Targeted Therapies
Several therapies that target tumors’ molecular vulnerabilities are being incorporated into the treatment of adult ALL to clinical benefit. "I think the most dramatic improvement has been seen with the use of tyrosine kinase inhibitors (TKIs) for the Philadelphia chromosome–positive subset," Dr. Kebriaei commented.
In trials, use of TKIs in these patients has led to higher rates of complete remission, transplantation eligibility, and survival without transplantation. "Now all of these trials allowed transplant as well, so it’s hard to ascertain how much of this impact is coming from more transplant eligibility and how much of it is coming from the impact of the TKIs," she cautioned.
The SWOG S0805 Intergroup trial, open to patients up 50 years old with newly diagnosed Philadelphia chromosome–positive ALL, is looking more closely at the issue, as well as the issue of using TKIs as maintenance therapy. Patients receive dasatinib (Sprycel)-containing induction therapy and, if they undergo transplantation, dasatinib thereafter as well.
In clinical practice, "there is great variation in practice patterns, ranging from providing no TKI in maintenance all the way up to providing 2 years of TKI," Dr. Kebriaei observed. "And unfortunately, there isn’t good data yet published to determine what the best approach will be."
A second targeted therapy being used is rituximab (Rituxan), for ALL expressing CD20, another poor prognostic marker. Adding rituximab to the hyper-CVAD regimen significantly improves survival for patients younger than 60 years (J. Clin. Oncol. 2010;28:3880-9). But in older patients, there was no survival benefit, in part because of increased induction-related mortality.
Novel Agents and Cellular Therapies
The Food and Drug Administration has approved three novel agents for ALL treatment: pegylated asparaginase (Oncaspar), clofarabine (Clolar), and nelarabine (Arranon), and has received a new drug application for liposomal vincristine (Marqibo).
Nelarabine, for example, is a prodrug of ara-G that achieves good response and survival rates in patients with relapsed T-cell ALL, with a dose-limiting toxicity of neurotoxicity. It is now being evaluated when added to hyper-CVAD up front for patients with T-cell ALL, according to Dr. Kebriaei.
The investigational agent inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, achieves an overall response rate of 61% when used as monotherapy in a trial among patients with refractory ALL (Jabbour et al. ASCO 2011 meeting. Abstract 6507).
"Interestingly, almost half of these patients were then able to go on to transplant in complete remission," she noted. Adverse effects included hepatotoxicity and veno-occlusive disease.
Another investigational antibody, blinatumomab, redirects T cells toward lysis of CD19-expressing cells and has been found to achieve complete remission in 13 of 16 patients with precursor B-ALL having persistent MRD (Topp et al. ASH 2009 meeting. Abstract 840).
A final novel strategy being tested is cellular therapy using chimeric antigen receptors (CARs), which are produced by fusing an extracellular single-chain antibody to an intracellular signaling domain. When expressed in T cells, these receptors redirect the cells’ antigen recognition toward a desired target, such as CD19.
"What’s very effective and interesting about this CAR strategy is that it doesn’t rely on preexisting antitumor immunity to generate an antitumor effector response," Dr. Kebriaei noted. "This is particularly important in the setting of ALL, where you have immune dysfunction."
Trials are assessing the use of CARs in the setting of stem cell transplantation, whereby donor T cells are transduced with anti-CD19 CARs and given as a targeted donor lymphocyte infusion.
"Perhaps by incorporating these targeted therapies and cellular therapies with the traditional cytotoxic therapies, we may be able to improve treatment outcomes without adding toxicity," concluded Dr. Kebriaei, who reported having no conflicts of interest related to her presentation.
The Oncology Congress is presented by Reed Medical Education. Reed Medical Education and this news organization are owned by Reed Elsevier Inc.