Association between gene polymorphisms in the cyclophosphamide metabolism pathway with complications after haploidentical hematopoietic stem cell transplantation

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for patients with hematologic malignances. Haploidentical HSCT (Haplo-HSCT) is an alternative option for patients who do not have an HLA-matched donor. The use of post-transplantation high dose cyclophosphamide (PT-Cy) is commonly employed for graft-versus-host disease (GVHD) prophylaxis in haplo-HSCT. Cyclophosphamide (Cy) is an alkylating agent with antineoplastic and immunosuppressive activity, whose bioactivation requires the activity of polymorphic enzymes in the liver to produce phosphoramide mustard, which is a DNA alkylating agent. To identify polymorphisms in the genes of Cy metabolism and correlate them with post-HSCT complications [GVHD, sinusoidal obstruction syndrome (SOS), hemorrhagic cystitis (HC) and transplant-related mortality (TRM)], we designed a custom next-generation sequencing panel with Cy metabolism enzymes. We analyzed 182 patients treated with haplo-HSCT with PT-Cy from 2007 to 2019, detecting 40 variants in 11 Cy metabolism genes. Polymorphisms in CYP2B6, a major enzyme involved in Cy activation, were associated with decreased activity of this enzyme and a higher risk of Graf-versus-host disease (GVHD). Variants in other activation enzymes (CYP2A6, CYP2C8, CYP2C9, CYP2C19) lead to decreased enzyme activity and were associated with GVHD. Polymorphisms in detoxification genes such as glutathione S-transferases decreased the ability to detoxify cyclophosphamide metabolites due to lower enzyme activity, which leads to increased amounts of toxic metabolites and the development of III-IV acute GVHD. GSMT1*0 a single nucleotide polymorphism previously recognized as a risk factor for SOS was associated with a higher risk of SOS. We conclude that polymorphisms of genes involved in the metabolism of cyclophosphamide in our series are associated with severe grades of GVHD and toxicities (SOS and TRM) after haplo-HSCT and could be used to improve the clinical management of transplanted patients.

ATG or post-transplant cyclophosphamide to prevent GVHD in matched unrelated stem cell transplantation?

“…The incorporation of genetic testing and pharmacovigilance into clinical practice could be beneficial, as it has been demonstrated that polymorphisms in the genes of cyclophosphamide metabolism correlate with alloSCT outcome. Polymorphisms in major enzymes involved in cyclophospamide activation, were associated with decreased enzyme activity and a higher risk of GVHD [ 12 ]. Polymorphisms in detoxification genes lead to increased amounts of toxic metabolites and increased risk of complications [ 12 ].…”

“…Polymorphisms in major enzymes involved in cyclophospamide activation, were associated with decreased enzyme activity and a higher risk of GVHD [ 12 ]. Polymorphisms in detoxification genes lead to increased amounts of toxic metabolites and increased risk of complications [ 12 ]. Recent research suggests that refining the dosing and timing of PTCy administration as well as it’s combination with other immunosuppressive drugs could enhance its efficacy while minimizing toxicity.…”

Genetic polymorphisms effect on cyclophosphamide’s tolerability and clinical efficacy in Egyptian patients with lupus nephritis

“…Another study conducted by Veal [31] and colleagues mentioned that in comparison to CYP2B6 *1/*1 (GT and GG), CYP2B6 *6 (TT) is associated with decreased CYC clearance in children with B-Cell lymphoma. A recent study conducted by Muñiz and his colleagues concluded that compared to CYP2B6 *1/*1 (GG genotype), CYP2B6 *6 (TT genotype) is associated with decreased CYC metabolism in non-Hodgkin lymphoma patients [32]. The effect of genetic polymorphisms on CYC's efficacy when it is used in combination with other chemotherapeutic agents was studied in another 2 studies and the results were CYP2B6 GT and TT are related to diminished effect to CYC and fludarabine in individuals with Leukemia, Lymphocytic, Persistent, B-Cell when contrasted with CYP2B6 GG [33].…”

A review and metanalysis of metronomic oral single-agent cyclophosphamide for treating advanced ovarian carcinoma in the era of precision medicine

“…Some studies explored the association between DNA repair gene polymorphisms and treatment response in EOC patients receiving chemotherapy. [42][43][44][45][46] These studies found that specific polymorphisms in DNA repair genes, such as XRCC1 and XRCC3, were associated with improved ORR and survival outcomes. These findings suggest that genetic variations in DNA repair pathways may influence the efficacy of CTX treatment in EOC.…”