Is the age of vincristine/steroid pulses over?

In this issue of Blood, Guolla et al present a systematic review meta-analysis of published studies of childhood acute lymphoblastic leukemia (ALL) and show that the survival benefit associated with the use of vincristine (VCR)/steroid pulses in maintenance therapy is no longer present in contemporary trials and that decreasing or removing these pulses reduced the rates of toxicity.¹ Notably, these results apply to low- and intermediate-/standard-risk patients, whereas the authors were unable to find any trial on high-risk patients that met the eligibility criteria. The findings reported by the authors have implications for future trials in childhood ALL, especially given the need to minimize treatment-related short- and long-term toxicities.

In the past decades, remarkable improvements have been achieved in the outcome of children and adolescents with ALL, with the current 5-year overall survival rates exceeding 90%.² Maintenance therapy is an indispensable element of the treatment strategy in childhood ALL and is part of all chemotherapy protocols.³ It typically consists of antimetabolite agents, such as daily 6-mercaptopurine and once-weekly methotrexate, for 1 to 2 years. Because maintenance therapy is prolonged and requires daily oral drug administration, adherence can be challenging. Around one-fifth of patients are <90% adherent, and decreased adherence correlates with a significantly higher risk of leukemia relapse. In the past, some clinical trial groups decided to intensify maintenance therapy with the goal of optimizing the balance between efficacy and toxicity, using pulses with VCR and steroids administered at regular intervals. In the 1980s, the addition of VCR/steroid pulses during maintenance therapy significantly improved the probability of event-free survival (EFS).³ In light of this evidence, most study groups then adopted this approach in maintenance therapy. In a more modern era, where intensive induction, consolidation, and delayed intensification schemes are used during the first 9 to 12 months of treatment, the use of pulses with VCR and steroids has lost importance. For example, in the 2007 study by the Berlin-Frankfurt-Münster cooperative pediatric group, children with intermediate-risk ALL did not benefit from intensification of the maintenance therapy phase with a schedule of 6 pulses of VCR and dexamethasone, and these pulses simply postponed the time of relapse in some subgroups at higher risk of relapse.⁴ More recently, the AALL0932 Children Oncology Group trial showed that, in National Cancer Institute standard-risk B-cell ALL, the outcome of patients given maintenance VCR/dexamethasone pulses administered every 12 weeks was not inferior to that of children receiving pulses every 4 weeks.⁵ Likewise, the Chinese Children’s Cancer Group ALL-2015 controlled trial confirmed that, in children with low-risk ALL, pulses of VCR/dexamethasone may be omitted after 1 year of treatment, without jeopardizing the probability of EFS compared with the control group that did not receive this intensified maintenance therapy.⁶ 

The results of the systematic review published in this issue of Blood provide definitive confirmation that children with low- and intermediate-/standard-risk B-cell ALL receiving intensified premaintenance therapy given in contemporary protocols do not obtain additional survival benefit from the use of VCR/steroid pulses administered in maintenance therapy.¹ For an appropriate interpretation of these results, it must always be remembered that successful ALL treatment strategies include sequential phases and the intensity/efficacy of all these phases contributes to the successful outcome. Most of the contemporary protocols in high-income countries utilize highly intensive induction and reintensification blocks. It is reasonable to hypothesize that the benefit conferred by VCR/steroid pulses in the past will become even less evident in the future because of the integration in frontline protocols of immune therapies, including bispecific T-cell engagers,⁷ antibody-drug conjugate,⁸ and chimeric antigen T cells,⁹ able to eradicate chemotherapy-resistant blasts, thus improving the outcome also of children with high-risk features.

The key message of the report by Guolla et al, despite the known limitations of systematic review meta-analysis, is that, in high-resourced countries, VCR/steroid pulses during maintenance therapy of both newly diagnosed patients with most favorable risk characteristics and likely also of first relapse standard-risk children should be either definitively abandoned or their frequency at least decreased. The situation may be different in those parts of the world with limited resources, where intensive therapy in the first year after diagnosis and the necessary supportive care to be used for preventing infectious complications are either not available or not feasible. In this particular context, the inclusion of VCR/steroid pulses during maintenance therapy may compensate for the lack of intensive therapy.¹⁰ However, it cannot be ignored that the VCR/steroid pulses during maintenance can cause severe, sometimes fatal, infections, mainly of either viral or fungal origins, especially with prolonged dexamethasone pulses of 2 weeks. In addition, it is well known that glucocorticoids may cause other significant toxicities, including increased emotional lability, disruptive behaviors leading to missed days of school, myalgias, myopathies, hyperglycemia, osteonecrosis, obesity, metabolic sequelae, and adrenal axis suppression. VCR administration may also result in declines in fine motor and sensory-perceptual performance. Thus, even in low- to medium-income countries, all that glitters may not be gold.

Conflict-of-interest disclosure: The author declares no competing financial interests.