Optimizing therapy in the modern age: differences in length of maintenance therapy in acute lymphoblastic leukemia

Abstract

A majority of children and young adults with acute lymphoblastic leukemia (ALL) are cured with contemporary multiagent chemotherapy regimens. The high rate of survival is largely the result of 70 years of randomized clinical trials performed by international cooperative groups. Contemporary ALL therapy usually consists of cycles of multiagent chemotherapy administered over 2 to 3 years that includes central nervous system (CNS) prophylaxis, primarily consisting of CNS-penetrating systemic agents and intrathecal therapy. Although the treatment backbones vary among cooperative groups, the same agents are used, and the outcomes are comparable. ALL therapy typically begins with 5 to 9 months of more-intensive chemotherapy followed by a prolonged low-intensity maintenance phase. Historically, a few cooperative groups treated boys with 1 more year of maintenance therapy than girls; however, most groups treated boys and girls with equal therapy lengths. This practice arose because of inferior survival in boys with older less-intensive regimens. The extra year of therapy added significant burden to patients and families and involved short- and long-term risks that were potentially life threatening and debilitating. The Children's Oncology Group recently changed its approach as part of its current generation of trials in B-cell ALL and now treats boys and girls with the same duration of therapy. We discuss the rationale behind this change, review the data and differences in practice across cooperative groups, and provide our perspective regarding the length of maintenance therapy.

Graphical abstract

Figure 1.

ALL therapy. Classic phases of ALL therapy. The approach is similar across cooperative groups; however, the nomenclature is different. (A) Names of phases used by some cooperative groups, including the Children’s Oncology Group (COG). (B) Names of phases used by other groups, including the Berlin-Frankfurt-Muenster (BFM). The first phase of therapy (induction or induction 1A) consists of 3 to 4 agents and lasts ∼4 weeks, with the goal of achieving remission. This is followed by 3 to 4 months of therapy to consolidate remission. These blocks classically include 1 to 2 months of multiagent chemotherapy with CNS prophylaxis and 2 months of further intensification using a variety of methotrexate-based regimens. The blocks are termed consolidation and interim maintenance (IM) by the COG and induction IB and protocol M by the BFM. The third phase of therapy is intensification, termed delayed intensification (DI) by the COG and protocol II by the BFM. Intensification essentially repeats the therapy used in the first 3 months, with substitution of some agents with drugs in the same class. Finally, the fourth phase of therapy is termed maintenance and consists of low-intensity chemotherapy lasting for 1 to 3 years. Some protocols include a second IM and/or a second DI after DI/protocol II and before maintenance.