Purine Analogues Increase the Risk of Lethal and/or Prolonged COVID19 While Obinutuzumab Increases the Risk of Prolonged but Not Lethal Infection in Patients Treated for Lymphoid Malignancies -a Study of Krohem, the Croatian Group for Hematologic Diseases

Patients with lymphoid malignancies are at increased risk of death due to COVID19. Currently, it is not completely clear whether this is mainly due to disease biology or to anti-lymphoma treatment and whether the prognosis of infection differs in patients treated with different therapies. Anti-CD20 monoclonal antibodies increase the risk of prolonged infection. It is not known whether this risk is affected by the choice of the antibody. To study these questions, KroHem collected data on patients with lymphoid malignancies diagnosed with COVID19 between October 2020 and April 2021. Death during infection was considered as due to COVID19. Patients were considered to have prolonged disease if they were continuously or repetitively positive by PCR for more than 6 weeks. Percentage of patients with prolonged disease was calculated based on the number of patients with available data who were alive 6 weeks after beginning of infection. Treatment regimens were divided into those containing purine analogues (PA), mainly bendamustine and fludarabine, standard-dose chemotherapy without PA (e.g. CHOP, CVP, chlorambucil, etc.), high-dose chemotherapy without PA (e.g. DHAP, ICE, etc.), B-cell receptor inhibitors (iBCR) and venetoclax. We identified 314 patients, 20-88 years old (median 66), 180 male and 134 female; 75 were untreated, 61 off treatment and 178 on treatment (Table). Eleven (15%) untreated patients died; 10% had prolonged infection none of whom died. Ten (16%) off-treatment patients died; 9% had prolonged infection none of whom died. In the on-treatment group 6 (3%) are still prolonged positive, 110 (62%) recovered and 62 (35%) died; 42% had prolonged infection of whom 47% recovered and 42% died. The single allografted patient died as did both patients treated with CAR-T cells after prolonged infection. We analyzed prognostic factors for lethal and prolonged infection in the 175 conventionally treated patients. Disease type, use of anti-CD20 monoclonal antibodies, prior autologous stem-cell transplantation (ASCT) and line of treatment did not significantly affect mortality. Mortality was higher in older (p=0.0078) and those treated with PA in comparison to standard-dose chemotherapy without PA and iBCR (47% vs. 26%, p=0.012). The effect of anti-lymphoma therapy on mortality was similar in all age groups. All of the 7 patients who received neither cytotoxic agents nor iBCR (4 were on rituximab monotherapy, 2 on cyclosporine and 1 on vemurafenib) recovered, none had prolonged infection. Prolonged COVID19 was significantly more frequent in patients treated with anti-CD20 monoclonal antibodies (p=0.012), especially obinutuzumab (67% in comparison to 42% in those treated with rituximab and 21% in those treated without anti-CD20 antibodies). Treatment with PA also increased the risk of prolonged disease (69% vs. 25-45% in other groups, p=0.012). The effect of PA on prolonged infection was similar in patients treated with rituximab and obinutuzumab. Age, prior ASCT and treatment line did not significantly affect risk of prolonged infection. Our data suggest that the type of anti-lymphoma therapy is, besides age, a main determinant of prognosis of COVID19 in patients with lymphoid malignancies. Use of purine analogues, such as bendamustine and fludarabine, is related to increased risk of lethal and/or prolonged COVID19. These drugs should probably be avoided in patients with indolent NHL and CLL, diseases for whom other effective treatments are available, during the current pandemia. Anti-CD20 monoclonal antibodies seem to have a smaller effect on mortality, with obinutuzumab increasing the risk of prolonged disease, but not of death, in comparison to rituximab. Figure 1 Figure 1. Disclosures Aurer: takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Swixx/BMS: Honoraria; Teva/Pilva: Honoraria; Abbvie: Consultancy, Honoraria; sanofi genzyme: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Eusapharma: Consultancy, Honoraria. Jaksic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Mrdenovic: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Ostojic Kolonic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Lozic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Holik: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Novakovic Coha: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Bernes: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Krecak: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Moric Peric: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria. Mitrovic: Roche, Oktal-Pharma/Celtrion, Sandoz: Honoraria.

Management of autoimmune complications in patients with lymphoid cancer

Autoimmune conditions can occur at any temporary relationship with malignant lymphomas. In many instances, treatment at diagnosis is not required, but symptomatic autoimmune conditions represent an indication for treatment particularly in chronic lymphoproliferative diseases. Treatment is selected depending on the predominant condition - autoimmune disease (immunosuppression) or lymphoma (anti-lymphoma therapy). Steroids as well as anti-CD20 antibodies are effective against both and may suppress the autoimmune complication for a prolonged period. Efficacy of B-cell receptor inhibitors has provided us with novel insights into the pathophysiology of antibody-producing B-cells. Screening for underlying autoimmune conditions is part of the lymphoma work-up since other drugs like immunomodulators or checkpoint inhibitors should be avoided or used with caution. Here we discuss diagnostic challenges and treatment approaches for different situations involving lymphomas and autoimmune cytopenias.

Biomimetic nanotherapy: core–shell structured nanocomplexes based on the neutrophil membrane for targeted therapy of lymphoma

Background Non-Hodgkin’s lymphoma (NHL) is a malignant disease of lymphoid tissue. At present, chemotherapy is still the main method for the treatment of NHL. R-CHOP can significantly improve the survival rate of patients. Unfortunately, DOX is the main cytotoxic drug in R-CHOP and it can lead to adverse reactions. Therefore, it is particularly important to uncover new treatment options for NHL. Results In this study, a novel anti-tumor nanoparticle complex Nm@MSNs-DOX/SM was designed and constructed in this study. Mesoporous silica nanoparticles (MSNs) loaded with Doxorubicin (DOX) and anti-inflammatory drugs Shanzhiside methylester (SM) were used as the core of nanoparticles. Neutrophil membrane (Nm) can be coated with multiple nanonuclei as a shell. DOX combined with SM can enhance the anti-tumor effect, and induce apoptosis of lymphoma cells and inhibit the expression of inflammatory factors related to tumorigenesis depending on the regulation of Bcl-2 family-mediated mitochondrial pathways, such as TNF-α and IL-1β. Consequently, the tumor microenvironment (TME) was reshaped, and the anti-tumor effect of DOX was amplified. Besides, Nm has good biocompatibility and can enhance the EPR effect of Nm@MSNs-DOX/SM and increase the effect of active targeting tumors. Conclusions This suggests that the Nm-modified drug delivery system Nm@MSNs-DOX/SM is a promising targeted chemotherapy and anti-inflammatory therapy nanocomplex, and may be employed as a specific and efficient anti-Lymphoma therapy.

Specific Targeting of Lymphoma Cells Using Semisynthetic Anti-Idiotype Shark Antibodies

The B-cell receptor (BCR) is a key player of the adaptive immune system. It is a unique part of immunoglobulin (Ig) molecules expressed on the surface of B cells. In case of many B-cell lymphomas, the tumor cells express a tumor-specific and functionally active BCR, also known as idiotype. Utilizing the idiotype as target for lymphoma therapy has emerged to be demanding since the idiotype differs from patient to patient. Previous studies have shown that shark-derived antibody domains (vNARs) isolated from a semi-synthetic CDR3-randomized library allow for the rapid generation of anti-idiotype binders. In this study, we evaluated the potential of generating patient-specific binders against the idiotype of lymphomas. To this end, the BCRs of three different lymphoma cell lines SUP-B8, Daudi, and IM-9 were identified, the variable domains were reformatted and the resulting monoclonal antibodies produced. The SUP-B8 BCR served as antigen in fluorescence-activated cell sorting (FACS)-based screening of the yeast-displayed vNAR libraries which resulted after three rounds of screening in the enrichment of antigen-binding vNARs. Five vNARs were expressed as Fc fusion proteins and consequently analyzed for their binding to soluble antigen using biolayer interferometry (BLI) revealing binding constants in the lower single-digit nanomolar range. These variants showed specific binding to the parental SUP-B8 cell line confirming a similar folding of the recombinantly expressed proteins compared with the native cell surface-presented BCR. First initial experiments to utilize the generated vNAR-Fc variants for BCR-clustering to induce apoptosis or ADCC/ADCP did not result in a significant decrease of cell viability. Here, we report an alternative approach for a personalized B-cell lymphoma therapy based on the construction of vNAR-Fc antibody-drug conjugates to enable specific killing of malignant B cells, which may widen the therapeutic window for B-cell lymphoma therapy.