Dag Heldal

Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: An individual patient data meta-analysis of nine randomized trials

PURPOSE Considerable uncertainty exists regarding relative effects of allogeneic peripheral blood stem cells transplantation (PBSCT) versus bone marrow transplantation (BMT) on outcomes of patients with hematologic malignancies. PATIENTS AND METHODS To provide the totality of research evidence related to the effects of PBSCT versus BMT, we conducted an individual-patient data meta-analysis using data from nine randomized trials enrolling 1,111 adult patients. RESULTS Compared with BMT, PBSCT led to faster neutrophil (odds ratio [OR] = 0.31; 95% CI, 0.25 to 0.38; P < .00001) and platelet engraftment (OR = 0.52; 95% CI, 0.44 to 0.61; P < .00001). PBSCT was associated with a significant increase in the development of grade 3-4 acute graft-versus-host disease (GVHD; OR = 1.39; 95% CI, 1.03 to 1.88) and extensive (47% v 31% at 3 years; OR = 1.89; 95% CI, 1.47 to 2.42; P < .000001) and overall chronic GVHD (68% v 52% at 3 years; OR = 1.92; 95% CI, 1.47 to 2.49; P < .000001), but not grade 2-4 acute GVHD (54% v 53%; P = .49). PBSCT was associated with a decrease in relapse (21% v 27% at 3 years; OR = 0.71; 95% CI, 0.54 to 0.93; P = .01) in both late-stage-(33% v 51% at 3 years; OR = 0.59; 95% CI, 0.38 to 0.93; P = .02) and early-stage-disease patients (16% v 20% at 3 years; OR = 0.69; 95% CI, 0.49 to 0.98; P = .04). Nonrelapse mortality was not different between groups. Overall and disease-free survival were only statistically significantly improved in patients with late-stage disease (overall survival: 46% v 31% at 3 years; OR = 0.64; 95% CI, 0.46 to 0.90; P = .01; disease-free survival: 41% v 27% at 3 years; OR = 0.63 95% CI, 0.45 to 0.87; P = .01). CONCLUSION PBSCT is associated with a decreased relapse rate in hematologic malignancies and improvement in overall and disease-free survival in patients with late-stage disease. PBSCT is also associated with a significant risk of extensive chronic GVHD.

Donation of stem cells from blood or bone marrow: results of a randomised study of safety and complaints

Biological consequences and physical complaints were compared for donors randomly assigned either to blood stem cell (BSC) or bone marrow (BM) donation. In the period 1994–1999, 61 consecutive donors were included. The BSC donors were given G-CSF 10 μg/kg s.c., daily during 5 days before the first leukapheresis. Nineteen donors had one leukapheresis, 10 required two and one donor needed three leukaphereses in order to reach the target cell number of 2 × 106 CD34+ cells/kg bw of the recipient. A median platelet nadir of 102 × 109/l was reached shortly after the last leukapheresis. Three weeks post harvest, 17 of 30 BSC donors had a mild leukopenia. Six had a leukopenia lasting more than a year before returning to normal values. Both groups were monitored prospectively through a standardised questionnaire completed by the donors. BSC donation was significantly less burdensome than BM donation and was preferred by the donors. The short-term risks of BSC mobilisation and harvest seem negligible. The potential long-term effects of G-CSF are unresolved and the donors must be followed closely.Bone Marrow Transplantation (2002) 29, 479–486. doi:10.1038/sj.bmt.1703418

Extracorporeal photopheresis (photochemotherapy) in the treatment of acute and chronic graft versus host disease: immunological mechanisms and the results from clinical studies

Abstract Extracorporeal photopheresis (ECP) is an immunomodulatory alternative for treatment of graft versus host disease (GVHD). The blood is then separated into its various components through apheresis; buffy coat cells are thereafter treated with 8-methoxypsoralen before exposure to ultraviolet light and finally reinfused into the patient. There is a general agreement that this treatment has an anti-GVHD effect, but the mechanisms of action behind this effect are only partly understood. However, altered maturation of dendritic cells (DC) and thereby indirect modulation of T-cell reactivity seems to be one important mechanism together with DC-presentation of antigens derived from apoptotic donor T cells and induction of regulatory T cells. The treatment has been best studied in patients with chronic GVHD (both pediatric and adult patients), but most studies are not randomized and it is difficult to know whether the treatment is more effective than the alternatives. The clinical studies of ECP in adults with acute GVHD are few and not randomized; it is not possible to judge whether this treatment should be a preferred second- or third-line treatment. There is no evidence for increased risk of leukemia relapse or suppression of specific graft versus leukemia reactivity by this treatment, so specific antileukemic immunotherapy may still be possible. Thus, even though the treatment seems effective in patients with GVHD, further clinical (especially randomized) as well as biological studies with careful standardization of the treatment are needed before it is possible to conclude how ECP should be used in acute and chronic GVHD.

Fewer relapses and increased chronic GVHD in patients transplanted with blood stem cells: a 5-year follow-up in a single centre study

Summary:A total of 61 consecutive adult patients with haematological malignancies with an HLA-identical or one antigen-mismatched haploidentical family donor were randomised to allogeneic transplantation with blood stem cells (BSC) or bone marrow (BM). The median observation time was 5 years. Apart from engraftment parameters and acute graft-versus-host disease (GVHD), transplant-related mortality (TRM), incidence and severity of chronic GVHD, relapse, leukaemia-free survival (LFS) and overall survival (OS) were recorded. In the BSC and BM group, respectively, TRM was 8/30 and 4/30 (P=0.405), the incidence of chronic GVHD was 15/26 and 11/30 (P=0.138), extensive chronic GVHD was 10/26 and 4/30 (P=0.034), and relapse one and 10 patients (P=0.007). In log-rank test restricted to the cases allografted from HLA-identical donors, the difference remained significant with regard to relapse incidence (P=0.039), but not extensive chronic GVHD (P=0.072). No difference in LFS and OS was observed. In conclusion, our study strongly indicates an enhanced graft-versus-leukaemia effect in BSC recipients, which is not expressed in increased survival. The increased chronic GVHD in these patients may contribute, but the relation is complex and not yet understood.

Skin biopsies for early diagnosis and prognosis of graft-versus-host disease in recipients of allogeneic stem cells from blood or bone marrow.

A total of 61 patients with haematological malignancies were randomised either to allogeneic transplantation with blood stem cells (BSC) or bone marrow (BM), of whom 37 patients gave their consent to participate in a skin biopsy trial. Skin biopsies were performed before and after transplantation. The main objective was to assess whether biopsies of normal and affected skin from patients allografted with BSC showed a different histopathological and immunohistochemical pattern as compared to biopsies taken from patients allografted with BM. In addition, we wished to clarify whether sequential skin biopsies could be of prognostic value with regard to graft-versus-host disease (GVHD). Biopsies from normal or affected skin in BSC allografted did not disclose a different pattern as compared to BM transplants. Biopsies taken before the outbreak of acute and chronic GVHD showed no substantial differences between the groups. Irrespective of the type of allograft, the immunohistochemical picture of affected skin consistent with acute GVHD was dominated by a significantly higher number of T-lymphocytes (CD8+). Biopsies from normal skin before the outbreak of GVHD had no predictive value with regard to the development of acute or chronic GVHD. Immunohistochemistry is of supplementary help in distinguishing changes caused by cytotoxic agents from those caused by acute GVHD.

Ultra-short course sirolimus contributes to effective GVHD prophylaxis after reduced-intensity allogeneic hematopoietic cell transplantation

Reduced-intensity conditioning (RIC) allo-SCT is a potentially curative treatment approach for patients with relapsed Hodgkin’s or non-Hodgkin’s lymphoma. In the present study, 37 patients underwent RIC allo-SCT after induction treatment with EPOCH-F(R) using a novel form of dual-agent immunosuppression for GVHD prophylaxis with CsA and sirolimus. With a median follow-up of 28 months among survivors, the probability for OS at 3 and 5 years was 56%. Treatment-related mortality was 16% at day +100 and 30% after 1 year of transplant. Acute GVHD grades II–IV developed in 38% of patients, suggesting that the regimen consisting of CsA and an ultra-short course of sirolimus is effective in the prevention of acute GVHD.

Treatment outcome in adults with acute lymphoblastic leukemia: 50% long-term disease-free survival

Treatment outcome in adults with acute lymphoblastic leukemia: 50% long-term disease-free survival

Short-term side effects and attitudes towards second donation: A comparison of related and unrelated haematopoietic stem cell donors

The Nordic Register of Haematopoietic Stem Cell Donors (NRHSD) has registered related and unrelated donors from 10 transplant centres in Sweden, Norway, Finland and Denmark since 1998. We present a prospective, observational study of 1,957 donors, focusing mainly on the differences between related and unrelated donors. Related donors are reported to have more comorbidities, but similar side effects compared with unrelated donors. Side effects after BM or PBSC donation are generally of short duration and in this study no deaths, myocardial infarctions, splenic ruptures, or thromboembolic events are reported. Interestingly, related donors express more hesitancy towards donating again when asked 1 month after donation.

Eltrombopag in Good’s Syndrome

Goods syndrome is a rare acquired immunodeficiency associated with thymoma. Eltrombopag is a thrombopoietin receptor agonist and has been shown to be a valuable supplement to the treatment of several types of refractory cytopenias. In this paper, we describe a male patient suffering from Goods syndrome with immune-mediated T-cell driven pancytopenia and absence of megakaryopoiesis. He was successfully treated with eltrombopag resulting in a multilineage clinical response.

Malignant Phyllodes Tumor and Acute Megakaryoblastic Leukemia Sharing a Common Clonal Origin

There is a well-known association in male patients between mediastinal germ cell tumors (GCT) and hematologic malignancies, with a propensity towards acute megakaryoblastic leukemia. These rare malignancies have been shown to share a common clonal origin, often deduced from the finding of isochromosome 12p, i(12p), in cells from both the solid tumor and the leukemia, and thus are now known to represent different manifestations of the same clonal process. We treated a young female patient with a malignant phyllodes tumor followed by an acute megakaryoblastic leukemia and found several of the same marker chromosomes by karyotype analysis of cells from both the tumor and the leukemia implying a common clonal origin of the two. To the best of our knowledge, this has not been demonstrated in phyllodes tumors before, but indicates that the same type of leukemization may occur of this tumor as has been described in mediastinal GCT.