Gregg. MB,. Stewart. iA,. Troupin. RH,. Thomas. ED: Cytomegalovirus ...... H, Curtis. iE,. Norman. C: Allogeneic bone marrow transplantation in patients with.
From www.bloodjournal.org by guest on January 24, 2018. For personal use only.
The
D 62,
NO.
The
Bone
Marrow
Transplantation:
DECADE,
marrow
shown to provide of a number of
disorders Marrow
leukemia, remission
a means for curative lethal congenital and
to the
and has emerged the treatment
particularly early in
Graft-versus-host rejection, and considerable
transplantation
of the hematopoietic and lymphoid transplantation is the treatment of
aplastic anemia approach to in
the
of a marrow
transplant.
sibling. of marrow
graft have to selected In this
in
and techT lympho-
allowed patients review,
transplantation
in the
extension of lacking an the current treatment
of
and congenital disorders of the hematowill be discussed in the light of these
foreign
marrow
or near
complete
and
for
intensive
between pression poietic
OF
MARROW
The
development modality
At the exclusively
advances ( I ) the
in transplantation definition of the (2)
allelic
biology. systems
as a three These of the
the major histocompatibility comthe development of chemothera-
and radiotherapeutic enough to allow
Vol. 62,
transplantation from at least
No. 5 (Novemberl,
techniques engraftment
1983:
pp.
941-964
immunosupof genetically
and support
enough
to achieve
of host
leukemic
(3)
of
complete cells
development
patients
present time, marrow reserved for the sibling inherited
autosome parental
prior
of systems
during
the
period
or immunosupdonor’s hematothe transplanted
the haplotypes can
tance
thus
ofthe
same
Charles
in
the
Charles
A. Dana
Judith
Dana Center,
by
Harris
in mixed
Transplant
Lucy
Selig
New
New
York.
Grants
Lila
Hope
Zelda
Fund.
Chapter.
Inc. and
and
Marrow Memorial
CA33050.
Institute,
Radow
Robert
International Acheson
Unit,
NY.
Fund.
Fund,
and
iden-
leukocyte
Pediatrics.
CA23766.
Cancer
Memorial
Moses
Fund,
of
P115
Frontiers
and
HLA-A,B,C,
of HLA-D
Marrow
Foundation,
Foundation,
Challenge Knecht
inheri-
by certifying typed
by the National
awarded
of
be established
A.
part
complex of the HLA
Cancer
Supported
gene
as a component
determinants coded by each are codominantly expressed.
Service-Department
Sloan-Kettering
HLA
nonresponsiveness
Transplantation
CA08748
The
and demonstration
tity by mutual culture (MLC).’
the
donor.
serologically
DR determinants
From
transplants are almost patient possessing an
in its entirety
6;b0
identity
Henry
of marrow has resulted
and
host.79
C. Kleberg
TRANSPLANTATION
potent
pretranspiant cytoreduction and reconstitution of the and lymphoid system within
Foundation-New
ASPECTS
Status
ablation
to transplantation;5’6
Fund,
FUNDAMENTAL
1983
J. O’Reilly
is usually
new immunosuppressive agents, and and therapeutic antiviral agents improvement in results. Advances in
marrow
Current
HLA-identical
How-
recent progress has been made these obstacles. Adva nced radiothera-
transplantation
acquired system
as a highly high-risk
when applied to course of their
of human histocompatibility for selective removal of alloreactive the
of
disease (GV H D), infection, leukemic relapse remain major
success
marked
from
of Hematology
Directions
By Richard
LAST
of
NOVEMBER
Future
been
Society
5
Allogeneic
THE
American
Journal
and
DHHS,’
Weintraub
the Sherman-Fairchild J. Kleherg,
Jr. and
Helen
Paper Co. Foundation ,
Frito-Lay/New
DeWitt
the Glenn
and Cancer
Wallace Edward
Fund.
York
Yankees
Fund,
Frances
Fletcher
Foun-
dation. Submitted Address Dana
Marrow
Department ter, New ((
November 10, 1982; accepted reprint requests to Dr. Richard Transplant of Pediatrics, York,
Unit,
Marrow
Memorial-Sloan
June 21. 1983. J. O’Reilly. Charles Transplantation Kettering
A.
ServiceCancer
Cen-
NY.
I 983 by Grune
& Stratton,
Inc.
0006-4971/83/6205-0001$02.OO/O
941
From www.bloodjournal.org by guest on January 24, 2018. For personal use only.
942
RICHARD
In the absence
of a genetically
at fertilization likelihood that
In practice, sibling; identified sons,
the
thus for
not
average
with
certain
types more commonly the population, thus tifying parental
For
HLA
to their
Major
ABO
incompatibilities
a significant
barrier
tion.’5”6
To circumvent
severe
(e.g.,
of unrelated phenotypically
replacement
with
from
donors
after
removal
antigen-bearing
on blood
adsorbents,’5’8
latter approach the fluid balance
pie volume
plasmaphereses
phamide-treated
in children
patients
with
Engraftment a donor
relatively ablation resist able,
of allogeneic
marrow,
other
an
than
(TBI)
immunosuppressive
with
aplastic
disease
with
2 days) irradiation a dose
for
twin,
is cyclophosphamide
of 5-7
Graft-versus-host
rad/min.6’35
by
posterior
filtration
of the
administration
by
success
graft
graft
are
of an
HLA-
graft-versus-host
rejection,
and
disease
However, relapse
leukemic
and
associated
these
in the
patients
remain
posttransplant
at risk
period.
disease (GVHD) is a pathologic engrafted immunocompetent lymphocytes responding to alloantigens on host cells, particularly cells derived from by
lymphohematopoietic
T lymphocytes tissues cell
system.2’26
are then
either
directly,
effector
thought
These
or indirectly,
systems.
GVHD
activated
to produce
injury
to
by educating
other
commonly
mani-
is most
by a generalized
pathognomonic, pathologic features include infiltration of lymphocytes and monocytes into perivascular spaces in the dermis and the dermoepidermal junction of the skin, into the epithelium of the oropharynx, crypts
and of
esophagus, the
areas in infiltrated
cells
cause
recipients
used for in patients
x
of
marrow
prior
as
on
of patients and
may
20%-40%
of
affected
from
be have
activity
grafts
to be coded
by genes
complex
female
to transplant,
disparities
HLA-matched
histocompatibility
of
characteristics
donors,39’4’ are
of natural
herpes-infected
alloantigenic
presumed
the
marrow host
grafts
who,
to increased
lowing
30%-70%
into necrosis
with an increased risk of GVHD in These include: increased host age,#{176}
have normal assessed
and
secondary
in
Certain
recipients
The
in
of death
of the intestinal
bowel,
HLA-identical
been associated multiple studies. and
the base
large
develops
with
individuals.27’38’39
is
and
of the liver, with tissues.22’337
GVHD
indirect
into
small
periportal
an
of 50 mg/kg
of modifica-
to the
marrow
initiated
Acute
with total body as a single dose at
A number
graft.
transplanted
immunosupto prepare
regimen
and
subsequent
donor
and
infections are problems affecting all allogeneic marrow graft recipients. Patients with leukemia, in contrast to patients with aplastic anemia, rarely reject a matched
tongue, a
prior graft or
(60 mg/kg/day
followed 3-4 days thereafter (1 ,000 rad administered rate
in
transplantation
at a dose
days.5 The standard and immunosuppression
ablation
leukemia
anemia
administered
on 4 consecutive
infections,
relapse.
Of
hematopoietic cells.5’6’21’22 The standard pressive regimen that has been developed patients
as
the agents currently availand total body irradiation in high doses are sufficiently to permit engraftment of foreign
administered
cyclophosphamide
such
that is, marrow
identical
immunocompetent patient necessitates of the host’s capacity to reject the
its development. only cyclophosphamide
It also
complications, (CMV) infection.
anesthetized
anterior
maculopapular rash, hepatitis, diarrhea, and a delayed reconstitution of hematopoetic and lymphoid function.2733 Distinctive, but not
it avoids multi-
toxicity.
the
the
obstacles
disease,
fested
and cyclophos-
cardiac
avoids other transfusion-related hepatitis and cytomegalovirus from
because attending
major sibling
the
or
red cell sedimentation.’9’2#{176}The
is increasingly used problems sometimes
from
pooling
identical
in reviewing
from
heparinization,
donor I expressed
(2) removal of ABO-bearing red cells from the marrow graft by differential centrifugation or by dextran or
Hetastarch-potentiated
The
discussed
procedure has been well harvesting of 500-800 cc of
marrow, and infusion.
process
plasma
of isoagglutinins
solid-state
crests,
be
Graft-versus-host
either isoagglutinin-
or autologous
marrow
aspirated intravenous
(1) multiple
specific
transplant It involves
for leukemic
of the host with
free
normal
two
will
aspirations
marrow
transplantareactions,
successfully:
immediate
group
or of
A into 0) do not
hemolytic
approaches have been used blood volume plasmaphereses
replacement
iliac
couples in of idensibling in a series
to marrow
actual
described.23 multiple
mothers.”
constitute
plasma
born
These
heparinized
cornforms
or full haplo-
identical Indeed,
complications. results.
The
of
Fanconi’s severe certain
than do other married increasing the probability
tions of these regimens have been recently introduced to improve the incidence of engraftment or to reduce the incidence of leukemic relapse or radiation-related
rca-
parents
and
1 1 patients with Fanconi’s anemia, parents, we found 5 to be HLA-A,B,D identical
be
unclear
determinants
an HLA phenotypically donor for these patients.
one
can
including
agranulocytosis,’2 (SCID),’2
share
than
consanguinity,
disorders,
congenital irnrnunodeficiency 1
bined
more
the is 1:4.
donors
of patients.
on parental
of leukemia,’3”4
has
sibling
35%-40%
selection
development, be matched
patient
HLA-identical
based
patients
determined
or during prenatal any one sibling will
J. O’REILLY
fibroblast
stimulating are
not
unrelated (MHC).
found
killer
to
cells,
targets.42’43
GVHD known, to the Initial
fol-
but
are
major reports
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ALLOGENEIC
MARROW
implicating
TRANSPLANTATION
disparities
(MNS) ofGVHD
for
or sex-linked in man have
series.
minor
red
cell
GVHD.
antigens
antigens45 in the pathogenesis not been substantiated in larger
Lymphocytoxins47
HLA
943
reactive
against
host
non-
determinants
frequently develop following transHowever, the allospecificities of these antinot been characterized. Furthermore, their
plantation.
bodies
have
appearance toxic I cells
has not been linked specifically reactive
(TNP)-modified detected
in
GVHD.48
Ihe
a
host
fibroblasts
high
proportion
functions
populations,
presumptively
cytotoxic
inhibiting the tors (CFU-C)
in the
of
patients
with
above,
non-I-cell type,
which
are
ural are
capable
of
myeloid progenito be enhanced in
with acute GVHD.49’5#{176} Recent studies by et al.5’ suggest that these radioresistant suppressor cells can be generated in mixed
leukocyte identical
cultures (MLC) between certain HLAsibling pairs. Generation of such suppressor a patient and highly predictive
of acute
GVHD.5’
Minor
parities between donor and recipient the generation of both the “alloreactive” and
“autoreactive”
during
acute
expanded
non GVHD.
from
pedigrees
of
related
should
individuals
ultimately
minor alloantigenic relationship to other genome.
for GVHD suppressive which, of
Accurate
immunologic
the
within
large
definition
prediction prevention may delay
reconstitution
in the
of family in the at risk
use of immunoof GVHD, hematopoietic
agents and
posttransplant
pen-
od.
The
pathophysiology
of HLA-matched stood. While
alloreactive
of acute
marrow it is generally
I
GVHD
in recipients
grafts is still poorly underaccepted that engrafted
lymphocytes
initiate
this
process,
the
period
in all patients, well before emergence of normal helper I-cell populations.5255 In our sequential studies of allogeneic marrow graft recipients, we have persistent
imbalances
patients with acute GVHD resolution of this process,52 suppressor/killer phenotype
of
I-cell
subsets
contribute
cells,
circu-
with
acute
also
shown
predominate
infiltrates
of cutaneous
are
I cells
of this
pathology.
populations,
(NK)
in the
that
to GVH
non-I-cell
growth
phenotype
lymphoid
suggesting
As
particularly
also
in
that have normalized with suggesting that I cells of might contribute to acute
I
patients
et al. have
and immunodeficiency yet unclear.
class
described
certain
prominent
The
treatment
marrow
observed
of acute
transplants
during
of corticosteroids ulin (AIG).57’58 cases.
during
GVHD
currently with This
natacute
Prophylactic
is as
in HLA-matched
administration
antithymocyte is still inadequate
administration
for the first to significantly
to
GVHD
involves
or without approach
globin
of methotrex-
100 days reduce
posttransplanthe incidence
and severity of GVHD when administered to dogs,59 and has become a standard, albeit only partially effective,
GVH
prophylaxis
Attempts
prophylactic have
to
for human further
administration
not been
marrow
abrogate
graft
antithymocyte GVHD, but Recently, particularly
globulin does not
lymphocytes, acute GVHD
have both
Studies
globulin
from
immunosuppressive and antibodies
the
acute GVHD will of this process.
hypothesized
emergence
GVH
reaction.49’70’7’
Univer-
adminissteroids and severity of survival.62 specific
agents, for I
shown promise in preventing severe in animal models and in man.639
Most patients with spontaneous resolution that
through
may reduce the improve overall
highly selective cyclosponine
recip-
GVHD
of antithymocyte
successful.#{176}2
the
ance is an active phenomenon, opment of suppressor cells
relative contributions of these cells and other cells of donor or host origin to the disease process are difficult to assess. Activated I lymphocytes with a suppressor/ killer phenotype develop early in the posttransplant
observed
of
sity of Minnesota suggest that prophylactic tration of a combination of methotrexate,
of these
inheritance within
CFU-C
Iutschka
further
detected
host cells during have also detected I
GVHD. Whether these cells directly contribute GVH pathology or to the prolonged myelosuppression
ients.
cells
of patients
selective
for
reactivity
et al.48 have
proportion
ate at low dosage tation was shown
observed against
and their determinants
more
HLAsubseallodis-
cells
permit
systems mapped
will permit agents themselves,
of
these
of inhibiting
subepidermal
killer
many
likely stimulate donor I cells
populations
Analysis
populations
derived
human
I-cell
his for
Isoi
of suppressor/killer
GVHD,56 directly
and
above,
for hapten-modified Delmonte et al.
a large
cells
been
growth of donor-type have also been found
development
of
that
patients Delmonte non-I-cell
quent
capable
lation
recently
fibroblasts
cells in an MLC between identical sibling has been
cells
have
of donor
for donor-type
cytotoxic GVHD.
GVHD.5#{176}Recently,
to GVHD.’47 Cytoagainst trinitrophenol
of “autoreactive”
As noted
cells acute
experience a It has been
of graft-host
toler-
dependent on the develcapable of controlling the
However,
while
the evidence
for a
suppressor-cell-mediated tolerance following allogeneic marrow grafts in rat models is impressive,70’7’ it has not been well documented in other species, including man. resolves tissues Elkins
Equally tenable is the hypothesis as critical blood-derived host
GVHD in the
are replaced by donor cells. Early studies et al.72 and Streihlein et al.25 had suggested
blood-derived
cells
in the
tissues,
such
cells in the skin, were the principal gressive donor cells in the GVH studies
that targets
in
transplant
models,
as Langerhans
targets reaction.
employing
by that
of alloagRecent techniques
From www.bloodjournal.org by guest on January 24, 2018. For personal use only.
RICHARD
944
such
as
cells
from
local
ultraviolet target
supported
irradiation
tissues,
this
such
hypothesis.
as
to deplete
these
the
have
Considerable
research
thus needed to define the reasons for and the basis for the durable graft-host ultimately Between
develops. I 5% and
develop chronic tinct from acute
skin,73
40%
of transplanted
GVHD, GVHD,
is
GVH resolution tolerance that patients
will
a process pathologically diswhich may result in localized
a significant mononuclear cell response for their pathology a re observed, particularly cytomegalovirus (C M V), adenovirus, and Pneumocystis-cariniiinduced donor severe
pneumonia ,96, I 07 The alloreaction between and host is important to the pathogenesis of CMV infections. Such infections are observed
rarely, if at all, following twin transplants, and are most common in patients with severe Whether such infections are activated by GVHD”#{176}”
or widespread scierodermatous changes of the skin, skin and joint contractures, xerostomia, xerophthalmia, biliary cirrhosis, malabsorption, and failure to
or promote expression
thrive.7479
the selective GVHD”3 is
immunodeficiencies unknown. In a
transplanted
for leukemia
chronic pressor
Immunologic
abnormalities
GVHD include I lymphocytes
specific
suppression
B-cell against
associated
increased populations and monocytes capable of I-cell
with of supof non-
transformation80’8’
antibody production,8284 host epithelial cells,85’86
in vitro immune
and
IgG antibodies complexemia
encapsulated term treatment prednisone
pathogenic bacteria.93 Recently, with a combination ofazathioprine has been
ing the clinical The infectious tation ment
distinguish of the donor
Prior
shown
to
induced
to fungi tions
due
patients
are
longand
infections period and
are may
also frequently produce hepatitis
of developperiod. sensi-
activated or mild
use
of prophylactic
reported serious
granulocyte
infusions
to be effective in reducing bacterial and fungal infections
have
the been
the incidence of in the immedi-
ate posttransplant period.99”#{176}#{176} However, prophylactic granulocyte infusions enhance the risk of acquiring certain virus infections, particularly infections due to C M V #{176}‘.102 Severe herpes plant recipients can be .
administration of does not compromise acycloguanosine disseminated tions,
such
infections in transby prophylactic
acycloguanosine. engraftment.’#{176}3
has herpes as occur
simplex prevented
been zoster
used and
in the early
This prophylaxis Studies in which
for the treatment of herpes simplex infecposttransplant
ing Cancer
period,
have also been encouraging.’#{176}’’#{176} During early engraftment, particularly in patients with GVI-ID, infections eliciting and possibly requiring
Center
observed
in
common
result
associated of 122
series
at Memorial
(MSKCC), (32%).
etiologies
were
from
with patients
Sloan-Ketter-
interstitial
patients
39
or merely
2
pneumonia
As in other CMV,
series,96
followed
by P.
carinii. However, in 22/39 cases (56%), no etiology could be defined. A small proportion of these cases might be ascribed to radiation injury.’#{176}7”#{176}8”4 However, the majority of these idiopathic cases probably reflect the continuing inadequacy of existing techniques for rapid and accurate detection and identificaof viral
of antigens tissues, improve
pathogens.
In the
immediate
future,
electron microscopic monoclonal antibodies
expressed
by viruses
tissue homogenates, the accuracy and
the
techniques and for detection
or other
pathogens
in
or body fluids”5”6 rapidity of diagnosis.
may Cur-
rent treatment for interstitial pneumonia in the posttransplant period remains largely ineffective. Pneumocystis carinii infection can be treated and prevented by the
administration
of
antiviral
arabinoside,
arrest
encephalitis.9798 Decontamination with nonabsorbable antibiotics in laminar flow protective isolation and
transformed
use of scanning pathogen-specific
those infections observed in chemotherapypancytopenic states, such as septicemias due and enteric bacteria, and disseminated infecto herpes simplex or herpes zoster.9496 Latent
papovavirus during this
(EBV)
tion
in ameliorat-
particularly
the GVHD process by altering cell surface of alloantigens, as is seen in Epstein-Barr
the most
ofchronic GVHD.79 of marrow transpian-
the three major stages marrow in the posttransplant
to engraftment,
tive
to be effective
manifestations complications
virus
was
resulting in complement activation,78’87 complex deposition (particularly in skin),889#{176} and profound and prolonged deficiences of humoral 98289,92 resulting in enhanced susceptibility to infection with
J. O’REILLY
17 A number interferon, adenine have failed either to due to cytomegalovi-
of
agents, specifically and acycloguanosine interstitial pneumonia
rus’’8’2#{176}or to prevent
its development.96”03”2’
nary
MSKCC
results
from
teams suggest hyperimmune
the
that the globulin
and
prophylactic or plasma
infections bacteria
and are
New
posttransplant infections
most
herpes
to encapsulated
seen
in is
with chronic Susceptibility
and
are
and may well immunodeficiency
GVHD.298284 to severe
forms
particularly
zoster pyogenic
patients with chronic GVHD.93 Indeed, the spectrum of bacterial infections observed in such patients similar to that seen in patients with Bruton’s agammaglobulinemia’25 state of humoral
common
of in
antivirals, such (FIAC), are also
period,
due
transplant
administration may be effective
preventing CMV infections.’22”23 as 2’-fluoro-5-iodo-arabinsylcytosine under trial.’24 Late in the
Prelimi-
UCLA
reflect
of
the affecting GVHD
prolonged patients and
to
From www.bloodjournal.org by guest on January 24, 2018. For personal use only.
MARROW
ALLOGENEIC
transplant-associated resulting in an patients
increased
transplanted
life. This comparison
patients in first
older
than
years
in both groups; were principally
tion-related deaths, younger and older age-related also
in the third
both
for
decades
,
of
displays a in “good-
differences in disease-free due to differences in early
suninfec-
transplant exploring
therapies
of the Similar
recovery. examined
For example, Atkinson whether administration
affected groups, in
1 5% and respectively.
disease-free groups
aplastic
40%
survival
anemia39’4#{176} and
recipients.
of GVHD,
forms
have
in patients for
to the in older
are
Immune
reconstitution
may
be limited in older patients, particularly patients 25, due to age-related deficiencies of the thymus
may also resistance
have a cumulative in older patients.
epidemiologic evidence patients in the second and
effect, Furthermore,
recipients.
to transplant
more
reduce A
recipients and
infections. measures
also
immunologic initially thymus
immune
recon-
deaths
In these early treated group.
in the trials, no However,
these therapeutic trials out prior determination tion. In future trials, who might be benefited
were initiated in patients withof their thymic secretory funcimproved selection of patients by thymus replacement may
yield
Additional
a different
to determine
result. the
therapeutic
immunomodulators,
trials effects
tive
over and
isolated thymic peptides, on the course immunologic recovery in older patients rently,
to assess
such
the
effects
of such
ulations on the susceptibility plantation-related infectious TRANSPLANTATION
Between applied already
1968
and
as
in progress
the
potentia-
interleukins
or
and quality of and, concur-
therapeutic
manip-
of older patients complications.
to trans-
FOR
1978,
are
of other
also
that likely
are
et al.’27 of cultured
infectious
period. in the
in older
of groups
enhance
reduce
Neihave GVHD
mortality
to facilitate
would
thereby
Indeed, patients against
early
number
designed
early posttransplant benefit was realized
reducing sero-
clearly establishes later decades are more
may
leuke-
factors such as thymic hormones and interleukins,’28’3#{176}which are necessary for expansion and differentiation of engrafted donor lymphoid elements. Insults sustained by lung, liver, or gastrointestinal tissue tissue
infections
stitution
high mcitransplant
which
viral
trans-
common in patients after the first decade,40’63”27 may delay immune and hematopoietic reconstitution. Immunosuppressive treatment of GVHD likely accenproblem.
of these viruses. that seropositive
and
Relapse
contribute observed
this
due to reactivation et al.96 have shown
was
age.
Multiple factors may dence of lethal infections
tuates
tion man
incidence
of
for acute are younger
to be seropositive and presumptively latently infected with CMV, herpes simplex virus (HSV), and herpes zoster,’3t’33 thereby enhancing their risk of an infec-
a higher incidence of CMV Improved prophylactic
by other
Severe
fourth
age, for
leuor
which patient
reported
and
Fig. 1 which survival observed
at MSKCC remission who
disparities
been
planted mia.’26
in
transplanted or second 20
945
infections increases with mortality, particularly
is illustrated of disease-free
risk” kemia equal vival
TRANSPLANTATION
marrow
LEUKEMIA
transplants
were
to the treatment of leukemia only in patients refractory to conventional antileukemic thera-
0
a
+ tLj
> -J
cz z 5
Fig. 1 . The Memorial Sloan-Kettering Cancer Center experience with allogeneic marrow transplantation for patients with AMI in first or second remission and ALL in second remission. (o) Age less than 20 yr (37 patients), () age greater than or
equal
indicates
to
last
20
yr
follow-up.
(26
patients).
Tick
mark
V 0 V
(‘)
,
MNTH8
FBM
TRRWSPLRW!
00.
From www.bloodjournal.org by guest on January 24, 2018. For personal use only.
946
RICHARD
py. As reported prepared irradiation
2)
by Thomas
and
transplanted
HLA-identical uous remission larly
et al.,38 of 100 such
with a lethal dose (1 ,000 and cyclophosphamide sibling, without
treated
patients
identical disease-free
twins
between
twin
reflected geneic
with
marrow
from
a
due
body x normal
13 survived over 5 yr in continfurther chemotherapy. Simitransplanted
with
marrow
enjoyed a 30% incidence survival’34”35 Differences and
patients
rad) of total (60 mg/kg/day
of long-term in results
HLA-matched
marrow
principally an increased marrow graft recipients
from
mortality caused
in allograft-
(AML) other
ing
centers
indicate
survival. Ihe posttransplant
a 60%
probability
cumulative period has
promising vival in
with long-term cases or more.’39’
approach, 40% of
experience mia (ALL) 2. As can relapse
in first
than
that
remission.
observed this Table
Fred Hutchinson Seattle
Marsden
relapse 1.
Marrow
Preparative Rejimen
Center
Royal
in
sunReported
in patients
Whether
CTX
+
1,000
CTX
+ FrTBI
CTX
+
CTX
+ Hyperfract.TBI
1 000
transplants groups
with rate
sion
16-37
been
recorded
to be deter-
analyzed
their
in second the results
described continuous
not
expeni-
remission. divergent.
24 such patients, remission 4-42
group, The
prepared regimen, mo
have
are
5 patients disease-free
8 of mo
relapsed, survival
differ from that in relapse. In our
for transplants by a different 7 survive in continuous remis-
postgrafting. in this
To
group.’37
date,
no relapse
The
3-yr
has
disease-free
to patients
with
needed
to assess
AML
in primary to a patient’s
remission long-term
or second
degree
are more disease-free
ment of AML While few
both in children now contest the
Transplantation:
AML
in First
No.
and adults. advantages
nemis-
transplants
clarify how and when transplants applied towards the curative
of chemotherapy treatment of acute
is
in first
to what
advansurvival, can be treat-
of marrow
in the treatment of relapsed during maintethe comparative merits
and transplantation nonlymphoblastic
in the initial leukemia (ANL)
Remission
of
Disease-Free
Relapse
Survival
Rate
(%)
(%)
Reference
75
55 (2 yr)
10
136,
22
64
(1
yr)
18
140
MTX
34
60
(2 yr)
8
137
Patients
MTX
138
rad Cyclosporine-A
London
Memorial
1 .320
Sloan-Kettering
York
New
UCLA
rad with
lung
shielding CTX +
1,000radTBl
MTX
22
52
20
142
CTX
1 .000
MTX
11
45
18
139
MTX
17
64 (2 yr)
12
143
CYA
11
64 (1 yr)
0
141
MTX
11
70 (2 yr)
0
144
Los Angeles
City of Hope
+
rad TBI
Duarte U. of Minnesota
CTX + 750
Johns
Hopkins
rad TBI
high
dose rate
Minneapolis
CTX
+ Bu
Baltimore Mondor
Creteil,
Hospital
CTX + 800
#{149}C1’X,cyclophosphami
rad TBI with
lung shielding
France de; TBI,
total
body
irradiation;
FrTBI,
4 at
of patients own series,
and to further most effectively
Prophylaxis
rad TBI
of
remains
for AML are small and
et a!.’5#{176} have survive, 7 in
GVH
1 200
two centers
transplants oven chemotherapy leukemic patients who have nance of their initial remission,
rad TBI -
only
ence with The patient
performed tageous
of transplants for acute lymphocytic leukein second remission is summarized in Table be seen, the incidence of posttnansplant
is higher
AML
disease-free
primary
mined. To date,
sion
in the
for acute lymphocytic leukemia has also emerged as a particularly
remission
patient’s
applied
of disease-free
Transplantation second remission
the
leukemia
and radiothermaintenance
survival for this group (64%) does not differ from that obtained for patients transplanted in first remission. More extensive comparative studies of transplants
these report-
incidence of relapse been low (12%).’’
lymphoblastic
to chemotherapy induction and
of 1 1 patients cytoreductive
in first remismajor centers
(summarized in Table i)’ have confirmed results. At present, the cumulative results from
of acute
2 yr was 24% and did with AML transplanted
grafts.’34”35 et al.’36 reported a 63% long-term in a series of patients transplanted
for acute myelogenous leukemia sion. Subsequent reports from
biology
posttransplant. In this within 6 mo of transplant.
versus-host disease and associated infections. Recurrence of leukemia was common in both transplant groups, but was particularly prominent (60%) in recipients of twin marrow In 1979, Ihomas disease-free survival
the
itself or to a resistance apy developed during
Buckner whom
grafts by
to
J. O’REILLY
fractionated
dose
total
body
irradiation;
M1’X,
methotrexate.
From www.bloodjournal.org by guest on January 24, 2018. For personal use only.
ALLOGENEIC
MARROW
TRANSPLANTATION
947
Table
2.
Marrow
Transplantation:
ALL in Second
Remission Disease-Free
Preparative Center
GVH
Regimen
Fred Hutchinson
(A) CTX + (B) CTX
Seattle
Sloan-Kettering
Prophylaxis
1 ,320
of
Survival
Patients
Relapse
(2 yr)
Rate
Reference
MTX
22 24 22
MTX
5
80%
20%
139
MTX
15
43%
33%
149
1 ,000
rad TBI
MTX
+ 1,000
rad TBl
MTX
+ Hyperfract.TBI
CTX
Memorial
No.
38% 38% 62.5%
54%
145
47%
147
14%
148
rad
New York City of Hope
CTX
+
1 ,000
rad TBI
Duarte
CTX
U. of Minnesota Minneapolis
dose
+ 750
rad TBI
high
rate
N.K.C. Ramsey, personal communication.
and some forms Until recently,
treatment
of
inductions
in only
3O9o-5O%
the
first
of more
patients,
sustaining In the intensive
with
their last
with
more
particularly experience, induction
remission,
33 (49%)
have
the
achieved
in patients However,
success
(55%
in younger
centers.’37”43”59 of relapse both
disease-free
patients
Of concern, during and
therapy, who
panison therapy
of the efficacies in the treatment appear early
chemotherapy, a transplant transplant
achieve
to hinge survival
for ANL principally
survival
a >70% survival
a by in
at 2 yr)
a group
for
probability in a number
of of
also, is the high incidence after completion of mainte-
initial
affecting
50%
remissiofl.’58
Thus,
of
the
a corn-
of transplantation or chemoof ANL in first remission on the relative observed in
advantages of the patients receiving
and the increased curative potential of that may significantly differentiate the group only later in the treatment course.
Such a comparison must associated with 1 5 or more chemotherapy,
also consider the morbidity months of intensive mainte-
a feature
mens that is rarely discussed, problem of graft-versus-host problem
sustained
in continuous
(< 1 7 yr),
a complication
patients
nance
Recently, stitutional
of the VAPA al.’55 have been update of this
transplanted these results
which a transplant now offers long-term (>3 yr) disease-free
would higher
transplanted
for a median of 19 months postinduction, survival comparable to that reported
several centers first remission.
nance
consolida-
remissions
survived
of GVHD
in perspective,
of chemotherapy and disease.
the
regi-
often cited To place the
it should
posttransplant
treatment of in 70%-90%
Mayer et al.’58 have reported a remission rate of 70%. Of 67 patients initially induced
remission disease-free
reflect
of the
1 yn.’5’57 The results developed by Weinstein et heartening. In a recent
bered that while GVHD affects 30%-70% of transplant recipients and is a major, albeit indirect, contributor to early mortality, it usually resolves early in the course
cant, long-term activity in only
3 yr. however,
than
protocol
into
up to 69%
only
remissions
induction,
and maintenance regimens to the has resulted in remission inductions
of patients, for
of
patients year.’’49
application
tion, AML
40%-60%
of these
through the
of ALL are subjects of intense debate. chemotherapeutic approaches to the AML have been marked by remission
be remem-
and
imposes
a clinically
impairment to a small fraction
normal (lO9o-l
signifi-
health and 5%) of the
population.79 a series cooperative
of single trials
institutional have been
and multiinestablished to
compare chemotherapy and marrow transplantation in the treatment of AML in first remission. A preliminary report of one such trial being conducted at MSKCC indicates tage in disease-free This advantage
some, as yet insignificant, survival for the transplant principally reflects the
advangroup.’#{176} excellent
results of transplants in patients under 20 yr of age. In older groups, there is, as yet, no discernible difference in disease-free survival between the chemotherapy arm and the transplant arm of the study. accrual and follow-up will be necessary tive
result The
can
Further before
patient a defini-
be established.
low incidence
of leukemic
relapse
and
of disease-free survival observed following for ANL in first remission has stimulated
high
rate
transplants a number
of
investigators to ask whether a transplant should be invoked in the primary management of patients with high-risk
forms
Children
developing
first year of life, mia-lymphoma
of ALL
who
achieve
lymphoblastic
adolescents syndrome,
initial
remission.
leukemia
presenting with the and patients with
in
the
leukeacute
B-cell leukemias have a high risk of relapse and have been considered for transplantation in first remission.’6’ However, experience with such transplants is still restricted. Furthermore, the acute mortality in reported cases has been high enough to obfuscate any short-term advantage of transplants.’6’ Recent improvements improved patients further candidates
in chemotherapy chances for with high-risk limiting for
have extended forms
also
significantly
remission, of ALL,’62’63
accurate
identification
transplants.
Thus,
even in thereby
of appropriate considerably
more
From www.bloodjournal.org by guest on January 24, 2018. For personal use only.
948
RICHARD
experience offer a
is needed to determine whether transplants higher probability of extended relapse-free to the patient who, by the phenotypic charac-
survival
teristics
of his/her
initial
leukemia
induction
high
risk
for early
Leukemic
relapse
is now
pretransplant
to at
the
mortality
may
major
obstacle
prove
to the
particularly attempts
regimens
to
in the early toxicity. in their
more
tolerable
and
be achieved by transfer of hematopoietic from genetically resistant donors. research
into
the
biology
of the
cells
allogeneic
advantage in leukemic patients may gous, genetically controlled resistance Allogeneic
marrow
transplantation
are such
effective.
marrow Hodgkin’s
from identical lymphoma.’79
twins in the treatment Reports of patients
Hodgkin’s
Burkitt’s
80
been evaluating the use irradiation with partial
trials in a number of transplant centers. marrow grafts for chronic myelogenous
to reduce such
(CML) patients
pneumonia, pretransplant marized
in an attempt to complications
in Table
2, are encouraging.
The
relapse in patients with remission transplanted
has been
tissue injury as interstitial
while increasing the antileukemic effect of cytoreduction.’46”66 Initial results, sum-
leukemic secondary
extraordinarily
low.
The
ALL with
incidence and this
of
AML in regimen
use of interferon
and
leukemia-reactive monoclonal antibodies to potentiate host resistance to leukemia in the posttransplant period is also under study.’68 The advantage of an allogeneic marrow graft in reducing increasingly of the
the
incidence apparent.
of posttransplant relapse For example, in a compilation
of relapse
incidence
been
found
to be
in the 12%
posttransplant
in recipients
has
of HLA-matched
grafts,
twin marrow grafts is over 50%. Weiden et presented evidence that patients with GVHD
experience and are
a lower incidence of leukemic p169.170 now exploring methods to potentiate this Marrow
Transplanta
incidence
of
marrow
3.
the
tion
for
in recipients
AML-First
RelapsesPosttransplantation
181
Allogeneic
Proportion
Relapsing
22
twins
‘Data
compiled
Cancer Royal
Center, Marsden
of Minnesota.
8
15
from
reported
experience
the Fred Hutchinson Hospital,
City of Hope
Cancer Medical
at Memorial Research Center,
53%
Sloan-Kettering Center,
UCLA,
with
of patients
over
transplant negative, tially
the
next
CML
5 yr will
recipients, remain free
curative
the
and the University
who
TRANSPLANTATION
in
count