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Key Studies in Myelodysplastic Syndromes and Myeloproliferative Neoplasms: CCO Independent Conference Highlights of the 2020 Virtual ASH Annual Meeting

Amy E. DeZern, MD, MHS
Srdan Verstovsek, MD, PhD
Released: February 16, 2021

Key Studies in Myeloproliferative Neoplasms

Imetelstat in Relapsed/Refractory Myelofibrosis: Background

Srdan Verstovsek, MD, PhD:
Patients with myelofibrosis (MF) who are relapsed/refractory to frontline therapy with JAK inhibitors (JAKi) have poor survival outcomes and quality of life (QoL).[1] The usual goals of therapy in this setting are to control spleen volume and symptoms. Imetelstat is a telomerase inhibitor that targets proliferation of malignant stem and progenitor cells.[2]

IMbark: Correlation of Survival and Other Clinical Benefits With Imetelstat in High-Risk, JAK Inhibitor–Refractory Myelofibrosis

Srdan Verstovsek, MD, PhD:
IMbark was a randomized, single‑blind phase II study comparing 2 doses of the JAKi imetelstat (9.4 vs 4.7 mg/kg) in patients with relapsed/refractory intermediate-2–risk/high-risk MF (N = 107).[3] Previously, results of IMbark suggested that imetelstat at the higher dose had an impact on OS in addition to some clinical benefit in controlling symptoms and spleen volume.

At ASH 2020, Mascarenhas and colleagues[4] presented an analysis of IMbark, which evaluated associations between OS and spleen response, symptom response, and bone marrow fibrosis improvement. Endpoints in this analysis included spleen volume reduction (SVR) by ≥ 35% at Week 24, total symptom score reduction by ≥ 50% (TSS50) at Week 24, and decrease in fibrosis by at least 1 grade. The prognostic value of pretreatment baseline characteristics regarding OS were also evaluated.

IMbark: Survival and Clinical Benefit

Srdan Verstovsek, MD, PhD:
Results showed a dose-dependent effect on OS, with 57.9% of the patients in the 9.4-mg/kg group (n = 59) surviving to 24 months compared with 42.0% of the patients in the 4.7-mg/kg group (n = 48). Median OS was 19.9 months at 4.7 mg/kg vs 28.1 months with 9.4 mg/kg.

Of note, the percentage of patients with improvement in marrow fibrosis of at least 1 grade rose from 20.0% of patients at 4.7 mg/kg to 43.2% of patients at 9.4 mg/kg (HR for improvement vs worsening 0.37; CI: 0.14-0.98; P = .0443). This was strongly correlated with OS. Likewise, the percentage of patients with ≥ 50% reduction in the total symptom score (TSS) by Week 24 rose from 6.3% at 4.7 mg/kg to 32.2% at 9.4 mg/kg (HR for ≥ 50% TSS reduction vs < 50% TSS or missing: 0.78; CI: 0.40-1.49; P = .4491). The percentage of patients with ≥ 35% SVR also rose, from 2.1% to 11.9% (HR: 0.44; CI: 0.11-1.85; P = .2647).

IMbark: Predictive Disease Characteristics for Survival

Srdan Verstovsek, MD, PhD:
A pooled analysis revealed baseline factors correlated with an increased risk of death.[4] Baseline factors predictive for poor survival included Dynamic International Prognostic Scoring System (DIPSS) high risk (high vs low risk: HR 2.16; P = .0014), Eastern Cooperative Oncology Group performance status of 2 (2 vs 0/1: HR 2.33; P = .0025), transfusion dependence (dependent vs independent: HR 1.78; P = .0320), and level of response to JAKi therapy (response/clinical improvement vs stable disease/progressive disease/unknown: HR 1.72; P = .0290).

IMbark: Conclusions

Srdan Verstovsek, MD, PhD:
Investigators concluded that imetelstat continued to show a dose-related OS benefit in patients with intermediate-2–risk/high-risk MF who relapsed or were refractory to JAKi. In this study, improvements in bone marrow fibrosis were significantly correlated with a lower risk of death, the SVR showed a trend in correlation with increased OS, and baseline factors were identified that correlate with increased risk of death (eg, DIPSS high risk, transfusion dependence, and level of response to JAKi).

We are all very excited about the phase III IMpactMF trial, which will further compare imetelstat with best available therapy in patients with JAKi-refractory MF (NCT04576156). If IMpactMF confirms the OS benefit seen in IMbark, imetelstat may become a standard second‑line medication for relapsed MF after ruxolitinib.

Novel BET Inhibitor, CPI-0610, Plus Ruxolitinib in JAKi-Naive Patients With Myelofibrosis: Background

Srdan Verstovsek, MD, PhD:
We do not have medications that will eliminate MF; therefore, we treat 3 symptomatic problems—anemia, poor QoL, and splenomegaly. The JAKi ruxolitinib helps manage splenomegaly and QoL. Ruxolitinib is the standard first‑line therapy for most patients with MF. Unfortunately, optimal benefits from ruxolitinib are only seen in a small number of patients and the benefits do not last long.

BET proteins regulate target genes that result in decreased cytokine production and atypical erythroid and megakaryocytic differentiation.[5] The combination of a BET inhibitor and ruxolitinib may offer better symptom control. CPI‑0610 is a novel, first-in-class, oral BET inhibitor found to reduce inflammation and regulate erythrocyte and megakaryocyte differentiation ex vivo.[6]

MANIFEST Arm 3: Novel BET Inhibitor, CPI-0610, Plus Ruxolitinib in JAKi-Naive Patients With Myelofibrosis

Srdan Verstovsek, MD, PhD:
MANIFEST is an ongoing, global, multicenter, open-label phase II trial of CPI-0610, with or without ruxolitinib, in MF.[7-9] At ASH 2020, Mascarenhas and colleagues presented results from arm 3, in which patients with no previous JAKi or BET inhibitor therapy and DIPSS scores of intermediate-2 or higher (N = 78) received the combination of CPI-0610 and ruxolitinib.[7] CPI-0610 was dosed at 125 mg once daily, 2 weeks on/1 week off and ruxolitinib 10 mg twice daily if platelets ≥ 100-200 x 109/L or 15 mg twice daily if platelets > 200 x 109/L.

The primary endpoint was an SVR ≥ 35% and the key secondary endpoint was a TSS50, both at Week 24.

MANIFEST Arm 3: Baseline Patient Characteristics

Srdan Verstovsek, MD, PhD:
The baseline characteristics of these patients are as expected for patients with JAKi‑naive MF. More than three quarters were intermediate‑2 risk/high risk by DIPSS and International Prognostic Scoring System (IPSS) measures. Patients with ≥ 3 mutations made up 50% of the study population, including mutations in HMR (55%), ASXL1 (45%), and JAK2 (72%). Of note, more than one half (54%) of patients had primary MF, with the remainder having post-PV or post–essential thrombocythemia MF.

Some patients were anemic, with a median hemoglobin level of 9.1 g/dL, and 65% of patients started the study with < 10 g/dL.

MANIFEST Arm 3: Outcomes

Srdan Verstovsek, MD, PhD:
The results were quite good, as SVR ≥ 35% was observed at Week 24 in 67% of patients, with a median SVR of 50%. In addition, continued therapy was associated with improvement in SVR. SVR was better in earlier‑phase patients (intermediate‑1) than in more advanced‑phase patients like intermediate‑2 or high risk.

Symptoms were also very well controlled. A TSS50 improvement was observed in 57% of the patients, with a median reduction of 59%. Of importance, both the SVR and symptom control were much higher than seen with the traditional use of ruxolitinib therapy alone. Increased hemoglobin was observed in some patients who had baseline levels < 10 g/dL. A reduction in bone marrow fibrosis was also observed in 33% of the patients.

MANIFEST Arm 3: Safety

Srdan Verstovsek, MD, PhD:
When agents are given in combination, a concern is overlapping toxicity. BET inhibitors, as a class, result in dose-limiting thrombocytopenia.[10] However, no major treatment-emergent adverse events were seen. Thrombocytopenia occurred in 32% of the patients, but only 8% were grade 3/4. Grade 3/4 anemia was observed in 29% of the patients, which is not unusual as many therapies for MF are myelosuppressive. There were no other unusual nonhematologic side effects of concern.

MANIFEST Arm 3: Investigator Conclusions

Srdan Verstovsek, MD, PhD:
Results with the combination of CPI‑0610 and ruxolitinib in JAKi-naive patients with MF compare favorably to ruxolitinib alone: 67% achieved SVR ≥ 35% at week 24 vs historical data of 29% to 42% for ruxolitinib.[7, 11,12] Most patients (57%) experienced TSS50 symptom improvement by Week 24. The improvements observed in hemoglobin and bone marrow fibrosis may reveal additional benefits of this combination.

MANIFEST‑2 is an ongoing, randomized, placebo‑controlled phase III trial of CPI‑0610 plus ruxolitinib in patients with JAKi‑naive MF (NCT04603495). If positive, this study may result in the combination of CPI‑0610 and ruxolitinib as a new standard of care in the frontline setting for MF.

Phase II Study of Luspatercept in Myelofibrosis: Background

Srdan Verstovsek, MD, PhD:
JAKi are the standard for treating MF but unfortunately worsen anemia in many patients.[13,14] Anemia affects dosing management of JAKi, potentially leading to underdosing or discontinuation of therapy. Currently, no agents targeting anemia are approved for patients with MF but erythropoietin‑stimulating agents or immunomodulatory inhibitory drugs are recommended.[15] Luspatercept is a first-in-class erythroid maturation agent recently approved for use in patients with MDS.[16,17] It binds TGF-β superfamily ligands to diminish aberrant SMAD2/3 signaling, thereby enhancing late‑stage erythropoiesis and reducing the transfusion burden.[18-21]

Phase II Study of Luspatercept in Myelofibrosis: Study Design

Srdan Verstovsek, MD, PhD:
An ongoing global phase II study is evaluating the clinical benefit of luspatercept in anemic patients with MF who were transfusion dependent (TD) or transfusion independent (TI) at time of enrollment (N = 79).[21] The analysis presented at ASH 2020 reported results from patients who were TD as defined by requiring ≥ 2 units of RBC every 28 days. Patients were categorized into cohorts based on current therapy with ruxolitinib. In the primary treatment phase, patients received luspatercept 1.0 mg/kg with titration to 1.75 mg/kg every 3 weeks for 168 days. Patients with a clinical benefit were allowed to continue treatment into the extension phase.

Primary endpoints in this study differ based on transfusion status. The primary endpoint in TI patients is an increase in hemoglobin ≥ 1.5 g/dL during any 12-week period and remaining TI. The primary endpoint for TD patients is being TI for ≥ 12 consecutive weeks. Secondary endpoints include treatment-emergent adverse events, increases in hemoglobin, and decreases in RBC transfusions.

Phase II Study of Luspatercept in Myelofibrosis: Baseline Characteristics

Srdan Verstovsek, MD, PhD:
The patient characteristics in each cohort were similar and standard for this type of study. The median age ranged from 64 to 75 years, 58% were male, and the majority (57%) had primary MF (vs post–essential thrombocythemia or post-PV MF). The DIPSS risk category was intermediate 1/2 for nearly all patients (89%) with only 8 in the high-risk category.

Phase II Study of Luspatercept in Myelofibrosis: Responses in Patients Receiving RBC Transfusions

Srdan Verstovsek, MD, PhD:
The response to luspatercept observed in TD patients is quite striking. In the first 24 weeks of the trial, a 12-week TI period or longer was achieved in 10% of patients not receiving ruxolitinib (n = 21) and in 27% of patients receiving ruxolitinib (n = 22). During the entire treatment period, 19% of patients not receiving ruxolitinib and 36% of patients receiving ruxolitinib became TI. The significance of these results cannot be understated since we do not currently have any approved medications for anemia in this population. (Current indication for luspatercept in patients with MDS/MPNs is for anemia failing an erythropoiesis-stimulating agent and requiring ≥ 2 RBC 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.)

Phase II Study of Luspatercept in Myelofibrosis: Reduction of Need for RBC Transfusions

Srdan Verstovsek, MD, PhD:
The benefit of luspatercept on anemia was further analyzed in TD patients. In addition to the 36% of patients receiving ruxolitinib who became and remained TI (n = 8), another 46% (n = 10) had their transfusion burden reduced by ≥ 50%. Clearly, luspatercept reduces the transfusion burden in the majority of patients taking ruxolitinib. Adding luspatercept to ruxolitinib may be a useful strategy in everyday practice once luspatercept is approved in this disease setting.

Phase II Study of Luspatercept in Myelofibrosis: Safety

Srdan Verstovsek, MD, PhD:
When combining 2 medications, it is important to investigate overlapping toxicity. Fortunately, this trial did not reveal any major safety concerns for luspatercept across the entire patient population and grade 3/4 treatment related adverse events were minimal. No safety concerns were raised about adding luspatercept to ruxolitinib.

Phase II Study of Luspatercept in Myelofibrosis: Conclusions

Srdan Verstovsek, MD, PhD:
The results of this study strongly support further investigations into the use of luspatercept in anemic patients with MF, particularly those taking ruxolitinib. In patients with TD MF-associated anemia, luspatercept showed durable activity, with 10% and 27% of patients achieving TI lasting ≥ 12 weeks in cohorts 2 and 3B, respectively. Also, 25% of patients achieved 2 periods of TI lasting ≥ 12 weeks.

As discussed, anemia affects the proper dosing of ruxolitinib and leads to unnecessary early discontinuations of therapy. A planned blinded, placebo-controlled phase III study will further evaluate luspatercept in anemic patients with MF on a stable dose of ruxolitinib (NCT04717414).

Developing second-line drugs, boosting the effectiveness of JAKi, and developing treatments for anemia are 3 areas of intense interest in MF. Many new drugs are already being developed in these areas, so it is possible that new therapies will receive approval in the next 3‑5 years. If approved, luspatercept plus ruxolitinib will likely become the new standard of care for MF.

Ropeginterferon α-2b in Polycythemia Vera: Background

Srdan Verstovsek, MD, PhD:
PV is a MPN associated with erythrocytosis and many patients also have elevated platelets and white blood cells. Thrombosis is a leading cause of death for patients with PV. For several decades, standard therapy has been cytoreduction with hydroxyurea plus low-dose baby aspirin. Interferon is also used off-label for cytoreduction in PV but toxicity precludes long-term treatment with interferon. Patients with PV live decades so there is a need for safe and effective therapy that can be given for much longer.

Ropeginterferon α-2b is a newer, monopegylated preparation of interferon α-2b with a longer half-life, allowing administration every 14 days instead of every 7 days. Ropeginterferon α-2b received approval in Europe in 2019 for patients with PV without symptomatic splenomegaly, and it has been submitted to the FDA for approval.

The phase III PROUD-PV and extension CONTINUATION-PV trials were randomized, open-label studies conducted in Europe comparing ropeginterferon α-2b to standard-of-care hydroxyurea in patients with PV.[22] Results from both studies showed that ropeginterferon α-2b was superior to hydroxyurea at 3 years, and that responses increased over time.

CONTINUATION-PV: 5-Year Results of Ropeginterferon α-2b in Polycythemia Vera

Srdan Verstovsek, MD, PhD:
At ASH 2020, Gisslinger and colleagues[23] presented 5-year results of treatment with ropeginterferon α-2b in the CONTINUATION-PV extension trial of PROUD-PV. In PROUD-PV, patients with PV were randomized to receive hydroxyurea (n = 127) or ropeginterferon α-2b (n = 127). Enrolled patients were treatment naive or hydroxyurea experienced for less than 3 years with no resistance, intolerance, or CR. After 1 year, the CONTINUATION-PV study extended treatment for an additional 48 months (n = 95 in ropeginterferon α-2b arm, 76 in the best available treatment arm).

CONTINUATION-PV: Hematologic Responses

Srdan Verstovsek, MD, PhD:
The complete hematologic response rate to ropeginterferon α-2b was significantly improved after the first year of therapy compared with hydroxyurea. Furthermore, significantly more patients were phlebotomy free in the fourth (P = .01) and fifth years of ropeginterferon α-2b compared with hydroxyurea (P = .01). At Year 5, 81.8% of patients in the ropeginterferon α-2b arm did not require phlebotomy vs 63.2% in the control arm.

Nearly all patients with PV have a JAK2 V617F mutation and change in JAK2 V617F allele burden is a marker of molecular response. It is now clear, after 5 years of follow-up, that there is a steady decline in the JAK2 V617F allele burden in patients receiving ropeginterferon α-2b that was not seen in the control arm. In fact, the statistical significance in allele burden between the 2 arms, where there was no significant effect of hydroxyurea, is so great that the P values are < .0001 starting from Year 3. A steady decline in the JAK2 V617F allele burden could lead to some patients reaching a complete molecular response after 5 years of therapy.

CONTINUATION-PV: Molecular Responses

Srdan Verstovsek, MD, PhD:
The use of ropeginterferon α-2b clearly improved the molecular response to malignant clones. And, as shown here, significantly more patients receiving ropeginterferon α-2b maintained a molecular response plus a hematocrit < 45% without phlebotomy at Year 5 (P < .0001).

CONTINUATION-PV: Specific Adverse Events

Srdan Verstovsek, MD, PhD:
No major thromboembolic adverse events were observed in the CONTINUATION-PV study. Overall, rates of serious adverse events, treatment-related adverse events, and grade ≥ 3 adverse events were similar across the entire 5-year period. Treatment-related adverse events of particular interest included endocrine events in 6 patients (thyroiditis and hypothyroidism/hyperthyroidism), psychiatric events in 1 patient, and musculoskeletal events and skin toxicity in 2 patients each.


Srdan Verstovsek, MD, PhD:
After 5 years of follow-up, results from the CONTINUATION‑PV study showed that ropeginterferon α-2b was associated with a significantly higher number of patients who were phlebotomy free during Years 4 and 5 compared with control. Moreover, long-term use of ropeginterferon α-2b was associated with durable molecular responses and fewer instances of disease progression to MF or acute myeloid leukemia. This gives hope that longer‑term follow-up will reveal continued decreases or even elimination of the malignant clones and a continued decrease in risk of disease progression. A continued decrease in the risk of progression to MF or acute myeloid leukemia is highly desirable for patients with PV as these are long‑term worries with the potential for significantly shorter life expectancy.

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