Abstract: 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.

Abstract: 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.

Abstract: Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with an excellent prognosis after treatment with cladribine (2CDA), although relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long-term remission rate, and overall survival (OS) in those patients who received 2CDA as first-line treatment. We retrospectively reviewed data of HCL patients treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers: 513 patients were evaluable for study purpose. The median age was 54 years (range 24–88) and ECOG was 0 in 84.9% of cases. A total of 330 (64.3%) patients received 2CDA intravenously and 183 (35.7%) subcutaneously. ORR was 91.8%: CR was obtained in 335 patients (65.3%), PR in 96 (18.7%), and hematological response in 40 (7.8%) patients; in 42 (8.2%) no response was observed. Hemoglobin value ( p  = 0.044), frequency of circulating hairy cells ( p  = 0.039), recovery of absolute neutrophil count ( p  = 0.006), and normalization of spleen ( p  ≤ 0.001) were associated with CR compared to PR in univariable analysis. At a median follow-up of 6.83 years (range 0.04–28.52), the median time to relapse was 12.2 years. A significant difference in duration of response was identified between patients that obtained a CR and PR (19.4 years versus 4.8 years, p   〈  0.0001). Non-hematological grade 3 or higher early toxicity was reported in 103 (20.1%) patients. Median OS was not reached: 95.3%, 92.4%, and 81.8% of patients were estimated to be alive at 5, 10, and 15 years, respectively. Forty-nine patients died (9.5%), following an infection in 14 cases (2.7%), natural causes in 14 (2.7%), cardiovascular events in 13 (2.5%), a second neoplasm in 6 (1.2%), and progression of HCL in 2 cases (0.4%). Following treatment of HCL with 2CDA, 80% of patients are estimated to be alive 15 years after diagnosis.

Abstract: Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with specific morphologic and molecular features and excellent prognosis. Although high rate of complete response (CR) has been reported after treatment with purine analogs, expecially cladribine (2CDA), relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long term remission rate and overall survival (OS) in those patients (pts) that received 2CDA as first line treatment. We retrospectively reviewed data of all HCL pts treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers. Among 553 pts reported, only 513 were evaluable because treated with 2CDA alone. Considering the clinical carachteristics, M/F ratio was 4.5 with a median age of 54 years (range 24-88) and ECOG 0 in 85% of cases. Splenomegaly and presence of circulating hairy cells recorded by morphology were reported in 241 (47%) and 138 (27%) pts, respectively. Thirty-seven (7%) pts presented with an infection. Other comorbidities were cardiovascular in 29 (6%) pts, a previous cancer or diabetes in 27 (5%) each, chronic hepatic disorders in 18 (3%), obstructive pulmonary disease in 16 (3%), chronic kidney disease in 3 (1%). Three hundred-thirty (64%) pts received 2CDA intravenously (253 as daily continuous infusion for 5-7 consecutive days and 77 as weekly infusion for 5-7 consecutive weeks) and 183 (36%) subcutaneously. Response criteria were defined as per recent consensus guidelines (Grever MR et al. Blood 2017). The overall response rate (ORR) was 83%: CR in 335 pts (65%) and partial response (PR) in 96 (19%); 40 (8%) pts obtained hematological improvement (HI) and in 42 (8%) no response was observed. Nine of 11 (82%) pts with HI and 18/25 (72%) non responders who received salvage therapy obtained a major response (fig. 1). A slightly higher hemoglobin value (12.4 vs 11.4 g/dl, p=0.044), a reduced frequency of circulating hairy cells (28.7% vs 31.8%, p=0.039), absence of palpable splenomegaly (p= & lt;0.001) and a faster recovery of ANC (28 days vs 41 days, p= 0.006) were associated with CR compared to PR in univariable analysis. No differences in terms of quality and duration of response, infection rate and time to blood counts recovery were reported according to the 2 routes of administration. Among pts receiving intravenous 2CDA, ORR was 85% for continuous infusion and 78% for weekly infusion: no statistically significant difference could be observed. Median duration of response was 12.2 years: 75.1%, 53.6% and 45.5% of responding pts are expected to be free from relapse at 5, 10 and 15 years, respectively. A statistically significant difference in duration of response was identified between pts that obtained a CR compared to pts in PR (19.4 years versus 4.7 years, p & lt;0.0001) (fig. 2). No other differences in relapse free survival (RFS) were identified. Non-hematological grade-3 or higher early toxicity was reported in 108 (21%) pts, due to infections in 102 cases (20%), mainly fever of unknown origin and pneumonia. In 6 cases infection due to invasive aspergillosis, bacteric pneumonia and bacteric sepsis caused the death of pts. Other non-hematological adverse events were almost all grade-1 allergy (47 pts, 9%). No late toxicity was reported, but 19 (4%) second cancers were observed. Among 118 pts relapsed after a median of 4.4 years (fig. 1), 85 (72%) were retreated with 2CDA, alone (65 cases) or associated with rituximab (20 cases); 11 (9%) with pentostatin, alone (7 cases) or associated with rituximab (4 cases), 8 (7%) with interferon α, 8 (7%) with rituximab alone, 1 (1%) with vemurafenib and zanubrutinib each; 2 were lost at follow-up and 2 died before retreatment. Overall, 58 (51%) retreated pts obtained a CR (42 after 2CDA), 37 (32%) a PR (32 after 2CDA), 7 (6%) a HI (4 after 2CDA) and 12 (11%) did not show any response (6 after 2CDA). Median OS was not reached; 95.7%, 92.8% and 82.3% of pts are expected to be alive at 5, 10 and 15 years, respectively (fig. 2). Overall 51 pts died (10%), during the induction phase in 6 cases and during follow-up in 45: overall, mortality was HCL-related in 14 patients (2 progression of disease and 12 infections) and HCL-unrelated in 37 patients (cardiovascular events in 16, natural causes in 15, a second cancer in 6). 2CDA is greatly effective in treating HCL, with an ORR of 83%. Early and long term adverse events were rare and easily managed: although HCL-related mortality is still possible, OS at 15 years is higher than 80% Disclosures Motta: Roche: Honoraria; Janssen: Honoraria. Offidani:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Tedeschi:Abbvie: Honoraria, Speakers Bureau; Sunesis: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Varettoni:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Visentin:Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Falini:Roche: Research Funding. Pulsoni:Sandoz: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Gilead: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; roche: Consultancy, Speakers Bureau; Merk: Consultancy. Tiacci:Roche: Research Funding; Abbvie: Other: Travel and meeting expenses. Zinzani:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract: We have shown previously that the chemokine receptors CXCR3 and CXCR6 are coexpressed by Th1 cells infiltrating the lung and the granuloma of patients with sarcoidosis. In this study, we evaluated the role of CCL20/CCR6 interaction in the pathogenesis of acute and chronic pulmonary sarcoidosis. By flow cytometry and molecular analyses, we have demonstrated that Th1 cells isolated from the bronchoalveolar lavage (BAL) of patients with sarcoidosis and T cell alveolitis are equipped with CCR6. Furthermore, CCR6+ T cells coexpressed the chemokine receptors CXCR3 and CXCR6. Immunohistochemical analysis of lung specimens has shown that CCR6+ T cells infiltrate lung interstitium and surround the central core of the granuloma. It is interesting that CCR6 was never detected on the alveolar macrophage (AM) surface, and it is observed in the cytoplasm of AMs from patients with sarcoidosis and alveolitis. The CCR6 ligand CCL20 was expressed by macrophages, multinucleated giant cells, and epithelioid cells infiltrating the granuloma. Furthermore, detectable levels of CCL20 protein are seen in the BAL fluid components of patients with active sarcoidosis, and sarcoid AMs release the CCR6 ligand in vitro. From a functional point of view, sarcoid Th1 cells were able to respond to CXCL10, CXCL16, and CCL20 in migratory assays. In vitro kinetic studies demonstrated that CCR6 is induced rapidly by IL-2, IL-18, and IFN-γ. In conclusion, T cells expressing CCR6, CXCR3, and CXCR6 act coordinately with respective ligands and Th1 inflammatory cytokines in the alveolitic/granuloma phases of the disease.

Abstract: 7519 Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of 1L I+V in CLL. The primary analysis (PA) evaluating FD tx with I+V was previously presented (Ghia et al., ASCO 2021). Here we present 3-y follow-up results from the FD cohort. Methods: Patients (pts) aged ≤70 y with previously untreated CLL/SLL received 3 cycles of I then 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). Responses were investigator assessed per iwCLL 2008 criteria. Undetectable minimal residual disease (uMRD; 〈 10 -4 ) was measured by 8-color flow cytometry. Serious AEs (SAEs) deemed related to I reported 〉 30 d after last dose of study drug were collected. Results: 159 pts were enrolled (median age 60 y), including pts with high-risk features of del(17p)/ TP53 mutation (17%), unmutated IGHV (uIGHV; 56%), and complex karyotype (19%). 147 (92%) and 149 (94%) pts completed tx with I and V, respectively. With 1 y of additional follow-up since PA, median time on study was 39 mo (range 1-41). ORR was 96% and was consistent (96%-97%) in pts with high-risk features (Table).The primary endpoint of complete response (CR) including CR with incomplete bone marrow recovery (CRi) rate in pts without del(17p) (n=136) increased nominally from 56% (95% CI, 48-64) to 58% (95% CI 50-66); in all pts, CR rate increased from 55% (95% CI 48-63) to 57% (95% CI 50-65). In pts achieving CR, 93% had durable responses lasting ≥12 mo post-tx. Of pts with uMRD in peripheral blood at 3 mo post-tx, 66/85 (78%) evaluable pts maintained uMRD through 12-mo post-tx. At 36 mo, PFS was 88% (95% CI 82‒92) and OS was 98% (95% CI 94‒99); similar rates were seen in pts with high-risk features (Table). All pts are off tx; no new SAEs of any kind have occurred since the PA. Available data on relevant mutations in BTK, PLCɣ2, or BCL-2 at time of PD will be presented. As of January 2022, 12 pts were retreated with single-agent I after PD (tx duration range 3-29 mo); of evaluated pts, 7/9 had partial responses and 2/9 had stable disease. Conclusions: Fixed duration I+V continues to provide deep, durable responses and clinically meaningful PFS, including in pts with high-risk disease features, representing an all-oral, once-daily, chemotherapy-free FD regimen for previously untreated pts with CLL/SLL. With an additional 1 y of follow-up, no OS events or SAEs occurred. Manageable safety profile is unchanged as previously reported. To date, successful single-agent I retreatment responses are observed. Clinical trial information: NCT02910583. [Table: see text]