Irradiated mononuclear cells express significant in vitro cytotoxic activity: promise for in vivo clinical efficacy of irradiated mismatched donor lymphocytes infusion.

BACKGROUND: Relapse of the original disease remains the most common cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-SCT). Patients who relapse post-allo-SCT can achieve prolonged remission after donor lymphocyte infusion. Donor lymphocyte infusion as well as other immunotherapeutic strategies are usually complicated by severe graft versus host disease. AIM: In the present study, we examined the effect of irradiation on the cytotoxic activity of mononuclear cells (MNCs). MATERIALS & METHODS: Cytotoxic activity of fresh and irradiated MNCs from healthy donors was tested against the leukemic cell line K562 and against fresh leukemic cells from patients with acute myeloid leukemia. Cytotoxicity was assessed by using a flow-cytometry assay. RESULTS & DISCUSSION: Interestingly, we observed that 25 Gy irradiated MNCs retain significant cytotoxic activity against K562. Based on these in vitro data, the safety and efficacy of irradiated haploidentical, IL-2-activated lymphocytes were tested in six patients after allo-SCT. Acute skin graft versus host disease developed in two patients and was resolved after a short course of steroids. One patient with mixed chimera converted to full donor chimera after infusion of irradiated donor cells. CONCLUSION: The efficacy of irradiated haploidentical lymphocytes should be further tested in a larger number of patients.

Post-autologous stem cell transplantation administration of rituximab improves the outcome of patients with aggressive B cell non-Hodgkin's lymphoma.

The major cause of treatment failure following high-dose therapy with autologous stem cell transplantation (ASCT) for aggressive B cell non-Hodgkin's lymphoma (NHL) is persistent disease or recurrence. We describe our experience with the administration of rituximab post-ASCT, either as maintenance therapy or for the treatment of relapsed disease in patients with aggressive B cell NHL. Fifty-six patients achieved complete remission post-transplant, and 19 of them received maintenance with rituximab. Maintenance with rituximab resulted in statistically significant superior outcome in terms of progression free (PFS; p = 0.002) and overall survival (OS; p = 0.011). The median PFS and OS of patients in the maintenance arm has not been reached yet, while the median PFS and OS of patients in the control arm were 29 and 42 months, respectively. Fifty-four patients had disease progression or relapsed post-ASCT, and 15 of them received rituximab in combination with chemo- and/or radiotherapy in order to achieve disease remission. Therapeutic administration of rituximab resulted in statistically significant prolongation of OS (p = 0.021). The median OS of patients treated with rituximab was 17 months, while median OS of patients in the control group was 10 months. We consider that the results of our study are promising but need to be verified within large randomized trials.

A retrospective review of the outcome after second or subsequent allogeneic transplantation.

The failure of allogeneic stem cell transplant (allo-SCT) is cumbersome. We analyzed our experience in a second allo-SCT. Between the years 1981 and 2007, 144 patients underwent 2 or more allo-SCT. The first to second transplant interval ranged from 18 days to 13.25 years (median 98 days). The most frequent indications for the second SCT were activity of the basic disease (78), rejection (37), and engraftment failure (25). Twenty-nine of the 144 (20%) patients transplanted survived more then a year with treatment-related mortality of 45.5% as the leading cause of death. Interestingly, despite the low rate of graft-versus-host disease (GVHD) prophylaxis used, only 51 and 16 of the patients developed acute and chronic GVHD (aGVHD, cGVHD), respectively. Factors indicating higher likelihood for survival were nonmalignant disease, a nonrelapse indication for the second SCT, full HLA-matching, and the use of reduced-intensity conditioning (RIC). Age at transplantation, time interval between transplants, the development of GVHD, conditioning regimen, GVHD prophylaxis, or graft source were not shown to influence the prognosis. With a median follow-up of 4.5 years, 25 patients (17.2%) are alive, and 18 are disease-free. We conclude that although toxic, a second allo-SCT can lead to long-term survival.

A new induction protocol for the control of steroid refractory/dependent acute graft versus host disease with alefacept and tacrolimus.

BACKGROUND AIMS: We have shown previously that alefacept is effective in acute steroid resistant/dependent and chronic extensive graft versus host disease (GvHD) with a protocol using timings similar to those used for psoriasis treatment. In this study, we describe the use of an alefacept induction (e.g. for 7 consecutive days) followed by a bi-weekly maintenance treatment in combination with tacrolimus for acute steroid resistant/dependent GvHD 1, 3. METHODS: Sixteen patients were treated in this cohort, most with refractory GvHD. The pre-treatment GvHD grade ranged from 2 to 4 (median 3), involving the skin 16, gut 11 and liver 5. RESULTS: Twelve out of the 16 patients showed a response. As with the first protocol, the response of GvHD in the skin was fastest. In contrast to our previous protocol, however, the gastro-intestinal (GI) GvHD response was faster (P=0.05 compared with the first cohort). A hepatic response was seen in 4/6 patients and was complete in three. All responses were durable, including mucocutaneous, gut and liver GvHD. In all responding patients we were able to decrease the steroid dose significantly and in seven it was completely withdrawn. CONCLUSION: Alefacept induction is safe in acute steroid resistant/dependent GvHD and may be more effective therapeutically than our previous alefacept protocol. We speculate that alefacept initiates an allo-versus-allo cellular effect through its Fc receptor.