Adoptive Immunotherapy in Chimeras with Donor Lymphocytes

Allogeneic stem cell transplantation has a well-defined indication in the treatment of hematological malignancies. The beneficial immune effect of allogeneic marrow transplantation has long been known, but only recently have methods been developed to separate the graft-versus-leukemia (GVL) effect from graft-versus-host disease (GVHD). Animal experiments have shown that lymphocytes from the marrow donor can be transfused without causing severe GVHD if stable chimerism and tolerance is established. First clinical studies have been preformed in patients with recurrent chronic myelogenous leukemia. In these patients complete molecular remissions were induced that persist without further maintenance treatment. These results have been confirmed in larger multicenter studies in Europe and the USA. The best results were obtained in chronic myelogenous leukemia (CML); repeated successes have been reported in relapsing acute myeloid leukemia (AML), myelodysplastic syndromes and multiple myeloma (MMY), and rare responses were reported for acute lymphoid leukemia. Contrary to animal experiments GVHD has been observed in human patients although to a lesser extent than expected in transplants not given immunosuppression. Secondly myelosuppression has been observed in patients treated with relapsing CML. In CML the incidence of GVHD could be reduced by depleting CD8(+) T cells from the donor lymphocyte concentrate. Alternatively only small numbers of T lymphocytes can be transfused and in the case of failing responses, the numbers of donor lymphocytes may be increased. Results in recurrent AML have been improved by the use of low-dose cytosine arabinoside, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor mobilized blood cells as compared to lymphocytes only. In MMY the response rate is higher than in AML, but the remissions are of limited duration in most patients. Several protocols have been designed to include preemptive donor lymphocyte transfusion in patients with a high relapse risk after transplantation. Problems remain to avoid chronic GVHD and to circumvent the immune escape mechanisms of leukemia. Copyright (C) 2003 S. Karger AG, Basel

Immunotherapy with FBTA05 (Bi20), a trifunctional bispecific anti-CD3 x anti-CD20 antibody and donor lymphocyte infusion (DLI) in relapsed or refractory B-cell lymphoma after allogeneic stem cell transplantation: study protocol of an investigator-driven, open-label, non-randomized, uncontrolled, dose-escalating Phase I/II-trial

Background: Patients with B cell malignancies refractory to allogeneic stem cell transplantation (SCT) can be treated by subsequent immunotherapy with donor lymphocyte infusions (DLI). But unlike myeloid leukemia, B cell leukemia and lymphoma are less sensitive to allogeneic adoptive immunotherapy. Moreover, the beneficial graft-versus-lymphoma (GVL) effect may be associated with moderate to severe graft-versus-host disease (GVHD). Thus, novel therapeutic approaches augmenting the anti-tumor efficacy of DLI and dissociating the GVL effect from GVHD are needed. The anti-CD20 x anti-CD3 trifunctional bispecific antibody (trAb) FBTA05 may improve the targeting of tumor cells by redirecting immune allogeneic effector cells while reducing the risk of undesirable reactivity against normal host cells. Hence, FBTA05 may maximize GVL effects by simultaneously decreasing the incidence and severity of GVHD. Methods/Design: Based on this underlying treatment concept and on promising data taken from preclinical results and a small pilot study, an open-label, non-randomized, uncontrolled, dose-escalating phase I/II-study is conducted to evaluate safety and preliminary efficacy of the investigational antibody FBTA05 in combination with DLI for patients suffering from rituximab-and/or alemtuzumab-refractory, CD20-positive low-or high-grade lymphoma after allogeneic SCT. During the first trial phase with emphasis on dose escalation a maximum of 24 patients distributed into 4 cohorts will be enrolled. For the evaluation of preliminary efficacy data a maximum of 12 patients (6 patients with low-grade lymphoma and/or Chronic Lymphocytic Leukemia (CLL) / 6 patients with high-grade or aggressive lymphoma) will attend the second phase of this clinical trial. Discussion: Promising data (e. g. induction of cellular immunity; GVL predominance over GVHD; achievement of partial or complete responses; prolongation of time-to-progression) obtained from this phase I/II trial would represent the first milestone in the clinical evaluation of a novel immunotherapeutic concept for treatment-resistant low- and high-grade lymphoma and NHL patients in relapse

High-risk additional chromosomal abnormalities at low blast counts herald death by CML

Blast crisis is one of the remaining challenges in chronic myeloid leukemia (CML). Whether additional chromosomal abnormalities (ACAs) enable an earlier recognition of imminent blastic proliferation and a timelier change of treatment is unknown. One thousand five hundred and ten imatinib-treated patients with Philadelphia-chromosome-positive (Ph+) CML randomized in CML-study IV were analyzed for ACA/Ph+ and blast increase. By impact on survival, ACAs were grouped into high risk (+8, +Ph, i(17q), +17, +19, +21, 3q26.2, 11q23, -7/7q abnormalities; complex) and low risk (all other). The presence of high- and low-risk ACAs was linked to six cohorts with different blast levels (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox model. One hundred and twenty-three patients displayed ACA/Ph+ (8.1%), 91 were high risk. At low blast levels (1-15%), high-risk ACA showed an increased hazard to die compared to no ACA (ratios: 3.65 in blood; 6.12 in marrow) in contrast to low-risk ACA. No effect was observed at blast levels of 20-30%. Sixty-three patients with high-risk ACA (69%) died (n = 37) or were alive after progression or progression-related transplantation (n = 26). High-risk ACA at low blast counts identify end-phase CML earlier than current diagnostic systems. Mortality was lower with earlier treatment. Cytogenetic monitoring is indicated when signs of progression surface or response to therapy is unsatisfactory

Influence of polymorphism within the heme oxygenase-I promoter on overall survival and transplantation-related mortality after allogeneic stem cell transplantation

AbstractAside from major and minor histocompatibility antigens, genetic polymorphisms of various donor and host genes have been found to be risk factors for graft-versus-host disease and transplantation-related mortality (TRM). The heme oxygenase I (HO-I) protein has been implicated in regulating inflammatory response and has been described as a “protective gene” in solid organ transplantation. In humans, the promoter region displays length polymorphism due to a variable number of GT repeats. Individuals exhibiting 29 or fewer GT repeats express higher levels of HO-I on cellular stress compared with individuals with 30 or more GT repeats. We retrospectively analyzed length polymorphisms of 92 donor–host pairs undergoing allogeneic stem cell transplantation. Our findings demonstrate that mainly donor polymorphism leading to high expression of HO-1 (<30 GT repeats) on stress signals is associated with reduced overall survival, and that TRM is significantly increased in this group. This reduction in survival was most prominent when unrelated donors were used. Polymorphisms of the recipient HO-1 genes did not influence posttransplantation outcomes. We conclude that HO-1 polymorphism represents a new genetic risk factor for TRM and overall survival

Bone Loss after Allogeneic Haematopoietic Stem Cell Transplantation: A Pilot Study on the Use of Zoledronic Acid

Purpose. Bone loss is a common phenomenon following allogeneic haematopoietic stem cell transplantation (allo-HSCT). The study aimed on tolerance and efficacy of zoledronic acid (ZA) in patients after allo-HSCT. Methods. 40 patients' with osteoporosis or osteopenia were recruited on this phase II study. ZA was given at a dose of 4 mg IV every 3 months for 2 years (yrs). BMD was determined by dual-energy X-ray absorptiometry (LS lumbar spine, FH femur hip). Patients were evaluated for deoxypyridinoline (Dpd) and calcium excretion by longitudinal measurements. Results. 36 patients who had received at least 3 doses of ZA were evaluable. 26 patients had at least two BMD measurements since baseline (BMD group). Among these patients, BMD increased from 0.97 ± 0.15 to 1.10 ± 0.18 g/cm² (LS baseline—2 yrs, Δ+11.6 ± 6.0%, P < 0.001) and from 0.82 ± 0.10 to 0.91 ± 0.10 g/cm² (FH baseline—2 yrs, Δ+7.5 ± 7.0%, P < 0.001). Factors associated with an increase in BMD were younger age, female donor sex, and immunosuppression with CSA/MTX. Conclusion. ZA was generally well tolerated; it increases BMD and reduces Dpd excretion significantly in patients with bone loss after allo-HSCT

Mesenchymal stromal cells for treatment of steroid-refractory GvHD : a review of the literature and two pediatric cases

Severe acute graft versus host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. Human mesenchymal stromal cells (MSCs) play an important role in endogenous tissue repair and possess strong immune-modulatory properties making them a promising tool for the treatment of steroid-refractory GvHD. To date, a few reports exist on the use of MSCs in treatment of GvHD in children indicating that children tend to respond better than adults, albeit with heterogeneous results. We here present a review of the literature and the clinical course of two instructive pediatric patients with acute steroid-refractory GvHD after haploidentical stem cell transplantation, which exemplify the beneficial effects of third-party transplanted MSCs in treatment of acute steroid-refractory GvHD. Moreover, we provide a meta-analysis of clinical studies addressing the outcome of patients with steroid-refractory GvHD and treatment with MSCs in adults and in children (n = 183; 122 adults, 61 children). Our meta-analysis demonstrates that the overall response-rate is high (73.8%) and confirms, for the first time, that children indeed respond better to treatment of GvHD with MSCs than adults (complete response 57.4% vs. 45.1%, respectively). These data emphasize the significance of this therapeutic approach especially in children and indicate that future prospective studies are needed to assess the reasons for the observed differential response-rates in pediatric and adult patients. Additional file 1: MSCs expansion and release criteria.his file contains a detailed description of the MSCs expansion and release criteria for Case A and Case B

Comparison of matched sibling donors versus unrelated donors in allogeneic stem cell transplantation for primary refractory acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT

Background: Primary refractory acute myeloid leukemia (PRF-AML) is associated with a dismal prognosis. Allogeneic stem cell transplantation (HSCT) in active disease is an alternative therapeutic strategy. The increased availability of unrelated donors together with the significant reduction in transplant-related mortality in recent years have opened the possibility for transplantation to a larger number of patients with PRF-AML. Moreover, transplant from unrelated donors may be associated with stronger graft-mediated anti-leukemic effect in comparison to transplantations from HLA-matched sibling donor, which may be of importance in the setting of PRF-AML. Methods: The current study aimed to address the issue of HSCT for PRF-AML and to compare the outcomes of HSCT from matched sibling donors (n = 660) versus unrelated donors (n = 381), for patients with PRF-AML between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results: HSCT provide patients with PRF-AML a 2-year leukemia-free survival and overall survival of about 25 and 30%, respectively. In multivariate analysis, two predictive factors, cytogenetics and time from diagnosis to transplant, were associated with lower leukemia-free survival, whereas Karnofsky performance status at transplant >= 90% was associated with better leukemia-free survival (LFS). Concerning relapse incidence, cytogenetics and time from diagnosis to transplant were associated with increased relapse. Reduced intensity conditioning regimen was the only factor associated with lower non-relapse mortality. Conclusions: HSCT was able to rescue about one quarter of the patients with PRF-AML. The donor type did not have any impact on PRF patients' outcomes. In contrast, time to transplant was a major prognostic factor for LFS. For patients with PRF-AML who do not have a matched sibling donor, HSCT from an unrelated donor is a suitable option, and therefore, initiation of an early search for allocating a suitable donor is indicated

Immunotherapy with FBTA05 (Bi20), a trifunctional bispecific anti-CD3 x anti-CD20 antibody and donor lymphocyte infusion (DLI) in relapsed or refractory B-cell lymphoma after allogeneic stem cell transplantation: study protocol of an investigator-driven, open-label, non-randomized, uncontrolled, dose-escalating Phase I/II-trial

BACKGROUND: Patients with B cell malignancies refractory to allogeneic stem cell transplantation (SCT) can be treated by subsequent immunotherapy with donor lymphocyte infusions (DLI). But unlike myeloid leukemia, B cell leukemia and lymphoma are less sensitive to allogeneic adoptive immunotherapy. Moreover, the beneficial graft-versus-lymphoma (GVL) effect may be associated with moderate to severe graft-versus-host disease (GVHD). Thus, novel therapeutic approaches augmenting the anti-tumor efficacy of DLI and dissociating the GVL effect from GVHD are needed. The anti-CD20 x anti-CD3 trifunctional bispecific antibody (trAb) FBTA05 may improve the targeting of tumor cells by redirecting immune allogeneic effector cells while reducing the risk of undesirable reactivity against normal host cells. Hence, FBTA05 may maximize GVL effects by simultaneously decreasing the incidence and severity of GVHD. METHODS/DESIGN: Based on this underlying treatment concept and on promising data taken from preclinical results and a small pilot study, an open-label, non-randomized, uncontrolled, dose-escalating phase I/II-study is conducted to evaluate safety and preliminary efficacy of the investigational antibody FBTA05 in combination with DLI for patients suffering from rituximab- and/or alemtuzumab-refractory, CD20-positive low- or high-grade lymphoma after allogeneic SCT. During the first trial phase with emphasis on dose escalation a maximum of 24 patients distributed into 4 cohorts will be enrolled. For the evaluation of preliminary efficacy data a maximum of 12 patients (6 patients with low-grade lymphoma and/or Chronic Lymphocytic Leukemia (CLL) / 6 patients with high-grade or aggressive lymphoma) will attend the second phase of this clinical trial. DISCUSSION: Promising data (e.g. induction of cellular immunity; GVL predominance over GVHD; achievement of partial or complete responses; prolongation of time-to-progression) obtained from this phase I/II trial would represent the first milestone in the clinical evaluation of a novel immunotherapeutic concept for treatment-resistant low- and high-grade lymphoma and NHL patients in relapse. TRIAL REGISTRATION: NCT0113857