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.

SARS-CoV-2 infection in patients with chronic lymphocytic leukemia: The Italian Hematology Alliance on COVID-19 cohort.

COVID-19, the disease caused by SARS-CoV-2, is still afflicting thousands of people across the globe. Few studies on COVID-19 in chronic lymphocytic leukemia (CLL) are available. Here, we analyzed data from the CLL cohort of the Italian Hematology Alliance on COVID-19 (NCT04352556), which included 256 CLL patients enrolled between 25 February 2020 and 1 February 2021. Median age was 70 years (range 38-94) with male preponderance (60.1%). Approximately half of patients (n = 127) had received at least one line of therapy for CLL, including 108 (83.7%) who were on active treatment at the time of COVID-19 or received their last therapy within 12 months. Most patients (230/256, 89.9%) were symptomatic at COVID-19 diagnosis and the majority required hospitalization (n = 176). Overall, after a median follow-up of 42 days (IQR 24-96), case fatality rate was 30.1%, and it was 37.5% and 24.4% in the first (25 February 2020-22 June 2020) and second wave (23 June 2020-1 February 2021), respectively (p = 0.03). At multivariate analysis, male sex (HR 1.82, 95% CI 1.03-3.24, p = 0.04), age over than 70 years (HR 2.23, 95% CI 1.23-4.05, p = 0.01), any treatment for CLL given in the last 12 months (HR 1.72, 95% CI 1.04-2.84, p = 0.04) and COVID-19 severity (severe: HR 5.66, 95% CI 2.62-12.33, p < 0.0001; critical: HR 15.99, 95% CI 6.93-36.90, p < 0.0001) were independently associated with poor survival. In summary, we report a dismal COVID-related outcome in a significant fraction of CLL patients, that can be nicely predicted by clinical parameters.

Lack of efficacy of convalescent plasma in COVID-19 patients with concomitant hematological malignancies: An Italian retrospective study.

A multicenter retrospective study was designed to assess clinical outcome of COVID-19 in patients with hematological malignancies (HM) following treatment with anti-SARS-CoV-2 convalescent plasma (CP) or standard of care therapy. To this aim, a propensity score matching was used to assess the role of non-randomized administration of CP in this high-risk cohort of patients from the Italian Hematology Alliance on COVID-19 (ITA-HEMA-COV) project, now including 2049 untreated control patients. We investigated 30- and 90-day mortality, rate of admission to intensive care unit, proportion of patients requiring mechanical ventilatory support, hospitalization time, and SARS-CoV-2 clearance in 79 CP recipients and compared results with 158 propensity score-matched controls. Results indicated a lack of efficacy of CP in the study group compared with the untreated group, thus confirming the negative results obtained from randomized studies in immunocompetent individuals with COVID-19. In conclusion, this retrospective analysis did not meet the primary and secondary end points in any category of immunocompromized patients affected by HM.

Secondary infections worsen the outcome of COVID-19 in patients with hematological malignancies: A report from the ITA-HEMA-COV.

The impact of secondary infections (SI) on COVID-19 outcome in patients with hematological malignancies (HM) is scarcely documented. To evaluate incidence, clinical characteristics, and outcome of SI, we analyzed the microbiologically documented SI in a large multicenter cohort of adult HM patients with COVID-19. Among 1741 HM patients with COVID-19, 134 (7.7%) had 185 SI, with a 1-month cumulative incidence of 5%. Median time between COVID-19 diagnosis and SI was 16 days (IQR: 5-36). Acute myeloid leukemia (AML) and lymphoma/plasma cell neoplasms (PCN) were more frequent diagnoses in SI patients compared to patients without SI (AML: 14.9% vs. 7.1%; lymphoma/PCN 71.7% vs. 65.3%). Patients with SI were older (median age 70 vs. 66 years, p = 0.002), with more comorbidities (median Charlson Comorbidity Index 5 vs. 4, p < 0.001), higher frequency of critical COVID-19 (19.5% vs. 11.5%, p = 0.046), and more frequently not in complete remission (75% vs. 64.7% p = 0.024). Blood and bronchoalveolar lavage were the main sites of isolation for SI. Etiology of infections was bacterial in 80% (n = 148) of cases, mycotic in 9.7% (n = 18) and viral in 10.3% (n = 19); polymicrobial infections were observed in 24 patients (18%). Escherichia coli represented most of Gram-negative isolates (18.9%), while coagulase-negative Staphylococci were the most frequent among Gram-positive (14.2%). The 30-day mortality of patients with SI was higher when compared to patients without SI (69% vs. 15%, p < 0.001). The occurrence of SI worsened COVID-19 outcome in HM patients. Timely diagnosis and adequate management should be considered to improve their prognosis.

Neutralizing monoclonal antibodies in haematological patients paucisymptomatic for COVID-19: The GIMEMA EMATO-0321 study.

COVID-19 continues to be a relevant issue among patients with haematological malignancies (HM). Vaccines are frequently not effective in subjects on active treatment. In this multicentre retrospective study of Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA), we collected data from 91 paucisymptomatic HM patients treated with anti-spike neutralizing monoclonal antibodies (nMoAbs) to determine time to viral clearance, referencing it to the expected value of 28 days from an historical group of untreated paucisymptomatic patients. Secondary endpoints included rate of hospitalization, intensive care unit (ICU) admission, COVID-19 related death and safety. SARS-CoV-2 molecular swab negativity was obtained in 86 patients (95%), with a median time of 18 days (IQR 13-26; p < 0.0001). We did not find significant variations according to age, diagnosis, treatment type, vaccination status or nMoAbs type. Rate of hospitalization due to COVID-19 progression was 12% (11/91), with 2 patients (2.2%) requiring ICU admission. With a median follow-up of 2.33 months, the overall mortality was 5.5% (5/91), with 3 deaths due to COVID-19. Side effects were rare and self-limiting. Our data suggest that nMoAbs can limit the detrimental effect of immunosuppressive treatments on COVID-19 clinical progression and time to viral clearance. The original trial was registered at www.clinicaltrials.gov as #NCT04932967.

A prognostic model for patients with lymphoma and COVID-19: a multicentre cohort study.

Lymphoma represents a heterogeneous hematological malignancy (HM), which is characterized by severe immunosuppression. Patients diagnosed of coronavirus disease 2019 (COVID-19) during the course of HM have been described to have poor outcome, with only few reports specifically addressing lymphoma patients. Here, we investigated the clinical behavior and clinical parameters of a large multicenter cohort of adult patients with different lymphoma subtypes, with the aim of identifying predictors of death. The study included 856 patients, of whom 619 were enrolled prospectively in a 1-year frame and were followed-up for a median of 66 days (range 1-395). Patients were managed as outpatient (not-admitted cohort, n = 388) or required hospitalization (n = 468), and median age was 63 years (range 19-94). Overall, the 30- and 100-days mortality was 13% (95% confidence interval (CI), 11% to 15%) and 23% (95% CI, 20% to 27%), respectively. Antilymphoma treatment, including anti-CD20 containing regimens, did not impact survival. Patients with Hodgkin's lymphoma had the more favorable survival, but this was partly related to significantly younger age. The time interval between lymphoma diagnosis and COVID-19 was inversely related to mortality. Multivariable analysis recognized 4 easy-to-use factors (age, gender, lymphocyte, and platelet count) that were associated with risk of death, both in the admitted and in the not-admitted cohort (HR 3.79 and 8.85 for the intermediate- and high-risk group, respectively). Overall, our study shows that patients should not be deprived of the best available treatment of their underlying disease and indicates which patients are at higher risk of death. This study was registered with ClinicalTrials.gov, NCT04352556.

COVID-19 elicits an impaired antibody response against SARS-CoV-2 in patients with haematological malignancies.

COVID-19 is associated with high mortality in patients with haematological malignancies (HM) and rate of seroconversion is unknown. The ITA-HEMA-COV project (NCT04352556) investigated patterns of seroconversion for SARS-CoV-2 IgG in patients with HMs. A total of 237 patients, SARS-CoV-2 PCR-positive with at least one SARS-CoV-2 IgG test performed during their care, entered the analysis. Among these, 62 (26·2%) had myeloid, 121 (51·1%) lymphoid and 54 (22·8%) plasma cell neoplasms. Overall, 69% of patients (164 of 237) had detectable IgG SARS-CoV-2 serum antibodies. Serologically negative patients (31%, 73 of 237) were evenly distributed across patients with myeloid, lymphoid and plasma cell neoplasms. In the multivariable logistic regression, chemoimmunotherapy [odds ratio (OR), 3·42; 95% confidence interval (CI), 1·04-11·21; P = 0·04] was associated with a lower rate of seroconversion. This effect did not decline after 180 days from treatment withdrawal (OR, 0·35; 95% CI: 0·11-1·13; P = 0·08). This study demonstrates a low rate of seroconversion in HM patients and indicates that treatment-mediated immune dysfunction is the main driver. As a consequence, we expect a low rate of seroconversion after vaccination and thus we suggest testing the efficacy of seroconversion in HM patients.

Dexamethasone, oxaliplatin and cytarabine (R-DHAOx) as salvage and stem cells mobilizing therapy in relapsed/refractory diffuse large B cell lymphomas.

Cisplatin-containing salvage regimens followed by autologous hematopoietic stem cell (HSC) transplantation are the current standard of care for relapsed or refractory (R/R) lymphomas. We retrospectively analyzed efficacy and stem cell mobilizing activity of oxaliplatin, cytarabine, dexamethasone and rituximab (R-DHAOx) in 53 R/R diffuse large B cell lymphomas (DLBCL) treated in our center (median lines 2, range 2-5; median age 59, range 22-79). Hematological toxicity was manageable and no patients experienced renal impairment. After 2 courses the overall response rate was 60% (CR 49%, PR 11%). Median overall survival (OS) was 30.53 months (95% CI 11.5-49.55), 3-year OS 40.5%. Twenty-two eligible patients collected HSC and transplantation was performed in 21/22 patients (95%), after a median of 52 days from last cycle. Our results suggest that in DLBCL R-DHAOx has an excellent stem cell mobilizing capability, response rate comparable to cisplatin-containing regimens and good toxicity profile.