Chemoimmunotherapy in acute lymphoblastic leukemia

Abstract

ALL blast cells express a variety of specific antigens e.g. CD19, CD20, CD22, CD33, and CD52, which serve as targets for Monoclonal Antibodies (MoAbs). So far, the most experience is available for anti-CD20 (rituximab), which has been combined with chemotherapy for treatment of mature B-ALL/Burkitt's lymphoma. Studies with rituximab have also been completed in B-precursor ALL. Another antigen, CD19, is of great interest due to a very high rate of expression in ALL. It can be targeted by a bispecific monoclonal antibody, Blinatumomab, directed against CD19 and CD3. Smaller studies or case reports are also available for the anti CD52 antibody (Alemtuzumab), for anti CD22 (Epratuzumab) or anti CD33 (Gemtuzumab). Available data demonstrate that MoAb therapy in ALL is a highly promising targeted treatment. However, several details for an optimal treatment approach e.g. the required level of antigen expression, timing, schedule, dosage and stage of disease still need to be defined.

Introduction

Treatment outcome of adult acute lymphoblastic leukemia (ALL) has been substantially improved in the last decade, mainly by intensification and optimization of chemotherapy, risk-adapted use of stem-cell transplantation, and improved supportive care.[1], [2] Individualized treatment strategies based on prognostic factors, including the evaluation and monitoring of Minimal Residual Disease (MRD) have contributed to improved outcomes. However, results in adult patients are still considerably inferior to those in pediatric ALL and treatment related toxicity is a barrier to further intensification of standard chemotherapy, particularly in older patients. A major breakthrough in the treatment of acute lymphoblastic leukemia was the availability of targeted therapies—either targeting specific transcripts as bcr-abl fusion protein by Tyrosine Kinase Inhibitors (TKI) or by targeting specific antigens by Monoclonal Antibodies (reviewed in³).

Therapy with MoAbs is not only targeted, but also subtype-specific, and compared to chemotherapy has different mechanisms of action and side-effects. MoAbs can be administered (1) in an unconjugated form (e.g. rituximab); (2) conjugated to immunotoxins or chemotherapeutic agents, which are delivered to the target cell by the antibody; (3) conjugated to radioactive molecules, which deliver radiation selectively to malignant cells; or (4) as bispecific antibodies, which are directed to two target antigens or recruit immunologically active cells to the leukemia blasts. In addition, the synergistic effect of combined antibody and chemotherapy can be utilized. MoAb therapy will be reviewed in depth based on the available clinical experience in ALL.

ALL blast cells express a variety of lineage-specific antigens and combinations of antigens are used for establishing the diagnosis and defining immunological subtypes. A prerequisite for MoAb therapy was generally the presence of the target antigen on at least 20% of the leukemic blasts, but this cut-point is not used by all investigators. Table 1 depicts the surface antigen expression with a cut of > 20% positive leukemia blast cells according to ALL subtypes. The results are from two large adult ALL series including more than 500 patients each for the most relevant surface antigens and the monoclonal antibodies directed against them.

It is presumed that the response to a MoAb correlates with the percentage of ALL cells expressing a specific antigen. There is also some evidence that the activity of antibodies depends on the amount of antigen expressed on the cell surface of individual cells, although only few data are available so far.[3], [4] The degree of antigen expression measured by mean fluorescence intensity (MFI) and/or the antibody capacity (ABC) very recently analyzed by Raponi et al.⁴ might influence the treatment outcome. Additionally B-or T-lineage ALL subtypes during different maturation stages have an individual antigen expression pattern and thus respond differentially to MoAb therapy.

Since target antigens are not expressed exclusively on malignant cells but also on the surface of normal hematopoietic cells, the cytotoxic effects are less selective and lead to MoAb specific side-effects such as profound B- or T-cell lymphopenia with related clinical consequences, particularly infections.