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Treatment Name: Rituximab + High Dose Methotrexate

Rituximab + High Dose Methotrexate is a Chemotherapy Regimen for Lymphoma, Primary CNS (PCNSL)

How does high-dose methotrexate work?
Rituximab + high-dose methotrexate is designed to slow the growth of cancer and kills cancer cells by affecting the most rapidly dividing cells. Not all cancer cells will be actively dividing during each cycle of chemotherapy, therefore, several cycles are usually prescribed to increase the likelihood of killing all cancer cells.

Rituximab is an FDA approved antibody that is designed to target and bind to a protein on the surface of cancerous b-cells. When rituximab binds to this protein, it helps your immune system destroy the cancer cell.  Another name for this is immunotherapy.

Methotrexate is a chemotherapy drug that stops certain cells from using folic acid to make DNA, thus causing cell death.

Goals of therapy:
Rituximab + high-dose methotrexate is given to eliminate lymphoma cells from the central nervous system. Rituximab + high-dose methotrexate is commonly given with the goal of cure.


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  • Methotrexate intravenous (I.V.) infusion over 6 hours on Day 1
  • Leucovorin oral tablet or I.V. infusion over 15 minutes given every 6 hours starting 24 hours after the START of the methotrexate infusion (or 18 hours after the END of the methotrexate infusion)
  • Rituximab I.V. infusion on Day 8. The time of infusion varies.

Estimated total infusion time for this treatment:

  • The total infusion time for this treatment varies on day 1 depending upon the time it takes for the urine to reach the desired pH level. On Day 8, the infusion time depends upon tolerability of the rituximab infusion. The first rituximab infusion may take as long as 8 hours.
  • IV sodium bicarbonate is typically given on Day 1 to make the urine pH > 7. On average, this takes between 4 to 6 hours, but in some cases may take even longer. Once the urine pH is > 7, methotrexate infusion can be started. The sodium bicarbonate infusion continues until methotrexate has been eliminated.

High-dose methotrexate usually requires a 4 or 5 day stay in a hospital (or sometimes longer). Levels of methotrexate are monitored in the blood to ensure that it is being eliminated from your body. Patients usually go home once the level of methotrexate reaches a very low level in the blood. Sometimes a short course of leucovorin tablets may be taken at home after leaving the hospital.

Rituximab is usually given in an outpatient infusion center, allowing the person to go home afterwards.

Rituximab + high-dose methotrexate is repeated every 14 days. This is known as one cycle. Each cycle may be repeated up to 6 times, depending upon the stage of the disease. A maintenance regimen consisting of 4 additional doses of methotrexate may be prescribed. These additional doses are repeated every 28 days, rather than every 14 days. Duration of therapy may last up to 8 months, depending upon response, tolerability, and number of cycles prescribed

Click here for common starting doses.


How often is monitoring needed?
Labs (blood tests) may be checked before each treatment and daily after receiving methotrexate. Labs often include: Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), blood methotrexate levels, plus any others your doctor may order. Urine pH levels are often checked several times per day until methotrexate has been eliminated.

How often is imaging needed?
Imaging may be checked before treatment then periodically during treatment until stable. Imaging may include: magnetic resonance imaging (MRI) and computerized tomography (CT) scans.

How might blood test results/imaging affect treatment?
Depending upon the results, your doctor may advise to continue rituximab + high-dose methotrexate as planned, or delay or switch therapy. Although the liver function tests on a CMP (click CMP above) often increase shortly after methotrexate, they almost always return to normal within a few days and a rarely a sign of long-term liver damage. The blood Scr (serum creatinine) and CO2 (carbon dioxide) values (also from a CMP) will be used to adjust the methotrexate dose and sodium bicarbonate infusion according to an individual’s kidney function.

Questions to Ask Your...

A better understanding of your treatments will allow you to ask more questions of your healthcare team. We then hope that with the answers, you will get better results and have greater satisfaction with your care. Because we know it's not always easy to know what questions to ask, we've tried to make it easy for you!

Choose any healthcare provider below to see common questions that you may want to ask of this person. Then, either print each list to bring to your clinic visits, or copy the questions and send them as a message to your healthcare team through your electronic medical record.

ChemoExperts Tips

  • Patients usually urinate frequently (several times day and sometimes hourly) due to the large amount of sodium bicarbonate fluid administered. It is important to expect this as you will need to be close to a bathroom.
  • Premedications such as diphenhydramine (Benadryl®), acetaminophen (Tylenol®), and dexamethasone (Decadron®) may be given before rituximab to help avoid infusion related reactions
  • The first dose of rituximab is often the hardest. It may lead to fever, shaking, and chills even if medications are given beforehand to help prevent these side effects. Side effects generally go away when the rituximab is stopped. It may be restarted at a slower rate. Most patients are able to receive the entire dose, although it may take longer. In most cases, after the first dose, rituximab can be given over 90 minutes
  • The pH of your urine will need to be higher than normal to help eliminate methotrexate from the body. To raise the pH, a continuous intravenous sodium bicarbonate-containing solution is given. Other methods that may also be used are sodium bicarbonate tablets or a medication called acetazolamide. The pH of your urine will be checked multiple times per day to make sure methotrexate is being eliminated appropriately
  • In some instances, the antidote known as glucarpidase (Voraxaze®), may need to be given to help eliminate methotrexate from your body. This medication may be given if your body is not eliminating methotrexate fast enough due to impaired kidney function. It is recommended that high-dose methotrexate only be administered in healthcare institutions with emergency access to glucarpidase
  • Methotrexate can interact with many other drugs. A pharmacist should ALWAYS review your medication list to ensure that drug interactions are prevented or managed appropriately.
  • Clinical trials may exist for CNS lymphoma. Ask your doctor if any studies are currently enrolling in your area. If not, go to to search for other centers offering study medications

Patient Assistance & Co-payment Coverage

Patients under the age of 65 years, or those with private insurance plans:
If you have insurance and are looking for patient assistance or copay assistance for Rituximab + High Dose Methotrexate, we have provided links that may help.

Visit our Patient Assistance page and click the links to various patient assistance programs for help paying for Rituximab + High Dose Methotrexate. Depending upon your income, they may be able to help cover the cost of:

  • Rituximab
  • Methotrexate
  • Leucovorin

For Branded medications (may be available for generic medications too), check with the manufacturer to determine if a co-pay card is offered and if it could reduce your monthly copay.

  • If you are uninsured, check with the manufacturer to determine if you are eligible to receive medication at no cost.

Medicare and Medicaid patients (Patients 65 years or older):
The clinic providing treatment will likely pre-authorize medications and immune therapies such as Rituximab + High Dose Methotrexate and are the best source to help you understand drug cost.

  • Ask to speak with a patient assistance technician or financial counselor at the clinic or hospital administering this therapy.

Emotional Wellness

What is Emotional Wellness?
Emotional wellness is having a positive outlook balanced with a realistic understanding of current life events. This requires both an awareness and acceptance of your emotions. It is with this knowledge that you can develop a plan to take the necessary actions to positively impact your life.

Emotional wellness uses an ongoing process to continually reflect on the stressors of life in a constructive manner to move forward and create happiness.

Because emotional wellness is deeply connected with physical, social, and spiritual wellness, pursuing it often becomes particularly difficult in times of major illness. Despite this difficulty, working toward emotional wellness has been connected to improved treatment outcomes and a higher likelihood of achieving goals of therapy.

Learn more about pursuing emotional wellness while receiving treatment with Rituximab + High Dose Methotrexate

Individual Drug Label Information

Rituximab (Rituxan®, Truxima®, Ruxience®)

  • Rituximab is an intravenous infusion
  • Acetaminophen (Tylenol┬«) and antihistamines (e.g. diphenhydramine = Benadryl┬«) should be given prior to each dose
  • Patients should be screened for hepatitis B as rituximab can cause a re-activation of this infection
  • May cause vaccines to work less well for 6 - 12 months after the last dose of rituximab. It is advised that vaccines be given two to four weeks prior to rituximab if possible
General Rituximab Side Effects
  • May cause an infusion reaction, which could include skin reaction, shaking, chills, fever, or shortness of breath. These reactions may be severe, but are very rarely life-threatening Infusion reactions does not usually happen after the first dose, but are possible
  • May increase the risk of infection. Your doctor may prescribe antibiotics to prevent certain infections associated with rituximab use
  • Click on the rituximab package insert below for reported side effects and potential drug Interactions

Side Effect Videos
Fatigue Fatigue

See DailyMed package insert.

Methotrexate (Trexall®)

  • Methotrexate is an intravenous infusion and is bright yellow in color 
  • Methotrexate has the following FDA Black-Box Warnings. The risk of experiencing these side effects is much higher if methotrexate is not cleared from the body appropriately:  
    1. Low red blood cells, white blood cells, and platelets
    2. Kidney injury
    3. Liver injury
    4. Severe diarrhea
    5. Mouth ulcers
    6. Stomach ulcers
  • Dosage adjustments may be required for poor kidney function or poor liver function 
  • May cause severe skin reactions a few days after administration 
  • Is harmful to the fetus during pregnancy. If you are of childbearing age, use multiple forms of birth control 
  • May interact with non-steroidal inflammatory drugs (NSAIDs), aspirin, proton-pump inhibitors, phenytoin, and sulfa or penicillin antibiotics. These drugs should NOT be used the day before or the day of therapy with methotrexate. 
  • Ask your doctor or pharmacist to review your medications prior to receiving methotrexate 
  • Click on the methotrexate package insert below for reported side effects and possible drug interactions

Side Effect Videos
Nausea and VomitingNausea and VomitingDiarrheaDiarrheaHair LossHair LossFatigue Fatigue PainPainAnemiaAnemiaNeutropenic FeverNeutropenic Fever

See DailyMed package insert.

Leucovorin (Folinic acid)

  • Leucovorin is an intravenous (I.V.) drug that is a derivative of folic acid, also known as vitamin B9
  • Is clear to slightly yellow in color 
General Leucovorin (Folinic Acid) Side Effects 
  • Seizures and fainting have been rarely reported 
  • Click on the leucovorin (Folinic Acid) package insert below for reported side effects and possible drug interactions
See DailyMed package insert.

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1) Chamberlain MC and Johnston SK. High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma. Neuro-Oncology. 2010;12:736-744.

2) Howard SC, McCormick J, Pui CH, et al. Preventing and Managing Toxicities of High-Dose Methotrexate. Oncologist. 2016 Aug 5. [Epub ahead of print]

Created: March 15, 2016 Updated: October 3, 2018

What is Lymphoma, Primary CNS (PCNSL)?

A rare disease of the white blood cells known as B-lymphocytes which are normally found in lymph nodes, blood, and throughout the body. Primary CNS lymphoma occurs when lymphoma cells form in the tissue in the brain, eye, or spinal cord and is not present anywhere else in the body.

Known causes of primary CNS lymphoma include infections such as HIV and Epstein-Barr, while some causes are still unknown. The effectiveness of the treatment may depend upon the stage and extent of the disease at diagnosis and if an HIV infection is also present.

NOTE: Treatment Options listed below are not all-inclusive. Other treatments may be available. ChemoExperts provides drug information and does not recommend any one treatment over another. Only your Doctor can choose which therapy is appropriate for you.

What does "Cure" mean?

The word “cure” means there are no cancer cells left in the body and cancer will never come back. Depending on the cancer type and stage, this may be the true goal of therapy. However, it is very difficult to prove all cancer cells are gone. Even though images, like X-rays and MRI’s, and blood tests may not show any signs of cancer, there can be a small amount of cancer cells still left in the body. Because of this, doctors use the word “remission” is used more often. This means there are no signs or symptoms of cancer.

Patients in remission are followed closely for any signs of cancer returning. Sometimes, more chemotherapy may be given while in remission to prevent the cancer from coming back. Doctors usually do not consider a patient “cured” until the chance of cancer returning is extremely low. If cancer does return, it usually happens within 5 years of having a remission. Because of this, doctors do not consider a patient cured unless the cancer has not come back within 5 years of remission. The five-year cutoff does not apply to all cancers.

Common Starting Doses

  • Methotrexate dose can range between 4000 - 8000 mg/m2 I.V. infusion over 6 hours on Day 1
    • 4000 mg/m2 if CrCl < 60 mL/min
    • 8000 mg/m2 if CrCl > 60 mL/min
  • Leucovorin 15 or 25 mg oral tablet [or I.V. infusion] over 15 minutes given every 6 hours starting 24 hours after methotrexate
  • Rituximab 375 mg/m2 intravenous (I.V.) infusion on Day 8

What is "Leucovorin"?

Leucovorin is NOT a chemotherapy agent. It is a special form of folic acid that helps decrease side effects from methotrexate. Doses may need to be increased during therapy depending on the amount of methotrexate in the blood.

What is a CBC?

A Complete Blood Count (CBC) is a frequently ordered blood test that tells clinicians the status of your: 1) White blood cell count, 2) Hemoglobin, and 3) Platelet count at the time the test was taken.

Common uses:
1) White blood cell count (WBC): is used to determine infection risk, or response to chemotherapy. Certain chemotherapy agents may harm our good infection-fighting cells. Sometimes chemotherapy may need to be delayed to allow these cells to recover.

2) Hemoglobin: is used to determine if someone is anemic. Anytime the hemoglobin is below 12 g/dL, the person is said to be anemic. Red blood cell transfusions, and sometimes iron can be given to restore the hemoglobin level, but anemia treatment should always aim at treating the underlying cause or condition.

3) Platelet count: is used to determine if the risk of bleeding is increased or if a platelet transfusion is required to prevent bleeding. Certain medications that increase bleeding risk, such as: aspirin, certain chemotherapy agents, and blood thinners, may need to be stopped temporarily until the platelet count is within a safe range.

What is a CMP?

A Comprehensive Metabolic Panel (CMP) is a frequently ordered blood test that tells clinicians the status of your: 1) Electrolytes & Acid/Base status2) Kidney function, 3) Liver function, 4) Blood sugar, and 5) Calcium at the time the test was taken. It is commonly used to monitor liver and kidney function when beginning new medications such as chemotherapy. A total of 14 tests are run simultaneously and are shown below.

Electrolytes & Acid/Base status:
1) Sodium, 2) Potassium, 3) Carbon dioxide, 4) Chloride

Kidney Function:
5) BUN (blood urea nitrogen), 6) Serum creatinine (Scr)

Liver Function:
7) AST, 8) ALT, 9) Total bilirubin, 10) Alk Phos, 11) Albumin, 12) Total protein

Blood sugar:
13) Serum glucose

14) Serum calcium