SemOpenAlex |

SemOpenAlex

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2040304882> ?p ?o ?g. }

Showing items 1 to 100 of ±222 with 100 items per page.

W2040304882 endingPage "254" @default.
W2040304882 startingPage "243" @default.
W2040304882 abstract "In developing a management plan for polycythaemia vera, the following issues must be considered. First, polycythaemia vera is a clonal disorder with the primary defect residing in a multipotent haematopoietic progenitor cell (Adamson et al, 1976). Second, there is currently no clinically applicable clonal marker to distinguish polycythaemia vera from non-clonal disorders when it presents with erythrocytosis (Szur et al, 1959; Najean et al, 1981) or from its' companion myeloproliferative disorders when it does not (Lopas & Josephson, 1964; Parmentier et al, 1977; Taylor et al, 1989; Janssen et al, 1990). Third, without a clonal marker, it is not possible to determine whether a particular therapy is potentially curative as opposed to merely palliative. Fourth, the natural history of polycythaemia vera is still not completely defined and there is good evidence that not only do the manifestations and tempo of the disease vary (Tinney et al, 1945a; Verel, 1958; Tubiana et al, 1968; Pettit et al, 1979; Messinezy et al, 1985; Najean & Rain, 1997a) but also that age and sex may have an important influence in this regard (Videbaek, 1950; Najean et al, 1987). Fifth, in contrast to idiopathic myelofibrosis (Visani et al, 1990; Rupoli et al, 1994; Dupriez et al, 1996; Cervantes et al, 1997; Kvasnicka et al, 1997; Reilly et al, 1997), the factors affecting prognosis in polycythaemia vera have not been identified and staging criteria for the disease have not been established. Unfortunately, the data accrued in the Polycythaemia Vera Study Group (P.V.S.G.) prospective clinical trial are not useful for these purposes because protocol design was fundamentally flawed with respect to the phlebotomy criteria (Wasserman, 1971; Berk et al, 1981). Sixth, as polycythaemia vera is probably a myeloaccumulative disorder (Moliterno et al, 1995; Silva et al, 1998) as opposed to a myeloproliferative one and usually an indolent and chronic illness that is compatible with a substantial lifespan (Harrop, 1928; Tinney et al, 1945a; Perkins et al, 1964; Rozman et al, 1991), a first principle is that its' treatment be consonant with its' behaviour and the primary objective should be to prevent or ameliorate the complications of the illness without compromising longevity. The management of polycythaemia vera begins with its' diagnosis and currently, if there is not a simultaneous increase in the red cell, white cell and platelet counts, we can do no better than the major criteria of the P.V.S.G. modification (Wasserman, 1971) of Osler's original diagnostic criteria (Osler, 1903), the most important of which is elevation of the red cell mass. Unfortunately, with disease, changes can occur in the red cell mass, the plasma volume and the plasma volume distribution that cannot be distinguished by haematocrit determination alone (Lawrence et al, 1953; Abbatt et al, 1954; Blum & Zbar, 1959; Szur et al, 1959; Huber et al, 1964; Pearson et al, 1984), and with erythrocytosis there is no direct correlation between the haematocrit and the red cell mass (Prentice et al, 1952; Abbatt et al, 1954; Huber et al, 1964; Weil et al, 1968; Najean et al, 1978; Barosi et al, 1981; Pearson et al, 1984). Furthermore, in polycythaemia vera, in contrast to other conditions causing erythrocytosis (Scott et al, 1951; Hume & Goldberg, 1964; Sanchez et al, 1970; Besa et al, 1974; Smith & Landaw, 1978; Valentine et al, 1998), there is a tendency for plasma volume expansion (Abbatt et al, 1954; Murray, 1965; Zhang & Lewis, 1989; Drenou et al, 1992) even in the absence of splenomegaly (Lamy et al, 1997). Therefore, simultaneous determination of both the red cell mass and plasma volume is the only way to substantiate the presence of an absolute erythrocytosis (Smith et al, 1921; Berson & Yalow, 1952; Blum & Zbar, 1959; Pearson et al, 1984). As erythrocytosis is the sine qua non for polycythaemia vera, both a red cell mass and a plasma volume determination are mandatory if polycythaemia vera is a diagnostic consideration. Attempts to derive the red cell mass indirectly from the plasma volume and haematocrit (Fairbanks et al, 1996), by mathematical formula (Fairbanks, 2000) or by haematocrit criteria alone (Fairbanks & Tefferi, 2000) by definition will be inaccurate (Smith et al, 1921; Ebert & Stead, 1941; Stead & Ebert, 1941; Strumia et al, 1968; Valeri et al, 1973) and therefore unacceptable. Given the many mechanisms for erythrocytosis, the presence of an elevated red cell mass does not prove that polycythaemia vera is its' cause and non-clonal causes still need to be excluded. However, erythrocytosis is the hallmark of polycythaemia vera and in its' absence the diagnosis cannot be established. Furthermore, as elevation of the red cell mass is the most frequent cause of serious complications in polycythaemia vera (Wasserman, 1954; Chievitz & Thiede, 1962; Barabas et al, 1973; Wasserman, 1976; Anger et al, 1989a), its' presence is also the starting point for therapy. It seems unnecessary for diagnostic purposes to resort to bone marrow aspiration and biopsy (Ellis et al, 1986), in vitro clonal assay of erythroid progenitor cells (Prchal & Axelrad, 1974), or ancillary measurements of the leucocyte alkaline phosphatase, serum vitamin B12 and the unbound vitamin B12 binding capacity (Wasserman, 1971; Berlin, 1975). Polycythaemia vera is still a clinical diagnosis, while these tests are non-specific, sometimes uninformative and none establish clonality. Furthermore, in the absence of other manifestations of disease, phlebotomy is the only therapy indicated for isolated erythrocytosis when its' mechanism cannot be established. Failure to adhere to this principle has led to the development of acute leukaemia in more than one patient who did not have polycythaemia vera (Perkins et al, 1964; Modan & Lilienfeld, 1965; Modan & Modan, 1968; Najean et al, 1981). Stated differently, there is no excuse for using agents that can permanently damage the bone marrow to control an abnormality that can be corrected simply by venesection, particularly when it has been repeatedly demonstrated that these agents are not more effective than venesection but actually more harmful (Modan & Lilienfeld, 1965; Berk et al, 1981; Gruppo Italiano Studio Policitemia, 1995). As befits a chronic disorder in which there is an increasing burden of haematopoietic progenitor cells and their progeny, the complications of polycythaemia vera are many and diverse and generally a consequence of the accumulation, metabolism or transformation of these cells. Thrombosis, haemorrhage and systolic hypertension are due to the hyperviscosity associated with red cell mass expansion (Prentice et al, 1952). Historically, thrombosis, both venous and arterial, occurred in up to 40% of patients during the course of the illness (Wasserman, 1976; Anger et al, 1989a) and was the cause of death in an equal proportion (Chievitz & Thiede, 1962; Gruppo Italiano Studio Policitemia, 1995). Importantly, thrombosis was the presenting manifestation in approximately 15% of patients (Wasserman, 1976; Gruppo Italiano Studio Policitemia, 1995); haemorrhage was less frequent but has been fatal in up to 30% (Videbaek, 1950), although later estimates are much lower (Wasserman et al, 1981). Although phlebotomy is a timely, effective and safe method for controlling the red cell mass (Harrop, 1928; Falconer, 1933; Stephens & Kaltreider, 1937; Dameshek, 1950; Perkins et al, 1964; Wasserman, 1968), its' efficacy was questioned on the basis of the P.V.S.G. major clinical trial (Berk et al, 1981) in which patients in the phlebotomy arm had a higher rate of thrombosis, 31%, than those undergoing chemotherapy or treatment with 32P. However, not only was the thrombosis rate in these latter groups still substantial, 20% and 25% respectively, but the number of fatalities owing to thrombosis was also identical in all three treatment arms (Berk et al, 1981). Furthermore, overall survival was not better with chemotherapy or 32P but there was a marked increase in the incidence of acute leukaemia compared with phlebotomy alone. Subsequent studies (Gruppo Italiano Studio Policitemia, 1995; Najean & Rain, 1997a) have also demonstrated that aggressive chemotherapy was not an anecdote to thrombosis or a substitute for adequate phlebotomy. The P.V.S.G. clinical trial data posed a therapeutic dilemma as the patients treated by phlebotomy alone had a high incidence of early thrombotic events, while those treated with chemotherapy or 32P had an increased risk of later developing leukaemia, lymphoma or cancer (Berk et al, 1986). However, this dilemma was more apparent than real as the target haematocrit for phlebotomy therapy in this trial was initially 50%, a level too high for any woman and some men (Pearson et al, 1984). Indeed, even the P.V.S.G.'s own data indicated that at least 15% of patients with a haematocrit of 50% had an elevated red cell mass (Berlin, 1975). After data were published demonstrating that the incidence of thrombosis in polycythaemia vera was directly related to the haematocrit when this was greater than 45% (Pearson & Weatherly Mein, 1978), the P.V.S.G. changed the trial's target haematocrit to 45% (Berk et al, 1981). While this was appropriate from a standard-of-care perspective, there is no information about the extent to which this change was implemented by the various participants in this multicentre trial or the extent to which this change influenced the thrombosis rate in the trial's three arms. Furthermore, even a haematocrit of 45% would still be too high for some women (Drenou et al, 1992; Lamy et al, 1997). In essence, the effectiveness of phlebotomy in this, the only randomized, prospective, therapeutic trial for polycythaemia vera, and the treatment option most unpopular with the organizing committee (Berlin, 1995), was rendered unevaluable. Thus, the contentions that both phlebotomy per se and an increased phlebotomy requirement were associated with an increased risk of thrombosis (Berk et al, 1986) are unproved; the former because of study design and the latter because the phlebotomy requirement in polycythaemia vera is directly related to the available iron supply and not to disease tempo (Finch et al, 1950; Messinezy et al, 1985). Furthermore, in the absence of a consistently adequate standard of care with respect to phlebotomy, it is also unclear whether a prior history of thrombosis or advanced age are truly risk factors for recurrent thrombosis (Berk et al, 1986; Gruppo Italiano Studio Policitemia, 1995), particularly as they have not been found to be risk factors by others (Wehmeier et al, 1991). As there is no evidence for an intrinsic hypercoagulable state in polycythaemia vera other than erythrocytosis-induced hyperviscosity, reduction of the red cell mass to 42% or less in women and 45% or less in men should be the initial goal of phlebotomy therapy. Thereafter, the haematocrit level can be measured at monthly intervals and lowered to the target level for gender as necessary. With the induction of iron deficiency, phlebotomy will not usually be necessary at less than 2–3 month intervals (Dameshek, 1950; Finch et al, 1950; Messinezy et al, 1985). Importantly, iron deficiency in the absence of anaemia was not detrimental to aerobic performance in adults (Rector et al, 1982), did not cause an increase in blood viscosity (Pearson et al, 1981; Birgegard et al, 1984) and neither iron deficiency nor phlebotomy per se can increase the platelet count in a disorder in which bone marrow function is autonomous (Falconer, 1933; Stephens & Kaltreider, 1937; Kutti & Weinfeld, 1971; Messinezy et al, 1985). In patients with substantial splenomegaly, an elevated red cell mass can be masked by plasma volume expansion (Rothschild et al, 1954; Huber et al, 1964; Lamy et al, 1997); this can lead to under-treatment, particularly if it is confused (Najean et al, 1984) with the so-called ‘spent phase’ (Minot & Buckman, 1923) of the disorder. Phlebotomy can also reduce splenomegaly (Stephens & Kaltreider, 1937; Hines & Darnall, 1943; Tinney et al, 1943; Prentice et al, 1952) and systolic hypertension (Prentice et al, 1952). What is also not usually appreciated is that phlebotomy, in contrast to 32P therapy (Segel & Bishop, 1967), stimulates an increase in the plasma volume that further serves to alleviate hyperviscosity (Murray et al, 1963). Finally, the claim that phlebotomy causes or accelerates myelofibrosis (Najean et al, 1994) is not only refuted by other studies (Dameshek, 1950; Chievitz & Thiede, 1962; Perkins et al, 1964) but is also not clinically relevant. Myelofibrosis per se is a reactive process common to many illnesses (McCarthy, 1985) and must be distinguished from the disease idiopathic myelofibrosis, in which it is associated with bone marrow failure (Ward & Block, 1971). Myelofibrosis is part of the natural history of polycythaemia vera (Roberts et al, 1969; Ellis et al, 1986) but has not been shown to influence either survival (Tubiana et al, 1968; Messinezy et al, 1985; Ellis et al, 1986) or bone marrow function (Ikkala et al, 1967; Najean et al, 1978; Pettit et al, 1979; Barosi et al, 1981; Talarico et al, 1989; Perez-Encinas et al, 1994). Furthermore, myelofibrosis was not prevented by irradiation (Chievitz & Thiede, 1962), 32P (Modan & Lilienfeld, 1965; Najean & Rain, 1997a) or hydroxyurea (Najean & Rain, 1997a,b). Dyspepsia and gastric or peptic ulceration appear to be more common in polycythaemia vera patients than in the general population (Videbaek, 1950; Lawrence et al, 1953; Wasserman, 1954; Szur et al, 1959; Perkins et al, 1964). Whether this is owing to promiscuous histamine production (Westin et al, 1975) or cytokine release (Gilbert et al, 1989), circulatory stasis or a combination of these is unknown. A relationship with specific blood groups was not observed (Perkins et al, 1964) and an H2 blocker is usually an effective therapy. Hyperuricaemia owing to increased cell turnover, not altered urate metabolism (Yu et al, 1956), is common (Stroebel et al, 1951; Wasserman, 1954), but gout and renal stones occur in only 2–10% of patients (Tinney et al, 1945b; Videbaek, 1950; Wasserman, 1954; Calabresi & Meyer, 1958; Szur et al, 1959; Chievitz & Thiede, 1962; Perkins et al, 1964); allopurinol alone is a sufficient remedy when dictated by symptoms or in anticipation of chemotherapy or radiotherapy. The most serious complications other than thrombosis are pruritis, characteristically aquagenic, platelet-related microvascular occlusive phenomena or haemorrhage, organomegaly owing to extramedullary haematopoiesis and transformation to acute leukaemia. Except for the latter, none of these is usually life-threatening, but how these complications are treated can shape a patient's future clinical course. For example, pruritis is probably the most distressing symptom of polycythaemia vera but fortunately one that, for unknown reasons, occurs in less than 50% of patients (Lawrence et al, 1953; Calabresi & Meyer, 1958; Szur et al, 1959; Chievitz & Thiede, 1962; Perkins et al, 1964). The aetiology may be multifarious as in some patients pruritis is triggered by exposure to water or a change in temperature (Fjellner, 1979), while in others it may be persistent in the absence of a specific stimulus. Evidence both for (Jackson et al, 1987) and against (Buchanan et al, 1994) cutaneous mast cell activity has been obtained, and a role for histamine (Westin et al, 1975), iron deficiency (Salem et al, 1982) or platelets (Fjellner, 1979) has not been conclusively established. Interestingly, the pruritis is not always correlated with clinical evidence of disease activity (Jeanmougin et al, 1996). Given the multiple possible aetiologies and the paucity of controlled clinical trials, it is not surprising that a number of different non-myelosuppressive remedies have been anecdotally successful. These include phlebotomy (Abdel-Naser et al, 1993), aspirin (Fjellner, 1979), various antihistamines (Weick et al, 1982), synthetic androgens (Kolodny, 1996) and phototherapy (Swerlick, 1985; Morison & Nesbitt, 1993); unfortunately, in some patients suppression of haematopoiesis is required. As suppression of haematopoiesis by chemotherapy is not without significant potential toxicities, including acute leukaemia, the approach to the alleviation of pruritis should exhaust all non-mutagenic remedies first, including alpha interferon (Finelli et al, 1993; Muller et al, 1995), and starting with the least toxic of these. The second important principle in managing polycythaemia vera, particularly as it relates to leucocytosis and thrombocytosis, is to avoid over-treatment. This was best stated by Dameshek (Wasserman, 1968), ‘There seems to be a tendency in medical practice – by no means limited to haematologists – to treat almost every condition as vigorously as possible. In haematology, this consists in attempting to change an abnormal number- whether this number is haemoglobin, haematocrit, white cell count, platelet count to get normal values, whether the patient needs it or not!’ Leucocytosis per se in polycythaemia vera is rarely extreme in the absence of splenectomy and requires no therapy except for the associated hyperuricaemia. As there is no evidence that thrombocytosis causes major vessel thrombosis in polycythaemia vera (Szur et al, 1959; Berger et al, 1973; Pearson & Weatherly Mein, 1978; Kessler et al, 1982; Messinezy et al, 1985; Berk et al, 1986; Randi et al,1987; Wehmeier et al, 1991; Schwarcz et al, 1993; Najean & Rain, 1997b), asymptomatic thrombocytosis also requires no therapy unless there is evidence of a haemorrhagic diathesis. Given the potential tendency for peptic ulcer disease or haemorrhage, as well as a lack of controlled studies, the practice of routinely administering aspirin, even at a low dose (Gruppo Italiano Studio Policitemia, 1997), is unjustified. Aspirin is, of course, no substitute for adequate phlebotomy (Tartaglia et al, 1986) and at low doses can block uric acid excretion. Furthermore, a number of studies have indicated that certain patients with thrombocytosis are very sensitive to the platelet-inhibitory effects of salicylates (Barbui et al, 1987; Cortelazzo et al, 1998). The use of anagrelide (Anagrelide Study Group, 1992) to reduce the platelet count in the absence of symptoms is also unjustified as there is no evidence that an elevated platelet count per se is harmful (Wehmeier et al, 1991; Ruggeri et al, 1998) except, perhaps, to the extent that it distracts from the more important issue, the red cell mass, or the possibility that another unrelated cause for thrombosis such as the antiphospholipid syndrome (Harrison & MacHin, 1997; Randi et al, 1999) or other risk factors (Watson & Key, 1993; Lamparter et al, 1997) are present. Aspirin or ibuprofen are appropriate for the treatment of erythromelalgia (Kurzrock & Cohen, 1989) and its' central nervous system equivalent (Michiels, 1997), unless the platelet count is so high that there is a risk of haemorrhage owing to a decrease in high-molecular-weight von Willebrand multimers and low ristocetin cofactor activity (Budde et al, 1993; van Genderen et al, 1996). In this situation, a reduction in platelet number is probably indicated and anagrelide is the initial therapy of choice because it is not known to cause permanent bone marrow injury. However, it must be remembered that a reduction in platelet number alone is not a guarantee against platelet-related microvascular phenomena (Regev et al, 1997) or thrombosis (Cortelazzo et al, 1995), nor will reduction of the platelet count protect against the effects of an elevated red cell mass. In this regard, it is instructive that, in a series of patients experiencing an intrabdominal venous thrombosis, haematocrit elevation was present before the event and platelet count elevation only afterwards (Anger et al, 1989b). Finally, the safety of oral contraceptives and oestrogen replacement therapy in women with thrombocytosis is an unresolved issue. Extramedullary haematopoiesis causing organ enlargement or compromise of organ function is the most difficult management problem in polycythaemia vera because of the toxicity and temporary influence of the treatments generally used to control it. After more than a half century, it should be apparent that attempts to suppress extramedullary haematopoiesis by irradiation (Modan & Lilienfeld, 1965), 32P (Modan & Lilienfeld, 1965; Berk et al, 1981; Najean et al, 1988; Nand et al, 1990; Najean & Rain, 1997a), alkylating agents (Berk et al, 1981) or hydroxyurea (Nand et al, 1990; Weinfeld et al, 1994; Sterkers et al, 1998; Merlat et al, 1999), alone or in combination (Nand et al, 1990; Najean & Rain, 1997a), caused an unacceptable incidence of acute leukaemia (Landaw, 1986; Najean et al, 1988) without being curative, consistently effective (Stroebel et al, 1951; Szur & Lewis, 1966; Tubiana et al, 1968; Gruppo Italiano Studio Policitemia, 1995; Najean & Rain, 1997a, b) or even prolonging survival (Modan & Lilienfeld, 1965; Berk et al, 1981). Based on this accumulated experience, it is naive to assume that one chemotherapeutic agent will be less toxic than another based on observational or retrospective analysis (West, 1987; Petti et al, 1998; Passamonti et al, 2000). Just because marrow suppression caused by hydroxyurea is generally less severe and more transient than that caused by other agents does not mean that this drug is safer or more suitable for chronic use. It is clear from cytogenetic studies (Swolin et al, 1988) that there is both clonal expansion and clonal evolution in polycythaemia vera and chronic hydroxyurea therapy could conceivably facilitate the selection of more aggressive clones in addition to the drug's intrinsic mutagenic effect (Sterkers et al, 1998; Merlat et al, 1999). In this regard, there has recently been sentiment for the reintroduction of 32P for the treatment of polycythaemia vera (Brandt & Anderson, 1995; Berlin, 2000). However, the well-documented evidence that 32P is leukaemogenic and did not prolong survival as well as the fact that it was least effective when it was most needed, support the contention that 32P has no role in the routine management of polycythaemia vera. Similarly, while busulphan is effective in controlling organomegaly in polycythaemia vera (Wasserman, 1968; Brodsky, 1982), because of its' potential to cause serious tissue damage (Perkins et al, 1964; Buggia et al, 1994) as well as leukaemia (Weinfeld et al, 1977; Haanen & Mathe, 1981) it is difficult to recommend this or other alkylating agents (Logue et al, 1970; Nand et al, 1990) for routine use in this disease. Splenectomy to alleviate portal hypertension, chronic abdominal discomfort or cachexia may be necessary when splenomegaly cannot be controlled by other means, but brings with it the risk of exuberant leucocytosis, thrombocytosis (Schilling, 1980), elevation of alkaline phosphatase, extramedullary haematopoiesis in the liver (McBrine et al, 1980; Towell & Levine, 1987), the potential for intra-abdominal venous thrombosis (Broe et al, 1981) and bleeding or thrombosis if the red cell mass is increased (Wasserman & Gilbert, 1964). It has been suggested (Barosi et al, 1998) and refuted (Tefferi et al, 2000) that splenectomy is associated with the development of acute leukaemia, at least in a companion myeloproliferative disorder, idiopathic myelofibrosis, but this dispute may only reflect the fact that transformation to acute leukaemia in the chronic myeloproliferative disorders can be associated with exuberant extramedullary haematopoiesis (Porcu et al, 1999). To reduce postoperative complications, an adequate nutritional status is essential before splenectomy and this may require parenteral hyperalimentation. Preoperative evaluation for portal hypertension owing to portal vein thrombosis is also mandatory as splenectomy alone will be insufficient correct this (Tefferi et al, 1994). The risk of postoperative venous thrombosis is unknown, clinically unpredictable and may involve uncontrollable factors such as the size of the splenic vein remnant (Broe et al, 1981). The role of post-splenectomy thrombocytosis as a risk factor for postoperative thrombosis is also unresolved; it was not a risk factor for patients without myleoproliferative disorders (Boxer et al, 1978; Coon et al, 1978) and evidence for its' role in patients with these disorders is contradictory (Broe et al, 1981; Tefferi et al, 2000), in part because of failure to control for red cell mass elevation (Tefferi et al, 2000). Early postoperative ultrasound surveillance for intra-abdominal thrombosis can be hampered by bowel distension and computerized axial tomography may be necessary to establish its' presence (Petit et al, 1994; Chaffanjon et al, 1998; Loring et al, 1998). The first 4 weeks is the period of greatest risk for intra-abdominal thrombosis (Petit et al, 1994; Chaffanjon et al, 1998; Loring et al, 1998). Whether patients should be anticoagulated prophylactically after surgery has not been studied prospectively (Loring et al, 1998), but is not without risk because of the presence of a haemorrhagic diathesis in many of these patients (Malmaeus et al, 1986; Brenner et al, 1988). Postoperative bleeding, not amenable to surgical correction, can be managed effectively with epsilon amino caproic acid using a 5-g loading dose and 2 g every 2 to 4 h until haemostasis is achieved. Although hepatic enlargement owing to extramedullary haematopoiesis can be expected, it is not usually sudden in onset or massive (Towell & Levine, 1987; Brenner et al, 1988). When necessary, there are a variety of therapeutic options for suppressing hepatic myeloid metaplasia, such as alpha interferon, hydroxyurea, cytoxan, busulphan, 2-chlorodeoxyadenosine (2-Cda) (Tefferi et al, 1997) or irradiation (Tefferi et al, 2001), but the relative efficacy of these has not been evaluated in a controlled fashion. Splenic irradiation is effective in reducing spleen size (Parmentier et al, 1977) but may provide only short-term relief for a chronic problem (Elliott et al, 1998). Its' myelotoxicity is unpredictable (Parmentier et al, 1977; Elliott et al, 1998) and occasionally fatal; it may also make subsequent splenectomy more hazardous owing to the formation of adhesions (Elliott et al, 1998). Splenic irradiation is probably best reserved for splenomegaly refractory to other therapies in patients who are not surgical candidates. The introduction of alpha interferon provided a safe alternative to irradiation, chemotherapy or surgery for controlling the effects of haematopoietic cell accumulation in polycythaemia vera. First reported for this purpose by Silver (1990), the drug proved effective in suppressing red cell production in 82% of patients, alleviating pruritis in 81% and reducing splenomegaly in 77% (reviewed in Lengfelder et al, 2000). In a few patients, there was complete (Messora et al, 1994; Sacchi et al, 1994; Massaro et al, 1997) or partial (Hino et al, 1993; Petrini et al, 1996) cytogenetic conversion. However, in some studies, despite normalization of peripheral blood counts, erythropoietin-independent colony formation persisted, histamine levels were not reduced and bone marrow hyperplasia was sustained (Silver, 1997), suggesting that the malignant clone was not eradicated. The experience in essential thrombocytosis has been similar (Sacchi et al, 1998). It should also be emphasized that cytogenetic conversion may not be synonymous with suppression or eradication of the malignant clone, as the cytogenetic abnormalities in polycythaemia vera are not specific for the disease, not commonly present at onset (Swolin et al, 1988) and not necessarily representative of all clones in the bone marrow (Kanfer et al, 1992; Asimakopoulos et al, 1996). Furthermore, alpha interferon did not influence myelofibrosis (Kreft et al, 2000), prevent thrombotic events (Heis et al, 1999), completely suppress erythropoiesis (Lengfelder et al, 2000) in some patients or prevent the development of acute leukaemia in a patient previously exposed to alkylating agent therapy (Foa et al, 1998). The drug also has substantial toxicities (Kurschel et al, 1991; Sacchi et al, 1995; Silver et al, 1999), occurring both early and late, particularly when taken chronically and in patients over 60 years of age (Foa et al, 1998), and the discontinuation rate varied from 5% to 40% (Lengfelder et al, 2000). The duration of therapy before observing an effect varied from weeks for the relief of pruritis (Finelli et al, 1993) to more than a year for the reduction of organomegaly (Silver, 1997), with dose requirements varying from 1·8 to 70 million IU per week (Silver, 1997). In sensitive patients, the dose of interferon could be reduced and some were able to sustain an unmaintained remission for 35–70 weeks, depending on the stage of the disease at the start of treatment (Gilbert, 1998). Patients who relapsed off therapy remained interferon responsive (Gilbert, 1998). Given the obligatory toxicity of alpha interferon, to ensure compliance it seems prudent to initiate therapy at a very low dose (500 000–1000 000 units) with escalation as tolerated to achieve the desired effect. Antidepressant therapy may be necessary to alleviate the neuropsychiatric side-effects of alpha interferon (Valentine et al, 1998). Alpha interferon is an attractive option for alleviating the complications of cell accumulation in polycythaemia vera because it does not predispose patients to acute leukaemia. However, what is currently unknown, because only observational studies have been performed, is whether this agent improves survival or whether it is best reserved for alleviation of complications such as pruritis unresponsive to conventional measures and extramedullary haematopoiesis causing organomegaly or organ dysfunction. Its' effect on survival will be difficult to assess given the longevity of polycythaemia vera patients in general and the current lack of a clonal marker. Although in chronic myelogenous leukaemia the best results were obtained when interferon therapy was initiated early in the disease (Silver et al, 1999), the natural history of chronic myelogenous leukaemia is measured in years while that of polycythaemia vera is measured in decades (Rozman et al, 1991). Finally, the possibility that modified forms of interferon such as its' pegylated derivative, which has a longer biological half-life (Heathcote et al, 2000), might be more efficacious has not been examined. At this juncture, until the appropriate data with respect to the natural history and staging of polycythaemia vera have been obtained, it seems prudent to reserve alpha interferon for when it can be most useful, e.g. to supplant chemotherapy or radiotherapy in the control of intractable pruritis, thrombocytosis and extramedullary haematopoiesis. It is no substitute for phlebotomy. Given the average age of onset of polycythaemia vera, pregnancy is not a common occurrence in this patient population. However, there remains a small group of patients for whom this is an issue and it is the same group in whom substantial splenomegaly is not uncommon (Videbaek, 1950; Najean et al, 1987). Although there is little published information on pregnancy in polycythaemia vera, the data suggest that the association need not be unfavourable (Centrone et al, 1967; Harris & Conrad, 1967; Ferguson et al, 1983). As in non-pregnant patients, erythrocytosis is the most significant clinical problem, particularly because the expected physiological expansion of the plasma volume in pregnancy only serves to mask the true extent of red cell mass expansion. Given the experience in polycythaemia vera patients in general (Drenou et al, 1992; Lamy et al, 1997), it would be prudent to consider the haematocrit expected for the particular pregnancy stage to be indicative of an elevated red cell mass and an indication for phlebotomy. Stated differently, the haematocrit in a polycythaemia vera patient during pregnancy should never exceed 36%. This approach should also reduce the potential for hypertension and haemorrhage as well as thrombosis. Iron supplementation is contraindicated but folic acid supplementation is mandatory (Gisslinger et al, 1999; Faurschou et al, 2000). It is of interest that in polycythaemia vera, as in essential thrombocytosis (Samuelsson & Swolin, 1997; Bangerter et al, 2000), the platelet count (Ferguson et al, 1983) as well as clonal haematopoiesis (Turhan et al, 1988) can remit during pregnancy. Asymptomatic thrombocytosis requires no therapy while aspirin can be used for erythromelalgia or ocular migraine. Certainly, judging from the experience with pregnant essential thrombocytosis patients (Beressi et al, 1995; Bangerter et al, 2000), an elevated platelet count is not a significant adverse prognostic factor. Leucocytosis is usually mild and requires no therapy. Splenomegaly may require correction in anticipation of conception or control during pregnancy. Alpha interferon is the agent of choice for this. Epsilon amino caproic acid is a remedy for post-partum haemorrhage not surgically correctible. Chemotherapeutic agents or irradiation have no role in the management of the pregnant polycythaemia vera patient. A role for anagrelide remains to be established. As polycythaemia vera is a stem cell disease, curative therapy requires eradication of the malignant clone. Allogeneic bone marrow transplantation is a definitive therapy for this purpose (Anderson et al, 1997) while autologous stem cell transplantation was recently shown to have a palliative effect (Anderson et al, 2001). However, it is too early to define the role for either allogeneic or autologous bone marrow transplantation in polycythaemia vera given the median age of onset, the long survival of most patients and what needs to be learned about the disorder with respect to staging and prognosis. An exception to this may be individuals developing the disease in the first three decades of life, especially those who present with extensive extramedullary haematopoiesis (Najean et al, 1987). In the future, with further development of non-myeloablative techniques (Slavin et al, 1998), this recommendation could change. Although neoangiogenesis is a feature of the chronic myeloproliferative disorders (Wolf & Neiman, 1985) and most marked in idiopathic myelofibrosis (Mesa et al, 2000), a role for angiogenesis inhibitors (Mangi & Newland, 2000; Talks & Harris, 2000) in the management of polycythaemia vera remains to be established. The conundrum of polycythaemia vera is that it is a hybrid disorder combining the complications of a stem cell disease with the survival characteristics of a benign one. After 109 years, this conundrum remains unresolved because we still know less about the disease than we should. Fortunately, there are currently both simple and relatively non-toxic remedies for many of its' complications. Further progress with respect to the therapy of polycythaemia vera will require greater insight into its' molecular basis, as well as the identification of a clinically applicable clonal marker and the development of clinical criteria for staging and prognosis. Until these goals are achieved, the treatment of polycythaemia vera should be based on physiological principles and tailored to meet patients' clinical needs while following the doctrine of prima non nocere." @default.
W2040304882 created "2016-06-24" @default.
W2040304882 creator A5017159299 @default.
W2040304882 date "2002-02-01" @default.
W2040304882 modified "2023-10-17" @default.
W2040304882 title "THE OPTIMAL MANAGEMENT OF POLYCYTHAEMIA VERA" @default.
W2040304882 cites W135049235 @default.
W2040304882 cites W1446966563 @default.
W2040304882 cites W1484304255 @default.
W2040304882 cites W1524473364 @default.
W2040304882 cites W1538988072 @default.
W2040304882 cites W1546217975 @default.
W2040304882 cites W1555518704 @default.
W2040304882 cites W1614611218 @default.
W2040304882 cites W176998439 @default.
W2040304882 cites W1917754692 @default.
W2040304882 cites W1963876174 @default.
W2040304882 cites W1964263010 @default.
W2040304882 cites W1964900372 @default.
W2040304882 cites W1965176757 @default.
W2040304882 cites W1966839236 @default.
W2040304882 cites W1968408608 @default.
W2040304882 cites W1968887993 @default.
W2040304882 cites W1969382756 @default.
W2040304882 cites W1972837140 @default.
W2040304882 cites W1973372776 @default.
W2040304882 cites W1974576856 @default.
W2040304882 cites W1978339271 @default.
W2040304882 cites W1978513346 @default.
W2040304882 cites W1980334255 @default.
W2040304882 cites W1980464575 @default.
W2040304882 cites W1983667133 @default.
W2040304882 cites W1986004639 @default.
W2040304882 cites W1986329429 @default.
W2040304882 cites W1986623762 @default.
W2040304882 cites W1992572108 @default.
W2040304882 cites W1993687050 @default.
W2040304882 cites W1994992859 @default.
W2040304882 cites W1995096894 @default.
W2040304882 cites W1996307086 @default.
W2040304882 cites W1997867585 @default.
W2040304882 cites W1997924478 @default.
W2040304882 cites W1997944331 @default.
W2040304882 cites W1998101819 @default.
W2040304882 cites W2001307675 @default.
W2040304882 cites W2001483839 @default.
W2040304882 cites W2001758295 @default.
W2040304882 cites W2001901845 @default.
W2040304882 cites W2006799284 @default.
W2040304882 cites W2007020905 @default.
W2040304882 cites W2011707824 @default.
W2040304882 cites W2012928598 @default.
W2040304882 cites W2015203815 @default.
W2040304882 cites W2016417342 @default.
W2040304882 cites W2016807322 @default.
W2040304882 cites W2021044663 @default.
W2040304882 cites W2024051800 @default.
W2040304882 cites W2026629325 @default.
W2040304882 cites W2026777158 @default.
W2040304882 cites W2029353341 @default.
W2040304882 cites W2029800516 @default.
W2040304882 cites W2030913019 @default.
W2040304882 cites W2032801230 @default.
W2040304882 cites W2033522143 @default.
W2040304882 cites W2033946159 @default.
W2040304882 cites W2034604260 @default.
W2040304882 cites W2035969354 @default.
W2040304882 cites W2038000277 @default.
W2040304882 cites W2038611905 @default.
W2040304882 cites W2039629968 @default.
W2040304882 cites W2039956148 @default.
W2040304882 cites W2040846879 @default.
W2040304882 cites W2041084610 @default.
W2040304882 cites W2042947968 @default.
W2040304882 cites W2043656046 @default.
W2040304882 cites W2045831870 @default.
W2040304882 cites W2047449101 @default.
W2040304882 cites W2049928251 @default.
W2040304882 cites W2053047123 @default.
W2040304882 cites W2054212076 @default.
W2040304882 cites W2054653356 @default.
W2040304882 cites W2058156607 @default.
W2040304882 cites W2059046900 @default.
W2040304882 cites W2059511422 @default.
W2040304882 cites W2062538378 @default.
W2040304882 cites W2065255694 @default.
W2040304882 cites W2065575310 @default.
W2040304882 cites W2066567885 @default.
W2040304882 cites W2067309745 @default.
W2040304882 cites W2067773916 @default.
W2040304882 cites W2068068809 @default.
W2040304882 cites W2070333384 @default.
W2040304882 cites W2071080900 @default.
W2040304882 cites W2071665978 @default.
W2040304882 cites W2071788667 @default.
W2040304882 cites W2072691059 @default.
W2040304882 cites W2074319130 @default.
W2040304882 cites W2074668955 @default.