Role of F-araA PK and PG on HCT outcome:
None of F-araA PK parameters was
associated with OS, EFS, TRM, and RRTs in 169 patients for whom PK data
was available. Interestingly, patients carrying the NT5E promoter
variant (rs2295890) showed a trend to no rejection (0% vs 7.7%,
p=0.07), better EFS (87.5% vs 75.7%, p=0.1), lower late TRM D+100
(0.3% vs 12.5%, p=0.08), better OS (89.7% vs 78%, p=0.25) and lower
early TRM D+30 (0.3% vs 8.8%, p=0.2) (Figure 2) .
Additionally, none of the patients carrying the NT5E promoter
variant developed SOS compared to those with wild-type genotype for this
variant (0% Vs 19%, p=0.0007). Logistic regression using the penalized
maximum likelihood estimation method highlighted that NT5Epromoter variant (rs2295890) has a protective effect on HCT outcome(Table-3) . No association was observed between DCK polymorphism
and outcomes.
Discussion :
Although the toxicity-reduced conditioning regimen containing
F-araA/Treo/Thiotepa has a favorable toxicity profile and has shown to
improve HCT outcome in high-risk TM patients 1, graft
rejection and RRTs still present a roadblock in a subset of patients3,4. In this first single centre study, we have
evaluated the PK and PG as well as the dose-exposure-response
relationship to F-araA in a large uniform cohort of patients with
high-risk TM undergoing HCT.
F-araA PK has been reported previously in patients undergoing HCT for
both malignant, benign conditions and in various combination7–11,29–34. Despite wide IIV in F-araA PK in the
present study, none of the biochemical or demographic parameters
explained this variability. Previous F-araA PopPK studies have
identified Glomerular filtration rate (GFR) 11,34 and
creatinine clearance 8,10 as significant predictors of
F-araA CL. In the present study, we did not include GFR as a covariate
in the PopPK model as the patients enrolled in the study had a normal
renal function and all the patients received a fixed initial dose of
F-araAMP. The dose of F-araA used and the PK parameters in the present
study are comparable to the existing reports (Table 4) .
Although the dose-exposure response relationship has been explored
previously for Bu 35–40, Cy 41,42,
and Treo 43, no such attempt had been made for F-araA
in patients with TM. Several studies have described the influence of
F-araA PK in HCT outcomes, albeit majority of the studies were conducted
in patients undergoing HCT for malignant conditions6,7,10. A recent study carried out in a mixed cohort
of patients with malignant and non-malignant 34conditions did not identify any relationship between F-araA PK and HCT
outcomes. Despite significant IIV in F-araA PK observed in the present
study, none of the F-araA PK parameters was associated with HCT
outcomes. This could probably be because of the decreased incidence of
events such as rejection or TRM in this non-malignant condition. A
recent study in F-araA PK also predicted optimal cumulative exposure of
20 mg*h/L for better EFS, lower TRM, and lower rejection44. However, the study cohort was heterogeneous, and
the optimal exposure range was not confirmed in an independent cohort44.
Genetic variants in drug-metabolizing enzymes and transporters may also
contribute to PK variability, which in turn could influence HCT outcome.
Similar to our previous report on F-araA PK in patients with AA/FA
undergoing HCT 9, the patients carrying rs2295890
variant genotype exhibited significantly lower plasma F-araA CL compared
to those with wild-type genotype in the present study (Figure
1) . This variant also explained 4.5% of the IIV in F-araA clearance in
the POPPK model. Apart from its role in the biotransformation of F-araA45, NT5E/CD73 is a multifunctional ectoenzyme
involved in immunosuppression 46, cancer progression47, and tumor microenvironment48,49. When we compared the role of this polymorphism
on HCT outcomes, we observed that patients carrying the rs2295890
variant genotype showed better OS, EFS, lower rejection and lower TRM,
consistent with our previous finding in AML cohort 50.
Low NT5E activity has been reported to be associated with a good
prognosis in many malignancies 46,51,52 probably due
to the production of less adenosine that suppresses antitumor immunity
and by not contributing to metastasis. The role of NT5E activity in HCT
setting has not been explored except for few mice model studies, where
it was suggested that low NT5E activity could lead to GvL/GvT
(Graft Versus Leukemia/Tumor) phenomenon favoring HCT outcome, again
reinstating the probable role of Adenosine 5’-triphosphate
(ATP)-Adenosine axis in transplant immunology 53–56.
We could thus hypothesize that due to the reduced NT5E activity in
patients carrying the variant genotype for this polymorphism, there is a
lower production of adenosine and higher extracellular ATP activity,
which in turn could prevent graft rejection and help in
immunosuppression, eventually favoring better HCT outcome. In addition,
we observed that none of the patients carrying the rs2295890 variant
genotype had SOS. This could also be due to decreased NT5Eactivity in patients carrying the variant genotype for this polymorphism
resulting in decreased production of adenosine, thus protecting the
liver from fibrosis 57,58. However, the exact
mechanism between decreased NT5E activity and SOS needs to be
explored further for its implication in pharmacogenetics testing as a
plausible biomarker for HCT outcome.