Doctor's Brochure 2004
Myeloproliferative Disorders: MPDs
Essential Thrombocythemia: ET
Polycythemia Vera: PV
Chronic Idiopathic Myelofibrosis: IMF
Jan Jacques Michiels
Goodheart Institute Rotterdam, MPD Center Europe
Department of Hematology, Antwerp University Hospital
Hans Michael Kvasnicka
and
Juergen Thiele
Institute of Pathology, University of Cologne
This Doctor's MPD Brochure provides basic information for MPD patients and their
doctors to better find their way in order to improve proper diagnosis and
manage-ment of the Ph
1-MPDs: ET, PV and IMF
MPD Stichting NL
MPD Foundation NL
Grondelsloot 61
2724 BT Zoetermeer
Phone 31 79 3432423
Website: www.MPD-Stichting.nl
page
Introduction . . . .2
Definition of chronic myeloproliferative disorders (MPDs) . . . .2
Tools to diagnose, characterize and stage MPDs . . . .3
Thrombocytosis in various MPDs . . . .3
Diagnostic criteria of essential thrombocythemia (ET) . . . .5
Morphological features of ET . . . .6
Presenting features of ET . . . .8
The paradox of thrombotic and bleeding complications in ET . . . .9
Risk stratification and treatment of ET patients . . . .9
Platelet lowering agents in ET . . . .12
Diagnostic criteria of polycythemia rubra (PV) . . . .13
Morphological features PV . . . .16
Signs and symptoms of PV . . . .17
The microvascular syndrome of thrombocytosis . . . .17
Hypervolemic symptoms . . . .17
Vascular complications . . . .17
Treatment of PV patients . . . .18
Phlebotomy and low dose aspirin . . . .18
Hydroxyurea . . . .19
Interferon-alpha . . . .20
First and second treatment options in PV . . . .21
Diagnostic criteria of prefibrotic and (classical) chronic idiopathic . . . .21
myelofibrosis (IMF) or myelofibrosis with myeloid metaplasia (MMM)/agnogenic myeloid metaplasia (AMM) Morphological features - problems to recognize prefibrotic/early IMF . . . .22
Clinical impact of prefibrotic early IMF . . . .24
Cytogenetic findings in IMF . . . .25
Signs and symptoms of classical IMF . . . .26
Prognosis in IMF . . . .26
Management of IMF patients . . . .28
Therapy of thrombocytosis . . . .29
Management of symptomatic anemia . . . .29
Treatment of splenomegaly . . . .30
References . . . .31
Chronic Ph1- negative Myeloproliferative Disorders (MPDs):
A concise update
Jan Jacques Michiels
Goodheart Institute Rotterdam, MPD Center Europe Department of Hematology, Antwerp University Hospital
Hans Michael Kvasnicka
Institute of Pathology, University of Cologne
Juergen Thiele
Introduction
About thirty years ago the philosopher Ivan Illich accused the medical establishment of being a major threat to health [91]. He argued that it was responsible for a growing epidemic of iatro-genic morbidity, and referred to this as a form of medical nemesis. Today he would doubtless express his opinion that little has changed, and, as far as the Philadelphia chromosome neg-ative (Ph1-) chronic myeloproliferative disorders (MPDs) are concerned, he would be right. It is evident that clinicians and hematopathologists may often make matters confounding and worse in the way they manage this condition by lack of available knowledge and ill-defined criteria for the diagnosis of patients presenting with essential thrombocythemia (ET), poly-cythemia vera (PV) and chronic idiopathic myelofibrosis (IMF). In this context doctors may also offer self-defensive and over-cautious advice on risk management, creating a desperate state in some MPD patients by applying under - and over - treatment regimens and even improper medical therapeutic strategies. Patients are still too often taken through despair, hope, confusion, and back to an overall desperate mood because they do not understand or do not get the proper information or what an MPD really implies or what is going to happen to their lives. The MPD support groups founded by concerned patients are doing much to improve this overall adverse situation. Through its website, seminars, and newsletters, MPD patients now feel less lonely, know more about their disease and are taking a greater part in self management and in deciding how to handle their manifold emerging problems more or less adequately. This, in turn, is the beginning of a change in the medical practice by inform-ing and educatinform-ing the MPD patients and their attendinform-ing physicians. This approach, aiminform-ing at a better understanding and advance of knowledge, works for hemophilia, it works for leukemia and there are reasons enough to believe that it would also work for MPDs.
Definition of chronic myeloproliferative disorders (MPDs)
Blood consists of red blood cells (erythrocytes), white blood cells (myelocytes - leukocytes, granulocytes, monocytes and lymphocytes), platelets (thrombocytes) and plasma. The bone marrow is the source for generating all blood cells and platelet formation (hematopoiesis). Hematopoiesis includes erythro-, myelo-, megakaryo- and finally lymphocytopoiesis. The ery-thropoiesis consists of nucleated red blood cell precursors which loose their nuclei and mature into red blood cells. The myelopoiesis or precursors of the granulopoiesis differentiate into a variety of nucleated white blood cells (leukocytes) while megakaryopoiesis consists of large cells with lobulated nuclei that produce platelets. Red blood cells transport oxygen from the lungs to all tissues of the body. The optimal hematocrit to transport oxygen from the lungs to tissues is 0.38. Leukocytes play a major role in inflammation and the defence against micro-organism like bacteria. Platelets are involved in blood coagulation and lymphocytes mediate various immunological process.
A MPD is featured by the proliferation of one, two or three hematopoietic cell lineages: megakaryopoiesis in ET, erythropoiesis and megakaryopoiesis in initial and early PV plus additional granulopoiesis in progressive (polycythemic) PV or megakaryopoiesis and
granu-PV9.9%(n=83) IMFclassical 14.9%(n=125) Clinical presumptive “ET” 75.2% (n=631) ? UC 23.4%(n=148) “ET” 76.6% (n=483) ET 33.5% (n=162) IMF-038.1% (n=184) IMF-2 (n=84) IMF-3 (n=41) PV Differentiation of Ph1- MPDs with thrombocythemia(n=839) PVSG
criteria Histopathology(WHO criteria)
IMF-128.4% (n=137) 10 20 30 40 “ET” 0 10 20 30 40 IMFclassical PV PV IMF-2 & IMF-3 IMF-1 IMF-0 ET 0 8.9% 21.6% 32.3% 37.5% 20.3% 20.3% 37.5% 16.5%
Loss of life expectancy Loss of life expectancy
Loss of life expectancy in Ph1- MPDs
with thrombocythemia(n=839)
PVSG
criteria Histopathology(WHO criteria)
Fig. 1Comparison of diagnostic classification systems for MPDs and accordingly calculated disease specifc loss of life expectancy [236].
lopoiesis with suppression of erythropoiesis in IMF [51,52, 70,227].
ET is a dominated by a proliferation of mature megakaryocytes and clinically characterized by a normal life expectancy when properly treated to prevent thrombotic and bleeding symptoms. PV consists of a trilineage proliferation including megakaryocytes, erythro- and granulopoiesis (panmyelosis) with a normal survival rate in the majority of the cases when properly treated to prevent thrombotic complications.
Thrombocytosis is usually associated with early stage PV and progresses during the advanced stages. About 30% of PV patients develop a significant proliferation of granu-lopoiesis in the bone marrow and myelofibrosis leading to so-called postpolycythemic myeloid metaplasia within 10 to 15 years [61]. The latter feature indicates endstage disease and there-fore worsening of prognosis. Pronounced thrombocytosis is usually present in the prefibrotic and early fibrotic stages of IMF and frequently mimicks ET, but platelet counts decrease when early stage IMF progresses to classical myelofibrosis with myeloid metaplasia [223, 226,229,234,236]. Classical IMF is a relative slowly progressive MPD featured by overt retic-ulin and collagen fibrosis of the bone marrow, splenomegaly (large spleen), anemia, throm-bocytopenia and a shortened life expectancy [11,13,34,35]. Regarding the disease-specific loss of life expectancy for the Ph1- negative MPDs which is adjusted to age and gender [83,84,103,104] a value ranging from 8% to 38% is observed. Impact of disease is significant-ly higher in eldersignificant-ly patients (Figure 1), especially in IMF and PV. In contrast, patients with ‘true’ ET reveal no relevant reduction of life expectancy [236].
Thrombocytosis in various MPDs
Thrombocytosis may occur in association with all variants of MPDs [75,172,252]. The major-ity of PV patients do present with an elevated platelet count [23,190]. Pronounced thrombo-cytosis is frequently observed in prefibrotic and early fibrotic IMF and often regarded as ET [226,235,236]. Thrombo-cytosis may preceed or accompany Ph-positive chronic myeloid leukemia (CML) or myelodysplastic syndrome (MDS) including the 5q-minus syndromes [27,49,121,251] and thus again may be confused with (true ET) as so-called ET with ringed sideroblasts [186]. In contrast with the typically enlarged and giant megakaryocytes in ET and PV [149,218], the megakaryocytes in so-called Ph1+ (bcr/abl-positive) thrombocythemia [25,120,145,194] are significantly smaller than normal with rounded nuclei [132,143] consis-tent with features observed in CML [29,68,213,217]. Therefore the term Ph1+ ET is a mis-nomer and should be discarded because it significantly adds to the confusion associated with
Tools to diagnose, characterize and stage the MPDs
• Careful registration of complaints, signs and symptoms characteristic for ET, PV and/or IMF.
• Physical examination to document all findings related to ET, PV and/or IMF.
• Measurement of spleen size by palpation and more preferably in length diameter on ultra-sound echogram.
• Routine measurement of peripheral blood parameters including hemoglobin, hematocrit, mean red cell volume, erythrocytes, leukocytes, white blood cell differential count, leuko-cyte alkaline phosphates (LAP) score, platelet count, serum lactate dehydrogenase activ-ity (LDH), creatinine, uric acid, bilirubine and liver enzymes
• Peripheral blood and bone marrow smears morphology and differential counts.
• In any case where an MPD is suspected, representative pretreatment bone marrow biop-sy (minimal length 15 cm) for histopathology and immunohistochemistry in search for characteristic morphological features of ET, PV or IMF using a proper evaluation form for a clear-cut documentation of findings (Figure 2).
• Biological markers like erythropoietin (EPO) level and optional parmeters like sponta-neous endogenous erythroid colony formation (EEC), PRV-1 gene expression (PRV-1 positivity), clonality studies (women only), cMPL (thrombopoietin receptor expression) expression of peripheral blood platelets and bone marrow megakaryocytes.
a clear-cut diagnosis of this condition [44,62]. The megakaryocytes in MDS show overt dys-plastic features and are different from ET and CML [220]. On the other hand, essential throm-bocythemia (ET) is due to a proliferation of only one of the three major hematopoietic cell lin-eages in the bone marrow, the megakaryocytes leading to a persistent increase in the num-ber of platelets (thrombocytes) in the peripheral blood (thrombocythemia ). The megakary-ocytes in ET are significantly enlarged and mature with hyperlobulated (staghorn-like) nuclei
[69,70,223,226,235]. ET should be clearly distinguished from reactive thrombocytosis (RT). RT is usually transient [75] and associated with diseases like chronic infections and inflam-matory systemic diseases, malignancies, iron deficiency and may occur after splenectomy (surgical removal of the spleen). The megakaryocytes in RT are increased, but usually exhib-it a normal size [140,226]. RT is not associated wexhib-ith an increased risk for thrombosis or bleed-ing.
It has to be emphasized that the PVSG criteria do not distinguish between true ET, prefibrot-ic or early IMF without a leukoerythroblastprefibrot-ic peripheral blood pprefibrot-icture [140,142,216,223, 226,228,235,236,240] and also fail to regard initial (latent) PV [127,150,162] with
thrombocy-Diagnostic criteria of essential thrombocythemia (ET)
Strict inclusion and exclusion criteria for the diagnosis of ET have been established by the Polycythemia Vera Study Group (PVSG) [146-148,163-165,205].
• In addition to platelet count greater than 600 x109/l megakaryocytic “hyperplasia” was an absolute requirement. For protocols, involving myelosuppressive therapy a platelet count greater than 1,000 x109/l was generally required.
• A normal red cell mass or a hemoglobin (Hb) of less than 13 g/dl was required to exclude overt PV.
• No stainable marrow iron, and no more than 1g/dl increase in Hb after iron therapy. • Collagen fibrosis more than one-third the cross-sectional area of marrow biopsy, and only
mild fibrosis in patients that presented with splenectomy and a leukoerythroblastic reac-tion.
• Absence of the Philadelphia chromosome.
European clinical and pathological (ECP) criteria for the diagnosis of ET [140]
Clinical criteria Pathological criteria
A1 Persistent increase of platelet count: in excess of 400 x 109/l
A2 Normal spleen or only minor splenomegalyon echogram
B1 Predominant proliferation of enlarged to giant megakaryocytes with hyperlobulated nuclei and maturecytoplasm, lacking conspicuous cytological abnormalities.
No proliferation or immaturity of granulopoiesis orerythropoiesis A3 Normal or increased
LAP-score, and normal ESR
B2 No or only borderline increase in reticulin
A4 Spontaneous
megakaryocyte colony formation (CFU-Meg) and or endogenous erythroid colony formation (EEC) A5 No signs or cause of reactive thrombocytosis (RT) A6 No preceding or allied other subtype ofMPD, CML or MDS A7 Absence of the Ph-chromosome
A1 and B1 + B2 establish (true) ET. Any other additional A criterion confirms ET. ET: Grade I: platelet counts between 400 and 1,000 x109/l;
Fig. 3Morphological features of ET
Table 2. Clinical, biological and some pathological features of conditions that may mimic (true) ET, in particular when following the PVSG criteria [129,147,148,163,165]
Features Hereditary ET True ET (WHO-criteria) Initial PV (false ET) False ET (IMF) Estimated incidence (%) < 0.01 20-30 < 10 50-60 Blood: Thrombocytes ↑/↑↑ ↑/↑↑ ↑/↑↑ ↑/↑↑ Erythrocytes N N ↑↑ N/↓ Hematocrit N N ↑↑ N/↓ Bone marrow: Erythropoiesis N N ↑↑ N/↓ Megakaryocytes ↑↑ ↑↑↑ ↑↑ ↑↑↑
Features Normal large/giant mature abnormal
Myelofibrosis - - - -/+
Splenomegaly - - -/+ +/++
EEC - -/+ +++ -
PVR-1 0 -/+ +++ -/++
↑ = increased, ↑ slight, ↑↑ moderate, ↑↑↑pronounced. ↓ = decreased, ↓ slight, ↓↓ moderate, ↓↓↓ pronounced
tosis that may mimick ET, however, later show full-blown PV [147,233]. As compared with the WHO classification [92,236] and the clinicopathological MPD criteria [136,137,140,226,227], the PVSG criteria include true ET (Table 1) as well as “thrombocythemias” associated with initial-early stage IMF and even PV (Table 2). Moreover, symptomatic ET patients with microvascular circulation disturbances and increased platelet counts above normal and between 400 and 600 x109/l [114,140,184] are disregarded and overlooked by the PVSG cri-teria [146-148,165]. These obvious shortcomings prompted us to incorporate the WHO bone marrow criteria [92] by the combined use of the European pathological criteria and clinical (ECP) criteria as specific clues for the differential diagnosis of true ET, and “thrombo-cythemias” associated with PV and IMF [140,226,227,236]. Finally, the term “hyperplasia” should never be used in conjunction with a MPD, because in general pathology this implies a reactive increase in number.
Morphological features of ET (Figure 3)
Megakaryocytes in true ET are characterized by an enlarged to giant size and exhibit deeply lobulated nuclei with mature cytoplasm randomly dispersed or loosely clustered in a normo-cellular bone marrow (Table 1). There is no hypercellular bone marrow according to an age-matched population and contrasting PV [231] no increase or left-shifting of the nucleated ery-throid precursors or granulocytes is detectable [17,29,69,70,140,223,226,235]. Reticulin myelofibrosis is extremely rare in true ET at presentation and very few ET patients develop MF during long-term follow-up [30,70,234] indicating that true ET is the most benign variant of MPD with a normal life expectancy [236].
Moreover, there are very rare cases of congenital (familiar, hereditary) ET [170] and a minor-ity of young ET patients that have polyclonal hematopoiesis [71,243,258,259]. By definition polyclonal ET is not a MPD since its cause lies outside the hematopoietic stem cell and is based on a mutation of the thrombopoietin gene[71,243,258]. The majority of ET and all PV patients have clonal hematopoiesis consistent with a manifest MPD. About half of the ET and nearly all PV patients exhibit spontaneous EEC [54,63,96,113,253]. In this regard, the devel-opment of a sensitive and specific assay for the EPO is more important. While a significantly elevated EPO level suggests tissue hypoxia as the (reactive) cause for erythrocytosis, a nor-mal or slightly raised value does not exclude this pathomechanism [24,32,76,128,255]. Altogether ET according to the PVSG criteria [146-148,165] may present as true ET, howev-er, in the majority of cases of “ET” as prefibrotic and early IMF [236], and finally as “ET” with features of latent or initial PV that is difficult to discriminate [90,94,147,181] when not apply-ing modern means of bone marrow processapply-ing and stainapply-ing techniques [233]. This salient point has been repeatedly demonstrated by a scrutinized evaluation of bone marrow trephine biopsy specimens showing a heterogenous picture that was significantly associated with prognostic impact [7,234-236]. Over-expression of the mRNA of a novel gene, designated as PRV-1 was identified in mature peripheral blood neutrophil leukocytes and hailed with great enthusiasm as a molecular marker of PV [156,157,212]. Recently expectations were deflated by the demonstration that PVR-1 is constitutively expressed in bone marrow cells and there-fore, does not distinguish PV from reactive and other MPDs [26]. This statement was support-ed by the finding that some patients with EEC formation and clinical as well as laboratory characteristics of PV failed to exhibit raised mRNA levels of PVR-1 [117]. Finally, a prospec-tive study where real-time PCR-based assay showed a PVR-1 expression across the MPDs and also in secondary (reactive) polycythemia and therefore it was concluded that quantify-ing PRV-1 mRNA is not self-sufficient for the diagnosis of PV [211].The suggestion that PVR-1 positive cases with “ET” comprise a distinctive subgroup [78] should therefore be discussed with caution, because it is tempting to speculate that these patients may actually present with an initial [233] or latent PV [181] that is accompanied by an elevated platelet count, but does not fulfill the relevant criteria yet [128,150,162]. This heterogeneity of so-called ET as diag-nosed by the stringent postulates of the PVSG is shown in Table 2. Although in PV onset is difficult to recognize, it is reasonable to assume that a number of patients formerly described as idiopathic erythrocytosis [127,150,162] may fall into this group of initial PV that occasion-ally present with an excess in platelets and may mimick ET [140,233].
Presenting features of ET
ET may be diagnosed in asymptomatic individuals and picked up by routine blood testing. The majority of ET individuals present with typical platelet-mediated microvascular circulation disturbances [38,40,75,89,93,172,173]. As prospective studies are lacking, the relative inci-dence and the spectrum of microvascular disturbances, major thrombosis and bleeding com-plications in true ET and variants preceding or associated with initial (latent) PV and IMF are unknown. Mean age of ET patients at time of diagnosis is about 50 to 60 years. About 20 to 25% of ET patients are younger than 40 years of age. ET occurs 1½ to 2 times more frequent in women than in men. This female preponderance is more pronounced at young ages. The signs and symptoms of platelet-mediated microvascular disturbances are located in the end- arterial circulation of the peripheral, cerebral, coronary, skin and abdominal microcircu-lation [38,40-42,74,98,130,131,133,134,139,144,172,185,244,246]. The typical ET-related microvasular disturbances in the peripheral circulation include a broad spectrum of acropres-thesias, erythromelalgia and its ischemic complications of acrocyanosis or even gangrene of one or more toes or fingertips [130,131,144]. Erythromelalgia is characterized by warm, red, congested extremities and painful burning sensations [130,131]. Acroparesthesias like tin-gling, pins and needles sensations and numbness in the toes or fingers usually precede the disabling burning distress. Warmth intensifies the discomfort and cold provides relief. If left untreated erythromelalgia may lead to painful acrocyanosis and gangrene of one or more toes or tips of the fingers. The burning distress is always associated with local swelling with mot-tled redness and blue spots. At more advance stage intense burning, throbbing and aching with peeling of the skin of the affected toes or fingers that become cold and ischemic. When erythromelalgia progress to ischemic acrocyanosis or gangrene of a toe or fingertip, the peripheral arterial pulsations are usually normal [130,131,144].
The typical ET-related microvascular disturbances of the cerebral and ocular circulation include a broad spectrum of migraine like headache, atypical transient ischemic attacks (TIAs), typical TIAs, occasionally minor stroke, and rarely major stroke [40,98,133,134]. ET-patients may present focal symptoms: transient monocular blindness, transient mono- or hemiparesis, both of these, migraine accompaniments, and partial stroke. Non-focal symp-toms presenting ET-patients include transient attacks of postural instability, dysarthria, and scintillating scotomas. The transient focal and non-focal neurological and visual symptoms all display a sudden onset, usually occur with a march rather than all at one time, lasted a few seconds to several minutes and were usually associated with or followed by a dull or pulsatile migraine-like headache. This clinical presentation is very atypical for transient ischemic attacks caused by atherosclerosis, but the striking similarity with migraine accompaniments supports the crucial of platelets in the pathogenesis of ischemic neurological disturbances in essential thrombocythemia. Acute coronary syndromes, including myocardial infarction and unstable angina pectoris, have been described as the presenting symptom of ET like a thun-der clap at the blue sky [185] .
The paradox of thrombotic and bleeding complications in ET
In 809 ET patients from 11 retrospective studies, 36% were asymptomatic, 58% experienced thrombotic and 17% bleeding symptoms while not on aspirin. The arterial thrombotic manifes-tations were described as microvascular disturbances in 41% involving the extremities (24%) or cerebral circulation (17%), and as major thrombosis in 20% [40-42,74,173].
The paradoxical occurrence of microvascular disturbances and mucocutaneous bleedings is usually seen at platelet counts between 1,000 and 2,000 x109/l. At increasing platelet counts from below 1,000 to in excess of 2,000 x109/l, the arterial thrombophilia of thrombocythemia vera changes into a spontaneous bleeding tendency as the consequence of a platelet-medi-ated increased proteolysis of the large von Willebrand factor (VWF) multimers leading to a type II acquired von Willebrand syndrome [139]. At platelet counts between 1,000 and 2,000 x109/l, thrombosis (erythromelalgic thrombotic thrombocythemia - ETT) and bleeding (Figure 4) frequently occur in sequence or paradoxically and low dose aspirin does prevent
thrombot-ic complthrombot-ications but aggravates or may elthrombot-icit bleeding symptoms. In this situation aspirin should not be discontinued, but there is an urgent need to reduce the platelet count to below 1,000 x109/l by anagrelide, interferon or hydroxyurea (Figure 4).
Hemorrhagic thrombocythemia (HT) is a spon-taneous bleeding tendency that occurs at extremely high platelet counts far in excess of 1,000x 109/l. HT is a clinical syndrome of recur-rent spontaneous mucocutaneous bleedings (including bruises and hematomas of the skin, epistaxis, gum bleeding, silent gastrointestinal bleeding leading to iron deficiency) and second-ary hemorrhages after surgery and trauma. Frequency and severity of hemorrhages in patients with HT is directly related to the pro-nounced increased number of circulating platelets. HT is caused by an acquired VWF deficiency type II at increasing platelet counts in excess of 1,000 to 2,000 x109/l.
The laboratory features of acquired von Willebrand syndrome in reported cases of HT are characterized by:
• a very high platelet count (range 1,285 to 5,860 x109/l), • a prolonged Ivy or Simplate bleeding time,
• a normal factor VIII coagulant activity and VWF antigen (VWF:Ag) concentration,
• a very low VWF-ristocetine cofactor activity (VWF:RCo) and vWF-collagen binding activ-ity (VWF:CB) and
• absence of large VWF multimers simulating a type II von Willebrand disease.
Reduction of the platelet count to below 1,000 x109/l by platelet lowering agents usually results in the disappearance of the bleeding tendency and improvement of the von Willebrand syndrome, but the thrombotic tendency persists as long as platelet counts are between 400 and 1,000 x109/l. The microvascular disturbances already occur at platelet counts between 400 and 1,000 x109/l [114,184]. Low-dose aspirin (50 to 100 mg/day) is highly effective and safe in the cure and prevention of thrombotic and ischemic events and does not elicit bleed-ings at platelet counts below 1,000 x109/l (Figure 4). Relief of microvascular circulation dis-turbances in ET is not obtained with dipyridamol, ticlopedine, coumadin or heparin.
Risk stratification and treatment of ET patients
The main challenge for treating ET patients is to select cohorts who will benefit form a cytore-ductive or antiplatelet therapy, because it remains doubtful whether the positive effects of treatment outweigh the potential hazards in all cases [77] The Bergamo criteria for thrombot-ic risk stratifthrombot-ication are derived from a cohort of 100 ET patients (mean platelet count 1,135, age below 40 in one third, between 40 and 60 in one third and above 60 years in nearly one third) treated in the 1980s with busulfan (short-remitters and long-remitters) and who did not receive aspirin [41]. Platelet counts in the ET patients at time of thrombotic event or recur-rence were increase platelet counts between normal and more than 3,000 indicating that
Fig. 4 The paradox phenomenon of blee-ding and thrombosis in ET related to plate-let count and ensuing therapeutic strategies (Rotterdam concept)
excess in thrombocytes is the determinative factor of thrombotic events with a statistical high-er incidence in ET patients above 60 years as compared to less than 40 years in ET patients not in remission and not on aspirin. Low-risk ET patients are below 60 years of age, have no history or manifestations of major thrombosis or bleeding symptoms, and exhibit platelet counts <1,500 x109/l. All four features must be present to establish a low risk group. High risk ET is defined by age
above 60, a history of major thrombosis, spon-taneous bleeding mani-festations and/or platelet counts in excess of 1,500 x109/l [41,42] . Only one criterion need be present to define high risk. However, the majority of ET patients above the age of 60 years do have platelet counts below 1,500 x109/l, and do not have a history of major thrombosis/bleeding with the absence of a vascu-lar risk factor, which according to Rotterdam criteria should be
consid-Table 3. Risk stratification of ET patients: therapeutic implications [40 -42,244-247]
Low thrombotic and bleeding risk
• Age up to 80 years,
• No vascular risk factor or previous thrombosis • No associated disease and normal life expectancy • No history or signs of bleeding
• Platelet count between 400 and <1,500 x109/l and completely asymptomatic in whom the
use and indication of aspirin is uncertain.
• Platelet count between 400 and <1,000 x109/l and symptoms for microvascular disturbances with a clear indication for low dose aspirin 50-100 mg/day
Intermediate thrombotic and bleeding risk Age up to 80 years.
*Symptomatic for microvascular disturbances and platelet count between 1,000 and 1,500 x109/l with a clear indication for low dose aspirin 100 mg/day.
• No history of bleeding or major arterial or venous thrombosis.
• Absence of any vascular risk factor.
• At platelet counts in excess of 1,000 x 109/l aspirin may elicit bleeding symptoms, which will disappear after reduction of platelet counts to below 1,000 x109/l.
• High thrombotic and/or bleeding risk
Clear indication for platelet reduction plus low dose aspirin except when contraindicated • Platelets >1,500 x 109/l
• History of major thrombosis ( myocardial infarction, stroke, peripheral vascular diseas e) • Presence of vascular risk factor (hypertension, diabetes, hypercholesterolemia etc) • History or presence of spontaneous or major bleedings.
• Bleedings elicited by low dose aspirin at platelets <1,500x109/l. • Progression from low risk to high risk ET -patients.
Platelet lowering agents:
Anagrelide or interferon below the age of 65 years Hydroxyurea above the age of 65 years
0 20 40 60 80 100 0 2 4 6 8 10 12 14 ET total
ET history of thrombosis or hemorrhage ET no history of thrombosis or hemorrhage
%
Survi
val
Years after diagnosis
ered as low risk (platelet <1,000) or intermediate risk (platelets 1,000-1,500) [244,246]. This constellation is regarded in Table 3. However, regarding the age- and sex-adjusted relative survival rate [83,84,104], age at diagnosis has no significant impact on the disease progress, but only a history of thrombosis or hemorrhage in the prediagnostic period. These patients reveals a significant higher rate of clinical complications which is responsible for the overall worsening of prognosis (Figure 5).
Besses et al retrospectively assessed the clinical and hematological factors predictive for the occurrence and recurrence of microvascular disturbances and macrovascular thrombosis in 148 consecutive ET patients [22]. Aspirin was given in only 61 for secondary prevention of thrombotic complications. Among 63 (43%) symptomatic patients at presentation, 43 (29%) experienced microvascular disturbances at a mean platelet count of 1,050 ± 556 x109/l, and 9 (6%) with hemorrhagic complications were registered at a mean platelet count of 1,325 ± 146 x109/l. During follow-up while not on aspirin in the majority of them, 73 (49%) ET patients were symptomatic for microvascular disturbances in 41 (28%), macrovascular thrombosis in 33 (22%) and bleeding complications in 17 (11%). A total of 37 (25%) ET patients had major vascular complications with a mean platelet count of 956 ± 321 x109/l, and 2 (1.3%) patients died of major thrombosis. At multivariate analysis, age >60 years, history of major thrombo-sis and hypercholesterolemia were the variables associated with increased risk of major thrombosis in symptomatic ET patients while not on aspirin in the majority of them [22]. ET patients with symptoms or a history of microvascular disturbances in the absence of vascular disease and risk factors are candidates for low dose aspirin at platelet counts between 400 and 1,500 x109/l [244,246]. The main question to be answered is whether low dose aspirin at platelet count between 400 and 1,500 x10/l versus correction of platelet counts to normal by platelet lowering agents are equally effective in preventing minor and major thrombotic events in ET patients with symptoms or a history of TIAs, minor stroke, or myocardial infarction in the absence of vascular disease and risk factors [22,41,42,244,246]. In the Italian prospective trial, 144 high risk ET patients with a mean platelet count of 788 x109/l , range 53-1,240 x109/l were randomized for hydroxyurea and placebo [42]. In this study 70% in the hydroxyurea arm and 69% in the placebo arm received antiplatelet drugs, aspirin or ticlopedine. Two of 56 (3.6%) patients in the hydroxyurea arm developed major thrombosis, and 14 of 58 patients (24%) in the placebo arm developed ischemic events: major thrombosis 2 (3.4%: 1 stroke, 1 deep vein thrombosis), and microvascular thrombosis in 12 (20,6%: 5 TIAs, 5 digital artery occlusion and 2 superficial thrombophlebitis). At least 10 of these 14 symptomatic ET patients in the placebo arm were not on aspirin at time of ischemic event. Therefore, a direct compar-ison of hydroxyurea versus low dose aspirin in high risk ET at platelet count between 400 and 1,500 x109/l would predict to be equally effective [244,246].
Table 4. Proposed risk stratification of ET patients: therapeutic implications
Platelets:
400 – 1500 x109/l 400 – 1500 x109/l 400 – 1500 x109/l > 1500 x109/l
Symptoms:
Completely Microvascular Major Irrespective of Asymptomatic disturbances only* Thrombosis age and symptoms No vascular risk No vascular risk Bleeding Symptoms
Age < 60 All ages All ages All ages
Aspirin uncertain Low dose aspirin Continue aspirin Platelet reduction to Wait and see If aspirin side effects ÆPlatelet reduction* <1000 plus aspirin
*At platelet counts in excess of 1000 x109/l aspirin will usually elicit bleeding symptoms, which
disappear after reduction of platelet counts to below 1000 x109/l with continuation of aspirin.
Age > 60, no vascular risk
• Platelets < 1000: aspirin only
• Platelets > 1000: aspirin plus platelet reduction from above to below 1000 Age >60 and presence of vascular risk factor: aspirin plus platelet reduction to normal Vascular risk include: atherosclerosis, hypertension, hypercholester olemia, diabetes.
The Bergamo and Rotterdam criteria for thrombotic risk assessment are very similar [41,42,244,246], but differ with regard to age and clear indication for aspirin in low and clear indications for platelet lowering agents in intermediate and high risk ET. In our experience true ET patients above the age of 60 years, platelet counts below 1,000, asymptomatic or microvascular symptoms, but with no history of major thrombosis or bleeding and absence of vascular risk factors are not at high risk for a first major thrombotic event while on low dose aspirin (Table 4).
The risk assessment in the UK PT-1 study is problematic [164]. In the UK PT-1 study, low risk ET is defined by age below 40 years and completely asymptomatic and randomized for place-bo versus low dose aspirin. The intermediate risk group is defined age 40 to 60, completely asymptomatic and randomized for aspirin versus aspirin plus hydroxyurea, which according to the Bergamo and Rotterdam criteria [41,42,244,246] means over-treatment. According to the Bergamo and Rotterdam criteria the intermediate risk group in the UK PT-1 study is in fact low risk and should have been included in the low risk for the randomization placebo versus low dose aspirin. In the UK PT-1 study, symptomatic ET patients including erythromelalgia, TIAs, major thrombosis, and asymptomatic ET patients with the presence of vascular risk fac-tors or age above 60 are labelled as high risk (Table 4). The high risk of the UK PT-1 study consists of low, intermediate and high risk ET according to the Rotterdam criteria [244,246]. The Rotterdam criteria recognize an intermediate group with increased risk on bleeding and thrombosis who may be candidate for platelet lowering therapy and this group of patients is labelled as low risk by the Bergamo criteria [41,42] and as high risk by the UK PT-1 criteria. In this context it should not be overlooked that inconsistencies in diagnostic criteria significant-ly incfluence risk calculations in ET [236]. Improvement of the diagnostic reliability for ET seems to be largely based on the recognition of BM histopathology [235] that has been explic-itly accomplished by the WHO classification [92,230] and thus represents a major advance in comparison to the PVSG criteria [148]. By separating IMF from (true) ET it has been realized that outcome is also significantly different in both series of patients (Figure 1). This impres-sion of a heterogeneity of ET patients diagnosed according to PVSG with respect to their sur-vival pattern has been recently confirmed [7,235,240]. Evaluation of certain BM features revealed that in 40 of the 93 patients from the Italian ET Study Group [38] an increased cel-lularity was present including myeloid precursors, a higher content of fibers and trapped “dys-plastic” megakaryocytes [7]. These results fit well with other descriptions of corresponding BM findings in initial and early IMF [70][30,31]. These studies provide persuasive evidence that a considerable number of patients assumed to present with ET according to the PVSG criteria [102,147,148] are more likely to have IMF and consequently are characterized by an unfavor-able prognosis.
Platelet lowering agents in ET
Anagrelide is a selective inhibitor of megakaryocyte differentiation (endoreduplicative activi-ty) [237], but does not reduce the number of megakaryocytes [242]. By this pathomechanism this agent lowers platelet production without a significant effect on bone marrow erythro- and myelopoiesis, and without an increased risk concerning development of myelofibrosis and leukemia [2,28,73,167,189,199,235,260]. The average dose to control thrombocytosis is 2.0 to 2.4 mg/day [205]. The overall response for both complete and partial response in a large group of thrombocythemic patients was 76 to 79% [2,73,166]. The most common adverse event of anagrelide was headache in 37%. It was controlled by acetaminophen and lasted <2 weeks. Palpitations were reported in 26%, diarrhoea accounted for 25%, and fluid retention was seen in 22% [166,195,199,202]. Other less frequent adverse effects caused withdrawal side effects included nausea, abdominal pain, asthenia, flatulentia and bleeding [5,107,168,195]. Adverse side effects caused 13% of these patients to withdraw anagrelide [195,198,199].
Interferon is effective in the treatment of ET to reduce the excessive platelet count without an increased risk on cancer and leukemia [56,198]. A relative low dose of 3 to 5 million units sub-cutaneously 3 times a week will induce a complete and partial response in 70 to 80%. Adverse
side effects will cause withdrawal of interferon in 20 to 25%. The new PEG-interferon to be given subcutaneously once a week has less side effects and is predicted to be as effective as interferon [77].
Hydroxyurea is currently the palliative treatment of choice for the MPDs including ET. Hydroxyrea is an effective cytostatic agent to reduce not only platelet but also erythrocyte and leukocyte counts in MPD patients without side effect during the first 5 years of follow-up, but the degree of increased risk on leukemia and cancer after long-term follow-up of more than 10 to 15 years in ET patients is unknown [77]. There is a legitimate concern regarding the leukemogenic potential of hydroxyurea [67,88,116,118,171]. In a large study, 251 of 357 ET patients were treated with hydroxyurea either alone or in combination with other agents and followed for 8 years [193]. The comparative rates of evolution into acute leukemia or myelodysplastic syndromes were 3.5% for hydroxyurea alone, 14% for hydroxyurea in com-bination with other agents busulfan or 32P, 7% for 32P, and 3% for busulfan [193]. This study showed a high frequency of 17p deletions in the patients with acute transformations treated with hydroxyurea. There has been no randomized study with an appropriate control arm which implicates hydroxyurea as being leukemogenic in previously untreated ET patients with ade-quate baseline clinical, pathological, cytogenetic and molecular examinations of blood and bone marrow. The current availability of non-leukemogenic platelet-lowering agents (anagre-lide and PEG-interferon) provides the opportunity to investigate the very long-term safety (more than 10 to 15 years) of hydroxyurea in a controlled fashion, but is very difficult to real-ize. Alternatively, large scale observational studies of ET patients treated with hydroxyurea alone for more than 10 to 15 years are lacking and should be initiated.
Hydroxyurea and busulfan are the two candidates for a first choice treatment option in high risk ET patients older than 65 to 70 years [202,205]. If anagrelide and interferon fail in high risk ET patients younger than 65 years, hydroxyurea but not busulfan should be the choice. Radioactive phosphor, 32P, should not be used for the treatment of ET and PV because of its high risk of leukemia and cancer after long-term follow-up. In a recent retrospective study, 259 MPD patients (183 PV and 76 ET with a mean age 72 years, range 28-95 years) were treat-ed with 32P in a regional nuclear medicine department [9]. After a median follow-up of 5 years (range 2 to 11 years) 18 (7.6%) developed leukemia and cancer arose in 19 (8%) patients [9].
Diagnostic criteria of polycythemia rubra (PV)
Strict inclusion and exclusion criteria for the diagnosis of PV were established by the PVSG in 1975 [20,21,23,129,148,202]. Three major and a few minor criteria were postulated (Table 5) to ensure that patients who entered into the PVSG prospective trials were indeed suffering from that disease and not from secondary erythrocytosis-polycythemia (SP) to be treated with potential leukemogenic drugs. However, the original set of PVSG criteria failed to add bone marrow histopathology proposed by the German pathologists as a specific pathognomonic criterion for PV and the differentiation between PV and SP [17,29,68-70,214,227,231,233]. The original PVSG criteria in Table
5 overlook by definition the latent and the early stage of PV [233], the so-called idiopathic erythrocytosis characterized by a mild increase in hemoglobin (Figure 6) or red cell mass, normal leukocyte count, no splenomegaly, and absence of any cause of SP [127,138,150,162]. This comprises about 15 to 30% of early stage 1 and 2 PV patients fea-tured by EEC and frequent PVR-1 positivity, and a typical PV bone marrow picture [140,233]. These
Table 5. The PVSG diagnostic criteria for PV [21,23,148]
A. Major criteria
A1.Raised red cell mass. Male > 36 ml/kg, female >32 ml/kg A2. Normal arterial oxygen saturatin >92%.
A3. Splenomegaly on palpation. B. Minor criteria
B1. Thrombocythemia. Platelet count >400 x109/l B2. Leukocytosis >12 x109/l (no fever or infection)
B3. Raised leukocyte alkaline phosphatase (LAF) score >100 or raised B12 (>900 ng/l), or raised unsaturated B12
early stages of PV are not treated, but at very high risk for potential fatal macrovascular com-plications.
Based on new labo-ratory investigations including sponta-neous EEC [256], serum EPO levels [24,43], clonality markers and spleen size on echogram, Pearson proposed his modification of the PVSG criteria, however, again with-out reference to bone marrow mor-phology (Table 6) [ 1 2 9 , 1 6 3 , 1 6 5 ] . Spontaneous EEC and especially EPO levels [24,32,43,53, 128, 129] have out-standing diagnostic specificity and sensitivity to differentiate between PV and and SP comparable to characteris-tic bone marrow features [231,233], while the discriminating impact regarding the distinctive power of the PVR-1 positive expression remains debatable [39,65, 78,97,99,117, 156, 211, 212]. Altogether their positive predictive and diagnostic value is far less as compared to the WHO classification [169] and the new European clinical and pathological criteria (ECP) for PV (Table 7). Therefore, we recently introduced the ECP criteria that are essential based on the WHO guidelines as the current gold standard for the diagnosis of PV and its differentia-tion from SP [138,140]. The quantitative measurement of the PRV-1 gene RNA expression reflects the polyclonal marker expression of “activated” granulocytes [26] very similar to the leukocyte alkaline phosphatase (LAP) score (Figure 6), whereas the autonomous EEC indi-cates the spontaneous growth of monoclonal erythroid precursor cells which are hypersensi-tive to EPO [24,43,163]. The EEC-posihypersensi-tive and PRV-1-posihypersensi-tive MPDs consist of a broad spec-trum of disorders including ET, early
and advanced stage PV and IMF [158]. About half of the ET patients according to the WHO and ECP crite-ria are predicted to be EEC-negative and PRV-1 negative [78,99], but we do not know whether this EEC/PRV-negative ET is polyclonal or mono-clonal and whether these are true ET or “variants” of ET as the presenting symptom of prefibrotic or early fibrot-ic IMF, because a considerable frac-tion of patients with (classical) IMF do exhibit PRV-1 positivity [158]. Therefore this finding is not unex-pected and again demonstrates the pitfalls when relying alone on this
ill-Table 6. Modified PVSG criteria for the diagnosis of PV [129,163,165]
A. Major criteria
A1. Raised red cell mass (>25% above mean normal value)
A2. Absence of secondary polycythemia A3. Palpable splenomegaly.
A4. Clonality marker e.g. abnormal marrow kar yotype B. Minor criteria
B1. Thrombocythemia. Platelet count >4009/l
B2. Neutrophil leukocytosis (neutrophil count >10 x109/l) B3. Splenomegaly on isotope/ultrasound scanning B4. Characteristic spontaneous EEC or reduced serum EPO level
A1 + A2 + A3 or A4 establishes PV, and A1 + A2 + two of B establishes PV
defined polyclonal molecular marker that is also expressed in reactive inflammatory condi-tions and resembles very strikingly the activity of the LAP.
Regarding prognosis an overall loss of life expectancy of about 20% is observed (Figure 1), however disease impact is significantly higher in older patients [105]. Beside the age at diag-nosis, signs of generalisation of disease like liver size and increase in leukocytes are gener-ally associated with a worsening of prognosis. Based on these findings a simplified prognos-tic score can be calculated [105], which helps to discriminate into low- and high risk patients (Figure 7).
Prognostic staging for PV: Cologne score Parameter Prognostic impact Age (years) > 60 2 Liver size (cm) > 2 1 Leukocytes (×109/l) > 20 1 0 20 40 60 80 100 0 2 4 6 8 10 12 14 PV total Age < 60 yrs. Age ≥60 yrs. Liver size≥2 cm WBC ≥20 x 109/L
Years after diagnosis
%
Su
rviva
l
Fig. 7Prognostic factors in PV
Table 7. European clinical and pathological (ECP) criteria for the diagnosis of Polycythemia Vera (PV) [140]
Clinical criteria Pathological criteria
A1 Erythrocytes >6 x1012/l, hemoglobin: male >18.5 g/dl, female >16.5 g/dl and hematocrit: male >0.51 %, female >0.48 %).
Raised red cell mass (optional) RCM: male >36 ml/kg, female >32 ml/kg.
B1 Increased cellularity with trilineage myeloproliferation (i.e. panmyelosis). Proliferation and clustering of small to giant (pleiomorphic) megakaryocytes. Absence of stainable iron.
No pronounced inflammatory reaction (plasmacytosis, cellular debris). A2 Persistent increase of platelet
count: grade I: 400-1,500, grade II: >1,500.
B2 Spontaneous erythroid colony formation.
A3 Splenomegaly on palpation or on ultrasound or CT (>12 cm length diameter). Grading of myelofibrosis in (MF) PV MF 0 prefibrotic stage PV A4 Granulocytes >10 x109/l and/or raised LAP-score in the
absence of fever or infection. MF 1 early fibrotic stage PV MF 2 manifest myelofibrosis in PV
A5 Absence of any cause of secondary erythrocytosis.
MF 3 advanced myelofibrosis in PV A6 Low plasma EPO level MF >3 osteosclerosis, decreased cellularity
Morphological features of PV (Figure 8)
In contrast to the predominant megakaryocytic proliferation in a normocellular bone marrow in ET, PV usually shows a slight to moderate hypercellularity and a marked proliferation of all cell lineages termed panmyelosis [17,69,70,231], but especially of erythroid precursors [221,227], even in the latent (subclinical) or initial or early stages [233] as shown in Tables 7 and 8. In PV, megakaryocytes are either dispersed or loosely grouped, especially in the patients presenting with elevated platelet counts [59-61,68-70]. Unlike those in SP, megakary-ocytes in PV show a pleiomorphous aspect featured by a loose clustering of giant to small megakaryocytes displaying regularly lobulated nuclei, and lack of maturation defects of nuclei and cytoplasm [70,231]. There is always a proliferation and left-shifting of the neutrophil gran-ulopoiesis and especially erythroid precursor cells [221,227] with formation of extended sheets. Contrasting SP, a lack of iron-laden macrophages or inflammatory reactions of the myeloid stroma (perivascular plasmacytosis), eosinophils, accumulation of cell debris is remarkable [227,231,233]. Endstages of PV [61] reveal predominant granulocytic proliferation associated with grossly abnormal megakaryocytes and reticulin-collagen myelofibrosis con-sistent with the so-called post-polycythemic myelofibrosis/metaplasia and splenomegaly (Tables 7 and 8). Whether EEC/PRV-1-positive and EEC/PRV-1-negative IMF patients are linked to this kind of myelofibrosis and agnogenic myeloid metaplasia respectively remains to be elucidated [211]. Using the ECP criteria including bone marrow morphology and repeated-ly performed trephine biopsies [30,70] and the biological markers EEC, PRV-1 and serum EPO levels, we are able to distinguish at least 6 stages of PV with typical bone marrow fea-tures (Table 8). These are grossly reflecting the dynamics of this condition starting with an ini-tial (latent) phase and finally terminating into a fibro-osteosclerotic stage consistent with post-polycythemic myeloid metaplasia.. However, chemo- or interferon therapy was not able to inhibit the progress of myelofibrosis [100] comparable to IMF [238,239,241].
Signs and symptoms of PV
The microvascular syndrome of thrombocytosis
As shown in Figure 7at time of diagnosis, PV is associated with thrombocytosis in about 65 to 75% of the cases [23,56,129,160,165,202]. Nearly all PV patients will develop an elevated platelet count during follow-up. Complete remission of polycythemia by bloodletting alone aiming at a hematocrit near to 0.40 is featured by persistence or appearance of thrombocy-tosis [131,144]. Signs and symptoms of the latter feature in PV patients in complete remission by phlebotomy as only treatment exhibit exactly the same broad spectrum of platelet-mediat-ed microvascular disturbances as describplatelet-mediat-ed above for ET [131,135,144].
Hypervolemic symptoms
On top of the microvascular syndrome of thrombocytosis PV patients have typical hyperv-olemic symptoms due to the increased red cell mass, hematocrit and associated increase whole blood viscosity . Complaints of hypervolemia include fatigue, dizziness, apathy, dull-ness, headache, dyspnea, lack of attention, no drive to work or joy in life [129,190,202]. Signs of hypervolemia are a plethoric face, red handpalm, fingers, toes and footsole. Acrocyanosis of the tip of nose and of toes and fingers may be present.
Vascular complications
Between 30 to 50% of PV patients present with minor and major vascular complications. These occur both in arteries and in veins [53,165]. If PV patients remain untreated, the medi-an survival is only 18 months with the majority dying of vascular events. The distribution of arterial complications in PV is different from age-matched population with atherosclerosis without this disorder. However, in the atherosclerosis group males predominate but there is equal gender distribution in PV. The intrinsic blood changes of increased red cells and platelets are responsible for this altered distribution of vascular complications in PV [144]. Cerebral artery complications are far more common than coronary artery conditions in PV compared with non-polycythemic atherosclerosis patients [10,79,126,135,161]. The
thrombot-Table 8. The six stages of polycythemia vera according to Wasserman and Michiels
Stage 0 1 2 3 4 5
“ET” PV PV PV PostPVMF Spent Hemoglobin mmol/l N/↑ ↑↑ ↑↑ ↑↑ ↑ N/↑ Erythrocytes N/↑ ↑↑ ↑↑ ↑↑ ↑ N/↑ Hematocrit 0.40- 0.50- 0.50- ↑↑ ↑ N/↑ 0.50 >0.60 >0.60 Thrombocytes x109/l </>400 <400 >400 >1000 variabel N/↑ Leukocytes x109/l N N N >15 variabel >20 Spleen on echogram <15 <12 <15 >15 > 20 >20 cm Bone marrow: Cellularity, erythropiesis ↑ ↑ ↑↑ ↑↑ ↑↑ ↑↑ Megakaryocytes ↑ ↑ ↑↑ ↑↑ ↑↑ ↑ Myelofibrosis (MF) grade 0 0 0/1 1/2 2/3 3 Spontaneous EEC + + + + + + PVR-1 gene expression + + + + + + Serum Epo N/↓ N/↓ ↓ ↓ ↓ ? N= normal, - = absent, + = present, ↑ = increased, ↑↑ = pronounced increased.
ic events in PV patients include transient ischemic attacks (TIAs), facial weakness or apha-sia, TIAs followed by stroke, attacks of transient blindness (amaurosis fugax), acute coronary artery disease, sudden ischemia of a toe or finger leading to amputation of one or more dig-its, femoral artery occlusion, superficial thrombophlebitis, deep vein thrombosis, splanchnic vein thrombosis, pulmonary embolism and priapism. Arterial complications occurred in about one third and venous thromboembolism in about one fourth of the PV patients at time of pres-entation [21,23,190].
Itching
Itching in particular after a warm bath is very typical of PV, is difficult to treat, cryptoheptadine may help, and interferon may have a favorable response.
Gout
Gout is related due to increased uric acid levels in PV patients (Figure 6).
Treatment of PV patients
Phlebotomy and low dose aspirin
Phlebotomy is the cornerstone of therapy for PV. Before the use of phlebotomy, survival of symptomatic PV patients was curtailed to less than two years as a result of premature death from major thrombotic complications including stroke, myocardial infarction [45,179,192]. With the use of phlebotomy alone as initial therapy, the estimated median survival is between 12.5 to 13.5 years. The PVSG 01 study showed that overall survival was significantly compromised due to excess of leukemia and cancer when the alkylating agents chlorambucil or 32P was added to phlebotomy as initial therapy with a median survival of 9.1 and 10.9 years compared with 12.6 years for phlebotomy alone [19]. The risk of leukemia was 12% for chorambucil, 9.6% for 32P and less than 1.5% for phlebotomy alone during long-term follow-up of more than 10 years [19,66]. In the PVSG 01 study approximately 35% of PV patients in the phlebotomy-only arm aiming at a hematocrit of less than 0.50 and not on aspirin experienced major throm-botic events in the first three years [66]. This high incidence of thromthrom-botic events in PVSG 01 study can readily be explained by the poor control of the hematocrit and the persistence of thrombocytosis after bloodletting alone without the use of aspirin. A positive correlation has been found between the hematocrit level and the incidence of major arterial and venous thrombotic complications [141,161]. The risk of major vascular episodes was highest at hema-tocrits above 0.50, moderately increased at hemahema-tocrits between 0.45 and 050 and low at hematocrits between 0.40 and 0.45 [141,161]. The optimal hematocrit in the treatment of PV for the prevention of major thrombotic events appeared to be much lower (below 0.45 and near to 0.40) than was assumed (0.45-0.50) [10,19,66,79,126,141,161]. Recent clinical stud-ies on primary and secondary secondary intervention and prevention studstud-ies on vascular events in thrombocytosis associated with PV in remission by bloodletting alone have clearly shown that low dose aspirin 50 to 100 mg/day is highly effective in terms of platelet COX 1 inhibition and prevention of microvascular circulation disturbances [74,80,98,108,109,131, 133,134,144,178,185,245-247]. Low dose aspirin 50 to 100 mg is associated with a very low gastrointestinal bleeding and toxicity rate [80,109]. Therefore, the microvascular ischemic syndrome of thrombocytoisis in polycythemia vera in remission after bloodletting is best con-trolled by low dose aspirin (40 to 100 mg/day) or reduction of platelet count to completely nor-mal levels (<400 x109/l) by anagrelide, interferon or hydroxyurea (Figure 6) [144]. The European collaboration on low dose aspirin in PV (ECLAP) recruited 1,638 PV patients diag-nosed and followed up in a qualified network of 94 European In the observational study of 1,120 PV patients, 66% had a clear indication for low dose aspirin, 23% displayed a con-traindication for aspirin, and 18% belonged to the group unwilling or unable to follow the pro-tocol recommendations. In the randomized trial of 580 patients (32%), who exhibited no clear indication and no contra-indication to aspirin, these patients were randomly allocated to
aspirin 100 mg/day or placebo [109]. Treatment of PV was according to the generally accept-ed recommendation and includaccept-ed hydroxyurea in 44%, pipobroman in 5.4% interferon in 4.2% and phlebotomy alone or as an adjuvant in 72% of the randomized PV patients. Median fol-low-up was three years. Mean values were 0.45 for hematocrit and 330 x109/l for platelet count. On top of this, treatment with low dose aspirin as compared to placebo significantly reduced the overall risk of a combined end-point of microvascular and major vascular compli-cations including cardiac death, no fatal myocardial infarction, no fatal stroke, pulmonary embolism and major venous thrombosis from 15.1 % to 6.7% [109]. Major, total and gastroin-testinal hemorrhages were slightly increased in the aspirin group without reaching a statisti-cal significance. These data confirm the Rotterdam concept, that low dose aspirin should be included on top of treatment in early stage PV patients by bloodletting alone, but also on top of treatment in advanced stage PV patients with hydroxyurea [74,80,98,108,109,131,133,134, 144,178,185,245-247].
Hydroxyurea
Because of its potential leukemogenic risk, cytoreductive agents like hydroxyurea and busul-fan [64,67,88,122,152,153,171,193,206,210,254] should be used with caution and withheld as long as the combination of bloodletting and low-dose aspirin is effective in preventing thrombotic events in the early stages of PV without significant myelofibroic splenomegaly [138,151,190,191,196]. The shortcomings of phlebotomy alone include the lack of effect in controlling red cell mass, splenomegaly, itching, and increased proliferative activity such as leukocytosis, thrombocytosis, postpolycythemic myelofibrosis and spent phase PV. Retrospective analysis of newly diagnosed 114 PV patients (mean age 63 years) initially ran-domized to phlebotomy alone showed that 50% by the 5thyear and 90% by the 10thyear had received myelosuppression either 32P or hydroxyurea because of progressive myeloprolifera-tive disease [138]. The median survival of these 114 PV patients was 18 years as compared to 20 years of similar age indicating a 10% loss of life expectancy. In a recent update, patients with PV that entered into the PVSG 08 and who received hydroxyurea and no prior therapy were compared retrospectively to PV patients included in the phlebotomy arm of the PVSG 01. At a median follow up of 8.6 years and a maximum of 15 years, 5.9% of the hydroxyurea treated and 1.5% of the phlebotomised patients developed acute leukemia; On the other hand, 7.8% of the hydroxyurea treated and 11.2% of phlebotomised treated patient devel-oped spent phase by 15 years. By 15 years 31% of hydroxyurea treated and 40% of phle-botomy treated patients had died. These data are evidence-based and not statistically differ-ent, but a paradoxical trend for increased leukemia and improved survival in PV patients treat-ed with hydroxyurea is evident. This paradox may be explaintreat-ed by the observation that hydroxyurea therapy of stage 3 symptomatic PV patients delays the development of postpoly-cythemic myelofibrosis and spent phase PV [109].
The French prospective PV study evaluated hydroxyurea with regard to clinical safety, hema-tological efficacy, frequency of progression to myeloid metaplasia and myelofibrosis or spent phase and risk of carcinoma or leukemia in a long-term follow-up study of 133 previously untreated PV-patients below the age of 65 [151]. Complete remission was defined by a hema-tocrit lower than 0.50 and platelet count lower than 400 x109/l. The long-term use of aspirin was let free at the decision of the physician. Toxicity of hydroxyurea was observed in 29% of 133 patients, which was limited to dry skin and acne in 7%, gastric pain/diarrhea in 9%, aph-thous ulcers in the mouth in 10%, and leg ulcers in 9%. Leg ulcers only healed after discon-tinuation of hydroxyurea; these complications appear generally late (5 years or more after ini-tial treatment). Dry skin in 1, aphthous stomatitis in 4 and leg ulcers in 10 cases were reasons to replace hydroxyurea by pipobroman in 9%. Leg ulcers generally resolved when hydrox-yurea was replaced by pipobroman. Efficient control of hematocrit <0.50 and platelet count <400 x109/l was obtained by hydroxyurea in 82% and 55% respectively. The frequency of pro-gression to (postpolycythemic) myeloid metaplasia and overt myelofibrosis (MMM) or spent phase in the hydroxyurea treated PV patients was 17% at 10 years and 40% at 16 years. The high incidence of MMM or spent phase in the hydroxyurea treated arm was only slightly dif-ferent from those patients treated by phlebotomy alone in a previous study. Seventy-six
per-cent of cases who devel-oped MMM had a per-manent high platelet count in excess of 400 x109/l despite mainte-nance of myelosuppres-sive treatment. The inci-dence of leukemia was about 10% at 13 years in hydroxyurea treated PV patients. Life expectancy was 70% at 14 years as compared to 83.7% in age-matched controls. In another study, 71 newly diagnosed PV patients were phlebotomized to a hematocrit of <0.45 and then therapy was started with hydroxyurea daily [197]. Median duration of the disease was 10.9 years and the median duration of treatment with hydroxyurea was 7.3 years. Maintaining the hematocrit under 0.45 and platelet count below 400 x109/l, the incidence of acute leukemia was 4 in 71 patients (5.6%). As the life expectancy of newly diagnosed and properly treated PV patients is completely normal for the first decade but compromised after more than 10 years follow-up due to progression to postpolycythemic mylofibrosis, spent phase, or leukemia [180], there is a need to compare hydroxyurea with the non-leukemogenic agent interferon-alpha in terms of side effect, toxicity and very long-term survival.
Interferon-alpha
Therapeutic benefits reported include induction of hematological remission, significant improvement in the platelet counts, iron status, and leukocytosis, resolution of disease-asso-ciated symptoms in particular, relief from thrombohemorrhagic events and refractory pruritis, and resolution of splenomegaly [187]. Hematological remission has been reported differently by authors, but in general, a complete response (CR) implies maintenance of a hematocrit less than 0.45 without the need of phlebotomy and partial response (PR) refers to mainte-nance of a hematocrit between 0.45 and 0.50 with a 50% reduction in phlebotomy require-ments to reduce the hematocrit to below 0.45 [115]. Overall, hematological responses were achieved in 76% of cases within 6 months (range 3 to 12 months). Approximately 15% of patients failed to gain any benefit from IFN-alpha therapy. In those studies that clearly defined a CR as described above, this response was achieved in approximately 60% of cases. Doses of IFN-alpha used to obtain hematological responses varied between 4.5 and 25 million units weekly, with a majority of patients receiving 9 million units weekly, generally given three times a week. IFN-alpha seems to be most effective when started in the early plethoric stage of PV. In a proposed trial, clear indications for the start of interferon or hydroxyurea in stage 3 PV include:
• Uncontrolled platelet count of >1,000 x109/l during aspirin therapy.
• Side effects of aspirin or anagrelide, symptomatic and platelet count >600 x109/l. • Increase spleen size more than 2 cm per year, or exceeding 15 cm length diameter. • Symptomatic large spleen (splenomegaly).
• PV-related constitutional symptoms including pruritis etc. • Leukocyte count in excess of 25 x109/l.
• Leukoerythroblastic blood picture and signs of myeloid metaplasia. • Major arterial or venous thromboembolic complications.
• Symptomatic iron deficiency.
• High frequency of phlebotomy of >8 per year to maintain the hematocrit normal (<0.45).
Table 9. Proposed clinical trial in previously untreated PV patients Stage 1 and 2 Bloodletting plus low dose aspirin
Age 18-80 yr Anagrelide optional to control platelet number
Stage ≥3
Age < 50 yr Interferon first choice
Age 50-65 yr Randomize for interferon versus hydroxyurea Age > 65 yr Hydroxyurea first choice
If side effects interferon change to hydroxyurea If side effect s hydroxyurea change to interferon
The required IFN-alpha dose in early stage PV is lower and less toxic and does not interfere with the working and recreation ability. Side-effects remain a significant problem, occurring in over 30% of patients, and may be related to the high mean age of the patients. Approximately 20% of patients discontinued IFN-alpha therapy due to intolerance.
Rational for using IFN-alpha for the treatment of PV include:
1.) Abatement of constitutional symptoms; 2.) Maintenance of hematocrit and platelet sup-pression in the normal or near normal range; 3.) Avoidance of phlebotomy, iron deficiency, and macrocytosis due to hydroxyurea; 3.) Lack of mutagenicity; 4.) May prevent or delay post-polycythemic myelofibrosis if used early in the course of the disease; 4.) Effectiveness/toxic-ity (risk/reward) ratio is positive.
The rational for using PEG-Intron is its much favorable efficacy, safety and toxicity profile. Therefore, an open label randomized treatment program is warranted to establish the effica-cy and safety of PEG-Intron concerning the induction of complete haematological remission as compared to standard phlebotomy/low dose aspirin in previously untreated patients with early stage PV.
First and second treatment options in PV
A primary rigid venesection regimen to maintain the hematocrit below 0.45 near to 0.40 is cur-rently accepted as a nonleukemogenic approach and first choice treatment in newly diag-nosed PV patients [41,74,98,134,139,185,202]. The microvascular syndrome of thrombo-cythemia in PV in remission by bloodletting is easily and best controlled by low dose aspirin (50 to 100 mg/day) [42,244]. Anagrelide can be considered to control extreme thrombocyto-sis (>1,000 x109/l) particularly when associated with microvascular or bleeding complications [198]. The combination of bloodletting plus low dose aspirin (ASA) has recently become the recommended first line treatment option for PV stage 1 and 2 for as long as possible until pro-gression to stage 3 PV occurs. Many stage 1 and stage 2 PV patients require no other treat-ment for many years (up to more than 10 to 15 years); stage 3 PV calls for the introduction of cytoreductive therapy.
Hydroxyurea is the less expensive and most frequently used cytoreductive agent, althought serious doubts persist about its long-term toxicity and leukemogenicity [64,67,88,122,152, 153,171,193,254]. Interferon-alpha is a promising alternative in case of no or minor side effect, but it is expensive and its side-effects can be unbearable. A reasonable approach could be to reserve interferon for younger patients below the age of 50 to 55 as long as it works without significant side effects. Hydroxyurea is a good choice for older patients over 65 and 70 years of age. Whether interferon or hydroxyurea at ages between 50 and 65 in terms of quality of life and life expectancy is the best option remains uncertain and should be addressed in a randomized clinical trial. We propose to perform a large scale prospective ran-domized trial using a flexible study design to compare the efficacy, toxicity, leukemogenicity of hydroxyurea versus interferon-alpha in newly diagnosed and previously untreated PV patients.
Diagnostic criteria of prefibrotic and (classical) chronic idiopathic myelofibrosis (IMF) or myelofibrosis with myeloid metaplasia (MMM) / agnogenic myeloid metaplasia (AMM)
The third category of MPD is usually termed agnogenic myeloid metaplasia (AMM) or idio-pathic myelofibrosis (IMF), but various other designations have been used, such as primary myelofibrosis, myelosclerosis, osteomyelofibrosis, and myelofibrosis with myeloid metaplasia (MMM) [13,200,209]. This disorder is generally defined as a clinicopathological entity not pre-ceeded by any other or allied haematological disorder. Diagnostic features of classical IMF usually include anemia, splenomegaly, leukoerythroblastic blood picture, tear drop erythrocy-tosis, and varying degrees of bone marrow reticulin and collagen fibrosis [11,13,14]. Different sets of prognostic and clinical parameters of IMF have been proposed [11,13,34,35,103,104, 140,182,226,227,250], but all agree on the clinical scoring system in Table 10 [130,140], that
