Autologous transplantation of ex vivo expanded bone marrow cells grown from small aliquots after high-dose chemotherapy for breast cancer

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 2169-2174 ◽  
Author(s):  
Patrick Stiff ◽  
Bohao Chen ◽  
Wilbur Franklin ◽  
David Oldenberg ◽  
Eric Hsi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Stem Cell ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Ex Vivo ◽  
Autologous Transplantation ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Small Aliquot

Abstract The collection of small aliquots of bone marrow (BM), followed by ex vivo expansion for autologous transplantation may be less morbid, and more cost-effective, than typical BM or blood stem cell harvesting. Passive elimination of contaminating tumor cells during expansion could reduce reinoculation risks. Nineteen breast cancer patients underwent autotransplants exclusively using ex vivo expanded small aliquot BM cells (900-1200 × 106). BM was expanded in media containing recombinant flt3 ligand, erythropoietin, and PIXY321, using stromal-based perfusion bioreactors for 12 days, and infused after high-dose chemotherapy. Correlations between cell dose and engraftment times were determined, and immunocytochemical tumor cell assays were performed before and after expansion. The median volume of BM expanded was 36.7 mL (range 15.8-87.0). Engraftment of neutrophils greater than 500/μL and platelets greater than 20 000/μL were 16 (13-24) and 24 (19-45) days, respectively; 1 patient had delayed platelet engraftment, even after infusion of back-up BM. Hematopoiesis is maintained at 24 months, despite posttransplant radiotherapy in 18 of the 19 patients. Transplanted CD34+/Lin−(lineage negative) cell dose correlated with neutrophil and platelet engraftment, with patients receiving greater than 2.0 × 105 CD34+/Lin− cells per kilogram, engrafting by day 28. Tumor cells were observed in 1 of the 19 patients before expansion, and in none of the 19 patients after expansion. It is feasible to perform autotransplants solely with BM cells grown ex vivo in perfusion bioreactors from a small aliquot. Engraftment times are similar to those of a typical 1000 to 1500 mL BM autotransplant. If verified, this procedure could reduce the risk of tumor cell reinoculation with autotransplants and may be valuable in settings in which small stem cell doses are available, eg, cord blood transplants.

scholarly journals Amifostine (WR-2721) shortens the engraftment period of 4- hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support

Blood ◽  
1994 ◽  
Vol 83 (11) ◽  
pp. 3132-3137 ◽  
Author(s):  
EJ Shpall ◽  
SM Stemmer ◽  
L Hami ◽  
WA Franklin ◽  
L Shaw ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cancer Patients ◽  
Ex Vivo ◽  
Autologous Bone Marrow ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Breast Cancer Patients ◽  
Significant Difference ◽  
Autologous Bone

4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty- three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high- dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.

scholarly journals Amifostine (WR-2721) shortens the engraftment period of 4- hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support

Blood ◽  
1994 ◽  
Vol 83 (11) ◽  
pp. 3132-3137 ◽  
Author(s):  
EJ Shpall ◽  
SM Stemmer ◽  
L Hami ◽  
WA Franklin ◽  
L Shaw ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cancer Patients ◽  
Ex Vivo ◽  
Autologous Bone Marrow ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Breast Cancer Patients ◽  
Significant Difference ◽  
Autologous Bone

Abstract 4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty- three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high- dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.

Occult tumor contamination of hematopoietic stem-cell products does not affect clinical outcome of autologous transplantation in patients with metastatic breast cancer.

1998 ◽  
Vol 16 (11) ◽  
pp. 3509-3517 ◽  
Author(s):  
B W Cooper ◽  
T J Moss ◽  
A A Ross ◽  
J Ybanez ◽  
H M Lazarus
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Stem Cell ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Time To Progression ◽  
Hematopoietic Stem ◽  
Occult Tumor

PURPOSE To determine whether occult tumor contamination of autologous bone marrow or peripheral-blood progenitor cells (PBPC) influences clinical outcome after high-dose chemotherapy in patients with stage IV breast cancer. PATIENTS AND METHODS We used an immunocytochemical assay capable of detecting one tumor cell in 5 x 10(5) hematopoietic cells to analyze bone marrow and/or PBPC collections obtained from 57 consecutive women with chemotherapy-sensitive metastatic breast cancer who received high-dose chemotherapy. The influence of occult tumor on time to progression, overall survival, and first site of recurrence (old or new) was studied. RESULTS Twenty-three of 57 (40%) patients received bone marrow (n=6) or peripheral-blood progenitor collections (n=17) that contained microscopic cancer. Median time to progression and overall survival were 9 and 22 months in patients who did not receive infused tumor cells, compared with 10 and 24 months, respectively, in those who received occult tumor (P=not significant [NS]). Worse survival, but not time to progression, was observed in six patients who received > or = 2/100,000 tumor cells. Regardless of whether occult tumor was infused, the majority of relapses occurred in prior, rather than new sites of disease. Three patients who received stem-cell products contaminated by microscopic breast cancer remain free from progression at 21+, 47+, and 52+ months. CONCLUSION Microscopic tumor was frequently detected by immunocytochemistry in hematopoietic stem-cell products, but did not predict for inferior treatment outcome in this cohort of patients with metastatic breast cancer. Quantitative information regarding infused tumor burden may have prognostic significance.

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