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Summary Multiple myeloma (MM), one of the most frequent haematological malignancies, significantly increases the risk of bacterial infections due to treatment‐related side effects, comorbidities and cancer‐induced immune deficiencies. Recently, CD71+ erythroid cells (CECs) have been identified as key immunomodulators in neonates and cancer patients, but their role in MM progression remains unclear. Using a murine MM model, closely resembling human disease, we observed that MM progression is associated with anaemia and an increase in immature CECs, which are characterized by elevated arginase 2 (ARG2) expression. These MM‐associated CECs suppress T‐cell proliferation, contributing to impaired immune responses. Notably, ARG2 deficiency in mice led to slower MM progression and improved survival. Furthermore, MM‐bearing mice exhibited higher susceptibility to Listeria monocytogenes infections, mirroring the increased infection risk in MM patients. Our findings suggest that ARG2‐expressing CECs play a critical role in MM‐associated immune suppression and infection susceptibility, pointing out ARG2 as a potential therapeutic target to enhance immune function and reduce infection risks in MM patients. [ABSTRACT FROM AUTHOR]

Tubercidin, an adenosine analogue, is toxic to human neuroblastoma cell lines, to peripheral blood mononuclear cells (PBMCs), and to myeloid colony-forming cells (CFU-C) as tested by a short-term labeled precursor uptake and by a clonogenic assay. When it was co-administered with a potent purine transport inhibitor, nitrobenzyl thioinosine (NBTI), the cytotoxic effect of tubercidin was abolished in PBMCs but not in neuroblastoma cells. Studies of nucleoside transport in neuroblastoma cells demonstrate that although [3H]NBTI binds to the plasma membrane of these cells, the transport of thymidine into the cells is only partially inhibited in the presence of excess NBTI. These data imply that neuroblastoma cells contain a nucleoside transport mechanism which is insensitive to NBTI. "Host protection" with a nucleoside transport inhibitor such as NBTI, may allow effective therapy with otherwise toxic dosages of tubercidin and other cytotoxic nucleosides in patients with neuroblastoma. [ABSTRACT FROM AUTHOR]

Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized by a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate that CD20 and CD37 form a complex, and hypothesize that the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates (ADCs). Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Multiple myeloma (MM), a hematological malignancy of plasma cells, has remained incurable despite the development of novel therapies that improve patients' outcome. Recent evidence indicates that the stimulator of interferon genes (STING) pathway may represent a novel target for induction of antitumor immune response in multiple myeloma. Here, we investigated antitumor effects of STING agonist with bortezomib with or without checkpoint inhibitor in the treatment of MM., Methods: STING expression in bone marrow plasma cells of 58 MM patients was examined by immunohistochemical staining. The effectiveness of the proposed therapy was evaluated in vivo in a syngeneic transplantable mouse model of MM (Vĸ*MYC) in immunocompetent mice. Flow cytometry was used to assess tumor burden and investigate activation of immune response against MM. ELISA was performed to measure serum inflammatory cytokines concentrations upon treatment., Results: Combining a STING agonist [2'3'-cGAM(PS) 2 ] with bortezomib significantly decreased tumor burden and improved the survival of treated mice compared to either of the compounds used alone. The combination treatment led to secretion of pro-inflammatory cytokines and increased the percentage of neutrophils, activated dendritic cells and T cells in the tumor microenvironment. However, it resulted also in increased expression of PD-L1 on the surface of the immune cells. Addition of anti-PD1 antibody further potentiated the therapeutic effects., Conclusions: Our findings indicate high antimyeloma efficacy of the three-drug regimen comprising bortezomib, STING agonist, and a checkpoint inhibitor., (© 2022. The Author(s).)

Introduction: Venetoclax combined with azacitidine (AZA-VEN) constitutes an option for the treatment of acute myeloid leukemia. There are, however, no data on the COVID-19 incidence and outcome in patients treated with AZA-VEN., Methods: Patients with acute leukemia treated with AZA-VEN at a single institution were included in this prospective observational study., Results: Thirteen patients were enrolled, 46% with treatment-naïve, and 56% with relapsed/refractory disease. Fifty-four percent of patients were males; the median age was 69 years. Six patients (46%) developed COVID-19 during the observation time. The median time to COVID-19 was 24 days from the initiation of AZA-VEN. The 2-month cumulative incidence of COVID-19 was 46.2%. Two patients (33%) succumbed to COVID-19. The 100-day COVID-19-free survival from AZA-VEN initiation was 61%. The median follow-up time was 4.3 months., Discussion/conclusion: COVID-19 constitutes a frequent complication of AZA-VEN treatment in the era of the COVID-19 pandemic, leading to death in a significant proportion of patients., (© 2022 S. Karger AG, Basel.)

Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine levels. In MM-bearing mice antigen-induced proliferation of adoptively transferred T-cells was strongly suppressed and T-cell proliferation was restored by pharmacological arginase inhibition. Progression of Vκ*MYC tumors was significantly delayed in mice with myeloid-specific ARG1 deletion. Arginase inhibition effectively inhibited tumor progression although it failed to augment anti-myeloma effects of bortezomib. However, arginase inhibitor completely prevented development of bortezomib-induced cardiotoxicity in mice. Altogether, these findings indicate that arginase inhibitors could be further tested as a complementary strategy in multiple myeloma to mitigate adverse cardiac events without compromising antitumor efficacy of proteasome inhibitors., (© 2022. The Author(s).)

Multiple myeloma (MM) is the second most common hematological malignancy with a recurrent clinical course. The introduction of immunomodulatory drugs (IMiDs) was one of the milestones in MM therapy leading to a significant improvement in patients' prognosis. Currently, IMiDs are the backbone of MM therapy in newly diagnosed and relapsed/refractory settings. It is now known that IMiDs exert their anti-myeloma activity mainly by binding cereblon (CRBN), the substrate receptor protein of the CRL4 E3 ubiquitin ligase (CRL4 CRBN ) complex. By binding CRBN, IMiDs alter its substrate specificity, leading to ubiquitination and proteasomal degradation of proteins essential for MM cell survival. Following the success of IMiDs, it is not surprising that the possibility of using the CRL4 CRBN complex's activity to treat MM is being further explored. In this review, we summarize the current state of knowledge about novel players in the MM therapeutic landscape, namely the CRBN E3 ligase modulators (CELMoDs), the next generation of IMiDs with broader biological activity. In addition, we discuss a new strategy of tailored proteolysis called proteolysis targeting chimeras (PROTACs) using the CRL4 CRBN to degrade typically undruggable proteins, which may have relevance for the treatment of MM and other malignancies in the future.

Bing-Neel syndrome (BNS) is a rare presentation of Waldenström macroglobulinemia (WM). BNS is a consequence of the central nervous system (CNS) involvement by lymphoplasmacytic lymphoma (LPL) and, rarely, the peripheral nervous system. The data on BNS are extremely scarce. Therefore, we performed a multicenter retrospective analysis of BNS patients diagnosed and treated in centers aligned with the Polish Lymphoma Research Group. The analysis covers the years 2014-2021. Eleven patients were included, 55% females and the median age at BNS diagnosis was 61 years. The median time from WM to BNS was 3.5 years; 27% of patients did have a diagnosis of WM and BNS made simultaneously or within 30 days from each other. Isolated parenchymal involvement was the least frequent (20%). Patients were treated with different regimens, mostly able to cross the blood-brain barrier, including 18% treated with ibrutinib first line. The cumulative objective response to treatment was 73%. With the median follow-up of 20 months (95% CI, 2-32), the 36-month estimates were: overall survival (OS) 47%, progression-free survival (PFS) 33%, and cumulative incidence of BNS-associated death 41%. The performance status according to ECOG was significant for PFS (HR = 7.79) and the hemoglobin concentration below 11 g/dL was correlated with PFS. To conclude, BNS is a very rare manifestation of WM. It is associated with a poor outcome with most patients succumbing to BNS.

Clonal evolution drives treatment failure in multiple myeloma (MM). Here, we used a custom 372-gene panel to track genetic changes occurring during MM progression at different stages of the disease. A tumor-only targeted next-generation DNA sequencing was performed on 69 samples sequentially collected from 30 MM patients. The MAPK/ERK pathway was mostly affected with KRAS mutated in 47% of patients. Acquisition and loss of mutations were observed in 63% and 37% of patients, respectively. Four different patterns of mutation evolution were found: branching-, mutation acquisition-, mutation loss- and a stable mutational pathway. Better response to anti-myeloma therapy was more frequently observed in patients who followed the mutation loss-compared to the mutation acquisition pathway. More than two-thirds of patients had druggable genes mutated (including cases of heavily pre-treated disease). Only 7% of patients had a stable copy number variants profile. Consequently, a redistribution in stages according to R-ISS between the first and paired samples (R-ISS″) was seen. The higher the R-ISS″, the higher the risk of MM progression and death. We provided new insights into the genetics of MM evolution, especially in heavily pre-treated patients. Additionally, we confirmed that redefining R-ISS at MM relapse is of high clinical value.

Regulatory T cells (Tregs) are capable of inhibiting the proliferation, activation and function of T cells and play an important role in impeding the immune response to cancer. In chronic lymphocytic leukemia (CLL) a dysfunctional immune response and elevated percentage of effector-like phenotype Tregs have been described. In this study, using the Eµ-TCL1 mouse model of CLL, we evaluated the changes in the Tregs phenotype and their expansion at different stages of leukemia progression. Importantly, we show that Tregs depletion in DEREG mice triggered the expansion of new anti-leukemic cytotoxic T cell clones leading to leukemia eradication. In TCL1 leukemia-bearing mice we identified and characterized a specific Tregs subpopulation, the phenotype of which suggests its role in the formation of an immunosuppressive microenvironment, supportive for leukemia survival and proliferation. This observation was also confirmed by the gene expression profile analysis of these TCL1-specific Tregs. The obtained data on Tregs are consistent with those described so far, however, above all show that the changes in the Tregs phenotype described in CLL result from the formation of a specific, described in this study Tregs subpopulation. In addition, functional tests revealed the ability of Tregs to inhibit T cells that recognize model antigens expressed by leukemic cells. Moreover, inhibition of Tregs with a MALT1 inhibitor provided a therapeutic benefit, both as monotherapy and also when combined with an immune checkpoint inhibitor. Altogether, activation of Tregs appears to be crucial for CLL progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Goral, Firczuk, Fidyt, Sledz, Simoncello, Siudakowska, Pagano, Moussay, Paggetti, Nowakowska, Gobessi, Barankiewicz, Salomon-Perzynski, Benvenuti, Efremov, Juszczynski, Lech-Maranda and Muchowicz.)

The family of PIM serine/threonine kinases includes three highly conserved oncogenes, PIM1, PIM2, and PIM3 , which regulate multiple prosurvival pathways and cooperate with other oncogenes such as MYC . Recent genomic CRISPR-Cas9 screens further highlighted oncogenic functions of PIMs in diffuse large B-cell lymphoma (DLBCL) cells, justifying the development of small-molecule PIM inhibitors and therapeutic targeting of PIM kinases in lymphomas. However, detailed consequences of PIM inhibition in DLBCL remain undefined. Using chemical and genetic PIM blockade, we comprehensively characterized PIM kinase-associated prosurvival functions in DLBCL and the mechanisms of PIM inhibition-induced toxicity. Treatment of DLBCL cells with SEL24/MEN1703, a pan-PIM inhibitor in clinical development, decreased BAD phosphorylation and cap-dependent protein translation, reduced MCL1 expression, and induced apoptosis. PIM kinases were tightly coexpressed with MYC in diagnostic DLBCL biopsies, and PIM inhibition in cell lines and patient-derived primary lymphoma cells decreased MYC levels as well as expression of multiple MYC-dependent genes, including PLK1 . Chemical and genetic PIM inhibition upregulated surface CD20 levels in an MYC-dependent fashion. Consistently, MEN1703 and other clinically available pan-PIM inhibitors synergized with the anti-CD20 monoclonal antibody rituximab in vitro , increasing complement-dependent cytotoxicity and antibody-mediated phagocytosis. Combined treatment with PIM inhibitor and rituximab suppressed tumor growth in lymphoma xenografts more efficiently than either drug alone. Taken together, these results show that targeting PIM in DLBCL exhibits pleiotropic effects that combine direct cytotoxicity with potentiated susceptibility to anti-CD20 antibodies, justifying further clinical development of such combinatorial strategies. SIGNIFICANCE: These findings demonstrate that inhibition of PIM induces DLBCL cell death via MYC-dependent and -independent mechanisms and enhances the therapeutic response to anti-CD20 antibodies by increasing CD20 expression., (©2021 American Association for Cancer Research.)

Acute myeloid leukemia (AML) in older unfit patients is a therapeutic challenge for clinical hematologists. We evaluated the efficacy and safety of a novel low-intensity regimen consisting of low-dose cytarabine and cladribine (LD-AC+cladribine) in first-line treatment of elderly (≥60 years) AML patients not eligible for intensive chemotherapy (IC) who had either the Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 or the hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥3. The induction phase included two cycles of LD-AC+cladribine. Patients who achieved at least partial remission (PR) received maintenance treatment with LD-AC alone. Overall, 117 patients with a median age of 70 years were enrolled. Adverse cytogenetics, ECOG PS ≥2 and HCT-CI score ≥3 was observed in 43.5%, 60%, and 58% of patients, respectively. The response rate (≥PR) was 54% (complete remission [CR], 32%; CR with incomplete hematologic recovery [CRi], 5%). A median overall survival (OS) was 21 and 8.8 months in CR/CRi and PR group, respectively. Advanced age (≥75 years) and adverse cytogenetics had a negative impact on OS. The 56-day mortality rate was 20.5%. In conclusion, LD-AC+cladribine is a beneficial therapeutic option with a predictable safety profile in elderly AML patients not eligible for IC.

Immunomodulatory drugs (IMiDs) are effective in the treatment of multiple myeloma (MM), myelodysplastic syndrome with deletion of chromosome 5q and other haematological malignancies. Recent studies showed that IMiDs bind to cereblon (CRBN), a substrate receptor of the CRL4-CRBN complex, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in MM cells, contributing to their anti-myeloma activity. We aimed to determine whether the CRL4-CRBN complex proteins' expression predicts the prognosis of MM patients treated with IMiDs. Here, we evaluated the expression of CRL4-CRBN complex proteins and their downstream targets with immunohistochemistry (IHC) staining in 130 bone marrow samples from MM patients treated with thalidomide or lenalidomide-based regimens. We found that the expression of CRBN and CUL4A was associated with the superior IMiD-based treatment response ( p = 0.007 and p = 0.007, respectively). Moreover, the CUL4A expression was associated with improved PFS (HR = 0.66, 95% CI 0.44-0.99; p = 0.046) and DDB1 expression showed a negative impact on OS both in the univariate (HR = 2.75, 95% CI 1.65-4.61; p = 0.001) and the multivariate (HR 3.67; 95% CI 1.79-7.49; p < 0.001) analysis. Overall, our data suggest that the expression of DDB1, CUL4A and CRBN assessed by IHC predicts the clinical course of MM patients and identifies patients with a high probability of responding to IMiD-based therapy.