Authors: Juan Pablo Alderuccio, Lakshmi Nayak, Kate Cwynarski...

Secondary central nervous system (CNS) lymphoma (SCNSL) is a rare but clinically challenging scenario with historically disappointing outcomes. SCNSL refers to lymphoma that has spread into the CNS concurrently with systemic disease or CNS relapse during or after frontline immunochemotherapy, presenting with or without systemic lymphoma. Diffuse large B-cell lymphoma (DLBCL) denotes the most common entity, but an increased incidence is observed in other histologies, such as Burkitt lymphoma and mantle-cell lymphoma. The incidence, timing in disease course, location, evidence supporting the use of CNS prophylaxis, and treatment pathways vary according to histology. No randomized data exist to delineate the best treatment approaches with current recommendations based on retrospective and single-arm studies. However, a regimen comprising immunochemotherapy, incorporating agents that cross the blood-brain barrier, followed by thiotepa-containing conditioning and autologous stem-cell transplant outlined in the international MARIETTA study demonstrated improvement in outcomes, representing a major accomplishment in the care of patients with DLBCL with SCNSL. Anti-CD19 chimeric antigen receptor T cell denotes a paradigm shift in the treatment of patients with systemic aggressive lymphomas, with emerging data also demonstrating efficacy without higher neurotoxicity in those with SCNSL. In this manuscript we discuss 5 clinical scenarios and review the evidence supporting our recommendations.

Topics: Humans; Adult; Retrospective Studies; Neoplasm Recurrence, Local; Lymphoma, Large B-Cell, Diffuse; Central Nervous System Neoplasms; Thiotepa; Antineoplastic Combined Chemotherapy Protocols

PubMed: 37702537
DOI: 10.1182/blood.2023020168

Observational Study

Authors: Michael Scordo, Trent P Wang, Kwang W Ahn...

IMPORTANCE

Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens.

OBJECTIVE

To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM).

DESIGN, SETTING, AND PARTICIPANTS

This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021.

INTERVENTIONS

Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65).

MAIN OUTCOMES AND MEASURES

The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival.

RESULTS

Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P < .001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P = .03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P = .01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P = .10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC.

CONCLUSIONS AND RELEVANCE

In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Cohort Studies; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Recurrence, Local; Thiotepa

PubMed: 33956047
DOI: 10.1001/jamaoncol.2021.1074

Authors:

Topics: Animals; Antineoplastic Agents, Alkylating; Carcinogens; Chemosterilants; Female; Neoplasms; Thiotepa

PubMed: 21863106
DOI: No ID Found

Authors:

Topics: Animals; Aziridines; Carcinogenicity Tests; Carcinogens; Humans; Kidney; Mutagenicity Tests; Mutagens; Salmonella typhimurium

PubMed: 10476433
DOI: No ID Found

Review

Authors:

Topics: Animals; Carcinogens; Female; Humans; Male; Molecular Structure; Pregnancy; Reproduction; Thiotepa

PubMed: 2127291
DOI: No ID Found

Review

Authors:

Topics: Animals; Aziridines; Carcinogenicity Tests; Carcinogens; Humans; Mutagenicity Tests; Mutagens; Neoplasms, Experimental; Occupational Exposure

PubMed: 10476450
DOI: No ID Found

Authors: Shengchun Wang, Pengjie Wang, Shu-Jin Li...

Aziridines derived from bioactive molecules may have unique pharmacological activities, making them useful in pharmacology (e.g. mitomycin C). Furthermore, the substitution of the epoxide moiety in epothilone B with aziridine, an analog of epoxides, yielded a pronounced enhancement in its anticancer efficacy. Thus, there is interest in developing novel synthetic technologies to produce aziridines from bioactive molecules. However, known methods usually require metal catalysts, stoichiometric oxidants and/or pre-functionalized amination reagents, causing difficulty in application. A practical approach without a metal catalyst and extra-oxidant for the aziridination of bioactive molecules is in demand, yet challenging. Herein, we report an electro-oxidative flow protocol that accomplishes an oxidant-free aziridination of natural products. This process is achieved by an oxidative sulfonamide/alkene cross-coupling, in which sulfonamide and alkene undergo simultaneous oxidation or alkene is oxidized preferentially. Further anticancer treatments in cell lines have demonstrated the pharmacological activities of these aziridines, supporting the potential of this method for drug discovery.

PubMed: 38059062
DOI: 10.1093/nsr/nwad187

Authors:

Topics: Animals; Aziridines; Carcinogenicity Tests; Carcinogens, Environmental; Environmental Exposure; Government Regulation; Guidelines as Topic; Humans; Molecular Structure; Occupational Exposure; Rats

PubMed: 21860477
DOI: No ID Found

Review

Authors: Tsutomu Ishikawa

Guanidines are categorized as strong organobases; however, their catalytic utility in organic synthesis has not been discussed thoroughly. The author's group has extensively and systematically studied their potential ability focusing on: 1) modified guanidines as chiral auxiliaries; 2) guanidinium ylides for aziridine formation; 3) the affinity of bisguanidine for proton and metal salts; and 4) the potential chirality of bisguanidine. Under the first topic, a variety of chiral guanidines was designed by the introduction of chirality on the three guanidinyl nitrogens, and the modified guanidines prepared using our original methods were found to be effective not only in catalytic but also in stoichiometric asymmetric syntheses. Under the second topic, the reaction of guanidinium salts carrying a glycinate function with aromatic or unsaturated aldehydes under basic conditions unexpectedly afforded aziridine-2-carboxylates, which were available as useful building blocks in organic synthesis due to their convertibility to functionalized amino acid derivatives in the ring-opening reaction, together with urea compounds recyclable to the starting guanidinium salts. The introduction of a chiral template to the guanidinium salt allowed us to expand the cyclic aziridination reaction to an asymmetric version. Under the third topic, effective complexabilty of bisguanidines with either proton or metal ions in water was observed, suggesting their possible application to the removal of toxic substances from polluted water and recovery of rare elements as material sources. Under the final topic, monomethylation or monoethylation of bisguanidine afforded a chiral product via asymmetric crystallization, indicating that bisguanidines have a potential chiral character due to the plane asymmetry.

Topics: Alkylation; Aziridines; Catalysis; Guanidines; Stereoisomerism

PubMed: 21139254
DOI: 10.1248/cpb.58.1555

Review

Authors: Allan Ribeiro da Silva, Deborah Araujo Dos Santos, Marcio Weber Paixão...

Small ring heterocycles, such as epoxides and aziridines, are present in several natural products and are also highly versatile building blocks, frequently involved in the synthesis of numerous bioactive products and pharmaceuticals. Because of the potential for increased efficiency and selectivity, along with the advantages of environmentally benign synthetic procedures, multicomponent reactions (MCRs) have been explored in the synthesis and ring opening of these heterocyclic units. In this review, the recent advances in MCRs involving the synthesis and applications of epoxides and aziridines to the preparation of other heterocycles are discussed emphasizing the stereoselectivity of the reactions.

Topics: Aziridines; Biological Products; Epoxy Compounds; Green Chemistry Technology; Molecular Structure; Stereoisomerism

PubMed: 30754666
DOI: 10.3390/molecules24030630