Allogeneic transplantation after immunotherapy for relapsed/refractory non-Hodgkin lymphoma: a comparison with a historical cohort.

BACKGROUND AIMS: New immunotherapy drugs, such as bispecific T-cell engager antibodies, checkpoint inhibitors and antibody-drug conjugates, are commonly used as salvage therapy for patients with non-Hodgkin lymphoma relapsing after chimeric antigen receptor (CAR) T-cell therapy. Nevertheless, their potential long-term effects on the outcome of allogeneic stem cell transplantation (Allo-SCT) are not well known. METHODS: We retrospectively analyzed the outcomes of 27 relapsed/refractory non-Hodgkin lymphoma patients receiving Allo-SCT after immunotherapy in the pre-CAR T-cell therapy era and compared them with a historical cohort of 28 subjects undergoing Allo-SCT after conventional therapy. RESULTS: The two cohorts had similar outcomes in terms of graft-versus-host disease/relapse-free survival (4 years, 59% versus 46%), overall survival (4 years, 77% versus 44%), non-relapse mortality (4 years, 19% versus 22%) and acute (6 months, 15% versus 21%) and chronic (4 years, 18% versus 24%) graft-versus-host disease. Of note, the cumulative incidence of relapse was lower after immunotherapy (4 years, 4% versus 14%), although significance was not reached. The cumulative incidence of cytomegalovirus and fungal infection did not differ among the two cohorts. CONCLUSIONS: Consolidation with Allo-SCT is a safe and curative option for patients achieving disease response after new immunotherapy drugs that could represent a desirable salvage strategy for patients relapsing after CAR T-cell therapy.

Outcome of High-Dose Chemotherapy Followed by Autologous Stem Cell Transplantation in Relapsed/Refractory Hodgkin Lymphoma after Different Numbers of Salvage Regimens.

The introduction of novel drugs (PD-1 inhibitors and/or brentuximab vedotin) into salvage regimens has improved the response rate and the outcome of patients with relapsed/refractory Hodgkin lymphoma. However, the impact of new drugs on the outcome has not been adequately investigated so far. We retrospectively analyzed 42 consecutive patients treated at our institution with high-dose chemotherapy/autologous stem cell transplantation after either one standard chemotherapy represented by BEGEV (n = 28) or >1 salvage therapy (ST) comprising novel drugs (n = 14). With a median follow-up of 24 months, the 2-year cumulative incidence of relapse was similar between the two cohorts: 26% for 1 ST and 18% for >1 ST (p = 0.822). Consistently, overall survival and progression-free survival did not differ among the two groups: 3-year overall survival was 91% and 89% (p = 0.731), respectively, and 3-year progression-free survival was 74% and 83% (p = 0.822) for only one and more than one salvage regimens, respectively. Of note, the post-transplant side effects and engraftment rates were similar between the 1 ST and >1 ST cohorts. In conclusion, consolidation with high-dose chemotherapy/autologous stem cell transplantation is a safe and curative option, even for patients achieving disease response after more than one rescue line of therapy.

Impact of Preemptive Use of Tocilizumab on Chimeric Antigen Receptor T Cell Outcomes in Non-Hodgkin Lymphoma.

Despite the impressive results of chimeric antigen receptor (CAR) T cell treatment for lymphomas, adverse events such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections are major issues that can lead to intensive care unit (ICU) admission and death. Current guidelines recommend tocilizumab for treating patients with CRS grade (G) ≥2; however, the optimal timing of intervention has yet to be determined. Our institution adopted the preemptive use of tocilizumab in cases of persistent G1 CRS, defined as fever (≥38 °C) for >24 hours. This preemptive tocilizumab treatment aimed to reduce evolution to severe (G≥3) CRS, ICU admission, or death. We report on 48 prospectively collected consecutive patients with non-Hodgkin lymphoma treated with autologous CD19-targeted CAR T cells. In total, 39 patients (81%) developed CRS. CRS started as G1 in 28 patients, as G2 in patients, and as G3 in 1 patient. Tocilizumab was administered in 34 patients, including 23 patients who received "preemptive" tocilizumab and 11 patients who received tocilizumab for G2 or G3 CRS from the onset of symptoms. CRS resolved without worsening severity in 19 patients out of 23 (83%) who received preemptive tocilizumab; 4 patients (17%) progressed from G1 to G2 for the development of hypotension and quickly responded to the introduction of steroids. No patients treated with a preemptive approach developed G3 or G4 CRS. Ten out of 48 patients (21%) were diagnosed with ICANS, including 5 patients with G3 or G4. Six infectious events occurred. The overall ICU admission rate was 19%. ICANS management was the most relevant reason for ICU admission (7 patients), and no patient required ICU to manage CRS. No deaths from CAR-T toxicity were observed. Our data indicate that preemptive tocilizumab use is feasible and useful in reducing severe CRS and CRS-related ICU admission, with no impact on neurotoxicity or infection rate. Therefore, early use of tocilizumab can be considered, especially for patients at high risk of CRS.

EASIX predicts non-relapse mortality after haploidentical transplantation with post-transplant cyclophosphamide.

Endothelial Activation and Stress Index (EASIX) is a prognostic score reflecting endothelial damage. It can identify cohorts of patients at higher risk of non-relapse mortality (NRM) after allogeneic stem cell transplantation (SCT) from a matched-related or -unrelated donor. No data are available in the setting of haploidentical-SCT with post-transplant cyclophosphamide (PT-Cy). We retrospectively analyzed the role of EASIX score in a cohort of 266 patients receiving Haplo-SCT with PT-Cy at our center. By a decision-tree model, 1-year NRM was 16% vs. 29% and overall survival was 59% vs. 32%, respectively, for patients with a pre-transplant EASIX (EASIX-PRE) <0.8 vs. ≥0.8 (p < 0.001). By multivariable analysis, EASIX-PRE was an independent predictor of NRM (hazard ratio [HR] 2.43, p < 0.001) and overall survival (HR: 1.64, p = 0.011). EASIX-PRE did not predict patients at higher risk of developing acute graft-versus-host disease (GVHD) but was an independent predictor of 1-year NRM (3.2 cutoff, HR 6.61, p = 0.002; <3.2 vs. ≥3.2: 10% vs. 56%, p < 0.001) in patients developing acute GVHD. EASIX score can also represent an important tool to predict mortality in the setting of Haplo-SCT with PT-Cy. It may help to make therapeutic decisions both before the transplant and at the onset of acute GVHD.

Frequency, characteristics, and outcome of patients with COVID-19 pneumonia and "silent hypoxemia" at admission: a severity-matched analysis.

BACKGROUND: An aspect of COVID-19 baffling physicians is the presentation of patients with acute respiratory failure, but normal mental faculties and no perception of dyspnea (i.e. "silent hypoxemia"). The aim of this study was to investigate the frequency, characteristics, and outcome of COVID-19 patients with silent hypoxemic status and comparing them with a symptomatic severity-matched group. METHODS: This is a retrospective monocentric observational study involving all patients with PCR confirmed SARS-CoV-2 pneumonia, admitted at Papa Giovanni XXIII Hospital, Bergamo (Italy) from Emergency Department due to acute respiratory failure, during the first Italian pandemic peak (February-April 2020). RESULTS: Overall 28-day mortality in 1316 patients was 26.9%. Patients who did not report dyspnea at admission (N 469, 35.6%) had a lower 28-day mortality (22.6 vs. 29.3%, P=0.009). The severity matching analysis (i.e. PaO2/FiO2 and imaging) led to the identification of two groups of 254 patients that did not differ for sex prevalence, age, BMI, smoking history, comorbidities, and PaCO2 at admission. The use of CPAP during the first 24 hours, such as the need of endotracheal intubation (ETI) during the overall admission were significantly lower in matched patients with silent hypoxemia, whereas 28-day mortality resulted similar (P=0.21). CONCLUSIONS: Lack of dyspnea is common in patients suffering from severe COVID-19 pneumonia leading to respiratory failure, since up to a third of them could be asymptomatic on admission. Dyspnea per se correlates with pneumonia severity, and prognosis. However, dyspnea loses its predictive relevance once other findings to evaluate pneumonia severity are available such as PaO2/FiO2 and imaging. Silent hypoxemic patients are less likely to receive CPAP during the first 24 hours and ETI during the hospitalization, in spite of a comparable mortality to the dyspneic ones.

Sequential allogeneic transplantation and ruxolitinib maintenance for a synchronous PCM1-JAK2 positive myeloid sarcoma and acute B-lymphoblastic leukemia.

The translocation t(8;9)(p22;p24) results in the production of a chimeric PCM1-JAK2 fusion protein leading to the constitutive activation of the Janus Kinase 2 that renders this disease potentially sensitive to ruxolitinib. Here, we report an interesting case of PCM1-JAK2 myeloproliferative neoplasm evolving in myeloid sarcoma and B precursor ALL.

Concurrent Diagnosis of Acute Myeloid Leukemia and Symptomatic COVID-19 Infection: a Case Report Successfully Treated with Azacitidine-Venetoclax Combination.

SARS-COV2 pandemic has caused profound challenges in health care systems worldwide. Patients affected by hematological neoplasms appear to be particularly at risk of developing COVID-19 complications, with unfavorable outcomes. Here, we present the case of a 57-years-old woman diagnosed with severe COVID-19 pneumonia and concurrent acute myeloid leukemia (AML). At the time of diagnosis, it was decided to postpone leukemia therapy to enable adequate COVID-19 pneumonia treatment. When her conditions related to pneumonia improved, the combination of Azacitidine-Venetoclax was used as first-line treatment instead of conventional intensive chemotherapy. At the end of the first two cycles, the patient showed complete remission, and a post-remission consolidation with allogeneic hematopoietic stem cell transplantation has been planned. This case suggests that Azacytidine-Venetoclax induction may represent a valid and safe alternative to intensive chemotherapy in the challenging setting of patients with a concomitant diagnosis of AML and severe COVID-19 infection.

Light-Emitting Textiles: Device Architectures, Working Principles, and Applications.

E-textiles represent an emerging technology aiming toward the development of fabric with augmented functionalities, enabling the integration of displays, sensors, and other electronic components into textiles. Healthcare, protective clothing, fashion, and sports are a few examples application areas of e-textiles. Light-emitting textiles can have different applications: sensing, fashion, visual communication, light therapy, etc. Light emission can be integrated with textiles in different ways: fabricating light-emitting fibers and planar light-emitting textiles or employing side-emitting polymer optical fibers (POFs) coupled with light-emitting diodes (LEDs). Different kinds of technology have been investigated: alternating current electroluminescent devices (ACELs), inorganic and organic LEDs, and light-emitting electrochemical cells (LECs). The different device working principles and architectures are discussed in this review, highlighting the most relevant aspects and the possible approaches for their integration with textiles. Regarding POFs, the methodology to obtain side emissions and the critical aspects for their integration into textiles are discussed in this review. The main applications of light-emitting fabrics are illustrated, demonstrating that LEDs, alone or coupled with POFs, represent the most robust technology. On the other hand, OLEDs (Organic LEDs) are very promising for the future of light-emitting fabrics, but some issues still need to be addressed.

Pretransplant active disease status and HLA class II mismatching are associated with increased incidence and severity of cytokine release syndrome after haploidentical transplantation with posttransplant cyclophosphamide.

Cytokine release syndrome (CRS) represents a life-threatening side effect after haploidentical stem cell transplantation (Haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). Factors predictive of CRS development is still a matter of debate. We retrospectively analyzed 102 consecutive patients receiving a bone marrow (BM) (n = 42) or peripheral blood stem cells (PBSC) (n = 60) Haplo-SCT with PT-Cy. The two cohorts were similar in main patients' characteristics besides disease type (P = .02). Cumulative incidence of grades 1, 2, and ≥3 CRS was 80%, 52%, and 15% at a median of 2, 4, and 7 days, respectively. Moderate/High-grade fever (39°-41°), grade 1 and grade ≥3 CRS occurred more frequently after PBSC relative to BM grafts (68% vs 33%, P = .0005; 87% vs 71%, P = .009; 20% vs 7%, P = .07). Only patients experiencing grade ≥3 CRS had a worse outcome in terms of 1-year overall survival (OS) and nonrelapse mortality (NRM): 39% vs 80% (P = .002) and 40% vs 8% (P = .005), respectively. By univariate analysis the only factors associated with the increased risk of ≥3 CRS were pretransplant disease status (8% for complete remission, 11% for partial remission, and 38% for active disease, P = .002), HLA-DRB1 mismatching (57% vs 14%, P = .007), and PBSC graft (P = .07). By multivariable analysis, only pretransplant disease status (hazard ratio, HR: 6.84, P = .005) and HLA-DRB1 mismatching (HR: 17.19, P = .003) remained independent predictors of grade ≥3 CRS. Only grade ≥3 CRS is clinically relevant for the final outcome of patients receiving Haplo-SCT with PT-Cy, is more frequent after a PBSC graft and is associated with pretransplant active disease and HLA-DRB1 mismatching.

Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth.