Transplant breakthrough

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By Gardner

HealthDay Reporter 2 hours, 3 minutes ago

WEDNESDAY, Sept. 28 (HealthDay News) -- A more focused

approach to bone marrow transplant in patients with

blood cancers dramatically lowered the incidence of

graft versus host disease (GVHD) -- a potentially

deadly complication of the procedure -- in a small

group of patients, researchers report.

The approach has the potential to provide an easier

alternative for people with leukemia, lymphoma and

other related cancers, especially people over the age

of 50, who typically have trouble withstanding

conventional bone marrow transplantation procedures.

The findings appear in the Sept. 29 issue of the

New England Journal of Medicine.

" We need replication in other studies but, if it is

verified, it means there would be another approach to

conditioning a patient that would greatly minimize

acute GVHD but lead to the same beneficial effects, "

said Dr. Marshall Lichtman, executive vice president

of research and medical programs for the Leukemia &

Lymphoma Society.

Bone marrow transplants can cure some cases of

leukemia, lymphoma and related blood cancers. The

procedure is a severe one, however, and involves

knocking out the patient's existing bone marrow with

chemotherapy and/or radiation, then replacing the

diseased blood stem cells with healthy stem cells from

a donor.

People over the age of 50, in particular, have a hard

time tolerating the standard form of transplantation,

which can cause GVHD in about 50 percent of cases. In

GVHD, the donor's immune cells attack the patient's

body, causing intense diarrhea and severe rashes,

among other things.

Recently, researchers have managed to show that, in

mice, a less severe procedure had good results with

fewer side effects.

Instead of receiving the blanket chemotherapy and

radiation typical before bone marrow transplantation,

the mice received radiation only to the

lymph-node-bearing areas. They also received

antithymocyte globulin, an immunosuppressive agent

that destroys immune T-cells.

However, instead of destroying all of the patient's

immune T-cells, this treatment selectively depleted

just certain subsets of T-cells and allowed others,

namely regulatory T-cells, to survive. The researchers

explain that regulatory T-cells can hold attacking

immune cells at bay.

" The regulatory T-cells are there in a high enough

ratio to be able to shape and modify the donor immune

cells to protect against GVHD, but still allow donor

T-cells to mediate a graft anti-tumor effect, " said

study author Dr. Lowsky, an assistant professor

of medicine at Stanford University School of Medicine.

In other words, the donor T-cells attacked the tumor,

but nothing else.

In the mouse study, regulatory T-cells went from a

comprising 1 percent of total T-cells to more than 90

percent. The mice also had a significant reduction in

acute GVHD.

The current study replicated that procedure in humans.

Thirty-seven patients with lymphoid malignant diseases

or acute leukemia underwent an experimental

conditioning regimen starting with radiation to the

lymph nodes only plus antithymocyte globulin, followed

by a bone marrow transplant.

Only two of the patients developed acute GVHD and only

one of those had " clinically significant " disease. In

addition, patients with lymphoid malignant diseases

who were in partial remission went into a complete

remission.

Rates of chronic GVHD, a less serious form of the

disorder, were no different, the researchers note.

" What these folks are saying is that if you use this

conditioning regimen, you can get very good results

and you eliminate or you greatly minimize acute GVHD, "

Lichtman said. " You keep the good effects while

reducing the bad. "

An accompanying editorial pointed out some caveats,

however, including the small number of patients

involved in the study and the inability to discern

exactly what was responsible for the low incidence of

GVHD.

The follow-up time was also not particularly long

(seven months to three years), Lichtman added.

Lowsky and colleagues say they are making plans to

study the procedure in a larger number of patients.

" The findings were pretty striking, " Lichtman. " It

would be a step forward in making transplant more

accessible to more people, especially older people,

and reducing the morbidity and mortality from acute

GVHD. "

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NEJM 353:1321-1331, September 29, 2005

Protective Conditioning for Acute Graft-versus-Host

Disease

Lowsky, M.D., Tsuyoshi Takahashi, M.D., Ph.D.,

Yin Ping Liu, M.D., Sussan Dejbakhsh-, M.S., F.

Carl Grumet, M.D., Judith A. Shizuru, M.D., Ph.D.,

Ginna G. Laport, M.D., E. Stockerl-Goldstein,

M.D., J. ston, M.D., T. Hoppe, M.D.,

A. Bloch, Ph.D., Karl G. Blume, M.D., S.

Negrin, M.D., and Strober, M.D.

From the Departments of Medicine (R.L., T.T., Y.P.L.,

S.D.-J., J.A.S., G.G.L., K.E.S.-G., L.J.J., K.G.B.,

R.S.N., S.S.), Pathology (F.C.G.), Radiation Oncology

(R.T.H.), and Health Research and Policy (D.A.B.),

Stanford University School of Medicine, Stanford,

Calif.

Background Conditioning with total lymphoid

irradiation plus antithymocyte serum protects mice

against acute graft-versus-host disease (GVHD) after

hematopoietic-cell transplantation. We tested this

strategy in humans.

Methods Thirty-seven patients with lymphoid malignant

diseases or acute leukemia underwent an experimental

conditioning regimen with 10 doses of total lymphoid

irradiation (80 cGy each) plus antithymocyte globulin,

followed by an infusion of HLA-matched

peripheral-blood mononuclear cells from related or

unrelated donors who received granulocyte

colony-stimulating factor.

Results Of the 37 transplant recipients, only 2 had

acute GVHD after hematopoietic-cell transplantation.

Potent antitumor effects in patients with lymphoid

malignant diseases were shown by the change from

partial to complete remission. In the transplant

recipients who underwent conditioning with total

lymphoid irradiation and antithymocyte globulin, the

fraction of donor CD4+ T cells that produced

interleukin-4 after in vitro stimulation increased by

a factor of five, and the proliferative response to

alloantigens in vitro was reduced, as compared with

normal control subjects and control subjects who

underwent conditioning with a single dose of

total-body irradiation (200 cGy).

Conclusions A regimen of total lymphoid irradiation

plus antithymocyte globulin decreases the incidence of

acute GVHD and allows graft antitumor activity in

patients with lymphoid malignant diseases or acute

leukemia treated with hematopoietic-cell transplantation.