Drug-resistance Profile in Multiple-relapsed Childhood Acute Lymphoblastic Leukemia

Discussion

Relapse remains a significant problem for patients with ALL. Despite significant progress, the introduction of molecularly-targeted therapies and innovative immunotherapeutic approaches that include specialized monoclonal antibodies and cellular therapies that hold promise of enhanced leukemia-cell killing with non-overlapping toxicities, the outcome in relapsed pediatric ALL is not satisfactory. Improved biological understanding of mechanisms of relapse and drug resistance, the identification of actionable molecular targets by studying leukemia cell and host genetics, precise risk stratification with minimum residual disease measurement, and the development of new therapeutic drugs and approaches are needed to improve outcomes of patients with relapse (10).

Without HSCT, relapsed ALL has a dismal prognosis both in children and adults, mainly related to the time interval between initial diagnosis and relapse, and cellular drug resistance can play a key role in therapy failure. Since HSCT is inevitably burdened with an unacceptable risk of toxicity, conventional and innovative chemo- and immunotherapies are important therapeutic options. Most children worldwide with relapse of ALL are still treated with conventional chemotherapy (10).

It is commonly assumed that patients with relapse are more drug resistant than those diagnosed de novo. We previously showed that patients with relapse were resistant to busulfan, which is a key compound used in conditioning of patients with acute leukemia before HSCT. On the other hand, no significant differences were found between de novo and relapsed cases for cyclophosphamide and treosulfan (5). In currently used clinical therapeutic regimens, based on reduced-intensity conditioning, these drugs play an important role in the HSCT setting.

The role of the drug-resistance profile in pediatric newly-diagnosed ALL is relatively well known. Since it is correlated with outcome, the PVA score was incorporated into the therapeutic program CoALL-06-97, showing the possibility of reducing treatment intensity for patients with a sensitive ex vivo profile without jeopardizing treatment outcome. However, it only moderately correlates with assessment of minimal residual disease in B-precursor ALL (8). We demonstrated significantly higher drug resistance at first relapse of pediatric ALL to prednisolone, vincristine, L-asparaginase and daunorubicin, and the trend towards higher resistance for most other tested drugs (5). Recently, new compounds were shown to have good anti-leukemic activity in childhood ALL, such as clofarabine and bortezomib (5, 11). Both compounds also showed relatively good activity in multiple relapses in the present study. In contrast, patients with multiple relapses showed increased resistance to glucocorticoids, vincristine and L-asparaginase, the key compounds in therapy of de novo ALL. Glucocorticoid resistance may be a fundamental biological aspect that explains the difference in prognosis. It seems that in vitro resistance to prednisolone might be a continuous variable in patients with ALL, with respect to progression of the disease. This may be due to induction of various defense mechanisms, such as an activation of variety of resistance mechanisms, which develop throughout life and protect humans from xenobiotics (12).

It is important to note that chemosensitivity of leukemia cells at multiple relapses did not significantly decrease for most of the drugs which are often used in high-dose therapy before HSCT. Similar findings in the drug-resistance profile were also observed in relapsed pediatric acute myeloid leukemia (13). Even though this finding did not apply to etoposide and melfalan in relapsed ALL, advances in preparative regimens, donor selection, and supportive care should improve the success of HSCT for patients with relapse.

In conclusion, the IC₅₀s for the ex vivo drug-resistance profile in multiple relapsed childhood ALL are higher in comparison to those at first relapse, which also indicates the higher drug resistance than at initial diagnosis. It seems that poor outcome in subsequent relapses in pediatric ALL can partially be explained by cellular drug resistance.