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PubMed1994

High-dose therapy and autologous bone marrow transplantation in first complete remission for adult patients with high-grade non-Hodgkin's lymphoma: the EBMT experience. Lymphoma Working Party of the European Group for Bone Marrow Transplantation.

One hundred and eighteen patients presenting with high-grade non-Hodgkin's lymphoma, undergoing autologous bone marrow transplantation (ABMT) in first complete remission (CR), have been reported to the European Group for Bone Marrow Transplantation (EBMT). Of these, 102 were eligible for inclusion in this study following review of registration forms. Patients with lymphoblastic lymphoma were excluded. Remission induction and high-dose regimens varied between contributing centres. A maintained CR was observed in 90% of patients. Early relapse was observed in 6%, and 4% suffered toxic deaths. With a median follow-up of 45 months (3-112 months), the 5-year actuarial overall and progression-free survivals are both 70%. Nineteen (18%) patients relapsed at a median of 3.5 months (0.25-52 months) after ABMT, only 1 achieving a further durable CR. The only factor with prognostic significance was histological subtype, with diffuse small noncleaved-cell lymphoma having a significantly worse outcome. High-dose therapy and ABMT has produced effective consolidation of first remission in this group of patients, even in those with poor prognostic features at presentation.

Adolescent↗
PubMed2002

The effect of growth hormone therapy on mandibular and cranial base development in children treated with total body irradiation.

The aim of the present investigation was to study craniomandibular development during growth hormone (GH) therapy in nine girls and one boy, aged between 7.3 and 16 years, who exhibited pronounced growth reduction after total body irradiation (TBI) and bone marrow transplantation (BMT). Age- and sex-matched healthy children with normal dentofacial development constituted the control material. The investigation data were based on measurements made on lateral skull radiographs taken at the start and, on average, 6 months after cessation of GH treatment. The control group comprised similar longitudinal cephalographic records. The results showed that GH therapy in patients who exhibited growth retardation after TBI and BMT had only a minor effect on cranial base dimensions, probably due to the fact that the development of this area is completed at a relatively early age. The effect of GH treatment on mandibular growth was very obvious. The dimensional increase of the mandibular variables in the patients was equivalent to, or in some cases even exceeded, that of the controls. In relation to basion, the mandibular condyles were displaced in a backward/upward direction in the patient group. Displacement in the opposite direction was recorded in the controls. It seems likely that the development seen in the patients is a reflection of a normalization of the condyle-fossa relationship made possible by enhanced condylar growth. This change should be advantageous for the function of the craniomandibular complex.

Acute Disease↗
PubMed1997

Transplantation in patients with multiple myeloma: a multicenter comparative analysis of peripheral blood stem cell and allogeneic transplant.

We performed a multicenter comparative analysis of autologous peripheral blood stem cell transplantation (PBSCT) and allogeneic bone marrow transplantation (alloBMT) in multiple myeloma. Forty-eight consecutive patients received either PBSCT (24 patients) or alloBMT (24 patients) at one of three institutions in the study group. Preparatory regimens consisted of melphalan and total body irradiation (TBI) or melphalan alone in the PBSCT group. The alloBMT group received one of four regimens: cyclophosphamide and TBI; cyclophosphamide, VP-16 and 1,3-bis(2-chloroethyl)-1-nitrosourea (CVB); busulfan and cyclophosphamide (BU/CY) and total marrow irradiation (TMI); or melphalan and TBI. Procedure-related mortality was 12.5% for the PBSCT group and 25% for the alloBMT group. With a median follow-up for survivors in the PBSCT and alloBMT groups of 11 months (range, 4-46) and 15 months (range, 2-84 months), respectively, there was no significant difference in median overall survival (33.5 versus 38.6 months, p = 0.7637) or event-free survival (16.7 versus 31 months, p = 0.8450). There was, however, a plateau in survival at 40% in the alloBMT group. No plateau in survival was seen in the PBSCT group. Clinical relapses occurred as late as 39 months posttransplant. Patients have survived up to 28 months postrelapse.

Adult↗
PubMed1992

Supportive care in marrow transplantation.

Marrow transplantation is now an accepted form of therapy for patients with aplastic anemia, genetic diseases, and a variety of malignant diseases. Intensive chemotherapy and radiotherapy regimens are necessary to eradicate cancer cells and allow engraftment of the transplanted marrow. Patients undergoing such treatment suffer prolonged marrow aplasia and immunosuppression and experience significant nonmarrow toxicities. This requires maximum supportive care including hyperalimentation, fluid and blood transfusions, antibacterial and antiviral prophylaxis, and measures to reduce organ toxicities and accelerate engraftment. The use of drugs to suppress the production of antitumor necrosis factor-alpha has shown promise in reducing the nonmarrow toxicities of the conditioning regimen. Prophylactic antibiotics that reduce gastrointestinal colonization with aerobic bacteria yet preserve anaerobic flora may more effectively reduce not only systemic bacteria but fungal infections as well. The impact of infections due to cytomegalovirus has been reduced by more effective prevention in patients who are cytomegalovirus negative and reactivation in patients who are cytomegalovirus positive. The use of recombinant growth factors will significantly reduce morbidity after transplantation by reducing the period of marrow aplasia.

Adult↗
PubMed1993

High-dose therapy for lymphoma.

Use of modern chemoradiotherapy for Hodgkin's disease and non-Hodgkin's lymphoma has increased the number of patients with these malignancies who are cured. However, patients who fail to achieve or maintain a complete remission using these advanced therapies have a poor prognosis and are appropriate candidates for high-dose therapy that requires some type of hematopoietic stem cell support. The patterns of use of this therapy in such patients, the attempts to predict which patients will most benefit from high-dose therapy, and the various ancillary measures that can be taken to decrease the toxicity of high-dose therapy with stem cell rescue are the subject of this review.

Bone Marrow Purging↗
PubMed1996

Allogeneic bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) after high-dose, marrow-ablative chemoradiotherapy has been established as the treatment of choice for various hematologic, neoplastic, and congenital disorders. The most common type of marrow graft is an allogeneic one from a sibling donor who has compatible human leukocyte antigen (HLA). Only 30% of patients requiring allogeneic BMT have an HLA-compatible sibling donor. Over the past few years, marrows from unrelated HLA-compatible donors have been used with increasing frequency and promising outcome in certain hematologic malignancies. Despite the morbidity and mortality associated with this treatment modality, allogeneic BMT may provide a 20% to 90% chance of long-term, disease-free survival to patients with a wide variety of neoplastic and abnormal marrow disorders.

Bone Marrow↗
PubMed1991

The effect of antilymphocyte serum, fractionated donor bone marrow, and cyclosporine on renal allograft survival in mongrel dogs.

The effect of combined treatment with antilymphocyte serum, fractionated donor bone marrow, and a limited course of cyclosporine on renal allograft survival in mongrel dogs was examined. Recipients were treated with ALS from day -5 to day +7, relative to transplantation on day 0 with an MLR-mismatched donor. Fractionated donor bone marrow cells (BMFr3) obtained by density gradient separation were infused 3-7 days after ALS treatment. CsA treatments were begun either 3-7 days after ALS plus BMFr3 infusion or 3-7 days after treatments with ALS alone. Extended allograft survival was achieved at all CsA doses in BMFr3-infused, ALS-treated recipients. Allografts were sustained throughout the CsA treatment period without rejection in the majority of recipients (6 of 8) receiving ALS plus BMFr3 and CsA at 20 Mg/kg/day for 60 days. By contrast, few grafts were sustained through 30 days of treatment with CsA at 3.2 (1 of 12) or 10 mg/kg/day (2 of 9) in ALS plus BMFr3-treated recipients. Cyclosporine treatment was ineffective at all doses in augmenting allograft prolongation in ALS-treated recipients that did not receive BMFr3. Nearly all (6 of 7) long-term survivors (greater than 180 days) were BMFr3-treated. Peripheral blood lymphocytes or bone marrow cells of these long-term survivors proliferated normally in response to Con A and PWM, and were MLR responsive to third-party cells but did not have reduced MLR responsiveness to donor alloantigen in all cases. These long-term survivors promptly rejected third-party renal allografts without adverse effects on the original transplant's function. These results show that long-term renal allograft survival with specific unresponsiveness to the donor can result from the combined treatment with ALS plus donor BMFr3 and a limited course of CsA.

Animals↗
PubMed1993

Graft versus leukemia effect after transplantation with interleukin-2-activated bone marrow. Correlation with eradication of residual disease.

IL-2 has been used after autologous BMT (ABMT) with the aim of inducing graft versus leukemia (GVL) effect. Our studies in mice have shown that IL-2 therapy induces GVL effect when employed after BMT with bone marrow (BM) that has been activated with IL-2 in vitro (ABM). The present study was carried out to define the time of optimal GVL effect after BMT so that the immunomodulatory approaches could be concentrated at the time of maximum GVL effect. Our data show that GVL effect was induced if IL-2 was instituted immediately after BMT with ABM in mice with acute myeloid leukemia; institution of IL-2 1 week after BMT with ABM did not induce GVL effect. IL-2 therapy instituted immediately or 1 week after BMT with fresh bone marrow (FBM) did not induce any GVL effect. A significant increase in the NK activity was noticed whether IL-2 was instituted immediately or 1 week after BMT, either with FBM or with ABM. To evaluate the ability of IL-2 in the eradication of residual disease from the autograft and the host, BM with variable infiltration with leukemia was activated with IL-2 and used for BMT in leukemic mice. The GVL effect of BM with minimal leukemic infiltration (absence of morphologically demonstrable disease) was comparable to the GVL effect of normal BM. These findings suggest that: (a) maximum GVL effect after BMT with ABM is concentrated in the early post-transplant period possibly because of minimal residual disease during this time; (b) an increase in the NK activity induced by IL-2 therapy may not predict for an improved GVL effect; and (c) for optimum GVL effect, BM with minimal leukemic infiltration should be activated with IL-2 before BMT.

Animals↗
PubMed1996

Serum levels of cytokines and secondary messages after T-cell-depleted and non-T-cell-depleted bone marrow transplantation: influence of conditioning and hematopoietic reconstitution.

Cytokines are increasingly recognized as important mediators of graft-versus-host disease (GVHD). Measurements of cytokine serum levels in patients with GVHD, and successful prevention and treatment of the disease with the use of cytokine antagonists to either the cytokine or its receptor, are only two of several factors demonstrating the involvement of cytokines in GVHD. To further investigate the role of cytokines in the pathomechanism of acute GVHD, we investigated endogenous serum levels of various cytokines and dependent molecules in sera of 14 patients after T-cell-depleted (TCD) bone marrow transplantation (BMT) and compared the results with those of 12 patients undergoing non-TCD BMT. The effect of various conditioning regimens and of hematopoietic reconstitution on cytokine serum levels was analyzed in detail in these cohorts of patients by measuring interferon (IFN)-gamma, IFN-alpha, tumor necrosis factor-alpha, interleukin-6, neopterin, and beta2-microglobulin. The analyses showed that an increase in IFN-gamma and neopterin serum levels was a specific feature of cyclophosphamide administration and was not observed after other cytostatic drugs or total body irradiation, and that an increase in IFN-gamma, neopterin, beta2-microglobulin, and IFN-alpha release depends on the presence of T cells in the graft. We conclude that significant cytokine serum alterations were noted after TCD BMT as compared with after non-TCD BMT. These alterations, besides depletion of cytotoxic effector cells, might be involved in preventing GVHD after TCD BMT. In addition, more attention should be devoted to the cytokine release-inducing capacity of the conditioning regimen, because such a release might influence the occurrence of transplant-related complications after BMT.

Animals↗
PubMed1997

Permanent and specific transplantation tolerance induced by a nonmyeloablative treatment to a wide variety of allogeneic tissues: I. Induction of tolerance by a short course of total lymphoid irradiation and selective elimination of the donor-specific host lymphocytes.

The long-term success of organ transplantation is limited by complications resulting from consistent nonspecific immunosuppression. Induction of stable, donor-specific tolerance remains the main goal of transplantation immunology. In this article, a new, nonmyeloablative method is described for induction of transplantation tolerance to fully mismatched bone marrow cells (BMC), bone marrow stromal precursors, heart muscle, and skin allografts. The method is based on pretransplant conditioning with no postgraft immunosuppression, and consists of a short course (six daily fractions of 200 cGy) of total lymphoid irradiation (sTLI), followed by selective elimination of donor-specific alloreactive cells of the host escaping low-dose sTLI. Donor-specific alloreactive cells were activated by intravenous inoculation with a high dose of donor BMC (3 x 10(7) cells) 1 day after sTLI, and eliminated by a single intraperitoneal dose (200 mg/kg) of cyclophosphamide given 1 day after cell transfer. Infusion of a low number of T cell-depleted BMC (3 x 10(6) cells) after tolerogenic preconditioning converted recipients to stable mixed chimeras free of graft-versus-host disease. The same treatment provided long-lasting acceptance of heterotopically transplanted allografts of the heart muscle and of the stromal precursors to the hematopoietic microenvironment. This treatment also led to acceptance and life-long survival of full-thickness donor skin allografts. However, skin allografts survived only in mice that received donor T cell-depleted BMC after cyclophosphamide and had 20-50% donor cells in the blood. Our results suggest that after sTLI, additional selective clonal deletion of residual host cells induces a state of long-lasting specific tolerance to a wide variety of donor-derived tissues.

Animals↗
PubMed1991

Growth after bone marrow transplantation in children.

Growth of the patients with hematological malignancies, aplastic anemia, Fanconi's anemia, and Wiscott-Aldrich syndrome who had been treated with bone marrow transplantation (BMT) was studied. Fourteen out of 21 patients showed suppression of linear growth after BMT. Recovery of the growth velocity after 1-2 years tended to occur if BMT was performed at younger age. Six of eight patients with chronic graft-versus-host-disease (CGVHD) had impaired growth after BMT, whereas eight of 13 (61%) without CGVHD did. Provocative tests for growth hormone (GH) performed 5-72 months after BMT revealed three boys who showed poor response to more than two different stimuli. Two of these three boys had prolonged suppression of growth. Neither the age at BMT, difference in disease, nor presence of posttransplant growth retardation gave significant difference in the response of GH to provocative tests. It was concluded that approximately two-thirds of marrow-grafted children experienced transient decrease in growth velocity after BMT.

Adolescent↗
PubMed1991

Recurrent disseminated retinoblastoma treated by high-dose chemotherapy, total body irradiation, and autologous bone marrow rescue.

A case of recurrent, disseminated retinoblastoma is presented. The primary intraocular tumor, a metastatic mass at recurrence, and the tumor cells infiltrating bone marrow were all positive for the anti-GD2 monoclonal antibody (Mab) 3A7. Indirect immunofluorescence using the monoclonal antibody 3A7 was an effective method of detecting residual disease in the marrow. After remission was achieved by conventional therapy, the patient underwent autologous bone marrow transplantation (ABMT). The preparative regimen consisted of VP-16, cisplatinum, high-dose melphalan, and total body irradiation. The autologous marrow inoculum was clean of tumor cells at the detection level of 1:10,000. The transplant course was uneventful, and the patient is well and disease-free 17 months after ABMT. We conclude that high-dose chemotherapy and total body irradiation in an ABMT setting is feasible and a potentially curative approach to disseminated retinoblastoma.

Antibodies, Monoclonal↗
PubMed1993

Mechanisms in immune recovery after bone marrow transplantation. Management of posttransplant immune deficiency.

PURPOSE: Bone marrow transplantation usually entails the ablation of the recipient's immune system. The recovery of immunity post-marrow transplantation is a complex process dependent on a number of pre- and posttransplant factors. This knowledge has led to the development of novel approaches to supportive care of the patient, as well as to methods of augmenting immunity. DESIGN: Hematopoietic growth factors are now used to speed neutrophil recovery. Certain lymphokines are being investigated for the enhancement of cell-mediated immunity, and gamma globulin preparations are used to support the deficiency in humoral immunity. CONCLUSIONS: This review summarizes the basic concepts of immune reconstitution posttransplant and discusses some of the therapeutic interventions that have been investigated. In addition, some general recommendations are offered regarding supportive care.

Anti-Infective Agents↗
PubMed1991

New approaches to the treatment of follicular lymphoma.

The major avenues of clinical research into the treatment of follicular lymphoma, 'more, if so when?', interferon therapy, and antibody therapy, have been presented in the light of present knowledge about the clinical course of the disease. They must be seen within the context of the current philosophical approach to the illness, and the economic climate which prevails, at a time when new drugs, for example fludarabine (Leiby et al, 1987; Reman et al, 1988; Whelan et al, 1991), are showing promise, and differentiating agents are being tested in remission (Cunningham et al, 1985). There can be little doubt that the objective of future research should be to eliminate the disease altogether at the time of initial presentation, since patients entering remission and never having a recurrence have a far greater probability of longevity than those in whom recurrences occur (Lister, 1991). There can also be little doubt that when lymphoma is present and causing symptoms, treatment should be given, since survival is longer for those in whom a response is achieved, at least at presentation, and at first recurrence (Lister, 1991). Since the latter is sadly the reality for the majority, improving treatment at the time of recurrence must also be a priority. Time will tell whether any of the options presently under investigation will be appropriate at all, and if so when. It is certainly the case that some of them will be entirely inappropriate for some patients, because the risk of toxicity will outweigh the potential benefit, especially for the elderly. Further careful identification of prognostic variables may allow for individualization of therapy. It would be comforting to know that the newly found molecular marker of the disease would help us. Its absence may do--but its presence certainly does not, since t(14;18) containing cells may seemingly be present for many years of clinical normality (Price et al, 1991, in press). The challenge to find the right treatment at the right time--or perhaps to identify the 'right patient' for the therapy continues.

Antibodies, Monoclonal↗
PubMed1992

Second transplants for patients with chronic myeloid leukaemia in relapse after original transplant with T-depleted donor marrow: feasibility of using busulphan alone for re-conditioning.

Between July 1986 and March 1991, 16 patients who had relapsed after T-lymphocyte depleted bone marrow transplantation (BMT) for chronic myeloid leukaemia (CML) received a second transplant using unmanipulated marrow cells from the same HLA-identical sibling donor. The median numbers of days from first BMT to haematological relapse and to second BMT were 557 (range 273-1543) and 1211 (range 476-2310) respectively. 11 patients were in uncomplicated chronic phase at time of second BMT, and five had more advanced disease. As conditioning for second BMT, eight patients received various combinations of cytotoxic drugs, and eight received high-dose busulphan alone. Eight (50%) patients survive at a median of 424 d post-second BMT (range 158-1789) and all are free of leukaemia by conventional criteria: five had been conditioned with high-dose busulphan alone. Causes of death in the eight patients who died included relapse (n = 2), graft-versus-host disease (n = 2), interstitial pneumonitis (n = 2), and infection (n = 2). We conclude that patients relapsing into chronic phase after BMT with T-lymphocyte depleted donor marrow may be offered the option of second BMT with unmanipulated marrow from the original donor. Conditioning with high-dose busulphan alone may be safer than use of more intensive schedules.

Adolescent↗