Clinical trial puts Philadelphia chromosome-positive leukemia survivor in remission

When Jorge Castillo’s back began to ache, he thought he’d injured himself at work.

“I install and repair electrical power grids, so I do a lot of climbing, twisting and bending,” he says. “It’s a physically demanding job.”

But Jorge soon learned that his back pain signaled the onset of acute lymphoblastic leukemia, or ALL – an aggressive cancer of the blood and bone marrow.

In patients with acute lymphoblastic leukemia, white blood cells are overproduced in the bone marrow. The marrow then prematurely releases these cells into the bloodstream. Because they’re not yet fully developed, these immature cells, called “blasts,” are unable to fight infection like fully developed white blood cells.

The blasts rapidly make copies of themselves and overtake the blood and bone marrow, crowding out red blood cells that carry oxygen around the body, and platelets that help stop bleeding.

This causes bone and joint pain, tiredness, breathlessness, fever and night sweats, and an increased risk of excessive bleeding.

Jorge was experiencing all these symptoms by the time he sought medical attention.

“It all happened so quickly,” he recalls. “Within a week, I went from feeling perfectly healthy to feeling so sick that I could hardly get out of bed.”

Jorge’s daughter, Sandra, drove him to the emergency room at a local hospital, where tests showed that blasts had invaded 70% of his bone marrow. Normally, bone marrow contains 1% to 5% blasts.

The doctor arranged for Jorge to be transferred by ambulance to MD Anderson.

“You need immediate treatment,” the doctor said. “MD Anderson is where you need to be.”

Genetic test pinpoints aggressive form of acute lymphoblastic leukemia

At MD Anderson, Jorge met leukemia specialists Abhishek Maiti, M.D., and Hagop Kantarjian, M.D., who diagnosed him with acute lymphoblastic leukemia. Maiti ordered a FISH test.

FISH tests detect chromosome rearrangements. Jorge’s test results revealed that pieces of chromosome 9 and 22 had broken off and switched places. This is called the Philadelphia chromosome rearrangement, named for the city where it was discovered.

Patients who have this rearrangement have the most aggressive form of ALL.

“Philadelphia-positive ALL moves quickly from the marrow into the blood, and from there can travel to the lymph nodes, liver, brain and spinal fluid,” Maiti says. “Patients with this diagnosis need to be hospitalized and start treatment without delay.”

Acute lymphoblastic leukemia treatment: immunotherapy and targeted therapy

Traditionally, acute lymphoblastic leukemia is treated with high doses of chemotherapy to wipe out leukemia cells in the bone marrow and restore the balance of cells in the blood. The chemotherapy is systemic, meaning it is injected into a vein and travels through the bloodstream to all parts of the body.

A stem cell transplant may also be needed to reduce the chance of the disease coming back.

The treatment can be effective, but it may produce unwanted side effects, including nausea and vomiting, hair loss, fatigue, infections, and heart damage.

Maiti and Kantarjian offered an alternative: They invited Jorge to participate in a new MD Anderson clinical trial for patients with Philadelphia-positive ALL.

Patients on the trial receive an immunotherapy drug called blinatumomab, delivered continuously through a vein. The drug works by forming a bridge between a protein called C19 that lives on the surface of acute lymphoblastic leukemia cells and a protein called CD3 that lives on disease-fighting T cells. This bridge brings the T cells close enough to the ALL cells to recognize and kill them.

Patients receive the drugs in six cycles, each lasting four weeks. Between each cycle, there’s a two-week break.

Throughout the clinical trial, patients also take an oral targeted therapy pill called ponatinib once a day. The drug zeros in on and “turns off” a protein known as BCR-ABL1, which is produced by the Philadelphia chromosome. It’s this protein that activates the bone marrow to make too many blasts, which leads to acute lymphoblastic leukemia.

Because immunotherapy drugs can cause a cascade of exaggerated immune system responses that can cause the body to attack its own healthy cells and tissues rather than just fighting off cancer, patients in the clinical trial are carefully monitored.

Jorge tolerated the treatment well and experienced no side effects.

"Every time I see him in clinic, he's feeling well," Maiti says. "It's very encouraging."

Killing runaway cancer cells with chemotherapy

To kill any remaining cancer cells that may have escaped and fled to the brain, patients receive the chemotherapy drugs methotrexate and cytarabine through a series of 12 lumbar punctures, also known as spinal taps.

With a needle and syringe inserted between two vertebrae, the drugs are delivered directly into the fluid that surrounds and protects the brain and spinal cord.

“Up to one-third of patients with Philadelphia-positive ALL may relapse when leukemia cells spread to the fluid around the brain,” Maiti explains. “Cancer drugs taken by mouth or delivered through a vein have a hard time crossing over into this fluid. So we help the drugs get where they need to go.”

A compete molecular remission

After only 27 days of participating in the clinical trial, Jorge achieved a complete molecular remission, a scientific way of saying all evidence of leukemia cells in his bone marrow disappeared.

Others in the trial experienced similar results.

“Almost 90% of clinical trial participants no longer showed evidence of leukemia, even with highly sensitive lab tests designed to detect the disease,” says Elias Jabbour, M.D., who leads the trial at MD Anderson. “That’s a dramatic improvement over traditional treatment, which produces a complete molecular remission in only 20% of patients. Furthermore, all patients in our trial avoided the need for a stem cell transplant.”

These results were presented at the 2021 American Society of Clinical Oncology (ASCO) annual meeting by Nicholas Short, M.D., a leukemia physician and researcher at MD Anderson. 

The clinical trial is ongoing, and MD Anderson is still accepting patients.

“Our findings may change as more participants join the study, but I can say with certainty that we’re very excited by what we’re seeing,” says Jabbour. “The fact that we’re not able to detect any cancer at all in the majority of our trial participants so early in their treatment tells us how promising this regimen is.”

The clinical trial is available only at MD Anderson, but Jabbour says it may be expanded to other centers now that the results are published.

Jorge, for one, is grateful to be among the first to benefit.

“Only four months ago I was facing a serious diagnosis and an unknown future,” he says. “Today, I’m feeling great. I want to see every patient with ALL have the success I’ve had. Thank God for clinical trials and MD Anderson.”

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