The very-long-term follow-up of patients initially included in the PVSG protocols provides useful information. The excess risk of cancer after chlorambucil appears to persist for 5 years after stopping this treatment. The risk of leukaemia induced by marrow suppression (32P or chemotherapy) was marked before the 10th year, but low thereafter. Phlebotomy is unacceptable as permanent treatment because of the poor clinical tolerance and the frequency of vascular complications. This treatment is also associated with a risk of early progression towards myelofibrosis with myeloid splenomegaly. In the very long term, 15 years or more after the diagnosis, this complication is the major clinical risk, affecting almost 50% of our patients surviving at this time. The prevention of this type of complication could constitute one of the objectives of future protocols dealing with this disease.

Fifty-one cases of pure, primary erythrocytosis were identified and followed at Hôpital Saint-Louis, Paris, and compared with 350 cases of polycythemia vera (PV) observed during the same period. At the initial evaluation, these cases did not differ from PV cases with respect to age, sex ratio, degree of red cell volume increase, and clinical symptoms. They did differ by the absence of splenomegaly, granulocytosis and thrombocytosis. At a late stage of evolution only a few cases developed classical criteria of PV. From this group of apparently homogeneous cases, two subgroups evolved. Sixty percent of the cases were highly responsive to myelosuppression with 32P. The median duration of the first remission was greater than five years, the mean yearly dose of 32P was very low, and there was a low incidence of complications. The other group (40% of cases) was relatively resistant to myelosuppressive agents. The development of better methods of investigate this disorder might help in discriminating these two groups from both an etiological and pathophysiological viewpoint. The thromboembolic risk of these diseases suggests that myelosuppressive therapy should be utilized in older patients with higher risk of vascular accidents, reserving phlebotomy for younger patients and those who are shown to be resistant to 32P therapy.

SUMMARY The site of sequestration of 51Cr‐labelled platelets has been studied in 465 subjects, of whom 317 suffered from idiopathic thrombocytopenic purpura. The validity of the method was demonstrated in several ways: a given subject usually showed the same site of platelet sequestration when investigated more than once even after a long interval; there were characteristic and very different platelet sequestration curves in the thrombocytopenias due to bone marrow hypoplasia, hypersplenism or ITP; and there was a correlation between the preoperative in vivo results and the radioactivity found in the spleen after splenectomy. In ITP the destruction of labelled platelets was more often splenic in children and in patients whose thrombocytopenia responded to steroid therapy. There was a perfect correlation between the site of platelet destruction and the platelet rise immediately after splenectomy. There was a good correlation between the site of platelet destruction and the long‐term effectiveness of splenectomy.

Over 20 years, 58 cases of PV in young people (46 meeting the full PVSG criteria, 12 with elevated red cell volume and leucocytosis or thrombocytosis, without splenomegaly) were studied and have been followed for periods of 3-24 years. These cases represent approximately 5% of the cases of PV referred to the Department of Nuclear Medicine of St Louis Hospital during this period. They differ from older patients in the initial clinical severity, the short interval between the first symptoms and the diagnosis, frequent presentation with a life-threatening complication (two cases of hepatic vein thrombosis, six thrombotic or haemorrhagic events, six splenectomies, two abortions) and a very enlarged spleen in half the cases. However, after the initial complications, the overall survival is very long (exceeding 70%, even when including the initial complications, at 15 years). The vascular accidents occur exclusively in the phlebotomized patients, the main risk factor being the poor stability of the haematocrit. Only one acute leukaemia was observed among the 14 cases treated by radioactive phosphorus and/or alkylating chemotherapy. The most frequent late complication was evolution towards myelofibrosis. This spent phase seemed to occur earlier in patients treated by phlebotomy. On the basis of this data, we would advise the following therapeutic strategy: phlebotomies, as soon as the diagnosis is established, and a systematic long-term treatment by hydroxyurea with the hope of reducing the number of vascular complications and of delaying the evolution towards the spent phase and the myelofibrosis.

The analysis of 288 cases of polycythemia vera (PV) with a minimal follow-up of 10 years enabled us to study the characteristics of acute leukemia as observed in 33 patients (11.4%). In 50% of the patients (16 of 33), the malignant transformation is of the refractory anemia with excess of blasts (RAEB) type. Half of these further transform to acute nonlymphocytic leukemia (ANLL). Their life expectancy is not better than patients who abruptly develop ANLL. Leukemic transformation shows a frequency peak in the eighth year after initial evaluation in PV treated with chemotherapy and in the 11th year in patients treated with radiotherapy. In 30% of the patients myelofibrosis, or the spent phase of PV, is present before the transformation to acute leukemia (AL). This complication is, however, part of the natural history of PV and is observed in 20% of PV patients at 10 years when leukemic transformation is absent. Marrow fibrosis can therefore not be considered as a preleukemic phase. It was also noted that the occurrence of myeloid metaplasia/myelofibrosis is more frequent and begins earlier in patients treated by phlebotomy alone, and who do not transform to leukemia. The clinical characteristics of these AL, including high frequency of partial marrow invasion, difficulties in cytologic classification, a peak incidence similar to that in patients treated by chemotherapy or radiotherapy for a prior malignancy, multiple chromosome abnormalities, and poor response to therapy are all highly suggestive of secondary leukemias.

Eighty-three patients with myelofibrosis have been studied by erythrokinetics and have been followed up until death or for at least 12 months. Because of a large plasma volume the venous haematocrit gives only a poor idea of the red blood cell volume. The red cell survival was reduced in the majority of cases but significant haemolysis was rare. The amount of haemolysis of autologous and isologous red cells was similar, suggesting an extra-corpuscular origin for the haemolysis. Plasma iron turnover was always increased, sometimes markedly, but red cell iron incorporation was reduced in 70% of cases, indicating ineffective erythropoiesis. Surface counting showed an absence on diminution of sacral iron fixation and a rapid and marked splenic uptake in more than 90% of the cases; uptake of iron by the liver occurred in half the cases, usually not very high; iron release from the spleen was absent or reduced in 67% of the cases. The degree of ineffective erythropoiesis as measured by radio-iron incorporation and release by the spleen, the amount of haemolysis, and the red cell volume were strongly correlated with prognosis. These factors enabled a more precise prediction to be made of the clinical outcome in the 2 years following the study, than the clinical data alone. A prospective study might show whether erythrokinetic studies are also useful in determining the choice of treatment.

An analysis of the risk of progression towards leukemia, carcinoma and myelofibrosis was performed in 93 patients treated by 32P alone (PVSG protocols) since 1970-1979, 395 patients over the age of 65 years treated by 32P with or without maintenance therapy using hydroxyurea (French protocol) since 1980-1994, and 202 patients under the age of 65 treated by either hydroxyurea or pipobroman since 1980. The risk of leukemia, or myelodysplasia, or lymphoma in the 32P-treated patients was 10% at the 10th year, but increase after that time to reach a value of about 30% at the 20th year, in the surviving case. This risk was not dose-related. Despite a marked reduction of the cumulative 32P dose in the patients maintained by hydroxyurea, the actuarial risk was 19% at the 10th year. In the patients treated exclusively by non radio-mimetic agents (hydroxyurea or pipobroman) a risk of 10% at the 10th year was observed. The risk of carcinoma (excluding skin cancers) was about 15% at the 10th year in the 32P-treated cases, a value similar to that generally reported by the French statistics. There was no prevalence of digestive carcinomas. In contrast, the patients receiving 32P and hydroxyurea as maintenance had an excess risk: 29% at the 10th year. In the relatively young cases treated by non radio-mimetic agents, the risk was similar in both arms: 9% at the 10th year, similar to the expected incidence at this age. The risk of myelofibrosis with myeloid metaplasia was still relatively low at the 10th year, about 15% in all arms, but increased towards a value higher than 30% in the patients surviving at the 20th year. At the present time, but in only a few cases with long-term following, no myelo-fibrosis with splenic metaplasia has been observed in the pipobroman-treated cases. The present results, which need to be confirmed (the present analysis has been done in spring 95) suggest that:-the use of non radio-mimetic agents does not protect against leukemic transformation, which may be a consequence of the disease; rather than of the treatment,-maintenance therapy after initial use of 32P increases the risk of both leukemia and carcinoma,-and hydroxyurea does not delay the risk of developing myelo-fibrosis, in comparison with 32P alone.

In vivo kinetic studies of granulocytes labelled in vitro with 51Cr and DF32P were carried out in nine haematologically normal subjects by isolation of the cells in the blood samples by the Ficoll-Isopaque flotation method. 51Cr and 32P specific activity of blood samples made of 93-98% granulocytes was studied. Distribution between marginated and circulating granulocyte pools was identical for both labelled cells and the marginated pool was similar to the circulating pool, except that it was lower in one subject who had a previous splenectomy. The half-disappearance time (T 1/2) was 16.1+/-2.2 h for 51Cr-labelled and 5.4+/-2.1 hr for DF32P-labelled granulocytes. In one case of a normal subject who previously received multiple transfusion homologous 51Cr-labelled granulocytes had a T 1/2 of less than 1 h.