The use of novel monoclonal antibodies in the treatment of acute lymphoblastic leukemia

Abstract

Regardless of age, patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have extremely poor outcomes. The success of reinduction chemotherapy remains dismal, because complete remission rates are low and seldom durable. Clearly, new and novel strategies are needed to improve the outcome of patients with relapsed or refractory ALL. Patients with early relapse, especially those still receiving chemotherapy, tend to have a much poorer outcome and are often chemotherapy resistant. Although high-dose approaches may overcome chemotherapy resistance, long-term disease-free and overall survival remains limited. Several approaches have been used to target antigens, including cluster of differentiation (CD) 19, CD20, CD22, and CD52, on the surface of the malignant lymphoblast with striking efficacy. This review will focus on the clinical application of the major classes of antibodies, including naked antibodies, drug-antibody conjugates, immunotoxins, and T cell-engaging bispecific antibodies. Hopefully, these novel monoclonal antibodies will result in a significant improvement in the outcome of patients with relapsed or refractory ALL.There has been tremendous progress in the treatment of patients with acute lymphoblastic leukemia (ALL). Currently, pediatric patients with ALL have a complete remission (CR) rate of 95% with estimated 5-year event-free survival (EFS) rates of 80%-85%. 1 The results of adult patients with ALL have not kept pace with their pediatric counterparts. In comparison, although the current adult regimens have CR rates of ϳ85%, the 3-year disease-free survival (DFS) and overall survival (OS) rates remain Ͻ45%. 2,3 Pediatric inspired regimens are currently being explored for young adult patients, which has led to improvements in the EFS and OS rates compared with historical controls. [4][5][6] Despite the high CR rates in both pediatric and adult patients with ALL, relapse is an insurmountable problem for many individuals. The higher rate of relapse in adult patients with ALL is likely attributable to higher risk disease. For example, more adult patients have adverse cytogenetics, such as the Philadelphia chromosome or translocations involving the mixed lineage leukemia gene on 11q23, persistent minimal resistant disease (MRD), and poor tolerance of the intense and prolonged chemotherapy protocols. Salvage chemotherapy regimens have shown only modest activity in patients with relapsed or refractory ALL with median remission duration of only 2-7 months (Table 1). 7,8 The outcome is particularly poor in patients who relapse while on therapy or with CR duration (CRD) of Ͻ24 months. In this group of patients, long-term survival is Ͻ5%.The success of long-term outcomes for patients with relapsed or refractory ALL involves the ability to obtain a CR. However, for the majority of adults, despite the ability to achieve a CR, these are seldom durable in patients with refractory or relapsed disease. 7,8 Therefore, the ability to achieve a CR and to have the opportunity to obtain a hematopoieti...

Pediatric haematopoiesis and related malignancies

“…The rationale for the use of monoclonal antibodies is that lymphoblasts express various cell-surface antigens that may be favourable targets for this therapy. For instance, over 95% of B-cell ALL and more than 90% of lymphoblasts express CD19 and CD22, respectively (32). Monoclonal antibody therapy has been recently used in clinical trials to treat children and adults with relapsed or refractory ALL.…”

Induction of Apoptosis in U937 Cells by Using a Combination of Bortezomib and Low-Intensity Ultrasound

“…Apart from this standard approach, novel treatment methods have been also proposed in the recent decade, including monoclonal antibodies [42], immuno-chemotherapy [43], interferon-α-maintenance therapy [44], radio-immunotherapy [45], and stem cell transplantation [46]. Despite promising results, most of these methods are in preclinical or clinical trials.…”

New targeted therapies for relapsed pediatric acute lymphoblastic leukemia

“…The follow up phase III, randomized control trial comparing INO with standard of care treatment in adult patients with ALL, Study NCT01564784 (INO-VATE Trial), revealed the superiority of INO [82,83]. Two hundred and eighteen adults were randomized to receive either weekly doses of INO (0.8 mg/m 2 on day 1 followed by 0.5 mg/m 2 on days 8 and 15) or standard of care, intensive chemotherapy.…”