marrow transplantation in severe aplastic anemia ...

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1980 55: 344-346

Total lymphoid irradiation and cyclophosphamide as preparation for bone marrow transplantation in severe aplastic anemia NK Ramsay, T Kim, ME Nesbit, W Krivit, PF Coccia, SH Levitt, WG Woods and JH Kersey

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CONCISE

REPORT

Total

Lymphoid for Bone

By

A new an

Norma

K.

C. Ramsay,

combination

attempt

severe

of total

to achieve aplastic There

patients.

7

were

(78%)

Taehwan

lymphoid

decreased

anemia

regimen. combination

Irradiation and Cyclophosphamide Marrow Transplantation in Severe

no are

of total

Kim,

Mark

E.

William

G.

Woods,

irradiation rejection

received

marrow

episodes

of graft

surviving

lymphoid

with

a

irradiation

and and

from

an

rejection, and

William and

Krivit,

John

H.

cyclophosphamide

rates

median

Nesbit,

only

follow-up

used

F. Coccia,

prior

disease.

HLA-identical, and

Peter

to bone

Nine

of

patient

400

cyclophosphamide

H.

Levitt,

The

warrants

transplantation

transfused

sibling

developed

days.

marrow

previously

MIC-compatible one

Seymour

Kersey

was

graft-versus-host

as Preparation Aplastic Anemia

following

this

graft-versus-host

excellent

application

with

preparative

disease.

results

of this

in

patients

of

regimen

this

Of

the

9

pretransplant

to a larger

series

of

patients.

B

ONE MARROW transplantation is the of choice for patients with severe aplastic who have matched donors. Major obstacles

therapy anemia to allo-

geneic marrow grafting are graft rejection and graftversus-host disease. The incidence of graft rejection is reported to be from 25% to 60% in various centers using utilized body prior graft

preconditioning regimen,

with the cyclophosphamide

rienced

with

the

patients

who

aplastic

use

disease

of total

body

continues

receive

bone

irradiation.4 in 25%-50%

marrow

transplants

Nine

for

Selective irradiation of the lymphoid system has been reported to provide excellent conditioning for bone marrow grafting in mice, rats, and dogs with very low rates of rejection and no graft-versus-host disease.57 Based on these data, we developed a new method of pretransplant immunosuppression using total lymphoid irradiation combined with cyclophosphamide for patients with aplastic anemia. The main objective of this regimen was to reduce the rejection rate seen with cyclophosphamide alone without increasing the morbidity experienced with total body who with

at the University

the

Departments

Laboratory

Health

Sciences

Supported 15548,

Address ment

Center, in part

ilL 5T32,

Submitted of

Memorial ©

Medicine

1980

reprint Bldg..

Therapeutic

Pathology.

University

Minneapolis.

of I 1 yr. Seven

patient

had

The duration a median

sions

from

The

-

3), a day 1) followed

in Fig.

Minneapolis. & Stratton.

0006-4971/80/5502-0002$0l.00/0

344

CA

I 9527.

accepted of Minn. Inc.

October

CA

55455.

had

including

radiation

was

through

anterior

to transplantation

All

patients

had

prior for

1977 with

1-8

multiple

mo,

transfu-

to transplantation.

field and

included (days

that

is used

includes

spleen,

and

administered posterior

a one

posthepatitic

4 days - 6,

-

5,

2), and total lymphoid irradiation infusion (day 0). The radiation field

the thymus,

to

anemia, was

received

intravenously

disease

750 rads

from

had

transplantation

the same

Hodgkin

patient

the were

18 yr.

aplastic

one

donors

and

idiopathic

and

I , was essentially

organs,

1 to

prior

of rest (day by marrow

with

from

using

Group,t

Hospitals

in age

50 mg/kg/day

patients

fields

(day shown

for treatment

all

lymph

of -4,

major nodes.

The

dose of

at 26 rads/min

in a single

using

linear

a 4 MeV

of

lymphoid dose

accelera-

tor.9 The

marrow

patibility x

l0

donor

complex cells/kg

received mg/sq

was a sibling

in all 9 cases.

with

transplantation,

globulin

21 737,

a median

all

patients

of prophylaxis methotrexate, m iv.

days

identical

40 mg/sq

were

methotrexate days every

x l0

randomized

major

cell

disease.

in combination

other

day

Minnesota

x 7 doses

one of two Six

(iv.)

therapy

2.4-5.2

Following

to receive

to 100 days,

and

was

cells/kg.

weekly 7-21

histocom-

dose

m intravenously

3, 6, 1 1, and

iv.

at the

marrow

graft-versus-host

15 mg/sq

m orally

15 mg/kg

matched The

dose of 3.9

for

patients day

and

I,

10

3 patients

with

predni-

antithymocyte starting

on day

8.

Of the phamide-total

M.D. Box

RESULTS

CA

2. 1979.

K. C. Ramsay. Minnesota,

of Minnesota

regimen

cyclophosphamide,

anemia, Study

anemia,

Minn. Grants

to Norma

University

by Grune

Radiology.

non-family

aplastic

Anemia

ofdisease

of 2 mo.

preparative

severe

ranged patients

Fanconi

with

with

of Minnesota

07145.

24, /979; requests

Pediatrics,

Pediatrics,

by USPHS

and HL

August

of and

patients

aplasia.

sone From

severe

METHODS

Aplastic

The

regimens

the results of nine patients lymphoid irradiation combined

patients

transplanted 1979.

AND

International

early

received

and

consecutive of the

median

of

for

ence.

criteria

anemia.”2

irradiation. We describe received total

to transplantation

MATERIALS

Graft-

to occur

prior

aplastic anemia at the University of Minnesota. The results indicate reduced graft rejection and graftversus-host disease from previously reported expeni-

most frequently alone.’ Total

irradiation in combination with other agents to transplantation is associated with decreased rejection, however, significant morbidity is expe-

versus-host

cyclophosphamide

,

366,

DepartMayo

nine

patients lymphoid

who received the cyclophosirradiation combination prior

to transplantation of matched sibling marrow, 7 (78%) are alive from >200 to >650 days, with a median follow-up of 400 days as of August 1979 (Fig. 2). Two patients died. One patient had Candida albicans sepsis Blood,

Vol. 55, No.

2 (February),

1980


TRANSPLANTATION

FOR APLASTIC

Total

ANEMIA

345

Irradiation Field of Minnesota Hospitals

Lymphoid

University

resolved

-

in one

patient,

The surviving values.

and

patients

four

have

episodes

of

normal

sepsis.

hematologic

DISCUSSION

for Lower margin: Ischial tuberosity

Bone marrow transplantation treatment of patients with

is accepted severe aplastic

with matched graft-versus-host

donors. Graft rejection, disease remain areas

morbidity

mortality.’

and

therapy anemia

infection, and of significant

Cyclophosphamide, when utilized alone for pretransplant immunosuppression, has been associated with a high bone marrow rejection rate, especially in patients ANTERIOR

FIELD

POSTERIOR

FIELD

Fig. 1 . Radiation field of total Iymphoid irradiation for pretransplant conditioning for severe aplastic anemia. Black areas are irradiated and include major lymphoid organs. e.g.. thymus. spleen. lymph nodes. White areas in the rectangular field are shielded.

prior

to transplantation

plant

from

occurred anemia

and

Candida

at 20 days who developed

host disease. engraftment red cell and Marrow

died

infection.

The surviving with donor cells, chromosome rejection

markers. did not occur

in combination in 6 of I0.

patient with graft-versus-host any

of

acute

the

or

disease. The morbidity associated stomatitis in one patient,

c

in

prompt utilizing

any

of

the

other agents, rejection exception of the one

Fanconi anemia, who developed acute disease, no other patients developed

evidence

l.00

had by

of 10 matched patients alone or cyclophos-

with With

death

with Fanconi graft-versus-

patients confirmed

chronic

with the regimen included interstitial pneumonia that

-

0.80 /

0.60

-

0.40

-

0.20

-

C 0

who

We

oo

I 300

200

Days Fig.

2.

anemia who phosphamide

from

I 400

I 500

600

700

Transplant

Survival curve of 9 patients with received bone marrow transplants and total lymphoid irradiation.

severe following

aplastic cyclo-

transfusions,’#{176}

with The

as

retransplantation need for further

without

with

aplastic

total

body

significant anemia

rate;

however,

malignan-

as part have

an

morbidity

has and

improve-

and

irradiation

immunosuppression

of their

extremely

in this

group

is

‘

elected

to use

cyclophosphamide sion in an attempt

total

lymphoid

irradiation

as pretransplant to take advantage

oral pharynx, etc.) irradiation. Morbidity regimen. No patient

in

with

i mmunosuppresof the immuno-

suppressive qualities of irradiation, organs associated with significant

while morbidity

sparing (lung,

patients receiving total body was minimal with the present who received matched sibling

marrow following total lymphoid irradiation and cyclophosphamide experienced graft rejection Radiation may, of course, be associated with late effects a .

of years

posttransplant

and

long-term

follow-

up is necessary. We are interested in the possibility that some patients may not require irradiation and a recent report suggests that nontransfused patients may successfully

grafted

following

conditioning

cyclophosphamide alone.’0 The low incidence of graft-versus-host matched patients is encouraging and

when

low incidence I

_o

receive

low rejection significant.

diation

0 0.

cies

globulin,

Patients

reported in patients cyclophosphamide Slavin et al., have

U) 0

ment.’2

previous

here, cases.”

to reduce this rejection rate of agents, such as procarbazine

antithymocyte

be 1

received

reported in most

immunosuppression led to the addition

number

graft-versus-host

1

have

pretransplant

posttrans-

second

in the patient sepsis and acute

patients. In our previous group who received cyclophosphamide phamide occurred

1 3 days The

that

in the group unsuccessful

given

disease active

in fractionated bone marrow.7 low incidence

in the animal experiments suppression of graft-versus-host

Studies are a suppressive

disease in our is lower than that

prepared for transplantation alone or with other reported that total lymphoid

of graft-versus-host

receive allogeneic responsible for the

with

doses disease

using irra-

results

in a

in mice

that

The mechanism of graft-versus-host is in part reactive

presently underway to determine mechanism is responsible for

due to cells. whether the low


RAMSAY

346

incidence of graft-versus-host disease in our patient population. In conclusion, this new pretransplant immunosuppressive regimen has resulted in a low incidence of graft rejection and graft-versus-host disease with minimal morbidity in a high-risk group of patients.

application anemia.

provided

by Sharon

The

transplant

nurses,

present

marrow

survival from

is 78%

matched

for patients

sibling

who

donors

received

and

warrants

to a larger

group

of patients

ET

with

AL.

aplastic

ACKNOWLEDGMENT The

authors

want

to

acknowledge

Roell, and

RN.,

the

excellent

Jeanette

the secretarial

nursing

Mefford,

assistance

RN.,

care and

of Maureen

the

Zielin-

ski.

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