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•In adult KMT2A-r BCP-ALL, TP53and IKZF1alterations are associated with very poor outcome.•KMT2Agenomic fusion should be the preferred MRD marker over IG/TRto assess early treatment response and predict long-term outcome.

•IL-7R/CD127 expression is frequent in T-ALL (∼70%) and aberrantly diverges from normal thymocytic development.•IL-7R/CD127 expression predicts sensitivity to JAK inhibition in T-ALL and synergism with BCL2 inhibition.

Tandem duplications (TDs) of the UBTFgene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18–60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n= 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4–78.5%) and 57.1% (95%CI: 39.5–82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.

DDX41 germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGL myeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We describe here the clinical and biological features of 191 patients with DDX41MutGL AML. Baseline characteristics and outcome of 86 of these patients, treated with intensive chemotherapy in 5 prospective Acute Leukemia French Association/French Innovative Leukemia Organization trials, were compared with those of 1604 patients with DDX41 wild-type (DDX41WT) AML, representing a prevalence of 5%. Patients with DDX41MutGL AML were mostly male (75%), in their seventh decade, and with low leukocyte count (median, 2 × 109/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%), and few additional somatic mutations (median, 2). A second somatic DDX41 mutation (DDX41MutSom) was found in 82% of patients, and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41MutGL patients displayed higher complete remission rates (94% vs 69%; P < .0001) and longer restricted mean overall survival censored at hematopoietic stem cell transplantation (HSCT) than 2017 European LeukemiaNet intermediate/adverse (Int/Adv) DDX41WT patients (5-year difference in restricted mean survival times, 13.6 months; P < .001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGL patients (15% vs 44%) but later increased to be similar to Int/Adv DDX41WT patients at 3 years (82% vs 75%). HSCT in first complete remission was associated with prolonged relapse-free survival (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88; P = .02) but not with longer overall survival (hazard ratio, 0.77; 95% confidence interval, 0.35-1.68; P = .5).

Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cisfrom the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4activating mutations. Within adult patients with Ph−B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P= .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P= .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10−4, 93% vs 46%, P< .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P= .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3fusion, representing a high-risk disease in young adults.

Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph− B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10−4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.

IMPORTANCE: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described severe adult-onset autoinflammatory disease that is associated with myeloid lineage-restricted ubiquitin-activating enzyme 1 (UBA1) somatic variations that primarily affect the skin (Sweet syndrome), cartilage, and bone marrow. Skin symptoms have been poorly described. OBJECTIVE: To better describe clinical and pathological skin manifestations and their pathophysiology in VEXAS syndrome. DESIGN, SETTING, AND PARTICIPANTS: This multicenter retrospective case series study of clinical and histological features of 8 patients with VEXAS syndrome and skin involvement was conducted in France from December 2007 to March 2021, with molecular data obtained from March to April 2022. Any UBA1 variations were detected by Sanger or next-generation sequencing that was performed on bone marrow and formalin-fixed paraffin-embedded tissue sections of skin lesion biopsies. RESULTS: All 8 patients were men, and the median age at symptom onset was 65.5 years (interquartile range, 54-76 years). All patients had neutrophilic dermatosis skin lesions, including tender red or violaceous papules, sometimes edematous, without fever, arthralgia, recurrence or pathergy, inflammatory edematous papules on the neck and trunk (sometimes umbilicated), and firm erythematous purpuric or pigmented infiltrated plaques and nodules. Three patients had livedo racemosa. The infiltrates were perivascular and consisted of mature neutrophils with leukocytoclasia, which were admixed with myeloperoxidase-positive CD163-positive myeloid cells with indented nuclei and lymphoid cells in all cases. A sequencing analysis of paired bone marrow samples and skin lesion biopsies identified the same loss-of-function UBA1 variation in both samples for all patients. CONCLUSIONS AND RELEVANCE: This case series study describes the different clinical presentations of skin lesions found in VEXAS syndrome, which is characterized histologically by neutrophilic dermatosis. The findings suggested that the dermal infiltrates seen in VEXAS skin lesions are derived from the pathological myeloid clone. This suggests that using therapies that target the pathological clone may be effective in the long-term management of the disease.

Intra-tumor heterogeneity portends poor outcome in many cancers. In AML, a higher number of drivers worsens prognosis. The Shannon Index is a robust metric of clonal heterogeneity that accounts for the number of clones, but also their relative abundance. We show that a Shannon Index can be estimated from bulk sequencing, which is correlated (ρ= 0.76) with clonal diversity from single-colony genotyping. In a discovery cohort of 292 patients with sequencing of 43 genes, a higher number of drivers (HR = 1.18, P= 0.028) and a lower Shannon Index (HR = 0.68, P= 0.048), the latter reflecting clonal dominance, are independently associated with worse OS independently of European LeukemiaNet 2017 risk. These findings are validated in an independent cohort of 1184 patients with 111-gene sequencing (number of drivers HR = 1.16, P= 1 × 10−5, Shannon Index HR = 0.81, P= 0.007). By re-interrogating paired diagnosis/relapse exomes from 50 cytogenetically normal AMLs, we find clonal dominance at diagnosis to be correlated with the gain of a significantly higher number of mutations at relapse (P= 6 × 10−6), hence with clonal sweeping. Our results suggest that clonal dominance at diagnosis is associated with the presence of a leukemic phenotype allowing rapid expansion of new clones and driving relapse after chemotherapy.

The prognostic value of IL7-receptor pathway (IL7Rp) mutations in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. We performed a comprehensive study of 200 adult patients with T-ALL included in the GRAALL2003/2005 protocols to address the clinical significance of IL7Rp mutations. Next-generation sequencing of the IL7Rp (IL7R/JAK1/JAK3/STAT5B) revealed that IL7Rp mutations were frequent in adult T-ALL (28%) particularly in immature/early T-cell progenitor (ETP)-ALL. They were associated with mutations of NOTCH-pathway, PHF6, and PRC2components but not with K/NRAS. IL7Rp mutated (IL7Rpmut) T-ALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7RpWT) T-ALL (p= 0.002) and minimal residual disease positivity at 6-weeks (MRD1) (p= 0.008) but no difference in MRD2 positivity at 12-weeks. Despite this, no adverse prognosis was evidenced when censored for allogeneic hematopoietic stem cell transplantation (HSCT). In time-dependent analysis, HSCT did not benefit IL7Rpmutpatients whereas it was of marked benefit to IL7RpWTcases. IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.

DDX41germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGLmyeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We described here the clinical and biological features of 191 patients with DDX41MutGLAML. Baseline characteristics and outcome of 86 of them, treated with intensive chemotherapy in 5 prospective ALFA/FILO trials were compared with those of 1604 DDX41wild-type (DDX41WT) AML patients, representing a prevalence of 5%. DDX41MutGLAML patients were mostly males (75%) in their seventh decade, with low leukocyte count (median, 2x109/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%) and few additional somatic mutations (median, 2). A second somatic DDX41mutation (DDX41MutSom) was found in 82% of patients and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41MutGLpatients displayed higher complete remission (CR) rates (94% vs.69%, p<0.0001) and longer restricted mean overall survival (OS) censored at hematopoietic stem cell transplantation (HSCT) than ELN-2017 intermediate/adverse (Int/Adv) DDX41WTpatients (5-year ΔRMST of 13.6 months, p < 0.001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGLpatients (15% vs.44%) but later increased to join that of Int/Adv DDX41WTpatients at 3 years (82% vs 75%). HSCT in first CR was associated with prolonged relapse-free survival (RFS; HR, 0.43 [95%CI, 0.21-0.88]; p = 0.02) but not with longer OS (HR=0.77 [95%CI, 0.35-1.68], p=0.5).

•Alternating reduced-intensity and conventional chemotherapy with nilotinib followed by SCT resulted in 4-year OS of 79.4% in Ph+ALL.•The omission of high-dose Ara-C during consolidation resulted in a significantly higher rate of relapses without affecting overall survival.

In Acute Myeloid Leukemia (AML), distinguishing between chemoresistance driver mechanisms and cell plasticity in response to chemotherapy is challenging due to their interconnectedness. To address this issue, we generated an MLL-AF9-driven syngeneic mouse model of AML, which we evolved to develop resistance to a front-line chemotherapy regimen by repetitive exposure to a maximally-tolerated combination of cytarabine and doxorubicin. An RNA sequencing (RNAseq)-based profiling of the chemoresistant (Chemo R) AML subpopulation and its naive (Chemo N) counterpart revealed a significant upregulation in the expression of 326 genes in Chemo Rcells which were markedly enriched in gene sets related to splicing/mRNA processing. Notably, single-sample GSEA analysis of relapsed AML samples from the BEAT-AML cohort supported these findings, as they were enriched for the upregulation of genes in our chemoresistance gene signature. A combined in vivofunctional screening endeavor using a pool of 2098 shRNAs targeting these upregulated genes and a motif discovery analysis performed on the set of dysregulated transcripts in Chemo Rcells identified three candidate hits, Srrm1, Sf3b3, and Prpf8, which scored as chemotherapy-specific dependencies and were found to interact with central regulators of alternative splicing ( Figure 1A). Silencing these three candidate genes in our chemoresistant mouse model and the human AML cell lines, MOLM-14, MV4-11, and U937, evolved to become resistant to the combination of cytarabine and daunorubicin, revealed that the splicing regulator, SRRM1, is a critical vulnerability of chemoresistant leukemic cells.

Introduction.Adults with Philadelphia (Ph)-negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL) benefit from blinatumomab (BLIN) in first-line consolidation. However, the magnitude of this benefit according to baseline patient and disease characteristics remains largely unexplored. In the GRAALL-2014/B QUEST sub-study, patients with high-risk (HR) features (i.e. post-induction MRD1 ≥10 -4, IKZF1intragenic deletion, or KMT2Arearrangement) received BLIN during consolidation. Patients eligible to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR) (i.e. those with late CR, or post-induction MRD1 ≥10 -3, or post-consolidation MRD2 ≥10 -4) received only one BLIN cycle before transplant. A control cohort was established from patients enrolled in the same protocol who exhibited the same HR criteria but did not receive BLIN in first CR. The objective of this analysis was to identify patient- and disease-related factors associated with response to BLIN, and to understand how BLIN influences the outcome after allo-HSCT.

Fanconi anemia (FA) patients experience chromosome instability, yielding hematopoietic stem/progenitor cell (HSPC) exhaustion and predisposition to poor-prognosis myeloid leukemia. Based on a longitudinal cohort of 335 patients, we performed clinical, genomic, and functional studies in 62 patients with clonal evolution. We found a unique pattern of somatic structural variants and mutations that shares features of BRCA-related cancers, the FA-hallmark being unbalanced, microhomology-mediated translocations driving copy-number alterations. Half the patients developed chromosome 1q gain, driving clonal hematopoiesis through MDM4trisomy downmodulating p53 signaling later followed by secondary acute myeloid lukemia genomic alterations. Functionally, MDM4triplication conferred greater fitness to murine and human primary FA HSPCs, rescued inflammation-mediated bone marrow failure, and drove clonal dominance in FA mouse models, while targeting MDM4 impaired leukemia cells in vitroand in vivo. Our results identify a linear route toward secondary leukemogenesis whereby early MDM4-driven downregulation of basal p53 activation plays a pivotal role, opening monitoring and therapeutic prospects.

We here report for the first time that low levels of interleukin (IL)-10 do not exclude lymphomatous meningitis (LM) in B-cell lymphoproliferative disorders (CLPD). Unexpectedly, IL-10 levels and IL-10:IL-6 ratio in CLPD differed from the levels observed in diffuse large B-cell lymphoma (DLBCL). We report the usefulness of adding the IL-10:IL-6 ratio in order to potentially reveal more aggressive lymphomas: either a transformation or an association with another “hidden” lymphoma such as primary CNS lymphoma (PCNSL).

Rousselot: Incyte:Consultancy, Research Funding;Pfizer:Consultancy, Research Funding;Bristol-Myers Squibb:Consultancy;Novartis:Consultancy;Takeda:Consultancy.Itzykson:Jazz Pharmaceuticals:Honoraria, Membership on an entity's Board of Directors or advisory committees;Daiichi Sankyo:Honoraria;BMS (Celgene):Honoraria;Sanofi:Honoraria;Astellas:Honoraria;Oncoethix (now Merck):Research Funding;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Research Funding;Stemline:Membership on an entity's Board of Directors or advisory committees;Karyopharm:Membership on an entity's Board of Directors or advisory committees;Otsuka Pharma:Membership on an entity's Board of Directors or advisory committees;Amgen:Membership on an entity's Board of Directors or advisory committees;Abbvie:Honoraria.Cayuela:Incyte:Speakers Bureau;Novartis:Speakers Bureau.Rea:BMS:Membership on an entity's Board of Directors or advisory committees;Novartis:Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer:Honoraria, Membership on an entity's Board of Directors or advisory committees;Incyte:Honoraria, Membership on an entity's Board of Directors or advisory committees.

Le syndrome VEXAS (Vacuoles, enzyme E1, lié à l’X, Auto-inflammatoire, Somatique) est une maladie auto-inflammatoire sévère de découverte récente, en lien avec l’acquisition d’une mutation somatique du gène UBA1 dans la lignée myéloïde, caractérisée par des atteintes cutanées de type syndrome de Sweet, articulaires et hématologiques. Les manifestations cutanées du VEXAS, bien que fréquentes, ont été peu caractérisées. Notre étude avait pour objectif de préciser la clinique et l’histologie des atteintes cutanées du VEXAS et d’en comprendre les mécanismes physiopathologiques.

Background

Introduction:Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) with high-risk genetics and/or measurable residual disease (MRD) are at high-risk of disease recurrence. In the previous GRAALL-2005 study, we identified KMT2Arearrangements (KMT2A-r), IKZF1intragenic deletion (IKZF1del) and post-induction (TP1, week 6) MRD ≥ 0.01% as independent factors to predict relapse in Ph-negative B-cell precursor (BCP) ALL (Beldjord K, Blood 2014). In the GRAALL-2014 trial, high-risk (HR) patients were thus defined by the presence of at least one of these three factors. Among them, only those with higher MRD levels defined as TP1-MRD ≥ 0.1% and/or week 12 (TP2) MRD ≥ 0.01% were considered at very high risk (VHR) and proposed allogeneic hematopoietic stem cell transplant (alloSCT) in first remission (Dhedin et al., Blood 2015). Since October 2018, all these patients were eligible to be included in the GRAALL-2014-QUEST phase 2 study to receive blinatumomab as part of consolidation and maintenance phases or as a bridge to transplant.

Introduction

Sebert: BMS: Consultancy; Abbvie: Consultancy. Dalle: Jazz Pharmaceuticals: Honoraria. Socie: Alexion: Research Funding. Peffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding.

Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Straetmans: Alexion: Membership on an entity's Board of Directors or advisory committees. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Boissel: SANOFI: Honoraria; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; PFIZER: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding.

Boissel: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; CELGENE: Honoraria; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Dombret: Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; NOVARTIS: Research Funding; pfizer: Honoraria, Research Funding; servier: Research Funding; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria.Blinatumomab in frontline high-risk acute lymphoblastic leukemia

Choquet: Roche: Consultancy; Janssen: Consultancy. Leblond:Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Mundipharma: Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau.

Identifying the etiology of neurological symptoms in hematological malignancies is still a challenging issue. Lymphomatous meningitis (LM) is mainly described in aggressive systemic B-cell lymphomas (diffuse large B-cell (DLBCL) and Burkitt lymphomas), and is associated with poor prognosis. Leptomeningeal involvement in small B-cell lymphoproliferation is a rare, poorly described condition, mentioned only in case reports. The diagnosis relies on the combination of non-specific central nervous system (CNS) symptoms (headaches, paraplegia, etc.) or psychiatric symptoms, and the cytological detection of tumor cells in the cerebrospinal fluid (CSF). However, cell analysis has a low sensitivity here due to the small drawn volumes of CSF samples, their poor cellularity and cell viability. Soluble biomarkers can be measured by multiplex techniques on small sample volumes, hence can overcome cytological limitations and seem fairly interesting for further investigations.