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Blood, 1 June 2002, Vol. 99, No. 11, pp. 4234-4236
BRIEF REPORT
Nonmyeloablative conditioning followed by hematopoietic cell
allografting and donor lymphocyte infusions for patients with
metastatic renal and breast cancer
Marco Bregni,
Anna Dodero,
Jacopo Peccatori,
Alessandra Pescarollo,
Massimo Bernardi,
Isabella Sassi,
Claudia Voena,
Alberto Zaniboni,
Claudio Bordignon, and
Paolo Corradini
From the Bone Marrow Transplant Unit and Gene
Therapy Program and the Division of Pathology, Istituto H San Raffaele,
Milano, Italy; and the Division of Medical Oncology, Casa di Cura
Poliambulanza, Brescia, Italy.
 |
Abstract |
The feasibility and toxicity of allogeneic stem cell
transplantation after nonmyeloablative conditioning including thiotepa, fludarabine, and cyclophosphamide have been investigated in 6 patients
with breast cancer and 7 patients with renal cell cancer. The program
included the use of escalating doses of donor lymphocyte infusions
(DLI) and/or interferon alpha (IFN ) for patients showing no
tumor response and no graft-versus-host disease (GVHD). Patients were
at high risk of transplant-related mortality (TRM) because of age,
advanced stage, and previous treatments. We observed a partial
remission in 4 renal cancer and in 2 breast cancer patients (one at the
molecular level in the bone marrow), occurring after cyclosporine
withdrawal or after DLI and/or IFN. All the responses were
accompanied by the occurrence of acute GVHD. We conclude that
reduced-intensity allogeneic stem cell transplantation is a feasible
procedure in renal and breast cancer, and that the exploitation of
graft-versus-tumor effect after DLI is a promising finding.
(Blood. 2002;99:4234-4236)
© 2002 by The American Society of Hematology.
| |
Introduction |
Allogeneic hematopoietic stem cell
transplantation (HSCT) with myeloablative conditioning has been
used in few patients with metastatic solid tumors: a graft-versus-tumor
(GVT) effect has been postulated for breast cancer (BC)1,2
and ovarian cancer.3 Very recently, a nonmyeloablative
regimen was employed by Childs et al4 in malignant
melanoma and renal cell cancer (RCC). The rationale was based on the
concept that HSCT can be considered a form of adoptive immunotherapy in
chemoresistant tumors. The results in RCC were encouraging, showing a
disease regression in 53% of the patients.4 It is
noteworthy that the response was associated with graft-versus-host
disease (GVHD) occurrence and full donor T-cell engraftment. It has
been shown that nonmyeloablative regimens have a lower
treatment-related mortality (TRM),5 and thus can be used
also in old and heavily pretreated patients. Donor lymphocyte infusions
(DLI) are a well-estabilished treatment for patients with hematologic
malignancies relapsing after allogeneic transplantation,6,7 but their potential role in programs of allogeneic transplantation for advanced solid tumors is
currently unknown.
We have recently shown that a reduced-intensity conditioning with
thiotepa, fludarabine, and cyclophosphamide can provide a successful
engraftment with a rather low TRM.8 Here, we report the
preliminary results of a pilot study exploring the role of nonmyeloablative conditioning followed by allogeneic HSCT in metastatic BC and RCC. To further enhance the GVT effect, we planned escalating doses of DLI for patients not responding, without any sign of acute GVHD.
| |
Study design |
There were 6 patients with advanced BC and 7 patients with RCC,
ages 18 to 60 years, with an HLA-identical sibling donor, enrolled in
the study from December 1998 to May 2001 (Table
1). Patients had metastatic tumors
refractory to standard treatment, evaluable disease, and a life
expectancy of more than 6 months. Patients with BC had received a
median number of 3 previous chemotherapy lines, including autologous
transplantation, and 3 patients had bone marrow involvement at trephine
biopsy. All RCC patients had undergone nephrectomy and had previously
been treated with cytokine-based therapy.
The preparative regimen consisted of 10 mg/kg thiotepa on day  6
(5 mg/kg was used for RCC); 30 mg/kg cyclophosphamide followed by 30 mg/msq fludarabine on days 4 and 3. Patients received lenograstim-mobilized peripheral blood stem cells from their sibling donor on day 0 (median dose, 5.33 × 106
CD34+ cells/kg of recipient's body weight; range,
1.89-7.22).
Cyclosporine A (CSA; target blood levels, 150 ng/mL-300 ng/mL) and
short-course methotrexate (MTX; 10 mg/msq day 1; 8 mg/msq days 3 and 6) were used for acute GVHD prophylaxis. CSA was
administered at full dose through day +70 and, if GVHD was absent, the
dose was tapered by 20% every week. Donor-recipient chimerism analysis was carried out on bone marrow mononuclear cells and on
CD3+ and CD13/CD33+ cell subsets obtained by
cell sorting from peripheral blood mononuclear cells using polymerase
chain reaction (PCR) of informative minisatellite regions.9 In patients with mixed donor/recipient
T-lymphocyte chimerism or progressive disease on day +60, CSA was
tapered off over a 2-week period. Patients who had stable or
progressive disease after the withdrawal of CSA and had no evidence of
GVHD were eligible to receive up to 3 infusions of DLI, given monthly
in escalating doses (1-2 × 107, 5 × 107,
and 1 × 108 CD3+ cells/kg recipient's
weight). Patients who had no response to DLI and no GVHD were eligible
to receive low-dose subcutaneous interferon alpha (IFN;
3 × 106 IU × 3 per week).
All patients were evaluated by bone marrow biopsy, total-body
computed tomographic (CT) scan, and other examinations depending on
particular sites of disease, before transplantation and monthly thereafter. Reverse transcriptase (RT)-PCR analysis of maspin and
mammaglobin expression was carried out on bone marrow cells, as
originally described.10,11
| |
Results and discussion |
All patients had a sustained myeloid and platelet
engraftment (neutrophils  500/mcL median day 12, range 10-14;
platelets 20 000/mcL median day 12, range 8-16 days). On day ±60,
bone marrow chimerism was more than or equal to 80% donor in 12 of 13 patients; peripheral blood (PB) myeloid engraftment was
more than or equal to 80% in 10 of 11 patients, and PB lymphoid
chimerism was more than or equal to 80% in 9 of 11 evaluable patients.
No early TRM was observed during the first 100 days; one patient
died of late TRM for lung and brain aspergillus infection. Acute GVHD
grades II-III developed in 8 patients (3 after DLI) a median of 95 days
after transplantation (range, 12-208 days). Of these 8 patients, 7 progressed to chronic GVHD: 2 limited and 5 extensive forms. The median
follow-up was 417 days (range, 194-1003 days) with an overall response
rate of 46% (6 partial remission according to RECIST
criteria).12 No complete responses were observed; 4 patients responded following CSA withdrawal. DLIs were given to 7 patients progressing after allografting, and 3 achieved a partial
remission. All responses occurred after the development of acute GVHD,
and with full donor T-cell chimerism.
There were 3 of 7 RCC patients who progressed soon after the
transplantation (median time, 61 days). There were 4 patients who
responded after CSA withdrawal; patient no. 7 relapsed but eventually
responded again to DLIs plus IFN (Figure
1A). The other 2 RCC patients had stable
disease, and patient no. 11 (papillary RCC) died of progressive disease
10 days after the first DLI. In all BC patients, disease progressed at
a median of 69 days after the transplantation (range, 41-232 days). In
order to induce a GVT effect, all patients (except patient no. 5 who
died of progressive disease at day +109) received escalating doses of
DLIs, at a median of 51 days after disease progression (range, 12-78).
We observed 2 partial responses (patients no. 3 and no. 6): one after a
single-dose DLI, the other after 2 infusions followed by IFN.
Patient no. 3 had an extensive skin and lymph node involvement before
allografting that partially regressed along with a grade II acute
GVHD developing after DLI. Patient no. 6 was unique
since she had bone marrow involved by disease before and after
allografting, and bone lytic metastases. BC cells were still present in
the marrow before DLI, as assessed by morphology, cytokeratine
immunohistochemistry, and by RT-PCR for maspin and mammaglobin genes.
After DLI plus IFN she developed a grade II acute GVHD, and then
marrow samples became PCR-negative for maspin and mammaglobin
gene expression (Figure 1B). We and others have previously shown that
RT-PCR for maspin and mammaglobin is a sensitive and specific
assay for detecting occult BC cells.13 This finding
suggests a GVT effect at the marrow level.
View larger version (68K):
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| Figure 1.
Responses to allografting
in renal cell cancer and breast cancer.
(A) CT thorax scan of patient no. 7 before (i) and after (ii) DLI
plus IFN. (B) RT-PCR analysis of mammaglobin and maspin expression
in bone marrow cells of patient no. 6 before and after DLI. Bone marrow
mononuclear cells were analyzed for mammaglobin and maspin expression
preallograft (lane 1), before DLI (lane 2), and after DLI (lane 3),
respectively. Lane 4: negative control; lane 5: no DNA. MW indicates
molecular weight marker.
|
|
Our data confirm the existence of a graft-versus-RCC effect
demonstrated by Childs et al.4 There were 4 of 6 patients with renal clear cell carcinoma and a sufficient follow-up who
achieved a PR after withdrawal of CSA or after DLI plus IFN.
Clinical evidence of graft-versus-BC effect has been reported in a
limited number of patients (2/10) by Ueno et al,2 and in
one anecdotal case by Eibl et al.1 However, the study by
Ueno et al was different from ours in that it included patients without
progressive disease, adopted a myeloablative conditioning regimen with
demonstrated antitumor activity, and performed DLI in only one case
without response. The dose of T cells to induce a clinical response may vary in different malignancies: Lokhorst et al14 have
shown that effective DLI doses for relapsed multiple myeloma are higher than those used for chronic myeloid leukemia. Whether this
principle applies to solid tumors, and in particular to BC, is still
uncertain. Further, the utilization of specific T-cell subsets, the
optimal time interval from allograft to DLI, and the schedule of IFN administration to enhance a GVT effect remain to be determined.
| |
Footnotes |
Submitted October 1, 2001; accepted January 24, 2002.
Supported in part by CNR grant no. 00.00026.ST97 to M.B.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Marco Bregni, Bone Marrow Transplant Unit and Gene
Therapy Program, Istituto H San Raffaele, Via Olgettina 60, 20132 Milano, Italy; e-mail: marco.bregni{at}hsr.it.
| |
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Abstract
Introduction