Salvage Strategies for Relapsed or Refractory Acute Lymphoblastic Leukemia
Leukemia Insights - Spring 2010
Deborah Thomas, M.D.
In this issue, we review the clinical trials available for adolescents and adults with relapsed or refractory acute lymphoblastic leukemia (ALL). Overall, improvements in outcome for adults with ALL have lagged behind those achieved in the pediatric population. However, in certain subtypes of ALL, significant advances have been made, particularly for those where targeted agents have been successfully incorporated into frontline chemotherapy. Examples include use of imatinib for Philadelphia (Ph) or BCR-ABL positive ALL and rituximab for Burkitt and precursor B-lineage ALL [Thomas D, Blood 2004 103:4396; Thomas D, Cancer 2006 106:1569].
This overview emphasizes novel agents and chemotherapy combinations which target several known pathophysiological mechanisms of resistance in ALL including (1) novel tyrosine kinase inhibitors (TKIs) of BCR-ABL, including those with activity against the ABL tyrosine kinase domain mutation T315I, (2) novel inhibitors of proteins which confer a proliferative survival advantage to lymphoblasts, such as murine double minute (MDM2), mitogen-activated protein kinase (MEK), PIM kinase, and JAK kinase, (3) novel anti-CD22 monoclonal antibodies such as the bispecific diphtheria toxin-linked antibody DT2219ARL and the calecheamycin-linked CMC-544, (4) novel chemotherapeutics such as the alkyating agent bendamustine and deoxycitidine nucleoside analog triarabine, and (5) targeted agent-chemotherapy combinations such as dastinib, decitabine or everolimus administered concurrently with the hyper-CVAD regimen. Figure 1 shows the interactions of several of these pathways and the agents which target them. Several show encouraging preliminary activity.
Future research efforts in ALL will focus on the interactions of lymphoblasts with their marrow microenvironment by using agents that either disrupt or exploit them (e.g., inhibitors of the chemokine receptor CXCR4 and hypoxia-activated prodrugs that target therapy to marrow “niches”).
Figure 1. Simplified schematic representation of various signaling pathways and potential targets for therapeutic intervention. Agents currently in clinical trials are indicated in association with the presumed primary target. Note this diagram is not intended to be entirely representative and is provided for illustration purposes only.
In This Issue
- Salvage Strategies for Relapsed or Refractory Acute Lymphoblastic Leukemia