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Biomedical subjects

M Korbling

Publications and source records attributed to M Korbling.

36 records · Page 2Linked to original sources
PubMed1997

Allogeneic transplantation for recurrent or refractory non-Hodgkin's lymphoma with poor prognostic features after conditioning with thiotepa, busulfan, and cyclophosphamide: experience in 44 consecutive patients.

We report the outcomes of 44 consecutive patients with non-Hodgkin's lymphoma (NHL) who participated in prospective studies of allogeneic transplantation after conditioning with thiotepa, busulfan and cyclophosphamide. Within a range of 27-57 years, the median age was 37. Of the 44 patients, 12 (27.2%) had high-grade lymphomas, 27 (61.4%) had intermediate-grade lymphomas, and five (11.3%) had low-grade lymphomas. Twenty-eight (63.6%) patients had chemotherapy refractory disease. Thirty (68.2%) patients had stage IV disease at the time of transplantation, involving the bone marrow in 19 (43.2%). Eight (18.1%) patients had undergone previous transplantation, and 13 (29.5%) patients had received high-dose CVP as induction within 2 months prior to transplantation. Thirty-eight (86.3%) patients had an HLA-identical donor, and 6 (13.6%) had a one-antigen mismatched related donor. Twenty (45.4%) patients received bone marrow and 24 (54.6%) received granulocyte colony-stimulating factor (G-CSF) mobilized stem cells. The graft-versus-host disease (GVHD) prophylaxis contained cyclosporine or tacrolimus in combination with either methylprednisolone in 32 (72.7%) patients or with methotrexate in 12 (27.2%) patients. The actuarial probability of disease-free survival at 2 years is 23% (95% CI 13%-40%). Donor stem cell use was associated with a significantly decreased risk of treatment-related toxicity (p < 0.001), but with an increased risk for GVHD and delayed fungal and viral infections. These infections are linked not only to the use of donor-stem cells, but also to the methylprednisolone in the GVHD prophylaxis regimen. Improvements in the outcome of patients with advanced NHL and undergoing allogeneic transplantation will depend on the development of effective and non-toxic regimens for conditioning, GVHD prophylaxis, and opportunistic infections prophylaxis.

Adult↗
PubMed1996

Allogeneic transplantation for advanced leukemia: improved short-term outcome with blood stem cell grafts and tacrolimus.

We have evaluated the use of blood stem cell grafts for rapid hematopoietic recovery and tacrolimus (FK506) as GVHD prophylaxis to reduce early mortality after allogeneic transplantation. Eighty-five adults with advanced leukemia received high-dose thiotepa, busulfan, and cyclophosphamide as a preparative regimen in a prospective Phase II study. All donors were HLA-matched and related. Marrow (BMT) was used for 44 patients and filgrastim-mobilized blood stem cells (SCT) for 41 patients. GVHD prophylaxis consisted of cyclosporine (CsA) or FK506 with methotrexate (MTX) or methylprednisolone (MP). The median time to neutrophil recovery was earlier after SCT than after BMT (day 10 vs. 17, P<0.001), but this was due to the selective use of MTX only in the BMT patients. The risk of grades 2-4 GVHD was lower with FK506 than with CsA (16% vs. 45%, P=0.02) and was the same for SCT recipients as for BMT recipients (33% vs. 34%). Regimen-related toxicity was significantly lower after SCT than after BMT but did not differ between the FK506 and CsA patients. In comparison with those receiving the standard transplant (BMT with CsA and MTX), only the SCT recipients using FK506 and MP had a significantly higher survival at day 180 posttransplant (84% vs. 53%, P=0.014). In multivariate analyses, use of FK506 was associated with a lower risk of treatment-related mortality and a higher survival at day 180, while the diagnosis of acute lymphoblastic leukemia was associated with a higher risk of treatment-related mortality. These data suggest that the use of blood stem cell grafts and FK506 can reduce the early mortality after allogeneic transplantation for advanced leukemia.

Adolescent↗
PubMed1996

Results of MDR-1 vector modification trial indicate that granulocyte/macrophage colony-forming unit cells do not contribute to posttransplant hematopoietic recovery following intensive systemic therapy.

To formally test the hypothesis that the granulocyte/macrophage colony-forming unit (GM-CFU) cells can contribute to early hematopoietic reconstitution immediately after transplant, the frequency of genetically modified GM-CFU after retroviral vector transduction was measured by a quantitative in situ polymerase chain reaction (PCR), which is specific for the multidrug resistance-1 (MDR-1) vector, and by a quantitative GM-CFU methylcellulose plating assay. The results of this analysis showed no difference between the transduction frequency in the products of two different transduction protocols: "suspension transduction" and "stromal growth factor transduction." However, when an analysis of the frequency of cells positive for the retroviral MDR-1 vector posttransplantation was carried out, 0 of 10 patients transplanted with cells transduced by the suspension method were positive for the vector MDR-1 posttransplant, whereas 5 of 8 patients transplanted with the cells transduced by the stromal growth factor method were positive for the MDR-1 vector transcription unit by in situ or in solution PCR assay (a difference that is significant at the P = 0.0065 level by the Fisher exact test). These data suggest that only very small subsets of the GM-CFU fraction of myeloid cells, if any, contribute to the repopulation of the hematopoietic tissues that occurs following intensive systemic therapy and transplantation of autologous hematopoietic cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Collection of peripheral-blood diploid cells from chronic myelogenous leukemia patients early in the recovery phase from myelosuppression induced by intensive-dose chemotherapy.

PURPOSE: To evaluate whether intensive chemotherapy followed by peripheral stem-cell (PSC) collections during early hematopoietic recovery results in a higher percentage of diploid cell collections in patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). PATIENTS AND METHODS: Fifty-five adults with Ph-positive CML received intensive chemotherapy with daunorubicin and high-dose cytarabine (ara-C) (DAUNO-HDAC; 26 patients) or fludarabine, high-dose ara-C, and mitoxantrone (FAM; 29 patients). Collections of the peripheral mononuclear cells were initiated when the WBC count was > or = 0.8 x 10(3)/microL. Simultaneous peripheral and marrow samples were subjected to cytogenetic studies. RESULTS: Thirty-eight of 55 patients (69%) were able to undergo the PSC collections. The rate of collection was higher in chronic phase (26 of 30 patients; 87%) than in accelerated (11 of 17; 65%) and blastic phases (1 of 8; 12%). Among the 30 patients in chronic phase, cytogenetic analyses of PSC showed cytogenetic responses (Ph-positive < 95%) in 60%, which were major (Ph < 35%) in 43% and complete (Ph = 0%) in 27%. Seven of 19 patients with simultaneous studies (37%; 23% of total) had a significantly lower percentage of Ph-positive cells in the peripheral collection compared with the marrow collection; one had the reverse phenomenon (5%; 3% of total). Cytogenetic responses were modest in both peripheral and marrow collections in CML accelerated and blastic phases. Myelosuppression-associated complications were frequent, resulting in febrile episodes in 76% of patients. CONCLUSION: PSC collection during early hematopoietic recovery from intensive chemotherapy allowed the collection of diploid-rich stem cells, mostly in chronic-phase CML. The approach could be used for in vivo purging before autologous stem-cell transplantation (ASCT).

Adolescent↗
PubMed1995

Chemotherapy resistance to taxol in clonogenic progenitor cells following transduction of CD34 selected marrow and peripheral blood cells with a retrovirus that contains the MDR-1 chemotherapy resistance gene.

A retrovirus containing the multiple drug resistance (MDR-1) cDNA, was used to transduce cultures of CD34 selected human marrow cells, on stromal monolayers in the presence of hematopoietic growth factors IL-3 and IL-6, following collection from patients recently recovered from chemotherapy-induced myelosuppression. In one experiment, these CD34 selected cells were grown in Dexter cultures for 35 days or more following MDR-1 transduction, and then plated in methylcellulose. Polymerase chain reaction (PCR) analysis of colonies picked after 10-14 days of methylcellulose culture, using a set of primers that are specific for the endogenous or the retrovirally transduced MDR-1, showed that the long-term culture initiating cells (LTCICs) were transduced by the MDR-1 virus. Analysis of the colonies from the CD34 selected MDR-1 transduced cells, with a reverse transcription (RT) PCR assay that could distinguish viral MDR-1 mRNA from endogenous MDR-1 mRNA, showed that the viral MDR-1 mRNA levels were much higher than that of the MDR-1 mRNA from the endogenous MDR-1 gene in the transduced CD34 selected cells. Fluorescence activated cell sorting (FACS) analysis of the CD34 selected transduced marrow cells within 48 h after the transduction, using the C219 and UIC2 monoclonal antibodies for p-glycoprotein, showed that the transduction frequency under these conditions varied from 7 to 20%. Rhodamine efflux studies showed that this additional p-glycoprotein was functional and that the frequency of cells with high p-glycoprotein levels was higher in the transduced cells than in the non-transduced cells. The resistance to taxol of the CD34 selected transduced cells, as judged by the plating efficiency of clonogenic progenitor cells derived from these cells by growth in methylcellulose supplemented with taxol was much higher in the transduced cells than in untransduced cells. In order to test the reproducibility of the transduction frequency of the retroviral supernatants from PA317 MDR-1 viral producer cells on CD34 selected cells, the virus produced from 12 different lots of supernatants from the PA317 MDR-1 producer cell line was used to transduce CD34 selected marrow cells from four different patients, and to transduce the peripheral blood cells of two additional patients collected following chemotherapy-induced myelosuppression. The supernatant lots used for these transduction experiments were tested by Microbiological Associates (Rockville, MD, USA), by the Mus dunni co-cultivation and amplification tests in the S+L-assay and found to be negative for replication-competent retrovirus, and later approved for human use by the Food and Drug Administration.(ABSTRACT TRUNCATED AT 400 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Utilization of recombinant human GM-CSF to enhance peripheral progenitor cell yield for autologous transplantation.

Evidence has accumulated which indicates that efficacy of chemotherapy correlates with dose intensity and with total dose. For most cytotoxic agents, the major limiting factor for escalation of dose intensity is myelotoxicity. Attempts have been made to circumvent myelotoxicity by autologous bone marrow transplantation. Recently, it has been demonstrated that progenitors enriched from the peripheral blood can also be used successfully for autografting. The concentration of progenitor cells in peripheral blood is lower than that in bone marrow but myelosuppressive chemotherapy or hematopoietic growth factors, or a combination of both can be exploited to enhance the progenitor cell yield. The studies reported here are sequential. In the first study, eight patients with advanced Hodgkin's disease received myelosuppressive regimen consisting of cytarabine (100 mg/m2/12h SC days 1 to 5) and daunorubicin (45 mg/m2/d, days 3 and 4). Progenitor cell leukapheresis was performed during the rebound phase of hematopoiesis. All eight patients were treated with super-dose chemotherapy with progenitor cell transplantation. One patient died of CNS toxicity 48 days after transplantation but all other seven had sustained engraftment. In the second study, human recombinant GM-CSF (at 250 micrograms/m2/d as continuous infusion) was administered to twelve patients. Leukapheresis was started at a white blood count (WBC) of greater than 10 x 10(9)/L and the dosage of rhGM-CSF adjusted to keep the WBC between 10 x 10(9)/L and 20 x 10(9)/L. The median duration of rhGM-CSF application was 11.5 days and a median number of six leukaphereses performed. The median increase in the number of granulocyte-macrophage colony forming units (CFU-GM)/ml of peripheral blood was 8.5 fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Autologous bone marrow transplantation for acute myeloblastic leukemia in Europe: further evidence of the role of marrow purging by mafosfamide. European Co-operative Group for Bone Marrow Transplantation (EBMT).

Fifty-nine European teams have reported 919 autografts for the consolidation of acute myelocytic leukemia (AML) up to December 31, 1989. The distribution for autologous bone marrow transplantation (ABMT) was 671 in first complete remission (CR1) and 196 in CR2. Pretransplantation regimes were: total-body irradiation (TBI), 456; busulfan plus cyclophosphamide (BU-CY) 174; marrow purging with mafosfamide, 269 (corresponding to 26% of all patients in CR1 and 41% in CR2). Patients autografted in CR1 with no high risk factor (standard risk) had a leukemia-free survival (LFS) and relapse rate at 7 years of 48 +/- 2 and 41 +/- 3%, respectively. Of all the prognostic factors studied, only secondary leukemia was correlated with a poorer LFS (19 +/- 9% at 1 year) and a higher relapse rate (76 +/- 11%) (p less than 0.0001). For patients autografted in CR2, the LFS and relapse rate were 34 +/- 4 and 54 +/- 5%. With the restriction of a shorter follow-up, the results achieved with the BU-CY combinations (LFS and relapse rate at 3 years, CR1 47 +/- 6 and 45 +/- 7%; CR2, 37 +/- 9 and 50 +/- 10%) did not differ from those with TBI or other chemotherapy combinations. LFS and relapse rates were correlated with several pretransplant intervals: in CR1, patients reaching CR more rapidly (less than or equal to 40 days) had a better LFS (53 +/- 3 versus 42 +/- 3%; p = 0.03) and a lower relapse rate (46 +/- 3 versus 57 +/- 3%; p = 0.03). In patients autografted less than 3 months, 3-6 months and more than 6 months after CR, the LFS was 26 +/- 5, 49 +/- 3, and 55 +/- 4%, respectively, and the relapse rates 63 +/- 5, 38 +/- 3, and 36 +/- 4% (p less than 0.0001 for both). In CR2, patients autografted more than 18 months after the initial diagnosis had a better LFS (42 +/- 5 versus 24 +/- 5%; p less than 0.001) and a lower relapse rate (45 +/- 6 versus 65 +/- 6%; p less than 0.001). For those autografted less than 3 months, 3-6 months and more than 6 months after CR, the probability of LFS was 30 +/- 5, 30 +/- 7, and 50 +/- 9% (p = 0.06), respectively and the relapse rates 63 +/- 6, 50 +/- 8, and 36 +/- 8% (p = 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1990

Autologous bone marrow transplantation for acute myelocytic leukemia in first remission: a European survey of the role of marrow purging.

We analyzed data from 263 patients with acute myelocytic leukemia (AML) autografted in first remission (CR) during the period from January, 1982 to January, 1987 at one of 34 centers in the European Bone Marrow Transplant Group. The median age of patients was 30 years (range, 1 to 65). The median interval between achieving CR and autografting was 5 months (range, 1 to 23). Of the 263 patients, 131 patients received cytoreductive regimens that included total body irradiation (TBI); the remainder received various combinations of cytotoxic drugs. Sixty-nine patients received autologous marrow purged in vitro with mafosfamide, and 194 received unpurged marrow. The median follow-up was 28 months (range, 12 to 97). For patients with standard risk AML in CR1 autografted after TBI (n = 107), the leukemia-free survival (LFS) was higher, and the probability of relapse was lower in recipients of purged than of unpurged marrow (63% versus 34%, P = .05 and 23% versus 55%, relative risk 0.34, P = .005, respectively). The superior results of purging were most obvious in patients autografted within 6 months of achieving CR (probability of relapse, 20% versus 61%, P = .01). Patients with longer intervals between CR and autografting had higher LFS and lower probability of relapse than those autografted early in CR (intervals greater than 9 months, 7 to 9 months, 4 to 7 months, and less than or equal to 3 months: LFS = 56%, 40%, 35%, 27%, P = .007, probability of relapse = 25%, 56%, 59%, 67%, P = .005; respectively). We conclude that marrow purging with mafosfamide may be valuable for patients autografted early in first CR.

Adolescent↗
PubMed1990

Autologous bone marrow transplantation (ABMT) in acute myelogenous leukaemia--Heidelberg experience.

Thirty-seven patients with acute myelogenous leukaemia, 17 in the first clinical remission (CR; low risk) and 20 in the second or subsequent CR (high risk), underwent total body irradiation (12.1-16.7 GY) and cyclophosphamide treatment (200 mg/kg), followed by autologous bone marrow transplantation. The autograft was incubated with the active cyclophosphamide derivative mafosfamide to reduce the number of possible contaminating clonogenic tumour cells. The transplant related death rate was low (8.1%). The probability of disease free survival after marrow transplantation in the first CR was 62% compared to 28% in the second or subsequent CR at a median follow up to 22 months. The survival plateau of low risk patients after transplantation seems to be stable with no relapses occurring more than one year later, whereas three late relapses were seen in high risk patients.

Adolescent↗
PubMed1985

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

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.

Acute Disease↗
PubMed1985

Elimination of clonogenic Burkitt's lymphoma cells from human bone marrow using 4-hydroperoxycyclophosphamide in combination with monoclonal antibodies and complement.

One requirement for autologous bone marrow transplantation is the selective removal of malignant cells from normal marrow precursors. Development of a clonogenic assay that detects elimination of up to 5 logs of Burkitt's lymphoma cells in the presence of a 20-fold excess of human bone marrow has permitted the evaluation of two different methods for the selective removal of malignant cells. Treatment with 4-hydroperoxycyclophosphamide (4-HC) (60 to 100 micrograms/mL) eliminated 2.0 to 3.5 logs of clonogenic cells. Antitumor activity depended upon the concentration of 4-HC and the length of incubation, but not upon the concentration of normal bone marrow cells. Comparable removal of clonogenic Burkitt's cells was achieved by treatment with rabbit complement (C') and a combination of J5 anti-common acute lymphoblastic leukemia antigen (J5 anti-CALLA), J2 anti-gp 26, and the B1 anti-B1 murine monoclonal antibodies. A combination of 4-HC and monoclonal antibodies proved slightly but significantly more effective than either single agent in eliminating clonogenic tumor cells. Although treatment with 4-HC markedly reduced granulocyte-macrophage colony-forming units-C (GM-CFU-C) content of human bone marrow, neither treatment with 4-HC nor treatment with monoclonal antibodies and C' eliminated precursor cells that could generate new GM-CFU-C after growth in continuous bone marrow cultures. Our data suggest that treatment with 4-HC in combination with multiple monoclonal antibody reagents could be a safe and effective method of eliminating clonogenic tumor cells from human bone marrow.

Antibodies, Monoclonal↗