Description
Mitomycin is an alkylating drug isolated from the broth of Streptomyces caespitosus. A cytotoxic drug, mitomycin inhibits the synthesis of deoxyribonucleic acid (DNA) and at high concentrations, cellular RNA and protein synthesis are also suppressed. In a gel preparation strictly for pyelocalyceal solution, the solution consists of mitomycin 40 mg and mannitol 80 mg in each single-dose vial. 

The mitomycin gel-form must be reconstituted in sterile hydrogel and administered by instillation into the pyelocalyceal system via ureteral catheter or nephrostomy tube. There it forms a semisolid gel which dissolves from normal kidney urine flow, releasing mitomycin for up to 4 to 6 hours.

While primarily metabolized in the liver, metabolism occurs in other tissues as well. The rate of clearance is likely inversely proportional to the maximal serum concentration due to saturation of the degradative pathways.

Policy
Mitomycin Gel is considered medically appropriate if ALL of the following criteria are met and The prescriber is a specialist in the area of the patient’s diagnosis (e.g., oncologist, urologist) or has consulted with a specialist in the area of the patient’s diagnosis.

I.Jelmyto (mitomycin for pyelocalyceal solution) is considered MEDICALLY NECESSARY for the FDA-approved treatment of adults with low-grade upper tract urothelial cancer (LG-UTUC) who meet ALL of the following criteria:

• Member is least 18 years of age
• Member has low grade, non-invasive urothelial cancer (LG-UTUC) in the pyelocalyceal system
• Member does not have untreated concurrent urothelial cancer (UC) outside the target area (unless already treated)
• Member has at least one measurable papillary tumor 5 to ≤ 15 mm located above the ureteropelvic junction
• Member has not received Bacillus Calmette-Guerin (BCG) treatment for urothelial cancer in the last 6 months
• Member does not have a perforation of the bladder or upper urinary tract

II. When Jelmyto (mitomycin for pyelocalyceal solution) is considered MEDICALLY NECESSARY, initial therapy will be authorized for a period of 6 weeks based on the FDA dosing recommendations:

• Jelmyto is for pyelocalyceal use only and not for intravenous use, topical use, or oral administration.
• Jelmyto will be given via pyelocalyceal route once weekly for six weeks (6 doses total).
• The dose of Jelmyto to be instilled is 4 mg per mL via ureteral catheter or nephrostomy tube, with total instillation volume based on volumetric measurements using pyelography, not to exceed 15 mL (60 mg of mitomycin).

INFORMATIONAL NOTE: As stated in package insert, member will receive 1.3 g of sodium bicarbonate orally the evening prior to, the morning of, and 30 minutes prior to instillation procedure (total of 3.9 g).

General anesthesia, local anesthesia, sedation, prophylactic antibiotics and/or antihistamines may be used at the discretion of the treating urologist. If the patient is to be anesthetized, advise the patient not to take sodium bicarbonate within 30 minutes prior to the treatment. Consider withholding diuretics one day prior to instillation until 4 hours post-instillation.)

III. Continued therapy will be authorized for 11 months (11 once a month instillations) when the following criteria are met:

• Only if member has had a complete response 3 months after Jelmyto initiation (initial 6 weekly doses), then Jelmyto may be administered once a month for a maximum of 11 additional instillations.
• The total number of instillations the patient does not exceed 17 instillations of Jelmyto (6 initial weekly doses, 11 maintenance monthly doses)
• There is absence of unacceptable toxicity from the drug (e.g., severe ureteric obstruction, bone marrow suppression, etc.)

INFORMATIONAL NOTE: As per the clinical trials, only those patients that showed a complete response to Jelmyto 3 months after initial initiation went onto the maintenance phase. Those in the maintenance phase were allowed to receive up to 11 additional instillations at once a month dosing.)

IV. Jelmyto (mitomycin for pyelocalyceal solution) is considered MEDICALLY NECESSARY for the following off-label uses:

• Bladder Cancer — Upper GU Tract Tumors
  • Primary treatment for a non-metastatic, residual, low-grade, low volume (5 – 15 mm), solitary tumor in the upper urinary tract for a patient who is not a candidate for or not seeking nephroureterectomy as a definitive treatment
    • Complete or near complete endoscopic resection or ablation is recommended prior to mitomycin ureteral gel application
    • Mitomycin for pyelocalyceal application may be administered via ureteral catheter or a nephrostomy tube

V. Jelmyto (mitomycin for pyelocalyceal solution) is  investigational/unproven therefore considered NOT MEDICALLY NECESSARY for all other uses.

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be MEDICALLY NECESSARY if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and NOT MEDICALLY NECESSARY.

Rationale 
While the majority of urothelial cancers occur in the bladder, upper tract urothelial cancer (UTUC) corresponds to a subset of urothelial cancers that arise in the lining of the kidney or the ureter (the long, thin tube that connects that kidney to the bladder). UTUC can block the ureter or kidney, causing swelling, infections and impairment of kidney function in some patients. UTUCs can develop as low-grade or high-grade tumors. In general, low-grade tumors are not invasive and very rarely spread from the kidney or ureter. However, they often recur and management involves treating visible tumors and trying to preserve the urinary tract, as these tumors are more likely to recur in the urinary system than they are to spread. UTUC is rare and accounts for 5 – 10% of all urothelial cancers. The peak incidence is in age 70 to 90 years of age. There are about 5,000 cases every year in the United States.

On April 15, 2020, the U.S. Food and Drug Administration approved Jelmyto (mitomycin for pyelocalyceal solution), the first therapy to treat low-grade upper tract urothelial cancer (UTUC). The FDA approved Jelmyto is based on the results of a prospective, multicenter, phase 3, open-label, single-arm clinical trial involving 71 patients with low-grade UTUC (OLYMPUS — NCT02793128). These patients had never undergone treatment or had recurrent low-grade non-invasive UTUC with at least one measurable papillary tumor (a tumor shaped like a small mushroom with its stem attached to the inner lining of an organ). Patients received Jelmyto once a week for six weeks and, if assessed as a complete response (complete disappearance of the papillary tumor), monthly for up to 11 additional months. Efficacy of Jelmyto was evaluated using urine cytology (a test to look for abnormal cells in a patient’s urine), ureteroscopy (an examination of the upper urinary tract) and biopsy (if warranted) three months following the initiation of therapy. The primary endpoint was complete response at three months following initiation of therapy. A complete response was found in 41 of the 71 patients (58%) following six treatments of Jelmyto administered weekly. Durability of the effect of Jelmyto in patients with a complete response was also evaluated using urine cytology, ureteroscopy and biopsy (if warranted) every three months for a year following the initiation of therapy. Nineteen patients (46%) who achieved a complete response continued to have a complete response at the 12-month mark.

Common side effects for patients taking Jelmyto were ureteric obstruction (narrowing or blockage of the ureter that may lead to excess fluid in the kidney due to a backup of urine), flank pain (pain occurring on the side of the body), urinary tract infection, hematuria (blood in the urine), renal dysfunction (inability of the kidney to function in its designed capacity), fatigue, nausea, abdominal pain, dysuria (painful or difficult urination) and vomiting. Jelmyto can cause serious side effects including ureteric obstruction, flank pain and urosepsis (bacteria in the bloodstream from a urinary tract infection). Patients with ureteric obstruction may require transient or long-term stents to relieve this obstruction. The obstruction may be persistent and did not resolve or did not resolve completely in 51% of patients who experienced obstruction due to Jelmyto. Jelmyto should be avoided in patients with a glomerular filtration rate (a test used to check how well the kidneys are working) of less than 30mL/min. Jelmyto is contraindicated in patients with perforation of the bladder or upper urinary tract.

INFORMATIONAL NOTE: In the OLYMPUS study, ureteric obstruction was reported in 58% (n = 41) of patients receiving Jelmyto, including 17% (n = 12) of patients who experienced Grade 3 obstruction. The median time to first onset was 72 days (range: 15 – 462). Interventions in the 41 patients experiencing ureteric obstruction included ureteral stent placement (88%), balloon dilatation (32%), and nephroureterectomy (4.9%). In the 36 patients who required ureteral stent placement, the median duration of indwelling stents was 51 days (range: 1 – 292). Ureteric obstruction did not resolve or resolved with sequelae in 51% (n = 21) of these patients. Of the 41 patients who experienced ureteric obstruction, 17% (n = 7) experienced Grades 1 – 2 increase in serum creatinine. In the 42 patients who only received Jelmyto during the treatment phase (no maintenance therapy), ureteric obstruction was reported in 40% (n = 17).

References 

1. Jelmyto (mitomycin). (Prescribing Information) UroGen Pharma, Inc. Princeton, NJ. April 2020. 
2. FDA Approves First Therapy for Treatment of Low-Grade Upper Tract Urothelial Cancer. FDA News Release. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-treatment-low-grade-upper-tract-urothelial-cancer. April 15, 2020. 
3. National Comprehensive Cancer Network. Bladder Cancer (Version 4.2020). https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed May 4, 2020. 
4. Jelmyto. National Comprehensive Cancer Network: Drugs and Biologics Compendium. [Available at http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=367 (accessed 5/4/2020) 
5. Roupret M, Babjuk M, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. Eur Urol. 2018:73(1):111-122.
6. MICROMEDEX Healthcare Series. Drugdex Evaluations. (2020, April). Mitomycin. Retrieved April 29, 2020 from MICROMEDEX Healthcare Series.
7. National Comprehensive Cancer Network. (2020). NCCN Drugs & Biologics Compendium^®. Mitomycin; solution, pyelocalyceal. Retrieved April 29, 2020 from the National Comprehensive Cancer Network.
8. U. S. Food and Drug Administration. (2020, April). Center for Drug Evaluation and Research. JELMYTO™ (mitomycin) for pyelocalyceal solution. Retrieved April 29, 2020 from:
9. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211728s000lbl.pdf.

Coding Secrtion 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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