Search

Objectives: We recently performed a single‐arm phase II trial of DA‐EPOCH in adults with acute lymphoblastic leukemia (ALL). We sought to compare these results to those with standard Hyper‐CVAD. Methods: We created a retrospective matched cohort of patients who received Hyper‐CVAD (n = 69) at our center and otherwise met eligibility criteria for the DA‐EPOCH trial (n = 53). Results: Our outcomes support the use of Hyper‐CVAD over DA‐EPOCH in Ph− disease for both overall survival (OS; HR 0.18, p =.004) and event‐free survival (EFS; HR 0.51, p =.06). In contrast, outcomes were similar in Ph+ disease (OS HR 0.97, p =.96; EFS HR 0.65, p =.21). Rates of morphologic remission and measurable residual‐disease negativity were similar between the regimens. Hyper‐CVAD was associated with significantly more febrile neutropenia (OR 1.9, p =.03) and a greater incidence of Grade 4 or 5 adverse events (20% vs. 6%). Average transfusions per cycle of both red blood cells (p <.001) and platelets (p <.001) were five‐fold higher with Hyper‐CVAD. Conclusions: Our findings support continued use of Hyper‐CVAD for Ph− ALL but suggest that DA‐EPOCH may be a reasonable alternative for Ph+ ALL. These data also highlight a potential role for DA‐EPOCH in resource‐limited settings or when more intense therapy is not feasible. [ABSTRACT FROM AUTHOR]

Session 3 of the lymphoma workshop of the XXI joint meeting of the European Association for Haematopathology and the Society for Hematopathology took place in Florence, Italy, on September 22, 2022. The topics of this session were splenic and nodal marginal zone lymphomas, transformation in marginal zone lymphomas, and pediatric nodal marginal zone lymphomas and their differential diagnosis as well as related entities. Forty-two cases in these categories were submitted to the workshop, including splenic lymphomas (marginal zone and diffuse red pulp lymphomas), transformed marginal zone lymphomas (splenic and nodal), nodal marginal zone lymphomas with increased TFH-cells, and pediatric nodal marginal zone lymphomas. The case review highlighted some of the principal problems in the diagnosis of marginal zone lymphomas, including the difficulties in the distinction between splenic marginal zone lymphoma, splenic diffuse red pulp lymphoma, and hairy cell leukemia variant/splenic B-cell lymphoma with prominent nucleoli which requires integration of clinical features, immunophenotype, and morphology in blood, bone marrow, and spleen; cases of marginal zone lymphoma with markedly increased TFH-cells, simulating a T-cell lymphoma, where molecular studies (clonality and mutation detection) can help to establish the final diagnosis; the criteria for transformation of marginal zone lymphomas, which are still unclear and might require the integration of morphological and molecular data; the concept of an overlapping spectrum between pediatric nodal marginal zone lymphoma and pediatric-type follicular lymphoma; and the distinction between pediatric nodal marginal zone lymphoma and "atypical" marginal zone hyperplasia, where molecular studies are mandatory to correctly classify cases. [ABSTRACT FROM AUTHOR]

Follicular helper T-cell lymphomas (TFH lymphomas) were discussed in session V of the lymphoma workshop of the European Association for Haematopathology (EA4HP)/Society for Hematopathology (SH) 2022 meeting in Florence, Italy. The session focused on the morphologic spectrum of TFH lymphoma, including its three subtypes: angioimmunoblastic-type (AITL), follicular-type, and not otherwise specified (NOS). The submitted cases encompassed classic examples of TFH lymphoma and unusual cases such as those with early or indolent presentations, associated B-cell proliferations, or Hodgkin/Reed–Sternberg-like cells. The relationship between TFH lymphoma and clonal hematopoiesis was highlighted by several cases documenting divergent evolution of myeloid neoplasm and AITL from shared clonal mutations. The distinction between TFH lymphoma and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), was stressed, and many challenging examples were presented. Various cases highlighted the difficulties of differentiating TFH lymphoma from other established types of lymphoma and reactive conditions. Cutaneous T-cell lymphoma expressing TFH markers, particularly when resulting in lymph node involvement, should be distinguished from TFH lymphomas. Additional immunophenotyping and next-generation sequencing studies were performed on various cases in this session, highlighting the importance of these technologies to our current understanding and classification of TFH lymphomas. [ABSTRACT FROM AUTHOR]

Emerging entities and molecular subgroups in large B-cell lymphomas (LBCLs) were discussed during the 2022 European Association for Haematopathology/Society for Hematopathology workshop in Florence, Italy. This session focused on newly recognized diseases and their diagnostic challenges. High-grade/large B-cell lymphoma with 11q aberration (HG/LBCL-11q) is defined by chromosome 11q-gains and telomeric loss. FISH analysis is recommended for the diagnosis. HG/LBCL-11q can occur in the setting of immunodeficiency, including ataxia-telangiectasia, and predominates in children. The morphological spectrum of these cases is broader than previously thought with often Burkitt-like morphology and coarse apoptotic bodies. It has a Burkitt-like immunophenotype (CD10+, BCL6+, BCL2−) but MYC expression is weak or negative, lacks MYC rearrangement, and is in contrast to Burkitt lymphoma 50% of the cases express LMO2. LBCL with IRF4 rearrangement (LBCL-IRF4) occurs mainly in the pediatric population but also in adults. LBCL-IRF4 has an excellent prognosis, with distinguishing molecular findings. IRF4 rearrangements, although characteristic of this entity, are not specific and can be found in association with other chromosomal translocations in other large B-cell lymphomas. Other molecular subgroups discussed included primary bone diffuse large B-cell lymphoma (PB-DLBCL), which has distinctive clinical presentation and molecular findings, and B-acute lymphoblastic leukemia (B-ALL) with IGH::MYC translocation recently segregated from Burkitt lymphoma with TdT expression. This latter disorder has molecular features of precursor B-cells, often tetrasomy 1q and recurrent NRAS and KRAS mutations. In this report, novel findings, recommendations for diagnosis, open questions, and diagnostic challenges raised by the cases submitted to the workshop will be discussed. [ABSTRACT FROM AUTHOR]

BACKGROUND. T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR-T cell products were prepared from unselected T cells. METHODS. We conducted a clinical trial to evaluate CD19 CAR-T cells that were manufactured from defined [CD4.sup.+] and [CD8.sup.+] T cell subsets and administered in a defined [CD4.sup.+]:[CD8.sup.+] composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy. RESULTS. The defined composition product was remarkably potent, as 27 of 29 patients (93%) achieved BM remission, as determined by flow cytometry. We established that high CAR-T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity. Moreover, we identified serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity. Risk-stratified CAR-T cell dosing based on BM disease burden decreased toxicity. [CD8.sup.+] T cell-mediated anti-CAR transgene product immune responses developed after CAR-T cell infusion in some patients, limited CAR-T cell persistence, and increased relapse risk. Addition of fludarabine to the lymphodepletion regimen improved CAR-T cell persistence and disease-free survival. CONCLUSION. Immunotherapy with a CAR-T cell product of defined composition enabled identification of factors that correlated with CAR-T cell expansion, persistence, and toxicity and facilitated design of lymphodepletion and CAR-T cell dosing strategies that mitigated toxicity and improved disease-free survival. TRIAL REGISTRATION. ClinicalTrials.gov NCT01865617. FUNDING. R01-CA136551; Life Science Development Fund; Juno Therapeutics; Bezos Family Foundation., Introduction The administration of lymphodepleting chemotherapy followed by adoptive transfer of autologous T cells that are genetically modified to express a chimeric antigen receptor (CAR) specific for CD19 (CD19 CAR-T [...]

Treatments for adults with newly-diagnosed acute lymphoblastic leukemia (ALL) may be prohibitively toxic and/or resource-intense. To address this, we performed a phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH). Imatinib or dasatinib was added for Ph + disease; rituximab was added when CD20+. Fifty-three patients were evaluable: 28 with Ph + disease, and 25 with Ph−. All patients had ≥1 high-risk clinical feature. Measurable residual disease-negativity by multiparameter flow cytometry within 4 cycles was achieved in 71% in patients with Ph + ALL and 64% in Ph − ALL. Median overall survival (OS) was 49 months, with a 2-year OS of 71%. Median relapse-free survival (RFS) in the 47 patients that attained morphologic remission was 24 months, with a 2-year RFS of 57%. Early mortality was 2%. In summary, DA-EPOCH yields deep and durable remissions in adults with ALL comparable to some resource-intense strategies but with a low rate of treatment-related death. [ABSTRACT FROM AUTHOR]

Summary: Currently, there is no convincing evidence that the grade of follicular lymphoma (FL) impacts patient outcome. We correlated grades in 33 925 patients with nodal FL during 1992–2018 in the SEER database with disease‐specific survival (DSS) and overall survival (OS). Patients with FL grade 3 had lower DSS and OS as compared to FL grades 1–2. During 1992–2005, the 10‐year DSS for patients with FL grades 3 and grades 1–2 were 68.6%, and 71.4%, respectively, and in 2006–2018, they were 77.7% and 82.6%, respectively. The 10‐year OS estimates in 1992–2005 were 49.9% and 54.2% for grade 3 and grades 1–2 respectively, and in 2006–2018, they were 59.1% and 63.5% for grade 3 and grades 1–2, respectively. After adjustment for stage and age, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 during 1992–2005 were 1.09 (1.02–1.16) and 1.07 (1.02–1.12), respectively, compared to FL grades 1–2; and during 2006–2018, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 were 1.34 (1.22–1.45) and 1.16 (1.10–1.23), respectively compared to FL grades 1–2. The grade of FL is an important determinant of disease biology. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate clinicopathologic features, management, and behavior of colorectal extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT).Methods: Clinical data, laboratory studies, and radiographic records were reviewed (2005-2018), and fluorescence in situ hybridization studies were performed.Results: Eleven patients were identified, six of whom were discovered as an incidental finding on endoscopy. Morphologic and immunophenotypic features were similar to MALT lymphomas at other sites except that lymphoepithelial lesions were uncommon. Three of nine patients were positive for BIRC3/MALT1 fusions, two of whom had identical B-cell clones identified in subsequent gastric biopsy specimens. Eight of 10 patients had no clinically evaluable disease after observation (±antibiotics; n = 4) or radiation/chemotherapy (n = 4).Conclusions: Patients with incidental and localized colonic MALT lymphoma demonstrated an excellent prognosis with conservative management, although longer follow-up and data based on consistent staging and surveillance methods (including gastric evaluation) are necessary for informed management. [ABSTRACT FROM AUTHOR]

Objectives: Assessment for minimal/measurable residual disease (MRD) is a powerful prognostic factor in B lymphoblastic leukemia/lymphoma (B-LL/L) that is quickly becoming standard of care in assessing patients with B-LL/L posttherapy. MRD can be assessed using methodologies including flow cytometry and molecular genetics, with the former being rapid, relatively inexpensive, and widely applicable in many hematopathology/flow cytometry laboratories.Methods: This article presents an approach to MRD detection in B-LL/L by flow cytometry through case presentations with illustration of several potential pitfalls. We review normal maturation patterns, antigens used for assessment, flow panels that can be utilized, considerations to be made during therapy, and clinical impact. The benefits and drawbacks when using the "different from normal" and "leukemia associated phenotype" approaches are considered.Results: Evaluation for MRD in B-LL/L by flow cytometry relies on a knowledge of normal immunophenotypic patterns associated with B-cell maturation in states of rest and marrow regeneration so that one can identify patterns of antigen expression that differentiate abnormal, leukemic populations from regenerating hematogones or B-cell precursors. The nature of therapy can affect normal patterns, a phenomenon especially important to take into consideration given the increased use of targeted therapies in the treatment of B-LL/L.Conclusions: Flow cytometry is widely available in many laboratories and is a cost-effective way to evaluate for B-LL/L MRD. However, panel validation and interpreter education are crucial for accurate assessment. [ABSTRACT FROM AUTHOR]

Objectives: Given the increased complexity of molecular and cytogenetic testing (MOL-CG), the Society for Hematopathology Education Committee (SH-EC) was interested in determining what the current expectations are for MOL-CG education in hematopathology (HP) fellowship training.Methods: The SH-EC sent a questionnaire to HP fellowship program directors (HP-PDs) covering MOL-CG training curricula, test menus, faculty background, teaching, and sign-out roles. These findings were explored via a panel-based discussion at the 2018 SH-EC meeting for HP-PDs.Results: HP fellows are expected to understand basic principles, nomenclature, and indications for and limitations of testing. Interpretation of common assays is within that scope, but not necessarily proficiency in technical troubleshooting of testing or analysis of complex raw data.Conclusions: The consensus was that HP fellows should understand the components of MOL-CG testing necessary to incorporate those results into an accurate, clinically relevant, and integrated HP report. [ABSTRACT FROM AUTHOR]

The article discusses research which focused on the use of B-lymphocyte antigen CD19-specific chimeric antigen receptor (CAR)-modified T cells in immunotherapy of patients with non-Hodgkin's lymphoma. Topics explored include the observed effects of CD19 CAR-T cells on antitumor activity, the CAR-T cell manufacturing process, and the patient response and CD19 CAR-T cell toxicity recorded following treatment.

Historically, the presence of clonal B cell populations has been associated with malignancy in lymphoid proliferations. However, several studies have demonstrated that clonal B cell populations can be present in histologically reactive settings, but this has not been described in gastric samples. These studies have primarily shown clonality using molecular methods, with only a few studies showing clonality by flow cytometry. We evaluated 16 histologically benign gastric biopsies with CD10+ B cell populations identified by flow cytometry (13 clonal, 3 with kappa skew) and reviewed the morphology, endoscopic findings, and clinical course. Although the presence of clonal populations initially raised a diagnostic possibility of lymphoma in each case, morphologic examination supported a non-neoplastic reactive process. The CD10+ B cell populations typically demonstrated increased or slightly increased CD38 (88 %), increased or slightly increased CD20 (81 %), decreased surface light-chain expression (69 %), normal CD19 (94 %), and those that were studied (n = 12) were BCL-2 negative or indeterminate by flow cytometry. Polyclonal B cells were present, and the CD10+ B cell population comprised less than 50 % of the B cells in all cases. The available clinical information revealed no evidence of lymphoma in all 16 cases (follow-up ranging from 2months to 10 years). The presence of a CD10+ B cell clone (or lightchain skew) by flow cytometry in a gastric biopsy is not specific for lymphoid neoplasia and should be interpreted in the context of other immunophenotypic features as well as clinical and morphologic data. [ABSTRACT FROM AUTHOR]

MUM1/IRF4 is normally expressed in late germinal center/post germinal center B-cells. Previous studies of chronic lymphocytic leukemia in bone marrow and lymph node have demonstrated variable expression of MUM1/IRF4 and conflicting prognostic significance. In this study we evaluated MUM1/IRF4 expression in peripheral blood CLL cells utilizing Histogel™ cell blocks. MUM1/IRF4 was absent in 4/36 (11%) specimens. The remaining cases demonstrated variable intensity and proportion of positive cells: <20% positive 16/36 (44%), 20 - 50% positive 12/36 (33%), >50% 4/36 (11%). No correlation was identified between MUM1/IRF4 and percent of CD38 positive cells, CD38 status (+/-), ZAP-70 status (+/-), and IgVH mutational status. The variability in MUM1/IRF4 staining suggests a level of biologic complexity that is not adequately reflected in the current binary models of CLL pathobiology. This heterogeneity may reflect the role of MUM1/IRF4 as an effector and integrator of several lymphocyte activation pathways including antigenic and environmental stimuli. [ABSTRACT FROM AUTHOR]

Summary: Isolated chromosomal translocations are important defining features of many non-Hodgkin lymphomas, especially of B-cell type. In contrast to some other translocations, the significance of IGH/BCL3 translocations is not well defined. Although often considered a feature of the ill-defined entity atypical chronic lymphocytic leukemia, very few cases are reported in which involvement of BCL3 and the precise B-cell neoplasm are both well documented. For this reason, we report a splenic-based CD5−, CD10−, CD43−, CD23−, CD103−, FMC7+, CD25+ small B-cell lymphoma associated with epithelioid histiocyte clusters and a t(14;19)(q32;q13) representing an IGH/BCL3 translocation based on classical cytogenetic studies, chromosomal painting, and fluorescence in situ hybridization studies. The previously reported neoplasms with t(14;19)(q32;q13) or IGH/BCL3 translocations are also reviewed. The present case did not fall into any of the classic B-cell lymphoma categories and clearly did not represent chronic lymphocytic leukemia/small lymphocytic lymphoma. This case suggests that the IGH/BCL3 translocation may help to define a new clinicopathologic entity. [Copyright &y& Elsevier]

Summary: Prognostication in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) based, in part, on ZAP-70 and CD38 expression, and to a lesser extent, on MUM1/IRF4 expression, is currently of great interest. The more aggressive type of CLL/SLL is reportedly characterized by neoplastic cells that are more responsive to B-cell signaling with proliferation centers (PCs), a potentially important site of neoplastic cell stimulation. To study the relationship of these markers to each other and to the pattern of PCs, immunohistochemical stains for ZAP-70 and MUM1/IRF4 were performed and the PC patterns assessed (where possible) in 29 tissue biopsies with CLL/SLL. CD38 expression was assessed in 18 cases using flow cytometry. Ten evaluable cases had a typical PC pattern and 16 an atypical pattern with larger or more confluent PCs and/or more numerous paraimmunoblasts/transformed cells. ZAP-70 was positive in 14 of 28 cases, including 3 with atypical PCs and enhanced PC staining. All 29 cases showed MUM1/IRF4 expression in PCs. Seven cases, none with atypical PC, also showed uniform positivity throughout, 14 showed weaker staining of surrounding lymphocytes, and 8 had PC staining only. CD38 was positive in 14 of 18 cases. The only significant association identified was between uniform MUM1/IRF4 positivity and typical PCs (P = .004). These findings highlight the complex interrelationship of prognostic markers in CLL/SLL and demonstrate potentially important microenvironmental variations in their expression. They support the hypothesis that PCs are a site for B-cell receptor signaling, which helps explain reported site-dependent antigenic variation in CLL/SLL, and suggest that PC morphology may correlate with other biological features. [Copyright &y& Elsevier]

Microglia (MG) are enigmatic cells of the central nervous system (CNS). MG are morphologically, antigenically and functionally flexible, and have the potential for mobility and proliferation. MG are professional antigen-presenting cells and constitute part of the local CNS innate immune system, communicating with other immune cells via chemokines, cytokines and growth factors. MG contain several antigenic and functional markers similar to macrophages and dendritic cells (DCs), but also present several differences from DCs. The exact role(s) played by MG in the normal human CNS is the topic of lively debate. MG participate in many reactive processes in the CNS and are therefore an integral part of lesions in a variety of pathologic conditions. It is thought that MG may exacerbate diverse neurological conditions, including viral encephalitis, AIDS, Multiple Sclerosis (MS) and Alzheimer's disease. A recurrent theme is the perpetuation by MG of pathological cycles of monocyte recruitment, activation and cytopathic secretions, and/or auto antigen presentation. [ABSTRACT FROM AUTHOR]

Distinguishing neoplastic from reactive cutaneous lymphoid infiltrates remains a diagnostic challenge. While flow cytometry is broadly used in hematopathology, it is only now emerging as a method for determining the immunophenotype and clonality of cutaneous lymphocyte populations. Cutaneous marginal zone lymphomas are particularly challenging; these cases often have lymphoid follicles with reactive features, and the neoplastic cells can be greatly outnumbered by the associated reactive, polyclonal B- and T-lymphocyte populations. We present the case of a 53-year-old man who presented with a three-year history of a patch on the left cheek. Two biopsies, taken a year apart, showed a dense nodular superficial and deep perivascular, perifollicular, and peri-eccrine mixed lymphoid infiltrate (60% B-cells and 40% T-cells), composed mainly of small lymphocytes with focal reactive germinal centers. These findings were initially interpreted as being most consistent with a reactive process, or pseudolymphoma. Because the lesion failed to regress after multiple steroid injections, a third biopsy was taken. Although this specimen had similar morphologic features, flow cytometry was performed and revealed a small abnormal B-cell population comprising 1.14% of total white blood cells. These B-cells showed abnormal expression of CD11c and were lambda light chain restricted with normal expression of CD19, CD20, CD38, and CD45 without CD5, CD10, or CD43. In addition, a small lambda light chain restricted plasma cell population was identified (0.01% of total white blood cells). No abnormal T-cells were identified. Molecular studies confirmed the presence of a clonal immunoglobulin gene rearrangement. Taken together, these findings were interpreted as cutaneous marginal zone lymphoma; the patient was then referred to oncology for staging and further management. The case underscores the limitations of morphology and immunohistochemistry alone in the diagnosis of cutaneous lymphomas and demonstrates the sensitivity of flow cytometry in detecting small, abnormal lymphocyte populations that might otherwise be overlooked. [ABSTRACT FROM AUTHOR]

Presents a case study of chronic lymphocytic thyroiditis in a 41-year-old woman. Medical history of the patient; Laboratory analysis; Surgical treatment.