Cancer-related Cognitive Impairment in Patients With Newly Diagnosed Aggressive Lymphoma Undergoing Standard Chemotherapy: a Longitudinal Feasibility Study

PurposeCancer-related cognitive impairment (CRCI) is a recognised adverse consequence of cancer and its treatment. This study assessed the feasibility of collecting longitudinal data on cognition in patients with newly diagnosed, aggressive lymphoma undergoing standard therapy with curative intent via self-report, neuropsychological assessment, peripheral markers of inflammation and neuroimaging. An exploration and description of patterns of cancer-related cognitive impairment over the course of treatment and recovery was also explored. MethodsEligible participants completed repeated measures of cognition including self-report, neuropsychological assessment, blood cell–based inflammatory markers, and neuroimaging at three pre-specified time-points, Time 1 (T1) – pre-treatment (treatment naïve), Time 2 (T2) – mid-treatment, and Time 3 (T3) – six to eight weeks post-completion of treatment. ResultsOf 33 eligible participants, 30 (91%, 95% CI: 76%, 97%) were recruited over 10 months. The recruitment rate was 3 patients/month (95% CI: 2.0, 4.3 patients/month). Reasons for declining included feeling overwhelmed and rapid treatment commencement. Mean age was 57 years (SD=17 years) and 16/30 (53%) were male. Most patients (20/30, 67%) had diffuse large B cell lymphoma or Hodgkin lymphoma (4/30, 13%). The neuroimaging sub-study was optional, 11/30 participants (37%) were eligible to take part, and all agreed. Retention and compliance with all assessments was very high at all time-points. Only one patient was withdrawn from the study due to disease progression.ConclusionsFindings from this study demonstrate that it is feasible to longitudinally assess cognitive status and impairment in people with newly diagnosed aggressive lymphoma during their initial treatment and recovery and larger studies should be undertaken within other cancer groups.

The Diverse Roles of γδ T Cells in Cancer: From Rapid Immunity to Aggressive Lymphoma

γδ T cells are unique players in shaping immune responses, lying at the intersection between innate and adaptive immunity. Unlike conventional αβ T cells, γδ T cells largely populate non-lymphoid peripheral tissues, demonstrating tissue specificity, and they respond to ligands in an MHC-independent manner. γδ T cells display rapid activation and effector functions, with a capacity for cytotoxic anti-tumour responses and production of inflammatory cytokines such as IFN-γ or IL-17. Their rapid cytotoxic nature makes them attractive cells for use in anti-cancer immunotherapies. However, upon transformation, γδ T cells can give rise to highly aggressive lymphomas. These rare malignancies often display poor patient survival, and no curative therapies exist. In this review, we discuss the diverse roles of γδ T cells in immune surveillance and response, with a particular focus on cancer immunity. We summarise the intriguing dichotomy between pro- and anti-tumour functions of γδ T cells in solid and haematological cancers, highlighting the key subsets involved. Finally, we discuss potential drivers of γδ T-cell transformation, summarising the main γδ T-cell lymphoma/leukaemia entities, their clinical features, recent advances in mapping their molecular and genomic landscapes, current treatment strategies and potential future targeting options.

PROGNOSTIC SIGNIFICANCE OF PLATELET- NEUTROPHIL COMPLEXES IN NON-HODGKIN’S LYMPHOMA PATIENTS

Non-Hodgkin's lymphomas (NHL) are a group of lymphoproliferative diseases with a heterogeneous spectrum of clinical, morphological, and immunophenotypic characteristics. Non-Hodgkin’s lymphoma is characterized by abnormal proliferation or accumulation of B or T lymphocytes. Circulating neutrophils and platelets have a proven role in both the pathogenesis of inflammatory processes and thrombosis and in the processes of tumorigenesis.The formation of complexes between neutrophils and circulating platelets (PNC) is a fundamental mechanism that is known but poorly studied in non-Hodgkin's lymphomas. Aim: To investigate the levels of circulating neutrophil-platelet complexes in newly diagnosed patients with aggressive and indolent NHL and the relationship of those levels with prognostic risk, prognosis, overall survival, and therapeutic response. Methods: PNC levels were analyzed by flow cytometry of peripheral blood from 88 patients with histologically verified NHL before chemotherapy. The results were statistically analyzed using dispersion, variable, comparison, correlation, and regression methods. Results: The mean age of the studied patients was 60.6 years ± 11.8 years (range 28–88 years), with men and patients with aggressive lymphoma accounting for just over half the population (52.3% each). A significant difference (p = 0.005) and an inversely weak dependence was found between IPI risk and survival (r = -0.277; p = 0.009) in aggressive lymphomas. A significant difference was found between the type of lymphoma and the therapeutic response (p = 0.030). A complete response was achieved in 42 (47.7%) patients with NHL, while progression was observed in 17 (19.3%) and relapse in 2 (2.3%) There was a strong significant correlation between PNC and IPI (р=0.021), PNC and therapeutic response (р=0.044). Conclusion: PNC measurement could be a useful diagnostic and prognostic marker in many diseases.

A Simplified Geriatric Assessment (sGA) Can Identify Older Patients with Relapse/Refractory (R/R) Aggressive Lymphoma Suitable for Autologous Stem Cell Transplantation (ASCT): Final Results of Recanz Multicentre Prospective Phase 2 Study By the Fondazione Italiana Linfomi (FIL)

Introduction: We recently demonstrated in a large multicentre study that sGA can identify fit older patients with aggressive lymphoma able to tolerate first-line intensive treatment with curative intent and to obtain similar results than younger people (Merli at al JCO 2021). Regardless of age, about 40% of patients with aggressive lymphoma are either refractory or will eventually relapse after treatment with curative intent. Salvage platinum-based regimens followed by ASCT in responsive disease is a standard of care to obtain longer second remission. However, in many case series, patients over 65 years are excluded from the transplant approach because of potential severe toxicities of high-dose therapy in older patients. This study was designed to evaluate the feasibility and activity of high-dose treatment followed by ASCT in older FIT patients with R/R aggressive lymphoma selected with a sGA. Methods: Patients with R/R aggressive lymphoma after one line of treatment, aged between 65 and 75, and FIT to sGA were eligible for the study. Salvage treatment could be chosen between R-DHAP, R-ICE or other platinum or gemcitabine-containing regimens and stem cells were mobilized after 1 or 2 cycles. Patients achieving at least partial response after 3 courses and who remained FIT to sGA evaluation were eligible for ASCT and were conditioned with either BEAM or FEAM. Results: From May 2014 to August 2019, seventy-five patients from 16 FIL centres were enrolled and 70 were eligible for the study. Sixty-six of them had a diffuse large B-cell lymphoma, one had follicular 3b, 2 mantle cell and 1 Burkitt histology. Salvage treatment was R-DHAP in 48 patients, R-ICE in seven and gemcitabine or oxalyplatinum containing regimens in the remaining ones. Overall response rate after three courses was 44% (21 complete and 10 partial remission). Among the 39 unresponsive patients, 29 had progressive and 4 stable disease, 2 patients died of septic shock and heart failure during salvage and 4 patients withdrew their consent to ASCT. Four patients relapsed soon after response achievement before undergoing the transplant. ASCT was performed in 27 patients with a median of 5.6 x 10 6 CD34/Kg reinfused. No differences emerged in demographic and clinical characteristics between patients reaching the ASCT timepoint or not (Tab 1a). By intention to treat analysis, 2-y overall survival (OS) and PFS of the entire intention-to-treat population were 65% (95%CI: 50-76%) and 34% (95%CI: 22-46%) respectively, without differences according to age (Tab 1b). After a median of 27 months, 2-y OS was 79% (95CI: 51-86%) and EFS 56% (95CI: 32-75%). Twenty-four patients obtained a complete remission (CR) and 20 of them are in continuous CR after more than 12 months. Three patients progressed 1-8 months after ASCT and died. Most common non-hematologic grade 3-4 adverse events were gastrointestinal (10%) and infectious (8%). Conclusion: This study shows that sGA can identify older patients with R/R aggressive lymphoma who are able to tolerate and can benefit from high-dose therapy and ASCT. The poor response to second-line immunochemotherapy remains the major drawback of this approach since less than 50% of patients could actually receive ASCT. Nevertheless the 2-y survival of 65% in the intention to treat population is remarkable and sets the stage for the evaluation of new approaches such as CAR-T or bispecific antibodies also in older patients. A next step should be to explore the usefulness of sGA in the selection of candidates to these innovative treatments. Figure 1 Figure 1. Disclosures Tucci: Takeda: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Gilead: Speakers Bureau. Zilioli: Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau; Takeda: Other: travel expenses, accommodation. Merli: EUSA Pharma: Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses. Marcheselli: sandoz: Membership on an entity's Board of Directors or advisory committees. Rossi: Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees.

Autologous Stem Cell Transplantation after Conditioning with Chidamide Plus Carmustine, Etoposide, Cytarabine, and Cyclophosphamide (Chi-BEAC) for Treatment of High-Risk and Relapsed/Refractory Aggressive Lymphoma: Multi-Center, Single-Arm, Open-Label Phase II Clinical Trial

Background: Chidamide, as a novel subtype-selective histone deacetylase inhibitors (HDACi), can directly inhibit tumor cell cycle progression and induce tumor cell apoptosis, inhibit phenotypic transformation of tumor cells and pro-drug resistance/pro-metastasis activity of the microenvironment, induce differentiation of tumor stem cells, and reverse epithelial-mesenchymal transformation of tumor cells, thereby restoring the sensitivity of drug-resistant tumor cells to drugs and enhancing the effect of chemotherapy agents through loosening chromatin and exposing DNA. The efficacy and safety of chidamide-BEAC (carmustine, etoposide, cytarabine, and cyclophosphamide, Chi-BEAC) conditioning regimen combined with autologous stem cell transplantation (ASCT) were evaluated in a current phase II clinical trial for the treatment of high-risk and relapsed/refractory aggressive lymphoma. Methods: A total of 70 patients with high-risk diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), or mantle cell lymphoma (MCL) who had achieved complete remission (CR) or partial remission (PR) after first-line therapy or second-/third-line therapy were recruited from January 2018 to June 2021. Three of the patients were not evaluated after ASCT and two patients withdrew from the study; 65 patients were then evaluated for the effectiveness of Chi-BEAC treatment. Results: DLBCL and MCL are referred as B-cell non-Hodgkin lymphoma (B-NHL) and PTCL is referred as T and NK-cell non-Hodgkin lymphoma (T&NK-NHL) in the study. The median neutrophil engraftment time was 10 d (7-13 d) and median platelet engraftment time was 11 d (8-13 d). The CR rate at 3-6 months after transplantation was 75.4% in the 65 evaluable patients. The median progression free survival (PFS) and overall survival (OS) had not reached at the end of the follow-up period (median 18.1 month; range 1.8-42.0 months). The estimated PFS and OS at 24 months was 78.5% and 84.2%, respectively. Stratified analyses showed that in patients with B-NHL who previously received first-line treatment, the CR rate at 3-6 months after transplantation was 77.8%, and 2-year PFS was 74.8%. The survival rate might be better than previously reported for SWOG9704 (Stiff et al., 2013; PMID 24171516)-a 2-year PFS of 69%-and for DLCL04 (Chiappella et al., 2017; PMID 28668386)-a 2-year failure-free survival of 71%. In our patients with B-NHL who previously received second-/third-line treatments, the CR rate at 3-6 months after transplantation was 71.4%, and 2-year PFS was 77.1%. The survival rate might also be higher than previously reported for the CORAL trial (Gisselbrecht et al., 2010; PMID: 20660832), which showed a 2-year PFS of approximately 65%. In our patients with T&NK-NHL the CR rate at 3-6 months after transplantation was 73.3%, and 2-year PFS was 93.3%, The survival rate might be higher than previously reported for the NLG-T-01 trial (Francesco d'Amore et al., 2012; PMID: 22851556), which showed a 2-year PFS of approximately 55%. PFS stratification analysis showed that previous treatment outcomes affected the PFS: patients who had achieved CR before transplantation demonstrated better PFS than patients who had achieved PR (P = 0.199), while there was no significant difference between patients with different pathological subtypes (B or T&NK-NHL) or different risk groups. Most non-hematological adverse events (AEs) were of grade 1/2. Grade 4 AE only occurred in one patient, i.e., γ-glutamyl transpeptidase (GGT) elevation. Grade 3 AEs that occurred in ≥ 5% of the patients included febrile agranulocytosis (37.7%), hypokalemia (24.7%), hyponatremia (23.4%), GGT elevation (9.1%), and diarrhea (5.2%), which were well tolerated. Conclusions: This study showed that inclusion of the HDACi chidamide in conditioning regimen for ASCT greatly increased the PFS and OS, especially in patients with T&NK-NHL, and revealed an acceptable safety profile for refractory and relapsed lymphoma patients. Therefore, chidamide-containing conditioning regimen may be a great choice for patients with refractory and relapsed lymphoma, and awaits further confirmation by additional large-scale multi-center investigations. Disclosures No relevant conflicts of interest to declare.

Encouraging Survival and High Rates of Toxicity: Allogeneic Hematopoietic Cell Transplantation after Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy in Aggressive Lymphoma Patients

Background Approximately 60% of patients with aggressive large B-cell lymphoma (ALBCL) treated with anti-CD19 chimeric antigen receptor T-cell (CAR T) will ultimately progress or relapse. Allogeneic hematopoietic cell transplantation (Allo-HCT) is a potentially curative treatment for lymphoma patients who relapse after CAR T-cell therapy. However, the efficacy and toxicity profile of allo-HCT following CAR T in aggressive lymphoma patients are not well defined. Herein, we report our experience. Methods and patients A total of 29 adult patients (median age 45 years [IQR 40-55]) who received allo-HCT for ALBCL between 2017 to 2021 were included. All patients were previously treated with anti-CD19 CAR T-cell (academic CD28-costimulatory domain product [n=23, 79%]; tisagenlecleucel [n=6, 21%]). Twenty-five (86%) and 4 (14%) had a diagnosis of DLBCL and PMBCL, respectively. Median number of previous therapies before CAR T was 3 (IQR 2-4). Eight (28%) patients underwent a previous autologous HCT. No patient underwent a previous allo-HCT. Median hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was 3 (IQR 2-3). Six (21%) patients had a Karnofsky performance status ≤ 80%. Allo-HCT was performed at a median of 4.1 months (IQR 2.2-5.4) post CAR T, with the majority of patients (48%) receiving transplant as first-line post CAR T. Reasons for allo-HCT were consolidation of complete response (CR) to CAR T in high-risk disease (n=4, 14 %), partial response (PR) to CAR T (n=7, 24%) and relapse /progression after CAR T (n=18, 62%). Disease response before allo-HCT was CR (n=11, 38%), PR (n=11, 38%) and progressive disease (n=7, 24%). Donors were matched siblings (n=13, 45%), matched unrelated (n=9, 31%) and mismatched unrelated /haploidentical donors (n=7, 24%). Myeloablative and reduced-intensity conditioning regimens were given in 13 (45%) and 16 (55%) patients, respectively. Methotrexate-based graft versus host disease (GVHD) prophylaxis was used in 20 (69%) patients. Antithymocyte globulin and post-transplantation cyclophosphamide were administered in 13 (45%) and 5 (14%), respectively. Results Median follow-up was 33 months (IQR 13-41). Neutrophil engraftment rate was 93% (two early deaths before engraftment due to infection and multi-organ failure). Two-year overall survival (OS) and progression-free survival were 44% (95% CI: 28-68) and 30% (95% CI: 17-55), respectively. Two-year cumulative relapse incidence and non-relapse mortality were 45% (95% CI: 25-63) and 25% (95% CI: 11-43), respectively (Figure). In a univariable Cox regression, factors significantly associated with a shorter OS were number of interim therapies between CAR T and allo-HCT (Hazard ratio [HR] 2.2 [95% CI: 1.3-3.9], p 0.006) and the length of time between CAR T and allo-HCT (HR 3.8 [95% CI: 1.2-12.1], p 0.02). Best response to CAR T and disease response before allo-HCT were not significant risk factors for a shorter OS. High rates of grade ≥ 3 hyperbilirubinemia (total bilirubin >3 ULN) and hepatic sinusoidal obstruction syndrome (SOS) were observed in 10 (35%) and 5 (17%) patients, respectively. These liver insults were not contributed to acute GVHD. All patients with SOS were treated with defibrotide and two patients died from related complications. Interestingly, 4/5 patients with SOS were conditioned with fludarabine and thiotepa. One-year cumulative incidence of grade II-IV acute GVHD was 34% (n=10; 95% CI: 18-52). Notably, 6 patients had grade IV acute GVHD, 4 of them were refractory to corticosteroids and 3 patients died due to acute GVHD. Two-year cumulative incidence of chronic GVHD was 23% (n=5; 95% CI: 7-46). Chronic GVHD was considered extensive in 4 of them. Bloodstream bacterial infection was documented in 11 (38%) patients. Invasive fungal infection occurred in 6 (21%) patients and included brain aspergillosis, cutaneous aspergillosis, 2 lung aspergillosis, hepatosplenic candidiasis and an ocular mucor mycosis. Conclusion Allogeneic hematopoietic cell transplantation is feasible after failure of CAR T-cell therapy in aggressive lymphoma, although with a relatively high rate of SOS and severe acute GVHD in these heavily pretreated patients. Overall survival is encouraging with approximately 30% of patients remaining alive and disease-free at two years. Larger scale studies are required to better define the role of allo-HCT in this setting. Figure 1 Figure 1. Disclosures Shouval: Medexus: Consultancy. Jacoby: NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avigdor: Takeda: Consultancy, Honoraria; Janssen: Research Funding; BMS: Research Funding; Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Blinatumomab for Patients with Richter's Syndrome: A Multicenter Phase 2 Trial from the Filo Group

Background Richter syndrome (RS) refers to the onset of aggressive lymphoma, mostly diffuse large B cell lymphoma (DLBCL), in patients with chronic lymphocytic leukemia (CLL). The outcome of RS patients is usually very poor with both low response rates to chemoimmunotherapy and short survival. While BCR and BCL2 inhibitors have transformed the management of CLL patients, these drugs do not prevent the onset of RS. Modulating anti-tumor immunity has recently been suggested as a promising approach in RS (Ding, 2017). Blinatumomab is a bi-specific T-cell engaging antibody construct that transiently links CD3-positive T cells to CD19-positive B-cells, inducing T-cell activation and subsequent lysis of tumor cells. It has been approved for the treatment of patients with relapsed or refractory B-ALL and has also been evaluated in the setting of persisting minimal residual disease. Recently, blinatumomab (stepwise dosing 9-28-112 μg/d) has been evaluated in patients with relapsed or refractory DLBCL and demonstrated promising results (ORR 43%) with acceptable safety (Viardot, 2016). We hypothesized that blinatumomab would improve response in RS patients failing to achieve CR after initial debulking with R-CHOP. Methods We report here the first results of a phase 2 multicenter study investigating the efficacy and safety of blinatumomab after R-CHOP debulking therapy for patients with untreated RS of DLBCL histology (NCT03931642). The patients with persisting (PR, SD) or progressive disease (PD) after 2 cycles of R-CHOP were eligible to receive an 8-week course of blinatumomab induction. Blinatumomab was administered at a stepwise dose of 9 μg/d in the first week, 28 μg/d in the second week, and 112 μg/d thereafter. The primary endpoint was CR rate according to the revised Lugano criteria after the 8-week induction course of blinatumomab. An additional 4-week consolidation cycle was optional. Allo-HSCT was further allowed for eligible patients. Results A total of 34 patients out of 41 has already been enrolled in the trial to date. Median age was 66 years (range, 38-82) and sex ratio M/F was 23/12. CLL features at baseline were as follows: 57% had 17p deletion and 67% TP53 mutations. Sixty-five percent had complex karyotype and 79% unmutated IGHV status. Median number of prior therapeutic lines for CLL was 2 (range, 0-7): 19 (54%) patients previously received chemo-immunotherapy, 23 (66%) patients were exposed to ibrutinib and 11 (31%) to venetoclax. As of the data cut-off of June 1st, 2021, the blinatumomab induction course has been completed for 18 patients. Ten patients did not receive blinatumomab for the following reasons: 7 patients achieved CR after R-CHOP, 2 patients died because of febrile neutropenia after R-CHOP and 1 patient presented severe pneumonia after R-CHOP. Three patients are still on R-CHOP and 3 others on blinatumomab to date. Regarding toxicity during blinatumomab, data are available for the 18 patients having completed the blinatumomab induction to date. All patients had at least one grade 1 adverse event (AE), 10 had grade ≥3 AE. The most common AE (> 1 case), regardless of relationship to blinatumomab, were fever (4 patients), CRS (2 patients), sepsis (2 patients), vein thrombosis (2 patients), anemia (4 patients), neutropenia (3 patients), lymphopenia (5 patients), thrombocytopenia (3 patients) and hyperglycemia (5 patients). In terms of neurologic events, 5 (28%) experienced neurotoxicity (all recovered) including grade 3 encephalopathy, grade 4 confusion, grade 3 anxiety, grade 1 myoclonus, grade 2 ataxia, grade 1 sleep disorder and grade 1 ICANS (each in 1 pt). Blinatumomab was temporarly stopped in 3 patients and permanently in 2. In terms of efficacy, after R-CHOP debulking therapy (n=31 evaluable patients), 7 patients achieved CR, 6 patients were in PR, 7 patients were stable and 11 patients were progressive. At evaluation after the blinatumomab induction (n=18 evaluable patients), 4 (22.2%) patients achieved CR, 4 (22.2%) patients PR, 2 (11.1%) patients were stable and the remaining 8 (44.5%) were progressive. Considering the whole strategy (including R-CHOP debulking) (n=28), 15 (54%) patients achieved overall response including 11 (39%) CR. Conclusions Our preliminary data suggest that blinatumomab suggests encouraging anti-tumor activity and acceptable toxicity in patients with RS. Disclosures Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. Ferrant: AstraZeneca: Honoraria; Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses. de Guibert: Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Laribi: Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Novartis: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; IQONE: Other: Personal Fees; Jansen: Research Funding; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding. Feugier: Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. OffLabel Disclosure: blinatumomab is approved for acute lymphoblastic leukemia. The aim of this phase 2 study is to evaluated it in patients with Richter's syndrome.

COVID-19 Among Patients with Hematological Malignancies: Experience from a Tertiary Center Showing Lower Than Expected Mortality and Establishing the Safety of in-Hospital Patient Care during the Pandemic

Previous studies and meta-analyses addressing COVID-19 in patients with hematological malignancies (HM) have reported dramatically high mortality rates of up to 34% [Vigenthira 2020, Garcia-Suarez 2020, Sharafeldin 2021]. These studies, however, were strongly biased towards hospitalized patients, and poorly represented patients who experienced a milder course of COVID-19, not requiring hospitalization. Jerusalem and its metropolitan area, comprising of over 1.3 million inhabitants, was the epicenter of Israel's COVID-19 crisis, with over 200,000 cases. Hadassah Medical Center, one of only two tertiary centers serving this multi-ethnic population, houses a Hematology Department that includes inpatient services, a hematopoietic stem cell transplant (HSCT) center, day care services and in-campus outpatient clinics. From February 20 th, 2020, we tracked patients with confirmed COVID-19 reporting to their treating hematologists while being hospitalized due to COVID-19, at routine visits to the hematology services, or remotely via phone or email communication. This assured the representation of COVID-19 cases of various clinical severities. Data were collected retrospectively and included demographics, comorbidities, hematological diagnoses and treatments, course of COVID-19 and, importantly, source of infection. Univariate and multivariate analyses were used to assess association between prognostic factors and outcomes including hospitalization, severe COVID-19 (per updated WHO criteria) and critical COVID-19, defined as a composite of ICU admission and mortality. Almost all the patients in this series were diagnosed prior to their vaccination. To the best of our knowledge, this is the largest single center series of HM patients with COVID-19 reported to date. Our series included 183 patients. Median age was 62.5 years, 57% were men, and 72% had at least one comorbidity. The most frequent hematological diagnoses were indolent lymphoma and CLL (40%), aggressive lymphoma (20%) and multiple myeloma (19%). At the time of COVID-19 diagnosis, 41% of the patients were receiving systemic anti-neoplastic treatment (excluding TKIs for CML and hydroxyurea for MPN), and 16% had undergone a previous allogeneic or autologous HSCT. Overall mortality, severe COVID-19, and hospitalization rates in the entire group were 9.8%, 14.2% and 32%, respectively, remarkably lower than in previous reports. Of the patients not receiving anti-neoplastic treatment, mortality and severe COVID-19 rates were comparable to those of the age-matched general population according to the Israeli Ministry of Health database [Table 1]. Consistent with previous studies, ischemic heart disease (IHD), dyslipidemia, chronic kidney disease, smoking and hypertension, as well as age and active anti-neoplastic treatment, each emerged as a risk factor significantly associated with hospitalization due to COVID-19 [Fig. 1, Table 2]. IHD, smoking, age and active treatment remained significant in multivariate analysis. Age and active treatment as well as ≥4 comorbidities were significantly associated with critical COVID-19. Interestingly, we observed a strong association between the number of prior anti-neoplastic treatment lines and critical COVID-19. Neither history of HSCT nor treatment with monoclonal antibodies were associated with COVID-19 outcomes. Notably, we did not detect any patient that contracted COVID-19 within the Hematology Department services, both inpatient and outpatient. Taken together, we present a different COVID-19 severity landscape in patients with HM as compared to previous observations. While active treatment was significantly associated with COVID-19 hospitalization and mortality, these rates were remarkably lower than previously reported. Despite harboring various degrees of immune suppression, patients with stable or indolent diseases not receiving active treatment appeared to be at a risk comparable to that of the age-matched general population, which depended largely on age and comorbidities. Routine preventive measures including symptom questioning, masks, and social distancing in both our inpatient and outpatient services provided a COVID-19-safe environment, obviating the need for changes in treatment schedules or assignment. These findings may have important consequences for future management of patients with HM in COVID-19 affected regions. Figure 1 Figure 1. Disclosures Lavie: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Fees for lectures; Roche: Other: Fees for lectures; Novartis: Other: Fees for lectures; Takeda: Consultancy. Goldschmidt: AbbVie: Consultancy, Research Funding.