437 REVERSAL OF BLAST-CELL CRISIS IN C.G.L. BY TRANSFUSION OF STORED AUTOLOGOUS BUFFY-COAT CELLS

SIR,-We have treated

with chronic granulocytic teukxmia (c.G.L.) in blast-cell transformation with five cytotoxic drugs followed immediately by transfusion of his own buffy-coat cells that had been collected 15 months previously and stored in liquid nitrogen.1.2 We hoped by this manoeuvre to restore his disease to a chronic phase that could once again

1.

a

patient

Lowenthal, R. M., Park, D. S., Goldman, J. M.,

34,105. 2. Goldman, J. M., Th’ng, K.

et

al.

Br. J. Hœmat. 1976,

H., Park, D. S., et al. ibid. (in the press).

be controlled

by simple chemotherapy.

rapidly re-established but so far been required over a 6-month period. was

A second chronic

no

further

phase

treatment

has

34-year-old man presented with headaches and lassitude April, 1976. His spleen was palpable 15 cm below the left costal margin. Hb 9.00 g/dl, leucocytes 360x 109/1, and platelets 142xl09/1. The blood-film was typical of C.G.L. and the neutrophil alkaline phosphatase (N.A.P.) score was 0 (normal 30-96). The Philadelphia (Ph’) chromosome was present in dividing marrow cells. Buffy-coat cells were collected from the blood by leucapheresis on three occasions over a 2-week period, frozen, and stored in liquid nitrogen. He was then treated with single doses of busulphan (100 or 150 mg) whenever the leucocyte-count rose above 15.0x109/1. Splenectomy was done A

in

Fig. I--Clinical and haematological course from onset of transformation. Cytotoxic drugs: course 1, daunorubicin 90 mgx3, cytarabine (Ara-C) 180 mg/day i.v. infusionx7 days, 6-thioguanine 280 mg/dayx7 days; course 2, doxorubicin 50 mgx3, Ara-C 180 mg/day i.v. infusionx7 days, VP 16-213 180 mg/dayx7 days. Bone-marrow cellularity: +=reduced, ++=normal, +++=increased, ++++=packed. Carb.=carbenicillin, Gent.=gentamicin.

Fig. 2-C.F.U.c and leucocyte numbers in the blood at diagnosis and subsequently. Leucocyte and C.F.u.c numbers are shown immediately before and 1h after the transfusion on each of the 2 days.

438 in September, 1976. On May 2, 1977, he received his ninth dose of busulphan (150 mg), but 6 weeks later (fig. 1) the peripheral-blood leucocyte-count was 114 x 109/1 with 37% blast

cells, 8% promyelocytes, 14% myelocytes, 3% metamyelocytes, 12% neutrophils, 1% eosinophils and 25% lymphocytes. The was 42. Bone-marrow showed densely cellular with 23% blast cells and 16% promyelocytes. The blast cells resembled myeloblasts: myeloperoxidase was identified by light and electron microscopy and tests for B and T cell markers, acute lymphoblastic leukxmia antigen, and terminal deoxynucleotidyl transferase3 all gave negative results. A single Ph’ chromosome was present in all marrow metaphases examined. On June 16 the first of two courses of the regimen we now use for acute myeloid leukaemia (A.M.L.) (fig. 1) was given. Blast cells quickly disappeared from the blood. A high fever developed and the patient was treated with antibiotics and granulocyte transfusions. (Granulocytes collected from a donor with C.G.L., but not those collected from normal donors, were routinely irradiated in vitro to 1500 rad.) A marrow trephine biopsy on July 4 showed extreme hypocellularity. The second course of cytotoxic drugs was started on July 5. On July 11 the leucocyte-count was 0-3x10 VI (all lymphocytes) and platelets were 53 x 109/1 (after platelet transfusions). 2 days later stored buffy-coat cells were rapidly reconstituted and transfused over 2 h periods on 2 consecutive days. He received 7. X 1010 leucocytes each day. 2 h after the first transfusion the leucocyte-count had risen to 2.3x109/1 (5% myelocytes, 10% metamyelocytes, 76% neutrophils, 9% lymphocytes) and the platelets to 233xl0"/l. Thereafter the leucocyte-count fell steadily, reaching a nadir on the sixth day, and then began to rise rapidly. The platelet-count also fell, reaching a nadir on the 13th day, and then it too rose. By the 23rd day the leucocyte-count was 3-7x109/1 with 56% neutrophils, 3% basophils, and 16% monocytes. The N.A.P. score was 2 and Ph’ chromosome was present in all 7 metaphases examined. The patient had been discharged from hospital on the 17th day post-autotransfusion and subsequently returned to work. When seen as an outpatient on Jan. 13, 1978, his Hb was 15.6 g/dl, leucocytes 14-0xl0"/l (neutrophils 51%, basophils 6%, lymphocytes 31%, monocytes 12%), and platelets 350x 109/1. The N.A.P. was 2. The bone-marrow was hypercellular with 1.8% blast cells. The Ph’ chromosome was present in all 30 metaphases examined. 14 of these had in addition a B marker chromosome, not identified in previous preparations. He remains in good health 26 weeks after the autotransfusion. No cytotoxic drugs or other treatment has been necessary. Successful autografts of stored chronic-phase bone-marrow cells have been established in patients with C.G.L. in transformation4 but long survival has not yet been reported. However, lethally irradiated dogs can be rescued by transfusion of stem cells collected from the blood of syngeneic donors,s so at least in one laboratory animal pluripotential stem cells are present in the peripheral blood as well as in marrow. In untreated patients with C.G.L. the concentration of committed granulocyte/ monocyte precursor cells (agar colony-forming cells, c.F.u.c) in the blood greatly exceeds that in the marrow.6 Moreover, the transfusion of C.G.L. buffy-coat cells can establish temporary grafts in the marrow of immunosuppressed allogeneic recipients.7 For these reasons we chose to use stored buffy-coat rather than bone-marrow cells to reconstitute the patient’s marrow after intensive cytotoxic drug therapy. In transformed C.G.L., in contrast to A.M.L., recovery of the bone-marrow after eradication of the blast-cell population is exceptional and is slow when it does occur. The rapid return

N.A.P.

score

fragments

Hoffbrand, A. V., Ganeshaguru, K., Janossy, G., Greaves, M. F., Catovsky, D., Woodruff, R. K. Lancet, 1977, ii, 520. 4. Buckner, C. D., Stewart, P., Clift, R. A., et al. Exp. Hemat. 1978, 6, 96. 5. Fliedner, T. M., Flad, H. D., Bruch, C., et al. Hæmatologica, Pavia, 1976, 61, 141. 6. Goldman, J. M., Th’ng, K. H., Lowenthal, R. M. Br. J. Cancer, 1974, 30, 3.

1. 7.

Graw, R. G., Jr, Buckner, C. D., Whang-Peng, J., Leventhal, B. G., Krüger, G., Berard, C., Henderson, E. S. Lancet, 1970, ii, 338.

of this patient’s blood values to normal and of the bone-marrow to hypercellularity suggests that the autograft was successful. Moreover the observation that c.F.u.c circulated in the blood immediately after, but not before, the autotransfusion on day 0 and were still present in the blood on day 2 (fig. 2) is evidence that transfused precursor cells were viable and survived at least 24 h in vivo. The steady rise in c.F.u.c numbers over the next 12 weeks presumably reflects an increasing total granulocyte mass, but the subsequent fall in leucocyte and c.F.u.c numbers suggests that a presumed normal inhibitory mechanism is again partially able to control the leucocytecount.

it is not possible to prove that regeneration of maroccurred as a result of the transfused cells, it seems unlikely that enough residual chronic phase stem cells could have survived the two courses of cytotoxic drugs to account for the very rapid recovery observed. We believe that further study of this approach to the treatment of C.G.L. in transformation is

Though

row

justified. M.R.C. Leukæmia Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London W12

M. GOLDMAN DANIEL CATOVSKY D. A. G. GALTON

JOHN

NEURAL-TUBE DEFECTS

SIR,-Your editorial of Feb. 11, whilst repeating the uncertainties of accurate antenatal diagnosis, fails to recognise the greatest trap of all in the arguments concerning the termination of pregnancies with a positive amniotic-fluid alpha-fetoprotein (A.F.P.) test. It cannot be assumed that a high A.F.P. indicates a severe lesion, for many of the low sacral lesions are associated with a large amount of exposed superfluous neural tissue. There are today scores of happy useful citizens earning their living who were born with an open spinal defect. Many have little disability beyond a mild degree of club foot, not all are incontinent and others who are incontinent, with urinary diversion stomas, are no worse off than the many patients with ulcerative colitis who have an ileostomy. The screening tests do not distinguish between those whose paraplegia will be mild and those whose paraplegia will be severe, nor do they distinguish between those who will have hydrocephalus and those whose brains are normal. There can be no doubt that with this D.H.S.S. backed campaign to prevent the birth of children who might be born with this disability, many pregnancies will be terminated unjustifiably. Economic factors have played a part in encouraging the elimination of children with spina bifida, and often in the immediate postnatal period parents have been confused by an overdramatic presentation of the possible disability by those who have not had the privilege of watching many of these children grow into mature citizens. As far as disability is concerned what really matters is the level of the lesion, and none of the scanning techniques is sufficiently advanced to delineate this. You assume that accurate antenatal detection of a neural-tube defect should automatically lead to termination. Are we to apply a similar veterinary-type of husbandry to those pregnancies which may be affected by other disabling diseases in which the genetic risk is high or the cost to the community is likely to

be too great?

10 Kingswood Drive, London SE19 1UT

D. F. ELLISON NASH

SiR,—You refer to a decrease in the number of children born alive with spina bifida in England and Wales between 1970 and 1976 and ask why this decrease happened in the absence of routine screening. Part of the explanation lies in the birth-rate. The table shows that while there was a 40% decrease in the number of affected infants between 1970 and 1976, the incidence fell by only 20%. Most of this decline hap-

Reversal of blast-cell crisis in C.G.I. by transfusion of stored autologous buffy-coat cells.

437 REVERSAL OF BLAST-CELL CRISIS IN C.G.L. BY TRANSFUSION OF STORED AUTOLOGOUS BUFFY-COAT CELLS SIR,-We have treated with chronic granulocytic teuk...
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