Outcomes With Pediatric-Inspired Regimens Warrant Further Exploration in AYA PH- ALL

Omar Shahin, MBChB

Varying outcomes were observed among adolescent and young adult (AYA) patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) who were treated with pediatric-inspired protocols (PIPs) vs adult chemotherapy regimens, according to findings from a single-center retrospective review presented at the Society of Hematologic Oncology 2023 Annual Meeting.¹

HyperCVAD/MA (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with methotrexate and cytarabine), is a regimen used for the treatment of adult patients with Ph-negative ALL.^1,2 Pediatric patients, however, receive modified treatments, most of which feature higher doses of asparaginase and corticosteroids.² In the analysis, investigators compared treatment outcomes of patients treated with hyperCVAD (n = 57) or a PIP (n = 56), which included regimens from the phase 2 CALGB 10403 trial (NCT00558519), augmented Berlin-Frankfurt-Münster,³ or the phase 3 GRAALL-2005 trial (NCT00327678).

At a median follow-up of 24 months (range, 1-135), the 2-year event-free survival (EFS) rate for all treated patients (n = 113) was 65.8% (95% CI, 56%-75%). For patients who received PIP the 2-year EFS rate was 80.6% (95% CI, 68%-90%) vs 52.6% (95% CI, 39%-65%) for those who received hyperCVAD, translating to a statically significant difference (log-rank P = .004).¹

The 2-year recurrence-free survival (RFS) rate for all evaluable patients (n = 103) was 75.6% (95% CI, 66%-84%). Among those who received a PIP (n = 50), the 2-year RFS rate was 93.7% (95% CI, 85%-98%) compared with 59.6% (95% CI, 45%-73%) for those who received hyperCVAD (n = 53), again resulting in a statistically significant difference (log-rank P = .0001).¹

Although overall survival (OS) outcomes were numerically improved among those who received a PIP vs hyper CVAD, the difference was not statistically significant, explained Omar Shahin, MBChB, who presented the data during the meeting. The 2-year OS rate for all treated patients (n = 113) was 72.2% (95% CI, 63%-80%). Patients in the PIP group had a 2-year OS rate of 80.3% (95% CI, 68%-90%) vs 65.7% (95% CI, 52%-77%) for those in the hyperCVAD arm (P = .158).¹

“Pediatric-based treatment protocols lead to better 2-year EFS and RFS than hyperCVAD for AYA patients with Ph-negative ALL…prospective trials comparing both adult treatment and PIPs are warranted,” Shahin, a medical oncologist at the King Hussein King Hussein Cancer Foundation and Center in Cairo, Jordan said. “Over the past decades, researchers have identified a distinct group known as AYAs with ages between 15 and 39 years. This group has higher survival rates than adults but lower rates than children [and] this [has] prompted many research groups to evaluate pediatric-inspired regimens in the treatment of AYA patients with ALL.”

Shahin showed that in an analysis of SEER data, the 5-year survival rates of patients with ALL aged younger than 15 years was 92.1% compared with 77% among those age 15 to 19 years, 66.8% among those age 20 to 39 years, and 43% among those age 40 to 64 years.¹

The analysis evaluated outcomes from patients ages 18 to 39 years treated at King Hussein Cancer Center between 2010 and 2022. Shahin noted that baseline characteristics were well balanced between the groups. Overall (n = 113), most patients were men (77.9%), had T-cell ALL (63.8%) or B-cell ALL (36.2%), and cytogenetic risk factors as follows: diploid (51.3%), other (16.8%), failed (11.5%), unknown (20.4%). High-risk disease was reported in 4.4% of patients.¹

A notable difference was observed in age. Among those who were treated with a PIP, the median age was 23 years (SD, ± 4.7) vs 27 years (SD, ± 7.4) for those who received hyperCVAD. This was deemed significant (P= .018).¹

“Looking at secondary outcomes, almost 93% of all patients [92.8%] achieved complete remission [CR] at the end of induction with no difference between the groups and we had 8 [patients with] refractory disease distributed evenly between the hyperCVAD group and the PIP [group],” Shahin said.

Other outcomes included 22.5% of patients having relapse, with 22 patients who received hyperCVAD (38.6%) experiencing disease relapse vs only 3 patients in the PIP group (5.6%) for a statistically significant difference (P = .005). Extramedullary relapse occurred in the central nervous system in 5 patients, all of whom were in the hyperCVAD group. Other sites of extramedullary relapse included skin, lymph nodes, lungs, and testicular sites and were reported in 4 patients in the hyperCVAD group (7.0%) and 2 patients in the PIP group (3.7%).¹

Overall, 23.9% of patients received allogeneic stem cell transplant, which included 16 patients in the hyperCVAD group and 11 patients in the PIP group. Among the 27 patients, the primary indications for proceeded to transplant were high-risk characteristics (n = 13), refractory disease (n = 4), relapse (n = 8), or unknown (n = 2). None of these were statistically significant between the groups.

Outcomes at last follow-up deemed statistically significant included CR and relapse (P = .004). In the hyperCVAD group, the CR rate at last follow-up was 71.9% compared with 89.1% in the PIP group. The relapse rate was 28.1% vs 7.3% in the hyperCVAD and PIP groups, respectively.¹

“We had 2 unfortunate deaths during induction, and both of those occurred during induction with PIP, 1 [because of] liver failure and cerebral hemorrhage and 1 [because of] septic shock,” Shahin said. “We had 11 deaths during CR occurring during maintenance or consolidation distributed evenly between both the groups with no significant difference most of these death occurred [because] of neutropenic complications, with [others attributed to] COVID-19 and GVHD [graft-vs-host disease].”

References

1. Shahin O, Mokoseh M, Al Rabie K, et al. Comparison of treatment outcomes in adolescents and young adults (AYA) with Philadelphia negative acute lymphoblastic leukemia (ALL) treated with HyperCVAD and pediatric-inspired protocols (PIPs). Presented at: Society of Hematologic Oncology 2023 Annual Meeting; September 6-9, 2023; Houston, TX.
2. Salama H, Eldadah S, Omer MH, et al. Comparison of a modified pediatric protocol versus a hyper-CVAD protocol in adolescents and young adults with Philadelphia-negative acute lymphoblastic leukemia: a multicenter retrospective analysis. Leuk Res. 2023;130:107316. doi:10.1016/j.leukres.2023.107316
3. Chang JE, Medlin SC, Kahl BS, et al. Augmented and standard Berlin-Frankfurt-Munster chemotherapy for treatment of adult acute lymphoblastic leukemia. Leuk Lymphoma. 2008;49(12):2298-2307. doi:10.1080/10428190802517732