Rituximab, a monoclonal antibody that targets the CD20 cell surface antigen, has clinical activity in patients with non-Hodgkin's lymphoma and other B-lymphocyte disorders when administered alone or ...in combination with chemotherapy. Promising results have previously been reported in nonrandomized studies in patients with chronic lymphocytic leukemia (CLL). This trial was designed to compare chemoimmunotherapy with chemotherapy alone in patients with previously treated CLL.
This international, multicenter, randomized trial compared six cycles of rituximab plus fludarabine and cyclophosphamide (R-FC) with six cycles of fludarabine and cyclophosphamide alone (FC) in patients with previously treated CLL. A total of 552 patients with Binet stage A (1%), B (59%), or C (31%) disease entered the study and were randomly assigned to receive R-FC (n = 276) or FC (n = 276).
After a median follow-up time of 25 months, rituximab significantly improved progression-free survival in patients with previously treated CLL (hazard ratio = 0.65; P < .001; median, 30.6 months for R-FC v 20.6 months for FC). Event-free survival, response rate, complete response rate, duration of response, and time to new CLL treatment or death were also significantly improved. Although the rates of adverse events, grade 3 or 4 events, and serious adverse events were slightly higher in the R-FC arm, R-FC was generally well tolerated, with no new safety findings and no detrimental effect on quality of life.
R-FC significantly improved the outcome of patients with previously treated CLL.
Polymorphisms of activating Fc-γ receptors (FCGRs) on natural killer cells and macrophages result in variable affinity for immunoglobulin G1 monoclonal antibodies and subsequently modulate ...antibody-dependent cellular cytotoxicity (ADCC) activity. Whether single-nucleotide polymorphisms of FCGRs correlate with survival of chronic lymphocytic leukemia (CLL) patients treated with a monoclonal antibody containing regimen is unclear. We assessed the FCGR3A and FCGR2A genotype of patients enrolled in the REACH trial, where patients received fludarabine and cyclophosphamide (FC) or rituximab plus FC (R-FC). FCGR3A and FCGR2A polymorphisms did not demonstrate prognostic significance in the FC arm (P = .42 and P = .64, respectively) or R-FC arm (P = .41 and P = .88, respectively) with respect to progression free survival. Patients with intermediate affinity genotypes (FV and HR) benefited significantly from addition of rituximab (hazard ratio = 0.55 0.37-0.8 CI; P = .0017 and hazard ratio = 0.63 0.44-0.9 CI; P = .011, respectively). Similar benefit was suggested for patients with high- affinity VV and HH (hazard ratio = 0.86 0.4-1.84 CI; P = .7 and hazard ratio = 0.7 0.41-1.18 CI; P = .18, respectively) and low-affinity FF and RR (hazard ratio = 0.85 0.56-1.29 CI; P = .44 and hazard ratio = 0.82 0.47-1.42 CI; P = .48, respectively). Overall, our results suggest that FCGR2A and FCGR3A polymorphisms do not significantly influence the outcomes of relapsed or refractory CLL patients treated with FC or the monoclonal antibody regimen R-FC.
Summary
We prospectively observed 36 haematological patients with mucormycosis from nine hospitals of St. Petersburg during 2004–2013. The most frequent underlying diseases were acute leukaemia ...(64%), and main risk factors were prolonged neutropenia (92%) and lymphocytopenia (86%). In 50% of the patients, mucormycosis was diagnosed 1–65 days after invasive aspergillosis. Main clinical form of mucormycosis was pulmonary (64%), while two or more organ involvement was noted in 50% of the cases. The most frequent aetiological agents of mucormycosis were Rhizopus spp. (48%). Twelve‐week survival rate was 50%. Combination therapy (echinocandins + amphotericin B forms) and recovery from the underlying disease significantly improved the survival rate.
High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is a new and promising approach to the treatment of multiple sclerosis (MS) patients ...because currently there are no effective treatment methods for this disease. In this article, we present results of a prospective clinical study of efficacy of HDIT + auto-HSCT in MS patients. The following treatment strategies were employed in the study: “early,” “conventional,” and “salvage/late” transplantation. Fifty patients with various types of MS were included in this study. No toxic deaths were reported among 50 MS patients; transplantation procedure was well-tolerated by the patients. The efficacy analysis was performed in 45 patients. Twenty-eight patients achieved an objective improvement of neurological symptoms, defined as at least 0.5-point decrease in the Expanded Disability Status Scale (EDSS) score as compared to the baseline and confirmed during 6 months, and 17 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed during 6 months). The progression-free survival at 6 years after HDIT + auto-HSCT was 72%. Magnetic resonance imaging data were available in 37 patients before transplantation showing disease activity in 43.3%. No active, new, or enlarging lesions were registered in patients without disease progression. In conclusion, HDIT + auto-HSCT suggests positive results in management of patients with different types of MS. Identification of treatment strategies based on the level of disability, namely “early,” “conventional,” and “salvage/late” transplantation, appears to be feasible to improve treatment outcomes.
Abstract
AIM
Medulloblastoma is a highly lethal disease when it recurs. Very few patients survive with second line conventional treatment after relapse. This study evaluated the use of high-dose ...thiotepa, carboplatin and etoposide with autologous hematopoietic stem-cell transplantation (HSCT) in patients with recurrent medulloblastoma.
METHODS
From 2010 to 2019, 60 patients at the age 4–32 years (median, 12) with recurrent medulloblastoma were received high-dose chemotherapy (HDCT) with auto-HSCT after induction second line chemotherapy. HDCT included thiotepa 150 mg/m2 #4; carboplatin 500 mg/m2 #4; etoposide 250 mg/m2 #4 and +/- etoposide 1 mg intraventricular on days #5 if patient had Ommaya reservoir; followed by HSCT. At the moment of HDCT 24 patients were in complete response (CR), 31 patients were in partial response (PR) and 5 patients had stable disease (SD) after second line conventional chemotherapy.
RESULTS
The median follow-up is 65 months (range, 24–227). The median time to engraftment after auto-HSCT was day +11 (range, 8–39). Five-year overall survival (OS) was 58% and disease free survival (DFS) was 46%. DFS was significantly better among patients in CR or PR 50% in compared to children in SD 20% at the moment of HDCT (p=0,002). Transplant related mortality were 12%, there were 7 patients died because of severe complications within 14 days after transplantation.
CONCLUSIONS
HDCT with auto-HSCT in pediatric patients with recurrent medulloblastoma may be a feasible option for cases who had CR or PR after induction chemotherapy. It is ineffective as a salvage therapy in refractory patients.
Introduction. Several alternative donor sources are currently available for patients who lack an HLA-matched related or unrelated donor, including haploidentical, cord blood and one antigen ...HLA-mismatched donors (9/10 mMUD). Use of post-transplant (allo-HSCT) cyclophosphamide (PTCY) as graft-versus-host disease (GVHD) prophylaxis allowed outcome improvements in the haploidentical setting. Its use has also been reported as a safe and feasible option in 9/10 mMUD transplants. However, to date, the main strategy used as GVHD prophylaxis in 9/10 mMUD allo-HSCT is in vivo T-cell depletion with antithymocite globulin (ATG). Data comparing these two different anti GVHD prophylaxis strategies in 9/10 mMUD allo-HSCT are limited.
Methods. We compared PTCY versus ATG as GVHD prophylaxis in patients undergoing 9/10 mMUD allo-HSCT for which high-resolution HLA-allele typing was available in the ALWP/EBMT data registry. Included were adult patients (age>18 years) undergoing their first allo-HSCT for acute myeloid leukemia (AML) during the period 2007-2017. All disease status were allowed. Propensity score matching was performed to reduce and eliminate confounding effects. Each patient receiving PTCY was matched with two patients receiving ATG using the nearest neighbor or exact matching. Variables included in the propensity score model were: disease status at time of allo-HSCT, conditioning regimen, age, secondary AML, female donor to male recipient, source of stem cells, patient and donor CMV serology status.
Results. Globally, 93 patients receiving PTCY were identified and matched with 179 patients receiving ATG. Secondary AML was reported in 20% and 18% of patients in ATG and PTCY groups, respectively. Most patients were in first complete remission at time of allo-HSCT (55% and 56% in PTCY and ATG group, respectively), while nearly 29% of patients in both groups underwent allo-HSCT with active disease. Ciclosporine (csA) and mycophenolate mofetil (MMF) were the systemic immunosuppressive agents more frequently associated to either PTCY (42%) or ATG (49%). Other well represented associated immunosuppressive agents were tacrolimus and MMF in ATG group (20%), followed by 14% of patients receiving csA alone with ATG. In PTCY group, 39% of patients received csA and methotrexate as associated immunosuppressive agents. Conditioning regimen was myeloablative in 50% of patients in both groups. Peripheral blood was the preferred stem cell source (91% in both groups). Among the variables not included in the propensity score model, some differences were observed between the two groups. Median follow-up was longer in the ATG group (27.4 versus 14.2 months, p<0.01). Gender was more frequently male in PTCY group (60% versus 45%, p<0.02). Median year of allo-HSCT was 2014 and 2015 in ATG and PTCY groups, respectively (p<0.01). Similar engraftment rates were observed for both groups (95% and 96% in PTCY and ATG groups, respectively). At 2 years, leukemia-free survival (LFS) was higher in patients receiving PTCY (55% vs 35%, p<0.05), severe (grade III-IV) acute GVHD was lower (9% vs 19%, p<0.04) and GRFS higher (37% vs 21%, p<0.02) as compared to patients receiving ATG, while no differences were observed in relapse incidence (RI)( 29% vs 37%, p=0.31), overall survival (OS, 56% vs 38%, p=0.06) and in non-relapse mortality (NRM) (16% vs 29%, p=0.06). Main causes of death were similarly distributed in both groups, with infectious complications being more frequently represented (25% and 22% in the PTCY and ATG groups, respectively). Grade II-IV acute GVHD (30% vs 32%, p=0.39) and chronic GVHD (39% vs 36%, p=0.35) were also similar in the two groups.
Conclusions. In patients undergoing 9/10 mMUD allo-HSCT, use of PTCY as GVHD prophylaxis is a safe and feasible option, representing a possible valid and superior alternative to ATG. Use of PTCY, indeed, may ensure a lower incidence of severe acute GVHD and higher LFS and GRFS as compared to ATG. These registry based results may serve the basis for a prospective randomized trial comparing PTCY to ATG as anti GVHD prophylaxis in 9/10 mMUD allo-HSCT.
Hilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding. Mohty:MaaT Pharma: Consultancy, Honoraria.
While DNA and messenger RNA (mRNA) based therapies are currently changing the biomedical field, the delivery of genetic materials remains the key problem preventing the wide introduction of these ...methods into clinical practice. Therefore, the creation of new methods for intracellular gene delivery, particularly to hard-to-transfect, clinically relevant cell populations is a pressing issue. Here, we report on the design of a novel approach to format 50-150 nm calcium carbonate particles in the vaterite state and using them as a template for polymeric core-shell nanoparticles. We apply such core-shell nanoparticles as safe and efficient carriers for mRNA and pDNA. We prove that such nanocarriers are actively internalized by up to 99% of primary T-lymphocytes and exert minimal toxicity with the viability of >90%. We demonstrate that these nanocarriers mediate more efficient transfection compared with the standard electroporation method (90%
vs.
51% for mRNA and 62%
vs.
39% for plasmid DNA) in primary human T-lymphocytes as a model of the hard to transfect type that is widely used in gene and cell therapy approaches. Importantly, these polymeric nanocarriers can be used in serum containing basic culture medium without special conditions and equipment, thus having potential for being introduced in clinical development. As a result, we have provided proof-of-principle that our nanosized containers represent a promising universal non-viral platform for efficient and safe gene delivery.
The polyelectrolyte nanocarriers' based on nanosized vaterite particles as a novel tool for genetic material delivery into the clinically relevant cell types and potential application of described technology in gene therapy approaches.
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Introduction: Primary refractory or relapsing acute myeloid leukemia (R/R-AML) has very poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) may be the only chance of cure. ...Therefore a suitable donor should be rapidly searched for, in this setting. In those patients (pts) lacking an HLA-matched sibling donor (MSD), mismatched family donor (haploidentical, Haplo) may represent a valid and rapidly available option.
Methods: Herein, we compared the outcomes of pts with R/R-AML undergoing first HSCT from either a MSD (n=1654) or Haplo (n=389) in the period 2007-2015. The Haplo group included pts receiving a T-repleted graft with post-transplant cyclophosphamide (PTCY, n=278), in vivo T-cell depletion (TCD, n=95), or both (n=16).
Results: Median age at HSCT was 52 (range 18-74) years. Median follow-up was 16 and 22 months for MSD and Haplo recipients, respectively (p=0.11). At time of HSCT, 41% and 56% presented a primary refractory AML in Haplo and MSD groups, respectively (p<0.01). Compared to MSD, Haplo HSCT were performed more recently (median year 2013 versus 2011, p<0.01) with a higher number of pts having a poor Karnofsky performance status (22% versus 16%, p<0.01) and a positive serology for CMV (83% versus 71%, p<0.001) at time of HSCT, respectively. The latter also had more frequently undergone a previous autologous HSCT (8% vs 3%, p<0.01), had a longer interval from diagnosis to HSCT (7 versus 5 months, p<0.01), received more frequently bone marrow as stem cell source (47% vs 8%, p<0.01), a reduced intensity conditioning regimen (50% vs 43%, p<0.03), and a graft from a male donor (59% versus 53%, p<0.03) as compared to MSD recipients. Compared to Haplo, cumulative incidence (CI) of neutrophil engraftment was higher (93% versus 83%, p<0.01) and associated to a shorter median time to engraftment (15 versus 18 days, p<0.01) in MSD recipients. According to donor type, no differences were found in univariate analysis for the CI of grade II-IV acute graft-versus host disease (aGVHD)(28% versus 27%, p=0.37), while a lower CI of chronic GVHD (cGVHD) (27% versus 42%, p<0.01) and extensive cGVHD (12% and 19%, p<0.01) was observed in HSCT from Haplo compared to MSD, respectively. At two years, overall survival (OS) was 25% and 32% (p<0.01), leukemia-free survival (LFS) 19% and 27% (p<0.01) and GVHD/relapse-free survival (GRFS) 18% and 26% (p<0.01) in HSCT from Haplo and MSD, respectively. Relapse incidence (RI) was similar following HSCT from Haplo and MSD (50% vs 51%, p=0.60), while non-relapse mortality (NRM) was higher for Haplo transplants (31% vs 22% in HSCT from MSD, p<0.001), respectively. In a multivariate analysis adjusted for the differences between the two groups, Haplo HSCT was associated with lower OS (HR 1.19, p<0.04), LFS (HR 1.17, p<0.05) and GRFS (HR 1.22, p<0.02). Higher grade II-IV aGVHD was observed in Haplo recipients. Neither cGVHD (any grade) nor RI differed according to donor type (p=ns). Compared to MSD, Haplo recipients experienced a higher NRM (HR 1.4, p<0.02) mainly related to a higher incidence of infections (41% versus 25%, p<0.01). Regardless of donor type, age as a continuous variable was associated with lower RI (HR 0.99, p<0.01), lower OS (HR 1.01, p<0.01) and higher NRM (HR 1.02, p<0.01). The use of peripheral blood as stem cell source was independently associated with a higher risk of cGVHD (HR 1.64, p<0.01).
Conclusions: Our results indicate that for pts with R/R-AML outcome is better with HSCT from a MSD compared to unmanipulated Haplo donor, mainly due to the higher NRM associated with transplants from Haplo and most probably related to a higher incidence of infections and grade II-IV aGVHD. Chronic GVHD as well as RI are similar, indicating once again that despite the broader HLA disparities with Haplo HSCT the graft versus leukemia effect is probably not stronger than after HSCT from MSD (Ringden O, on behalf of the ALWP; Leukemia 2016). In the absence of a MSD, Haplo HSCT may represent a valid alternative, with nearly one quarter of the R/R-AML pts surviving at 2 years from transplant. Future goals in the Haplo setting should be to reduce NRM and rate of infections in order to further improve outcomes.
Ciceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Mohty:Sanofi: Honoraria, Speakers Bureau.