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Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3481-3486
Identification of Patients Who May Benefit From Prophylactic
Immunotherapy After Bone Marrow Transplantation for Acute Myeloid
Leukemia on the Basis of Lymphocyte Recovery Early After
Transplantation
By
Ray Powles,
Seema Singhal,
Jennifer Treleaven,
Samar Kulkarni,
Clive Horton, and
Jayesh Mehta
From the Leukaemia Unit, Royal Marsden Hospital, Surrey, UK.
 |
ABSTRACT |
Two hundred and one patients (median age, 29 years) with acute
myeloid leukemia (AML) underwent bone marrow transplantation (BMT) from
HLA-identical sibling donors after conditioning with melphalan-total-body irradiation (TBI) (57%), cyclophosphamide-TBI (35%), or chemotherapy alone (8%). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine alone (68%),
cyclosporine-methotrexate (26%), or T-cell depletion (6%). The
probability of relapse was calculated as a function of the absolute
lymphocyte count (109/L) on days 27 to 30 posttransplant
(<0.1 v  0.1, <0.2 v 0.2, and <0.3 v
0.3). In each of these 12 comparisons, the probability of relapse
was higher for the group with the lower lymphocyte count. Because the
difference was most significant (P = .004) for an absolute
lymphocyte count of <0.2 on day 29 (3-year relapse probability, 42%)
versus 0.2 (16%), this variable was included in a Cox model to
determine factors independently affecting relapse. Multivariate
analysis showed that conditioning regimens other than melphalan-TBI, a
low lymphocyte count on day 29, French-American-British (FAB) subtypes
M4-7, and a nucleated cell dose of > 2.42 × 108/kg was
associated with a higher risk of relapse. We conclude that slow
lymphocyte recovery after allogeneic BMT, to < 0.2 × 109/L 29 days in this analysis, appears to be associated
with a higher risk of relapse in patients with AML. This group of
patients may benefit from posttransplant immune manipulations such as
abbreviated GVHD prophylaxis, or donor cell or cytokine administration
to enhance graft-versus-leukemia reactions to reduce relapse.
| |
INTRODUCTION |
ALONG WITH transplant-related mortality,
relapse is an important cause of failure of allogeneic bone marrow
transplantation (BMT) for hematologic malignancies. Depending on
various factors such as the chromosomal karyotype of the malignant
clone, the stage of the disease, the conditioning regimen used, the
graft-versus-host disease (GVHD) prophylaxis, and the development of
GVHD, the risk of relapse after allogeneic BMT for acute myeloid
leukemia (AML) in the first complete remission varies from 10% to
40%.1-15
The outcome of patients relapsing after allogeneic BMT is generally
very poor.16 Although second allogeneic transplants and
adoptive immunotherapy can result in long-term remission in a
proportion of patients, both of these approaches are associated with
considerable toxicity.16,17
Postallograft approaches aimed at exploiting graft-versus-leukemia
reactions18 more effectively to prevent or minimize relapse could include administration of donor cells,19,20
cytokines, such as interferon- ,21 or
interleukin-2,22 or individualizing GVHD
prophylaxis.23 All of these approaches are potentially risky because they can cause or aggravate GVHD and are best confined to
patients with a high risk of relapse.
The aim of this analysis was to see if lymphocyte recovery 4 weeks
after allogeneic BMT from HLA-identical sibling donors could identify
patients with AML in first remission who were at a high risk of
relapse, so that patients with poor lymphocyte recovery after
allografting in the future could undergo immune manipulation to enhance
graft-versus-leukemia.18
| |
MATERIALS AND METHODS |
The database of the Leukaemia Unit contains prospectively-collected
information on over 1,600 patients treated in the Royal Marsden
Hospital since 1978.24,25 This was searched to identify a
group of 201 AML patients who underwent allogeneic BMT in the first
complete remission (CR) from HLA-identical sibling donors between 1981 and 1995. Patients receiving blood-derived stem cells or blinded
marrow/blood cells26 were excluded. Patient characteristics are shown in Table 1.
Conditioning regimens.
These consisted of 110 mg/m2 of melphalan or 120 mg/kg
cyclophosphamide with 950 to 1,150 cGy single-fraction total-body
irradiation (TBI)3,15 or chemotherapy alone (240 mg/m2 melphalan alone27 or 16 mg/kg busulfan
with 120 mg/kg cyclophosphamide28) and have been described
in detail elsewhere.
GVHD prophylaxis.
Before the intravenous formulation of cyclosporine became
available, the drug was administered intramuscularly at a dose of 25 mg/kg from day  1 for 5 days and then orally at a dose of 12.5 mg/kg. After the intravenous formulation of cyclosporine became available, the drug was administered intravenously at a dose of 3 mg/kg
from day 1 until oral intake was resumed. The drug was then given
orally at a dose of 12.5 mg/kg. Patients receiving a short course of
methotrexate in addition to cyclosporine received 15 mg/m2
of the drug on day 1 and 10 mg/m2 on days 3 and 6, or on
days 3, 6, and 11.
The murine anti-CD52 monoclonal antibodies Campath-1G or Campath-1M
(kindly provided by Drs G. Hale and H. Waldmann, Cambridge, UK) were
used to deplete the donor marrow of T cells in a minority of
patients.29
Acute GVHD was usually diagnosed and graded on the basis of clinical
findings and was treated with conventional (2 mg/kg) or high (10 to 20 mg/kg) dose corticosteroids.
Donor marrow.
Marrow was harvested from the iliac crests of HLA-identical sibling
donors under general anesthesia on the day of transplantation. The
target cell number for the harvest was 2 × 108
nucleated cells per kg recipient body weight. The marrow was usually
not depleted of T cells and was infused into the patient essentially
unmanipulated except as required for donor-recipient ABO blood group
incompatibility.30
Supportive care.
All patients were treated in protective isolation in rooms with
positive-pressure ventilation. Blood products transfused were not
screened for cytomegalovirus (CMV) antibody before 1985. After that
time, CMV-seronegative patients with CMV-seronegative donors received
screened, CMV-negative blood products. Fever during the neutropenic
phase was treated with broad-spectrum antibiotics and amphotericin as
necessary. Antibiotic prophylaxis and therapy varied in accordance with
prevalent practices and research programs. All research protocols were
approved by the local institutional review board, and all patients and
donors gave informed consent.
Statistical analysis.
Serial blood counts obtained by automated counters were analyzed to see
if the lymphocyte counts 4 weeks after BMT (days 27 to 30; the day of
marrow infusion being designated as day 0) were predictive of relapse.
Although we would have liked to look at the effect of lymphocyte counts
earlier (at the end of 3 weeks), as we have outlined
elsewhere,31,32 differential counts are not very accurate
with very low total leukocyte counts in the second and third weeks
after BMT. Lymphocyte subset data were not available.
For each of these 4 days, patients were grouped on the basis of the
absolute lymphocyte counts (109/L) in three ways ( 0.1
v >0.1, 0.2 v >0.2, and 0.3 v >0.3), and the probability of relapse calculated using the method of Kaplan
and Meier.
Patients were censored at the time of nonrelapse death (death in
remission) or the last follow-up in continuous remission. The log-rank
test was used to compare the differences.
The following factors were also analyzed in univariate and multivariate
fashion to determine their effect on the probability of relapse: age
(<20 v 20 years), conditioning regimen (melphalan-TBI v cyclophosphamide-TBI v chemotherapy only),
donor-recipient ABO blood group compatibility (match v
mismatch), French-American-British (FAB) subtype (M1-3 v M4-7
v unknown), GVHD prophylaxis (cyclosporine alone v
cyclosporine-methotrexate v T-cell depletion), leukocyte count
at presentation (<5.1 × 109/L v 5.1),
nucleated cell dose (2.42 v >2.42 × 108/kg), occurrence of acute or chronic GVHD (yes v
no), remission-transplant interval (<4 months v 4 months),
and the absolute lymphocyte count on day 29 after BMT (0.2 × 109/L v >0.2). The effect of the karyotype could
not be analyzed because results were not available for more than half
the patients (who were referred for BMT in remission after prior
therapy elsewhere).
Among the different variables, a very strong correlation was seen
between GVHD prophylaxis and conditioning regimen (r =.35; P < .0001) with 11 of 12 T-cell-depleted grafts being
conditioned with cyclophosphamide-TBI and 47 of 53 cyclosporine-methotrexate grafts being conditioned with melphalan-TBI.
| |
RESULTS |
Twenty-five patients relapsed at 3 to 46 months (median, 10); 23 died
of relapsed disease and 2 are alive after cell- and cytokine-mediated
immunotherapy.17 Ninety-two patients died of
transplant-related causes at 0.5 to 123 months (median, 3). Eighty-four
patients are alive in continuous remission at 12 to 191 months (median,
91). Four of 12 patients receiving T-cell-depleted marrow relapsed, as
did 14 of 136 patients receiving cyclosporine, and 7 of 53 patients
receiving cyclosporine-methotrexate.
As Table 2 shows, for each of the
lymphocyte levels compared on the 4 posttransplant days studied,
patients with the lower lymphocyte counts had higher relapse rates.
This difference was significant at the P < .01 level for 3 of
the 12 comparisons. The significance was the highest (P = .004)
for day 29 and lymphocytes <0.2 versus 0.2 × 109/L (Fig 1).
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Table 2.
Probability of Relapse on the Basis of the Absolute
Lymphocyte Count 4 Weeks After Bone Marrow Transplantation
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| Fig 1.
The effect of the day 29 lymphocyte count on relapse in
188 patients (13 of 201 patients died before day 29 or did not have lymphocyte counts available).
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Table 3 shows that the mode of GVHD
prophylaxis including the administration of methotrexate did not affect
the lymphocyte count significantly.
Table 4 shows the results of the Cox analysis. Patients
conditioned with melphalan-TBI had a significantly lower probability of
relapse (Fig 2), and this factor dominated the risk of
relapse. An absolute lymphocyte count of <0.2 × 109/L on day 29 was also significantly associated with a
higher risk of relapse, as were FAB subtypes other than M1-3 and a
higher infused cell dose. Because of the strong correlation between the conditioning regimen and GVHD prophylaxis, the effect of the latter, if
any, was not discernible.
The higher lymphocyte count on day 29 was also associated with a
significant survival benefit (Fig 3). This effect was
partly also due to a lower toxic death rate among patients with the
higher lymphocyte count (59 of 153 v 22 of 35; 1-year
probabilities 35% v 65.5%; P = .003).
View larger version (15K):
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| Fig 3.
The effect of the day 29 lymphocyte count on survival in
188 patients (13 of 201 patients died before day 29 or did not have lymphocyte counts available).
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Finally, the beneficial effect of the higher lymphocyte count on
relapse was independent of GVHD because, as Fig 4 shows, the lower
lymphocyte count was associated with a slightly higher probability of GVHD.
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| Fig 4.
The relation between the day 29 lymphocyte count and the
cumulative probability of acute or chronic GVHD. The lower count is
associated with a higher risk of GVHD.
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| |
DISCUSSION |
Our data show that slower lymphocyte recovery in the fourth week after
allogeneic BMT for AML in first remission, as reflected by an absolute
lymphocyte count of <0.2 × 109/L on day 29, is
associated with an increased risk of disease recurrence independent of
GVHD. This observation has practical significance because this
identifies a group of patients who may be suitable candidates for early
intervention to enhance graft-versus-leukemia.
Can factors operating so early in the course of an allograft really
make a difference? In the early days or weeks after the allograft, the
disease burden is at its lowest. At this time, the chances of
eliminating it completely through immune mechanisms should logically be
the highest. There is evidence to show that factors operating very
early in the course of the transplant can affect relapse
rates.33-35
A study from the International Bone Marrow Transplant Registry showed
that the use of methotrexate for GVHD prophylaxis in patients with
acute lymphoblastic leukemia decreased relapse independently of its
effect on GVHD, possibly due to the direct antileukemic action of
methotrexate.33 Blaise et al34 showed that the
addition of an antibody against the interleukin-2 receptor (33B3.1) to standard GVHD prophylaxis early after transplantation delayed acute
GVHD, but did not decrease its incidence. This delay was associated
with an increased relapse rate and poorer leukemia-free survival. Jiang
et al35 found an association between lower CD8+
and natural killer cell numbers after allogeneic BMT in patients with
chronic myeloid leukemia and an increased relapse rate.
Hancock et al36 in a retrospective study of children with
acute lymphoblastic leukemia receiving T-cell-depleted marrow from
unrelated donors, found that mixed chimerism on day 21 (persistent recipient hematopoiesis) was associated with a significantly higher probability of relapse. Although no data were available from their group of patients, it is possible that complete elimination of recipient hematopoiesis, and consequently a lower risk of relapse, may
have been correlated with adequate lymphocyte
reconstitution.
It would be interesting to look at lymphocyte subset data to see if
there was any correlation between specific subsets and the observed
outcome. Unfortunately, these investigations were either not available
or were not routinely performed. A higher nucleated cell dose would be
expected to contain a higher number of lymphocytes, and thus, possibly
a lower relapse rate. Thus, the observation of a higher relapse rate
with higher nucleated cell doses is difficult to explain. Although the
difference is significant in the Cox analysis, it is not
significant in univariate analysis (16 of 101 v 9 of 100;
3-year probabilities 24.5% v 13.4%; P = .11). Unlike
those between marrow and blood,26 the differences between
lymphocyte numbers at various nucleated marrow cell doses are likely to
be rather modest and may not have any impact on immune recovery.
The risk of relapse as a result of slow lymphocyte recovery has to be
interpreted in the context of other factors, which are known to (or
would be expected to) increase relapse rates such as adverse
chromosomal abnormalities.14 Thus, in a patient with a
high-risk chromosomal abnormality, a low lymphocyte count could be a
clear indication for action. In a patient without such abnormalities, it may simply call for careful monitoring for the earliest evidence of
recurrence. It would be worthwhile to see if our data can be duplicated
by other centers and in other diseases.
The potential therapeutic options in patients identified as being at a
high risk of relapse a month after allografting could include
administration of interferon-, interferon- , interleukin-2 or more
donor leukocytes, or modification (curtailment) of immunosuppression. Administration of interferon- (in fact given for its potential antiviral effects) has been shown to reduce relapse
rates,21 but has also been reported to increase the
incidence and severity of GVHD.37 Interferon- can
sometimes increase the CD4 count in patients with lymphopenia
(unpublished observations). The administration of interleukin-2 after
T-cell-depleted BMT has been shown to increase the natural killer cell
numbers and reduce relapse without any effect on the lymphocyte
numbers.22 Administration of graded increments of donor
lymphocytes to acute leukemia patients after T-cell-depleted BMT
decreased relapse of acute leukemia, but was associated with clinically
significant GVHD.20 Curtailing the immunosuppression can
reduce relapse rates,23 but may also give rise to severe
GVHD, if tapered too rapidly.38 This could also be an
appropriate setting to test active specific immunotherapy using
inactivated malignant cells,39 possibly in combination with
stimulatory cytokines.
In conclusion, our data suggest that poor lymphocyte recovery a month
after allogeneic BMT is associated with an increased risk of relapse.
Because the relapse risk is a combined function of the conditioning
regimen and GVHD prophylaxis, it may be best for each transplant team
to define their own criteria for identifying patients at risk of
relapse. Patients identified on the basis of this could be candidates
for prophylactic immunotherapy to enhance graft-versus-leukemia.
| |
FOOTNOTES |
Submitted October 14, 1997;
accepted December 11, 1997.
Supported by the Cancer Research Campaign, the Bud Flanagan Leukaemia
Fund, and the Leukaemia Research Fund, UK.
Presented at 38th Annual Meeting of the American Society of Hematology,
Orlando, FL, December 7-10, 1996.
Address reprint requests to Jayesh Mehta, MD, Division of
Hematology/Oncology, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 508, Little Rock, AR 72212.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract
