Genetics and Ring Sideroblasts Impact ESA-Refractory Anemia in MDS

Azra Raza, MD

Professor of Medicine

Director, Myelodysplastic Syndrome Center

Columbia University Herbert Irving Comprehensive Cancer Center

New York, NY

CASE SUMMARY

• A 67-year-old post-menopausal woman​
• Up-to-date on colonoscopy and other screenings​
• No family history of cancer or significant genotoxic agent exposure​
• Presentation​
• Presented to community practice with symptomatic anemia; fatigue and dyspnea on exertion worsening gradually over the past 6 months
• This was concerning to the patient as she is planning to leave next week for a 2-week safari in Africa ​
• No other symptoms​
• Hemoglobin: 8.4 g/dL​
• Received 2 units of packed red blood cells in clinic​
• Work-up delayed until 1 month post initial visit due to her travels​
• Working diagnosis of myelodysplastic syndrome (MDS); other causes of anemia were excluded​
• Serum EPO (erythropoietin): 270m U/L​
• Ring sideroblast (RS) positive ​
• Hemoglobin: 8.5 g/dL; absolute neutrophil count and platelet count within normal limits​
• Ferritin level: 120 ng/mL
• Next-generation sequencing: SF3B1 mutation negative​
• Bone marrow biopsy: 4% blasts; non-deletion 5q ​
• Revised International Prognostic Scoring System: Low​ risk
• Based on hemoglobin level, she received 1 unit of packed red blood cells​

Targeted Oncology: When do you consider initiating treatment for anemia, and what patient-related factors are most important in this decision?

Azra Raza, MD: [At my institution], we like to go by symptoms. For somebody who has 8 g/dL hemoglobin, but no symptoms, it's OK to wait and let them be at 8 g/dL and continue if they can have a good quality of life and remain functional. I have several younger patients in their fifties to sixties who we are not giving anything to, including ESAs [erythropoiesis-stimulating agents] because they go to work with their busy lives, and they don't want to become tied to a schedule of every week or every 2 weeks. But if there are any symptoms, any compromised quality of life, something made them go to the doctor, or something that led to being diagnosed with [anemia], it's OK to start with an ESA. Reimbursement and insurance is always very important, and if the patient is not approved by their insurance, then it's too expensive for anyone to pay for it themselves.

CASE UPDATE

• The patient was started on epoetin at 150 U/kg every 2 weeks​
• At 9 weeks, she required 2 additional units of packed red blood cells, continued to be fatigued
• Hemoglobin: 8.1 g/dL​

How effective are epoetin-α and darbopoetin-α in anemic patients with low-risk myelodysplastic syndrome?

The time to first transfusion independence is 3 to 4 months or so [for epoetin-α].¹ In the phase 3 darbepoetin trial in anemic patients with lower-risk MDS, this was compared with a placebo arm and darbopoetin produced transfusion independence in 50% of patients.² Approximately 34% responded based on the data [with hematologic improvement-erythroid].

What treatment option would you offer this ESA-refractory patient?​

I think all of us would pick luspatercept [Reblozyl] given the patient's RS, and that is based on the MEDALIST trial [NCT02631070] where luspatercept was compared with a placebo in a 2:1 randomization. The dose was titrated up to a maximum of 1.75 mg/kg and there was disease and response assessment every 6 months. Treatment was discontinued after 6 months for lack of clinical benefit or disease progression. Independence from red blood cell transfusions was reached by approximately 38% of patients in this direct comparison to a placebo arm at 8 weeks and 28% at 12 weeks [vs 13% and 8% with placebo, respectively], and 33% [at 12 weeks for patients treated from week 1 to 48].³ Basically, between 30% to 40% of patients would acquire transfusion independence with luspatercept if they have RS.

I always wonder that at best, 38% patients responded. What about the rest? The majority doesn't respond, so what is the mechanism of response? What is this drug working on? If it is directly affecting the RS, then everybody should respond, but they don't, which means it is just one of the factors that is suggestive that patient would respond, but definitely not the ultimate.

The treatment safety outcomes with luspatercept, [considering] all the dose escalations and the dose reductions that were needed, showed it's a fairly well tolerated drug.

What is the significance of the SF3B1 mutation for anemia in this population?

When this drug first came, we went to our tissue repository and I pulled out something like 600 patients with refractory anemia and RS who I have seen over the years, and I went to see how many of them have the SF3B1 mutation. In my cohort, it was not 98% or 95%; it was about 70% who had the SF3B1 mutation. The other 30% to 35% had other splicing factor mutations: SRSF2, U2AF1, and RS. So once again, it's an interesting thing to note that if you see SF3B1 mutation, then the patient will definitely have RS. But if you see RS, it's only a 70% chance that they would have a SF3B1 mutation because 30% could be another splicing factor or no mutation at all. But what we showed was that the survival for patients who have RS plus SF3B1 is much better overall compared with the survival of SF3B1 negative, other splicing factor positive.

REFERENCES:

1. Fenaux P, Santini V, Spiriti MAA, et al. A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic patients with low-risk MDS. Leukemia. 2018;32(12):2648-2658. doi:10.1038/s41375-018-0118-9

2. Platzbecker U, Symeonidis A, Oliva EN, et al. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 2017;31(9):1944-1950. doi:10.1038/leu.2017.192

3. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892