Report of consensus panel 5 from the 11th international workshop on Waldenstrom's macroglobulinemia on COVID-19 prophylaxis and management.

Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11; held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2; thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for preexposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Coadministration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza, and S. pneumoniae.

Report of Consensus Panel 5 from the 11th International Workshop on Waldenstrom's Macroglobulinemia on COVID-19 Prophylaxis and Management

Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11;held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2;thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for pre-exposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Co-administration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza and S. pneumoniae.

SEROLOGIC RESPONSE TO THE SECOND AND THIRD DOSE OF THE SARS-COV-2 VACCINE IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: RESULTS OF A PROSPECTIVE, CENTRALIZED, MULTICENTER STUDY

Background: Patients with chronic lymphocytic leukemia (CLL) show high infection-related morbidity and mortality due to variable degree of humoral and cellular immune deficiency. High Covid-related mortality and reduced response to the SARS-Cov-2 vaccine have been reported in this patient population. Aims: We carried out a prospective multicenter study to define the rate of CLL patients with an appropriate immune response after the mRNA SARS-CoV2 vaccine (Pfizer-BioNTech;Moderna). Methods: Two-hundred patients with CLL received the first dose of the SARS-CoV-2 vaccine between February and August 2021. Centralized assessment of the anti-SARS-Cov-2 IgG levels (Sero Index, Kantaro Quantitative SARS-CoV-2 IgG Antibody, RUO-R&D System) was performed at the Istituto Superiore di Sanità of Rome, Italy. The median followup of this study is 10.7 months (range 1-12.9). Results: The median age of patients was 70 years, the median IgG level was 635 mg/dl, 61% of patients were IGHV unmutated, and 34% showed TP53 disruption. The majority of patients, 83.5%, were previously treated. Prior treatment included chemoimmunotherapy in 20 (10%) patients, ibrutinib-based therapy in 72 (36%;front-line, 21%;advanced line, 15%), venetoclax-based therapy in 75 (37.5%;front-line, 13.5%;advanced line, 24%). Overall, 135 (77.5%) patients had been previously treated with rituximab, 33 (16.5%) of them within 12 months before vaccination. We assessed the serologic response after the second dose of the SARS-CoV2 vaccine in 195 patients while five were excluded from the analysis (positive test before vaccination, 3 patients;lost to the follow-up, 1;Richter syndrome, 1). Adequate levels of anti-SARS-Cov-2 IgG were detected in 76/195 (39%) patients. Age (<70 vs.≥ 70 years;p <0.0001), CIRS value (<6 vs. ≥6;p=0.005), beta-2 microglobulin (<3.5 vs. ≥ 3.5mg/dl;p=0.04), IgG levels (<550 vs. ≤ 550 mg/dl;p <0.0001), prior treatment (p=0.0001), number of prior treatments (0+1 vs. ≥ 2;p=0.002) and the time between prior rituximab and vaccination (>12 vs. ≤12 month;p=0.001) showed a significant impact on the humoral response. In multivariate analysis only age (OR: 0.92 [95% CI: 0.92-0.97] p=0.0001), IgG levels (OR: 0.28 [95% CI: 0.13-0.58] p<0.001), and the time between prior rituximab and vaccination (OR: 0.10 [95% CI: 0.03-0.37] p=0.001), revealed a significant and independent impact on response. When the analysis was restricted to patients who received targeted therapy, in addition to the younger age (OR: 0.96 [95% CI: 0.92-0.99] p=0.04), higher IgG levels at baseline (OR: 0.31 [95% CI: 0.12-0.79] p=0.014), longer time between the start of ibrutinib or venetoclax-based therapy and vaccination (<18 vs.≥18 months;OR: 0.17 [95% CI: 0.06-0.44], p <0.0001) showed a favorable and independent impact on response. Ninety-three% (182/195) of patients received a third dose of the vaccine. A significant increase in the rate of serologic responses, 51.5% (85/165 evaluated patients, p=0.019), was observed after the booster dose. Moreover, a response was detected in 25% (26/103 evaluated patients) of previously seronegative patients. Summary/Conclusion: In this prospective, multicenter, centralized study, we recorded an effective immune response to the SARS-CoV-2 vaccine in about a third of patients with CLL. Younger age, higher IgG levels, no prior treatment, or stable disease after targeted therapy that suggest preserved immunocompetence were associated with a greater likelihood of achieving an effective immune response. A booster dose of the SARS-CoV-2 vaccine proved beneficial also in previously seronegative patients.

COVID-19 PANDEMIC IMPACT ON CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS' PREFERENCES TOWARDS THERAPIES: THE ITALIAN EXPERIENCE (CHOICE STUDY)

Introduction: The CHOICE study was primarily designed to capture CLL patients' (pts) preferences towards different treatment attributes through a Discrete Choice Experiment (DCE) in Italy. This study was carried out in the period Feb-Jul 2020, during the 1st wave of COVID19 pandemic, and provides an insight of the pts' perception. about treatments available in CLL (1-2). Methods: This cross-sectional multicenter observational study enrolled, WATCH&WAIT (W&W) or TREATED CLL pts (~50% each, controlled at site level). Exclusion criteria were inability to take oral drugs, cognitive disorders that could impair questionnaire's comprehension and concomitant therapy for other malignancies. Pts were asked to fill in aDCE Questionnaire, composed of 9/10 blocks (for W&W/TREATED respectively) each composed of 8 comparisons between 2 profiles with the following attributes: treatment and relevant duration, PFS, risk of infection, risk of organ damage, risk of diarrhea (levels specified in Figure 1). Each pt was centrally assigned to 1 block of 8 comparisons. Pts could ask questionnaire explanations to the medical staff, but they were asked to self-complete it. Results: 401 pts from16 centers were enrolled in the study,199 W&W and 198 TREATED pts completed the questionnaire and were considered evaluable. Main pts' characteristics are shown in Table 1. Of the 198 TREATED pts, 73.7% were ON-treatment (30.8% 1st-line, 69.2% further lines) while 26.3% were OFF-treatment. W&W pts rated as the most attribute of treatment important the 'Possibility of infections' (relative importance, RI=36.2%), followed by 'Treatment and Relevant duration' (RI=28.0%) and 'PFS' (RI=16.9%). (Figure1A). When stratifying pts by geography, W&W pts from the North regions (more impacted during the 1st wave) rated as most important the 'Treatment and Relevant duration' (RI=40.3%) followed by the 'Possibility of infection' (RI=27.2%). Pts from the Center-South regions rated as most important the 'Possibility of infection' (RI=43.4%) followed by the 'Possible occurrence of Organ damage' (RI=21.6%). TREATED pts gave more importance to the 'Treatment and relevant duration' (RI =33.3%) followed by the 'Possibility of infections' (RI =28.8%) (Figure1B) with no difference between patients from the north and center-south areas. Conclusions: Unlike other DCE studies available in the current literature (1-2), the results of the CHOICE study may have been influenced by the pandemic. While the essential attribute in pre-pandemic DCE studies was the PFS, the most important attribute in DCE studies conducted during the first pandemic wave was represented by the infection concerns. Hospital access constraints, the necessity for personal protective equipment, and social distance may have influenced patient responses. (Table Presented).

COVID-19 Pandemic Impact on Chronic Lymphocytic Leukemia (CLL) Patients' Preferences Towards Therapies: The Italian Experience (CHOICE Study)

Introduction: All the available CLL therapies differ for relevant aspects as duration of response, mode of administration, treatment duration and adverse events: the CHOICE study was designed to investigate CLL patients' Quality of Life (QoL) and preferences towards different treatment attributes through a Discrete Choice Experiment (DCE) in Italy. Due to the timeline of the study, started in Feb2020, the collected data offer an insight of patients' perception and attitude during the 1 st wave of the COVID-19 pandemic, as opposed to other DCE results available in CLL (1-2). Methods: This cross-sectional multi-center observational study enrolled patients (pts) with CLL, WATCH&WAIT (W&W) or already TREATED (around 50% each, controlled at site level), who signed the informed consent for study participation. Exclusion criteria were inability to take oral drugs, cognitive disorders that could impair questionnaire's comprehension and concomitant therapy for other malignancies. Pts were asked to fill in 3 QoL questionnaires: EQ-5D-5L, EORTC QLQ-C30, QLQ CLL-16, described elsewhere. DCE Questionnaire was composed of 9/10 blocks (for W&W/TREATED, respectively) each composed of 8 comparisons between 2 profiles with the following attributes: “Treatment and relevant duration”, “PFS”, “Possibility of infections”, “Possible occurrence of organ damage”, “Possible occurrence of diarrhea”, with levels specified in Fig1. Each patient (pt) was centrally assigned to 1 block of 8 comparisons. Each pt could ask questionnaire explanations to the medical staff but self-completed it on an App specifically developed for the study. Results: 401 pts were enrolled in Italy across 16 centers (Feb-Jul 2020),199 W&W and 198 TREATED pts completed the DCE questionnaire and were included in the evaluable population. Main pts' characteristics are shown in Table 1. 73.7% of TREATED pts were ON-treatment (30.8% in 1st-line, 69.2% in further lines) and 26.3% were OFF-treatment. DCE results showed that W&W pts rated as most important the ‘Possibility of infections’ (relative importance, RI=36.2%), followed by ‘Treatment and Relevant duration’ (RI=28.0%), ‘PFS’ (RI=16.9%), while ‘Possible occurrence of organ damage’ (RI=12.5%) and ‘Possible occurrence of Diarrhea’ (RI=6.4%) had lower impact on the preference (Fig 1A). DCE in TREATED pts showed that they gave more importance to ‘Treatment and relevant duration’ (RI =33.3%) followed by ‘Possibility of infections’ (RI =28.8%). The RI of the other attributes was lower: ‘Possible occurrence of organ damage’ (RI =19.4%), ‘PFS’ (RI =9.8%), ‘Possible occurrence of diarrhea’ (RI =8.7%, Fig 1B). A sub-analysis stratifying pts from Northern regions (more impacted during the 1 st wave of the pandemic) and Center-Southern regions showed that in W&W pts from North Regions the attribute with a higher impact is ‘Treatment and Relevant duration’ (RI=40.3%) followed by ‘Possibility of infection’ (RI=27.2%), while in W&W pts from Central-Southern area, the attribute with a higher impact is ‘Possibility of infection’ (RI=43.4%) followed by ‘Possible occurrence of Organ damage’ (RI=21.6%). In TREATED pts no difference between the 2 groups has been shown and the results are consistent with the total population. Conclusions: CHOICE study was planned to understand CLL patients' preferences towards different treatment attributes, but the results have been impacted by the concurrent COVID-19 pandemic. In contrast to previously published DCEs (1-2), where PFS was the most important attribute, in the CHOICE study pts put much more emphasis on their concerns about possible infections: this could be due to the influence of the 1 st Covid-19 pandemic wave, with the relevant feeling of uncertainty, also due to the great attention that media has dedicated to the issue of infection in general, especially for vulnerable individuals such as CLL pts. The limitation in hospital access during the 1 st wave and the overall need of personal protection (masks usage) and s cial distancing might have influenced patients' responses too. The “infodemic” and the uncertainty had probably such a strong effect on patient's feelings, that PFS was no longer the most important attribute being substituted by the fear of hospitals access and infections. We thereby suggest that the pandemic had a great impact not only on the conduct of the study but also on patients' perception of their disease, if not properly reassured. [Formula presented] Disclosures: Molica: Astrazeneca: Honoraria;Abbvie: Consultancy, Honoraria;Janssen: Consultancy, Honoraria. Laurenti: AbbVie: Consultancy, Honoraria, Research Funding;Gilead: Honoraria;Roche: Honoraria, Research Funding;Janssen: Consultancy, Honoraria;AstraZeneca: Consultancy, Honoraria;BeiGene: Honoraria. Ghia: Gilead: Consultancy, Research Funding;Celgene/Juno/BMS: Consultancy, Honoraria;BeiGene: Consultancy, Honoraria;ArQule/MSD: Consultancy, Honoraria;AstraZeneca: Consultancy, Honoraria, Research Funding;Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding;AbbVie: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding;Roche: Consultancy, Honoraria;Sunesis: Research Funding. Coscia: Gilead: Honoraria;Janssen: Honoraria, Other, Research Funding;AstraZeneca: Honoraria;AbbVie: Honoraria, Other. Cuneo: AstraZeneca: Consultancy, Speakers Bureau;Janssen: Consultancy, Speakers Bureau;Gilead: Consultancy, Speakers Bureau;AbbVie: Consultancy, Speakers Bureau. Gaidano: Beigene: Honoraria;Janssen: Honoraria, Speakers Bureau;AstraZeneca: Honoraria;AbbVie: Honoraria, Speakers Bureau;Incyte: Honoraria. Mauro: Takeda: Consultancy, Speakers Bureau;Gilead: Consultancy, Research Funding, Speakers Bureau;Roche: Consultancy, Speakers Bureau;Janssen: Consultancy, Speakers Bureau;AstraZeneca: Consultancy, Speakers Bureau;AbbVie: Consultancy, Speakers Bureau. Pane: AbbVie;Amgen;Novartis: Other: Travel, accommodation, expenses;AbbVie;Amgen;Novartis, GSK, Incyte: Speakers Bureau;Novartis Pharma SAS;: Research Funding;AbbVie;Amgen;Novartis, GSK, Incyte: Consultancy. Gualberti: AbbVie: Current Employment. Iannella: AbbVie: Current Employment. Finsinger: AbbVie: Current Employment. Caira: AbbVie: Current Employment. Sportoletti: AstraZeneca: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria.