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Specific elevated levels of methotrexate may lead to significant increases in severe complications for lymphoma patients.

High-dose methotrexate, defined as doses 500 mg/m² or higher, is an important component of lymphoma therapy, but may cause significant toxicity typically associated with elevated levels of the drug. Serum methotrexate monitoring at 48 hours is the standard approach to identify those at increased risk of developing toxicity.

A recent retrospective review of electronic medical records at the Mayo Clinic, published in , was used to characterize the incidence of acute kidney injury (AKI), intensive care unit (ICU) admission, length of hospital stays, and 30-day mortality across 48-hour methotrexate levels.

In the following interview, Nelson Leung, MD, of the Mayo Clinic in Rochester, Minnesota, discusses the levels of methotrexate that may alert clinicians to complications and to initiate measures to reduce methotrexate levels.

What does the study add to the literature?

Leung: We have known for a long time that methotrexate at supratherapeutic levels can lead to toxicities. At what level do we see complications? We consider toxicity at about 0.1 micromol/L after 48 hours. We wanted to find out at what level we started to see significant complications.

We included 642 lymphoma patients who had received high-dose methotrexate. Some patients had received multiple cycles and developed complications in only one cycle. After 48 hours we looked for complications -- most commonly AKI, prolonged hospital stay, ICU admission, and death.

We found that methotrexate levels of more than 1.28 micromol/L at 48 hours significantly increased AKI, ICU admission, prolonged length of hospital stay, and 30-day mortality. We now have solid numbers to suggest when certain interventions may be necessary. This is a single-center study that shows cutoffs can be derived from hospital data.

At higher levels of 5 micromol/L and above we see severe complications, such as a tremendous increase in hospital stays and ICU stays. We need to determine when to use glucarpidase [Voraxaze], which is an antidote for methotrexate, but that is very costly. If we know at which point complications and hospital stays increase, we can establish a benchmark to show at which point methotrexate is cost effective and justify when a possible intervention is necessary because of severe complications.

Were there surprises in the data?

Leung: We were surprised that the results were so linear and that at certain cut points we can predict significant increases in complications. The other surprise was the unpredictability of when patients developed supratherapeutic levels of methotrexate.

Patients with multiple cycles of high-dose methotrexate might develop a supratherapeutic level in one cycle, but not the rest of their cycles. About 50% of patients had supratherapeutic levels in cycle 2, but not in cycle 1, even though we used the same formula for cycle 2. I expect this is experienced at other centers as well.

What is the importance of your definition of the threshold at which acute kidney injury grade 2 or higher increases?

Leung: Besides methotrexate level, AKI stage 2 is also associated with increased hospital stays and an increase in 30-day mortality. If patients develop AKI stage 2 and above, it's likely that more complications are coming.

What further evidence do you provide that obesity is a risk factor for elevated methotrexate levels?

Leung: Our analysis showed that obesity was a risk factor associated with supratherapeutic levels of methotrexate. But we are not sure how obesity causes supratherapeutic levels yet. One hypothesis is based on how kidney function is calculated. The current formula uses body weight adjusted to an ideal body weight. Obesity may alter true kidney function. We plan to investigate different formulas to calculate kidney function to see whether that provides different doses for obese patients.

What is the next step in this research?

Leung: We need to drill down the risk factors for supratherapeutic levels and also begin a multicenter trial to confirm our findings. We have plans for a multicenter study through the American Society of Onconephrology to guide the practice of interventions based on post-48-hour methotrexate levels.

It will be interesting to see whether the cutoffs we established are the same at other hospitals. Each hospital may have a different cutoff based on experience and number of patients seen on high-dose methotrexate. Our findings need to be confirmed to establish a basis for cutoffs that can be derived and used to help determine interventions.

What message would you give to practicing oncologists?

Leung: Even without confirmation from a multicenter study, we have established levels at which risks of complications increase significantly with high-dose methotrexate.

Oncologists treating lymphoma patients need to know that complications are more common at certain methotrexate levels and they should consider using additional interventions to reduce methotrexate levels. For example, if a patient has intact kidney function, use urine alkalinization and forced diuresis. If levels are greater than 5 micromol/L, a drug that metabolizes methotrexate, such as glucarpidase, may be needed.

Read the study here and expert commentary about it here.