Updated Results on a Multicenter Phase II Study of a Dose Intensified Pediatric Regimen in Adults with Acute Lymphoblastic Leukemia: The 06-254 DFCI ALL Consortium Trial

Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) have good outcomes when treated with pediatric regimens (DeAngelo Leukemia 2014; Stock Blood 2019). Here we update our multi-center Phase II study (06-254) applying the DFCI pediatric regimen to young adults, as well as our post-trial experience. The 06-254 protocol is based on the very high-risk arm of the DFCI Pediatric Protocol 05-001. This report focuses on Philadelphia negative (Ph-) pts. Methods: Pts between 18-50 years (yrs) with de novo ALL were eligible. The primary objective was to determine the feasibility of a single dose of pegylated-asparaginase (PEG-ASP) during induction followed by a 30 week PEG-ASP consolidation. Induction chemotherapy included doxorubicin, prednisone, vincristine, PEG-ASP, and intra-thecal chemotherapy (IT). Consolidation I consisted of high-dose methotrexate (A), followed by a BFM-like intensification (B), and a course of high-dose cytarabine, etoposide and dexamethasone (C). Central nervous system prophylaxis included intrathecal therapy and cranial radiation. Intensification therapy consisted of eight 3-week courses of doxorubicin, vincristine, dexamethasone, 6-MP and 30 weeks of PEG-ASP. Dosing of PEG-ASP was initially 2500 IU/m2 every 2 weeks but due to toxicity was reduced to 2000 IU/m2 every 3 weeks and given concomitantly with consolidation. Body surface area was capped at 2.3m2 for PEG-ASP dosing. Continuation therapy consisted of 3 week courses of vincristine, dexamethasone, methotrexate, and 6-MP until 2 yrs from complete remission (CR). Additional consecutive Ph- pts treated “as per” 06-254 (2009-2021) were identified; these pts received treatment following 06-254 including PEG-ASP 2000 IU/m2 every 3 weeks in consolidation. Median follow-up was calculated with the reverse Kaplan Meier indicator. The chi square test was used to compare categorical characteristics. Overall survival (OS) and event free survival (EFS) among groups were compared with the log rank test. Results: A total of 152 Ph- pts were treated from 2007 to 2021 (89 pts on protocol and 63 “as per”). Median follow up was 3.5 yrs for pts treated on protocol and 3.8 yrs for pts treated “as per.” Characteristics at diagnosis: Median age 27.9 yrs (82, 54% < 30 yrs); 39.5% female; 31.6% T-lineage; 53.3% overweight/obese BMI per CDC criteria. Older pts (30-50 yrs) were more likely to be overweight/obese than younger (18-29y) pts (71.4% vs. 37.8%, p < 0.001) and were more frequently allografted in CR1 (21.4% vs. 9.8%, p = 0.045). CR was achieved by 142 (92.1%) pts. Among 81 (53.3%) pts with known end-induction measurable residual disease (MRD) status, 68 (84.0%) were MRD negative. In total, 88 (57.9%) pts completed all protocol treatment, 9 (5.9%) had induction failure, 3 (2.0%) died during treatment, 13 (8.6%) relapsed during treatment, 16 (10.5%) exited the protocol for other reasons, and 22 (15.1%) were consolidated with bone marrow transplant (BMT) in CR1. Among the 95 patients who remained on protocol for at least 1 year, 73 (76.8%) had ≥ 26 wks of asparagine depletion. Regarding toxicity: 21 pts (13.8%) had clinical pancreatitis, 98 (64.5%) experienced grade 3-4 laboratory hepatotoxicity, and 20 (13.1%) had allergic reactions to ASP. OS of the entire cohort was 84.4% (95% CI 77.4-89.3) at 3 yrs and 75.8% (95% CI 67.0-82.6) at 5 yrs. Pts aged 18-29 yrs had superior 5-yr OS to those aged 30-50 yrs (82.4% [95% CI 69.4-90.2] vs. 67.1% [95% CI 53.3-77.7], p = 0.004), and pts with a BMI < 25 at diagnosis had superior 5-yr OS than those with BMI ≥ 25 (87.1% [95% CI 73.5-94.0] vs. 66.5% [95% CI 53.9-76.5], p = 0.002). Patients with negative MRD at end of induction had a 5-yr OS of 80.7% (95% CI 66.7-89.3) and those with positive MRD 59.1% (95% CI 21.8-83.4) (p = 0.16). Pts treated “as per” had superior 5-yr OS to those treated on protocol (86.0% [95% CI 71.3-93.5] vs. 68.7% [95% CI 56.5-78.1], p = 0.012). EFS was 77.1% (95% CI 69.0-83.3) at 3 yrs and 70.6% (95% CI 61.4-78.0) at 5 yrs. Pts aged 18-29 yrs had superior 5-yr EFS compared to those aged 30-50 yrs (76.3% [95% CI 63.0-85.3] vs. 62.8% [95% CI 48.8-74.0], p = 0.033). Treatment on trial (compared to “as per”), BMI, and MRD status were not statistically associated with EFS. Conclusions: The administration of a pediatric regimen with dose intensified PEG-ASP to population between 18-50 is feasible and results in a high remission rate with 5-yr OS 75.8%.

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