Novel Antibody-Based Therapies For Acute Lymphoblastic Leukemia

Abstract

A major breakthrough in the treatment of acute lymphoblastic leukemia (ALL) was the availability of targeted therapies targeting either specific transcripts, such as bcr-abl fusion protein by tyrosine kinase inhibitors (TKIs), or specific antigens by mAbs. ALL blast cells express a variety of specific antigens (eg, CD19, CD20, CD22, CD33, and CD52) that serve as targets for mAbs. To date, the most data are available for anti-CD20 (rituximab), which has been combined with chemotherapy for the treatment of mature B-ALL/Burkitt 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 mAb, blinatumomab, directed against CD19 and CD3. Smaller studies or case reports are also available for the anti-CD52 (alemtuzumab), anti-CD22 (epratuzumab), and anti-CD33 (gemtuzumab) mAbs. Available data demonstrate that mAb therapy in ALL is a highly promising treatment approach. However, several details for an optimal treatment approach, such as the required level of antigen expression, timing, schedule, dosage, and stage of disease, still need to be defined.

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

“…Similarly, in all the above studies, short-intensive chemotherapy improved the outcome of adult Burkitt lymphoma/ leukemia, but not further; therefore, rituximab was added, with the rationale that the CD20 antigen is highly expressed. 12,13 There is still the need to improve the outcome in elderly Burkitt lymphoma/leukemia patients as evident from recent surveys. [14][15][16] Also considering that the median age for this disease is 43 years in a survey from 2002 to 2008, 14 and 49 years in another study, 15 the GMALL study group decided to implement a dose-reduced protocol for patients aged .55 years to avoid substantial toxicity and thereby guarantee a high treatment-realization rate for this age cohort.…”

Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab

“…[20][21][22] Pediatric B-precursor ALL blasts show a stable and sufficient expression of CD19 to make it a good target for immunotherapeutic approaches. [23][24][25][26][27][28] Furthermore, an excellent standard of detection of MRD levels can be achieved with high specificity and sensitivity. Multicolor flow cytometry enables complex patient-specific aberrant immunophenotyping of the blasts with a regular detection level of 1x10 -4 .…”

Cytogenetics, Molecular Genetics and Epigenetics and Their Impact on The Management of Acute Lymphoblastic Leukemia

“…Knowledge concerning ALL has advanced greatly to the extent that precision medicine may become a reality in the near future [132]. However, the latest successes in the treatment of childhood ALL can be Page 11 of 15 attributed to the careful personalized adaptation of treatment by means of risk stratification [134].…”

“…Hence, new treatments that are tailored to patient-specific tumor vulnerabilities are required to further improve treatment outcomes and limit toxicities [124]. Examples of the novel agents and targeted therapies that are either currently used or being under development are shown in Table 11 [60,66,[126][127][128][129][130][131][132].…”