HYDERGINE AND REVERSIBILITY OF CYCLOSPORIN NEPHROTOXICITY

394 then done in the fully or partly informative families, and after a further 7-8 days the status of the fetus should be known. Such hurried arrangements are not ideal. The couple’s decisions and consideration of the options may be rushed and less clearsighted than usual, while clinical and laboratory staff are under pressure. CVS is ideally done between 9 and 11weeks, so late referral in the first trimester is an especially difficult problem. Planned schedules of laboratory work are disrupted, results on other families are delayed, and small batches of work escalate costs. Unexpected results cause additional problems-for example, when we identified two sets of twins at the time of ultrasound scan, the couples required further counselling and we had to consider double chorionic biopsy. Several couples with affected children would like to plan pregnancies if their DNA tests prove informative, and reliable first trimester prenatal diagnosis is possible. There will always be some who become interested only after a pregnancy ensues. The 48 families who attend our CF clinic include 15 couples at risk who are still fertile, and 6 of these are interested in the possibility of prenatal testing. Proportions elsewhere are likely to be similar, and we recommend that paediatricians and general practitioners should offer to arrange testing for fertile parents of their CF patients, before the onset of a further pregnancy. Laboratories like ours would like to give priority to the testing of such couples. If we know whether the RFLPs are informative before a pregnancy this will permit calm counselling and a more dispassionate consideration of the options. Pregnancies will be reported earlier and clinicians and laboratory workers will be able to plan their work better. We thank the

Cystic Fibrosis Research Group,

St

Mary’s Hospital,

London, for their invaluable help and Irene Smeaton for technical assistance. Cystic Fibrosis Clinic and Clinical Genetics Unit, Royal Manchester Children’s Hospital, Manchester M27 1HA; and Department of Medical Genetics, St Mary’s Hospital, Manchester 1.

MAURICE SUPER GARRY HAMBLETON ROB ELLES MARTIN SCHWARTZ RODNEY HARRIS

Super M. Prenatal diagnosis of cystic fibrosis. Lancet 1986; i

510

BONE MARROW TOXICITY OF CYCLOSPORIN IN A KIDNEY TRANSPLANT PATIENT

SiR,—The bone marrow toxicity of azathioprine is well recognised but reported cases of such toxicity with cyclosporin are rare and not clear-cut.1,2 We report a case of profound leucopenia in a renal transplant patient treated with cyclosporin. This 30-year-old man was first transplanted in September, 1983, and conventional therapy (azathioprine 100 mg daily and low-dose prednisone) was given. Because of progressive leucopenia, beginning 3 weeks after transplantation, the azathioprine dose had to be tapered to 25 mg

daily, which allowed the white blood cell count (WCC) to stabilise at 0x10’/I. A year later renal function gradually declined and the patient went back on dialysis in December, 1984. Progressive withdrawal of immunosuppression allowed the WCC to return to normal. This patient received a second graft in January, 1986, and was given oral cyclosporin (8 mg/kg daily in two divided doses, then adjusted according to whole blood concentration) and prednisone 0-3 mg/kg daily. No other drug was added. 2 weeks after transplantation, a rejection episode was treated with three courses of intravenous methylprednisolone 1 g daily. The WCC, which had been normal until rejection occurred, progressively fell a week later and in the fourth week after transplantation it was 0-12 x 109/1

(neutrophils 23%, basophils 2%, eosinophils 1%, lymphocytes 13%, monocytes 11 %). Red cells and platelet counts were normal. Bone marrow biopsy was compatible with drug toxicity. Granulopoietic tissue was almost totally destroyed and replaced by extended islets of fatty tissue. A pronounced proliferation of histiocytic reticulum cells was noted which displayed phagocytosis of neutrophilic granulocytes. Erythropoiesis and megakaryopoiesis lineages were not altered.

WCC and serum creatinine in relation to cyclosporin dose. Solumedrol

=

intravenous

methylprednisolone.

There were no symptoms of infection and the patient had no serological evidence of cytomegalovirus or herpesvirus infection. No circulating antibodies against granulocytes were found. Cyclosporin was withdrawn. As the WCC rose graft function deteriorated, indicating rejection. In week 5 (WCC 0-4 x 109/1) cyclosporin was reintroduced, but despite the low dose (2-4 mg/kg daily) the WCC again fell. Graft biopsy revealed severe rejection without signs of nephrotoxicity. Renal function deteriorated and dialysis was required. Immunosuppressive therapy was interrupted’ when the WCC was 0-34 x 109/1. 1 week after withdrawal of cyclosporin the WCC was normal and it remained normal thereafter. This case demonstrates cyclosporin bone marrow toxicity. It appears that, besides being nephrotoxic, cyclosporin may adversely affect bone marrow, the mechanism being unknown. Abnormal of to conventional myeloid sensitivity precursors immunosuppressive agents, as in our patient, may be a factor. Urology Clinic, Hôpital Tenon, 75020 Paris; and Nephrology Service, Hôpital St Jacques, Clermont Ferrand, France

F. MICHEL J. C. BAGUET CH. GRAPIN L. MONJOT PH. THIBAULT N. GAZUY

Bradley M. Side effects of cyclosporine in 100 renal allograft recipients Transplant Proc 1983; 15: 3150. Tilney NL, Strom TB, Garovoy MR, Lazarus JM. Cyclosporine A in cadaver renal allografts. Kidney Int 1981; 19: 265.

1. Ota B, 2.

HYDERGINE AND REVERSIBILITY OF CYCLOSPORIN NEPHROTOXICITY

SIR,-Dr Nussenblatt and colleagues (May 24, p 1220) found hydergine unhelpful in reducing cyclosporin-induced renal toxicity in uveitis patients. They suggest that the hydergine dosage of 3 mg daily may have been insufficient and that the renal changes may have become structural and irreversible.1 We have found that larger

395 INFLUENCE OF HYDERGINE ON ERPF AND GFR (ML/MIN) IN THREE PATIENTS TREATED WITH CYCLOSPORIN

doses of hydergine are not helpful either. Three patients with a successful kidney graft were studied 8, 22, and 24 months after transplantation. No patient showed signs of chronic rejection. Patients were maintained on unchanged therapeutic regimens throughout. Cyclosporin levels in whole blood were 0-15,0-23, and 0-16, respectively. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined simultaneously by a continuous infusion method (lz5I-iothalamate/l3lI-hippurate) before, after 4 weeks’ treatment with 6 mg hydergine daily, and after four weeks of treatment with 12 mg daily. Neither dosage regimen improved renal function (table) and the ERPF fell slightly. Is cyclosporin nephrotoxicity reversible? In our study in twelve kidney graft patients2 who had been on the drug for 6 weeks to 24 months cyclosporin levels were 0-15-0-20. ERPF and GFR were measured before and after an infusion of low-dose dopamine (0-8 g/kg/min) over 2 h. No cardiac effects were observed. GFR was not significantly influenced by dopamine infusion. These observations accord with the findings of Nussenblatt et al. However, ERPF rose significantly from 190 to 209 ml/min (p < 0-005), which proves that there was no irreversible vascular damage to the kidney.

Department of Internal Medicine, Academic Hospital Maastricht, P.O. Box 1918, NL-6201 BX Maastricht, The Netherlands

T. L. KHO R. KENGEN K. M. L. LEUNISSEN J. TEULE J. P. VAN HOOFF

AG, Austin HA III, Balow JE, et al. Renal histopathologic alterations in patients treated with cyclosporine for uveitis. N Engl J Med (in press) 2. Kho TL, Teule J, Leunissen KML, et al. Nefrotoxic effect of cyclosporin A (CyA) can be reversed by dopamine. Transpl Proc (in press) 1. Palestine

BONE MARROW TRANSPLANTATION IN CHILDHOOD LYMPHOBLASTIC LEUKAEMIA

SIR,—Dr Chessells and her colleagues (May 31, p 1239) compare chemotherapy and allogeneic bone marrow transplantation (BMT) in children with acute lymphoblastic leukaemia (ALL) and found no significant difference between the two groups. We question the selection of patients for this study and suggest an alternative interpretation of the data. Allogeneic BMT has generally been used for high-risk patients with ALL. The reason for the inclusion of patients who relapse after cessation of therapy as part of Chessells and colleagues’ BMT study is not clear since results from several centres-and this is confirmed by Chessells’ reports-indicate that children with ALL who relapse after cessation of therapy are generally not high-risk patients in that many have long remissions with conventional chemotherapy.1 On the other hand, in patients relapsing while still on therapy, allogeneic BMT has been shown to be superior to chemotherapy in patients followed up for five or more years in studies from two centres.24 The superiority of transplantation in patients who relapse on therapy is also suggested by Chessells’ limited data where one of five transplant patients survives disease-free, compared with one of twenty-one chemotherapy patients. An alternative approach to Chessells’ data is to evaluate patients by the treatment administered rather than by the arm to which they were assigned. 3 non-transplanted patients were included in the

transplant arm and 1 transplanted patient was in the non-transplant arm. 2 of the 3 non-transplanted patients were in relapse when admitted for transplant, which indicates that there was some delay in admission for transplant. If then data are evaluated by treatment administered, 6 of 11 (55%) of the marrow transplant patients are alive and off all treatment from 14 months to 5 years. Also, inspection of the disease-free survival curve (which includes the 3 questionable patients) indicates that the last relapse or death in the transplant arm occurred before 1years and that the curve appears to plateau at about 35% while death or relapses continue to almost four years in the chemotherapy group with the curve currently at about 20%. We suspect that by limiting the analysis to high-risk patients who relapse on therapy, by analysis using treatment received, and with more patients and longer follow-up, Chessells et al will be able to conclude that marrow transplantation should not be delayed in second remission, and that the imperfect procedure of allogeneic or autologous5 marrow transplantation is the best available treatment for high-risk refractory ALL,2-4,6 WILLIAM WOODS NORMA RAMSAY

University of Minnesota, Minneapolis, Minnesota 55455 USA 1. Rivera

G, Aur RJA, Dahl GV, et al. Second cessation of therapy in childhood lymphocytic leukemia. Blood 1979; 53: 1114-20. 2. Woods WG, Nesbit ME, Ramsay NKC, et al. Intensive therapy followed by bone marrow transplantation for patients with acute lymphocytic leukemia in second or subsequent remission: Determination of prognostic factors (a report from the University of Minnesota Bone Marrow Transplant Team). Blood 1983; 61: 1182-89. 3. Woods W, Ramsay NKC, Kersey JH. Long term follow up of individuals undergoing allogeneic bone marrow transplantation for acute lymphocytic leukemia. J Clin Oncol (in press). 4. Thomas ED, Sanders JE, Flournoy N, et al. Marrow transplantation for patients with acute lymphoblastic leukemia: a long term follow up. Blood 1983; 62: 1139-41. 5. Ramsay N, Le Bien T, Nesbit M, et al. Autologous bone marrow transplantation for patients with acute lymphoblastic leukemia in second or subsequent remission: Results of bone marrow treated with monoclonal antibodies BA-1, BA-2, BA-3 plus complement. Blood 1985; 66: 508-13. 6. Dinsmore R, Kirkpatrick D, Flomenberg N, et al. Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia. Blood 1983; 62: 381-88.

SIR,—The analysis of the relative benefits of bone-marrow transplantation (BMT) versus chemotherapy alone as forms of therapy for lymphoblastic leukaemia continues to cause problems. Like Dr Trigg (July 12, p 102), we do not think that the conclusions drawn by Chessells et al from 11 children receiving BMT in second or subsequent complete remission (CR) are accurate. We have also noted in

our

series of

over

100 bone-marrow

transplants for acute lymphoblastic leukaemia (ALL) that the length of first remission is highly significant in predicting the subsequent behaviour of the disease. 27 of these patients were children. Comparison of groups of patients with ALL is particularly difficult since each patient has an individual "pace" of disease. Success or failure of a form of treatment (chemotherapy or BMT) is therefore best judged in the light of each patient’s prior track record-the length of their first remission. Chessells et al did not give data to show how many of their 11 patients survived for longer than the duration of their first remission, and how many of the group receiving chemotherapy did so? This would be interesting even though such small numbers are involved. Criticisms of patient selection causing bias to one or other group can be partially eliminated in this way. Data so far suggests that individual patients with relapsed ALL given chemotherapy alone only rarely survive for longer than the duration of their first remission. However, patients who received inadequate primary therapy (for example, in the early UKALL trials) may well have long subsequent remissions with adequate therapy. In our series of 27 children (age < 14 years at the time of BMT), 12 are alive (11 in continuous complete remission and 1 in remission after a relapse post BMT 3 years ago). 15 are dead (9 relapses and 6 transplant-related deaths). In 9 of the living patients survival after BMT has exceeded the lengths of their first remission, as was the case in 1 patient who subsequently relapsed and died. Our overall actuarial survival

at

6 years for BMT in childhood is

43.5%. The length of first CR is plotted against the duration of