ABSTRACT
OBJECTIVES: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE. METHODS: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders. RESULTS: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83). CONCLUSIONS: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.
Subject(s)
Autoimmune Diseases , Leukemia, Myelomonocytic, Chronic , Myelodysplastic Syndromes , Venous Thromboembolism , Autoimmune Diseases/complications , Autoimmune Diseases/epidemiology , Case-Control Studies , Humans , Leukemia, Myelomonocytic, Chronic/complications , Leukemia, Myelomonocytic, Chronic/epidemiology , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/epidemiology , Retrospective Studies , Venous Thromboembolism/diagnosis , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiologyABSTRACT
Monoclonal immunoglobulin M (IgM) anti-myelin-associated glycoprotein (MAG) neuropathy is a rare disabling condition, most commonly treated with rituximab monotherapy (R), which leads to neurological improvement in only 30%-50% of patients. The combination of rituximab plus chemotherapy has been proven to improve the level of responses. We studied the outcomes of anti-MAG neuropathy patients treated either by R, or by immunochemotherapy (ICT) in our centre, focusing on the incidence of the first neurological response evaluated by the modified Rankin scale (mRS). From 2011 to 2018, 64 patients were studied: 34 were treated with R and 30 with ICT. According to our treatment decision-making process, the median mRS was higher in the ICT group (mRS 2) than in the R group (mRS 1). At one year, improvements of the mRS rates were 46% and 18% in the ICT and R groups of patients respectively, with median times to response of eight and 13 months (p = 0.023). Adverse effects were higher in the ICT group: 62% vs 15% (p Ë 0.01), all grades included. One secondary acute leukaemia occurred five years after treatment with ICT. In conclusion, ICT may be used as a valid option for patients with rapidly progressive and/or severe anti-MAG neuropathy symptoms.
Subject(s)
Peripheral Nervous System Diseases , Autoantibodies , Humans , Immunoglobulin M , Immunotherapy/adverse effects , Paraproteins , Peripheral Nervous System Diseases/therapy , Rituximab/adverse effectsABSTRACT
R-CHOP immuno-chemotherapy significantly improved clinical management of diffuse large B-cell lymphoma (DLBCL). However, 30-40% of DLBCL patients still present a refractory disease or relapse. Most of the prognostic markers identified to date fail to accurately stratify high-risk DLBCL patients. We have previously shown that the nuclear protein CYCLON is associated with DLBCL disease progression and resistance to anti-CD20 immunotherapy in preclinical models. We also recently reported that it also represents a potent predictor of refractory disease and relapse in a retrospective DLBCL cohort. However, only sparse data are available to predict the potential biological role of CYCLON and how it might exert its adverse effects on lymphoma cells. Here, we characterized the protein interaction network of CYCLON, connecting this protein to the nucleolus, RNA processing, MYC signaling and cell cycle progression. Among this network, NPM1, a nucleolar multi-functional protein frequently deregulated in cancer, emerged as another potential target related to treatment resistance in DLBCL. Immunohistochemistry evaluation of CYCLON and NPM1 revealed that their co-expression is strongly related to inferior prognosis in DLBCL. More specifically, alternative sub-cellular localizations of the proteins (extra-nucleolar CYCLON and pan-cellular NPM1) represent independent predictive factors specifically associated to R-CHOP refractory DLBCL patients, which could allow them to be orientated towards risk-adapted or novel targeted therapies.
ABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous entity, in which the first-line treatment currently consists of an immuno-chemotherapy regimen (R-CHOP). However, around 30% of patients will not respond or will relapse. Overexpression of c-MYC or p53 is frequently found in DLBCL, but an association with prognosis remains controversial, as for other biomarkers previously linked with DLBCL aggressivity (CD5, CD23, or BCL2). The aim of this study was to explore the expression of these biomarkers and their correlation with outcome, clinical, or pathological features in a DLBCL cohort. Immunohistochemical (c-MYC, p53, BCL2, CD5, and CD23), morphological ('starry-sky' pattern [SSP]), targeted gene panel sequencing by next-generation sequencing (NGS), and fluorescence in situ hybridisation analyses were performed on tissue microarray blocks for a retrospective cohort of 94 R-CHOP-treated de novo DLBCL. In univariate analyses, p53 overexpression (p53high ) was associated with unfavourable outcome (p = 0.04) and with c-MYC overexpression (p = 0.01), whereas c-MYC overexpression was linked with an SSP (p = 0.004), but only tended towards an inferior prognosis (p = 0.06). Presence of a starry-sky morphology was found to be correlated with better survival in p53high DLBCL (p = 0.03) and/or c-MYC-positive DLBCL (p = 0.002). Furthermore, NGS data revealed that these three variables were associated with somatic mutations (PIM1, TNFRSF14, FOXO1, and B2M) involved in B-cell proliferation, survival, metabolism, and immune signalling. Taken together, these results show that the SSP pattern seems to be a protective factor in high-risk DLBCL subgroups and highlight cell death as a built-in failsafe mechanism to control tumour growth.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Lymphoma, Large B-Cell, Diffuse/drug therapy , Proto-Oncogene Proteins c-myc/analysis , Tumor Suppressor Protein p53/analysis , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Female , High-Throughput Nucleotide Sequencing , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Lymphoma, Large B-Cell, Diffuse/chemistry , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Prednisone/therapeutic use , Proto-Oncogene Proteins c-myc/genetics , Retrospective Studies , Rituximab/therapeutic use , Tissue Array Analysis , Treatment Outcome , Tumor Suppressor Protein p53/genetics , Vincristine/therapeutic useABSTRACT
B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.
Subject(s)
Leukemia, Prolymphocytic, B-Cell/genetics , Proto-Oncogene Proteins c-myc/genetics , Tumor Suppressor Protein p53/genetics , Aged , Aged, 80 and over , Chromosome Aberrations , Cytogenetic Analysis , Female , Humans , Male , Middle Aged , PrognosisABSTRACT
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).
Subject(s)
Biomarkers/cerebrospinal fluid , Central Nervous System Neoplasms/diagnosis , Interleukin-10/metabolism , Interleukin-6/metabolism , Aged , Aged, 80 and over , Central Nervous System Neoplasms/pathology , Female , Humans , Male , Middle AgedABSTRACT
OBJECTIVES: This study investigates whether achieving complete remission (CR) with undetectable minimal residual disease (MRD) after allogeneic stem cell transplantation (allo-SCT) for chronic lymphocytic leukemia (CLL) affects outcome. METHODS: We retrospectively studied 46 patients transplanted for CLL and evaluated for post-transplant MRD by flow cytometry. RESULTS: At transplant time, 43% of the patients were in CR, including one with undetectable MRD, 46% were in partial response, and 11% had refractory disease. After transplant, 61% of the patients achieved CR with undetectable MRD status. By multivariate analysis, reaching CR with undetectable MRD 12 months after transplant was the only factor associated with better progression-free survival (P = 0.02) and attaining undetectable MRD, independently of the time of negativity, was the only factor that correlated with better overall survival (P = 0.04). CONCLUSION: Thus, achieving undetectable MRD status after allo-SCT for CLL is a major goal to improve post-transplant outcome.
Subject(s)
Flow Cytometry/methods , Hematopoietic Stem Cell Transplantation , Leukemia, Lymphocytic, Chronic, B-Cell , Allografts , Disease-Free Survival , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Male , Middle Aged , Neoplasm, Residual , Survival RateSubject(s)
Blindness/diagnosis , Blindness/etiology , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Evoked Potentials, Visual , Fluorescein Angiography , Humans , Magnetic Resonance Imaging , Male , Optic Nerve Diseases/complications , Optic Nerve Diseases/diagnosis , Optic Nerve Diseases/drug therapy , Slit Lamp Microscopy , Syndrome , Tomography, Optical Coherence , Waldenstrom Macroglobulinemia/complications , Waldenstrom Macroglobulinemia/drug therapyABSTRACT
No data are available on outcomes of patients with lymphoma requiring intensive care unit (ICU) admission. We retrospectively studied 190 patients admitted to our ICU between 2000 and 2010, before or during the first chemotherapy course for lymphoma. Reasons for ICU admission were renal failure (36%), shock (28%), respiratory failure (26%), coma (22%) and monitoring (12%). Mechanical ventilation was needed in 45% of patients, dialysis in 41% and vasoactive drugs in 30%. ICU, hospital and 1-year mortality rates were 22%, 37% and 51%. By multivariate analysis, factors associated with higher hospital mortality were age > 50 years (odds ratio [OR], 2.23; 95% confidence interval [CI], 1.02-4.9), poor performance status (OR, 3.36; 95% CI, 1.47-6.54), high Sequential Organ Failure Assessment (SOFA) score (OR, 1.15/point; 95% CI, 1.04-1.27), hemophagocytic syndrome (OR, 2.57; 95% CI, 1.03-6.40), Burkitt lymphoma (OR, 3.36; 95% CI, 1.38-8.19) and primary cerebral lymphoma (OR, 7.32; 95% CI, 1.06-50.54). Admission after 2004 was associated with better survival (OR, 0.35; 95% CI, 0.15-0.78).
Subject(s)
Hospitalization , Intensive Care Units , Lymphoma/epidemiology , Adult , Comorbidity , Female , France/epidemiology , Humans , Lymphoma/diagnosis , Male , Middle Aged , Mortality , Odds Ratio , Outcome Assessment, Health Care , Retrospective StudiesABSTRACT
Deletions of the long arm of chromosome 14 [del(14q)] are rare but recurrently observed in mature B-cell neoplasms, particularly in chronic lymphocytic leukemia (CLL). To further characterize this aberration, we studied 81 cases with del(14q): 54 of CLL and 27 of small lymphocytic lymphoma (SLL), the largest reported series to date. Using karyotype and fluorescence in situ hybridization (FISH), the most frequent additional abnormality was trisomy 12 (tri12), observed in 28/79 (35%) cases, followed by del13q14 (12/79, 15%), delTP53 (11/80, 14%) delATM (5/79, 6%), and del6q21 (3/76, 4%). IGHV genes were unmutated in 41/53 (77%) patients, with a high frequency of IGHV1-69 (21/52, 40%). NOTCH1 gene was mutated in 14/45 (31%) patients. There was no significant difference in cytogenetic and molecular abnormalities between CLL and SLL. Investigations using FISH and SNP-array demonstrated the heterogeneous size of the 14q deletions. However, a group with the same del(14)(q24.1q32.33) was identified in 48% of cases. In this group, tri12 (P = 0.004) and NOTCH1 mutations (P = 0.02) were significantly more frequent than in the other patients. In CLL patients with del(14q), median treatment-free survival (TFS) was 27 months. In conclusion, del(14q) is associated with tri12 and with pejorative prognostic factors: unmutated IGHV genes (with over-representation of the IGHV1-69 repertoire), NOTCH1 mutations, and a short TFS.