Ongoing Investigations of Nelabarine and Daratumumab May Improve Outcomes in T-ALL

Kristen O’Dwyer, MD

Investigating the addition of novel agents to cytotoxic chemotherapy may help prevent relapse in patients with T-cell acute lymphoblastic leukemia (T-ALL) by bolstering the efficacy of these standard frontline therapies, according to a presentation by Kristen O’Dwyer, MD, at the 2023 SOHO Annual Meeting.

O'Dwyer, an associate professor, Department of Medicine, Hematology/Oncology at the University of Rochester Medical Center School of Medicine and Dentistry, Rochester, New York, discussed monoclonal antibodies and small molecule therapies combined with high-dose chemotherapy for adult ALL. These ongoing clinical trials seek to improve minimal residual disease (MRD)-negative rates and further improve event-free survival (EFS).¹

Nelarabine

In the Children’s Oncology Group AALL0434 trial (NCT00408005) a total of 1562 evaluable patients with T-cell ALL (T-ALL) were stratified into 3 groups: low risk, intermediate and high risk, and by M3 marrow, defined as greater than 25% of blast cells.² Patients in the low-risk group were randomized to receive chemotherapy vs high-dose methotrexate, patients in the intermediate and high-risk group were randomized to receive chemotherapy vs high-dose methotrexate with or without nelarabine (Arranon). The remaining group received high-dose methotrexate plus nelarabine if M1 (fewer than 5% blast cells) at end of consolidation (EOC). In the group who randomly received nelarabine (n = 323) or no nelarabine (n = 336), the 5-year disease-free survival (DFS) rates were 88.2% and 82.1%, respectively (P = .029).

In the frontline setting, ongoing trials evaluating nelarabine include the GRAALL-2014/T trial (NCT02617004) and the JPLSG T-11/JALSG T-ALL-211-U trial (UMIN000006851).^3,4

The GRAALL-2014 trial used a modified regimen, based on the historical GRAALL-2005 trial. Findings were also retrospectively compared between studies. For GRAALL-2005, patients with Philadelphia chromosome-negative ALL who were 18 to 59 years old received a pediatric-inspired chemotherapy regimen, regardless of age. In GRAALL-2014, similar patients were enrolled but those age 45 to 59 received a less intense chemotherapy regimen with a modified HSCT. Nelarabine (1.5 g/m2) was administered on days 1, 3, and 5 during consolidation and maintenance for a total of 15 doses.

The 3-year overall survival rate was 71% with the modified dose vs 64% without in the historical trial (HR, 0.89; 95% CI, 0.66-1.21; P = .46).3 “However, because this trial is ongoing, the nelarabine data have not been reported yet,” O’Dwyer said.

In the JPLSG T-11/JALSG T-ALL-211-U trial, nelarabine (650 mg/m2) was administered for 5 days during intensification and maintenance and involved 62 patients at a median age of 17 years (range, 15-24 years). Investigators reported that at 3 years, the EFS rate was 88.6%, the OS rate was 93.4%, and the cumulative incidence of relapse rate was 5.3%.⁴ “As these trials reach their conclusion, the question arises: ‘Should nelarabine be incorporated into frontline therapy for adults?’” O’Dwyer asked.

Venetoclax and Navitoclax

Venetoclax (Venclexta)and low-dose navitoclax plus chemotherapy was evaluated in pediatric and adult patients with relapsed/refractory (R/R) ALL or lymphoblastic lymphoma in a phase 1 dose-escalation trial (NCT03181126).⁵ Investigators reported that venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in this population.

“Patients with T-ALL had quite a good response and the overall response to the combination was about 60% in a highly-treated population in relapsed patients who had been treated with a median of 4 regimens,” O’Dwyer said. “We know that once patients relapse, the outcomes are very important and having a good response rate in this patient population of [52.6%] suggests that this combination is worthy of further evaluation.”

Daratumumab

Prior trials evaluating daratumumab (Darzalex)have demonstrated that blasts in patients with T-ALL maintain CD38 surface expression, even after exposure to multiple chemotherapy regimens.⁶ Further, Vogiatzi F, et al, showed that both single-agent daratumumab and daratumumab plus chemotherapy improved OS and cleared MRD, and CD38 expression did not correlate with response.⁷

Bride KL, et al, evaluated daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found efficacy in 14 of 15 different PDX.6 Their findings suggest that daratumumab is highly effective, demonstrating an antileukemic effect. Emerging evidence suggests that the agent can be combined with chemotherapy agents in multiple myeloma. Findings from the DELPHINUS study (NCT03384654),8 which evaluated the safety and efficacy of daratumumab in pediatric and young adult patients with R/R T-ALL or lymphoblastic lymphoma (LL), showed an objective response rate (ORR) in patients with T-ALL of 83.3% in pediatric patients and 60% in adult/young adult (AYA) patients. The ORR in pediatric and AYA patients with T-cell LL was 40%, according to researchers.

O’Dwyer concluded noting that “improving frontline therapy to prevent relapse remains the optimal approach for treating patients with T-ALL. These ongoing trials involving novel agents will inform us about future developments.”

References

1. O’Dwyer K. Acute lymphoblastic leukemia in adults: Novel agents (for T-ALL). Presented at 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023). September 6, 2023. Houston, Texas.
2. 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
3. Boissel N, Huguet F, Leguay T, et al. In adults with Ph-negative acute lymphoblastic leukemia (ALL), age-adapted chemotherapy intensity and MRD-driven transplant indication significantly reduces treatment-related mortality (TRM) and improves overall survival - results from the GRAALL-2014 Trial. Blood. 2022;140(suppl 1):112-114. doi: 10.1182/blood-2022-157903
4. Hatta Y, Sato A, Kada A, et al. Risk stratified therapy with nelarabine and intensified administration of l-asparaginase for newly diagnosed T-cell acute lymphoblastic leukemia in adolescents and young adults (JPLSG T-11/JALSG T-ALL-211-U): An intergroup phase 2 study. Blood. 2022;140 (suppl 1):124–126. doi:10.1182/blood-2022-156613
5. Pullarkat VA, Lacayo NJ, Jabbour E, et al. Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. Cancer Discov. 2021;11(6): 1440–1453. doi:10.1158/2159-8290.CD-20-1465
6. Bride KL, Vincent TL, Im SY, et al. Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. Blood. 2018;131(9):995-999. doi:10.1182/blood-2017-07-794214
7. Vogiatzi F, Winterberg D, Lenk L, et al. Daratumumab eradicates minimal residual disease in a preclinical model of pediatric T-cell acute lymphoblastic leukemia. Blood. 2019;134(8):713-716. doi:10.1182/blood.2019000904
8. 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):10001-10001. doi: 10.1200/JCO.2022.40.16_suppl.10001