Evidence that conventional treatment ( chemotherapy and/or immunotherapy)
produces a substantial number of cures in acute myeloid leukaemia
(AML) is lacking (Powles et al. 1980a). Thomas et al. (1977) showed
that there was a proportion of long-term survivors of a group of
AML patients treated with high-dose cyclophosphamide, total body
irradiation (TBI) and allogeneic bone marrow transplantation (BMT).
The purpose of the study reported here is to define the place for
BMT in the treatment of AML and involves a comparison of two groups
of first remission patients treated either with BMT or chemoimmunotherapy.
This study is an extension of the results published earlier this
year (Powles et al. 1980c).
A. Patients and Methods
Since August 1977 , 33 1st remission AML patients have received
a BMT -27 from HLA-identical and MLC-compatible sibling donors,
two from identical twin donors and four from related mis-matched
donors (three sibling and one paternal, incompatible in MLC). The
outcome of the matched allografted patients has been compared with
the simultaneous group of 33 patients with AML in first remission,
who lacking a suitable donor did not receive a transplant and were
maintained on chemotherapy and immunotherapy. Patients details are
shown in Table I. Remission was induced by various regimes using
cytosine arabinoside, thioguanine and anthracycline-daunorubicin
alone or with adriamycin, or rubidazone. Consolidation with the
same three agents or with thioguanine and cytosine arabinoside followed.
Twenty of the transplanted patients had their remission induction
given elsewhere and were referred to our unit when in remission.
Those patients who did not receive a transplant were given maintenance
chemotherapy consisting of courses of cytosine arabinoside (10 mg/kg
as 24 h intravenous infusion) followed by daunorubicin ( 1.5 mg/kg
intravenously). given at intervals of 2,4,6,8. 10 and 12 weeks after
consolidation for a total period of 42 weeks (Powles et al. 1979).
or 3 day courses of cytosine arabinoside ( 1.5 mg/kg sub-cutaneously,
12 hourly) and 6-thioguanine (8O mg orally. 12 hourly) given every
3 weeks for 27 weeks. In addition they received continuous weekly
immunotherapy consisting of subcutaneous injections of irradiated
myeloblasts and intradermal BCG .
Table I. Details of patients studied
Patients with a suitable donor received a transplant as soon as
practicable after achieving remission. They were conditioned according
to the Seattle schedule with high-dose cyclophosphamide (60 mg/kg
intravenously for two doses) followed by total body irradiation
( 1,000 rad mean midline dose given from a cobalt source at 2.5
rad/min). No anti-Ieukaemic chemotherapy was given after transplantation
except low-dose methotrexate (Mtx) for six patients to prevent graft
versus host disease. Subsequently, Cyclosporin A (CSA) was used
instead of Mtx for 21 patients (Powles et al. 1980b ). Patients
were nursed in cubicles with filtered positive pressure ventilation,
received sterile food and non-absorbable anti-microbials as gut
decontamination. Systemic antibiotics and platelet transfusions
were given as indicated. No patient required granulocyte transfusions.
They were discharged from hospital after marrow reconstitution,
3 to 4 weeks after transplantation.
Actuarial analysis of complete remission duration is shown in Figure
1. Of the 33 patients treated with chemo-immunotherapy 20 have relapsed
with a median remission duration of 12 months compared with four
of the matched allografted patients. This difference is highly significant
(P<0.001) using the log-rank test. Twelve of the 33 chemo-immunotherapy
patients have died (11 of relapse and one of infection while in
remission) with a median survival of 21 months from date of complete
remission. There have been five deaths in the 27 matched allografted
patients, one of relapse, four of GVHD with or without pneumonitis,
( two of these patients received methotrexate prophylaxis and one
only a short course of CSA). Actuarial analysis of survival from
complete remission of these two groups (Fig. 2) shows that while
there is not at present a statistically significant difference between
them, at no time do the transplanted patients fare worse and they
have a 75% 3 year actuarial survival compared with 45% for the chemoimmunotherapy
patients. Survival from graft date is shown in Figure 3. Nineteen
(70% ) matched allografted patients remain alive in continuous remission
compared with 12 (33%) of chemoimmunotherapy patients (P= <0.01
). The syngeneic and mis-matched allografts received the same conditioning
regimen and supportive care. The mis-matched allografts all received
prolonged CSA as prophylaxis against GVHD. Their outcome is shown
in Table 2.
Fig. I. Actuarial life table analysis of complete remission
Fig. 2. Actuarial life table analysis of survival from
complete remission date
Fig. 3. Actuarial life table analysis of survival from transplant
Table 2. Outcome of patients transplanted
for AML in first remission
C. Discussion and Conclusions
The results show clearly that allogeneic BMT significantly reduces
the risk of relapse in AML in first remission compared with conventional
chemoimmunotherapy, although it is too early to state what the long-term
(greater than 2 years) remission rate may be. The transplanted patients
at no time fare worse than the non-transplanted controls, despite
four deaths from GVHD. With the greatly reduced mortality from GVHD
in patients on long-term CSA (Powles et al. 1980b) this may be a
much less severe problem in future. Of the 21 patients with AML
in first remission who received CSA after matched allografts 20
received the drug for a period of at least 4 months (Powles et al.
1980b) and 18 are alive and 16 (80% ) free from leukaemia. Cyclosporin
A does not seem to influence the relapse rate after transplantation
when compared with methotrexate; so far only 3 of the 21 matched
patients on CSA have had recurrent leukaemia (Table 2). We feel
that patients under the age of 45 with AML in a first remission
who have a suitable donor should be offered as an alternative to
chemoimmunotherapy a bone marrow transplant, but at present this
should only be done in a suitably experienced centre.
Powles RL, Selby PJ, Palu G, ( 1979) The nature of remission in
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Powles RL, Palu G, Raghavan D ( 1980a) The curability of acute leukaemia.
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Powles RL, Clink HM, Spence D ( 1980b ) Cyclosporin A to prevent
graft-versus-host disease in man after allogeneic bone marrow transplantation.
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Powles RL, Morgenstern G, Clink HM (1980c) The place of bone marrow
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