Contemporary outcomes in IDH-mutated acute myeloid leukemia: The impact of co-occurring NPM1 mutations and venetoclax-based treatment.

Isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations occur frequently in newly diagnosed (ND) acute myeloid leukemia (AML) often with co-occurring NPM1 mutations, which may influence treatment outcomes. Detailed analysis of IDH-mutated AML treated with venetoclax and influence of co-occurring NPM1 mutations remains unclear. This retrospective single-center cohort study evaluated clinical and molecular demographics,response and survival, and impact of co-occurring NPM1 mutations in patients with IDH1 or IDH2-mutated AML. 556 patients with IDH1, IDH2, and/or NPM1 mutated AML were included. Patients with IDH1mut AML (N = 119) were more likely to have older age, sAML, ELN-adverse risk disease, and adverse-risk cytogenetics compared to those with IDH2mut (N = 229) or IDHwt /NPM1mut AML (N = 208). In multivariate analysis, patients with IDH2mut (HR 0.61 [95%CI: 0.43-0.88], p value: .007) or IDHwt /NPM1mut (HR 0.65 [95% CI: 0.45-0.94], p value: .024) AML had a decreased risk of death versus IDH1mut AML. Venetoclax-based lower-intensity regimens partially abrogated the detrimental effect of IDH1mut with similar OS observed between IDH1mut /NPM1wt , IDH2mut /NPM1wt , and IDHwt /NPM1mut AML. With regards to the influence of IDHmut /NPM1mut cases, IC improved survival in IDH2mut /NPM1mut versus IDH2mut /NPM1wt AML (HR: 0.54 [95% CI: 0.2644-1.082], p value: .077), while venetoclax-based therapy improved survival in IDH1mut /NPM1mut versus IDH1mut /NPM1wt AML (HR: 0.094 [95% CI: 0.01-0.74], p value: .0056). Differing outcomes were observed in IDH1mut versus IDH2mut or NPM1mut AML which were influenced by co-occurring NPM1 mutations and partially abrogated with venetoclax-based therapy. Given the differing biology and survival in IDH1mut AML, investigations incorporating molecularly targeted therapies such as IDH inhibitors remain warranted in this subgroup.

Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.

Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) harbors somatic hypermutation (SHM) in the immunoglobulin heavy chain and light chain variable region genes, IGHV and IGK/LV. Recent studies have revealed that IGV SHM creates neoantigens that activate T-cell responses against B-cell lymphoma. METHODS: To determine the clinical relevance of IGV SHM in DLBCL treated with standard immunochemotherapy, we performed next-generation sequencing of the immunoglobulin variable regions and complementarity determining region 3 (CDR3) for 378 patients with de novo DLBCL. The prognostic effects of IGV SHM and ongoing SHM or intra-clonal heterogeneity were analyzed in the training (192 patients), validation (186 patients), and overall DLBCL cohorts. To gain mechanistic insight, we analyzed the predicted IG-derived neoantigens' immunogenicity potential, determined by the major histocompatibility complex-binding affinity and the frequency-of-occurrence of T cell-exposed motifs (TCEMs) in a TCEM repertoire derived from human proteome, microbiome, and pathogen databases. Furthermore, IGV SHM was correlated with molecular characteristics of DLBCL and PD-1/L1 expression in the tumor microenvironment assessed by fluorescent multiplex immunohistochemistry. RESULTS: SHM was commonly found in IGHV and less frequently in IGK/LV. High levels of clonal IGHV SHM (SHMhigh) were associated with prolonged overall survival in DLBCL patients, particularly those without BCL2 or MYC translocation. In contrast, long heavy chain CDR3 length, the presence of IGHV ongoing SHM in DLBCL, and high clonal IGK/LV SHM in germinal center B-cell-like (GCB)-DLBCL were associated with poor prognosis. These prognostic effects were significant in both the training and validation sets. By prediction, the SHMhigh groups harbored more potentially immune-stimulatory neoantigens with high binding affinity and rare TCEMs. PD-1/L1 expression in CD8+ T cells was significantly lower in IGHV SHMhigh than in SHMlow patients with activated B-cell-like DLBCL, whereas PD-1 expression in CD4+ T cells and PD-L1 expression in natural killer cells were higher in IGK/LV SHMhigh than in SHMlow patients with GCB-DLBCL. PD-L1/L2 (9p24.1) amplification was associated with high IGHV SHM and ongoing SHM. CONCLUSIONS: These results show for the first time that IGV SHMhigh and ongoing SHM have prognostic effects in DLBCL and potential implications for PD-1/PD-L1 blockade and neoantigen-based immunotherapies.

Phase II Study of Bortezomib in Combination with Cyclophosphamide and Rituximab for Relapsed or Refractory Mantle Cell Lymphoma.

BACKGROUND: Relapsed or refractory mantle cell lymphoma (MCL) has a poor prognosis. The best outcome is achieved in patients who have a partial or complete response to salvage treatment and proceed to allogeneic stem cell transplant. PATIENTS AND METHODS: Twenty-one patients were given a combination regimen of bortezomib, cyclophosphamide, and rituximab at MD Anderson Cancer Center as part of a single-arm, prospective, open-label phase II clinical trial. The median age was 66 years, with a median number of prior treatments of three. Sixty-seven percent had failed intensive chemoimmunotherapy and 43% were intermediate/high risk according to the MCL international prognostic index score, with a median Ki-67 proliferation index of 45% in those who were tested. RESULTS: The rates of overall and complete response achieved were 74% and 42%, respectively, with median progression-free and overall survivals of 9 months and 36.4 months, respectively. The regimen's toxicity profile was acceptable; only 25% of the cycles resulted in grade 3 or 4 neutropenia or thrombocytopenia, and only 3% of cycles produced grade 3-4 fatigue. There were no episodes of grade 3-4 neuropathy. CONCLUSION: The combination of bortezomib with cyclophosphamide and rituximab is an effective and well-tolerated regimen in patients with relapsed/refractory MCL. Because of its low toxicity, future combinations of this regimen with other promising drugs that have different mechanisms of action offer a realistic possibility that may improve outcomes for patients who have MCL. The Oncologist 2017;22:549-553 IMPLICATIONS FOR PRACTICE: The combination of bortezomib with cyclophosphamide and rituximab represents an additional effective novel salvage regimen for mantle cell lymphoma. This combination adds to the growing list of treatment options available for patients with mantle cell lymphoma.

Survival Outcomes of Primary Intraocular Lymphoma: A Single-institution Experience.

OBJECTIVES: We report the clinical outcomes of 22 patients with primary intraocular lymphoma (PIOL) treated over a 15-year period. MATERIALS AND METHODS: Patients with confirmed PIOL by central pathology review treated from 1994 to 2010 with isolated ocular (N=13) or central nervous system (CNS) plus ocular involvement (N=9) were included. Intraocular and CNS failure-free survival, relapse-free survival, and overall survival outcomes were analyzed. RESULTS: Median follow-up was 29.0 (range, 10.2 to 96.4) months. Sixteen patients (9 with isolated ocular, 7 with ocular and CNS disease) received combined modality therapy (CMT) consisting of systemic chemotherapy (usually high-dose methotrexate based) and orbital +/- whole-brain radiation. Two patients were treated with chemotherapy and 4 with local ocular therapy alone. Among patients with isolated ocular versus CNS involvement, CNS failure-free survival was 79% versus 57%, and intraocular failures were 62% versus 78% at 24 months. Median relapse-free survival was 34.0 versus 21.3 months (P=0.368), and overall survival 43.4 versus 30.3 months (P=0.744), respectively. Three patients treated with CMT (2 with isolated ocular and 1 with CNS involvement) with >1-year follow-up alive at the time of analysis never relapsed, and one remains disease-free >4.5 years after treatment. CONCLUSIONS: In this series of patients with PIOL+/- CNS disease, CNS and intraocular relapse were common. A trend toward better survival was seen among patients with isolated ocular presentation, and a limited number of long-term disease-free survivors seen after CMT.

Burkitt lymphoma and atypical Burkitt or Burkitt-like lymphoma: should these be treated as different diseases?

Burkitt lymphoma (BL) is a mature B-cell non-Hodgkin lymphoma with an aggressive clinical course. Since the advent of short, intensive, multiagent chemoimmunotherapy regimens, it has carried a favorable prognosis. BL has been rather well characterized, whereas the other lymphomas morphologically resembling it are more heterogeneous. The cases classified as atypical BL/Burkitt-like lymphoma by the 2001 World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissue were thought to represent a continuum between BL and diffuse large B-cell lymphoma (DLBCL). The optimal therapeutic strategy for this provisional entity was not definitively established. However, recent incorporation of molecular genetic data into the 2008 WHO Classification has allowed further refinements with significant therapeutic implications, including the designation of a new provisional entity, "B-cell lymphoma, unclassifiable, with features intermediate between BL and DLBCL." This review presents a comprehensive overview of the previously designated provisional entity of atypical BL/BLL in conjunction with a detailed comparison with BL and DLBCL.

Plasma cell dyscrasias and the head and neck.

Structures in the head and neck (bones, soft tissues, lymph nodes, mucosa) are variably affected by plasma cell dyscrasias. Involvement can be manifested by localized lesions (extramedullary plasmacytoma or solitary plasmacytoma of bone) or by more diffuse disease (multiple myeloma). We present a contemporary review of these disorders with emphasis on patient outcomes.

Linfomas primarios de hueso: reporte de 3 casos en Costa Rica / Primary bone lymphoma: report of 3 cases in Costa Rica

Los linfomas óseos primarios son raros; en este trabajo se presentan tres casos encontrados en 25 años en los archivos de Anatomía Patológica del Hospital México, San José, Costa Rica. Dos pacientes eran mujeres y uno varón, con edades de 31, 36 y 52 años . Todos los casos ameritaron tratamiento combinado de cobalto y quimioterapia eventualmente, a pesar de que los estudios iniciales determinaron que la neoplasia estaba localizada (estadío IEA). Los tres casos fueron clasificados histológicamente como linfomas de células grandes no hendidas, según la Formulación de Trabajo para Uso Clínico (1), con inmunofenotipo B demostrado por análisis inmunohistoquímicos. Dos pacientes están vivos y uno falleció con linfoma, con un seguimiento promedio de 48 meses