Which Patients Are Eligible for Coverage?:

Reblozyl should only be covered to treat patients who have failed or are not suitable for erythropoietin-based therapy.

What Are the Conditions for Reimbursement?:

Reblozyl should only be reimbursed if prescribed by a specialist in MDS and if the cost of Reblozyl is reduced. Reimbursement should only be renewed if Reblozyl shows benefit to the patient such that the patient no longer requires RBC transfusions.

Why Did CADTH Make This Recommendation?

• Evidence from 1 study showed that more patients who received Reblozyl did not need a blood transfusion than patients who received placebo.
• Patients expressed the need to reduce blood transfusions, and evidence from the reviewed study suggests that Reblozyl may meet some of the needs expressed by patients.
• Based on public list prices, Reblozyl is not cost-effective compared with best supportive care (RBC transfusions and iron chelators).
• The cost of Reblozyl needs to be reduced by 85% for it to be considered cost-effective at a $50,000 per quality-adjusted life-year threshold.
• Based on public list prices, Reblozyl will cost the public drug plans $101,479,111 in the first 3 years.

What Are Myelodysplastic Syndromes?:

Myelodysplastic syndromes are a group of diseases that prevent the body from making healthy blood cells. Patients may need frequent blood transfusions and may develop blood cancer. Approximately 4 people per 100,000 persons in Canada are diagnosed with a myelodysplastic syndrome each year.

Unmet Needs in Myelodysplastic Syndromes:

There is a need for a treatment that reduces the frequency of blood transfusions in patients who fail erythropoietin-based therapy and improves patients’ quality of life.

How Much Does Reblozyl Cost?:

Treatment with Reblozyl is expected to cost between $152,188 to $228,281 per patient annually.

Input From Clinical Experts Consulted by CADTH

The clinical experts stated there are no funded or approved treatments available to address key outcomes for patients with transfusion-dependent anemia associated with MDS. Moreover, not all patients respond or tolerate these treatments even if they are obtained (privately or through a compassionate access program). The only therapeutic intervention for the treatment of lower-risk MDS which has demonstrated improvement in OS is iron chelation therapy. Of the disease-modifying therapies used for low-risk MDS, lenalidomide has been shown to improve HRQoL in patients both with and without the del(5q) cytogenetic abnormality. However, lenalidomide has been associated with causing significant neutropenia or thrombocytopenia.

The clinical experts anticipated that luspatercept would be used second line in erythropoiesis-stimulating agent (ESA) failures or first line in patients not expected to respond to ESAs. The clinical expert noted that therapies that increase hemoglobin and decrease RBC transfusion dependence cannot be assumed to improve patient symptoms or HRQoL, particularly when those therapies themselves can have adverse effects.

The clinical experts noted that luspatercept has only been studied in low-risk MDS patients with ringed sideroblasts and who have failed ESA therapy, and there is no evidence that it is in fact superior to ESA therapy in this setting. Luspatercept would either need to establish superiority through a direct comparison with ESAs (i.e., via a randomized controlled trial), or establish a stronger evidence base (i.e., through direct comparison with a control) that it can directly improve a patient-related outcome such as HRQoL, to be a preferred treatment of symptomatic anemia. The clinical experts consulted by CADTH suggested that patients with low-risk IPSS with ringed sideroblasts are the most likely to respond to therapy with luspatercept. The patients who require regular RBC transfusions are the ones most in need of this intervention since transfusion dependency is associated with shorter OS, more cardiac events, and inferior HRQoL. The clinical experts further noted that to identify patients who are most likely to exhibit a response to treatment with luspatercept would be on the basis of their IPSS score, endogenous erythropoietin level, and monthly transfusion needs. A variety of scoring systems are available for this purpose. The clinical experts noted that a clinically meaningful response to treatment would be an improvement in HRQoL using a validated scoring system (e.g., FACT or EQ-5D score). They also noted that a reduction in or elimination of transfusions would be clinically meaningful.

There were 2 opinions among the clinical experts. One expert expressed that since luspatercept is administered as a subcutaneous injection every 3 weeks; reviewing quality of life and/or complete blood count at each visit would be an appropriate interval. Transfusion independence may be evaluated every 8 weeks (with review conducted at the 9-week visit). The second expert expressed that assessment to treatment response should be every month for 6 months then every 3 months.

The clinical experts concurred that no meaningful response, disease progression, intolerable adverse events which do not respond to dose reduction, and failure to achieve a response criterion after 9 weeks, despite dose escalation to 1.75 mg/kg, could be reasonably interpreted as a lack of meaningful response and treatment would be discontinued.

The clinical experts noted that while many patients will likely receive their first subcutaneous injection in a medical setting and would be administered by a health care professional (either inpatient or outpatient), as per the product monograph, the majority of patients should be able to self-administer in the community setting. The diagnosis of low-grade MDS requires a specialist consultation, and the prescription of luspatercept should be limited to individuals with special training in managing the diagnosis (typically a hematologist or oncologist), although once initiated it would be reasonable for non-specialists to continue prescribing and monitoring.

Clinician Group Input

Clinician input on the review of luspatercept for the treatment of adult patients with very low- to intermediate-risk MDS-associated anemia who have ring sideroblasts and require RBC transfusions was received from 2 groups: the OH-Hematology DAC and the ATB-MPG.

Both groups agreed that the current treatment for patients involves transfusion support with red cell transfusions and ESAs. The clinicians from Alberta noted that ESAs are most effective in patients with low transfusion requirements and erythropoietin levels and are variably funded across the country. They added that there is currently no funding for ESAs in Alberta, although commonly used and considered standard of care, and erythropoietin is recommended in the Alberta clinical practice guidelines for patients with lower-risk MDS. Both groups agreed that patients with del[5q] MDS (approximately 10% of patients) may be treated with lenalidomide. With respect to needs that are not being met with the currently available treatments, both clinician groups agreed that currently there are no other treatment options other than transfusion, ESAs for some patients, and — for a small subset of patients — hypomethylating agents such as azacitidine or decitabine-cedazuridine.

Both clinician groups agreed that luspatercept would be an additional line of therapy for symptomatic anemia for patients who have progressed on ESAs, have not responded to ESAs, or have a high erythropoietin level precluding response to ESA therapy to reduce transfusion and their consequences (i.e., iron overload). Both clinician groups agreed that patients best suited for treatment with luspatercept are lower-risk MDS patients with symptomatic anemia who have failed ESAs or are inappropriate for ESA therapy. The clinicians from Alberta added that patients in this group have no other effective treatment options other than long-term transfusions and iron chelation to help manage the related iron overload with associated side effects of chelation.

Both clinician groups agreed that transfusion frequency (reduction in transfusion requirements) and improvement in hemoglobin are outcomes used to determine whether a patient is responding to treatment in clinical practice. Both groups also agreed that a clinically meaningful response to treatment would be a reduction in transfusions.

With respect to factors that should be considered when deciding to discontinue treatment, the clinicians from Ontario noted that worsening of MDS, progression to a higher risk category, or transformation to AML should be considered. The clinicians from Alberta note that a decrease in hemoglobin without an alternative cause, an increase in transfusion requirements, or the need to introduce regular transfusions in patients who have been transfusion independent would be factors to consider.

According to both clinician groups, the most appropriate settings for treatment are community settings such as pharmacies, outpatient clinics, and specialty clinics. The clinicians from Alberta added that a hematology or medical oncology specialist would be required to diagnose, treat, and monitor patients who might receive the drug under review. The clinicians from Alberta noted that the benefit to patients who can become transfusion independent (or remain so after developing symptomatic anemia) is very significant and can reduce a significant burden on both patients and the health care institutions who provide regular transfusion support over long time periods to these patients.

Efficacy Results

In the MEDALIST study, the efficacy outcomes identified in the protocol were hematologic response, HRQoL, OS, iron accumulation, iron chelation therapy use, progression to AML, and health care resource utilization. The primary and 2 key secondary efficacy outcomes were analyzed using an intention-to-treat population.

At week 24, a greater proportion of patients in the luspatercept treatment group achieved the primary outcome of RBC transfusion independence for at least 8 weeks or longer (any consecutive 56-day period) than the placebo group. In the luspatercept treatment group, 37.9% of the patients responded to the treatment; 13.16% of the patients in the placebo group achieved the primary end point, with a common risk difference on response rate being 24.56 (95% CI, 14.48 to 34.64). The odds ratio of 5.06 (95% CI, 2.28 to 11.26; P < 0.0001) favoured the luspatercept treatment over placebo. The clinical experts consulted by CADTH were of the opinion that the results were not clinically meaningful because 8 weeks is a short duration to assess response.

At week 48 and week 24, a greater proportion of patients in the luspatercept treatment group achieved the 2 key secondary outcomes of RBC transfusion independence for at least 12 weeks or greater (any consecutive 84-day period) than the placebo group. During week 1 to week 48, 33.3% of the patients in the luspatercept treatment group responded to the treatment and 11.84% of the patients in the placebo group responded to the treatment, with a common risk difference on response rate being 21.37 (95% CI, 11.23 to 31.51). The odds ratio of 4.04 (95% CI, 1.83 to 8.96; P = 0.0003) favoured the luspatercept treatment over placebo. During week 1 to week 24, 28.1% of the patients in the luspatercept treatment group responded to the treatment and 7.89% of the patients in the placebo group responded to the treatment, with a common risk difference on response rate being 20.00 (95% CI, 10.92 to 29.08). The odds ratio of 5.07 (95% CI, 2.00 to 12.84; P = 0.0002) favoured the luspatercept treatment over placebo.

Other efficacy outcomes identified in the CADTH review protocol were reported descriptively, including the number of RBC units transfused, duration of RBC transfusion independence, time to RBC transfusion independence, mean change in hemoglobin, modified hematologic improvement), OS, iron accumulation (through serum ferritin levels), iron chelation therapy use, progression to AML, and health care resource utilization. In the absence of any formal statistical testing, whether luspatercept has an effect on any of these outcomes remains unknown. HRQoL was a secondary and exploratory outcome in the MEDALIST study and was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and QoL-E instruments; however, none of these outcomes were controlled for multiplicity. For HRQoL outcomes, no difference in the treatment groups was observed and no minimally important difference for patients with transfusion-dependent anemia associated with MDS was identified from the literature.

Subgroup analyses identified in the CADTH review protocol for which results were available in the MEDALIST study included IPSS-R score (very low risk or low risk versus intermediate risk), and baseline hematological status. The results of the subgroup analysis were aligned with the results of the full study population.

Harms Results

In the MEDALIST study, 98.0% and 92.1% of the patients in the luspatercept and placebo groups, respectively, reported at least 1 adverse event. The most commonly occurring adverse events were fatigue (26.8% and 13.2% of the patients in the luspatercept and placebo groups, respectively), diarrhea (22.2% and 9.2% of the patients in the luspatercept and placebo groups, respectively), nausea (20.3% and 7.9% of the patients in the luspatercept and placebo groups, respectively), and dizziness (19.6% and 5.3% of the patients in the luspatercept and placebo groups, respectively).

In the MEDALIST study, serious adverse events were reported by 31.4% of the patients in the luspatercept treatment group and 30.3% of the patients in the placebo group. The most commonly reported serious adverse event was pneumonia, which was reported by 2.0% patients in the luspatercept group and 2.6% patients in the placebo group. The proportion of patients who stopped treatment due to an adverse event was 8.5% and 7.9% in the luspatercept and placebo treatment groups, respectively. |||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.

During the treatment period, 3.3% (n = 5) of patients in the luspatercept treatment group and 5.3% (n = 4) of patients in the placebo treatment group had died. In the luspatercept treatment group, 1 patient died due to multiple organ dysfunction syndrome, 2 patients died of sepsis, 1 patient died due to renal failure, and 1 patient died of a hemorrhagic shock. In the placebo treatment arm, 1 patient died due to general physical health deterioration, 1 patient died due to urosepsis, 1 patient died of sepsis, and 1 patient died of respiratory failure. During the posttreatment period, an additional |||||||||||| and |||||||||||| patients died in the luspatercept treatment group and the placebo treatment group, respectively.

The notable harms identified in the CADTH review protocol included the following: thromboembolic events, hypertension, hepatic and renal events, hypersensitivity reactions, and malignancies. In the luspatercept treatment group, 2.6% (n = 4) of patients experienced a thromboembolic and thrombophlebitis event; in the placebo treatment group, 3.9% (n = 3) of patients experienced a thromboembolic and thrombophlebitis event. Under the system organ class (SOC) of hepatobiliary disorders, || of patients in the luspatercept treatment group and || of patients in the placebo group reported at least 1 associated adverse event. Under the SOC of renal and urinary disorders, |||| of patients in the luspatercept treatment group and |||| of patients in the placebo group reported at least 1 associated adverse event. Hypertension was reported as an adverse event in 8.5% of the patients in the luspatercept treatment group and 7.9% patients in the placebo group.

Critical Appraisal

MEDALIST was a randomized, placebo-controlled, double-blind study. Overall randomization (using an interactive response technology system) and treatment allocation (stratified by RBC transfusion burden at baseline [≥ 6 units/8 weeks versus < 6 units/8 weeks] and IPSS-R score at baseline [very low or low versus intermediate]) were appropriately conducted; however, as noted by the US FDA, blinding in the study may have been inadequate due to the production of the placebo control syringe onsite and the lack of specific instructions to mask the product. This increases the risk of accidental unblinding unacceptably, which may have introduced bias in the results.

The baseline patient, disease, and MDS treatment history characteristics were generally well balanced. A higher number of patients in the luspatercept treatment group progressed to AML, developed nervous system disorders, or fatigue, which led to study drug discontinuation.

The clinical experts consulted by CADTH were of the opinion that the duration of hematologic response of the primary end point — at least 8 weeks (i.e., any consecutive 56 days) — was not clinically meaningful. The appropriate measure for clinical meaningfulness would be transfusion independence for at least 16 weeks, which is in accordance with the proposed IWG 2018 Hematological Response Criteria. A hematologic response of transfusion independence for 12 weeks (i.e., any consecutive 84 days) is more clinically meaningful than 8 weeks. The effect size of the primary end point of transfusion independence for 8 weeks in the study was small; transfusion independence of 8 weeks was obtained in only approximately 38% of patients with a differential response compared with placebo of about 25%; hence, only approximately one-quarter of the patients exposed to luspatercept had any apparent benefit, assuming that fulfillment of the primary objective represents a benefit to the patient.

Only a subset of patients who initially responded in the first 24 weeks were eligible for the extension phase. The interpretation of this end point is therefore problematic because few patients were eligible for the extension phase and therefore could not achieve the end point of 12 weeks response due to the study design.

The clinical experts noted that, based on baseline demographic and disease characteristics, the study population was representative of Canadian patients with transfusion-dependent anemia associated with MDS. In Canada, the average age of an MDS patient is 74 years, which is similar to the mean age of the study population, which was 70.5 years.