scholarly journals Application of hyperthermia to the treatment of human acute leukemia: purging human leukemic progenitor cells by heat

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 802-804 ◽  
Author(s):  
Y Moriyama ◽  
M Narita ◽  
K Sato ◽  
M Urushiyama ◽  
S Koyama ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Progenitor Cells ◽  
Autologous Bone Marrow Transplantation ◽  
Leukemic Cell ◽  
Autologous Bone Marrow ◽  
Leukemic Cells ◽  
Neoplastic Disease ◽  
Myeloid Progenitor Cells

Abstract The application of hyperthermia to the treatment of neoplastic disease has focused on solid tumors. Since the hyperthermic sensitivity of human acute leukemia cells is not known, we have studied the in vitro response of human leukemic progenitor cells (L-CFU) to hyperthermia using a quantitative assay system for L-CFU. Human L-CFU were found to be more sensitive than committed normal myeloid progenitor cells to hyperthermic killing (41 to 42 degrees C). In addition, in the five acute myelogenous leukemic patients studied, it was shown that their leukemic progenitor cells--all types were studied according to the French-American-British diagnosis--were unable to form colonies when exposed to a temperature of 42 degrees C for 60 minutes, whereas the residual normal clones suppressed by the leukemic cell population were found to recover and to form more colonies in vitro as compared with untreated leukemic marrows. This strongly suggests that in vitro hyperthermia may selectively purge residual leukemic cells, especially L-CFU in stored remission bone marrow before autologous bone marrow transplantation.

scholarly journals Application of hyperthermia to the treatment of human acute leukemia: purging human leukemic progenitor cells by heat

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 802-804
Author(s):  
Y Moriyama ◽  
M Narita ◽  
K Sato ◽  
M Urushiyama ◽  
S Koyama ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Progenitor Cells ◽  
Autologous Bone Marrow Transplantation ◽  
Leukemic Cell ◽  
Autologous Bone Marrow ◽  
Leukemic Cells ◽  
Neoplastic Disease ◽  
Myeloid Progenitor Cells

The application of hyperthermia to the treatment of neoplastic disease has focused on solid tumors. Since the hyperthermic sensitivity of human acute leukemia cells is not known, we have studied the in vitro response of human leukemic progenitor cells (L-CFU) to hyperthermia using a quantitative assay system for L-CFU. Human L-CFU were found to be more sensitive than committed normal myeloid progenitor cells to hyperthermic killing (41 to 42 degrees C). In addition, in the five acute myelogenous leukemic patients studied, it was shown that their leukemic progenitor cells--all types were studied according to the French-American-British diagnosis--were unable to form colonies when exposed to a temperature of 42 degrees C for 60 minutes, whereas the residual normal clones suppressed by the leukemic cell population were found to recover and to form more colonies in vitro as compared with untreated leukemic marrows. This strongly suggests that in vitro hyperthermia may selectively purge residual leukemic cells, especially L-CFU in stored remission bone marrow before autologous bone marrow transplantation.

scholarly journals Purging murine leukemic marrow with alkyl-lysophospholipids

Blood ◽  
1984 ◽  
Vol 64 (6) ◽  
pp. 1288-1291 ◽  
Author(s):  
L Glasser ◽  
LB Somberg ◽  
WR Vogler
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cytotoxic Effect ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Myelomonocytic Leukemia ◽  
In Vitro Treatment

Abstract Autologous bone marrow transplantation is potentially curative in the treatment of acute leukemia if residual leukemic cells in the marrow can be eliminated prior to transplantation. We studied the purging effects of a synthetic alkyl-lysophospholipid (ALP) on marrow containing leukemic cells from a transplantable myelomonocytic leukemia (WEHI-3B) in BALB/c mice. Simulated remission bone marrow containing 2% leukemic cells treated in vitro with 20 and 100 micrograms/mL of ET-18- OCH3 (1-octadecyl-2-methyl-sn-glycerol-3-phosphocholine) significantly prolonged survival of lethally irradiated transplanted recipients. At a dose of 100 micrograms/mL, 88% of the mice survived for the duration of the experiment (approximately five months). Autopsies showed that 25% of these survivors had microscopic evidence of leukemia. Thus, in vitro treatment of marrow eliminated leukemic blasts and spared sufficient normal stem cells to allow hematologic reconstitution. The effect of ET- 18-OCH3 is not entirely selective for leukemic cells. A spleen colony assay showed that ALP has some cytotoxic effect on normal hematopoietic stem cells.

scholarly journals Correlation of occult clonogenic leukemia drug sensitivity with relapse after autologous bone marrow transplantation

Blood ◽  
1991 ◽  
Vol 78 (4) ◽  
pp. 1125-1131 ◽  
Author(s):  
CB Miller ◽  
BA Zehnbauer ◽  
S Piantadosi ◽  
SD Rowley ◽  
RJ Jones
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Complete Remission ◽  
Acute Leukemia ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Therapeutic Results ◽  
Autologous Bone ◽  
Minimal Residual

Abstract Despite initial complete remission rates exceeding 70%, the majority of patients with acute myeloid leukemia (AML) and adults with acute lymphocytic leukemia (ALL) eventually relapse. Improving the therapeutic results in acute leukemia requires detecting, and understanding the biology of, the minimal residual leukemia remaining after therapy and responsible for relapse. To investigate the biologic relevance of an in vitro assay for clonogenic leukemia (leukemia colony- forming units [CFU-L]) as a measure of minimal residual leukemia, we studied 58 consecutive patients with acute leukemia in complete remission undergoing autologous bone marrow transplantation (BMT) with cyclophosphamide-based therapy. CFU-L were cultured from the pretransplant remission marrows in 45 of 58 patients: 35 of 43 patients with AML and 10 of 15 with ALL. Clonal rearrangements, identical to the patients' overt leukemia when available, were detected in the occult CFU-L from four of the eight patients with ALL in whom adequate DNA for analysis could be obtained from the CFU-L. None of the uncultured pretransplant remission marrows from the 15 ALL patients showed clonal gene rearrangements. We also determined the in vitro sensitivity of the occult CFU-L to 4-hydroperoxycyclophosphamide (4HC), and correlated these results with the outcome of the patients. The sensitivity of the occult CFU-L to 4HC was the only factor that predicted relapse following BMT. The actuarial probability of relapse was 18% in the 23 patients whose CFU-L were sensitive to 4HC compared with 77% in the 22 patients whose CFU-L were resistant (P less than .001). The only factor that influenced the CFU-L sensitivity to 4HC was the type of leukemia. The CFU-L from the AML patients were more sensitive to 4HC than the CFU- L from the ALL patients (P = .001). Occult CFU-L genetically and functionally represent occult leukemia. Therefore, the CFU-L assay should provide a means for studying the biology of minimal residual leukemia and improving the therapeutic results in patients with acute leukemia.

scholarly journals Monoclonal antibody BA-1 does not bind to hematopoietic precursor cells

Blood ◽  
1982 ◽  
Vol 59 (5) ◽  
pp. 1029-1035 ◽  
Author(s):  
J Jansen ◽  
RC Ash ◽  
ED Zanjani ◽  
TW LeBien ◽  
JH Kersey
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Hematopoietic Precursor ◽  
Proliferation In Vitro

Abstract Monoclonal antibody BA-1 binds to B lymphocytes, to cells from most cases of non-T acute lymphoblastic leukemia (ALL), and weakly to neutrophils. To determine whether BA-1 also reacts with hematopoietic progenitor cells (HPC), we studied the effect of removal of BA-1+ cells from human bone marrow on the proliferation in vitro of the trilineage precursor cell CFU-GEMM, and on the committed progenitor cells of granulopoiesis (CFU-C) and erythropoiesis (BFU-E/CFU-E). Complement- mediated cytotoxicity using BA-1 at concentrations far beyond those required to lyse BA-1+ bone marrow cells and ALL cells did not result in inhibition of colony formation in any of the assays. A rosette separation method, using ox red blood cells coated with BA-1, resulted in enrichment of HPC in the BA-1-depleted interface, whereas very few HPC were found in the BA-1-enriched pellet. Both methods indicate that BA-1 does not bind to HPC, although binding of the antibody to the lymphohematopoietic stem cell cannot be excluded yet. The high cytotoxic capacity of the IgM antibody BA-1, and the lack of reactivity with HPC, make the antibody particularly suitable for use in autologous bone marrow transplantation for patients with ALL.

scholarly journals Autologous bone marrow transplantation in acute leukemia: a phase I study of in vitro treatment of marrow with 4- hydroperoxycyclophosphamide to purge tumor cells

Blood ◽  
1985 ◽  
Vol 65 (6) ◽  
pp. 1504-1510 ◽  
Author(s):  
H Kaizer ◽  
RK Stuart ◽  
R Brookmeyer ◽  
WE Beschorner ◽  
HG Braine ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Acute Leukemia ◽  
Phase I Study ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Autologous Bone ◽  
In Vitro Treatment ◽  
Safe Concentration

Abstract This phase I study was conducted to determine the maximal safe concentration of 4-hydroperoxycyclophosphamide (4HC) that could be used for in vitro treatment of bone marrow from patients with acute leukemia undergoing autologous bone marrow transplantation. Concentrations of 40 to 120 micrograms/mL of 4HC were used in 30 patients with relapsed or high-risk acute leukemia and in six patients with nonleukemic malignancies. All patients received marrow-lethal cytoreductive therapy followed by infusion of the 4HC-treated marrow. Complete inhibition of granulocyte and macrophage colony-forming cells was obtained at 80 micrograms/mL. Nevertheless, only one transplant-related death and otherwise full hematologic recovery was observed at concentrations of 4HC up to 100 micrograms/mL. At 120 micrograms/mL, there were three transplant-related deaths, including two of the three patients who required the infusion of reserve marrow. Among the acute leukemia patients, three remain in complete remission at 1,337, 1,017, and 967 days after transplant. Among the nonleukemic patients, two remain in complete remission at 1,081 and 1,017 days after transplant. At the maximum safe concentration of 4HC (100 micrograms/mL), satisfactory hematologic recovery can be obtained, despite elimination of detectable hematopoietic progenitors.

scholarly journals Correlation of occult clonogenic leukemia drug sensitivity with relapse after autologous bone marrow transplantation

Blood ◽  
1991 ◽  
Vol 78 (4) ◽  
pp. 1125-1131 ◽  
Author(s):  
CB Miller ◽  
BA Zehnbauer ◽  
S Piantadosi ◽  
SD Rowley ◽  
RJ Jones
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Complete Remission ◽  
Acute Leukemia ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Therapeutic Results ◽  
Autologous Bone ◽  
Minimal Residual

Despite initial complete remission rates exceeding 70%, the majority of patients with acute myeloid leukemia (AML) and adults with acute lymphocytic leukemia (ALL) eventually relapse. Improving the therapeutic results in acute leukemia requires detecting, and understanding the biology of, the minimal residual leukemia remaining after therapy and responsible for relapse. To investigate the biologic relevance of an in vitro assay for clonogenic leukemia (leukemia colony- forming units [CFU-L]) as a measure of minimal residual leukemia, we studied 58 consecutive patients with acute leukemia in complete remission undergoing autologous bone marrow transplantation (BMT) with cyclophosphamide-based therapy. CFU-L were cultured from the pretransplant remission marrows in 45 of 58 patients: 35 of 43 patients with AML and 10 of 15 with ALL. Clonal rearrangements, identical to the patients' overt leukemia when available, were detected in the occult CFU-L from four of the eight patients with ALL in whom adequate DNA for analysis could be obtained from the CFU-L. None of the uncultured pretransplant remission marrows from the 15 ALL patients showed clonal gene rearrangements. We also determined the in vitro sensitivity of the occult CFU-L to 4-hydroperoxycyclophosphamide (4HC), and correlated these results with the outcome of the patients. The sensitivity of the occult CFU-L to 4HC was the only factor that predicted relapse following BMT. The actuarial probability of relapse was 18% in the 23 patients whose CFU-L were sensitive to 4HC compared with 77% in the 22 patients whose CFU-L were resistant (P less than .001). The only factor that influenced the CFU-L sensitivity to 4HC was the type of leukemia. The CFU-L from the AML patients were more sensitive to 4HC than the CFU- L from the ALL patients (P = .001). Occult CFU-L genetically and functionally represent occult leukemia. Therefore, the CFU-L assay should provide a means for studying the biology of minimal residual leukemia and improving the therapeutic results in patients with acute leukemia.

scholarly journals Monoclonal antibody BA-1 does not bind to hematopoietic precursor cells

Blood ◽  
1982 ◽  
Vol 59 (5) ◽  
pp. 1029-1035
Author(s):  
J Jansen ◽  
RC Ash ◽  
ED Zanjani ◽  
TW LeBien ◽  
JH Kersey
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Hematopoietic Precursor ◽  
Proliferation In Vitro

Monoclonal antibody BA-1 binds to B lymphocytes, to cells from most cases of non-T acute lymphoblastic leukemia (ALL), and weakly to neutrophils. To determine whether BA-1 also reacts with hematopoietic progenitor cells (HPC), we studied the effect of removal of BA-1+ cells from human bone marrow on the proliferation in vitro of the trilineage precursor cell CFU-GEMM, and on the committed progenitor cells of granulopoiesis (CFU-C) and erythropoiesis (BFU-E/CFU-E). Complement- mediated cytotoxicity using BA-1 at concentrations far beyond those required to lyse BA-1+ bone marrow cells and ALL cells did not result in inhibition of colony formation in any of the assays. A rosette separation method, using ox red blood cells coated with BA-1, resulted in enrichment of HPC in the BA-1-depleted interface, whereas very few HPC were found in the BA-1-enriched pellet. Both methods indicate that BA-1 does not bind to HPC, although binding of the antibody to the lymphohematopoietic stem cell cannot be excluded yet. The high cytotoxic capacity of the IgM antibody BA-1, and the lack of reactivity with HPC, make the antibody particularly suitable for use in autologous bone marrow transplantation for patients with ALL.

scholarly journals Autologous bone marrow transplantation in acute leukemia with marrow purged with alkyl-lysophospholipid

Blood ◽  
1992 ◽  
Vol 80 (6) ◽  
pp. 1423-1429
Author(s):  
WR Vogler ◽  
WE Berdel ◽  
AC Olson ◽  
EF Winton ◽  
LT Heffner ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Median Time ◽  
Bone Marrow Cells ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Platelet Recovery ◽  
Autologous Bone

Alkyl-lysophospholipids are anticancer agents that are selectively toxic to leukemic cells and relatively sparing of normal bone marrow cells. Thus, they would be likely candidates for purging remission marrows before autologous bone marrow transplant. One of the more promising agents is edelfosine, which could be safely used for purging without prolonging marrow recovery. Assays for marrow progenitor cells were performed before and after purging and cryopreservation in 64 patients. There was no significant reduction in colony formation after purging when compared with unpurged cryopreserved marrow, but there was a significant reduction after cryopreservation. Twenty-four patients with acute leukemia in second (16 patients) or third remission (3 patients), early relapse (3 patients), or in first remission with successfully treated extramedullary relapse (2 patients) received marrow-ablative chemotherapy and total body irradiation followed by infusion of marrow purged for 4 hours with 50 to 100 micrograms/mL of edelfosine. There were 9 lymphoblastic and 15 myelogenous leukemia patients. The median time to granulocyte recovery to 500/microL was 26 and 33 days for the 50 and 75 microgram/mL doses, respectively. The patient whose marrow was purged at the dose of 100 micrograms/mL failed to engraft. The median time to platelet recovery to 25,000/microL was 45 and 37 days for the 50 and 75 micrograms/mL doses, respectively. Twenty-nine percent of the patients remain disease free from 131 to 1,291 days, with a median of 356 days. These results have established that purging with 75 micrograms/mL of edelfosine is a safe dose and is recommended for a phase II trial.

scholarly journals Purging murine leukemic marrow with alkyl-lysophospholipids

Blood ◽  
1984 ◽  
Vol 64 (6) ◽  
pp. 1288-1291
Author(s):  
L Glasser ◽  
LB Somberg ◽  
WR Vogler
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cytotoxic Effect ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Myelomonocytic Leukemia ◽  
In Vitro Treatment

Autologous bone marrow transplantation is potentially curative in the treatment of acute leukemia if residual leukemic cells in the marrow can be eliminated prior to transplantation. We studied the purging effects of a synthetic alkyl-lysophospholipid (ALP) on marrow containing leukemic cells from a transplantable myelomonocytic leukemia (WEHI-3B) in BALB/c mice. Simulated remission bone marrow containing 2% leukemic cells treated in vitro with 20 and 100 micrograms/mL of ET-18- OCH3 (1-octadecyl-2-methyl-sn-glycerol-3-phosphocholine) significantly prolonged survival of lethally irradiated transplanted recipients. At a dose of 100 micrograms/mL, 88% of the mice survived for the duration of the experiment (approximately five months). Autopsies showed that 25% of these survivors had microscopic evidence of leukemia. Thus, in vitro treatment of marrow eliminated leukemic blasts and spared sufficient normal stem cells to allow hematologic reconstitution. The effect of ET- 18-OCH3 is not entirely selective for leukemic cells. A spleen colony assay showed that ALP has some cytotoxic effect on normal hematopoietic stem cells.

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