part 6
by: soldier30 11/12/01 08:59 pm
Msg: 1297 of 1302
Abstract number 1753
Achievement of Sustained Remissions Despite Loss of Donor Chimerism (DC) in
Patients with Chemotherapy-Refractory Non-Hodgkin's Lymphoma (NHL) Treated with
Nonmyeloablative Conditioning and Allogeneic Stem Cell Transplantation (SCT).
Bimalangshu R. Dey, Steven L. McAfee, Robert Sackstein, Christine Colby, Seema
Sahai, Susan Saidman, Karen Power, Annette Kraus, David H. Sachs, Megan Sykes,
Thomas R. SpitzerMassachusetts General Hospital Harvard Medical School, Boston,
MA, USA.
Based on a murine model, we initiated a trial of non-myeloablative therapy with
HLA-matched or mismatched related donor SCT with intentional induction of
mixed chimerism (MC) followed by prophylactic donor leukocyte infusions (DLI)
for advanced hematologic malignancies. Of 69 evaluable patients (NHL, n=43; HD,
n=8; AML, n=8; ALL, n=1; CLL, n=5; MM, n=3) 46 received a SCT from an
HLA-matched donor, while 23 received an HLA 1-3 antigen-mismatched donor
transplant. Preparative therapy consisted of cyclophosphamide 50 mg/kg on days
-6 or -5 through day -3, equine antithymocyte globulin (ATG) 15-30 mg/kg on
days -2, -1 and +1 or -1, +1, +3 and +5, thymic irradiation on day -1 in
patients without previous mediastinal radiotherapy and cyclosporine beginning
on day -1. Chimerism was assessed by microsatellite analysis. In an attempt to
convert the mixed chimeric state to full donor chimerism (FDC), DLI(s) were
given beginning 5 weeks post-SCT in patients having MC but without evidence of
graft-vs-host disease (GVHD). Initial MC (>1% donor cells) was demonstrated in
all evaluable patients. Forty-nine patients maintained MC or converted to FDC
either spontaneously or following DLI and 20 patients ultimately lost their
graft 1 to 12 months post-transplant despite DLI(s). Seventeen of 49 (35%)
patients who maintained donor chimerism achieved a CR or CR with residual
radiologic abnormality compared with 4 of 20 (20%) patients who lost donor
chimerism (<1% donor cells) despite prophylactic DLI. Three of these 4
patients, all of whom had chemotherapy-refractory NHL, developed an engraftment
syndrome (ES) characterized by fever, rash, weight gain and abnormal liver
function tests and received low-dose corticosteroids, while 1 did not have ES.
Initial skin biopsies performed at the time of ES lacked the findings of GVHD.
However, when later (beyond 6 months post transplant) skin biopsies in 3 of
these 4 patients, who were sex-mismatched with their donors, were tested for
the presence of donor cells by the FISH method, one patient had 1.1%
donor-derived cells, while the other 2 had no chimerism. Flow cytometric
analyses on weekly blood samples have not revealed a distinctive pattern in
T-cell subsets, B cells, NK cells, or in expression of CD25, CD45RA, CD45RO,
CD62L and CD28 on CD4 or CD8 cells in these 4 patients compared to patients who
lost chimerism and did not achieve a CR. In addition, although mixed
lymphocyte reaction and cell-mediated lysis assays demonstrated an anti-donor
response in some of these 20 patients we have not noticed a different pattern
in the 4 patients with CR. Two of the 4 patients are without evidence of
disease 2 years after SCT; the other two had recurrent lymphoma 6 and 8 months
post-SCT. In summary, it is possible to achieve a sustained remission in
patients with chemorefractory lymphoma following nonmyeloablative allogeneic
SCT despite loss of the graft. We hypothesize that underlying immunological
mechanism(s), that are correlated with rejection of the graft which may or may
not be involved with the pathogenesis of ES, have a role in anti-tumor
responses via a cell or cytokine-mediated pathway. Alternatively, a
microchimerism-conferred graft-vs-tumor effect may be a mechanism of the
anti-tumor response.
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