Imatinib and Methotrexate Concurrent Use in Leukemia

Imatinib is a tyrosine kinase inhibitor mainly used in Chronic Myeloid Leukemia (CML), gastrointestinal tumors, Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL), Hypereosinophilic Syndrome etc. But the problem is its a expensive drug. Its available is Gleevec in USA. But the price in Bangladesh is comparetively lower. Acute lymphoblastic leukemia (ALL) is the most common cancer in children, with the Philadelphia (Ph) chromosome and BCR:ABL1 fusion gene being significant cytogenetic abnormalities. Due to increased ABL tyrosine kinase activity, tyrosine kinase inhibitors (TKIs) are used alongside chemotherapy in patients with Ph+ and ABL-class fusion-positive ALL.

High-dose methotrexate (HDMTX) is used in treating acute lymphoblastic leukemia (ALL) as it inhibits folic acid metabolism and DNA synthesis. However, it can cause serious side effects, including kidney failure, mucositis, and hepatotoxicity etc. Thus, minimizing prolonged exposure and avoiding factors that hinder its clearance is essential. Tyrosine kinase inhibitors (TKIs) may reduce methotrexate (MTX) clearance in Ph+ ALL patients resulting in fewer courses or reduced doses of MTX due to the delayed clearance and observed toxicity.

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This post is about an article review.

Title and Source

Higher incidence of delayed methotrexate clearance in pediatric acute lymphoblastic leukemia patients treated with imatinib.

It was published in the EJC: Paediatric Oncology, Volume 2, December 2023.

The objective of this study was to: To Compare the MTX clearance in pediatric Ph+/ABL-class fusion positive ALL patients concomitantly receiving HDMTX and imatinib with ALL patients only receiving HDMTX. In addition, toxicities including kidney failure, oral mucositis, and nausea are also described in the imatinib group.

It was a Retrospective observational case control study that took place in the six paediatric oncology centers in Netherlands.

Source

Inclusion and Exclusion Criteria

Newly diagnosed pediatric ALL patients treated between 2004 and 2022 in six pediatric oncology centers in the Netherlands. Patients with Ph+ ALL or ABL class fusion positive ALL patients treated with HD-MTX and Imatinib. 281 Controls were selected age matched patients with ph- ALL treated with HDMTX without imatinib from larger pool of 718 children.

Ph+ patients in the imatinib group were treated according to the EsPhALL2004, EsPhALL2010, EsPhALL2017/COGAALL1631 protocols and ABL-class fusion positive patients with the ALLTogether1 protocol. The control group was treated according to the DCOG ALL11 protocol (2012–2020).

Patients in EsPhALL2004 and EsPhALL2010 received a daily dosage of 300 mg/m2 imatinib and two courses of HDMTX (5 g/m2).

In the EsPhALL2017/COGAALL1631 study, the imatinib dosage increased to 340 mg/m2 and patients received two to four HDMTX courses (5g/m2). In the ALLTogether1 study patients with an ABL-class fusion received four courses of HDMTX (5 g/m2) and 340 mg/m2/day imatinib. Serum MTX concentrations for both the imatinib group and control group and were measured 48 h after the start of HDMTX administration (T48). Several MTX toxicities within two weeks after HDMTX administra­tion were recorded for the imatinib group. Serum bilirubin, aspartate transaminase (AST), alanine aminotransferase (ALT), creatinine, nausea, and oral mucositis were graded according to the CTCAE v5.0 criteria.

higher-incidence-of-delayed-methotrexate-clearance-1

WHO List of Essential Medicines & Drugs For Children [Updated 2023]

Key findings of this imatinib study

The study assessed the impact of imatinib on methotrexate (MTX) clearance in pediatric patients with Philadelphia chromosome-positive (Ph+) or ABL-class fusion-positive acute lymphoblastic leukemia (ALL). Imatinib, a tyrosine kinase inhibitor, was combined with high-dose MTX (HDMTX) chemotherapy to manage these leukemias. The researchers retrospectively analyzed 24 pediatric patients treated with imatinib alongside HDMTX and compared them to 281 age-matched Ph-negative ALL patients receiving HDMTX alone.

    1. Delayed MTX Clearance: Patients in the imatinib group had a significantly higher incidence of delayed MTX clearance compared to the control group (55.7% vs. 41.1%, p = 0.036). Severe delayed clearance was notably higher after the first HDMTX course (12.5% in the imatinib group vs. 2.3% in controls, p = 0.039)​
    2. Toxicity and Side Effects: Increased serum creatinine, indicative of nephrotoxicity, was observed in 8.3% of the imatinib group, leading to delayed MTX elimination (DME). Additionally, the imatinib group experienced higher rates of mucositis, nausea, and liver enzyme elevations (ALT and AST). Glucarpidase was administered in cases of severe delayed MTX clearance, more frequently in the imatinib group.
    3. Mechanisms and Implications: The study suggests that imatinib may interfere with MTX clearance mechanisms, potentially through inhibition of transport proteins like BCRP and SLCO1B1, leading to MTX accumulation. The researchers recommend stringent supportive care, including hyperhydration, alkalinization of urine, and folinic acid rescue to manage the risks. They also propose considering temporary discontinuation of imatinib or lower doses of MTX during subsequent courses for patients showing severe delayed clearance to prevent toxicities.

Imatinib increases the risk of delayed MTX clearance in Ph+ or ABL-class fusion positive pediatric ALL patients. Careful monitoring, dose adjustments, and enhanced supportive care are essential to mitigate this risk. This study underscores the need for tailored treatment strategies when combining TKIs like imatinib with MTX

Recommendations:

  • Supportive Care: Enhanced hyperhydration, adequate alkalinization, and folinic acid rescue.
  • For Severe Delayed MTX Clearance: Consider temporary discontinuation of imatinib during high-dose MTX courses. Alternatively, reduce the MTX dose.

Cross Reference Links:

  • Concurrent Imatinib Dosing With High-dose Methotrexate Leads to Acute Kidney Injury and Delayed Methotrexate Clearance in Pediatric Patients With Philadelphia Chromosome-positive B-Cell Acute Lymphoblastic Leukemia. Link
  • Delayed methotrexate clearance in patients with acute lymphoblastic leukemia concurrently receiving dasatinib. Link

Download The Article I have presented in PPT Format

Know more about Imatinib (Glivec) Cancer Research

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