AUTOLOGOUS BLOOD STEM CELL TRANSPLANTATION IN ACUTE MYELOID LEUKAEMIA

419 relief from the GTN patch but did not the lumbar sympathectomy. respond Therefore the GTN patch predicted the outcome of lumbar sympathectomy in 15 of 16 patients (94%). The only side-effect noted was headache in 1 patient who responded to paracetamol. This hypothesis and preliminary study warrant further

patient had symptomatic to

investigation. Department of Surgery, St Mary’s

HAMID T. KHAWAJA PAUL C. WEAVER

Hospital,

Portsmouth PO7 7JH

Topical glyceryl trinitrate as adjunctive treatment in Raynaud’s disease. Lancet 1982, i: 76-77. 2 Hecker JF, Lewis GBH, Stanley H. Nitroglycerine ointment as an aid to venepuncture. Lancet 1983; i: 332-33. 3. Mason DT, Braunwald E. The effects of nitroglycerin and amyl nitrite on artenolar and venous tone in the human forearm. Circulation 1965; 32: 755-66. 1 Franks AG Jr

AUTOLOGOUS BLOOD STEM CELL TRANSPLANTATION IN ACUTE MYELOID LEUKAEMIA

SIR,-Our experience with autologous blood stem cell transplantation (ABSCT) in acute myeloid leukaemia (AML) differs from that of Dr Laporte and colleagues (Dec 12, p 1393). Of the 26 patients treated by ABSCT in our unit in 1984-87, 18 had AML and 12 of these patients were transplanted during first or second complete remission. 5 patients (median age 36 years, range 19-50) were transplanted during their first complete remission, achieved after one course of chemotherapy with intravenous daunorubicin 60 mg/m2 daily x 3 and cytarabine 100 mg/m2 daily by continuous infusion x 10. They then received consolidation with high-dose cytarabine 3 g/m2 x 8 and daunorubicin 45 mg/m2 x 3. Five or six leukaphereses were done" during the marrow regeneration period. 4 weeks after the leukaphereses the patients were conditioned with oral busulphan 4 mg/kg for 4 days and intravenous melphalan 140 mg/m2 before ABSCT. A median number of 15.1 x 10 CFU-GM/kg (3’5-26’8) was infused (table). Engraftment was observed in every case. However, 1 patient is still thrombocytopenic (30 x 109/1) 90 days after ABSCT. No further chemotherapy was given to these patients, who remain in continuous complete remission 3-10 months after ABSCT and 6-13 months after initial diagnosis. 7 other AML patients (median age 32 years, range 15-51) relapsed after a first remission lasting 9-60 months (median 16-5) and were treated in first relapse by high dose cytarabine 3 g/m2 x 4 doses and intravenous amsacrine 150 mg/m2 daily x 5 .2 as were for the first-remitters. were done, Leukaphereses They given ABSCT 1-3 months later, after a preparative regimen including etoposide (600 mg/m), cyclophosphamide (120 mg/kg), and fractionated total body irradiation (400 Gy x 3) (5 patients), or busulphan-melphalan, as used for patients transplanted in first EXPERIENCE OF ABSCT IN

I

*CFU-GM dose infused ( 10’; kg) thaemopoietic recovery to PNtN

12

AML PATIENTS

I

1

I .

polymorphonuclears (0 5 x 10"!1L leucocytes ’10"’)), R=renculocytes (20xt0"/t), P=platelets (50 x 10°/I or normal marrow megakaryocytes); ND = not done =

=

complete remission.

1 patient had no megakaryocyte engraftment and died from intestinal haemorrhage.3 The other 6 patients had complete engraftment (table) but 2 patients had a prolonged thrombocytopenia, probably due to immune destruction since normal megakaryocytes were present in bone marrow smears. 3 of these patients had recurrent leukaemia 3-5 months after ABSCT while the other 3 remain in complete remission at 7, 15, and 26 months. In 1 patient the completed remission after ABSCT lasted longer than the first, pre-ABSCT, remission had done. Haemopoietic reconstitution can be achieved after ABSCT. Such findings have previously been reported in patients with acute leukaemias, non-Hodgkin lymphomas, solid tumours, and myeloma.4-{, However, unlike- Laporte et al we did not see early leukaemic relapses after ABSCT: 5 patients transplanted in first complete remission are still alive and in remission. These encouraging results must now be confirmed in a larger series with longer follow-up-but the pessimistic report of Laporte et al, on only 4 patients, does not seem definitive.

J. REIFFERS Bone Marrow Transplant Unit, Hôpital Haut Levêque, Centre Hospitalier Regional Bordeaux, 33604 Pessac, France

G. MARIT B. DAVID PH. BERNARD A. BROUSTET

J, Vezon G, Bernard Ph, et al. Collection of circulating granulocytemacrophage precursors in patients with acute non lymphocytic leukaemia Plasma Ther Transfus Technol 1986; 7: 93-95. Marit G, David B, Reiffers J, et al. Traitement des leucémies aigues myeloides par amsacrine et hautes doses de cytosine arabinoside. essai phase II. Bull Cancer 1985;

1. Reiffers

2

72: 37-41 3. Reiffers J, Mant G, Bernard Ph, et al. Autologous transplantation of circulating stem cells in acute non lymphocytic leukaemia. In: Dicke KA, Spitzer G, Jagannath S, eds Autologous bone marrow transplantation. Houston University of Texas MD Anderson Hospital and Tumour Institute, 1987. 675-79 4. Reiffers J, Castaigne S, Tilly H, et al. Hematopoietic reconstitution after autologous blood stem cell transplantation. a report of 46 cases Plasma Ther Transfus Technol

(in press). LB, Jutmer CA Penpheral blood stem cell autografting. a new therapeutic option for AML? Br J Haematol 1987; 66: 285-88 6. Bell AJ, Hamblin TJ, Oscier DJ Circulating stem cell autografts. Bone Marrow Transpl 1986, 1: 103-10 5. To

SiR,—We share Dr Laporte and colleagues’ anxiety about relapses after autografting with peripheral blood stem cells (PBSC) in acute myeloid leukaemia (AML). However, several firstremission patients transplanted with PBSC have not relapsed beyond one year.’We have used this approach in three such patients. None have relapsed 13, 9, and 2 months after autotransplantation. Our conditioning regimen uses the busulphan/ cyclophosphamide combination, which may be associated with a lower relapse rate in both allogeneic and autologous transplantation.’-’ The risk of relapse should now be evaluated in a, larger series, and the multicentre study of PBSC autografting that has started in Australia may provide an answer within 3 years. The results of purged autologous bone marrow transplants in AML reported on by Laporte et al are impressive, but results may worsen as further cases accumulate. The relapse rate in first remission allogeneic transplantation, where there is no question of leukaemic contamination of the stem cells, is 20-25%, and it is hardly conceivable that purged autologous bone marrow transplantation in unselected patients would give better results. Patient selection is important. "Standard risk" AML has been defmed in a way that excludes many patients likely to relapse early. Were the patients receiving PBSC autografts reported on by Laporte et al standard risk? The timing of autotransplantation is also important. Patients already in remission for a long time are less likely to relapse. We have studied 106 patients with AML treated with DAT induction chemotherapy and consolidationbut no maintenance. Survival and the apparent plateau in the survival curve for the 59 patients (56%) who achieved complete remission and for those patients who were still in remission at 3, 6, 9, 12, 18, and 24 months are shown in the table. A patient in remission for a long time seems more likely to remain in remission and become "a likely cure", even without further chemotherapy or transplantation. Thus, series which include patients who have been in remission for a year or more before transplantation will have a low post-graft relapse rate because of this selection bias. This is an important factor

420 RELAPSE AND DISEASE-FREE SURVIVAL

the addition of desmopressin (’DDAVP’, Ferring) to the regimen resulted in an almost normal bleeding time. A 36-year-old woman with medullary cystic disease treated by haemodialysis since 1975 complained of nosebleeds and subcutaneous haematomas. Kidney transplantation in 1977 and de-transplantation in 1982 were by severe blood losses and large deep haematomas, and the patient needed 10 packed red-cell transfusions and 15 platelet concentrates. The only abnormal haemostatic test was increased bleeding time ("Simplate", Organon Technika). Von Willebrand factor, platelet aggregation by ADP and collagen, thrombin and ristocetin times, and prothrombin and partial prothromboplastin times were normal. Although bleeding time remained high (table), the nosebleeds were occasionally controlled,1,2 either by desmopressin infusion (0-3 3 Ilg/kg) or by oestrogen. The steroid could not be used more than once because of menorrhagia two weeks after the injection. The patient has been receiving rHu-EPO since 1986 (haemoglobin [Hb] 8-4 g/dl), with a weekly dose of 192 U/kg3 (Hb in December, 1987, 11-5 g/dl), with incomplete improvement of bleeding time and nosebleeds. The addition of desmopressin then made bleeding time nearly normal. Under this combined regimen subtotal parathyroidectomy was done without any abnormal blood loss.

complicated

in all transplantation series. In our prospective multicentre study all patients will have transplants within 3 months of diagnosis to avoid

this bias. Stem cell dose (CFU-GM) is important too.8,9 Our recent experience with patients who had low levels of PBSC very early in remission is that sufficient stem cells can be collected after consolidation with 2 days of daunorubicin 60 mg/m2 and 5 days of intravenous cytarabine 100 mg/m2 12-hourly and oral thioguanine 100 mg/m2 12-hourly. In two such patients four aphereses yielded 84 x 104 and 107 x 104 CFU-GM/kg body weight. While our intention remains to use cells collected during the recovery after induction chemotherapy-because of the simplicity of this approach and its ability to shorten the total treatment phase-the feasibility of post-consolidation PBSC collection will allow the technique to be used in more patients. The post-consolidation stem cell collections may also have lower leukaemic contamination, as suggested by Laporte et al. We agree that the number ofleukaphereses done should be as few as possible. With the assistance of the Baxter Centre for Medical Reseach, we hope to refme the collection technique to make it possible to collect an adequate stem cell dose with two or three

aphereses. C. A. JUTTNER Division of Haematology, Institute of Medical

and Veterinary Science, Adelaide, South Australia 5000

P. G. DYSON L. B. TO J. Q. K. HO D. N. HAYLOCK M. M. ROBERTS

AJ, Hamblin TJ, Oscier DG. Circulating stem cell autograft. Bone Marrow Transpl 1986; 1: 103-10. 2. Reiffers J, Bernard Ph, Marit G, et al. Collection of blood-derived haemopoietic stem cells and applications for autologous transplantation. Bone Marrow Transpl 1986;1 (suppl 1): 371-72. 3. Tilly H, Bastit D, Lucet JC, Esperou H, Monconduit M, Piguet H. Haemopoietic reconstitution after autologous peripheral blood stem cell transplantation m acute leukaemia. Lancet 1986; ii. 154. 4. Castaigne S, Calvo F, Douay L, et al. Successful haematopoietic reconstitution using autologous peripheral blood mononucleated cells in a patient with acute promyelocytic leukaemia. Br J Haematol 1986; 63: 209-11. 5. Santos GW, Tutschka PJ, Brookmeyer R, et al Marrow transplantation for acute non-lymphocytic leukaemia after treatment with busulfan and cyclophosphamide. N Engl J Med 1983; 22: 1347-53. 6. Yeager AM, Kaizer H, Santos GW, et al. Autologous bone marrow transplantation in patients with acute non-lymphocytic leukaemia, using ex vivo marrow treatment with 4-hydroperoxycyclophosphamide. N Engl J Med 1986; 315: 141-47. 7. Tutschka PJ, Copelan EA. Bone marrow transplantation following a new busulfan and cyclophosphamide regimen-results after 3 years of observation. Exp Hematol 1987; 15: 601 (abstr). 8. To LB, Dyson PG, Juttner CA. Cell-dose effect in circulating stem cell autografting. 1. Bell

Lancet 1986; i 404-05 9. To LB, Juttner CA

for AML?

Peripheral blood stem cell autografting: a new therapeutic option Br J Haematol 1987, 66: 285-88.

ADDITION OF DESMOPRESSIN TO RECOMBINANT HUMAN ERYTHROPOIETIN IN TREATMENT OF HAEMOSTATIC DEFECT OF URAEMIA

SIR,-Dr Moia and colleagues report (Nov 28,

p

1227)

improvement in the haemostatic defect plus correction of anaemia in uraemic patients treated with recombinant human erythropoietin (rHu-EPO, Cilag-Ortho-Amgen). Their patient 7 only partly responded. We have seen a similar case. In our patient on rHu-EPO treatment we noticed incomplete correction of bleeding time, but

December,

EFFECTS OF DRUGS AND rHu-EPO ON BLEEDING TIME

(MIN)

The improvement of bleeding time during treatment with rHu-EPO might be related either to the correction of anaemia and/or to the qualitative improvement of red cells. A possible effect of rHu-EPO on megakaryocytes has also been reported.’ However, both Moia and colleagues’ experience and our case indicate that the correction is incomplete in a few patients. Our observation suggests that supplementary administration of demopressin may achieve normal bleeding time in these patients. r’...... T.

"-’r>....-.-,",""-’

CH JACQUOT

AURA Haemodialysis Centre, 75015 Paris, France; and Hôpital Broussais, Paris

J. P. MASSELOT J. M. BERTHELOT

CILAG Laboratories

F. PETERLONGO J. P. CASTAIGNE

PM, Remuzzi G, Pusineri F, et al. Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia. N Engl J Med 1983; 308: 8-12. 2. Liu YK, Kosfeld RE, Marcum SG. Treatment of uraemic bleeding with conjugated oestrogen. Lancet 1984; ii: 887-90. 3. Jacquot Ch, Ferragu-Haguet M, Lefebvre A, Berthelot J-M, Peterlongo F, Castaigne JP. Recombinant erythropoietin and blood pressure. Lancet 1987; ii: 1083. 4. Ishibashi T, Koziol JA, Burstein SA. Human recombinant erythropoietin promotes differentiation of murine megakaryocytes in vitro. J Clin Invest 1987; 79: 286-89. 1. Mannucci

ANALGESIC EFFECTS OF ORAL FLECAINIDE

SIR,-Dr Dejgard and colleagues (Jan 2/9, p 9) show that mexilitine was superior to placebo in relieving the pain of chronic diabetic neuropathy. This finding supports the potential role of membrane-stabilising agents in the management of pain associated with damage to the nervous system. There is another important clinical application of these findings, namely the control of pain associated with malignant infiltration of nerves. We have treated 17 patients with oral flecainide, 100 mg twice daily. These patients have had pain in one or more dermatomes, associated with sensory changes in the painful area. The patients have had malignant infiltration of brachial plexus (6), lumbar plexus (4), sacral plexus (2), or individual nerve roots (2); 1 patient had pain associated with paraneoplastic peripheral neuropathy. 2 patients had coeliac plexus involvement. The patients had either been unsuitable for or had failed nerve blocks; some had refused to have nerve blocks. 15 patients were already receiving morphine and still had severe pain. 6 patients had complete analgesia, lasting until death 1-26 weeks later. 4 patients are alive and pain-free after up to 8 months on