Feasibility and Outcome of Late Intensification with Native L-Asparaginase for Acute Lymphoblastic Leukemia in the Elderly: A Single Center Experience

Background: The prognosis of Philadelphia-negative Acute Lymphoblastic Leukemia (Ph-neg ALL) in patients over 55 years of age is dismal. The European Working Group for Adult ALL (EWALL) backbone, adapted for elderly patients, reported a poor 3 year overall survival (3y-OS) of about 24% due to high relapse rates. Many attempts to improve this outcome have failed due to increased toxicity. In a report, the French Group for Research on Adult ALL (GRAALL) considered that adjunction of L-Asparaginase (L-Asp) seemed too toxic to be recommended during induction chemotherapy in older patients. The GRAALL-SA2 study recently showed no advantage to the adjunction of erythrocytes encapsulated L-Asp to the EWALL backbone. The question of whether L-Asp could be included in a more intensive consolidation regimen has not been addressed so far.

Methods: Since 2012, patients > 60-years-old with Ph-neg ALL were treated in our center according to the EWALL first induction backbone. Patients achieving complete response (CR) were eligible to receive a pediatric-inspired consolidation phase designed for younger patients. After two consolidations courses, patients received late intensification phase (with 6 intravenous infusions of native L-Asparaginase 6000 UI/m² at Days 8, 10, 12, 20, 22 and 24) according to the GRAALL-2005 (previously published, Huguet et al. 2009). Antithrombin (AT) and fibrinogen levels were monitored prospectively on alternate days. No other coagulation factor was systematically evaluated. Fresh frozen plasma was recommended if fibrinogen levels were below 0.5 g/L, platelet transfusion support was recommended for platelets levels below 20 x 10⁹/L and AT concentrate substitution therapy (Aclotine 25 U/kg) was recommended to maintain AT levels above 60%. AT levels were re-evaluated the days following AT infusion. L-ASP was administrated after correcting the acquired deficiency in AT. Unfractionated heparin at 100 UI/kg/day in continuous infusion or low molecular weight heparin at prophylactic doses in subcutaneous injection was also used. Broad-spectrum antibiotics were administered in case of fever and prophylactic antifungal prophylaxis using micafungin was provided with a daily dose of 50 mg, from the start to the end of neutropenic period (ANC ≤ 0.5×10⁹/L). Toxicity and outcomes were retrospectively analyzed.

Results: Twenty-four patients were included in this study between 2012 and 2016 in our single center. Median age was 67 [IQR: 64-71]. Nineteen patients (79%) had B-phenotype ALL. Four (13%) patients had adverse cytogenetics, three (13%) had hyperleukocytosis, none had CNS involvement. Twenty nine percent of patients had a Charlson Comorbidity Index > 1. Nineteen (79%) patients were in CR and all received a pediatric-inspired consolidation. One patient (4%) died during induction and 4 (17%) were alive with primary refractory disease. After two consolidation courses, 16/19 of CR patients were eligible for late intensification (two relapses and one renal failure). During late intensification, the median duration with neutrophils < 0.5 X 10⁹/L was 8 days [IQR: 4-14]. A platelet unit transfusion was necessary on 3/16 patients. Infection was diagnosed in 3/16 patients. Eighty-one percent of patients eligible to late intensification received over 80% of the scheduled dose of L-ASP. A patient was switched to Erwinia chrysanthemi L-Asp (Erwiniase 12,000 UI/m²/IV) due to suspected allergic reaction and 2 patients stopped because of grade 4 elevated bilirubin. The rates of grade 3-4 cytolysis, cholestasis and elevated bilirubin were respectively 38%, 25% and 13%. No elevation of amylase or lipase was noticed. No thrombo-embolic event and no grade 3-4 renal, cardiac or neurological event was reported. The median AT nadir was 46% [IQR 42-53]. The median dose of AT substitution for the patients who underwent late intensification was 166 UI/kg [IQR: 135-243]. No patient needed insulin therapy. No death was observed during late intensification. With a median follow up of 2.6 years, the 2y-EFS and 2y-OS were 54% and 55% respectively, highlighting a marked improvement compared to historical controls.

Summary/conclusion: Late intensification with high dose of L-ASP according to GRAALL-2005 pediatric-inspired protocol for ALL in the elderly is feasible and well tolerated in this population with an unmet medical need.