Alemtuzumab use in relapsed and refractory chronic lymphocytic leukemia: a history and discussion of future rational use

Abstract

Abstract:In this review, we outline the clinical experience with single-agent alemtuzumab as a treatment for relapsed and refractory chronic lymphocytic leukemia (CLL) in both prospective and retrospective trials and describe the multiagent use of the drug with the goal of updating clinicians on recent developments and possible future rational combinations. Alemtuzumab, an antibody targeting the lymphocyte-specific surface marker CD52, is an approved agent for the treatment of CLL. Despite its demonstrated efficacy, likely secondary to concerns regarding infectious complications, it is most commonly used in the relapsed and refractory setting. Given alemtuzumab's unique mechanism of action it has been demonstrated to have activity in disease that is refractory to both alkylating agents and purine analogs. Furthermore, it has activity in TP53-mutated disease, which has the worst prognosis of any subset of CLL. Alemtuzumab has greater efficacy on circulating disease relative to nodal disease. Rational combinations are attempting to use these attributes to increase response rates in patients with relapsed and refractory disease.

Delineation of target expression profiles in CD34+/CD38− and CD34+/CD38+ stem and progenitor cells in AML and CML

“…GO and alemtuzumab also counteracted engraftment of LSCs in NSG mice. However, these drugs also produce cytopenia and, thus, hematologic toxicity, 80,81 because CD33 and CD52 are also expressed on normal HSCs. Therefore, the dose of these antibody conjugates may play a decisive role.…”

“…One is that LSCs in AML and CML exhibit subclone-specific heterogeneity; therefore, not all LSCs in a given neoplasm may express the same targets. 17,81,84,85 Rather, smaller subsets of LSCs may lack certain targets, and these cells may survive therapy. In addition, LSCs may exhibit intrinsic resistance and escape toxin conjugate-based therapies.…”

Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities

“…The biotherapeutic is directed against CD52 cells and is approved for the intravenous treatment of chronic lymphocytic leukemia. Small pilot studies using subcutaneous infusion reported that immediate flu-like toxicities associated with intravenous treatment were less severe when using the subcutaneous route of administration [ 80 ]. Furthermore, acute subcutaneous IRRs, such as rigor, rash or urticaria, nausea, hypotension, or bronchospasm, were rare or absent in contrast to the observations previously made for intravenous infusions [ 81 ].…”

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Introduction)

“…However, in clinical practice, such associations are far from deterministic because they are modulated by a plethora of factors, such as the nature and stage of the underling condition, the prior or concurrent receipt of other immunosuppressive agents, the duration of therapy or the accumulative exposure to the agent. This concept is well exemplified by the notable differences in the rates of infection observed with the use of the anti-CD52 mAb alemuzumb according to the indication of therapy, multiple sclerosis or B-cell malignancy (because the corresponding maximum annual doses vary from 36 to 1080 mg respectively) [53,54]. In the case of immune checkpoint inhibitors targeting inhibitory T-cell receptors, such as nivolumab or ipilimumab, the risk is not driven by the use of the agent itself but by the subsequent requirement of additional immunosuppression therapy to manage the immune-related adverse effects emerging from the upregulation of immune response [55].…”