Real-World Outcomes and Adverse Events of Elderly Patients with Ph-Negative Acute Lymphoblastic Leukemia Treated with a Pediatric-Inspired Protocol

Poor outcomes in elderly patients with Acute Lymphoblastic Leukemia (ALL) result from the disease's adverse biology and poor tolerance to chemotherapy, leading to dose reductions, treatment delays, and high rates of early death and treatment-related mortality. Some reports indicate that pediatric-inspired chemotherapy protocols can be safely and efficiently used in older adults, resulting in improved median overall survival (mOS) ranging from 17 to 40 months. Despite such reports, front-line implementation of pediatric-inspired approaches to elderly patients with ALL remains a topic of discussion. Our goal is to estimate OS and define adverse events (AEs) in patients with ALL, aged > 60 years, and treated with a pediatric-inspired protocol.

Methods

All newly diagnosed patients aged > 60 years with Ph-negative ALL who received induction chemotherapy with a modified, asparaginase-intense, pediatric-inspired regimen between January 2002 and January 2022 were included. The treatment regimen consisted of induction, central nervous system prophylaxis, 7 cycles of intensification, and 24 cycles of maintenance. During these 20 years, we switched from native to pegylated E.coli asparaginase. Standard descriptive statistics were used to summarize patients’ demographics and outcomes of interest. 95% confidence intervals were provided where possible. Fisher's exact test was used to assess the impact of categorical covariates of interest on induction mortality. Using Fine-Gray methods, the Multivariable Cox proportional hazards regression model was used to determine the joint effect of potential factors for outcomes. P<0.05 was considered significant.

Results

A total of 76 patients were included. Patient and disease characteristics are presented in table 1. The median dose of Peg-asparaginase and L- asparaginase were 935 iu/m2 (477-1,111 iu/m2) and 5,944 iu/m2 (4,388-15,000 iu/m2) respectively. AEs rates found were severe pancreatitis 3.9%, thrombosis at any time during treatment 43.2%, hypofibrinogenemia <1g/L 30.6%, CTCAE grade IV transaminases, and total bilirubin 35.2%, and 17.3% respectively. The induction mortality rate was 12% (N=9) and the complete remission rate after induction (CR1) was achieved at 79% (n=60). Allogeneic hematopoietic stem cell transplantation in CR1 was carried out for 9.2% (N=7).

The median follow-up among survivors was 49.7 months (range: 9-155) and the mOS was 35.1 months (95%CI: >19.3) (figure 1). OS rate at 1 and 4 years was 73.6% (95%CI: 62 - 82) and 42.2% (95%CI: 29.3 - 54.6) respectively, with a cumulative incidence of relapse from the date of diagnosis at 12 months of 12% (95% CI: 5.8 - 20). Leukemia-free survival rate at 4 years was 42.4% (95% IC 30 - 53).

For the patients with early mortality, 5 patients had L-asparaginase, 3 patients had no asparaginase, and one Peg-asparaginase (11.11%). In contrast, in the no early mortality group, 46 (68.6%) patients received L-asparaginase, 2 (2.9%) patients had no asparaginase, and 19 (28.3%) patients received Peg-asparaginase (p=0.011). In univariate analysis, variables significantly associated with worse OS were: older age [<70 years old (n=46) median OS 70.8 months (95%CI >31.1) vs >70 years old (n=30)14.4 months (95%CI 9.2-54.2) (p=0.016)], higher WBC count [<11x10e9/L (n=54) median OS was 70 months (95%CI 27-NA), while in those with WBC >11x10e9/L (n=22) was 17.2 months (95%IC 6-31) (p= 0.004)], and no asparaginase given [OS at 12 months was: 85% (95%CI 60.4 -94.9) in patients treated with Peg-asparaginase; 72.4% (95%CI 57.9-82.6) in patients treated with L-asparaginase, and 40% (95%CI 5.2-75.3) in patients that did not receive asparaginase (p=0.0021). In multivariable analysis, younger age and lower WBC remained independent significant prognostic factors for increased OS [Patients <70 years old HR 2.67 (95% CI[1.38 - 5.17], p=0.0034) and patients with WBC <11x10e9/L HR 2.5 (95% CI [1.30- 4.82], p= 0.007)].

Conclusions

The use of a pediatric-inspired chemotherapy protocol is shown to be effective and well tolerated in patients with Ph-negative ALL aged >60 years. Although AE rates were not negligible, outcomes were excellent and, early mortality improved over prior reports (Marc Poch Martell et al, BJH 2013, early mortality 20%). Further research will be needed to understand how the outcomes could be improved further using newer targeted treatments.

Perusini:Pfizer: Consultancy. Gupta:Sierra Oncology: Consultancy; AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board; Roche: Other: Participation on a Data Safety or Advisory board; Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board. Schimmer:BMS: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; UHN: Patents & Royalties: the use of DNT cells to treat AML; Otsuka Pharmaceuticals: Consultancy, Honoraria; Medivir AB: Research Funding; Takeda Pharmaceuticals: Consultancy, Honoraria, Research Funding. Richard-Carpentier:BMS: Other: Advisory Board Participation; Taiho: Other: Advisory Board Participation; Astellas: Consultancy, Honoraria, Other: Advisory Board Participation; AbbVie: Consultancy, Honoraria, Other: Advisory Board Participation; Pfizer: Consultancy, Other: Advisory Board Participation. Kim:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Paladin: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Sanof: Consultancy, Honoraria. Yee:Takeda: Consultancy; Astex: Research Funding; Shattuck Labs: Consultancy; Pfizer: Consultancy; Janssen: Research Funding; Geron: Research Funding; Abbvie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Consultancy; F. Hoffmann La Roche: Consultancy, Research Funding; Treadwell: Research Funding; Jazz: Consultancy, Research Funding; Forma Therapeutics: Research Funding; Gilead: Research Funding; GlaxoSmithKline: Consultancy; Karyopharm: Research Funding; TaiHo: Consultancy; Astellas: Consultancy. Schuh:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Phebra: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceutical Industries: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.