Vincristine-Induced Peripheral Neuropathy in Childhood Acute Lymphoblastic Leukemia: Genetic Variation as a Potential Risk Factor

Vincristine (VCR) is the first-line chemotherapeutic medication often co-administered with other drugs to treat childhood acute lymphoblastic leukemia. Dose-dependent neurotoxicity is the main factor restricting VCR’s clinical application. VCR-induced peripheral neuropathy (VIPN) sometimes results in dose reduction or omission, leading to clinical complications or affecting the patient’s quality of life. With regard to the genetic basis of drug responses, preemptive pharmacogenomic testing and simultaneous blood level monitoring could be helpful for the transformation of various findings into individualized therapies. In this review, we discussed the potential associations between genetic variants in genes contributing to the pharmacokinetics/pharmacodynamics of VCR and VIPN incidence and severity in patients with acute lymphoblastic leukemia. Of note, genetic variants in the CEP72 gene have great potential to be translated into clinical practice. Such a genetic biomarker may help clinicians diagnose VIPN earlier. Besides, genetic variants in other genes, such as CYP3A5, ABCB1, ABCC1, ABCC2, TTPA, ACTG1, CAPG, SYNE2, SLC5A7, COCH, and MRPL47, have been reported to be associated with the VIPN, but more evidence is needed to validate the findings in the future. In fact, a variety of complex factors jointly determine the VIPN. In implementing precision medicine, the combination of genetic, environmental, and personal variables, along with therapeutic drug monitoring, will allow for a better understanding of the mechanisms of VIPN, improving the effectiveness of VCR treatment, reducing adverse reactions, and improving patients’ quality of life.

Antileukemic Effects of Anti-miR-146a, Anti-miR-155, Anti-miR-181a, and Prednisolone on Childhood Acute Lymphoblastic Leukemia

Prednisolone has been used frequently in the treatment of acute lymphoblastic leukemia. However, to overcome the challenges of the treatment, the development of additional therapies is of great importance. Small, non-protein-coding RNAs, namely, microRNAs (miRNAs), are critical epigenetic regulators with physiological and pathological importance. This study is aimed at determining the effects of miR-146a, miR-155, and miR-181a inhibition with their corresponding anti-miRs on both leukemic and healthy cells, individually and with prednisolone. Leukemic (SUP-B15) and healthy B-lymphocyte (NCI-BL 2171) cell lines were used in this study. A total of 12 experimental groups included individual and combinational silenced ALL-associated miRNAs (hsa-miR-155, hsa-miR-146a, and hsa-miR-181a) and their combination with prednisolone. Cytotoxicity, proliferation, cell cycle, and apoptosis analyses were performed by using WST-1, trypan blue, APC-BrdU, Annexin V, and JC-1 methods in each study group, respectively. To control the effectiveness of anti-miR transfection and prednisolone application, miRNA expression analysis was performed from all groups. Anti-miR application was effective on the viability, proliferation, cell cycle, and apoptosis of leukemia cells, and this effect was increased with prednisolone administration. In addition, this activity was found to be very low on healthy cells. In conclusion, anti-miR applications may have the potential for clinical use of adjuvant to or as an alternative to conventional therapies for childhood acute lymphoblastic leukemia.

Childhood Acute Lymphoblastic Leukemia (ALL): Four Years Evaluation of Protocols 2013 and 2016 in a Single Center in Indonesia, a Low-Middle Income Country

Background: As in LMICs, the prognosis of childhood ALL in Indonesia was lower than in HICs. Indonesian-ALL2013 protocol resulted in more toxicities and abandonments than expected. Therefore, it was modified into a pilot ALL2016 protocol. Changes to the ALL2013 protocol: no anthracyclines in SR, dexamethasone replaced prednisone in reinduction for HR and some drugs were rescheduled. Procedure: We compare the outcome of ALL2013 and ALL2016. Results: A total of 383 children with ALL were diagnosed, 21 were excluded. ALL2013 included 174 patients (106 SR and 68 HR) and ALL2016 188 (91 SR and 97 HR). The outcome of the ALL2016 was better than the ALL2013 (pOS 67.0% vs 60.3%; p=0.087 and pEFS 50.0% vs 37.9%; p=0.012) even when the number of HR patients was significantly higher in ALL2016 (51.6% vs 39.1%). The ALL2016 showed an early advantage for SR patients (pEFS 56.7% vs 47.2%; p=0.114 and pOS 74.4% vs 69.8%; p=0.298) due to the decrease of toxic deaths (10.4% vs 5.5%; p=0.211) however the number of late relapses were still high (19.5% vs 13.2%; p=0.282). In the HR group, both pEFS and pOS were significantly better in ALL2016 (pEFS 43.3% vs 23.5%; p=0.010 and pOS 59.8% vs 45.6%; p=0.036) due to less relapses (14.4% vs 29.4%; p=0.019). Both SR and HR showed a smaller number of abandonments in ALL2016. Conclusions: After small changes in protocol, initial toxicity and abandonments were reduced and the pOS and pEFS were improved. However, relapses still need to be lessened in the next protocol.