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P Dreger

Publications and source records attributed to P Dreger.

At least 37 records · Page 2Linked to original sources
PubMed2000

A prospective study of positive/negative ex vivo B-cell depletion in patients with chronic lymphocytic leukemia.

OBJECTIVE: Autologous peripheral blood stem cell (PBSC) transplantation is increasingly being used in patients with chronic lymphocytic leukemia (CLL). As the autografts are frequently contaminated with large numbers of tumor cells, we have prospectively investigated the feasibility and efficacy of ex vivo double purging of PBSC grafts in an open, nonrandomized, single-center phase I/II clinical study. MATERIALS AND METHODS: Twenty consecutive patients with poor-risk CLL underwent uniform stem cell mobilization with chemotherapy and granulocyte colony-stimulating factor (G-CSF). Double B-cell depletion of the harvested PBSC products was performed using immunomagnetic CD34(+) cell selection (Isolex300i Nexell, Irvine, CA) followed by a negative step with anti-CD19/20/23/37-labeled immunomagnetic beads. The purified PBSC were reinfused after myeloablative treatment with TBI/CY. RESULTS: A total of 25 separation runs was accomplished using collection products containing 3.4% (1.1-8.1) CD34(+) cells and 1.2% (0.1-42) CD19(+)CD5(+) CLL cells. After double selection, 33% (15-67) CD34(+) cells were recovered with a purity of 98.8% (89.1-99. 8). CLL cells were undetectable by high-resolution flow cytometry in 15 of 25 final products; median purging efficacy was 5 (4.1-6) log. The CD34(+) content of the 20 final grafts was 4.6 (2.2-6.5) x 10(6)/kg. Rapid and durable engraftment developed in all cases. With a median follow-up of 20 (6-29) months, 17 patients live in complete clinical remission, two have recurrent disease, and one patient died due to pulmonary embolism five months after transplant. Persistence of the leukemic clone on the molecular level was demonstrated by dot blotting with clone-specific CDR3 probes in an additional five patients. Serious or unexpected infectious complications did not occur. CONCLUSIONS: Positive/negative purging with the Isolex system allows preparation of highly purified CD34(+) fractions and up to six log of tumor cell depletion in patients with B-CLL and can be safety reinfused after myeloablative therapy without affecting hematopoietic engraftment.

Adult↗
PubMed2000

Epstein-Barr virus-associated post-transplant lymphoproliferative disease after bone marrow transplantation mimicking graft-versus-host disease.

In contrast to solid organ transplantation (Tx), the incidence of post-transplant lymphoproliferative disease (PTLD) after hematopoietic stem cell Tx (HSCT) is generally low. This risk, however, is significantly elevated in patients receiving human leukocyte antigen (HLA) mis-matched or T-cell-depleted grafts, or after treatment for severe graft-versus-host disease (GvHD). An 18-yr-old patient with positive Epstein-Barr virus (EBV) serology received a fully matched, unmanipulated bone marrow graft from an unrelated EBV-positive donor for treatment of acute myeloid leukemia (AML) in second complete remission. GvHD prophylaxis was performed with cyclosporin A (CsA) and a short course of methotrexate. Four months after Tx, the patient developed ulcerative tonsillitis that was unresponsive to antibiotic treatment. Diarrhea appearing simultaneously was interpreted as gastrointestinal GvHD and steroids were added to CsA. A few days later the patient was admitted to hospital because of generalized seizure and pneumonia. Despite reduction of immunosuppression, intensification of anti-viral treatment, and subsequent mechanical ventilation, the patient died of acute respiratory distress 6 days later. Autopsy demonstrated disseminated EBV-induced, multi-nodular lymphoma infiltration of the entire colon but no signs of GvHD. Moreover, both lungs, paratracheal lymph nodes, kidneys, thyroid gland, and liver were infiltrated with large B-cell non-Hodgkin's lymphomas. This case underlines the rapid and aggressive course of EBV-induced disseminated PTLD after HSCT, initially mimicking intestinal GvHD because of massive colonic lymphoma infiltration. Tissue biopsies should be performed early for establishing correct diagnosis, thus enabling specific therapy, e.g. infusion of donor leukocytes with cytotoxic T-lymphocytes.

Adolescent↗
PubMed2000

The impact of autologous stem cell transplantation on the prognosis of mantle cell lymphoma: a joint analysis of two prospective studies with 46 patients.

INTRODUCTION: The purpose of this analysis was to investigate if early sequential high-dose therapy with autologous stem cell transplantation (ASCT) can improve the poor prognosis of patients with disseminated mantle cell lymphoma (MCL). PATIENTS AND METHODS: A joint analysis of two parallel single center studies was performed. Both were characterized by a sequential high-dose therapy consisting of an intensive chemotherapy ('HAM' or 'Dexa-BEAM') for mobilization of peripheral blood stem cells and induction of minimal disease followed by a total body irradiation-containing myeloablative regimen and ASCT. Forty-six patients with reference panel-confirmed stage III/IV MCL were included. Thirty-four patients were accrued to the protocol immediately after diagnosis ('upfront ASCT' group). These 34 patients received a standard first-line regimen prior to mobilization. The remaining 12 patients were put on the protocol later during the course of their disease ('delayed ASCT' group). RESULTS: All patients were in remission after mobilization chemotherapy and proceeded to ASCT; there were no exclusions due to poor response, poor mobilization, or patient refusal. With a follow-up of 24 (2-73) months post transplant, the event-free and overall survival probabilities at 2 years were 77 and 100% for the upfront ASCT group compared to 30% (P=0.0007) and 54% (P=0.0016) for the delayed ASCT group. Event-free and overall survival tended to be longer in the upfront ASCT group than in the delayed ASCT group also if calculated from initial diagnosis (76 and 93% vs 42 and 63%, respectively, at 4 years after diagnosis; median follow-up 35 months), although this was not statistically significant. Besides timing of ASCT, only spleen size was identified as an independent predictor of survival by univariate and multivariate analysis. CONCLUSION: ASCT is not curative but may improve the prognosis of patients with MCL if performed as part of an intensive first-line treatment strategy. In contrast, the benefits of this approach for salvaging individuals with relapsed disease appear to be limited.

Adult↗
PubMed2000

Peripheral blood stem cell (PBSC) mobilization and transplantation after fludarabine therapy in chronic lymphocytic leukaemia (CLL): a report of the European Blood and Marrow Transplantation (EBMT) CLL subcommittee on behalf of the EBMT Chronic Leukaemias Working Party (CLWP).

We performed a survey from 122 centres of the European Group of Blood and Marrow Transplantation (EBMT) concerning peripheral blood stem cell (PBSC) mobilization after fludarabine treatment of patients with chronic lymphocytic leukaemia (CLL). A total of 101 leucaphereses from 29 patients was performed. The median cell numbers collected were: CD34+ cells, 2.2 x 106/kg (0.1-15.3); granulocyte-macrophage colony-forming units (GM-CFU), 4.29 x 104/kg (0.4-177); and mononuclear cells, 6.4 x 108/kg (1.3-63). In univariate and multivariate analyses, the numbers of cells collected were not significantly influenced by the nature of mobilizing regimen and there was a trend towards the collection of a higher number of CD34+ cells from patients who received fludarabine only before mobilization. There was a significant correlation between the median number of CD34+ cells collected and the number of courses of fludarabine (higher CD34+ cell numbers were related to more than six courses) and the interval between the last dose of fludarabine and the start of mobilizing therapy (higher CD34+ cell numbers were related to a delay > or = 2 months). Sixteen patients have subsequently undergone autologous transplantation and showed rapid engraftment. In conclusion, the results reported favour early stem cell mobilization in CLL patients who are in remission after first-line therapy. However, attention should be given to the timing of mobilization with respect to the time since the last dose of fludarabine.

Antineoplastic Agents↗
PubMed2000

Stem-cell transplantation for chronic lymphocytic leukemia: the 1999 perspective.

BACKGROUND: The use of myeloablative intensive therapy followed by autologous or allogeneic stem-cell transplantation (SCT) for treatment of chronic lymphocytic leukemia (CLL) has largely increased over the last years. DESIGN: The present overview updates the available clinical results and discusses important aspects of SCT in patients with CLL including the type of SCT (autologous vs. allogeneic), myeloablative regimens, purging, the predictive value of molecular monitoring of residual disease, and prognostic factors for the outcome of transplant approaches. RESULTS: With appropriate supportive care, autologous SCT is safe and can induce long-lasting clinical and molecular remissions, which may improve the prognosis of patients with CLL. Feasibiliy and efficacy of autologous SCT appears to be best early during the course of the disease, but it is still unclear if autotransplantation can cure the disease even in this favorable subgroup. The role of purging is still unclear. The better disease control observed after allografting appears to be due to graft-versus-leukemia activity and may allow cure in at least a subset of poor-risk patients. Due to the extraordinarily high treatment-related mortality, however, the outcome after allogeneic SCT is still inferior to that after autologous SCT. CONCLUSIONS: Autologous transplantation is a valuable treatment option for younger patients with early or sensitive poor-risk CLL. Selected patients with advanced poor-risk disease and low probability of successful auto-SCT should be considered for allografting. However, it must be kept in mind that both autologous and allogeneic stem-cell transplantation are still experimental procedures and clinical trials further elucidating their value in the treatment of patients with CLL are warranted.

Clinical Trials as Topic↗
PubMed1999

Autografting of highly purified peripheral blood progenitor cells following myeloablative therapy in patients with lymphoma: a prospective study of the long-term effects on tumor eradication, reconstitution of hematopoiesis and immune recovery.

In a prospective study, we have investigated CD34+ selection of peripheral blood progenitor cells (PBPC) for autotransplantation in patients with lymphoma. Twenty-six consecutive patients (10 follicular lymphomas, seven mantle cell lymphomas, seven B-CLL, two immunocytomas) were mobilized using chemotherapy plus G-CSF. Sufficient numbers of PBPC could be collected from 24 patients and were immunoselected with the semiautomated Isolex 300 (n = 17) or the fully integrated Isolex 300i (n = 7) devices. The selection products were assayed by PCR amplification of clonal CDRIII or t(14;18) rearrangements for residual tumor cell content. Residual disease and long-term hematopoietic and immune recovery were studied by assessing the following parameters at 3, 6, and 12 months post-transplant: CDRIII or t(14;18) PCR, platelet count, lymphocyte subsets, serum IgG, serum IgA, and measles titer. With the Isolex 300 device 26% (10-65) of input CD34+ cells were recovered with a median purity of 89.2% (49.4-98.9) after CD34+ selection. The Isolex 300i device allowed significantly better recoveries (46% (22-86)) and purities of CD34+ cells (98.8% (92.2-99.2)). The overall purging efficacy was 3.2 (0.6-5.1) log. Twenty patients have been reinfused with CD34+ selected grafts after myeloablative preparation. Rapid engraftment occurred in all patients. With a median follow-up of 28 (19-42) months, 14 patients are alive without clinical or molecular evidence of disease recurrence, whereas five have relapsed and one additional patient shows persistent presence of the disease-specific molecular marker without clinical progression. Cellular and serological parameters of hematopoietic and immune functions were largely normal at 12 months post-transplant including the measles titer which was present in all patients. Kinetics of immunohematopoietic recovery were similar to those of 12 control patients who had received unmanipulated PBPC during the same time period except for the recovery of CD4+ CD45RA+ T cells which was significantly delayed in the CD34+ group. During the first year post-transplant, transient monoclonal or oligoclonal gammopathies were observed in seven of 16 study patients. We conclude that CD34+ selection with the Isolex system allows preparation of highly purified CD34+ fractions and effective tumor cell depletion. The CD34+ products can be reinfused safely after myeloablative treatment and result in sustained hematopoietic and immune recovery. The fact that all patients retained their specific measles immunity suggests that myeloablative treatment with reinfusion of highly purified CD34+ PBPC is not immunoablative.

Adult↗
PubMed1999

Myeloablative radiochemotherapy followed by reinfusion of purged autologous stem cells for Waldenström's macroglobulinaemia.

Waldenström's macroglobulinaemia (WM) is an incurable lymphoproliferative disorder. The purpose of this study was to investigate the role of autologous peripheral blood stem cell transplantation (ASCT) for the treatment of WM. Seven patients (untreated or after first-line therapy) with symptomatic WM underwent two or three cycles of Dexa-BEAM chemotherapy + G-CSF with stem cell harvesting and proceeded to total body irradiation and high-dose cyclophosphamide followed by reinfusion of ex-vivo B-cell-depleted stem cells. Engraftment was prompt, and procedure-related deaths did not occur. A strong reduction or normalization of BM infiltration and serum IgM levels occurred in all evaluable patients, but immunofixation electrophoresis revealed persistent paraproteinaemia in five of them. With 3-30 months of follow-up, all patients are alive without clinical or serological signs of disease progression. This pilot trial shows for the first time that high-dose radiochemotherapy with purged stem cells is effective and may improve the course of patients with WM. In the majority of cases, however, complete eradication of the disease does not appear to be possible with ASCT alone.

Adolescent↗
PubMed1998

Early stem cell transplantation for chronic lymphocytic leukaemia: a chance for cure?

B-cell chronic lymphocytic leukaemia (CLL) cannot be cured by conventional therapy. To improve the prognosis of patients with CLL, we have designed a sequential treatment strategy that comprises intensive chemotherapy for mobilization of peripheral blood progenitor cells (PBPCs) and induction of minimal disease, followed by high-dose radiochemotherapy with stem cell reinfusion and post-transplant molecular monitoring by polymerase chain reaction (PCR) amplification of the complementary determining region III (CDRIII) gene. In a prospective study, we have evaluated this protocol in 18 patients with CLL, also including early stages of the disease. The median age was 49 (29-61) years; Binet stages were A, six; B, nine; and C, three. Adverse prognostic factors [high lymphocyte count and/or diffuse bone marrow (BM) infiltration] were present in 16 out of 18 patients. All patients showed a clone-specific molecular marker as demonstrated by PCR amplification of CDRIII rearrangements. For stem cell mobilization and reduction of tumour load, one to two cycles of Dexa-BEAM chemotherapy were administered, resulting in minimal disease (circulating lymphoma cells <1 x 10(9) l(-1); BM infiltration <20%; lymphomas <2 cm) in 16 out of 18 patients, including four patients who already had minimal disease before Dexa-BEAM. Stem cell harvesting was successful in 14 patients. All grafts [three BM, 11 peripheral blood (PB)] were purged from leukaemic cells using immunomagnetic methods. Thirteen patients having achieved minimal disease were reinfused with purged autologous stem cells (ASC) after preparation with total body irradiation and cyclophosphamide. Engraftment was delayed in patients receiving BM (n = 3) but prompt [neutrophils >0.5 x 10(9) l(-1) after 10 (9-13) days, platelets >20 x 10(9) l(-1) after 11 (9-214) days] in patients restored with PBPCs (n = 10). Procedure-related deaths did not occur. Although the results of CDRIII PCR suggest persistence or recurrence of the leukaemic clone in at least three cases, to date only one patient has relapsed, whereas all others survive without clinical evidence of disease with a maximum follow-up of 48 months. We conclude that sequential high-dose therapy using Dexa-BEAM and autologous stem cell transplantation is a safe and highly effective treatment for patients with CLL. However, a longer follow-up is needed to assess whether definite cures can be achieved using this strategy.

Adult↗
PubMed1998

Long-term disease-free survival of patients with advanced mantle-cell lymphoma following high-dose chemotherapy.

In advanced stage mantle cell lymphoma, conventional chemotherapy yields a complete remission rate below 40%, and the median survival rate is only about 3 years. Between 1991 and 1996 we treated nine such patients (six male; three female) with high-dose chemotherapy (six of these also with 12 Gy fractionated total body irradiation (TBI)) and peripheral stem cell support (n = 8) or allogeneic bone marrow transplantation (n = 1). The median age was 47 years (range, 28-61). At the time of high-dose chemotherapy, five patients were in first complete remission (CR), two in first partial remission (PR) and two in second remission (CR = 1; PR = 1). High-dose chemotherapy included TBI (12 Gy), etoposide and cyclophosphamide (patients 1-5), TBI and cyclophosphamide (patient 7), busulfan, etoposide and cyclophosphamide (patients 6 and 9), cyclophosphamide and busulfan (patient 8). The patterns of toxicity according to the Bearman score were usually mild (mucositis grade 2, n = 7; renal grade I, n = 2) with no therapy-related fatality. Only one patient developed hepatic toxicity grade III (veno-occlusive disease) but recovered completely. The median time to neutrophil engraftment was 10 days (range, 8-15). After high-dose chemotherapy all patients achieved complete remission. After a median follow-up of 22 months (range, 9.4-64) all patients remain in continuous complete remission. These encouraging results suggest that high-dose chemotherapy can be applied safely and leads to long-term disease-free survival in otherwise incurable disease.

Adult↗
PubMed1998

Comparison of different strategies of molecular genetic monitoring following autologous stem cell transplantation in patients with follicular lymphoma.

Two different molecular genetic methods were compared for their suitability for monitoring minimal residual disease in patients with follicular lymphoma (FL) treated with high-dose therapy and autologous stem cell transplantation. Fifteen patients were selected because of a specific PCR-amplifiable t(14;18) mbr translocation. PCR amplification of rearrangements of the complementary region III (CDRIII) of the immunoglobulin heavy chain gene was also carried out. After autologous stem cell transplantation, patients were prospectively monitored with both molecular genetic methods. Seven of the 15 patients with detectable t(14;18) prior to transplantation were persistently negative during follow-up to 32 months post transplant. None of these patients relapsed, whereas four of eight patients with positive PCR signals post transplant relapsed. Comparing t(14;18) and PAGE results, we observed six patients showing clonal signals in CDRIII PAGE in spite of persistent negativity of t(14;18) PCR. We concluded that in patients with FL, t(14;18) PCR is superior to CDRIII PCR in terms of sensitivity and specificity. A positive t(14;18) PCR during the first year post transplant is highly predictive for disease recurrence. CDRIII PCR may be used for monitoring in t(14;18) negative lymphomas. However, due to the poor specificity of conventional gel electrophoresis PCR, the use of clone-specific probes is highly desirable.

Adult↗
PubMed1998

Abrogation of graft-vs.-leukemia activity after depletion of CD3+ T cells in a murine model of MHC-matched peripheral blood progenitor cell transplantation (PBPCT).

Using a murine transplantation model, we simulated a clinical situation in which major histocompatibility complex (MHC)-identical allogeneic peripheral blood progenitor cells (PBPCs) are transplanted for the treatment of a malignant disease that is resistant to resting natural killer (NK) cells but sensitive to cytokine-activated NK cells and T cell-mediated antitumor activity. We determined the influence of selective T cell depletion of allogeneic PBPC grafts on graft-vs.-leukemia (GVL) activity and investigated the effectiveness of ex vivo treatment with NK cell-activating cytokines to compensate for the putative loss of T cell-derived factors stimulating natural cytotoxicity. After pretreatment of Balb/c (H-2d) recipients with 7.5 Gy of total body irradiation, 2x10(7) rhG-CSF-mobilized PBPCs of splenectomized syngeneic or MHC-identical DBA (H-2d) mice were transferred. Selective T cell depletion (TCD) was performed by immunomagnetic purging with a mononoclonal antibody directed against CD3. In some experimental groups, T cell-depleted PBPCs were incubated with 200 U/mL interleukin (IL)-2 and 100 U/mL IL-12 for 24 hours. To investigate antileukemic activity in vivo, recipient mice were inoculated with 1x10(5) A20 cells (a B-lymphoblastic leukemia of Balb/c origin) 2 days before PBPC transplantation (PBPCT). After transplantation of unmanipulated allogeneic cells, 25% of the animals died with signs of graft-vs.-host disease (GVHD) but 71% were free from relapse 100 days after PBPCT. After TCD of allogeneic grafts with anti-CD3, the incidence of GVH-related mortality was below 5% but the leukemia-free survival rate was significantly (p < 0.05) decreased to 25% and thus was similar to that observed after syngeneic PBPCT (17%). When CD3-depleted grafts were incubated with IL-2 and IL-12, 45% of the animals remained free from leukemia; however, the difference was not statistically significant. Our results suggest that ex vivo activation of residual NK cells with IL-2 and IL-12 does not fully compensate for the abrogation of GVL activity after depletion of CD3+ T cells from MHC-matched PBPCT.

Animals↗
PubMed1998

Immunotherapeutic aspects of allogeneic peripheral progenitor cells.

In a newly developed murine model of allogeneic peripheral progenitor transplantation (PBPCT) we investigated the immunotherapeutic potential of allogeneic peripheral stem cells. The following topics were addressed by our experiments: (1) comparison of the graft-versus-leukemia effect exerted by allogeneic PBPCT compared to allogeneic BMT; (2) the influence of T-lymphocytes on GVL activity; (3) the possibility to enhance the GVL activity of allogeneic PBPCT grafts by ex vivo cytokine incubation. Balb/c mice received cells of the syngeneic B-lymphatic leukemia A20 2 days prior to TBI (7.5 Gy) and the respective graft. The recipients received allogeneic bone marrow grafts or allogeneic peripheral progenitor cells obtained after mobilization of the donors (DBA/2) with either G-CSF in a dose of 250 microg/kg/day for 5 days. In some experiments T lymphocytes were removed by immunomagnetic depletion with CD3-coated beads. An additional group received T cell-depleted and IL-2/IL12-activated PBPCT grafts. The antileukemic activity of an allogeneic PBPCT graft was significantly greater than the antileukemic activity of an allogeneic BMT graft of the same size. Relapse rates were 80% in syngeneic PBPCT, 60% after allogeneic BMT and 34% after allogeneic PBPCT. This rise in antileukemic activity is not accompanied by a rise in GVHD mortality. Depletion of T lymphocytes by CD3-coated beads resulted in a nearly complete loss of the GVL activity with a relapse rate of 75%. Incubation of the T-depleted graft with IL-2 and IL-12 to enhance NK-based GVL activity has only limited success after MHC-matched transplantation with a relapse rate of 55%. Allogeneic PBPC exert a pronounced antileukemic effect. After MHC-matched PBPCT, this GVL effect resides mostly on the T cells of the graft. Ex vivo activation of T cell-depleted grafts by IL-2 and IL-12 is accompanied by an only limited reduction of relapse rate. PBPC are a valuable modality for primary transplantation in situations with high risk of relapse and for the treatment of relapse after BMT.

Animals↗
PubMed1998

Superior antileukemic activity of murine peripheral blood progenitor cell (PBPC) grafts mobilized by G-CSF and stem cell factor (SCF) as compared to G-CSF alone.

We have established a murine model to compare the antileukemic effect of PBPC grafts obtained after treatment with SCF + G-CSF and G-CSF alone. C57/BL6, DBA and Balb/c mice were splenectomized and injected with optimal doses of rhG-CSF (250 microg/kg/day s.c.) or rrSCF (100 microg/kg/day s.c.) or with a combination thereof. On day 5, we determined the hematopoietic potential (number of CD34+ cells, CFUs, total CFC, CFU-gm), the proportion of lymphoid (T, NK and B cells) and myeloid components and graft-versus-leukemia activity after allogeneic and syngeneic PBPCT and BMT in Balb/c mice bearing a B-lymphoblastic leukemia cell line (A20). The absolute number of progenitor cells increased two-fold after administering a combination of G-CSF and SCF as compared to G-CSF alone (1500 vs 940 CD34+ cells/microl; 190 vs 70 total CFC/microl; 150 vs 50 CFU-gm/microl and 6600 vs 3000 CFUs/ml). Although no differences could be detected in the cellular composition, especially in the number of T cells, PBPC grafts mobilized by the combination of G-CSF + SCF demonstrated significantly higher antileukemic activity compared to G-CSF alone (94% vs 71% freedom from leukemia, P < 0.05). Because the incidence of lethal GVHD was similar in both groups, improved GVL activity resulted in superior overall survival. Our data suggest that the higher number of progenitor cells can be harvested after G-CSF + SCF and that grafts mobilized by G-CSF + SCF exert significantly enhanced antileukemic activity compared to those harvested after treatment with G-CSF alone.

Animals↗
PubMed1998

Eradication of residual disease by administration of leukemia-specific T cells after experimental allogeneic bone marrow transplantation.

It is now well established that allogeneic lymphocytes can mediate a potent graft-vs.-leukemia (GVL) reaction when administered to bone marrow transplant (BMT) recipients. The benefit of allogeneic lymphocyte transfusion is limited because many patients develop graft-vs.-host disease (GVHD) with prolonged pancytopenia, which sometimes proves fatal. The object of the present study was to determine the antileukemic potential and GVHD risk of in vivo-generated tumor-specific allogeneic T cells given shortly after BMT. BALB/C (H-2d) mice were inoculated with different cell doses (10(5) and 5 x 10(5)) of the A20 leukemia (BALB/C origin) 2 days prior to lethal total-body irradiation (TBI) and transplantation of allogeneic, major histocompatibility complex (MHC)-matched DBA marrow grafts (H-2d, minor difference to BALB/C). Donors of BM grafts and T cells were allogeneic, MHC-matched mice (DBA, H-2d, minor difference to BALB/C). Donor-type T cells were generated from mice immunized with irradiated A20 leukemia cells or nonmalignant BALB/C splenocytes and restimulated in vitro. Whereas no significant immunotherapeutic effect was seen in mice with high tumor burden (5 x 10(5)), allogeneic BMT in mice inoculated with 1 x 10(5) A20 cells resulted in a modest antileukemic effect. This survival rate remained unchanged when 10(6) T cells obtained from donors immunized with nonmalignant BALB/C derived cells were given posttransplantation. In contrast, a single injection of 10(6) T cells from leukemia-immunized donors led to potent GVL effects without mediating clinically overt GVHD. Our data provide evidence for the hypothesis that minimal residual disease can be eradicated without inducing GVHD by administering small amounts of specific allogeneic cytotoxic T cells after BMT.

Animals↗
PubMed1997

Allogeneic peripheral blood progenitor cell transplantation in a murine model: evidence for an improved graft-versus-leukemia effect.

Peripheral blood progenitor cells (PBPCs) are increasingly being used to replace bone marrow cells (BMCs) as a source of hematopoietic stem cells also in the field of allogeneic transplantation. Whereas it is well known that PBPC grafts and BM differ significantly in progenitor cell content and lymphocyte dose, the clinical consequences of these differences with respect to engraftment, graft-versus-host disease (GVHD), and the graft-versus-leukemia (GVL) effect are more difficult to assess. We present a murine model that allows us to evaluate engraftment, GVHD, and GVL effect of allogeneic PBPC transplantation (PBPCT). Balb/c mice (H-2d) served as recipients. Donors were major histocompatibility complex-matched DBA/2 mice or syngeneic Balb/c mice, respectively. Experiments with increasing numbers of BMCs or Filgastrim-mobilized PBPCs showed that the number of progenitor cells in the graft was correlated with the probability to engraft, irrespective of the graft type. With identically high cell numbers transferred (1 x 10(9) nucleated cells/kg body weight [BW]), the mortality rates due to GVHD (25%) were about the same after allogeneic BM transplantation (BMT) and allogeneic PBPCT, although PBPC grafts contained four times more CD3+ T cells as compared with BM grafts (6.2 x 10(8) v 1.4 x 10(8)/kg BW). For investigation of GVL activity, Balb/c recipients were injected with syngeneic cells of the B-lymphocytic leukemia cell line A20 2 days before transplantation. After total body irradiation to a dose of 7.5 Gy, 1 x 10(9)/kg BW Balb/c PBPCs, DBA BMCs, or DBA PBPCs were infused. The relapse rates observed were 80% after syngeneic PBPCT (n = 22), 60% after allogeneic BMT (n = 23), and 34% after allogeneic PBPCT (n = 26) (allogeneic BMT v PBPCT, P = .032). We conclude that transplantation of allogeneic PBPCs instead of BM may enhance the GVL effect without an increase of GVHD.

Animals↗