Mats Bengtsson

High-dose therapy with autologous stem cell transplantation in patients with peripheral T cell lymphomas

Peripheral T cell lymphomas (PTCL) have a poorer prognosis after conventional treatment than do high-grade B cell lymphomas. The place for high-dose therapy (HDT) with autologous stem cell support in these patients is still not clear. Forty patients, 10 women and 30 men, median age 41.5 years (range 16–61) with PTCL were treated with HDT and autologous stem cell support at The Norwegian Radium Hospital, Oslo, Norway and The University Hospital, Uppsala, Sweden, between February 1990 and September 1999. The histologic subtypes were: PTCL unspecified, 20 patients; intestinal, two patients; angioimmunoblastic (AILD), two patients; angiocentric, two patients and anaplastic large cell lymphoma (ALCL), 14 patients. All patients had chemosensitive disease and had received anthracycline-containing regimens prior to transplantation. At the time of HDT, 17 patients were in first PR or CR and 23 were in second or third PR or CR. Conditioning regimens were BEAM in 15 patients, BEAC in 14 patients, cyclophosphamide and total body irradiation (TBI) in eight patients, BEAC, without etoposide and TBI in one patient and mitoxantrone and melphalan in two patients. There were three (7.5%) treatment-related deaths. The estimated overall survival (OS) at 3 years was 58%, the event-free survival (EFS) 48% and the relapse-free survival (RFS) 56%, with a median follow-up of 36 months (range 7–100) for surviving patients. The patients with ALCL tended to have a better prognosis compared to those with other PTCL subtypes, OS 79% vs 44%, respectively. In conclusion, patients with chemosensitive PTCL who are failing to achieve CR with first-line chemotherapy or are in relapse can successfully be treated with HDT and autologous stem cell support. Bone Marrow Transplantation (2001) 27, 711–716.

Mobilization of CD34+ cells by glycosylated and nonglycosylated G‐CSF in healthy volunteers — a comparative study

Abstract: In vitro studies indicate that lenograstim (glycosylated G–CSF) is more potent than filgrastim (nonglycosylated G–CSF) on a weight for weight basis. However, such a difference has not yet been shown in vivo. The primary objective of this trial was to compare the efficacy of equivalent doses (μg) of lenograstim and filgrastim in mobilizing CD34+ cells. Thirty‐two healthy male volunteers, median age 27 yr (19–44 yr), were randomized to receive either lenograstim 10 μg/kg followed by filgrastim 10 μg/kg or vice versa with a washout period of a minimum 4 wk. Both drugs were administered as s.c. injections once daily for 5 d (d 1–5). CD34+ cells were mobilized with a similar kinetics, peaking at median d 6 (5–6) for both drugs. A significant difference in favour of lenograstim was shown for peak number of CD34+ cells/μl blood (104±38 vs. 82±35, mean±l SD, p<0.0001, paired t‐test, n=30) and number of CFU‐GM/μl blood at d 6 (14.6±8.4 vs. 10.2±4.6, p<0.0001), respectively. There was no difference in the d 6 number of CD3+ cells. Both drugs were generally well tolerated and did not differ with respect to number of adverse events. In conclusion, lenograstim 10 μg/kg/d mobilizes PBPC more efficiently than the identical dose of filgrastim, indicating a difference in in vivo potency between the two G–CSFs.

Stimulation of NK cell, T cell, and monocyte functions by the novel immunomodulator Linomide after autologous bone marrow transplantation. A pilot study in patients with acute myeloid leukemia.

Immunostimulatory therapy is at present considered after autologous bone marrow transplantation (ABMT) in order to mimic the allogeneic graft-versus-leukemia effect and thereby reduce the relapse rate. In a pilot study, five adults with acute myeloid leukemia were treated with the new immunomodulator Linomide post-ABMT. Linomide (0.3 mg/kg/week orally) was given in cycles of three weeks followed by three weeks of rest for up to six months. During treatment periods cyclic increases of CD56+CD3- and CD16+ NK cells were observed in parallel with enhanced cytotoxic activity of patient cells against both the NK-sensitive K562 and NK-resistant Daudi cell lines. A cyclic increase of CD14+ monocytic cells was also recorded. The proliferative responses of patient cells to PHA and allogeneic cells (MLC) were enhanced during Linomide therapy. The in vitro production of TNF alpha, IFN gamma, and IL-1 followed the same cyclic increase during treatment periods. Side effects were generally mild, and no harmful effects on engraftment were seen. Linomide therapy after ABMT thus induces a broad immunostimulation that offers a potential benefit with regard to leukemia-free survival.

Donor safety: The role of the WMDA in ensuring the safety of volunteer unrelated donors: Clinical and ethical considerations

Since the beginning of hematopoietic stem cell harvesting from volunteer unrelated donors, ensuring donor safety has been a necessary goal of all parties involved in the process. As donation of BM or PBSCs is not in the interest of the donors own physical health, donor registries and transplantation centers must take into account both medical and ethical aspects involved in the donation procedure. One of the principal goals leading to the formation of the World Marrow Donor Association (WMDA) was to establish internationally acceptable standards for all aspects of unrelated donor care.

B lymphocyte regeneration in marrow and blood after autologous bone marrow transplantation: Increased numbers of B cells carrying activation and progression markers

The reconstitution of B cells in the bone marrow and peripheral blood was prospectively studied in 27 patients undergoing autologous bone marrow transplantation (ABMT). No major differences in B cell regeneration patterns were recorded between patients receiving marrows purged of B cells (anti-CD10 + 19; n = 17) and patients receiving unpurged marrows (n = 10). Compared with healthy controls, elevated absolute and relative numbers of B cells were recorded in the blood and marrow at +6 and +12 months in both groups of patients. CD23+ B cells were severely depressed during the first three months post ABMT, indicating immaturity. A twofold increase in B cells carrying the activation marker 4F2 was recorded in the marrow at +1 month. Serum immunoglobulin levels (IgG, IgA, IgM) were within low-normal range throughout the study. The depressed B cell responses reported after allogeneic and autologous BMT could in part be explained by the low expression of the CD23 antigen on B cells after such therapy.

Treatment of pure red-cell aplasia and aplastic anaemia with ciclosporin: long-term clinical effects.

6 patients with pure red‐cell aplasia were treated with Ciclosporin (Cyclosporine A; CS) alone or combined with prednisolone for a period of 9–46 (median 27) months. Prior to study, 5 cases had refractory disease, steroids were contraindicated in 1, and 4/6 patients, including 2 cases with congenital disease, had a disease duration exceeding 11 years. A complete haematological response was obtained in 5/6 subjects, and a partial response in 1. When the pre‐treatment Hb levels (mean±S.D. = 64±13 g/l, range 41–80) for all 6 PRCA patients were compared with the Hb levels after 6 months of CS therapy (104±17 g/1, 80–125), a significant improvement was registered (p < 0.005). In half of the patients, remission is maintained with CS as single drug in a dose‐dependent manner. We also treated 5 patients with refractory severe aplastic anaemia with CS (1 case) or CS plus prednisolone (4 cases) for 3–27 (median 10) months. Only 1 patient responded. In this case, a complete haematological remission was induced with CS alone, and remission has been maintained for 27 months. Side effects of CS therapy were common but were dose‐dependent and reversible, with the exception of persistent nephrotoxicity in 1 patient with pure red‐cell aplasia. Based on our present results and a survey of the literature, we conclude that CS therapy is effective and indicated in refractory pure red‐cell aplasia. In severe aplastic anaemia resistant to conventional immunosuppression, the response rate is lower, but a small proportion (around 15%) of patients may benefit from CS therapy. Longer treatment periods may, however, be needed to evaluate the role of CS in aplastic anaemia.

Regeneration of CALLA (CD10+), TdT+ and double-positive cells in the bone marrow and blood after autologous bone marrow transplantation.

Abstract:  In this prospective study we investigated the frequency of CD10+, TdT+ and CD10+ TdT+ mononuclear cells in the bone marrow (BM) and peripheral blood (PB) before and after autologous bone marrow transplantation (ABMT). 49 patients treated for acute lymphoblastic or myeloblastic leukaemia, malignant lymphoma or multiple myeloma were included. A significant increase in CD10+ cells occurred in BM in both children and adults after ABMT. In children, we also found a significant increase in CD10+ cells in PB. In individual patients remaining in remission, up to 34% CD10+ cells having a normal Ig kappa/lambda light chain ratio were recorded after ABMT. In children, the percentage of TdT+ and CD10+ TdT+ cells increased significantly in BM. In most cases the CD10/TdT‐ratio was greater than 1.0, but during early regeneration after ABMT this ratio was less than 1.0 in several patients remaining in complete remission. In patients remaining in remission, CD10+ TdT+ cells were detected in the blood in only 2 out of 140 samples tested, and the proportion of these cells never exceeded 0.03%. We conclude that quantitation of CD10+ TdT+ cells in peripheral blood is helpful in the evaluation of complete remission in patients treated for pre‐B‐ALL.

Screening of mortality in transplant patients using an assay for immune function

BACKGROUND So far, the ImmuKnow Immune Cell Function Assay (Cylex, Inc., Columbia, MD, USA) has been used to assess risks of infection and rejection in transplant patients. We hypothesized that the ImmuKnow assay might be used for mortality screening in transplant patients overall. METHODS In the period of February 2007 to December 2009, at the Uppsala University Hospital, 362 patients who received either kidney, kidney+pancreas, kidney+islet cells, liver or liver+kidney allografts were randomly screened using the ImmuKnow assay. All causes of mortality were compared between two groups: patients with at least one ImmuKnow assay below 175ng/mL and patients with all ImmuKnow assays from 175ng/mL and above. Subsequently, the frequency of rejection within thirty days of the ImmuKnow assay was compared between these two groups. RESULTS The study included 1031 ImmuKnow assays obtained from the 362 patients. A total of 111 patients had at least one ImmuKnow below 175ng/mL and 251 patients had all their ImmuKnow assays from 175ng/mL and above. By January 31st 2010, 16 of 111 patients (14.4%) with at least one ImmuKnow assay below 175ng/mL were deceased, compared to 13 of 251 patients (5.2%) with all ImmuKnow assays from 175ng/mL and above (p=0.0053, Fishers exact test). There was no difference in the frequency of rejection between the two groups (19.8% versus 17.5%, p=0.66). CONCLUSIONS In addition to assessing relative risks of infection and rejection in transplant patients, the ImmuKnow assay may be used to identify patients with increased risk of short-term mortality. Transplant patients being highly overimmunosuppressed as assessed by the ImmuKnow assay do not seem to have a lower risk of short-term rejection.

Unrelated adult stem cell donor medical suitability: recommendations from the World Marrow Donor Association Clinical Working Group Committee

The World Marrow Donor Association (WMDA) fosters collaboration between international registries to facilitate the exchange of hematopoietic stem cell products for unrelated stem cell donor transplantation. As indications for hematopoietic SCT grow, the movement of products across the world will increase. Although competent authorities may regulate products within their country, there is a need to protect the best interests of donors and recipients by identifying universal donor medical suitability criteria. Within this report the WMDA provides a background to unrelated adult donor and recipient safety, recommends a common framework for assessing the health of unrelated adult donors at each stage of the donation pathway and presents a novel mechanism for sharing international consensus criteria for individual medical and lifestyle conditions. Wherever possible, these criteria are evidence-based. By establishing a donor medical suitability working group, the WMDA has developed a process through which donor centers and registries may request a consensus opinion on conditions not already listed, as well as challenge existing criteria. Guidance from the WMDA is intended to complement, not supersede, guidance from national competent authorities and international regulatory bodies.

Suitability Criteria for Adult Related Donors: A Consensus Statement from the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues

The number of allogeneic hematopoietic stem cell (HSC) transplants performed globally each year continues to increase. Advances in HLA typing, better supportive care, and administration of reduced-intensity conditioning regimens allow treatment of older patients with older sibling donors. Pretransplant donor assessment and testing are very important processes affecting the quality and safety of donation. For unrelated HSC donors detailed recommendations for health assessment have been published, allowing donation only if they are unrestrictedly healthy. Eligibility criteria for related donors are less strict and vary significantly between centers. In situations where a family donor does not meet the suitability criteria for unrelated donors, involved physicians often struggle with the decision whether the matched relative is suitable for donation or not. On behalf of the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues, we intended to develop a consensus document with recommendations for donor workup and final clearance of family donors who would not be able to serve as unrelated donors because of their age or pre-existing diseases. This article covers different topics intending to support decision-making, with the goal of minimizing medical risk to the donor and protection of the recipient from transmissible diseases.