Aleksander Weinfeld

Acute leukaemia after hydroxyurea therapy in polycythaemia vera and allied disorders: Prospective study of efficacy and leukaemogenicity with therapeutic implications

Abstract:  Fifty consecutive patients, 30 of whom had polycythaemia vera (PV), 10 essential thrombocythaemia (ET), and 10 myelofibrosis (MF), entered a long‐term prospective study of hydroxyurea (HU) therapy. The indication for treatment was mainly thrombocytosis or symptomatic splenomegaly. Control of erythrocytosis and thrombocytosis was achieved in 70% of the patients. Continuous maintenance treatment was required. In 15% of responding patients with thrombocytosis, unexpected rises of the platelet count occurred during maintenance therapy. Severe thrombo‐embolic events occurred in 6 patients. The size of the spleen decreased in all patients who did not develop thrombocytopenia and could absorb adequate HU doses. Acute leukaemia (AL) was diagnosed in 9 patients and a myelodysplastic syndrome in one. Seven of them had been treated with HU alone. Among the patients with PV and ET, 6 developed AL and 4 of them were treated with HU alone (3 PV and 1 ET), giving an incidence of 10.5%. In previously untreated patients with initially normal karyotypes (n = 19), chromosome abnormalities developed during HU therapy in 7 (37%). Our results indicate that HU should be regarded as leukaemogenic, at least when used for treatment of PV and allied diseases. Since myelosuppressive treatment of PV does not prolong survival, the use of HU should be restricted to patients in whom the treatment indication outweighs the risk of leukaemia induction.

Platelet survival and platelet production in idiopathic thrombocytopenic purpura (ITP).

Summary. Platelet mean life span (MLS) and platelet production were measured in 3–5 patients with idiopathic thrombocytopenic purpura (ITP) and in 21 healthy subjects.

Karyotypic evolution in Ph-positive chronic myeloid leukemia in relation to management and disease progression

In a prospective study of 32 patients with chronic myeloid leukemia the frequency of chromosome abnormalities in addition to the Philadelphia chromosome (Ph) increased when the disease progressed. Before metamorphosis, 10 patients (31%) had developed additional abnormalities. Such abnormalities were present in three of them at the time of diagnosis; in the other seven, they were detected late in the chronic phase. New clonal abnormalities heralded or accompanied a more malignant phase of the disorder, usually a blastic leukemia. During metamorphosis, 78% of the patients had additional abnormalities, which in 68% of these cases comprised at least one of +8, +22q- or i(17q). Clones with additional abnormalities disappeared in eight cases, either spontaneously or in association with cytostatic therapy during the chronic or blastic phase. Involvement of chromosome #8, usually in the form of a trisomy, was found in 7 of 12 patients treated with busulfan, but was not found in any of the 10 hydroxyurea-treated patients, of whom 8 were splenectomized early during the chronic phase. Cells from the spleen, obtained by fine needle aspiration or splenectomy were cytogenetically examined in 18 cases during the chronic phase, but abnormalities in addition to the Ph were noted in only one patient, who was examined in the late chronic phase. The same abnormalities were present in bone marrow cells of this patient.

Cytogenetic studies of bone marrow and extramedullary tissues and clinical course during metamorphosis of chronic myelocytic leukemia

Of 33 consecutive patients with chronic myelocytic leukemia, examined during metamorphosis, 82% showed chromosome abnormalities in addition to the Ph1. Aberrations most frequently encountered were +8 (39%), +22q - (30%), and i(17q) (18%). Translocations other than the Ph1 were observed in four cases and - Y clones in four cases. Discrepancies in the cytogenetic pattern between bone marrow and extramedullary tissues or blood were noted in a total of 15 patients. In six cases, transformation occurred in extramedullary organs at a time when it was not present in the marrow. In three cases the bone marrow transformation was preceded by a lymph node blastic infiltrate; in one case, by a skin infiltrate; and in one case, by a subdural blastoma. Clonal abnormalities additional to the Ph1 were identified in the tumor tissue from all these cases. Patients with primary extramedullary transformation tended to have a lower median age at onset of metamorphosis, shorter survival, and higher incidence of chromosome abnormalities than the cases without extramedullary involvement. Patients with only Ph1-positive cells and no other anomalies had a slightly longer duration of metamorphosis and longer total survival. Basophilia and thrombocytopenia were more marked in cases with i(17q) than in the rest of the series.

Cytogenetic abnormalities in acute leukemia complicating melphalan-treated multiple myeloma

The cytogenetic findings in 11 patients with multiple myeloma in whom a myelodysplastic syndrome or an acute nonlymphocytic leukemia developed are reported. All patients were treated with oral melphalan for 2-9 years in a total dose of 0.5-4.1 g. When examined during the myelodysplastic or leukemic phase, all patients had an abnormal bone marrow karyotype, hypodiploid in nine of the 11 cases. The chromosome abnormalities were clearly nonrandom and comprised a 5q deletion in three cases, monosomy 5 in four cases, deletion 7q--in two cases, and monosomy 7 in three cases. Loss of material from the long arm of chromosomes 5, 7, or both was found in eight patients. The different chromosome abnormalities were not associated with any specific morphological or clinical features.

Histamine symptoms and histamine metabolism in chronic granulocytic leukaemia

Histamine metabolism was investigated in three patients with chronic granulocytic leukaemia (CGL) during symptoms suspected to be caused by histamine release. Plasma histamine levels were excessively high compared with periods when the patients were symptomless or with CGL patients without such symptoms. The patients seemed to be adapted to high plasma histamine levels as the symptoms were not typically systemic in nature, but rather localized phenomena like oedema and pruritus in the extremities. Also CGL patients without symptoms showed abnormally high plasma histamine concentrations, which were significantly related to the whole blood histamine concentration. The possibility must be considered that part of the plasma histamine increase is artificial due to rupture of the basophils during the blood collection procedure.

In vitro Labelling of Platelets

Duplicate platelet survival studies, using autologous platelets labelled in vitro with radioactive sodium chromate, were carried out on 5 lymphoma patients who had been splenectomized 14–21 months ear