Allogeneic Bone Marrow Transplantation: Current ...

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


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


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


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


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.


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.


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


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