Characterizing second line and beyond therapies for primary central nervous system lymphomas.

Primary central nervous system (CNS) lymphoma (PCNSL) is a rare and aggressive lymphoma that affects the CNS without other systemic involvement. High-dose methotrexate (HDMTX)-based regimens are recommended frontline treatment, followed by consolidation with either high-dose chemotherapy, whole brain radiation (WBRT) +/- sequential temozolomide (TMZ), or autologous stem cell transplant (autoSCT). Despite advancements with HDMTX and rituximab, up to half of patients will relapse. Treatment for relapsed or refractory (R/R) disease varies widely as preferred regimens are not well-established. Our study aimed to provide real-world characterization of R/R PCNSL therapies. The secondary objective was characterization of consolidation methods after frontline treatment. This retrospective, descriptive analysis included 54 adult PCNSL patients that received a HDMTX-based frontline regimen between 4/1/2016 and 7/1/2022. Patients receiving HDMTX for the purpose of secondary CNS lymphoma, non-B cell origin PCNSL, and intraocular lymphoma were excluded. Thirty-one patients (57%) received consolidation therapy with rituximab and high-dose cytarabine (R-HDAC), WBRT, or both. Thirteen patients (24%) proceeded with autoSCT. Twenty-five patients had disease progression, with 17 patients receiving second line treatment. The second line treatments were WBRT (24%), clinical trial (18%), rituximab with lenalidomide (R2; 18%), re-induction with HDMTX-based regimens (18%), ibrutinib with rituximab (12%) and R-HDAC (12%). Seven patients progressed, and all received third line treatment. Treatments varied, including R2; ibrutinib +/- HDMTX; rituximab, methotrexate, and cytarabine; R-HDAC; R-nivolumab; and WBRT. Five patients received a fourth line regimen of R +/- lenalidomide, R-HDMTX, or nivolumab monotherapy. Regimens used for the three patients who received fifth line treatment and beyond included R-TMZ and pembrolizumab monotherapy in addition to previously described regimens. Regimen selection is varied and highly dependent on physician preference and patient factors, including clinical trial eligibility, prior therapies, performance status, organ function, and treatment intent. Prospective clinical trials are needed to guide optimal management.

Evaluation of second-generation Bruton's tyrosine kinase inhibitors for the treatment of mantle cell lymphoma.

INTRODUCTION: Second-generation Bruton's tyrosine kinase (BTK) inhibitors, acalabrutinib and zanubrutinib, are preferred agents for the treatment of relapsed and/or refractory mantle cell lymphoma (MCL) over first-generation BTK inhibitor, ibrutinib. The comparative safety and efficacy of these two agents have not been studied. Currently, the decision between using one second-generation BTK inhibitor over the other is largely dependent on provider preference, cost, organ dysfunction, presence of drug-drug interactions, adherence considerations, and theorized differences in safety outcomes due to the lack of head-to-head trials in MCL. METHODS: This retrospective, observational study seeks to provide real-world data on the safety and efficacy of second-generation BTK inhibitors in the setting of relapsed and/or refractory MCL. RESULTS: Thirty-eight patients treated with a second-generation BTK inhibitor were evaluated. Ten percent of patients experienced a select adverse drug event (ADE) in the acalabrutinib group that included hypertension and major hemorrhage with no patients experiencing a select ADE in the zanubrutinib group. CONCLUSIONS: Results support historical data that acalabrutinib and zanubrutinib have a more favorable safety profile compared to ibrutinib in MCL.

Cyclophosphamide desensitization in patients with severe hypersensitivity reactions to bendamustine.

INTRODUCTION: Cyclophosphamide is a nitrogen mustard alkylator employed in the treatment of many malignancies and autoimmune disorders. Despite reports of cyclophosphamide hypersensitivity ranging from rash to anaphylaxis, no cases of desensitization have been reported in the oncologic setting. CASE REPORT: We report a cyclophosphamide desensitization protocol used for two patients who experienced severe hypersensitivity to bendamustine, a structurally related drug with potential cross immunogenicity. MANAGEMENT AND OUTCOME: An interdisciplinary approach including immunologist, oncologist, and clinical pharmacists resulted in the development of a multi-step desensitization protocol for cyclophosphamide. The desensitization protocol described enabled the safe administration of cyclophosphamide for the two patients with limited treatment alternatives. DISCUSSION: To the authors' knowledge, this is the first report of cyclophosphamide desensitization in the oncologic setting. Two patients with advanced hematologic malignancies were able to receive cyclophosphamide with minimal adverse effects, despite experiencing previous severe hypersensitivity to another nitrogen mustard analogue.

Supratherapeutic INR resulting from the initiation of warfarin in a patient receiving axitinib.

Axitinib is a vascular endothelial growth factor receptor inhibitor indicated for advanced renal cell cancer after failure of one prior systemic therapy. We report a case where a patient receiving axitinib experienced a supratherapeutic INR soon after initiation of an age-appropriate warfarin dose. We propose two possible mechanisms for this interaction, including competitive protein binding and decreased metabolism. Close INR monitoring and dose adjustments of warfarin may be necessary in patients receiving concomitant axitinib and warfarin in order to decrease the risks associated with this interaction.

Orlistat limits cholesterol intestinal absorption by Niemann-pick C1-like 1 (NPC1L1) inhibition.

The known mechanism by which orlistat decreases the absorption of dietary cholesterol is by inhibition of intestinal lipases. The aim of this study was to investigate the ability of orlistat to limit cholesterol absorption by inhibition of the cholesterol transport protein Niemann-Pick C1-like 1 (NPC1L1) as another mechanism of action. In situ rat intestinal perfusion studies were conducted to study the effect of orlistat on jejunal cholesterol absorption. Inhibition kinetic parameters were calculated from in vitro inhibition studies using Caco2 and NPC1L1 transfected cell lines. The in situ studies demonstrated that intestinal perfusion of orlistat (100µM) was able to reduce cholesterol absorption by three-fold when compared to control (i.e. in the absence of orlistat, P<0.01). In vitro studies using Caco2 cells demonstrated orlistat to reduce the cellular uptake of cholesterol by 30%. Additionally, orlistat reduced the cellular uptake of cholesterol in dose dependent manner in NPC1L1 transfected cell line with an IC50=1.2µM. Lineweaver-Burk plot indicated a noncompetitive inhibition of NPC1L1 by orlistat. Beside the already established mechanism by which orlistat reduces the absorption of cholesterol, we demonstrated for the first time that orlistat limits cholesterol absorption by the inhibition of NPC1L1 transport protein.