Peripheral blood stem-cell transplantation in intensive treatment of multiple myeloma.
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Biomedical subjects
Publications and source records attributed to J Reiffers.
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Eighty-five adult patients under the age of 50 years with acute myeloid leukaemia (AML) were entered into a prospective controlled study conducted to compare the effectiveness of allogeneic or autologous bone marrow transplantation and intensive chemotherapy for patients in first complete remission. Sixty-one patients (72%) achieved complete remission then received a consolidation treatment. After consolidation, 58 patients who were still in remission were assigned to three different therapeutic modalities. Fifty-two patients were evaluable: 20 patients who had an HLA-identical sibling donor underwent allogeneic bone marrow transplantation within 3 months after achievement of complete remission; the other 32 patients were randomized to receive autologous bone marrow transplantation or intensive sequential chemotherapy. The actuarial risk of relapse at 3 years was 18% for the allogeneic patients, 50% for the autologous patients and 83% in the chemotherapy group. The difference was highly significant (P less than 0.0002). The disease-free survival was respectively 66% (95% confidence interval 41-85%), 41% (95% confidence interval 16-66%) and 16% (95% confidence interval 0-31%) (P less than 0.004). We conclude that allogeneic bone marrow transplantation is presently the best therapeutic approach for patients with AML in first complete remission.
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Seven years after a cadaver kidney transplantation a 33-year-old man presented with a monoclonal gammopathy secondarily complicated by AL amyloidosis mainly expressed as a sicca syndrome, gammopathy that ultimately developed into multiple myeloma. The mechanisms responsible for the occurrence of monoclonal gammopathy in renal transplant recipients are discussed.
High-dose cytarabine (HDARA-C) is an effective but toxic treatment for acute myeloid leukemia (AML). In order to reduce the incidence of severe complications noted with HDARA-C-containing regimens, we used a combination of intravenous (IV) idarubicin (IDARUB) at optimal dosage and cytarabine (ARA-C) at intermediate dosage. Thirty-five patients aged 23 to 78 years (median, 56) with AML in first relapse received IDARUB, 8 mg/m2/d for five days, and ARA-C, 1 g/m2 every 12 hours for six doses. Of the 35 patients, 21 achieved a complete remission (CR), four had a partial remission (PR), four died in aplasia, and six were nonresponders. The only factor influencing the CR rate was the duration of the first CR (35% for patients relapsing before 16 months v 83% for patients relapsing after 16 months, P = .003). Mucositis was the most significant extrahematologic side effect. Diarrhea, skin toxicity, and hepatic disturbances were rare and mild. There was no cerebellar toxicity, even in 25 patients greater than 50 years of age. This regimen is effective and well tolerated even in elderly patients, and could be used either as induction or consolidation therapy for the treatment of AML.
Thirty-two children ranging in age from 1.5 to 16 years with poor-prognosis acute lymphoblastic leukemia (ALL) were treated with myeloablative immunosuppressive therapy consisting of cyclophosphamide (CPM) and total body irradiation (TBI) followed by allogeneic bone marrow transplantation (BMT) while in first complete remission (CR). The main reasons for assignment to BMT were WBC count greater than 100,000/microL, structural chromosomal abnormalities, and resistance to initial induction therapy. All children were transplanted with marrow from histocompatible siblings. Twenty-seven patients are alive in first CR for 7 to 82 months post-transplantation (median, 30 months). The actuarial disease-free survival rate is 84.4% (confidence interval, 7.2% to 29%) and the actuarial relapse rate is 3.5% (confidence interval, 0.9% to 13%). Four patients died of transplant-related complications, 16 developed low-grade acute graft-v-host disease (GVHD), and six developed chronic GVHD. The very low incidence of relapse (one of 28 long-term survivors) precluded the determination of the prognostic significance of the different poor-outcome features. Moreover, two infants treated with busulfan, CPM, and cytarabine (Ara-C) relapsed promptly in the marrow. In summary, as a means of providing long-term disease-free survival and possible cure, BMT should be considered for children with ALL presenting poor-prognostic features, particularly certain chromosomal translocations [t(4;11), t(9;22)], very high WBC counts, notably if associated with a non-T immunophenotype, and, perhaps, a poor response to initial therapy with corticosteroids (CS), or infants less than 6 months of age.
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We have studied peripheral blood stem cells (PBSC) collected by cytapheresis following intensive chemotherapy, from 13 patients with acute leukemia, in long term culture (LTC). Peripheral blood was cultured with (n = 10) and without (n = 21) the addition of a preformed, irradiated stromal layer. In this latter LTC our results confirm that peripheral blood is capable of producing CFU-GM and nucleated cells in the absence of the formation of an adherent stromal layer. However, peripheral blood cultured in the presence of an irradiated stromal layer is capable of a significantly higher proliferative response (total production of CFU GM per flask - mean = 57529) than in the absence of an irradiated stromal layer (total production of CFU GM per flask - mean = 26739, p less than 0.03). Our results suggest that PBSC contain a primitive nonplastic adherent cell that requires the presence of a stromal layer for its expression. These findings provide further support for the use of peripheral blood stem cells for autologous transplantation.
Autologous blood stem cell transplantation (ABSCT) is a new technique which has been increasingly used in recent years. It is now well established that ABSCT can be performed as safely as autologous bone marrow transplantation (ABMT) when high numbers of hemopoietic precursors are infused. Multiple leukophoreses are performed during marrow regeneration following chemotherapy-induced aplasia. Hemopoietic recovery (predominantly the granulocytic series) is probably faster after ABSCT than after ABMT. Among other advantages there may be minimal contamination by residual tumor cells in buffy-coats; however, this has not been fully investigated.
A mouse IgG monoclonal antibody (MoAb) directed against the human LFA1 molecule (25.3 MoAb) was used in nine adult leukemic patients to prevent graft rejection after T cell-depleted HLA matched bone marrow transplantation. Based on the results of a previous study in children 0.1 mg/kg of 25.3 was given on days -3, -1, +1, +3, +5 in addition to a standard conditioning regimen with cyclophosphamide (120 mg/kg) and fractionated total body irradiation. The marrow transplant was T cell-depleted using T101 Fab immunotoxin ricin A chain. Seven patients received post-graft immunosuppression with methotrexate and cyclosporine A; two patients received no immunosuppression post-graft. A mean T cell depletion of 98.3% (80-100%) was achieved. Tolerance to the infusions of 25.3 MoAb was excellent. No patient developed any form of graft-versus-host disease. However two patients failed to engraft and three patients had delayed graft failures. These results show that this regimen of anti LFA1 MoAb, which was extremely good at permitting engraftment of HLA mismatched T cell-depleted transplant in children with constitutional diseases, is not able to prevent graft failure and rejection of T cell-depleted HLA matched transplants in adults with leukemia. Further efforts are needed to overcome graft failures in this clinical situation.
This article reports 18 cases of acute nonlymphocytic leukemia (ANLL) and abnormal chromosome 16. Thirteen had the same hematological pattern at diagnosis, i.e., peripheral blood hyperleukocytosis with high percentage of monocytes and blast cells, and bone marrow showing three different cell populations: (a) myeloblasts, (b) monocytes and promonocytes, and (c) abnormal eosinophils. In these cases the diagnosis was acute myelomonocytic leukemia with bone marrow eosinophilia, as described. However three other cases were of the M5 type and two others of the M2 type, all showing an abnormal eosinophilia in their bone marrow. All cases showed an abnormal chromosome 16 in the bone marrow cells: inv (16) in 13 cases, t (16;16) in two, del (16) in one of poor quality, and in two other translocations involving band 16q22. In one case the inv (16) was found in a subclone, indicating that it could be a secondary cytogenetic defect. Five patients died soon after diagnosis; the other 13 had a median complete remission duration of 8 months. The central nervous system was frequently involved upon relapse. We do not support the hypothesis that patients with M4-Eo ANLL and chromosome 16 abnormality have a favorable prognosis.
Thirty-eight patients with haematological malignancies were treated with bone marrow transplantation using histocompatible immunotoxin T cell-depleted marrow siblings. All patients received conventional postgraft immunosuppression (methotrexate and/or cyclosporin A). Donor bone marrow was treated ex vivo with T101 Fab fragment coupled to ricin A-chain (T101 Fab-RTA) at a concentration of 10(-8) M of A-chain in association with NH4Cl (2 x 10(-2) M) in pH adjusted (7.8) incubation medium. A median cytoreduction of 99.5% (91-99.5) was obtained. The median of follow-up was 300 days. Only three patients developed grade II acute graft-versus-host disease (GVHD) (actuarial rate of acute GVHD: 9.1%). No chronic GVHD occurred. All patients but one engrafted. Six out of the 37 patients developed a documented bone marrow rejection (actuarial rate of graft failure: 18%). Ten patients relapsed (actuarial rate of relapse: 36.9%). These findings demonstrate that treatment of donor marrow with T101 Fab-RTA in association with NH4Cl at critical pH value can achieve a high level of mature T cell depletion and greatly reduce the incidence of bone marrow rejection and relapse after T cell-depleted allogeneic bone marrow transplantation.
In a prospective study, 157 patients with prolonged aplasia (PMN less than 500/mm3 during more than 21 days), hospitalized in a protected environment unit, were randomly assigned to receive ceftazidime alone or cefotaxime + tobramycin for initial febrile episodes. Age, sex, underlying diseases, duration of neutropenia, digestive decontamination regimen, clinical and microbiological characteristics of infections were similar in the two groups. Patients were evaluated for their initial response to antibiotics (defervescence in 48 hours, maintained 7 days) and long term response (prevention of another infection during aplasia). The overall initial response to ceftazidime was 48/71 (68 per cent) and to cefotaxime + tobramycin 55/86 (64 per cent). The long term response to ceftazidime was 33/71 (46.5 per cent) and to cefotaxime + tobramycin 31/86 (36 per cent). In conclusion, ceftazidime alone was as effective as cefotaxime + tobramycin in the first line treatment of febrile episodes in neutropenic patients.
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Six patients with acute non-lymphocytic leukemia underwent autologous transplantation of circulating stem cells collected during remission. They were given cyclophosphamide (120 mg/kg) and total body irradiation (1,000-1,200 rads) (five patients) or busulfan (16 mg/kg) and melphalan (140 mg/m2) before the transfusion of 6.7 X 10(8) nucleated cells/kg corresponding to 19.7 X 10(4) CFU-GM/kg. Granulopoietic engraftment was observed in every case and was influenced by the number of CFU-GM injected. Megakaryocytic recovery was obtained in four cases.