Onset and outcome of pregnancy after autologous haematopoietic SCT (AHSCT) for autoimmune diseases: a retrospective study of the EBMT autoimmune diseases working party (ADWP).

Autologous haematopoietic SCT (AHSCT) is increasingly used to control severe and refractory autoimmune diseases (AD). Many patients are women of reproductive age with a potential desire for children. We present a multicentre retrospective analysis of pregnancy and childbirth in patients who underwent AHSCT for AD. The databases of the European Blood and Marrow Transplantation and University of Sao Paulo, Ribeirão Preto, Brazil were searched for female patients aged 18-50 years who had received AHSCT for AD between 1994-2011. In 324 adult female patients, 22 pregnancies were reported in 15 patients between 1997-2011. Indications for AHSCT included multiple sclerosis (n=7), systemic sclerosis (n=5), rheumatoid arthritis (n=1), juvenile idiopathic arthritis (n=1) and Takayasu disease (n=1). Of the 22 reported pregnancies, 20 followed natural conception. 15 pregnancies (68%) resulted in healthy life births, whereas 7 (32%) failed. Exacerbations of AD occurred in two patients during second pregnancies. No maternal mortality was associated with pregnancy or postpartum. There were no reports of congenital, developmental or any other disease in the children. This retrospective analysis confirms the possibility of pregnancy and childbirth following AHSCT for severe AD. The outcome of pregnancy is generally good and most led to the birth of a healthy child.

Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study.

BEAM is a widely used conditioning regimen for relapsed/refractory lymphoma patients undergoing auto-SCT. We conducted a multicenter study with an alternative regimen (fotemustine plus etoposide, cytarabine and melphalan (FEAM)) in which BCNU was substituted by the chloroethylnitrosourea fotemustine (FTM). Eighty-four patients with relapsed/refractory Hodgkin's (n=20) and non-Hodgkin's lymphoma (n=64) were conditioned with a FEAM regimen (FTM 150 mg/m(2) on days -7, -6, etoposide 200 mg/m(2) and cytarabine 400 mg/m(2) on days -5, -4, -3, -2 and melphalan 140 mg/m(2) on day -1). Patients were evaluated for toxicity and engraftment parameters. Median times to neutrophil (>500 x 10(9)/l) and plt (>20 000 x 10(9)/l) engraftment were 11 and 13 days, respectively. Grade 3 mucositis occurred in 19 patients (23%), while G3 nausea/vomiting and G3 diarrhea were observed in 13 (15%) and 6 (7%) patients, respectively. No severe hepatic, renal or pulmonary toxicity was detected. Seven patients (7%) experienced G4 mucositis, while no other G4 toxicities or unexpected adverse events of any grade were recorded. Transplant-related mortality was 2.4%. We conclude that a FEAM regimen is feasible and safe. Although toxicity and engraftment times compared favorably with BEAM, longer follow-up is needed to evaluate fully its efficacy and long-term safety.

Palonosetron and dexamethasone for prevention of nausea and vomiting in patients receiving high-dose chemotherapy with auto-SCT.

The aim of this study was to determine the efficacy of palonosetron combined with dexamethasone in prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) in patients receiving high-dose (HD)-CT with auto-SCT, and the efficacy of a second dose of palonosetron in treating breakthrough emesis. One hundred thirty-four patients treated with HD-CT and auto-SCT for hematologic malignancies received palonosetron as prophylaxis for CINV on the first day of conditioning; patients were also administered dexamethasone throughout the entire period of conditioning. If breakthrough emesis occurred, a second dose of palonosetron was administered at 72 h after the first administration. Complete response and complete protection were observed in 36 and 26% of patients, respectively. One-half of the patients, re-treated with palonosetron for breakthrough emesis, were successfully rescued. Treatment with palonosetron plus dexamethasone seems to be encouraging in terms of prophylaxis of CINV and treatment of breakthrough emesis in the setting of HD-CT.

Donor lymphocyte infusions for refractory pure red cell aplasia relapsing after both autologous and nonmyeloablative allogeneic peripheral stem cell transplantation.

Pure red cell aplasia (PRCA) is characterized by a selective marrow aplasia of the erythroid compartment. Immunosuppressive therapy achieves good results in about 25% of cases, but relapses are frequent. Autologous or allogeneic haematopoietic stem cell transplantation (HSCT) may be valuable in selected patients. Here, we report details of a 29-year-old woman treated successfully by donor lymphocyte infusions (DLIs) following allogeneic HSCT for acquired refractory relapsed PRCA. The nonmyeloablative conditioning regimen consisted of cyclophosphamide 60 mg/kg/day for 2 days and fludarabine 30 mg/m(2) daily for 4 days. Haematopoiesis was still completely 'recipient' 1 month after allo-HSCT, but progressed to full donor engraftment after three doses of 'escalating' DLI. The possible role of a graft-versus-autoimmunity effect induced by allogeneic HSCT followed by DLI infusions in the treatment of the disease is discussed.

Intense immunosuppressive therapy followed by autologous peripheral blood selected progenitor cell reinfusion for severe autoimmune disease.

Autologous stem cell transplantation (HSCT) has been shown to be effective in curing a large spectrum of autoimmune disorders. Case reports are being collected in the EBMT/EULAR Autoimmune Disease Stem Cell Project registry, which reports transplant-related mortality (TRM) of 6%. In order to reduce TRM and preserve the anti-autoimmune effect we evaluated a more immunoablative as opposed to myeloablative conditioning regimen for the autotransplant of severe immunomediated diseases. We enrolled patients affected by systemic lupus erythematosus (SLE: 3 patients), by autoimmune thrombocytopenic purpura (AITP: one patient), by thrombotic thrombocytopenic purpura (TTP: one patient), by pure red cell aplasia (PRCA: one patient), and by a severe cryoglobulinemia (one patient). All patients were mobilized with cyclophosphamide (Cy) 4 g/m2 + G-csf. Conditioning regimen consisted of Cy 50 mg/kg/day (days -6 and -5); anti-T-globulin (ATG) 10 mg/kg/day and 6-methylprednisolone (PDN) 1 g/day (days -4, -3, and -2). Immunomagnetically selected CD34+ cells were re-infused on day 0. In three patients neutrophil count fell below 0.5 x 10(9)/l, while a PLT count below 20 x 10(9)/l was registered in two patients. Extrahematological toxicity was very low. Four patients (2 SLE, 1 TTP, 1 cryoglobulinemia) are in complete corticosteroid-free remission with a median follow up of 335 days. The third SLE patient improved considerably; however, he still needs low-dose corticosteroid maintenance. The AITP and PRCA patients achieved a CR but soon relapsed; nevertheless, the procedure restored a steroid-sensitive status. The use of this immunoablative conditioning regimen in auto-HSCT transplant was shown to be effective in controlling disease progression and could be a valuable strategy in reducing TRM.

Crohn's disease complicated by relapsed extranodal Hodgkin's lymphoma: prolonged complete remission after unmanipulated PBPC autotransplant.

Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD), which are thought to result from an inappropriate immunologic (autoimmune) response to luminal antibodies. Allogeneic stem cell transplantation (SCT) performed for coincidental diseases is able to cure both leukaemia and Crohn's disease. Autologous SCT is currently performed worldwide for severe autoimmune diseases (SADs) because of its reduced transplant-related mortality (TRM). We report the case of a 30-year-old male patient with a 10-year history of severe Crohn's disease, who developed Hodgkin's disease and received an unmanipulated peripheral blood autologous transplant. Three years after the transplant the patient is in complete treatment-free remission of both diseases.

Successful treatment of resistant thrombotic thrombocytopenic purpura/hemolytic uremic syndrome with autologous peripheral blood stem and progenitor (CD34+) cell transplantation.

The first-line treatment of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS syndrome) induces a response and survival rate of approximately 85%, even if a considerable number of patients relapse; nevertheless, a number of these patients are resistant to conventional management. Immunoablation followed by stem cell transplantation has been shown to be capable of inducing remissions in a large spectrum of experimental autoimmune disorders. We report here the case of a 20-year-old male patient with the TTP-HUS syndrome who was resistant to conventional treatment and was transplanted with autologous immunoselected CD34+ PBPC after conditioning with cyclosphosphamide, anti-T lymphocyte globulin and prednisone. Seven months after transplant the patient is alive and well, without any further treatment being given.

Autologous peripheral blood stem and progenitor (CD34+) cell transplantation for systemic lupus erythematosus complicated by Evans syndrome.

Immunoablation followed by allogeneic stem cell (SC) transplantation has been shown to be capable of curing a large spectrum of experimental autoimmune disorders, hereditary and/or induced. Superimposable results, albeit with some exceptions, have been obtained in human patients affected by coincidental autoimmune and blood diseases. However, both because of encouragine experimental results and of the procedure's greater safety, autologous SC are being increasingly utilized worldwide. Case reports are being collected in the registry of the European Group for Blood and Marrow Transplantation (EBMT)/European League against Rheumatism (EULAR) Autoimmune Disease Stem Cell Project. Among the severe autoimmune diseases (SADs), which are the target of autologous transplantation, severe refractory systemic lupus erythematosus (SLE) is a condition which may benefit from this procedure. We report here the case of a 19 year old female patient with a six year history of SLE with secondary antiphospholipid syndrome (APS), who later developed refractory Evans syndrome. She was transplanted with autologous mobilized CD34+ SC and progenitor cells after conditioning with cyclosphosphamide, anti-T lymphocyte globulin and prednisone. Eight months after transplant, the patient is alive and well, with normal blood counts and persistent low-titre direct antiglobulin (DAT, Coombs) and anti-nuclear antibody (ANA) tests. Anti-double stranded DNA antibody (Anti-dsDNA), lupus anticoagulant tests and anti-cardiolipin antibody (ACA) test are negative.

PBSC mobilization, collection and positive selection in patients with chronic lymphocytic leukemia.

We report the results of PBSC mobilization and immune selection in 17 patients with advanced chronic lymphocytic leukemia (CLL) enrolled in a multicenter Italian study of autologous transplantation with peripheral CD34+ selected cells. Mobilization was achieved by cyclophosphamide (CY) 4 g/m2 + G-CSF 5 microg/kg. CD34+ cells were positively selected by means of avidin-biotin immunoaffinity columns (Ceprate SC) or immunomagnetic beads (Isolex 300i) systems. Evaluation of minimal residual disease was performed by PCR analysis of the IgH gene rearrangment on the apheresis product before and after selection. Our results showed that after CY a median of 3.6 x 10(6)/kg (0.5-12.8) CD34+ cells were collected with a median of two aphereses in 14 out of 17 patients; three failed to mobilize a number of CD34+ cells adequate for subsequent manipulation. We found that in CR patients CD34+ cell yield per apheresis was significantly higher than in PR patients (P < 0.05). Sixteen selection procedures were performed in 13 patients. CD34+ cell recovery was 33.5% (10-85) with a median final yield of 1 x 10(6)/kg CD34+. Two patients underwent marrow collection due to the low number of CD34+ cells recovered. Final purity was 59% (range 22-94) and CD5/20+ cell depletion was 2.7 log (1.6-4.4). Our data showed a statistically higher CD34+ cell recovery and purity with the Isolex device compared to Ceprate (P < 0.01 and 0.01, respectively). All the evaluable samples remained PCR positive after selection. The main issues to be addressed in the future are the identification of patients who fail mobilization and the improvement of purging methods.

Low-dose long-term oral idarubicin in maintenance treatment of elderly acute myeloid leukemia.

BACKGROUND AND OBJECTIVE: Low-dose long-term oral IDA may play a role in maintainance treatment of elderly patients with AML; in fact, continuous exposure to IDA and IDAol could be efficacious in the disease control possibly inducing cell-differentiation and/or apoptosis. METHODS: We enrolled 25 previous responder patients in standard induction therapy to receive maintenance oral IDA 5 mg daily on days 1-14 at 2-week intervals for at least 6 months. We also evaluated the cell-cycle and apoptosis in leukemic cells from patients after IDA administration and, as a control, from HL60 lines exposed to IDA and IDAol in vitro. RESULTS: Long-term long-dose IDA was well-tolerated. Neutrophil and platelet count never below under 1 x 10(9)/L and 50 x 10(9)/L respectively in CR patients, and no infectious complications were encountered. Non-hematological toxicity was also acceptable: easily controlled nausea and vomiting, non-recorded diarrhea or mucositis were reported. The convenience of oral administration contributed to excellent compliance. DNA analysis performed in vivo after IDA and IDAol exposure showed an increase of G2/M cell frequencies and evidence of sub-G1 peak. INTERPRETATION AND CONCLUSIONS: In conclusion, long-term low doses of oral IDA would appear valuable as a maintenance regimen for elderly patients. Our results seem to confirm the preliminary hypothesis that IDA + IDAol induce an increase of apoptosis in leukemic cells.

ANLL patients with normal karyotype are not a homogeneous prognostic group.

BACKGROUND AND METHODS: Karyotype in ANLL is referred as an independent prognostic factor. The prognosis of diploid ANLL subjects has been defined as "good" by some authors, or, more recently, "intermediate" by others. This is a retrospective study on 30 consecutive heavy treated ANLL diploid patients with the aim to make a correlation among age, normal karyotype and response. Chromosomal banding studies were performed at presentation with GTG technique. Diploid patients were divided into two age groups < 60 years (17 cases) and > or = 60 (13 cases). Data were analyzed by NCSS software. RESULTS AND CONCLUSIONS: CR rate for the two diploid age groups was 94% and 38% respectively (p = 0.002). Median DFS and overall survival were 14.4 and 23.3 months, 4 and 5 months for the two subgroups respectively: these data were not statistically significative. The probability of achieving CR was not affected by blood counts and Karnofsky performance status on admission, but only by age. Though ANLL patients with the same karyotype have the same course regardless of other prognostic factors, this does not occur in our series of diploid patients. We suggest that a normal karyotype, at least as defined with the GTG technique, does not characterize a homogeneous group of patient. Heterogeneity in this group might be due to submicroscopic or molecular genetic changes; it can enhance the age as prognostic factor.