- Email: [email protected]
How We Treat Myeloproliferative Neoplasms
SOHO Supplement 2015
How We Treat Myeloproliferative Neoplasms Claire N. Harrison,1 Donal P. McLornan,1 Yvonne A. Francis,1 Claire Woodley,1 Lizzie Provis,2 Deepti H. Radia1 Abstract The phildelphia-negative myeloproliferative neoplasms were defined based upon careful clinical review and an analysis almost a century ago. Increasingly this field is becoming more complex in terms of diagnostic information, treatment options have however been following behind. Here we present our approach to the management of these entities. The present report focuses on management strategies for the myeloproliferative neoplasm according to the structure and processes we use within our center, a large tertiary unit in central London. The standard procedures for achieving an accurate diagnosis and risk stratification and therapeutic strategies for these diseases with a detailed focus on contentious areas are discussed. In the 9 years after the description of the Janus kinase 2 mutation, this field has altered quite radically in several aspects. For example, a new therapeutic paradigm exists, especially for myelofibrosis. We share how our unit has adapted to these changes. Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. S1, S19-26 ª 2015 Elsevier Inc. All rights reserved. Keywords: Erythrocytosis, Myelofibrosis, Polycythemia, Thrombocythemia, Thrombocytosis
Achieving an Accurate Diagnosis The recent advances in our repertoire of molecular tests and in our knowledge of the natural history of myeloproliferative neoplasms (MPNs) means that our diagnostic approach has become increasingly laboratory based and involves several disciplines, including cellular pathology, blood film morphology, molecular biology, and cytogenetics. The implication is that in clinical practice, the hematologist must be able to synthesize these data and accurately communicate the clinical scenario and questions. Unless this conversation occurs, the risk of inaccurate diagnosis and overinterpretation of a single piece of the diagnostic puzzle will be unacceptably high. An example of the flow process that we follow for classic MPN is shown in Figure 1. To achieve a diagnosis of MPN, the exclusion of underlying reactive conditions has been simplified by the expanding repertoire of molecular abnormalities, which has been exemplified by the recent description of calreticulin (CALR) mutations.1,2 These secondary causes are listed in a footnote to Figure 1. Having excluded a reactive disorder, it would be ideal to use as much diagnostic information as possible to be able to assign 1
Department of Haematology Pharmacy Service Guy’s and St. Thomas’ National Health Service Foundation Trust, London, United Kingdom 2
Submitted: Dec 6, 2014; Revised: Feb 6, 2015; Accepted: Feb 26, 2015; Epub: Mar 3, 2015 Address for correspondence: Claire N. Harrison, DM, FRCP, FRCPath, Department of Haematology, Guy’s and St. Thomas’ Foundation Trust, London SE1 9RT, UK E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.02.032
the patient to a particular category of MPN. Although the MPN unclassified category exists, the information to make robust management recommendations for this entity is insufficient. It is important to note that although the molecular abnormalities identified in MPN likely define a neoplastic process, they are not specific to the subtype of MPN. Although the recent iterations of the World Health Organization diagnostic criteria are welcome, in some areas, difficulty and controversy remain. One example is in discriminating between Janus kinase 2 (JAK2) Val617Phe (V617F)-positive essential thrombocythemia (ET) and polycythemia vera (PV). This is clearly an important issue owing to the different management strategies for these diseases and the importance of controlling the hematocrit in PV. A recent report from a well-respected Spanish group illustrates these difficulties perfectly and highlights the British Committee for Standards in Haematology diagnostic criteria of PV3 (Table 1), as the most sensitive and specific criteria.4 The report from Alvarez-Larran et al4 deserves additional mention because of their work to evaluate the diagnostic accuracy of the histologic features and to assess its correlation with the presence of mutations and clinical outcomes. Two pathologists reviewed the bone marrow biopsies corresponding to 211 patients with MPN. They reported that the specificity of the histologic findings was 100%, 98.5%, and 98% for PV, ET, and primary myelofibrosis (PMF), respectively. However, the sensitivity of the histologic diagnosis was low for PV and ET (32.5% and 54%, respectively) and acceptable for PMF (75%). Of 146 patients with clinical ET, 13 (9%) were diagnosed with prefibrotic PMF. Regarding the issues with
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How We Treat Myeloproliferative Neoplasms Figure 1 Algorithm for Diagnosis of Myeloproliferative Neoplasms
Abbreviations: CALR ¼ calreticulin; CML ¼ chronic myelogenous leukemia; EPO ¼ erythropoietin; ET ¼ essential thrombocythemia; LDH ¼ lactate dehydrogenase; MDS ¼ myelodysplastic syndrome; PMF ¼ primary myelofibrosis; PV ¼ polycythemia vera.
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discriminating PV from ET, other investigators have also suggested using a hematocrit level close to that recommended by the British Committee for Standards in Haematology, because it improves the diagnostic accuracy.4 One of the major difficulties inherent in discriminating between ET and PV is the limited availability of red blood cell mass testing. Alvarez-Larran et al4 was also one of several groups to highlight that the entity of prefibrotic MF remains controversial, and additional international collaboration and educational efforts are widely acknowledged to be required.5,6 Specifically, the issues concerning the discrimination of ET and prefibrotic MF revolve around the reproducibility of the specific histologic features, predominantly megakaryocyte abnormalities, which enable discrimination of these entities. The incorporation of clinical criteria (ie, anemia, leukoerythroblastic blood film, and splenomegaly) are important. The major clinical differences in outcomes and the management strategy for patients with ET (the most indolent MPN) compared with those with PMF (the most aggressive MPN) highlight the importance in achieving an accurate diagnosis. To achieve as accurate a diagnosis as possible, our team have used the document “Improving Outcomes Guidance” mandated in the United Kingdom (available at: www.nice.org.uk/Guidance/ CSGHO) in facilitating a multidisciplinary conversation, which is hosted by a video conference across several different hospital sites and involving all the contributing disciplines. This also enables us to perform a coordinated management decision and to discuss the options potentially available at different sites (eg, clinical trials). Patients with refractory or progressive disease can also be discussed at this meeting. Patients with MPN, chronic and acute myeloid
Clinical Lymphoma, Myeloma & Leukemia June 2015
leukemia, myelodysplasia, and other bone marrow failure disorders are discussed in a myeloid-specific setting. Other general management approaches are available. The National Institute for Health and Care Excellence guidance also incorporates the role of clinical nurse specialist in the management of chronic conditions such as MPN. This role is a cornerstone of management in our service, because the clinical nurse specialist is the key point of contact, information, and support for the patients and their families. In our service, many stable patients are reviewed by the clinical nurse specialist by telephone interview or in separate clinics, with a consultant or medical review annually. The role is also critical because of the flux of staff that is often seen in at inner city tertiary service to provide continuity for patients beyond that of the consultant physician and education for the nursing and other staff. This infrastructure is also critical to incorporating symptom assessment for these patients, because it is an increasingly important aspect of care. In addition to this role, we also have a prescribing pharmacist present in the clinics available to assess and provide prescriptions for stable patients and as a source of expert pharmacy advice for the clinicians.
Management of ET and PV The treatment of those with ET and PV is considered jointly in this section, although clearly differences exist in the natural history and clinical manifestations. These patients will undoubtedly benefit from aggressive risk management for vascular disease. We use lowdose aspirin for these groups of patients. However, although this is evidence-based medicine for PV in accordance with the findings from the European collaboration on low-dose aspirin in polycythemia vera (ECLAP) study,7 aspirin remains controversial for
Claire N. Harrison et al Table 1 Diagnostic Criteria for Polycythemia Vera, as Recommended in the British Committee for Standards in Haematology Guidelines JAK2þ polycythemia vera A1—High hematocrit (>0.52 in men, >0.48 in women) OR elevated red blood cell mass (>25% above predicted)a A2—Mutation in JAK2 The diagnosis requires both criteria to be present JAK2 polycythemia vera A1—Elevated red blood cell mass (>25% above predicted) OR hematocrit >0.60 in men, >0.56 in women A2—Absence of mutation in JAK2
and thus whom to treat. However, although, as discussed earlier, the red blood cell mass test is not widely available. The discovery of the CALR mutations might ultimately result in the field adopting different treatment schedules for patients with CALR-mutated ET compared with JAK2-mutated ET. Increasing evidence has shown that the clinical behavior of patients with a CALR mutation is different from that of those with a JAK2 mutation. At present, no evidence is available for a different management strategy nor is any evidence available to support treating patients with JAK2 exon 12-mutated PV differently from those with JAK2 V617F-mutated PV.
A3—No cause of secondary erythrocytosis
Cytoreductive Therapy for PV and ET
A4—Palpable splenomegaly
When and Who
A5—Presence of an acquired genetic abnormality (excluding BCR-ABL) in hematopoietic cells
Cytoreductive therapy for ET and PV is currently used to reduce the risk of thrombosis and control disease-related symptoms. Ideally, such therapy should reduce the risk of progression to MF. However, cytoreductive therapies have not currently been shown to achieve this. Risk stratification is widely used, and a number of such risk stratification schemes have been proposed14-18 (Table 2). These stratification schemes are based on the risk of thrombosis. For patients with ET, the recently described International Prognostic Score System [IPSS] for (ET)19 will recategorize a significant number of patients previously considered high and low risk and generates a large intermediate-risk category for which no treatment algorithm has been tested. We do not currently use this risk score. Also, the intermediate-risk patient group in ET is controversial, with the group variably defined. Data from the ongoing PT-1 trials will describe the natural history of and response to aspirin versus aspirin plus hydroxycarbamide (HU) for an intermediate-risk group. The risk group was defined by the investigators as patient age 40 to 60 years without high risk (age < 60 years, no previous thrombosis, platelets < 1500 109/L) or cardiovascular risk factors. For patients with ET, the presence of the CALR mutations seems to correlate with a better prognosis and lower risk of thrombosis2,20; however, this has not yet been incorporated into risk stratification schemes. Recent publications have addressed the lack of clear data regarding the definition of high-risk (for thrombosis) PV.21 The predominant factors are age, previous thrombosis, vascular risk factors. The current additional candidates include the leukocyte count,21,22 reticulin grade,6,23,24 and JAK2V617F allele burden.24 The effect of conventional risk factors for atherosclerosis has been assessed in MPN with variable results. Also, whether these risk factors should contribute to risk group allocation for patients with ET and PV, especially if they are well-controlled, is unclear. Communication with the patient and family physician is critical in managing these aspects of disease.
B1—Thrombocytosis (platelet count >450 109/L) B2—Neutrophil leukocytosis (neutrophil count >10 109/L in nonsmokers; >12.5 109/L in smokers) B3—Radiologic evidence of splenomegaly B4—Endogenous erythroid colonies or low serum erythropoietin Diagnosis requires A1 þ A2 þ A3 þ either 1 additional A or 2 B criteria Abbreviations: JAK2 ¼ Janus kinase 2; MPN ¼ myeloproliferative neoplasm. a Dual pathologic features (coexistent secondary erythrocytosis or relative erythrocytosis) will rarely be present in patients with JAK2þ MPN; in this situation, it would be prudent to reduce the hematocrit to the same target as for polycythemia vera.
patients with in ET.8 In our clinical practice, we generally use lowdose aspirin for all patients, except for those with bleeding and other clear contraindications, for whom we might consider the use of alternative antiplatelet agents such as clopidogrel. If the patient has difficulty in tolerating the aspirin (eg, because of an increase in minor bleeding), for particular groups of patients for whom the evidence base for the use of aspirin is less well defined, we withdraw the therapy. These patients include those with JAK2 V617F lowrisk ET and patients with ET lacking cardiovascular risk factors. Bleeding is a particular risk for patients with very high platelet counts but can occur with more modestly elevated platelet counts. Although we do not regularly measure our patient’s blood pressure and cholesterol or glucose levels, we do encourage this dialogue with their family physician in primary care. The target for venesection in PV (hematocrit or packed cell volume 0.45) has been controversial. This was based on an previous study from our center,9 although the findings from the ECLAP study appeared to conflict.10 The findings from the recently reported CYTOreductive Therapy in Polycythemia Vera (CYTO-PV) study strongly support the control of the hematocrit level to 0.45, although importantly, differences were found in the leukocyte counts of the 2 arms of that study that might have accounted for some of the 44% reduction in thrombosis.11,12 Just as was first identified by analyzing the Primary Thrombocythaemia-1 trial (PT1) cohort of patients, considerable overlap can exist between JAK2V617Fþ ET and PV.13 In clinical practice, the question of whether to control the hematocrit of a patient with a diagnosis of ET who has the JAK2V617F mutation and whose hematocrit is > 0.45 but is within the normal range is unclear. We would use a red blood cell mass test in this situation to identify “masked PV”
Which Agent and What Target? A better evidence base would be desirable. The current published recommendations are summarized in Table 3. Generally, interferon (IFN) and hydroxycarbamide (hydroxyurea or HU) form a mainstay of therapy, and interest is increasing in IFN therapy, especially pegylated forms, to treat these conditions with a disease-moderating effect. However, IFN is not widely available. Also, statements
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How We Treat Myeloproliferative Neoplasms Table 2 Risk Stratification for Thrombosis in PV and ET and Risk Stratification for PMF
Table 2 Continued Hemoglobin (<10 g/dL [score 2])
Polycythemia vera
Peripheral blasts (<1% [score 0], >1% [score 1])
Conventional risk stratificationa
Constitutional symptoms (no [score 0], yes [score 1])
High-risk PV: any one of the following factors Age >60 years Previous documented thrombosis, erythromelalgia (if refractory to aspirin) Platelets >1000 109/Lb Diabetes or hypertension requiring pharmacologic therapyb
Risk assignment: low (sum 0); intermediate 1 (sum 1 or 2); intermediate 2 (sum 3 or 4); high (sum 5 or 6); median survival: not reached, 14.2, 4, and 1.5 years, respectively DIPSS plus prognostic score18 Possible points from DIPSS: 0-3; DIPSS prognostic group points: low risk, 0; intermediate 1, 1; intermediate 2, 2; high risk, 3 To the DIPSS prognostic group, add 1 point each for
Low-risk PV
Platelet count <100 109/L
None of the above risk factors Significant (ie, >5 cm below costal margin on palpation) or symptomatic (pain, early satiety) splenomegaly might be an indication for treatment, rather than a risk factor for thrombosis per seb Essential thrombocythemia Conventional risk stratificationc High-risk ET: any one of the following factors Age >60 years Platelet count >1500 109/L Previous thrombosis, erythromelalgia (if refractory to aspirin) Previous hemorrhage related to ET Diabetes or hypertension requiring pharmacologic therapya Low-risk ETd Age <40 years None of the above risk factors Intermediate-risk ETd
Red blood cell transfusion required Unfavorable karyotypeg Risk assignment by number of points: low (sum 0); intermediate 1 (sum 1); intermediate 2 (sum 2 or 3); high (sum 4 to 6); corresponding median survival estimate: 185, 78, 35 and 16 months, respectively Abbreviations: DIPSS ¼ Dynamic International Prognostic Scoring System; ET ¼ essential thrombocythemia; IPSS ¼ International Prognostic Scoring System; PMF ¼ primary myelofibrosis; PV ¼ polycythemia vera; WBC ¼ white blood cell. a Predicts for thrombosis but has not been tested prospectively. b These risk factors are more controversial and have not been fully agreed on (eg the degree of leukocytosis or grade of reticulin). c Predicts for thrombosis. d These categories are contentious and some recommend low and high risk only or classify individuals with cardiovascular risk factors as intermediate risk. e Predicts overall survival but not the development of postessential thrombocythemia myelofibrosis. f IPSS for ET for thrombosis also available, although in our practice we do not use this score. g Unfavorable karyotype includes þ8, 7/7q, i(17q), inv(3), 5/5q, 12p11q23 rearrangements and complex karyotypes.
Age 40-60 years None of the above markers for high-risk disease International Prognostic Score for ETe (a novel risk stratification based on histopathologically defined ETf) Risk factors Age 60 years (2 points) Leukocyte count 11 109/L (1 point) Previous thrombosis (1 point) Risk categories Low (sum ¼ 0) Intermediate (sum ¼ 1 or 2) High (sum ¼ 3 or 4) Risk stratification for PMF IPSS prognostic score16 Prognostic variable Age (<65 years [score 0], >65 years [score 1]) WBC count (<25 109/L [score 0], >25 109/L [score 1]) Hemoglobin (>10 g/dL [score 0], <10 g/dL [score 1]) Peripheral blasts (<1% [score 0], >1% [score 1]) Constitutional symptoms (no [score 0], yes [score 1]) Risk assignment Low (sum 0), intermediate 1 (sum 1), intermediate 2 (sum 2), high (sum 3); median survival: 135, 95, 48, and 27 months, respectively DIPSS prognostic score17
Novel Therapies
Age (<65 years [score 0], >65 years [score 1]) WBC count (<25 10 /L [score 0], >25 10 /L [score 1]) 9
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regarding disease modification require large randomized trials with comprehensive evaluations for long-term side effects for their validation. Two such trials are currently ongoing (MPD RC112, a phase 3 randomized study of HU vs. peginterferon alfa-2a [Pegasys] in newly diagnosed high-risk ET and PV; and phase III study of patients with PV with ropeginterferon a2B vs. hydroxyurea [PROUD-PV]). The latter uses a novel formulation of IFN from AOP Orphan Pharmaceutical is also of interest in this context, with provisional results approximately equivalent to that for other formulations of IFN.25,26 The European Leukemia Net has produced by consensus the criteria to determine a patient’s response. These criteria are designed primarily for clinical trials and include reference to bone marrow morphology and molecular markers.27 The criteria for resistance or intolerance to HU28,29 were also reported by the same group. This phenomenon of HU resistance is important and identifies a group of patients with a poor prognosis,30 who require a change of treatment and for whom novel therapies could be attractive. The options for management in the case of HU resistance that we use includes adjusting the therapeutic targets (eg, to a platelet count of 600 109/L) or switching to an alternative agent either alone or in combination; noneleukemogenic agents such as IFN or anagrelide will be more appropriate in this setting.14
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Data are available supporting the ability of JAK inhibitors to control myeloproliferation in patients with PV and ET. However,
Claire N. Harrison et al Table 3 Recommendations for Therapy in Polycythemia Vera and Essential Thrombocythemia Polycythemia vera All patients: assess for and manage cardiovascular risk factors; screen for disease-related symptoms Treat with low-dose aspirin (unless contraindicated); venesection to target PCV 0.45 High-risk patientsa Age >60 yearsa: hydroxycarbamide or interferon; second line, consider clinical trial or interferonb, if age >75 years, busulfan or 32P Age <60 yearsa: interferonb; second line, consider clinical trial or hydroxyurea or anagrelideb,c Essential thrombocythemia All patients: assess and manage cardiovascular risk factors; screen for disease-related symptoms Treat with low-dose aspirin (unless contraindicated) High-risk patientsa Age >60 yearsa: hydroxycarbamide; second line, consider clinical trial or interferonb, anagrelidec alone or combined; if age >75 years, busulfan or 32P Age <60 yearsa: hydroxycarbamide or interferonb; second line, consider clinical trial; line interferonb, anagrelidec, alone or combined Abbreviations: ET ¼ essential thrombocythemia; PCV ¼ packed cell volume; PV ¼ polycythemia vera. a Treatment recommendations made for high-risk patients only; high-quality, clear evidence for low- or intermediate-risk ET or PV management is unclear. b Not currently licensed for this indication. c Current British guidelines recommend regular monitoring of patients treated with anagrelide for the development of fibrosis.28,42
whether they might prevent thrombosis, affect the probability of accelerated or more aggressive disease such as post-ET or post-PV MF or, indeed, leukemia is unclear. Hexner et al,31 who treated 39 patients (12 ET, 27 PV) with CEP 701 (cephalon) is of note in this aspect. CEP 701 induced responses in splenomegaly, pruritus, and phlebotomy requirements (after 6 months); however, 5 thrombotic events occurred during treatment. In an initial report of the study using ruxolitinib in 39 patients with ET and 34 patients with PV, similar rates of reduction of splenomegaly and symptom scores were reported; however, all patients had a leukocyte count < 10 109/L, and 41% achieved a complete response with a platelet count of < 400 109/L, with no thrombotic events reported.32 That study was recently updated for the patients with PV33; however, no additional data for the ET cohort are available. The PV cohort received ruxolitinib for a median of 152 weeks, and a hematocrit < 45% without phlebotomy was achieved in 97% of the patients by week 24, with only 1 patient requiring phlebotomy after week 4. Among patients with palpable splenomegaly at baseline, 44% and 63%, respectively, achieved nonpalpable spleen measurements at weeks 24 and 144. Clinically meaningful improvements in pruritus, night sweats, and bone pain were observed within 4 weeks of the initiation of therapy and were maintained with continued treatment. Thrombocytopenia and anemia were the most common adverse events. Thrombocytopenia of grade 3 or greater or anemia of grade 3 or greater occurred in 3 patients each (9%; 1 patient had both) and were managed with dose modification. Two large phase III commercially sponsored studies of ruxolitinib have been fully recruited. The results of one of these studies (A randomised phase 3 study of ruxolitinib in high risk PV patients
who are refractory or intolerant of HU [RESPONSE]) was reported at the recent American Society of Clinical Oncology and European Hematology Association meetings. Ruxolitinib was superior to the best available therapy (BAT) for the composite primary endpoint of a 35% spleen size reduction and freedom from venesection. That trial studied a highly selected group of patients who were intolerant or resistant to HU yet had splenomegaly and still required venesection. A confounding aspect was that > 50% of the control arm was treated with HU, perhaps reflecting limited options for these patients. Most interesting was the reduction in thrombosis for the ruxolitinib-treated patients; however, this is an observation and was not a prespecified endpoint, because the follow-up duration was short. This point is made for interest only. Additional updates of this important data are awaited. One academic study of ruxolitinib to treat patients with ET who are resistant or refractory to HU is ongoing.34 Also, HDAC inhibitors, such as vorinostat35 and givinostat,36,37 have been used in patients, although the toxicities with these agents have varied, and with vorinostat led to high discontinuation rates. The oral telomerase inhibitor imetelstat was investigated in ET, demonstrating molecular responses but also significant rates of hematologic toxicity.38 Additional studies of sufficient duration to permit the evaluation of the safety and efficacy of this and other novel agents are needed.
Management of MF Several prognostic scoring systems are available to support the management of MF (Table 2). If the results might alter the management, we perform a karyotype analysis for the patient at diagnosis and for selected patients to monitor the disease course. A likely modification to these scores will incorporate screening for mutations in the following genes: ASXL1, EZH2, IDH1/2, and SRSF2. These genes have been associated with worse survival outcomes and a greater likelihood of transformation to acute leukemia in a recent study.39,40 At present, however, screening for such mutations is not performed in routine practice nor has it been incorporated into the prognostic scores. We perform these screening tests for young patients for whom we might use allogeneic hematopoietic stem cell transplantation (alloHSCT) sooner. Patients lacking mutations in JAK2, CALR, and MPL deserve specific mention. In the past year, these have become designated as a subgroup termed “triple negative.” This subgroup has been shown by several investigators to have a much worse prognosis than the subgroups with the other mutations, in particular the patients with CALR-mutated MF.41 In our practice, we carefully evaluate these patients for the presence of an alternative diagnosis, such as myelodysplasia. Until recently, the therapeutic options for patients with MF, including PMF, post-PV (PPV), and post-essential thrombocythemia (PET) myelofibrosis, consisted of alloHSCT, cytoreductive agents, splenectomy or splenic irradiation, and the treatment of anemia with transfusions, erythropoiesis-stimulating agents, androgens, and immunomodulatory agents. We have generally used these agents in line with what has been suggested in the national guidelines.42,43 Ruxolitinib is now widely used in our clinical practice. It is the first JAK inhibitor to gain approval, which was based on data from the phase III trials known as the Controlled Myelofibrosis Study with Oral JAK Inhibitor
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How We Treat Myeloproliferative Neoplasms
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Treatment (COMFORT) trials. These trials included patients with MF with intermediate 2-risk or high-risk disease (assessed using the IPSS), splenomegaly (5 cm minimum below the costal margin), and platelet count > 100 109/L.44,45 In the COMFORT-I, the patients (n ¼ 309) were randomized 1:1 to ruxolitinib or placebo. In COMFORT-II, the patients (n ¼ 219) were randomized 2:1 to ruxolitinib or the BAT. The primary endpoint of both trials was achieved, with a proportion of patients in the ruxolitinib arms exhibiting a 35% reduction in spleen volume measured on magnetic resonance imaging scans at 24 weeks in the COMFORT-I trial (41.9% ruxolitinib vs. 0.7% placebo; P < .0001) and at 48 weeks in the COMFORT-II trial (28.5% ruxolitinib vs. 0% BAT; P < .0001). These responses in both studies were observed regardless of JAK2 V617F mutation status. The COMFORT trials also demonstrated that, in addition to the profound effects on splenomegaly, ruxolitinib provided statistically significant and very rapid improvements in the patients’ symptoms and quality of life. Increasingly, these trials have provided strong evidence for a survival benefit associated with ruxolitinib therapy, at least in the population of patients matching those from the COMFORT trials. In analyses reported at the American Society of Hematology 2013 annual meeting, the survival benefit across both studies was assessed in the pooled patient population. The effect of crossover was accommodated using the rank-preserving structural failure time (RPSFT) analysis. The hazard ratio (HR) for survival for ruxolitinib versus control (placebo plus BAT) was 0.65 (95% confidence interval [CI], 0.46-0.90; P ¼ .01) and for ruxolitinib versus control (RPSFT-corrected for crossover), it was 0.29 (95% CI, 0.13-0.63).46 A comparison between the Dynamic International Prognostic Scoring System (DIPSS) cohort of patients, and the COMFORT-II cohort demonstrated that the risk of death is halved by introducing ruxolitinib in the treatment of patients with PMF. After adjustment for age > 65 years in a multivariable Cox regression, the HR was still consistent with a survival advantage (HR, 0.54; 95% CI, 0.31-0.93; P ¼ .027).47 The potential reasons for this survival advantage include improved performance status, a reduction of proinflammatory cytokines, improved nutritional status, and better overall physical functioning. The pooled analysis across the COMFORT studies suggested that an incrementally larger spleen volume is associated with worse outcome (for every 5 cm3 of spleen volume, the risk of death increased by 9%). This is the first link between spleen size and prognosis. The survival advantage showed a weak correlation with the degree of spleen response to ruxolitinib only, just as did female sex, higher hemoglobin level, platelet count, and PET or PPV-MF versus PMF. We have yet to incorporate the spleen volume assessment into our clinical practice but act promptly for patients with a significant increase in spleen size. Overall, the results from the COMFORT studies showed that anemia and thrombocytopenia were the most frequently reported adverse events (AEs). Of the grade 3 or greater toxicities in the ruxolitinib-treated patients, the hemoglobin levels reached a nadir at week 12 and then stabilized at an average reduction of about 10 g/L below baseline at week 24. The platelet counts decreased by an average of 40% and remained stable. Anemia and thrombocytopenia rarely led to treatment discontinuation (< 1% of patients in
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any treatment group) and were manageable with dose modifications and/or blood transfusions. We have used these data and will begin therapy at a lower dose in patients with marked anemia or thrombocytopenia. An emergent low level signal is the risk of infection with JAK inhibition. We currently screen all patients for hepatitis B and C and human immunodeficiency virus before starting this agent. Patients with recurrent herpes infections are given prophylaxis with acyclovir or an equivalent agent. A second issue is the phenomenon of “withdrawal syndrome.” Early reports suggested an apparent risk of a severe inflammatory syndrome with a poor outcome after ruxolitinib withdrawal.48 COMFORT-I trial patients recorded symptom scores on a daily basis and demonstrated that the disease-related symptoms had returned to baseline levels within 1 week of discontinuing ruxolitinib. After a 3-year followup period, no consistent pattern of AEs was observed that would suggest a severe inflammatory syndrome after ruxolitinib discontinuation in the COMFORT trials.49,50 Nonetheless, it is important to be aware that the spleen size and symptoms will revert to baseline (or worse if the patient’s disease has progressed during ruxolitinib therapy). Therefore, careful dose tapering or concomitant steroids should be considered when discontinuing ruxolitinib therapy. This is an extremely important facet of patient education with this therapy.
Novel Approaches in the Management of MF Interest is significant in improving patient outcomes using the combination of JAK inhibitors and traditional and/or experimental agents. Combination studies offer patients the opportunity to perhaps avoid anemia or, more challengingly, to move toward ultimately attaining a possible cure or at least deeper or more meaningful responses. Studies assessing the JAK1/2 inhibitor ruxolitinib combined with immunomodulatory drugs, androgens, and DAC, PI3K, and smoothened inhibitors. Preliminary results in a small number of patients have been reported for panobinostat combined with ruxolitinib.12 The combination has been well tolerated, and reductions in spleen size and improvement of MF-related symptoms have been observed, even at doses less than the therapeutic dosage of each agent as monotherapy. Also, an interesting study reported the combination of ruxolitinib with Pegasys in a patient with advanced PV that induced a rapid molecular response and was well tolerated.51 An additional potential combination strategy is to use JAK inhibition to ensure patients are more likely to undergo alloHSCT, a highly attractive and logical approach. Because massive splenomegaly and poor performance status are major barriers to this therapy in MF. This approach is standard practice in our center; however, 2 trials are underway; one of these, the JAK-ALLO (a study of ruxolitinib prior to allogeneic transplant in MF) study in France, recently suggested that risks could exist in using JAK inhibition with ruxolitinib before alloHSCT. A preliminary report highlighted unexpected severe AEs (ie, tumor lysis syndrome in 3 and cardiogenic shock in 3). This should be carefully considered in other prospective trials and clinical practice.52 Recent data suggest that ruxolitinib might be used in the post-transplant setting; however, we have not yet used this approach and regard it as of major interest but experimental.53
Claire N. Harrison et al Conclusion Advances in the field have radically altered the diagnostic and therapeutic approach to the MPN. An additional and much welcomed change has also been the use of the Internet and social media to empower patients, providing them with unprecedented access to state of the art knowledge, expert opinion, and dialogue with each other. This has been fostered within our own center, which has strong links to several such groups, in particular, MPN Voice (available at: www.MPNvoice. org,uk). We hold several dialogues with this and other organizations in the hope of making our services more attuned to the needs of our patients.
Clinical Practice Points The burden of MPN therapy may therefore clearly and
significantly increase in the coming years. The evidence based approach will be needed to produce fair
and balanced guidelines for the management of MPNs and these will increasingly be based upon a personalized approach.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013; 369:2391-405. 2. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369:2379-90. 3. McMullin MF, Bareford D, Campbell P, et al. Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 2005; 130:174-95. 4. Alvarez-Larran A, Ancochea A, Garcia M, et al. WHO-histological criteria for myeloproliferative neoplasms: reproducibility, diagnostic accuracy and correlation with gene mutations and clinical outcomes. Br J Haematol 2014; 166:911-9. 5. Barbui T, Thiele J, Vannucchi AM, Tefferi A. Problems and pitfalls regarding WHO-defined diagnosis of early/prefibrotic primary myelofibrosis versus essential thrombocythemia. Leukemia 2013; 27:1953-8. 6. Wilkins BS, Erber WN, Bareford D, et al. Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes. Blood 2008; 111:60-70. 7. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350:114-24. 8. Harrison C, Barbui T. Aspirin in low-risk essential thrombocythemia, not so simple after all? Leuk Res 2011; 35:286-9. 9. Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978; 2:1219-22. 10. Di Nisio M, Barbui T, Di Gennaro L, et al. The haematocrit and platelet target in polycythemia vera. Br J Haematol 2007; 136:249-59. 11. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 2013; 368:22-33. 12. McMullin MF, Harrison CN, Kiladjian JJ. Treatment target in polycythemia vera. N Engl J Med 2013; 368:1554-5. 13. Campbell PJ, Scott LM, Buck G, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005; 366:1945-53. 14. Harrison CN, Bareford D, Butt N, et al. Guideline for investigation and management of adults and children presenting with a thrombocytosis. Br J Haematol 2010; 149:352-75. 15. Passamonti F. How I treat polycythemia vera. Blood 2012; 120:275-84. 16. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009; 113:2895-901. 17. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010; 115:1703-8. 18. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 2011; 29:392-7.
19. Barbui T, Finazzi G, Carobbio A, et al. Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood 2012; 120:5128-33. 20. Rotunno G, Mannarelli C, Guglielmelli P, et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 2014; 123:1552-5. 21. Tefferi A, Rumi E, Finazzi G, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia 2013; 27:1874-81. 22. Campbell PJ, MacLean C, Beer PA, et al. Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort. Blood 2012; 120:1409-11. 23. Abdulkarim K, Ridell B, Johansson P, Kutti J, Safai-Kutti S, Andreasson B. The impact of peripheral blood values and bone marrow findings on prognosis for patients with essential thrombocythemia and polycythemia vera. Eur J Haematol 2011; 86:148-55. 24. Passamonti F, Rumi E, Pietra D, et al. A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia 2010; 24:1574-9. 25. Gisslinger H, Buxhofer-Ausch V, Greil R, et al. Analysis of molecular responses and chromosomal aberrations in patients with polycythemia vera treated with pegproline-interferon alpha-2b (AOP2014/P1101) in the Peginvera study. Blood 2013; 122:1589. 26. Buxhofer-Ausch V, Thaler J, Schloegl E, et al. Efficacy and safety of AOP2014/ P1101, a novel, investigational mono-pegylated proline-interferon alpha-2b, in patients with polycythemia vera (PV): update on 51 patients from the ongoing phase I/II Peginvera study. Blood 2013; 122:4046. 27. Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood 2013; 121:4778-81. 28. Barosi G, Birgegard G, Finazzi G, et al. A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol 2010; 148:961-3. 29. Barosi G, Besses C, Birgegard G, et al. A unified definition of clinical resistance/ intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group. Leukemia 2007; 21:277-80. 30. Hernandez-Boluda JC, Alvarez-Larran A, Gomez M, et al. Clinical evaluation of the European LeukaemiaNet criteria for clinicohaematological response and resistance/intolerance to hydroxycarbamide in essential thrombocythaemia. Br J Haematol 2011; 152:81-8. 31. Hexner E, Roboz G, Hoffman R, et al. Open-label study of oral CEP-701 (lestaurtinib) in patients with polycythaemia vera or essential thrombocythaemia with JAK2-V617F mutation. Br J Haematol 2014; 164:83-93. 32. Verstovsek S, Passamonti F, Rambaldi A, et al. Durable responses with the JAK1/ JAK2 inhibitor, INCB018424, in patients with polycythemia vera (PV) and essential thrombocythemia (ET) refractory or intolerant to hydroxyurea (HU), November 19, 2010, Abstracts. ASH Annual Meeting 2010; 116:313. 33. Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer 2014; 120:513-20. 34. Verstovsek S, Kiladjian J, Griesshammer M, et al. Results of a prospective, randomized, open-label phase 3 study of ruxolitinib (RUX) in polycythemia vera (PV) patients resistant to or intolerant of hydroxyurea (HU): the RESPONSE trial. J Clin Oncol 2014; 32(suppl; abstr 7026):5s. 35. Andersen CL, McMullin MF, Ejerblad E, et al. A phase II study of vorinostat (MK-0683) in patients with polycythaemia vera and essential thrombocythaemia. Br J Haematol 2013; 162:498-508. 36. Finazzi G, Vannucchi AM, Martinelli V, et al. A phase II study of givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. Br J Haematol 2013; 161:688-94. 37. Rambaldi A, Dellacasa CM, Finazzi G, et al. A pilot study of the histonedeacetylase inhibitor givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol 2010; 150:446-55. 38. Baerlocher GM, Leibundgut EO, Ayran C, et al. Imetelstat rapidly induces and maintains substantial hematologic and molecular responses in patients with essential thrombocythemia (ET) who are refractory or intolerant to prior therapy: preliminary phase II results. ASH Annual Meeting 2012; 120:179, Abstracts, November 16, 2012. 39. Biamonte F, Pieri L, Rotunno G, et al. Impact of prognostically detrimental mutations (ASXL1, EZH2, SRSF2, IDH1/2) on outcomes in patients with myelofibrosis treated with ruxolitinib in COMFORT-II. Blood 2013; 122:107. 40. Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013; 27:1861-9. 41. Tefferi A, Guglielmelli P, Lasho TL, et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia 2014; 28:1494-500. 42. Reilly JT, McMullin MF, Beer PA, et al. Use of JAK inhibitors in the management of myelofibrosis: a revision of the British Committee for Standards in Haematology Guidelines for Investigation and Management of Myelofibrosis 2012. Br J Haematol 2014; 167:418-20. 43. Reilly JT, McMullin MF, Beer PA, et al. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol 2012; 158:453-71. 44. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366:799-807.
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How We Treat Myeloproliferative Neoplasms 45. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012; 366:787-98. 46. Hagop K, Kiladjian J-J, Gotlib J, et al. A pooled overall survival analysis of the COMFORT studies: 2 randomized phase 3 trials of ruxolitinib for the treatment of myelofibrosis. Blood 2013; 122:2820. 47. Passamonti F, Maffioli M, Cervantes F, et al. Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT2 cohorts. Blood 2014; 123:1833-5. 48. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011; 86:1188-91. 49. Verstovsek S, Gotlib J, Levy RS, et al. Long-term outcomes of ruxolitinib therapy in patients with myelofibrosis: 3-year update from COMFORT-I. Blood 2013; 122:396.
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50. 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; 122:4047-53. 51. Bjørn ME, de Stricker K, Kjær L, Ellemann K. Rapid clearance of JAK2 V617F allele burden in patient with advanced polycythemia vera (PV) during combination therapy with ruxolitinib and peg-interferon alpha-2a. Blood 2013; 122:5241. 52. Francois S, Huynh A, Cassinat B, et al. Ruxolitinib before allogeneic hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis: a preliminary descriptive report of the JAK ALLO study, a phase II trial sponsored by Goelams-FIM in collaboration with the SFGMTC. Blood 2013; 122:306. 53. Spoerl S, Mathew NR, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014; 123:3832-42.
How We Treat Myeloproliferative Neoplasms Claire N. Harrison,1 Donal P. McLornan,1 Yvonne A. Francis,1 Claire Woodley,1 Lizzie Provis,2 Deepti H. Radia1 Abstract The phildelphia-negative myeloproliferative neoplasms were defined based upon careful clinical review and an analysis almost a century ago. Increasingly this field is becoming more complex in terms of diagnostic information, treatment options have however been following behind. Here we present our approach to the management of these entities. The present report focuses on management strategies for the myeloproliferative neoplasm according to the structure and processes we use within our center, a large tertiary unit in central London. The standard procedures for achieving an accurate diagnosis and risk stratification and therapeutic strategies for these diseases with a detailed focus on contentious areas are discussed. In the 9 years after the description of the Janus kinase 2 mutation, this field has altered quite radically in several aspects. For example, a new therapeutic paradigm exists, especially for myelofibrosis. We share how our unit has adapted to these changes. Clinical Lymphoma, Myeloma & Leukemia, Vol. 15, No. S1, S19-26 ª 2015 Elsevier Inc. All rights reserved. Keywords: Erythrocytosis, Myelofibrosis, Polycythemia, Thrombocythemia, Thrombocytosis
Achieving an Accurate Diagnosis The recent advances in our repertoire of molecular tests and in our knowledge of the natural history of myeloproliferative neoplasms (MPNs) means that our diagnostic approach has become increasingly laboratory based and involves several disciplines, including cellular pathology, blood film morphology, molecular biology, and cytogenetics. The implication is that in clinical practice, the hematologist must be able to synthesize these data and accurately communicate the clinical scenario and questions. Unless this conversation occurs, the risk of inaccurate diagnosis and overinterpretation of a single piece of the diagnostic puzzle will be unacceptably high. An example of the flow process that we follow for classic MPN is shown in Figure 1. To achieve a diagnosis of MPN, the exclusion of underlying reactive conditions has been simplified by the expanding repertoire of molecular abnormalities, which has been exemplified by the recent description of calreticulin (CALR) mutations.1,2 These secondary causes are listed in a footnote to Figure 1. Having excluded a reactive disorder, it would be ideal to use as much diagnostic information as possible to be able to assign 1
Department of Haematology Pharmacy Service Guy’s and St. Thomas’ National Health Service Foundation Trust, London, United Kingdom 2
Submitted: Dec 6, 2014; Revised: Feb 6, 2015; Accepted: Feb 26, 2015; Epub: Mar 3, 2015 Address for correspondence: Claire N. Harrison, DM, FRCP, FRCPath, Department of Haematology, Guy’s and St. Thomas’ Foundation Trust, London SE1 9RT, UK E-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2015.02.032
the patient to a particular category of MPN. Although the MPN unclassified category exists, the information to make robust management recommendations for this entity is insufficient. It is important to note that although the molecular abnormalities identified in MPN likely define a neoplastic process, they are not specific to the subtype of MPN. Although the recent iterations of the World Health Organization diagnostic criteria are welcome, in some areas, difficulty and controversy remain. One example is in discriminating between Janus kinase 2 (JAK2) Val617Phe (V617F)-positive essential thrombocythemia (ET) and polycythemia vera (PV). This is clearly an important issue owing to the different management strategies for these diseases and the importance of controlling the hematocrit in PV. A recent report from a well-respected Spanish group illustrates these difficulties perfectly and highlights the British Committee for Standards in Haematology diagnostic criteria of PV3 (Table 1), as the most sensitive and specific criteria.4 The report from Alvarez-Larran et al4 deserves additional mention because of their work to evaluate the diagnostic accuracy of the histologic features and to assess its correlation with the presence of mutations and clinical outcomes. Two pathologists reviewed the bone marrow biopsies corresponding to 211 patients with MPN. They reported that the specificity of the histologic findings was 100%, 98.5%, and 98% for PV, ET, and primary myelofibrosis (PMF), respectively. However, the sensitivity of the histologic diagnosis was low for PV and ET (32.5% and 54%, respectively) and acceptable for PMF (75%). Of 146 patients with clinical ET, 13 (9%) were diagnosed with prefibrotic PMF. Regarding the issues with
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How We Treat Myeloproliferative Neoplasms Figure 1 Algorithm for Diagnosis of Myeloproliferative Neoplasms
Abbreviations: CALR ¼ calreticulin; CML ¼ chronic myelogenous leukemia; EPO ¼ erythropoietin; ET ¼ essential thrombocythemia; LDH ¼ lactate dehydrogenase; MDS ¼ myelodysplastic syndrome; PMF ¼ primary myelofibrosis; PV ¼ polycythemia vera.
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discriminating PV from ET, other investigators have also suggested using a hematocrit level close to that recommended by the British Committee for Standards in Haematology, because it improves the diagnostic accuracy.4 One of the major difficulties inherent in discriminating between ET and PV is the limited availability of red blood cell mass testing. Alvarez-Larran et al4 was also one of several groups to highlight that the entity of prefibrotic MF remains controversial, and additional international collaboration and educational efforts are widely acknowledged to be required.5,6 Specifically, the issues concerning the discrimination of ET and prefibrotic MF revolve around the reproducibility of the specific histologic features, predominantly megakaryocyte abnormalities, which enable discrimination of these entities. The incorporation of clinical criteria (ie, anemia, leukoerythroblastic blood film, and splenomegaly) are important. The major clinical differences in outcomes and the management strategy for patients with ET (the most indolent MPN) compared with those with PMF (the most aggressive MPN) highlight the importance in achieving an accurate diagnosis. To achieve as accurate a diagnosis as possible, our team have used the document “Improving Outcomes Guidance” mandated in the United Kingdom (available at: www.nice.org.uk/Guidance/ CSGHO) in facilitating a multidisciplinary conversation, which is hosted by a video conference across several different hospital sites and involving all the contributing disciplines. This also enables us to perform a coordinated management decision and to discuss the options potentially available at different sites (eg, clinical trials). Patients with refractory or progressive disease can also be discussed at this meeting. Patients with MPN, chronic and acute myeloid
Clinical Lymphoma, Myeloma & Leukemia June 2015
leukemia, myelodysplasia, and other bone marrow failure disorders are discussed in a myeloid-specific setting. Other general management approaches are available. The National Institute for Health and Care Excellence guidance also incorporates the role of clinical nurse specialist in the management of chronic conditions such as MPN. This role is a cornerstone of management in our service, because the clinical nurse specialist is the key point of contact, information, and support for the patients and their families. In our service, many stable patients are reviewed by the clinical nurse specialist by telephone interview or in separate clinics, with a consultant or medical review annually. The role is also critical because of the flux of staff that is often seen in at inner city tertiary service to provide continuity for patients beyond that of the consultant physician and education for the nursing and other staff. This infrastructure is also critical to incorporating symptom assessment for these patients, because it is an increasingly important aspect of care. In addition to this role, we also have a prescribing pharmacist present in the clinics available to assess and provide prescriptions for stable patients and as a source of expert pharmacy advice for the clinicians.
Management of ET and PV The treatment of those with ET and PV is considered jointly in this section, although clearly differences exist in the natural history and clinical manifestations. These patients will undoubtedly benefit from aggressive risk management for vascular disease. We use lowdose aspirin for these groups of patients. However, although this is evidence-based medicine for PV in accordance with the findings from the European collaboration on low-dose aspirin in polycythemia vera (ECLAP) study,7 aspirin remains controversial for
Claire N. Harrison et al Table 1 Diagnostic Criteria for Polycythemia Vera, as Recommended in the British Committee for Standards in Haematology Guidelines JAK2þ polycythemia vera A1—High hematocrit (>0.52 in men, >0.48 in women) OR elevated red blood cell mass (>25% above predicted)a A2—Mutation in JAK2 The diagnosis requires both criteria to be present JAK2 polycythemia vera A1—Elevated red blood cell mass (>25% above predicted) OR hematocrit >0.60 in men, >0.56 in women A2—Absence of mutation in JAK2
and thus whom to treat. However, although, as discussed earlier, the red blood cell mass test is not widely available. The discovery of the CALR mutations might ultimately result in the field adopting different treatment schedules for patients with CALR-mutated ET compared with JAK2-mutated ET. Increasing evidence has shown that the clinical behavior of patients with a CALR mutation is different from that of those with a JAK2 mutation. At present, no evidence is available for a different management strategy nor is any evidence available to support treating patients with JAK2 exon 12-mutated PV differently from those with JAK2 V617F-mutated PV.
A3—No cause of secondary erythrocytosis
Cytoreductive Therapy for PV and ET
A4—Palpable splenomegaly
When and Who
A5—Presence of an acquired genetic abnormality (excluding BCR-ABL) in hematopoietic cells
Cytoreductive therapy for ET and PV is currently used to reduce the risk of thrombosis and control disease-related symptoms. Ideally, such therapy should reduce the risk of progression to MF. However, cytoreductive therapies have not currently been shown to achieve this. Risk stratification is widely used, and a number of such risk stratification schemes have been proposed14-18 (Table 2). These stratification schemes are based on the risk of thrombosis. For patients with ET, the recently described International Prognostic Score System [IPSS] for (ET)19 will recategorize a significant number of patients previously considered high and low risk and generates a large intermediate-risk category for which no treatment algorithm has been tested. We do not currently use this risk score. Also, the intermediate-risk patient group in ET is controversial, with the group variably defined. Data from the ongoing PT-1 trials will describe the natural history of and response to aspirin versus aspirin plus hydroxycarbamide (HU) for an intermediate-risk group. The risk group was defined by the investigators as patient age 40 to 60 years without high risk (age < 60 years, no previous thrombosis, platelets < 1500 109/L) or cardiovascular risk factors. For patients with ET, the presence of the CALR mutations seems to correlate with a better prognosis and lower risk of thrombosis2,20; however, this has not yet been incorporated into risk stratification schemes. Recent publications have addressed the lack of clear data regarding the definition of high-risk (for thrombosis) PV.21 The predominant factors are age, previous thrombosis, vascular risk factors. The current additional candidates include the leukocyte count,21,22 reticulin grade,6,23,24 and JAK2V617F allele burden.24 The effect of conventional risk factors for atherosclerosis has been assessed in MPN with variable results. Also, whether these risk factors should contribute to risk group allocation for patients with ET and PV, especially if they are well-controlled, is unclear. Communication with the patient and family physician is critical in managing these aspects of disease.
B1—Thrombocytosis (platelet count >450 109/L) B2—Neutrophil leukocytosis (neutrophil count >10 109/L in nonsmokers; >12.5 109/L in smokers) B3—Radiologic evidence of splenomegaly B4—Endogenous erythroid colonies or low serum erythropoietin Diagnosis requires A1 þ A2 þ A3 þ either 1 additional A or 2 B criteria Abbreviations: JAK2 ¼ Janus kinase 2; MPN ¼ myeloproliferative neoplasm. a Dual pathologic features (coexistent secondary erythrocytosis or relative erythrocytosis) will rarely be present in patients with JAK2þ MPN; in this situation, it would be prudent to reduce the hematocrit to the same target as for polycythemia vera.
patients with in ET.8 In our clinical practice, we generally use lowdose aspirin for all patients, except for those with bleeding and other clear contraindications, for whom we might consider the use of alternative antiplatelet agents such as clopidogrel. If the patient has difficulty in tolerating the aspirin (eg, because of an increase in minor bleeding), for particular groups of patients for whom the evidence base for the use of aspirin is less well defined, we withdraw the therapy. These patients include those with JAK2 V617F lowrisk ET and patients with ET lacking cardiovascular risk factors. Bleeding is a particular risk for patients with very high platelet counts but can occur with more modestly elevated platelet counts. Although we do not regularly measure our patient’s blood pressure and cholesterol or glucose levels, we do encourage this dialogue with their family physician in primary care. The target for venesection in PV (hematocrit or packed cell volume 0.45) has been controversial. This was based on an previous study from our center,9 although the findings from the ECLAP study appeared to conflict.10 The findings from the recently reported CYTOreductive Therapy in Polycythemia Vera (CYTO-PV) study strongly support the control of the hematocrit level to 0.45, although importantly, differences were found in the leukocyte counts of the 2 arms of that study that might have accounted for some of the 44% reduction in thrombosis.11,12 Just as was first identified by analyzing the Primary Thrombocythaemia-1 trial (PT1) cohort of patients, considerable overlap can exist between JAK2V617Fþ ET and PV.13 In clinical practice, the question of whether to control the hematocrit of a patient with a diagnosis of ET who has the JAK2V617F mutation and whose hematocrit is > 0.45 but is within the normal range is unclear. We would use a red blood cell mass test in this situation to identify “masked PV”
Which Agent and What Target? A better evidence base would be desirable. The current published recommendations are summarized in Table 3. Generally, interferon (IFN) and hydroxycarbamide (hydroxyurea or HU) form a mainstay of therapy, and interest is increasing in IFN therapy, especially pegylated forms, to treat these conditions with a disease-moderating effect. However, IFN is not widely available. Also, statements
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How We Treat Myeloproliferative Neoplasms Table 2 Risk Stratification for Thrombosis in PV and ET and Risk Stratification for PMF
Table 2 Continued Hemoglobin (<10 g/dL [score 2])
Polycythemia vera
Peripheral blasts (<1% [score 0], >1% [score 1])
Conventional risk stratificationa
Constitutional symptoms (no [score 0], yes [score 1])
High-risk PV: any one of the following factors Age >60 years Previous documented thrombosis, erythromelalgia (if refractory to aspirin) Platelets >1000 109/Lb Diabetes or hypertension requiring pharmacologic therapyb
Risk assignment: low (sum 0); intermediate 1 (sum 1 or 2); intermediate 2 (sum 3 or 4); high (sum 5 or 6); median survival: not reached, 14.2, 4, and 1.5 years, respectively DIPSS plus prognostic score18 Possible points from DIPSS: 0-3; DIPSS prognostic group points: low risk, 0; intermediate 1, 1; intermediate 2, 2; high risk, 3 To the DIPSS prognostic group, add 1 point each for
Low-risk PV
Platelet count <100 109/L
None of the above risk factors Significant (ie, >5 cm below costal margin on palpation) or symptomatic (pain, early satiety) splenomegaly might be an indication for treatment, rather than a risk factor for thrombosis per seb Essential thrombocythemia Conventional risk stratificationc High-risk ET: any one of the following factors Age >60 years Platelet count >1500 109/L Previous thrombosis, erythromelalgia (if refractory to aspirin) Previous hemorrhage related to ET Diabetes or hypertension requiring pharmacologic therapya Low-risk ETd Age <40 years None of the above risk factors Intermediate-risk ETd
Red blood cell transfusion required Unfavorable karyotypeg Risk assignment by number of points: low (sum 0); intermediate 1 (sum 1); intermediate 2 (sum 2 or 3); high (sum 4 to 6); corresponding median survival estimate: 185, 78, 35 and 16 months, respectively Abbreviations: DIPSS ¼ Dynamic International Prognostic Scoring System; ET ¼ essential thrombocythemia; IPSS ¼ International Prognostic Scoring System; PMF ¼ primary myelofibrosis; PV ¼ polycythemia vera; WBC ¼ white blood cell. a Predicts for thrombosis but has not been tested prospectively. b These risk factors are more controversial and have not been fully agreed on (eg the degree of leukocytosis or grade of reticulin). c Predicts for thrombosis. d These categories are contentious and some recommend low and high risk only or classify individuals with cardiovascular risk factors as intermediate risk. e Predicts overall survival but not the development of postessential thrombocythemia myelofibrosis. f IPSS for ET for thrombosis also available, although in our practice we do not use this score. g Unfavorable karyotype includes þ8, 7/7q, i(17q), inv(3), 5/5q, 12p11q23 rearrangements and complex karyotypes.
Age 40-60 years None of the above markers for high-risk disease International Prognostic Score for ETe (a novel risk stratification based on histopathologically defined ETf) Risk factors Age 60 years (2 points) Leukocyte count 11 109/L (1 point) Previous thrombosis (1 point) Risk categories Low (sum ¼ 0) Intermediate (sum ¼ 1 or 2) High (sum ¼ 3 or 4) Risk stratification for PMF IPSS prognostic score16 Prognostic variable Age (<65 years [score 0], >65 years [score 1]) WBC count (<25 109/L [score 0], >25 109/L [score 1]) Hemoglobin (>10 g/dL [score 0], <10 g/dL [score 1]) Peripheral blasts (<1% [score 0], >1% [score 1]) Constitutional symptoms (no [score 0], yes [score 1]) Risk assignment Low (sum 0), intermediate 1 (sum 1), intermediate 2 (sum 2), high (sum 3); median survival: 135, 95, 48, and 27 months, respectively DIPSS prognostic score17
Novel Therapies
Age (<65 years [score 0], >65 years [score 1]) WBC count (<25 10 /L [score 0], >25 10 /L [score 1]) 9
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regarding disease modification require large randomized trials with comprehensive evaluations for long-term side effects for their validation. Two such trials are currently ongoing (MPD RC112, a phase 3 randomized study of HU vs. peginterferon alfa-2a [Pegasys] in newly diagnosed high-risk ET and PV; and phase III study of patients with PV with ropeginterferon a2B vs. hydroxyurea [PROUD-PV]). The latter uses a novel formulation of IFN from AOP Orphan Pharmaceutical is also of interest in this context, with provisional results approximately equivalent to that for other formulations of IFN.25,26 The European Leukemia Net has produced by consensus the criteria to determine a patient’s response. These criteria are designed primarily for clinical trials and include reference to bone marrow morphology and molecular markers.27 The criteria for resistance or intolerance to HU28,29 were also reported by the same group. This phenomenon of HU resistance is important and identifies a group of patients with a poor prognosis,30 who require a change of treatment and for whom novel therapies could be attractive. The options for management in the case of HU resistance that we use includes adjusting the therapeutic targets (eg, to a platelet count of 600 109/L) or switching to an alternative agent either alone or in combination; noneleukemogenic agents such as IFN or anagrelide will be more appropriate in this setting.14
9
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Data are available supporting the ability of JAK inhibitors to control myeloproliferation in patients with PV and ET. However,
Claire N. Harrison et al Table 3 Recommendations for Therapy in Polycythemia Vera and Essential Thrombocythemia Polycythemia vera All patients: assess for and manage cardiovascular risk factors; screen for disease-related symptoms Treat with low-dose aspirin (unless contraindicated); venesection to target PCV 0.45 High-risk patientsa Age >60 yearsa: hydroxycarbamide or interferon; second line, consider clinical trial or interferonb, if age >75 years, busulfan or 32P Age <60 yearsa: interferonb; second line, consider clinical trial or hydroxyurea or anagrelideb,c Essential thrombocythemia All patients: assess and manage cardiovascular risk factors; screen for disease-related symptoms Treat with low-dose aspirin (unless contraindicated) High-risk patientsa Age >60 yearsa: hydroxycarbamide; second line, consider clinical trial or interferonb, anagrelidec alone or combined; if age >75 years, busulfan or 32P Age <60 yearsa: hydroxycarbamide or interferonb; second line, consider clinical trial; line interferonb, anagrelidec, alone or combined Abbreviations: ET ¼ essential thrombocythemia; PCV ¼ packed cell volume; PV ¼ polycythemia vera. a Treatment recommendations made for high-risk patients only; high-quality, clear evidence for low- or intermediate-risk ET or PV management is unclear. b Not currently licensed for this indication. c Current British guidelines recommend regular monitoring of patients treated with anagrelide for the development of fibrosis.28,42
whether they might prevent thrombosis, affect the probability of accelerated or more aggressive disease such as post-ET or post-PV MF or, indeed, leukemia is unclear. Hexner et al,31 who treated 39 patients (12 ET, 27 PV) with CEP 701 (cephalon) is of note in this aspect. CEP 701 induced responses in splenomegaly, pruritus, and phlebotomy requirements (after 6 months); however, 5 thrombotic events occurred during treatment. In an initial report of the study using ruxolitinib in 39 patients with ET and 34 patients with PV, similar rates of reduction of splenomegaly and symptom scores were reported; however, all patients had a leukocyte count < 10 109/L, and 41% achieved a complete response with a platelet count of < 400 109/L, with no thrombotic events reported.32 That study was recently updated for the patients with PV33; however, no additional data for the ET cohort are available. The PV cohort received ruxolitinib for a median of 152 weeks, and a hematocrit < 45% without phlebotomy was achieved in 97% of the patients by week 24, with only 1 patient requiring phlebotomy after week 4. Among patients with palpable splenomegaly at baseline, 44% and 63%, respectively, achieved nonpalpable spleen measurements at weeks 24 and 144. Clinically meaningful improvements in pruritus, night sweats, and bone pain were observed within 4 weeks of the initiation of therapy and were maintained with continued treatment. Thrombocytopenia and anemia were the most common adverse events. Thrombocytopenia of grade 3 or greater or anemia of grade 3 or greater occurred in 3 patients each (9%; 1 patient had both) and were managed with dose modification. Two large phase III commercially sponsored studies of ruxolitinib have been fully recruited. The results of one of these studies (A randomised phase 3 study of ruxolitinib in high risk PV patients
who are refractory or intolerant of HU [RESPONSE]) was reported at the recent American Society of Clinical Oncology and European Hematology Association meetings. Ruxolitinib was superior to the best available therapy (BAT) for the composite primary endpoint of a 35% spleen size reduction and freedom from venesection. That trial studied a highly selected group of patients who were intolerant or resistant to HU yet had splenomegaly and still required venesection. A confounding aspect was that > 50% of the control arm was treated with HU, perhaps reflecting limited options for these patients. Most interesting was the reduction in thrombosis for the ruxolitinib-treated patients; however, this is an observation and was not a prespecified endpoint, because the follow-up duration was short. This point is made for interest only. Additional updates of this important data are awaited. One academic study of ruxolitinib to treat patients with ET who are resistant or refractory to HU is ongoing.34 Also, HDAC inhibitors, such as vorinostat35 and givinostat,36,37 have been used in patients, although the toxicities with these agents have varied, and with vorinostat led to high discontinuation rates. The oral telomerase inhibitor imetelstat was investigated in ET, demonstrating molecular responses but also significant rates of hematologic toxicity.38 Additional studies of sufficient duration to permit the evaluation of the safety and efficacy of this and other novel agents are needed.
Management of MF Several prognostic scoring systems are available to support the management of MF (Table 2). If the results might alter the management, we perform a karyotype analysis for the patient at diagnosis and for selected patients to monitor the disease course. A likely modification to these scores will incorporate screening for mutations in the following genes: ASXL1, EZH2, IDH1/2, and SRSF2. These genes have been associated with worse survival outcomes and a greater likelihood of transformation to acute leukemia in a recent study.39,40 At present, however, screening for such mutations is not performed in routine practice nor has it been incorporated into the prognostic scores. We perform these screening tests for young patients for whom we might use allogeneic hematopoietic stem cell transplantation (alloHSCT) sooner. Patients lacking mutations in JAK2, CALR, and MPL deserve specific mention. In the past year, these have become designated as a subgroup termed “triple negative.” This subgroup has been shown by several investigators to have a much worse prognosis than the subgroups with the other mutations, in particular the patients with CALR-mutated MF.41 In our practice, we carefully evaluate these patients for the presence of an alternative diagnosis, such as myelodysplasia. Until recently, the therapeutic options for patients with MF, including PMF, post-PV (PPV), and post-essential thrombocythemia (PET) myelofibrosis, consisted of alloHSCT, cytoreductive agents, splenectomy or splenic irradiation, and the treatment of anemia with transfusions, erythropoiesis-stimulating agents, androgens, and immunomodulatory agents. We have generally used these agents in line with what has been suggested in the national guidelines.42,43 Ruxolitinib is now widely used in our clinical practice. It is the first JAK inhibitor to gain approval, which was based on data from the phase III trials known as the Controlled Myelofibrosis Study with Oral JAK Inhibitor
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Treatment (COMFORT) trials. These trials included patients with MF with intermediate 2-risk or high-risk disease (assessed using the IPSS), splenomegaly (5 cm minimum below the costal margin), and platelet count > 100 109/L.44,45 In the COMFORT-I, the patients (n ¼ 309) were randomized 1:1 to ruxolitinib or placebo. In COMFORT-II, the patients (n ¼ 219) were randomized 2:1 to ruxolitinib or the BAT. The primary endpoint of both trials was achieved, with a proportion of patients in the ruxolitinib arms exhibiting a 35% reduction in spleen volume measured on magnetic resonance imaging scans at 24 weeks in the COMFORT-I trial (41.9% ruxolitinib vs. 0.7% placebo; P < .0001) and at 48 weeks in the COMFORT-II trial (28.5% ruxolitinib vs. 0% BAT; P < .0001). These responses in both studies were observed regardless of JAK2 V617F mutation status. The COMFORT trials also demonstrated that, in addition to the profound effects on splenomegaly, ruxolitinib provided statistically significant and very rapid improvements in the patients’ symptoms and quality of life. Increasingly, these trials have provided strong evidence for a survival benefit associated with ruxolitinib therapy, at least in the population of patients matching those from the COMFORT trials. In analyses reported at the American Society of Hematology 2013 annual meeting, the survival benefit across both studies was assessed in the pooled patient population. The effect of crossover was accommodated using the rank-preserving structural failure time (RPSFT) analysis. The hazard ratio (HR) for survival for ruxolitinib versus control (placebo plus BAT) was 0.65 (95% confidence interval [CI], 0.46-0.90; P ¼ .01) and for ruxolitinib versus control (RPSFT-corrected for crossover), it was 0.29 (95% CI, 0.13-0.63).46 A comparison between the Dynamic International Prognostic Scoring System (DIPSS) cohort of patients, and the COMFORT-II cohort demonstrated that the risk of death is halved by introducing ruxolitinib in the treatment of patients with PMF. After adjustment for age > 65 years in a multivariable Cox regression, the HR was still consistent with a survival advantage (HR, 0.54; 95% CI, 0.31-0.93; P ¼ .027).47 The potential reasons for this survival advantage include improved performance status, a reduction of proinflammatory cytokines, improved nutritional status, and better overall physical functioning. The pooled analysis across the COMFORT studies suggested that an incrementally larger spleen volume is associated with worse outcome (for every 5 cm3 of spleen volume, the risk of death increased by 9%). This is the first link between spleen size and prognosis. The survival advantage showed a weak correlation with the degree of spleen response to ruxolitinib only, just as did female sex, higher hemoglobin level, platelet count, and PET or PPV-MF versus PMF. We have yet to incorporate the spleen volume assessment into our clinical practice but act promptly for patients with a significant increase in spleen size. Overall, the results from the COMFORT studies showed that anemia and thrombocytopenia were the most frequently reported adverse events (AEs). Of the grade 3 or greater toxicities in the ruxolitinib-treated patients, the hemoglobin levels reached a nadir at week 12 and then stabilized at an average reduction of about 10 g/L below baseline at week 24. The platelet counts decreased by an average of 40% and remained stable. Anemia and thrombocytopenia rarely led to treatment discontinuation (< 1% of patients in
Clinical Lymphoma, Myeloma & Leukemia June 2015
any treatment group) and were manageable with dose modifications and/or blood transfusions. We have used these data and will begin therapy at a lower dose in patients with marked anemia or thrombocytopenia. An emergent low level signal is the risk of infection with JAK inhibition. We currently screen all patients for hepatitis B and C and human immunodeficiency virus before starting this agent. Patients with recurrent herpes infections are given prophylaxis with acyclovir or an equivalent agent. A second issue is the phenomenon of “withdrawal syndrome.” Early reports suggested an apparent risk of a severe inflammatory syndrome with a poor outcome after ruxolitinib withdrawal.48 COMFORT-I trial patients recorded symptom scores on a daily basis and demonstrated that the disease-related symptoms had returned to baseline levels within 1 week of discontinuing ruxolitinib. After a 3-year followup period, no consistent pattern of AEs was observed that would suggest a severe inflammatory syndrome after ruxolitinib discontinuation in the COMFORT trials.49,50 Nonetheless, it is important to be aware that the spleen size and symptoms will revert to baseline (or worse if the patient’s disease has progressed during ruxolitinib therapy). Therefore, careful dose tapering or concomitant steroids should be considered when discontinuing ruxolitinib therapy. This is an extremely important facet of patient education with this therapy.
Novel Approaches in the Management of MF Interest is significant in improving patient outcomes using the combination of JAK inhibitors and traditional and/or experimental agents. Combination studies offer patients the opportunity to perhaps avoid anemia or, more challengingly, to move toward ultimately attaining a possible cure or at least deeper or more meaningful responses. Studies assessing the JAK1/2 inhibitor ruxolitinib combined with immunomodulatory drugs, androgens, and DAC, PI3K, and smoothened inhibitors. Preliminary results in a small number of patients have been reported for panobinostat combined with ruxolitinib.12 The combination has been well tolerated, and reductions in spleen size and improvement of MF-related symptoms have been observed, even at doses less than the therapeutic dosage of each agent as monotherapy. Also, an interesting study reported the combination of ruxolitinib with Pegasys in a patient with advanced PV that induced a rapid molecular response and was well tolerated.51 An additional potential combination strategy is to use JAK inhibition to ensure patients are more likely to undergo alloHSCT, a highly attractive and logical approach. Because massive splenomegaly and poor performance status are major barriers to this therapy in MF. This approach is standard practice in our center; however, 2 trials are underway; one of these, the JAK-ALLO (a study of ruxolitinib prior to allogeneic transplant in MF) study in France, recently suggested that risks could exist in using JAK inhibition with ruxolitinib before alloHSCT. A preliminary report highlighted unexpected severe AEs (ie, tumor lysis syndrome in 3 and cardiogenic shock in 3). This should be carefully considered in other prospective trials and clinical practice.52 Recent data suggest that ruxolitinib might be used in the post-transplant setting; however, we have not yet used this approach and regard it as of major interest but experimental.53
Claire N. Harrison et al Conclusion Advances in the field have radically altered the diagnostic and therapeutic approach to the MPN. An additional and much welcomed change has also been the use of the Internet and social media to empower patients, providing them with unprecedented access to state of the art knowledge, expert opinion, and dialogue with each other. This has been fostered within our own center, which has strong links to several such groups, in particular, MPN Voice (available at: www.MPNvoice. org,uk). We hold several dialogues with this and other organizations in the hope of making our services more attuned to the needs of our patients.
Clinical Practice Points The burden of MPN therapy may therefore clearly and
significantly increase in the coming years. The evidence based approach will be needed to produce fair
and balanced guidelines for the management of MPNs and these will increasingly be based upon a personalized approach.
Disclosure The authors have stated that they have no conflicts of interest.
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