Targeted Therapies, Immunotherapies Slated to Propel T-cell ALL Treatment Paradigm Forward

The cure rate for patients with T-cell acute lymphoblastic leukemia (T-ALL) has improved dramatically over the past few decades, with outcomes becoming comparable to what is observed in those with B-cell acute lymphoblastic leukemia (B-ALL), David T. Teachey, MD, said in a presentation during the 2021 SOHO Annual Conference, and emerging novel approaches seek to further boost survival rates from 90% to 100%.

Over the past 60 years, overall improvements in the cure rate for patients with T-cell acute lymphoblastic leukemia (T-ALL) have been one of the great success stories of modern medicine, according to David T. Teachey, MD, attending physician and researcher at Children’s Hospital of Philadelphia. When compared with patients with B-cell acute lymphoblastic leukemia (B-ALL), patients with T-ALL had inferior outcomes. In the last 10 years, however, those rates have become more comparable. Yet, despite a survival rate of close to 90% in T-ALL, investigators continue to strive to attain 100% survival.

“I think introducing targeted therapies and incorporating immunotherapies are the 2 areas where we continue to make improvements in outcomes and survival in these diseases,” Teachey, attending physician and researcher at Children’s Hospital of Philadelphia, said during his presentation. In addition, methods to improve risk stratification can lead to optimal benefit.

There are several potential new agents under development that are based on the biology of T-ALL, including signal transduction inhibitors, notch pathway inhibitors, CDK4/6 inhibitors, BCL-2 family inhibitors, epigenetic modulators, next-generation chemotherapeutics, and immunotherapies.

“T-ALL is far more biologically complex than B-ALL, so it’s harder to find a one-size-fits-all [treatment] but you can [stratify] patients with T-ALL into different groups who are more likely to respond to different small molecule inhibitors and other novel therapies based on the biology of leukemic blasts,” Teachey said.

In preclinical models, proteasome inhibitors have demonstrated encouraging activity, especially the ability to synergize with chemotherapeutics that can overcome resistance to steroids and other drugs. Further, these agents have shown promise in relapse trials, said Teachey. A number of relapsed trials are ongoing with a focus on proteasome inhibitors, including first-generation proteasome inhibitor bortezomib (Velcade) and second-generation inhibitors, including carfilzomib (Kyprolis).

The phase 3 AALL1231 trial (NCT02112916) randomized patients with T-ALL or T-cell lymphoblastic lymphoma (T-LL) to receive a modified augmented Berlin-Frankfurt-Münster chemotherapy backbone with or without bortezomib during induction and delayed intensification.1 Patients were stratified as standard, intermediate, or very high risk.

Investigators reported a 3-year overall survival (OS) rate for the control group (Arm A) of 85.5% compared with 88.2% for the treatment arm (Arm B). In patients with T-LL, the 3-year OS rate was 78.0% in Arm A and 89.5% in Arm B. The 3-year OS rate for patients with T-ALL was 88.2% in Arm A compared with 87.7% for patients in Arm B. Overall, bortezomib significantly improved event-free survival for these patient populations. “We found that there was a trend towards improved survival in patients who received bortezomib, but it didn’t rise to statistical significance,” Teachey said. “What we found that was interesting, though, was if you broke out patients on this trial who had T-ALL vs T-LL, we found there was no survival benefit.”

JAK/STAT inhibition is another potential pathway to be explored, Teachey said. This pathway is particularly attractive in patients with early T-cell precursor phenotype where JAK/STAT signaling is commonly dysregulated. Teachey noted several trials evaluating JAK inhibitors including ADVL1011 (NCT01164163), which is a phase 1 trial evaluating ruxolitinib (Jakafi) to determine the maximum tolerated or recommended phase 2 dose, dose-limiting toxicities, pharmacokinetics, and pharmacodynamics in children with recurrent/refractory solid tumors;2 and the phase 2 trial AALL1521 (NCT02723994), which is exploring ruxolitinib in combination with a standard multi-agent chemotherapy regimen in CRLF2/JAK-altered ALL.

Other inhibitors that are undergoing evaluation are CDK4/6 inhibitors. Specifically, the AINV18P1 trial (NCT03792256) is exploring palbociclib (Ibrance) in combination with a standard re-induction regimen.3 In the dose-determination portion of the study (part 1; n = 6), palbociclib was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently in combination with 4-drug re-induction chemotherapy. In the ongoing expansion cohort (part 2; n = 2), patients will undergo further assessment for safety and feasibility of combination therapy.

Another target undergoing evaluation is BCL-2. Chonghaile et al4 found that T-ALL cell lines and primary patient samples are dependent upon BCL-XL, except when the cancer has an early T-cell progenitor (ETP) phenotype, in which case the cancer is BCL-2 dependent. The investigators described a change in antiapoptotic protein dependence that is related to the differentiation stage of the leukemic clone. Teachey said their findings demonstrate that BCL-2 is a potential target for therapeutic intervention and that ETP may be sensitive to venetoclax (Venclexta) monotherapy, as demonstrated by Pullarkat et al.5

“Pediatric oncologists found [the venetoclax] data exciting because it included 7 relapsed/refractory pediatric patients and a response rate of 86%. I think we need more data and more patients, but this is a promising pathway,” Teachey said.

Turning to immunotherapies, Teachey said that there are several approaches in B-ALL, but that T-ALL poses some challenges. “The field has lagged a little in T-ALL because it’s more difficult to develop chimeric antigen receptors [CARs] against T-ALL for a number of reasons,” Teachey said. He noted that toxicity and CAR T-cell fratricide add to the difficulty in developing CARs in this setting. Despite the challenges, however, Teachey was encouraged because a few T-cell immunotherapy trials are underway that focus on daratumumab (Darzalex), pembrolizumab (Keytruda), nivolumab (Opdivo), and isatuximab-irfc (Sarclisa).

References

1. Teachey DT, Devidas M, Wood BL, et al. Cranial radiation can be eliminated in most children with t-cell acute lymphoblastic leukemia (t-all) and bortezomib potentially improves survival in children with t-cell lymphoblastic lymphoma (t-ll): results of children’s oncology group (COG) trial AALL1231. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020. Abstract 266. Accessed September 8, 2021. https://bit.ly/3DXViLp
2. Loh ML, Tasian SK, Rabin KR, et al. A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: A children’s oncology Group phase 1 consortium study (ADVL1011). Pediatr Blood Cancer. 2015;62(10):1717-1724. doi:10.1002/pbc.25575
3. Raetz EA, Teachey DT, Minard C, et al. Safety of Palbociclib in combination with chemotherapy in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia and lymphoma: a children’s oncology group pilot study. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020. Abstract 1018. Accessed September 8, 2021. https://bit.ly/3yP1TnG
4. Chonghaile TN, Roderick JE, Glenfield C, et al. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer Discov. 2014;4(9):1074-1087. doi:10.1158/2159-8290.CD-14-0353
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