Increased incidence of delayed methotrexate elimination in pediatric patients with Philadelphia-chromosome positive (Ph+) or ABL-class fusion positive (ABL-Class) acute lymphoblastic leukemia treated with imatinib: Results of a retrospective cohort study by the italian association of pediatric hematology-oncology (AIEOP)

Abstract

Abstract Background: High-dose methotrexate (HDMTX) is a key component of the treatment of pediatric acute lymphoblastic leukemia (ALL). Though generally well tolerated, HDMTX can be associated with delayed methotrexate elimination (DME) and several additional toxicities, primarily acute kidney injury (AKI). Previous studies on limited case series suggested that the concomitant administration of tyrosine kinase inhibitors (TKIs) during HDMTX may result in an increased risk of DME and HDMTX-related toxicities (van der Sluis I., 2023; Pommert L., 2021; Ramsey LB., 2019; Loue C.,2015). However, currently available data do not allow fo firm conclusions to be drawn in this regard. Methods: A national retrospective multicenter cohort study comparing the incidence of DME and HDMTX-related toxicities was conducted in patients (pts) aged <18 years with de novo ALL diagnosis. One cohort included Ph+/ABL-class ALL pts who received imatinib (340 mg/m²/day) during HDMTX (IMA+ cohort) in 13 AIEOP centers between Jan 2017 and Dec 2024, whilst the other included consecutive Ph-negative (Ph–) ALL pts treated without TKI (IMA– cohort) in the Monza AIEOP center between Jan 2020 and Dec 2021. Ph+/ABL-class pts were treated according to the EsPhALL2017/COG AALL1631 protocol (NCT03007147): standard risk pts randomized to Arm B received 4 HDMTX courses (5 g/m² in 24h) (Interim Maintenance HDMTX); all other pts received 2 HDMTX courses as part of Blocks 1 and 2. Ph- ALL pts were treated according to the AIEOP-BFM ALL 2017 protocol (NCT03643276): standard and medium risk pts received 4 HDMTX courses (Protocol M), whereas high-risk pts received 2 HDMTX courses as part of the high-risk blocks (HR1 and HR2). The two protocols had very similar supportive care guidelines for the management of HDMTX: hyperhydration (3000 ml/m²/day) with sodium bicarbonate (100 mEq/m²/day) and folinic acid administration (7.5 mg/m²/dose IV levo-product) at fixed time points (42h, 48h, and 54h post-infusion). Based on serum MTX levels measured at the time points (T24, T42, T48h post-infusion), hyperhydration and folinic acid rescue could be modified by protocol. DME was defined as MTX>120μM T24, >1μM T42 or >0.4μM T48 and categorized as mild DME (1μM<T42≤5μM; 0.4μM<T48≤2μM), moderate DME (5μM<T42≤10μM; 2μM<T48≤5μM) and severe DME (T42>10μM; T48>5μM). AKI was defined as an increase in serum creatinine ≥1.5x baseline value or ≥0.3 mg/dl after HDMTX and was graded according to KDIGO criteria. Non-renal toxicities were graded using CTCAE version 5.0. Results: Fifty-five IMA+ pts and 93 IMA- pts received 144 and 301 HDMTX cycles, respectively.Considering all HDMTX cycles combined, a mild to severe DME was more frequently observed in the IMA+ cohort compared to the IMA- cohort (at T42: 25.7% vs 13.3%, p=0.004; at T48: 41.6% vs 26.2%, p=0.0018). Moderate to severe DME was seen in 6.2% vs 1.7% (p=0.027) and in 8.3% vs 3.6% (p=0.047) for the IMA+ and IMA- cohort, at T42 and T48, respectively. After the first HDMTX course, mild to severe DME at T48 was observed in 49.1% of IMA+ vs 35.5% of IMA– pts (p=0.2). AKI was found in 11.8% of the HDMTX courses in the IMA+ cohort vs 9.9% in the IMA- cohort. Glucarpidase was administered in 3 pts in the IMA+ (5.4%) and in 2 in the IMA- cohort (3.2%). Grade 3-4 hematological toxicity occurred more often in the IMA+ compared to the IMA- cohort (IM HDMTX vs Protocol M, 65.4% vs 14%, p<0.0001; Block 1-2 vs HR1-HR2, 83.6% vs 27.9%, p<0.0001). Rates of grade ≥3 AST/ALT increase, mucositis and infections did not differ significantly between the two cohorts. In the IMA+ group, imatinib was temporarily discontinued after HDMTX in 20/55 pts (36%) across 26 courses (18%) for a median of 6.5 days (range 1–34). Due to prior DME, Imatinib was held in subsequent cycles in 2 pts, and HDMTX was administered at a decreased dose in subsequent cycles in 11 pts (20%). Conclusions: This is the largest currently available study reporting the clinical and pharmacological effects of imatinib given during HDMTX. Our findings suggest that the concurrent administration of imatinib during HDMTX is associated with an increased rate of mild to severe DME but does not significantly increase the incidence of typical HDMTX-related toxicities. Further prospective studies are needed to determine whether a short discontinuation of imatinib during HDMTX may contribute to a safer HDMTX administration without jeopardizing the antileukemia effects in pts with Ph+/ABL-class ALL.