A Targeted Effort

Promising drug offers targeted therapy for children with high-risk acute myeloid leukemia.

by Mike O'Kelly

A targeted effort

Harshitha Bhandaru wriggles across an examination table wearing a smile as bright as the fluorescent lights that illuminate the cozy room inside the Leukemia and Lymphoma clinic at St. Jude Children’s Research Hospital. A playful shadow on the table’s crinkling white paper mirrors the 14-month-old’s every move. Harshitha’s father, Muraly, and her mother, Chandana, steady the toddler while her 6-year-old brother, Praneeth, employs an amusing variety of methods to elicit grins from his younger sister.

In two days, Harshitha will receive a bone marrow transplant to treat high-risk, relapsed acute myeloid leukemia (AML).

When she was 3 months old, Harshitha was found to have leukemia cutis—an abnormal proliferation of white blood cells or leukocytes that create lesions under the skin. Tiny bumps formed on her body and face. Four rounds of chemotherapy sent the AML into remission, but by summer 2011, a large lump had developed on her forehead. The cancer had returned.

“Harshitha started chemotherapy again, but it was no use,” Muraly says. “The bumps continued to get bigger, and she had more leukemic blasts in her blood.”

As treatment options became ineffective, Muraly desperately searched the Internet for alternatives. He found the St. Jude website during a 2 a.m. search. After receiving a referral, the family arrived at the hospital days later. Hoping to achieve remission and make a transplant possible, physicians enrolled Harshitha in a treatment study designed specifically for relapsed AML.

Phase I

Using research gleaned from the laboratory of Sharyn Baker, PharmD, PhD, of St. Jude Pharmaceutical Sciences, oncologist Hiroto Inaba, MD, PhD, had developed a Phase I study of 11 children with leukemia who had relapsed or failed to respond to therapy.

The patients received the drug sorafenib as part of multi-drug therapy that included the conventional chemotherapy drugs clofarabine and cytarabine. Clinicians administered sorafenib twice a day during the study’s first week. For days eight through 12, the children received that medication plus the standard chemotherapy drugs; afterward, the patients received only sorafenib.

Leukemic blast cells decreased in 10 of the children after the study’s eighth day. Eight patients experienced remissions following the combination of sorafenib with clofarabine and cytarabine. A ninth child had a partial remission.

The goal of the combination therapy is to achieve remission—a level of less than 5 percent of leukemic blasts in the bone marrow. These remissions were obtained not only in all five patients with a rare FLT3-ITD genetic mutation, but also in four of the six patients without the mutation such as Harshitha.

“For these patients, sorafenib offers hope for the first time that their disease can be controlled so that they can be considered for a bone marrow transplant,” Inaba says.

Replacing the diseased bone marrow with cells from a healthy donor currently offers such high-risk AML patients the best chance for cures.

Harshitha’s protocol was based on the results of that Phase I study. A week after beginning the treatment plan, her bumps disappeared. After a month, her leukemic blasts were drastically reduced and her AML was in remission—meaning that she could now receive a transplant.

St. Jude has taken care of everything. They helped to save my daughter’s life,” Muraly says.

Bridging lab and clinic

Stories like Harshitha’s are made possible at St. Jude through partnerships between researchers in the laboratory and health care practitioners in the clinic who are all on the same campus.

“Communication and teamwork are important here at St. Jude,” Inaba says. “When I visit other places to explain our research, I talk not only of the close distance between the buildings that allows us to bridge clinical and basic research, but I talk about the value of collaboration.”

Inaba and Baker worked together to first identify a signaling-inhibiting drug for use in the study. Sorafenib is a tyrosine-kinase inhibitor, which means that the drug targets the tyrosine family of proteins and the receptors on the surface of cells where the proteins act. Mistakes in these proteins, including FLT3-ITD, are associated with the unchecked growth and survival that characterizes cancer.

Baker’s laboratory had already shown that combining sorafenib with cytarabine produced a strong anti-cancer effect against human AML cells in the laboratory and in a model of the disease. Sorafenib had also been approved for use by the Food and Drug Administration in the treatment of adults with kidney and liver cancers.

Baker’s research found that sorafenib is metabolized differently in adults and children, resulting in higher levels of a compound with potent toxicity against normal and leukemia cells. Because of the differences, St. Jude investigators made adjustments to the treatment and closely monitored patients to avoid temporary but debilitating skin complications.

In the laboratory, Baker’s team pinpointed the exact combination of drugs that proved most effective.

“We looked into the mechanisms of why treatment might be more effective when they are given together,” Baker says. “There can be many mechanisms, but we focused on efflux pumps, which are drug transporters that sit on the cell membrane. Drugs like sorafenib can prevent cytarabine from being pumped out of the leukemic blasts. When you combine the drugs, sorafenib allows cytarabine and its active metabolites to accumulate and get more anti-tumor activity.”

There is still more to be learned about sorafenib’s effects and when to properly administer it, Baker says. Observations made through application in the clinic are used as a checklist in the laboratory to determine which methods should be investigated further and what should not be pursued.

“These are questions and issues that we are looking at now in our laboratory models,” Baker says. “We still have a lot to learn about the drug and its role in AML and how best to combine it with chemotherapy and with other targeted agents.”

If these results are confirmed in larger studies, the drug will mark a new era in the treatment of AML and offer new opportunities for patients like Harshitha.

Promise magazine, Winter 2012

Editor's note: Harshitha Bhandaru lost her battle with cancer in January of 2012.

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