Endothelial Injury Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation: Angiopetin-2 as a Novel Predictor of the Outcome and the Role of Functional Autoantibodies against Angiotensin II Type 1 and Endothelin A Receptor.

Transplant-associated thrombotic microangiopathy (TMA) occurs in a significant percentage of patients after allogeneic stem cell transplantation (allo-SCT) and is associated with significant morbidity and mortality. The aim of the present study was to examine the association of serum angiopoetin-2 (Ang2) levels and the presence of antibodies against angiotensin II type 1 (AT1R) and ndothelin A Recreptor (ETAR) with the outcome of patients with TMA and/or graft-versus-host disease (GVHD) after allo-SCT. Analysis of our data showed that elevated serum Ang2 levels at the time of TMA diagnosis are significantly associated with increased non-relapse mortality and decreased overall survival. To our knowledge, this is the first study demonstrating an association between raised Ang2 levels and poor outcomes in patients with TMA. Antibodies against AT1R (AT1R-Abs) and ETAR (ETAR-Abs) were detected in 27% and 23% of the patients, respectively, but there was no association between the presence of autoantibodies and the outcome of patients with TMA. However, a significant finding was the strong positive correlation between the presence of AT1R-Abs with the occurrence of chronic fibrotic GVHD, such as scleroderma and cryptogenic organizing pneumonia, raising the possibility of the contribution of autoantibodies in the pathogenesis of fibrotic GVHD manifestations.

Allogeneic Stem Cell Transplantation with a Novel Reduced Intensity Conditioning Regimen for the Treatment of Patients with Primary Cutaneous T-cell Lymphomas.

The prognosis of patients with mycosis fungoides (MF) and Sezary Syndrome (SS) varies greatly, from near normal life expectancy in patients with early stage, to a median survival of less than 2 years for those diagnosed with advanced stage disease. Initial response to treatment is almost always followed by relapse and, finally, most of patients enter a phase of advanced multi-drug resistant disease with a short life expectancy after multiple lines of treatment. Allogeneic stem cell transplantation (allo-SCT) is usually limited to patients with advanced disease resistant to multiple treatments. Retrospective registry-based studies have shown increased Non-relapse Mortality (NRM) rates in patients with poor performance status, as well as in patients treated with myeloablative conditioning regimens. Another major limitation of allo-SCT is the increased relapse rate which occurs in nearly 50% of the cases, and is probably due to the fact that only heavily pretreated patients with advanced disease are referred for allo-SCT. Due to the paucity of data, the ideal conditioning regimen which will provide the maximum therapeutic benefit without the cost of increased NRM is not currently known. In this article we present our experience with a novel regimen in the treatment of patients with advanced MF/SS.

Repetitively Administered Low-Dose Donor Lymphocyte Infusion for Prevention of Relapse after Allogeneic Stem Cell Transplantation in Patients with High-Risk Acute Leukemia.

BACKGROUND: Patients with high-risk acute leukemia have a high risk of relapse after allogeneic stem cell transplantation (allo-SCT). In an effort to reduce the relapse rate, various therapeutic methods have been implemented into clinical practice. Among them, prophylactic donor lymphocyte infusion (pro-DLI) has shown significant efficacy. However, the widespread application of pro-DLI has been restricted mostly due to concerns regarding the development of graft versus host disease (GVHD). In the present study, we tested the safety and efficacy of a novel method of prophylactic-DLI based by repetitive administration of low lymphocyte doses. METHODS: DLI was administered to patients with high-risk acute leukemia at a dose of 2 × 106/kg CD3-positive cells. DLI at the same dose was repeated every two months for at least 36 months post-allo-SCT, or until relapse or any clinical or laboratory feature suggested GVHD, whichever occurred first. Forty-four patients with a median age of 53 years (range 20-67) who underwent allo-SCT between 2011 and 2020 were included in our study. Thirty-three patients with high-risk acute myeloid leukemia (AML) and 11 with high-risk acute lymphoblastic leukemia (ALL) after allo-SCT from a matched sibling (MSD, no = 38 pts) or a matched-unrelated donor (MUD, no = 6 pts) received pro-DLI. Twenty-three patients were in CR1, all with unfavorable genetic features; 12 patients were in CR2 or beyond; and 9 patients had refractory disease at the time of transplant. Ten out of 23 patients in CR1 had detectable minimal residual disease (MRD) at the time of allo-SCT. Disease risk index (DRI) was high and intermediate in 21 and 23 patients, respectively. Conditioning was myeloablative (MAC) in 36 and reduced intensity (RIC) in 8 patients, while GVHD prophylaxis consisted of cyclosporine-A in combination with low-dose alemtuzumab in 39 patients or with low-dose MTX in 5 patients, respectively. RESULTS: Thirty-five patients completed the scheduled treatment and received a median of 8 DLI doses (range 1-35). Fifteen out of 35 patients received all planned doses, while DLI was discontinued in 20 patients. Reasons for discontinuation included GVHD development in nine, donor unavailability in seven, disease relapse in three, and secondary malignancy in one patient, respectively. Nine patients were still on treatment with DLI, and they received a median of four (range 2-12) doses. Fourteen percent of patients developed transient grade-II acute GVHD while 12% developed chronic GVHD post-DLI administration. Acute GVHD was managed successfully with short course steroids, and four out of five patients with cGVHD were disease-free and off immunosuppression. With a median follow-up of 44 months (range 8-120), relapse-free (RFS) and overall survival (OS) were 74%, (95% CI, 54-87%) and 78%, (95% CI, 58-89%) respectively, while the cumulative incidence of non-relapse mortality (NRM) was 13% (95% CI, 4-28%). The cumulative incidence of relapse in patients with intermediate and high DRI is 7% and 15%, respectively. CONCLUSION: Prolonged-up to three years-low-dose pro-DLI administered every two months is safe and effective in reducing relapse rate in patients with high-risk acute leukemia. The low-dose repetitive administration DLI strategy reduced the risk of DLI-mediated GVHD, while the prolonged repeated administration helped in preventing relapse, possibly by inducing a sustained and prolonged immunological pressure on residual leukemic cells. This novel strategy deserves testing in larger cohort of patients with high-risk acute leukemia.

Extramedullary leukemia relapse after allogeneic stem cell transplantation: a novel mechanism of immune escape?

Background: Relapse is a significant cause of treatment failure after allogeneic stem cell transplantation. In many cases relapse occurs when leukemic cells escape from immune surveillance. Methods & results: In the setting of haploidentical transplantation, immune escape is usually the result of the loss of the mismatched haplotype from leukemic cells, while downregulation of HLA-expression has been postulated as a significant cause of immune escape after transplantation with the use of HLA-matched donors. We observed that patients with acute leukemia who relapse at the time of active graft-versus-host-disease, usually develop extramedullary leukemia while they remain free of leukemia in peripheral blood and bone marrow. Conclusion: Our observation points toward a novel mechanism of immune escape which is microenvironment-specific.

Coexistence of Myeloid and Lymphoid Neoplasms: A Single-Center Experience.

The coexistence of a myeloid and a lymphoid neoplasm in the same patient is a rare finding. We retrospectively searched the records of the Hematology Division of the Second Department of Internal Medicine and Research Institute at Attikon University General Hospital of Athens from 2003 to 2018. Nine cases have been identified in a total of 244 BCR-/ABL1- negative MPN and 25 MDS/MPN patients and 1062 LPD patients referred to our institution between 2003 and 2018. Each case is distinct in the diversity of myeloid and lymphoid entities, the chronological occurrence of the two neoplasms, and the patient clinical course. All of them exhibit myeloproliferative (6 JAK2 V617F-positive cases) and lymphoproliferative features, with 1 monoclonal B-cell lymphocytosis (MBL), 3 B-chronic lymphocytic leukemias (B-CLL), 3 B-non-Hodgkin lymphomas (B-NHL), 1 multiple myeloma (MM), and 1 light and heavy deposition disease (LHCDD), while in three cases myelodysplasia is also present. The challenges in identifying and dealing with these rare situations in everyday clinical practice are depicted in this article.

Myelodysplastic syndromes and idiopathic pulmonary fibrosis: a dangerous liaison.

Previous studies have shown that the co-existence of bone marrow failure and pulmonary fibrosis in a single patient or in a family is suggestive of telomere related genes (TRG) germline mutations. This study presents the genetic background, clinical characteristics, and outcome of a group of five Greek patients co-affected with IPF and MDS. Four out of five patients developed an IPF acute exacerbation that was not reversible. We failed to detect any mutation in the TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2 and NOP10 genes in any patient. Moreover, telomere length was normal in the two patients tested. This could suggest that although the co-occurence of IPF and MDS are suggestive of TRG mutation in patients < 65 years old, in the elderly it may occur without germline mutations and could negatively affect prognosis. Physicians should be aware for possible IPF deterioration and therapeutic options for MDS should be wisely considered.

Natural killer cell cytotoxicity is a predictor of outcome for patients with high risk myelodysplastic syndrome and oligoblastic acute myeloid leukemia treated with azacytidine.

The aim of the present study was to identify biomarkers predictive of the outcome of patients with high-risk myelodysplastic syndrome and oligoblastic acute myeloid leukemia (AML) treated with 5-azacytidine (AZA). We prospectively examined the association between NK-cytotoxic activity, myeloid-derived suppressor cells (MDSCs), and T-regulatory cells (Tregs) on the overall survival (OS) of patients. Patients with NK-cytotoxicity above a critical threshold had a longer duration of response and survived longer than patients with severe impairment of NK-cytotoxicity. The numbers of MDSCs, and Tregs in the PB of patients after a short exposure to AZA were not different from normal donors. In conclusion, the results of our study suggest that the therapeutic activity of AZA is at least partly mediated by an immunomodulatory effect. To our knowledge, this is the first study reported so far, that shows a positive correlation between NK cytotoxicity and OS of AZA-treated patients.

Positive impact of brentuximab vedotin on overall survival of patients with classical Hodgkin lymphoma who relapse or progress after autologous stem cell transplantation: A nationwide analysis.

The outcome of patients with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after autologous stem cell transplantation (auto-SCT) is poor. Recently, the anti-CD30 monoclonal antibody-drug conjugate, brentuximab vedotin (BV), has shown remarkable activity in the setting of R/R cHL. In the pivotal phase II study, BV produced an overall response rate of 75% and a median progression-free survival of 6.7 months. Although these results have been reproduced by large registry studies, the impact of BV on the overall survival (OS) of patients with R/R cHL has not been addressed so far. The aim of this study was to examine the impact of BV on OS in the setting of post auto-SCT R/R cHL. Analysis was performed in a group of patients with R/R cHL after a previous auto-SCT reported in the Greek registry during the last 2 decades. By using a multivariate model and censoring patients at the time of subsequent allo-SCT or treatment with immune checkpoint inhibitors, we showed that treatment with BV in the posttransplant relapse setting has a positive impact on the outcome and results in significant improvement of OS. To our knowledge, this the first published study, addressing the impact of BV on the OS in the setting of posttransplant relapse.

Brentuximab vedotin in relapsed/refractory Hodgkin lymphoma. The Hellenic experience.

This retrospective study aimed to describe the Hellenic experience on the use of brentuximab vedotin (BV) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) given within its indication. From June 2011 to April 2015, ninety-five patients with R/R HL, who received BV in 20 centers from Greece, were analyzed. Their median age was 33 years, and 62% were males. Sixty-seven patients received BV after autologous stem cell transplantation failure, whereas 28 patients were treated with BV without a prior autologous stem cell transplantation, due to advanced age/comorbidities or chemorefractory disease. The median number of prior treatments was 4 and 44% of the patients were refractory to their most recent therapy. The median number of BV cycles was 8 (range, 2-16), and the median time to best response was the fourth cycle. Fifty-seven patients achieved an objective response: twenty-two (23%), a complete response (CR), and 35 patients (37%), a partial, for an overall response rate of 60%. Twelve patients (13%) had stable disease, and the remaining twenty-six (27%) had progressive disease as their best response. At a median follow-up of 11.5 months, median progression-free survival and overall survival were 8 and 26.5 months, respectively. Multivariate analysis showed that chemosensitivity to treatment administered before BV was associated with a significantly increased probability of achieving response to BV (P = .005). Bulky disease (P = .01) and response to BV (P <.001) were significant for progression-free survival, while refractoriness to most recent treatment (P = .04), bulky disease (P = .005), and B-symptoms (P = .001) were unfavorable factors for overall survival. Among the 22 CRs, 5 remain in CR with no further treatment after BV at a median follow-up of 13 months. In conclusion, our data indicate that BV is an effective treatment for R/R HL patients even outside clinical trials. Whether BV can cure a fraction of patients remains to be seen.

Deformation Analysis of Myocardial Layers Detects Early Cardiac Dysfunction after Chemotherapy in Bone Marrow Transplantation Patients: A Continuous and Additive Cardiotoxicity Process.

BACKGROUND: Chemotherapy-induced cardiotoxicity has not been extensively validated in bone marrow transplantation (BMT) patients. Speckle-tracking echocardiography is a sensitive method for the detection of subclinical cardiac dysfunction. METHODS: Cardiac function was prospectively assessed in 80 patients (44 men; mean age, 45 ± 11 years) after BMT for non-Hodgkin's lymphoma and acute or chronic myeloid leukemia by means of various echocardiographic techniques. Before chemotherapy for BMT, 89% of the patients had previously been treated with anthracyclines. Patients had normal left ventricular ejection fraction (LVEF). Left ventricular (LV) global longitudinal strain (GLS), subendocardial and subepicardial longitudinal strain, circumferential strain, LV twist, and right ventricular GLS were measured by speckle-tracking, and (2) three-dimensionally derived LVEF and right ventricular ejection fraction were also assessed. Abnormal LVEF was defined as <53%. Studies were performed before (baseline) and 1, 3, 6, and 12 months after chemotherapy conditioning followed by BMT. RESULTS: Impaired LV GLS values were observed at 1 month after chemotherapy and at 3, 6, and 12 months compared with baseline (-20 ± 2.2% at baseline, -18.4 ± 2.1% at 1 month, -17.3 ± 2.2% at 3 months, -17.1 ± 2.1% at 6 months, and -17.1 ± 2.2% at 12 months; P = .001). Early LV GLS changes were driven mostly by changes in subendocardial longitudinal strain (-22.5 ± 2.4% at baseline, -20.5 ± 2.3% at 1 month, -19.2 ± 2.3% at 3 months, -19.2 ± 2.4% at 6 months, and -19.1 ± 2.4 at 12 months; P = .001), whereas significant subepicardial strain changes were observed at 3 months after BMT. Compared with baseline, right ventricular GLS was also impaired early after chemotherapy. Compared with baseline, LVEF was slightly reduced (P = .02) at the end of the follow-up. Among echocardiographic markers, LV GLS at 1 month had the strongest predictive value for abnormal LVEF (<53%) at 12 months (area under the curve 0.86; 95% CI, 0.76-0.96). A cutoff LV GLS value of -18.4% had sensitivity of 84.6% and specificity of 71.9% for the identification of abnormal LVEF at the end of follow-up. CONCLUSIONS: In BMT patients, myocardial deformation analysis detected early and progressive subclinical cardiac dysfunction. Impaired LV GLS had predictive value for the detection of abnormal LVEF at 12-month follow-up. Thus, myocardial deformation study should be applied early after BMT to prevent irreversible cardiac dysfunction by appropriate treatment.

Balanced control of both hyper and hypo-inflammatory phases as a new treatment paradigm in sepsis.

The immune response of the host against invading pathogens is clinically manifested as sepsis. Sepsis is a complicated process characterized by distinct phases that usually occur in a sequential manner. The initial hyper-inflammation helps in elimination of the pathogen, but potentially may lead to excessive tissue injury. Hypo-inflammation helps in restoring immune homeostasis, but may lead to significant immune suppression and death from secondary infections if not appropriately controlled. Immune-modulating intervention in sepsis should be based on a balanced control of both the hyper and the hypo-inflammatory phase.

Thrombocytopenia in critically ill patients with severe sepsis/septic shock: Prognostic value and association with a distinct serum cytokine profile.

PURPOSE: The purpose of the study is to evaluate the incidence, association with serum cytokine profile, and prognostic value of thrombocytopenia, in critically ill patients with severe sepsis/septic shock. METHODS: A cohort of 105 consecutive patients admitted in intensive care unit was included in our analysis. Serum levels of intercellular adhesion molecule, vascular cell adhesion molecule, interferon γ, interleukin 8, and soluble form of the urokinase-type plasminogen activator receptor (suPAR) were measured. RESULTS: Thrombocytopenia was observed in 53% of patients at the time of admission. Platelet counts showed a statistically significant negative correlation with serum levels of intercellular adhesion molecule, suPAR, and interleukin 8 (P < .0001). In multivariate analysis, high Acute Physiological and Chronic Health Evaluation II score, high serum suPAR, and low platelet counts were associated with increased mortality, and receiver operating characteristic curve analysis was used to determine the best cutoff value for mortality prediction. Each variable with a value above or below the predefined cutoff levels were given 1 point. Patients were categorized in risk groups based on total point score. High-risk (2-3), intermediate-risk (1), and low-risk (0 points) groups consisted of 43%, 22%, and 35% and 28-day mortality was observed in 69%, 26%, and 3% of the patients in each group, respectively. CONCLUSION: Thrombocytopenia is associated with poor prognosis and a distinct serum cytokine profile.

Strategies for improving the efficacy of donor lymphocyte infusion following stem cell transplantation.

Donor lymphocyte infusion (DLI) is an effective immunotherapeutic approach with significant activity in the treatment and prevention of relapse after allogeneic stem cell transplantation. DLI is associated with significant toxicity mainly due to graft-versus-host disease. Moreover, DLI does not produce durable responses in aggressive malignancies like acute leukemia. Improvement in DLI efficacy requires dissociation of graft-versus-leukemia effect from graft-versus-host disease. Minor histocompatibility antigens with tissue restriction and leukemia or tumor-associated antigens represent ideal antigenic targets. A brief overview of the existing methods of DLI administration is the topic of this article. T cells transduced with genes encoding for T-cell receptors with reactivity against minor histocompatibility antigens or leukemia-associated antigens is a promising option.