Bone Marrow Transplantation for Children With Acute Leukemia and Down Syndrome

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Bone

Marrow

Transplantation

for Children

With

Acute

Leukemia

and Down

Syndrome

Charles

M. Rubin,

MD,

Maura

O’Leary,

MD, Penelope

A. Koch,

MD,

and

Mark

E. Nesbit,

Jr, MD

From the Bone Marrow Transplant Centers at the University of Minnesota, Minneapolis, Roswell Park Memorial Institute, Buffalo, New York, and Montreal Children’s Hospital, Montreal

ABSTRACT.

Four children with acute leukemia and

Down syndrome received high-dose cyclophosphamide therapy and total body irradiation in preparation for bone

marrow transplantation. Skin and mucous membrane

toxicity was pronounced. Furthermore, three children died during the immediate posttransplantation period of infectious and hemorrhagic pulmonary complications. One patient had hematologic recovery and is surviving disease-free 1 year following transplantation. These

pre-liminary observations are in agreement with previous data suggesting that children with Down syndrome are

at higher risk for toxicity, pneumonitis, and, possibly,

death following administration of intensive therapy for leukemia in comparison with children without Down syndrome. Improvements in the management of these children in the future will depend upon a better under-standing of the biologic and pathophysiologic aspects of

Down syndrome and additional clinical experience.

Pe-diatrics 1986;78:688-691; bone marrow transplantation, acute leukemia, Down syndrome.

In 1957, Krivit and Good’ made the original

observation that Down syndrome and leukemia

oc-cur in combination at a frequency greater than that

expected by chance alone. Among children, the risk

ofleukemia developing appears to be ten to 30 times

greater for those with Down syndrome.2 In a review

of a large number of children treated for acute

lymphoblastic leukemia and acute

nonlymphoblas-tic leukemia, Robison et a13 found that 2.1% had

the diagnosis of Down syndrome, the incidence of

which is approximately 1 in 660 births.

Received for publication May 28, 1985; accepted July 3, 1985. Presented, in part, at the 26th Annual Meeting of the American

Society of Hematology, December 1-4, 1984, Miami Beach.

Reprint requests to (C.M.R.) Department of Pediatrics,

Univer-sity of Minnesota, Box 484 Mayo Memorial Building, 420 Del-aware St SE, Minneapolis, MN 55455.

American Academy of Pediatrics.

Recently, bone marrow transplantation has

emerged as a promising approach to the

manage-ment of patients with poor-risk leukemia.4

Occa-sionally,

individuals with Down syndrome are

con-sidered to be candidates for this procedure. We

report experience with four children with acute

leukemia and Down syndrome who underwent bone

marrow transplantation.

MATERIALS

AND

METHODS

Patients included in this report were identified

retrospectively through a mail survey of pediatric

bone marrow transplantation centers. The patients

had been selected for bone marrow transplantation based on the following eligibility criteria: (1) diag-nosis of acute nonlymphocytic leukemia in first or

greater remission or acute lymphoblastic leukemia

in second or greater remission, and findings of less

than 5% blast forms in bone marrow aspirate; (2)

absence of any major organ dysfunction as defined

by the individual

institution; and (3) availability of

a suitable related marrow donor. Bone marrow

transplantation protocols were approved by each

institution’s review committee, and written

in-formed consent was obtained from the patients’

parents.

Patient characteristics including age, sex,

diag-nosis, and leukemia status are summarized in Table

1. All patients had the typical stigmata of Down

syndrome. Three patients had congenital anomalies

involving the heart: patient 1 had a ventricular

septal defect that was surgically repaired at 4 years

of age, patient 3 had a small unrepaired ventricular

septal defect, and patient 4 had a small patent

ductus arteriosus. A history of extramedullary

leu-kemia involving the CNS was present in one child

(patient 3). All patients had been receiving

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TABLE

Marrow

1.

Characteristics of Four

Transplantation*

Patients With Acute Leukemia and Down Syndrome Who Underwent Bone

Patient No.

Age (yr)/Sex/ Time Between Diagnosis Diagnosis and

Transplantation (mo) Leukemia Status at Trans-plantation Donor: Histocom-patibility Cytoreductive Regimen

Graft vHost

Disease Prophylaxis Regimen 1 2 3 4 10/F/ALL 28 14/F/AMMoL 3 3/F/AML 14 2/F/AMoL 1 2nd remission 1st remission 2nd remission 1st remission

Mother: HLA par-tial match; MLC

nonreactive

Brother: HLA identi-cal; MLC

nonreac-tive

Brother: HLA identi-cal; MLC

nonreac-tive

Sister: HLA identical;

MLC nonreactive

TB! 13.2 Gy (1.2 Gy TID x 11 doses

with partial lung shielding)4; CPM 60

mg/kg x 2 doses

CPM 60 mg/kg x 2 doses; TBI 7.5 Gy

(single dose)

CPM 60 mg/kg x 2 doses; TB! 7.5 Gy (single dose)

CPM 60 mg/kg x 2 doses; TBI 12 Gy (2 Gy BID x 6 doses)

T lymphocyte

de-pletion of donor marrow Methotrexate, prednisone, aza-thioprine Methotrexate, prednisone, an-tithymocyte globulin Methotrexate, prednisone

* Abbreviations used are: ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; AMoL, acute monoblastic leukemia;

AMMoL, acute myelomonocytic leukemia; MLC, mixed lymphocyte culture; CPM, cyclophosphamide; TBI, total body irradiation; Gy, Gray (1 Gy = 100 rads); TID, three times per day; BID, twice per day.

ARTICLES 689

through the time of transplantation. Excessive or

unusual complications were not observed in any of

these children during prior therapy; however,

pa-tient 3 had experienced one episode of pneumonia.

At the time of transplantation, the patients were in

good physical condition and had no evidence of

preexisting pulmonary disease.

Histocompatibility data, cytoreductive regimens,

and methods of graft v host disease prophylaxis are

summarized in Table 1. Patients 2, 3, and 4 had

HLA-A,

HLA-B,

and HLA-C identical and mixed

leukocyte culture nonreactive sibling donors. The

donor for patient 1 was her mother who was

HLA-B, HLA-C,

and HLA-DR

identical

and

mixed

leu-kocyte culture nonreactive but was mismatched at

the HLA-A locus. Transplantation conditioning

consisted of high-dose cyclophosphamide therapy

and total body irradiation. Bone marrow was

col-lected from the posterior iliac crests of the donors

under general anesthesia and infused intravenously

following completion of the cytoreductive

condi-tioning regimen. Graft v host disease prophylaxis

was administered systemically to patients 2, 3, and

4 after marrow infusion and patient 1 received

marrow that was depleted of T cells in vitro prior

to infusion.5

RESULTS

The posttransplantation courses are summarized

in Table 2. At least one severe side effect was

observed in every case. In patient 1 hemorrhagic

cystitis developed on day +9 which was complicated

by obstructive renal disease. Later, at autopsy, the

process was found to be extensive and involve the

muscular coat of the bladder. In patient 2 a

gener-alized erythematous rash developed on day +3. In

some areas, the skin became denuded of the

over-lying epidermis. No clinical evidence of graft v host

disease was present. A drug reaction could not be

excluded as the cause of the rash. Resolution was

observed by day +11. This patient also had severe

mucositis. In patient 3 mucositis developed on day

+7. On day +17 she required intubation for airway

obstruction that was believed to be an extension of

the mucositis. Findings on biopsy of the epiglottis

and cultures for herpes simplex virus failed to

in-dicate any secondary infectious process to account

for the unusual clinical findings. Successful

extu-bation took place on day +27. In patient 4 severe

diarrhea developed on day +4. The stools were

watery and the total volume on the worst day was

500 mL. The diarrhea persisted through day +28

and subsequently resolved. No infectious agent was

identified, and there was no clinical or laboratory

evidence of graft v host disease. The early onset of

the diarrhea suggested that the cause was radiation entenitis.

In patients 1, 2, and 3 acute pulmonary infiltrates

developed on days +30, 17, and 28, respectively,

leading to respiratory failure and death.

Postmor-tem examination of the lungs of patient 1

demon-strated an extensive alveolitis characterized by the

presence of multinucleated giant cells suggesting a

viral etiology. Patients 2 and 3 had extensive

pul-monary hemorrhage at autopsy. Postmortem lung

cultures from patient 2 were positive for anaerobic

bacteria (Capnocytophaga species). The patient also

had disseminated candidiasis. Blood cultures from

patient 3 were positive for Escherichia coli and

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Infection Graft Engraft- Outcome

V Host ment

Disease

None Yes Death, day Respiratory

+35 failure

Interstitial

pneumonitis

day +30

Sepsis day +12;

disseminated candidiasis; pneumonitis

day +17 Sepsis day +26;

pneumonitis

day +28

None

Skin

No Death, day Respiratory Pulmonary hemorrhage, +19 failure lung culture positive

for anaerobe

Pulmonary hemorrhage; lung culture positive for Escherichia coli

None Yes Alive and well at 12 mo

TABLE

2.

Posttransplantation Courses

Patient Skin and Mucous No. Membrane Toxicity

1 Severe hemorrhagic cystitis compli-cated by obstruc-tive renal disease

days +9-35;

mod-erate mucositis, mild skin reaction 2 Severe skin rash

with denudation

days +3-11, severe

mucositis

3 Severe airway edema

associated with mucositis requir-ing intubation

days +17-27, mild skin reaction

4 Severe, prolonged None diarrhea days +4-28, moderate skin

reaction

Cause of Death

Yes Relapse and Respiratory

death, failure day +28 Lung Findings at Autopsy Extensive alveolitis with multinucleated giant cells

Staphylococcus epidermidus prior to death and

cul-tures from the lungs at autopsy were positive for E

coli.

Engraftment was observed in the three children

(patients 1, 3, and 4) who survived to day +28 and

beyond,

based on peripheral

blood

counts or bone

marrow examination. Graft v host disease was

ob-served in one case (patient 3) and was limited to

the skin. Findings from a bone marrow aspirate

demonstrated a leukemic relapse on day +28 in

patient 3. Cytogenetic studies indicated that the

relapse occurred in female-recipient cells.

DISCUSSION

Theoretically, bone marrow transplantation

might pose a greater risk for a child with Down

syndrome than one without Down syndrome. Of

most concern is the increased chromosomal

radiosensitivity6 and possibly error-prone DNA

repair7’8 found in cells of those with Down

syn-drome. It is not known whether these poorly

under-stood biologic features would become manifest in

the bone marrow transplantation recipient with

Down syndrome who is receiving high-dose

cyclo-phosphamide therapy and total body irradiation.

Further concern for patients with Down syndrome

is raised by the current experience with patients

with Fanconi anemia undergoing bone marrow

transplantation. Individuals with Fanconi anemia

demonstrate high spontaneous chromosome

break-age and chromosomal sensitivity to physical and

chemical mutagens, possibly as the result of a DNA

repair defect.9”#{176}When patients with Fanconi

ane-mia undergo bone marrow transplantation using

conditioning regimens that include high-dose

cyclo-phosphamide therapy, they frequently have a

dif-ficult posttransplantation course characterized by

a high incidence of severe mucositis and

hemor-rhagic cystitis.”2

Additionally, the prolonged neutropenia and

im-munosuppression induced during bone marrow

transplantation might be expected to lead to a

higher risk of pneumonia in patients with Down

syndrome. Respiratory tract infection is a leading

cause of death among people with Down syndrome,

although the precise reason for this is unknown.”

Furthermore, recent data suggest that children with

Down syndrome are at a relatively high risk for

pneumonia during intensive chemotherapy. In a

large series, Robison et al3 found that mortality in

children with Down syndrome was increased

five-fold during induction for acute lymphoblastic

leu-kemia in comparison with that in patients without

Down syndrome and that half of the deaths were

caused by pneumonia.

The prediction based on the above considerations

that individuals with Down syndrome would

expe-rience a difficult postgrafting course is borne out

by our observations; however, the small number of

patients prevents a definitive conclusion. Skin and

mucous membrane toxicity appeared to exceed that

reported for transplantation recipients without

Down syndrome. Although hemorrhagic cystitis is

relatively common in bone marrow transplantation

(4)

ARTICLES 691

prophylactic measures are taken. Mild skin

reac-tions after total body irradiation are common, but

the skin rarely breaks down as in patient 2.’

Mu-cositis leading to airway obstruction, as in patient

3, is also unusual. Finally, the effects of radiation enteritis in patient 4 were prolonged in comparison

to the typical course which lasts only 1 to 2 weeks.’4

Three of four children with Down syndrome died

after bone marrow transplantation. All of the

deaths were caused by respiratory insufficiency

as-sociated with pulmonary infiltrates. One patient

had interstitial pneumonitis, possibly viral in

on-gin, and the other two children had pulmonary

hemorrhage in association with bacterial

patho-gens.

One patient has survived well beyond the grafting

period, demonstrating that bone marrow

transplan-tation using high-dose chemoradiotherapy can be

accomplished in an individual with poor-risk acute

leukemia and Down syndrome; however, the high

morbidity and mortality in this series suggest the

need for modification of the preparative regimen

and improvement in posttransplantation

manage-ment. At present, due to poor understanding of the

biologic and pathophysiologic aspects of Down

syn-drome in relationship to bone marrow

transplan-tation and limited clinical experience, specific

nec-ommendations cannot yet be made.

ACKNOWLEDGMENT

This work was supported, in part, by Public Health Service grant CA09445, awarded by the National Cancer Institute, US Department of Health and Human Services, and by the Children’s Cancer Research Fund of Minne-sota.

We thank Virginia Fosse for her expert assistance in the preparation of the manuscript and Dr Richard J.

O’Reilly for providing clinical information regarding

pa-tient 1.

Note added in proof. Patient 4 died 14 months following transplantation from an illness characterized by shock

and a fulminant course. The precise cause of death is not known.

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1986;78;688

Pediatrics

Charles M. Rubin, Maura O'Leary, Penelope A. Koch and Mark E. Nesbit, Jr

Syndrome