Ofatumumab with iphosphamide, etoposide and cytarabine for patients with transplantation-ineligible relapsed and refractory diffuse large B-cell lymphoma.

The efficacy of salvage treatment of diffuse large B-cell lymphoma (DLBCL) patients who relapse or progress (rrDLBCL) after initial therapy is limited. Efficacy and safety of ofatumumab with iphosphamide, etoposide and cytarabine (O-IVAC) was evaluated in a single-arm study. Dosing was modified for elderly patients. Patients received up to six cycles of treatment. The primary end-point was the overall response rate (ORR). Patients were evaluated every two cycles and then six and 12 months after treatment. Other end-points included progression-free survival (PFS), event-free survival (EFS), overall survival (OS) and safety. Seventy-seven patients received salvage treatment with O-IVAC. The average age was 56.8 years; 39% had an Eastern Cooperative Oncology Group (ECOG) performance status of at least 3; 78% had disease of Ann Arbor stage 3 or 4; 58% received one or more prior salvage therapies. The ORR for O-IVAC was 54.5%. The median duration of study follow-up was 70 months. The median PFS and EFS were 16.3 months each. The median OS was 22.7 months. Age, ECOG performance status and the number of prior therapy lines were independent predictors of survival. Treatment-related mortality was 15.5%. O-IVAC showed a high response rate in a difficult-to-treat population and is an attractive treatment to bridge to potentially curative therapies.

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study.

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

Vascular endothelial growth factor-activated basophils in asthmatics.

INTRODUCTION: Vascular endothelial growth factor (VEGF) is an angiogenic cytokine and a potential stimulator of permeability and lung neovascularization in asthmatics. It also plays an important role in the development of airway remodelling and in activation of many cells, including basophils. AIM: To reveal the possible role of VEGF in the activation of basophils in asthmatics - subgroups with and without irreversible bronchoconstriction. Protein CD203c on the basophils surface was used as the activation marker. To define the possible pathway of basophils VEGF-activation, the influence of a genetic factor (polymorphism del18/ins -2549 -2567 in the VEGF-promoter region) was also considered. MATERIAL AND METHODS: Our study involved 82 patients with asthma (40 patients without and 42 patients with irreversible bronchoconstriction) and a group of 40 controls. The flow cytometric methods with anti-CD203c in the samples of basophils with increasing concentrations of VEGF was used for analysis of their activity. Genotyping for VEGF-promoter region was performed by PCR-based methods. RESULTS: Patients with asthma and del/del genotype showed more significant differences in the basophils activation after stimulation with increasing concentrations of VEGF than asthmatics with ins/ins and ins/del genotype (p = 0.023) and controls with del/del genotype (p = 0.0006). CONCLUSIONS: Raised basophils VEGF-activation is characteristic for examined patients with asthma and might be associated with presence of polymorphism del18/ins -2549 -2567 in the VEGF-promoter region. Furthermore, it may contribute to the development of airways remodelling - this pathway has not been considered yet.

Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders.

BACKGROUND: Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). METHODS: Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. RESULTS: Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. CONCLUSION: RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

A Multicentre Study on the Efficacy, Safety and Pharmacokinetics of IqYmune®, a Highly Purified 10% Liquid Intravenous Immunoglobulin, in Patients with Primary Immune Deficiency.

This multicentre, open-label, prospective, single-arm study was designed to evaluate the efficacy, pharmacokinetics, and safety of IqYmune®, a highly purified 10% polyvalent immunoglobulin preparation for intravenous administration in patients with primary immunodeficiency. IqYmune® was administered to 62 patients (aged 2-61 years) with X-linked agammaglobulinemia or common variable immune deficiency at a dose from 0.22 to 0.97 g/kg every 3 to 4 weeks for 12 months with an infusion rate up to 8 mL/kg/h. A pharmacokinetic study was performed at steady state between the 8th and the 9th infusion. A single case of serious bacterial infection was observed, leading to an annualized rate of serious bacterial infections/patient (primary endpoint) of 0.017 (98% CI: 0.000, 0.115). Overall, 228 infections were reported, most frequently bronchitis, chronic sinusitis, nasopharyngitis and upper respiratory tract infection. The mean annualized rate of infections was 3.79/patient. A lower risk of infections was associated with an IgG trough level > 8 g/L (p = 0.01). The mean annualized durations of absence from work or school and of hospitalization due to infections were 1.01 and 0.89 days/patient, respectively. The mean serum IgG trough level before the 6th infusion was 7.73 g/L after a mean dose of IqYmune® of 0.57 g/kg. The pharmacokinetic profile of IqYmune® was consistent with that of other intravenous immunoglobulins. Overall, 15.5% of infusions were associated with an adverse event occurring within 72 h post infusion. Headache was the most common adverse event. In conclusion, IqYmune® was shown to be effective and well tolerated in patients with primary immunodeficiency.

Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial.

Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60-65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.

Role of Donor Activating KIR-HLA Ligand-Mediated NK Cell Education Status in Control of Malignancy in Hematopoietic Cell Transplant Recipients.

Some cancers treated with allogeneic hematopoietic stem cell transplantation (HSCT) are sensitive to natural killer cell (NK) reactivity. NK function depends on activating and inhibitory receptors and is modified by NK education/licensing effect and mediated by coexpression of inhibitory killer-cell immunoglobulin-like receptor (KIR) and its corresponding HLA I ligand. We assessed activating KIR (aKIR)-based HLA I-dependent education capacity in donor NKs in 285 patients with hematological malignancies after HSCT from unrelated donors. We found significantly adverse progression-free survival (PFS) and time to progression (TTP) in patients who received transplant from donors with NKs educated by C1:KIR2DS2/3, C2:KIR2DS1, or Bw4:KIR3DS1 pairs (for PFS: hazard ratio [HR], 1.70; P = .0020, Pcorr = .0039; HR, 1.54; P = .020, Pcorr = .039; HR, 1.51; P = .020, Pcorr = .040; and for TTP: HR, 1.82; P = .049, Pcorr = .096; HR, 1.72; P = .096, Pcorr = .18; and HR, 1.65; P = .11, Pcorr = .20, respectively). Reduced PFS and TTP were significantly dependent on the number of aKIR-based education systems in donors (HR, 1.36; P = .00031, Pcorr = .00062; and HR, 1.43; P = .019, Pcorr = .038). Furthermore, the PFS and TTP were strongly adverse in patients with missing HLA ligand cognate with educating aKIR-HLA pair in donor (HR, 3.25; P = .00022, Pcorr = .00045; and HR, 3.82; P = .027, Pcorr = .054). Together, these data suggest important qualitative and quantitative role of donor NK education via aKIR-cognate HLA ligand pairs in the outcome of HSCT. Avoiding the selection of transplant donors with high numbers of aKIR-HLA-based education systems, especially for recipients with missing cognate ligand, is advisable.

Beneficial effect of the CXCL12-3'A variant for patients undergoing hematopoietic stem cell transplantation from unrelated donors.

The present study aimed to assess the impact of the CXCL12 gene polymorphism (rs1801157) on clinical outcome of hematopoietic stem cell transplantation from unrelated donors. Toxic complications were less frequent among patients transplanted from donors carrying the CXCL12-3'-A allele (42/79 vs. 105/151, p=0.014 and 24/79 vs. 73/151, p=0.009, for grade II-IV and III-IV, respectively). Logistic regression analyses confirmed a role of donor A allele (OR=0.509, p=0.022 and OR=0.473, p=0.013 for grade II-IV and III-IV toxicity). In addition, age of recipients (OR=0.980, p=0.036 and OR=0.981, p=0.040, respectively) was independently protective while female to male transplantation and HLA compatibility were not significant. The incidence of aGvHD (grades I-IV) was lower in patients having A allele (52/119 vs. 113/204, p=0.043) and AA homozygous genotype (6/25 vs. 159/298, p=0.005). Independent associations of both genetic markers with a decreased risk of aGvHD were also seen in multivariate analyses (A allele: OR=0.591, p=0.030; AA homozygosity: OR=0.257, p=0.006) in which HLA compatibility seemed to play less protective role (p<0.1) while recipient age and donor-recipient gender relation were not significant. Moreover, CXCL12-3'-A-positive patients were less prone to early HHV-6 reactivation (2/34 vs. 19/69, p=0.026). The presence of the CXCL12-3'-A variant was found to facilitate outcome of unrelated HSCT.

NOD2/CARD15 single nucleotide polymorphism 13 (3020insC) is associated with risk of sepsis and single nucleotide polymorphism 8 (2104C>T) with herpes viruses reactivation in patients after allogeneic hematopoietic stem cell transplantation.

Three NOD2 polymorphisms (single nucleotide polymorphism [SNP]8 [2104C>T, Arg702Trp], SNP12 [2722G>C, Gly908Arg], and SNP13 [3020insC, Leu1007 fsins C]), identified as disease-associated variants in Crohn's disease, have recently been suggested as gene markers of the outcome of hematopoietic stem cell transplantation (HSCT). In the present multicenter study of 464 donor-recipient pairs, we focused on the effect of NOD2 mutation(s) on the risk of infections and acute graft-versus-host disease (aGVHD). The presence of SNP13 in recipients, donors, or both was more frequently seen in patients having sepsis than in those lacking sepsis (9 of 48 versus 33 of 386, P = .046). The presence of SNP8 (recipient and/or donor positive) was associated with a higher rate of Herpes viruses reactivation (17 of 21 versus 86 of 173, P = .007). In the SNP8-positive group, a trend for a higher rate of bacteremia well controlled by antibiotics was found (9 of 10 versus 47 of 81, P = .106). In contrast, the presence of SNP13 in recipient and/or donor resulted in a poor response to antibiotics (5 of 11 versus 9 of 10, P = .042). A statistically significant association between the presence of NOD2 SNPs and acute grade > II GVHD was found in a subgroup of HSCT patients who received transplants from unrelated donors with a myeloablative conditioning regimen that included antithymocyte globulin (ATG). In this subgroup of patients, donor positivity for any SNPs investigated (7 of 18 versus 17 of 113, P = .036) and, independently, only the presence of SNP8 (4 of 8 versus 20 of 123, P = .055) were associated with severe grade ≥ II aGVHD. In conclusion, SNP8 positivity in donors or recipients makes patients more prone to Herpes viruses reactivation and bacteremia but not to sepsis. Septic complications were associated with SNP13 polymorphism. SNP8 in donors constitutes a risk factor of severe aGVHD, but only if patients received transplants from unrelated donors and received ATG as part of a conditioning regimen.

Genetic variant of the G-CSF receptor gene is associated with lower mobilization potential and slower recovery of granulocytes after transplantation of autologous peripheral blood progenitor cells.

Peripheral blood mobilized by cytokines (i.e. granulocyte colony stimulating factor, G-CSF) and chemotherapy has become a major source of hematopoietic stem and progenitor cells for transplantation (PBPCT). In this study the effect of the G-CSF receptor (CSF3R) gene polymorphism was investigated. The presence of the CSF3R variant (T allele, rs3917924) was related to CD34(+) mobilization yield and the pace of granulocyte recovery after autologous PBPCT. The mobilization yield was higher in patients lacking the CSF3R variant (OR=4.756, p=0.046) and those with multiple myeloma (OR=10.534, p=0.019). The pace of granulocyte recovery was found to be associated with the CSF3R polymorphism and was significantly slower in patients carrying the CSF3R-T variant than in CC homozygotes (median of 17 vs. 13 days, p<0.001). This association was confirmed (OR=4.445, p=0.014) by multiple regression analysis considering patient age and sex, the number of transplanted CD34(+) cells, diagnosis and CSF3R polymorphism. These results imply that CSF3R gene polymorphism plays a significant role in PBPCT.

Cytokine Overproduction and Immune System Dysregulation in alloHSCT and COVID-19 Patients.

The COVID-19 pathomechanism depends on (i) the pathogenicity of the virus, (ii) ability of the immune system to respond to the cytopathic effect of the virus infection, (iii) co-morbidities. Inflammatory cytokine production constitutes a hallmark of COVID-19 that is facilitated by inability of adaptive immunity to control virus invasion. The effect of cytokine release syndrome is deleterious, but the severity of it depends on other confounding factors: age and comorbidities. In this study, we analyze the literature data on the post-transplant course of allogeneic hematopoietic stem cell transplanted (alloHSCT) patients, which is affected by generated inflammatory cytokines. The sequence of events boosting cytokine production was analyzed in relation to clinical and laboratory data highlighting the impact of cytokine generation on the post-transplant course. The collected data were compared to those from studies on COVID-19 patients. The similarities are: (i) the damage/pathogen-associated molecular pattern (DAMP/PAMP) stage is similar except for the initiation hit being sterile in alloHSCT (toxic damage of conditioning regimen) and viral in COVID-19; (ii) genetic host-derived factors play a role; (iii) adaptive immunity fails, DAMP signal(s) increases, over-production of cytokines occurs; (iv) monocytes lacking HLADR expression emerge, being suppressor cells hampering adaptive immunity; (v) immune system homeostasis is broken, the patient's status deteriorates to bed dependency, leading to hypo-oxygenation and malnutrition, which in turn stimulates the intracellular alert pathways with vigorous transcription of cytokine genes. All starts with the interaction between DAMPs with appropriate receptors, which leads to the production of pro-inflammatory cytokines, the inflammatory process spreads, tissue is damaged, DAMPs are released and a vicious cycle occurs. Attempts to modify intracellular signaling pathways in patients with post-alloHSCT graft vs host disease have already been undertaken. The similarities documented in this study show that this approach may also be used in COVID-19 patients for tuning signal transduction processes to interrupt the cycle that powers the cytokine overproduction.

Immune Response to COVID-19 mRNA Vaccine-A Pilot Study.

Twenty individuals (17 females, 3 males, aged 31-65 years (range), median: 46) who received both doses of the BioNTech Pfizer mRNA vaccine were examined (11 to 31 days, median: 25) after the second dose for the presence of antibodies against peptides of SARS-COV-2 and some of MERS-CoV, SARS-CoV1, HCov229E, and HCoVNL63. Clinical evaluation revealed that six people had COVID-19 in the past. We found that: (i) Six people claimed the presence of unwanted effects of vaccination, which were more frequent in those with a history of COVID-19 (4 out of 6 vs. 2 out of 14, p = 0.037); (ii) All individuals independent of the past history of COVID-19 responded equally well in IgG but those who experienced the disease tended to do better in IgA class (729.04 vs. 529.78 U/mL, p = 0.079); (iii) All those who had experienced the disease had IgG antibodies against nucleocapsid antigens but also 5 out of 14 who had not had the disease (6/6 vs. 5/14, p = 0.014); (iv) Anti S2 antibodies were present in the patients having COVID-19 in the past but also were found in those who had not had the disease (6/6 vs. 8/14, p = 0.144); (v) All vaccinated people were highly positive in the IGRA and the level of released IFN gamma was correlated with the numbers of HLADR positive lymphocytes in the blood (R = 0.5766, p = 0.008).

CD14 + HLADR - blood values in patients after alloHSCT are highly predictive of survival and infectious complications.

BACKGROUND: Cytokine storm described in patients after allogeneic haematopoietic stem cell transplantation (alloHSCT) is associated with the appearance of CD14 + HLADR - in the blood. METHODS: To study the role of CD14 + HLADR - cells 223 patients after alloHSCT followed from 1 month to 15 years. The methods used included flow cytometry for blood cells profiling, nucleic acid tests for viral reactivation, and physician care according to the Polish and international guidelines. RESULTS: We found that CD14 + HLADR - peak values determined during the first 60 post-transplant days were higher in the patients who died than in those who survived in this time interval (mean ± SEM: 3.78 ± 0.67% vs 2.38 ± 0.65%, p < 0.001). Receiver operating characteristic (ROC) analysis showed that CD14 + HLADR - cells level in the blood at cut-off point at 0.71% discriminated the patients as to survival; the patients above the threshold had poorer survival (Kaplan-Meier curve covering 15-year observation) than those below (0.19 vs 0.46, p < 0.001). Infections prevailed other causes of death in the high blood CD14 + HLADR - group (0.61 vs 0.38, p = 0.057). ROC analysis defined the CD4+ blood level at 17.70% as not significantly associated with survival. Multivariate analysis revealed that CD14 + HLADR - cells (HR = 3.47, p < 0.001) and the presence of acute graft-versus-host disease (aGvHD) grade ≥ 3 (HR = 3.82, p = 0.005) adversely impacted the survival. CONCLUSIONS: CD14 + HLADR - cells can serve as a biomarker for the risk of fatal complications frequently associated with infections.

Feasibility and Outcomes of a Third Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Few therapeutic options are available for patients with acute myeloid or lymphoblastic leukemia (AML/ALL) relapsing after a second allogeneic stem cell transplantation (alloSCT2). In selected patients a third allogeneic stem cell transplantation (alloSCT3) has been used, but no detailed analysis is available so far. The European Society for Blood and Marrow Transplantation (EBMT) registry was screened for patients with acute leukemia (AL) receiving alloSCT3 from an identical or alternative donor to treat AL in either haematological relapse or disease persistence after alloSCT2 between 2001 and 2018. Feasibility, efficacy, outcome, and risk factors of this approach were analyzed retrospectively. Forty-five patients (median age, 37 years, range 12-71) with AML (n=34) or ALL (n=11) were identified. Eleven patients received alloSCT3 in complete remission (CR), 34 had active disease. Fifteen patients were transplanted from the same donor at all three transplants, 30 patients had at least 2 different donors. Between alloSCT2 and alloSCT3, the donor was changed in 25 patients. After alloSCT3, 38 patients engrafted, and 26 achieved CR or CR with incomplete hematological reconstitution (CRi). Acute graft-versus-host disease (GvHD) grade II-IV was observed in 19%, chronic GvHD occurred in 13%. After 1-year, cumulative incidences of leukemia relapse and non-relapse mortality were 47% and 42%, respectively. Median progression free and overall survival (PFS/OS) from alloSCT3 were 2.5 and 4 months, respectively, 1-year PFS and OS were 11% and 20%,. Outcome was improved in patients with at least one donor change (1-year PFS/OS: 17%/30%), further factors for better outcome included an unrelated donor for alloSCT3, Karnofsky performance score >80, and more recent year of alloSCT3. Only patients with AML achieved >1 year OS. In conclusion, results after a third alloSCT are poor, limiting this procedure to few, highly selected patients. Recurrent relapses of acute leukemia after alloSCT remain an unmet therapeutic need.

Stem Cell Transplantation for Diamond-Blackfan Anemia. A Retrospective Study on Behalf of the Severe Aplastic Anemia Working Party of the European Blood and Marrow Transplantation Group (EBMT).

Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients.

Ability of the immune system to fight viruses highlighted by cytometry and T-cell receptor clonotype assessment: lessons taken before the coronavirus disease 2019 pandemic outbreak.

The intriguing aspects of severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) are the high rate of spread and rapid progression of pneumonitis. Confronted with thousands of deaths daily worldwide, we have to quickly build the rationale behind the treatment, taking advantage of past analogues. When a new virus strikes, T­cell receptor γδ cells are in the first line of defense, activated by stress molecules and recognizing some epitopes in a process that is major histocompatibility complex-independent but still specific, eg, cytomegalovirus, as well as participating in the regulatory mechanism-both characteristics are useful in fighting SARS­CoV­2. Most deaths occur due to pneumonitis, in the course of which overwhelming inflammation impairs blood oxygenation, calling for artificial ventilation. In fatal cases of coronavirus disease 2019, the balance between the immune response and the inflammatory outcome fails and, therefore, patients at risk, mostly the elderly, show higher levels of anti-SARS­CoV­2 antibodies and enhanced inflammation in the lungs. Apparently, there is no feedback control over the antibody production. The investigational use of convalescent plasma, providing antibodies taken from patients who have recovered, was shown to be effective, likely through exerting idiotype­associated negative control of antibody production. Similarly, the use of mesenchymal stem cells may assist the body regulatory mechanisms, considering the anti­inflammatory potential of these cells. The use of these 2 immunotherapeutic tools is understandable based on basic immunology and this knowledge may direct the efforts of the medical community aimed at combating the virus.

Interferon gamma 13-CA-repeat homozygous genotype and a low proportion of CD4(+) lymphocytes are independent risk factors for cytomegalovirus reactivation with a high number of copies in hematopoietic stem cell transplantation recipients.

Cytomegalovirus (CMV) reactivation was analyzed in 92 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) in relation to the proportion of CD4(+) lymphocytes in blood and a microsatellite polymorphism within the first intron of the interferon-gamma (IFNG) gene. CMV reactivation was found in 50% of the HSCT recipients; in 30% of these individuals, the level of CMV copies exceeded 100 per 10(5) peripheral blood (PB) cells on at least one occasion during the 100-day post-HSCT observation period. This high CMV copy level was most frequently found between 31 and 60 days post-HSCT (P = .021). Patients with > or = 100 CMV copies/10(5) cells were characterized by poorer overall survival (OS) compared with those lacking CMV copies or having < 100 CMV copies/10(5) cells (P = .04), and they suffered from severe post-HSCT complications, including acute graft-versus-host disease (aGVHD) and relapse. Thus, patients with > or = 100 CMV copies/10(5) cells were designated as having clinically significant CMV reactivation. Patients with < 10% CD4(+) lymphocytes had a higher number of CMV DNA copies than those with higher proportions of CD4(+) lymphocytes (0.62 vs 0.21, P = .001; mean +/- SEM, 4422 +/- 1667 vs 937 +/- 662 CMV copies/10(5) cells, P < .001, for the proportion of cases with reactivation and numbers of copies, respectively). Similarly, patients carrying 2 IFNG 13-CA-repeat alleles (homozygotes) had more frequent CMV reactivation (0.50 vs 0.26; P = .039) and a higher CMV load (4111 +/- 1699 vs 950+/-591 CMV copies/10(5) cells; P = .041) compared with those with other IFNG microsatellite allele constellations. Multivariate analysis demonstrated that the IFNG 13-CA-repeat homozygous genotype (odds ratio [OR] = 0.221; P = .044), a low proportion of CD4(+) lymphocytes (OR = 0.276; P = .050), and a lack of optimal (10/10 alleles) donor-recipient HLA match (OR = 15.19; P = .006) were independent risk factors for CMV reactivation with a high number of copies.

Outcome of HLA-matched related allogeneic hematopoietic stem cell transplantation for patients with acute leukemia in first complete remission treated in Eastern European centers. Better results in recent years.

The goal of this study was to analyze results and to determine factors affecting outcome of HLA-matched hematopoetic stem cells transplantation (MRD-HSCT) for patients with acute leukemia transplanted in first complete remission in Eastern European countries. Six hundred forty HSCT were performed between 1990 and 2006 for adults with acute myeloid (n = 459) and lymphoblastic (n = 181) leukemia. Two-year leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse incidence were 58 +/- 2%, 19 +/- 2%, and 23 +/- 2%, respectively. The cumulative incidence of NRM decreased from 22 +/- 2% for patients treated between 1990 and 2002 to 15 +/- 3% for transplantations performed between 2003 and 2006 (p = 0.02), despite increasing recipient age. In a multivariate analysis, time of HSCT affected both NRM and LFS. Among other prognostic factors, the use of TBI decreased relapse incidence and increased the LFS rate. We conclude that results of MRD-HSCT for acute leukemia in Eastern Europe improved over time as a consequence of decreased NRM. The use of TBI containing regimens appears advantagous.