The five-year survival rate for children and adolescents with acute lymphoblastic leukemia (ALL) has reached about 90% with chemotherapy. Clinicians increasingly are turning to immunotherapy for relapsed/refractory B-cell ALL (B-ALL).

Immunotherapy harnesses the innate power of the body’s own immune system to destroy cancer cells.

“It may be early to know definitively the full implications of this, but we’re potentially at the dawn of a new era,” said Esther E. Knapp, M.D., a pediatric hematologist/oncologist with Norton Children’s Cancer Institute, affiliated with the UofL School of Medicine. “Our entire approach to treating leukemia may be about to change radically.”

Leukemia — most commonly B-cell acute lymphoblastic leukemia — accounts for about 30% of childhood cancer diagnoses. ALL is characterized by excess lymphoblasts (cancer cells) in the bone marrow.

Approved immunotherapy for ALL

For relapsed/refractory ALL, the Food and Drug Administration has approved the antibody-based immunotherapy treatments blinatumomab and inotuzumab ozogamicin, and the T cell–based immunotherapy tisagenlecleucel, which uses chimeric antigen receptor T (CAR-T) cells. Norton Children’s Cancer Institute offers CAR-T immunotherapy.

Blinatumomab works by using bispecific T-cell engaging (BiTE) antibodies. Inotuzumab ozogamicin’s mechanism of action is targeting CD22, a specific cluster of surface molecules present on 90% of B-ALL cells and mature B lymphocytes but not on normal hematopoietic B-cell precursors or hematopoietic stem cells. CAR-T cell therapy targets CD19, which is highly expressed on many leukemia cells in B-ALL.

“A lot of us are excited about some of the newer agents out there and seeing whether we can cure more kids than we do now.” Dr. Knapp said.

Immunotherapy for relapsed and refractory B-cell ALL has created durable remissions for many patients. A number of these patients previously had little chance of a cure.

Balancing side effects with cure rate

As clinicians consider these new therapies in children, however, they need to weigh the side effects, not just the cure rate, according to Dr. Knapp.

Short-term, these targeted therapies carry some potentially significant side effects, such as cytokine release syndrome, high fevers, neutropenia, seizures and other neurologic issues. Some patients can get critically ill and may need to go to the intensive care unit. Data on the long-term effects of these drugs do not exist because they are so new, according to Dr. Knapp.

However, it is also important to consider the long-term effects of any treatment that is given to children. Standard chemotherapy carries many potential side effects, both short-term and long-term. Some of these side effects can be very serious and even deadly.

“We want our patients to live long, healthy lives — for years and decades. We need to make sure the side effects of those treatments don’t come back to bite us 20 years later,” she said.

Standard treatment for B-ALL with chemotherapy has potentially serious toxicities, both short-term and long-term, including life-threatening infections, heart issues, liver damage, thyroid dysfunction, neurological effects, depression, and anxiety and mood disorders. There is hope that immunotherapy may be able to cure leukemia effectively, but with fewer serious side effects, especially in the long term.

“The standard treatment is pretty lengthy and incorporates several different phases of chemotherapy. It’s not a quick and easy fix by any means. That’s based on lots of data,” Dr. Knapp said.

Indications for targeted therapies currently are defined narrowly.

“Are we going to do away with chemotherapy for everybody? I think it will take a while to get to that point. That’s an open question. And it’s not like the immunotherapy doesn’t have side effects,” Dr. Knapp said.

Researchers continue to identify new potential targeted therapies for B-ALL. Some may target cancer cells with more specificity and fewer side effects than existing therapies.

Dr. Knapp’s recently published research

Read more at PubMed.gov