Allogeneic Stem Cell Transplantation for Acquired Aplastic Anemia: Better Outcome with Bone Marrow as Compared to Peripheral Blood in HLA-Matched Sibling Donor Transplantation and Improved Outcome Over Time After Matched Unrelated Donor Transplantation. A Retrospective Analysis of Transplants Reported to the German Registry for Stem Cell Transplantation (DRST).

Abstract Abstract 876 Background: Transplantation of bone marrow (BM) from a HLA-matched sibling donor is an effective treatment for severe aplastic anemia (AA) with long-term survival in excess of 80%. In the recent years there were two trends in allogeneic stem cell transplantation (SCT) for AA: (1) increasing proportion of transplants performed from matched unrelated donors (MUD) and (2) increasing proportion of transplants using peripheral blood progenitor cells (PBSC) as stem cell source instead of BM. A similar switch to PBSC over BM grafts is reported in leukemia transplants. PBSC grafts for leukemia are associated with higher rates of chronic graft-versus-host disease (cGVHD). This …

IL-2, IL-3, and IFN-gamma differently affect in vivo frequencies of circulating precursors of cytotoxic T lymphocytes (CTL-p)

Experimental animal and human in vivo studies have previously demonstrated the impact of exogenous administration of various cytokines on frequencies of circulating myeloid and LAK precursor cells. For the first time we investigated whether exogenous cytokines, in the absence of antigenic challenge, may also influence frequencies of circulating antigen-specific cytotoxic T-lymphocyte precursor cells. We further asked whether triggering of autoimmune pathways as has been reported for several cytokines can be confirmed on the cellular level by demonstration of induction of autoreactive CTL-p. Limiting dilution analysis was used to determine alloreactive CTL-p frequencies in 31 patients with n…

Current results on the use of imatinib mesylate in patients with relapsed philadelphia chromosome positive leukemia after allogeneic or syngeneic hematopoietic stem cell transplantation

Here, we describe a patient diagnosed with chronic myelogenous leukemia who relapsed after matched unrelated donor SCT. The patient was treated with imatinib mesylate and donor lymphocyte infusions, and achieved a complete molecular remission. Additionally, safety and efficacy of imatinib mesylate in a total of 134 patients from 8 centers who underwent allogeneic or syngeneic stem cell transplantation (SCT) and had a relapse of Philadelphia chromosome positive leukemia was reviewed. Data was compiled from abstracts accepted as oral or poster presentations at the ASH (American Society of Hematology) 2001 and EBMT (European Group for Blood and Marrow Transplantation) 2001 & 2002 meetings and …

CD8-Depleted Donor-Lymphocyte Infusions After T-Cell Depleted Allogeneic Hemopoietic Stem Cell Transplantation

Related versus unrelated donor transplantation for high risk (HiRi) acute myeloid leukemia (AML) in first complete remission (CR1)

Abstract Allogeneic hematopoietic stem cell transplantation (allo-SCT) from an HLA-identical sibling donor (SIB) is considered the preferred postremission therapy for younger patients with HiRi AML in CR1. The role of allo-SCT from volunteer unrelated donors (VUDs) is less clear and randomized controlled trials addressing this issue do not exist. We performed an observational landmark analysis on parallel cohorts of patients aged <60 years with AML in CR1 and HiRi cytogenetics who had been enrolled into the AML Cooperative Group (AMLCG) 1999 trial. 2347 patients were evaluable for the present update. 243/2347 patients were <60 years of age and had unfavorable cytogenetics [com…

Salvage Therapy of Adult ALL

In a first study (1986 to 1992) the German Relapsing ALL Study Group (GRALLSG) has treated 67 adult patients with a first relapse of ALL. A first phase of induction consisted of vindesine, daunorubicin, asparaginase, and prednisone, a second phase of high-dose cytosine-arabinoside (Hd ara-C) and VP16. Results: 45 CR, 2 PR, 13 failures, 7 early death. 25 patients received a BMT. 10 had an allogeneic BMT in CR, 5 after another relapse or with refractory disease. Of 10 with autologous BMT 8 have been in 2nd CR. Only 4 of all 67 patients are surviving without relapse: One after unrelated BMT (36+mo), two after autologous BMT in 2nd CR (46+, 64+mo), and one after chemotherapy (61+mo). One patien…

CD8-Depleted Donor Lymphocyte Infusions Convert Mixed into Complete Donor T-Cell Chimerism after T-Cell Depleted Allogeneic Stem Cell Transplantation.

Abstract Donor lymphocyte infusions (DLI) are increasingly used to treat minimal residual disease or mixed hematopoietic donor-recipient chimerism in T-cell depleted allogeneic stem cell transplantation (SCT). In addition, several clinical trials currently investigate the prophylactic application of DLI to promote donor T-cell reconstitution after transplantation. However, DLI carry a substantial risk of inducing graft-versus-host disease (GVHD). We investigate DLI heavily depleted of CD8 T cells using a clinical grade immunomagnetic in vitro procedure in an ongoing clinical study [Meyer et al., Blood2007, 109:374]. These DLI are administered in a prophylactic setting to patients with hemat…

Safety and feasibility of CHOP/rituximab induction treatment followed by high-dose chemo/radiotherapy and autologous PBSC-transplantation in patients with previously untreated mantle cell or indolent B-cell-non-Hodgkin's lymphoma

Patients with no prior chemotherapy and with advanced and progressive follicular lymphoma (FCL) or mantle cell lymphoma (MCL) were enrolled into a treatment protocol combining CHOP/rituximab-CHOP therapy with subsequent consolidation high-dose therapy (HDT) to evaluate the safety and feasibility of this treatment. Overall, 15 patients were enrolled and 13 patients completed the entire treatment protocol without major toxicities or increased infectious complications. One patient withdrew consent after achieving complete remission (CR) prior to HDT. One patient was taken off study with signs of disease progression after induction treatment. All patients showed stable engraftment after HDT. Re…

Induction Therapy with Idarubicin, Ara-C, and VP-16, Followed by G-CSF and Maintenance Immunotherapy with Interleukin-2 for High-Risk AML

Aggressive chemotherapy followed by administration of G-CSF and maintenance therapy with interleukin-2 was evaluated in 16 patients with advanced myelodxysplastic syndrome, 47 patients with AML evolving from myelodysplastic syndromes, 3 patients with subacute myeloid leukemia and 5 patients with secondary AML. Median age was 59 years (range: 23 to 76 years). All patients achieving a complete remission (CR) after two induction courses went on to receive two consolidation courses, to be followed by randomization to either high-dose or low-dose IL-2 to evaluate the potential of IL-2 to eliminate residual leukemic cells and to prolong the duration of CR. Patients ≤ age 55 with an HLA identical …

Prophylactic transfer of CD8-depleted donor lymphocytes after T-cell–depleted reduced-intensity transplantation

AbstractAllogeneic hematopoietic stem cell transplantation (SCT) regimens incorporating the lymphocytotoxic CD52 antibody alemtuzumab demonstrate efficient engraftment and reduced graft-versus-host disease (GVHD). However, these protocols substantially impair posttransplantation antiviral and antitumor immunity. To accelerate immune reconstitution after alemtuzumab-based reduced-intensity SCT, we administered prophylactic CD8-depleted donor lymphocyte infusions (DLIs) starting on days 60 and 120 after transplantation. DLIs were processed in an immunomagnetic good manufacturing practice depletion procedure resulting in a 2.5- to 6-log reduction in CD8 T cells. Of 23 high-risk patients with h…

Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study.

Summary Salvage therapy followed by high-dose therapy (HDT) remains a mainstay for patients with relapsed lymphoma, however no optimal regimen has been defined. Here we report on the results of R-DexaBEAM (rituximab, dexamethasone, carmustine, etoposide, cytarabine, melphalan) followed by HDT. Patients aged 18–65 years, Eastern Cooperative Oncology Group performance score 0–2, with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) were eligible. R-Dexa-BEAM was given for two cycles followed by stem cell mobilization and HDT. Primary endpoint of the trial was progression-free-survival (PFS). One hundred and three patients were included: aggressive NHL (aNHL): diffuse large B-cell lymphom…

Improved multilineage response of hematopoiesis in patients with myelodysplastic syndromes to a combination therapy with all-trans-retinoic acid, granulocyte colony-stimulating factor, erythropoietin and alpha-tocopherol.

Differentiation induction therapy is being tested in myelodysplastic syndromes to ameliorate maturation defects and to restore normal hematopoietic function. To this end, 17 patients (eight with refractory anemia, two with refractory anemia and ring sideroblasts, and seven with refractory anemia and excess of blast cells) were treated with a combination of all-trans-retinoic acid (ATRA), granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and alpha-tocopherol for durations of 8-16 weeks. Absolute neutrophil counts increased in all patients; platelet counts increased in five patients with discontinuation of transfusion needs in two of four transfusion-dependent patients. Sti…

Chemotherapy with Idarubicin, Ara-C,VP-16, Amsacrine, Followed by G-CSF and Maintenance Immunotherapy with Interleukin-2 for Patients with High-Risk Acute Myeloid leukemia: a 3-Years Follow-Up

To improve the complete remission (CR) rate and to prolong CR duration in patients with advanced MDS, AML evolving from MDS, and secondary AML, a phase-III trial of aggressive chemotherapy followed by G-CSF was initiated in January 1992. Pts. achieving a CR were randomized to receive either high-dose or low-dose IL-2 to evaluate the potential of this cytokine to eliminate residual leukemic cells and to prolong the CR duration.

Low-Dose Aclacinomycin and Intermediate-Dose Cytosine Arabinoside in Relapsed and Refractory Acute Myelogenous Leukemia

Nineteen patients with relapsed or refractory acute myelogenous leukemia were treated with escalating doses of aclacinomycin (ACLA 20–30 mg/m2 daily for 5 days) and intermediate-dose cytosine arabinoside (Ara-C 1 g/m2 twice daily for 4 days). Most patients had received previous therapy with high- or intermediate-dose Ara-C plus mitoxantrone (HAM, IAM) and TAD (6-thioguanine, standard-dose cytosine arabinoside, and daunorubicin). Four patients had had repeated relapses and another three were treated for primary treatment failure following induction with HAM or I AM.

Peripheral blood stem cell (PBSC) mobilization with chemotherapy followed by sequential IL-3 and G-CSF administration in extensively pretreated patients

Extensive pretreatment has been identified as a significant risk factor for failure of sufficient PBSC mobilization. From published data and our own experience we defined pretreatment variables which render patients at risk for not collecting at least 2.5 x 10(6) CD34-positive cells per kg bodyweight (BW). These variables were previous unsuccessful PBSC mobilization trial, previous large field radiotherapy, four or more cycles of myelosuppressive chemotherapy regimens, and combinations of extended field radiotherapy plus chemotherapy. Based on these inclusion criteria we treated 19 patients with disease-specific conventional-dose chemotherapy followed by sequential subcutaneous administrati…

Filgrastim mobilization and collection of allogeneic blood progenitor cells from adult family donors: first interim report of a prospective German multicenter study.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) mobilized peripheral blood progenitor cells (PBPCs) from healthy individuals are a rapidly emerging alternative source to bone marrow for allogeneic transplantation. Although widely applied in the meantime, only limited information on feasibility and safety of mobilization and collection of PBPCs is currently available from prospective multicenter studies specifically designed to investigate this donation modality. This ongoing multicenter study on the performance as well as the short- and long-term safety profile of rhG-CSF-induced mobilization and collection of PBPCs was initiated in October 1999. The study is designed to r…

GM-CSF in a Double-Blind Randomized Placebo-Controlled Trial in Therapy of Adult Patients with De Novo Acute Myeloid Leukemia

Despite the fact that 60%–70% of patients with de novo acute myeloblastic leukemia (AML) achieve a complete remission (CR) of the disease only about 20%–30% of the patients remain in long term remission and are probably cured [1,2]. These rather disappointing long-term results argue in favor of an even more intensive induction and post-remission therapy. This intention is, however, at time limited by therapy associated toxicity. Especially haematotoxicity seems to be the limiting factor in that patients with profound neutropenia are at high risk of developing fatal infectious complications [3]. In this context haematopoietic growth factors, such as granulocyte-macrophage colony-stimulating …

Granulocyte–Macrophage Colony-Stimulating Factor in the Therapy of Adults with De Novo Acute Myeloblastic Leukemia: An Update of a Double-Blind Randomized, Placebo-Controlled Trial

We investigated whether granulocytemacrophage colony-stimulating factor (GMCSF) given concomitantly with chemotherapy (CT) improves the outcome of adults with de novo acute myeloblastic leukemia (AML) by increasing the efficacy of CT and reducing infections. CT included cytarabine (ara-C) daunorubicin, and etoposide (DAV) for induction and early consolidation therapy and one cycle with high-dose (patients aged ≤50 years) or intermediate-dose ara-C (patients aged >50 years) /daunorubicin for late consolidation therapy. Eighty patients were randomized after DAV 1 to receive either GM-CSF (Escherichia coli, 250 µg/m2 per day, s.c.) or placebo starting 48 h prior to DAV II and the subsequent co…

Relevance of the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) On Non-Relapse Related Mortality (NRM) in Patients with Acute Lymphoblastic Leukemia (ALL) Receiving Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in First Complete Remission: Results From the GMALL Study Group.

Abstract Abstract 3352 Poster Board III-240 Allogeneic HSCT is established as a potent curative therapy in adult patients with high risk ALL. However, due to transplant-related morbidity and lethality the gains in relapse prevention do not necessarily translate into survival advantages in the overall patient population. Defining the role of allogeneic HSCT in ALL patients in first complete remission (CR1) according to leukemia related risk factors, to transplant related risk factors (e.g. HLA matching, conditioning therapy and immunosuppressive treatment), and to comorbidity related risks, remains a major task for upcoming clinical trials. Several retrospective studies suggest that the HCT-…

Posaconazole concentrations in the central nervous system

more susceptible to the killing activity of caspofungin. This study is the first comparing caspofungin killing activity against the closely related species C. parapsilosis, C. orthopsilosis and C. metapsilosis. Killing curves, regardless of the medium used, showed a decreasing order of susceptibility to caspofungin: C. metapsilosis . C. orthopsilosis . C. parapsilosis. Based on high echinocandin MICs for C. parapsilosis sensu stricto, in the case of isolates identified as C. parapsilosis sensu lato low MICs of echinocandins may be regarded as an indicator that an isolate is in fact C. orthopsilosis or C. metapsilosis; in the case of isolates with low echinocandin MICs, DNA-based identificat…

Analysis of the p53 and MDM-2 gene in acute myeloid leukemia

The MDM-2 (murine double minute 2) gene codes for a cellular protein that can bind to the p53 tumor suppressor gene product, thereby functioning as a negative regulator of p53. In order to define the role of the MDM-2 gene in the pathogenesis of human acute myeloid leukemia, the expression and the sequence of the MDM-2 gene were examined in samples of bone marrow and/or peripheral mononuclear cells of 38 patients by using immunostaining, polymerase chain reaction (PCR), single strand conformation polymorphism, and sequencing. Immunohistochemical staining detected a weak accumulation of the MDM-2 protein in AML patients of FAB classification M4 and M5. RT-PCR analysis revealed a heterogeneou…

Do we Need a Triple Antibiotic Therapy?

To compare the efficacy and toxicity of triple antibiotic therapy in patients undergoing autologous peripheral blood-stem-cell transplantation (PBSCT) with literature data.

Transmission of angioimmunoblastic T-cell lymphoma by bone marrow transplant

Accidental transmission of lymphoma by bone marrow transplant is a rarely reported event [1–5], since candidates are only accepted for hematopoietic stem cell donation after a work-up that routinel...

Centre characteristics and procedure-related factors have an impact on outcomes of allogeneic transplantation for patients with CLL: a retrospective analysis from the European Society for Blood and Marrow Transplantation (EBMT)

Abstract Introduction:Even in the era of novel targeted therapies for the treatment of Chronic Lymphocytic Leukemia (CLL) patients, such as BTK, PI3K and BCL2 inhibitors, allogeneic hematopoietic stem cell transplantations (alloHCT) will remain an important treatment option for a subset of patients with very high risk CLL. The current study focused on the impact of center and procedure-related factors on outcomes after alloHCT, taking into account the impact of patient- and disease-related risk factors. Patients and Methods:Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analyzed. Their data were collected as part of the EBMT CLL Data Quality Initiative. Out…

Rituximab in vivo purging is safe and effective in combination with CD34-positive selected autologous stem cell transplantation for salvage therapy in B-NHL.

The purpose of this study was to evaluate feasibility and efficacy of Rituximab included into a sequential salvage protocol for CD20(+) B-NHL in relapse or induction failure. Twenty-seven patients with CD20(+) B-NHL in relapse or induction failure received Rituximab combined with DexaBEAM (R-DexaBEAM) for stem cell mobilization. Additional ex vivo selection of CD34-positive cells was performed using the CliniMacs device. Two doses of Rituximab were included in the high-dose therapy regimen (HDT). R-DexaBEAM was well tolerated and 26 of 27 patients mobilized sufficient numbers of CD34(+) blood stem cells. Application of R-DexaBEAM resulted in significant depletion of peripheral B cells. No t…

Campath-1H-Based Reduced-Intensity Conditioning Followed by Allogeneic Blood Stem-Cell Transplantation and Preemptive CD8-Depleted Donor Lymphocyte Infusions.

Abstract Recent reports have demonstrated the feasibility of using the anti-CD52 antibody Campath-1H for in vivo T-cell depletion (TCD) in the context of a fludarabine/melphalan-based reduced-intensity conditioning regimen (Kottaridis et al. Blood 2000, 96:2419). Major disadvantage of this protocol is the severe immunosuppression which results in an increased rate of opportunistic infections and disease relapses. Donor lymphocyte infusions (DLI) are frequently used to overcome this limitation. The application of DLI, however, is associated with a profound risk of GvHD. Depletion of CD8+ lymphocytes from either the allotransplant or from DLI has proven feasible to reduce the incidence of GvH…

Nonmyeloablative stem cell transplantation in adults with high-risk ALL may be effective in early but not in advanced disease

The feasibility of nonmyeloablative stem cell transplantation (NST) was evaluated in 22 adults with high-risk ALL. 16/22 patients had advanced disease and 11/22 had Ph+ ALL. Eleven patients received NST as first stem cell transplantation (SCT). Eleven patients had relapses after allogeneic or autologous SCT and underwent a salvage NST. 18/22 patients (82%) engrafted after NST. 13/16 patients (81%) with active disease reached complete remission (CR). 11 of 13 patients developed GVHD. After first NST 10/11 patients (91%) engrafted. Six of seven patients with active disease reached CR. Three of five relapsing patients reached subsequent CR after donor lymphocyte infusions, termination of immun…

Donor CD4 T cells convert mixed to full donor T-cell chimerism and replenish the CD52-positive T-cell pool after alemtuzumab-based T-cell-depleted allo-transplantation.

Donor lymphocyte infusions (DLI) are used to resolve mixed T-cell chimerism (TCC) after allo-SCT despite a substantial risk of GVHD. We analyzed the impact of prophylactic CD8-depleted (CD8(depl)) DLI in 20 recipients of anti-CD52 alemtuzumab in vivo T-cell-depleted allografts with declining donor TCC after day +60. A total of 13 patients received CD8(depl) DLI and 7 patients did not. All but one of the DLI patients converted to complete donor T-cell chimeras, whereas only one non-DLI patient converted spontaneously. DLI induced transient acute GVHD in five and extensive chronic GVHD in two patients. These data suggest the use of CD8(depl) DLI as an effective treatment for mixed TCC, partic…

Follow Up On CD8-Depleted Donor-Lymphocyte Infusions After T-Cell Depleted Allogeneic Hemopoietic Stem Cell Transplantation

We applied prophylactic CD8-depleted (CD8depl) donor lymphocyte infusions (DLI) in the setting of T-cell depleted reduced-intensity allogeneic hematopoietic stem cell transplantation (HSCT) in a phase I/II trial. T-cell depletion was carried out by the use of high-dose Alemtuzumab (100 mg or 60 mg for unrelated or sibling donor transplantation, respectively). We have demonstrated the feasibility of this approach after having treated 23 patients in this protocol (Meyer et al. Blood 2007). From 2004 to 2011, 134 patients with different hematologic diseases were included and followed for a median observation time of 1.5 years after transplantation (range, 1.5-9 years). Median age was 56 years …

Recovery of Varicella-Zoster Virus–Specific T Cell Immunity after T Cell–Depleted Allogeneic Transplantation Requires Symptomatic Virus Reactivation

Abstract Reactivated varicella-zoster virus (VZV) infection causes herpes zoster and commonly occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because VZV-specific T cell immunity is essential to prevent virus reactivation, we developed an interferon-γ enzyme-linked immunosorbent spot (ELISPOT) assay for the sensitive detection of VZV-reactive T cells at the single-cell level ex vivo. We used this assay to monitor the frequency of VZV-reactive T cells in 17 seropositive patients during the first year after T cell–depleted allo-HSCT. The patients did not receive anti-herpesvirus prophylaxis after stem cell engraftment. Independent of the magnitude of transferred d…

Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.

Abstract Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the contr…

Aggressive chemotherapy combined with G-CSF and maintenance therapy with interleukin-2 for patients with advanced myelodysplastic syndrome, subacute or secondary acute myeloid leukemia--initial results.

Aggressive chemotherapy of advanced myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) evolving from MDS, subacute AML and secondary AML has usually been associated with low complete remission (CR) rates, a high incidence of early death, and low disease-free survival. We therefore have initiated a phase-III trial of aggressive chemotherapy consisting of idarubicin, cytosine arabinoside, and VP-16 to improve the CR rate. Each chemotherapy cycle is followed by G-CSF to accelerate neutrophil recovery and to reduce the incidence of infections. Until now, 19 patients with high-risk AML have been entered. The CR rate is 47%, with only one death during induction. Patients achieving CR ar…

Quantification of fluorescent STR genotyping results for chimerism control after bone marrow transplantation

1. IntroductionEngraftment of donor stem cells after allogeneic bone marrow transplantation can begenetically monitored by PCR typing of DNA polymorphisms [1]. Successful engraftmentwith complete chimerism and presence of the donor’s genotype in the bone marrow has tobe demonstrated, and the presence of the patient’s alleles has to be excluded. Detection ofthe patient’s alleles provides evidence for an incomplete chimerism or for a relapse ofmalignant disease. STRs have been used successfully for this type of genetic monitoring[2]. For the present study, we have developed an approach to quantify the ratio of donorchimerism using mock mixture experiments. The usefulness of our approach is de…

Busulfan systemic exposure after oral administration of extemporeanously prepared high-dose busulfan capsules.

Purpose. The aim of the study was to analyze patients’ busulfan (BU) exposure after oral administration of extemporeanously prepared BU capsules prior to blood stem cell transplantation. Methods. Patients were treated with 1 mg/kg body weight BU administered orally every 6h on each of 4 consecutive days prior to blood stem cell transplantation. Each BU dose was administered in 1 gelatine capsule to be swallowed and containing the individually calculated dose of pure BU active substance. Blood samples were obtained from 6 adult patients 0, 30, 60, 90, 120, 180, 240, 300, and 360 min after the 1st, 5th, and 13th BU dose, frozen and analyzed subsequently by using a HPLC assay with UV detectio…

Prognostic Factors Affecting Outcome after Allogeneic Transplantation for Hematological Malignancies from Unrelated Donors: Results from a Randomized Trial

Several prognostic factors for the outcome after allogeneic hematopoietic stem-cell transplant (HSCT) from matched unrelated donors have been postulated from registry data; however, data from randomized trials are lacking. We present analyses on the effects of patient-related, donor-related, and treatment-related prognostic factors on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) in a randomized, multicenter, open-label, phase III trial comparing standard graft-versus-host-disease (GVHD) prophylaxis with and without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative co…

Impact of Prophylactic CD8-Depleted Donor-Lymphocyte Infusions After Allogeneic Hematopoietic Stem Cell Transplantation and Alemtuzumab Mediated T-Cell Depletion,

Abstract Abstract 4109 We have previously demonstrated that the application of CD8-depleted donor-lymphocyte infusions (DLI) is feasible after reduced-intensity conditioning and in vivo T-cell depletion by alemtuzumab. DLI overcome slow lymphocyte recovery associated with alemtuzumab-administration and improve anti-infectious immunity and reliably convert a decreasing T-cell chimerism (Meyer et al. Blood 2007 & BMT 2010). Here we provide clinical follow up data of 117 patients with different hematological diseases and a median observation time of 1 year (range, 1–86 months) post hematopoietic stem cell transplantation (HSCT). The majority of patients either suffered from an acute leukem…

Effect of Granulocyte-Macrophage Colony-Stimulating Factor on Neutropenia and Related Morbidity Induced by Myelotoxic Chemotherapy

Myelosuppression-related neutropenia is the major side effect of most anticancer chemotherapy. Despite considerable improvements in supportive care due to the advent of a variety of new antibiotic combinations, infection remains the main risk arising during the neutropenic period that follows intensive chemotherapy for cancer [1]. In addition, neutropenia is the major obstacle to dose escalation, frequency of cytoreductive treatment, and thus to improved cancer control. Regarding reduction of the period of neutropenia and increase of the maximum tolerated dose of effective anticancer agents, autologous bone marrow transplantation (ABMT) has recently offered new promise. However, as many as …

Prior Treatment with Alemtuzumab Interferes with T-Cell Engraftment After Allogeneic Stem Cell Transplantation in Patients with Chronic Lymphocytic Leukemia.

Abstract Abstract 3351 Poster Board III-239 Objectives: The majority of patients with chronic lymphocytic leukemia (CLL) who receive allogeneic hematopoietic cell transplantation (HCT) have fludarabine-refractory disease. The most active single agent in this disease stage is alemtuzumab. Alemtuzumab has a long half-life and induces profound T-cell depletion (TCD). Since TCD may mitigate graft-versus leukemia effects we evaluated „pre-conditioning“ with alemtuzumab followed by a washout period in order to minimize in vivo T-cell depletion of the graft in a phase II study (NCT 00337519). Methods: Patients received cytoreductive treatment with 3 × 30 mg alemtuzumab weekly prior to HCT. The sch…

Effect of granulocyte-macrophage colony-stimulating factor on neutropenia and related morbidity induced by myelotoxic chemotherapy.

Abstract purpose: A phase Ib/II clinical study was undertaken to assess the efficacy of recombinant human (rh) granulocyte-macrophage colony-stimulating (GM-CSF) factor in attenuating neutropenia and associated morbidity caused by high-dose anticancer chemotherapy administered in the presence or absence of autologous bone marrow support. patients and methods: Twenty-two patients with various solid tumors and lymphoid neoplasias were treated with a single daily subcutaneous dose of rh GM-CSF (250/μg/m 2 ) 48 hours after receiving a second cycle of highly myelotoxic chemotherapy for a period of 10 days. Within-subject comparisons on neutropenia-related clinical and laboratory variables were m…

AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION (AUTOHSCT) IN CLL: FIRST RESULTS OF AN EBMT RANDOMIZED TRIAL COMPARING AUTOTRANSPLANT VERSUS WAIT AND WATCH

Abstract Abstract 877 This phase-III randomized EBMT-intergroup trial studied the impact of a consolidating autoHSCT vs no consolidation for patients with CLL in Binet stage A progressive, B or C , in CR, nodular PR or VGPR after first or second line therapy. The primary objective was to show that autoHSCT increased the 5-year progression-free survival (PFS) by 30%. Although it had been calculated that 270 patients were to be randomized, the study was terminated by the steering committee in July 2007 due to poor accrual. Here we present a first analysis based on 69% of expected follow-up forms. Results: Between November 2001 and July 2007, 223 patients were enrolled (SFGM-TC/FCLLG n=98, MRC…

Failure of sustained engraftment after non-myeloablative conditioning with low-dose TBI and T cell-reduced allogeneic peripheral stem cell transplantation

We investigated whether a T cell-reduced allogeneic stem cell transplant (SCT) with minimal conditioning and subsequent donor lymphocyte infusions (DLI) could reduce the incidence and severity of GVHD while retaining stable engraftment. Five patients with hematological malignancies (three MM, one CLL, one Chediak-Higashi syndrome) were conditioned with TBI (200 cGy). One patient additionally received fludarabine (120 mg/m(2)). CsA and mofetyl-mycophenolate (MMF) were administered to prevent GVHD. All patients were grafted with >3 x 10(6)/kg highly purified CD34(+) cells together with 2 x 10(6)/kg CD3(+) cells (three patients) or 1 x 10(5)/kg CD3(+) cells (two patients). Quick hematopoietic …

Preemptive Transfer of GMP-Grade CD8-Depleted Donor Lymphocytes after T-Cell Depleted Reduced-Intensity Transplantation.

Abstract The combination of fludarabin (150mg/m2) / melphalan (140mg/m2) based reduced-intensity allo-transplantation (RIT) with in vivo T-cell depletion (TCD) by the anti-CD52 antibody alemtuzumab (100mg) has demonstrated efficient engraftment and reduced graft-versus-host disease (GVHD) (Kottaridis et al., Blood 2000). However, the slow lymphocyte recovery following this protocol is associated with reduced anti-infectious and antitumor immunity. In an attempt to improve immune-reconstitution after TCD / RIT, we investigated the early preemptive use of CD8-depleted donor lymphocyte infusions (DLIs). For CD8 depletion of donor leukaphereses, a new depletion protocol using clinical grade CD8…

Intensive chemotherapy with idarubicin, ara-C, etoposide, and m-AMSA followed by immunotherapy with interleukin-2 for myelodysplastic syndromes and high-risk Acute Myeloid Leukemia (AML)

Intensive chemotherapy followed by treatment with interleukin-2 (IL-2) was evaluated in a prospective, randomized, multicenter trial including 18 patients with refractory anemia with excess of blasts in transformation (RAEB-T), 86 patients with acute myeloid leukemia (AML) evolving from myelodysplastic syndromes, and six patients with secondary AML after previous chemotherapy. Median age was 58 years (range: 18-76 years). Forty-nine patients (45%) achieved a complete remission (CR) after two induction cycles with idarubicin, ara-C, and etoposide, 52% of them aged/=60 years and 35% aged60 years (p=0.06). After two consolidation courses, patients were randomized to four cycles of either high-…

Effect of interleukin-3 pretreatment on granulocyte/macrophage colony-stimulating factor induced mobilization of circulating haemopoietic progenitor cells.

Recombinant human colony stimulating factors (CSFs) as single agents are increasingly used for mobilizing peripheral blood progenitor cells (PBPCs) for stem cell transplantation. We have shown in rhesus monkeys that interleukin-3 (IL-3) pretreatment markedly potentiated the increase in PBPC numbers of subsequent administration of granulocyte/macrophage-CSF (GM-CSF). Here we studied the effect of IL-3 pretreatment on GM-CSF-induced mobilization of PB progenitors in patients who were potential candidates for autologous stem cell transplantation (n = 16). Patients were treated with GM-CSF at a dose of 5 micrograms/kg/d for 5 d and after a treatment free interval received another cycle of GM-CS…

Infectious complications during neutropenia subsequent to peripheral blood stem cell transplantation

Type, severity and incidence of infection during the neutropenic period after peripheral blood stem cell transplantation (PBSCT) for treatment of malignant disease were studied in 66 patients treated at a single institution. Data of 34 female and 32 male patients with a median age of 43 years suffering from leukemia (12), lymphoma (35), multiple myeloma (six) or solid tumors (13) were retrospectively analyzed. All patients had received at least 2.5 x 10(6) CD34-positive cells for stem cell rescue after high-dose chemotherapy. Ninety-four percent of the patients experienced at least one febrile episode during their post-transplant course. The patients recovered quickly and defervesced after …

Die Hochdosischemotherapie in der Behandlung des Mammakarzinoms: Gegenwärtiger Stand und Grenzen der Therapiemethode

Current Status and Limits: High-dose chemotherapy with autologous haematopoietic stem cell rescue has become in recent years a widely accepted therapeutic modality for advanced stage breast cancer in North America. The emergence of modern supportive measures like peripheral blood stem cell rescue has significantly decreased the toxicity and cost of high-dose chemotherapy. The rationale for use of escalated chemotherapy doses in breast cancer is the establishment of a dose-response relationship, with higher doses producing increased response rates in preclinical studies as well as in clinical trials. The dose limiting myelotoxicity of several active agents in breast cancer can only be overco…

Graft-Versus-Host Disease or Infection: Rapid Detection of HLA Mismatch-Reactive T Cells Ex Vivo Can Facilitate Diagnosis and Guide Therapy after Allogeneic Transplantation.

Abstract Diagnosis of graft-versus-host disease (GVHD) is mainly based on clinical features and on tissue biopsies. However, clinicians and pathologists are well aware of cases, in which GVHD cannot be distinguished from infections arising from severe immunodeficiency after allogeneic stem-cell transplantation (SCT). This may pose a deep therapeutic dilemma of whether to modify immunosuppressive treatment or to use donor lymphocyte infusion (DLI) for promoting anti-microbial immunity. We observed a 68-year-old patient with myelodysplastic syndrome who developed acute GVHD grade II of skin and gut at d+16 after T-cell depleted reduced-intensity SCT (Fig. 1). GVHD was confirmed by histology a…