Rituximab, Other Antibodies Offer Hope In Advancing ALL Treatment

Taking aim at relapse rates and overall poor outcomes among adult patients with acute lymphoblastic leukemia (ALL) demands both new therapies and new ways of thinking, according to Anjali S. Advani, MD, of the Cleveland Clinic. Antibodies, which have produced success in treating other blood cancers, offer promise because in some cases the same antigens are involved.

In her education session at the 55^th American Society of Hematology Annual Meeting and Exposition in New Orleans, Dr Advani presented evidence that antibody-based therapy, which in some cases could tap existing drugs, may soon offer better options for adults with ALL.

Rituximab, already approved to treat non-Hodgkin’s lymphoma, destroys B-cells and is known to be effective against CD20. This protein appears in about half of precursor B-cell ALL patients and is linked to shorter periods of remission. Hence, rituximab has been seen as an obvious candidate to pair with chemotherapy for clinical trials with newly diagnosed ALL patients. While CD20 is not involved in all adult ALL cases, it is associated with some of the most difficult ones, Dr Advani said. “Those who were CD20-positive had significantly worse overall survival rates,” she said.

She reviewed a 2003 study that paired rituximab with chemotherapy, which improved outcomes with younger adult patients but not older patients. A follow-up is underway that should “clarify” these results. Dr Advani also reported on the rituximab results in a companion paper with her talk.¹

She next moved to epratuzumab, which targets CD22, a protein that regulates B-cell activation and the interplay between B-cells and T-cells. “If adding epratuzumab would improve outcomes, the first part was feasibility,” Dr Advani explained. Adding epratuzumab to chemotherapy would prove more effective than using the antibody alone; she reviewed trials that showed what happened to the surface CD22: Twenty-four hours after receiving therapy, CD22 was “undetectable” for flow cytometry, which suggests that epratuzumab is effectively hitting its target.

Dr Advani has high hopes for BiTE antibodies, a term that refers to bispecific single-chain antibodies, which retarget cytotoxic T lymphocytes at surface antigens on tumor cells. Among the therapies in this class are blinatumomab, which targets C19, a type I transmembrane protein in the immunoglobulin family. Blinatumomab targets two things at once: the binding sites for T-cells and the C19 binding site for B-cells; thus, it creates the opportunity for the T-cell to kill the B-cell.

Immunotoxins and immunoconjugates make greater use of linkages in going after target cells, thus producing the desired results with fewer targets. Dr Advani spent some time discussing inotuzumab ozogamicin, which she reports “is one of the best studied and most promising new agents.”¹ This drug conjugate combines a monoclonal antibody against CD22 with calicheamicin, a powerful anti-tumor antibiotic. She reviewed results from research at MD Anderson Cancer Center in Houston, Texas, which found this therapy was not only well-tolerated but also proved a useful treatment for preparing patients for allogenic hematopoietic cell transplant (AHCT), where that is possible.

“The response rate was 57%; considering the patients were high risk, this was very encouraging,” She said.

Based on results seen in her own clinic and those elsewhere, Dr Advani expects more approvals for widespread antibody use to make their way through the US Food and Drug Administration. “We have several novel antibody-based therapies demonstrating very encouraging results,” she said. Current trials are revealing the importance of sequencing in treatment, which, she said, “may change the paradigm of which patients we need to take to transplant.”

Reference

Advani, AS. New immune strategies for the treatment of acute lymphoblastic leukemia: antibodies and chimeric antigen receptors. Hematology Am Soc Hematol Edu Program, 2013; 2013:131-137.