B-cell Lymphoproliferation Research Articles

Cancer Immunotherapy Trials Network 12: Pembrolizumab in HIV-Associated Kaposi Sarcoma.

Cancer Immunotherapy Trials Network 12 demonstrated safety of pembrolizumab in treating advanced cancer in people with HIV. Here, we report results of the Kaposi sarcoma (KS) cohort. In this multicenter phase I trial, we enrolled participants with HIV-associated KS on antiretroviral therapy with CD4+ ≥50 cells/μL and HIV plasma RNA <200 copies/mL. Pembrolizumab 200 mg intravenously was administered once every 3 weeks for up to 35 cycles. The primary end point was safety, and the secondary end point was KS response by modified AIDS Clinical Trials Group Criteria. Thirty-two cisgender men enrolled with baseline median CD4+ T-cell count of 274 cells/µL. All but nine participants had received previous systemic KS therapy. Participants received a median of 11 cycles of pembrolizumab (range, 1-35). Sixty-six percent had grade ≥1 treatment-emergent adverse events, including one death from polyclonal KS herpesvirus-related B-cell lymphoproliferation. Thirty-one percent had ≥one immune-mediated AEs (imAEs) with 25% requiring systemic steroids. In 29 participants with evaluable KS, the overall response rate (ORR) was 62.1% (95% CI, 42.3 to 79.3) and did not differ by CD4+ T-cell count. ORR in the eight participants with evaluable disease without previous KS therapy was 87.5% (95% CI, 47.3 to 99.7). Median duration of response (DOR) was not reached, and the Kaplan-Meier estimate of DOR of ≥12 months was 92.3% (95% CI, 56.6 to 98.8). Median progression-free survival was 28.2 months (95% CI, 4.2 to noncalculable). Pembrolizumab yielded a high rate of durable responses in HIV-associated KS. imAEs were successfully managed with standard guidelines.

Hyperviscosity-Related Retinopathy and Serous Macular Detachment in Waldenstrӧm Macroglobulinemia Managed With Zanubrutinib

Waldenstrom macroglobulinemia (WM) is an uncommon lymphoproliferative B-cell disorder characterized by overproduction of monoclonal...

Deciphering the association between biopsy-confirmed systemic small vessel vasculitis and Epstein-Barr virus-positive polymorphic B-cell lymphoproliferation.

The Epstein-Barr virus (EBV) is associated with various lymphoproliferative disorders (LPD). Additionally, EBV infection has correlated with diverse autoimmune diseases. However, the association between EBV and systemic small vessel vasculitis (SVV) remains controversial. Here, we report a case of SVV with pauci-immune glomerulonephritis accompanied by an EBV-positive polymorphic B-cell LPD, not otherwise specified. The intricate distinction between EBV-positive B-cell LPD and SVV was difficult, as both diseases demonstrated similar clinical presentations. Lymph node and kidney biopsies facilitated the accurate diagnosis of these two conditions. The administration of high-dose prednisolone, combined with rituximab, proved efficacious, with no instances of relapse over the subsequent 2-year period. This case indicates an association between EBV-positive B-cell LPD and SVV. The diligent execution of biopsies is a crucial diagnostic and interpretive strategy, generating precise comprehension of this condition and guiding its appropriate therapeutic management.

Rituximab Is Associated with an Increased Risk of Malaria Infection in a Malaria-Endemic Region

Rituximab has become a standard of care for the treatment of lymphoproliferative B-cell neoplasms, such as diffuse large B cell lymphoma (DLBCL). As an anti-CD20 monoclonal antibody, rituximab depletes the B lymphocyte compartment and is associated with downstream impairment in humoral immunity and increased risk of infections. While such infections are often bacterial, non-bacterial infections also do occur. Malaria is a vector-borne protozoal infection caused by plasmodium species and is endemic in most parts of sub-Saharan Africa (SSA) where HIV infection is also endemic and an independent risk factor for malaria. Most studies evaluating the safety and efficacy of rituximab were in non-endemic malaria areas with a low prevalence of HIV in the US and Europe. Therefore, the effect of rituximab-induced immunodeficiency on malaria-specific immunity and the risk of malaria among DLBCL in malaria-endemic regions is not well established. The incidence of DLBCL in SSA is increasing due to the growth and aging of the population as well as epidemic levels of HIV infection. The objective of this retrospective study is to evaluate the risk for malaria infection among DLBCL patients treated with standard chemotherapy in Malawi, a malaria-endemic country with high HIV prevalence. We performed a retrospective analysis of 96 patients, aged ≥18 with DLBCL from the Kamuzu Central Hospital (Lilongwe, Malawi) Lymphoma Study, a prospective observational cohort treated with CHOP or R-CHOP 2013-2019. Symptomatic malaria cases were determined by retrospective chart review and defined as individuals with documented positive malaria rapid diagnostic test (MRDT) or peripheral blood film (PBF) during treatment or up to one year of follow-up. Laboratory malaria cases were individuals with positive P. falciparum histidine-rich protein 2 (HRP2) antigenemia using quantitative ELISA at mid-treatment (2 months), completion (4 months), or post-treatment (12 months). HRP2 antigenemia is suggestive of current or very recent P. falciparum malaria infection. Unadjusted odds ratios were calculated for risk factors for malaria using logistic regression. Treatment regimens varied slightly with 59 patients (62%) receiving CHOP, and 37 (38%) receiving R-CHOP. Fourteen of the 96 DLBCL (14.6%) patients developed symptomatic malaria during the treatment period and the remainder remained free of malaria-associated symptoms. Symptomatic malaria was not significantly associated with age, gender, DLBCL stage, number of treatment cycles received, prior history of TB, performance status, HIV infection, or HIV RNA viral load &amp;gt; 1,000 copies. However, among the symptomatic malaria cases, five (36%) received CHOP, and nine (64%) received R-CHOP. Patients treated with R-CHOP were more likely to develop symptomatic malaria than CHOP patients (OR 3.38, 95% CI 1.05-12.26; p=0.03). Thirty-two (24 CHOP, 8 R-CHOP) patients were positive for malaria based on the HRP-2 antigen test and there was no correlation with rituximab treatment. However, HRP-2 antigen concentrations were significantly higher in R-CHOP patients compared to CHOP patients (2.3 OD vs 0.58 OD; p=0.01). To our knowledge, this is the first study to evaluate the effect of rituximab on malaria risk among DLBCL patients treated with chemotherapy in a malaria-endemic region. This study suggests that rituximab increases the risk of symptomatic malaria in adult DLBCL patients. Data investigating the effect of rituximab on malaria-specific antibody production is currently being analyzed. Further studies are needed to determine whether antimalarial chemoprophylaxis should be implemented to improve the comprehensive care of cancer patients residing in malaria-endemic areas.

Rapidly Progressive Aneurysmal Disease Associated with Epstein Barr Virus-Positive Lymphoproliferative Disease in a CVID patient with NFKB-1 Mutation

IntroductionCommon variable immunodeficiency (CVID) is a genetically heterogeneous group characterized by hypogammaglobulinemia and poor immune response to vaccines. CVID patients are at higher risk for autoimmune diseases or malignancy. We demonstrate a rare case of a patient with CVID (NFKB-1 mutation) presenting with features of vasculitis and rapidly progressive aneurysmal disease secondary to an Epstein Barr Virus (EBV)-associated lymphoproliferative disorder. Case descriptionA 36-year-old man with CVID presented with hoarseness and left vocal cord paralysis. Imaging revealed an aortic arch and descending thoracic aorta abnormality concerning for a plaque, vasculitis or focal thrombosed dissection. He later devloped severe back pain and imaging studies demonstrated an abdominal aortic aneurysm, thickening of the common iliac arteries and a focal aneurysm of the right common iliac artery. PET CT scan showed uptake in the upper abdominal aorta extending to the right renal artery and the distal abdominal aorta near the bifurcation extending to the right common iliac artery, concerning for large vessel vasculitis. He was started on high-dose steroids for large vessel vasculitis. One month later, he was hospitalized for disseminated histoplasmosis and disseminated varicella zoster virus (VZV) and started on amphotericin B and acyclovir with steroid taper. Whole exome next-generation sequencing (NGS) revealed NFKB-1 mutation consistent with CVID-12 with autoimmunity. He later developed worsening back pain prompting repeat imaging which showed further progression of his aneurysmal disease. He was also found to have EBV viremia with a titer of 33,700 IU/mL. A left superior gluteal artery biopsy was performed which showed evidence of an EBV+ lymphoproliferative disorder with concern for an EBV-positive fibrin-associated diffuse lymphoproliferative B-cell lymphoma (DLBCL). DiscussionCVID-12 is an autosomal dominant disease resulting from a mutation in NFKB-1. This mutation leads to an impaired immune response associated with recurrent infections and approximately 20% of patients developing lymphomas at some point in their lifetime. However, there are few case reports of CVID associated large vessel aneurysms or vasculitis. Our patient with CVID demonstrated a rare presentation of an EBV-positive lymphoproliferative disorder driving progression of large vessel disease.

EBV-driven lymphoid neoplasms associated with pediatric ALL maintenance therapy

AbstractThe development of a second malignancy after the diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHLs) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients who developed NHL following ALL diagnosis and were enrolled in 12 collaborative pediatric ALL trials between 1980-2018. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56 of 85 cases). Forty-six of these 56 cases (82%) occurred during or within 6 months of maintenance therapy. The majority exhibited histopathological characteristics associated with immunodeficiency (65%), predominantly evidence of Epstein-Barr virus–driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, the 5-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% confidence interval [CI], 56-81). Five-year cumulative risks of lymphoid neoplasm– and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7-22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (hazard ratio, 7.32; 95% CI, 1.62-32.98; P = .01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

CLL-240 Frequency of IKZF3 L162R Mutation in B-Cell Lymphoproliferative Disorders

A mutation of AIOLOS/IKZF3, a member of the IKAROS family transcription factors has been identified as a putative driver of chronic lymphocytic leukemia (CLL) through large-scale WES studies of CLL patients, with a frequency of ~3% CLLs. The mutation has been detected uniquely as a hotspot mutation (L162R), localized within the DNA binding domain, conferring a gain-of-function by altering DNA binding specificity and expression of IKZF3 target genes, resulting in overexpression of B-cell receptor (BCR) signaling genes. Apart from CLL, IKZF3 mutations are rarely described in other B-cell lymphomas. In this study, we aimed to evaluate the frequency of IKZF3 mutations in lymphoproliferative B-cell disorders. By reviewing the literature and reanalyzing the cBioPortal database, IKZF3 was reported to be mutated in 31 cases, including 16 CLL, 10 DLBCL, 1 MCL, 1 MW, and 3 FL. Interestingly, the p.L162R hotspot mutation identified in CLL occurred in 17/31 cases, suggesting a selection of this gain-of-function mutation and a common mechanism of lymphomagenesis. Targeted NGS sequencing of a 13-gene panel, including exon 5 of IKZF3, was used to analyze a French multicentric prospective cohort of 650 CLL patients. We confirmed the presence of the IKZF3-L162R mutation with a frequency of 2% (n=13/650) in CLL. We next designed a droplet digital PCR assay, allowing the detection of the IKZF3-L162R mutation with high sensitivity in a retrospective cohort of 48 patients harboring an MYD88 L265P mutation, including 2 DLBCL and 46 Waldenstrom's macroglobulinemia (WM) cases. Among the 48 patients tested, the mutation was detected in 3 patients with WM disease (3/46; 6.5%) with a variant allelic frequency (VAF) of 0.7%, 1%, and 3%. These patients were symptomatic with anti-MAG antibodies or organomegaly. Targeted NGS sequencing confirmed the presence of the IKZF3-L162R mutation in the samples with VAF >1%. Altogether, IKZF3-L162R mutation occurs in CLL but also in other B-cell neoplasms with similar frequencies, suggesting a common mechanism of lymphomagenesis related to the dysregulation of BCR-signaling genes. We are currently sequencing more samples, including marginal zone lymphoma, to better appreciate the distribution of this mutation among B-cell lymphomas.

Cold Agglutinin Disease: Improved Understanding of Pathogenesis Helps Define Targets for Therapy

The last 2 decades have seen great progress in understanding the pathogenesis of cold agglutinin disease (CAD) and development of effective therapies. Cold agglutinins can cause hemolytic anemia as well as peripheral circulatory symptoms such as acrocyanosis. We distinguish CAD, a well-defined clinicopathologic entity, from secondary cold agglutinin syndrome. This review addresses the histopathologic, immune phenotypic, and molecular features that allow CAD to be classified as a distinct clonal lymphoproliferative disorder of the bone marrow, recently recognized in the WHO classification. We discuss recent data on the possible overlap or distinction between CAD and Waldenström’s macroglobulinemia. Two major steps in the pathogenesis of CAD are identified: clonal B-cell lymphoproliferation (leading to monoclonal IgM production) and complement-mediated hemolysis. Each of these steps constitutes a target for treatment. Established as well as novel and experimental therapies are reviewed.

Clonality assessment and detection of clonal diversity in classic Hodgkin lymphoma by next-generation sequencing of immunoglobulin gene rearrangements

AbstractClonality analysis in classic Hodgkin lymphoma (cHL) is of added value for correctly diagnosing patients with atypical presentation or histology reminiscent of T cell lymphoma, and for establishing the clonal relationship in patients with recurrent disease. However, such analysis has been hampered by the sparsity of malignant Hodgkin and Reed-Sternberg (HRS) cells in a background of reactive immune cells. Recently, the EuroClonality-NGS Working Group developed a novel next-generation sequencing (NGS)-based assay and bioinformatics platform (ARResT/Interrogate) to detect immunoglobulin (IG) gene rearrangements for clonality testing in B-cell lymphoproliferations. Here, we demonstrate the improved performance of IG-NGS compared to conventional BIOMED-2/EuroClonality analysis to detect clonal gene rearrangements in 16 well-characterized primary cHL cases within the IG heavy chain (IGH) and kappa light chain (IGK) loci. This was most obvious in formalin-fixed paraffin-embedded (FFPE) tissue specimens, where three times more clonal cases were detected with IG-NGS (9 cases) compared to BIOMED-2 (3 cases). In total, almost four times more clonal rearrangements were detected in FFPE with IG-NGS (N = 23) as compared to BIOMED-2/EuroClonality (N = 6) as judged on identical IGH and IGK targets. The same clonal rearrangements were also identified in paired fresh frozen cHL samples. To validate the neoplastic origin of the detected clonotypes, IG-NGS clonality analysis was performed on isolated HRS cells, demonstrating identical clonotypes as detected in cHL whole-tissue specimens. Interestingly, IG-NGS and HRS single-cell analysis after DEPArray™ digital sorting revealed rearrangement patterns and copy number variation profiles indicating clonal diversity and intratumoral heterogeneity in cHL. Our data demonstrate improved performance of NGS-based detection of IG gene rearrangements in cHL whole-tissue specimens, providing a sensitive molecular diagnostic assay for clonality assessment in Hodgkin lymphoma.

PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice

While Epstein–Barr virus (EBV) establishes a life-long latent infection in apparently healthy human immunocompetent hosts, immunodeficient individuals are at particular risk to develop lymphoproliferative B-cell malignancies caused by EBV. A key EBV protein is the transcription factor EBV nuclear antigen 2 (EBNA2), which initiates B-cell proliferation. Here, we combine biochemical, cellular, and in vivo experiments demonstrating that the mitotic polo-like kinase 1 (PLK1) binds to EBNA2, phosphorylates its transactivation domain, and thereby inhibits its biological activity. EBNA2 mutants that impair PLK1 binding or prevent EBNA2 phosphorylation are gain-of-function mutants. They exhibit enhanced transactivation capacities, accelerate the proliferation of infected B cells, and promote the development of monoclonal B-cell lymphomas in infected mice. Thus, PLK1 coordinates the activity of EBNA2 to attenuate the risk of tumor incidences in favor of the establishment of latency in the infected but healthy host.

Lymphocytoma cutis (cutaneous B-cell pseudolymphoma): study of 102 cases with emphasis on the histological characteristics and immunohistochemistry of the miliarial type.

Lymphocytoma cutis (LC) is a benign reactive lymphoproliferative B-cell process. It has two variants: localized type with solitary lesions and miliarial type with numerous lesions. The objective was to investigate the characteristics of LC with emphasis on the miliarial type. Retrospective study, patients with clinical and histopathological diagnosis of LC were included. Age, sex, evolution time, affected site, and type of treatment were investigated. In miliarial-type LC, the histological and immunohistochemical characteristics were also investigated. In an 18-year period, there were 102 patients found with LC: 72 (71%) corresponded to females, the median age was 45 years, the median evolution time was 4 months, and the face was the most predominant affected area in 81 (79%) cases. Localized-type LC corresponded to 88 (86%) cases, and miliarial type in 14 (14%). The most common treatment was surgery, which was used in 32 (31%) patients, all of whom had localized type (P < 0.01). The most frequent treatment for miliarial-type LC was corticosteroids in five (36%, P = 0.32), the predominant histopathological pattern was nodular in 10 (71%) specimens, and immunohistochemistry was performed in 11 (79%), where all were positive for CD20 with polyclonality to kappa and lambda light chains. The importance of LC lies in that it can be clinically and histopathologically confused with cutaneous lymphoma and that it is a rare entity, with its miliarial variant being rarer still. This study provides information on the clinical-histological characteristics of LC and its immunohistochemistry.

Waldenstrom Macroglobulinemia and the Eye: A case report and review

Waldenstrom macroglobulinemia (WM) is a rare, malignant lymphoproliferative B-cell disorder causing an excessive buildup of monoclonal protein. WM is associated with excessive buildup of IgM, which can cause blood hyperviscosity and damage many organ systems. This case report describes a patient who was followed annually but rapidly developed posterior pole and significant midperipheral hemorrhages secondary to a hyperviscosity condition of the retina. Management of this condition is dependent on macular involvement and must be co-managed with an oncologist.

Lipoprotein-Associated Phospholipase A2: A Novel Contributor in Sjögren's Syndrome-Related Lymphoma?

BackgroundB-cell non-Hodgkin’s lymphoma (B-NHL) is one of the major complications of primary Sjögren’s syndrome (SS). Chronic inflammation and macrophages in SS minor salivary glands have been previously suggested as significant predictors for lymphoma development among SS patients. Lipoprotein-associated phospholipase A2 (Lp-PLA2)—a product mainly of tissue macrophages—is found in the circulation associated with lipoproteins and has been previously involved in cardiovascular, autoimmune, and malignant diseases, including lymphoma.ObjectiveThe purpose of the current study was to investigate the contributory role of Lp-PLA2 in B-NHL development in the setting of primary SS.MethodsLp-PLA2 activity in serum samples collected from 50 primary SS patients with no lymphoma (SS-nL), 9 primary SS patients with lymphoma (SS-L), and 42 healthy controls (HC) was determined by detection of [3H]PAF degradation products by liquid scintillation counter. Moreover, additional sera from 50 SS-nL, 28 SS-L, and 32 HC were tested for Lp-PLA2 activity using a commercially available ELISA kit. Lp-PLA2 mRNA, and protein expression in minor salivary gland (MSG) tissue samples derived from SS-nL, SS-L patients, and sicca controls (SC) were analyzed by real-time PCR, Western blot, and immunohistochemistry.ResultsSerum Lp-PLA2 activity was significantly increased in SS-L compared to both SS-nL and HC by two independent methods implemented [mean ± SD (nmol/min/ml): 62.0 ± 13.4 vs 47.6 ± 14.4 vs 50.7 ± 16.6, p-values: 0.003 and 0.04, respectively, and 19.4 ± 4.5 vs 15.2 ± 3.3 vs 14.5 ± 3.0, p-values: <0.0001, in both comparisons]. ROC analysis revealed that the serum Lp-PLA2 activity measured either by radioimmunoassay or ELISA has the potential to distinguish between SS-L and SS-nL patients (area under the curve [AUC]: 0.8022, CI [95%]: 0.64–0.96, p-value: 0.004 for radioimmunoassay, and AUC: 0.7696, CI [95%]: 0.66–0.88, p-value: <0.0001, for ELISA). Lp-PLA2 expression in MSG tissues was also increased in SS-L compared to SS-nL and SC at both mRNA and protein level. ROC analysis revealed that both MSG mRNA and protein Lp-PLA2 have the potential to distinguish between SS-nL and SS-L patients (area under the curve [AUC] values of 0.8490, CI [95%]: 0.71–0.99, p-value: 0.0019 and 0.9444, CI [95%]: 0.79–1.00, p- value: 0.0389 respectively). No significant difference in either serum Lp-PLA2 activity or MSG tissue expression was observed between SS-nL and HC.ConclusionsLp-PLA2 serum activity and MSG tissue mRNA/protein expression could be a new biomarker and possibly a novel therapeutic target for B-cell lymphoproliferation in the setting of SS.

Single-Cell RNA-Seq Reveals LGALS1 and LAG3 as Novel Drivers of Ibrutinib Resistance in Chronic Lymphocytic Leukemia

Background: Chronic lymphocytic leukemia (CLL) is a highly heterogeneous malignant lymphoproliferative B-cell disorder that can be treated using ibrutinib, a Bruton’s tyrosine kinase inhibitor. However, the ibrutinib resistance of CLL patients has caused widespread concerns, necessitating the development of novel treatment strategies. Methods: Here, we identified lectin galactoside-binding soluble 1 (LGALS1) and lymphocyte-activating gene 3 (LAG3) as potential markers for ibrutinib-resistant CLL using single-cell RNA sequencing (scRNA-seq), and the results were validated in an ibrutinib-resistant CLL cell line (MEC1-IR) and primary cells from CLL patients. Marker-gene expression was detected while functional analyses were conducted with or without OTX008, a selective Galectin-1 inhibitor. ScRNA-seq revealed that the biological features, gene expression profiles, and clonal signatures of peripheral blood mononuclear cells (PBMCs) from patients with ibrutinib-resistant CLL were distinct from those displayed by PBMCs from ibrutinib-sensitive patients. Findings: A close correlation between LGALS1 and LAG3 expression was observed and these factors were found to be highly expressed in ibrutinib-resistant CLL, with diagnostic and prognostic stratification, indicating that they may serve as drivers of ibrutinib-resistant CLL. Concordantly, LGALS1 and LAG3 expression was higher in ibrutinib-resistant CLL cells and primary cells, and OTX008 suppressed proliferation and induced apoptosis in both cells. Interpretation: LGALS1 and LAG3 gene panel is promising indicator of ibrutinib-sensitivity and prognosis marker of CLL. LGALS1 inhibitor OTX008 is effective in CLL patients, both those naive to and those resistant to ibrutinib. This work highlights the pathogenic mechanism and represents a novel therapeutic target for CLL. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (Grant #81720108002, 81970146, 81770166, 81972358 and 91959113), Key Research & Development Program of Jiangsu Province (Grant #BE2017733), Basic Research Program of Jiangsu Province (Grant #BK20180036), Jiangsu Province’s Medical Elite Programme (Grant #ZDRCA2016022), Project of National Key Clinical Specialty, Jiangsu Provincial Special Program of Medical Science (Grant #BE2017751), Six Top Talent Project of Jiangsu Province (Grant #WSN-001). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Human sample study was approved by the Medical Ethics Committee of First Affiliated Hospital of Nanjing Medical University. Written informed consent was obtained from all participants.

Targeted therapy of multiple myeloma.

Multiple myeloma (MM) is a malignant proliferative disease of monoclonal plasma cells (PCs) and is characterized by uncontrolled proliferation of PCs and excessive production of specific types of immunoglobulins. Since PCs are terminally differentiated B cells, the World Health Organization (WHO) classifies MM as lymphoproliferative B-cell disease. The incidence of MM is 6–7 cases per 100,000 people in the world every year and the second most common cancer in the blood system. Due to the effects of drug resistance and malignant regeneration of MM cells in the microenvironment, all current treatment methods can prolong both overall and symptom-free survival rates of patients with MM but cannot cure MM. Both basic and clinical studies have proven that targeted therapy leads to a clear and significant prolongation of the survival of patients with MM, but when the disease recurs again, resistance to the previous treatment will occur. Therefore, the discovery of new targets and treatment methods plays a vital role in the treatment of MM. This article introduces and summarizes targeted MM therapy, potential new targets, and future precision medicine in MM.

Lymphomatoid papulosis mimicking relapsed angioimmunoblastic T-cell lymphoma on histology: the importance of clinicopathological correlation.

Angioimmunoblastic T-cell lymphoma (AITL) is one of the commonest subtypes of peripheral T-cell lymphoma (PTCL) world-wide and the most common non-cutaneous PTCL in Western Europe. Despite aggressive chemotherapy +/- consolidation autologous stem cell transplant relapse occurs in >50% of cases which is either treated aggressively with high dose chemotherapy followed by allogeneic transplant or with therapy aimed at producing prolonged disease control.1 Biopsy of relapsed disease is essential as a subset may be complicated by a B-cell (often EBV+) lymphoproliferation. Histological progression may occur with a monomorphic/'tumour cell rich' appearance rather than the polymorphous appearance seen in typical AITL.2.

Maladie des chaînes lourdes de type gamma associée à un lymphome B diffus à grandes cellules dans un contexte de myélodysplasie

IntroductionHeavy chain disease is a rare entity characterized by the production of incomplete immunoglobulin heavy chain without associated light chain. It is a B-cell lymphoproliferation, categorized according to the immunoglobulin involved. It is often associated with lymphomas but also with autoimmune diseases. ObservationWe report the case of a 70-year-old patient who presented a gamma-type heavy chain disease, associated with a diffuse large B-cell lymphoma in the context of myelodysplastic syndrome. ConclusionThis is the first case of diffuse large B-cell lymphoma associated gamma heavy chain disease described in the context of myelodysplastic syndrome.

Modern view on LRBA deficiency

Facilities of molecular genetic methods allow to distinguish several monogenic deficiencies in the general group of primary immunodeficiencies, including common variable immune deficiency (CVID), which have peculiarities of the natural course, therapy, and prognosis. One of these nosologies is LRBA deficiency. In this article a number of foreign sources were reviewed, systematized and classified to define a comprehensive understanding of the LRBA deficiency phenomenon . The most relevant scientific studies of North America and Europe and publications from various ranking medical journals were analyzed.&#x0D; LRBA deficiency is a PID caused by mutations inLRBAgene that disrupt the immune system regulation. It is characterized by lymphoproliferation, autoaggression, hypogammaglobulinemia and recurrent infections. Sometimes LRBA deficiency is called LATAIE disease (LRBA deficiency with autoantibodies, regulatory T-cell defects, autoimmune infiltration, and enteropathy).&#x0D; Special attention was given to the mutation ofLRBAgene and the connection to the defects caused in T- and B-lymphocytes, the clinical picture and diagnostics. It was suggested that LRBA protein reduces the level of autophagy, leading to increased apoptosis, impared T- and B-cell immune response, lymphoproliferation and autoimmune disorders. LRBA protein is especially expressed in the immune cells, its deficiency leads to defects of B-cells differentiation. However, LRBA deficiency does not affect T-regulatory cells differentiation. Main approaches to the treatment of patients with LRBA deficiency are presented in the article.&#x0D; Methods of systemic and content analysis of Russian and foreign sources were used when writing the article.

Management of PTLD After Hematopoietic Stem Cell Transplantation: Immunological Perspectives.

Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening complications of iatrogenic immune impairment after allogeneic hematopoietic stem cell transplantation (HSCT). In the pediatric setting, the majority of PTLDs are related to the Epstein–Barr virus (EBV) infection, and present as B-cell lymphoproliferations. Although considered rare events, PTLDs have been increasingly observed with the widening application of HSCT from alternative sources, including cord blood and HLA-haploidentical stem cell grafts, and the use of novel agents for the prevention and treatment of rejection and graft-vs.-host disease. The higher frequency initially paralleled a poor outcome, due to limited therapeutic options, and scarcity of controlled trials in a rare disease context. In the last 2 decades, insight into the relationship between EBV and the immune system, and advances in early diagnosis, monitoring and treatment have changed the approach to the management of PTLDs after HSCT, and significantly ameliorated the prognosis. In this review, we summarize literature on the impact of combined viro-immunologic assessment on PTLD management, describe the various strategies for PTLD prevention and preemptive/curative treatment, and discuss the potential of novel immune-based therapies in the containment of this malignant complication.

Cutaneous manifestations of Castleman disease.

Castleman disease (CD) is a lymphoproliferative B-cell disease that is diagnosed from lymphoid hyperplasia with vascular proliferation. Symptoms may include fever, night sweats, and weight loss. Cutaneous manifestations often may go unnoticed since little has been described in the literature regarding them. A search of CD with cutaneous manifestations was performed in PUBMED, ProQuest, Ovid, Scopus, EMBASE, and Medline. All articles included patients over 18years of age with a diagnosis of CD and cutaneous manifestations. A total of 68 articles were included. The most common cutaneous manifestations include paraneoplastic pemphigus and erythematous-brown plaques, papules, or nodules. Patients presenting with these manifestations should always have a thorough physical exam, and clinicians should try to identify any palpable lymph nodes. A complete workup to rule out other neoplasias needs to be performed as well. A better understanding of these skin manifestations of CD may help physicians promptly diagnose and reconsider the path of diagnostic tests to identify this entity.