[Strategies in the treatment of acute granulocytic leukemias].
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Adolescent↗
Biomedical subjects
D Maraninchi
Publications and source records attributed to D Maraninchi.
Partial chimerism after T-cell-depleted allogeneic bone marrow transplantation in leukemic HLA-matched patients: a cytogenetic documentation.
We evaluated serially by cytogenetics the blood and marrow chimerism of 38 leukemic recipients of HLA-matched bone marrow transplants (BMT) who were prepared by high doses of alkylating agents and fractionated total-body irradiation (2.2 Gy X 5). Donor or host mitoses were identified by examination of sex chromosomes in 32 patients or by evaluation of the polymorphism of other chromosomes after specific banding in six patients. Twenty-four patients were recipients of untreated BMT, and 14 were recipients of T-cell-depleted BMT. In the 24 patients who received untreated BMT, all showed successful engraftment, and only three had a transient mixed chimera. In the 14 recipients of T-cell-depleted BMTs, four rejected their grafts, and seven had mixed chimeras; these mixed chimeras were more frequent in blood lymphocytes than in marrow cells and could be detected up to 26 months after BMT. This high frequency of partial chimerism after T-cell-depleted BMT by comparison with a control group suggests that the donor's T cells play an important role in the eradication of host residual hematopoiesis after allogeneic BMT.
Adolescent↗
Impact of T-cell depletion on outcome of allogeneic bone-marrow transplantation for standard-risk leukaemias.
71 leukaemic patients having HLA-matched bone-marrow transplants (BMT) were randomised to receive whole marrow (group A) or marrow depleted of T cells by treatment with monoclonal antibodies (anti CD4-CD5-CD8, group B; anti CD2-CD5-CD7, group C) plus complement. All patients received cyclophosphamide and total body irradiation before transplantation and cyclosporin after BMT. Marrow treatment removed 97% of T cells (median) in group B and 99% in group C. Although both serious and mild graft-versus-host disease (GVHD) were reduced in T-cell depleted patients, graft failure and relapse were increased. Graft failure was caused by GVHD and transplant complications in the controls and by rejection and relapse in the T-cell depleted groups; relapse-free survival did not differ between the groups. Without better control of host immunity and of the residual leukaemia T-cell depletion of the marrow, BMT should not be pursued in standard-risk patients.
Adolescent↗
The value of splenectomy in chronic lymphocytic leukemia.
Between January 1, 1980, and July 31, 1985, 168 patients were treated at our institution for chronic lymphocytic leukemia (CLL). Splenectomy was performed on 32 (23 men and 9 women). The mean age of these surgical patients was 59.4 years (range, 43-75). Twenty-four patients had received chemotherapy and/or corticotherapy prior to surgery and 1 of these 24 also underwent splenic radiotherapy. The interval between diagnosis and splenectomy ranged from 1 to 108 months (mean, 33.6 months +/- 28.6). Before splenectomy, 9 patients had platelet counts greater than 100,000/mm3 (3 with normal counts), 18 had counts between 50,000 and 100,000/mm3, and 5 had less than 50,000/mm3. Seven patients had anemia with hemoglobin levels less than 10 g/dl (3 associated with thrombocytopenia); in the other 25 patients, hemoglobin levels were between 10 and 11 g/dl in 12 (9 associated with thrombocytopenia) and greater than 11 g/dl in 13. All patients but one had splenomegaly (mean spleen weight 1780 g +/- 938.7 range, 160-4300 g). One postoperative death was recorded. Postoperative morbidity occurred in 7 of 31 cases; severe infection was never observed. The average duration of hospitalization was 15 +/- 4.7 days (range, 9-28). Twenty-two of the 23 patients with thrombocytopenia less than 100,000/mm3 had complete remission after splenectomy. One had a partial remission that was later completed by means of drug therapy. Two patients relapsed within 6 months and one after 32 months. All but two cases of anemia responded to splenectomy; one patient relapsed. In 15 of 31 surviving patients, further treatment was required within a few weeks or months after surgery. Five patients died at 8, 17, 22, 26, and 35 months, respectively. The other 26 patients are alive and well with a mean follow-up of 34 months (range, 11-71 months). Splenectomy may be an effective treatment for CLL patients with splenomegaly, thrombocytopenia, and/or anemia.
Adult↗
Bone marrow transplantation for chronic granulocytic leukemia: results of the French Cooperative Group (GEGMO).
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Adult↗
Treatment of acute myeloid leukemia and blastic phase of chronic myeloid leukemia with combined eflornithine (alpha difluoromethylornithine) and methylglyoxal-bis-guanyl hydrazone (methyl-GAG).
A combined eflornithine-MGBG treatment was studied in patients with acute myeloid leukemia (AML) or blastic transformation of chronic myeloid leukemia (BT CML). The first ten patients (5 AML, 5 BT CML) received i.v. or p.o. eflornithine 6 g m-2 day-1 and i.v. MGBG 500 mg/m2 once a week. The duration of treatment was 5-37 days (median 15) with one to five MGBG infusions (median 2). The results were complete response (CR) in one patient, partial response (PR) in four, minimal response (MR) in one and failure (F) in four. Pronounced side effects, including severe mucositis, gastrointestinal disturbances and skin infiltration, were observed in eight patients. As the four PRs were achieved in patients with BT CML, it was decided also to study ten patients with this indication. In attempts to decrease the incidence and severity of unwanted effects, lower doses of eflornithine-MGBG were used, i.e., eflornithine 4 g m-2 day-1 and MGBG 200 mg m-2 once a week. The duration of treatment was 9-110 days (median 46), with 2-14 MGBG infusions (median 6). Responses observed were CR in two patients (in one of whom it was only transient), transient PR in two, transient MR in four, and F in two. Treatment at lower doses was better tolerated, thus allowing a longer duration of treatment. Five of ten patients had moderate or severe gastrointestinal disturbances and one patient had a severe subjective hearing loss. The eflornithine-MGBG combination may prove to be a useful alternative treatment for AML and BT CML, but comparative trials will ultimately be necessary for a more definitive assessment of the combination.
Adult↗
Generation of CD8 cytolytic T cells early after autologous or allogeneic bone marrow transplantation.
Longitudinal in vitro assays related to cell-mediated immunity were performed in patients following allogeneic (32) or autologous (15) bone marrow transplantation (BMT). In both groups of reconstituted patients, low CD4+/CD8+ T cell ratio and weak allogeneic mixed lymphocyte reactions were found in the first 6 months after BMT, progressively reaching values similar to controls (bone marrow donors or unrelated individuals). In contrast, a strong generation of allogeneic cytotoxic cells, assessed by the number of lytic units per 10(6) cells, was frequently found (18/38 patients tested in both groups) in the first 4 months, despite the quantitative deficit of the CD4+ subset. This in vitro differentiation was found to be independent of in vivo acute graft-versus-host disease (GVHD) and chronic GVHD in allo-transplanted patients. As also documented in autologous recipients, this observation suggests that this phenomenon could be, at least partially, related to the transplantation per se. Preliminary characterization of the effector cells indicates that they belong to the CD8+ subset and that their differentiation is interleukin-2-dependent. Experimental depletion of the CD4+ subset in normal subjects did not increase the number of lytic units in allogeneic cultures. This implies qualitative differences between BMT recipients and normal subjects, namely in CD8+ subset: i.e. that following BMT early CD8+ T cells appear to produce their own growth factor (IL-2), while in normal adult individuals, such autocrine CD8+ T cells, if present, are very rare.
Antigens, Differentiation, T-Lymphocyte↗
Cytogenetic evidence of partial chimerism after T cell-depleted allogeneic bone marrow transplantation in leukemic HLA-matched patients.
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Adolescent↗
[Allogenic bone marrow grafts in acute myeloid leukemias. A retrospective study in 111 grafted patients in first complete remission].
Between 1978 and 1984, in 13 French Transplant Centers, 111 patients with acute myelogenous leukaemia underwent allogeneic bone marrow transplantation while in first complete remission. The conditioning regimen consisted of cytoxan 60 mg/kg X 2 and 10 Gy total body irradiation. To prevent graft-versus-host disease, 75% of the patients were given methotrexate and 25%, cyclosporine A. The probability of remaining in complete remission was 61% at 5 years. The probability of survival was 43% at 5 years, with a plateau between 2.5 and 6 years. The most frequent causes of death were interstitial pneumonia, relapses and graft-versus-host disease. Relapses were more frequent in cases with M 4-5 cytology than in those with M1 to M3 cytology (P less than 0.01). Transplant-related deaths were mainly consecutive to graft-versus-host disease and its facilitating effect on pneumonia (P less than 0.05). These results indicate that bone marrow transplantation can cure a large proportion of patients with acute myelogenous leukaemia, especially AML subtypes without monocytic differentiation. Improvements in conditioning regimens for the M 4-5 subtypes and in prevention of graft-versus-host reaction and cytomegalovirus infection should give rise to further developments in this field.
Adolescent↗
Treatment of malignant lymphoma with high dose of chemo or chemoradiotherapy and bone marrow transplantation.
Twenty-eight patients with malignant lymphoma were treated with high dose chemo or chemoradiotherapy and allogeneic or autologous bone marrow transplantation. They can be divided in two groups: Group 1: (19 pts) consisted in patients in relapse or in n complete remission (n greater than 2) (high risk patients); Group 2 (9 pts) consisted in patients in first or second complete remission at time of bone marrow graft (standard risk patients). Complete remission was achieved in 11/17 patients evaluable for response (65%). Duration of response is very different for two groups: in group 1, all patients relapsed within a median of 2 months (range: 1-12) and died within a median of 7 months (range: 2.5-15). In group 2, 7/9 are alive and well in unmaintained CCR in a median of greater than 18 months (range: greater than 15- greater than 36) (P less than 0.01). This experience shows the feasibility of this approach, the obvious antitumoral activity of these conditioning regimens and invited us to use such therapy at an earlier stage of the disease.
Adolescent↗
High dose chemotherapy and autologous bone marrow transplantation in refractory Hodgkin's disease.
Seventeen patients with Hodgkin's disease (HD) were treated with high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT). Eleven patients were resistant to initial therapy. Three patients had relapsed and were still responders to second or third line therapy. Three patients had relapsed but were progressing under second or third line therapy. Pre-ABMT chemotherapy included high dose cyclophosphamide in all patients (50 mg Kg-1 day-1 bolus for 4 days), most often associated with BCNU or CCNU, aracytine and 6 thioguanine. Four patients received additional TBI (10 Gy). In 9 patients complete remission (CR) was achieved, 4 failed to respond and 4 cases were not evaluable due to early death. Among CR patients, 2 died from late toxicity, 4 relapsed between the 2nd and 5th months, but 3 patients remain in CR, off therapy at 25+, 43+, and 66+ months, including 1/11 initially resistant and 2/6 who had relapsed. There were 9 treatment related deaths: 6 due to infection, 1 cardiac failure and 2 multiorgan failure. The high complete response rate in these heavily pretreated patients suggests that there may be an indication for high dose therapy earlier in resistant HD. Moreover under such conditions, treatment related morbidity would be expected to be lower.
Adolescent↗
Autologous bone marrow transplantation for acute leukaemia in remission.
Between 1980 and 1985, 175 patients with acute leukaemia in first or subsequent complete remission (CR) were treated by chemotherapy or chemoradiotherapy followed by transfusion of autologous bone marrow cells that had been collected days or months previously. In 85 cases, autologous marrow cells were treated ex vivo with cytotoxic drugs or monoclonal antibodies with the intention of removing residual leukaemic cells. The actuarial relapse-free rate was 52% at 2 years. Of 89 patients autografted for acute non-lymphocytic (myeloid) leukaemia (ANLL), 60 were treated in first remission and 18 in second CR; their relapse-free rates at 2 years were 67% and 41% respectively (P less than 0.001). In contrast, of 77 patients autografted for acute lymphoblastic leukaemia (ALL), 32 were treated in first CR and 28 in second CR and their actuarial relapse free rates at 2 years were 56% and 55% respectively (P = NS). There was no significant difference in leukaemia relapse rates between patients autografted with purged and those autografted with non-purged marrow cells. These preliminary results suggest that autologous bone marrow transplantation may be valuable if offered to patients with ANLL in first CR or to patients with ALL in first or second CR but the need for marrow purging remains uncertain.
Acute Disease↗
Marrow transplantation for non-Hodgkin's lymphoma: a multi-centre study from the European Co-operative Bone Marrow Transplant Group.
Twenty-five patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) were treated by allogeneic bone marrow transplantation. For the nine patients transplanted in first complete remission the disease-free survival was 100%; of the nine patients transplanted in subsequent remissions four (44%) achieved long-term disease-free survival but two died of relapsed lymphoma. For the seven patients transplanted at a time when they had active disease, the initial complete remission rate was high but four died of progressive lymphoma and no patient achieved long-term disease-free survival. The incidence of complications associated with allogeneic bone marrow transplantation was similar to that observed in other series of patients transplanted for haematological malignancy and was related to the status of the disease at the time of transplant. Thus allogeneic bone marrow transplantation is a radical but effective treatment for patients with NHL who have 'minimal residual disease'. Efforts to define further the subset of patients who can most successfully be treated by transplantation may improve the overall results.
Adolescent↗
High-dose melphalan with or without marrow transplantation: a study of dose-effect in patients with refractory and/or relapsed acute leukemias.
Dose-effect relationships of high-dose melphalan were evaluated in 37 patients with measurable relapsed or refractory acute leukemias. Thirteen patients (Group 1) received 70-100 mg/m2 of melphalan without marrow rescue and 24 patients (Group 2) received 140-180 mg/m2 of melphalan followed by marrow transplantation. Patients in both groups were comparable with respect to age, sex, diagnosis, and status of the leukemia. The complete remission rate was 23% in Group 1 versus 75% in Group 2 (P less than 0.01). Hematological recovery of remission patients was not statistically different in either group. Nonhematological toxicity was comparable in the two dose ranges examined. These results demonstrate the existence of a dose-response effect of high-dose melphalan regimens in relapsed acute leukemias, without marked increases in nonhematological toxicity with these doses.
Acute Disease↗
Modified chemotherapy with carmustine, cytarabine, cyclophosphamide, and 6-thioguanine (BACT) and autologous bone marrow transplantation in 24 poor-risk patients with acute lymphoblastic leukemia.
Twenty-four poor-risk patients with acute lymphoblastic leukemia received a modified regimen of carmustine, cytarabine, cyclophosphamide, and 6-thioguanine (BACT) followed by autologous bone marrow transplantation (ABMT). Nineteen patients were in second or subsequent complete remission (CR) when treated with this regimen; 3 died early, 2 died of pneumonia in CR, 11 relapsed within 3 months (median), and 3 remain in CR with no maintenance therapy 14-24 months after ABMT. Of the 5 patients with measurable disease who were treated, 3 had CR and 1 remains in CR without maintenance therapy more than 28 months after ABMT. The toxicity of this regimen was acceptable, but late pulmonary toxic effects remain a major concern. These results are poor in terms of efficacy, and new effective methods of eradicating acute lymphoblastic leukemia in patients with poor prognosis should be investigated.
Adolescent↗
Autografting for chronic granulocytic leukemia in transformation.
Forty-five patients were treated for chronic granulocytic leukemia (CGL) in transformation by intensive chemotherapy (23 patients) or radiochemotherapy (22 patients) followed by autologous transplantation of bone marrow (17 patients) or blood-derived hematopoietic stem cells (28 patients). Hematopoiesis was reestablished in most evaluable patients and was significantly more rapid in previously splenectomized patients or in those receiving more than 10 X 10(8) nucleated cells/kg. However, partial or complete failure of engraftment was observed in 11 patients, in most cases after autografting with marrow cells. The median survival of all patients was 4.5 months. The major cause of death was the rapid recurrence of the blast cells not eradicated by the conditioning regimen. However, 4 of the 11 patients treated during the accelerated phase are still alive in the chronic phase, 17, 23, 35, and 54 months after autografting. These results and the restoration of hematopoiesis without the Philadelphia chromosome in 5 patients suggest that autografting could be used in CGL before the onset of the blast crisis.
Adult↗
[Chromosome polymorphism in allogeneic bone marrow grafts. Methods and results].
Cytogenetic studies using constitutive heterochromatin variations represent one of the best method in documentation of allogeneic bone marrow transplantation (BMT). Sex mismatched transplants are evaluated by gonosomal examination. In sex matched patients, several banding techniques are performed before BMT to detect autosomal polymorphism in donor and recipient. Can be informative: chromosomes 3 and 4 centromere, acrocentric centromere and satellites, chromosomes 1, 9 and 16 secondary heterochromatic constriction. Authors describe their methodology for these studies and results about 81 patients.
Bone Marrow Transplantation↗
[Allogeneic bone marrow transplantation in acute lymphoblastic leukemia of children. Analysis of prognostic factors. GEGMO (Bone Marrow Study Group) study].
Sixty-five children with acute lymphoblastic leukemia (ALL) underwent allogenic bone marrow transplantation (BMT) from an HLA identical donor, following cytoreduction with cyclophosphamide and total body irradiation (TBI): 15 were transplanted in 1st remission, 43 in 2nd and 7 in 3rd or in 4th. The Kaplan Meier estimate of surviving disease free at 4 years post BMT was 49.9% and the probability of continued remission at 4 years was 63.3%. Fourteen patients relapsed between 90 and 690 days (mean: 240 +/- 88) post BMT. The other causes of BMP failure included: graft versus host disease, veno-occlusive disease and sepsis. No interstitial pneumonitis has been reported. Patients who had a relapse while on chemotherapy had a higher probability of relapse than those who had a relapse while off therapy (p less than 0.01). We conclude that allogeneic BMT is the treatment of choice for children with ALL in second hematologic remission, the interval between diagnosis and first relapse being the most significant prognostic factor. Patients with poor prognosis might benefit from a more intensive chemotherapy/total body irradiation schedule or a BMT earlier in the course of their disease.
Adolescent↗