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  • Review Article
  • Published:

New therapeutic strategies for the treatment of acute lymphoblastic leukaemia

Nature Reviews Drug Discovery volume 6, pages 149–165 (2007)Cite this article

Key Points

  • Steady progress in the development of protocol-based therapy has led to a cure rate of more than 80% in children and up to 40% in adults with acute lymphoblastic leukaemia (ALL). However, innovative approaches to therapy are needed to further improve the cure rates and to reduce the toxic side effects of current intensive regimens.

  • Most of the conventional drugs used to treat leukaemia are nonspecific and work either by targeting DNA directly, inhibiting nucleic acid synthesis, blocking protein synthesis or interfering with the mitotic spindle apparatus. These, therefore, have a narrow therapeutic index.

  • Strategies to improve delivery and therapeutic index of conventional drugs include the encapsulation of drugs into liposomes or binding drugs covalently to monomethoxy-polyethylene glycol.

  • Newer antifolates have been designed to improve membrane support, and/or circumvent resistance due to impaired polyglutamation or inability to deplete reduced folate pools.

  • Newer nucleoside analogues have been developed to improve bioavailability and to decrease neurotoxicity.

  • Monoclonal antibodies, targeted towards leukaemia-associated antigens, have been administered in the unconjugated forms or conjugated to antileukaemic drugs, immunotoxins or radioactive molecules.

  • Molecular therapeutic agents have been developed to inhibit certain key enzymes, such as tyrosine kinases, DNA methyltransferases, histone deacetylases, γ-secretase, serine and threonine kinase and proteosomes.

  • As strategies to analyse the molecular genetic and epigenetic aberrations in cancer cells yield ever greater insights into ALL pathogenesis, one can expect an expanding repertoire of targeted therapies. This might result in an era of individualized molecular medicine and lead to more effective and less toxic regimens.

Abstract

Although contemporary treatments cure more than 80% of children with acute lymphoblastic leukaemia (ALL), some patients require intensive treatment and many patients still develop serious acute and late complications owing to the side effects of the treatments. Furthermore, the survival rate for adults with ALL remains below 40%. Therefore, new treatment strategies are needed to improve not only the cure rate but also the quality of life of these patients. Here, we discuss emerging new treatments that might improve the clinical outcome of patients with ALL. These include new formulations of existing chemotherapeutic agents, new antimetabolites and nucleoside analogues, monoclonal antibodies against leukaemia-associated antigens, and molecular therapies that target genetic abnormalities of the leukaemic cells and their affected signalling pathways.

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Figure 1: Schematic of B- and T-cell development.
Figure 2: Cytogenetic and molecular genetic abnormalities of childhood and adult acute lymphoblastic leukaemia (ALL).
Figure 3: Cell-cycle phases targeted by agents that are conventionally used in acute lymphoblastic leukaemia.
Figure 4: A simplified diagram of molecular target sites for potential new therapeutic agents.

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Acknowledgements

This work was supported by grants from the United States National Institutes of Health and by the American Lebanese Syrian Associated Charities.

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Authors and Affiliations

  1. Department of Oncology, St Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, 38105, Tennessee, USA

    Ching-Hon Pui & Sima Jeha

  2. University of Tennessee Health Science Center, Memphis, 38163, Tennessee, USA

    Ching-Hon Pui & Sima Jeha

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Competing interests

S.J. is a consultant for Genzyme Pharmaceuticals, Bioenvision Pharmaceuticals and Enzon Pharmaceuticals.

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DATABASES

OMIM

Acute myeloid leukaemia

Acute promyelocytic leukaemia

Chronic lymphocytic leukaemia

Chronic myeloid leukaemia

Hodgkin's disease

Lung cancer

Mixed-lineage leukaemia

Non-Hodgkin's lymphoma

FURTHER INFORMATION

St Jude Children's Research Hospital

University of Tennessee Health Science Center

Glossary

Allogeneic haematopoietic stem-cell transplantation

Transplantation with haematopoietic stem cells obtained from different individuals of the same species.

Apoptosis

Programmed cell death.

Aneuploidy

Having a chromosome number that is not the normal diploid number.

FLT3

This class 3 receptor tyrosine kinase (fms-related tyrosine kinase-3) has an important role in normal haematopoiesis. Constitutive activation of the gene contributes to the abnormal growth of leukaemic cells.

MLL

This gene (mixed-lineage leukaemia), located on chromosome 11, is homologous to the trithorax gene of Drosophila and displays many features of a transcription factor and of a DNA methytransferase. It fuses with AF4 (ALL fused gene from chromosome 4) to form t(4;11) translocation. The MLL–AF4 fusion protein disrupts the normal expression pattern of homeobox genes, causing a change in the self-renewal and growth of leukaemia stem cells and progenitor cells.

NOTCH1

This gene — Notch homologue-1, translocation-associated (Drosophila) — encodes a member of the transmembrane protein family, which has a role in the developmental processes of various tissues. Constitutive Notch signalling in haematopoietic progenitors disrupts both normal T-cell and B-cell development and leads to T-cell ALL.

FLAG regimen

A combination chemotherapy with fludarabine followed by Ara-C (cytarabine) once daily for 5 days, followed by G-CSF (granulocyte colony stimulating factor) daily for 7 days.

Platelet-count recovery

Recovery of the number of platelets in the blood towards a normal count.

Hand–foot syndrome

A chemotherapy-induced cutaneous reaction characterized by painful, oedematous symmetrical erythema on the palms and soles.

Tumour-lysis syndrome

Lysis of a large number of malignant cells resulting in biochemical abnormalities and dysfunction of multiple organs.

CNS relapse

Recurrence of leukaemia in the central nervous system (CNS).

Extramedullary relapse

Recurrence of leukaemia at a site other than bone marrow, such as the central nervous system, testes, ovary, thymus or lymph node.

Hyper CVAD chemotherapy regimen

A combination chemotherapy with hyperfractionated cyclophosphamide, vincristine, adriamycin (doxorubicin), and dexamethasone.

Pancytopaenia

An abnormal reduction in the number of erythrocytes, leukocytes and platelets in the blood.

ABL, KIT and PDGFR kinases

The ABL (Abelson) gene is located on chromosome 9 and encodes a tyrosine kinase, the role of which in normal haematopoiesis is unclear. It fuses with BCR gene on chromosome 22 to form BCR–ABL fusion gene, resulting in unregulated tyrosine kinase activity in t(9;22) Philadelphia-chromosome-positive CML or ALL. KIT gene encodes a transmembrane receptor in the PDGF (platelet-derived growth-factor receptor) family that has tyrosine kinase activity and has a role in haematopoiesis.

SRC

This non-receptor sarcoma virus oncogene (SRC) is a tyrosine kinase that is involved in several cellular processes, including growth-factor and integrin-dependent signalling, cell-cycle control and regulation of apoptosis.

T315I

A single mutation deep in the ATP-binding pocket of the ABL tyrosine kinase (T315I) confers a high degree of resistance to imatinib mesylate.

Accelerated or blastic phase

A more symptomatic phase of chronic myeloid leukaemia, characterized by increased numbers of bone-marrow blasts and blood basophils, increased spleen size, appearance of extramedullary tumour masses and poor response to therapy. Blast crisis is the most severe manifestation of the accelerated phase.

FHIT

FHIT (fragile histidine triad) is a candidate tumour suppressor gene located at chromosome 3p14.

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Pui, CH., Jeha, S. New therapeutic strategies for the treatment of acute lymphoblastic leukaemia. Nat Rev Drug Discov 6, 149–165 (2007). https://doi.org/10.1038/nrd2240

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