Haploidentical age-adapted myeloablative transplant and regulatory and effector T cells for acute myeloid leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective treatment in eradicating high-risk acute myeloid leukemia (AML). Here, we present data from a novel HLA-haploidentical HSCT protocol that addressed the 2 remaining major unmet medical needs: leukemia relapse and chronic graft-versus-host disease (cGVHD). Fifty AML patients were enrolled in the study. The conditioning regimen included total body irradiation for patients up to age 50 years and total marrow/lymphoid irradiation for patients age 51 to 65 years. Irradiation was followed by thiotepa, fludarabine, and cyclophosphamide. Patients received an infusion of 2 × 106/kg donor regulatory T cells on day -4 followed by 1 × 106/kg donor conventional T cells on day -1 and a mean of 10.7 × 106 ± 3.4 × 106/kgpurified CD34+ hematopoietic progenitor cells on day 0. No pharmacological GVHD prophylaxis was administered posttransplantation. Patients achieved full donor-type engraftment. Fifteen patients developed grade ≥2 acute GVHD (aGVHD). Twelve of the 15 patients with aGVHD were alive and no longer receiving immunosuppressive therapy. Moderate/severe cGVHD occurred in only 1 patient. Nonrelapse mortality occurred in 10 patients. Only 2 patients relapsed. Consequently, at a median follow-up of 29 months, the probability of moderate/severe cGVHD/relapse-free survival was 75% (95% confidence interval, 71%-78%). A novel HLA-haploidentical HSCT strategy that combines an age-adapted myeloablative conditioning regimen with regulatory and conventional T-cell adoptive immunotherapy resulted in an unprecedented cGVHD/relapse-free survival rate in 50 AML patients with a median age of 53 years. This trial was registered with the Umbria Region Institutional Review Board Public Registry as identification code 02/14 and public registry #2384/14 and at www.clinicaltrials.gov as #NCT03977103.

Oral iron-based interventions for prevention of critical outcomes in pregnancy and postnatal care: An overview and update of systematic reviews.

OBJECTIVE: The aim of this work was to summarize and update the evidence concerning oral iron-based interventions compared to placebo or no iron-based interventions to prevent critical outcomes in pregnancy or treat critical outcomes in the postpartum phase. METHOD: Published systematic reviews (Feb 2018) and primary studies (from 2015 to March 2018) retrieved from MEDLINE, EMBASE, and the Cochrane Library were examined. The AMSTAR (Assessing the Methodological Quality of Systematic Reviews) tool was used to assess the quality of reviews. GRADE was used to rate the quality of the evidence for critical outcomes. RESULTS: Antenatal care: Compared to placebo/no treatment, iron-based therapies reduced maternal anemia at term by 59% (seven trials at low risk of bias, RR 0.41, 95% CI 0.23-0.73; I2  = 86%; moderate-quality evidence) and maternal iron deficiency anemia by 67% (RR 0.33, 95% CI 0.16-0.69; I2  = 49%). There was no evidence of difference between iron-based therapies vs control in terms of side effects (RR 1.42, 95% CI 0.91-2.21), preterm delivery (13 studies: RR 0.93, 95% CI 0.84-1.03; low-quality evidence), low birthweight (RR 0.94, 95% CI 0.79-1.13; low-quality evidence) and infant mortality (RR 0.93, 0.72-1.20; low-quality evidence). POSTNATAL CARE: There was insufficient evidence to determine whether iron-based therapies can reduce postpartum anemia. CONCLUSION: Iron supplementation is effective in preventing maternal anemia at term but not low birthweight, preterm delivery or infant mortality.

The Molecular Spectrum of ß- and α-Thalassemia Mutations in Non-Endemic Umbria, Central Italy.

The aim of this study was to describe the mutational spectrum of hemoglobinopathies during the period 1988-2015 in Umbria, Central Italy, which has never been considered endemic for these conditions. Twenty-four different ß-globin gene mutations were identified in 188 patients and eight different α-globin gene mutations in 74 patients. Sixty percent ß-thalassemia (ß-thal), 85.0% sickle cell disease, 44.0% Hb S (HBB: c.20A>T)/ß-thal and 85.0% compound heterozygotes for hemoglobin (Hb) variant-carrying patients were diagnosed or molecularly characterized in the last 3 years. Moreover, most homozygous or compound heterozygous patients (84.5%) came from foreign countries, while only 15.5% were of Italian origin. These data are in accordance with the increasing foreign resident population in Umbria, which has nearly doubled in 10 years (2004-2014). Different from ß-globin gene variations, no increasing trend in α defects was observed in our study cohort. Consistently, 58.0% of patients have an Italian origin, suggesting no broad influence of foreign migration in the α-globin genes genetic background. As few defects are prevalent in each country of origin or ethnic group, their knowledge may provide a proper strategy for the identification of mutations in immigrant individuals in a non-endemic region and be important for carrier identification and prenatal screening.

High-dose thiotepa, etoposide and carboplatin as conditioning regimen for autologous stem cell transplantation in patients with high-risk Hodgkin's lymphoma.

BACKGROUND: Autologous stem cell transplantation (ASCT) generally provides good results in Hodgkin's lymphoma (HL). We studied a high-dose chemotherapy regimen based on thiotepa, etoposide and carboplatin (TECA). METHODS: Fifty-eight patients with advanced HL were treated with thiotepa, etoposide and carboplatin for transplant induction. RESULTS: The overall response rate was 79·3% (39 CR: 67·2%; and 7 PR: 12·1%); 12 patients (20·1%) were non-responders. The 5-year overall survival rate was 77·6%; five initially responder patients relapsed within the first 5 years of follow-up and underwent salvage therapy. CONCLUSION: The TECA conditioning regimen for ASCT in HL results in a good anti-HL effect, positive response to treatment and high 5-year overall survival rate. It was also well tolerated and did not induce excessive toxicity, suggesting that TECA may be a very useful conditioning regimen for HL.

High-dose thiotepa, etoposide and carboplatin as conditioning regimen for autologous stem cell transplantation in patients with high-risk non-Hodgkin lymphoma.

High-dose chemotherapy conditioning regimens followed by autologous stem cell transplantation generally provide good results in non-Hodgkin lymphoma. We have evaluated the effects of a high-dose regimen comprising thiotepa, etoposide and carboplatin. After debulking and mobilization with high-dose cyclophosphamide or other schedules, forty-five patients at various disease stages were conditioned with thiotepa, etoposide and carboplatin prior to autologous stem cell transplantation. The overall response rate was 77.8% (30 CR, 66.7%; 5 PR, 11.1%). Ten patients (22.2%) did not respond. Two patients (4.4%) died from transplant-related complications. The mean 5-year overall survival was 71.1%: 12 patients relapsed within the first 5 years of follow-up. The overall response rate and 5-year overall survival were better for patients with an International Prognostic Index (IPI) 1 at diagnosis than for those with IPI 2 and IPI 3 (P<0.005 for all). The thiotepa, etoposide and carboplatin conditioning regimen for autologous stem cell transplantation in non-Hodgkin lymphoma has a good anti-lymphoma effect and provides encouraging results in terms of response to treatment and 5-year overall survival. Its good tolerance and acceptable toxicity suggest that it may a very useful in the management of non-Hodgkin lymphoma.

Graft engineering for allogeneic haploidentical stem cell transplantation.

Haploidentical stem cell transplantation has became a clinical reality in the last 10 years as it provides the chance of transplant for about 50% of patients with hematological malignancies who do not have a matched related or unrelated donor. Proper graft preparation for this type of transplant is crucial and this paper analyses our work over the past decade in the search for the optimal graft processing procedure moving from E-rosetting and soybean agglutination, through a combination of negative or positive selection of hematopoietic stem cells to the current method of one-step positive selection. In preparing a graft for haploidentical transplant, three essential requisites must be met. It must contain (1) a megadose (>10 x 10(6) x kg recipient b.w.) of hematopoietic stem cells to overcome the HLA histocompatibility barrier; (2) very few T-lymphocytes (CD3+ cells < 3 x 10(4)/kg recipient b.w.) to prevent severe acute and chronic graft-versus-host disease (GvHD); (3) very few B-lymphocytes to prevent Epstein-Barr virus-related lymphoproliferative disorders. With current graft processing technologies based on positive selection of hematopoietic stem cells, these requirements can be met. A 70-80% hematopoietic stem cell recovery ensures the target megadose is achieved in over 70% of cases with a T-cell depletion of more than 4 logs and a B-cell depletion of over 3 logs. Progress in graft processing has ensured primary, sustained engraftment rates of over 90% and has significantly reduced the incidence of severe acute GvHD and EBV-related lymphoproliferative disorders. Modern time-saving automated graft processing devices ensure reproducibility, reliability, and biological safety, which make widespread application of the haploidentical transplant currently feasible.

Melphalan versus melphalan plus busulphan in conditioning to autologous stem cell transplantation for low-risk multiple myeloma.

INTRODUCTION: High-dose chemotherapy conditioning regimens for autologous stem cell transplantation generally give similar results in multiple myeloma. We compared two regimens: melphalan versus melphalan plus busulphan. METHODS: In all, 30 untreated patients with stage III low-risk multiple myeloma were studied. After induction with three VAD courses and mobilization with cyclophosphamide 7 g/m(2) and recombinant human granulocyte-colony stimulating factor (rHuG-CSF) (10 microg/kg b.w./die), they received melphalan 200 mg/m(2) (arm A) or busulphan 16 mg/kg plus melphalan 100 mg/m(2) (arm B) for conditioning for transplantation. All patients received maintenance therapy with Interferon 3 MU x 3/week. RESULTS: Time to engraftment after transplantation was similar in both groups. All patients received rHuG-CSF after reinfusion of peripheral stem cells. No differences emerged in transplant-related infective and noninfective complications. There were no transplant-related deaths. A better response was observed in the melphalan plus busulphan regimen (85 versus 75%, P<0.05). The 5-year overall survival with this regimen was 56 versus 49% with melphalan, and the median survival was 126 months versus 108 months for melphalan (P=0.7). The median progression-free survival was 121 months for melphalan plus busulphan versus 97 months for melphalan (P=0.05). CONCLUSION: These two conditioning regimens showed similar overall response rate and overall survival, though progression-free survival was better with busulphan plus melphalan.