In studies to determine the optimal treatment for polycythemia vera, 431 previously untreated patients whose disease met established diagnostic criteria were entered into a prospective, randomized controlled trial between 1967 and 1974. Three treatment regimens were used: phlebotomy alone, chlorambucil supplemented by phlebotomy, or radioactive phosphorus supplemented by phlebotomy. Despite minor differences in age and sex, the three groups were comparable in initial hematocrit, white-cell and platelet counts, and disease-related symptoms. The median duration of follow-up is now more than 6 1/2 years. As of February 15, 1980, there were no statistically significant differences in survival among the groups. However, the risk of acute leukemia in patients given chlorambucil was 2.3 times that in patients given radioactive phosphorus and 13 times that in patients treated with phlebotomy alone. The increased incidence of leukemia during chlorambucil treatment is statistically significant (P less than or equal to 0.002); accordingly, the Polycythemia Vera Study Group has discontinued the use of chlorambucil in the treatment of polycythemia vera.

Essential thrombocythemia is a clonal myeloproliferative disorder, characterized predominantly by a markedly elevated platelet count without known cause. We report a case that was recognized during investigation of a transient ischemic attack, and review the neurologic findings in 33 patients with unequivocal essential thrombocythemia under prospective study by the Polycythemia Vera Study Group. Twenty-one patients had neurologic manifestations at some point during their course, including headache (13 patients), paresthesiae (10), posterior cerebral circulatory ischemia (9), anterior cerebral circulatory ischemia (6), visual disturbances (6) and epileptic seizures (2). All patients with neurologic symptoms responded satisfactorily to treatment, although continuous or repeated treatment was often required. Therapeutic recommendations include plateletpheresis for major thrombo-hemorrhagic phenomena, or megakaryocyte suppression with radioactive phosphorus, alkylating agents (such as melphalan), or hydroxyurea; minor symptoms may respond to platelet antiaggregating agents.

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Six women presented with the clinical picture of essential thrombocythemia (ET) without the anemia, marked splenomegaly, and extreme leukocytosis characteristic of chronic myelogenous leukemia (CML). All had the Philadelphia chromosome on karyotype analysis of the bone marrow. Peripheral basophilia was present in four cases, providing a clinical clue that the Philadelphia chromosome might be present. Marrow biopsy showed granulocytic hyperplasia and either small megakaryocytes or sheets of megakaryocytes with marked atypia, findings that are more typical of CML than ET. The clinical importance of finding the Philadelphia chromosome in patients who seem to have ET is in assessing prognosis. ET generally follows a chronic, indolent course. However, five of these six patients who had the Philadelphia chromosome underwent clinical transition to the accelerated phase of CML or blastic leukemia in 4-7 years.

Hemoglobin M Milwaukee (beta67E11 Val leads to Glu) is a naturally occurring valency hybrid containing two permanently oxidized hemes on the beta chains. In this mutant, the two abnormal beta chains cannot combine with ligands whereas the two alpha chains are normal and can combine with oxygen with a Hill coefficient varying from 1.1 to 1.3 [Udem et al. (1970), J Mol. Biol. 48, 489]. High-resolution proton nuclear magnetic resonance spectroscopy at 250 MHz has been used to investigate the exchangeable, ring-current shifted, ferrous and ferric hyperfine shifted resonances of Hb M Milwaukee in the absence and presence of organic phosphates. The alpha-heme environment, as manifested by the ring-current shifted resonances in the liganded form as well as the ferrous hyperfine shifted resonances in unliganded form, and subunit interactions, as manifested by the exchangeable resonances, are similar in Hb M Milwaukee to those in normal adult human hemoglobin. Organic phosphates can partially or completely inhibit the structural transformation which normally accompanies the binding of oxygen or carbon monoxide to Hb M Milwaukee. Upon stepwise addition of oxygen to deoxy Hb M Milwaukee, the hyperfine shifted resonance spectra of ferric beta chains show features which cannot be attributed to either fully deoxy or oxy species. However, the spectra for partially oxygenated Hb M Milwaukee can be described as an appropriately weighted average of the spectra of sero, singly, and doubly oxygenated species. The ferric hyperfine shifted resonance spectrum of the singly oxygenated intermediate has been calculated by a method employing least-squares analysis of the spectra of partially oxygenated Hb M Milwaukee at several values of oxygen saturation. The spectrum of this intermediate exhibits features which cannot be accounted for by a two-structure model. The present results are consistent with a sequential model for the oxygenation of this mutant hemoglobin. In view of the similarities between normal adult hemoglobin and Hb M Milwaukee, it is suggested that a two-state concerted allosteric model does not provide an adequate description of the structure-function relationship in normal adult hemoglobin.