forodesine and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Advances in acute lymphocytic leukemia (ALL) therapy has led to long-term survival rates in children. However, only 30%-40% of adults achieve long-term disease-free survival. After relapse, the outcome of salvage chemotherapy is very disappointing with less than 10% of long survival. Novel agents are therefore desperately required to improve response rates and survival, but also the quality of life of patients. Areas covered: The following review is a comprehensive summary of various novel options reported over the past few years in the therapeutic area of adult ALL. Expert opinion: Identifying key components involved in disease pathogenesis may lead to new approaches. In a near future, the incorporation of monoclonal antibodies and T-cell directed approaches including blinatumomab and chimeric antigen receptor T cells may increase the cure rates and may reduce the need for intensive therapy.

Topics: Adenine Nucleotides; Adult; Antibodies, Monoclonal; Antineoplastic Agents; Arabinonucleosides; Clofarabine; Disease-Free Survival; Drug Discovery; Humans; Molecular Targeted Therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleosides; Pyrimidinones; Quality of Life; Recurrence; Salvage Therapy

The search for more effective and safer anti-leukemia therapies has led to the identification of several new agents that show activity against specific types of acute lymphoblastic leukemia (ALL). Recently, three novel purine nucleoside analogues (nelarabine, clofarabine, and forodesine) have shown promising activity in patients with relapsed or refractory ALL. Of these, nelarabine has shown clinically meaningful benefit in patients with T-cell ALL, with overall response rates ranging from 33% to 60%, the induction of durable complete remissions, and an overall 1-year survival rate of 28% in adults. Clofarabine has also shown promising clinical activity in pediatric patients, with an overall response rate of 30%, and some patients are able to proceed to allogeneic hematopoietic cell transplantation. Forodesine is the most recent novel agent, with a unique mechanism that has shown single-agent activity in relapsed and refractory T- and B-cell leukemias and cutaneous lymphomas. Although clinical experience is limited, treatment-related toxicities appear to be mild. The rationale, pharmacology, and clinical experience to date with these agents in the treatment of patients with refractory acute leukemia are reviewed, with a highlight on ALL.

Topics: Adenine Nucleotides; Antineoplastic Agents; Apoptosis; Arabinonucleosides; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clofarabine; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Pyrimidinones