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- PATIENTS AND METHODS
Myelofibrosis with myeloid metaplasia (MMM) is an uncommon disorder in young individuals, for whom haemopoietic stem cell transplantation offers the only possibility of cure. However, although the latter procedure is associated with significant morbidity and mortality, the clinical course of MMM is variable, with some patients surviving for less than a year and others showing an indolent course. Selection of young MMM patients for transplantation or other newer therapies is currently difficult since no prognostic data exists for this subgroup. In the present collaborative study a number of initial clinical and laboratory parameters have been evaluated for prognosis in 121 MMM patients aged 55 years or less. Median survival of the series was 128 months (95% CI 90–172). In the Cox proportional hazard regression model three initial variables were independently associated with shorter survival: Hb <10 g/dl (P < 0.0001), the presence of constitutional symptoms (fever, sweats, weight loss) (P = 0.001), and circulating blasts ≥ 1% (P = 0.003). Based on the above three criteria, of the 116 patients with complete data, two groups were identified: a ‘low-risk’ group, characterized by 88 patients with up to one adverse prognostic factor, in whom MMM had an indolent course (median survival 176 months, 95% CI 130–188), and a ‘high-risk’ group, including 28 patients with two or three factors, who had a more aggressive disease (median survival 33 months, 95% CI 20–42). The above prognostic scoring system showed a high positive predictive value, sensitivity and specificity to predict survival in the series, and could be of help in making treatment decisions in young patients with MMM.
Myelofibrosis with myeloid metaplasia (MMM) is an infrequent chronic myeloproliferative disorder characterized by bone marrow fibrosis and extramedullary haemopoiesis ( Bouroncle & Doan, 1962; Burkhardt et al, 1986 ), in which the fibrosis is a reactive phenomenon secondary to a clonal haemopoietic disorder ( Jacobson et al, 1978 ). The disease affects mainly old people, with the median age at presentation of approximately 65 years in most series ( Dupriez et al, 1996 ; Cervantes et al, 1997 ; Reilly et al, 1997 ). Although patients with MMM survive for a median of 3.5–5 years ( Dupriez et al, 1996 ; Cervantes et al, 1997 ; Reilly et al, 1997 ; Barosi et al, 1988 ; Visani et al, 1990 ), there is a wide variation, with some patients surviving for decades. However, due to the low incidence of MMM in young individuals, information on the disease characteristics and prognosis in such a subpopulation is scarce ( Morel et al, 1997 ). Since no effective treatment for MMM is available, haemopoietic cell transplantation offers the only possibility of cure for young patients ( Guardiola et al, 1997 ; Anderson et al, 1997 ), but it is associated with significant morbidity and mortality. In addition, for young patients who lack a suitable donor the use of newer therapies may be justified ( Reilly, 1997). As a result, a better understanding of the disease characteristics and prognosis of younger MMM patients is important, not only to select those patients who may benefit from transplantation, but also to define the appropriate timing of the procedure, as well as to evaluate the possible survival benefit derived from newer therapeutic modalities.
To gain a better understanding of MMM and its prognosis in young patients, the main clinical and haematological features at diagnosis, as well as the clinical outcome, were analysed in 123 patients aged 55 years or younger presenting at four European centres.
- Top of page
- PATIENTS AND METHODS
Myelofibrosis with myeloid metaplasia (MMM), also known as idiopathic or primary myelofibrosis, is a chronic myeloproliferative disorder characterized by the presence of increased bone marrow fibrosis as a secondary phenomenon to the neoplastic proliferation of a pluripotent haemopoietic stem cell ( Jacobson et al, 1978 ). The disease is heterogenous in its presentation and clinical course, with median survival ranging from 3.5 to 5.5 years in recent series, although there is a wide individual variation ( Dupriez et al, 1996 ; Cervantes et al, 1997 ; Reilly et al, 1997 ; Barosi et al, 1988 ; Visani et al, 1990 ). Although MMM is considered a disease of the elderly, a number of young patients have been reported in all series. In recent years various studies have identified a number of prognostic factors in MMM, and, as a result, several prognostic scoring systems have been proposed ( Dupriez et al, 1996 ; Cervantes et al, 1997 ; Reilly et al, 1997 ; Barosi et al, 1988 ; Visani et al, 1990 ). However, there is little information on young MMM patients ( Barosi et al, 1988 ; Morel et al, 1997 ), although the identification of prognostic factors and risk-groups in this subgroup is of great clinical importance. This is because, whereas no effective therapy for MMM is currently available ( Reilly, 1997), allogeneic bone marrow transplantation offers a potential cure for young patients ( Guardiola et al, 1997 ; Anderson et al, 1997 ). However, both the substantial morbidity and the 30% mortality associated with the procedure, and the indolent clinical course of many MMM patients, makes the choice and timing of transplantation difficult ( Guardiola et al, 1997 ; Anderson et al, 1997 ). As a result, a better understanding of the prognosis in young patients with MMM is needed to enable treatment strategies to be designed for these patients. In addition, the identification of prognostic factors may be of help in evaluating the survival benefit that could result from the use of experimental treatment modalities ( Reilly, 1997).
In view of the above, we have undertaken a prognostic study of young MMM patients aged 55 years or younger, the age limit currently used by most transplant centres. Using this definition, 123 patients were identified from a total of 550 cases, representing almost a quarter of the general MMM population. The initial clinico-haematological characteristics of the 121 evaluable patients fitted the typical picture of MMM, except for a lower frequency of chromosome abnormalities when compared to that reported for the general MMM population ( Dupriez et al, 1996 ; Cervantes et al, 1997 ; Reilly et al, 1997 ; Demory et al, 1988 ). The most striking feature of young MMM patients was, however, their prolonged survival, with median survival being more than twice that reported in recent MMM series ( Dupriez et al, 1996 ; Cervantes et al, 1997 ; Reilly et al, 1997 ; Barosi et al, 1988 ; Visani et al, 1990 ). This longer survival of younger patients is also seen in other haematological neoplasias ( Montserrat et al, 1991 ), and probably reflects a better host's physical state. However, no differences were observed in either the frequency of acute transformation or the causes of death in this patient subgroup ( Dupriez et al, 1996 ; Cervantes et al, 1997 ).
In the current study three presenting features were associated with survival in young patients with MMM (anaemia, presence of constitutional symptoms, and circulating blasts). The prognostic importance of anaemia in MMM has been universally recognized ( Dupriez et al, 1996 ; Cervantes et al, 1997 ; Reilly et al, 1997 ; Barosi et al, 1988 ; Visani et al, 1990 ; Varki et al, 1983 ; Njoku et al, 1983 ; Manoharan, 1988; Rupoli et al, 1994 ). With regard to constitutional symptoms, their unfavourable prognostic influence has been demonstrated in all studies in which such clinical features were evaluated ( Dupriez et al, 1996 ; Cervantes et al, 1997 ; Varki et al, 1983 ; Njoku et al, 1983 ), and the prognostic value of circulating blasts has also been emphasized ( Dupriez et al, 1996 ; Cervantes et al, 1997 ). The lack of prognostic value of bone marrow histological findings is in agreement with the results from previous studies, both by us and others ( Varki et al, 1983 ; Pereira et al, 1990 ). In contrast, the prognostic significance of chromosomal abnormalities ( Reilly et al, 1997 ; Demory et al, 1988 ; Lawler & Swansbury, 1985) could not be confirmed, although this may reflect the small number of patients with this finding.
In the past, several attempts at defining prognostic groups in MMM have been carried out ( Dupriez et al, 1996 ; Cervantes et al, 1997 ; Reilly et al, 1997 ; Barosi et al, 1988 ; Visani et al, 1990 ; Njoku et al, 1983 ; Rupoli et al, 1994 ). Among them, those by Visani et al (1990 ) and the Lille score ( Dupriez et al, 1996 ), based on the analysis of a large number of patients, are noteworthy. Visani's scoring system is based on the presence of two adverse prognostic factors (Hb < 10 g/dl and blood granulocyte precursors >10%), and separates a low-, an intermediate- and a high-risk groups in MMM, with median survival of 81, 39 and 31 months, respectively. The Lille score, based on two features (Hb <10 g/dl and WBC < 4 or >30 × 109/l), similarly identifies three prognostic groups, with median survivals of 93, 26 and 13 months. When applied to young patients, the above scoring systems clearly identified a low-risk group of patients, but were unsuccessful in separating the intermediate- and high-risk groups. The discriminating power of both scores in the present series, however, improved when the intermediate- and high-risk groups were pooled to generate a new high-risk group of patients. The prognostic staging system recently proposed by Reilly et al (1997 ) combines age, Hb value and karyotype to identify good- and poor-risk groups in MMM. However, the low frequency of chromosome alterations observed in young MMM patients appears to limit the value of this approach. Finally, the prognostic scoring system by Cervantes et al (1997 ) enables a clearcut separation of low- and high-risk IM patients, on the basis of the presence or absence of constitutional symptoms, Hb < 10 g/dl and circulating blasts.
In the present collaborative study, in which a large number of young MMM patients were analysed, prognostic factors were identified which allowed the separation of ‘low-risk’ and ‘high-risk’ groups. The former included three-quarters of the patients, with a median survival of > 14 years, whereas the latter contained a quarter of the patients, with a median survival of < 3 years. No overlapping was observed between the standard errors of the two survival curves. The high positive predictive value, sensitivity and specificity of this staging system makes it of value for the identification of patients suitable for haemopoietic stem cell transplantation or other newer therapeutical strategies. Moreover, the above prognostic system proved to be of value also in the subgroup of younger patients (≤ 45 years), who are potential candidates for transplantation from unrelated donors.
In conclusion, the present study shows that the combination of three simple clinical and haematological features at diagnosis can provide a prognostic model in young patients with MMM. Such a schema could facilitate the therapeutic decision in such patients.