Human cyclic neutropenia transferred by allogeneic ...

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1982 60: 1263-1266

Human cyclic neutropenia transferred by allogeneic bone marrow grafting RA Krance, WE Spruce, SJ Forman, RB Rosen, T Hecht, WP Hammond and KG Blume

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Human Cyclic by Allogeneic By

Robert

A.

Krance,

Wayne

Neutropenia Bone Marrow

E. Spruce,

William Human

cyclic

with

the

dogs.

neutropenia

shows

model

of cyclic

animal

Until

now.

neutropenia

however,

in man

transplantable

D

as in the

was

dog

hematopoietic

several

PAST

serious

bone

marrow

marrow suitable

donor. However, in rare alternative was available,

example, bone with Gaucher’s

have

drome

from with

relapse.

in a

as the

marrow

a bone

donors. from with

a patient with severe aplastic

For

a patient relapsed

Down’s anemia

synhave

ible

while

CASE

suffered any adverse bone marrow transfrom cyclic neutro-

I ) was a 3.75-yr-old mia

was diagnosed

cell

count

Bone

was by

in May

when

1978.

On

with

aspiration

demonstrated

leukemic

non-T/non-B

female

155,00O/zl

marrow

marrow

white

94%

blasts

type.

There

acute

nonreactive

with

to have

cyclic

neutropenia

but

known was

not

sister

severe.

were

complete

immunologically

PAS

with

marrow

ablation

bone

marrow

aspiration

characterized

was no evidence

patient’s

family

members

of her family

pedigree

is presented

in the patient’s was studied

blood counts

over

neutrophil

counts.

ble with

autosomal

The

were

sisters during

remission

history

received

cytosine

-

mg/kg

and

This

therapy

1 .

acute

crests

the

clinical

patient

Only

mild

the

were

(grade

third

I . Cyclic

during

the first

first least

The

vous

induction

remission

system

cranial reinduction treatment

2 mo

and

was

duction was L-asparaginase,

the

The

of life

not

patient with

A

arabinoside,

attained.

Prophylaxis of

show

In May

cycling

of

had

2.5

the

first

successfully established and hydroxydaunomycin.

Vol. 60, No. 6 (December),

1982

leukopenic that

against

she had

methotrexate

received

6 mo after bone

marrow

donor

out

the aplastic

as

phase

after

was

previously was benign,

marrow

transplantawas present day

(administered

therapy)

were +

15,

counts blood

highest

total

cyclic

antigen

Red

to normal

white

cell

transfusion.

counts

showed

blood

analysis, was

patient’s

and do not cycle. that

She

anti-

typing

The

she remained

cell count

neutropenia.

+273 leuke-

to donor-type

positive). RBC

marrow

and

of recurrent

converted

returned cell

Bone + 180,

by red cell

the last

+ 105,

graft-versus-host

+ 100,

no evidence

Kell

by

discontinued.

had

to

for

+30,

revealed

recipient

acquired

marrow

therapy

the

plantation.

320O/I)

is currently

and I I .5 mo

the

A ncrand

Supported

by NIH

Submitted

remission,

ment of

relapse.

been Rein-

National

and Medical

ofMedicine

in part

supported Address

vincristine, prednisone, Tissue typing revealed

of Hematology

of Hope

Department

rotational had

Department City

at the

Bone

Marrow

Center,

University

Trans-

Duarte.

Calif.

of Washington

at

Dr.

is

Seattle.

vincris-

central

yr of continuous

with

(so far

From

her

is compati-

and L-asparaginase.

intrathecal

1981,

white

the carried

the

intrave-

herself

prednisone,

the patient

After

platelet

serial

from

sequential

in this family

included

cytosine consisted

patient

neutropenia.

and

However,

harvested

disease

after

hematocrit

on with

and

negative

120 days

dose)

patients

transplantation,

the

(Kell

performed

and

treatment

Subsequently,

stopped.

did

of cases

7

pattern

vincris-

5,

was documented

of life. year

at least

inheritance.

chemotherapy.3

discontinued,

8/cod,

was

leukemia

irradiation.

second

dominant

cyclic

neutropenia year

and

distribution

tine, cyclophosphamide, complete

to have

in that

gen

3, the

-

-

(single for

were

time, was

was confirmed

that

and

7

graft-versus-host

but

Engraftment

-

and administered

30 days

on days

hypocellular

were

the patient

after

and

performed

in early

cells

on day

study

donor

during

prednisone

prevention

was

marrow

I) skin

week

and

still

mia.

course

A for

On day 0, the day of marrow

this

was discharged

with

to proceed

patient

bone

cells

care

was illness

admission

body irradiation

of the marrow At

of

on days

leukemia.

recipient.4

the

a pilot

HLA

her

transplantation,

nucleated

108

Posttransplant The

the

x

sibling

transplantation.

26 10 mg/kg

represents

lymphoblastic

iliac

that

I 000 rad total

2.8

to

VM

fully

This

associated

time

of her

5 mg/kg

compound

was

decided

marrow at the

198 1 ) revealed

arabinoside

I)

prognosis

allogeneic

to marrow

blasts.

Fig.

it was

performed

Preparatory

Ieukemic

aspirations

leuke-

and

25%

tion.

as a

of extramedullary

remarkable

reported

in Fig. the at

was

in

histocompat-

symptomatically

grave

(July

and

mia. The

her

the patient.

leukemia,

approximately

relapse;

described.

of

the

transplantation

demonstrating

replacement

of

1115 in

second

nously

blood

as

lymphoblastic

neutropenic.

positive.

(shown

Because

acute

posterior

leuke-

the white

that

transplantaleukemia

from

MLC

transplantation,

as 1117 in Fig.

lymphoblastic

presentation, blasts

neutropenia

and

disease I 19; shown

cyclic

eldest

during

Number

marrow

lymphoblastic

the

relapsed

REPORT

Patient

bone

acute

compatible

tine 0.02

grafting.

(Unique

Hecht,

donor.

methotrexate

propositus

for

acquired

sibling

day

a patient with relapse acute lymphoblastic This clinical observation provides a unique opportunity to demonstrate that the stem cell abnormality in human cyclic neutropenia can be transferred

The

Thomas

undergoing

epipodophyllotoxin

into

marrow

B. Rosen,

treatment

relapsed

leukemia.

by allogeneic

who,

as

that

marrow therapy

instances where no persons with signifi-

been

Robert

is pre-

Usually

serves

been performed.”2 Neither donor effect. We report an allogeneic plantation from a sibling suffering penia

cyclic

bone

marrow transplantations disease into a sibling

leukemia and into a sibling

acute

that

disorders.

sibling

problems

tion

an accepted

histocompatible

medical

collie

A patient

DECADE

has become

sented

in common

by a defect

cell.

J. Forman,

and Karl G. Blume

in grey lacking

is caused

stem

healthy

cant

features

neutropenia

evidence

URING THE transplantation

for

many

Stephen

P. Hammond,

Transferred Grafting

Hope calif ©

May reprint

by

Grant

Grant

AM

18951.

CA

6. 1982;

accepted

requests

to K. G. Blume,

Hematology

National

NC!

and Medical

Bone

July

30206. 6, 1982. M.D..

Marrow

Center.

1500

Hammond

Director,

Transplantation. E.

Duarte

DepartCity

Road,

of

Duarte.

91010.

l 982 by Grune

& Stratton,

Inc.

0006-497l/82/6006-0005$0l.00/0

1263


1264

KRANCE

counts

I

of

all

observation. episodes cycles,

counts

Follow-up

ni

synchronously

relative

transplant

leukopenia.

cyclic

sisters

was

did

counts

the

period

present

of

during

cycling

was

the noted.

not vary

during

neutropenia

of the marrow

donor

clearly

show

fluctuation.

examination

between

recipient

continues

Absolute

during

monocytosis no compensatory

of the three

but the reticulocyte

a low amplitude the

cycled

of granulocytopenia,

Platelet

II

three Although

ET AL.

days

+ I 80 and

to have

neutrophil

counts

cyclic cycle

+

show

neutropenia between

that and

50

and

I 620/al.

‘7

DISCUSSION Fig. 1 . A pedigree showing the propositus who had acute lymphoblastic leukemia (1117) and 1 5 family members. 7 of whom have cyclic neutropenia. Open symbols. unaffected individuals; dark symbols. individuals with cyclic neutropenia. BMT. bone marrow transplantation.

after

marrow

without

any

Between

transplantation further day

100 and

and

platelet

and reticulocyte absolute

based

her

counts

on 100 white

hematology

complete

remission

and

therapy. +

patient The

both

in continued

laboratory,

sisters

day

+ 180

had

complete

counts of cell

performed

neutrophil differential are

after

presented

blood every

Ieukocytes counts in

transplantation, counts, second of the

performed Fig.

2. The

the including

or third three

day.

sisters,

Human regularly thous 19-22

cyclic neutropenia recurrent episodes

is a rare disease in which of fever, malaise, aph-

stomatitis, and cervical adenopathy occur every days in association with neutropenia.69 Genetic

analysis consistent

of case clusters in families shows patterns with either autosomal dominant or autoso-

mal recessive i nheritance, suggesti the pathophysiology of this disorder of patients with cyclic neutropenia

phils have a normal

in the clinical

periodic

granulocyte

cycling

interruption of the

ng heterogeneity in in man.9’2 Studies showed that neutro-

survival in the circulation of marrow cell production

neutrophil

counts.8”2’4

and that causes

Demonstration

10,000

5,000

1,000

N (I)

500

0.

0

100

50

Fig. 2. Absolute neutrophil counts per microliter of the patient (lll). who received an allogeneic bone marrow transplantation (solid lines). and of her two sisters, who

0 180

DAYS

AFTER

BMT

have inherited cyclic neutropenia. ted lines) and lll (broken lines). as bone marrow donor.

1115(dotIlls served


CYCLIC

NEUTROPENIA

that

monocytes,

AND

MARROW

lymphocytes,

discovery

penia in grey demonstrated

1265

reticulocytes,

lets also cycled in some disease be called cyclic demonstration of a stem not been reported. The

GRAFTING

and

plate-

patients suggested that this hematopoiesis,’2 but direct cell abnormality in man has

of an animal

model

of cyclic

neutro-

collie dogs led to a series of studies close parallels between the human

then showed that the cyclic hematopoiesis could be transferred to an unaffected littermate or conversely cured in an affected grey collie by appropriate bone marrow cell infusions.2224 Thus, in dogs, cyclic neutroby a regulatory defect in hematopoiesis at the transplantable stem cell level. It has been shown that cyclic neutropenia in dogs can

to be caused

be induced

by chemotherapeutic

cyclophosphamide.25 intense

It

treatment

may

required

row transplantation nomenon in our

preparatory

may patient.

marrow

treatment 1976: 36

such that

patients healthy

to bone

who sibling

for acute leukemia in our patients died between days

as the

mar-

have induced a similar For this reason, we

I 22 consecutive transplants from

evaluated

agents

be speculated

phehave

had received donors as a program -2 and

patients had reached normal white blood cell counts day + 100 and remained within the normal range; but

7 patients

reached

were

the

still

normal

leukopenic

white

on day

blood

cell

bone

marrow

inoculum

the range

she

received

normally

cer-

contained

in

fected sister by bone marrow transplantation. extraordinary situation demonstrates that cyclic tropenia in man, as in the grey collie dog, is caused defect in a transplantable hematopoietic stem cell. Although healthy histocompatible siblings are a donor

ferred,

a significant

by an

+

100

range

in

transmissible

This neuby a pre-

defect

is the only available option. In this case, the was a patient with acute lymphoblastic leuke-

sometimes recipient mia

with

in second

relapse

who had no chance

for long-term

survival without bone marrow transplantation, so that the potential benefit clearly outweighed the risks of her developing cyclic neutropenia. However, because she was in relapse at the time of transplantation, her

likelihood remains

of developing high.26

since +99

because of infection, bleeding, graft-versus-host disease, or recurrent leukemia and were not evaluated for white cell pattern in respect to cycling; 79 surviving

additional

in the

tainly is well within marrow grafts.

In the family reported here, cyclic neutropenia occurred in an autosomal dominant pattern and was transferred from one affected daughter to her unaf-

diseases.’521 In the dogs, cycling of the neutrophil counts was shown to be due to a production defect and cycling of other blood cell counts was also demonstrated. Bone marrow transplantation experiments

appears

months. None of the patients who lived 100 days after marrow grafting showed

cyclic neutropenia. The reason for the persisting leukopenia in our patient, up to I 1 .5 mo after marrow transplantation, is not clear. The number of nucleated cells

that and

canine

penia

subsequent longer than

another

leukemic

recurrence

ADDENDUM

The marrow transplantation tological

graft recipient is now I 5 mo after and continues to be in complete hema-

remission.

Her

total

white

blood

cell

count

has risen to 4600/,.d. The amplitude of her neutrophil cycles currently ranges from 62 to 2350 tl and is in the same order of magnitude as in the two genetically affected

sisters.

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