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Follicular lymphoma (FL) is a common, indolent small B-cell lymphoma. While the Follicular Lymphoma International Prognostic Index is widely used, reliable prognostic and predictive biomarkers are needed. A recent study suggested that architectural patterns of CD10, BCL6, and Ki67 expression may correlate with progression-free survival (PFS) in FL patients treated with chemotherapy-free regimens. We examined the prognostic and predictive utility of architectural patterns of CD10, BCL6, Ki67, and FOXP1 in 90 patients treated with immunochemotherapy (bendamustine-rituximab [BR] and R-cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP]). We found that high follicular Ki67 (≥30%) was associated with longer PFS in the subgroup of patients treated with R-CHOP but not among those treated with BR. Validation of this biomarker may support routine use of Ki67 as a predictive marker in FL. [ABSTRACT FROM AUTHOR]

Myeloid sarcoma (MS) is currently considered equivalent to de novo acute myeloid leukemia (AML); however, the relationship between these entities is poorly understood. This retrospective multi-institutional cohort study compared 43 MS with NPM1 mutation to 106 AML with NPM1 mutation. Compared to AML, MS had more frequent cytogenetic abnormalities including complex karyotype (p =.009 and p =.007, respectively) and was enriched in mutations of genes involved in histone modification, including ASXL1 (p =.007 and p =.008, respectively). AML harbored a higher average number of gene mutations (p =.002) including more frequent PTPN11 mutations (p <.001) and mutations of DNA-methylating genes including DNMT3A and IDH1 (both p <.001). MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p =.037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation. First study comparing genetic profiles of MS and AML with a common disease-defining lesion. NPM1Mut MS may be genetically distinct from NPM1Mut AML. NPM1Mut MS may have inferior overall survival compared to NPM1Mut AML. [ABSTRACT FROM AUTHOR]

Application of next generation sequencing (NGS) has shed light on the molecular heterogeneity of hematological malignancies. NGS panels targeting recurrent mutations have become common in many large centers and commercial laboratories. However, its impact in clinical practice is unclear. We sought to characterize the use of NGS at a tertiary care center in an observational study of 343 patients with suspected hematological malignancies. We found that NGS changed or refined the clinical and pathologic diagnosis in 9% of patients and affected management decisions in 65% (including clinical trial eligibility, targeted therapy selection, and consideration for stem cell transplantation). This study emphasizes early incorporation of NGS in clinical practice while also highlighting the present limitations. As our understanding of these disorders increases and more clinically relevant genetic targets emerge, it will be important to refine the molecular testing strategy to deliver personalized medicine given the high cost associated with this technology. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical significance and immunological effect of mutation numbers in 424 DLBCL patients treated with standard immunochemotherapy. We found that KMT2D and TP53 nonsynonymous mutations (MUT) were significantly associated with increased nonsynonymous mutation numbers, and that high mutation numbers (MUThigh) were associated with significantly poorer clinical outcome in germinal center B-cell-like DLBCL with wild-type TP53. To understand the underlying mechanisms, we identified a gene-expression profiling signature and the association of MUThigh with decreased T cells in DLBCL patients with wild-type TP53. On the other hand, in overall cohort, MUThigh was associated with lower PD-1 expression in T cells and PD-L1 expression in macrophages, suggesting a positive role of MUThigh in immune responses. Analysis in a whole-exome sequencing dataset of 304 patients deposited by Chapuy et al. validated the correlation of MUT-KMT2D with genomic complexity and the significantly poorer survival associated with higher numbers of genomic single nucleotide variants in activated B-cell-like DLBCL with wild-type TP53. Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type TP53 treated with standard immunochemotherapy. The oncoimmune data in this study have important implications for biomarker and therapeutic studies in DLBCL. [ABSTRACT FROM AUTHOR]

The role of radiotherapy (RT) in the management of advanced Hodgkin Lymphoma (HL) is inadequately defined in this era of functional imaging with PET scan. SWOG-S0816 treated advanced stage Hodgkin lymphoma patients with ABVD+/- escBEACOPP and no RT. We queried whether RT might have benefited patients in S0816 who would have met the GHSG-HD15 criteria for RT by simulating RT use as per HD15 criteria of PET + residual disease ≥2.5 cm. Receiver-operating-characteristics analyses were performed by varying disease-control rates within radiation fields and size cutoffs for residual disease. Among the 49 PET3+ S0816 patients, RT would have raised the 2-year PFS from 30.6% to 50.2–58.1% using three residual disease cutoffs (1.5, 2.0 and 2.5 cm) and assuming 80 and 90% in-field control rates. Although there may be improvement in PFS as size cutoff point is lowered, consequential toxicities from RT require further definition to assess relative benefits. [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency (CVID) is a primary immunodeficiency manifesting as a reduction in the level of total immunoglobulin (Ig) G, a reduction in the level of either IgA or IgM, poor response to polysaccharide vaccine, and usually frequent infections. The association of CVID with an increased risk of malignancy, specifically lymphoma, is well known. A 63-year-old female with a past medical history significant for CVID presented with a 1-month history of dull, left eye pain with proptosis, hypoglobus, and left upper lid fullness without a discrete palpable mass. Magnetic resonance imaging (MRI) of the orbits revealed a diffuse infiltrating orbital mass superonasally with extension into the superior rectus muscle, medial rectus muscle, and optic nerve up to the orbital apex and ethmoid sinus. A superonasal orbital biopsy with a caruncular approach was performed and demonstrated a sparse lymphoid infiltrate that was suggestive for a large B-cell neoplasm. Positron emission tomography (PET) scan demonstrated a hypermetabolic right lymph node, anterior to the right submandibular gland, which was biopsied and histopathology confirmed diffuse large B-cell lymphoma (DLBCL). Our patient achieved a very good response to chemotherapy with minimal residual disease on PET scan at the end of treatment. She attained a complete remission after radiation therapy. In conclusion, patients with new orbital and adnexa masses in the setting of a primary immunodeficiency can have an aggressive malignancy such as DLBCL and early diagnosis and systemic treatment carries a good prognosis. [ABSTRACT FROM AUTHOR]

Objectives and methods:Splenic marginal zone lymphoma (SMZL) is a rare non-Hodgkin lymphoma. We sought to identify prognostic factors and define outcomes in a cohort of 64 patients with SMZL who were treated at two large academic medical centers in North America in the rituximab era. Results:Over a median follow-up of 37.8 (range 6–167.1) months, Kaplan–Meier estimate of median OS was 156.3 months and median PFS was 52.9 months. On univariate analysis, baseline hemoglobin <12 g/dl was associated with inferior OS (p = 0.045). High-risk FLIPI score was associated with inferior PFS when compared with intermediate/low risk (p = 0.05) and marginally significant with regard to OS (p = 0.056). Splenectomy was not predictive of OS or PFS (p = 0.563 and 0.937, respectively). Transformation to diffuse large B-cell lymphoma occurred in four (6.3%) patients during the observation period. OS was comparable to contemporaneous cohorts of patients with extranodal and nodal marginal lymphomas and FLIPI score was highly predictive for inferior PFS and OS when all three cohorts were analyzed together. Conclusion:Outcomes of SMZL, in our series, were excellent, with a median OS of >13 years. Low hemoglobin and high-risk FLIPI were associated with inferior outcomes. [ABSTRACT FROM AUTHOR]

Recent studies suggested that MYC and BCL2 protein co-expression is an independent indicator of poor prognosis in diffuse large B-cell lymphoma. However, the immunohistochemistry protocols for dual-expression staining and the scoring cut-offs vary by study. Sixty-nine cases of diffuse large B-cell lymphoma were evaluated for MYC and BCL2 protein expression using various cut-offs that have been recommended in prior studies. Independent of the International Prognostic Index risk group, cases with dual protein expression of BCL2 and MYC using ≥50%/40% cut-offs and ≥70%/40% had significantly shorter overall survival than cases without. It was verified in this patient population that the use of BCL2 and MYC immunohistochemistry, performed with availablein vitrodiagnostic-cleared antibodies, provides rapid prognostic information in patients withde novodiffuse large B-cell lymphoma. This study has practical implications for diagnostic laboratories and serves as a guide for implementation in the setting of future clinical trials. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding survival outcomes and molecular and phenotypic heterogeneity of patients with refractory anemia associated with ring sideroblasts and marked thrombosis.

Over the past decade, it has become increasingly clear that mantle cell lymphoma (MCL) is a more heterogeneous disease than originally recognized. Several groups have reported on a subgroup of patients with a less aggressive course than expected resulting in the term 'indolent MCL'. Unlike the recognized histologic variants, the definition of indolent mantle cell lymphoma is unclear, and patients with indolent MCL are often identified only after having undergone prolonged periods of observation. In this review, we will discuss clinical and biologic features and provide a framework for the approach in identifying patients with indolent MCL. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding the randomized phase II study of the comparison between rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) and R-CHOP + enzastaurin in B-cell lymphoma patients.

We hypothesized that the number of tumor infiltrating cytotoxic T-cells (CTCs) and regulatory T-cells (Tregs), shown to have prognostic value in other lymphoproliferative disorders, could predict survival in post-transplant lymphoproliferative disorder (PTLD). Sixty-two patients were diagnosed with PTLD between 1987 and 2007, with 44 cases representing monomorphic B-cell PTLDs with diffuse aggressive morphologic features. Of these 44 cases, 31 had sufficient tissue for further study. On univariate analysis, high tumor infiltrating CD3+ T-cell (≥550/10 hpf) and TIA-1+ CTC (≥300/10 hpf) counts were associated with favorable overall survival (OS), PTLD-specific survival (PTLD-SS), and progression-free survival (PFS) while Treg counts were not predictive of outcome. However, on multivariate analysis, clinical factors were the most powerful predictor of PTLD outcome (performance status and CHOP as first line therapy for OS; performance status and number of extranodal sites for both PTLD-SS and PFS). [ABSTRACT FROM AUTHOR]

Transformed lymphoma (TL) is historically associated with a poor prognosis, though autologous stem cell transplantation (ASCT) has been applied successfully. Better patient selection is needed for this intensive therapy. We analyzed the outcomes between de novo and transformed large B-cell lymphoma in patients undergoing ASCT, with regard to the immunohistochemical (IHC) features of potential prognostic utility including CD10, BCL6, MUM-1, Ki67, and BCL2. Of all patients undergoing ASCT for large B-cell lymphoma at the Cleveland Clinic Taussig Cancer Institute between 2003 and 2008, 56 patients (31 de novo and 25 TL) had undergone detailed IHC analysis. Three-year relapse-free-survival (RFS) and overall survival (OS) for TL vs. patients with de novo large B-cell lymphoma were 64%vs. 59% and 63%vs. 59%, respectively. More patients with TL were characterized as germinal-center B cell-of-origin (92%) than patients with de novo large B-cell lymphoma (71%). Immunohistochemistry did not predict relapse-free or overall survival, and ASCT afforded a high rate of PFS in patients with TL. [ABSTRACT FROM AUTHOR]

The proliferation index in mantle cell lymphoma (MCL) has not been validated in the context of aggressive therapy regimens in the rituximab era. We assessed Ki67 and PIM1 (a cell cycle-related gene upregulated in blastoid MCL) expression by immunohistochemistry in a phase II study Cancer and Leukemia Group B 59909 of aggressive chemotherapy and rituximab followed by autologous stem cell transplantation plus rituximab in untreated MCL patients <70 years of age. As a continuous variable or using a cutoff of 35%, higher image analysis (IA Ki67, n = 52) was associated with shorter progression free survival (PFS) (P ≤ 0.030) and event free survival (EFS) (P ≤ 0.017). PIM1 expression (n = 50) was associated with PFS (P = 0.033) and EFS (P = 0.043). Bivariate Cox models showed IA Ki67 and PIM1 were independent of clinical factors. High Ki67 (>35%) is an important independent prognostic marker in aggressively treated MCL in the rituximab era. PIM1 expression predicts poor outcome and, given its potential role as a therapeutic target, deserves further study. [ABSTRACT FROM AUTHOR]

Classical Hodgkin lymphoma is now recognised as a B-cell lymphoma. Improved therapy has increased cure rates dramatically; however, relapse and death still occurs in a minority of patients. Much has been learned about the biology of Hodgkin and Reed Sternberg cells and their interactions with the microenvironment, which has informed studies exploring biologic markers that may improve upon clinical prognostic models. This manuscript reviews recent advances in our understanding of the pathobiology of cHL with an emphasis on biologic prognostic markers. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about Hodgkin's lymphoma treatment, which appeared in the previous issue.

Nelarabine (compound 506U78), a novel purine nucleoside, is a soluble pro-drug of 9-beta-d-arabinofuranosylguanine (ara-G). Nelarabine is rapidly demethoxylated in blood by adenosine deaminase to ara-G. Pre-clinical and clinical studies have demonstrated the selective cytotoxicity of ara-G to T-lineage derived cells. CALGB Protocol 59901 was a Phase II study of nelarabine in patients with systemically untreated cutaneous T-cell lymphoma (CTCL) or refractory/relapsed systemic T-cell lymphoma (STCL). The objectives were to determine response rate, remission duration and safety profile associated with nelarabine given at 1.5 g m-2 per day on days 1, 3 and 5 as an intravenous infusion every 21 days for a minimum of two cycles and to continue up to two cycles beyond CR up to a maximum of eight cycles. Nineteen patients were enrolled in the study: 11 CTCL and eight STCL patients. Grade 3 or 4 adverse events were documented in 50% and 28%, respectively. In particular, 33% of patients experienced Grade 3 or 4 neurologic toxicities. There were two partial remissions lasting 3 months and 5.5 months, respectively. Median event-free survival was 1.2 months and median overall survival was 3 months. Due to lack of efficacy and excessive toxicity, nelarabine is not recommended as monotherapy in adult patients with CTCL and STCL at this dose schedule. [ABSTRACT FROM AUTHOR]

Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) lymphomas are a well-described type of low-grade B-cell non-Hodgkin lymphoma. They typically arise adjacent to mucosal surfaces in the gastrointestinal tract, lung and conjunctiva, and, less frequently, in the skin, salivary gland and thyroid gland. Unusual locations, such as the genitourinary tract, thymus and meninges, have also been reported. We recently encountered a case of an intracranial MALT lymphoma in a 53-year-old man who presented with persistent headaches and a seizure. The lesion developed as a mass within the lateral ventricle, appeared to be arising from the choroid plexus, and was not associated with meninges. Histologically, there was a vaguely nodular, dense lymphoid infiltrate with occasional benign follicles colonized by marginal zone lymphoma, suggesting derivation from a focus of prior inflammation. Translocations involving the MALT1 gene were not identified but karyotypic evaluation highlighted a complex cytogenetic profile with many chromosomal abnormalities. This rare case provides insight into the pathophysiology of MALT lymphomas. [ABSTRACT FROM AUTHOR]

Different subtypes of acute myelogenous leukemia have distinct clinical presentations and courses. The specific clinical and molecular aspects of these leukemias have helped modify and create specific strategies for their management. We observed an increased incidence of pulmonary complications in patients with acute myelomonocytic leukemias (AMML) with inversion of chromosome 16 [inv(16)] irrespective of the presence of hyperleukocytosis. We reviewed patient records available over a period of 12 years at The Cleveland Clinic Foundation of patients with AMML with inv(16) and compared the incidence of pulmonary complications to a matched control group of patients with AMML but without inv(16). We found an increased incidence of pulmonary complications in the AMML with inv(16) group when compared to the control group. Two of these patients demonstrated brochiolitis obliterans with organizing pneumonia (BOOP) on lung biopsy. No specific etiology for the pulmonary complications was identified. These findings represent the first observation of an association between WHO-AMML with inv(16) [FAB-AML M4 with inv(16)] with a pulmonary syndrome at presentation. BOOP should be suspected in these cases. A larger prospective study to evaluate this association is warranted. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding a study on the use of Splicing factor 3b, subunit 1 ( SF3B1 ) mutations as a diagnostic for acquired clonal sideroblastic anemia (SA) patients with cytopenias.

The letter to the editor in Leukemia & Lymphoma discusses the link between a high Ki67 index and shorter progression-free survival in patients with Follicular Lymphoma undergoing frontline immunochemotherapy. The study underscores the significance of Ki67 as a prognostic factor for evaluating the proliferative activity of lymphoma cells. Research conducted at two tertiary care medical centers revealed that an IF Ki67 index ≥ 30% was associated with an elevated risk of disease progression, emphasizing the necessity for further investigations to identify predictive baseline characteristics in Follicular Lymphoma. The study examined the correlation between FLIPI/Ki67 (FKi) score and progression-free survival (PFS) in FL patients receiving frontline immunochemotherapy, with the FKi score predicting an increased risk of progression and being linked to PFS. Despite limitations like a retrospective analysis and a small sample size, the study suggests the potential value of integrating Ki67 into prognostic indices for FL, calling for additional research to validate these findings and explore the incorporation of FLIPI and Ki67 in contemporary FL treatment protocols. [Extracted from the article]

In this article, the authors discuss the article by Zhang and colleagues related to the microenvironmental components in peripheral T-cell lymphoma, not otherwise specified (PTCL NOS). It says that the recent models of tumor associated macrophages (TAMs) offer insight to their effects at a specific tumor site. It states that macrophages have a certain degree of plasticity and have differing effects on cancer. Furthermore, TAMs have a prognostic and biological significance in T-cell lymphomas.

The article comments on issues related to the treatment and management of T-cell lymphoma in the head and neck particularly adult T-cell leukemia/lymphoma (ATLL). ATLL is associated with HTLV-1 infection. It is endemic to Japan, South America, Africa and the Caribbean Islands. It is a disease with multiple clinical forms with varying clinical outcomes.

Diffuse large B-cell lymphomas (DLBCLs) consist of clinically distinct subtypes: germinal center B-cell (GCB)-like and activated-B-cell (ABC)-like tumors, characterized by long and short survival, respectively. We reported distinct interleukin 4 (IL-4) responsiveness and STAT6 signaling in these DLBCL subtypes. Increased nuclear dephosphorylation of phospho-STAT6 (pSTAT6) was observed in ABC-like tumors, which exhibited a different expression profile of protein tyrosine phosphatases (PTPs). Among the differentially expressed PTPs, only T-cell PTP (TCPTP) localizes to the nucleus. Herein, we report that the elevated expression of TCPTP in ABC- versus GCB-like DLBCL tumors is not due to the distinct ontogeny of these neoplasms but rather may be an acquired feature of the tumors. Moreover, we report that STAT6 may serve as a physiological nuclear substrate for TCPTP. We demonstrate interactions between endogenous TCPTP and STAT6 and delineate the domains responsible for the interaction. Overexpression of TCPTP ameliorates IL-4-induced STAT6 phosphorylation and associated gene transcription, whereas knockdown of endogenous TCPTP results in increased IL-4-induced STAT6 signaling. Moreover, we report that TCPTP protein levels may be increased in response to IL-4 and that TCPTP may serve in a negative feedback loop for the suppression of IL-4-induced signaling. Taken together, these results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors. [ABSTRACT FROM AUTHOR]