British Journal of Haematology, 1989, 72, 467-474
`
`Case Reports
`
`5-AZACYTIDINE TREATMENT IN A p0 -THALASSAEMIC PATIENT UNABLE TO BE TRANSFUSED
`DUE TO MULTIPLE ALLOANTIBODIBS
`
`-
`
`We report here on a patient with homozygous beta0
`thalassaemia of known molecular genotype who survived
`without need for transfusion until age 11. Red cells were then
`given because of severe anaemia, pneumonia and congestive
`heart failure. Splenectomy was performed and he did well until
`age 14. when he began an elective hypertransfusion regi(cid:173)
`men. He experienced a catastrophic haemolytic transfusion
`reaction and was found to have anti-E, c, Jkb, fyb, s and Kell
`antibodies, as well as a panagglutinin with H and I reactivity
`(Giblett et al. 1965). No compatible blood could be found
`thereafter, but the patient remained relatively well with a
`haemoglobin concentration ranging from 6 ·0 to 9·0 g/dl.
`At age 29 he was evaluated for iron overload due primarily
`to hyperabsorption. Remarkable marrow hyperexpansion
`was evident, especially in the ribs as revealed by chest X-ray
`(Fig IA). He had evidence of mild end organ damage, and iron
`was chelated with desferrloxamine over the next several
`years: liver iron. as measured non-invasively, fell to 2 5 S µg/g
`wet Uver, within the normal range.
`At age 36 the patient developed exercise intolerance and
`was found to have right-sided heart failure and hypoxaemia.
`Cardiac catheterization revealed normal wall motion. a
`cardiac output of 18 I/min, and a mean pulmonary artery
`pressure of 5 5 mm. No intracardiac or intrapulmonary
`shunts were present, but massive peripheral shunting in his
`abnormally expanded marrow space (Fig 1 A) was postulated
`to account for his high cardiac output and pulmonary
`hypertension. Pulmonary function tests revealed a profound
`restrictive defect also contributing to his hypoxaemia.
`
`By age 38 t he patient was severely incapacitated despite
`optimal supportive care. On physical examination he had
`severe cachexia, signs of right-sided heart failure, and
`hepatomegaly. The haemoglobin concentration was 6· 2 g/dl
`and the reticulocyte count 3· 2%. A trial of 5-azacytidine was
`begun. Four separate courses were given (Fig I C): after the
`first two intravenous courses of 2 mg/kg/d for 5 d, his
`haemoglobin recorded a maximum of 9· 2 g/dl; his weight
`increased 1 · 5 kg, his oxygen requirements decreased, and he
`reported increased exercise tolerance. No significant de(cid:173)
`creases in white blood cell or platelet counts occurred. An
`oral course of 5-azacytidine 2 mg p.o. three times a day given
`with tetrahydrouridlne was ineffective and his haemoglobin
`fell. He experienced a spontaneous rib fracture while stretch(cid:173)
`ing. His cardiopulmonary function continued to deteriorate.
`despite improvement of his Hb concentration after a third i. v.
`course of 5-azacytidine. He became progressively more
`hypoxaemic and died of respiratory failure.
`This patient illustrates the complexity of classification of
`the severe beta thalassaemla syndromes. Genetically he was
`homozygous for two beta0 alleles. and ultimately he experi(cid:173)
`enced major complications characteristic of the untransfused
`thalassaemia major syndrome. However. he survived for over
`two decades without transfusion. and indeed often had a Hb
`concentration consistent with the classification of thalassae(cid:173)
`mia intermedia. Ultimately severe anaemia and progressive
`lung disease due to marrow expansion (Fig lA) led to
`symptomatic deterioration and prompted a trial of 5-azacyti(cid:173)
`dine.
`
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`
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`
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`April
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`May
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`30 10 20 30 10 20 30 10
`July August
`June
`
`Fig 1. (A) Chest roentgenogram obtained at age 29. (B) 500 x magnification of rib bone marrow obtained at autopsy, stained with Periodic-acid
`Schiff. (C) Haemoglobin levels during the 4-month period described. Solid bars above the graph denote administration of 5-azacytidine.
`467
`
`

`

`468
`
`Case Reports
`
`5-Azacytidine has been shown to increase HbF synthesis
`and partially correct anaemia in thalassaemic individuals,
`while hydroxyurea, another agent that increases HbF syn(cid:173)
`thesis, has been less effective (Ley et al, 1982, 1983). The
`potential carcinogenicity of 5-azacytidine has prohibited its
`use in patients for whom other therapy is feasible. In this
`patient we hoped that 5-azacytidine would increase the
`percentage of erythroblasts making significant amounts of
`gamma chains and thereby diminish ineffective erythropoie(cid:173)
`sis. The regimen chosen was that shown to be most effective
`in earlier studies, namely continuous intravenous infusion
`over 5 d (Nienhuis et al. 1985). Dramatic increases in Hb
`concentration occurred at times consistent with effects of 5-
`azacytidine (Fig IC). Our experience with this patient
`suggests that 5-azacytidine may be useful in severely anae(cid:173)
`mic thalassaemic individuals in whom transfusions are
`contraindicated.
`Unfortunately, by the time this patient received 5-azacyti(cid:173)
`dine his cardiopulmonary deterioration proved irreversible,
`despite his promising haematologic response. Autopsy
`revealed massive expansion of the marrow space, with
`marked thickening of the ribs and resultant contracted lung
`volumes. Histologically there was profuse erythroid hyper(cid:173)
`plasia. Numerous histiocytes containing abundant Periodic(cid:173)
`acid-Schiff positive cytoplasmic material took up greater than
`50% of the marrow space (Fig 18). These cells have
`previously been reported to occur in untransfused patients
`with thalassaemia major and resemble the foamy histiocytes
`found in primary phospholipid storage disorders (Sen Gupta
`et al, 1960). They are presumed to result from phagocytosis
`
`and incomplete digestion of the huge load of phospholipids
`derived from cell membranes of mature and immature
`erythrocytes. This degree of extramedullary haematopoiesis
`and erythrophagocytosis has rarely been seen since the
`advent of aggressive transfusional therapy.
`
`Clinical Haematology Branch,
`National Heart, Lung and Blood Institute,
`Bethesda, Maryland 20892, U.S.A.
`
`CYNTHIA DuNBAR
`WILLIAM TRAVIS
`Y. w. KAN
`ARTHUR NIENHUIS
`
`REFERENCES
`
`Giblett, E.R .. Hillman, R.S. & Brooks, L.E. (1965) Transfusion
`reaction during marrow suppression in a thalassemic patient with
`a blood group anomaly and an unusual cold agglutinin. Vox
`Sanguinis. 10, 448-459.
`Ley, T.J .. DeSimone, J., Anagnou, N.P., Keller, G.H., Humphries, R.K.,
`Turner, P.H .. Young, N.S .. Heller, P. & Nienhuis A.W. (1982) 5-
`Azacytidine selectively increases y-globin synthesis in a patient
`with p+ thalassemia. New England fournal of Medicine, 307, 1469-
`1475.
`Ley, T.J .. DeSimone, J .. Noguchi, C.T., Turner, P.H., Schecter. A.N.,
`Heller, P. & Nienhuis. A.W. (1983) 5-Azacytidine increases y(cid:173)
`globin synthesis and reduces the proportion of dense cells in
`patients with sickle cell anemia. Blood, 62, 370-380.
`Neinhuis, A.W., Ley, T.J., Humphries, R.K .. Young, N.S. &Dover, G.
`(1985) Pharmacological manipulation of fetal hemoglobin syn(cid:173)
`thesis in patients with severe P-thalassemia. Annals of the New York
`Academy of Sciences, 445, 198-211.
`Sen Gupta, P.C., Chatterji, J.B .. Mukherjee, A.M. & Chatterji, A.
`(1960) Observations on the foam cell in thalassemia, Blood, 16,
`1039-1044.
`
`TREATMENT OF CHRONIC MYELOMONOCYTIC LEUKAEMIA WITH LOW DOSE ETOPOSIDE
`
`The optimal management of chronic myelomonocytic leuk(cid:173)
`aemia (CMML) is unknown. It is agreed that those patients
`who are asymptomatic with a slight monocytosis should be
`kept under observation only. For those in whom the disease
`follows an aggressive course with increasing leucocytosis,
`anaemia and/or thrombocytopenia, or who develop extrame(cid:173)
`dullary effects such as hepatosplenomegaly. serous effusions
`(Mufti et al, 1984) or skin infiltrations (Copplestone et al,
`1986) and for the 30% that transform to AML (Worsley et al,
`1988) treatment remains controversial. Hydroxyurea, 6-
`mercaptopurine, 6-thioguanine, razoxane and low-dose sub(cid:173)
`cutaneous cytosine arabinoside have all been used with some
`success but there is no evidence to suggest which agent is
`most effective or even whether survival is improved.
`Between 1983 and 1987 we treated 10 consecutive
`patients with CMML with oral etoposide. Details are given in
`Table I. We have found empirically that a dose of 100 mg a
`day for 3 d is sufficient to achieve a rapid fall in WBC and
`resolution of serous effusions and that 50 mg twice weekly is
`effective both as a maintentance dose and as initial treatment
`when there is less need for a rapid response.
`Sustained clinical benefit was obtained in seven of the I 0
`patients treated. The most dramatic response was seen in two
`patients who presented with life-threatening pericardial and
`
`pleural effusions, which resolved after 1 week of treatement.
`Similarly good results were obtained in those patients with
`monocytic skin infiltrates. Approximately 50% of the patients
`with anaemia or thrombocytopenia responded, especially
`when there was concomitant spenomegaly. Less benefit was
`obtained in those patients with increased blasts in the blood
`or marrow.
`This regimen was extremely well tolerated with only two
`patients developing minor degrees of hair loss and one patient
`experiencing mild gastrointestinal side effects. Whether
`etoposide has any advantage over other oral cytotoxic agents
`or over low dose cytosine arabinoside is uncertain. We have
`treated a further 10 patients with hydroxyurea. In nine there
`was control of the leucocytosis but five developed a trans(cid:173)
`fusion requirement during maintenance therapy; a problem
`we did not encounter with etoposide. A further eight patients
`received razoxone in doses ranging from 12 5 mg twice
`weekly to 2 50 mg daily. Seven achieved good control of the
`leucocytosis and in four there was an improvement in the
`platelet count. One patient had rapid resolution of a pleural
`effusion. Only one patient (patient 1) sequentially received all
`three drugs in an attempt to control a rapidly rising white cell
`count and pleural and pericardial effusions. There was no
`response to hydroxyurea 2 g daily for 3 d but transient benefit
`
`