Expanding Use of a Modified Pediatric Intensive Regimen for Acute Lymphoblastic Leukemia (ALL) into an Older Adult Population: Feasibility and Efficacy Results
Authors: Patel Anand Ashwin , Heng Joseph , Dworkin Emily , Monick Sarah , Derman Benjamin A , Gurbuxani Sandeep , Kosuri Satyajit , Liu Hongtao , Thirman Michael , Godley Lucy A. , Odenike Olatoyosi , Larson Richard A. , Stock Wendy 
Published: February 2021

Background:

The CALGB 10403 protocol (10403) is an intensive pediatric regimen that has demonstrated a median event-free survival (EFS) of 78.1 months and an estimated 3-year overall survival (OS) of 73% in adolescents and young adults (18-39 yrs) (AYA) with ALL (Stock et al, Blood 2019). The backbone of this regimen includes pegylated asparaginase (PEG-ASP) and steroids, both of which have significant toxicities that increase with age and co-morbidities including obesity. These toxicities have traditionally precluded extending pediatric-inspired regimens to older pts. We have previously demonstrated that adequate asparaginase activity levels and less toxicity were achieved with reduced PEG-ASP dosing (Derman et al, Leukemia & Lymphoma 2020). Therefore, we performed a single-institution retrospective analysis of AYAs and adults up to age 60 yrs with ALL treated using a modified 10403 regimen with reduced dose PEG-ASP and glucocorticoids to evaluate treatment response. Modifications to PEG-ASP/steroid dosing in patients on a reduced-dose (RD) regimen are summarized in Figure 1. We evaluated characteristics and outcomes of these patients (pts).

Methods:

Retrospective cohort analysis identified pts with ALL who received RD 10403. RD was defined as receiving ≤ 1000IU/m2 of PEG-ASP along with dexamethasone 10mg/m2 on Days 1-7 and Days 15-21 during induction. Dose reduction for PEG-ASP was made for all pts ≥ 50 years old, body mass index (BMI) ≥ 30, diabetes mellitus and/or underlying liver dysfunction (including cirrhosis, non-alcoholic fatty liver disease; liver chemistry cut-off was not used). In patients with severe metabolic syndromes steroids were further reduced to administration on days 1-7 alone. Patients with CD20+ disease received rituximab during Course I, II, and III. Survival curves (EFS and OS) were constructed using the Kaplan-Meier method and compared with the log-rank test.

Results:

30 consecutive pts with Ph negative B-cell or T-cell ALL and treated with RD from 8/2014-4/2019 were identified. Pt characteristics are outlined in Table 1. Median age in RD cohort was 46 years old. 53% of RD patients were identified as having high-risk disease (Ph-like ALL, MLL-rearranged, TP53-mutated, and/or early T-cell precursor (ETP) ALL). Median PEG-ASP dose during induction was 1000IU/m2 and 83% of patients achieved therapeutic asparaginase levels at Day 11 of induction (≥0.1IU/mL). 13 patients received 1000IU/m2, 12 patients received 500IU/m2, 4 patients received 250IU/m2, and 1 patient had PEG-ASP held during induction. Median total dexamethasone dose during induction was 140mg/m2; 22 patients received 140mg/m2, 7 received 70mg/m2, and 1 received 113mg/m2. At least one Grade 3+ toxicity was seen in 40% of patients during induction (hepatotoxicity in 8 pts, thrombosis in 4 patients, pancreatitis in 2 patients). Treatment related mortality (TRM) during induction was 3%; overall TRM attributable to 10403 was 10%. The morphologic complete remission (CR) rate was 77% (n=23) at 28 days. Measurable residual disease (MRD) was assessed by multicolor flow cytometry (sensitivity 10-4) and 18 patients (78% of all patients in a CR) achieved MRD-negativity by Day 28. 8 patients underwent allogeneic stem cell transplant (allo-SCT); 4 in first complete remission (3 with MLL-rearrangement and 1 with persistent MRD positivity) and 4 in a second complete remission (CR2) or later. Of the patients that did not go onto transplant, 6 have completed maintenance therapy per 10403 and 5 are still being treated per 10403. Median EFS of the entire cohort of patients was 54.5 months; estimated 3-year OS was 55% and estimated 3-year EFS was 54% (Figure 2A, 2B). For the 16 high-risk patients, the CR rate was 69% at 28 days and estimated 3-year OS was 61% (Figure 3).

Conclusions:

Our retrospective analysis demonstrates that a modified 10403 regimen with dose reduction of PEG-ASP and dexamethasone in older adults up to 60 years old or younger patients with comorbid conditions is feasible. We found that the RD 10403 regimen mitigates toxicity while still achieving high post-induction CR and MRD negativity rates. Our preliminary analysis demonstrates encouraging 3-year EFS and OS in this high-risk cohort. Prospective evaluation of RD 10403 for older adults can be recommended.

Disclosures

Gurbuxani: UpToDate: Honoraria. Liu:BMS: Research Funding; Agios: Honoraria, Other: Regional Advisory board meeting; Karyopharm: Research Funding. Thirman:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Syndax: Research Funding; TG Therapeutics: Research Funding; Tolero: Research Funding. Godley:Invitae, Inc.: Membership on an entity's Board of Directors or advisory committees; UptoDate, Inc.: Honoraria. Odenike:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Incyte: Other: Institutional research funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Larson:Novartis, Takeda, CVS/Caremark, Celgene, Amgen, Epizyme: Consultancy; Astellas, Celgene, Daiichi Sankyo, Novartis, Rafael Pharmaceuticals, Cellectis, Forty Seven: Research Funding. Stock:Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Research Funding; Novartis: Research Funding; Abbvie: Honoraria, Research Funding; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Honoraria; Research to Practice: Honoraria; American Society of Hematology: Honoraria.