Rare germline complement factor H variants in patients with paroxysmal nocturnal hemoglobinuria.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) are susceptible to complement-mediated intravascular hemolysis and thrombosis. Factor H (FH) is the main regulator of the complement alternative pathway, which protects cells from unwanted complement-mediated damage. Although FH is not a glycosylphosphatidylinositol-linked molecule, it may play a role in PNH. We sought to determine if rare germline variants in complement factor H (CFH) affect the PNH course, screening 84 patients with PNH treated with eculizumab for rare variants in CFH, CFI, and C3 genes. We compared the allelic frequencies with populational data and a geographically-matched control group, looking for an association between presence of the variants and treatment response (transfusion independence by 6 months). Sixteen patients presented rare variants, 9 in CFH (10.7%). Germline CFH variants were more frequent among patients with PNH than among controls (P = .02) or public data (P < .001) and were more likely to be transfusion-dependent at 6 months after eculizumab initiation (P = .015). With a median follow-up of 5.8 years, 8 of 9 patients with the CFH variant received transfusions, and 2 developed thromboses. None of the patients with the CFH variant had severe aplastic anemia from eculizumab initiation until 6 months. We demonstrated for the first time that rare CFH variants are over-represented among patients with PNH and that germline genetic background may affect the response to eculizumab.

Tolerance of radiotherapy with concomitant glofitamab in diffuse large B cell lymphoma: a case report.

Glofitamab, an anti-CD20 antibody, is approved as a third-line treatment for relapsed or refractory (r/r) diffuse large-cell B lymphoma (DLBCL), achieving a complete response in nearly 40% of patients. This humanized IgG1 bispecific monoclonal antibody binds to CD20 on malignant B lymphocytes and to CD3 on cytotoxic T cells. This dual binding forms an immunological synapse, activating T lymphocytes and leading to the lysis of tumor cells. Salvage radiotherapy is also effective for r/r DLBCL, but its combination with systemic treatments like glofitamab may increase radiation-induced toxicity. We report the first case of a patient with r/r DLBCL receiving concurrent salvage radiotherapy and glofitamab. A 68-year-old female diagnosed with stage IV DLBCL underwent initial treatment with R-CHOP, then Car-T cell therapy, followed by glofitamab for recurrence. Upon early metabolic progression detected by 18FDG-PET/CT, salvage radiotherapy was administered to the refractory site concurrently with glofitamab. The patient experienced mild para-spinal pain post-radiotherapy but no other significant toxicities. Three months post-treatment, she showed a complete metabolic response with no radiotherapy toxicity, as evidenced by PET-CT, and no signs of radiation pneumonitis. This case indicates that combining glofitamab with salvage radiotherapy is tolerable and suggests potential efficacy, warranting further investigation in prospective studies for r/r DLBCL.

APR-246 induces early cell death by ferroptosis in acute myeloid leukemia.

APR-246 is a promising new therapeutic agent that targets p53 mutated proteins in myelodysplastic syndromes and in acute myeloid leukemia (AML). APR-246 reactivates the transcriptional activity of p53 mutants by facilitating their binding to DNA target sites. Recent studies in solid cancers have found that APR-246 can also induce p53-independent cell death. In this study, we demonstrate that AML cell death occurring early after APR-246 exposure is suppressed by iron chelators, lipophilic antioxidants and inhibitors of lipid peroxidation, and correlates with the accumulation of markers of lipid peroxidation, thus fulfilling the definition of ferroptosis, a recently described cell death process. The capacity of AML cells to detoxify lipid peroxides by increasing their cystine uptake to maintain major antioxidant molecule glutathione biosynthesis after exposure to APR-246 may be a key determinant of sensitivity to this compound. The association of APR-246 with induction of ferroptosis (either by pharmacological compounds, or genetic inactivation of SLC7A11 or GPX4) had a synergistic effect on the promotion of cell death, both in vivo and ex vivo.

Accuracy and safety of 101 consecutives neurosurgical procedures for newly diagnosed central nervous system lymphomas: a single-institution experience.

INTRODUCTION: Brain surgery is required to ascertain the diagnosis of central nervous system lymphoma. We assessed the diagnostic yield and safety of the surgical procedures, the predictors of postoperative morbidity, and of overall survival. METHODS: Observational single-institution retrospective cohort study (1992-2020) of 101 consecutive adult patients who underwent stereotactic biopsy, open biopsy, or resection for a newly diagnosed central nervous system lymphoma. RESULTS: The diagnostic yield was 100% despite preoperative steroid administration in 48/101 cases (47.5%). A preoperative Karnofsky Performance Status score less than 70 (p = 0.006) was an independent predictor of a new postoperative focal neurological deficit (7/101 cases, 6.9%). A previous history of hematological malignancy (p = 0.049), age 65 years or more (p = 0.031), and new postoperative neurological deficit (p < 0.001) were independent predictors of a Karnofsky Performance Status score decrease 20 points or more postoperatively (13/101 cases, 12.9%). A previous history of hematological malignancy (p = 0.034), and preoperative Karnofsky Performance Status score less than 70 (p = 0.024) were independent predictors of postoperative hemorrhage (13/101 cases, 12.9%). A preoperative Karnofsky Performance Status score less than 70 (p = 0.019), and a previous history of hematological malignancy (p = 0.014) were independent predictors of death during hospital stay (8/101 cases, 7.9%). In the 82 immunocompetent patients harboring a primary central nervous system lymphoma, age 65 years or more (p = 0.044), and time to hematological treatment more than 21 days (p = 0.008), were independent predictors of a shorter overall survival. A dedicated hematological treatment (p < 0.001) was an independent predictor of a longer overall survival. CONCLUSION: Brain biopsy is feasible with low morbidity for central nervous system lymphomas. Postoperatively, patients should be promptly referred for hematological treatment initiation.

Pharmaceutical cancer care for haematology patients on oral anticancer drugs: Findings from an economic, clinical and organisational analysis.

OBJECTIVE: The clinical benefit of pharmaceutical cares in improving the quality-of-care outcomes is well demonstrated. Clinical pharmacy services are not systematically deployed in cancer units in the absence of economic data. The aim of this prospective, observational 1-year study was to evaluate the clinical, economic and organisational impacts of pharmaceutical care into a multidisciplinary day hospital for patients treated with oral cancer drugs. METHODS: All pharmacists' interventions (PI) were documented and their impact and the probability of adverse drug events were assessed using the clinical, economic and organisational tool. RESULTS: Among 360 admissions, an average of 1.81 PI per admission was accepted. Among 452 PI leading to a clinical benefit on the patient, 16.9% had a major impact, and 1.9% had an impact on survival. The large majority of PIs (87%) increased the quality-of-care organisation. The budget impact model showed a total cost savings and cost avoidance of €539,047 per year and a cost-benefit ratio of 7.07:1. The direct cost-benefit was €201,741, and the cost avoidance was €337,306. CONCLUSION: Multidisciplinary care and pharmaceutical care are key elements to improve cancer patients' outcomes and avoid evitable healthcare costs.

When refeeding is not enough: severe and prolonged pancytopenia in an adolescent with anorexia nervosa.

A 15-year-old female patient with anorexia nervosa presented an unusually prolonged and severe episode of pancytopenia with severe thrombopenia and severe leucopenia. Despite effective refeeding, active specialized interventions were necessary. Upon admission, the patient presented with severe and symptomatic thrombopenia, severe neutropenia and gelatinous marrow transformation. In addition to refeeding, active interventions such as platelet transfusion and granulocyte-colony stimulating factor were successful to manage the patient's complications. The etiological search for pancytopenia was negative. The patient's prolonged starvation was probably a key factor. Medical history, clinical presentation, evolution, and biological data including bone marrow aspiration results are presented. Management of cytopenia and of their complications in a context of severe starvation is discussed in regard of existing literature. A simple monitoring attitude may prove insufficient in cases of severe pancytopenia in anorexia nervosa.Level of evidence V, descriptive study.

Pairing MCL-1 inhibition with venetoclax improves therapeutic efficiency of BH3-mimetics in AML.

OBJECTIVES: Venetoclax combined with hypomethylating agents is a new therapeutic strategy frequently used for treating AML patients who are not eligible for conventional chemotherapy. However, high response rates are heterogeneous due to different mechanisms mediating resistance to venetoclax such as up-regulation of MCL-1 expression. We thus tested the anti-leukemic activity of S63845, a specific MCL-1 inhibitor. METHODS: Apoptosis induces by S63845 with or without venetoclax was evaluated in primary AML samples and in AML cell lines co-cultured or not with bone marrow (BM) mesenchymal stromal cells. Sensitivity of leukemic cells to S63845 was correlated to the expression level of BCL-2, MCL-1, and BCL-XL determined by Western Blot and mass spectrometry-based proteomics. RESULTS: We observed that even if MCL-1 expression is weak compared to BCL-2, S63845 induces apoptosis of AML cells and strongly synergizes with venetoclax. Furthermore, AML cells resistant to venetoclax are highly sensitive to S63845. Interestingly, the synergistic effect of S63845 toward venetoclax-mediated apoptosis of AML cells is still observed in a context of interaction with the BM microenvironment that intrinsically mediates resistance to BCL2 inhibition. CONCLUSION: These results are therefore of great relevance for clinicians as they provide the rational for combining BCL-2 and MCL-1 inhibition in AML.

Management of central nervous system involvement in chronic lymphocytic leukaemia: a retrospective cohort of 30 patients.

Central nervous system involvement (CNSi) is a rare and poorly reported complication of chronic lymphocytic leukaemia (CLL). Establishing cause and effect between the CLL and the neurological symptoms remains challenging. We have analysed a retrospective cohort of 30 CLL patients with CNSi, documented by lymphocytic infiltration either by flow cytometry of the cerebrospinal fluid (CSF; n = 29) or CNS biopsy (n = 1). Neurological symptoms were heterogeneous. At the time of CNSi, less than half of the patients had a progressive CLL and 20 had never been treated for CLL. Initial treatment with fludarabine-based immuno-chemotherapy, with or without intra-CSF therapy, led to durable response in eight out of nine untreated patients. In contrast, 50% patients receiving various prior treatments needed additional therapy within a median of 4 months (1-16). Ibrutinib led to complete response in 4/4 heavily pre-treated patients. From CNSi, 5-year overall survival was 72% and 48% for treatment-naïve and previously treated patients respectively (P = 0·06); 5-year progression-free survival (PFS) was 43% and 0% (P = 0·125). 17p deletion was significantly associated with poor PFS (P = 0·006). CNSi may be the only sign of progression of CLL and should be considered an initiation criterion of systemic treatment. Prognosis seemed to be related to CLL characteristics rather than to CNSi itself.

Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition.

Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34(+) progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GAC(K320A) allele and the addition of the tricarboxyclic acid cycle product α-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML.

Severe bleeding events among critically ill patients with haematological malignancies.

BACKGROUND: Bleeding events are common complications in critically ill patients with haematological malignancies. The objective of this study was to assess the incidence and identify determinants of ICU-acquired severe bleeding events in critically ill patients with haematological malignancies. We conducted a single-center retrospective study including all adult patients with a history of haematological malignancy requiring unplanned ICU admission over a 12-year period (2007-2018). The primary endpoint was the occurrence of ICU-acquired (i.e. after the first 24 h in the ICU) severe bleeding events, as defined as grades 3 or 4 of the World Health Organization classification. RESULTS: A total of 1012 patients were analysed, mainly with a diagnosis of lymphoma (n = 434, 42.9%) and leukaemia or myelodysplastic syndrome (n = 266, 26.3%). Most patients were recently diagnosed (n = 340, 33.6%) and under active cancer treatment within the last 3 months (n = 604, 59.7%). The main cause for admission was infection (n = 479, 47.3%), but a significant proportion of patients were admitted for a primary haemorrhage (n = 99, 10%). ICU-acquired severe bleeding events occurred in 109 (10.8%) patients after 3.0 days [1.0-7.0] in the ICU. The main source of bleeding was the gastrointestinal tract (n = 44, 40.3%). Patients experiencing an ICU-acquired severe bleeding event displayed prolonged in-ICU length of stay (9.0 days [1.0-6.0] vs. 3.0 [3.5-15.0] in non-bleeding patients, p < 0.001) and worsened outcomes with increased in-ICU and in-hospital mortality rates (55% vs. 18.3% and 65.7% vs. 33.1%, respectively, p < 0.001). In multivariate analysis, independent predictors of ICU-acquired severe bleeding events were chronic kidney disease (cause-specific hazard 2.00 [1.19-3.31], p = 0.008), a primary bleeding event present at the time of ICU admission (CSH 4.17 [2.71-6.43], p < 0.001), non-platelet SOFA score (CSH per point increase 1.06 [1.01-1.11], p = 0.02) and prolonged prothrombin time (CSH per 5-percent increase 0.90 [0.85-0.96], p = 0.001) on the day prior to the event of interest. CONCLUSIONS: Major bleeding events are common complications in critically ill patients with haematological malignancies and are associated with a worsened prognosis. We identified relevant risk factors of bleeding which may prompt closer monitoring or preventive measures.

Proton Therapy Reduces the Effective Dose to Immune Cells in Mediastinal Hodgkin Lymphoma Patients.

Purpose: Effective dose to circulating immune cells (EDIC) is associated with survival in lung and esophageal cancer patients. This study aimed to evaluate the benefit of intensity-modulated proton therapy (IMPT) for EDIC reduction compared with volumetric modulated arc therapy (VMAT) in mediastinal Hodgkin lymphoma (mHL) patients. Materials and Methods: Ten consecutive mHL patients treated with involved-site IMPT after frontline chemotherapy were included. The mean dose to the heart, lung, and liver and the integral dose to the body were obtained, and we calculated EDIC based on these variables. The effective dose to circulating immune cells was compared between IMPT and VMAT schedules. Results: The median EDIC was reduced from 1.93 Gy (range: 1.31-3.87) with VMAT to 1.08 Gy (0.53-2.09) with IMPT (P < .01). Integral dose reduction was the main driver of EDIC reduction with IMPT, followed by lung sparing. Conclusion: Intensity-modulated proton therapy significantly reduced EDIC in mHL patients undergoing consolidation involved-site radiation therapy. Integral dose reduction combined with improved lung sparing was the main driver of EDIC reduction with IMPT.

Targeting ferritinophagy impairs quiescent cancer stem cells in acute myeloid leukemia in vitro and in vivo models.

Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Leukemic stem cells (LSCs) contribute to therapeutic failure, relapse, and adverse outcome. This study investigates the role of quiescence and related molecular mechanisms in AML pathogenesis and LSC functions to identify potential therapeutic targets. Transcriptomic analysis revealed that the LSC-enriched quiescent cell population has a distinct gene signature with prognostic relevance in patients with AML. Mechanistically, quiescent blasts exhibit increased autophagic activity, which contributes to their sustained viability. Proteomic profiling uncovered differential requirements for iron metabolism between quiescent and cycling cells, revealing a unique dependence of quiescent cells on ferritinophagy, a selective form of autophagy mediated by nuclear receptor coactivator 4 (NCOA4), which regulates iron bioavailability. We evaluated the therapeutic potential of inhibiting NCOA4-mediated ferritinophagy using genetic knockdown and chemical inhibition approaches. In vitro assays showed that suppression of NCOA4 was toxic to leukemic blasts, particularly the CD34+CD38- LSC-enriched population, without affecting normal CD34+ hematopoietic progenitors. In vivo studies using murine patient-derived xenograft (PDX) models of AML confirmed that NCOA4 inhibition reduced tumor burden and impaired LSC viability and self-renewal, indicating a specific vulnerability of these cells to ferritinophagy disruption. Our findings underscore the role of NCOA4-mediated ferritinophagy in maintaining LSC quiescence and function and suggest that targeting this pathway may be an effective therapeutic strategy for AML. This study highlights the potential of NCOA4 inhibition to improve AML outcomes and paves the way for future research and clinical development.

Maternal and obstetric outcomes in women with pregnancy-associated haematological malignancies: an observational nationwide cohort study.

BACKGROUND: Pregnancy-associated haematological malignancy is a rare event; therefore, data available to guide the treatment are scarce. We aimed to evaluate the incidence, overall survival, and maternal morbidity and mortality of women with pregnancy-associated haematological malignancies. METHODS: We conducted a nationwide observational cohort study using the French National Healthcare Data System (SNDS), a health-care administrative database covering up to 99% of the French population. We included all pregnancies in France ending between Jan 1, 2012, and Dec 31, 2022. Pregnancies with terminations or miscarriages managed on an outpatient basis, and women with a history of haematological malignancies before pregnancy were excluded. A Cox proportional hazards model was used to assess overall survival, defined as the date of haematological malignancy diagnosis to either death or the end of the study follow-up, in the haematological malignancy during pregnancy group (pregnancies with a diagnosis of haematological malignancy during pregnancy) compared with the haematological malignancy post-pregnancy group (pregnancies with a diagnosis of haematological malignancy in the year following pregnancy). Severe maternal morbidity was compared in the haematological malignancy during pregnancy group versus the reference group (pregnancies without a history of haematological malignancy or a diagnosis of pregnancy-associated haematological malignancy). Births were classified as very preterm (<32 weeks of pregnancy), preterm (32-36 weeks), and term (≥37 weeks) and compared in the haematological malignancy during pregnancy group versus the reference group. Inverse probability weighting (IPW) was used for confounder adjustment, using maternal age (categorised), comorbidities, socioeconomic status, and year of delivery (as a category). FINDINGS: Of 9 996 523 pregnancies in 5 995 235 women, 1366 pregnancy-associated haematological malignancies were identified: 413 during pregnancy (4·13 per 100 000 pregnancies) and 953 (9·53 per 100 000 pregnancies) within 12 months of the end of pregnancy (post-pregnancy). No significant differences in overall survival were observed between the haematological malignancy during and post-pregnancy groups across all types of haematological malignancy (IPW-adjusted hazard ratio 0·91 [95% CI 0·62-1·34], p=0·63), specifically for Hodgkin lymphoma (0·56 [0·07-4·53], p=0·59), aggressive B-cell non-Hodgkin lymphoma (0·52 [0·12-2·38], p=0·40), and acute leukaemia alone (0·84 [0·50-1·41], p=0·51). Severe maternal morbidity was more frequent in the haematological malignancy during pregnancy group than in the reference group (86 [26·2%] of 328 completed pregnancies vs 120 335 [1·5%] of 7 945 909 completed pregnancies; IPW-adjusted odds ratio 22·71 [95% CI 17·72-29·10], p<0·0001). We observed an increase in very preterm birth (32 [9·8%] vs 92 712 [1·2%]; IPW-adjusted odds ratio 11·90 [95% CI 7·91-17·91], p<0·0001) and preterm birth (116 [35·4%] vs 430 472 [5·4%]; 11·76 [9·34-14·81], p<0·0001) in the haematological malignancy during pregnancy group compared with the reference group. INTERPRETATION: This nationwide observational study examines pregnancy-associated haematological malignancies in France, revealing no significant difference in overall survival between women diagnosed during pregnancy and post-pregnancy. Our data highlight an increased frequency of severe maternal morbidity and obstetric complications among women diagnosed during pregnancy. Notably, the study underscores the necessity for specialised care to manage these complex cases effectively. FUNDING: None. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Loss of hematopoietic progenitors heterogeneity is an adverse prognostic factor in lower-risk myelodysplastic neoplasms.

Myelodysplastic neoplasms (MDS) are characterized by clonal evolution starting from the compartment of hematopoietic stem and progenitors cells (HSPCs), leading in some cases to leukemic transformation. We hypothesized that deciphering the diversity of the HSPCs compartment may allow for the early detection of an emergent sub-clone that drives disease progression. Deep analysis of HSPCs repartition by multiparametric flow cytometry revealed a strong disorder of the hematopoietic branching system in most patients at diagnosis with different phenotypic signatures closely related to specific MDS features. In two independent cohorts of 131 and 584 MDS, the HSPCs heterogeneity quantified through entropy calculation was decreased in 47% and 46% of cases, reflecting a more advanced state of the disease with deeper cytopenias, higher IPSS-R risk and accumulation of somatic mutations. We demonstrated that patients with lower-risk MDS and low CD34 + CD38+HSPCs entropy had an adverse outcome and that this parameter is as an independent predictive biomarker for progression free survival, leukemia free survival and overall survival. Analysis of HSPCs repartition at diagnosis represents therefore a very powerful tool to identify lower-risk MDS patients with a worse outcome and valuable for clinical decision-making, which could be fully integrated in the MDS diagnostic workflow.