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.
Background: Haplo-identical stem cell transplantation is increasingly been used in recent years in the treatment of acute leukemia. In particular, the use of T-cell replete grafts with ...post-transplant cyclophosphamide (PTCy) for prevention of graft-vs-host disease (GVHD) is becoming a valid treatment option with encouraging outcome. The initial studies used bone-marrow as the stem-cell source, but more recently, peripheral blood stem cells (PBSC) are also used. There is more limited data on the prognostic factors following haplo-identical transplantation with PBSC. Natural killer (NK) allo-reactivity as predicted by missing killer-cell immunoglobulin-like receptor (KIR) ligands in the recipients that are present in the donors has been shown to be an important factor in the outcome of T-cell depleted haplo-identical transplants. NK alloreactivity is associated with reduced relapse risk and improved survival in patients with AML, but not in patients with adult ALL. In addition, patients with donor NK alloreactivity had better engraftment and lower risk of GVHD. The role of NK cell allo-reactivity in the setting of T-cell replete haplo-identical transplant with PBSC and PTCy is unknown.
Patients and Methods: The study included 238 patients, 139 male, 99 female, median age 45 years (range, 18-78) with AML (n=176) or ALL (n=62) who had T-replete haplo-identical transplant with PTCy between the years 2010-2015. All patients were given PBSC as their stem cell source. Patients were in CR1 (38%), CR2 (24%) or active disease (38%). Conditioning was myeloablative (47%) or reduced-intensity (53%). GVHD prevention included cyclosporine or tacrolimus with mycophenolate, in addition to PTCy, in 82%. KIR-ligand mismatching was predicted according to patient and donor HLA typing and correlated with transplantation outcomes. In all, 89 patients (37%) had a KIR mismatch in the GVHD direction, based on missing expression of C1, C2 or Bw4 ligands in the recipients that were expressed in their donors. There was no significant difference in patient characteristics between the group with and without KIR mismatch.
Results: The median follow-up was 14 months (range, 1-50). Ninety-four percent of patients engrafted. The 2-year relapse and non-relapse mortality (NRM) rates in the entire group were 36% (95%CI, 29-42) and 22% (17-27), respectively. The leukemia-free (LFS) and overall survival (OS) rates were 43% (36-50) and 49% (42-56), respectively. Acute GVHD grade II-IV and chronic GVHD occurred in 34% (29-40) and 32% (26-39), respectively. The 2-year OS was 35% (22-47) in patients with KIR mismatch and 51% (42-60) in patients with no KIR-ligand mismatching (P=0.02). 2-year LFS rates were 27% (16-38) and 47% (38-56), respectively (P=0.003). Multivariate analysis identified AML (compared to ALL) (HR 0.51, P=0.008), active disease at transplantation (HR 5.03, P<0.001) and KIR mismatching (HR 1.60, P=0.03) as factors associated with 2-year OS. A center effect was also identified (P=0.05). The same factors predicted for LFS. KIR mismatching was associated with a higher incidence of relapse, 47% (34-58) and 32% (24-41), respectively (P=0.05). Multivariate analysis identified active disease at transplantation (HR 6.38, P<0.001), KIR mismatching (HR 1.97, P=0.03), female donors (HR 0.58, P=0.03) and reduced-intensity conditioning (HR 1.71, P=0.05) as factors associated with 2-year relapse. KIR mismatching was not associated with NRM, acute or chronic GVHD.
Conclusions: Haplo-identical transplant with PTCy and PBSC graft is associated with favorable outcome in patients with acute leukemia. KIR ligand mismatching may be associated with increased relapse rate and worse survival in these patients. Donors with KIR mismatching should be avoided when possible in the PBSC haplo-identical setting.
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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.
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