Efficacy of CD19 directed therapies in patients with relapsed or refractory large b-cell lymphoma relapsing after CD19 directed chimeric antigen receptor T-cell therapy.

Outcomes are poor for patients with relapsed and/or refractory (R/R) large B-cell lymphoma (LBCL) post chimeric antigen receptor T-cell (CAR-T) therapy. Two CD19-directed therapies, tafasitamab- cxix plus lenalidomide (tafa-len) and loncastuximab tesirine (loncaT) are approved in R/R LBCL. The efficacy of these CD19 directed therapies in patients who relapse after CD19 directed CAR-T (CD19-CART) therapy is not well understood. We conducted a multi-center study of patients with R/R LBCL that received either tafa-len or loncaT at any timepoint for R/R disease after CD19-CART therapy. Fifty-three patients were included in this study with the median follow up of 56 (9.1-199) weeks from CAR-T infusion. Median number of systemic therapies pre-CAR-T therapy was 3 (range: 1-6); axicabtagene ciloleucel was the most utilized CAR-T product (n = 32,60%). Median time from CAR-T therapy to tafa-len or loncaT was 7.3 (1.2-38.2) months with median number of lines of therapy between CAR-T therapy and these regimens of 1 (0-5). Combined overall response rate and complete response rates were 27% and 10%, respectively. Median duration of response was 13.3 (2.1-56.7) weeks. In this real-world study, the use of currently approved CD19-directed therapies to treat R/R LBCL after CD19-CAR-T therapy showed limited clinical activity and duration of responses.

Epstein-Barr Virus: From Kissing Disease to Broken Heart.

We present a case of a 59 year old female patient that presented with exertional chest pain and palpitations. A workup revealed an EKG with signs of right ventricular hypertrophy, a high Pro-BNP and 3 sets of negative troponin levels. A CT scan of the chest was negative for pulmonary embolism (PE) but revealed a nodular thickening of the atrial septum with right atrial extension encasing the right coronary artery. A CT scan of the abdomen and pelvis with IV contrast revealed several nodular foci scattered in the subcutaneous fat of the abdominal wall bilaterally. An initial transthoracic echocardiogram (TTE) revealed thickening of the interatrial septum with a mass protruding from the interatrial septum into the left atrium and a secondary pedunculated mass protruding from the interatrial septum into the right atrium with significant obstruction within the right atrium. An ultrasound-guided biopsy of the soft tissue nodule in the right anterior abdominal wall and subcutaneous tissue showed the classical starry sky appearance pattern confirmed later to be a Burkitt lymphoma. The patient received chemotherapy and follow up CT of the abdomen and pelvis reported resolution of the soft tissue density involving the partially visualized portions of the heart. Although rare, cardiac lymphomas should be considered in the differential diagnosis of patients with identified cardiac masses. As the initial presentation is usually composed by non-specific symptoms, a detailed clinical history can identify certain constitutional symptoms and a thorough physical exam can lead to the suspicion of cardiac structural pathology prompting the need for the appropriate chest imaging. Further characterization may need TTE or TEE which are more sensitive and specific due to the tri-dimensional and temporal quality of the imaging. Appropriate biopsy with pathology and molecular studies are of utmost importance in making an accurate diagnosis in order to select the best management for this highly aggressive malignancy.

Brentuximab vedotin as frontline treatment for HIV-related extracavitary primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a rare and aggressive herpesvirus-8 (HHV-8) driven B cell non-Hodgkin's lymphoma (NHL) that is usually associated with human immunodeficiency virus (HIV) infection, and has a poor prognosis. PEL is comprised of two clinically distinct but pathologically similar variants: classic and extracavitary PEL. Based on retrospective series, treatment options include combined antiretroviral therapy (cART) in conjunction with chemotherapy regimens used in other forms of NHLs. Treatment outcomes with this approach are usually dismal and there is no standard of care. We present a case of a patient with HIV associated CD30+ extracavitary PEL unfit for multi-agent chemotherapy, who achieved a durable complete response with single agent brentuximab-vedotin and cART.

Allogeneic hematopoietic cell transplantation is potentially curative in mantle cell lymphoma: results from a single institution study.

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for mantle cell lymphoma (MCL). We retrospectively analyzed outcomes of 36 patients, median age of 54 (41-68) years, who underwent allo-HCT, mostly (66%) receiving a myeloablative (MAC) regimen. Median overall survival (OS) was 86 months and 5-year OS was 54%. Median progression-free survival (PFS) was 54 months and 5-year PFS was 49%. Cumulative incidence (CI) of non-relapse mortality (NRM) and 2-year progression were 20.1 and 22.1%, respectively. Day +100 CI of grade II-IV acute graft-versus-host disease (GVHD) was 38.1%; 2-year CI of moderate/severe chronic GVHD was 31.7%. Seven patients received allo-HCT as frontline consolidation and had better OS (median = not reached versus 54 months, p = .045). Notwithstanding the small sample size and retrospective study design, our findings suggest a role for allo-HCT in selected MCL patients. Future prospective studies would be needed to better define the role of allo-HCT in this disease.

Association between immunoglobulin heavy-chain variable region mutational status and isolated favorable baseline genomic aberrations in chronic lymphocytic leukemia.

Immunoglobulin heavy-chain variable region (IGHV) mutational status and karyotype abnormalities are important prognostic factors in chronic lymphocytic leukemia (CLL). The goal was to assess the impact of IGHV in CLL patients with isolated favorable genetic aberrations (del13q, trisomy 12, or negative fluorescence in situ hybridization [FISH]). We studied 273 CLL patients with both IGHV mutational status and cytogenetic information: 145 with isolated del13q 49 with sole trisomy 12 and 79 with negative FISH. After a median follow-up of 7.8 years, patients with del13q-unmutated IGHV had a shorter time to first treatment (TFT) (2.98 vs. 17.44 years; p < .001) and shorter overall survival (10.45 years vs. not reached; p = .0026). Patients with negative FISH-unmutated IGHV had shorter TFT (p = .02) (3.10 vs. 9.75 years, p = .053). IGHV status did not influence clinical outcomes in trisomy 12 CLL. In conclusion, IGHV mutational status shows prognostic impact in CLL patients with good prognosis genomic features.

Nivolumab as salvage treatment in a patient with HIV-related relapsed/refractory Hodgkin lymphoma and liver failure with encephalopathy.

BACKGROUND: We report the first case to our knowledge of a patient with relapsed/refractory classical hodgkin lymphoma and liver failure with encephalopathy along with human immunodeficiency virus/acquired immunodeficiency syndrome infection, successfully treated with nivolumab without major side effects and encouraging prolonged disease control. CASE PRESENTATION: In December 2015, at the time of the patient's progression from his Hodgkin lymphoma after fourth line treatment, he developed persistent fevers, abdominal distension, jaundice and worsening of his liver function tests. Magnetic resonance imaging of abdomen/pelvis demonstrated hepatomegaly with innumerable new liver lesions, splenomegaly with multiple splenic nodules and several new mediastinal, intraperitoneal and retroperitoneal lymphadenopathy. In accordance with the patient's wishes before admission, and after agreement with the family, nivolumab (3 mg/kg every 2 weeks) was given. Of note, antiretroviral therapy was on hold due to liver function tests, his viral load was undectable and cluster of differentiation 4 counts were 103/uL at the time of nivolumab administration. One week after the first dose of nivolumab both his hepatic encephalopathy and constitutional symptoms started to improve, and after 2 doses, (January 2016) his LFTs were almost back to normal. After 5 months of nivolumab treatment (10 doses), restaging (computerized tomography scans of neck, chest, abdomen, pelvis) done on May 2016 showed resolution of hepatosplenomegaly with two residual small hepatic lesions, heterogeneous spleen with no splenic lesions, and stable non-enlarged retroperitoneal lymph nodes without intraabdominal lymphadenopathy; consistent with partial response. CONCLUSIONS: We report a case of a patient with human immunodeficiency virus/acquired immunodeficiency syndrome -related relapsed/refractory classical Hodgkin lymphoma and acute liver failure with encephalopathy successfully treated with nivolumab after failing all standard therapeutic options. Unlike classic cytotoxic chemotherapy, which relies on preserved organ function to ameliorate potential severe side effects (i.e. myelosuppression), elimination of monoclonal antibodies is fairly independent of baseline renal and hepatic function since they are usually metabolized by circulating phagocytes and/or by their target antigen-expressing cell.

Mantle Cell Lymphoma: Contemporary Diagnostic and Treatment Perspectives in the Age of Personalized Medicine.

Mantle cell lymphoma is a clinically heterogeneous disease occurring within a heterogeneous patient population, highlighting a need for personalized therapy to ensure optimal outcomes. It is therefore critical to understand the benefits and risks associated with both intensive and deintensified approaches. In the following review we provide a therapeutic roadmap to strategically guide treatment for newly diagnosed and relapsed/refractory patients highlighting pivotal and recently published results involving known and novel therapies.

A New Therapeutic Era in GCB and ABC Diffuse Large B-cell Lymphoma Molecular Subtypes: A Cell of Origin-Driven Review.

In the past 15 years, advances in molecular biology have exposed the genetic and physiopathologic heterogeneity of diffuse large B-cell lymphoma (DLBCL). Subsets of patients have been identified in which current chemoimmunotherapies may not be as efficacious, such as the activated B-cell subtype (ABC). In this review, we present an in-depth study of the differences between the two main DLBCL subsets (germinal center B cell [GCB] and ABC), focusing specifically on their different genetic features, active tumoral pathways, and pathologic features. We also discuss the bridges that have been built from the bench to the forefront of patient care through translational research, including the use of immunohistochemistry versus gene profiling to categorize patients with DLBCL and current clinical trial data pertaining to new possible targeted therapies for patients with these two subtypes of DLBCL. We hope that clinicians use this review as a tool to better understand the complexity of the two more prevalent DLBCL subtypes seen in the day to day practice and update their knowledge in both current and upcoming novel treatment options that can potentially change the outcomes of this population.

Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma.

A phase II trial of R-MACLO-IVAM followed by thalidomide maintenance for mantle cell lymphoma (MCL) demonstrated promising progression-free survival (PFS) and overall survival (OS) rates. Thalidomide maintenance was associated with significant toxicity and was subsequently modified to rituximab maintenance. Herein, we present updated results and follow-up. Two sequential phase II trials included chemotherapy-naïve patients with MCL up to 75 years old. Four cycles of R-MACLO-IVAM chemotherapy were delivered as previously described. Patients who achieved complete responses (CR) were eligible for thalidomide or rituximab maintenance therapy. Among 36 patients enrolled, the MCL International Prognostic Index (MIPI) was low in 53%, intermediate in 36% and high in 11%. Thirty-five patients completed at least 2 cycles of chemotherapy; 34 (94%) achieved a CR. After a median follow-up of 74.4 months, the 5-year PFS was 51% (95% CI 33-68%) and the 5-year OS was 85% (95% CI 73-97%). Two deaths occurred during the chemotherapy phase due to disease progression and neutropenic sepsis, respectively. One patient developed secondary acute myeloid leukemia after 7 years. R-MACLO-IVAM chemotherapy is effective for patients with newly diagnosed MCL.

Rosai-Dorfman disease of the central nervous system: report of 6 cases and review of the literature.

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy (SHML), is an uncommon benign idiopathic lymphoproliferative disorder. The histologic hallmark of RDD is the finding of emperipolesis displayed by lesional histiocytes. While RDD most commonly affects lymph nodes, extranodal involvement of multiple organs has been reported, including the central nervous system (CNS). However, CNS involvement in RDD is rare and is not well characterized. As a result, therapeutic approaches to CNS involvement in RDD are not well established. Herein we report 6 cases of RDD with isolated CNS involvement and review the literature on RDD with CNS involvement. One of the presented cases exhibited intramedullary involvement of the spinal cord--a very rare form of RDD with CNS involvement.

Usefulness of HGAL and LMO2 immunohistochemistry in the identification of follicular lymphomas of the non-gastric gastrointestinal tract.

BACKGROUND: We studied the sensitivity of 2 relatively new markers of germinal center B-cell origin, namely human germinal center-associated lymphoma (HGAL) and Lim-only transcription factor 2 (LMO2), in the identification of follicular lymphomas (FLs) of the nongastric gastrointestinal (GI) tract. MATERIALS AND METHODS: We retrospectively reviewed cases of endoscopically derived primary, nongastric GI lymphomas including FL, grade 1 or 2, and extranodal marginal zone lymphoma (ENMZL) of mucosa-associated lymphoid tissue, classified based on morphologic features and immunohistochemical analysis. HGAL and LMO2 immunohistochemical stains were then prospectively performed in each case. When discrepant immunohistochemical results were obtained, fluorescent in situ hybridization was performed for t(14;18) IGH/BCL2 and IGH rearrangement using a dual color fusion and a dual color break-apart probe, respectively. RESULTS: All but one of the CD10-negative ENMZL cases were negative for both HGAL and LMO2. One case originally classified as ENMZL was positive for both HGAL and LMO2. Fluorescent in situ hybridization did not detect either t(14;18) IGH/BCL2 or IGH rearrangement in this case. It is likely, based on positivity of 2 established germinal center B-cell markers, that this represents a FL which was originally misclassified as an ENMZL based on CD10 negativity. Of the cases of FL (all CD10 and/or BCL-6 positive), 8 (80%) were positive for both HGAL and LMO2. CONCLUSIONS: Although HGAL and LMO2 did not demonstrate an increased sensitivity in the identification of FL of the nongastric GI tract in this series, they still were helpful in the reclassification of one of our cases, and may therefore be useful adjuncts in the identification of FL of the nongastric GI tract.