Page 92 - Read Online

Franca et al. Cancer Drug Resist 2019;2:256-70 I http://dx.doi.org/10.20517/cdr.2019.004 Page 259

are routinely detected in RBC rather than in leukocytes, although RBC lack IMPDH and have therefore a
thiopurine metabolism different from with that of principal target cells of these drugs. However, erythrocyte
TGN levels have been found to correlate to leukocyte TGN levels in pediatric patients [11,12] .

In ALL, thiopurines are always used in the context of a polychemotherapeutic protocol that comprises
glucocorticoids, vincristine, asparaginase, cytarabine, anthracyclines, cyclophosphamide and tyrosine-
kinase inhibitors such as imatinib; in particular, MP is used in combination with methotrexate [13-15] . Specific
ALL polychemotherapeutic approaches differ across worldwide protocols in terms of drugs, dosages and
combinations; however, they consistently share the therapeutic scheme with an initial remission-induction
phase to eradicate the burden of tumoral cells and restore normal hematopoiesis, followed by a remission-
consolidation therapy and then by a long-term maintenance regimen (up to 24 months after diagnosis) to
eliminate minimal residual leukemic cells. Such therapeutic scheme, combined with a risk-adapted intensive
polychemotherapy, has been extremely successful for children with ALL who have reached an outstanding
5-year survival greater than 90% in developed countries. Two of the currently running main clinical trials in
childhood ALL, the European AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica-
Berlin-Frankfurt-Munster) 2017 protocol and the Total Therapy XVII (TOTAL XVII) used at the St. Jude
Children’s Research Hospital (SJCRH) in Memphis, USA (ClinicalTrials.gov identifiers: NCT03643276 and
NCT03117751, respectively http://clinicaltrials.gov) are aimed at further improving cure rate and quality
of life of patients by exploring the effect of innovative drugs such as the proteasome inhibitor bortezomib
and the bi-specific T cell engager blinatumomab. Nevertheless, thiopurines continue to be of interest:
indeed, being administered daily throughout the duration of the entire therapy, although introduced 4/5
weeks after diagnosis and therapy start (i.e., after the induction phase), they remain the backbone of the
polychemotherapy in both clinical trials. A detailed assessment of thiopurine metabolism and, in particular,
of MP tolerance, toxicity and treatment outcome is one of the explorative objectives of the SJCRH TOTAL
XVII protocol.

The most common drug related adverse effect of thiopurines is bone marrow suppression: leukopenia is a
[16]
well-recognized effect occurring in more than 50% of ALL patients and 15%-20% in IBD patients , leading
to dose reductions or therapy interruption, with consequent increase of disease recurrence and infection
rate. Gastrointestinal complication are also very common in terms of anorexia, diarrhea, nausea, vomiting
and stomatitis; the use of thiopurines may be limited also by the development of pancreatitis, although
[17]
this complication is very rare in ALL patients (< 5%) . Among other drug related adverse effects, there are
hepatic toxicity and flu-like symptoms.

PHARMACOGENETICS
Pharmacogenetics of thiopurines in pediatric ALL is very well studied. Table 1 summarizes the genetic
factors involved in thiopurine toxicities and further discussed in this review: TPMT variants have the major
established role in clinics; clinical guidelines are now also available for NUDT15 polymorphisms, whereas
the pharmacogenetic contributions of other mentioned genes are either smaller or not yet steadily confirmed
and therefore require further studies for their clinical implementation.

TPMT
TPMT (EC 2.1.1.67) is ~30 kDa cytosolic enzyme expressed ubiquitously in cells. Its function on xenobiotics
is very well established: as already mentioned above, it is responsible for the formation of methylated
[18]
thiopurines derivatives and its activity is inversely related to the cytoplasmic accumulation of TGN . In
contrast, the endogenous function of TPMT is unknown: however, a role in the methylation of endogenous
selenoproteins has been hypothesized and a very recent study confirmed in vitro a role for TPMT in the
biosynthesis of selenocysteine . Additionally, also a role in the biosynthesis of the molibdenum-binding
[19]