590 Correspondence MEGA-DOSE METHYLPREDNISOLONE FOR APLASTIC ANAEMIA

In the recent Clinical Annotation about severe aplastic anaemia (Hows, 1991) several approaches to therapy were clearly discussed but megadose methylprednisolone (MDMP) treatment was not mentioned. This treatment could be important for children with aplastic anaemia without a suitable donor for bone marrow transplantation and also for children who do not have the opportunity to have transplant- ation (as in underdeveloped countries).

We have been using MDMP in the treatment of childhood aplastic anaemia since 1979 (c)zsoylu et a/, 1984). Only one of the 14 children originally treated died because of disease recurrence. There was recurrence in another patient when he started to work in a printing house, but he responded again to MDMP when he changed his job. Another patient died from a cause unrelated to his disease. Although acid haem and sucrose-water tests became positive in four patients during follow-up, clinically they are asymptomatic and haernatologically normal in terms of peripheral blood findings.

I would like to emphasize that MDMP is cheaper than the other approaches mentioned by Dr Hows. In addition, MDMP is available everywhere and the side-effects are minimal when used as advised by us (ozsoylu, 1990).

Since 5-1 0 mg/kg methylprednisolone has been described as 'high dose' (Suarez et a / . 1986: Forgeson et a/, 1988). we call the doses (of 30 mg/kg and greater) used by us 'megadose', although it is the same dose as in our previous studies (c)zsoylu et al, 1984: c)zsoylu. 1990).

advanced previously treated multiple myeloma patients. British journal of Cancer. 58, 469-473.

Hows. J.M. (1991) Severe aplastic anaemia: the patient without a HLA identical sibling. British journal o l hoe ma to log^/. 77, 1-4.

Oasoylu. S. (1 990) High dose intravenous methylprednisolone (HIVMP) in haematologic disorders. Hematolog/ Rfvirws, 4, 197- 207.

~zsoylu . $., Cogkun. T. & Minassasi. $. ( 1 984) High dose intravenous glucocorticoid in the treatment of childhood acquired aplastic anaemia. Scandinavian Iournal of Haeniatology. 33, 309-3 16.

Suarez. C.R.. Rademaker. D.. Hasson. A. & Mongogna. L. (1986) High dose steroids in childhood acute idiopathic thrombocytopenic purpura. American Joirrnal of Pediatric Hematology and Oncology. 8. 11 1-1 15.

Thank you for the opportunity to comment on Professor ozsoylu's letter about megadose methylprednisolone (MP) 3 0 mg/kg/d for treatment of severe aplastic anaemia (SAA).

This regimen was first developed in the early 1980s in Genova by Andrea Bacigalupo. Subsequent studies indicated that the regimen was ineffective compared with anti-lympho- cyte globulin. In addition, considerable toxicity has been reported by ourselves and other groups. Side-effects qf mega MP include infective risk, grand ma1 convulsions, diabetes mellitus. and, in the longer term, avascular necrosis of the femoral head.

While I accept Professor c)zsoylu's point about treatment costs, I think that there is good evidence that low-dose cyclosporin at 3-5 mg/kg/d for 3 months is more effective and less toxic than MP as a 'low cost' regimen. In addition, the former can be given on a n outpatient basis whereas the latter cannot: this certainly keeps the costs of treatment low. Cyclosporin is now available in most developing countries and has been successfully used to treat SAA in the [J.S.S.R.

SINASI OZSOYLII Hucettepe University Faculty of Medicine, Drpartment oj Paediatrics. Haematology Unit, and Hacettepe Children's Hospital, Ankara. Turkeu

REFERENCES

Department of Haematology, Rogal Postgraduate Medical School, Hammersmith Hospital.

JILL M. Hows

Forgeson. C.V.. Selby. P.. Lakhani. S.. et a1 (1988) Infused vincristine and adriamycin with high dose methylprednisolone (VAMP) in

DuCane Road, London W 1 2 U N N

THE TREATMENT OF MYELOFIBROSIS WITH ALFA-INTERFERON

Alfa-interferon suppresses proliferation of megakaryopoietic and other haemopoietic colony forming units in vitro (Ascari et a/. 1987: Carlo-Stella et a/, 1987). In addition, gamma- interferon suppresses collagen synthesis by murine fibro- blasts in vitro (Amarta et al, 1987) and reverses the increased platelet levels of platelet derived growth factor and transform- ing growth factor-B in patients with myelofibrosis in vitro (Calvo et al, 199 1). These activities suggest that it might be a useful agent for treating patients with idiopathic myelofibro- sis. A single case report suggested that alfa-interferon treatment improved a patient with idiopathic myelofibrosis (Gill rt al. 198 7). However, it appeared not to be of benefit in a

series of 10 myelofibrosis patients treated in Denmark (Hasselbach et al, 1988).

Recently Anthony et a1 (199 1 ) reported two patients whose spleens decreased in size during treatment with alfa- interferon. Treatment had to be discontinued in one because of thrombocytopenia.

We have treated eight patients for idiopathic myelofibrosis with recombinant alfa-interferon (Intron-A). Their median age was 45 (37-54) years. Seven were in chronic phase and, of these, two were transfusion dependent. One was in acute phase. The treatment (3 mu x 3/week) was tolerated for 6 months by six patients without significant side-effects other

Correspondence 59 1

than mild ‘flu-like’ symptoms. One discontinued after 4 weeks because of ‘flu-like’ side-effects and another required reduc- tion of the dose to 3 mu x 1 /week because of deterioration of pre-existing neutropenia. The general clinical status. spleen size, hirematological indices, peripheral blood granulocyte- macrophage precursors (CFIJ-GM) and amino terminal pro- collagen peptide (which reflects the level of collagen synthe- sis) were monitored approximately every h weeks. There was no improvement or deterioration in the performance status of any evaluable patient except in the patient in acute phase whose disease progressed with increasing numbers of blast cells in the blood. Their haemoglobin levels remained unchanged and the transfusion requirements did not alter in the transfusion-dependent patients. The platelet counts were constant in four patients but decreased in two patients from 22 I to 1 3 0 x 1 Oy/l and from 2 5 3 to 108 x I OY/L respectively. All patients had splenomegaly at the start of their treatment. After 3 months of treatment the spleen had decreased in size in three patients (1 8 to 1 3 , h to 3 , 12 to 6 cm below the left costal margin) but had increased to its original size in all by 6 months despite continuing treatment.

The peripheral blood CFU-GM numbers were evaluable in five patients. In three they decreased markedly to between 5% and 2Yj(, of the pre-treatment levels. Their numbers increased at least to pre-treatment levels within 2 months of stopping treatment. In two patients the CFU-GM levels did not change. In contrast, Anthony rL ul(1YY 1 ) detected transient elevations in the CFU-GM members during treatment. How- ever, the extent ofvariability over time ofprogenitor numbers in untreated patients with myelofibrosis is not well docu- mented.

We conclude that at this dose level alfa-interferon. as a single agent. is not a useful treatment for this group of patients. It does, however. have a biological effect as evidenced by the transient decrease in spleen size in some patients, Trephine biopsy was not performed after treatment to access fibrosis because of the lack of clinical benefit or fall in the procollagen amino terminal peptide level. It remains possible that at higher doses or in combination with new cytokines. alfa-interferon might be beneficial. However, when it was reintroduced because of progressive splenome- galy at a dose of 3 mu x 5/week 3 months after stopping

treatment in one patient whose spleen had initially res- ponded, it had no effect on the splenic enlargement over a period of 2 months.

ACKNOWLEDGMENTS

We are grateful to the haematology physicians who treated patients in this multicentre trial: Dr C. Costello. Westminster. Dr C. Barton, Royal Berkshire. Dr A. Mehta, Royal Free, Dr J. Shirley. Frimley Park, Dr M. Treacy. Chase Farm, and to Dr Anne Simmonds. Schering Plough, for the supply of Inter- feron and procollagen amino terminal peptide assay kit.

Cliaring Cross and Westminster

‘University Collegr Hospital, FRANK GILES* London

DONALD MCCARTHY Hospital. und JULIE CLARK

REFERENCES

Amarto. E.P.. Byrne. M.H.. Grantstein. R.D.. Margolis. R.J. & Murphy, C.F. (1987) Gamma interferon inhibits collagen synthesis in vivo in the mouse. lournal oICfirtiruf Ittvrstiyution. 79, 1 2 5 4 .

Anthony. R.S.. Craig. J.I. & Parker. A.C. ( 199 1 ) Circulating progeni- tor cells in myelotibrosis: the effect of recombinant alfa 28 interferon i n vivo and in vitro. British /ournu1 or Haematolny~y. 78,

Ascari. E., Baresi. G., Carlo-Stella, C.. Carzola. M.. Dazza. L.. Ganser. A,. Meloni. F.. Melzer. 11. & Pedrazzoli. P. (1987) Effects of recombinant and gamma interferons on the in vitro growth of circulating hematopoietic stem cells (CFIJ-GEMM. CFIJ-MK. BFU- C, and CFU-GM) from patients with myelotibrosis and with myeloid metaplasia. Blood. 70, 101 4- 1 0 19.

Calvo. F.. Magdelenat. H. & Martyre. M.C. (1991) Interferon-alfa in vivo reverses the increased platelet levels of platelet derived growth factor and transforming growth factor B in patients with myelofi- brosis with myeloid metaplasia. British /ournu/ ofHarrnnto/og.y. 77, 4 3 1 - 4 3 5 .

Carlo-Stella, C.. Ganser. A.. Creher. J . , Hoelzer. D. b; Vokers. B. (1987) Effects of recombinant interferons alpha and gamma OR human bone marrow derived megakaryocyte progenitor cells. Blood. 70,

Gill. D.S.. Peart. S. & Wickramasinghe, S. (1977) Alfa interferon in

Hasselbach. H. (1988) Interferon in myelofibrosis. Lancet. i. 3 5 5 .

1 5 5 - 1 6 0 .

1173-1 179.

primary idiopathic rnyelofibrosis. Lancet. ii, 1524-1 52 5.

A BS E N C E 0 F GRAFT- V ER S U S - 1, E 1J K A EM I A (G V 1, ) EFFECT BY LEU C OCY T ES TRANSFUSED : A PROSPECTIVE RANDOMIZED TRIAL I N ACUTE MYELOID LEUKAEMIA (AML) PATIENTS

Tucker rt ul ( 1 989) drew attention to the potential anti- leukaemic effect of blood transfusion and the loss of this benefit to leukaemic recipients of leurocyte poor (LP) blood components. In our institution. between 1984 and 1989. patients presenting with acute myeloid leukaemia (AML) were enrolled in a randomized prospective clinical trial to evaluate the efficacy of prophylactic granulocyte trans- fusions as a means of preventing infection. The patients were randomized to receive granulocyte transfusions and standard ( S ) blood components or LI’ red blood cells (RBC) and apheresis platelet concentrates (APC). This prompted us to

compare the disease-free survival (DFS). the risk of relapse and the survival of patients given granulocyte concentrates (GC) and standard blood products (S group) or LP red blood cells and APC (LP group).

Out of 1 0 5 AML adult patients, five with previous anti- HLA alloimmunization and four presenting with severe sepsis yielding to granulocyte transfusions, were not randomized in the initial trial. 21 patients with secondary AML. subtype known to affect prognosis (MRC. 1975) , and eight patients with promyelocytic leukaemia who received random platelet concentrates during haemorrhagic syndrome, were not