Special considerations in the management of adult patients with acute leukaemias and myeloid neoplasms in the COVID-19 era: recommendations from a panel of international experts

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts

The antigen recognition and the signal transduction components of the B cell antigen receptor are differentially localized following BCR aggregation

In order for humoral immune responses to develop, B cells must be able to bind and internalize antigens. These functions are performed by the B cell antigen receptor (BCR), which is also responsible for initiating and transducing activation signals necessary for B cell proliferation and differentiation. The BCR consists of a surface immunoglobulin (sIg) antigen-binding component and the Igα/Igβ heterodimer, which functions as the signal transduction complex. The association of sIg with the Igα/Igβ heterodimer is believed to be necessary for trafficking the BCR to the plasma membrane. Studies done in the early 1990s examined the requirements for trafficking of the BCR to the membrane, however they did not address what happens to the associated BCR components upon cell surface expression and antigen interaction. I have examined surface expression patterns of individual components of the BCR following anti-Ig and antigen-induced aggregation. Specifically, the localization and expression levels of sIg and the Igβ component of the Igα/Igβ signaling unit were investigated in order to determine their individual participation in the internalization and signal transduction. Using primary murine B cells, I found that while more than 95% of the sIg is internalized following anti-Ig induced aggregation, 20-30% of Igβ remains on the surface. This behavior is not specific to mature B cells, as it also takes place with the transitional immature B cells as well as cell lines. Using pharmacological inhibitors of endosomal trafficking I was able to conclude that new surface Igβ expression make only a small contribution to the overall levels of surface Igβ expressed. I also demonstrated that MHC class II molecules are not required for the Ig-independent cell surface expression of Igβ despite previous evidence suggesting an interaction between Igα/Igβ heterodimer and MHC class II. These results indicate that sIg and Igβ may function independently following the initial stages of signal transduction

The antigen recognition and the signal transduction components of the B cell antigen receptor are differentially localized following BCR aggregation

In order for humoral immune responses to develop, B cells must be able to bind and internalize antigens. These functions are performed by the B cell antigen receptor (BCR), which is also responsible for initiating and transducing activation signals necessary for B cell proliferation and differentiation. The BCR consists of a surface immunoglobulin (sIg) antigen-binding component and the Igα/Igβ heterodimer, which functions as the signal transduction complex. The association of sIg with the Igα/Igβ heterodimer is believed to be necessary for trafficking the BCR to the plasma membrane. Studies done in the early 1990s examined the requirements for trafficking of the BCR to the membrane, however they did not address what happens to the associated BCR components upon cell surface expression and antigen interaction. I have examined surface expression patterns of individual components of the BCR following anti-Ig and antigen-induced aggregation. Specifically, the localization and expression levels of sIg and the Igβ component of the Igα/Igβ signaling unit were investigated in order to determine their individual participation in the internalization and signal transduction. Using primary murine B cells, I found that while more than 95% of the sIg is internalized following anti-Ig induced aggregation, 20-30% of Igβ remains on the surface. This behavior is not specific to mature B cells, as it also takes place with the transitional immature B cells as well as cell lines. Using pharmacological inhibitors of endosomal trafficking I was able to conclude that new surface Igβ expression make only a small contribution to the overall levels of surface Igβ expressed. I also demonstrated that MHC class II molecules are not required for the Ig-independent cell surface expression of Igβ despite previous evidence suggesting an interaction between Igα/Igβ heterodimer and MHC class II. These results indicate that sIg and Igβ may function independently following the initial stages of signal transduction

Abstract 5517: Pegaspargase is a viable option in elderly adults with acute lymphoblastic leukemia

Abstract Pegaspargase (peg-asp) is a pegylated form of asparaginase with a longer half-life used in pediatric-inspired chemotherapy for treatment of adult acute lymphocytic leukemia (ALL). Peg-asp appears to confer a survival advantage, but use in older adults is limited by concern for toxicity, though incidence and associated factors are poorly characterized. Our primary objective was to compare peg-asp tolerability in different age groups; secondary objectives were assessment of patient- (pt) and disease-dependent factors associated with toxicity. We retrospectively reviewed 58 ALL pts treated with at least 1 dose of peg-asp (500-2500IU/m2) at our institution between 2016-2021. We used χ-squared- and Fisher’s test, and multivariable regression analysis to assess relationships between pt-factors and toxicities. Median doses received was 2 (range 1-7). 38 pts were 40 years or older, 20 were >60 years. 18 received PEG during induction only, 8 in consolidation only, 27 in both, and 5 during salvage therapy post-relapse. 17 had Philadelphia (Ph) positive B-ALL; 32 Ph negative B-ALL; 7 T-ALL; and 2 had mixed phenotype acute leukemia. Pts were 19-78 years old (median 48.5). Grade 3 or 4 toxicities observed in >10% of cases included hepatotoxicity (81%, 47/58); antithrombin 3 depletion (72.4%, 42/58); hypofibrinogenemia 60 years; p=0.025), likely due to older age strongly correlating (p 30 (OR 1.31, CI 1.05-1.62, and OR 1.31, CI 1.09-1.59, respectively). In summary, low dose pegaspargase is a viable option in ALL in adults over 60, with only hypertriglyceridemia associated with older age. Future work might correlate serum pegaspargase activity to intolerance and outcomes, and examine whether prophylactic treatment e.g. with levocarnitine might prevent toxicity. Citation Format: Yosef Joseph Rene Amel Riazat-Kesh, Hannah Levavi, Sangeetha Venugopal, Carli Beall, Ronald Hoffman, Marina Kremyanskaya, John Mascarenhas, Sara Kim, Michal Bar-Natan. Pegaspargase is a viable option in elderly adults with acute lymphoblastic leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5517