Prolonged disease control by nonmyeloablative allogeneic transplantation for metastatic breast cancer


We found earlier that high-dose chemotherapy with Allo-SCT produced a tumor response in patients with chemorefractory metastatic breast cancer. In this study, we examined the efficacy and toxicity of nonmyeloablative allogeneic PBSC transplantation in patients with chemosensitive metastatic breast cancer. Twelve patients with metastatic breast carcinoma who had stable disease after standard-dose chemotherapy and six who had a partial response underwent allogeneic transplantation. The conditioning regimen consisted of reduced-intensity fludarabine and melphalan. All patients achieved engraftment and hematopoietic recovery. Nine patients developed grade II or higher acute GVHD; seven of these nine responded to immunosuppressive therapy. Fourteen patients developed chronic GVHD. The treatment-related mortality rate was 11%. With a median follow-up of 565 days, the median survival duration was 643 days and the median progression-free survival duration was 202 days. Two patients are alive with a complete response 1555 and 2526 days after SCT, and one patient is alive with progressive bone disease at day 1118. We conclude that among patients with chemotherapy-sensitive metastatic breast cancer, a fraction will achieve a durable complete response after SCT with a reduced-intensity conditioning regimen. The question remains how to improve the overall efficacy and reduce the mortality rate for this approach.


Metastatic breast cancer still is an incurable disease with poor long-term disease-free survival. The median duration of response to conventional therapies is 6–12 months, and despite new advances, in the majority of patients, disease will eventually become resistant to therapy.1, 2

Since the initial reports of the use of allogeneic transplantation in breast cancer,3, 4, 5 nonmyeloablative approaches have been studied in preclinical6, 7 and clinical settings8, 9, 10, 11 with the goal of producing a graft-versus-tumor (GVT) effect against metastatic disease. However, it is still not known whether prolonged control of disease is achieved by this type of approach. Given the potential high risk compared with that of the standard approach, documentation of prolonged disease control is mandatory for this approach to be pursued further.

Here, we describe the largest single-institution series of patients with chemosensitive metastatic breast cancer treated with a uniform reduced-intensity regimen followed by Allo-SCT. The objectives of this study were to describe the tumor response and outcomes of these patients.

Patients and methods

Patient eligibility

Between January 1999 and December 2006, 19 patients with metastatic breast cancer were enrolled in this prospective clinical trial of fludarabine and melphalan with Allo-SCT at The University of Texas M.D. Anderson Cancer Center. This protocol (DM97-268) was reviewed and approved by the Institutional Review Board of M.D. Anderson Cancer Center.

The eligibility requirements included age 60 years and histological confirmation of metastatic or recurrent invasive breast cancer that had responded either completely or partially to standard-dose chemotherapy. Patients with bone involvement were eligible if they had stable disease (SD) that showed clinical improvement. Other requirements included having a donor who was related and HLA identical for the A and B antigens and the DR allele, or unrelated and HLA identical for the A, B and C antigens and the DR and DQ alleles; a Zubrod performance status of 0 or 1; and adequate organ function (creatinine level 2.0 mg per 100 ml, bilirubin level 2.0 mg per 100 ml, serum alanine aminotransferase level no more than three times the upper limit of normal, left ventricular ejection fraction of at least 50%, forced expiratory volume in 1 s and diffusion capacity of carbon monoxide of at least 50% of predicted values). Exclusion criteria included evidence of chronic active hepatitis or cirrhosis, active infection, HIV infection, a history of earlier allogeneic transplantation or brain metastasis. All patients signed informed consent to participate.

Preparative regimen and stem cell infusion

The reduced-intensity conditioning (RIC) regimen consisted of 5 days of fludarabine and 2 days of melphalan. Fludarabine was given at 30 mg/m2 i.v. daily from day −6 to day −2 (total dose 150 mg/m2), and melphalan was given at 70 mg/m2 i.v. daily from day −3 to day −2 (total dose 140 mg/m2). Donor PBSC or BM cells were infused on day 0, after premedication with 100 mg i.v. hydrocortisone and 25 mg i.v. diphenhydramine.

Stem cell collection

HLA-identical sibling donors were given s.c. G-CSF (filgrastim) at 6 μg/kg twice a day to mobilize PBSCs, which were collected by apheresis beginning on day 4; apheresis was repeated daily until at least 3 × 106 CD34+ cells per kg of recipient body weight were collected. No positive selection or T-cell depletion procedures were performed. The PBSCs were cryopreserved by programmed freezing in 5% DMSO and thawed for infusion on the day of transplantation. BM cells were used if donors were unrelated. For the marrow collection, at least 3 × 108 nucleated cells per kg of recipient body weight were harvested with the donor under general anesthesia. BM cells were harvested on the day of transplantation and infused while fresh.

GVHD prophylaxis and supportive care

Tacrolimus and MTX were administered as immunosuppressive therapy after transplantation for the prevention of GVHD. Patients were given tacrolimus at a dose of 0.03 mg/kg/day by continuous i.v. infusion over 24 h from day −2 until they were able to take oral medications. At that time, the i.v. tacrolimus was discontinued and oral tacrolimus was given instead (0.12 mg/kg/day in two divided doses). The serum tacrolimus level was monitored regularly to maintain a blood level of 5–15 ng/ml. Tacrolimus was generally continued for at least 3 months after the transplantation for patients without disease progression, after which the dose was tapered by 20% every week until discontinuation if GVHD did not occur. MTX 5 mg/m2 i.v. was administered on days 1, 3 and 6 (total dose 15 mg/m2), and an additional dose was given on day 11 if the donors were unrelated (total dose 20 mg/m2). Patients who developed grade II or greater acute GVHD were given methylprednisolone 2 mg/kg/day in divided doses that were tapered as tolerated.

All patients were given quinolones, fluconazole and antiviral agents (acyclovir or valacyclovir) for infection prophylaxis during admission until their ANCs exceeded 0.5 × 109/l. The fluconazole and the antiviral agents were continued until day 100. Patients were monitored for CMV antigenemia and were preemptively treated with ganciclovir if antigenemia was detected. Patients with active GVHD received prophylactic ganciclovir. Patients were also given anti-Pneumocystis jirovecii prophylaxis with trimethoprim/sulfamethoxazole, atovaquone or aerosolized pentamidine for 1 year after transplantation. Those with chronic GVHD received prophylactic antibiotics. All patients were given filgrastim 5 μg/kg s.c. daily from day 0 until the ANC exceeded 1.5 × 109/l for 3 days. Irradiated and filtered blood products were administrated to maintain a hemoglobin level of greater than 8 g per 100 ml and a platelet count of greater than 10 × 109/l.

Treatment of residual or recurrent disease

Patients with fulminant progressive disease or recurrent disease after day 30 or residual disease at day 100 were weaned from the tacrolimus if no signs of GVHD were present. If GVHD appeared, patients were given either topical corticosteroids or systemic methylprednisolone and observed for tumor response. If the tumor did not respond in 6 weeks and GVHD was not present, a donor lymphocyte infusion (DLI) consisting of 1 × 107 CD3+ cells/kg was given. If no response was seen over the next 6 weeks, a second DLI at a dose of 5 × 107 CD3+ cells/kg was administered. Similarly, if no response was seen after the next 6 weeks, a third DLI consisting of 1 × 108 CD3+ cells/kg was given. DLI was not given if symptomatic GVHD was present. Mononuclear cells were collected for DLI by leukapheresis without filgrastim priming from the same donors as those for the original transplantation.

Post transplantation evaluation, chimerism and response

The day of engraftment was defined as the first of 3 consecutive days with an ANC greater than 500 × 106/l. Failure to engraft by day 30 was considered primary graft failure. The day of platelet engraftment was defined as the first of 7 consecutive days with a platelet count of >20 × 109/l without platelet transfusion.

Toxicity was assessed in terms of the National Cancer Institute's Common Terminology Criteria, version 3.0. Hematopoietic chimerism was evaluated in BM and peripheral blood samples on day 30, on day 100 and then again every 3 months after transplantation by quantitative microsatellite polymorphism gene scanning using established techniques.12, 13, 14

For the BM sample, only total nucleated cells were used for the determination. For the peripheral blood sample, T cells and myeloid cells were sorted out separately by the use of the RosetteSep Lymphoid Cell Enrichment Kit and RosetteSep Myeloid Cell Enrichment Kit (StemCell Technologies, Vancouver, British Columbia, Canada), respectively. Complete donor chimerism was defined as 100% of cells having donor DNA. Mixed chimerism was defined as the presence of any detectable (1% or greater) recipient DNA or cells in addition to donor-derived DNA or cells. Acute and chronic GVHD were evaluated and scored according to standard criteria.15

Response to therapy was evaluated at 3-month intervals. Evaluations included a physical examination, blood counts, complete blood chemistry, chest X-ray, skeletal scintigraphy, chest and abdominal/pelvic computed tomography and BM aspiration and biopsy if the BM was involved. Tumor markers (carcinoembryonic antigen and CA 27–29) were also measured.

Complete response indicates the disappearance of all disease and symptoms related to the tumor for more than 4 weeks; partial response, a >50% reduction in the sum of the products of the perpendicular diameters of each measurable lesion for more than 4 weeks; minor response, a reduction in measurable lesions that was too small to qualify as a partial response; stable disease, no change in tumor size; and progressive disease, the appearance of new lesions or a >25% increase in the sum of the products of the perpendicular diameters of any measurable lesions.

Statistical considerations

Survival duration was calculated from the time of transplantation. Progression-free survival duration was measured as the time from transplantation to the development of disease progression or death from any cause, whichever occurred first. For patients lost to follow-up, the time from transplantation to last follow-up was used in these analyses with censoring. Progression-free and overall survival durations were estimated using the Kaplan–Meier product-limit method, with ‘time zero’ defined as the date of transplantation. All data were updated through August 2008.


Patient characteristics

Nineteen women were enrolled in the protocol, and eighteen women actually received the allogeneic transplantation. One patient was enrolled and did not receive the conditioning regimen because of progression of disease during initial workup. Fourteen patients received allogeneic PBSCs from a genotypically HLA-identical sibling donor, and four received marrow transplants from unrelated donors. Patients 1 and 8 were lost to follow-up at 95 and 345 days, respectively, after transplantation.

The median age of those treated was 41 years (range, 31–59), and the median follow-up was 565 days (range, 57–2526). Twelve of the 18 patients expressed the estrogen receptor, and seven overexpressed HER-2/neu. The median number of metastatic sites was two (range, 1–5); bone metastasis was found in 14 patients. All 18 patients had earlier undergone adjuvant chemotherapy, and all but one (patient 6) had undergone at least one course of salvage chemotherapy before the transplantation. The median number of salvage chemotherapy regimens received was two (range, 0–4). All patients had earlier received anthracycline or taxane-containing chemotherapy. Two patients had earlier undergone high-dose chemotherapy and autologous hematopoietic transplantation. Patient characteristics are summarized in Table 1.

Table 1 Baseline demographic and clinical characteristics of patients

Engraftment and donor chimerism

All the 18 treated patients achieved engraftment and hematopoietic recovery. The median time to reach an ANC of 0.5 × 109/l was 12 days (range, 9–16), and the median time to achieve a platelet count higher than 20 × 109/l was also 12 days (range, 9–21). Lineage-specific chimerism studies were performed using microsatellite PCR, and 17 patients showed 100% (complete) donor chimerism of T cells and myeloid cells at day 30 and at subsequent evaluations. Patient 17 had graft failure and required a second transplantation 86 days after the initial one. To enhance donor engraftment, patients 5, 6 and 10 underwent DLI according to the protocol.

Toxicities and infections

The incidence rates of infection and grade III–IV toxic effects are summarized in Table 2. Thirteen patients experienced reversible grade III–IV non-hematopoietic toxicity within the first year after transplantation. Nine patients developed grade II or higher acute GVHD, and seven responded to immunosuppressive therapy. Patients 15 and 18 had refractory grade IV acute gastrointestinal GVHD and died on days 95 and 57, respectively, after transplantation. Fourteen patients developed chronic GVHD, which was controlled by further immunosuppressive therapy. Table 3 summarizes the clinical outcomes.

Table 2 Toxic effects at 1 year after transplantation for the 18 evaluable patients
Table 3 Clinical outcomes

Antitumor response

Of the 19 patients enrolled, six had had a partial response and 13 had stable disease after standard-dose chemotherapy at the time of study entry. The antitumor responses of the 18 evaluable patients are listed in Table 3. The median overall survival duration was 643 days (Figure 1), and the median progression-free survival was 202 days (Figure 2).

Figure 1

Overall survival (OS) duration (days) for the 18 evaluable patients.

Figure 2

Progression-free survival duration for the 18 evaluable patients.

As of August 2008, patients 2 and 12 have had no disease progression and are still alive, and patient 17 is alive with bone disease. Initially, patient 2 had SD after the transplantation, but later, 13 months after the procedure, the disease resolved completely. She developed chronic GVHD 10 months after the transplantation and was also given tamoxifen; she ultimately switched to letrozole, which she is still on. Patient 12 had disease progression while on letrozole and received docetaxel and capecitabine, having had stable disease before the transplantation. After the transplantation, she developed acute GVHD of the skin and gastrointestinal tract followed by chronic GVHD of the gastrointestinal tract. After 8 months of transplantation, the patient developed anemia and thrombocytopenia resistant to i.v. Ig therapy and requiring frequent blood and platelet transfusions. After 16 months of transplantation, she received a CD34−selected PBSC infusion from her unrelated donor. She has been in remission since transplantation, and her chronic GVHD is currently quiescent, requiring no immunosuppressive treatment. She was kept on letrozole as her maintenance therapy. Patient 17 received tamoxifen for 2 years before transplantation and had it discontinued during a pregnancy. After delivery, she was found to have extensive disease that responded to paclitaxel and capecitabine. After transplantation, she had graft failure, which required a second transplantation, and developed chronic GVHD of the gastrointestinal tract, skin and lung. She was in remission and off hormonal therapy until day 1063, when she was noted to have progressive bone disease.

Six patients (no. 3, 5, 6, 11, 15 and 18) experienced disease progression before the first 100 days after transplantation. The other six patients (no. 4, 7, 9, 10, 13 and 19) experienced disease progression after the first 100 days and within a year of the transplantation. Patient 1 had a complete response at 3 months, but it did not last. She was lost to follow-up at day 95 and died of progressive disease at day 245. Patient 8 was alive with stable disease at day 47, was lost to follow-up and eventually died for unknown reasons at 1677 days after transplantation. Overall, the best responses among the 18 treated patients were five complete responses and one minor response. Three patients were alive at a median follow-up of 565 days (range, 57–2526). The actuarial 1-year overall survival rate was 72%.


The majority of patients with metastatic breast cancer have relapses after treatment and die of their disease. Nonmyeloablative Allo-SCT has been studied with interest as a means of inducing a GVT effect against solid tumors, as well as attempting to induce prolonged disease control without any sign of disease by conventional imaging techniques. High-dose regimens produce considerable morbidity and mortality and cannot eliminate all disease; moreover, many solid tumors that have reached an advanced stage already have developed resistance to chemotherapeutic agents. The relatively recent publications describing GVT in patients with a variety of solid tumors16 who underwent reduced-intensity SCT suggest this approach as a potential option for treating young patients with metastatic solid tumors under clinical trials.

Here, we report the largest single-institution trial of an RIC regimen associated with SCT in patients with metastatic breast cancer. Our goal was to determine whether an RIC regimen in chemosensitive metastatic breast cancer could induce clinically significant tumor control with an acceptable risk of treatment-related mortality. In this case, we defined clinically significant tumor control (complete or partial responses) as prolonged control of disease beyond 1 year.

In the past, we showed that an RIC regimen of fludarabine and melphalan was able to produce complete chimerism at the time of engraftment.11 This finding was important because antitumor response usually occurs after the development of complete donor chimerism. Using this same regimen, we expanded our sample of patients to 18 women with metastatic breast cancer. Among these 18 patients, with a median follow-up of 565 days, three with earlier stable disease showed a durable complete response and one a minor response. Two other patients developed a complete response but later had a relapse and died from disease progression at days 135 and 245, respectively. All patients who reached CR responded after GVHD developed with complete donor chimerism. The treatment-related mortality rate was 11%, in line with standard results for allogeneic transplantation. This result suggests that nonmyeloablative SCT could play a role in prolonged disease control in metastatic breast cancer. Although an obvious confounding factor, the use of hormonal therapy is the standard of care, and as such, all the hormone-positive tumor patients were given tamoxifen or aromatase inhibitors.

In 1996, a case report from Eibl et al.4 from Austria and another from Ben-Yosef et al.3 from Israel showed two separate successful experiences by using allogeneic transplantation for metastatic breast cancer. In 1997, Oblon et al.17 from the United States reported another case of allogeneic transplantation for metastatic breast cancer in which a different conditioning regimen—ifosfamide, carboplatin and etoposide—was used. The engraftment was successful, but no GVHD or GVT effects were seen, and the patient died of progressive disease about 4 months after transplantation.

In 1998, we reported the first series in which myeloablative allogeneic transplantation was used to treat metastatic breast cancer.5 The conditioning regimen was the high-dose regimen used for autologous transplantation at our institution, consisting of CY, carmustine and thiotepa. All patients were given PBSCs from HLA-matched sibling donors and had either responding disease or stable disease before transplantation. We concluded in that study that the use of allogeneic transplantation for poor-prognosis metastatic breast cancer is feasible, with acceptable rates of GVHD and treatment-related morbidity and mortality. This approach opened up another treatment option to patients who are not eligible for other standard treatments or Auto-SCT.

In 2005, Carella et al.18 described an innovative approach using tandem high-dose chemotherapy and autologous followed by nonmyeloablative allogeneic transplantation (RIC) for 17 patients with heavily pretreated metastatic breast cancer. Durable complete response after SCT was observed in three patients. Another patient did not respond to autografting but had PR after RIC, giving an overall response rate of 24%. Using the same approach, a subsequent patient was reported, with disappearance of the liver, adrenal, mediastinal, pleural and diffuse nodes and bone metastases, observed simultaneously with clinical chronic GVHD 5 months after RIC.19, 20 The fact that we did not use the initial step of high-dose chemotherapy and autografting may be related to the slightly lesser rate of remission and overall survival.

The existence of a GVT effect can be proven most directly by regression of tumor after a DLI.21 This is because estimating the cause of tumor shrinkage is not confounded by the coadministration of other therapies (such as, cytotoxic or hormonal therapies). In our earlier study, the demonstration of tumor regression associated with GVHD after withdrawal of immunosuppression provided indirect evidence of a GVT effect.11 Defining this immune-mediated cytoreduction phenomenon is important to the application of nonmyeloablative Allo-SCT in solid tumors. Finally, the essential step in the demonstration of a possible GVT effect is successful donor-cell engraftment, and thus the immunosuppressive property of the conditioning regimens is more important than the myelosuppressive property for ensuring complete donor engraftment.

Nonmyeloablative conditioning regimens have been accepted for use when allogeneic transplantation is evaluated for the treatment of solid tumors. A recent meta-analysis22 included 66 women with metastatic breast cancer, 39 of whom received myeloablative regimens and 27 of whom received RIC regimens. Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03), although more patients in the RIC group had poor pre-transplantation performance status. However, the myeloablative-regimen group had lower relapse and progression rates. The cumulative incidence rates of disease relapse or progression in the myeloablative group were 44% at 1 year and 62% at 2 years (vs 76% at 1 year and 84% at 2 years in the RIC group), and the probabilities of progression-free survival in the myeloablative group were 23% at 1 year and 5% at 2 years (vs 8% at 1 year and 0 at 2 years in the RIC group).

In conclusion, nonmyeloablative Allo-SCT for metastatic breast cancer enables the attainment of prolonged disease control. This approach may represent a unique immunotherapeutic modality with the promise of cure in a minority of patients. Given the intrinsic complications related to the transplantation itself, identifying patients who might benefit the most from this approach is vital. Patients with a good performance status and whose disease was chemotherapy responsive before transplantation seem to benefit the most.22 We know that the response can be related to the GVT effect, but a deeper understanding of the cellular basis and mechanism for the GVT effect produced by allogeneic lymphocytes is still to be elucidated. Further, we advocate the need for more prospective trials in this setting.


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We thank Sunita Patterson of the Department of Scientific Publications at M.D. Anderson Cancer Center for her expert editorial assistance.

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Correspondence to N T Ueno.

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de Souza, J., Davis, M., Rondon, G. et al. Prolonged disease control by nonmyeloablative allogeneic transplantation for metastatic breast cancer. Bone Marrow Transplant 44, 81–87 (2009).

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  • metastatic breast cancer
  • allogeneic hematopoietic cell transplantation
  • nonmyeloablative regimen
  • graft-versus-tumor effect

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