Performance status, comorbidities, and cycles of methotrexate exert the greatest influence on outcomes of primary and secondary CNS lymphomas: the Lexington experience.

Primary central nervous system lymphoma (PCNSL) occurs primarily in older patients and has a worse prognosis than other extranodal lymphomas. Contemporary treatment is based on high-dose methotrexate (HD-MTX), which crosses the blood-brain barrier. Secondary CNS lymphoma (SCNSL) can occur concomitantly with systemic lymphoma or later at relapse and generally has a dismal outcome. We reviewed disease characteristics and outcomes of 103 patients (44 PCNSL and 59 SCNSL) treated at our center between 2015 and 2020. Median ages at diagnosis were 64 and 62 years, respectively. In both groups, diffuse large B cell lymphoma (DLBCL) was the major histologic type; in SCNSL, other types were also seen. SCNSL, in contrast with PCNSL, manifested with smaller tumors or cerebrospinal fluid positivity. For SCNSL the mean interval to brain involvement was 18 months (0-138). The overall survival had a trend to worse in SCNSL; median survival 11 months versus 61 months in PCNSL (p = 0.089). Progression-free survival was similar in both groups. A significant proportion of SCNSL patients with poor performance status could not obtain CNS-directed treatments. The strongest predictor of poor outcome was ECOG performance status 2 + at diagnosis for both groups. Charlson comorbidity index was predictive only for the PCNSL cohort. Tumor size was not prognostic for survival. The number of HD-MTX cycles correlated with survival, whereas the regimen itself and average cumulative dose of methotrexate did not play a role. Our study is in line with the recent literature and confirms ongoing challenges. We discuss how the outcomes of CNS lymphomas can be improved.

Type B Lactic Acidosis Associated With Venlafaxine Overdose.

Lactic acidosis that is not secondary to tissue hypoperfusion or hypoxemia (type B lactic acidosis) is a rare but potentially fatal condition that has been associated with drugs like metformin, linezolid, and nucleoside reverse-transcriptase inhibitors in patients with HIV. We report the first case of type B lactic acidosis caused by overdose of the serotonin-norepinephrine reuptake inhibitor, venlafaxine. A 55-year-old man with no significant medical history was brought to the emergency department after intentional ingestion of around 80 capsules of venlafaxine (a total dose of over 6000 mg) in an attempt to commit suicide. Complete blood count and comprehensive metabolic panel were unremarkable except for a bicarbonate level of 13 mEq/L and an anion gap of 22 mEq/L. An arterial blood gas revealed a pH of 7.39, partial pressure of CO2 of 19 mm Hg, calculated bicarbonate of 11.5 mEq/L, and a lactate level of 8.6 mmol/L. The patient was started on aggressive intravenous hydration with normal saline along with oral activated charcoal with sorbitol. Repeat laboratory work after 4 hours showed an improvement in anion gap (15 mEq/L) and serum lactate (5.6 mmol/L). The patient remained stable throughout the hospital stay and lactic acidosis resolved in 24 hours. In the absence of hypotension, hypoxemia, kidney or liver dysfunction, myopathy, malignancy, or use of other medications, venlafaxine was the most likely cause of lactic acidosis in our case. Rapid improvement of acidosis was probably related to clearance of the drug.

Acquired von Willebrand syndrome in a patient with monoclonal gammopathy of unknown significance: A case report.

Monoclonal gammopathy of uncertain significance associated acquired von Willebrand syndrome is a serious bleeding condition driven by immunological clearance of von Willebrand factor and has limited treatment options. We present a patient who achieved durable remission through eradication of the monoclonal paraprotein with clonal directed therapy with bortezomib.

Lisocabtagene Maraleucel for the treatment of B-cell lymphoma.

Introduction: Lisocabtagene Maraleucel (Liso-cel) is a second-generation Chimeric Antigen Receptor T-cell (CAR-T) therapy product targeting CD19. It is currently being evaluated for B-cell lymphomas with pivotal trials conducted in Aggressive B-cell LymphomasAreas covered: To prepare this article reviewing preclinical and clinical data studying Liso-cel, we performed a Pubmed search using the terms 'JCAR017' and 'Lisocabtagene maraleucel'. Pre-clinical work done with Liso-cel demonstrate the synergistic activity of CD4 + T-cells and CD8+ central memory T-cells (TCM) at a predefined ratio of 1:1. The trial, TRANSCEND NHL001 in aggressive B-cell lymphoma, confirms robust antitumor activity while demonstrating manageable toxicity profile.Expert Opinion: There are inherent differences amongst the three CD19 directed CAR-T products. This could explain the differences in efficacy and safety profiles of the products. In the absence of randomized data, it would be scientifically unsound to prioritize one product over another. Nevertheless, when aiming to balance efficacy and safety, current prospective data indicate that Liso-cel is well positioned with impressive response rates.

Myocarditis Concurrent with Sweet Syndrome: A Presentation of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia in American adults and portends a poor prognosis if untreated. Commonly, AML presents with symptoms related to concurrent leukopenia, anemia, or thrombocytopenia; however, due to its ability to affect many organ systems in the body, AML can have a highly varied clinical presentation. One such presentation is myocarditis, which is a rarely reported manifestation of AML. Myocarditis can have a varied clinical picture and often requires exclusion of other causes of cardiac dysfunction. Sweet syndrome, also known as acute febrile neutrophilic dermatosis, is another presentation of AML; however, it is more commonly associated with AML than cardiac involvement. Sweet syndrome can occur in patients with an already established malignancy or can occur de novo in a patient with previously undiagnosed cancer and, interestingly, can also be accompanied by extracutaneous manifestations, one of which is myocarditis. Herein, we report a case of a 45-year-old male with a history of obesity and depression who presented with chest pain, a tender and diffuse rash, and pancytopenia. Heart catheterization performed at outside institution was negative for coronary artery disease. Cardiac MRI images were compatible with myocarditis. Dermal biopsy of the rash was consistent with sweet syndrome. Peripheral blood flow cytometry and bone marrow biopsy confirmed the diagnosis of AML. He was treated with an induction chemotherapy regimen of 7 days of cytarabine and 3 days of daunorubicin with resolution of his chest pain and skin lesions. The patient had persistent leukemia cells on day 14 postinduction bone marrow biopsy and was treated with high-dose cytarabine reinduction treatment. Bone marrow biopsy with count recovery after reinduction therapy revealed complete response (CR).

SRSF2 mutations in myelodysplasia/myeloproliferative neoplasms.

Recurrent gene mutations have been described with varying frequencies in myelodysplasia (MDS) /myeloproliferative neoplasm (MPN) overlap syndromes (MMOS). Recent work has placed significant focus on understanding the role of gene lesions involving the spliceosomal machinery in leukemogeneis. SRSF2 is a gene encoding critical spliceosomal proteins. SRSF2 mutations appear to play an important role in pathogenesis of MMOS, particularly in chronic myelomonocytic leukemia. Inhibition of splicing may be a new therapeutic approach. E7107, a spliceosome inhibitor, has been shown to differentially inhibit splicing more in SRSF2-mutant cells leading to decreased leukemia burden in mice. H3B-8800 is a small molecule modulator of spliceosome complex and has been shown to lower leukemia burden in SRSF2-P95H mutant mice. This review focuses on the incidence of mutant SRSF2 across various MMOS as well as recent clinical development of spliceosome inhibitors.

SETBP1 mutations as a biomarker for myelodysplasia /myeloproliferative neoplasm overlap syndrome.

Myelodysplasia (MDS) /myeloproliferative neoplasm (MPN) overlap syndrome has been described since the 2001 WHO classification as disorders that have both proliferative and dysplastic changes simultaneously. Specific disorders include chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), BCR-ABL negative atypical chronic myeloid leukemia (aCML) and unclassifiable MDS/MPN (MPN/MDS-U). Recurrent gene mutations in these conditions have been described. Among them, SETBP1 mutations have been identified in up to 32% of aCML, 24% of JMML, 18% of CMML and 10% of MDS/MPN-U patients. The mutation hotspot lies in the amino acid residues 858-871 in the SETBP1 protein. SETBP1 mutations in MDS/MPN overlap syndrome is associated with accelerated transformation to leukemia and poor prognosis. In this review, we summarized the latest data on the role of SETBP1 mutations in the overlap syndrome. SETBP1 mutations may serve as a biomarker for the diagnosis and poor prognosis of the overlap syndrome.

ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development.

With the advent of new agents targeting CD20, Bruton's tyrosine kinase, and phosphoinositol-3 kinase for chronic lymphoid leukemia (CLL), more treatment options exist than ever before. B-cell lymphoma-2 (BCL-2) plays a major role in cellular apoptosis and is a druggable target. Small molecule inhibitors of BCL-2 are in active clinical studies. ABT-199 (venetoclax, RG7601, GDC-0199) has been granted breakthrough designation by FDA for relapsed or refractory CLL with 17p deletion. In this review, we summarized the latest clinical development of ABT-199/venetoclax and other novel agents targeting the BCL-2 proteins.

Novel agents for advanced pancreatic cancer.

Pancreatic cancer is relatively insensitive to conventional chemotherapy. Therefore, novel agents targeting dysregulated pathways (MAPK/ERK, EGFR, TGF-ß, HEDGEHOG, NOTCH, IGF, PARP, PI3K/AKT, RAS, and Src) are being explored in clinical trials as monotherapy or in combination with cytotoxic chemotherapy. This review summarizes the most recent advances with the targeted therapies in the treatment of patients with advanced pancreatic cancer.

Novel ALK inhibitors in clinical use and development.

Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. ALK-1 was initially found in anaplastic large cell lymphoma (ALCL). ALK mutations have also been implicated in the pathogenesis of non-small cell lung cancer (NSCLC) and other solid tumors. Multiple small molecule inhibitors with activity against ALK and related oncoproteins are under clinical development. Two of them, crizotinib and ceritinib, have been approved by FDA for treatment of locally advanced and metastatic NSCLC. More agents (alectinib, ASP3026, X396) with improved safety, selectivity, and potency are in the pipeline. Dual inhibitors targeting ALK and EGFRm (AP26113), TRK (TSR011), FAK (CEP-37440), or ROS1 (RXDX-101, PF-06463922) are under active clinical development.