MF patients treated with lenalidomide were retrospectively reported, 15 of which were anaemic. A much lower response rate of 12.5% was seen (IWG) criteria. Specific anaemia data were not presented [38]. Similar low response rates were reported in a Spanish retrospective study of 32 MF patients [39]. The toxicity of lenalidomide is lower than for the mother substance thalidomide. However, cytopenia, including anaemia, is a problem. Furthermore, in one of the limited studies with 48 patients 3 thrombotic events were recorded [37] and in another a thrombosis of corpora cavernosus was seen [40]. Conclusion Lenalidomide has general effects that seems to make the drug preferable to thalidomide as a treatment for MF. However, the specific anaemia effect is difficult to evaluate from existing studies but seems to confer a response rate around 20e30%, at least in patients with del (5q31). Notable is a few cases with excellent Hb responses and reduction of bone marrow reticulin. It is also to be noted that anaemia is a common side effect of the treatment. Pomalidomide Pomalidomide is another second-generation immunomodulatory drug, derived from thalidomide with the aim to increase efficacy and reduce toxicity. Almost all published data on pomalidomide treatment comes from one group of authors, who since 2009 have published a series of studies, some of
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which are follow-up studies. The first study was a phase 2, four-armed dose-finding study randomized study in 84 MF patients with Hb < 10 g/dl, comparing effects with and without addition of prednisone [41]. Twenty patients had a Hb response, 4 of which to prednisone alone, which is 19% of the patients in that arm. The response rates in the 3 pomalidomide arms were 23% (pomalidomide 2 mg/d), 16% (pomalidomide 2 mg/d þ pred), 36% (pomalidomide 0.5 mg/d þ pred). This means that the response rates were similar in the prednisone alone and 2 of the pomalidomide arms. Fifteen patients were relieved of transfusion dependence, two of which, though, in the prednisone alone arm. Critically regarded, these results indicate a limited effect on anaemia, even though response duration was longer with pomalidomide and the effect on transfusion dependence seemed impressive. A later doseescalation study from the same group in 19 patients with Hb < 8 g/dl indicated that low dose pomalidomide may be more effective [42]. This was tested in 58 MF patients with Hb < 10 g/dl, 46 of whom were transfusion dependent. Anaemia response (17% in total) was only seen in10 JAK2-positive patients [43]. A follow-up study was then performed in 94 of the161 Mayo clinic patients from the previous 3 studies. Median time from drug initiation was 27 months (range 20e52 months). Pomalidomide therapy had been discontinued in 86 (91%) patients at a rate of 68% at 1 year and 89% at 2 years. The overall anaemia response was given as 27%, higher in JAK2-positive patients without marked splenomegaly and with <5% circulating blasts (53%) [44]. A less favourable study was published in 2013, reporting 3/29 patients to get a clinical improvement (Hb increase) as defined by IWG and 2 who became transfusion-independent after continuous low dose pomalidomide, 0.5 mg/d [45]. Finally, at ASH 2013, the Mayo clinic group reported a randomized international collaborative study in 252 transfusion-dependent MF patients receiving pomalidomide 0.5 mg/d or placebo that surprisingly showed response rates to be similar between the treatment and placebo arms (16% [95% CI, 11e23%] vs 16% [8e26%]), as were response durations. (ASH abstract #394, Tefferi, A [80]). Conclusion From the initial studies it could be hoped that this second-generation IMID would be at least as effective as thalidomide and lenalidomide and with fewer side effects. However, response rates are lower, and the two last presented studies have strongly questioned any role for pomalidomide. Interferon Interferon (IFN) was introduced in studies of PMF mainly due to theoretical considerations concerning its possible effect on the production of growth factors from abnormal megakaryocytes [46], with the aim to reduce collagen deposition in the bone marrow. Early anecdotal evidence and small pilot studies showed very limited effects on Hb levels [47e49] but occasional priomising redcutions of bone marrow fibrosist [50,51]. However, negative studies were also published [52], and still no study with more than 10 evaluable PMF patients was published until 2003, when 31 MF patients were part of a phase II study in MPN patients. The response rate for a composite endpoint was very low (3.2%) in MF, and the specific effect on anaemia cannot be evaluated from the paper [53]. In a large study of bone marrow progression in 153 PMF patients on different therapies, no relevant differences in the evolution of myelofibrosis were evident in the various therapy groups,” especially not following interferon treatment” [54]. In an MPN study from 2007, 11 PMF patients were treated with pegylated interferon IFN2a in a dose of 2e3 mg/kg/wk. Only one response was seen with Hb increase to >11 g/dl [55]. In a retrospective French study 18 PMF patiens were found who had been treated with pegylated IFN2a. Among the three transfusion-dependent patients, two became transfusion-independent. In addition, four of the five other anaemic patients increased their haemoglobin level to Hb > 10 g/l [56]. However, 4 of these had a baseline Hb > 9 g/dl, which means that the response criterion was not very strict. In a study aimed at investigating bone marrow effects of IFNa2b on 13 PMF patients, an increase in Hb > 2 g/dl was seen in only 2 patients; on the other hand, a reduction in Hct >15% was seen in 7 patients [57]. In an update of this study with 17 PMF patients, similarly treated, the Hb level was unchanged before and after treatment [58]. In a recent meta-analysis of 13 studies Nguyen and
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Kiladjian reported the overall effects of IFN in PMF and found problems in the evaluation due to great variation in response criteria [59]. However, their conclusion was that IFN may have a role in the early stages of the disease, when there is still residual haematopoiesis, as also suggested by Silver [47]. In contrast, the most recently published, retrospective, study reports high anaemia response rates [60]. Among 62 patients with pegylated IFNa2b, 25 had a Hb level <10 g/dl, and overall the overall response rate was 63.5% according to IWG-MRT criteria (i.e., Hb > 110 g/l). Interestingly, 10 of the patients were treated with a combination of IFN and ESA, and 9/10 were responders. Three patients responded to the combination after failure of initial IFN treatment. The time to achieve the best response was 7.1 months. There was a 38.5% response rate among the 13 patients requiring transfusions. Interestingly, most responses were obtained within the first 6 months of treatment. Of note, the addition of ESA did not affect the results of Peg-IFNa-2a treatment in transfusion-dependent patients. The only prospective study combining IFN and ESA was performed 17 years ago, a small study where 5/5 patients had a Hb response [6]. The toxicity of IFN is well known and consists both of mental effects like fatigue, depression and cognitive disturbances and of bone marrow depression. Dropout rates vary in different studies but are often reported as ~25%. Conclusion A large number of studies with IFN treatment of PMF patients have been performed with low response rates for anaemia. Positive effects on other disease variables than anaemia may give IFN a role, especially in early disease. Whether the two studies reporting combination with ESA and high response rates for anaemia indicate a true difference is too early to say; one was very small, and the other is limited and retrospective. It is also important to remember that IFN may give a general bone marrow depression with anaemia as a consequence. JAK2 inhibitors With regard to the anaemia effect, the JAK2 inhibitors generally have a detrimental rather than enhancing effect on Hb levels. In the 3-year follow up of the COMFORT II Ruxolitinib study, a lowering of Hb and an increase in need of transfusions was noted during the first 12e24 weeks of therapy, after which Hb levels returned to the same as in the “best available treatment” arm [61]. A similar pattern was seen in the COMFORT I study, with a Hb reduction of 10e12% at a nadir around week 12 and an increase in transfusion need, with recovery of Hb to a level around 5% below baseline after 24e36 weeks [62]. An exception seems to be CYT387, an orally available JAK1/2 inhibitor. In a recent phase I-II study, 41 anaemic MF patients with Hb < 10 (n ¼ 8) or transfusion dependency (n ¼ 33) were treated. Sixty-seven % of the transfusion dependent patients became independent with a minimum Hb of 8 g/dl for at least 12 weeks with a median duration of this response of 9.6 months [63]. Surprisingly, only 1/8 non-transfusion dependent patients with Hb < 10 g/dl achieved a response. Conclusion Anaemia and thrombocytopaenia are common side effects of treatment with JAK2 inhibitors. The only such drug with a positive anaemia effect is the oral CYT387, so far reported in one study to be effective in transfusion dependent patients but strangely enough not in other anaemic patients. Further studies are needed to clarify the role of this drug in anaemia. Other new drugs Generally speaking, two principles are the subject of testing for the relief of anaemia in MF: drugs that reduce the proliferative activity or otherwise may change the basic biology of MF, and drugs that may increase erythropoiesis without doing so. The histone deacetylase inhibitor pracrinostat and the mTOR inhibitor everolimus belong to the former category. Both have been tested in phase I-II trials with minimal or uncertain anaemia effects [64,65]. Drugs belonging to the latter category are being
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developed but have not been tested in MPN patients yet. A group of dioxygenases (Eg1N) that are active in the ubiquitination of the hypoxia-inducible factor HIF1a can be reduced by specific inhibitors, mimicking hypoxia and thereby increasing the endogenous EPO production [66]. Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein inhibits activin and was first developed to improve bone disease, i.e., in myeloma, but was also found to stimulate erythropoiesis by a different route than EPO [67]. No studies in MF patients have yet been published. Imetelstat, the first telomerase inhibitor, has been shown to give complete haematologic remissions in ET (Baerlocher GM, EHA 2013, abstract 4398 [81]), and the first study in MF has shown a Hb response (increase>2 g/dl or transfusion independence) in 4/12 patients (33%) (Tefferi A, ASH 2013, abstract 662 [82]). Red cell transfusion As the disease progresses, most MF patients become transfusion dependent. However, in spite of existing guidelines [68] trigger limits for this therapy vary widely, both between countries and between centres. In a large European study in 15,000 cancer patients, a trigger level of 8.1 g/dl was found [69]. For some patients transfusion is necessary for survival, for others it is a matter of quality of life (QoL). Improvements in QoL have been shown [70], but clinical practice is influenced by availability of stored red cells, patient and doctor attitudes, the fear of disease transmission, concern for iron overload, cost deliberations etc. A discussion of these factors is outside the scope of this paper. Iron chelation It has long been known that iron chelation may elicit an improvement in erythropoiesis, both in MDS, chronic renal anaemia and MF [71e74], with deferoxamine and deferiprone. Recently case reports have also emerged with similar anecdotal Hb improvements with deferasirox [75e77]. However, in a retrospective study on 25 iron-overloaded PMF patients where 10/25 were given iron chelation, no positive effect on anaemia was reported [78]. On the other hand, a significantly better survival was seen in the group with iron chelation (p ¼ 0.02). Similar results have been presented in MDS [79]. Conclusion There are two possible effects of iron chelation in MF. One is the anecdotally reported and sometimes dramatic improvement of erythropoiesis. No systematic study has investigated this phenomenon, for which there is no better explanation than that iron chelation may give biologically nonavailable iron a route to the erythroblasts in the bone marrow. The other issue is the toxicity of iron accumulation in transfusion-dependent MF patients and the possibility to improve survival with iron chelation, where evidence supports active iron chelation. Discussion Anaemia treatment in MF is a field with many small studies, mostly non-randomized and uncontrolled. Different selection principles of patients and a variety of response criteria have been used, making evaluation and comparison of result with various drugs difficult. Nonetheless, the treatment results of the most commonly used modalities in studies are better than what is generally believed. The response rates for the most commonly used treatments, ESAs, danazole and low dose thalidomide þ prednisone are in the order of 30e50% (Hb increase 2 g/dl or no need of transfusion). Still, this indicates that there is a need for more efficient treatments, especially in patients with more advanced disease. It is worth noticing that two small studies, one old and one recent, have presented very high response rates with a combination that has not been tested in any other study, namely ESA and IFN [6,60]. Some of the drugs used, like ESAs and androgens, act mainly by stimulating erythropoiesis, others by interfering with the disease activity. Unfortunately, some of the new drugs acting to reduce proliferative disease activity, like the JAK2 inhibitors, by inhibiting unmutated, non-clonal haematological
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stem cell proliferation, also reduce general bone marrow cell production, not least red cell production, thereby cytopenia as a side effect. Since Hb is an important part of the risk scores, anaemic patients often belong to high or intermediate risk categories. However, many of the patients who develop anaemia have years of life expectancy, and there is evidence enough to state that such treatment should be considered in all anaemic MF patients. It is, however, important to remember that an increase in Hb induced by a symptomatic drug like an ESA should not alter the risk classification of the patient (especially important in the consideration of stem cell transplantation) since it does not change the course of the disease. In several studies the patients with the best chance of response are those with a non-severe anaemia. This coincides with clinical practice experience and indicates that anaemia treatment should not wait until the patient is severely anaemic. In which order should the various treatment be tried? There is no “correct” answer to this question. My own choice is to start with a treatment with very little side effects that can be evaluated within a fairly short time, 6e8 weeks, namely ESA. Just as for general cancer anaemia, it has been shown that response is somewhat more likely if the S-Epo level is < 125 U/L. However, even if there is such a correlation on the group level, such a cut-off cannot be used for the individual patient. Patients with SEpo > 125 U/L still have a good chance to respond. If keeping costs down is a high priority, danazole is probably the first drug of choice. The disadvantage is that the median time to response is 3e6 months, and some patients respond much later than 6 months. For most haematologists, low dose thalidomide þ prednisone is the third choice. The evidence for response is as good as for the previously mentioned drugs, and the time to response about 3 months. However, even with low dose thalidomide (50e100 mg/d) some patients develop both central (fatigue) and peripheral neuropathy during prolonged use. Because of this, some advocate lenalidomide as the drug of choice, due to its lower toxicity. This may be true if the general effect on disease is considered, but the evidence for a specific anaemia response is weaker for lenalidomide, and anaemia is a common side effect of the drug. At present, anaemia treatments other than the three here suggested should be restricted to studies. Summary There is good evidence to recommend use of ESAs, androgens and low dose thalidomide þ cortisone for anaemia in MF. For the other drugs analysed here the evidence either shows a minimal effect or an uncertain effect making further studies necessary for evaluation. There is a disturbing lack of solid controlled studies with enough patients within the area of MF and anaemia. This is probably a situation that will prevail, due to the fact that many new drugs are in the pipe-line for clinical trials that are possible disease-modifiers, where the anaemia effect will be just a part of a broader evaluation. Hopefully, some of these new drugs will modify disease without interfering with the wild type haematopoietic proliferation, but until such a drug is found, there will be MF patients who need specific anaemia treatment, based on the existing evidence. Just as in MDS, iron chelation should be given in transfusion-dependent patients.
Practice points There is a lack of large controlled studies with comparable response criteria, making figures for efficacy approximate and uncertain. The three commonly used treatments for anaemia in MF, ESAs, androgens and low dose thalidomide, all have a response rate in studies of 30e50%. ESA or low dose thalidomide þ prednisone should be first line therapy for anaemia in MF. Response is more likely in patients with non-severa anaemia. The new drugs in MPN treatment so far have not been shown to be more effective.
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