Hematology 2022: MDS and MPNs

CME

Key Studies in Myelodysplastic Syndromes and Myeloproliferative Neoplasms: Independent Conference Coverage of ASH 2022

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit

Released: March 16, 2023

Expiration: March 15, 2024

Srdan Verstovsek
Srdan Verstovsek, MD, PhD
Amer Zeidan
Amer Zeidan, MBBS, MHS

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Advances in MPNs

Srdan Verstovsek, MD, PhD: 
At ASH 2022, several potentially practice-changing studies were presented that have the potential to improve outcomes for patients with MPNs, including MF, PV, and essential thrombocythemia (ET).

MOMENTUM Update: Momelotinib vs Danazol in Symptomatic, Anemic Patients With Previously Treated MF

Srdan Verstovsek, MD, PhD: 
I would like to begin the discussion with the MOMENTUM trial, for which updated results were presented at ASH 2022. Ruxolitinib is a current SoC first-line therapy for treating the symptoms of MF, but many patients with MF experience anemia, which can be exacerbated by ruxolitinib.19,20 Momelotinib has JAK1/2-inhibiting activity and, like ruxolitinib, can improve splenomegaly and MF-related symptoms. Unlike ruxolitinib, momelotinib also inhibits ACVR1, also called ALK2, which is a receptor on liver hepatocytes.21,22 By inhibiting ACVR1, momelotinib can decrease hepcidin levels, which increases iron availability and relieves iron-restricted erythropoiesis, thereby normalizing hemoglobin and red blood cell levels and ameliorating anemia.21

MOMENTUM was a randomized, double-blind phase III study assessing momelotinib vs danazol in patients who had previously received a JAK inhibitor and were anemic (hemoglobin <10 g/dL) and symptomatic (TSS ≥10) with a platelet level ≥25 x 109/L.23 Patients could cross over from danazol to momelotinib after Week 24 (earlier if confirmed progressive disease). The primary endpoint of this trial was TSS response (≥50% reduction from baseline per Myelofibrosis Symptom Assessment Form version 4.0) at Week 24. At ASH 2022, updated efficacy and safety results through Week 48 were presented.

MOMENTUM Update: TSS Response

Srdan Verstovsek, MD, PhD: 
Initial results demonstrated that MOMENTUM met its primary endpoint of improved TSS response with momelotinib vs danazol at Week 24.24 Of note, momelotinib was noninferior to danazol in TI, which is very important because, as mentioned, there is not a currently approved agent to control MF signs and symptoms and anemia in patients with MF. 

As presented at ASH 2022, TSS responses with momelotinib were durable, as 97% of patients who achieved TSS response at Week 24 maintained this response at Week 48.23 In addition, 12% of TSS nonresponders achieved a new response between Weeks 24 and 48. 

MOMENTUM Update: TI and Hemoglobin Levels

Srdan Verstovsek, MD, PhD: 
In addition to durable symptom control, changes in hemoglobin levels with momelotinib were maintained through Week 48.23 Of importance, TI, which is a key difference between momelotinib and other JAK inhibitor therapies, was prolonged with momelotinib. 

MOMENTUM Update: OS and LFS

Srdan Verstovsek, MD, PhD: 
Of interest, trial results suggest that momelotinib may affect OS. During the initial 24 weeks (pre‒open-label crossover period) of the trial, there were differences in the OS and LFS curves for momelotinib and danazol, suggesting that a longer-term follow-up may have demonstrated that momelotinib was superior to danazol with regard to survival.23    

At 24 weeks, all patients receiving danazol crossed over to momelotinib, and the results demonstrate that the patients who crossed over benefited from receiving momelotinib. Data are not yet available for assessing long-term OS. 

MOMENTUM Update: Safety During Open-Label Momelotinib

Srdan Verstovsek, MD, PhD: 
Data showed that, overall, momelotinib has a very favorable toxicity profile. Momelotinib was not associated with significant GI toxicity or major neurologic toxicity issues, and most patients receiving momelotinib remained on the therapy.23    

MOMENTUM Update: Patients With Thrombocytopenia

Srdan Verstovsek, MD, PhD: 
Data from a subgroup of patients with thrombocytopenia demonstrated that momelotinib is active in controlling spleen volume and MF-associated symptoms in these patients.23 TI was a benefit of momelotinib, regardless of the patient’s platelet count. 

In addition, the results showed that in patients with a platelet level <50 x 109/L, momelotinib was associated with prolonged OS compared with those receiving danazol. 

Data showed that momelotinib is safe in the subgroup of patients with thrombocytopenia, with an AE profile consistent with that observed in the intention-to-treat population.

MOMENTUM Update: Conclusions

Srdan Verstovsek, MD, PhD:
Data from the 48-week follow-up MOMENTUM trial are intriguing. Of special interest are the data suggesting the potential for prolonged OS with momelotinib vs danazol, as patients requiring second-line therapy for MF typically have a poor prognosis, with an average survival of approximately 2 years and a shorter average survival—approximately 7 months—in patients with a platelet level <50 x 109/L.23    

It will be interesting to follow the longer-term results from this study that will be presented in the future.

Parsaclisib Add-on Therapy in Patients With MF and Suboptimal Response to Ruxolitinib

Srdan Verstovsek, MD, PhD: 
Ruxolitinib and other JAK inhibitors, which act by inhibiting intracellular signaling pathways, are the SoC treatment for signs and symptoms of MF.15,20 Specifically, these therapies reduce symptomatic splenomegaly and other MF-related symptoms, including night sweats, fevers, itching bone aches and pains, cachexia, and weakness.19 

In some patients, JAK inhibitor therapy is either not effective or is effective only for a short time.25 JAK inhibitors can fail when accessory intracellular signaling pathways, including PI3K signaling pathways, are activated and bypass the JAK-inhibitor‒induced benefits. 

Parsaclisib is a PI3Kδ inhibitor that was assessed in an open-label, randomized, parallel-group phase II study as an add-on therapy to ruxolitinib in patients with MF and a suboptimal response to ruxolitinib.26 The study included multiple arms, each examining different parsaclisib dosing schedules. The primary endpoint for the study was change in spleen volume from baseline to Week 12.

Parsaclisib Add-on Therapy in MF: Change in Spleen Volume

Srdan Verstovsek, MD, PhD: 
Suboptimal responders can be considered to have obtained a benefit from therapy when spleen volume is reduced by 25%. This is in contrast to the 35% reduction that is considered to be the threshold for benefit in patients receiving first-line therapy.

Data presented from this study at ASH 2022 demonstrated that adding all-daily dosing of parsaclisib to ruxolitinib was associated with substantial improvements in SVR. Among patients receiving daily parsaclisib, 21.4% and 28.6% of patients experienced a ≥25% reduction in spleen volume at 12 weeks and 24 weeks, respectively.26   

Parsaclisib Add-on Therapy in MF: Change in MPN-SAF Symptom Score

Srdan Verstovsek, MD, PhD: 
Add-on parsaclisib therapy also was associated with rapid and substantial quality of life improvements, as gauged by TSS. At 24 weeks, 48.6% of patients receiving all-daily parsaclisib had achieved a 50% decrease in TSS.26 Improvements in spleen length and symptoms occurred relatively quickly, within 2-3 months. 

Parsaclisib Add-on Therapy in MF: Change in MPN-SAF Symptom Score (cont'd)

Parsaclisib Add-on Therapy in MF: TEAEs

Srdan Verstovsek, MD, PhD: 
Low-dose parsaclisib (5 mg once daily) was not associated with any notable major complications.26 Of note, patients experienced some concomitant nausea (any grade: 16.7%), and 33% of patients had grade 3/4 thrombocytopenia.

Parsaclisib Add-on Therapy in MF: TEAEs (cont'd)

Parsaclisib Add-on Therapy in MF: Conclusions

Srdan Verstovsek, MD, PhD: 
The results from this phase II study are promising and suggest that the combination of parsaclisib and ruxolitinib may have value in improving spleen volume and symptoms in patients with MF who have a suboptimal response to ruxolitinib monotherapy.26

To this end, a global phase III study is underway that may result in the approval of parsaclisib as an add-on therapy to ruxolitinib in patients with a suboptimal response to ruxolitinib monotherapy.

MANIFEST: Pelabresib Plus Ruxolitinib for JAK Inhibitor Treatment‒Naive Patients With MF

Srdan Verstovsek, MD, PhD: 
We will now discuss another investigational combination regimen that includes ruxolitinib, this time in the first-line setting. MANIFEST is an ongoing, multiarm, global, open-label phase II trial assessing pelabresib therapy for MF. At ASH 2022, results were presented from 1 arm of this trial, in which patients with intermediate/high-risk MF and no prior JAK inhibitor therapy (N = 84) received the combination of ruxolitinib plus pelabresib.27 The primary endpoint of this arm of the trial is SVR35. 

Pelabresib, a BET inhibitor, is an epigenetic modifier that downregulates the expression of genes that contribute to the heterogenous features of the pathology of MF. It may reduce spleen volume and improve MF-related symptoms and bone marrow function through improving the bone marrow environment.28 Ruxolitinib, the JAK inhibitor that is the SoC for MF, is not associated with bone marrow function improvement but reduces inflammation and spleen volume and improves quality of life.19,20 A combination of pelabresib and ruxolitinib as front-line therapy—vs initiating with ruxolitinib monotherapy—may result in a better, more durable response

MANIFEST: Spleen Volume Reduction

Srdan Verstovsek, MD, PhD: 
At 24 weeks, 68% of patients experienced SVR35. SVRs were durable, with 54% maintaining SVR35 at Week 60.27 The results also demonstrated that SVR occurred rapidly, typically within the first 3 months of initiating treatment. Furthermore, most patients experiencing reduced spleen volume had relatively more advanced disease, suggesting that pelabresib may be beneficial and provide durable responses for most patients.

MANIFEST Arm 3: Change in TSS at Week 24 and Best Reduction at Any Timepoint

Srdan Verstovsek, MD, PhD: 
At Week 24, 56% of patients experienced a ≥50% symptom reduction.27 As was observed with SVR, symptomatic improvements occurred rapidly, typically within the first 3 months of treatment. This result, when combined with the SVR response, demonstrates that the combination of pelabresib and ruxolitinib provides a desired overall benefit that is sought after with this combination.

MANIFEST: Change in Bone Marrow Fibrosis

Srdan Verstovsek, MD, PhD: 
The MANIFEST study also demonstrated intriguing changes in the bone marrow environment and JAK2 V617F allele burden with pelabrasib.27 

Regarding change in bone marrow fibrosis, 27% of patients had an improvement of ≥1 grade at Week 24, with 59% maintaining this improvement through ≥1 further assessment. 

Of note, 38% of patients also achieved a ≥20% reduction in JAK2 V617F variant allele frequency. Together, these changes suggest there is a biological modification that may explain the clinical benefits of pelabresib.

MANIFEST: Safety

BET inhibitors can be associated with myelosuppression and GI irritation (most often manifesting as nausea or diarrhea).29 However, most cases of myelosuppression and GI toxicity in MANIFEST were mild and/or manageable. Pelabresib was discontinued for treatment-emergent AEs in 14%.27

MANIFEST: Conclusions

Srdan Verstovsek, MD, PhD: 
Overall, preliminary results with the combination of pelabresib and ruxolitinib for patients with JAK inhibitor‒naive, higher-risk MF were promising. To this end, a randomized, double-blind phase III trial (MANIFEST-2) comparing ruxolitinib monotherapy with ruxolitinib plus pelabresib in a similar patient population is underway (NCT04603495).

Ropeginterferon Alfa-2b for Patients With Low/Intermediate-1‒Risk, Prefibrotic MF

Srdan Verstovsek, MD, PhD: 
Ropeginterferon alfa-2b is a long-acting interferon that is administered SC every 2 weeks.30,31 It is approved as a second-line therapy in patients with PV.31 An ongoing, randomized phase II trial also is examining the potential for ropeginterferon alfa-2b as a second-line therapy for high-risk ET (NCT04285086).30 

At ASH 2022, data were presented from a single-arm, open-label phase II trial examining the efficacy and safety of ropeginterferon alfa-2b for patients with Dynamic International Prognostic Scoring System (DIPSS) low- or intermediate-1‒risk or prefibrotic MF (NCT04988815).32 The primary outcomes for this study were hematologic response at 24 weeks and safety.

To the best of my knowledge, this is the first study of a treatment for patients with prefibrotic MF. Patients with prefibrotic MF and those with DIPSS low/intermediate-1‒risk MF do not have a substantial disease burden and are typically observed rather than being initiated on pharmaceutical therapy. In these patients, the only intervention may be reducing blood cell count to ameliorate their higher risk of thrombosis. 

Ropeginterferon Alfa-2b in Early/Prefibrotic MF: Baseline Characteristics

Srdan Verstovsek, MD, PhD: 
Of note at baseline, many patients had a high white blood cell and platelet count.32  

Ropeginterferon Alfa-2b in Early/Prefibrotic MF: JAK2 V617F Molecular Response 

Srdan Verstovsek, MD, PhD: 
A molecular response—defined as a JAK2 or other driver mutation allele burden that decreases over time—was achieved by some patients, with 8% achieving a >50% reduction in JAK2 V617F allele burden. These data are very preliminary, and more follow-up will be necessary to determine if molecular responses are clinically significant with this agent.32  

There were no major effects on the red blood cells with ropeginterferon alfa-2b, meaning that patients did not experience anemia. Patients experienced improvements in white blood cell count while on study, and platelet levels and lactate dehydrogenase levels were reduced. 

Ropeginterferon Alfa-2b in Early/Prefibrotic MF: Hematologic Response

Srdan Verstovsek, MD, PhD: 
Overall, most patients achieved a complete hematologic response, which can be defined as having obtained very good control over hemoglobin, white blood cells, and platelets.32 In many patients, a complete hematologic response was evident after 12 and 24 weeks of therapy.

Ropeginterferon Alfa-2b in Early/Prefibrotic MF: Safety

Srdan Verstovsek, MD, PhD: 
Ropeginterferon alfa-2b was associated with a good toxicity profile in the setting of patients with early/prefibrotic MF, and AEs were relatively uncommon.32 

Ropeginterferon Alfa-2b in Early/Prefibrotic MF: Conclusions

Srdan Verstovsek, MD, PhD: 
The data from this trial support the potential development of ropeginterferon alfa-2b for reducing blood-clotting risk by controlling blood cell count in patients with prefibrotic early-stage MF.32 

There certainly will be additional data from this and other trials in the future, as the pharmaceutical treatment of patients with prefibrotic early-stage MF is, to date, relatively unexplored.

Additional Studies of Note in Emerging Investigational Strategies for MF

Data from these additional studies of interest also were presented at ASH 2022. 

  • REFINE Cohort 3: In this report from a phase II trial in a cohort of patients with JAK inhibitor–naive, intermediate- or high-risk MF (N = 32), navitoclax (a BCL-XL/BCL-2 inhibitor) plus ruxolitinib was active in reducing spleen volume in several high-risk prognostic groups, and bone marrow fibrosis grade improvements and reductions in JAK2 V617 variant allele frequency were observed in some patients. A phase III study (TRANSFORM-1) is ongoing to further study this combination in this patient population.33 
  • A phase I study of selinexor plus ruxolitinib showed meaningful SVR, symptom improvement, and hemoglobin stabilization for patients with treatment-naive, intermediate- or high-risk MF (N = 24).34
  • ADORE: In a report from a phase I/II trial assessing ruxolitinib in combination with novel compounds, siremadlin (an HDM2 inhibitor) combination therapy was well tolerated and demonstrated activity at an established recommended phase II dose in patients with MF with suboptimal responses to ruxolitinib.35 

A patient with high-risk MF is anemic and has MF symptoms despite ruxolitinib therapy; they are now considering different treatment options. How would you counsel this patient regarding ASH 2022 findings with momelotinib from Week 24 to Week 48 in the phase III MOMENTUM trial, in which this agent was compared with danazol for treating patients with MF who had previously received a JAK inhibitor and were anemic and symptomatic?

Which of the following is a PI3K inhibitor for which positive symptom and spleen size outcomes were reported at ASH 2022 as an add-on therapy to ruxolitinib for patients with MF and a suboptimal response to ruxolitinib, with a current phase III trial underway in this population?

JAK2 V617F Molecular Response to Ruxolitinib in PV and ET

Srdan Verstovsek, MD, PhD: 
We will now conclude our discussion on key studies presented at ASH 2022 with a notable study in PV and ET. 

This study examined the JAK2 V617F molecular response to ruxolitinib in patients with PV or ET.36 Ruxolitinib is an approved therapy for PV in the second line for patients who have inadequate response to or are intolerant of hydroxyurea. It also is indicated for treating primary and secondary MF and, although not approved for treating patients with ET, has been shown to provide platelet control and symptom control in some patients.15,37  

In MF, ruxolitinib has been associated with JAK2 V617F molecular responses in a limited number of patients, but those with molecular responses can have improved outcomes. In PV and ET, the JAK2 V617F molecular response to ruxolitinib is of interest because, although ET and PV are benign conditions, approximately 15% of patients with ET and 25% of patients with PV progress to secondary MF, which is associated with a 5- to 7-year shortened life expectancy.38 Therefore, therapies that influence the transformation of ET and PV to secondary myelofibrosis may be highly valuable.

The current study included 77 patients (65 with PV and 12 with ET). Data were available from a series of samples accrued over several years, which is necessary to correlate molecular response with longer-term outcomes.36 

Molecular response was measured via polymerase chain reaction testing that assessed JAK2 V617F allele burden. A partial molecular response (PMR) was defined as a ≥50% allele burden decrease in patients with a 20% baseline allele burden. A deep molecular response (DMR) was defined as a JAK2 V617F allele burden <2%. A complete molecular response (CMR) was defined as an undetectable JAK2 and MPL mutation burden. Patients not meeting the definition of at least PMR were identified as having no molecular response.39

JAK2 V617F Molecular Response to Ruxolitinib: Baseline Characteristics

Srdan Verstovsek, MD, PhD: 
At baseline, most patients had a JAK2 mutation. A smaller percentage of patients had other mutations that were analyzed for their potential to affect the patient’s ability to achieve a significant molecular response with ruxolitinib monotherapy.36 

JAK2 V617F Molecular Response to Ruxolitinib: Molecular Response

Srdan Verstovsek, MD, PhD: 
Ruxolitinib was very effective in controlling the hematocrit-driven platelets in the spleen, as expected. Regarding molecular responses, PMR was achieved by approximately 44% of patients, CMR was achieved by 6%, and DMR was achieved by approximately 12%.36 Patients who had a lower baseline JAK2 mutation burden experienced better molecular responses compared with those who had a higher baseline JAK2 mutation burden.

Data also showed that ruxolitinib is associated with a reduction in inflammatory cytokine levels. However, there was no correlation between reduced cytokine levels and achievement of a molecular response. 

JAK2 V617F Molecular Response to Ruxolitinib: Outcomes

Srdan Verstovsek, MD, PhD: 
A correlation between depth of molecular response and MF-free survival was observed. In patients with CMR or DMR, there were no progressions to secondary MF (n = 14), but 3 patients who achieved a PMR (n = 20) and 21 patients who did not achieve a molecular response (n = 43) experienced a secondary MF event.36  

JAK2 V617F Molecular Response to Ruxolitinib: Conclusions

Srdan Verstovsek, MD, PhD: 
It is my opinion that the JAK2 allele burden is a significant prognostic marker for progression to MF in patients with ET and PVS.36 Based on the results from this study, incorporating testing for and monitoring the JAK2 allele burden is something to consider as a standard part of the treatment plan for patients with ET or PV, as it is indicative of the risk of progression to MF, which is a common concern among our patients. 

Until now, with the possible exception of interferon, which may be somewhat more toxic than ruxolitinib, there has not been good evidence for any therapy being able to induce a significant molecular response in patients with PV or ET. Clearly, this is an important study in terms of potentially changing current thinking regarding the overall value of therapies for these patients.