What Is Mitomisin, How Is It Used, and What Are Its Side Effects?

What Is Mitomisin?

Mitomisin, derived from Streptomyces caespitosus, a type of soil fungus, is an antibiotic chemotherapy drug with anti-tumor properties. Mitomisin produces DNA crosslinks to suppress DNA synthesis and ultimately stops cell proliferation, causing cell death; it is classified as an alkylating chemotherapy. In general, cancer cells are more susceptible to this damage because they divide faster and with less error correction than healthy cells. This cellular damage slows or stops the growth of cancer cells in your body.

Both “mitomisin” and “mitomisin-c” are used as active-ingredient names for this drug. It received its first Ministry of Health authorization in Türkiye in 2012; it is available as intravenous chemotherapy under the package names MITOMYCIN-C KYOWA and MİSİNTU. A gel formulation is also available in the US under the name Jelmyto.

Jelmyto, a UroGen product, was approved by the FDA (US Food and Drug Administration) on 15 April 2020 as first-line treatment for low-grade upper urinary tract cancer. Jelmyto is a drug administered as a gel into the bladder and urinary tract. This landmark approval is based on positive results from the phase 3 OLYMPUS clinical trial showing that Jelmyto provides an effective, kidney-sparing option for patients with this rare and difficult-to-treat cancer.

Jelmyto consists of a sterile hydrogel administered into the bladder and is designed to expose urinary tract tissue to mitomisin for longer, thereby allowing tumors to be treated without surgery.

Low-grade upper tract urothelial cancer is a rare type of cancer that can arise in the upper urinary tract, the ureters and the collecting system of the kidneys (the urinary tract outside the bladder and kidneys). Approximately 6,000 – 7,000 new or recurrent cases of low-grade upper tract urothelial cancer are diagnosed each year in the US; there are no cancer statistics specific to these urinary tract sites for Türkiye.

In this cancer, which is difficult to treat because of the complex anatomy of the urinary tract, the current standard of care involves many operations. Most patients also need a radical nephroureterectomy, which involves removal of the renal pelvis (the kidney collecting system), the ureter (the ducts between the kidney and bladder), and the bladder cuff.

Unfortunately, treatment is further complicated because this cancer is most often diagnosed in patients aged 70 and older. These patients may already have impaired kidney function and may experience further complications as a result of major surgery.

Jelmyto offers a new nonsurgical treatment approach for patients who might otherwise require radical nephroureterectomy, which is associated with reduced kidney function and other complications. This new minimally invasive, kidney-sparing treatment has the potential to change the treatment of low-grade upper tract urothelial cancer and help patients avoid the long-term complications associated with surgery and loss of a kidney.

There has been very little progress in the treatment of low-grade upper tract urothelial cancer for more than a decade, and this new option establishes a new standard of care for patients who often face recurrences and major operations involving kidney removal.

Breakthrough Treatment – Findings of the OLYMPUS Study

FDA approval is based on the results of the phase III OLYMPUS clinical study showing that Jelmyto provided clinically meaningful treatment of the disease in adult patients with upper tract urothelial cancer.

The study findings are detailed below;

• The complete response rate was 58% in the subgroup of patients considered to have surgically unresectable disease at diagnosis.
• At the 12-month assessment of durability, 19 patients maintained a complete response, 7 had recurrent disease, and 9 continued to be followed during the 12-month response period.
• The most commonly reported (≥20) side effects were ureteric obstruction, flank pain, urinary tract infection, hematuria, kidney dysfunction, fatigue, nausea, abdominal pain, dysuria (painful urination), and vomiting. Most of these side effects were mild to moderate and could be managed using well-known treatments. There were no treatment-related deaths.

The study included 74 clinical patients from the US and Israel. Participants treated with a 6-week course of Jelmyto administered through a standard catheter placed in the urinary tract were assessed for complete response, the primary endpoint of the study, 4 to 6 weeks after their last treatment. This assessment included ureteroscopy and washing cytology, a standard microscopic test of cells obtained from urine to detect cancer. Patients who achieved a complete response were then followed for up to 12 months to determine the durability of their response to Jelmyto.

The drug is a gel formulation administered by a urologist directly into a nephrostomy tube or urinary catheter. This blue drug may turn your urine blue-green. This is expected and may last a day or two after each dose. If you also have other urinary symptoms, such as frequent or painful urination, contact your healthcare team.

How Is Intravenous Mitomisin Chemotherapy Used?

Mitomisin available in Türkiye is given by intravenous (IV, into a vein) infusion. The dose and schedule are determined by the person’s height and weight, cancer type, and method of administration.

• Related topic: What is extravasation? What should be done if a cancer drug leaks under the skin?

Mitomisin is a vesicant drug, and great care must be taken regarding the risk of extravasation (leakage outside the vein) during intravenous administration. Even when administered carefully and correctly by trained personnel, it may cause burning and pain. There is a risk that the drug may leak from the vein at the injection site, causing potentially serious tissue damage. If redness, swelling, or pain develops at the injection site at any time during or after injection, inform healthcare staff immediately. Do not apply anything to the area unless instructed by healthcare staff.

Chemotherapies are listed below according to their vesicant potential:

What Is the Dose of IV Mitomisin?

The recommended dose range for mitomisin is 4-10 mg (0.06- 0.15 mg/kg), administered in combination with other drugs or at 1-6 week intervals depending on bone marrow recovery.

The general dosing schedule in combination treatment is 10 mg /m2 of body surface area, with the dose repeated as needed. Adequate responses have been achieved with doses of 40-80 mg (0.58- 1.2 mg/kg), either alone or in combination treatment. A higher-dose regimen of 2 mg/ kg as the total cumulative dose may also be administered alone or in combination.

Some of the Most Common Side Effects of IV Mitomisin

Infection and a Low White Blood Cell Count (Leukopenia or Neutropenia)

The drug can cause life-threatening infections, whether or not the white blood cell count is reduced. White blood cells (WBCs) are important for fighting infection. WBC counts may fall during treatment, increasing the risk of infection. If you have a high temperature (over 38 °C), a sore throat or a cold, shortness of breath, a cough, burning during urination, or pain that does not go away, consult a specialist immediately.

Recommendations for Preventing Infection

• Handwashing by both the person taking the drug and their visitors is the best way to prevent the spread of infection.
• Avoiding large crowds and people who are ill is also very important during this period (for example, those who have a cold, fever, or cough, or are experiencing these symptoms).
• Wear protective clothing, including long trousers and gloves, when working in your garden.
• Do not touch pet waste.
• Keep all cuts and scratches on your body clean.
• Shower or bathe daily and maintain your oral care.
• Do not have manicures or pedicures. Do not wear artificial nails. You may use nail polish.
• Consult your oncologist before planning dental appointments or procedure details.
• Consult your oncologist before you or someone living with you receives a vaccination.

Low Red Blood Cell Count (Anemia)

Red blood cells carry oxygen to tissues in the body. When the red cell count is low, you may feel tired or weak. If you experience any shortness of breath, difficulty breathing, or chest pain, consult a specialist immediately. You may need a blood transfusion if your red blood cell count falls very low.

Low Platelet Count (Thrombocytopenia)

Platelets help blood to clot, so a low platelet count increases the risk of bleeding. Consult a specialist immediately if you have excessive bruising, nosebleeds, bleeding gums, or blood in your urine or stool. You may need a platelet transfusion if your platelet count falls very low.

• Do not use a razor (an electric shaver is a better option).
• Avoid sports and activities that could result in injury or bleeding.
• Do not use anti-inflammatory drugs (NSAIDs) such as Motrin/Advil (ibuprofen), Aleve (naproxen), or Celebrex (celecoxib), Aspirin (salicylic acid), non-steroidal drugs, and similar medicines, as they all increase the risk of bleeding. Be sure to consult healthcare staff about the use of these agents and all over-the-counter medicines or supplements during treatment.
• Do not use dental floss or toothpicks, and choose a soft-bristled toothbrush to brush your teeth.

Hemolytic Uremic Syndrome (HÜS)

Mitomisin can also cause a rare syndrome called Hemolytic Uremic Syndrome (HUS), which destroys red blood cells, damages blood vessels, and can lead to kidney failure. Your healthcare staff will monitor you for signs of HÜS throughout treatment with mitomisin. Consult a specialist immediately if you have unusual bruising or bleeding, or notice reduced urine output.

Less Common Side Effects

Other side effects occur less often during treatment with mitomisin but are still important.

Lung Abnormalities

In rare cases, the drug may cause lung problems during treatment or months or years afterward. If you have shortness of breath, a dry cough without sputum, fever, wheezing, or difficulty breathing, contact a healthcare professional immediately.

Heart Problems

Mitomisin may cause or worsen preexisting heart problems such as congestive heart failure, restrictive cardiomyopathy, reduced heart function, and heart attack. Contact healthcare staff immediately if you notice sudden weight gain or swelling in your ankles or legs. Go to the emergency department immediately if you have chest pain or pressure, pain in the left arm, back or jaw, sweating, shortness of breath, cold sweats, nausea, or dizziness.

Reproductive Concerns

Exposure of an unborn child to this drug may cause birth defects. Therefore, having a child is not recommended while you or your partner is receiving this treatment. Effective birth control is necessary during treatment. Remember that pregnancy may still occur even if a woman has entered menopause or a man believes he is not producing sperm. Regarding breastfeeding while using the drug, consultation with a specialist before breastfeeding is recommended.