Novel Therapy for T-ALL and T-LBL Shows Promise

Blocking Leukemia Cell Survival and Expansion

T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LBL) are two aggressive blood and bone marrow cancers. They are rare in adults, with only 800 new cases each year in the United States. At Washington University School of Medicine and Siteman Cancer Center, physicians and scientists are working together to develop a more effective treatment for this uncommon yet serious diagnosis.

Geoffrey Uy, MD Medical Director for Clinical Research in Oncology at Washington University School of Medicine and principal investigator

T-ALL and T-LBL are more common diagnoses in children and teenagers. These fast-growing cancers begin when lymphocytes, or white blood cells, become abnormal and grow and multiply in an uncontrolled way. Without treatment, they are rapidly and uniformly fatal.

The standard treatment for adult T-ALL and T-LBL includes chemotherapy, and if possible, a stem cell transplant. Geoffrey Uy, MD, the trial’s principal investigator, and Daniel Link, MD, the lead scientist, are researching a new therapy that may provide another option. “As this is a relatively rare disease, there hasn’t been much extensive research on alternative therapies,” says Dr. Uy. “It’s an unmet need.”

Through preclinical evidence, an important cell receptor for T-ALL and T-LBL has been identified, called CXCR4. When bonded with the cytokine CXCL12, a protein important in cell signaling, this receptor sends a signal to leukemia cells that is critical for their survival and expansion. A drug called BL-8040 is a novel inhibitor of CXCR4, meaning it can inhibit, or block, this signal by preventing CXCL12 binding. In lab models, the drug has shown remarkable success in killing leukemia cells.

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“We’re trying to exploit the cancer’s weakness,” says Dr. Link. “This type of leukemia is dependent on that signal inside the body. We’ve found the Achilles heel of T-ALL and T-LBL so we’re attacking it. As the signal is key to survival, it is likely the leukemia cells will go through apoptosis, or cell death, without it, improving response and remission in patients.”

The research team is also studying the receptor to understand why the leukemia cells are so dependent on it. “We’re hoping to better understand the receptor, its role in leukemia and the drug’s ability to inhibit this,” says Dr. Uy.

From the Lab to the Patient

While the clinical trial began only a few months ago, the research leading up to it has been ongoing for several years. It started with basic observations in the lab that illustrated the importance of CXCR4 to leukemia cells. The ability of BL-8040 to stop the activation signal was then studied. While other drugs may also block the signal, BL-8040 was chosen because it is a very potent inhibitor and has been used in treatment of other leukemia diagnoses.

Patients eligible for this clinical trial are adults with with relapsed or refractory T-ALL or T-LBL. If a patient meets this criteria, further assessments are done to determine if the patient is a good candidate for the trial.

Patients admitted into the study receive both BL-8040 and standard chemotherapy. The treatment cycle includes a single dose of BL-8040 without chemotherapy on day one. “This allows us to identify if this novel agent alone causes any changes in the cells,” says Dr. Uy. On day 2, patients receive BL-8040 along with chemotherapy. This continues through day 6 with the chemotherapy administered only every other day. A subsequent cycle begins three weeks after.

Recently the first patient was officially enrolled into the study at Siteman Cancer Center. Led by Washington University, this multi-center study also includes MD Anderson Cancer Center, University of Chicago and Ohio State University, which can all accept up to 20 patients. The collaboration of these institutions is necessary to reach the small patient population affected by this rare disease.

SPORE: Fostering Translation
Daniel Link, MD Principal SPORE investigator and lead scientist

Drs. Uy and Link are optimistic that the combination of BL-8040 and chemotherapy will cause malignant tumors to shrink. Successful outcomes from this treatment may also allow for a bone marrow transplant when it previously might not have been possible. Another particularly exciting component of BL-8040 is that it preferentially affects the leukemia cells over healthy cells. On its own, it has very few side effects compared to chemotherapy.

If the trial is successful, it is possible that this therapy could be used for children with T-ALL. Acute lymphoblastic leukemia (ALL) is the most common form of leukemia in children.

“This could become the standard of care, sparing patients the toxicity of chemotherapy,” says Dr. Uy. “However, we’re in the initial stages of the trial, and will need much more data before we reach that threshold.”

This clinical trial and the lab work leading up to the patient trial has been possible, in part, by the financial support of the Specialized Program of Research Excellence (SPORE) in Leukemia grant for almost three years. “This is what the SPORE is designed to do. It’s meant to foster translation —  to make basic observations in the lab translate to clinical trials,” says Dr. Link.

Both Drs. Uy and Link believe this could be a better therapy option for patients with T-ALL and T-LBL, giving them a better chance to fight these aggressive diseases. “By making key observations in the laboratory and then conducting the clinical trials, we come up with new therapies. This is how science is done and this is how advancements are made.” says Dr. Link.

To learn more about this clinical trial, visit, identifier: NCT02763384.