MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma.

Multiple myeloma (MM) is an incurable hematological malignancy in which MYC alterations contribute to the malignant phenotype. Nevertheless, MYC lacks therapeutic druggability. Here, we leveraged large-scale loss-of-function screens and conducted a small molecule screen to identify genes and pathways with enhanced essentiality correlated with MYC expression. We reported a specific gene dependency in glutaminase (GLS1), essential for the viability and proliferation of MYC overexpressing cells. Conversely, the analysis of isogenic models, as well as cell lines dataset (CCLE) and patient datasets, revealed GLS1 as a non-oncogenic dependency in MYC-driven cells. We functionally delineated the differential modulation of glutamine to maintain mitochondrial function and cellular biosynthesis in MYC overexpressing cells. Furthermore, we observed that pharmaceutical inhibition of NAMPT selectively affects MYC upregulated cells. We demonstrate the effectiveness of combining GLS1 and NAMPT inhibitors, suggesting that targeting glutaminolysis and NAD synthesis may be a promising strategy to target MYC-driven MM.

Genomic profiling of mycosis fungoides identifies patients at high risk of disease progression.

ABSTRACT: Mycosis fungoides (MF) is the most prevalent primary cutaneous T-cell lymphoma, with an indolent or aggressive course and poor survival. The pathogenesis of MF remains unclear, and prognostic factors in the early stages are not well established. Here, we characterized the most recurrent genomic alterations using whole-exome sequencing of 67 samples from 48 patients from Lille University Hospital (France), including 18 sequential samples drawn across stages of the malignancy. Genomic data were analyzed on the Broad Institute's Terra bioinformatics platform. We found that gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), or mutations in JUNB and TET2 are associated with high-risk disease stages. Furthermore, gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), and del6q16.3 (TNFAIP3) are coupled with shorter survival. Del6q16.3 (TNFAIP3) was a risk factor for progression in patients at low risk. By analyzing the clonal heterogeneity and the clonal evolution of the cohort, we defined different phylogenetic pathways of the disease with acquisition of JUNB, gain10p15.1 (IL2RA and IL15RA), or del12p13.1 (CDKN1B) at progression. These results establish the genomics and clonality of MF and identify potential patients at risk of progression, independent of their clinical stage.

Combining blinatumomab and donor lymphocyte infusion in B-ALL patients relapsing after allogeneic hematopoietic cell transplantation: a study of the SFGM-TC.

Relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic stem cell transplantation (allo-HCT) still represents a major concern with poor outcomes. The aim of this study is to compare the efficacy and safety of blinatumomab and donor lymphocyte infusion (DLI) versus blinatumomab alone in this setting. This is a multicenter retrospective study from centers of SFGM-TC. All transplanted patients who received blinatumomab salvage therapy were included. Patients who received DLI from 1 month before to 100 days after the starting of blinatumomab were included in the blina-DLI group. Seventy-two patients were included. Medium follow-up was 38 months. Fifty received blinatumomab alone and 22 the association blinatumomab-DLI. Two-year overall survival (OS) was 31% in the blinatumomab group and 43% in the blinatumomab-DLI group (p = 0.31). Studying DLI as a time dependent variable, PFS did not significantly differ between the 2 groups (HR:0.7, 95% CI: 0.4-1.5). In multivariate analysis, DLI was not a prognostic factor for OS, progression-free survival and progression/relapse incidence. Adverse events and graft-versus-disease rates were comparable in the 2 groups. In conclusion, adding DLI between 1 month before and 100 days after start of blinatumomab is safe and does not seem to improve outcomes in B-ALL patients who relapsed after allo-HCT.

The promising efficacy of a risk-based letermovir use strategy in CMV-positive allogeneic hematopoietic cell recipients.

Letermovir is the first approved drug for cytomegalovirus (CMV) infection prophylaxis in adult patients who are CMV positive undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Because CMV infection risk varies from patient to patient, we evaluated whether a risk-based strategy could be effective. In this single-center study, all consecutive adult patients who were CMV positive and underwent allo-HCT between 2015 and 2021 were included. During period 1 (2015-2017), letermovir was not used, whereas during period 2 (2018-2021), letermovir was used in patients at high risk but not in patients at low risk, except in those receiving corticosteroids. In patients at high risk, the incidence of clinically significant CMV infection (csCMVi) in period 2 was lower than that in period 1 (P < .001) by week 14 (10.5% vs 51.6%) and week 24 (16.9% vs 52.7%). In patients at low risk, although only 28.6% of patients received letermovir in period 2, csCMVi incidence was also significantly lower (P = .003) by week 14 (7.9% vs 29.0%) and week 24 (11.2% vs 33.3%). Among patients at low risk who did not receive letermovir (n = 45), 23 patients (51.1%) experienced transient positive CMV DNA without csCMVi, whereas 17 patients (37.8%) experienced negative results. In both risk groups, the 2 periods were comparable for CMV disease, overall survival, progression-free survival, relapse, and nonrelapse mortality. We concluded that a risk-based strategy for letermovir use is an effective strategy which maintains the high efficacy of letermovir in patients at high risk but allows some patients at low risk to not use letermovir.

Successful and safe response to ibrutinib alone in treating relapsed Waldenström macrogobulinemia and related acquired von Willebrand syndrome: an option to consider.

Ibrutinib, a first-class Bruton tyrosine kinase inhibitor, is known to be associated with adverse bleeding events and has been recently approved for the treatment of relapse Waldenström macroglobulinemia (WM). Here, we report the exhaustive clinical and biological follow-up of 2 patients treated by ibrutinib alone in the context of relapsed WM with an acquired von Willebrand syndrome (AVWS) complication. In two cases, ibrutinib has been shown to be quickly efficient and safe for treating both AVWS and its underlying condition the WM, without bleeding complications. Interestingly, ibrutinib treatment brings a rapid and extended over time normalization of von Willebrand factor clearance. These observations show that ibrutinib is a valuable therapeutic option in relapsed WM patients associated with AVWS and highlighting the need for further cohort studies with long-term follow-up of patients to confirm the efficacy and safety of a treatment by ibrutinib for WM patients with AVWS complication.

Resurgence of myeloproliferative neoplasm in patients in remission from blast transformation after treatment with hypomethylating agents.

Subsequent blast (BP) or accelerated phase (AP) is a severe complication of Philadelphia-negative myeloproliferative neoplasms (MPNs). The prognosis is generally dismal, but hypomethylating agents (HMAs) may induce a long-lasting response in a minority of patients. Here, we report a cohort of six patients with BP/AP-MPN who experienced MPN relapse after a leukemia response was obtained with azacytidine. Five of the patients achieved complete remission despite the presence of characteristics associated with poor prognosis, such as complex and monosomal karyotypes, TP53 mutations, and EVI1 overexpression. These remissions persisted for over five years in four of the 6 patients. All patients showed rapid reemergence of MPN within a median of two months with thrombocytosis requiring the addition of anagrelide, hydroxyurea, or ruxolitinib given continuously in parallel with the azacytidine cycle. Serial JAK2 V617F allelic burden measurements showed little variation. Thromboembolic events occurred in 3 patients, one leading to death. These findings confirm that HMA may reverse the disease course in AP/BP-MPN to a more chronic phase that may last for years but also lead to morbidity and mortality. Combining maintenance therapy with HMA and MPN-specific drugs appears to be a possible approach to avoiding leukemia relapse and controlling MPN disease.

Single-agent 5-azacytidine as post-transplant maintenance in high-risk myeloid malignancies undergoing allogeneic hematopoietic cell transplantation.

Relapse is a major cause of treatment failure after allogeneic hematopoietic cell transplantation (allo-HCT) in myeloid malignancies. Additional strategies have been devised to further maximize the immunologic effect of allo-HCT, notably through maintenance therapy with hypomethylating agents such as 5-azacytidine (AZA). We conducted a single-center retrospective study to investigate the efficacy of AZA after allo-HCT for high-risk myeloid malignancies. All patients transplanted between Jan 2014 and Sept 2019 for high-risk acute myeloid leukemia (n = 123), myelodysplastic syndrome (n = 51), or chronic myelomonocytic leukemia (n = 11) were included. Patients who died, relapsed, or developed grade ≥ 2 acute graft-versus-host disease before day + 60 were excluded, as well as those who were eligible for anti-FMS-like tyrosine kinase 3 maintenance. Of the 185 included patients, 65 received AZA while 120 did not. Median age at transplant was 59 years; 51.9% of patients were males. The median follow-up was 24 months for both groups. Regarding main patient characteristics and transplantation modalities, the two groups were comparable. In multivariate analyses, there were no significant differences between the two groups in terms of 2-year cumulative incidence of relapse (HR = 1.19; 95% confidence interval (CI) 0.67-2.12; p = 0.55), overall survival (HR = 0.62; 95%CI 0.35-1.12; p = 0.12) and event-free survival (HR = 0.97; 95%CI 0.60-1.58; p = 0.91) rates. In conclusion, single-agent AZA does not appear to be an optimal drug for preventing post-transplant relapse in patients with high-risk myeloid malignancies. This study highlights the need for prospective studies of alternative therapies or combination approaches in the post-transplant setting.

Risk Factors for Invasive Pulmonary Aspergillosis in Critically Ill Patients With Coronavirus Disease 2019-Induced Acute Respiratory Distress Syndrome.

Severe coronavirus disease 2019 pneumonia can lead to acute respiratory distress syndrome. Recently, several publications reported on coronavirus disease 2019-associated pulmonary aspergillosis. However, risk factors remain unclear. We retrospectively collected all the cases of coronavirus disease 2019 acute respiratory distress syndrome patients (n = 46) admitted to our 34-bed ICU between March 24, 2020, and May 25, 2020, and identified six patients that met the diagnosis of invasive pulmonary aspergillosis according to previously established definitions. This population exhibited higher severity scores at admission and less hospital discharge compared with noninvasive pulmonary aspergillosis patients. Chronic obstructive pulmonary disease, malnutrition, and systemic corticosteroid use were identified as risk factors for invasive pulmonary aspergillosis in coronavirus disease 2019-induced acute respiratory distress syndrome patients. Coronavirus disease 2019-associated pulmonary aspergillosis may be a serious concern regarding corticosteroids use to control the inflammatory response of coronavirus disease 2019-induced acute respiratory distress syndrome.

Discontinuation of antimicrobial therapy in adult neutropenic haematology patients: A prospective cohort.

OBJECTIVES: Antibiotics for febrile neutropenia (FN) in acute myeloid leukaemia (AML) patients undergoing intensive chemotherapy are usually maintained until neutropenia resolution, because of the risk of uncontrolled sepsis in this vulnerable population. This leads to unnecessarily prolonged antimicrobial therapy. METHODS: Based on ECIL-4 recommendations, we modified our management strategy and discontinued antibiotics after a pre-established duration in patients treated for a first episode of FN between August 2014 and October 2017. RESULTS: Antibiotics were stopped during 62 FN episodes, and maintained in the control group (n = 13). Median age of patients was 54 years. A total of 39 (63%) patients received induction and 23 (37%) consolidation chemotherapy; 36 (58%) patients had fever of unknown origin. Median neutropenia length was 26 days (IQR 24-30). Antibiotics were started at day 9 (IQR 5-13). Most patients received piperacillin-tazobactam (56%) or cefepime (32%). Antimicrobial therapy was longer in the control group than in the policy compliant group, 10 (IQR 7-16) vs. 19 days (IQR 15-23), P = 0.0001. After antibiotics discontinuation, 20% patients experienced fever recurrence, within 5.5 days (IQR 3-7.5). None of these febrile episodes were severe and 80% patients remained afebrile, with neutrophil recovery occurring within 5 days (IQR 2-8.5). Overall, 287 antibiotics days were spared; this represents 49% of all days with antibiotics. No patient had died at day 30 from intervention; six died during late follow-up, two from graft-versus-host disease and four from relapsed or refractory leukaemia. CONCLUSIONS: Discontinuing antibiotics in neutropenic AML patients treated for a first episode of FN is safe, and results in significant antibiotic sparing.

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system.

Fingolimod could be efficient to treat GVHD of the central nervous system.Further research should explore the use of fingolimod and other sphingosine-1-phosphate receptor agonists to prevent or treat GVHD.

Deregulation and Targeting of TP53 Pathway in Multiple Myeloma.

Multiple Myeloma (MM) is an incurable disease characterized by a clonal evolution across the course of the diseases and multiple lines of treatment. Among genomic drivers of the disease, alterations of the tumor suppressor TP53 are associated with poor outcomes. In physiological situation, once activated by oncogenic stress or DNA damage, p53 induces either cell-cycle arrest or apoptosis depending on the cellular context. Its inactivation participates to drug resistance in MM. The frequency of TP53 alterations increases along with the progression of the disease, from 5 at diagnosis to 75% at late relapses. Multiple mechanisms of regulation lead to decreased expression of p53, such as deletion 17p, TP53 mutations, specific microRNAs overexpression, TP53 promoter methylations, and MDM2 overexpression. Several therapeutic approaches aim to target the p53 pathway, either by blocking its interaction with MDM2 or by restoring the function of the altered protein. In this review, we describe the mechanism of deregulation of TP53 in MM, its role in MM progression, and the therapeutic options to interact with the TP53 pathway.