Phase I/II study on cytarabine and idarubicin combined with escalating doses of clofarabine in newly diagnosed patients with acute myeloid leukaemia and high risk for induction failure (AMLSG 17-10 CIARA trial).

This open-label, multicentre phase I/II study determined the maximum tolerated dose (MTD), safety and efficacy of clofarabine administered with cytarabine and idarubicin in newly diagnosed acute myeloid leukaemia (AML) patients lacking favourable genetic aberrations. The MTD was 30 mg/m2 clofarabine for patients below and above 60 years. The most frequently reported grade 3-4 non-haematological adverse events were infectious and gastrointestinal toxicities. Complete remission (CR)/CR with incomplete recovery rate was 67%. Allogeneic haematopoietic cell transplantation in first remission was feasible in a high proportion of younger AML patients and probably contributed to the favourable outcome compared to historical controls.

Dual Role of the Adaptive Immune System in Liver Injury and Hepatocellular Carcinoma Development.

Hepatocellular carcinoma (HCC) represents a classic example of inflammation-linked cancer. To characterize the role of the immune system in hepatic injury and tumor development, we comparatively studied the extent of liver disease and hepatocarcinogenesis in immunocompromised versus immunocompetent Fah-deficient mice. Strikingly, chronic liver injury and tumor development were markedly suppressed in alymphoid Fah(-/-) mice despite an overall increased mortality. Mechanistically, we show that CD8(+) T cells and lymphotoxin ß are central mediators of HCC formation. Antibody-mediated depletion of CD8(+) T cells as well as pharmacological inhibition of the lymphotoxin-ß receptor markedly delays tumor development in mice with chronic liver injury. Thus, our study unveils distinct functions of the immune system, which are required for liver regeneration, survival, and hepatocarcinogenesis.

Donor lymphocyte infusions and second transplantation as salvage treatment for relapsed myelofibrosis after reduced-intensity allografting.

Thirty myelofibrosis patients (21 males, nine females) with relapse (n = 27) or graft-rejection (n = 3) after dose-reduced allografting underwent a salvage strategy including donor lymphocyte infusions (DLIs) and/or second allogeneic haematopoietic stem cell transplantation (HSCT). Twenty-six patients received a median number of three (range, 1-5) DLIs in a dose-escalated mode starting with a median dose of 1·2 × 10(6) (range, 0·003-8 × 10(6) ) up to median dose of 40 × 10(6) T-cells/kg (range, 10-130 × 10(6) ). 10/26 patients (39%) achieved complete response (CR) to DLIs. Acute (grade II-IV) and chronic graft-versus-host (GvHD) disease occurred in 12% and 36% cases. Thirteen non-responders to DLI and four patients who did not receive DLI due to graft-rejection or acute transformation of the blast phase underwent a second allogeneic HSCT from alternative (n = 15) or the same (n = 2) donor. One patient (6%) experienced primary graft-failure and died. Acute (II-IV) and chronic GvHD were observed in 47% and 46% of patients. Overall responses after second HSCT were seen in 12/15 patients (80%: CR: n = 9, partial response: n = 3). The 1-year cumulative incidence of non-relapse mortality for recipients of a second allograft was 6%, and the cumulative incidence of relapse was 24%. After a median follow-up of 27 months, the 2-year overall survival and progression-free survival for all 30 patients was 70% and 67%, respectively. In conclusion, our two-step strategy, including DLI and second HSCT for non-responding or ineligible patients, is an effective and well-tolerated salvage approach for patients relapsing after reduced-intensity allograft after myelofibrosis.

G-CSF as immune regulator in T cells expressing the G-CSF receptor: implications for transplantation and autoimmune diseases.

Results from experimental models, in vitro studies, and clinical data indicate that granulocyte colony-stimulating factor (G-CSF) stimulation alters T-cell function and induces Th2 immune responses. The immune modulatory effect of G-CSF on T cells results in an unexpected low incidence of acute graft-versus-host disease in peripheral stem cell transplantation. However, the underlying mechanism for the reduced reactivity and/or alloreactivity of T cells upon G-CSF treatment is still unknown. In contrast to the general belief that G-CSF acts exclusively on T cells via monocytes and dendritic cells, our results clearly show the expression of the G-CSF receptor in class I- and II- restricted T cells at the single-cell level both in vivo and in vitro. Kinetic studies demonstrate the induction and functional activity of the G-CSF receptor in T cells upon G-CSF exposure. Expression profiling of T cells from G-CSF-treated stem cell donors allowed identification of several immune modulatory genes, which are regulated upon G-CSF administration in vivo (eg, LFA1-alpha, ISGF3-gamma) and that are likely responsible for the reduced reactivity and/or alloreactivity. Most importantly, the induction of GATA-3, the master transcription factor for a Th2 immune response, could be demonstrated in T cells upon G-CSF treatment in vivo accompanied by an increase of spontaneous interleukin-4 secretion. Hence, G-CSF is a strong immune regulator of T cells and a promising therapeutic tool in acute graft-versus-host disease as well as in conditions associated with Th1/Th2 imbalance, such as bone marrow failure syndromes and autoimmune diseases.