Background Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19. Methods This multicentre, retrospective, cohort study included adult patients (aged ≥18 years) with diagnosis of a WHO-defined haematological malignancy admitted to 66 Italian hospitals between Feb 25 and May 18, 2020, with laboratory-confirmed and symptomatic COVID-19. Data cutoff for this analysis was June 22, 2020. The primary outcome was mortality and evaluation of potential predictive parameters of mortality. We calculated standardised mortality ratios between observed death in the study cohort and expected death by applying stratum-specific mortality rates of the Italian population with COVID-19 and an Italian cohort of 31 993 patients with haematological malignancies without COVID-19 (data up to March 1, 2019). Multivariable Cox proportional hazards model was used to identify factors associated with overall survival. This study is registered with ClinicalTrials.gov, NCT04352556, and the prospective part of the study is ongoing. Findings We enrolled 536 patients with a median follow-up of 20 days (IQR 10-34) at data cutoff, 85 (16%) of whom were managed as outpatients. 440 (98%) of 451 hospitalised patients completed their hospital course (were either discharged alive or died). 198 (37%) of 536 patients died. When compared with the general Italian population with COVID-19, the standardised mortality ratio was 2•04 (95% CI 1•77-2•34) in our whole study cohort and 3•72 (2•86-4•64) in individuals younger than 70 years. When compared with the non-COVID-19 cohort with haematological malignancies, the standardised mortality ratio was 41•3 (38•1-44•9). Older age (hazard ratio 1•03, 95% CI 1•01-1•05); progressive disease status (2•10, 1•41-3•12); diagnosis of acute myeloid leukaemia (3•49, 1•56-7•81), indolent non-Hodgin lymphoma (2•19, 1•07-4•48), aggressive non-Hodgkin lymphoma (2•56, 1•34-4•89), or plasma cell neoplasms (2•48, 1•31-4•69), and severe or critical COVID-19 (4•08, 2•73-6•09) were associated with worse overall survival. Interpretation This study adds to the evidence that patients with haematological malignancies have worse outcomes than both the general population with COVID-19 and patients with haematological malignancies without COVID-19. The high mortality among patients with haematological malignancies hospitalised with COVID-19 highlights the need for aggressive infection prevention strategies, at least until effective vaccination or treatment strategies are available. Funding Associazione italiana contro le leucemie, linfomi e mieloma-Varese Onlus.
The inclusion of ATG resulted in a significantly lower rate of chronic GVHD after allogeneic transplantation than the rate without ATG. The survival rate was similar in the two groups, but the rate of a composite end point of chronic GVHD-free survival and relapse-free survival was higher with ATG. (Funded by the Neovii Biotech and the European Society for Blood and Marrow Transplantation; ClinicalTrials.gov number, NCT00678275.).
In paroxysmal nocturnal hemoglobinuria (PNH) hemolytic anemia is due mainly to deficiency of the complement regulator CD59 on the surface of red blood cells (RBCs). Eculizumab, an antibody that targets complement fraction 5 (C5), has proven highly effective in abolishing complement-mediated intravascular hemolysis in PNH; however, the hematologic benefit varies considerably among patients. In the aim to understand the basis for this variable response, we have IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is a hematologic disorder characterized by the clonal expansion of one or a few hematopoietic stem cells that are incapable of glycosylphosphatidylinositol (GPI)-anchor biosynthesis, due to an acquired somatic mutation in the phosphatidylinositol glycan class A (PIG-A) gene. [1][2][3][4][5][6] Affected progeny cells are deficient in all GPI-anchored surface proteins, including the complement regulators CD55 and CD59. 7-9 Thus, PNH red blood cells (RBCs) are exquisitely vulnerable to activated complement, and particularly to the membrane attack complex (MAC), 10,11 resulting in chronic intravascular hemolysis with recurrent exacerbations, and consequent anemia.Eculizumab (Soliris; Alexion Pharmaceuticals, Cheshire, CT) is a humanized monoclonal antibody against complement fraction 5 (C5), which inhibits MAC formation. 12 Eculizumab has proven highly beneficial in the treatment of transfusion-dependent PNH patients. [13][14][15] In a placebo-controlled phase 3 trial, eculizumab led to a marked decrease in transfusion requirement, and improvement in anemia, fatigue, pain, shortness of breath, and QoL measures. 15 These data were confirmed in 2 subsequent studies, 16,17 the last one also suggesting that eculizumab may reduce the occurrence of thromboembolic events. 17 In the face of such gratifying clinical results, it is clear that not all patients respond equally to the treatment. In some patients there is only little improvement of anemia, and some still require blood transfusion at times, with signs of persistent hemolysis (reticulocytosis, elevated unconjugated bilirubin). 15,16 In this work, we have investigated the notion that in patients with suboptimal hematologic response to eculizumab there may be extravascular hemolysis mediated by complement effector mechanisms other than MAC. 15 Based on flow cytometry analysis of complement fraction 3 (C3) on RBCs, we provide evidence of selective C3 opsonization of GPI-negative red cells, the extent of which tends to correlate with the clinical response to eculizumab, and may be the manifestation of a novel phenomenon in the pathophysiology of PNH. Methods PatientsThe study was conducted in 56 Italian PNH patients (Table 1); biologic samples were collected by venipuncture according to standard procedures, after informed consent was obtained in accordance with the Declaration of Helsinki as approved within the study protocol by the Institutional Review Board at the Federico II University of Naples. Twenty-eight patients were studied at diagnosis, before any t...
Fas antigen, a receptor molecule that mediates signals for programmed cell death, is involved in T-cell-mediated killing of malignant, virus-infected or allogeneic target cells. Interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), potent inhibitors of haemopoiesis, enhance Fas receptor expression on bone marrow (BM) CD34+ cells, and both cytokines render haemopoietic progenitor cells susceptible to Fas-mediated inhibition of colony formation due to the induction of apoptosis. Haemopoietic suppression in aplastic anaemia (AA) has been associated with aberrant IFN-gamma, increased TNF-beta expression, and elevated numbers of activated cytotoxic T-cells in marrow. We have now examined Fas antigen expression in fresh AA BM samples. In normal individuals few CD34+ cells expressed Fas antigen and normal marrow cells had low sensitivity to Fas-mediated inhibition of colony formation. In contrast, in early AA, BM CD34+ cells showed markedly increased percentages of Fas receptor-expressing CD34+ cells, which correlated with increased sensitivity of AA marrow cells to anti-Fas antibody-mediated inhibition of colony formation. The proportion of Fas antigen-bearing cells was lower in recovered patients' BM. Fas antigen was also detected in the marrow of some patients with myelodysplasia, especially the hypocellular variant. These results are consistent with the hypothesis that AA CD34+ cells, probably including haemopoietic progenitor cells, express high levels of Fas receptor due to in vivo exposure to IFN-gamma and/or TNF-alpha and are suitable targets for T-cell-mediated killing. Our results suggest that the Fas receptor/Fas ligand system are involved in the pathophysiology of BM failure.
Activation of Fas antigen, a cell surface receptor molecule, by its ligand results in transduction of a signal for cell death. The Fas system has been implicated in target cell recognition, clonal development of immune effector cells, and termination of the cellular immune response. Fas antigen expression on lymphocytes is regulated by interferon gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha), cytokines that also have inhibitory effects on hematopoiesis. We investigated Fas antigen expression on human marrow cells and the effects of Fas activation on hematopoiesis in vitro. Freshly isolated immature hematopoietic cells, as defined by the CD34 marker, did not express Fas antigen at levels detectable by fluorescent staining. CD34+ cells, which include progenitors and stem cells, showed low levels of Fas expression in culture, even in the presence of growth factors. Stimulation by TNF alpha and IFN gamma markedly increased Fas antigen expression on CD34+ cells. Anti-Fas antibody, which mimics the action of the putative ligand, enhanced IFN gamma- and TNF alpha-mediated suppression of colony formation by bone marrow (BM) in a dose-dependent manner. This effect did not require the presence of accessory cells. Colony formation from mature (CD34+ CD38+) and immature (CD34+ CD38-) progenitor cells and long-term culture initiating cells were susceptible to the inhibitory action of anti-Fas antibody in the presence of IFN gamma and TNF alpha. Apoptosis assays performed on total BM cells and CD34+ cells showed that anti-Fas antibody induced programmed cell death of CD34+ BM cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Increased expression of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in bone marrow failure disorders suggests a possible pathophysiologic role of these cytokines in disease. In this study, we tested the action of TNF-alpha and IFN-gamma on phenotypically and functionally defined stages of hematopoietic development using highly purified progenitor cell populations assayed in standardized culture systems. We hypothesized that the inhibitory effects of IFN-gamma and TNF-alpha might be related to the induction of programmed cell death. In methylcellulose colony assays, IFN-gamma and TNF-alpha inhibited the growth of early hematopoietic cells, including committed CD34+CD38+ progenitor cells and phenotypically less mature CD34+CD38- cells, with 50% decreased colony formation occurring in the range of 750-1,000 U/ml of IFN-gamma and 10-15 ng/ml of TNF-alpha. More potent suppressive effects were observed in cultures supplemented with the combination of both cytokines than in cultures treated with IFN-gamma or TNF-alpha alone. When used at these concentrations, IFN-gamma and TNF-alpha inhibited growth of CD34(+)-enriched long-term culture-initiating cells by 88% and 68%, respectively. IFN-gamma and TNF-alpha triggered apoptosis of total bone marrow and CD34+ cells, recognized by the presence of a characteristic pattern of DNA degradation after low molecular weight DNA extraction, and by detection of apoptotic cells by the in situ terminal deoxynucleotidyl transferase assay. We speculate that chronic exposure of hematopoietic tissue to TNF-alpha and IFN-gamma in vivo may result in broad depletion of the stem and progenitor cell pools. Death of these cells due to apoptosis rather than transient inhibition of proliferation may be responsible for long-lasting hematologic consequences.
BACKGROUND. The progressively increasing number of long-term survivors after allogeneic bone marrow transplantation (allo-BMT) led researchers to focus on the early and late complications of this procedure. Endocrine dysfunction occurred mostly in patients who had undergone total body irradiation (TBI) as part of pretransplantation treatment. The extent to which chemotherapy and immune system derangement affect endocrine function in allo-BMT recipients is still unclear. METHODS. Forty consecutive patients (21 women, 19 men) with hematologic diseases surviving 12 or more months after allo-BMT from HLA-identical siblings were studied. Patients' age at transplantation ranged from 13 to 45 years and their post-BMT follow-up lasted 12-62 months. The conditioning regimen BUCY2 was employed. Graft versus host disease (GVHD) was observed in the acute form in 13 patients and in the chronic form in 26. The function of hypothalamic-pituitarygonad, thyroid, somatotrophic, and adrenal axes was assessed. RESULTS. The most common endocrine dysfunction was ovarian insufficiency (95% of women), followed by an increase in follicle-stimulating hormone in 47% of men, indicating spermatogenesis damage. Hormone replacement therapy was contraindicated in three women because of chronic liver GVHD and it was ineffective partially in four others because of reduced intestinal or cutaneous absorption. Thyroid dysfunction occurred in 47.5% of patients and included low T3 syndrome, chronic thyroiditis, and transient subclinical hyperthyroidism and subclinical hypothyroidism. Adrenal function was abnormal in 10%, mostly related to the prolonged corticosteroid treatment. IGF-I was lower than age-reference values in 27% of all patients and in 38% of those with chronic GVHD. Thyroid, adrenal, and IGF-I impairments were more frequent in patients with chronic GVHD than in patients without this disease (P ϭ 0.048). CONCLUSIONS. A high prevalence of endocrine dysfunction was detected in a cohort of allo-BMT recipients not treated by TBI. Although gonadal failure was likely related to intensive myeloablative treatments, thyroid, adrenal, and IGF-I impairments were late events, suggesting that immunosuppressive treatment and immune system derangement may play a role in the development of endocrine dysfunction after allografting. Cancer 2002;95:1076-84.
Newly diagnosed patients with acute graftversus-host disease (GvHD, grades I-IV; n ؍ 211) were given 6-methylprednisolone (6MPred) 2 mg/kg per day for 5 consecutive days; 150 patients (71%) tapered 6MPred on day ؉5 and were considered responders; 61 patients (29%) could not taper their steroid dose and were considered nonresponders. The cumulative incidence of transplant-related mortality (TRM) for responders and nonresponders is, respectively, 27% and 49% (P ؍ .009), and the 5-year survival is 53% and 35% (P ؍ .007). Nonresponders on day ؉5 (n ؍ 61) were randomized to receive 6MPred 5 mg/kg per day for 10 days alone (n ؍ 34) or in combination with rabbit anti-thymocyte globulin (ATG, 6.25 mg/kg in 10 days; n ؍ 27). The 2 groups were balanced for clinical and GvHD characteristics. One month after randomization, 26% had a complete response; 23%, a partial response; 33%, stable GvHD; 10%, worsened; and 8%, died. There was no significant difference in response, TRM, and survival between the non-ATG and ATG group.
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