mercaptopurine and Hematologic-Neoplasms

Therapeutic response and drug-induced toxicity have been reported to be associated with genetic variants of drug-metabolizing enzymes and transporters. Recently, new causative variants associated with drug response have been reported by genome-wide association studies (GWASs). Additionally, therapeutic response has been predicted using a model of multiple single-nucleotide polymorphisms. In acute lymphoblastic leukemia (ALL), the genetic variants of NUDT15 associated with therapeutic response to 6-mercaptopurine (6-MP) have been reported by GWASs, and the frequency of NUDT15 variants was higher in Asians. Then, several reports on NUDT15 genetic variants associated with 6-MP-induced toxicities and the tolerable doses and outcomes of 6-MP therapy for ALL have been published in Asian countries. The drugs used in treating hematological malignancies have reported new genetic variants associated with its therapeutic response. However, the association between these genetic variants has not been validated in other populations. Here, we reviewed recent reports on the association between the genetic variants and response to drugs used in treating hematological malignancies, such as 6-MP, cytarabine, methotrexate, and vincristine.

Topics: Antimetabolites, Antineoplastic; Genome-Wide Association Study; Hematologic Neoplasms; Humans; Mercaptopurine; Pharmacogenetics; Pyrophosphatases

The hyper-CVAD/methotrexate-cytarabine (H-CVAD/ MTX-AraC) chemotherapy protocol has been one of the standard treatments for hematological malignancies, such as mantle cell lymphoma (MCL), Burkitt lymphoma (BL), and B-cell and T-cell acute lymphoblastic leukemia. Because results of this therapy are poor, it has been progressively replaced with new specific regimens with better efficacy profiles (GELA protocol for MCL, BURKIMAB for BL, and PETHEMA for B-cell and T-cell acute lymphoblastic leukemia [ALL]). The objective of this study was to analyze the response rates and survival of these therapeutic regimens. This retrospective and descriptive observational study of 81 patients compared 42 patients treated with hyper-CVAD/methotrexate-cytarabine (group A) with 39 patients treated with GELA/BURKIMAB/PETHEMA (group B). More patients in group B than in group A completed the treatment (89.7% vs. 47.6%, p < 0.001). In group A, 14.3% did not complete treatment because of death compared with 7.7% in group B, and 29% in group A had cycle delays versus 6.7% in group B (p < 0.001). In group A, 78.6% of group A achieved a complete response (CR) compared with 94.9% of group B (p = 0.050). Disease-free survival (DFS) and overall survival (OS) were significantly higher in group B (p < 0.001 in both cases). Data for current therapeutic protocols have indicated superior efficacy, with higher complete response rates, as well as better disease-free survival and overall survival results. This article provides the best results in terms of the efficacy of treatment of four hematological malignancies (MCL, BL, B-cell ALL, and T-cell ALL) with the most current specific therapeutic regimens (GELA for MCL, BURKIMAB for BL, and PETHEMA for B-cell ALL and T-cell ALL) with respect to a classic general protocol (H-CVAD/MTX-AraC for all four). These results may represent a great advance in the treatment of these blood cancers, achieving an important long-term benefit for these hematological patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Burkitt Lymphoma; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Hematologic Neoplasms; Humans; Lymphoma, Mantle-Cell; Male; Mercaptopurine; Methotrexate; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Retrospective Studies; Treatment Outcome; Vincristine; Young Adult