乌鸦传媒

The addition of the proteasome inhibitor bortezomib to chemotherapy is safe and effective in children and young adults newly diagnosed with T-cell lymphoblastic lymphoma (T-LL), researchers reported. In addition, they said, cranial radiotherapy can be eliminated in 90% of young patients with T-cell acute lymphoblastic leukemia (T-ALL) when the chemotherapy regimen is intensified.

This is the first trial to demonstrate an overall survival benefit for newly diagnosed pediatric T-LL with a small molecule inhibitor, the team noted.

To improve outcomes in these young patients, Children's Oncology Group (COG) trials have focused on different strategies to prevent relapse in newly diagnosed patients, including refining risk stratification, introducing new drugs and treatments, and intensifying chemotherapy.

In the new study, David T. Teachey, MD, of the Children's Hospital of Philadelphia, and colleagues added bortezomib to chemotherapy for T-LL patients and modified the treatment for T-ALL, utilizing the steroid dexamethasone instead of prednisone during chemotherapy and adding two extra doses of pegaspargase with the goal of eliminating cranial radiotherapy.

The trial, which was published in the , enrolled 824 patients between 2014 and 2017. Four-year event-free and overall survival were both significantly improved for patients on bortezomib plus chemotherapy compared with those who had chemotherapy alone: 86.4% and 89.5% vs 76.5% and 78.3%, respectively, and there was no increased toxicity with bortezomib.

In the following interview, Teachey elaborated on the results.

What does this study add to the literature about newly diagnosed T-ALL and T-LL?

Teachey: The original study design included both T-cell lymphoma and T-cell leukemia. Dogma at the time was this was the same spectrum of disease. We found definite differences between the two diseases. Bortezomib was active with T-cell lymphoma and should be part of standard of care, and we now treat all young T-cell lymphoma patients in COG trials with bortezomib.

T-cell leukemia does not show the same benefits. Results were not worse and treatment was well-tolerated, but we did not see the same benefit in survival. More patients were cured in the T-cell lymphoma group.

We improved cure rates with T-cell lymphoma by using bortezomib. We were also able to eliminate cranial radiotherapy in T-cell leukemia patients. Prior to this study, 90% of young T-cell leukemia patients in the U.S. received cranial radiotherapy. We eliminated this radiation in all but 10% of patients. In general, T-cell lymphoma patients do not relapse, so historically they do not receive radiation.

Were there any surprises in the data?

Teachey: The big surprise was the fact that T-cell lymphoma and T-cell leukemia patients had different results. We changed corticosteroids from prednisone to dexamethasone to eliminate radiation. This was good for T-cell leukemia patients, but more intensive steroids did not help T-cell lymphoma patients. This is another difference between T-cell lymphoma and T-cell leukemia patients. We now use different corticosteroids as the backbone for treatment in T-cell leukemia.

Why is it important to eliminate cranial radiotherapy in these young patients?

Teachey: There are significant side effects from cranial radiotherapy, both short-term and long-term. Radiation in young patients affects development of the brain and impacts neurocognitive outcomes, including attention, concentration, and a slight loss in IQ. Thirty years down the road, some patients who received cranial radiotherapy have a harder time getting and maintaining a job, and they also have an increased risk of secondary brain tumors.

What is the next step in this research?

Teachey: We are in the process of developing a successor clinical trial in COG, taking these findings to include bortezomib in T-cell lymphoma but not T-cell leukemia patients, along with the backbone treatment. The intention is not to irradiate children with T-cell leukemia. A new trial is also testing immunotherapy with daratumumab in a front-line setting for T-cell lymphoma.

What are the bottom-line messages from this study?

Teachey: The study has two messages: bortezomib improves cure rates in T-cell lymphoma and should be part of standard of care, and children with T-cell leukemia can be cured without the need for cranial radiotherapy.

Read the study here.