Mitomycin (Jelmyto)

Number: 0972

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses mitomycin (Jelmyto) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of mitomycin (Jelmyto) is required of all Aetna participating providers and members in applicable plan designs. For precertification of mitomycin (Jelmyto), call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Urothelial Cancer

   Aetna considers mitomycin (Jelmyto) medically necessary for 6 doses of treatment of non-metastatic, low-grade, low volume (5-15 mm), upper tract urothelial cancer when all of the following criteria are met:

   1. The requested drug will be given via pyelocalyceal administration; and
   2. The requested drug will be administered once weekly for the first six weeks for initiation.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of mitomycin (Jelmyto) therapy medically necessary for a maximum of 11 additional doses for members requesting reauthorization for an indication listed in Section I when there has been a complete response (as defined as a complete absence of tumor lesions by urine cytology and ureteroscopy) at 3 months after the initiation of the requested drug.

Dosage and Administration

Jelmyto is a mitomycin solution for pyelocalyceal use only. Jelmyto is not for intravenous use, topical use, or oral administration.

• Recommended dose: Instill 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).
• Instill Jelmyto once weekly for six weeks. For persons with a complete response 3 months after Jelmyto initiation, Jelmyto instillations may be administered once a month for a maximum of 11 additional instillations.
• Prior to administration of Jelmyto, it is recommended that persons take 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).

Source: UroGen Pharma, 2021

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
50391	Instillation(s) of therapeutic agent into renal pelvis and/or ureter through established nephrostomy, pyelostomy or ureterostomy tube (eg, anticarcinogenic or antifungal agent)
52005	Cystourethroscopy, with ureteral catheterization, with or without irrigation, instillation, or ureteropyelography, exclusive of radiologic service
HCPCS codes covered if selection criteria are met:
J9281	Mitomycin pyelocalyceal instillation, 1 mg
Other HCPCS codes related to the CPB:
C9789	Instillation of anti-neoplastic pharmacologic/biologic agent into renal pelvis, any method, including all imaging guidance, including volumetric measurement if performed
ICD-10 codes covered if selection criteria are met:
C64.1 - C64.9	Malignant neoplasm of kidney, except renal pelvis
C65.1 - C65.9	Malignant neoplasm of renal pelvis
C66.1 - C66.9	Malignant neoplasm of ureter

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Jelmyto (mitomycin) is indicated for the treatment of adult patients with low-grade upper tract urothelial cancer (LG-UTUC).

Mitomycin is available as Jelmyto (UroGen Pharma, Inc) for pyelocalyceal use. Mitomycin inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed (UroGen Pharma, 2021).

Jelmyto is contraindicated in perforation of the bladder or upper urinary tract. The label includes warnings and precautions for ureteric obstruction, bone marrow suppression, and embryo-fetal toxicity. The most common adverse reactions (20% or more) are ureteric obstruction, urinary tract infection, hematuria, flank pain, nausea, dysuria, renal dysfunction, vomiting, fatigue, and abdominal pain.

Urothelial Cancer

Urothelial cancer is a cancer of the lining of the urinary system. While the majority of urothelial cancers occur in the bladder, 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. Low-grade UTUC is rare, but affects 6,000-8,000 new patients in the United States every year (FDA news release 2020).

On April 15, 2020, the U.S. Food and Drug Administration (FDA) approved Jelmyto (mitomycin gel) to treat low-grade upper tract urothelial cancer (UTUC). Jelmyto (also known as mitomycin or mitomycin-C) is an alkylating drug isolated from the broth of Streptomyces caespitosus. Mitomycin inhibits the transcription of DNA into RNA, stopping protein synthesis and taking away the cancer cell’s ability to multiply (Jelmyto Prescribing Information 2020).

The efficacy of Jelmyto is based on the results of the ongoing study OLYMPUS (NCT02793128), an open-label, single-arm, multicenter trial that enrolled 71 patients with treatment-naïve or recurrent noninvasive low-grade upper tract urothelial cancer (LG-UTUC) with at least one measurable papillary tumor 5 to ≤ 15 mm located above the ureteropelvic junction; patients who had larger tumors could have had tumor debulking prior to treatment, in order to meet the criteria. Patients were excluded from the trial for a history of carcinoma in situ (CIS) in the urinary tract, invasive urothelial carcinoma within 5 years, high grade papillary urothelial carcinoma within 2 years; or for BCG treatment within 6 months of Jelmyto treatment. Following biopsy and prior to treatment, patients were required to have at least one remaining visible tumor with a diameter of at least 5 mm.  The baseline demographic and disease characteristics for the trial population included: median age 71 years (range: 42-87 years); 68% male; 87% White; 90% Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 and 10% ECOG PS 2. The median number of papillary lesions subsequent to debulking and/or biopsy and prior to treatment was 1 lesion (range: 1, 5), the median diameter of the largest lesion was 8.0 mm (range: 5.0, 15.0), and the median total visible tumor burden was 10.0 mm (range: 5.0, 25.0). Twenty-six (37%) patients underwent tumor debulking during the six weeks preceding enrollment. Of 71 enrolled patients, 48% had tumors located in regions not amenable to endoscopic resection. General anesthesia was used in 37% of patients for at least one instillation during the treatment period and for 61% of patients for at least one instillation during the follow-up period.

Patients received Jelmyto 4 mg per mL via ureteral catheter or nephrostomy tube with total instillation volume based on individualized volumetric measurements using pyelography with the intent to fill the renal pelvis. Patients were treated with Jelmyto instillations once a week for 6 weeks. Patients who maintained a complete response (CR) after the initial treatment period were allowed to proceed to the follow-up period, which consisted of monthly instillations for up to 11 additional months. The major efficacy outcome measures were complete response at 3 months after initiation of Jelmyto, and durability of CR at 12 months after determination of CR. Complete response was defined as complete absence of tumor lesions at 3 months after initiation of Jelmyto by urine cytology and ureteroscopy. Biopsy was performed to evaluate complete response, if warranted. Durability of the effect of Jelmyto in patients with a complete response was also evaluated at 3, 6, 9 and 12 months following the initial assessment using urine cytology, ureteroscopy.

During the initial treatment period, 71 patients were treated with Jelmyto, of whom 41 (58%) achieved complete response and were subsequently continued in the follow-up period. During the follow-up period, 29 patients received at least one dose of maintenance therapy. Nineteen of the 41 patients who continued into the follow-up period (46%) continued to have a complete response at the 12-month mark.

From the clinical trial, the most common adverse reactions (≥ 20%) included ureteric obstruction, flank pain, urinary tract infection, hematuria, renal dysfunction, fatigue, nausea, abdominal pain, dysuria, and vomiting. Serious adverse reactions occurred in 37% of patients who received Jelmyto. Serious adverse reactions in > 3% of patients included ureteric obstruction (including ureteric stenosis and hydronephrosis), flank pain, and urosepsis. Two deaths occurred due to cerebrovascular accident and failure to thrive.

Mitomycin C in Otolaryngology Procedures

Luu et al (2022) stated that many studies have examined the effectiveness of topical intra-operative mitomycin usage in a wide range of otolaryngologic procedures with variable conclusions on effectiveness.  In a systematic review, these investigators provided a qualitative estimation of mitomycin C (MCC)'s treatment effectiveness in maintaining or preventing stenosis following surgical interventions.  By means of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline, these researchers carried out a comprehensive systematic search of Medline, Embase and CINAHL databases including hand-searching and cross-reference checking.  The search was limited to humans, sample size greater than 2 and study designs including a comparative arm.  Outcome measures varied but included rates of re-stenosis, number of procedures, and post-surgical patency.  A total of 571 unique abstracts and 109 full articles were reviewed; 77 studies were included in the final analysis . The available evidence ranged from case series to randomized control trials (RCTs).  Meta-analysis was deemed inappropriate due to heterogeneity of study design; 38 studies examined the effective of MCC in dacryocystorhinostomy, which was reported in a separate meta-analysis.  All other studies were categorized into otolaryngologic site and pathology including choanal atresia (n = 5), endoscopic sinus surgery (n = 12), airway procedures (n = 9), esophageal procedures (n = 8) and other (n = 2).  The authors concluded that the published literature on the effectiveness of MMC was mixed; but suggested topical MMC improved surgical outcomes in many otolaryngologic procedures compared to controls.  This was the 1st review to evaluate literature on MMC usage for different surgical procedures.  Comprehensive interpretation of the data was limited due to heterogeneity in primary outcome, procedure type and study quality.  These researchers stated that prospective, high-quality RCTs are needed to confirm the positive effect of MMC use on surgical outcomes.

Mitomycin C for the Prevention of Corneal Haze After Photo-Refractive Keratectomy

In a meta-analysis, Chang et al (2021) examined the anti-haze effect and visual outcome following intra-operative MMC use during photo-refractive keratectomy (PRK) in patients with myopia or myopic astigmatism.  These investigators searched in PubMed, Embase, Cochrane Library and Google Scholar to obtain studies comparing the clinical effects after PRK with and without MMC published until February 2020.  Meta-analysis of primary outcome (corneal haze rate) and secondary outcomes (predictability, efficacy, safety and corneal endothelial cell density (ECD)) were carried out.  They employed trial sequential analysis (TSA) in an effort to collect firm evidence supporting their conclusion.  Of the included 11 RCTs, 5 cohort and 1 case-control studies, 3,536 eyes (2,232 and 1,304 in the MMC and control groups, respectively) were enrolled for meta-analysis.  The TSA disclosed strong evidence of decline in corneal haze rate in the MMC group compared with that of the control group.  In the subgroup analysis of duration, MMC appeared to reduce corneal haze rate in early-onset and late-onset haze.  Predictability of refraction and visual acuity (VA) were greater in the MMC groups, although not significantly.  The proportion of patients losing at least 2 lines of best corrected VA (BCVA) post-operatively in the MMC groups was lower than that in the control groups.  The corneal post-operative ECD showed no significant difference between the MMC and control groups.  The authors concluded that this meta-analysis revealed that MMC was an important anti-haze agent in PRK for reducing both early- as well as late-onset haze, and could also aid in improving predictability of refraction and subjective post-operative VA.  Moreover, these researchers stated that the effect of MMC on corneal ECD loss rate needs to be further examined in larger RCTs.

The authors stated that this meta-analysis had several drawbacks.  First, these investigators included not only RCTs, but also non-RCTs in their analysis to obtain more relevant trials, which could have influenced the validity of their analysis; thus, they carried out subgroup analysis of the primary outcome, corneal haze rate, to reduce the bias.  However, high heterogeneity (I2 = 88 %, p < 0.01) was still observed in the non-RCTs.  Second, there was no standard protocol for MMC concentration and administration time.  Although the meta-regression did not show any significant interaction of the haze rate, these researchers still considered that differences in the applying the protocol may have led to potential clinical heterogeneity.  Third, owing to the relatively few inclusive studies for their secondary outcomes, further subgroup analyses were not carried out.  Fourth, different refraction errors and astigmatism can be confounding factors in the corneal haze rate, as these researchers included both myopia and myopic astigmatism patients without dividing these patients into subgroups.  Although the main outcomes did not reveal any differences, further analyses in line with the different refraction types could be considered in the future.

Ouerdane et al (2021) noted that PRK is considered a safe laser procedure with a clinical significance in correcting myopia; PRK requires removing the whole superficial epithelium.  The integrity of the epithelial basement membrane and the deposition of abnormal extracellular matrix could put the cornea in a vulnerable situation for corneal haze formation.  Mitomycin C is used after excimer laser ablation as a primary modulator for wound healing, limiting corneal haze formation.  In a systematic review and meta-analysis, these investigators examined the outcomes of MMC use following laser ablation.  They searched Scopus, PubMed, Cochrane CENTRAL, and Web of Science until December 2020 using relevant keywords.  Data were extracted and pooled as mean difference (MD) or risk ratio (RR) with a 95 % confidence interval (CI), using Review Manager software (version 5.4).  This analysis demonstrated a statistically significant result for MMC use over the control group in terms of corneal haze formation post-operatively (RR = 0.29, 95 % CI: 0.19 to 0.45, p < 0.00001).  Regarding corrected distance VA (CDVA), no significant difference was observed between the MMC group and the control group (MD = 0.02; 95 % CI: -0.04 to 0.07; p = 0.56).  Regarding the uncorrected distance VA (UDVA), the analysis favored the MMC application with (MD -0.03, 95 % CI: -0.06 to -0.00; p = 0.05).  There was no statistically significant increase in complications with MMC.  The authors concluded that MMC use after PRK was associated with a lower incidence of corneal haze formation with no statistically significant side effects.  There was no significant effect of MMC use on UDVA and CDVA in the short-term effect; however, the long-term effect showed improvement regarding UDVA favoring MMC use.  Moreover, these researchers stated that future studies are needed to show the difference between “epithelium off” versus trans epithelial PRK in terms of corneal haze.

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References