Expert Selections From ASH 2020: Myelodysplastic Syndromes and Myeloproliferative Neoplasms

In this commentary, Amy E. DeZern, MD, MHS, and Srdan Verstovsek, MD, PhD, share insights on selected abstracts from ASH 2020 about myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs), respectively, and how these data are poised to affect clinical practice.

Amy DeZern, MD, MHS: Myelodysplastic Syndromes

BMT CTN 1102 Trial: Reduced‑Intensity Conditioning for Allo-HSCT in Older Patients With MDS
BMT CTN 1102 was an open-label, multicenter, biological assignment phase II trial specifically in patients aged 50‑75 years with de novo intermediate risk–2 or high‑risk MDS who were deemed candidates for reduced‑intensity conditioning and allogeneic hematopoietic stem cell transplant (allo-HSCT) (N = 384). The study goal was to explore if allo-HSCT, a potential curative therapy for MDS, confers a survival benefit in this older group of patients, for whom the current standard of care is a hypomethylating agent. Of note, transplantation is not usually covered by Medicare for patients 65 years of age or older.

Patients were enrolled in the donor arm if an 8/8 HLA matched donor based on high‑resolution HLA typing was available. Patients initially assigned to the no donor arm could be reassigned to the donor arm if a suitable donor could be identified. The primary endpoint for this study was 3‑year OS and a key secondary endpoints were leukemia-free survival (LFS) and quality of life (QoL).

The donor arm had a 3‑year OS of 47.9% compared with 26.6% in the no donor arm. This is a significant absolute improvement for the donor arm of 21.3%. Absolute improvement was even greater at 31.4% among patients who ultimately went to transplant (the “as‑treated” analysis). This is a clinically very meaningful difference for our patients. The secondary endpoint of LFS found an absolute improvement for the donor arm of 15.2% for 3‑year LFS. A very thoughtful and important part of this study was extensive QoL assessments that showed no significant decrease in QoL in the donor arm compared with the no donor arm using several QoL tools and at all time points examined.

I think this is a practice‑changing study that suggests allo-HSCT with a suitable donor leads to improved outcomes with no decrease in QoL for patients aged 50‑75 years with higher‑risk MDS. Of importance, improvements in OS and LFS were similar for patients older than 65 years and those aged 65 years or younger, so I think that allo-HSCT should be considered a treatment option for patients with higher‑risk disease. Hopefully, this will encourage early referral to stem cell transplant centers and also provides a good argument for allo-HSCT coverage by Medicare in this patient population.

P-2001: Pevonedistat Plus Azacitidine in MDS
Another important presentation at ASH 2020 was a post hoc analysis of P-2001, a randomized, open-label phase II study of pevonedistat plus azacitidine compared with azacitidine monotherapy in higher‑risk MDS, chronic myelomonocytic leukemia, or low-blast acute myeloid leukemia. The analysis presented focused on the cohort of patients with higher-risk MDS (n = 67). Pevonedistat inhibits the NEDD8‑activating enzyme, which prevents protein ubiquitination upstream of the proteasome, disrupting the cell cycle, and ultimately resulting in apoptotic cell death. In mouse models of acute myeloid leukemia, pevonedistat in combination with azacitidine was synergistic.

Patients with MDS enrolled on the trial were treatment naive, with no previous hypomethylating agent, and ineligible for allo-HSCT. The primary endpoint was OS with a secondary endpoint of event-free survival. The study also reported data on molecular signatures of patients correlated with response.

The median event-free survival for the combination arm was 20.2 months vs 14.8 months for the monotherapy arm, which is statistically significant and clinically meaningful. Combination therapy was even more effective in patients categorized as high‑risk and very high–risk groups by the Revised International Prognostic Scoring System. Combination therapy improved OS vs azacitidine at 23.9 months vs 19.0 months, respectively; although not statistically significant, this difference is probably clinically meaningful for our patients. Pevonedistat plus azacitidine resulted in an ORR of 79%, of which 52% were CRs and 24% were hematologic improvement—this is also clinically very important for our patients. Additional outcomes that favored the combination included duration of response (34.6 vs 13.1 months) and transfusion‑independence rates (69.2% vs 47.4%). The time to acute myeloid leukemia transformation was also longer with pevonedistat, by more than 6 months—again, very clinically meaningful for the patients.

An important consideration for combination therapies, especially in higher‑risk MDS, is whether the combination is more toxic with limited clinical benefit. In this study, the combination of pevonedistat and azacitidine was not more toxic compared with azacitidine alone, and I find that encouraging.

The study also examined ORR by genetic mutation for many common higher‑risk adverse prognostic molecular features to determine if there is a mutational signature for response. I think this is an example of the type of analyses that we will be seeing more of in MDS trials.

In summary, for patients who have higher‑risk MDS, pevonedistat plus azacitidine prolongs event-free survival, with a trend for extended OS compared with azacitidine alone. Additional outcomes also favored the combination without an increase in toxicity, which is really important for our patients. The phase III PANTHER trial (NCT03268954) comparing pevonedistat plus azacitidine with azacitidine alone is fully enrolled, and we look forward to the results in the future.

Srdan Verstovsek, MD, PhD

CONTINUATION‑PV: Ropeginterferon α-2b in PV
Polycythemia vera (PV) is one of the chronic conditions of the bone marrow associated with erythrocytosis, and most patients also have elevated platelets and white blood cells. Patients with PV have an increased thrombotic risk that needs to be effectively decreased in everyday practice. Standard practice in the United States is to administer hydroxyurea or pegylated interferon, although there is no FDA-approved pegylated interferon. However; ropeginterferon α ‑2b is a pegylated interferon approved in Europe in 2019.

The 5‑year results of the CONTINUATION‑PV study of ropeginterferon α‑2b in PV were reported at ASH 2020. CONTINUATION-PV is a continuation study of PROUD-PV that randomized patients with PV to either ropeginterferon α‑2b or hydroxyurea (n = 127, each arm). Patients were treatment naive or hydroxyurea experienced for less than 3 years with no resistance, intolerance, or CR. Ropeginterferon α‑2b is administered as a subcutaneous injection every 2 weeks. 

Complete hematologic response rate was significantly improved with ropeginterferon α-2b after the first year of therapy compared with hydroxyurea, and the benefit was maintained for subsequent years. At Years 4 and 5, significantly more patients were phlebotomy free with ropeginterferon α-2b compared with hydroxyurea (P = .01, each year). The percentage of patients phlebotomy free at Year 5 was 81.8% in the ropeginterferon α-2b arm vs 63.2% with hydroxyurea. In contrast to hydroxyurea, ropeginterferon α‑2b decreased JAK2 V617F allele burden, implying that we can possibly eliminate disease in some patients, leading to cessation of therapy, or perhaps we can prevent disease progression.

The toxicities associated with ropeginterferon α‑2b were limited and no major thromboembolic events were observed, suggesting that patients may benefit from this therapy for long period of time.

Given these exciting data, an application for ropeginterferon α‑2b was sent to the FDA in June 2020. The combination of improved complete hematologic response, durability, and minimal toxicity lead to longer time on therapy and a greater benefit.

Luspatercept in MF
The 3 cardinal problems that patients with myelofibrosis (MF) have are symptomatic splenomegaly, poor QoL, and anemia. JAK inhibitors, like ruxolitinib or fedratinib, can control splenomegaly and symptoms but may worsen anemia, leading to dose reductions or treatment discontinuation. Many patients with MF become dependent on red blood cell transfusions due to anemia. At ASH 2020, results were presented from a phase II study of luspatercept, an erythroid maturation agent, in patients with MF who are red blood cell transfusion dependent. Luspatercept is currently indicated in patients with MDS/MPNs for anemia failing an erythropoiesis-stimulating agent and requiring ≥ 2 red blood cell units over 8 weeks in adult patients with very low–risk to intermediate-risk MDS with ring sideroblasts or with MDS/MPN with ring sideroblasts and thrombocytosis.

Data from 2 cohorts of patients who were transfusion dependent were reported: those receiving ruxolitinib (cohort 3b, n = 22) and those who were not receiving ruxolitinib (cohort 2, n = 21). All patients received luspatercept via subcutaneous injection every 3 weeks. In patients who were receiving ruxolitinib, 27% of the patients achieved ≥ 12-week period of transfusion independence with the addition of luspatercept vs 10% of patients not receiving ruxolitinib. Over the entire treatment period, 36% of the patients in the ruxolitinib cohort achieved transfusion independence compared with 19% in the no ruxolitinib cohort. Luspatercept also reduced transfusion burden in patients receiving ruxolitinib but not achieving transfusion independence. The safety profile revealed no significant concerns.  

These results indicate that luspatercept therapy could be a huge benefit because this addresses anemia as the third major issue in MF, for which there currently are no approved drugs. A randomized phase III registrational trial of luspatercept for patients with MF and anemia while being treated with a JAK inhibitor is planned (INDEPENDENCE, NCT04717414). This is a positive sign that our efforts in the management of MF are moving forward by trying to manage all of the major problems associated with MF.

IMbark: Imetelstat as Second-line Therapy in MF
Standard therapy for patients with MF, the most aggressive of MPNs, is a JAK inhibitor to control splenomegaly and symptoms, and most patients also have a prolongation of life. However, JAK inhibitors do not work forever and selecting therapy in the second-line setting is a major issue. In this setting, imetelstat, which is a telomerase inhibitor, has proven to be beneficial to the patient not only in terms of improving the symptoms of the disease but possibly prolonging life.

The IMbark study examined 2 different doses of imetelstat in the second‑line setting after ruxolitinib in intermediate 2–risk/high-risk MF (N = 107). An earlier analysis suggested that imetelstat had a positive effect on OS. The higher dose (9.4 mg/kg) had a 24-month survival rate of 57.9% compared with 42.0% in the 4.7-mg/kg dose arm. Associations between OS and spleen response, symptom response, and bone marrow fibrosis improvement with imetelstat were the focus of the presentation at ASH 2020.

Comparing the 2 arms, the 9.4-mg/kg dose of imetelstat resulted in a greater percentage of patients achieving a total symptom score reduction of ≥ 50% at 24 weeks (32.2% vs 6.3%) and a higher percentage of patients with spleen volume reduction of ≥ 35% (11.9% vs 2.1%). There is also a strong correlation between improvement in bone marrow fibrosis and OS.

A randomized phase III study of imetelstat, IMpactMF, is planned to start in 2021, in which patients in a second‑line setting will be randomized to imetelstat or the best available therapy, except a JAK inhibitor which these patients have failed before (NCT04576156). This is the first study in the MF field to test any medication with a goal of prolonging life. We are all excited to move beyond the obvious goals of symptomatic improvement to a higher level of prolonging the life of patients, especially in second‑line setting.

Conclusion
It is a very exciting time for patients with MPNs. For PV we are anticipating the possible approval of ropeginterferon α‑2b in 2021 in the United States, which has shown durable benefit in controlling blood counts in a great majority of the patients, without significant adverse events. In MF, the most aggressive of MPNs, we are now potentially subdividing patients by special needs, such as anemia and second-line therapy. Encouraging data were presented for luspatercept to control anemia, while imetelstat may offer clinical benefit to patients after failure of JAK inhibitor therapy. We are upping the bar on controlling the spleen, symptoms, or anemia to prolong survival, and the first ever study to examine a survival benefit is soon to open in United States for our patients in dire situations in second‑line setting.

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