Clonal B-Cell Lymphocytosis with Mariginal-Zone Features: Comparison with Overt Splenic Marginal-Zone Lymphomas in 77 Patients from a Monocentric Series

Diagnosis of non-CLL B Cell Chronic Lymphoproliferative Disorders (BCLPD), defined by the detection of peripheral blood (PB) B-Cell clone with flow cytometry (FC) Matutesscore≤3, is not an infrequent event in clinical daily practice. Only a portion of these cases may be actually classified according to the 2016 revision of WHO classification of lymphoid neoplasms, as in these cases a non-bone marrow (BM) tissue biopsy is rarely available due to "liquid-only disease" (BM, PB, splenomegaly) or difficult accessible sites. The two most likely diagnosis of BCLPD according to WHO 2016 are splenic marginal-zone lymphoma (SMZL) and monoclonal B Cell lymphocytosis (MBL) with non-CLL phenotype (CD19+, CD20+, SIg+, CD5-), sometimes reported as MZL-like, defined by monotypic clonal B lymphocytes (CBL) <5 x 109/l. A recent study pointed out a similar outcome regardless CBL value exceeding or not this arbitrary cut-off in strictly defined cases (absence of cytopenias, splenomegaly and adenopathy) of clonal B cell lymphocytosis with marginal-zone features (CBL-MZ) and confirmed the really indolent behaviour of this entity (Xochelli, Blood 2014). On these bases we decided to retrospectively collect clinical, immunophenotypic, molecular features and outcome of all consecutive patients (pts) with CD5- CBL-MZ owing to the Department of Hematology of University of Insubria (Varese, Italy) from 2011 to 2019 and to compare them with overt SMZL cases. Excluding 5 SMZL pts who were splenectomized, all cases were diagnosed by means of non-BM tissue biopsy, namely BM histology and PB/BM FC, FISH and molecular studies, when appropriate, and complete laboratory and imaging staging procedures (CT scan or US). The primary objective of the study was time to progression (TTP) for CBL-MZ group. Secondary objectives were overall survival (OS), progression-free survival (PFS) for treated pts and evaluation of early progression <24 months (Early POD) (Luminari, Blood 2019). Overall we collected complete data of 33 pts with CD5- CBL-MZ, and 44 with SMZL (Table 1). Focusing on CBL-MZ, FC immunophenotypic findings showed a B-Cell population with Matutes score 0 to 2 in all cases, uniform expression of B Cell antigens, namely CD19, CD20 strong, FMC7 (93%), SIg (intermediate/bright in 71%), while CD10 and CD5 were consistently negative. CD23 was expressed in 18%, CD38 in 9% and CD49b in 95%. BM sinusoidal infiltration pattern was detected in 50% of cases. TP53 mutation/deletion was detected in 4/16 pts (25%) while trisomy 12 and del13q in 1 pt each. Twenty pts presented with <5000/mmc CBL (MBL-MZ) and 13 with ≥5000/mmc CBL. With a median follow-up of 1.8 years, 6 pts (18%) progressed (4 in SMZL, 1 NMZL and 1 SLL; Fig 2) with a median TTP of 1.7 yrs (range 0.3- 12.3), while the remaining 27 remained completely stable. Among 4 pts treated, 2 received Rituximab-based regimen, both achieving CR and 2 with Chlorambucil both experiencing progression. Overall, 5 pts died (2 for progressive lymphoma), with an estimated 5-yrs of 80%. Concerning prognostic factors, after adjusting by competing risk method, at univariate analysis age >60 yrs, CBL >5000/mmc and albumin <3.5 g/dl, were associated to shorter TTP, while age >60 yrs, Hb <11 g/dl, ECOG PS ≥2 and albumin <3.5 g/dl resulted predictive of worse OS (Table 2). By applying multivariate Cox regression model, only age >60 yrs and CBL>5000/mmc retained prognostic significance for TTP (p<0.0001), while ECOG PS ≥2 and albumin <3.5 g/dl remained independently associated with inferior OS (p<0.0001). Considering the SMZL group, 34 pts underwent systemic treatment (rituximab-based in 32, including R-Bendamustine in 17). With a median follow-up time of 2.8 yrs, 9 pts progressed (4 of whom within 24 months from treatment initiation), with a median PFS 2.9 yrs, and 8 died (7 due to progression, including 3 DLBCL transformations) with an estimated 5-yrs OS of 79%. Notably, Early POD SMZL pts exhibited a significant increased risk of death (p<0.0001, fig.2), while in CBL-MZ did not (p=0.4). In conclusion, CBL-MZ confirmed to be associated with indolent course and preferential evolution toward SMZL, of which it can be viewed as an initial phase or a precursor entity. In contrast with previous findings, the WHO 16 CBL cut-off defining MBL (5 x 109/l), together with advanced age, retained prognostic relevance for TTP. Finally, we confirmed for the first time in an independent series of SMZL the highly prognostic impact of Early POD24. Disclosures Passamonti: Roche: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Download Full-text

Acquired Angioedema due to C1 Inhibitor Deficiency Preceding Splenic Marginal Zone Lymphoma: Further Insights from Clinical Practice

International Archives of Allergy and Immunology ◽

10.1159/000509805 ◽

2020 ◽

Vol 181 (12) ◽

pp. 941-946

Author(s):

Mariana Paes Leme Ferriani ◽

Orlando Trevisan-Neto ◽

Julia S. Costa ◽

Janaina M.L. Melo ◽

Adriana S. Moreno ◽

...

Keyword(s):

Clinical Practice ◽

Marginal Zone ◽

Marginal Zone Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

C1 Inhibitor ◽

C1 Inhibitor Deficiency ◽

Acquired Angioedema ◽

Risk Of Death ◽

Increased Risk

Background: Acquired angioedema due to C1 inhibitor deficiency (AAE-C1-INH) is a very rare disease. In clinical practice, it may be difficult to differentiate AAE-C1-INH from hereditary angioedema due to C1-INH deficiency (HAE-C1-INH). In both conditions, patients are at an increased risk of death from asphyxiation due to upper airway obstruction. The association of AAE-C1-INH with lymphoproliferative and autoimmune diseases, and with presence of anti-C1-INH antibodies has been well documented, and treatment of the underlying condition may result in complete remission of angioedema. Objectives: To discuss the clinical evaluation, diagnosis, and treatment outcomes of AAE-C1-INH in the context of the care of 2 patients with recurrent isolated angioedema. Methods: Two patients were followed up prospectively at our clinic. Measurements of C3, C4, C1-INH, and C1q levels were carried out by nephelometry, and the functional activity of C1-INH was determined by a chromogenic assay. Hematological investigation included morphological and immunophenotyping analysis of peripheral blood, bone marrow, and spleen histopathology. Sequencing of the 8 exons and adjacent intronic regions of the SERPING1 gene was performed using the Sanger method. Results: Two patients were diagnosed with AAE-C1-INH associated with splenic marginal zone lymphoma during follow-up. Conclusions: Close follow-up, including detailed clinical history, physical examination, and laboratory tests, of our patients with AAE-C1-INH was essential for the early diagnosis and successful treatment of the lymphoproliferative disease, leading to the resolution of the angioedema attacks.

Download Full-text

Prognostic impact of chemoradiation-related lymphopenia in patients with gastric and gastroesophageal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.249 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 249-249

Author(s):

Daniel W Kim ◽

Grace Lee ◽

Theodore S. Hong ◽

Guichao Li ◽

Eric Roeland ◽

...

Keyword(s):

Prognostic Factor ◽

Cox Model ◽

Gastroesophageal Junction ◽

Concurrent Chemotherapy ◽

Rank Test ◽

Prognostic Impact ◽

Poor Prognostic Factor ◽

Risk Of Death ◽

Increased Risk ◽

Ecog Ps

249 Background: Limited data exists on how chemoradiation (CRT)-induced lymphopenia affects survival outcomes in patients with gastric and gastroesophageal junction (GEJ) cancer. We evaluated the association between severe lymphopenia and its association with survival in gastric and GEJ cancer patients treated with CRT. We hypothesized that severe lymphopenia would be a poor prognostic factor. Methods: We performed a retrospective analysis of 154 patients with stage 1-3 gastric or GEJ cancer who underwent CRT at our institution. Patients underwent photon-based radiation therapy (RT) with a median dose of 50.4 Gy (IQR 45.0-50.4 Gy) over 28 fractions and concurrent chemotherapy (CTX) with carboplatin/paclitaxel, 5-fluorouracil based regimen, or capecitabine. 49% received CTX prior to RT. 84% underwent surgical resection, 57% pre-CRT and 26% post-CRT. Absolute lymphocyte count (ALC) at baseline and at 2 months since initiating RT were analyzed. Severe lymphopenia, defined as Grade 3 or worse lymphopenia (ALC < 0.5 k/μl), was analyzed for any association with overall survival (OS). Results: Median time of follow up was 48 months. Median age was 65. 77% were male and 86% were Caucasian. ECOG PS was 0 or 1 in 90% and 2 in 10%. Tumor location was stomach in 38% and GEJ in 62%. Timing of CRT was preoperative among 68% and postoperative among 32%. The median ALC at baseline for the entire cohort was 1.6 k/ul (range 0.3-7.0 k/ul). At 2 months post-CRT, 49 (32%) patients had severe lymphopenia. Patients with severe lymphopenia post-CRT had a slightly lower baseline TLC compared to patients without severe lymphopenia (median TLC 1.4 k/ul vs. 1.6 k/ul; p = 0.005). There were no differences in disease and treatment characteristics between the two groups. On the multivariable Cox model, severe lymphopenia post-CRT was significantly associated with increased risk of death (HR = 3.99 [95% CI 1.55-10.28], p = 0.004). ECOG PS 2 (HR = 34.97 [95% CI 2.08-587.73], p = 0.014) and postoperative CRT (HR = 5.55 [95% CI 1.29-23.86], p = 0.021) also predicted worse OS. The 4-year OS among patients with severe lymphopenia was 41% vs. 61% among patients with vs. without severe lymphopenia (log-rank test p = 0.041). Conclusions: Severe lymphopenia significantly correlated with poorer OS in patients with gastric or GEJ cancer treated with CRT. CRT-induced lymphopenia may be an important prognostic factor for survival in this patient population. Closer observation in high-risk patients and treatment modifications may be potential approaches to mitigating CRT-induced lymphopenia.

Download Full-text

Prognostic Impact of Transfusions Intensity on Survival and Development of Thrombocytopenia in Newly Diagnosed Lower-Risk MDS Patients Participating in the European Leukemianet EU-MDS Registry

Blood ◽

10.1182/blood.v126.23.1677.1677 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1677-1677

Author(s):

Louise De Swart ◽

Tom Johnston ◽

Alexandra Smith ◽

Pierre Fenaux ◽

Argiris Symeonidis ◽

...

Keyword(s):

Lower Risk ◽

Research Funding ◽

Control Group ◽

Rapid Decline ◽

Prognostic Impact ◽

Platelet Counts ◽

Risk Of Death ◽

Increased Risk ◽

The Impact

Abstract Background The outcome of lower-risk MDS patients with red blood cell transfusions (RBCT) dependency is inferior to that of RBCT independent patients, but whether the intensity of RBCT is important for prognosis is unknown. The EUMDS Registry is a non-interventional, observational longitudinal study enrolling patients with lower-risk MDS from 142 sites in 17 countries as described elsewhere (1). The EUMDS registry has accrued 1,902 patients as of July 21, 2015. We hypothesized that RBCT intensity is an independent prognostic factor for survival. Methods We first assessed the impact of RBCT intensity in the first year post-diagnosis (1yrPD) on progression-free survival among the 1034 patients who survived at least 1yrPD and had potential for a further year of follow-up. Secondly, we developed a longitudinal model of platelet counts throughout follow-up for 1660 patients in the registry with potential for at least one year follow-up. Results Among the 1034 patients, 323 patients had died: 67 after progression to higher-risk MDS/AML and 256 without progression. A further 41 surviving patients had progressed to AML. The overall 5-year survival was 52%. In a proportional hazards regression model (Table), the risk of death or progression increased in a non-linear fashion with age at diagnosis (p<0.001). The risk of death was increased in the intermediate IPSS-R risk group compared to low risk. Patients with RARS and 5q- syndrome had a better outcome compared to RCMD. Increased RBCT intensity in 1yrPD (Table, Figure) was strongly associated with an increased risk of death (p<0.001). In the 1660 patients no significant decline in platelet counts was observed (0.16x109 platelets/l average monthly decline, p=0.16) among patients who were not RBC transfused at any time during follow-up. However platelet counts of patients receiving RBCT declined more quickly (p<0.0001) at an average rate of 1.14x109 platelets/l/month. Among the 920 RBCT dependent patients, lower platelet counts were associated with receiving more RBCT units in the preceding six months. 185 Patients had at least 2 observations both before and after becoming RBCT dependent, defined as 1st RBCT. 50% of these patients had a decreasing trend of platelets prior to their 1st RBCT and 67% had a decreasing slope of platelets after their 1st RBCT. In the control group of RBC untransfused patients, decreasing slopes of platelets occurred in around 50% of the patients throughout the whole observation period of 4 visits. Logistic regression of the risk of having a post-1st RBCT decreasing trend in platelets showed that transfused patients were at a greater risk (OR=1.7, 95% CI: 1.1-2.7) of having a post-1st RBCT decreasing trend in platelets than untransfused patients. Conclusion These multivariate regression models including age, sex, country, IPSS and WHO classification showed that more intensive RBCT treatment is associated with poor prognosis and a more rapid decline of platelets. This indicates that the intensity of RBCT should be incorporated in the regular prognostic scoring systems and the choice of therapeutic interventions. (1): De Swart L et al. Br J Haematol 2015; 170: 372-83. Disclosures Fenaux: NOVARTIS: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding. Hellström-Lindberg:Celgene Corporation: Research Funding. Sanz:JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau. Mittelman:Roche: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Amgen: Research Funding. Almeida:Bristol Meyer Squibb: Speakers Bureau; Shire: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Park:Hospira: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Itzykson:Oncoethix: Research Funding. de Witte:Novartis: Research Funding.

Download Full-text

Long-term outcomes of survivors of autologous hematopoietic-cell transplantation for refractory and relapsed Hodgkin’s Disease

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.6554 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 6554-6554

Author(s):

K. A. Goodman ◽

V. Serrano ◽

E. R. Riedel ◽

S. Gulati ◽

C. H. Moskowitz ◽

...

Keyword(s):

Hematopoietic Cell Transplantation ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Hematopoietic Cell ◽

High Dose ◽

Cell Transplant ◽

Hematopoietic Cell Transplant ◽

Risk Of Death ◽

Increased Risk

6554 Background: With improvements in survival among refractory/relapsed Hodgkin’s Lymphoma (HL) patients after high-dose chemo-radiotherapy and autologous hematopoietic-cell transplant (AHCT), it is important to evaluate risk of late complications in this heavily treated population. Methods: From 1985–1998, 218 refractory/relapsed HL patients were treated on high dose chemo-radiotherapy and AHCT salvage protocols. 153 (70%) surviving ≥2 years after AHCT were analyzed. All received either radiotherapy with initial therapy or total lymphoid irradiation and involved field boost with the conditioning regimen (43%). Information from surviving patients was obtained through a self-administered questionnaire. The NDI was queried to determine vital status and cause of death. Primary endpoint was non-HL mortality, defined as mortality due to cardiac causes, infection or second malignancy (SM). Competing risk methods were used to calculate cause-specific mortality rates and examine its predictors. All events were calculated from 2 years post-AHCT to date of death/last follow-up. Results: Median follow-up time was 11 years. There have been 51 deaths, 32 due to HL and 19 due to other causes. Eleven deaths were due to SM: AML (3), MDS (2), NHL (2), NSCLC (2), gastric and colon cancer. There were 8 non-SM deaths: cardiac toxicity (4), infection, aplastic anemia, suicide, unknown causes (1 each). The 10 and 15-year overall survival (OS) rates are 64% and 57%, respectively. The 10-year cumulative incidence of death from HL and from non-HL causes were 22% and 13.5% ( table ). By univariate analysis, increased risk of death due to SM was associated only with higher age at AHCT (p=0.02). Conclusions: While HL initially accounts for the majority of deaths among patients surviving high-dose therapy, the HL mortality rate plateaus and risk of death from non-HL mortality increases after 5 years. Yet, even at 15-years, SM risk does not exceed that observed in patients treated with standard regimens. [Table: see text] No significant financial relationships to disclose.

Download Full-text

Cytogenetic aberrations and their prognostic value in a series of 330 splenic marginal zone B-cell lymphomas: a multicenter study of the Splenic B-Cell Lymphoma Group

Blood ◽

10.1182/blood-2010-02-267476 ◽

2010 ◽

Vol 116 (9) ◽

pp. 1479-1488 ◽

Cited By ~ 119

Author(s):

Marta Salido ◽

Cristina Baró ◽

David Oscier ◽

Kostas Stamatopoulos ◽

Judith Dierlamm ◽

...

Keyword(s):

B Cell ◽

Prognostic Value ◽

Marginal Zone ◽

Univariate Analysis ◽

Collaborative Study ◽

Prognostic Significance ◽

B Cell Lymphoma ◽

Splenic Marginal Zone Lymphoma ◽

B Cell Lymphomas ◽

Cytogenetic Aberrations

We conducted a retrospective collaborative study to cytogenetically characterize splenic marginal zone lymphoma (SMZL) and ascertain the prognostic value of chromosomal aberrations. Of 330 cases, 72% displayed an aberrant karyotype, 53% were complex, and 29% had a single aberration. The predominant aberrations were gains of 3/3q and 12q, deletions of 7q and 6q and translocations involving 8q/1q/14q. CD5 expression was detected in 39 of 158 cases (25%). The cytogenetic makeup of the CD5+ group differed significantly from that of the CD5− group. Cases with unmutated IGHV were significantly associated with deletions of 7q and TP53. A strong association was noted between usage of the IGVH1-2 and deletion 7q, 14q alterations, and abnormal karyotype. On univariate analysis, patients with more than or equal to 2 aberrations, 14q alterations, and TP53 deletions had the shortest survival; 7q deletion did not affect survival. On multivariate analysis, cytogenetic aberrations did not retain prognostic significance; the parameters negatively affecting survival were hemoglobin and age. In conclusion, the cytogenetic profile of SMZL is distinct from other B-cell lymphomas. Complexity of the karyotype, 14q aberrations, and TP53 deletions are poor prognostic indicators and may be considered together with other clinicobiologic parameters to ascertain the prognosis of SMZL.

Download Full-text

TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs)

Blood ◽

10.1182/blood-2009-04-215814 ◽

2009 ◽

Vol 114 (15) ◽

pp. 3285-3291 ◽

Cited By ~ 188

Author(s):

Olivier Kosmider ◽

Véronique Gelsi-Boyer ◽

Meyling Cheok ◽

Sophie Grabar ◽

Véronique Della-Valle ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Univariate Analysis ◽

Good Prognosis ◽

World Health ◽

International Prognostic Scoring System ◽

Prognostic Impact ◽

Missense Mutations ◽

Risk Of Death ◽

Increased Risk ◽

Tet2 Mutation

Abstract Oncogenic pathways underlying in the development of myelodysplastic syndromes (MDS) remain poorly characterized, but mutations of the ten-eleven translocation 2 (TET2) gene are frequently observed. In the present work, we evaluated the prognostic impact of TET2 mutations in MDS. Frameshift, nonsense, missense mutations, or defects in gene structure were identified in 22 (22.9%) of 96 patients (95% confidence interval [CI], 14.5-31.3 patients). Mutated and unmutated patients did not significantly differ in initial clinical or hematologic parameters. The 5-year OS was 76.9% (95% CI, 49.2%-91.3%) in mutated versus 18.3% (95% CI, 4.2%-41.1%) in unmutated patients (P = .005). The 3-year leukemia-free survival was 89.3% (95% CI, 63.1%-97.0%) in mutated versus 63.7% (95% CI, 48.2%-75.4%) in unmutated patients (P = .035). In univariate analysis (Cox proportional hazard model), the absence of TET2 mutation was associated with a 4.1-fold (95% CI, 1.4-12.0-fold) increased risk of death (P = .009). In multivariate analysis adjusted for age, International Prognostic Scoring System, and transfusion requirement, the presence of TET2 mutation remained an independent factor of favorable prognosis (hazard ratio, 5.2; 95% CI, 1.6-16.3; P = .005). These results indicate that TET2 mutations observed in approximately 20% of patients, irrespective of the World Health Organization or French-American-British subtype, represent a molecular marker for good prognosis in MDS.

Download Full-text

Treatment of Low-Grade Non-Hodgkin Lymphomas with Fludarabine and Mitoxantrone Followed by Rituximab Maintenance: Results of a Phase II Study.

Blood ◽

10.1182/blood.v108.11.4716.4716 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4716-4716

Author(s):

Amanda Psyrri ◽

Meletios A. Dimopoulos ◽

George Fountzilas ◽

Constantinos Tsatalas ◽

Athanasios Anagnostopoulos ◽

...

Keyword(s):

B Cell ◽

Marginal Zone ◽

Active Agent ◽

Stage Iv ◽

B Cell Lymphoma ◽

Low Grade ◽

Splenic Marginal Zone Lymphoma ◽

Rituximab Maintenance ◽

Indolent Lymphomas

Abstract The combination of fludarabine and mitoxantrone (FN) has been a well-tolerated and effective regimen for the treatment of indolent lymphomas. Rituximab is an active agent for the treatment of CD20-positive B-cell lymphomas. In the present study, we sought to determine the activity of FN chemotherapy followed by maintenance Rituximab in indolent lymphomas. Patients with indolent lymphoma received fludarabine 25 mg/m2 day 1–3 and mitoxantrone 10mg/m2 every 28 days. Patients who attained a response (CR or PR) received 4 weekly doses of Mabthera 375mg/m2 1 month and 3 months after completion of treatment. The primary endpoint of the study was to evaluate the response to this regimen and secondary endpoints were survival and toxicity. Forty-six patients were included in the study. The median follow-up time was 29 months. Six patients were stage I, 8 stage II, 3 stage III and 29 stage IV. Histology was distributed as follows: small lymphocytic lymphoma (SLL) 15 patients, splenic marginal zone lymphoma 3, lymphoplasmocytic lymphoma 1, marginal zone B-cell lymphoma 16 (extranodal 12 and nodal 4), follicular grade I 6 and follicular grade II 5 patients. The median number of delivered cycles was 6. Fifty-two percent of patients attained a complete response (CR) and 39% a partial response (PR) for an overall response rate of 91%. One patient had stable disease, one had progression of the disease, whereas 2 were non-evaluable. After a median follow-up of 29 months, 34 of 46 patients (74%) are alive and disease-free. Grade III and IV toxicities included neutropenia (28%), thrombocytopenia (7%), anemia (4%), and diarrhea (2%). In conclusion, FN followed by Rituximab maintenance is an active and well-tolerated regimen in the treatment of patients with indolent lymphomas.

Download Full-text

Clonal B-Cell Lymphocytosis with Marginal Zone Features and Splenic Marginal Zone Lymphoma Share a Similar Cytogenetic and Mutational Profile

Blood ◽

10.1182/blood.v128.22.2962.2962 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2962-2962

Author(s):

Paul Legendre ◽

Olivier Kosmider ◽

Coralie Derrieux ◽

Nicolas Chapuis ◽

Isabelle Radford-Weiss ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Marginal Zone ◽

Univariate Analysis ◽

Marginal Zone Lymphoma ◽

Fish Analysis ◽

Splenic Marginal Zone Lymphoma ◽

First Line ◽

Significant Difference ◽

First Line Treatment

Abstract Introduction: Clonal B-cell lymphocytosis with marginal zone features (CBL-MZ) is a non-CLL type B-cell monoclonal lymphocytosis that has been recently recognized in the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. Whether CBL-MZ corresponds to the early stage of splenic marginal zone lymphoma (SMZL) is not clearly defined. The aim of the study was to compare CBL-MZ and SMZL in patients diagnosed during the same period in two French university hospitals. Methods: We performed a retrospective study including all consecutive patients with a diagnosis of CBL-MZ or SMZL between 2010 and 2014. For the purpose of the present study, all CBL-MZ and SMZL were reclassified according to the 2016 WHO classification. Patient and disease characteristics comprised clinical data, immunophenotyping of lymphocytes by flow cytometry, cytogenetic studies (G-banding and TP53 FISH) and targeted gene sequencing (TP53, NOTCH2 and MYD88). We assessed progression-free survival (PFS), lymphoma-specific survival (LSS), overall survival (OS) and cumulative incidence of histologic transformation. Results: Forty-one patients were diagnosed with CBL-MZ (n=15) or SMZL (n=26) on consensus review. None had HCV infection. Median age was 74 years (range 43-93). At diagnosis, B symptoms (7% vs 46%, p=0.009), elevated lactate dehydrogenase (13% vs 50%, p=0.023) and elevated β2-microglobulin (50% vs 93%, p=0.039) were significantly more frequent in SMZL patients. HPLL score A was more frequent in patient with CBL-MZ (93% vs 58%, p=0.003). On lymphocyte immunophenotyping, CD23 was expressed only in SMZL (0% vs 38%, p=0.015). Aberrant karyotype was displayed in 5/7 CBL-MZ and 15/18 of SMZL (p=0.591). Fourteen patients (56%; 2 CBL-MZ and 12 SMZL, p=0.177) had at least 3 chromosomal abnormalities and were considered to have a complex karyotype. There was no significant difference between CBL-MZ and SMZL for the frequency of detection of +3, +12, +18, del(7q) or 14q alterations. A chromosome 17p abnormality or monosomy 17 was seen in 12/25 patients (48%) without significant difference between CBL-MZ and SMZL, and was confirmed in 11/11 cases by TP53 FISH analysis (one patient had an isochromosome 17q and TP53 FISH was not done). In 11 other patients, no TP53 deletion was detected by FISH. In the 2 remaining patients (one normal karyotype and one abnormal karyotype without abnormal 17p) there was no more material for FISH analysis. TP53 mutation was present in 1/15 (7%) CBL-MZ and 6/22 (27%) SMZL (p=0.161), NOTCH2 mutation in 1/15 (7%) CBL-MZ and 3/22 (14%) SMZL (p=0,632) and MYD88 mutation in 1/15 (7%) CBL-MZ and 3/22 (14%) SMZL (p=0.632). After a median follow-up of 47 months (CBL-MZ, 52 months; SMZL, 46 months, p=0.771), no CBL-MZ patients had event (progression, histologic transformation or death) or started treatment, whereas 24/26 (92%) SMZL patients started a first-line treatment (chemotherapy in 62%, rituximab in 42% and/or splenectomy in 39%). Twelve SMZL patients (50% of treated patients) relapsed or progressed after the first-line treatment. Among them, 6 had histologic transformation, either in diffuse large B-cell lymphoma (DLBCL, n=5) or Hodgkin lymphoma (HL, n=1). Finally, 5 SMZL patients died (3 of DLBCL, 1 of HL, 1 of SMZL). Overall, 4-year PFS was 100% and 31% (95% CI, 13% to 49%) for CBL-MZ and SMZL, respectively (p=0.002); 4-year LSS was 100% and 77% (95% CI, 61% to 93%) for CBL-MZ and SMZL, respectively (p=0.26); and 4-year OS was 100% and 71% (95% CI, 54% to 88%) for CBL-MZ and SMZL, respectively (p=0.25). Clinical, laboratory, cytogenetic and molecular features were subjected to univariate analyses to evaluate their impact on PFS, LSS, OS and histologic transformation in SMZL patients. In univariate analysis for PFS, only NOTCH2 mutations and TP53 inactivation (i.e. del(17p) or TP53 mutations) predicted poorer PFS, but in multivariate analysis NOTCH2 mutations were the sole factor significantly affecting PFS rates (p=0.041). For LSS, OS and histologic transformation, no prognostic factor was identified in univariate analysis. Conclusions: Our data suggest that CBL-MZ and SMZL share a similar cytogenetic and mutational profile. These findings suggest the possible involvement of a common oncogenic mechanism in the development of these lymphoid neoplasms. Disclosures Hermine: Novartis: Research Funding; Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Research Funding.

Download Full-text

Monitoring PD-L1 expression on circulating tumor cells (CTCs) in patients with NSCLC treated with PD1 inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.147 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 147-147

Author(s):

Nicolas Marie Guibert ◽

Myriam Delaunay ◽

Amellie Lusque ◽

Sandrine Gouin ◽

Nadia Boubekeur ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Nsclc Patient ◽

Standard Of Care ◽

Prognostic Impact ◽

Risk Of Death ◽

Non Invasive ◽

Increased Risk ◽

Coefficient Corrélation

147 Background: Inhibitors of the immune checkpoint PD-1/PD-L1 have become a standard of care in NSCLC. Patient selection, currently based on PD-L1 expression in tumor tissue, is limited by its temporal and spatial heterogeneity. We hypothesized that monitoring PD-L1 staining of circulating tumor cells (CTCs) could represent a valuable non-invasive biomarker. Methods: Up to 3 blood samples were prospectively collected from patients with advanced NSCLC: i) pretreatment (nivolumab), ii) first follow-up, iii) progression. CTCs were isolated from 10 mL of blood using cell size-based technology (ISET, Rarecells). PD-L1 expression was assessed by immunofluorescence on CTCs and immunohistochemistry on tissue. Results: 162 samples from 96 patients were collected. PD-L1 expression could be assessed pretreatment on tissue and CTCs in 72% and 93%, respectively; and was ≥1% in 37% and 83%; ≥5% in 35% and 79%, respectively. No correlation between tissue and CTCs PD-L1 expressions was observed (Spearman coefficient correlation = 0.04, p = 0.77). At baseline, each 10/7.5 ml increase in CTCs count was associated with increased risk of death and progression (HR[95%CI]: 1.06 [1.005;1.117] p = 0.03 for OS and HR[95%CI]: 1.05 [1.01;1.10] p = 0.02 for PFS). The presence of PD-L1(+)CTC (≥1%) had no prognostic impact (OS: p = 0.89 and PFS: p = 0.55), but pretreatment PD-L1(+)CTCs were more frequent in the “non-responders” group (PFS < 6 months) (p = 0.04). Median CTC count was 30 (n = 96), 68.3 (n = 44) and 50.3 (n = 22) pretreatment, at the first follow-up and at progression, respectively. The changes in CTC count at the first follow-up had no impact on PFS (p = 0.45) or OS (p = 0.68). 96% of patients had PD-L1(+)CTCs at progression. Further analyses are ongoing to assess the prognostic value of the persistence of CTCs and PD-L1(+)CTCs at the first follow up and at progression. Conclusions: Analysis of PD-L1 expression on CTCs is highly feasible. PD-L1 expressions on tissue and CTCs are discordant, CTCs being more likely positives, suggesting false negatives occurring in small biopsies. Further analyses of the kinetics of this biomarker throughout ICI treatment, along with other circulating biomarkers, are ongoing. Clinical trial information: NCT02827344.

Download Full-text

Risk factors and prognostic impact of post-discharge bleeding after endovascular therapy for peripheral artery disease

Vascular Medicine ◽

10.1177/1358863x21992863 ◽

2021 ◽

pp. 1358863X2199286

Author(s):

Keiichi Hishikari ◽

Hiroyuki Hikita ◽

Fumichika Abe ◽

Naruhiko Ito ◽

Yoshinori Kanno ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Major Bleeding ◽

Endovascular Therapy ◽

Prognostic Impact ◽

Peripheral Artery ◽

Post Discharge ◽

Risk Of Death ◽

Increased Risk ◽

Artery Disease

This study evaluated the incidence, predictors, and impact of bleeding requiring hospitalization following successful endovascular therapy (EVT) for peripheral artery disease. Platelet inhibition after EVT reduces the risk of major adverse limb events but increases the risk of bleeding. The incidence of post-discharge bleeding after EVT, its independent predictors, and its prognostic importance in clinical practice have not been fully addressed. We evaluated 779 consecutive patients who underwent EVT. We found that 77 patients (9.9%) were hospitalized for major bleeding during follow-up after EVT (median 39 months, range 22–66 months), with almost half (48.1%) of the bleeding categorized as gastrointestinal bleeding. Significant predictors of post-discharge bleeding were hemodialysis (hazard ratio (HR), 3.12; 95% CI: 1.93 to 5.05; p < 0.001) and dual antiplatelet therapy (DAPT) use (HR, 1.87; 95% CI: 1.03 to 3.41; p = 0.041). During follow-up, the all-cause mortality-free survival rate was significantly worse in patients who had experienced major bleeding than in those who had not (log-rank test χ2 = 54.6; p < 0.001). Cox proportional hazards analysis showed that major bleeding (HR, 2.78; 95% CI: 1.90 to 4.06; p < 0.001) was an independent predictor of all-cause death after EVT. Hospitalization for post-discharge bleeding after EVT is associated with a substantially increased risk of death, even after successful EVT. We concluded that patients’ predicted bleeding risk should be considered when selecting patients likely to benefit from EVT, and that the risk should be considered especially thoroughly in hemodialysis patients.

Download Full-text