Pharmacogenetic analysis in the treatment of Hodgkin lymphoma

Abstract

About 15-20% of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy ± radiotherapy still die following relapse or progressive disease. The outcome might be influenced by gene polymorphisms influencing chemotherapy metabolism. We studied 126 patients with HL treated with the ABVD regimen. We analyzed glutathione S-transferases (GSTT1, GSTM1 and GSTP1), cytochromes P450 (CYP3A4 and CYP2D6), UGT1A1 and BLMH gene polymorphisms and their association with clinical and outcome variables. Patients with a GSTM1 genotype associated with extensive or ultrahigh activity had a probability of 93.8% to achieve a complete response, while the remainder of the patients had a probability of 82.3% (p = 0.04). This variable maintained its statistical significance in multivariate analysis (hazard ratio 3.7, 95% confidence interval 1-13, p = 0.05). Patients with an extensive or ultrahigh GSTM1 genotype had better prognostic factors than those with poor or intermediate genotypes (hemoglobin level, p = 0.003; serum albumin, p = 0.05; and International Prognostic Score, p = 0.038). Thus, in the treatment of HL, clinical determinants might be more relevant than the pharmacogenetic parameters analyzed to date.

A Novel Gene Underlies Bleomycin-Response Variation inCaenorhabditis elegans

“…This result could suggest that SCB-1 might function as a hydrolase, which could be the mechanism by which scb-1 regulates cellular stress. This finding would be similar to clinical studies that have suggested a role for BLMH in bleomycin-response variation (Lazo and Humphreys 1983; Nuver et al 2005; de Haas et al 2008; Gu et al 2011; Altés et al 2013). Because scb-1 is expressed in the nucleus of all somatic cells, this gene might impact the ability of bleomycin to cause DNA damage within the cell nucleus (Turek et al 2016).…”

“…Many studies have attempted to identify the genetic variant(s) that underlie bleomycin-response differences across cancer patients, and some have identified potential connections between the metabolic enzyme bleomycin hydrolase (BLMH) and patient outcomes. However, none of these studies established a causal connection between genetic differences in BLMH and variation in bleomycin responses (Lazo and Humphreys 1983; Nuver et al 2005; de Haas et al 2008; Gu et al 2011; Altés et al 2013). The inability to identify a human genetic variant that causes differences in bleomycin responses might be attributed to limited sample sizes (Sham and Purcell 2014), confounding environmental factors (Hunter 2005; Liu et al 2013), variation in drug regimens across patients (Low et al 2013), or tumor complexity and progression (McClellan and King 2010; Dagogo-Jack and Shaw 2018).…”

BLMH and APOE genes in Alzheimer Disease: A possible relation

“…The BLMH 1450 G > A is localized in the C-terminal domain of the gene, which gives rise to Val443Ill isoforms and covers the active site of the enzyme [9,19]. In our analysis of the frequency of single nucleotide polymorphisms (SNP), allele 4 was most common in the AD groups, while for all subjects collectively, the 3/3 genotype was most frequent.…”

“…This subsequently leads to either isoleucine or valine as the amino acid in position 443 (Ile443Val) [9]. In patients with the polymorphism, the biotransformation is inefficient and resulting in an accumulation and toxic action of the bleomycin hydrolase [9,19].…”

Establishment of a Therapeutic Anti-Pan HLA-Class II Monoclonal Antibody That Directly Induces Lymphoma Cell Death via Large Pore Formation

“…However, there is currently no mAb therapy available for Hodgkin’s disease. Radiation therapy, chemotherapy, and combination therapy have been used to treat Hodgkin lymphoma (HL) for many years with relatively good outcomes [ 4 ]. But these therapies are associated with the risks of sterility, secondary leukemia, and therapy-related myelodysplastic syndrome [ 5 ].…”