Haploidentical related donor compared to HLA-identical donor transplantation for chemosensitive Hodgkin lymphoma patients.

BACKGROUND: Allogeneic stem cell transplantation from haploidentical donor using an unmanipulated graft and post-transplantation cyclophosphamide (PT-Cy) is growing. Haploidentical transplantation with PT-Cy showed a major activity in Hodgkin lymphoma (HL), reducing the relapse incidence. The most important predictive factor of survival and toxicity was disease status before transplantation, which was better in patients with well controlled disease. METHODS: We included 198 HL in complete (CR) or partial remission (PR) before transplantation. Sixty-five patients were transplanted from haploidentical donor and 133 from a HLA identical donor (both sibling and unrelated donors). Survival analysis was defined according to the EBMT criteria. Survival curves were generated by using Kaplan-Meier method and differences between groups were compared by the log rank test or by the log rank test for trend when appropriated. RESULTS: The PFS, OS, and RI were significantly better in patients in CR compared to PR (55% vs 29% p = 0.001, 74% vs 55% p = 0.03, 27% vs 55% p <  0.001, respectively). The 2-year PFS was significantly better for HAPLO than HLA-id (63% vs 37%, p = 0.03), without difference in OS. The 1-year NRM was not different. The 2-year relapse incidence (RI) was lower in the HAPLO group (24% vs 44%, p = 0.008). Patients in CR receiving haplo HSCT showed higher 2-year PFS and lower 2-year RI than those allografted with HLA-id donor (75% vs 47%, p <  0.001 and 11% vs 34%, p < 0.001, respectively). In multivariate analysis, donor type and disease status before transplantation were independent predictors of PFS as well as they predict the risk of relapse. Disease status at transplantation and age were independently associated to OS. CONCLUSIONS: Nonetheless this is a retrospective study, limiting the wide applicability of results, data from this analysis suggest that HLA mismatch can induce a strong graft versus lymphoma effect leading to an enhanced PFS.

Sign Change in the Anomalous Hall Effect and Strong Transport Effects in a 2D Massive Dirac Metal Due to Spin-Charge Correlated Disorder.

The anomalous Hall effect (AHE) is highly sensitive to disorder in the metallic phase. Here we show that statistical correlations between the charge-spin disorder sectors strongly affect the conductivity and the sign or magnitude of AHE. As the correlation between the charge and gauge-mass components increases, so does the AHE, achieving its universal value, and even exceeding it, although the system is an impure metal. The AHE can change sign when the anticorrelations reverse the sign of the effective Dirac mass, a possible mechanism behind the sign change seen in recent experiments.

Theory of the Spin Galvanic Effect at Oxide Interfaces.

The spin galvanic effect (SGE) describes the conversion of a nonequilibrium spin polarization into a transverse charge current. Recent experiments have demonstrated a large conversion efficiency for the two-dimensional electron gas formed at the interface between two insulating oxides, LaAlO_{3} and SrTiO_{3}. Here, we analyze the SGE for oxide interfaces within a three-band model for the Ti t_{2g} orbitals which displays an interesting variety of effective spin-orbit couplings in the individual bands that contribute differently to the spin-charge conversion. Our analytical approach is supplemented by a numerical treatment where we also investigate the influence of disorder and temperature, which turns out to be crucial to providing an appropriate description of the experimental data.

Covariant Conservation Laws and the Spin Hall Effect in Dirac-Rashba Systems.

We present a theoretical analysis of two-dimensional Dirac-Rashba systems in the presence of disorder and external perturbations. We unveil a set of exact symmetry relations (Ward identities) that impose strong constraints on the spin dynamics of Dirac fermions subject to proximity-induced interactions. This allows us to demonstrate that an arbitrary dilute concentration of scalar impurities results in the total suppression of nonequilibrium spin Hall currents when only Rashba spin-orbit coupling is present. Remarkably, a finite spin Hall conductivity is restored when the minimal Dirac-Rashba model is supplemented with a spin-valley interaction. The Ward identities provide a systematic way to predict the emergence of the spin Hall effect in a wider class of Dirac-Rashba systems of experimental relevance and represent an important benchmark for testing the validity of numerical methodologies.

Optimal Charge-to-Spin Conversion in Graphene on Transition-Metal Dichalcogenides.

When graphene is placed on a monolayer of semiconducting transition metal dichalcogenide (TMD) its band structure develops rich spin textures due to proximity spin-orbital effects with interfacial breaking of inversion symmetry. In this work, we show that the characteristic spin winding of low-energy states in graphene on a TMD monolayer enables current-driven spin polarization, a phenomenon known as the inverse spin galvanic effect (ISGE). By introducing a proper figure of merit, we quantify the efficiency of charge-to-spin conversion and show it is close to unity when the Fermi level approaches the spin minority band. Remarkably, at high electronic density, even though subbands with opposite spin helicities are occupied, the efficiency decays only algebraically. The giant ISGE predicted for graphene on TMD monolayers is robust against disorder and remains large at room temperature.

Validation of the acute leukemia-EBMT score for prediction of mortality following allogeneic stem cell transplantation in a multi-center GITMO cohort.

Predictive models may help in determining the risk/benefit ratio of allogeneic hematopoietic stem cell transplantation (HSCT) in acute leukemia (AL). Using a machine-learning algorithm we have previously developed the AL- European Society for Blood and Marrow Transplantation (EBMT) score for prediction of mortality following transplantation. We report here the first external validation of the AL-EBMT score in a cohort of AL patients from the Italian national transplantation network. A total of 1848 patients transplanted between the years 2000-2014 were analyzed. The median age was 45.9. Indications for HSCT were Acute Myeloid Leukemia (68.1%) and Acute Lymphoblastic Leukemia (31.9%). The majority of patients were in first complete remission (60.4%), and received myeloablative conditioning (81.3%). Median follow-up was 2 years. The score was well-calibrated for prediction of day 100 mortality and 2-year overall survival (OS), leukemia free survival (LFS), and nonrelapse related mortality, with corresponding area under the receiver-operator curves of 0.698, 0.651, 0.653, and 0.651, respectively. Increasing score intervals were associated with a decreasing probability of 2-year OS and LFS. The highest scoring group was associated with a hazard ratio of 3.16, 2.8, and 2.27 for 2-year OS, LFS, and NRM, respectively. In conclusion, the AL-EBMT score identified three distinct risk groups and was predictive of OS. It is a valid tool for stratifying the risk of acute leukemia patients undergoing allogeneic HSCT.

Achieving Molecular Remission before Allogeneic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Impact on Relapse and Long-Term Outcome.

Allogeneic stem cell transplantation (alloHSCT) in first complete remission (CR1) remains the consolidation therapy of choice in Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). The prognostic value of measurable levels of minimal residual disease (MRD) at time of conditioning is a matter of debate. We analyzed the predictive relevance of MRD levels before transplantation on the clinical outcome of Ph+ ALL patients treated with chemotherapy and imatinib in 2 consecutive prospective clinical trials. MRD evaluation before transplantation was available for 65 of the 73 patients who underwent an alloHSCT in CR1. A complete or major molecular response at time of conditioning was achieved in 24 patients (37%), whereas 41 (63%) remained carriers of any other positive MRD level in the bone marrow. MRD negativity at time of conditioning was associated with a significant benefit in terms of risk of relapse at 5 years, with a relapse incidence of 8% compared with 39% for patients with MRD positivity (P = .007). However, thanks to the post-transplantation use of tyrosine kinase inhibitors (TKIs), disease-free survival was 58% versus 41% (P = .17) and overall survival was 58% versus 49% (P = .55) in MRD-negative compared with MRD-positive patients, respectively. The cumulative incidence of nonrelapse mortality was similar in the 2 groups. Achieving a complete molecular remission before transplantation reduces the risk of leukemia relapse even though TKIs may still rescue some patients relapsing after transplantation.

Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. METHODS: We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957. FINDINGS: Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8-44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6-25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3-14·3) in the busulfan plus fludarabine group (Gray's test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event). INTERPRETATION: In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. FUNDING: Agenzia Italiana del Farmaco.

Design and Validation of an Augmented Hematopoietic Cell Transplantation-Comorbidity Index Comprising Pretransplant Ferritin, Albumin, and Platelet Count for Prediction of Outcomes after Allogeneic Transplantation.

Pretransplant values of serum ferritin, albumin, and peripheral blood counts were previously suggested to provide prognostic information about hematopoietic cell transplantation (HCT) outcomes. Whether these "biomarkers" have prognostic value independent of each other and the HCT-comorbidity index (HCT-CI) is unknown. We analyzed data from 3917 allogeneic HCT recipients at multiple sites in the United States and Italy using multivariate models including each biomarker and the HCT-CI. Data from all sites were then randomly divided into a training set (n = 2352) to develop weights for the relevant biomarkers to be added to the HCT-CI scores and a validation set (n = 1407) to validate an augmented HCT-CI compared with the original index. Multivariate analysis with data from one site showed that ferritin, albumin, and platelets-not neutrophils or hemoglobin-were independently associated with increased nonrelapse mortality (NRM) and decreased overall survival. Findings were validated in data from the other sites. Subsequently, in a training set from all sites, ferritin >2500 mg/dL (hazard ratio [HR], 1.69); albumin 3 to 3.5 g/dL (HR, 1.61) and <3.0 g/dL (HR, 2.27); and platelets 50 to <100,000 (HR, 1.28), 20 to <50,000 (HR, 1.29), and <20,000 (HR, 1.55) were statistically significantly associated with NRM. Weights were assigned to these laboratory values following the same equation used to design the original index. In the validation set, the addition of the biomarkers to the original index to develop an augmented HCT-CI resulted in a statistically significant increase in a higher c-statistic estimate for prediction of NRM (P = .0007). Ferritin, albumin, and platelet counts are important prognostic markers that further refine the discriminative power of the HCT-CI for transplant outcomes.

Spin Hall Effects Due to Phonon Skew Scattering.

A diversity of spin Hall effects in metallic systems is known to rely on Mott skew scattering. In this work its high-temperature counterpart, phonon skew scattering, which is expected to be of foremost experimental relevance, is investigated. In particular, the phonon skew scattering spin Hall conductivity is found to be practically T independent for temperatures above the Debye temperature T_{D}. As a consequence, in Rashba-like systems a high-T linear behavior of the spin Hall angle demonstrates the dominance of extrinsic spin-orbit scattering only if the intrinsic spin splitting is smaller than the temperature.

Evaluation of lymphocytes inactivation by extracorporeal photopheresis using tetrazolium salt based-assay.

Extracorporeal photopheresis (ECP) is accepted as a second-line therapy for the treatment of acute and chronic steroid-refractory graft versus host disease (GvHD), cutaneous T-cell lymphoma and solid organ transplantation. ECP should be validated: we compared in parallel apoptosis and proliferation analysis of patient lymphocytes treated with 8-MOP ECP using respectively Annexin V/7-aminoactinomycin D (7-AAD) and CFSE with a tetrazolium salt (WST-1) method. Using WST-1 assay we found a significant decrement (p < 0.01) of metabolic activity at 4 days between ECP-treated and untreated cells. This finding was confirmed by the significant decrease of cell proliferation and increase of cell death observed by CFSE and 7AAD-Annexin V, respectively. Accordingly, once validated against a reference method, WST-1 could represent a rapid and easy assay for routinely quality control of ECP.

Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index: a prospective, multicenter GITMO study.

The development of tools for the prediction of nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (HSCT) would offer a major guidance in the therapeutic decision. Recently, the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) has been associated with increased NRM risk in several retrospective studies, but its clinical utility has never been demonstrated prospectively in an adequately sized cohort. To this aim, we prospectively evaluated a consecutive cohort of 1937 patients receiving HSCT in Italy over 2 years. HCT-CI was strongly correlated with both 2-year NRM (14.7%, 21.3%, and 27.3% in patients having an HCT-CI score of 0, 1-2, and ≥ 3, respectively) and overall survival (56.4%, 54.5%, and 41.3%, respectively). There was an excellent calibration between the predicted and observed 2-year NRM in patients having an HCT-CI score of 0 and 1-2, whereas in the ≥ 3 group the predicted NRM overestimated the observed NRM (41% vs 27.3%). HCT-CI alone was the strongest predictor of NRM in patients with lymphoma, myelodysplastic syndrome, and acute myeloid leukemia in first remission (c-statistics 0.66, 064, and 0.59, respectively). We confirm the clinical utility of the HCT-CI score that could also identify patients at low NRM risk possibly benefiting from an HSCT-based treatment strategy.

Imatinib for refractory chronic graft-versus-host disease with fibrotic features.

We previously reported that patients with fibrotic, chronic graft-versus-host disease (cGVHD) have antibodies activating the platelet-derived growth factor receptor pathway. Because this pathway can be inhibited by imatinib, we performed a pilot study including 19 patients with refractory cGVHD, given imatinib at a starting dose of 100 mg per day. All patients had active cGVHD with measurable involvement of skin or other districts and had previously failed at least 2 treatment lines. Patient median age was 29 years (range, 10-62 years), and median duration of cGvHD was 37 months (range, 4-107 months). The organs involved were skin (n = 17), lung (n = 11), and bowel (n = 5); 15 patients had sicca syndrome. Imatinib-related, grade 3 to 4 toxicity included fluid retention, infections, and anemia. Imatinib was discontinued in 8 patients: in 3 because of toxicity and in 5 because of lack of response (n = 3) or relapse of malignancy (n = 2). Overall response rate at 6 months was 79%, with 7 complete remissions (CRs) and 8 partial remissions (PRs). With a median follow-up of 17 months, 16 patients are alive, 14 still in CR or PR. The 18-month probability of overall survival is 84%. This study suggests that imatinib is a promising treatment for patients with refractory fibrotic cGVHD.

Multiplex amplification and fluorimetric detection of short tandem repeats for mixed chimerism after bone marrow transplant.

We present the clinical application of a simple method for mixed chimerism analysis after allogeneic bone marrow (BM) or peripheral blood stem cell (PBSC) transplant. A commercial kit which enables multiplex amplification of 9 highly polymorphic short tandem repeats in a single reaction tube was used. Molecular size and relative quantities of each amplified fragment are subsequently measured using an automated fluorimeter. The sensitivity and linearity were tested using whole blood or genomic DNA from two subjects, mixed in various proportions from 0.25% to 99.75%. In 70 donor-recipient pairs the median number of informative alleles for the assessment of relapse was 5.9 (range 3-11). Results showed that the linearity between the measured and expected relative quantities of amplified DNA showed a regression coefficient of 0.99 in the interval 10-90%. The mean sensitivity was 1.5% (range 0.5-2.5), greater than previously reported. A total of 70 cases of allogeneic transplant (49 with family and 21 with unrelated donors) were monitored before transplant and after 1, 2, 4, 6 or 12 months thereafter and then at 6 months intervals (range 6-36). In 18 patients mixed chimerism was observed 1 month from transplant, with donor allele percentage ranging from 1 to 6%. Fragment dimension reproducibility (CV 0.34, range 0.52-0.66) was confirmed by an internal DNA control and by amelogenin fragment length repeatability on all patients. In conclusion, the proposed method is sufficiently simple, rapid, sensible, specific and cost effective for the evaluation of mixed chimerism after BM or PBSC transplant in a clinical setting.

The impact of histopathologic examination of graft-versus-host disease in the era of reduced-intensity conditioning regimen: a study from the Gruppo Italiano Trapianto di Midollo Osseo.

Reduced-intensity conditioning regimens have reshaped the clinical presentation of graft-versus-host disease after hematopoietic stem cell transplants. However, histopathologic features of graft-versus-host disease following reduced-intensity conditioning regimens have not been fully characterized. In a series of 112 biopsies (skin, n = 60; gastrointestinal [GI] tract, n = 44; liver, n = 8), we described the morphologic profile of graft-versus-host disease following reduced-intensity conditioning and investigated whether histopathologic changes of graft-versus-host disease following reduced-intensity conditioning have a diagnostic and/or prognostic value. Forty-four patients (49.5%) experienced acute graft-versus-host disease, 2 (2.2%) late-onset acute graft-versus-host disease (grade I, n = 13; grade II-IV, n = 33), 24 (27.0%) chronic graft-versus-host disease (de novo n = 12, progressive n = 12) and 19 (21.3%) overlap syndrome. In the skin, we observed: (i) phase-nonspecific changes, such as acute graft-versus-host disease features in chronic graft-versus-host disease patients (n = 4/24; 16.6%), (ii) subtle alterations such as superficial fibrosis in widened dermal papillae (n = 8), in acute graft-versus-host disease/late-onset graft-versus-host disease (n = 6/46; 13.0%) or chronic graft-versus-host disease (n = 2/24, 8.3%) patients, and (iii) features of chronic and acute graft-versus-host disease coexisting in the same specimen in overlap syndrome (n = 3/19; 15.7%). In the GI tract, we did not demonstrate peculiar features differing from those commonly observed in the myeloablative setting. By univariate analysis, a reduced overall survival was associated with graft-versus-host disease type (chronic graft-versus-host disease P = .006, acute graft-versus-host disease P = .03), older age (P = .04), and histopathologic diagnosis of "consistent with" + definite graft-versus-host disease (P = .02). Histopathologic diagnosis retained an independent prognostic value by multivariate analysis (P = .01). The present study indicates that pathologists should be aware of the peculiar morphologic changes of cutaneous graft-versus-host disease following reduced-intensity conditioning and further recommends histopathology in the diagnostic workup of graft-versus-host disease in patients undergoing reduced-intensity conditioning regimen.

Prolonged overall survival with second on-demand autologous transplant in multiple myeloma.

Between August 1993 and March 2003, 130 consecutive multiple myeloma (MM) patients eligible for high-dose treatment were offered a program including up-front autologous stem cell transplantation (ASCT) after conditioning with 200 mg/m(2) melphalan followed by a second ASCT in case of relapse or progression. A total of 107 (82%) patients completed the first ASCT. The best response obtained after ASCT was complete response (CR) 23%, very good partial response (VGPR) 28%, partial response (PR) 42%, and minimal response (MR) 7%. Median overall survival (OS) and event-free survival (EFS) were 65.4 and 27.7 months, respectively. Relapse or progression occurred in 70 patients; 26 received a second ASCT (with a median time of 20.4 months from first ASCT). A major response (> or =PR) was obtained in 69% of these patients. Median OS and EFS after the second ASCT were 38.1 and 14.8 months. Treatment-related mortality was 1.9% after the first ASCT but no deaths occurred after the second. Our experience suggests that elective up-front single ASCT followed by second ASCT after relapse or progression is a safe and effective global strategy to treat MM patients.

Temperature dependence of the tunneling amplitude between quantum hall edges.

Recent experiments have studied the tunneling current between the edges of a fractional quantum Hall liquid as a function of temperature and voltage. The results of the experiment are puzzling because at "high" temperature (600-900 mK) the behavior of the tunneling conductance is consistent with the theory of tunneling between chiral Luttinger liquids, but at low temperature it strongly deviates from that prediction dropping to zero with decreasing temperature. In this Letter we suggest a possible explanation of this behavior in terms of the strong temperature dependence of the tunneling amplitude.

Nonlinear quasiparticle tunneling between fractional quantum hall edges.

Remarkable nonlinearities in the differential tunneling conductance between fractional quantum Hall edge states at a constriction are observed in the weak-backscattering regime. In the nu=1/3 state a peak develops as temperature is increased and its width is determined by the fractional charge. In the range 2/3