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T de Witte

Publications and source records attributed to T de Witte.

At least 19 recordsLinked to original sources
PubMed1995

Expansion of CD8+CD57+ T cells after allogeneic BMT is related with a low incidence of relapse and with cytomegalovirus infection.

Peripheral blood lymphocytes of 46 recipients of lymphocyte-depleted bone marrow allografts were phenotypically analysed over a period of 1 year. We investigated the repopulation of lymphocyte subpopulations and their relation with clinical parameters such as graft-versus-host disease (GVHD), graft-versus-leukaemia and cytomegalovirus (CMV) infection. The number of repopulated T cells varied strongly between the blood samples of the recipients. In 45% of the recipients the number of T cells recovered to or above normal levels within 3 months after bone marrow transplantation (BMT), whereas the other recipients remained below normal up to 1 year after BMT. In recipients with a high repopulation, the CD8+ T-cell subset contributed more to this high repopulation than the CD4+ T-cell subset. We showed that the majority of T cells of these recipients expressed the alpha beta T-cell receptor, CD8, CD57 and CD11b. HLA-DR was also highly expressed reflecting the activation stage of T cells in these recipients. BMT recipients with a high repopulation of CD8+ T cells showed a lower incidence of leukaemic relapse than recipients with a low repopulation. The 3-year probability of relapse was 19% versus 64% (P = 0.03), respectively. The relative high number of CD8+ T cells at 3 months after BMT was not associated with the incidence of GVHD. In contrast, occurrence of CMV infection after BMT was significantly higher in these recipients. Our results indicate that CD8+ T cells, predominantly CD57+, of BMT recipients with an expansion of these cells represent an in vivo activated cell population. This CD8+ T-cell population may consist partially of cytotoxic cells with anti-leukaemic activity as suggested by a low relapse rate. The signal for the strong expansion of these CD8+CD57+ T cells after BMT is still unclear, but association with CMV infection suggests that viral antigens are involved.

Adolescent↗
PubMed1995

Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) following MDS of more than 6 months duration. A pilot study by the Leukemia Cooperative Group of the European Organisation for Research and Treatment in Cancer (EORTC-LCG).

We conducted a prospective, multicenter pilot study of remission induction therapy in patients with poor prognosis MDS and AML evolving from a preceding phase of MDS. Fifty evaluable patients from 15 institutions were treated with one or two remission-induction courses consisting of i.v. idarubicin 12 mg/m2/day on days 1, 2, and 3 combined with a continuous i.v. infusion of cytarabine of 200 mg/m2/day on days 1 to 7. Of the 27 complete remitters (54%), 23 received a consolidation course which was identical to the remission-induction course except for the idarubicin 12 mg/m2 which was given on day 1 only. Fifteen patients received maintenance therapy consisting of six courses of cytarabine 10 mg/m2, s.c. twice daily, for 14 days. Two complete remitters were allografted and five patients received an ABMT. The median survival of all 50 treated patients was 14 months. The median duration of disease-free survival was 11 months with two patients in CR more than 2 years after entering CR. Twenty-four of the 27 remitters have relapsed. Four patients died during remission-induction therapy, but no patient died as a result of persisting hypoplasia. No fatal complications occurred during the consolidation and maintenance courses. Age and stage of disease had no significant impact on CR rate nor on remission duration. The CR rate was significantly (P = 0.03) higher in patients with only normal metaphases compared to patients with cytogenetic abnormalities. The DFS at 2 years was 33 vs 8%, respectively, for patients without or with cytogenetic abnormalities (P = 0.02). This study shows that patients below the age of 60 years with poor risk features are candidates for treatment with combination chemotherapy. A complete remission rate of more than 50% may be expected. Maintaining remission after remission-induction chemotherapy is a difficult issue. Patients not eligible for allogeneic BMT may be treated with intensive post-remission chemotherapy or autologous BMT.

Adolescent↗
PubMed1994

Effect of isotype on internalization and cytotoxicity of CD19-ricin A immunotoxins.

We analyzed the effect of isotype variation on effectiveness of B-cell CD19 immunotoxins (IT) by using class switch variants (CLB-B4-IgG1 and CLB-B4-IgG2a) conjugated to ricin A. Notably, IgG1-IT appeared to be approximately 100-fold more potent than IgG2a-IT toward B-cell lines Daudi and KM3. Binding and internalization studies with 125I-labeled monoclonal antibodies (mAbs) revealed a higher cellular uptake of IgG1 compared to IgG2a, despite similar binding affinities. Following removal of the Fc part, both mAbs internalized at the same rate as IgG2a, indicating that the Fc part of IgG1 is involved in enhanced cellular uptake. The involvement of Fc gamma RII (CD32) in this process was demonstrated by a decreased cytotoxicity of IgG1-IT (and not IgG2a-IT) in the presence of Fc gamma RII-blocking mAbs AT10 or IV.3. To identify the isoform responsible for this phenomenon, internalization of IgG1 and IgG2a in 11 B-cell lines and malignant B-cells of 8 patients was compared with expression of Fc gamma RII subclasses. In addition to four cell lines (Daudi, KM3, Nalm6, and Raji), the malignant B-cells of two patients showed enhanced uptake of IgG1 relative to IgG2a. Only the Fc gamma RIIa transcript was found in all B-cells. Furthermore, enhanced uptake of IgG1 correlated with rosetting of erythrocytes sensitized with anti-glycophorin A mAb of IgG1 isotype rather than with Fc gamma RIIa membrane expression levels. These data support the idea that functional Fc gamma RIIa is involved in the enhanced IgG1 uptake observed in a subset of B-cells. Our study, therefore, points to an important role for the Fc region of IT in the delivery of cytotoxic effects.

Antibodies, Monoclonal↗
PubMed1994

Primitive multilineage progenitor cells predominate in peripheral blood early after mobilization with high-dose cyclophosphamide and GM-CSF or G-CSF.

The change in phenotype, number and proliferative capacity of peripheral blood hematopoietic progenitors (PBHP) was studied in six patients with multiple myeloma during hematopoietic recovery after mobilization with high-dose cyclophosphamide and GM-CSF or G-CSF. In all six patients the first CD34+ cells appearing in the peripheral blood (PB) after cytoreductive treatment were predominantly CD34+/33- (> 70%). At later stages when leukapheresis procedures were started, the CD34+/33+ cells predominated in five of six patients. In leukapheresis harvests of peripheral blood, and in bone marrow addition of SCF and IL-6 to the culturing medium enhanced the plating efficiency. In peripheral blood an increase from 12 to 22% for CD34+/33+ and from 6 to 14% for CD34+/33- was observed. In normal bone marrow we observed an increase from 15 to 23% for CD34+/33+ and from 7 to 17% for CD34+/33-. Highly proliferative progenitors (>500 cells) in the CD34+/33- fraction appeared to be dependent on the addition of 'stem cell recruiting factors' (SCF and IL-6); in bone marrow the percentage of wells with >500 cells increased from 0.9 to 12.6% after SCF+IL-6 and in PBHP from 2 to 9%. We conclude that the first progenitors appearing in the peripheral blood after priming with high-dose cyclophosphamide and GM- or G-CSF have a more primitive immunophenotype, CD34+/33-.

Adult↗
PubMed1992

Cytotoxicity of CD3-ricin A chain immunotoxins in relation to cellular uptake and degradation kinetics.

The cytotoxicity of WT32 (CD3)-ricin A immunotoxin (IT) to the acute lymphoblastic leukemia T-cell line Jurkat was compared with the rate of internalization and intracellular degradation of WT32 and WT32-ricin A during continuous exposure. Moreover, the influence of NH4Cl and monensin on these processes was studied. Based on protein synthesis inhibition ([3H]leucine incorporation), it appeared that cytotoxicity was not fully expressed directly after exposure to IT due to a delay in either the internalization of membrane-bound IT or the action of intracellular ricin A. Varying the duration of incubation and postponing [3H]leucine addition for up to 24 h after initiation showed that cytotoxicity occurred in two phases, rapid internalization of initially bound IT followed by a continuous but slower uptake, possibly due to reexpression of the CD3 antigen. No differences were found in the rate of internalization and degradation of 125I-labeled WT32 and WT32-ricin A. Internalization started rapidly after binding at 37 degrees C, was fastest during the first 12 h (+/- 360,000 molecules/cell), and continued for at least 24 h (+/- 420,000 molecules/cell). Exocytosis of intracellularly degraded molecules became measurable after 1 to 2 h of incubation at 37 degrees C and increased to approximately 400,000 molecules/cell in 24 h. After 4 h of incubation at 37 degrees C the number of internalized molecules exceeded the amount of WT32 that could maximally bind to the cell membrane (+/- 150,000 molecules/cell), confirming reexpression of antigen. The addition of NH4Cl and monensin enhanced the cytotoxicity of WT32-ricin A, probably due to an increased intracellular amount of IT. These agents appeared to reduce strongly the degradation of internalized WT32, resulting in an accumulation of intracellular molecules. NH4Cl was most effective during the first 12 h of incubation, whereas monensin increased the amount of intracellular WT32 molecules after 2 to 24 h. Our observations suggest that incubation conditions for the optimal cytotoxicity of IT treatment can be predicted by studying the internalization and degradation of the IT or respective monoclonal antibody.

Ammonium Chloride↗
PubMed1992

Treatment of myelodysplastic syndromes (MDS) and high leukaemic risk with low-dose cytosine arabinoside (LD-AraC) plus granulocyte-macrophage colony-stimulating factor (rh GM-CSF). The EORTC Leukaemia Group.

Symptomatic patients with myelodysplastic syndromes (MDS) and 10-30% blasts in the bone marrow were treated with low-dose AraC (2 x 10 mg/m2 subcutaneously (sc) days 1-14) and GM-CSF (fully glycosylated, Sandoz/Schering-Plough, 2 x 150 micrograms protein/day sc) given either subsequently (days 15-21) or simultaneously (days 8-14 and one week rest). Evaluations were carried out after three courses (nine weeks); responding patients could be continued for two further cycles. Eighty-two patients with refractory anaemia and excess of blasts (RAEB), with (RAEBt) or without transformation, were evaluable: 45 RAEB and 37 RAEBt, mean age 64 years (range 17-80 years). A complete remission was achieved in 14 cases (17%), 11 had a good response (13%), and 12 a partial response (15%). Stable disease was found in 21 cases (26%). There were 12 cases of toxic death (15%), progression was noted in eight patients (10%), and death due to disease in three (4%). No difference existed between the two treatment arms with respect to response. Major adverse events during treatment were haemorrhage (25%), infections (23%), and fever with GM-CSF (21%). GM-CSF did not induce leukaemia nor contribute to haemorrhage induced by AraC, but gave rise to an overall response rate of 46% which is high and relatively durable as compared to other treatments in this disease.

Acute Disease↗
PubMed1992

Influence of the conditioning regimen on erythrocyte chimerism, graft-versus-host disease and relapse after allogeneic transplantation with lymphocyte depleted marrow.

Three different conditioning regimens were applied to 144 patients undergoing allogeneic bone marrow transplantation (BMT) with HLA identical sibling marrow, depleted of lymphocytes by counterflow centrifugation. All regimens consisted of cyclophosphamide and fractionated total body irradiation (TBI). In 49 patients treated with regimen A the total TBI dose was 9 Gy. In regimen B the dose rate of TBI was increased and anthracyclines were added (n = 65). Thirty patients received regimen C with a total TBI dose of 12 Gy but no anthracyclines. The different conditioning regimens did not influence the percentage of patients with detectable recipient CFU-GM prior to infusion of donor marrow. The incidences of mixed erythrocyte chimerism at 6 months after BMT were 73, 33 and 20% for regimens A, B and C respectively. The conditioning regimen influenced significantly mixed erythrocyte chimerism from 6 to 24 months after BMT. Both age and the conditioning regimen influenced significantly the incidence of acute graft-versus-host disease (GVHD) (p = 0.017 and 0.0001 respectively). Acute GVHD greater than or equal to I occurred in 15, 29 and 77% of the patients treated with regimens A, B and C respectively. The incidence of acute and chronic GVHD was significantly higher in complete donor chimeras than in mixed chimeras (p less than 0.001 and p less than 0.01). The probability of relapse was 43% in 32 and 18% in 43 good risk patients treated with regimens A and B respectively (p = 0.07). Longer follow-up is needed to draw conclusions about relapse in regimen C.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

No advantage for patients who receive splenic irradiation before bone marrow transplantation for chronic myeloid leukaemia: results of a prospective randomized study.

A total of 239 patients with chronic myeloid leukaemia (CML) in chronic phase awaiting bone marrow transplantation (BMT) from an HLA-identical sibling donor were randomized to receive, as part of their conditioning, splenic irradiation (SI+) or no splenic irradiation (SI-). There was no difference between the SI+ and SI- groups regarding the distribution of age, sex, donor/recipient sex combination and blood counts at diagnosis and at BMT. Survival, leukaemia-free survival (LFS), incidence of transplant-related mortality, incidence of rejection and probability of relapse do not differ between the 117 SI+ and the 118 SI- patients at a median follow-up time of 2.5 years (minimum 0.5 years). LFS at 30 months is 56% (SE 5%) for the SI+ and 51% (SE 6%) for the SI- group (p = 0.65). LFS is better for younger patients (less than 25 years), for patients without T cell depletion and for those with a low white blood cell count at diagnosis (less than 30 x 10(9)/l) (p less than 0.05). It is worst for male recipients of a female marrow (p less than 0.05). The incidence of graft-versus-host disease grade greater than or equal to II was higher in the SI+ group, though not significantly. We conclude that routine splenic irradiation prior to BMT for patients with CML is of no benefit and should not be used as a routine procedure.

Adolescent↗
PubMed1992

Bone marrow transplantation for acute myeloid leukemia: the EBMT experience. A prospective analysis from HLA-typing. The EMBT Leukemia Working Party.

In 1990, 4,234 BMT were performed in Europe; 2,097 autologous BMT (388 AML) and 2,137 allogeneic BMT (494 AML). Although an established therapy with leukemia free survival (LFS) at five years of 41% +/- 5% (EBMT results) its value compared to alternative therapies remains controversial. During the year 1985, the EBMT conducted a prospective evaluation study. In 12 centres 168 patients with AML were registered at the time of HLA-typing. Basic patient data and treatment intention were recorded. 79 patients were HLA-typed at diagnosis. 68 patients in 1st CR and 21 at other stages. Follow-up of these patients was obtained as of January 1, 1991. Three-year LFS is 44% for patients with an HLA-identical donor and 21% for those without (p = 0.02). Of the 68 patients HLA-typed in first CR, 40 had an HLA-identical donor and 28 no donor. Three-year LFS is 42% and 35%. resp. (n.s.). The difference in results between patients typed at diagnosis and first CR patients illustrates the problem of selection. We conclude that patient registration early in the disease can give insight into the process of selection. Allogeneic BMT incorporated prospectively at diagnosis into therapy offers a survival advantage for patients in this age category compared to alternative therapies.

Acute Disease↗
PubMed1990

Clinical and physical aspects of total body irradiation for bone marrow transplantation in Nijmegen.

Eighty-nine patients were transplanted with allogeneic bone marrow after a standard conditioning regimen consisting of cyclophosphamide and fractionated total body irradiation (2 x 4.5 Gy) with average dose rates of 4.1 and 12.3 cGy/min, respectively. The average rectum and lung dose was 9.2 +/- 0.45 and 7.5 +/- 0.78 Gy. In vivo dosimetry was performed in 71 patients irradiated with 18 MV X-rays from left and right lateral. Forty-three patients (48%) died. After increasing the dose rate the incidence of interstitial pneumonitis increased, but the number of relapses decreased.

Adolescent↗