Refined Stratification and Frontline Targeted Therapies Explored in Pediatric T-ALL

The treatment of pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL) has benefited from numerous advancements in survival outcomes, but there are pressing needs for better risk assessment and the use of targeted therapies in the frontline setting.

In a presentation at the 2023 American Society of Pediatric Hematology/Oncology Conference, David T. Teachey, MD, an attending physician and researcher at the Children’s Hospital of Philadelphia in Pennsylvania, discussed the research that led to the current treatment approaches for patients with T-ALL, incorporating results from trials of various chemotherapy regimens to maximize outcomes for children with this malignancy.

“The improvements in cure rates for children with acute lymphoblastic leukemia, I think, is one of the great success stories in modern medicine,” said Teachey, who also is director of clinical research in the Center of Childhood Cancer Research and associate professor of pediatrics in the Perelman School of Medicine at the University of Pennsylvania.¹ “[For] a disease that was previously incurable, the vast majority of patients with ALL [now] survive.”

Past successes in treatment led to overall survival (OS) increasing drastically for patients with de novo disease, climbing from 80.8% for those who received a diagnosis in 2000 to 2005 to 90.6% for those who received a diagnosis in 2006 to 2010.² Those with relapsed disease still have poor outcomes, but the 5-year OS rate increased from 23% in 2008 to 33% in 2019.³

Teachey suggested that the current state of treatment may be reaching the limit of what chemotherapy regimens can provide for patients. “We’ve probably hit the tip of where we can improve outcomes just by increasing intensity or how we give our standard drugs,” he said.¹ “We need to improve risk stratification, and we need to start introducing targeted therapies and immunotherapies into the front line.”

Two Key Trials

The current landscape has been influenced by 2 key phase 3 trials, Children’s Oncology Group AALL0434 (NCT00408005) and AALL1231 (NCT02112916).1 In AALL0434, patients received the augmented Berlin-Frankfurt-Münster regimen and were randomly assigned to receive escalating-dose methotrexate without leucovorin rescue plus pegaspargase (C-MTX; Oncaspar) or high-dose MTX with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned to receive nelarabine (Arranon).¹

AALL0434 results showed that an escalating dose of methotrexate led to superior disease-free survival (DFS) and OS vs highdose methotrexate, and the patients with T-ALL who received C-MTX and nelarabine had the best disease-free survival at 5 years.⁴ Nelarabine was not effective in patients with T-cell lymphoblastic lymphoma (T-LL); Teachey stated in his presentation that this was due to its benefit in T-ALL coming from reducing central nervous system (CNS) relapses, which are more common in T-ALL.

In the AALL1231 trial, patients received a modified augmented Berlin-Frankfurt Münster regimen with or without bortezomib (Velcade).⁵ This trial also aimed to reduce the use of prophylactic cranial radiation therapy by adding dexamethasone instead of prednisone and adding 2 doses of pegaspargase. It demonstrated that adding bortezomib led to a significant improvement in 4-year event-free survival (EFS) and 4-year OS rates.⁵ Furthermore, more than 90% of patients avoided cranial radiation without excess relapse.⁵

An analysis of the patients enrolled in both of these studies based on degree of CNS involvement found that patients with CNS 2 status had similar DFS, EFS, and OS outcomes to patients with CNS 1 and do not need different therapy, but those with CNS 3 status had worse outcomes despite use of cranial radiation, though those with CNS 3 did respond to nelarabine in AALL0434.⁶

Teachey highlighted that when using current risk stratifi cation by minimal residual disease (MRD) status, the majority of patients who relapse are defi ned as having standard risk, meaning there is a need for better risk assessment.

A genomic analysis identifi ed 16 subtypes of T-ALL and the disease-classifying driver alterations, showing that 55% of driver alterations are in noncoding parts of the cancer genome.⁷ An improved risk classifi cation utilizing MRD, genomic subtype, and driver alteration enables stratifi cation of patients more accurately based on expected survival outcomes, he said.

Targeted therapies are an area of great interest in T-ALL, including signal transduction inhibitors, tyrosine kinase inhibitors, and next-generation chemotherapeutics, according to Teachey. Many trials are investigating the use of these agents in the relapsed population and some, such as dasatinib (Sprycel), are being investigated as additions to backbone therapy.

Immunotherapies are also under investigation, with certain antigens such as CD5, CD7, and CD38 being potential targets based on their expression in T-ALL.⁸

A trial of the anti-CD38 monoclonal antibody daratumumab (Darzalex) in relapsed patients led to a 58.3% overall response rate after 1 cycle, and a best overall response rate of 83.3% after 2 blocks of therapy.⁹ More than 60% of patients went on to receive stem cell transplant.

Daratumumab will be investigated in the front line in the upcoming AALL2331 trial, which is planned for 2024. Patients with T-ALL who are MRD positive at the end of induction will be randomly assigned to receive C-MTX with or without daratumumab, and those with T-LL will also be randomly assigned to receive daratumumab regardless of MRD.

The addition of nelarabine and bortezomib in appropriate patients has established current standards of care in T-ALL without decreasing tolerability.

Incorporating targeted therapies and immunotherapies early in treatment as well as utilizing genomic markers to assess risk will be the next step to preventing relapse in these pediatric patients.

REFERENCES

1. Teachey, DT. Current landscape and outcomes after treatment for upfront T-cell ALL. Presented at: 2023 American Society of Pediatric Hematology/Oncology Conference. May 10-13, 2023; Fort Worth, TX.

2. Raetz E, Lu X, Devidas M, et al. Continued improvements in overall survival (OS) in children with newly diagnosed acute lymphoblastic leukemia (ALL): a Children’s Oncology Group (COG) Report. Presented at: 2018 American Society of Pediatric Hematology/Oncology Conference; May 2-5, 2018; Pi sburgh, PA.

3. Rheingold SR, Ji L, Xu X, et al. Prognostic factors for survival after relapsed acute lymphoblastic leukemia (ALL): a Children’s Oncology Group (COG) study. J Clin Oncol. 2019;37(suppl 15):10008. doi:10.1200/JCO.2019.37.15_suppl.10008

4. Dunsmore KP, Winter SS, Devidas M, et al. Children’s Oncology Group AALL0434: a phase III randomized clinical trial testing nelarabine in newly diagnosed T-cell acute lymphoblastic leukemia. J Clin Oncol. 2020;38(28):3282-3293. doi:10.1200/JCO.20.00256

5. Teachey DT, Devidas M, Wood BL, et al. Children’s Oncology Group Trial AALL1231: a phase III clinical trial testing bortezomib in newly diagnosed T-cell acute lymphoblastic leukemia and lymphoma. J Clin Oncol. 2022;40(19):21062118. doi:10.1200/JCO.21.02678

6. Gossai NP, Devidas M, Chen Z, et al. Central nervous system status is prognostic in T-cell acute lymphoblastic leukemia: a Children’s Oncology Group report. Blood. 2023;141(15):1802-1811. doi:10.1182/blood.2022018653

7. Pölönen P, Elsayed A, Di Giacoma D, et al. Comprehensive genome characterization of childhood t-all links oncogene activation mechanism and subtypes to prognosis. Blood. 2022;140(suppl 1):1727.-1729. doi:10.1182/blood-2022-167157

8. Leong S, Inglo S, Papaleonidopoulou F, et al. CD1a is rarely expressed in pediatric or adult relapsed/refractory T-ALL: implications for immunotherapy. Blood Adv. 2020;4(19):4665-4668. doi:10.1182/bloodadvances.2020002502

9. Hogan LE, Bhatla T, Teachey DT, et al. Efficacy and safety of daratumumab (DARA) in pediatric and young adult patients (pts) with relapsed/refractory T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL): results from the phase 2 DELPHINUS study. J Clin Oncol. 2022;40(suppl 16):10001. doi:10.1200/JCO.2022.40.16_suppl.10001