Remestemcel-L-rknd (Ryoncil)

Number: 1077

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 remestemcel-L-rknd (Ryoncil) for commercial medical plans. 

Note: Requires Precertification: 

Precertification of remestemcel-L-rknd (Ryoncil) is required of all Aetna participating providers and members in applicable plan designs. For precertification of remestemcel-L-rknd (Ryoncil), 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

   Aetna considers a maximum of 8 infusions of remestemcel-L-rknd (Ryoncil) medically necessary for the treatment of acute graft-versus-host disease (aGVHD) when both of the following criteria are met:

   1. The member is a pediatric member; and
   2. The disease is steroid-refractory (progressed within 3 days or did not improve within 7 consecutive days of treatment with methylprednisolone 2 mg/kg/day or equivalent).

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers continuation of remestemcel-L-rknd (Ryoncil) therapy medically necessary for members requesting reauthorization for aGVHD when either of the following criteria is met:

   1. Partial or mixed response — there is an improvement in symptoms and there is no evidence of unacceptable toxicity while on the current regimen. (Maximum of 4 infusions); or
   2. Recurrence after complete response with the requested medication — all members (including new members) requesting authorization for continuation of therapy must meet all the requirements in the Criteria for Initial Approval section. (Maximum of 8 infusions).

3. Related Policies 

   1. CPB 0315 - Etanercept
   2. CPB 0341 - Infliximab
   3. CPB 0720 - Abatacept (Orencia)
   4. CPB 0799 - Tocilizumab

Dosage and Administration

Ryoncil is provided as a frozen cell suspension in a cryogenic vial. The active ingredient in Ryoncil, remestemcel-L-rknd, is comprised of culture-expanded mesenchymal stromal cells (MSCs) isolated from the bone marrow of healthy human adult donors. Each cryovial contains nominally 25 x 10⁶ MSCs in 3.8 mL (a target concentration 6.68 x 10⁶ cells/mL) formulated in Plasma Lyte®-A (70% v/v), Human Serum Albumin Solution (25%) (20% v/v) and Dimethyl sulfoxide (DMSO) (10% v/v). The product is thawed and combined with Plasma-Lyte® A prior to intravenous administration. 

The recommended dosage of Ryoncil is 2 × 10⁶ MSC/kg body weight per intravenous infusion given twice a week for 4 consecutive weeks for a total of 8 infusions. Infusions are administered at least 3 days apart. 

Response is assessed 28 ± 2 days after the first dose. Further treatment is administered as appropriate per the table below.  

Table: Recommended treatment based on Day 28 response

Response	Recommendation
Complete response	No further treatment with Ryoncil
Partial or mixed responseFootnote1*	Repeat administration of Ryoncil once a week for additional 4 weeks (4 infusions total)
No response	Consider alternative treatments
Recurrence of graft-versus-host disease	Repeat administration of Ryoncil twice a week for an additional 4 consecutive weeks (8 infusions total)

Footnote1*Partial response defined as organ improvement of at least one stage without worsening in any other organ, whereas mixed response was defined as improvement of at least one evaluable organ with worsening in another organ as per International Blood and Marrow Transplantation Registry Severity Index Criteria grading system.

Source: Mesoblast, 2025

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366	each additional hour (List separately in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
Remestemcel-L-rknd (Ryoncil) – No specific code
Other HCPCS codes related to the CPB:
J0702	Injection, betamethasone acetate 3mg and betamethasone sodium phosphate 3mg
J1020	Injection, methylprednisolone acetate, 20 mg
J1030	Injection, methylprednisolone acetate, 40 mg
J1040	Injection, methylprednisolone acetate, 80 mg
J1094	Injection, dexamethasone acetate, 1 mg
J1100	Injection, dexamethasone sodium phosphate, 1mg
J1700	Injection, hydrocortisone acetate, up to 25 mg
J1710	Injection, hydrocortisone sodium phosphate, up to 50 mg
J1720	Injection, hydrocortisone sodium succinate, up to 100 mg
J2650	Injection, prednisolone acetate, up to 1 ml
J2920	Injection, methylprednisolone sodium succinate, up to 40 mg
J2930	Injection, methylprednisolone sodium succinate, up to 125 mg
J7506	Prednisone, oral, per 5 mg
J7509	Methylprednisolone, oral, per 4 mg
J7510	Prednisolone oral, per 5 mg
J7512	Prednisone, immediate release or delayed release, oral, 1 mg
J8540	Dexamethasone, oral, 0.25 mg
ICD-10 codes covered if selection criteria are met:
D89.810	Acute graft-versus-host disease [steroid-refractory]

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Background

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

• Ryoncil is indicated for the treatment of steroid-refractory acute graft versus host disease (SR-aGvHD) in pediatric patients 2 months of age and older.

Remestemcel-L-rknd suspension is a mesenchymal stromal cell (MSC) therapy branded as Ryoncil (Mesoblast, Inc.). Remestemcel-L-rknd is comprised of culture-expanded MSCs isolated from the bone marrow of healthy human adult donors, and is believed to have immunomodulatory properties to counteract the inflammatory processes that are implicated in steroid-refractory acute graft-versus-host disease by down-regulating the production of pro-inflammatory cytokines, increasing production of anti-inflammatory cytokines, and enabling recruitment of naturally occurring anti-inflammatory cells to involved tissues. Acute graft-versus-host disease (aGVHD) occurs when alloreactive donor-derived T cells within the donated tissue (graft) trigger an immunological response, and alloreactive donor-derived T cells play a role in mediating the systemic inflammation, cytotoxicity and potential end organ damage associated with aGVHD (Mesoblast, 2024, 2025).

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor, and potentially fatal, clinical outcomes. Kurtzberg et al. (2020) state that safe and effective therapies are needed for the pediatric population under the age of 12 years. Thus, the authors report on a multicenter, prospective, single-arm, phase 3 study (NCT02336230) in which 54 children with primary SR-aGVHD who were naïve to other immunosuppressant therapies for aGVHD were treated with an intravenous infusion of MSC product (remestemcel-L) dosed at 2 × 10^6 cells/kg twice weekly for 4 weeks, for a total of 8 infusions. Patients with partial or mixed response at Day 28 received additional infusions of remestemcel-L at 2 × 10^6 MSCs/kg once a week for an additional 4 consecutive weeks. Patients with complete response at Day 28 who experienced recurrence of aGVHD received infusions of remestemcel-L at 2 × 10^6 MSCs/kg twice a week for an additional 4 consecutive weeks. The main efficacy outcome measures were Day 28 overall response rate (OR) (complete response rate and partial response rate) and the duration of response. Outcomes of the study found that remestemcel-L therapy significantly improved Day 28 OR compared with the prespecified control OR value of 45% (70.4% versus 45%, P = .0003). The statistically significant OR (70.4%) was sustained through Day 100, including an increase in complete response from 29.6% at Day 28 to 44.4% at Day 100. Overall survival was 74.1% at Day 100 and 68.5% at Day 180. Overall response in all participants at Day 28 was highly predictive of improved survival through 180 days, and survival was significantly greater in Day 28 responders compared with non-responders through Day 100 (86.8% versus 47.1% for responders and non-responders, respectively, P = .0001) and through Day 180 (78.9% versus 43.8%, P = .003). Moreover, remestemcel-L was well tolerated, with no identified infusion-related toxicities or other safety concerns. The authors concluded that this study provides robust, prospective evidence of the safety, tolerability, and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD.

The study enrolled pediatric patients (age range: 7 months to 17 years) with SR-GvHD Grade B to D (excluding Grade B skin alone) as per International Blood and Marrow Transplantation Registry Severity Index Criteria after receiving allogeneic HSCT. SR-aGVHD was defined as aGVHD that progressed within 3 days or did not improve within 7 consecutive days of treatment with methylprednisolone 2 mg/kg/day or equivalent. Patients who received a second-line therapy for aGVHD prior to screening were excluded.

On December 18, 2024, the U.S. Food and Drug Administration (FDA) approved remestemcel-L-rknd (Ryoncil, Mesoblast, Inc.) for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in pediatric patients 2 months of age and older. Ryoncil is the first FDA-approved MSC therapy (FDA, 2024). Approval was based on the MSB-GVHD001 (NCT02336230) study, as described by Kurtzberg et al. (2020).

Labeled contraindications include known hypersensitivity to dimethyl sulfoxide (DMSO) or porcine and bovine proteins. Warnings and precautions include hypersensitivity/acute infusion reactions, transmission of infectious agents, and ectopic tissue formation. Transmission of infectious disease or agents may occur with administration because it contains cells from human donors and is manufactured using human, porcine, and bovine-derived reagents. Ectopic tissue formation may occur following treatment due to the ability of human MSCs to differentiate into mesenchymal lineage cells such as bone, cartilage, and fat cells.

There are no available data for Ryoncil use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with Ryoncil to assess whether it can cause fetal harm when administered to a pregnant woman. Moreover, there is no information regarding the presence of Ryoncil in human milk, the effect on the breastfed infant, and the effects on milk production.

The most common non-laboratory adverse reactions (incidence 20% or more) include viral infectious disorders, bacterial infectious disorders, infection – pathogen unspecified, pyrexia, hemorrhage, edema, abdominal pain, and hypertension.

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References