The First Successful Allogeneic Bone-Marrow Transplant:Georges Mathe

Jan Jansen

GEORGES MATHE WAS born in 1922 in a

small town in central France. He studied

Medicine at the University of Paris in the chaotic

years during and after the Second World War.

Subsequently he first worked with Jean Ham-

burger and Baruj Benacerraf in the Department

of Physiology at Hospital Necker in Paris. Then,

in the mid 1950s, he spent a sabbatical with

Joseph Burchenal and David Karnofsky at

Memorial Hospital in New York. This experience

gave him his first exposure to aggressive therapy

of leukemia with chemotherapy. He rapidly

concluded that bchemotherapy will never cure

cancer,Q and on his return to France, he joined

Jean Bernard’s new research group at Hospital St

Louis in Paris. His focus was the study of

immunological approaches to leukemia therapy.

He and others found that transplanted bone

marrow/spleen cells from one mouse strain could

salvage mice of a different strain that had been

treated with total body irradiation (TBI) as

specific leukemia treatment. This therapeutic

approach was often complicated by a fatal

reaction called bsecondary disease.Q Secondary

disease was later shown to be identical with

bgraft-vs-host diseaseQ (GvHD), the immunolog-

ical attack of recipient tissues by immune cells

from the donor. The powerful effect of TBI and

allogeneic bone-marrow transplantation in ani-

mals led to clinical bone-marrow transplantation.

He performed allogeneic transplants in 3 patients

with acute leukemia in end-stage relapse. The

preparative regimen consisted of 200 to 400 cGy

of TBI. None of the patients showed evidence

of either permanent donor-cell engraftment or

antileukemic effect.1

In November 1958, 6 physicists of the Vinca

Nuclear Center in Belgrade (formerly Yugoslavia,

Transfus246

From the Indiana Blood and Marrow Transplantation, Beech

Grove.

Address reprint requests to Jan Jansen, MD, PhD, Indiana

Blood and Marrow Transplantation, 1500 Albany, Suite 911,

Beech Grove, IN 46107. E-mail: jjansen@ibmtindy.com

0887-7963/05/$ – see front matter

n 2005 Published by Elsevier Inc.

doi:10.1016/j.tmrv.2005.02.006

now Serbia) were accidentally exposed to lethal

or near lethal doses of TBI. They were trans-

ferred for treatment to the Institute Curie in Paris,

under the care of Raymond Latarjet (1911-1998),

the Father of French radiobiology. Georges

Mathe seized the opportunity to become inde-

pendent and joined the Institute Curie team to

treat these patients. Because of the risk of

transplant-induced GvHD, in a time when ad-

vanced donor selection through HLA match-

ing was not yet possible, the patients were

treated only with supportive care. When their

marrow aplasia persisted and their clinical con-

dition deteriorated, 5 of the 6 patients received

infusions of 180 to 300 mL of bone marrow

(about 1010 nucleated cells per patient) from

ABO-compatible unrelated donors, without addi-

tional preparative therapy. One patient rapidly

died from intestinal complications, but 4 patients

showed signs of hematologic recovery. It was

difficult to document that the donor cells had

indeed engrafted, because most modern techni-

ques to document engraftment were not yet

available. Leon Schwarzenberg, who later became

a politician, social activist, and cabinet minister

in France, was responsible for the blood bank

support during these transplants. The investiga-

tors studied the days from bone-marrow transplant

until hematologic recovery, as the dates of

transplant had been staggered with up to 7 days

interval. In addition, they showed, on the basis of

erythrocyte phenotypes, that many of the red

cells were from the marrow donors. Ultimately,

all patients rejected their stem-cell grafts and

experienced autologous bone-marrow recovery.

Graft-vs-host disease did not occur, probably

because the patients always were only bmixed

chimerasQ with a mixture of donor and recipient

immunocompetent cells.2 Recently looking back

on these transplants, and considering that nonmyel-

oablative allogeneic transplants (bminitransplantsQ)have become so popular in the last 5 years, Mathe

considered this unintended mixed chimerism as his

most important contribution to allogeneic bone-

marrow transplantation!

Mathe soon moved his program to the Institute

Gustave Roussy in Villejuif, a suburb south of

ion Medicine Reviews, Vol 19, No 3 (July), 2005: pp 246-248

GEORGES MATHE 247

Paris. There he built a transplant team that

included Schwarzenberg, Jean-Louis Amiel, and

also the radiation therapist, Maurice (Rene)

Tubiana. From 1960 until 1963, they performed

allogeneic bone-marrow transplants in a series of

patients with acute lymphoblastic leukemia, some

of whom were in remission at the time of

transplant.3 The preparative regimen consisted of

800 cGy of TBI. The donors were either relatives

(parents, siblings, cousins) or were selected from

a pool of 150 unrelated volunteers. In 1963, the

group decided to use bone-marrow grafts from

several different donors to allow the patient to

select the graft that was most compatible. In fact,

some patients received up to 6 simultaneous

bone-marrow grafts from various relatives.

Engraftment was documented with red cell

phenotypes, sex chromosomes, and/or immuno-

globulin groups. The newly developed technique

of leukocyte typing, which later became HLA

typing (Jean Dausset), was used to select com-

patible donors. Many recipients died rapidly

from infection or never showed signs of bone-

marrow recovery. Other patients succumbed to

hyperacute GvHD.

BB was a 26-year-old physician with relapsed

acute lymphoblastic leukemia, which was refrac-

tory to chemotherapy. After TBI on April 17

and 18, 1963, he was given 2000 mL of bone

marrow obtained in equal proportions from

6 donors: his father, his mother, a sister, and

3 brothers. Neutrophils reappeared in his periph-

eral blood at 23 days after transplant and reached

the normal range about 1 month later. Signs of

GvHD were seen 2 weeks after the transplant and

caused rapid weight loss, diarrhea, desquamative

erythroderma, and eosinophilia. This reaction

subsided after 2 months; the patient regained his

weight and was discharged. It was shown that his

bone marrow was mainly repopulated by cells

from one brother, although some female cells

were also present. Small skin grafts from all

donors except the one brother and the patient

himself were rejected, indicating that the induced

tolerance was specific. BB remained in remission

and did well for 20 months; then he died from

varicella encephalitis. No evidence of leukemia

was found at autopsy. This patient undoubtedly

represents the first case of successful allogeneic

bone-marrow transplantation in man.4 The patient

had permanent donor-cell engraftment, survived

acute GvHD, and may well have been cured of

his leukemia. He died from the state of prolonged

immunosuppression that remains a common

complication after allogeneic stem-cell transplan-

tation. This groundbreaking case has rarely

received the attention it deserved.5 As a result,

transplants for immunodeficiency syndromes per-

formed and published in 1968 (five years later)

are often cited as the first successful allogeneic

bone-marrow transplants.6,7

Georges Mathe introduced the term badoptiveimmunotherapyQ for the transfer of allogeneic

lymphocytes/stem cells with the primary goal

of immunotherapy for malignant diseases.

Although already recognized as an important part

of experimental allogeneic transplantation in the

mid 1950s, adoptive immunotherapy has recently

again become the central focus of allogeneic

stem-cell transplantation with increasing pop-

ularity of reduced intensity allografts (‘‘nonmye-

loablative allografts,’’ ‘‘minitransplants,’’

‘‘transplant-lite’’) and of donor lymphocyte infu-

sions. Interestingly, Mathe’s interest in bone-

marrow transplantation diminished not long after

his series of transplants in the early to mid 1960s.

He felt that the proof of principle for allogeneic

bone-marrow transplantation had been estab-

lished, and he began to study a more universal

form of immunotherapy for leukemia. He studied

the therapeutic effects of tuberculin (BCG)

vaccines and of the injection of allogeneic

leukemic cells on the survival of patients with

acute leukemia. In 1962, he became the founding

president of the European Organization for

Research on the Treatment of Cancer, which

now includes clinical cancer research programs

in about 40 countries. He has been the Editor of

Biomedicine and Pharmacotherapy since its incep-

tion 47 years ago.

After his retirement as Professor at the Univer-

sity of Paris, Mathe moved to the Hospital Suisse

de Paris in Issy-les-Moulineaux, a western suburb

of Paris. He continues his work in immunother-

apy, although he focuses now mostly on the

immunological therapy of HIV/AIDS. He has

introduced several unconventional therapies to

that field.

JAN JANSEN248

REFERENCES

1. Mathe G, Bernard J, de Vries MJ, et al: Essai de

traitement de sujets atteints de leucemie aiguJ en remission

par irradiation totale suivie de transfusion de moelle osseuse

homologue. Rev Fr Etud Clin Biol 4:675-704, 1959

2. Mathe G, Jammet J, Pendic L, et al: Transfusions et

greffes de moelle osseuse homologue chez des humains

irradies a haute dose accidentellement. Rev Fr Etud Clin Biol

4:226-245, 1959

3. Mathe G, Amiel JL, Schwarzenberg L: Bone marrow

transplantation and leukocyte transfusions. Springfield, IL,

Thomas CC, 1971

4. Mathe G, Amiel JL, Schwarzenberg L, et al: Haemato-

poietic chimera in man after allogenic (homologous) bone-

marrow transplantation. BMJ 2:1633-1635, 1963

5. Brent L: A History of Transplantation Immunology. San

Diego, Academic Press

6. Gatti RA, Meuwissen HJ, Allen HD, et al: Immunological

reconstitution of sex-linked lymphopenic immunological defi-

ciency. Lancet 2:1366-1369, 1968

7. Bach FH, Albertini RJ, Joo P, et al: Bone arrow

transplantation in a patient with Wiskott-Aldrich syndrome.

Lancet 2:1364-1366, 1968

Georges Mathe spent only a relatively brief part of his career in stem-cell

transplantation. Nevertheless, he was a pioneer in the field and was among the

very first to translate data from animal studies into the clinical care of patients.

The transplant and hematology communities are indebted to him for his many

insightful contributions.