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Where Has All the Methotrexate Gone


When parents are told their child has a form of cancer called acute lymphoblastic leukemia (ALL), but that it can be treated and cured with therapy that involves injections of preservative-free methotrexate, families can feel some relief and hope. But when they are told this life-saving drug is running out, their hope can turn to panic.

Children with ALL need preservative-free methotrexate

Acute lymphoblastic leukemia, also known as acute lymphocytic leukemia or acute lymphoid leukemia, is the most common leukemia in children. Approximately 4,000 new cases of ALL are diagnosed in the United States each year, according to the National Marrow Donor Program. Two-thirds of those cases involve children, and the majority of children with ALL are younger than age 10.

ALL progresses rapidly, and so prompt treatment is critical. That’s where the chemotherapy drug methotrexate comes in, and it can be a life-saver: the overall survival rate after chemotherapy is nearly 80%. Here’s why methotrexate is so important.

The bone marrow produces unformed cells called blasts that are supposed to develop into white blood cells called lymphocytes, which fight infections. In people who have acute lymphoblastic leukemia, however, the blasts are abnormal and do not develop into lymphocytes.

This means leukemia cells have an opportunity to grow and spread quickly, crowding out not only lymphocytes but also red blood cells and platelets the body needs to function properly. The disease typically spreads to the lining of the brain and spine, but treatment with large doses of methotrexate, injected directly into the spinal fluid, can prevent this, because it slows the growth of cancer cells.

Not just any methotrexate will do, however: it must be preservative-free because the preservative can cause paralysis when it is injected into the spinal column.

The problem now is that the five pharmaceutical companies that make the injectable preservative-free methotrexate have either slowed or ceased production of the drug, according to the Food and Drug Administration. One of the largest producers of the drug, Ben Venue Laboratories (Bedford Labs), voluntarily ceased production in November 2011 because of concerns over quality and production.

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This manufacturing shut-down, along with production delays or higher than anticipated demand at the other companies (APP, Hospira Inc., Mylan Institutional, Sandoz), have placed parents of children with ALL as well as hospitals and physicians on alert.

The longer this shortage continues, the greater the number of children who will be at risk of not receiving the chemotherapy drug they need to help them stay alive. In an ABC News report, Dr. Michael Link, who is a pediatric oncologist and also president of the American Society of Clinical Oncology, noted that some hospital pharmacies have only enough preservative-free methotrexate for a few weeks.

Other treatments for ALL
All patients who have ALL receive some form of chemotherapy as part of their treatment program. Chemotherapy may be divided into three stages:

  • Induction chemotherapy is the first stage, and it is designed to reduce the number of cancer cells
  • Consolidation chemotherapy enhances the effect of induction treatment, with the goal of reaching complete remission
  • Maintenance chemotherapy may be administered to prevent cancer relapse

In some cases, children receive radiation therapy to the brain if they have signs the disease has spread to the brain and spinal cord or if they are at high risk of this occurring. A bone marrow or cord blood transplant is usually reserved for patients who have the least chance of achieving remission with chemotherapy alone.

Methotrexate and rheumatoid arthritis
Methotrexate is also used to treat rheumatoid arthritis. For this disease, it can be taken either by mouth or by injection. Methotrexate is considered to be a disease-modifying antirheumatic drug (DMARD), as it helps reduce inflammation caused by rheumatoid arthritis and also helps slow progression of the disease.

The two main issues concerning oral or injectable methotrexate for rheumatoid arthritis patients are convenience and effectiveness. A January 2008 study found methotrexate injections were significantly more effective than the oral form of the drug when given at the same dosage. However, some patients prefer taking weekly oral doses rather than getting an injection once a week.

It is uncertain how long the methotrexate shortage will last or what the final impact will be on ALL patients. Parents need to discuss their questions and concerns with their physician so the best course of action can be taken.

ABC News report
Braun et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis. Arthritis & Rheumatism 2008 Jan; 58(1): 73-81
Food and Drug Administration
National Marrow Donor Program

Image: Courtesy Wikimedia Commons/National Cancer Institute



My 6 year old daughter is undergoing treatment for ALL Leukemia. The day we received the diagnosis was the worst day of our lives. We took comfort on the excellent prognosis despite the very harsh and intense treatment that our sweetheart would have to endure. When I read this report yesterday on the NYT I had immediate flashbacks to the same feelings of despair and frustration but this time it was not due to an unfortunate act of nature but to human mismanagement, lack of planning and misplaced priorities. Please, please, help spread the word around of this crisis. I cannot bear the though of loosing my girl because of this. My girl and hundreds of ALL children are at very serious risk of relapse and potential death.
My best wishes to your daughter for a full recovery and good health. Hopefully the wide news coverage this drug shortage is getting will trigger more efforts by drugs companies as well as individuals who have the capacity to turn this situation around quickly.
I feel your pain :( My daughter which is an ALL relapse patient at the moment is also facing this crisis...I do NOT understand how our country can or would let this happen. It breaks my heart. Our voices need to be heard! This problem started several years back and should've been addressed then! Prayers for your daughter, mine, and every other child fighting. ~hugs~
Do you know if the shortage will become world wide?
No, I do not know. That is a good question, although there are efforts to obtain the drug from foreign sources, so that seems to indicate the drug is available elsewhere.
Does my childs life not matter to anyone but me? How could these companies do this. She has fought the fight and now something like this could hurt her chances to get "cured"? How could they do this?????? I am so upset, she is scheduled for a spinal with Methotrexate next week, are they going to have enough to give her? She takes these pills once a week, will they run out? I am at a lose for words, my heart is aching for my little miracle.
I am appalled that my great niece, who suffers with T-Cell Lymphoma may not be able to recieve the drugs that she has been recieving because the pharmacies may not be able to provide them due to the lack of the drug. This should not be happening and makes me wonder why it isn't going to be available. No one should suffer due to the lack of a medication. It makes me wonder if there really is a shortage of the medication or possibly another ploy by a large conglomate that wants to get richer off the suffering of others. Not like it hasn't happened before. I pray to God that this is not the case. Please remedy this situation before the drug is not available.
The preservative free form is used in a disease called HLH. My daughter had this disease and required methotrexate to be injected into her spinal fluid because her disease was attacking her brain causing seizures. HLH is an autoimmune/blood disease of the lymphocytes and macrophages that kick start the immune system into hyperactivity causing death within 2 months if not treated. Intrathecal methotrexate is a huge part of treatment for children with HLH. My daughter would have died without it because the disease was progressing so rapidly in her central nervous system. To be told that my daughter could not receive that, as many parents and doctors are going to be told, I cannot believe the pharmaceutical companies and their ever growing greed.
I'm hearing some indication that supplies of methotrexate may be available as soon as mid-February (right about now), with more coming in March. Does anyone know specific quantities and if these new shipments will be enough to alleviate the current shortfall? Specifically, the FDA reportedly issued a statement that the production issues at Ben Venue were fixed, and they are producing again. I'd like to see some reporting on the "next steps" and/or pinning pharmaceutical execs down on specific issues and reasons for their apparent lack concern on this topic.