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A letter to the editor is presented which discusses a case of a 26-year old man with severe aplastic anemia who was treated with the allogeneic hematopoietic stem cell transplantation co-administered with mesenchymal stem cell (MSC).

The immunosuppressive properties of mesenchymal stem cells (MSC) make them particularly attractive to manipulate graft-versus-host disease (GVHD). So far, the experience of using MSC to treat GVHD is limited to a few cases, controversial results come from preclinical models and several issues remain to be clarified. The present studies were designed to address these questions in a xenogenic model testing the ability of umbilical cord blood-derived MSC (UCB-MSC) to prevent and/or treat GVHD. Sublethally irradiatiated non-obese diabetic/severe combined immunodeficiency NOD/SCID mice transplanted with human peripheral blood mononuclear cells (huPBMC) showed extensive human T-cell proliferation in the peripheral blood, lymphoid and non-lymphoid tissues, which evolved in extensive GVHD (wasting, ruffled hair and hunched back). The mice treated with a single dose of UCB-MSC did not behave differently form the controls. However, when UCB-MSC were given at weekly intervals, there was a marked decrease in human T-cell proliferation and none of the mice developed GVHD. No therapeutic effect was obtained if UCB-MSC were administered at onset of GVHD. This work supports the clinical use of MSC in stem cell transplantation as a prophylaxis rather than treatment of GVHD.Leukemia (2007) 21, 1992–1999; doi:10.1038/sj.leu.2404847; published online 12 July 2007 [ABSTRACT FROM AUTHOR]

Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3+ cell dose 107/kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility.Leukemia (2007) 21, 943–948. doi:10.1038/sj.leu.2404641; published online 15 March 2007 [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of allogeneic hemopoietic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) largely relies on the graft-versus-leukemia (GvL) effect exerted by donor T cells. CD4+CD25high regulatory T cells (Tregs) have been shown to downregulate antitumor responses but their role on GvL has not been evaluated. We performed a cross-sectional study in which we enumerated and characterized CD4+CD25high Tregs in the peripheral blood of CML patients undergoing allogeneic SCT. We documented higher frequencies of Tregs in patients after transplant as compared to normal controls and newly diagnosed patients. The increment was particularly evident in patients who had received their SCT 18 months before. In vitro functional studies demonstrated that the Tregs purified from SCT patients exhibited a more potent suppressive activity than Tregs isolated from healthy volunteers. Patients in whom Tregs numbers were higher than controls more than 18 months after SCT showed evidence of disease relapse. Although the increment in Tregs might have an advantageous effect on graft rejection in the early phase post-transplant, our data suggest that Tregs exert an inhibitory effect on GvL.Leukemia (2007) 21, 472–479. doi:10.1038/sj.leu.2404522; published online 18 January 2007 [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSC) have received much attention in the field of hematopoietic stem cell transplantation because not only do they support hematopoiesis but also exhibit a profound immunosuppressive activity that can be exploited to prevent undesired alloreactivity. We have previously shown that their immunosuppressive activity is mainly exerted at the level of T-cell proliferation. Here, we show that MSC exhibit a similar antiproliferative activity on tumor cells of hematopoietic and non hematopoietic origin. In vitro, MSC produced the transient arrest of tumor cells in the G1 phase of cell cycle; this was accompanied by a reduction in the apoptotic rate even when survival factors were limiting. However, when tumor cells were injected into non-obese diabetic–severe combined immunodeficient mice in conjunction with MSC, their growth was much faster as compared to the group receiving only tumor cells. To explain the discrepancy between the in vitro and in vivo behavior, we suggest that MSC have the ability to form a cancer stem cell niche in which tumor cells can preserve the potential to proliferate and sustain the malignant process. We conclude that the clinical use of MSC in conditions in which a malignant disease is involved should be handled with extreme caution.Leukemia (2007) 21, 304–310. doi:10.1038/sj.leu.2404489; published online 14 December 2006 [ABSTRACT FROM AUTHOR]

We monitored BCR-ABL transcript levels by quantitative real-time PCR in 103 patients treated with imatinib for chronic myeloid leukaemia in chronic phase for a median of 30.3 months (range 5.5-49.9) after they achieved complete cytogenetic remission (CCyR). The patients could be divided into three groups: (1) in 32 patients transcript levels continued to decline during the period of observation (nadir BCR-ABL/ABL ratio 0.015%); in five of these patients BCR-ABL transcripts became undetectable on repeated testing, (2) in 42 patients the transcript levels reached a plateau and (3) in 26 patients transcript numbers increased and the initial CCyR was lost. Three patients were not evaluable. Patients who remained in CCyR for at least 24 months appeared to have a low risk of subsequent cytogenetic relapse. We conclude that the pattern of‘residual’disease after achieving CCyR on imatinib is variable: some patients in CCyR show a progressive reduction in the level of residual disease, some reach a plateau where transcript numbers are relatively stable and others relapse with Ph-positive metaphases.Leukemia (2005) 19, 507-512. doi:10.1038/sj.leu.2403664 Published online 10 February 2005 [ABSTRACT FROM AUTHOR]

The ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML and is increasingly used in the stem cell transplantation (SCT) setting. Since ABL-dependent intracellular signaling molecules are involved in T-cell activation, imatinib may affect T-cell responses in vivo, thus affecting T-cell function in CML patients, disrupting immune reconstitution after allogeneic SCT and/or impeding the graft-versus-leukemia effect. Here we demonstrate that imatinib inhibits PHA-induced proliferation of normal peripheral blood mononuclear cells at in vitro concentrations (1-5?µmol/l) representative of the pharmacological doses used therapeutically in vivo. The effect is not dependent on antigen-presenting cells because CD3/CD28-induced T-cell stimulation was similarly inhibited by imatinib. Dose-dependent inhibition of the proliferative response of purified CD8+ and CD4+ T lymphocytes to anti-CD3/CD28 was similarly observed and associated with reduction in IFN-? production. The inhibitory effect could not be ascribed to an increased rate of apoptosis but the expression of activation markers on CD3+ T cells was significantly reduced in the presence of imatinib (1-5?µmol/L). Inhibition of T-cell proliferation was reversible after removal of the drug from the cultures. Thus, imatinib inhibits T-cell proliferation in vitro, an effect that is APC-independent, reversible, and does not involve apoptosis induction.Leukemia (2004) 18, 1332-1339. doi:10.1038/sj.leu.2403401 Published online 10 June 2004 [ABSTRACT FROM AUTHOR]

At the cellular level, expansion of haemopoiesis in chronic myeloid leukaemia (CML) must involve some imbalance in cell production along the myeloid maturation pathway. The relevant kinetic parameters are cell loss by apoptosis and differentiation and cell gain by proliferation (self-renewal). In spite of the predominance of the BCR-ABL-positive leukaemic cells, some BCR-ABL-negative, presumably normal, progenitor cells remain for long periods in chronic phase CML. Thus, understanding the kinetics of CML and normal progenitor cells may lead to therapeutic strategies capable of reducing malignant cell growth and reactivating normal haemopoiesis. [ABSTRACT FROM AUTHOR]

The article discusses various reports published withitn the issue including one by H. Ning and colleagues on the study results regarding the use of mesenchymal stem cell (MSC) for the prevention of graft-versus-host disease (GVHD) in patients with hematological malignancies, and another by S. Glennie and colleagues on the MSC-mediated immunosuppression produced via an antiproliferative effect.

A response by F. Dazzi and C. Fozza to a letter to the editor about their article "Splenectomy status of the patient may have impact on response to donor lymphocyte infusions" in the June 28, 2007 issue is presented.

Presents a letter to the editor related to imatinib.