Serotonin re-uptake transporter gene polymorphisms are associated with imatinib-induced diarrhoea in chronic myeloid leukaemia patients
SCIENTIFIC REPORTS
Authors: Davies, Andrea; Eugenia Rodriguez-Vicente, Ana; Austin, Gemma; Loaiza, Sandra; Foroni, Letizia; Clark, Richard E.; Pirmohamed, Munir
Abstract
Tyrosine kinase inhibitors (TKIs), the treatment of choice for chronic myeloid leukaemia (CML), can cause lower gastrointestinal (GI) toxicity which is manifested as diarrhoea. The mechanisms are not fully understood. The enteroendocrine signalling compound, serotonin (5-HT), is important for regulating peristaltic motion, fluid secretion and visceral hypersensitivity in the GI tract, and has been implicated in diseases such as irritable bowel syndrome. In this study, we have evaluated whether TKI-induced diarrhoea may be related to variation in the serotonin re-uptake transporter (SERT) gene. CML patients with and without diarrhoea on the SPIRIT2 trial (imatinib, n=319; and dasatinib, n=297) were genotyped for the promoter 5-HTTLPR, intron 2 VNTR and rs25531 polymorphisms by PCR-based methods. Diarrhoea was more prevalent in imatinib, than in dasatinib treated patients (P=0.015), which when stratified by gender was seen to be driven by female patients (P=0.036). Logistic regression analysis revealed that age, and the dominant HTTLPR with the rs25531 single nucleotide polymorphism (SNP) model, explained the occurrence of diarrhoea in similar to 10% of imatinib-treated female CML patients. These data suggest SERT polymorphisms influence imatinib-induced diarrhoea but not that of dasatinib.
Timing of allogeneic hematopoietic cell transplantation (alloHCT) for chronic myeloid leukemia (CML) patients
LEUKEMIA & LYMPHOMA
Authors: Hu, Bei; Lin, Xiao; Lee, Hans C.; Huang, Xuelin; Tidwell, Rebecca S. Slack; Ahn, Kwang Woo; Hu, Zhen-Huan; Jabbour, Elias; Verstovsek, Srdan; Ravandi, Farhad; Garcia-Manero, Guillermo; Kharfan-Dabaja, Mohamed A.; Hossain, Nasheed M.; Marks, David I.; Kamble, Rammuriti T.; Inamoto, Yoshihiro; Kindwall-Keller, Tamila; Saad, Ayman; Litzow, Mark R.; Savani, Bipin N.; Hale, Gregory A.; Bacher, Ulrike; Gerds, Aaron T.; Liesveld, Jane L.; Ustun, Celalettin; Olsson, Richard F.; Daly, Andrew; Grunwald, Michael R.; Solh, Melhem; DeFilipp, Zachariah; Aljurf, Mahmoud; Wirk, Baldeep; Akpek, Gorgun; Nishihori, Taiga; Cerny, Jan; Seo, Sachiko; Hsu, Jack W.; Champlin, Richard; de Lima, Marcos; Alyea, Edwin; Popat, Uday; Sobecks, Ronald; Scott, Bart L.; Kantarjian, Hagop; Cortes, Jorge; Saber, Wael
Abstract
While TKI are the preferred first-line treatment for chronic phase (CP) CML, alloHCT remains an important consideration. The aim is to estimate residual life expectancy (RLE) for patients initially diagnosed with CP CML based on timing of alloHCT or continuation of TKI in various settings: CP1 CML, CP2 + [after transformation to accelerated phase (AP) or blast phase (BP)], AP, or BP. Non-transplant cohort included single-institution patients initiating TKI and switched TKI due to failure. CIBMTR transplant cohort included CML patients who underwent HLA sibling matched (MRD) or unrelated donor (MUD) alloHCT. AlloHCT appeared to shorten survival in CP1 CML with overall mortality hazard ratio (HR) for alloHCT of 2.4 (95% CI 1.2-4.9;p = .02). In BP CML, there was a trend toward higher survival with alloHCT; HR = 0.7 (0.5-1.1;p = .099). AlloHCT in CP2 + [HR = 2.0 (0.8-4.9),p = .13] and AP [HR = 1.1 (0.6-2.1);p = .80] is less clear and should be determined on a case-by-case basis.
COA
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