Mycoplasma hominis as Cause of Extragenital Infection in Patients with Hypogammaglobulinemia: Report of 2 Cases and Literature Review.

Mycoplasma hominis can be a part of human urogenital tract microbiome, and it is a frequent cause of urogenital infections. In rare cases, it can also cause extragenital infections, especially in immunocompromised patients. In this case series, we report two cases and provide a literature review of extragenital infections caused by M. hominis in patients with hypogammaglobulinemia. Patient 1 was a 61-year-old woman with diffuse large B-cell lymphoma who, after rituximab-containing chemotherapy and CAR-T therapy, developed M. hominis spondylodiscitis. Patient 2 was a 50-year-old woman with congenital hypogammaglobulinemia who developed disseminated M. hominis infection involving pleura, muscles, and right ankle. Antibiotic therapy with levofloxacin and doxycycline for 10 weeks in patient 1 and with levofloxacin alone for 6 weeks in patient 2 led to infection resolution. The literature review identified 14 additional cases reporting M. hominis extragenital infection in patients with hypogammaglobulinemia. M. hominis should also be suspected as an etiological agent of extragenital infection in patients with B-cell immunodeficiency with a clinical picture of persistent, standard-culture negative infection, particularly with arthritis or abscess formation. Even if M. hominis can grow on standard bacterial medium, in suspected cases molecular methods should be promptly used for correct diagnostic work-up and successful therapy.

The HSCT procedure (II): Conditioning, hematopoietic stem cell infusion, supportive care, and monitoring.

Autologous hematopoietic stem cell transplantation (aHSCT) is a complex process, designed to replace the blood and lymphoid systems of a patient with hematopoietic stem cells (HSCs) that have been previously collected and cryopreserved, derived from the same patient. The rationale of aHSCT in neurologic diseases is to eliminate self-reacting cell clones and induce self-tolerance through a profound renewal of the immune system. The steps analyzed in this chapter are conditioning, HSCs infusion, supportive care, and monitoring. Before transplantation, ablation of the hemato-lymphopoietic system is achieved with chemotherapy; this stage is known as the conditioning regimen. The EBMT guidelines support the use of "intermediate intensity" regimens, either cyclophosphamide 200mg/kg or BEAM (bis-chloroethyl-nitrosourea, etoposide, cytarabine, and melphalan), in combination with serotherapy that consists of rabbit antithymocyte globulin (ATG) in most protocols. The infusion of HSC is performed through a central intravenous line, after being thawed at 37°C using either a water bath or a heat bath; in this phase, the prevention and management of infusion-related adverse events are crucial. The supportive care consists mainly of infection prophylaxis and treatment, administration of blood product transfusions, and nutritional and electrolyte support. The monitoring phase is focused on hematologic recovery and monitoring for early and late complications of aHSCT.

Improved outcome of COVID-19 over time in patients treated with CAR T-cell therapy: Update of the European COVID-19 multicenter study on behalf of the European Society for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party (IDWP) and the European Hematology Association (EHA) Lymphoma Group.

COVID-19 has been associated with high mortality in patients treated with Chimeric Antigen Receptor (CAR) T-cell therapy for hematologic malignancies. Here, we investigated whether the outcome has improved over time with the primary objective of assessing COVID-19-attributable mortality in the Omicron period of 2022 compared to previous years. Data for this multicenter study were collected using the MED-A and COVID-19 report forms developed by the EBMT. One-hundred-eighty patients were included in the analysis, 39 diagnosed in 2020, 35 in 2021 and 106 in 2022. The median age was 58.9 years (min-max: 5.2-78.4). There was a successive decrease in COVID-19-related mortality over time (2020: 43.6%, 2021: 22.9%, 2022: 7.5%) and in multivariate analysis year of infection was the strongest predictor of survival (p = 0.0001). Comparing 2022 with 2020-2021, significantly fewer patients had lower respiratory symptoms (21.7% vs 37.8%, p = 0.01), needed oxygen support (25.5% vs 43.2%, p = 0.01), or were admitted to ICU (5.7% vs 33.8%, p = 0.0001). Although COVID-19-related mortality has decreased over time, CAR T-cell recipients remain at higher risk for complications than the general population. Consequently, vigilant monitoring for COVID-19 in patients undergoing B-cell-targeting CAR T-cell treatment is continuously recommended ensuring optimal prevention of infection and advanced state-of-the art treatment when needed.

Early CAR- CD4+ T-lymphocytes recovery following CAR-T cell infusion: A worse outcome in diffuse large B cell lymphoma.

CAR- CD4+ T cell lymphopenia is an emerging issue following CAR-T cell therapy. We analyzed the determinants of CD4+ T cell recovery and a possible association with survival in 31 consecutive patients treated with commercial CAR-T for diffuse large B-cell (DLBCL) or mantle cell lymphoma. Circulating immune subpopulations were characterized through multiparametric-flow cytometry. Six-month cumulative incidence of CAR- CD4+ T cell recovery (≥200 cells/µL) was 0.43 (95% confidence interval [CI]: 0.28-0.65). Among possible determinants of CD4+ T cell recovery, we recognized infusion of a 4-1BB product (tisagenlecleucel, TSA) in comparison with a CD28 (axicabtagene/brexucabtagene, AXI/BRX) (hazard ratio [HR] [95% CI]: 5.79 [1.16-24.12] p = 0.016). Higher CD4+ T cell counts resulted with TSA at month-1, -2 and -3. Moderate-to-severe infections were registered with prolonged CD4+ T cell lymphopenia. Early, month-1 CD4+ T cell recovery was associated with a worse outcome in the DLBCL cohort, upheld in a multivariate regression model for overall survival (HR: 4.46 [95% CI: 1.12-17.71], p = 0.03). We conclude that a faster CAR- CD4+ T cell recovery is associated with TSA as compared to AXI/BRX. Month-1 CAR- CD4+ T cell subset recovery could represent a "red flag" for CAR-T cell therapy failure in DLBCL patients.

Adenovirus infection in adult patients undergoing allogeneic hematopoietic stem cell transplant: Incidence, clinical management, and outcome.

BACKGROUND: Adenovirus infection (ADVi) is an emergent complication in adult patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with poor outcome. Available data on risk factors and optimal management of ADVi in adult allo-HSCT recipients are limited, and recommendations on monitoring and pre-emptive therapy are mainly based on pediatric data. METHODS: In this single-center, retrospective study, we reported all cases of positive ADV-DNA from adult patients undergoing allo-HSCT in the period 2014-2019. The study aimed to describe the incidence of ADVi at day +180 post-transplant. Secondly to describe timing, clinical presentation, risk factors, and outcome of ADVi and to analyze the application of a screening strategy in our cohort. RESULTS: In 445 allo-HSCT recipients, the day +180 incidence was: 9% (39/445) for ADVi, 5% (24/445) for ADV viremia (ADVv), and 3% (15/445) for localized ADVi. The median time to ADVi was 65 (IQR 19; 94) days after HSCT. ADVv-related mortality was 13% (3/24), all cases occurring with blood max-ADV-DNA > 10^3 cp/mL. Independent risk factors for ADVi were diagnosis of lymphoproliferative disease (p = .011) and acute graft-versus-host-disease (p = .021). CONCLUSIONS: In our cohort, ADVi and ADVv were more frequent than previously reported. ADVv with max-ADV-DNA > 10^3 cp/mL was associated with ADV-related mortality, thus careful monitoring and early initiation of treatment are advisable.

An aggressive form of MOGAD treated with aHSCT: A case report.

BACKGROUND: Although myelin-oligodendrocyte-glycoprotein (MOG)-antibody-associated disease (MOGAD) has been considered a more favorable demyelinating central nervous system disorder, recent data evidence that some patients might experience severe relapses and high disability. Actual treatment-options are acquired mostly from anti-aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder and rely on clinical experience. Therefore, treatment of aggressive forms of MOGAD can be challenging. OBJECTIVES AND METHODS: To describe a patient with an aggressive MOGAD treated with autologous hematopoietic stem cell transplantation (aHSCT). RESULTS: A 56-year-old man was diagnosed with MOGAD in 2017 because of right optic-neuritis and anti-MOG-antibody positivity. In the following 2 years, he experienced two optic neuritis with good recovery after high-dose steroid. At the end of 2019, he presented sensory and motor impairment at lower limbs with evidence of several spinal, longitudinally extended, tumefactive inflammatory lesions. Despite sequential treatment with rituximab and tocilizumab alongside high-dose steroid, intravenous immunoglobulins and plasma-exchange, he experienced several clinical relapses and exhibited persistent magnetic resonance activity. He was finally addressed to intense immunosuppression with myeloablative conditioning regimen followed by autologous hematopoietic stem cell transplantation (aHSCT). After 2 years follow-up, he is free from disease-activity. CONCLUSIONS: In a patient affected by aggressive, treatment-refractory MOGAD, aHSCT resulted as safe and was able to suppress disease-activity for over 2 years.

Brain FDG-PET findings in chimeric antigen receptor T-cell therapy neurotoxicity for diffuse large B-cell lymphoma.

BACKGROUND AND PURPOSE: Chimeric antigen receptor (CAR) T-cell therapy is potentially associated with treatment-related toxicities mainly consisting of cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS). We evaluated brain metabolic correlates of CRS with and without ICANS in diffuse large B-cell lymphoma patients treated with CAR-T. METHODS: Twenty-one refractory DLCBLs underwent whole-body and brain [18 F]-fluorodeoxyglucose (FDG) PET before and 30 days after treatment with CAR-T. Five patients did not develop inflammatory-related side effects, 11 patients developed CRS, while in 5 patients CRS evolved in ICANS. Baseline and post-CAR-T brain FDG-PET were compared with a local controls dataset to identify hypometabolic patterns both at single-patient and group levels (p < .05 after correction for family-wise error [FWE). Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were computed on baseline FDG-PET and compared between patients' subgroups (t-test). RESULTS: ICANS showed an extended and bilateral hypometabolic pattern mainly involving the orbitofrontal cortex, frontal dorsolateral cortex, and anterior cingulate (p < .003 FWE-corrected). CRS without ICANS showed significant hypometabolism in less extended clusters mainly involving bilateral medial and lateral temporal lobes, posterior parietal lobes, anterior cingulate, and cerebellum (p < .002 FWE-corrected). When compared, ICANS showed a more prominent hypometabolism in the orbitofrontal and frontal dorsolateral cortex in both hemispheres than CRS (p < .002 FWE-corrected). Mean baseline MTV and TLG were significantly higher in ICANS than CRS (p < .02). CONCLUSIONS: Patients with ICANS are characterized by a frontolateral hypometabolic signature coherently with the hypothesis of ICANS as a predominant frontal syndrome and with the more prominent susceptibility of frontal lobes to cytokine-induced inflammation.

Haploidentical Hematopoietic Cell Transplantation for Myelofibrosis in the Ruxolitinib Era.

Haploidentical stem cell transplantation is a viable strategy in the absence of an HLA-identical donor, but in myelofibrosis (MF), concerns may rise due to the risk of graft failure. Considering that engraftment is a major issue in MF, we sought to highlight its impact on survival outcomes. In addition, we explored the impact of pretransplantation ruxolitinib administration as an independent variable on outcomes. Here we report the results of a retrospective, monocentric experience with T cell-replete haploidentical bone marrow transplantation with post-transplantation cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis in 51 consecutive MF-affected patients. The median duration of follow-up was 47 months. All 51 patients received a double-alkylating conditioning regimen, and 21 patients (41%) received pretransplantation ruxolitinib. Thirty-seven of 49 evaluable patients (76%) achieved full donor chimerism with neutrophil engraftment, 8 of 49 (16%) experienced graft rejection, and 4 of 49 (8%) had primary poor graft function. Splenectomy was more frequent among patients who engrafted (P = .06). Graft rejection was the sole factor negatively impacting overall survival (hazard ratio [HR], 4.19; 95% confidence interval [CI], 1.37 to 12.80; P = .01) and the major determinant for nonrelapse mortality (HR, 10.31; 95% CI, 2.54 to 41.82; P = .001). The 24-month incidence of relapse was 19% and was negatively impacted by splenectomy (HR, 5.84; 95% CI, 1.28 to 26.72; P = .02). The cumulative incidence of grade II-IV acute GVHD was 27% (95% CI, 20% to 33%), and that of grade III-IV acute GVHD was 8% (95% CI, 4% to 12%). The 24-month cumulative incidence of all-grade chronic GVHD was 28% (95% CI, 21% to 35%). Our data show that T cell-replete haploidentical bone marrow transplantation following double-alkylating conditioning in patients with MF is associated with favorable rates of GVHD and an acceptable relapse risk; nevertheless, rejection is not negligible and is associated with significant mortality. Splenectomy, which favors engraftment, is predictive of a higher risk of relapse.

CD19-Targeted Immunotherapies for Diffuse Large B-Cell Lymphoma.

Surgical resection, chemotherapy and radiotherapy were, for many years, the only available cancer treatments. Recently, the use of immune checkpoint inhibitors and adoptive cell therapies has emerged as promising alternative. These cancer immunotherapies are aimed to support or harness the patient's immune system to recognize and destroy cancer cells. Preclinical and clinical studies, based on the use of T cells and more recently NK cells genetically modified with chimeric antigen receptors retargeting the adoptive cell therapy towards tumor cells, have already shown remarkable results. In this review, we outline the latest highlights and progress in immunotherapies for the treatment of Diffuse Large B-cell Lymphoma (DLBCL) patients, focusing on CD19-targeted immunotherapies. We also discuss current clinical trials and opportunities of using immunotherapies to treat DLBCL patients.

Cutaneous manifestations of hematologic malignancies the experience of an Italian dermatology department.

In recent years, dermatologic manifestations in oncohematologic patients have become more common. The aim of our study was to determine the incidence and heterogeneity of skin manifestations in patients followed at our Hematology Department. This observational monocentrical study was conducted on 60 patients. We divided the observed conditions in exanthematous, purpuric, vesicular-bullous, papulonodular, urticarial, and eczematous manifestations. Moreover, all lesions were classified according to pathogenesis, in (a) specific skin manifestations, caused by neoplastic skin infiltration; (b) immune-mediated manifestations, based on immunological mechanisms; and (c) skin lesions due to immunodeficiency. Altogether, 73 clinical manifestations were reported. Specific manifestations (a) were detected in 15.1% of the cases, mainly with papulonodular appearance. Immune-mediated manifestations (b) were found in 37 cases (50.7%), particularly with eczematous or exanthematous appearance, and leukemia was the malignancy most frequently reported in these patients. Eventually, lesions due to immunosuppression (c) were reported in 34.2% of the cases. They were represented by infections and cutaneous malignancies, and usually manifested with papulonodular lesions. Skin lesions in oncohematologic patients are a common event. A multidisciplinary approach based on the collaboration between the hematologist and the dermatologist is crucial to achieve a proper diagnosis, and correctly manage these manifestations.