Transplant of hematopoietic stem cells in childhood: where we are and where we are going

Over the past decade, relevant improvements and refinements have significantly changed the indications, technique and results obtained with allogeneic transplantation of hematopoietic stem cells (HSC) in childhood. In this review the most important innovations that have characterized the practice of HSC transplantation in childhood during this decade will be discussed. We will analyze the clinical and biological advantages or disadvantages which characterize most typically HSC transplantation procedure in terms of the source of these cells (bone marrow, peripheral blood, placental blood). A fundamental turning point in the history of allogeneic transplantation of HSC is represented by the use of placental blood, which was first employed in 1988. Autologous, peripheral blood progenitor cells are increasingly being used as a source of HSC following high-dose therapy for malignant disease, because of the ease of collection and the markedly faster kinetics of engraftment in comparison with bone marrow. In particular, over the past decade, due to the much faster recovery of all hematopoietic lineages in comparison with bone marrow and due to the short duration of antibiotic therapy and hospitalization, also in pediatric patients, auto-transfusion of circulating hematopoietic progenitors is rapidly replacing autologous bone marrow transplantation after high-dose chemotherapy for lymphomas and solid tumors. On the contrary, due to concerns in pediatric patients related to the use of hematopoietic growth factors in a healthy donor, allograft of peripheral blood progenitor cells is not routinely used. Since indications for allogeneic HSC transplantation that had already been well established in the recent past have been complemented by others and a relevant number of disorders are no longer considered to be eligible for allograft, the evolution in the indications for allogeneic transplant of HSC in childhood will be discussed. Likewise, biotechnological, social and organizational refinements which have allowed the greatest advances of allogeneic HSC transplantation in this decade will be analyzed, as well as some still open bioethical question regarding this procedure.     

Allogenic transplantation of hematopoietic stem cells in the treatment of children with high-risk acute leukemia

BACKGROUND: Most children with acute lymphoblastic leukemia (ALL) and increasing number of children with acute myelogenous leukemia (AML) are currently cured with conventional chemotherapy. Despite of this success there is a subset of patients with high-risk features at diagnosis who are predisposed to a very high risk of relapse. Relapse of AML and early bone marrow relapse of ALL can not be cured by conventional chemotherapy. Allogeneic hematopoietic stem cell transplantation (HSCT) is therapeutic option in these children with very high-risk acute leukemia. METHODS AND RESULTS: Between XI/1989-XII/1996 33 children with acute leukemia (ALL: 22, AML: 11) underwent an allogeneic HSCT from HLA identical related donors (HLA-identical sibling: 30, twin: 1, other HLA-identical relative: 2) at the 2nd Dept. of Pediatrics, University Hospital Motol. Median age of our group was 9 years (1.5-19 y.), boys (n = 23) clearly dominated over the girls (n = 10). The resource of stem cells was bone marrow in 31 children, bone marrow and peripheral blood progenitor cells (PBPC) and PBPC in one child respectively. Myeloablative conditioning regimen varied, consisting of total body irradiation and chemotherapy in 21 children and chemotherapy in 12 children. HSCT was performed in first complete remission of acute leukemia in 9 children (AML: 7, ALL: 2), in second remission in 14 children (AML: 2, ALL: 12), in third remission in 4 children (ALL: 4). Six children underwent HSCT in first partial remission (n = 1) and in second (n = 4) or third (n = 1) chemoresistant relapse. Seven (21%) children died due to post-transplant complications. Nine (28%) children suffered from clinically significant acute graft-versus-host reaction (GVH) and 15% (4/27) children who survived 100 days post-transplant suffered from chronic GVH disease. Relapse of leukemia was diagnosed in 39% (12/31) children. Fourteen (42%) children are alive and well in continuous remission with median follow-up 42 months. CONCLUSIONS: Allogeneic HSCT can cure children with very high-risk acute leukemia in the situations where conventional chemotherapy fails. Relapse of leukemia and GVH reaction are most important causes of post-transplant morbidity and mortality.     

Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy

The immune-mediated graft-versus-leukemia effect is important to prevent relapse after allogeneic progenitor cell transplantation. This process requires engraftment of donor immuno-competent cells. The objective of this study was to assess the feasibility of achieving engraftment of allogeneic peripheral blood or bone marrow progenitor cell after purine analog containing nonmyeloablative chemotherapy. Patients with advanced leukemia or myelodysplastic syndromes (MDS) who were not candidates for a conventional myeloablative therapy because of older age or organ dysfunction were eligible. All patients had an HLA-identical or one-antigen-mismatched related donor. Fifteen patients were treated (13 with acute myeloid leukemia and 2 with MDS). The median age was 59 years (range, 27 to 71 years). Twelve patients were either refractory to therapy or beyond first relapse. Eight patients received fludarabine at 30 mg/m2/d for 4 days with idarubicin at 12 mg/m2/d for 3 days and ara-c at 2 g/m2/d for 4 days (n = 7) or melphalan at 140 mg/m2/d (n = 1). Seven patients received 2-chloro-deoxyadenosine at 12 mg/m2/d for 5 days and ara-C 1 at g/m2/d for 5 days. Thirteen patients received allogeneic peripheral blood stem cells and 1 received bone marrow after chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methyl-prednisolone. Treatment was generally well tolerated, with only 1 death from multiorgan failure before receiving stem cells. Thirteen patients achieved a neutrophil count of greater than 0.5 x 10(9)/L a median of 10 days postinfusion (range, 8 to 17 days). Ten patients achieved platelet counts of 20 x 10(9)/L a median of 13 days after progenitor cell infusion (range, 7 to 78 days). Eight patients achieved complete remissions (bone marrow blasts were < 5% with neutrophil recovery and platelet transfusion independence) that lasted a median of 60 days posttransplantation (range, 34 to 170+ days). Acute GVHD grade > or = 2 occurred in 3 patients. Chimerism analysis of bone marrow cells in 6 of 8 patients achieving remission showed > or = 90% donor cells between 14 and 30 days postinfusion, and 3 of 4 patients remaining in remission between 60 and 90 days continued to have > or = 80% donor cells. We conclude that purine analog-containing nonmyeloablative regimens allow engraftment of HLA-compatible hematopoietic progenitor cells. This approach permits us to explore the graft-versus-leukemia effect without the toxicity of myeloablative therapy and warrants further study in patients with leukemia who are ineligible for conventional transplantation with myeloablative regimens either because of age or concurrent medical conditions.     

Gene transfer for the therapy of hematologic malignancy

Gene transfer has allowed a number of biologic issues in the therapy of hematologic malignancy to be addressed. In autologous bone marrow transplantation, gene marking studies have shown that infused marrow contributes to relapse in acute myeloid leukemia, neuroblastoma, and chronic myeloid leukemia. In addition, double gene marking with distinguishable retroviral vectors has allowed comparison of purging techniques and the ability of different sources of stem cells to repopulate. In allogeneic bone marrow transplantation, genetically modified T cells have proven valuable for the prophylaxis and treatment of viral diseases and may be of use to treat disease relapse. Gene transfer is also being used to modify tumor function, enhance immunogenicity, modify function of adoptively transferred immune system cells, and confer drug resistance to normal hematopoietic stem cells.     

Sources of human hematopoietic stem cells for transplantation--a review

Transplantation of hematopoietic stem cells provides a means of replacing a defective hematopoietic system in patients with a wide range of malignant and nonmalignant disorders that affect the blood forming tissue. The same procedure has also allowed dose-escalation of standard chemotherapy and radiotherapy in the treatment of malignant disease of nonhematological origin. Unit recently, bone marrow has been the sole source of hematopoietic stem cells, but limitations of conventional bone marrow transplantation have stimulated a search for alternative sources and uses of stem cells. Fetal tissues (especially liver) are a recognized source of transplantable stem cells and offer the great advantage of reduced immunogenicity, potentially removing the problems of tissue type matching. Umbilical cord blood is also a rich source of stem cells and, although it contains alloreactive cells, it is readily available without special ethical constraints. Both fetal tissue and cord blood suffer the disadvantages of limited numbers of stem cells per donation, and there is much interest in the development of technologies for the safe and reliable expansion and/or pooling of stem and progenitor cells. The observation that small numbers of stem cells are found in the peripheral blood of adults has led to the exploitation of the blood as a further source of stem cells. The ability to mobilize these cells from the medullary compartment into the periphery by the use of chemotherapy and/or recombinant hematopoietic growth factors has enabled the collection of sufficient numbers of cells for transplantation purposes. All of these advances are increasing the options and the range of choices available to clinicians and patients in the arena of hematopoietic stem cell transplantation.     

Gene transfer into hematopoietic stem cells

The ability to insert a gene into hematopoietic stem cells and achieve lineage specific expression of the transferred gene within hematopoietic organs following bone marrow transplantation would create the potential to effectively treat many genetic and acquired diseases. The use of retroviral vectors to achieve this purpose has been investigated extensively in animal models and most recently, in humans. In the murine model, about 20-30% of repopulating stem cells can be genetically modified with a retroviral vector. Peripheral blood stem cells, mobilized by cytokine administration in splenectomized animals, are readily transduced and are capable of long-term reconstitution of transplant recipients with genetically modified cells. Similar protocols have been utilized to transduce highly purified stem cells from rhesus monkeys. Although long-term repopulation with cells that persistently express the transferred gene has been achieved, the frequency of cells containing the vector genome is only about 1-2%. Genetic marking of human bone marrow and peripheral blood cells has been utilized to investigate their potential for contributing to long-term reconstitution following autologous transplantation. Future work will focus on improving gene transfer efficiencies for specific therapeutic applications.     

Methylsulfonyl metabolites of PCBs and DDE in human tissues

More than 15 years passed since bone marrow transplantation (BMT) have first introduced to the field of treatment of pediatric cancer. During this period, technology and modality of BMT have been improved steadily and several kinds of hemopoietic stem cell transplantation, for instance, allogeneic BMT from related or unrelated donor, unpurged or purged autologous BMT by 4-hydroperoxycyclophosphamide (4-HC) or magnetic immuno-beads, allogeneic or autologous peripheral blood stem cell transplantation and cord blood stem cell transplantation became available. Now we can choose the most suitable transplantation method for each patient from our repertory according to the patient's condition. In this article, treatment result of allogeneic BMT and 4-HC purged autologous BMT for children with acute leukemia and several kinds of hematopoietic stem cell transplantation for children with solid tumors in my hospital were reported.     

Indications and relative indications for stem cell transplantation in non-Hodgkin's lymphoma

High dose chemotherapy with or without total body irradiation and autologous stem cell rescue has proven to be effective treatment to cure patients with relapsed intermediate grade and high grade non-Hodgkin's lymphoma. Important factors for selection of candidates most likely to do well with these approaches include patients whose disease is responsive to conventional therapy and those who have minimal disease volume at the time of transplant. The treatment-related mortality of autologous stem cell transplantation has diminished from 20% to less than 5% with improved supportive care and selection of patients with less advanced disease. Although the treatment-related mortality of allogeneic stem cell transplantation may be as high as 20-40%, a graft versus lymphoma effect may decrease relapse with the result that overall survival is not substantially different between autologous and allogeneic transplantation. The definitive indications for stem cell transplantation include patients who have relapsed with intermediate or high grade NHL. Relative indications include intermediate/high grade non-Hodgkin's lymphoma patients, "high risk" first complete remission (CR), resistant relapse; low grade non-Hodgkin's lymphoma in sensitive or resistant relapse, advanced disease (sensitive or resistant relapse, transformation), first CR (younger patients). Relative contraindications include specific patient profiles such as bulky high grade lymphoma which progresses on appropriate conventional therapy, poor performance status, active serious infection, serious cardiac, renal, pulmonary or liver dysfunction, active, central nervous system (CNS) disease unresponsive to cranial irradiation/intrathecal therapy. For patients with previous marrow involvement or active marrow involvement at the time of harvest or transplant, "purged" autografts, peripheral blood stem cell transplantation and allografts have been used successfully.     

急性白血病患者造血干细胞P-选择素表达的研究

目的 研究急性白血病(AL)患者骨髓白血病干细胞表面分子P-选择素(CD62P)的表达情况及其临床意义.方法 采用流式细胞术(FCM)检测56例初治AL患者骨髓CD62P的表达情况,以15例健康成年人骨髓标本为对照.结果 38例急性髓系白血病(AML)患者干细胞(CD+45CD+34CD-38)中CD62P平均表达水平为(6.72±7.64)%,12例急性B淋巴细胞白血病(B-ALL)患者干细胞(CD+45CD+34CD+19)为(3.46±2.51)%,6例急性T淋巴细胞白血病(T-ALL)患者干细胞(CD+45 CD+34CD+7)为(6.23±4.95)%,均明显高于健康对照组[(1.04±1.23)%](t值分别为2.847、3.284、3.091,P＜0.01).经过正规方案治疗后,完全缓解组患者CD62P表达与健康对照差异无统计学意义(t=0.397,P＞0.05).另外CD+62P的AML及T-ALL患者白细胞计数、血红蛋白及血小板计数均明显高于CD-62P患者(t值分别为4.153、8.095、8.289、7.235、8.692、9.832,P＜0.05);而CD+62P与CD-62P的B-ALL患者无明显差异(t值分别为0.340、1.142、0.019,P＞0.05).结论 CD62P是血小板活化的标志物之一,在不同类型的AL中有不同程度的表达.AL骨髓造血干细胞中CD62P可能作为白血病造血干细胞的标志,以及临床疗效观察预后判断的指标之一.     

Engraftment of HLA-matched sibling hematopoietic stem cells after immunosuppressive conditioning regimen in patients with hematologic neoplasias

BACKGROUND AND OBJECTIVE: The main objective of this pilot study was to assess the possibility of achieving engraftment of HLA-matched sibling donor mobilized hematopoietic stem cells after immunosuppressive non-myeloablative therapy. The second objective was to verify whether high-dose therapy with autologous stem cells rescue followed by allografting conditioned by only an immunosuppressive regimen, can be combined in order to achieve the reduction of tumor burden after autografting and the control of residual disease with immune-mediated effects after allografting. DESIGN AND METHODS: To enter the pilot study the patients had to fulfil the following criteria: advanced resistant disease, presence of an HLA matched sibling donor, no general contraindications to stem cell transplantation. Our data refers to 9 patients: Hodgkin's disease (n = 4), non-Hodgkin's lymphoma (n = 2), advanced chronic myelogenous leukemia (n = 2) (one patient with accelerated phase Ph-negative but p190 BCR-ABL gene positive by RT-PCR and one with Ph-positive blastic phase), refractory anemia with excess of blasts t(1;3) (p36;q21) (n = 1). All patients but one received the combined approach. At a median of 40 days (range 30-96), after high-dose therapy and autologous stem cell engraftment, the patients were treated with immunosuppressive therapy consisting of fludarabine and cyclophosphamide (Flu-Cy protocol) and then HLA matched donor mobilized stem cells were infused into the patients. GvHD prophylaxis consisted of cyclosporin and methotrexate. RESULTS: To date, with a median observation period of 4 months (range, 2-10), complete chimerism (100% donor cells) has been achieved in 6 patients. Three patients did not achieve complete chimerism: one patient died of progressive Hodgkin's disease when he reached 55% of donor cells, another patient is now in increasing phase of donor cell engraftment and the last patient (blastic phase-CML) was the only case who appears to have had autologous recovery. Two of the Hodgkin's disease patients, who were in partial remission after autografting, achieved complete remission after allografting and both are disease free 2 and 6 months after. Another Hodgkin's disease patient is alive at 10 months but she has progressive disease. One of the two patients with non-Hodgkin's lymphoma, who achieved partial remission after autografting, obtained complete remission and he is disease free 2 months after allografting. The other patient maintains partial remission obtained after autografting. The accelerated phase-CML patient obtained hematologic and molecular remission; the RAEB patient achieved hematologic and cytogenetic remission. In two patients severe aGVHD (grade II-III) was the single major complication but neither patient died of it. Mild aGVHD was seen in another patient. In only one patient did the ANC decrease to below 1 x 10(9)/L and in no case did platelets decrease below 20 x 10(9)/L. No patients required a sterile room or any red cell or platelet transfusions. INTERPRETATION AND CONCLUSIONS: Immunosuppressive therapy with a Flu-Cy protocol allowed engraftment of HLA-matched sibling donor stem cells without procedure-related deaths; moreover, we have demonstrated that this combined procedure can be pursued in safety in a serious ill population and some of these patients achieved a complete remission. This procedure is not likely to be curative, but a fascinating step along the path to curing these diseases. Of course, the follow-up is too short to document the incidence of cGvHD.     

Therapy of highly malignant non-Hodgkin lymphoma with high-dose chemotherapy and stem cell transplantation

Patients with intermediate or high-grade non-Hodgkin's lymphoma are rarely cured of their disease after the failure of conventional therapy. High-dose chemotherapy followed by transplantation of either autologous marrow (ABMT) or peripheral stem cells (PBSCT) offers such patients a new possibility of cure. To patients younger than 60 years and without contraindications high-dose chemotherapy should be offered in case of relapse and bad prognosis. The PARMA-study demonstrated, that high-dose chemotherapy with subsequent autologous stem cell transplants is superior to conventional chemotherapy for relapsing patients. However high-dose chemotherapy in first complete or partial remission followed by ABMT and PBSCT as post-remission therapy for adult NHL has yielded only similar results randomized to those achieved with conventional chemotherapy in several prospectively studies. This approach should be limited to patients with bad prognostic factors (high-intermediate or high-risk groups according to the International Prognostic Factor Project). The success of ABMT and PBSCT in treating these diseases mandates exploration of the best high-dose chemotherapy, the use of autologous or allogenic bone marrow resp. peripheral stem cell for haematopoietic reconstitution and technical aspects such as purging of tumor cells, the short- and long-term transplant-related mortality continues to be a major concern.     

The mechanisms involved in the impairment of hematopoiesis after autologous bone marrow transplantation

Hematopoiesis after autologous bone marrow transplantation (BMT) is characterized by a prolonged and severe deficiency of marrow progenitors for several years, especially of erythroid and megakaryocyte progenitors, while the peripheral blood cells and marrow cellularity have reached relatively normal values within a few weeks. These anomalies are comparable to those reported for allogeneic BMT, despite the absence of any allo-immune reaction or post-graft immunosuppressive therapy. Post-graft hematopoietic impairment is the consequence of quantitative and qualitative changes involving both stem cell and stromal compartments which are expressed by an impaired capacity of stem cell self-renewal and commitment towards erythroid and megakaryocytic lineages. Besides the toxicity of conditioning regimens, hematopoietic reconstitution using autologous grafts is particularly dependent on a combination of factors related to the patient, such as underlying disease and pre-graft chemotherapy regimens, and to the graft processing itself, such as in vitro purging with chemotherapeutic agents.     

Characterization of the cadmium-binding capacity of Chlorella vulgaris

BACKGROUND & AIMS: Remission of several autoimmune diseases has been described after allogeneic marrow transplantation. The aim of this study was to determine if the natural history of Crohn's disease was altered by hematopoietic cell transplants from healthy allogeneic donors. METHODS: Between 1982 and 1992, 6 patients with Crohn's disease and leukemia underwent allogeneic marrow transplantation and were followed up clinically. RESULTS: Five patients had active Crohn's disease before transplantation, and 3 had clinical evidence of sclerosing cholangitis. Four marrow donors were HLA-identical siblings, 1 related donor was mismatched at the DR locus, and 1 unrelated donor was HLA-matched. One patient died of septicemia 97 days after transplantation; 5 patients were observed for 4.5, 5.8, 8.4, 9.9, and 15.3 years after transplantation. Four of 5 patients evaluated had no signs or symptoms of Crohn's disease after transplantation. One patient with mixed donor-host hematopoietic chimerism had a relapse of Crohn's disease 1.5 years after transplantation. CONCLUSIONS: Four of 5 patients followed up for 4.5 to 15.3 years after allogeneic hematopoietic cell transplantation remained free of Crohn's disease. These observations suggest that host immune dysregulation plays a role in the perpetuation of Crohn's disease that can be corrected by allogeneic hematopoietic cell transplantation.     

间充质干细胞在造血干细胞移植中的应用

间充质干细胞是一种能够从各种人成体组织分离出来的非造血多能干细胞,近年来,许多研究表明间充质干细胞具有免疫调节能力及促进组织重建等功能.就其在造血干细胞移植中的应用,如急慢性移植物抗宿主病(GVHD)、GVHD造成的移植失败、纯红细胞再生障碍性贫血及免疫性血小板减少性紫癜、出血性膀胱炎作以综述.     

Prolonged molecular remission after PML/RAR alpha-positive autologous peripheral blood stem cell transplantation in acute promyelocytic leukemia: is relevant pretransplant minimal residual disease in the graft?

The contribution of residual malignant cells contaminating the autologous graft with the occurrence of post-transplant relapse in acute myeloid leukemia (AML) is still unclear. The presence of a specific molecular marker (the PML/RAR alpha rearrangement) in acute promyelocytic leukemia (APL) offers the opportunity to investigate better the pathogenesis of disease recurrence after transplant. We report an APL patient who received high-dose chemotherapy and peripheral blood stem cell (PBSC) autograft in second hematologic remission. Two leukaphereses that tested PML/RAR alpha positive by RT-PCR were obtained during the post-reinduction hematopoietic recovery, while the patient also tested PCR positive in the BM, and was reinfused after myeloablative chemotherapy (BUCY4), when the patient had spontaneously converted to PCR negative in the marrow. At present, he remains in continuous molecular and hematologic remission 22 months after PBSC transplantation. This is the second report of an APL patient who was transplanted in molecular remission with a PML/RAR alpha-positive PBSC autograft. As in the previous report, the prolonged clinical and molecular remission experienced post-transplant suggests that autologous PBSC infusion is still worthy of consideration for patients with APL in spite of the detection of PML/RAR alpha-positive cells in the PBSC collections. Possible underlying mechanisms and the potential role of molecular monitoring of the graft, as well as the host, before and after transplant, in patients with APL undergoing autologous HSCT are also discussed.     

Indications and donor source of hematopoietic stem cell transplants in Europe 1993: report from the European Group for Blood and Marrow Transplantation (EBMT)

This report details the evolution of bone marrow transplantation in Europe over a 20-year period. In 1973, 8 teams undertook a total of 16 allogeneic bone marrow transplants; in 1983, 97 teams performed 1353 transplants. In 1993, the numbers had risen to 260 teams and 7737 transplants. Donor source in 3092 cases was an allogeneic donor (2464 HLA-identical sibling transplants, 147 non-identical family donor transplants, 25 twin donor transplants and 456 unrelated donor transplants). For 4645 patients the transplant was autologous (2450 autologous bone marrow transplants, 1830 autologous peripheral blood stem cell transplants and 365 combined autologous peripheral blood and bone marrow transplants). Indications for transplants in 1993 were leukemias in 3419 patients (44%; 2332 allogeneic, 1087 autologous), lymphoproliferative disorders in 2666 patients (34%; 197 allogeneic, 2469 autologous), solid tumors in 1077 patients (14%; 9 allogeneic, 1068 autologous), aplastic anemia in 251 patients (3%; 250 allogeneic, 1 autologous), inborn errors in 244 patients (3%; 242 allogeneic, 2 autologous) and miscellaneous disorders in 80 patients (1%; 62 allogeneic, 18 autologous). These data illustrate the increase of hematopoietic stem cell transplants as a therapeutic modality over the last 20 years in Europe.     

Indications, technique and risks in bone marrow transplantation in adulthood

The option of bone marrow transplantation (BMT) significantly improved prognosis of adult patients with hematologic malignancies aged less than 50 years. Allogeneic BMT using the marrow of an HLA-identical family member still provides the most effective method of BMT. Conventional indications for this form of BMT are chronic myeloid leukemia (CML), acute leukemias presenting with adverse risk factors, myelodysplastic syndromes and severe aplastic anemia. If performed early in the disease course (e.g. during the chronic phase of CML or first remission of acute leukemia and MDS) allogeneic BMT cures 50 to 60% of patients. About 20% die of therapy related complications, e.g. graft versus host disease (GvHD), fatal infections or venoocclusive disease of the liver (VOD) and about 20% of patients succumb to relapse of their hematologic disorder. 80% presenting with severe aplastic anemia can be cured, if allogeneic BMT is performed soon after diagnosis without previous immunosuppressive therapy and blood transfusions. BMT with the marrow of a matched unrelated donor or autologous BMT are increasingly used as alternative procedures. A rate of lethal complications as high as 50% hinders rapid extension of BMT with unrelated donors. Therefore, this form of BMT should be restricted to young patients with leukemias, who cannot achieve long-term remission with conventional chemotherapy (in case of acute leukemias) or alpha-interferon (in case of CML). Reconstitution of hematopoiesis is more rapid after peripheral blood stem cell transplantation (PBSCT) compared with autologous BMT. Therefore, PBSCT will replace autologous BMT in most cases. Most favourable results of PBSCT have been reported in patients with malignant lymphomas after relapse or inferior response to primary induction therapy. Due to the higher relapse rate autologous BMT is inferior to allogeneic BMT in leukemia patients. Trials are required to clarify the potential role of myeloablative therapy with stem cell support in the treatment of patients with solid tumors. Many of the preliminary results already published are unsatisfactory and data of larger trials are still lacking. Therefore, BMT or PBSCT cannot be recommended generally for the therapy of patients with solid tumors.     

Serum interleukin-3 levels following autologous or allogeneic bone marrow transplantation: effects of T-cell depletion, blood stem cell infusion, and hematopoietic growth factor treatment

Engraftment of marrow following autologous or allogeneic bone marrow transplantation (BMT) may be influenced by quantity and function of stem cells. T lymphocytes, supporting microenvironmental cells, and hematopoietic growth factors (HGF). To elucidate the physiologic role of interleukin-3 (IL-3) in the engraftment process, serum IL-3 levels were measured in over 400 samples from 77 transplant recipients before and for up to 3 weeks following transplantation using a novel enzyme-linked immunoabsorbent assay (ELISA) with a sensitivity of > or = 78 pg/mL. Thirty-seven patients received two to three log T-cell-depleted allografts. In the remaining 40 patients (18 autologous marrow, 12 allogeneic marrow, and 10 autologous peripheral blood [PB] stem cell), T cells were not depleted (non-TCD) from the grafts. A burst of IL-3 (peak levels, 1,500 to 6,000 pg/mL) was detected in the immediate posttransplant period between day 0 and day 14 in all non-TCD recipients and in 21 of 37 (57%) of TCD recipients. A strong inverse relationship between IL-3 levels and absolute neutrophil count (ANC) was observed in both non-TCD recipients (r = -.796) and in TCD recipients (r = -.897). However, both peak IL-3 levels and mean IL-3 levels from day 0 through 14 were significantly lower in TCD recipients compared with either autologous or unmodified allogeneic marrow recipients (P < .01). The lowest peak or mean day 0 through 14 IL-3 levels were observed in matched related recipients undergoing the most aggressive (2.5 to 3.0 log) T-cell-depleted BMT. Autografted patients receiving blood stem cell transplants alone or posttransplant granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) also had significantly lower peak IL-3 levels (P < .01). In patients receiving TCD grafts, administration of antithymocyte globulin (ATG) posttransplant significantly increased peak IL-3 levels compared with patients not treated with ATG (P < .04). This study shows that endogenous release of IL-3 is strongly associated with myeloid engraftment and inversely related to ANC. Removal of T lymphocytes from donor marrow or acceleration of engraftment by use of stem cells or growth factors appears to blunt the endogenous release of IL-3 whereas use of ATG posttransplant increases IL-3 release.