Lymphoproliferative Neoplasms Research Articles

Thyroid Complications Negatively Affect Therapeutic Response and Survival in Waldenstrom Macroglobulinaemia/ Lymphoplasmacytoid Lymphoma

Introduction: Waldenström macroglobulinaemia/ Lymphoplasmacytoid lymphoma (WM/LPL) is a rare lymphoproliferative neoplasm characterized by small B lymphocytes proliferation. Abnormalities of thyroid hormones are common in clinical courses. Yet, the role of thyroid complications has not been explored in WM/LPL. Hence, the aim of this study was to investigate the clinical significance of thyroid complications in WM/LPL.Methods: 105 clinically diagnostic WM/LPL patients from Shandong Provincial Hospital were enrolled with informed consents. Baseline and clinical data concerning sex, age, International Staging System Waldenstrom Macroglobulinemia (ISSWM) score et al were collected. Chi-square test was used for comparison of clinical characteristics. The Kaplan-Meier method was used for analysis of survival outcomes. Cox regression analyses were utilized to identify prognostic-related key factors associated with overall survival (OS) and progression-free survival (PFS) in WM/LPL patients. Microarray datasets GSE6691 were obtained from Gene Expression Omnibus.Results: Over the 105 WM/LPL patients, the median overall survival (OS) was not reached and median progression-free survival (PFS) was 96 months (Figure 1A, 1B). Patients classified as complete response (CR)/ partial response (PR)/ stable disease (SD), showed better OS and PFS than patients with progression disease (PD) (Figure 1C, D).There were 13.3% of enrolled patients with mixed thyroid complications. The results of Chi-square test showed that thyroid complications were significantly associated with reduced IgM level (p=0.036) and elevated β2-macroglobulin (p=0.032). Moreover, patients without thyroid comorbidities were more likely to get overall response (CR+PR) to the first-line treatment (p=0.004). Kaplan-Meier curves showed patients with thyroid complications had significantly shorter OS (p=0.02) and PFS (p<0.001) versus those without thyroid complications (Figure 1E, F).In the univariate Cox regression model, age (p=0.022), ISSWM score (p=0.014) and thyroid complications (p<0.001) were significantly associated with an increased risk of progression developed. Subsequent multivariate analysis showed the presence of thyroid complications was an independent prognostic indicator for PFS in WM/LPL patients (p=0.03). However, there was no statistical significance of thyroid complications in OS.Microarray dataset analysis was conducted to further investigate the role of thyroid-related genes in WM/LPL patients. A network of interactions among thyroid-related genes and critical factors in WM/LPL, including MYD88 and CXCR4, was shown in Figure 1G. Correlations were statistically significant between SLC5A5 (p<0.05), TG (p<0.01), TPO (p<0.01) and CXCR4 by Spearman correlation analysis (Figure 1H, I). In addition, differential gene expression analysis between the WM and normal lymphocytes was assessed (Figure 1J). Thyroid-related genes with statistical significance were annotated in the volcano plots (Figure 1K). Enrichment analysis indicated that differential genes were involving in PI3K-Akt signaling pathway and response to peptide hormone (Figure 1L). Moreover, five of them reached statistical significance, illuminating the potential importance of thyroid-related genes in WM/LPL (Figure 1M).Conclusion: Taken together, the present study was the first investigation on the role of thyroid complications in WM/LPL. Patients with thyroid complications showed worse clinical characteristics and conferred independent prognostic significance. The primary strength of this study is that it provides robust real-world evidence on the prognostic role of thyroid complications, highlighting the need to monitor and appropriately manage WM/LPL patients with thyroid complications in medical admissions. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

M100 PROPHYLACTIC PLASMA-DERIVED C1-ESTERASE-INHIBITOR REPLACEMENT IN A PATIENT WITH ACQUIRED ANGIOEDEMA AND POSSIBLE PRE-CLL CLONE

Acquired Angioedema (AAE) represents an extremely rare disorder with an estimated prevalence of 1:500,000. AAE pathogenesis involves decreased C1-esterase-inhibitor (C1-INH) function, leading to excess bradykinin. C1-INH deficiency may be attributed to consumption or C1-INH auto-antibody, sometimes with concomitant lymphoproliferative neoplasm or autoimmune disease.

The value of a new prognostic model developed by lymphocyte-monocyte ratio and platelet-monocyte ratio in peripheral T-cell lymphoma

Peripheral T-cell lymphoma(PTCL) is a group of lymphoproliferative tumors originated from post-thymic T cells or mature natural killer (NK) cells. It shows highly aggressive clinical behaviour, resistance to conventional chemotherapy, and a poor prognosis. Although a few prognostic models of PTCL have been established in retrospective studies, some high-risk patients still can not be screened out. Therefor we retrospectively studied 347 newly diagnosed PTCL patients and assessed the prognostic role of lymphocyte-monocyte ratio (LMR) and platelet-monocyte ratio (PMR) in the complete response (CR) and survival of PTCL patients. Patients with LMR ≤ 1.68 and PMR ≤ 300 achieved a lower CR rate and a poor survival. In multivariate analysis, LMR ≤ 1.68 (HR = 1.751, 95% CI 1.158–2.647, p < 0.05) and PMR ≤ 300 (HR = 1.762, 95% CI 1.201–2.586, p < 0.05) were independently associated with short survival. On this basis, a new prognostic model of PTCL was established to screen out high-risk patients. In our "Peripheral Blood Score (PBS)" model, three groups were identified at low risk (178 patients, 51.3%, score 0), intermediate risk (85 patients, 24.5%, score 1), and high risk (84 patients, 24.2%, score 2), having a 1-year OS of 86%, 55.3% and 22.6% (p < 0.05), and a 3-year OS of 43.4%, 20% and 13.1% (p < 0.05), respectively. Optimal strategies for identifying high-risk patients with PTCL are urgently needed. Our new PBS model is simple, inexpensive and widely available to screen out the high risk patients.

Lymphoproliferative Neoplasms With Plasmablastic Morphology

Plasmablastic morphology can be seen in several uncommon lymphoproliferative neoplasms. Sometimes it is difficult to distinguish these neoplasms from each other. To review the current understanding of major lymphoproliferative neoplasms with plasmablastic morphology; summarize the clinical, morphologic, immunophenotypic, cytogenetic, and molecular characteristics of each disease entity; and highlight a practical approach for differential diagnosis. Peer-reviewed medical literature and the authors' personal experience. Plasmablastic lymphoma; plasmablastic myeloma; primary effusion lymphoma; human herpesvirus 8-positive diffuse large B-cell lymphoma, not otherwise specified; and anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma are major lymphoproliferative neoplasms with plasmablastic morphology. These neoplasms share many common morphologic and immunophenotypic characteristics. Definitive diagnosis requires a thorough understanding of disease phenotype and diagnostic criteria of each category. Recognition of expression pattern of Epstein-Barr virus-encoded small RNA, human herpesvirus 8, and ALK in these neoplasms is critical for diagnosis in cases with typical presentation. Additional ancillary studies and clinical findings may help in difficult cases.

Primary gastric non-Hodgkin lymphomas: Recent advances regarding disease pathogenesis and treatment.

Primary gastric lymphomas (PGLs) are distinct lymphoproliferative neoplasms described as heterogeneous entities clinically and molecularly. Their main histological types are diffuse large B-cell lymphoma (DLBCL) or mucosa-associated lymphoma tissue. PGL has been one of the main fields of clinical research of our group in recent years. Although gastric DLBCLs are frequent, sufficient data to guide optimal care are scarce. Until today, a multidisciplinary approach has been applied, including chemotherapy, surgery, radiotherapy or a combination of these treatments. In this minireview article, we provide an overview of the clinical manifestations, diagnosis and staging of these diseases, along with their molecular pathogenesis and the most important related clinical published series. We then discuss the scientific gaps, perils and pitfalls that exist regarding the aforementioned studies, in parallel with the unmet need for future research and comment on the proper methodology for such retrospective studies. Aiming to fill this gap, we retrospectively evaluated the trends in clinical presentation, management and outcome among 165 patients with DLBCL PGL who were seen in our institutions in 1980-2014. The study cohort was divided into two subgroups, comparing the main 2 therapeutic options [cyclophosphamide doxorubicin vincristine prednisone (CHOP) vs rituximab-CHOP (R-CHOP)]. A better outcome with immunochemotherapy (R-CHOP) was observed. In the next 2 mo, we will present the update of our study with the same basic conclusion.

ESPLENECTOMÍA LAPAROSCÓPICA EN ESPLENOMAGALIA MASIVA POR LINFOMA NO HODGKIN DE ZONA MARGINAL.

Introduction: despite the fact that laparoscopic splenectomy for massive and supramassive splenomegaly constitutes a technical challenge, it is a feasible and safe procedure in the context of institutions with experienced teams in laparoscopic surgery.Objective: to present the first case of laparoscopic splenectomy for massive splenomegaly in Uruguay.Clinical case: the study presents the case of a 70-year-old patient carrier of peripheral pancytopenia, massive splenomegaly and a diagnosis of type B lymphoproliferative neoplasm based on bone marrow aspiration and biopsy, who underwent diagnostic and therapeutic splenectomy.The patient was operated in supine position with a 15-degree tilt, the trocars were placed under direct view, adapted to the size of the spleen which went from the diaphragm until the superior pelvic outlet. Splenectomy was performed in 220 minutes, the entire piece was removed through a hemi Pfannenstiel incision, without placing it in a bag, the wall being protected with a surgical wound retractor. There were no complications and the patient was discharged from hospital 48 hours. The blood count performed after 24 hours evidenced increase in all cell series and the pathology report confirmed diagnosis of marginal zone non- Hodgkin lymphoma.Discussion: laparoscoppic splenectomy in massive splenomegaly requires of a greater surgical time, although blood loss and hospital star are lower when compared to conventional procedures and evidence similar morbility. The initial experience of surgical teams reports 30% of conversions and readmissions.

ABCL-193: Insights into Diagnosis and Treatment of Nasopharyngeal Non-Hodgkin Lymphomas

Context Non-Hodgkin lymphomas (NHL) are heterogeneous lymphoproliferative tumors with different disease burdens (DB) and responses to treatment. Objective Identification of the diagnosis patterns and assessment of the short-term results of treatment in primary nasopharyngeal NHL. Design This analytical and cohort study included 66 patients with nasopharyngeal NHL who were managed at the Institute of Oncology from Moldova between 2014–2020. The diagnosis was proved by cytological, histopathological, and immunohistochemical examinations. Setting The patients’ follow-up and study were performed at the comprehensive cancer center. Patients The patients age ranged between 19–86 years (average age: 58.4±2,14 years). Stage I was diagnosed in 10 (15.2%) cases, stage II in 36 (54.5%), stage III in 8 (12.1), and stage IV in 12 (18.2). Main Outcomes Measures The ECOG-WHO score and complete response (CR) rate should estimate the short-term results of combined chemotherapy (CChT) and CChT followed by locoregional radiotherapy (LRT). Interventions The eligible patients underwent mostly CVChlP, R-CVChlP, CHOP, and R-CHOP regimens combined with LRT on bulky or residual tumors. Results The aggressive NHL were diagnosed mostly (76.1%) at stage I and II due to the earlier developed DB. The ECOG-WHO score accounted for 1–3. CR was achieved in 10 (100%) stage I cases after CChT and RT. CR occurred in 21 (67.7%) and partial response (PR) in 7 (22.6%) in stage II NHL after CChT and RT. In stage II NHL treated with CChT also, CR was achieved in 1 (25%) and PR in 2 (50%) cases. In stage III treated with CChT and RT, CR was registered in 1 (20%) and PR in 2 (40%) cases. Only PR occurred in 2 (66.7%) stage III cases and 1 (33.3%) stage IV case after CChT alone. In stage IV NHL, CR was obtained in 1 (11.1%) case and PR in 5 (55.6%) after CChT and RT. The ECOG-WHO score reached 0–1 as a result of CChT and RT in cases with CR and PR. Conclusions Aggressive NHLs were diagnosed mostly in localized stages due to the earlier developed DB. Regardless of stage, the highest response rates were achieved after R-CHOP regimen combined with LRT.

The "Undetermined Significance" of 18F-FDG PET/CT or PET/MRI in Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS).

Monoclonal gammopathy of undetermined significance (MGUS) is a highly prevalent condition with the possible risk of progression to multiple myeloma (MM) or a lymphoproliferative neoplasm in a small percentage of patients. Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) or positron emission tomography/magnetic resonance imaging (PET/MRI) are imaging methods increasingly used in patients with MM. The aim of this communication is to underline that, taking into account current evidence-based data, compared to MM the role of 18F-FDG PET/CT or PET/MRI in MGUS is still undetermined and more studies should be performed before suggesting 18F-FDG PET/CT or PET/MRI for evaluation of MM progression in patients with MGUS.

Late onset neutropenia after rituximab and obinutuzumab treatment – characteristics of a class-effect toxicity

Late onset neutropenia (LON) after rituximab is a previously described complication. We aimed to assess and characterize LON after obinutuzumab, a novel anti-CD20 antibody, in the real-world setting and compare it to LON after rituximab therapy. We retrospectively analyzed 330 consecutive patients with lymphoproliferative neoplasms (rituximab-treated n = 283; obinutuzumab-treated n = 47). LON occurred in 23% patients with similar incidence in rituximab (n = 66, 23%) or obinutuzumab (n = 10, 21%) groups (p = 0.853). Patients treated for CLL and post-transplantation lymphoproliferative disease (PTLD) were at higher risk to develop LON (multivariate analysis: HR for CLL − 6.62 CI 95% 1.33–32.92; HR for PTLD 15.82 CI 95% 2.04–122.4). Febrile neutropenia was uncommon during LON and occurred in 15 patients (4.5%; rituximab (n = 14) and obinutuzumab (n = 1). These data suggest that LON after obinutuzumab treatment is as common as with rituximab. The similarities in LON after rituximab and obinutuzumab argue for a possible class effect for anti-CD20 monoclonal antibodies.

The Role of Tumor-Associated Macrophages in Hematologic Malignancies.

Simple SummaryTumor-associated macrophages (TAM) represent a leading component of the tumor microenvironment in hematologic malignancies. TAM could display antitumor activity or, conversely, could contribute to tumor growth and survival, depending on their polarization. TAM are polarized towards form M1, with a pro-inflammatory phenotype and an antineoplastic activity, or M2, with an alternately activated phenotype, associated with a poor outcome in patients presenting with leukemia, lymphoma or multiple myeloma. The molecular mechanisms of TAM in different types of hematologic malignancies are different due to the peculiar microenvironment of each disease. TAM could contribute to tumor progression, reduced apoptosis and angiogenesis; a different TAM polarization could explain a reduced treatment response in patients with a similar disease subtype. The aim of our review is to better define the role of TAM in patients with leukemia, lymphoma or multiple myeloma. Finally, we would like to focus on TAM as a possible target for antineoplastic therapy.The tumor microenvironment includes dendritic cells, T-cytotoxic, T-helper, reactive B-lymphoid cells and macrophages; these reactive cells could interplay with malignant cells and promote tumor growth and survival. Among its cellular components, tumor-associated macrophages (TAM) represent a component of the innate immune system and play an important role, especially in hematologic malignancies. Depending on the stimuli that trigger their activation, TAM are polarized towards form M1, contributing to antitumor responses, or M2, associated with tumor progression. Many studies demonstrated a correlation between TAM, disease progression and the patient’s outcome in lymphoproliferative neoplasms, such as Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), even if with conflicting results. A critical hurdle to overcome is surely represented by the heterogeneity in the choice of the optimal markers and methods used for TAM analysis (gene-expression profile vs. immunohistochemistry, CD163vs. CD68vs. CD163/CD68 double-positive cells). TAM have been recently linked to the development and progression of multiple myeloma and leukemia, with a critical role in the homing of malignant cells, drug resistance, immune suppression and angiogenesis. As such, this review will summarize the role of TAM in different hematologic malignancies, focusing on the complex interplay between TAM and tumor cells, the prognostic value of TAM and the possible TAM-targeted therapeutic strategies.

Presence of Rare Germline Variants in Fanconi Anaemia Pathway Genes Confers a Poor Prognosis Comparable to TP53 Mutations in Therapy-Related Myeloid Neoplasms

Introduction: T-MN inclusive of therapy related myelodysplastic syndrome (T-MDS) and acute myeloid leukemia (T-AML) are aggressive neoplasms occurring after exposure to chemo (CT) and/or radiotherapy (RT) and are characterized by high frequency of complex cytogenetics and poor prognosis. TP53 and other genes involved in DNA repair such as Fanconi Anaemia(FANC) pathway are critical in maintaining genomic stability. TP53 mutations are associated with complex karyotype and poor prognosis in myeloid malignancies. Further, variants in the FANC pathway are a risk factor for malignancies, but remain less well studied in T-MN. Churpek et al . (Cancer 2016) reported germline mutations in BRCA1, BRCA2, TP53, CHEK2 and PALB2 in 8/43 (19%) treated breast cancer patients who developed T-MN. However, their interaction with TP53 mutations and impact on survival is unknown. Here we investigate the genomic architecture of T-MN patients from the South Australian Myelodysplastic Syndrome (SA-MDS) registry.Methods: Demographic, clinical and laboratory data including cytogenetic profile of 147 T-MN patients were analysed. Targeted Massively Parallel Sequencing of a custom panel of 63 genes (43 myeloid neoplasms associated genes & 20 FANC; all coding regions) was performed on diagnosis bone marrow samples from 101 T-MN samples. Rare FANC variants were selected based ExAC MAF <0.2% and variants only with VAL ≥20% were selected for further analysis. FANC variants were called deleterious if predicted to be deleterious by atleast two in-silico prediction model (e.g. CADD, SIFT, POLYPHEN and Mutation taster) and/or reported in COSMIC, gene specific databases or in literature.Results: Median age of T-MN was 71 (20-91) years and the most frequent primary neoplasms were lymphoproliferative neoplasms (n=56, 38%) and prostate cancer (n=22, 15%). Sixty-three (43%), 34 (23%) and 48(33%) patients received CT, RT and CT plus RT respectively. The T-MN group consisted of 104 T-MDS (71%) and 43 T-AML (29%). Poor risk cytogenetics were more frequent in T-MN cases following CT than after RT alone.Somatic mutations in myeloid genes were detected in 95/101 (94%) of T-MN cases. Notably, all normal karyotype T-MN (29/29, 100%) were mutated. Mutations were most frequently seen in transcriptional factors (35%), TP53 (32%) and splicing factors (26%). Significantly higher proportion of TP53mut T-MN patients had complex karyotype (22/32, 84%) compared to TP53wt (5/69; 7%, p<0.0001).Examination of 20 FANC pathway genes identified 38 rare variants in 31(31%) T-MN at a variant allele frequency (VAF) of ≥20% and most of the variants were missense (35/38; 92%). These were mostly seen in BRCA1, FANCA, FANCM, BRCA2, FANCL and SLX4 genes. Of patients with FANC variants, 42% (13/31) had concomitant TP53 mutations. The median VAF was 49% (range 20-100%) with no significant difference between the deleterious (n=13; 34%) and non-deleterious variants (n=25). Out of 13 deleterious variants (including 2 BRCA1 variants previously reported pathogenic on BIC database), ten variants were seen in nine TP53wt patients. We compared the disease characteristics, prior chemotherapy and survival outcome in patients with TP53mut (n=32), TP53wt harbouring predicted deleterious FANC variants (TP53wt /FANCdel var; n=9), TP53wt harbouring predicted non-deleterious FANC variants (TP53wt /FANCnon-del var; n=9) and TP53wt /FANCwt (n=51). There was no difference in bone marrow blast %, type of prior malignancy, prior therapy (CT vs RT vs combination), proportion of T-AML and treatment for T-MN between the groups. Interestingly, median number of mutations were significantly lower in TP53mut group (1; range 0-11) compared to TP53wt /FANCdel var, TP53wt /FANCnon-del var (both groups - 3; range 0-6) and TP53wt /FANCwt (3; range 0-9) (p=0.0005). Importantly, median OS of TP53wt /FANCdel var and TP53wt /FANCnon-del var groups was identical and significantly shorter than TP53wt /FANCwt (9.7 vs. 9.9 vs. 19.1 months; p=0.00485), and similar to TP53mut group (8.9 months).Conclusions: In our cohort, somatic mutations were seen in 90% of T-MN patients, comparable to primary MDS, contrary to previously published literature. Somatic TP53 mutations and FANC variants are seen in 32% and 31% of cases respectively and 13% harboring both. This study demonstrating that rare FANC variants are associated with significantly poor survival comparable to TP53 mutated T-MN patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Preliminary Results from an Ongoing Phase 1/2 Study of INCB053914, a Pan-Proviral Integration Sites for Moloney Virus (PIM) Kinase Inhibitor, in Patients with Advanced Hematologic Malignancies

Preliminary Results from an Ongoing Phase 1/2 Study of INCB053914, a Pan-Proviral Integration Sites for Moloney Virus (PIM) Kinase Inhibitor, in Patients with Advanced Hematologic Malignancies

Alvocidib Enhances Venetoclax Sensitivity in Unfavorable-Risk Multiple Myeloma Cells In Vitro and In Vivo

▪Abstract:Background: Multiple myeloma (MM) is a lymphoproliferative neoplasm involving mature plasma cells and remains incurable. New and more effective treatment options are clearly needed for higher-risk MM groups. The BCL-2-specific BH3-mimetic venetoclax (ABT-199) has been reported to be active in patients with the t(11;14) translocation, an intermediate risk group in response to immunomodulatory drugs (IMiDS) and proteasome inhibitors (PIs), prompting efforts to extend venetoclax activity to include more resistant, higher-risk MM subsets.Methods:Effects of the CDK9 inhibitor alvocidib (flavopiridol; FP) on responses to the BCL-2-specific BH3-mimetic venetoclax (ABT-199) were examined in multiple myeloma (MM) cells, including higher-risk sub-types exhibiting low BCL-2/MCL-1 expression profiles and limited sensitivity to venetoclax alone. Cell death and protein expression were evaluated by western blot, and immunofluorescence. Xenograft models, including an orthotopic murine model (NOD/SCID-γ mice) and an immune-competent model (C57BL/KaLwR1 mice) were used to characterize combination effects in vivo.Results:Alvocidib (100-200 nM; 24 h) synergistically increased ABT-199 (250-750 nM) lethality in both ABT-199-sensitive and insensitive MM cells, and these interactions were synergistic by Median Dose Effect analysis with CI values < 1.0 in both t(4;14) H929 and OPM-2 cells. Synergistic interactions or markedly enhanced lethality were also observed in multiple other intermediate or high-risk models (e.g., KMS11(t(4;14)), OPM2(t(4;14)), RPMI8226 (t(14;16) and t(8;22)), and KMS28-PE (t(4;14))). The alvocidib/venetoclax regimen was effective in various drug-resistant MM lines e.g., bortezomib, melphalan, and revlimid. Alvocidib blocked CDK9 activation and P-TEFb phosphorylation, down-regulated MCL-1, increased BCL-2/MCL-1 ratios, and up-regulated BIM. MCL-1 ectopic expression or knock-down in MM cells significantly diminished or increased ABT-199 sensitivity respectively. CDK9 shRNA knock-down triggered MCL-1 down-regulation and increased ABT-199 activity, while BIM knock-down significantly reduced alvocidib/venetoclax lethality. HS-5 cell co-culture failed to protect MM cells from the FP/ABT-199 regimen, suggesting circumvention of microenvironmental signals. The effects of venetoclax +/- alvocidib were investigated in a larger number of primary specimens (N =23). Combined treatment very significantly reduced the survival of cells compared to single agent treatment (24 h; P < 0.0001 and 0.0016). In the sub-set of specimens in which primitive progenitor cells could be identified (CD138-/CD19+/CD20+/CD127+; N=18), significant reductions in survival following combined treatment were also observed (P < 0.0074 and 0.0001). In contrast, alvocidib did not increase ABT199 lethality in normal CD34+ cord blood cells. To assess the in vivo relevance of these findings, NOD/SCID-γ mice were inoculated with fluorescently-labled bortezomib-resistant PS-R cells. Combined treatment sharply reduced tumor burden and significantly prolonged survival compared to single-agent treatment (P < 0.0001). Median survival was 79 days for animals in the combined treatment group, versus 62, 63, and 71 days for those in vehicle, venetoclax, or alvocidib groups, respectively. In addition, combined treatment was not associated with significant increases in weight loss or other forms of toxicity e.g., behavioral changes, fur loss etc. Finally, parallel studies were performed in an immune-competent model. C57BL/KaLwR1 mice were injected intravenously with murine MM 5TGM1 cells stably expressing luciferase. Combined administration suppressed tumor growth, manifested by clearly diminished intensity and significantly prolonged survival compared to single agents (P < 0.001), but did not lead to increases in toxicity e.g., weight loss. Specifically, median survival was 69 days for animals in the combined treatment group, versus 39, 49, and 53 days for those in vehicle, venetoclax, or alvocidib groups, respectively.Conclusions:These findings argue that CDK9 inhibitors e.g., FP may increase the anti-myeloma activity of ABT-199, including in unfavorable-risk MM minimally responsive to ABT-199 alone. DisclosuresOrlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Immunophenotypic and Cytogenetic Characteristics of B Cell Acute Lymphoblastic Leukaemia (ALL). the Tawam Hospital (tertiary referral centre UAE) Experience

Acute Lymphoblastic Leukaemia (ALL) is an aggressive malignant lympho-proliferative neoplasm. Although excellent results are seen in paediatric population the same does not hold true in the adult population. In this retrospective study we looked at the patient characteristics of B cell ALL at Tawam hospital which is a tertiary care referral hospital for cancer therapy in the United Arab EmiratesMethods: Tawam hospital tumour registry was used to identify patients diagnosed with ALL aged 15 years and above between January 2010 till June 2017. Medical records were reviewed to collect data about age, sex, presenting hemogram, immuno-phenotyping, karyotype and outcome.Results: Seventy patients were identified with diagnosis of ALL in the defined period. Sixteen (23 %) patients had diagnosis of T cell ALL. Fifty four (77%) patients had B cell ALL. The median age was 26 years (range 15-71 years). Male to female ratio was 2.85:1. T cell ALL patients were excluded from further analysis.Immuno-phenotypically 29 patients (54 %) were CD 20 positive ALL (> 20 % CD 20 expression) while the other 25 (46%) were CD 20 negative ALL. The median white blood count (WBC) at presentation was 7000 (range 1 to 495 thousand) per millilitre for CD 20 positive ALL while the median WBC was 12000 (range 1-240 thousand) per millilitre for CD 20 negative cohort.Cytogenetic and/or molecular diagnostics showed the presence of Philadelphia chromosome or BCR-ABL positivity in nine patients with CD 20 positive ALL (31 %) while only 4 patients (13%) with CD 20 negative ALL were positive for BCR-ABL. (Table 1)Five patients refused therapy and were lost to follow up after diagnosis. Five patients died of therapy related complications in complete remission (CR) while one patient developed secondary malignancy (Acute myeloid leukaemia and expired). Fifteen patients are in CR1 and in continuous follow up while another twelve patients have been lost to follow up while in CR1. Sixteen patients had either primary refractory or relapsed disease. Ten (62 %) of those had CD 20 positivity while the rest six (38%) were CD 20 negative.Conclusion: In our experience more than half (54 %) of B cell ALL had a CD 20 positive immuno phenotype. Patients with CD 20 positive ALL had a lower median WBC at presentation as compared to the CD 20 negative cohort. Of greater interest is the higher rate of Philadelphia chromosome positivity in CD 20 positive observed in CD 20 positive cohort as compared to CD 20 negative cohort (31% versus 13 %). Patients with CD 20 appear to have a higher rate of relapsed refractory disease (62% versus 38%).CD 20 expression in ALL has been reported as ranging from 30 to 60 %. Similarly there has been controversy of CD 20 positive disease being associated with poor patient outcome. The majority of the previous reports either exclude Philadelphia chromosome positive disease or report no significant difference.Even though CD 20 antibodies have been used previously with variable results, the large disparity in the treatment protocols for ALL for adults makes it difficult to choose a standard approach. Similarly the role of humanized CD 20 anti-bodies like Obinutuzumab and ofatumumab remains undefined.Although our cohort has a big disparity in Philadelphia chromosome positivity between the two sub groups the small sample size makes it difficult to make a definite conclusion and these results should be validated in a larger cohort. [Display omitted] DisclosuresAlam:BMS: Honoraria; Biologix: Honoraria.

NODULAR SCLEROSIS HOGDKINS LYMPHOMA GRADE 2 MIMICKING ANAPLASTIC LARGE CELL LYMPHOMA - A CASE REPORT

INTRODUCTION: Hodgkin's lymphoma (HL) is a lymphoproliferative neoplasm constituting less than 1% of all neoplasms. It has been categorized into- nodular lymphocyte predominant HL and classical type with subtypeslymphocyte rich, lymphocyte depleted, nodular sclerosis and mixed cellularity. Nodular sclerosis Hodgkin's lymphoma (NSHL) is difcult to diagnose on FNA because of the lack of Reed Sternberg (RS) cells, low cellularity and difculty in identifying the counterpart of lacunar cells. CASE A 16-year-old female presented with anterior chest wall swelling si REPORT: nce 6 months measuring 5x4cm along with incidentally noted cervical lymph nodes measuring 2x2cm and 1x1cm. On examination, multiple papular skin lesions were observed. FNAC smears from cervical lymph node showed high cellularity, with sheets of binucleated and multinucleated cells having multiple nucleoli, some showing pale bluish abundant cytoplasm whereas others showing dense cytoplasm; in a background of reactive lymphoid population with few neutrophils. Few giant cells showed hyperchromatic nuclei. Abnormal mitosis seen. No typical RS cell was seen. Peripheral blood smear showed neutrophilic leukocytosis with no atypical cell. Possibility of NSHL was considered and biopsy advised to rule out ALCL. Histological sections showed near total effacement of lymph node architecture by nodules separated by broad brotic bands. These nodules exhibit proliferating lymphocytes with clustered lacunar cells along with some mononucleate, binucleate and multinucleated cells. Prominent mitotic activity, angiogenesis, focal micro abscesses were noted. Immunohistochemistry showed CD 15+ and CD 30+ expression in the giant cells, conrming diagnosis of NSHL grade 2. NSHL poses a cytological diagnostic dilemma specially in abse CONCLUSION: nce of sclerosis on FNA, making histological examination and IHC mandatory

The role of puncture biopsy in the treatment of pathological fractures of the cervical vertebrae

The aim is to analyze the data obtained during biopsy of primary and secondary lesions and pathological fractures of the cervical vertebrae and their influence on the tactics of treatment of patients. Evaluation of the effectiveness of biopsy of pathological processes in the cervical vertebrae.&#x0D; Materials. The results of biopsies of 20 patients with lesions of the cervical vertebrae of unknown etiology or with the presence of pathological fractures with compression of the spinal cord and roots by a vertebra or a soft tissue component were analyzed.&#x0D; The following results were obtained: the presence of a secondary lesion of the cervical vertebrae was revealed: metastatic nature – 10, primary tumors – 1, lymphoproliferative tumors – 3, no tumor lesion was detected – 3, not enough material for the study – 3.&#x0D; Conclusion. The results obtained indicate the high efficiency and sufficient safety of puncture biopsy in diagnosing lesions of the cervical vertebrae, even in complex localizations (C2). Revealing the nature of vertebral lesions in the absence of absolute indications for decompression and stabilization interventions significantly affects the tactics and order of treatment of the patient.

A 71-Year-Old Man Presenting with Anemia and a Solitary Skin Lesion Associated with Primary Cutaneous Marginal Zone Lymphoma

A 71-year-old man with a solitary red lesion on his left arm, which initially thought to be a hematoma, was admitted for inpatient evaluation of anemia, which after a positive direct Coombs test was qualified as autoimmune hemolytic anemia. The patient also presented with hoarseness and biopsies from the swelled nasopharynx and an enlarged right tonsil were obtained. Due to uncertain diagnosis and the patient’s previous history of malignancy, (low grade lymphoproliferative lymphoma) skin and bone marrow biopsies were performed. Unfortunately, the patient’s status rapidly deteriorated as a result of septic shock. The obtained skin, nasopharynx, and tonsil biopsies became available after the patient died and showed marginal zone lymphoma with no evidence of lymphoproliferative neoplasm in the bone marrow. &#x0D; This case demonstrates the diagnostic complexity of nodal marginal zone lymphoma complicated by severe life-threatening autoimmune hemolytic anemia in an elderly patient with multimorbidity, which presents management challenges for health care providers.

Gastrointestinal Tract Lymphomas.

The gastrointestinal (GI) tract is the most common site of extranodal non-Hodgkin lymphoma, accounting for 20% to 40% of all extranodal lymphomas. The majority of these are systemic processes secondarily involving the GI tract. Primary GI lymphomas are less common, accounting for approximately 10% to 15% of all non-Hodgkin lymphomas. Most non-Hodgkin lymphomas involving the GI tract are of B-cell lineage, of which diffuse large B-cell lymphoma is the most common subtype, irrespective of location. To review the lymphoproliferative neoplasms of B-cell and T-cell lineage involving the luminal GI tract according to the most prevalent subtypes at each anatomic site. Systematic search of the PubMed database for updated literature on GI lymphoma epidemiology, subtypes, clinical, endoscopic, and genetic findings. Histologic images are derived from our collection of clinical cases. The GI tract is the most common site of extranodal lymphoproliferative neoplasms. Recognition of the most frequently encountered GI lymphomas is imperative for patient management and treatment.

Modern diagnostic capabilities of neonatal screening for primary immunodeficiencies in newborns.

Population screening of newborns is an extremely important and informative diagnostic approach that allows early identification of babies who are predisposed to the development of a number of serious diseases. Some of these diseases are known and have effective treatment methods. Neonatal screening enables the early diagnosis and subsequent timely initiation of therapy. This helps to prevent serious complications and reduce the percentage of disability and deaths among newborns and young children. Primary immunodeficiency diseases and primary immunodeficiency syndrome (PIDS) are a heterogeneous group of diseases and conditions based on impaired immune system function associated with developmental defects and characterized by various combinations of recurrent infections, development of autoimmune and lymphoproliferative syndromes (genetic defects in apoptosis, gene mutation Fas receptor or ligand), granulomatous process, and malignant neoplasms. Most of these diseases manifest in infancy and lead to serious illness, disability, and high mortality rates. Until recently, it was impossible to identify children with PIDS before the onset of the first clinical symptoms, which are usually accompanied by complications in the form of severe coinfections of a viral-bacterial-fungal etiology. Modern advances in medical laboratory technology have allowed the identification of children with severe PIDS, manifested by T- and/or B-cell lymphopenia and other disorders of the immune system. This review discusses the main existing strategies and directions used in PIDS screening programs for newborns, including approaches to screening based on excision of T-cell receptors and kappa-recombination excision circles, as well as the potential role and place of next-generation sequencing technology to increase the diagnostic accuracy of these diseases.

Mesenchymal Tumors and Lymphoproliferative Diseases of the Stomach and Duodenum

AbstractNeoplasms of the stomach are classified into two large categories on the basis of the cell of origin: epithelial and nonepithelia. The vast majority of both benign and malignant tumors of the stomach are of epithelial origin, with mesenchymal and neuroendocrine tumors being much less common. The epithelial tumors arise from the mucosa while the nonepithelial tumors arise from the submucosa, muscularis propria, or serosa. The nonepithelial or intramural tumors of stomach include gastrointestinal stromal tumors, leiomyomas, schwannoma, granular cell tumors, glomus tumor, leiomyosarcoma, Kaposi sarcoma, lymphoma, and others. In this review, radiological appearance of mesenchymal tumors and lymphoproliferative tumors are described.