High-Dose Chemotherapy and Autologous Bone Marrow Transplantation in Acute
Myeloid Leukemia
ByA.K. McMillan, A.H. Goldstone, D.C. Linch, J.G. Gribben, K.G. Patterson, J.D.M. Richards, I. Franklin,
B.J. Boughton, D.W. Milligan, M. Leyland, R.M. Hutchison, and A.C. Newland
For younger patients with acute myeloid leukemia (AML), high-dose chemotherapy and ABMT. The procedure re-
an allogeneic transplant from a matched sibling may afford lated mortality rate was 6%. The projected leukemia-free
the best chance of cure. In patients who are older or survival (LFS) at 5 years is 48% for all 82 patients and 50%
without a matched sibling donor, dose intensification can for the 76 patients with no known preceding myelodysplas-
be achieved with an autologous bone marrow transplant tic syndrome. For those patients with primary AML who
(ABMT). We report here the results of a high-dose chemo- received a double ABMT the projected LFS is 67%. The
therapy regime with nonpurged ABMT in 82 adult patients interval between remission and ABMT did not predict for
in first remission of AML with a median follow-up of 31 either relapse or LFS. ABMT using a multidrug chemother-
months. The median age was 40 years (range 16 to 57 apy protocol is less toxic than allogeneic BMT yet results in
years). The median interval between remission and ABMT a similar LFS.
was 5 months (range 1 to 12 months). Twenty-eight of 0 1990 by The American Society of Hematology.
these patients received a second course of the same
C URRENT CONVENTIONAL chemotherapy in adults
with acute myeloid leukemia (AML) results in a high
remission rate with a subsequent high relapse rate. Several
if only offered to those less than 30 years with a matched
sibling, will be available to less than 10% of patients with
AML.
studies have indicated that less than one third of patients To extend the role of very intensive consolidation therapy
obtaining remission are cured of their disease.’-5 This has to a wider patient population, autologous bone marrow
lead to a search for an effective postremission therapy in rescue has been used.I3-l7Although there is a risk of leukemic
AML. The use of maintenance therapy has not been shown to contamination of the harvested marrow and there will be no
improve leukemia-free survival (LFS).2*6 Single-center “allogeneic graft-versus-leukemia effect,” the morbidity of
studies7 and data from registrie~’.~ have suggested that the procedure is likely to be less than with allografts due to
long-term survival is improved in patients treated in first the freedom from problems with either graft-versus-host
remission by ablative chemo-radiotherapy and allogeneic disease or ongoing immunosuppression.
bone marrow transplantation, and this has been confirmed We report here that patients with A M L treated in first
recently in prospective comparative studies”-” in which remission with high dose chemotherapy and autologous bone
actuarial event-free survivals of approximately 50% have marrow transplantation (ABMT) have a similar projected
been reported. survival to patients treated by allogeneic bone marrow
Allogeneic transplantation is generally only applicable to transplantation.
the younger patient with an HLA-identical sibling. Reports
from the Seattle Marrow Transplant Team suggest that the PATIENTS AND METHODS
good results with allografting are mainly restricted to those Patients. Eighty-two adult patients have now been treated by
patients under the age of 30 years,7 and yet the majority of our collaborative group using an identical protocol. The median
patients with AML are over the age of 50 years. In the UK follow-up of this group is 3 1 months with a range between 6 and 110
Medical Research Council (MRC) AML eighth trial 73% of months. All patients with AML in first complete remission were
patients were less than 60 years but only 34% were less than entered into the program if (1) they gave informed consent; (2) they
40 years, and only 21% were less than 30 years.’ Further- had a good performance status (Karnofsky greater than 70%); (3)
more, since only about 1 in 4 patients in most Western age 16 to 40 years with no HLA-compatible sibling donor or age 41
societies have a matched sibling, allogeneic transplantation, to 60 years, regardless of donor status. However, it must be noted
that because some patients were referred to the transplant centers
already in remission, an element of patient selection by the primary
physician on other undefined criteria cannot be excluded. There were
From the University College and Middlesex Schools of Medicine: 38 males and 44 females with a median age of 40 years (range 16 to
The London Hospital; Queen Elizabeth Hospital and East Birming- 57 years).
ham Hospital, Birmingham; and Leicester Royal Infirmary, Leices- Four patients were excluded as they were found to be in early
ter, UK. relapse at time of assessment for bone marrow harvest, and three
Submitted December 7. 1989; accepted April 4. 1990. patients relapsed after the bone marrow harvest while awaiting the
A.K.M. and J.G.G. were supported by the Leukaemia Research transplant procedure. Six patients had a preceding myelodysplastic
Fund of Great Britain. state (MDS), which in all cases had progressed to AML at time of
Address reprint requests to A.H. Goldstone, MD. Department of commencement of induction therapy.
Haematology. University College Hospital, Gower St. London WCI Therapy before ABMT. The patients were all induced with a
6AU. UK. combination of daunorubicin and cytosine arabinoside normally in
The publication costs of thisarticle were defrayed in part by page combination with 6-thioguanine.The earlier patients received courses
charge payment. This article must therefore be hereby marked of 1 day of daunorubicin at 50 mg/m2 and 5 days of cytosine
“advertisement” in accordance with 18 U.S.C.section 1784 solely to arabinoside at 100 mg/m2 every 12 hours as per the UK MRC AML
indicate this fact. eighth trial, while the more recent patients received 3 days of
0 1990 by The American Society of Hematology. daunorubicin and 10 days of cytosine arabinoside at the same doses
OOO6-4971/90/7603-0027$3.00/0 again as in the more recent MRC AML ninth trial. Some patients
480 Blood, Vol 76, No 3 (August 1). 1990: pp 480-488
ABMT IN ACUTE MYELOID LEUKEMIA 48 1
who failed initial induction therapy received second line induction median number of days to achieve a platelet count of
therapy with other agents such as amsacrine, mitozantrone and 2 5 0 x 109/L, unsupported by platelet transfusion, was 38
etoposide. The treatment plan was for patients to receive two (range 21 to 98). Paired analysis of the times for hematologic
consolidation courses with daunorubicin and cytosine arabinoside recovery after the first and second procedures in the 26
after the achievement of a complete remission; however, some patients who received two grafts showed a highly significant
patients received a different number of consolidation courses, as can
delay for both neutrophil ( P = .004) and platelet recovery
he seen in Tables 1 through 3. The mean number of consolidation
courses received was 2.3 with a range from 0 to 6. Sixteen of the 82 ( P = .001) after the second procedure.
patients in this report were previously reported in 1986.13 The Selection o patients for second ABMT. There were four
f
median time to achieve remission for the whole group was 51 days procedure-related deaths from the first ABMT procedure
(range 20 to 338 days), and the median time from attainment of (5%), and nine patients relapsed within 90 days of the first
remission to ABMT was 162 days (range 23 to 365 days). For the procedure. Five of these nine patients who relapsed early had
patients without a preceding MDS who received a double graft, the temporally recovered hematologically before their early
median time to achieve remission was 40 days (range 20 to 94 days), relapse prevented the second procedure. Of the remaining 69
and the interval between remission and ABMT was 112 days (range patients, 54 (78%) achieved full hematologic reconstitution
57 to 277 days). For the patients without a preceding MDS who
received a single graft the time to achieve remission was 61 days by day 42. These 54 patients were eligible to proceed to the
(range 24 to 369 days), and the time from remission to ABMT was planned second ABMT; however, only 25 of these patients
190 days (range 23 to 365 days). actually received the second cycle of chemotherapy and
Bone marrow harvest. All patients had a marrow aspirate ABMT, and in addition three patients who had regenerated
performed before harvesting to confirm, on morphologic analysis, after day 42 following the first procedure (unique patient
that they remained in remission. Bone marrow was harvested under numbers [UPNs] EB2, EB4, and L06) also proceeded. The
general anesthesia and cryopreserved in the manner previously reasons for cancellation of the second graft in the 29 patients
described." No in vitro purging was undertaken. Patients who did who did not proceed were: patient refusal (22 patients);
not have a Hickman line in situ had one inserted at the time of the cardiac problems (3 patients: 1 poor left ventricular function,
harvest. Patients underwent a second bone marrow harvest as soon as
1 unexplained bradycardia, and 1 unexplained tachycardia);
possible after recovery from the first procedure was complete.
Transplunt procedure. The high-dose chemotherapy,which was non-A non-B hepatitis (1); severe pseudomonas cellulitis in
identical in all cases, was BCNU 300 mg/m2 day - 5; doxorubicin part one (1); failed second bone marrow harvest (1); and
50 mg/m2 day -5; cyclophosphamide 1.5 g/m2 day - 5 to -3 with severe psychological problems during part one (1).
mesna 1 to 2 g/g of cyclophosphamide; cytarabine 100 mg/m2 every Procedure-related morbidity and mortality. All patients
12 hours day - 5 to -2, and 6-thioguanine 100 mg/m2 every 12 developed fever and required antimicrobial therapy. There
hours day - 5 to -2. The autologousmarrow was thawed rapidly at were no cases of pneumonitis during a first procedure. The
the bedside and reinfused on day 0. Patients who achieved satis- causes of the procedure-related deaths that occurred after a
factory hematologic regeneration from the first procedure
first procedure were cerebral hemorrhage (2 cases); hepato-
(neutrophils 20.5 x 109/L and unsupported platelet count of
250 x 109/L by Day 42), and in whom there was no contra-
renal failure ( l ) , and aspergillus pneumonia (1). There were
indication to further intensive therapy, were advised to proceed to a two cases of pneumonitis during a second procedure (UPN:
second ABMT as soon as possible after the first with a second cycle UCH 307 and UPN:UCH 323), and both were due to
of the same high-dose chemotherapy.No posttransplant therapy was cytomegalovirus and neither was fatal. However, one (UPN:
administered while patients remained in remission. All patients were UCH 307) had not recovered normal respiratory function by
treated in single rooms with simple reverse barrier nursing proce- the time of her death, after relapse, 11 months later. There
dures without laminar flow facilities. Blood products were not was a single death after a second procedure due to a varicella
irradiated and were not screened for cytomegalovirus. Platelets were pneumonia. Overall, in 110 procedures in 82 patients there
given prophylactically when the count was below 20 x 109/L. No have been five procedure-related deaths. Therefore, the risk
prophylactic antibiotics were administered during the period of
of a procedure-related death is 4.5% per procedure or 6%
neutropenia, but empirical antibacterial therapy was given for
febrile neutropenic episodes. overall per patient. There were no cases of graft-versus-host
Statistical methods. Statistical analyses were performed by disease despite the fact that random donor platelet and red
Student's test and chi-squared analysis. Survival curves were drawn blood cell transfusions were not irradiated. There has been no
by the Kaplan-Meier life table method and compared by the long-term morbidity from the procedure, except for the one
log-rank test. The relationship of clinical features to the outcome of case referred to previously, and all the survivors have a
the procedure were analyzed by univariate analysis. Events were Karnovsky status of 100%. There has been a single case of
included in the analysis up to March 1, 1990. late pneumonitis (greater than 3 months) that occurred in a
patient who had received a double graft (UPN:UCH245),
RESULTS
but this resolved completely with a short course of oral
Hematologic recovery. For all 82 patients the median steroid therapy. The cause of this pneumonitis was ascribed
number of days, after the first marrow infusion, to achieve a to the cumulative dose of BCNU received. There has been no
total neutrophil count of 20.5 x 109/L was 22 (range 11 to case of cataract in any patient.
73), and the median number of days to achieve a platelet Outcome. The median follow-up for the whole group is
count of 2 5 0 x 109/L, unsupported by platelet transfusion, 31 months, and a t 5 years the projected overall survival is
was 34 (range 13 to 300). The median number of days after 53% with a relapse rate of 48% and a projected LFS of 48%
the second ABMT procedure to achieve a total granulocyte (Fig 1). The outcome in the six patients with a known
count of 20.5 x109/L was 27 (range 12 to 48), and the preceding myelodysplastic state has been poor, with only 2 of
P
Q)
N
Table 1. Single-Autograft Data
Diagnosis R
C to No. of
Ageat FAB to CR ABMT Consolidation Reason for
UPN Sex T x ( d TvDe (mos) (mos) Drugs in InductionIConsolidation Courses No Part 2 LFS (mod Status
~ ~~ ~~
81 1 M 54 M4 2 8 DNR. Ara-C. 6TG. cyclo, vinc. pred 4 Refused 48 Alive-cr
812 M 51 M4 2 10 DNR, Ara-C, 6TG. cyclo, vinc. pred 4 TD 1 TD
B16 M 57 M1 2 8 DNR, Ara-C, 6TG. m-AMSA, AzaCyt, VP16 5 Refused 26 DR
819 F 44 M2 2 12 DNR, Ara-C, 6TG. cyclo, vinc, pred 5 Refused 26 Alive-cr
820 M 48 M4 1 11 DNR, Ara-C, 6TG. m-AMSA, AzaCyt. VP16 3 Slow recov 25 Alive-cr
822 F 24 M4 3 6 DNR, Ara-C, 6TG. cyclo, vinc. pred 3 Refused 9 AR
825 M 43 M5 1 6 DNR, Ara-C, Ara-CID, 6TG. mitoz 2 Refused 12 OR
83 M 42 M4 3 1 DNR, Ara-C,6TG 0 Relapsed 2 DR
84 F 55 M2 2 10 DNR. Ara-C, 6TG 1 Refused 6 OR
B6 M 49 M4 1 10 DNR, Ara-C, 6TG. cyclo, vinc. pred 4 Slow recov 58 Alive-cr
E83 M 43 M3 2 6 DNR, Ara-C, 6TG 3 Relapsed 2 DR
E85 F 23 M2 2 7 DNR, Ara-C, 6TG 2 Refused 28 Alive-cr
E86 F 28 M2 3 6 DNR, Ara-C, 6TG 2 Slow recov 26 Alive-cr
E88 M 39 M3 1 4 DNR, Ara-C, 6TG 2 Refused 20 OR
LE 1 F 32 M3 2 6 DNR, Ara-C, 6TG 1 Slow recov 55 Alive-cr
LE2 M 40 M4 2 2 DNR, Ara-C. 6TG 1 Refused 4 DR
LO 1 F 28 M4 3 11 DNR. Ara-C, 6TG. m-AMSA, VP16 2 Slow recov 18 AR
LO2 F 42 M4 4 6 DNR, Ara-C, 6TG. m-AMSA, VP16 2 Refused 8 DR
LO3 M 20 M4 3 7 DNR, Ara-C, 6TG. m-AMSA. VP16 2 Refused 9 AR
LO4 F 27 M5 2 6 DNR, Ara-C, Ara-C:ID, 6TG, m-AMSA, VP16, mitoz 3 Relapsed 3 DR
UCH 128 F 32 M2 1 4 DNR. Ara-C, 6TG 2 Slow recov 74 Alive-cr
UCH131 F 45 M4 3 5 DNR, Ara-C, 6TG 6 Slow recov 73 Alive-cr
UCH 132 M 45 M1 2 4 DNR, Ara-C, 6TG. vinc. pred 1 Failed 2nd BMH 11 DR
UCH 156 F 19 M2 3 9 DNR, Ara-C, 6TG 5 Refused 7 DR
UCHl6O M 36 M1 3 3 DNR, Ara-C, 6TG 0 Cardiac 65 Alive-cr
UCH 163 F 36 M4 4 2 DNR. Ara-C, 6TG. m-AMSA, AzaCyt, VP16, cyclo, 1 Cardiac 7 OR
UCH 174 F 40 M2 3 4 DNR. Ara-C, 6TG 4 Relapse 0 DR
UCH 194 F 46 M4 1 4 DNR, Ara-C, 6TG 2 Slow recov 4 DR
UCH220 F 39 M1 1 2 DNR, Ara-C, 6TG 2 TD 2 TO
UCH236 M 55 M4 2 11 DNR, Ara-C. 6TG. cyclo, vinc. pred 3 Cardiac 6 DR
UCH248 M 25 M2 7 8 DNR, Ara-C, Are-C:ID, 6TG. m-AMSA, VP16, mitoz 2 Hepatitis 41 Alive-cr
(Continued on following page)
m
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3
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Table 1. Single-Autograft Data (Cont’d) x
Diagnosis R
C to No. of a
Age at FAB to CR ABMT Consalidation Reason for 5
UPN Sex Tx(~s) Type lmos) Imos) Drugs in Induction/Consolidation Courses No Part 2 LFS lmos) Status
UCH264 F 48 M6 1 6 DNR, Ara-C. 6TG 2 TD 1 TD
UCH267 F 54 M4 1 5 DNR, Ara-C, 6TG 2 Relapse 1 DR
UCH287 M 50 M3 1 4 DNR, Ara-C, 6TG 2 Slow recov 32 Alive-cr
UCH30 M 38 M3 1 7 DNR, AraC, 6TG 2 Inf in part 1 103 Alive-cr
UCH303 F 34 M4 1 4 DNR, Ara-C, 6TG 2 Slow recov 11 Lost t o follow-up
UCH311 M 45 M5 1 8 DNR, Ara-C, 6TG. cyclo. vinc. pred 2 Psych problem 27 Alive-cr
UCH325 F 48 M1 2 2 DNR, DOX, Ara-C, Ara-C:ID, BTG, VP16. mitoz 1 Relapse 1 DR
UCH328 M 49 M2 3 4 DNR, Ara-C, 6TG 2 TD 1 TD
UCH339 F 44 M2 1 3 DNR, AraC, 6TG 2 Slow recov 22 Alive-cr
UCH356 F 34 M2 1 5 DNR, AraC, 6TG 2 Relapsed 2 DR
E81 1 F 38 M2 1 10 DNR, AraC, 6TG 2 Refused 11 Alive-cr
E810 M 30 M2 1 3 DNR, AreC, 6TG 2 Refused 10 AR
E89 F 18 M4 1 3 DNR, Ara-C, 6TG 2 Refused 14 Alive-cr
E812 F 51 M1 1 6 DNR, AraC, 6TG. AraC:ID. m-AMSA, VP16. mitoz 3 Slow recov 10 Alive-cr
LO6 F 24 M3 12 5 DNR, AraC, 6TG. AraC:ID, m-AMSA, VP16, mitoz 0 Slow recov 9 Alive-cr
829 F 24 M3 2 6 DNR, Ara-C, 6TG 2 Refused 14 Alive-cr
E26 M 41 M4 1 10 DNR, Ara-C, 6TG 2 Refused 8 AR
827 M 48 M4 1 10 DNR, Ara-C. 6TG. AraC:ID. m-AMSA, VP16, mitoz 4 Refused 10 Alive-cr
828 M 21 M2 1 7 DNR, Ara-C, 6TG 3 Slow recov 7 Alive-cr
Abbreviations: Tx. time of transplantation; Diagnosis t o CR. time interval between diagnosis and remission; CR to ABMT, time interval between remission and first transplant: Drugs in Induction/Consolidation, chemotherapy drugs
received during induction and consolidation; Reason for No Part 2. reason for not proceeding t o second graft: DNR, daunorubicin; Ara-C, cytarabine: 6TG. 6-thioguanine; cyclo, cyclophosphamide, vinc. vincristine: pred, prednisalone;
m-AMSA. amsacrine; AzaCyt. azacytidine; VP16. etoposide: Ara-C:ID, intermediate-dose cytarabine; mitoz, mitoxantrone; TD, toxic death; Slow recov. slow hematologic reconstitution; Failed 2nd BMH. failed bone marrow harvest:
Cardiac, cardiac problem preventing second part: Inf in part 1, serious infection in part 1: Psych problem. psychologicalproblem preventingsecond part; Alive-cr, alive in remission; DR, dead in relapse: AR, alive in relapse; DOX, doxorubicin.
P
OD
w
484 McMlLLAN ET AL
Table 2. Double-Autograft Patient Data
Time
FAB Diagnosis CR to No. of Between
Ageat Type toCR ABMT Drugs in Induction/ Consolidation Grafts LFS
UPN Sex Transplant lpl (mosl (mod Consolidation Courses lmos) (mosl Status
UCH 19 M 24 M1 2 2 DNR, Ara-C, 6TG 1 2 110 Alive-cr
UCH 105 F 44 M4 2 6 DNR, Ara-C, 6TG 2 3 80 Alive-cr
UCH108 F 39 M1 1 8 DNR, Ara-C, 6TG 6 2 79 Alive-cr
UCH 143 M 48 M1 1 3 DNR, Ara-C, 6TG 1 2 69 Alive-cr
UCH 147 M 35 M5 2 4 DNR, Ara-C, 6TG 3 3 69 Alive-cr
UCH 148 M 26 M1 1 5 DNR, Ara-C, 6TG 2 3 68 Alive-cr
UCH209 M 17 M2 1 4 DNR, Ara-C, 6TG 1 2 49 Alive-cr
UCH2 18 M 26 M4 1 7 DNR, Ara-C, 6TG. cyclo, 4 2 21 AR
vinc, pred
UCH223 F 43 M4 1 2 DNR, Ara-C, 6TG 2 2 47 Alive-cr
UCH237 M 16 M1 3 3 DNR, Ara-C, 6TG. VP 16 1 4 44 Alive-cr
UCH241 F 55 M5 2 3 DNR, Ara-C, 6TG. VP16 2 4 15 DR
UCH245 M 46 M4 1 5 DNR, Ara-C, 6TG. cyclo, 5 5 42 Alive-cr
vinc. pred
UCH259 M 16 M2 2 4 DNR, Ara-C. 6TG 2 2 18 Lost to
follow-up
UCH272 F 32 M2 1 3 DNR, Ara-C, 6TG 2 3 36 Alive-cr
UCH307 F 21 M5 1 5 DNR, Ara-C, 6TG 2 4 9 DR
UCH320 F 41 M1 1 3 DNR, Are-C, 6TG. cyclo, 3 2 25 Alive-cr
vinc. pred
UCH324 M 26 M4 1 5 DNR, Ara-C, 6TG 2 3 125 Alive-cr
UCH33 1 F 48 M2 1 3 DNR, Ara-C, 6TG 2 2 10 DR
UCH38 1 M 45 M4 2 6 DNR, Ara-C, ID ARA-C, 2 3 16 Alive-cr
mAMSA, VP 16
E10 M 23 M4 2 9 DNR, Ara-C, 6TG. cyclo, 5 4 7 DR
vinc. pred
E8 1 F 30 M1 1 3 DNR, Ara-C, 6TG 2 3 6 TD
E82 M 34 M5 1 3 DNR, Ara-C, 6TG 2 3 20 DR
EB4 F 47 M3 2 3 DNR, Ara-C, 6TG 2 2 39 Alive-cr
EB7 F 37 M2 3 6 DNR, Ara-C, 6TG. cyclo, 2 3 14 AR
vinc, pred
LE3 F 36 M2 1 9 DNR, Ara-C, 6TG 1 2 38 Alive-cr
UCH 426 F 35 M4 1 3 DNR, Ara-C, 6TG 2 3 8 Alive-cr
Abbreviations: Time between grafts, interval between first and second BMT; see Table 1 for other abbreviations.
6 remaining in remission at 12 months and 28 months cyclophosphamide autograft (UPN:UCH 21 8) and a second
post-ABMT. In the 76 patients with an apparently primary who relapsed with a myelodysplastic marrow picture (UPN:
disorder at diagnosis, the projected overall survival at 5 years UCH 236). In the 26 patients with an apparently primary
is 55%, with a relapse rate of 47% and a projected LFS of disorder who completed the double autograft protocol, the
50% (Fig 2). There have been no relapses later than 26 projected overall survival at 3 years was 73%, with a
months after ABMT. Of the 27 patients who relapsed there projected relapse rate of 30%and projected LFS of 67%.
are only two survivors of greater than 1 year’s duration after To analyze the effect of the second graft, the survival of 25
relapse: one following a second remission busulphan and patients with an apparently primary disorder who had a
Table 3. MDS Patient Data
Time
Age at Diagnosis CR to No.of Reason No. Between
Transplant FAB toCR ABMT Drugs in Induction/ Consolidated fwNo of Grafts LFS
UPN Sex Irl
vs Tvoe (mas) (mod Consolidation Courses Part2 Grafts (mo4 (mod Status
~~ ~ ~ ~~
UCH215 F 55 M4 1 4 DNR, Ara-C, 6TG 2 Relapse 1 - 4 DR
UCH231 M 55 M2 4 8 DNR, Ara-C, 6TG. VP16 3 Refused 1 - 12 DR
UCH239 F 50 M4 1 6 DNR, Ara-C, 6TG 2 Relapse 1 - 3 DR
UCH323 F 39 M2 2 3 DNR, Ara-C, 6TG 2 - 2 3 7 DR
E17 M 45 M6 4 9 DNR, Ara-C, 6TG. m-AMSA, 4 Refused 1 - 28 Alive-cr
AzaCyt, VP 16
LO5 F 34 M1 11 4 DNR, Ara-C, , Ara-C:ID, 6TG. 0 - 2 4 12 Alive-cr
m-AMSA, VP 16, mitoz
Abbreviations: see Tables 1 and 2.
ABMT IN ACUTE MYELOID LEUKEMIA 485
Leukaemia
Free
80 i
l
Survival
("A)
Fig 1. LFS of all 82 patients.
_1
20
J '1 2 3 4 5
TIME (YEARS)
b '
I 8 4
single graft with rapid hematologic recovery and remained in remission, interval from remission to transplant, and the
remission at 90 days was examined. The median interval number of consolidation courses given. No factor was signifi-
between grafts in the double-graft group was 90 days. Rapid cant in predicting relapse or LFS. In particular, when the
hematologic recovery was defined as up to 49 days, as this patients are divided into two groups, those grafted within 6
was the latest day on which a patient with primary AML months of remission (n = 50) and those grafted between 6
recovered from the first graft and then received a second and 12 months into remission (n = 32), there is no signifi-
procedure. However, this comparison single-graft group cant difference between the two groups in terms of LFS (49%
differed from the double group in that the interval between v 46%). If those who only received a single ABMT are
remission and ABMT was significantly longer (P = .003). analyzed alone there is a small advantage (P = .14) to those
The projected overall survival at 3 years for this group who receiving ABMT between 6 months and 1 year into remis-
did not receive the second graft for a nonhematologic reason sion, but this does not reach significance.
was 47%, with a projected relapse rate of 60% and a
projected LFS of 40%. The difference between these patients DISCUSSION
who did not receive the second graft for a nonhematologic The chemotherapy autografting procedure used in this
reason and those who did receive the second graft approaches study has resulted in a low early procedure-related mortality
significance (P = .052) (Fig 3. Seven patients receiving a
) (6%) compared with the 20% procedure-related deaths in the
double ABMT for primary AML have relapsed, and four of first 100 days after allogeneic BMT reported by the Seattle
these relapses occurred beyond 1 year from the first ABMT, group.' In addition, in allograft recipients there is also a 10%
while only 2 of 14 relapses occurring in the comparison group incidence of late procedure-related deaths7compared with no
occurred after 1 year. late nonleukemic deaths after ABMT in this study. There
Prognostic factors for outcome of ABMT that have been has been almost no significant long-term morbidity from
analyzed by univariate analysis included age, sex, French- cataracts or pneumonitis observed with this regime, and this
American-British (FAB) type, interval from diagnosis to contrasts with the sequelae of conventional allografting
Leukaemia
Free
Survival
("w
1h
80
"PRIMARY" AML patients n =76
MDS patients n = 6
p is NS.
'1 2 3 4 5 6 I
' 8 4
Fig 2. LFS of 76 patients without evidence of a
TIME (YEARS) preceding myelodysplastic syndrome.
486 McMlLLAN ET AL
Leukaemia
Free
I0rk4
80
Survival I I Lu I I I I I I Ill I1 I
(W
“‘“It 1-i
2o t1 ‘1 2 3 4
0
5
p = 0.052
6 7 8 4 Fig 3. LFS: double ABMT versus single ABMT
in patients with hematologic recovery by day 49
TIME (YEARS) who remain in remissionat 90 days.
protocols. We believe that the early procedure-related mortal- justifiable to compare these two transplant groups as it is
ity and late morbidity are also reduced when compared with likely that any selection in the two groups will be similar. The
autografting regimes that use total body irradiation (TBI). favorable comparison of these results with those of allogeneic
Comparisons with autografts using busulphan and cyclophos- BMT is underlined by the fact that the age of many of these
phamide without TBI are difficult because this has been used patients would have put them in a high-risk group for
mainly in second remission; although in that context it has transplant-related complications after allogeneic BMT.’,19
considerable toxicity, it is not possible to say if this will also They can also be compared favorably with the results of
be true of its use in first remission. However, the early autografting regimes using TBI reported to the European
morbidity with our protocol is considerable compared with Bone Marrow Transplant Group (EBMT)?’where the LFS
conventional therapy as evidenced by the fact that only 41% at 5 years is 42%. A study of 22 patients from Germany using
of patients alive in remission after the first procedure TBI has reported an LFS of 6195.’’ There is an apparent
proceeded to the second autograft as originally planned. advantage in favor of the use of a double-autograft procedure
The rationale of the double-autograft program is based on when patients who received a second procedure are compared
two premises. Reharvesting of the bone marrow after comple- with those who did not receive a second graft for a nonhema-
tion of the first course of chemotherapy when leukemic tologic reason, although this does not quite achieve statistical
contamination is likely to be at a nadir effects an in vivo significance (P = .052). Furthermore, it is noteworthy that
purge, and the two-stage process allows the overall dose of this group has a significantly shorter remission to transplan-
drug that is delivered to be increased without a correspond- tation interval than the comparison group. The only defini-
ing increase in toxicity. For three reasons there has been tive way of resolving the value of the second graft would be to
failure to complete the double-graft program in the majority randomize patients who are ready to proceed, immediately
of patients. First, there is a population of patients who before the second procedure, to proceed to a second graft or
relapse early (less than 90 days) after the first graft and who not. This would pose major logistical difficulties.
cannot therefore receive the second graft. Second, as regener- No in vitro purging procedures, using cyclophosphamide
ation after the second course of intensive chemotherapy is derivatives, were used in this study as we believe that, unlike
significantly delayed compared with the first, in those cases the situation in the rat model,2’ there is no clear in vitro
where recovery from part 1 was slow it was thought unjusti- evidence of their selectivity for leukemic cells in human^.^^.*^
fied to proceed to a second graft. This selection has kept the The use of these drugs may slow recovery and therefore
procedure-related mortality of the second graft to a mini- increase the risk of procedure-related death. Recovery times
mum but reduced the proportion receiving it. Third, because were observed in this study that were shorter than those
the first autograft follows intensive induction and consolida- reported with regimes using TBI, especially if combined with
tion therapy, some patients are unwilling to complete such an purged marrow. 1 4 ~ ’ 5 ~ 1 7 . 2Although hematologic recovery was
3
arduous treatment program. slower with the second autograft, no patient in remission
The advantage of decreased toxicity compared with alloge- remained platelet-dependent beyond 100 days, which is not
neic BMT is balanced by the increased relapse rate seen after The
infrequent with purged marrow.14si5*17,23 most widely
ABMT (48% v 25% in the Seattle study of allogeneic BMT in quoted evidence that purging may be efficacious in AML
first remission7). However, the projected LFS at 5 years for autografting comes from retrospective analysis of the EBMT
the two groups is very similar, with an LFS of 48% in this registry,20which suggests that in a group of patients ablated
study compared with 45% in a recent report from Seattle” with cyclophosphamide and TBI, LFS was significantly
and 48% reported by the International BMT Registry’ for greater in those patients whose marrow was purged with
allogeneic BMT in AML in first remission. It is, we believe, derivatives of cyclophosphamide and that this advantage was
ABMT IN ACUTE MYELOID LEUKEMIA 487
most marked in patients transplanted less than 6 months into sion, and the results of large prospective randomized trials
remission. This is multicenter data in which some centers are needed. A recent small trial comparing allogeneic BMT,
performed purging and others did not, and it may be ABMT, and conventional chemotherapy reported a signifi-
susceptible to differing selection policies. It must also be cant advantage to allogeneic BMT compared with conven-
noted that the excellent results reported by Korbling et all’ tional chemotherapy.” The results of autografting were
were obtained with purged marrow. intermediate and not significantly different from either the
The key question in this study is whether survival has been allogeneic BMT or the conventional therapy groups. Confir-
improved compared with using conventional chemotherapy mation of these findings will have to await the results of
alone. Unlike the comparison of transplant series, the effect larger studies. When the results of comparative trials are
of selection of patients for transplantation and the effect of examined it must be remembered that the ablative therapy
the delay between remission and transplantation (“time used may influence the outcome; eg, the use of single-agent
censoring”) needs to be considered when these results are high-dose melphalan as opposed to TBI or a multidrug
compared with those of conventional chemotherapy. As this regime in the study by Reiffers et allz may have affected the
group of patients had been in remission for a median of 5 outcome of the ABMT arm.
months before ABMT we have compared their outcome to In conclusion, we have found that ABMT using a multi-
that of patients in the ninth MRC A M L trial who main- drug chemotherapy protocol appears less toxic than alloge-
tained first remission for a minimum of 6 months. This shows neic BMT, yet results in a similar LFS. The relatively low
that compared with the projected LFS of 48% a t 5 years mortality and morbidity is particularly important when the
reported here, the projected LFS a t 4 years with conventional use of autografting is extended, as in this study, to patients
therapy in the ninth MRC A M L trial of those in remission up to age 60 years, which thus enables intensive therapy to be
for a minimum of 6 months is 40%. (R. Gray, personal applied to a much higher proportion of the A M L patient
communication, November 1989). The difference is clearly population than allogeneic BMT. The results of ABMT
small and any advantage for ABMT is attributable to those compare favorably with conventional consolidation and main-
who received the double procedure. However, comparison of tenance therapy, but definitive proof of improved survival
patients in different studies cannot justify a definite conclu- must await the outcome of prospective randomized trials.
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