Autologous and allogeneic transplantation with peripheral blood CD34+ cells: a pediatric experience.
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BACKGROUND AND OBJECTIVE: Peripheral blood stem cells (PBSC) have replaced bone marrow (BM) as the primary form for autologous hematopoietic stem cell transplantation. Furthermore, the use of allogeneic PBSC transplantation is now rapidly expanding and several centers have adopted this procedure. A new strategy in the use of PBSC is positive selection of CD34+ hematopoietic progenitor (CD34+) cells, and indeed large-scale devices for the clinical exploitation of CD34+ cell selection are now commercially available. In the autologous setting, the primary advantage of using CD34+ selected PBSC is reduced tumor cell contamination during PBSC preparation. On the other hand, in the allogeneic setting, CD34+ selection methods are used to reduce the incidence and severity of GvHD. Initial trials of CD34+ selected PBSC transplants have mainly been performed in adult cancer patients, and experience with CD34+ selected PBSC transplantation in pediatric populations is still limited. The purpose of this review is to clarify the status of CD34+ selected PBSC transplantation in the pediatric population. EVIDENCE AND INFORMATION SOURCES: All authors of the present review work in the field of pediatric stem cell transplantation and in a stem cell processing laboratory, and have contributed to original papers published in peer-reviewed journals. The materials examined in the present review include articles and abstracts published in journals covered by the Science Citation Index and Medline. However, since there is still limited experience with CD34+ cell selection in pediatric populations, information on experience in adults will be discussed regarding the CD34+ cell-selection procedures and transplantation. Pediatric experience with transplants with CD34+ selected cells will be presented and discussed primarily based on our own experience. Specific problems related to PBSC mobilization and collection in children will also be discussed. STATE OF THE ART: A review of the literature shows that with current CD34+ selection methods, purity of the CD34+ cell fraction can range from 30% to 90%, and two to three logs of T-cell depletion can be achieved. Tumor cell contamination has not yet been fully evaluated. The clonogenic activity of progenitor cells after CD34+ selection from PB remains high. Transplantation of autologous selected CD34+ cells from PBSC gives prompt and stable engraftment. The long-term therapeutic efficacy should be evaluated with regard to tumor recurrence. Allogeneic CD34+ selected cells successfully engraft immunomyeloablated recipients though a mega-cell dose effect between HLA-matched pairs. The results of allogeneic CD34+ selected cell transplantation from HLA-mismatched donors are, so far, not satisfactory because of the high rate of rejection, severe infectious complications and relapse of the disease. CD34+ selection may also be used as a target of gene therapy, as a source of dendritic cells for cancer immunotherapy and for the treatment of patients with autoimmune disease. (+info)
Ifosfamide and etoposide-based chemotherapy as salvage and mobilizing regimens for poor prognosis lymphoma.
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We treated 40 patients with poor prognosis lymphomas. Patients with non-Hodgkin's lymphoma (NHL, n = 14) received MINE chemotherapy (mesna, ifosfamide 1330 mg/m2 and etoposide 65 mg/m2 by i.v. infusions on days 1-3, mitoxantrone 8 mg/m2 i.v. on day 1), and those with Hodgkin's disease (HD, n = 26) received VIM chemotherapy (mesna, ifosfamide 1200 mg/m2 by i.v. infusion on days 1-5, etoposide 90 mg/m2 by i.v. infusion on days 1, 3 and 5, and methotrexate 30 mg/m2 i.v. on days 1 and 5). Chemotherapy was followed by G-CSF (10 or 16 microg/kg in two divided doses daily) to mobilize PBSC. We performed 134 aphereses (median three leukaphereses per patient) starting on either day 13 (median; VIM) or day 12 (median; MINE). The median yield was 9.9x10(6) CD34+ cells/kg and 53.2x10(4) CFU-GM/kg for VIM, and 13.5x10(6) CD34+ cells/kg and 53.4x10(4) CFU-GM/kg for MINE. Except for predictable myelosuppression, no serious toxicity was seen. Response rate using MINE was 63% (18% CR, 45% PR) and using VIM 50% (17% CR, 33% PR). We conclude that VIM and MINE are effective and well-tolerated salvage regimens in patients with lymphomas and, followed by G-CSF, they also exhibit good capacity to mobilize stem cells in a predictable time interval. (+info)
Autologous stem cell transplantation for T and null cell CD30-positive anaplastic large cell lymphoma: analysis of 64 adult and paediatric cases reported to the European Group for Blood and Marrow Transplantation (EBMT).
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Anaplastic large cell lymphoma (ALCL) is a heterogeneous family of lymphoid tumours, among which the T and null cell types were recently listed in the REAL classification as a distinct entity. Reports on autologous stem cell transplantation (ASCT) in this group are only occasional. Sixty-four patients with T and null cell ALCL from 25 European centres had been registered with the European Group for Blood and Marrow Transplantation (EBMT) at the onset of this study. The median age was 25 years (range 3.2-53.0). Thirty of the 64 patients (47%) were in complete remission (CR), 18 (28%) in partial remission (PR), and the remaining 16 (25%) had a more advanced or chemotherapy-refractory disease at transplant. Eighty-one percent of the patients were conditioned with chemotherapy alone and 75% received marrow stem cells. All the patients transplanted in first CR (15), except one, maintained the CR over time; six of 15 transplanted in CR subsequent to first, six of 18 transplanted in PR and 14 of 16 transplanted in refractory or relapsed disease progressed. Actuarial overall survival (OS) at 10 years is 70%. Multivariate analysis showed that good status at transplant, younger age, absence of B symptoms and absence of extranodal disease indicated a better prognosis. These data suggest that ASCT should be considered as a possible treatment for chemosensitive patients in CR or PR. However, definitive conclusions cannot be drawn from this study and a prospective randomised trial between ASCT and conventional chemotherapy may be indicated. (+info)
Varicella zoster virus infection associated with high-dose chemotherapy and autologous stem-cell rescue.
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A retrospective evaluation of 215 consecutive recipients of high-dose chemotherapy (HDC) and autologous stem cell rescue (ASCR) was conducted to ascertain the incidence, temporal course, and outcome of varicella zoster virus (VZV) infection. Herpes zoster was identified in 40 individuals at a median of 69 days following ASCR. Six of these cases occurred at a median of 33 days prior to ASCR but following the initiation of high doses of stem cell mobilization chemotherapy. Twenty-five percent of patients demonstrated cutaneous or systemic dissemination and 32.5% required medical intervention for post-herpetic neuralgia. All except two individuals received antiviral chemotherapy. One patient with active VZV infection died of multiorgan failure 39 days after ASCR. Multivariate analysis of risk factors disclosed the significance of prophylactic acyclovir use in Herpes simplex virus seropositive individuals in reducing the risk of VZV infection. Moreover, the use of busulfan, thiotepa and carboplatin as the conditioning chemotherapy regimen was associated with an increased risk of subsequent VZV infection. The incidence of VZV reactivation after HDC and ASCR is similar to that observed following bone marrow transplantation but has an earlier onset. This may be related to an earlier induction of immunosuppression by stem cell mobilization chemotherapy administered prior to ASCR. We demonstrated a marked reduction in the proliferative and synthetic capacities of peripheral blood mononuclear cells obtained prior to and following stem cell mobilizing chemotherapy. Moreover, greater than 80% of VZV infections occurred within 6 months following ASCR and late cases were seldom observed compared to allogeneic and autologous bone marrow transplantation. The role of antiviral chemoprophylaxis during the period of maximum immunocompromise needs to be studied further in the HDC-ASCR setting. (+info)
Pulmonary enterovirus infections in stem cell transplant recipients.
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In recent years, it has been recognised that the community respiratory viruses are a frequent cause of upper and lower respiratory tract infections in immunocompromised hosts such as bone marrow transplant recipients. By contrast, infections by non-polio enteroviruses have rarely been reported after stem cell transplantation. We present four cases of acute respiratory illness with enterovirus isolated as the sole pathogen from bronchoalveolar lavage. All four patients developed pneumonia and three died of progressive pneumonia, which reflects the severity of this complication. We conclude that enteroviral pulmonary infections may be a cause of severe pneumonia in immunocompromised hosts. (+info)
Induction therapy with vincristine, adriamycin, dexamethasone (VAD) and intermediate-dose melphalan (IDM) followed by autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma.
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We performed a phase II study to test the efficacy and feasibility of induction therapy with vincristine, adriamycin and dexamethasone (VAD) and intermediate-dose melphalan, 70 mg/m2 (IDM), to autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma (MM). A total of 77 patients received two cycles of VAD (n = 62) and/or two cycles of i.v. IDM 70 mg/m2 (n = 15) combined with G-CSF. PBSC were harvested after the first IDM, successfully in 87% of patients. Patients with a response to induction received myeloablative therapy with PBSCT (n = 50) followed by IFN maintenance or allo-BMT (n = 11). Seventy-two per cent of patients achieved a response after VAD which increased to 85% after IDM. Of patients who received PBSCT and allo-BMT, 24% and 45% achieved CR, respectively. Toxicity of induction consisted mainly of bone marrow suppression after IDM (median 8 days) with prolonged aplasia in 11% of patients after the second IDM. Only six infections WHO grade 3 occurred during induction. Treatment-related mortality of PBSCT and allo-BMT was 6% and 18%, respectively. Median time of follow-up is 44 months, and 50% of patients after PBSCT and 60% of patients after allo-BMT are still in remission. Survival rates of all patients were 82%, 75% and 63%, and for transplanted patients 86%, 79% and 68% after 12, 24 and 36 months. Well known prognostic factors, including alpha-IFN maintenance after PBSCT, were not significant for response or survival although patients in CR after allo-BMT had a strong tendency for better outcome. VAD/IDM is an effective and safe induction therapy for autologous and allogeneic stem cell transplantation. Based on these observations a phase III trial was started in October 1995 comparing IFN maintenance with PBSCT and allo-BMT after response to induction with VAD and IDM. (+info)
Cells with clonal light chains are present in peripheral blood at diagnosis and in apheretic stem cell harvests of primary amyloidosis.
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In primary systemic amyloidosis, small numbers of bone marrow plasma cells secrete monoclonal light chains that form extracellular fibrils (amyloid) in various organs. Evidence limited to a few cases suggests that rare clonal elements can also be found in the peripheral blood (PB), and this may be relevant in PB stem cell autotransplantation. Since up to 40% of amyloid clones do not synthesize heavy chains, in order to detect tumor cells with high specificity and sensitivity we developed a seminested allele-specific oligonucleotide polymerase chain reaction for tumor light chains. Clone-related sequences were detected in DNA and/or cDNA from the PB cells of eight of 10 patients at diagnosis and from apheretic collections of three of four cases undergoing PB progenitor autotransplantation. Since there are experimental data suggesting that circulating tumor cells may be involved in the growth of the amyloidogenic clone and may be chemoresistant, these findings are relevant to the use of leukapheresis purging strategies for PB progenitor autotransplantation in amyloidosis. (+info)
Rejection of an MHC class II negative tumor following induction of murine syngeneic graft-versus-host disease.
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Cyclosporin A (CsA) has been used clinically to induce graft-versus-host disease following autologous bone marrow transplantation in an attempt to destroy residual leukemia cells and reduce relapse. To analyze the antitumor potential of murine syngeneic graft-versus-host disease (SGVHD), C3H/HeN mice were lethally irradiated, reconstituted with T cell-depleted syngeneic bone marrow (ATBM) and treated with CsA for 21 days. Graft-versus-leukemia activity was assessed by challenging groups of olive oil-treated control ATBM (OO-ATBM) and CsA-treated (CsA-ATBM) mice 1 week after CsA therapy with graded doses of the syngeneic 38C13 B cell lymphoma. Following CsA treatment, up to 70% of CsA-ATBM developed SGVHD and more than 70% of the animals injected with 500 38C13 cells exhibited long-term survival (MST >80 days). In contrast, none of the OO-ATBM control mice developed SGVHD, and more than 75% of these mice died following injection of 500 38C13 tumor cells (MST = 34 days). Long-term survivors were not resistant to tumor challenge suggesting that tumor-specific immunity did not develop. Finally, class II negative 38C13 cells cultured in IL-4 or IL-10 were not inducible for MHC class II molecules, demonstrating that class II-independent antitumor mechanisms exist in SGVHD mice. (+info)