FDA Grants Priority Review to Luspatercept for First-line Treatment of Anemia in Lower-risk MDS

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May 1, 2023

Chris Ryan

The FDA has granted a priority review to the supplemental biologics license application seeking to expand the current indication of luspatercep to include treatment of anemia in patients with very low- to intermediate-risk myelodysplastic syndrome who have not previously received erythropoiesis-stimulating agents and who may require red blood cell transfusions.

The FDA has granted a priority review to the supplemental biologics license application (sBLA) seeking to expand the current indication of luspatercept-aamt (Reblozyl) to include treatment of anemia in patients with very low- to intermediate-risk myelodysplastic syndrome (MDS) who have not previously received erythropoiesis-stimulating agents (ESAs) and who may require red blood cell (RBC) transfusions.1

Additionally, the European Medicines Agency (EMA) has validated the type II variation application for luspatercept in the same indication.

The applications were supported by data from the phase 3 COMMANDS trial (NCT03682536), which showed that luspatercept demonstrated a statistically significant and clinically meaningful improvement vs epoetin alfa in RBC transfusion independence of 12 weeks or more with a concurrent hemoglobin increase of at least 1.5 g/dL in patients with very low-, low- or intermediate-risk MDS requiring RBC transfusions.

Detailed findings from COMMANDS will be presented at an upcoming medical meeting.

The FDA has assigned a target action date of August 28, 2023, under the Prescription Drug User Fee Act. The EMA will also begin its centralized review process after validating the application.

“Initial treatment options for [patients with] very low- to intermediate-risk MDS, including ESAs, can alleviate anemia in some patients but others will either not respond or become resistant to therapy, and additional therapy options have remained urgently needed,” Noah Berkowitz, MD, PhD, senior vice president, Hematology Development, Bristol Myers Squibb, stated in a news release. “Results from the COMMANDS study showed [luspatercept] significantly improved transfusion independence and elevated hemoglobin compared [with the] ESA therapy, epoetin alfa. [Luspatercept] is an important option available for the treatment of anemia in patients with transfusion-dependent, lower-risk MDS who have experienced ESA failure, and we look forward to working with the FDA and EMA to expand its potential use as a first-line therapy in eligible patients.”

In November 2019, the FDA approved luspatercept for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions.2 Additionally, in April 2020, the FDA approved the agent for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.3

The open-label, randomized COMMANDS study enrolled patients with a documented diagnosis of MDS per World Health Organization 2016 classification meeting revised international prognostic scoring system (IPSS-R) classification of very-low, low-, or intermediate-risk disease.4 Other key inclusion criteria included bone marrow blasts of less than 5%, an endogenous serum erythropoietin level of less than 500 u/L, and an ECOG performance status of 0 to 2. Patients must have required RBC transfusions, which was defined by an average transfusion requirement of 2 to 6 units every 8 weeks of packed RBCs confirmed for a minimum of 8 weeks immediately preceding randomization.

Patients were excluded if they had clinically significant anemia due to iron, vitamin B12, or folate deficiencies; autoimmune or hereditary hemolytic anemia; hypothyroidism; or any type of known clinically significant bleeding or sequestration or drug-induced anemia. Other key exclusion criteria included a known history of acute myeloid leukemia or uncontrolled hypertension.

The study enrolled 363 patients who were randomly assigned to receive luspatercept or epoetin alfa.

RBC transfusion independence for 12 weeks with a mean hemoglobin increase at least 1.5 g/dL served as the trial’s primary end point. Key secondary end points included RBC transfusion independence for 24 weeks, and RBC transfusion independence for at least 12 weeks and erythroid response of at least 8 weeks during weeks 1 to 24.

Regarding safety, findings from COMMANDS were reported to be consistent with the toxicity profile of luspatercept observed in previous clinical trials and in the post-marketing setting.

References

  1. US FDA accepts for priority review supplemental biologics license application and EMA validates application for Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS). News release. Bristol Myers Squibb. May 1, 2023. Accessed May 1, 2023. https://news.bms.com/news/details/2023/
  2. FDA approves luspatercept-aamt for anemia in patients with beta thalassemia. FDA. November 8, 2019. Accessed May 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-patients-beta-thalassemia
  3. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA. April 3, 2020. Accessed May 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds
  4. A study to compare the efficacy and safety of luspatercept (ACE-536) versus epoetin alfa for the treatment of anemia due to IPSS-R very low, low, or intermediate risk myelodysplastic syndromes (MDS) participants who require red blood cell transfusions and are ESA naïve (COMMANDS). ClinicalTrials.gov. Updated April 18, 2023. Accessed May 1, 2023. https://clinicaltrials.gov/ct2/show/NCT03682536

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CTI BioPharma Announces Two Abstracts Accepted for Presentation at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting

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Mon, May 1, 2023 at 7:03 AM EDT

– Data presentation on spleen volume reduction in patients with myelofibrosis also accepted for poster discussion –

SEATTLE, May 1, 2023 /PRNewswire/ — CTI BioPharma Corp. (Nasdaq: CTIC), a commercial biopharmaceutical company focused on the development and commercialization of novel targeted therapies for blood-related cancers, today announced that two abstracts have been accepted for presentation at the upcoming 2023 American Society of Clinical Oncology (ASCO) Annual Meeting taking place June 2-6, 2023 in Chicago, IL.

Presentation details are as follows:

Title: Spleen volume reduction (SVR) predicts overall survival (OS) in myelofibrosis (MF) patients on pacritinib (PAC) but not best available therapy (BAT): PERSIST-2 landmark OS analysis
Abstract #: 7018
Presenter: Helen Ajufo, M.D., Memorial Sloan Kettering Cancer Center
Session Title: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Session Date and Time: Monday, June 5, 2023, 8:00 – 11:00 a.m. CT
Location: Hall A, Poster #148
Poster discussion: In addition to the poster presentation, Dr. Ajufo will host a poster discussion session on Monday, June 5, 2023 from 11:30 a.m. – 1:00 p.m. CT in Room E450.

Title: Consistency of pacritinib for spleen and symptom reduction in patients with myelofibrosis regardless of cytopenias
Abstract #: 7068
Presenter: Dr. Prithviraj Bose, M.D., The University of Texas MD Anderson Cancer Center
Session Title: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Session Date and Time: Monday, June 5, 2023, 8:00 – 11:00 a.m. CT
Location: Hall A, Poster #198

About CTI BioPharma Corp.

CTI BioPharma is a commercial biopharmaceutical company focused on the development and commercialization of novel targeted therapies for blood-related cancers that offer a unique benefit to patients and their healthcare providers. CTI has one FDA-approved product, VONJO® (pacritinib), a JAK2, ACVR1,­­ and IRAK1 inhibitor, that spares JAK1. VONJO is approved for the treatment of adults with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. This indication is approved under FDA accelerated approval based on spleen volume reduction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). CTI is conducting the Phase 3 PACIFICA study of VONJO in patients with myelofibrosis and severe thrombocytopenia as a post-marketing requirement. For more information, please visit www.ctibiopharma.com.

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Looking Ahead in Treating Myeloproliferative Neoplasms

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Aaron Gerds, MD
Pankit Vachhani, MD
Naveen Pemmaraju, MD

Naveen Pemmaraju, MD: In this booming time of research for our patients with MPNs [myeloproliferative neoplasms], particularly myelofibrosis [MF], I’m energized by the worldwide community that has not only persisted during the time of the pandemic but has really augmented. I recently returned from presenting at the ESH [European Society of Hypertension] meeting in Berlin, Germany, for MPN and CML [chronic myelogenous leukemia]. And I was energized to talk to my fellow colleagues from around the world. I think we identified 3 major areas to focus on in terms of emerging trends and special considerations over the coming year. One, I believe, is the further investigation of these novel combinations. So far, we have focused on JAK inhibitors plus novel agents, but the discussions will be over the coming years together. What about different JAK inhibitors as the backbone beyond ruxolitinib? What about newer targets, and novel agents? And then, of course, novel, novel agents, as we call them, which is the combination of 2 beyond JAK inhibitor agents in a non-JAK inhibitor-containing regimen. So, I think those clinical trials would be of the highest importance to the field based hopefully on rational design and preclinical signals.

The number 2 concern I think is that of toxicity. I think as we introduce these novel agents and novel combinations, we, our patients, and scientists need to be thinking about what the new toxicities. What are the emerging toxicities? What are the unexpected ones that either result in longer-term follow-up or unexpected toxicities and side effects from combinations? What is the benefit to the patients in terms of adding a second and potentially even a third drug at some point vis-a-vis the toxicity, financial toxicity, the cost of these drugs, access to them, monitoring of them, and then the medical adverse effects.

Then I think the third area for us is the optimization of stem cell transplants. We know that transplant remains the only curative approach thus far in the myelofibrosis space, but with improvements in immune modulation, GVHD [graft-vs-host disease] monitoring, new medicines, pre-, and poststem cell transplant, can we optimize the transplant by offering it to more patients in a safe way, improving transplant access across the world, and reducing the short and long-term risks and mortality that are associated with transplant in some cases?

I think on that note of immune modulation, another exciting area to keep in mind is the development of immune therapies beyond interferon and stem cell transplants, which admittedly are the original immune therapies in our field. And so, entities such as CAR [chimeric antigen receptor] T-cell therapies, and monoclonal antibodies, we heard about the new mutant CalR-specific antibody, perhaps other immune approaches, combined vaccines against CalR with immune therapy drugs that are starting in clinical trials. So, an exciting area, we’ll call that immune modulation. So, optimization of the existing forms, the interferons, the stem cell transplant, and then keeping an eye towards the new ones. I think those are some of the emerging areas to keep our eyes on for 2023 and beyond.

Aaron Gerds, MD: The treatment of MPNs is a field that is rapidly evolving, and it has rapidly evolved over the last 5 years. And it’s exciting to see that we’re moving past simply giving JAK inhibitors to patients and looking to combination therapies to better the outcomes of these patients. And certainly, that’s the big next wave of therapy where we’re not just giving JAK inhibitors, but we’re giving combinatorial therapies to try to illicit a deeper effect on the disease. I think we need to continue to work to find better biomarkers of this disease modification, and we often look at changes in allele burden and changes in the scar tissue in the bone marrow, but this is often a biomarker of a biomarker or a reflection of a reflection. I think it doesn’t really get to the true modification of the pathobiology of the disease.

Many are looking at additional markers, like Dr Joseph Michael Scandura, MD, PhD, whom I mentioned earlier, who’s looking at megakaryocyte density and spacing within the marrow it has a perhaps better predictor of disease modification, so better biomarkers are needed, better therapies are needed. And again, it’s super exciting to see these combinatorial therapies as the next wave in drug development in therapy development in myelofibrosis. But we can look even further onto the horizon into some of the exciting things that might be coming in the future. The plenary session at this year’s ASH [American Society of Hematology] Annual Meeting was a monoclonal antibody targeting calreticulin disease protein. And so, that’s really exciting.

And this is a monoclonal antibody. You think about how much rituximab revolutionized the care of b-cell malignancies, and you can see that calreticulin may do the same for myelofibrosis. Not only could we use just the negative antibody, but you think about all this you can build bispecific antibodies or even modified cellular therapies like CAR T-cells or end-modified NK [natural killer] cells to really dramatically change the way we treat these patients. So, you can see that being the wave after the next wave, which is absolutely mind-blowing and exciting to think about.

Pankit Vachhani, MD: There are several areas that we are looking to improve upon and bring new options for our patients and also trying to sort out with all this new knowledge that is coming along in the field. Patients with cytopenic fibrosis, despite the numerous therapies that have come and are coming, continue to do worse than other patients. We need to improve their outcomes. It is tremendous that we have pacritinib [CPI-0610] now, whereby patients with thrombocytopenia have a good treatment option available for them to benefit from, but I think more agents like that and momelotinib [C23H22N6O2] for sure, is looking promising to deliver outcomes for thrombocytopenic and anemic patients, but I think we need some additional disease-modifying agents in this space, especially for cytopenic myelofibrosis patients. That is something that I’m definitely looking forward to coming about in the field over the next few years.

Along that same vein, we need to improve the survival outcomes of patients, more so than what we have already done with ruxolitinib. Many of these combination therapies which are ongoing are great, but I’m looking forward to seeing genuine, good survival outcomes happening from that. That would be the ultimate marker of a disease-modifying agent. While we are on the topic of combination therapies, should 1 or more of these combination therapies come out and there is a very high likelihood that that’s going to happen, I think the very next question that will come about in the field, is sorting out what biomarkers can we identify either at baseline, or let’s say, at 3 months, 6 months, or a year, to identify patients who are going to benefit or not going to benefit from one combination therapy vs the other, who may benefit on the initial half vs through continuous maintenance of a combination therapy. The field of biomarkers is going to evolve in line with the new therapies that are going to come out. After all, biomarkers have to be looked upon in the context of treatment as well.

While these are the 3 points that I think need to be answered and need to be looked into, there are some additional things that I do want to mention. JAK2 Keller vaccines are being developed and these hold tremendous promise. We are hoping that they work out. They may really help us down the line in thwarting the progression of a disease in its very early course and may serve as a brand-new way of treating our patients with myelofibrosis, PV [polycythemia vera], or ET [essential thrombocythaemia]. For polycythemia vera patients, there are many drugs that are currently being developed, which work on the iron homeostasis pathway. Should 1 or more of these drugs come out to the market, they may offer yet another option for our patients, and in doing so, they may help eliminate phlebotomies. While not directly a supportive care method, it may very well help in supporting patients on their other therapies as well. Not to mention, they may help in maintaining a target hematocrit of 45% or more on a long-term basis and in a consistent manner and therefore, also decrease the need for phlebotomies and prevent thrombotic episodes.

Last but not least, interferon-based therapies have always been talked about, but they’re probably being talked about now more than ever before and these truly may slow the progression of myeloproliferative neoplasms speed that ET, PV, or maybe even profibrotic MF and in selected cases, even possibly overt myelofibrosis. But more studies need to be done and I think there is more and more emerging evidence suggesting the use of interferon as early as possible in patients with MPNs.

Transcript edited for clarity.

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QW Selinexor 60 mg Plus Ruxolitinib Elicits Lasting Responses in Myelofibrosis

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Nichole Tucker

Researchers are backing further investigation of 60 mg selinexor plus ruxolitinib based on positive phase 1/2 findings presented at the AACR Annual Meeting 2023.

Once-weekly (QW) selinexor administered at 60 mg in combination with ruxolitinib (Jakafi) achieved rapid and deep spleen responses that were sustained, as well as robust symptom improvements in patients with treatment-naïve myelofibrosis, according to phase 1/2 study (NCT04562389) results presented at the American Society for Cancer Research (AACR) Annual Meeting 2023.1

“There remains significant unmet need in the treatment of myelofibrosis, with less than half of patients achieving an SVR35 with the current standard of care therapy,” said Haris Ali, MD, City of Hope Comprehensive Cancer Center, presenter of the data, in a press release. “The spleen responses and symptom improvements seen across all patients with the 60 mg selinexor dose is very compelling. These data suggest this tolerable and unique combination of XPO1 and JAK inhibition has the potential to significantly improve these key efficacy measures first-line myelofibrosis.”

As of the data cutoff date of February 24, 2023, 24 patients with treatment-naïve myelofibrosis were randomized 1:1 to receive selinexor (40 mg or 60mg) QW plus ruxolitinib (15 mg or 20 mg), or ruxolitinib alone.

At week 12, the rate of 35% spleen volume reduction rate (SVR35) was 83.3% with selinexor 60 mg in the efficacy evaluable population. In the intent-to-treat (ITT) population, the SVR35 rate was 71.4% with selinexor 60 mg. The rate of ≥ 50% reduction in total symptom score (TSS50) at the 60-mg dose level was 80.0% in the efficacy evaluable population and 66.7% in the ITT population.

The 24-week SVR35 rate was 91.7% in the efficacy evaluable population, and the rate of TSS50 was 78.6%. In the ITT population, the 78.6% of patients had SVR35 and the rate of TSS50 was 58.3%.

Response rates were consistent in the subgroup population assessed, which included male patients, and those who received low-dose ruxolitinib. In addition, selinexor 60 mg plus ruxolitinib led to improvements in major spleen- and cytokine-related symptoms all Myelofibrosis Symptom Assessment Form areas.

At the 40 mg dose level, selinexor in combination with ruxolitinib achieved a 30.0% SVR35 and 66.7% TSS50 in the efficacy evaluable population, and a 40.0% SVR35 and 40.0% TSS50 in the ITT population.

“We are enthusiastic about the impressive spleen volume reductions and robust symptom improvement observed with the 60 mg dose of selinexor and ruxolitinib combination at week 24, which represent very meaningful improvements relative to the current standard of care of ruxolitinib alone. These data suggest that the combination of selinexor and ruxolitinib has the potential to be a transformative therapy for first line myelofibrosis patients,” said Reshma Rangwala, MD, PhD, chief medical officer of Karyopharm, in the press release. “We are also very encouraged by the preliminary data showing rapid normalization in platelets and stability of hemoglobin levels, as potential evidence of disease modification for these patients. We look forward to building upon these findings as we plan the initiation of a pivotal phase 3 study in front-line myelofibrosis later this quarter.”

The safety analysis showed that selinexor was well-tolerated at both dose levels and toxicities were manageable. Due to the safety profile of selinexor in this study, most patients remained on the study for up to 68 weeks.

The most common any-grade treatment-emergent adverse events (TEAEs) in the 40 mg and 60 mg dose cohorts, respectively, were nausea (70.0% and 78.6%), anemia (40.0% and 64.3%) and fatigue (60.0% and 57.1%). These TEAEs were predominantly grade 1 or 2 in severity. Grade 3 or higher TEAEs that occurred frequently during the study included anemia (30.0% and 42.9%), thrombocytopenia (10.0% and 28.6%) and neutropenia (20.0% and 7.1%).

Two patients in the study discontinued treatment due to cases of thrombocytopenia and peripheral neuropathy. Notably, 75% of nausea were grade 1 and did not required patients to discontinue treatment. Treatment with prophylactic antiemetics reduced nausea rates and grades.

According to the study investigators, these data support proceeding with 60 mg as the recommended dose of selinexor when used in combination with ruxolitinib. A phase 3 study of selinexor plus ruxolitinib vs placebo is planned to being this year.

“JAK does afford our patients benefit, but unfortunately, doesn’t cure our patients and outcomes are dismal when the dose is reduced or the drug has to be stopped,” said John Mascarenhas, MD, during a conference call hosted by Karyopharm Therapeutics following the AACR presentation.2 “Over the next 3 years, a likely paradigm shift to upfront combination therapy approach is being explored with selinexor. and given novel agents in late-stage development, I think that a new era of treating myelofibrosis is ahead. I think the opportunity to exploit non-JAK2 inhibitor sequencing such with imetelstat, or an MDM2 inhibitor like naphthalene, offer other opportunities to treat patients down the line,” Mascarenhas added.

REFERENCES:

1. Karyopharm Announces presentation of updated phase 1 selinexor data in patients with treatment-naïve myelofibrosis at AACR 2023. News release. Karyopharm Therapeutics, Inc. April 18, 2023. Accessed April 19, 2023. https://bit.ly/3KRRpM9

2. AACR 2023 – Karyopharm Therapeutics Virtual Investor Presentation. Karyopharm Therapeutics Presented April 18, 2023. Virtual. https://bit.ly/3LaQcjx

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Abbas Weighs Options in Patient With JAK2-Mutated Polycythemia Vera

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Apr 15, 2023

Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Jonathan Abbas, MD, discussed data on therapies for a patient with polycythemia vera who did not adequately respond to hydroxyurea.

February 2018

  • A 67-year-old man presented with frequent headache and dizziness.
  • His medical history was notable for smoking.
  • Physical exam: unremarkable, no splenomegaly
  • Laboratory results:
    • Hemoglobin level: 20.5 g/dL
    • White blood cell count: 13 K/mcL
    • Platelet count, 380 K/mcL
    • Hematocrit level: 48%
    • Mean corpuscular volume: 72 fL
  • The patient had the JAK2 V617F mutation, with an allelic burden of 65%.
  • A bone marrow biopsy showed trilineage proliferation and pleomorphic megakaryocytes.
  • The patient started phlebotomy and aspirin.

May 2018

  • The patient underwent 3 phlebotomies in the last 3 months.
  • He complained of continuing dizziness, headaches, and nausea.
  • He remained on phlebotomy as needed and aspirin. Hydroxyurea (Hydrea) at 1000 mg per day was started.

August 2018

  • The patient had 5 phlebotomies since May.
  • Hydroxyurea was increased to 1500 mg per day.

November 2018

  • The patient was still dependent on phlebotomy and also complained of pruritus.
  • Hydroxyurea was increased to 2000 mg per day

February 2019

  • The patient had 2 phlebotomies since the last visit.
  • He was experiencing abdominal fullness and dysgeusia.
  • His spleen was palpable 6 cm below the costal margin.

Targeted OncologyTM: What are the preferred therapy options in uncontrolled polycythemia vera (PV)?

ABBAS: We can use the NCCN [National Comprehensive Cancer Network] guidelines to look at therapy options in the setting of inadequate response or loss of response to hydroxyurea [Hydrea] plus phlebotomy. Peginterferon alfa-2a [Pegasys] is on the list, and the preferred category 1 treatment is ruxolitinib [Jakafi].1

During decision-making for patients with inadequate response/loss of response to cytoreductive therapy, do you consider the NCCN or other guidelines?

I usually don’t unless it’s more of an outlier situation. In this clinical case, I don’t think I would have gone to it…. If you’re down to every 6 to 8 weeks on phlebotomy and on a low to intermediate dose of hydroxyurea that’s well tolerated—no leg ulcers, no concerns, no other effects of the hydroxyurea— then that’s not a terribly burdensome disease for the patient if they agree with that assessment and say they are fine with getting phlebotomies done every 6 to 8 weeks.

One should keep an eye out for an increased frequency of phlebotomies. That might be where real-world experience and the NCCN guidelines don’t perfectly align. I don’t know if phlebotomy independence needs to be an end point. I think what’s considered an acceptable degree of phlebotomy is a perfectly fine end point to use.

Which data support the use of ruxolitinib as second-line treatment for PV?

The RESPONSE trial [NCT01243944] was the trial looking at ruxolitinib vs best available therapy [BAT]. It was a 1:1 [randomized trial] with about 200 patients. It does have data from a longer, 5-year follow-up that came out in around 2020.2

The study had an interesting composite end point of hematocrit control and spleen volume reduction, which was a challenging end point to meet. It met that end point in only 1 in 5 patients, so 20%, compared with BAT, [which met the end points] in less than 1% of patients. About 40% of patients had the reduction in spleen volume and about 60% had hematocrit control with ruxolitinib.

[Total] symptom scores…were grouped into 3 different clusters and compared with the BAT arm, there was dramatic improvement in all 3 arms with ruxolitinib.3 So this was the trial that led to the FDA approval for ruxolitinib in the second-line setting. [Using] BAT in many cases unfortunately [meant] continuing what we knew wasn’t working and keeping patients on hydroxyurea and phlebotomy because there were so few options.

What did the long-term follow-up of the RESPONSE trial show for these patients?

[We have] the long-term safety and efficacy data, and this is about durability. For the responders, most patients—over 70%—have maintained their response now 5 years out.2 So, it is key that we tell patients this is a chronic, lifelong disease, but we’re getting very durable responses with ruxolitinib.

A complete hematologic remission [CHR] is a nice thing to get. Is it certainly necessary? By no means, but it is lovely when we do achieve it. CHR means complete normalization of the complete blood count.

While some patients fall off, long term, about 55% of patients at 5 years have maintained a CHR. Again, [this shows] excellent durability. For hematocrit control now, most patients 5 years out have been able to maintain their hematocrit. [The 2 groups of patients] with or without splenomegaly showed no appreciable differences. We don’t see it breaking it down by the group with or without splenomegaly, so there is no tremendous variability.3,4

How did the dosing of ruxolitinib affect toxicity in RESPONSE?

It is important to remember dosing here. In PV, we’re now at 10 mg twice daily, not 20 mg twice daily. We’re not using a thrombocytopenia-based dosing, so we’re using a lower dose. Predictably, the degree of anemia and thrombocytopenia is better. We don’t see too many cases where ruxolitinib is driving the red blood cell count down so much that you’re creating new issues. The BAT had 23% fatigue of all grades vs 5% for ruxolitinib, and 12% for night sweats vs 3%, respectively, which are suggestive data. I don’t think there’s anything that’s going to jump out as a major flag here. Infections should be noted. There were more infections in the BAT group [59.8%] than in the ruxolitinib group [18.9%].2 But the point here is that ruxolitinib tolerability is, like we’ve seen across all other disease states, excellent.

There was a low rate of thrombotic events, at 5% for all grades, and 3% for grades 3 or 4. So getting good control of the disease is what we’re doing to decrease them. A secondary malignancy is not something we think about as often with ruxolitinib as you do with some other classes of drugs, like immunomodulatory drugs, but it is important to note that it was 7 [per 100 patient-years of exposure].

Most of these were non-melanoma skin cancers.2 There are, however, more serious hematologic malignancies and even solid tumor malignancies that have been seen after prolonged JAK2 [drug] exposure. So it’s something to think about and counsel patients on. For patients who are already [diagnosed] with basal cell or squamous cell carcinoma, you want to keep an eye on that and make sure they’re staying on top of it.

What data support the use of pegylated interferon as second-line treatment for PV?

The studies of hydroxyurea vs ropeginterferon alfa-2b [Besremi] include PROUD-PV [NCT01949805] and CONTINUATION-PV [NCT02218047]. The PROUD-PV study was looking at 1 year of treatment randomized to hydroxyurea or ropeginterferon. Patients who had been on hydroxyurea were randomized to continue it vs peginterferon or ropeginterferon. Then the CONTINUATION-PV study moved further [out], to 3 to 5 years.5

While it might take time to work, the CHR rate of the interferon vs control group—the group continuing hydroxyurea, which we knew wasn’t working well—[at months 24 and 36] was 70% vs 50%, respectively.5 So compared with the control group, we are seeing some clinical benefit that was statistically significant at the molecular level where they were measuring JAK2 allele burdens.

In the setting of hydroxyurea failure, interferon is an excellent treatment. It is better than continuing hydroxyurea? Has it been pushed [back in] the line of therapy behind ruxolitinib? I think so, but it is an excellent treatment. If you run into a ruxolitinib-intolerant patient, it is something to absolutely keep in mind. Adverse events [AEs] were very low. There is a lot of concern about things like some of the psychiatric AEs, but ropeginterferon had 4% of psychiatric AEs of all grades.

Endocrine events and musculoskeletal events were low, too.5 It’s a drug that we have heard nightmares about from the days before the pegylated versions of it, but it does have an impressive safety profile. I have not been forced into using this in several years, which is a great testament to how good something like ruxolitinib is, but when I have had to use it, I was a believer. One of my myeloproliferative neoplasms mentors, Ruben Mesa, MD, is an enormous believer in it, and he probably at any given point has 200 patients on interferon who are doing great.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms; version 3.2022. Accessed March 6, 2023. https://bit.ly/2E77tIB

2. Kiladjian JJ, Zachee P, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020;7(3):e226-e237. doi:10.1016/S2352-3026(19)30207-8

3. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426-435. doi:10.1056/NEJMoa1409002

4. Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol. 2017;18(1):88-99. doi:10.1016/S1470-2045(16)30558-7

5. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196- e208. doi:10.1016/S2352-3026(19)30236-4

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Pruritus May Mark Severe Symptomology in Myeloproliferative Neoplasms

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April 11, 2023

Jessica Nye, PhD

In myeloproliferative neoplasms (MPNs), patients reporting pruritus had more symptoms, greater symptoms severity, and were more likely to experience disease evolution, according to results of a questionnaire-based study published in Journal of the European Academy of Dermatology and Venerology.

Researchers from Brest University Hospital in France sourced data for this study from the Observatoire Brestois des Néoplasies Myéloprolifératives (OBENE) database. Patients (N=504) with MPNs were given a questionnaire about symptoms and quality of life prior to consultations between 2015 and 2020. Symptoms and severity were self-reported using the Visual Analogue Scale score.

Participants had a median age of 68.6 years, 56.5% were women, 54.4% had essential thrombocythemia (ET), 37.7% had polycythemia vera (PV), and 7.9% primary myelofibrosis (PMF). Most participants (77.4%) had Janus activated kinase 2 (JAK2)-mutated disease. The most common treatments were hydroxyurea (35.1%), pegylated-interferon treatment (8.9%), and anagrelide (7.1%).

Overall, 49.8% of patients reported pruritus. Study participants with pruritus were older (P =.01), more had PV and fewer had ET or PMF (P =.004), more had JAK2-mutated disease (P <.0001), and fewer abstained from treatment (P =.014) compared with those in the nonpruritus group.

We clearly showed the importance of identifying patients with pruritus, who are more symptomatic and at the highest risk of phenotypic evolutions.
Participants with pruritus were more likely to report abdominal discomfort (odds ratio [OR], 3.8), perspiration (OR, 3.29), fatigue (OR, 2.68), concentration problems (OR, 2.65), bone pain (OR, 2.31), early satiety (OR, 2.27), and inactivity (OR, 2.06) and all symptoms were reported to be more intense (all P ≤.00007) compared with patients without pruritus.

Among those in the pruritus group, nearly one-half (44.6%) had aquagenic pruritus (AP). The patients with AP were more likely to be men (P =.0015), more had PV and fewer had ET or PMP (P <.0001), more had JAK2-mutated disease (P =.005), and fewer abstained from treatment (P =.001) compared with those in the non-AP group with pruritus.

These findings may have been biased, as patients completed the questionnaires prior to consultation with the clinician.

Researchers conclude, “We clearly showed the importance of identifying patients with pruritus, who are more symptomatic and at the highest risk of phenotypic evolutions. Furthermore, we found differences in patients with AP compared to those with non-AP. […] Therefore, clinicians must go beyond simply determining the presence or absence of pruritus to determine whether patients are experiencing AP.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.References:

Gall-Ianotto CL, Ficheux A-S, Lippert E, et al. Differences between aquagenic and non-aquagenic pruritus in myeloproliferative neoplasms: an observational study of 500 patients. J Eur Acad Dermatol Venereol. Published online February 21, 2023. doi:10.1111/jdv.18990

Adding Patient-Specific Comorbidities May Improve Risk Evaluation in Myelofibrosis

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Apr 11, 2023

Jason Harris

Adding patient-specific comorbidities improved the prognostic effect of risk prediction models for patients with primary or secondary myelofibrosis, according to findings from an assessment of data collected in Vanderbilt’s Synthetic Derivative and BioVU Biobank comprehensive electronic health record.

Adding patient-specific comorbidities improved the prognostic effect of risk prediction models for patients with primary myelofibrosis (PMF) or secondary myelofibrosis (sMF), according to findings from an assessment of data collected in Vanderbilt’s Synthetic Derivative and BioVU Biobank comprehensive electronic health record (EHR).

Discrimination power was significantly higher using the extended Dynamic International Prognostic Scoring System (DIPSS) model that incorporated renal failure/dysfunction, intracranial hemorrhage, invasive fungal infection, and chronic encephalopathy (C-index, 0.81; 95% CI, 0.78-0.84) compared with the original DIPSS model (C-index, 0.73; 95% CI, 0.70-0.77).

All 4 of the comorbidities were individually associated with poorer survival (TABLE 1).In particular, renal failure may play a greater-than-expected role in patient outcomes.

“PMF remains a complex and challenging disease that will require a continued effort to improve patient outcomes. BioVU is unique as a fully annotated deidentified patient record of millions of patients, and to our knowledge, a similar deidentified data source, with this level of necessary annotation, is not available,” investigators wrote. “Still, we have demonstrated reliable identification of myelofibrosis within an EHR, and further implementation of natural language processing and data extraction algorithms are actively being pursued to leverage our ability to identify hematologic malignancy in these databases.”

There are several prognostic systems available for myelofibrosis. Each includes validated disease-specific parameters such as high molecular risk, peripheral blood counts, cytogenetics, and disease-specific clinical characteristics. However, none of the current models take comorbidities into account. Previous data have shown that increased comorbidity burden is associated with reduced overall survival (OS). These previous studies, however, included only a limited selection of selected comorbidities in each validated tool and failed to account for the broad assortment of comorbid conditions that affect prognosis and treatment decisions.

Investigators at Vanderbilt set out to build an unbiased EHR evaluation based on genotypic risk scores that makes use of DNA collected in the BioVU Biobank to determine the role comorbidities play in survival. In this analysis, investigators evaluated data collected from approximately 300,000 patients treated at Vanderbilt University Medical Center from 1995 to 2016. They reviewed patient phecodes to evaluate overall comorbidity burden for each patient, excluding the codes related to PMF, such as acute myeloid leukemia (AML) and variables dependent on Dynamic International Prognostic Scoring System (DIPSS), such as leukocytosis.

Investigators evaluated peripheral blood DNA collected in Vanderbilt’s biobank using established PMF risk assessors including DIPSS, DIPSS plus, the Genetics-Based Prognostic Scoring System (GPSS), and the Mutation-Enhanced International Prognostic Scoring System 70+ (MIPSS70+) along with comorbidities using EHRs and next-generation sequencing (NGS).

Age, race, gender, and clinical and laboratory parameters were automatically excluded.

In a cohort of 193 patients with PMF or sMF, investigators identified 374 phecodes at diagnosis. Investigators conducted risk score recapitulation for these patients using DIPSSA and DIPSS plus.

There was biobanked DNA for another 140 patients that was available for NGS. Investigators used this data to conduct risk score recapitulation for all 140 using the GPSS and MIPSS70+.

These methods included prognostic predictors such as score-specific cutoffs for age, circulating myeloid blasts, leukocyte count, hemoglobin, and platelets. Investigators used phenome-wide association study (PheWAS) to determine the correlation between OS and comorbidity burden. Investigators conducted PheWAS to evaluate how each phecode related to survival.

To further investigate how comorbidity influences survival in myelofibrosis, we developed a simple prognosis model that accounts for comorbidity burden at PMF diagnosis. In this model, Investigators segregated patients into quartiles based on cutoff values for the number of distinct phecodes at PMF diagnosis. The low-risk quartile included patients with 0 to 2 phecodes; the intermediate-low risk group included patients with 3 to 7 phecodes; the high-risk quartile included patients with 8 to 17 phecodes; and the very high-risk quartile included patients with more than 18 phecodes at diagnosis.

The median patient age at diagnosis was 59 years (range, 24-87) and women made up 42% of the population. The median OS was 39 months (range, 1-265). Twenty-three patients developed AML at a median of 37 months (range, 1-265). Forty patients received allogeneic hematopoietic stem cell transplantation at a median of 30 months from diagnosis. Of the 193 patients in the study, 158 were treated at Vanderbilt within 1 year of diagnosis and 35 were treated there at least 1 year after diagnosis.

Most patients (80.8%) had PMF, 15% had polycythemia vera, and 13.5% had essential thrombocythemia. Median follow-up was 4 years (range, 1-22).

As determined by DIPSS, the 5-year OS was 94% in the low-risk group, 91% in the intermediate-low risk group, 78% in the high-risk group, and 0% in the very high–risk group. DIPSS plus, the 5-year OS was 94% in the low-risk group, 93% in the intermediate-low–risk group, 81% in the high-risk group, and 0% in the very high–risk group. As assessed by MIPSS70+ (n = 113) the 5-year OS was 96% in the low-risk group, 93% in the intermediate-low group, 79% in the high-risk group, and 32% in the very high–risk group. (P ≤.0010).

Using GPSS (N = 140), the 5-year OS rate was 100% in the low-risk and intermediate low-risk quartiles, 83% in the high-risk group, and 77% in the very high–risk group (P = .03; TABLE 2).

“Our repurposing of an institution-wide biobank for hematologic malignancy evaluation, with the potential for clonal evolution assessment, is a novel use of a tool in a manner to study relatively large populations of otherwise rare myeloid disease,” lead study author Andrew L. Sochacki, MD, and coinvestigators wrote in the paper. “In aggregate, our findings suggest that a more objective measurement of patient-specific comorbidities is needed to best individualize therapy in this highly comorbid patient population.”

Reference

Sochacki AL, Bejan CA, Zhao S, et al. Patient-specific comorbidities as prognostic variables for survival in myelofibrosis. Blood Adv. 2023;7(5):756-767. doi:10.1182/bloodadvances.2021006318

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When Your Physician Isn’t A Good Fit

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Everyone has had good and bad experiences with physicians. When the experience is so bad, we never go back. When we need to see specialists, like those diagnosed with an MPN, it can be challenging when your connection with the physician is not what you had expected. All of us have different personalities and quirks and physicians are no different. Bedside manners are still very much a part of the conversations we hear when sharing stories about a doctor’s care. Those stories can influence others to either seek out care from a particular physician or go to someone else. What if the physician is one of the best doctors in the particular area of medicine you need and has a reputation for being rude, condescending, abrupt, and dismissive?

Dealing with difficult people is challenging for sure, but when it is someone you must rely on to be well there are other strategies that may help. Just like all of us, we have good days and bad days, days that are overwhelmingly busy, days dealing with home repairs, kids, financial issues, and so much more. Doctors deal with those same issues coupled with a patient load that sometimes exceeds the standard number. Their days never end if there is an emergency and some are available to their patients via texts to answer simple questions 24/7. That does not excuse poor manners and bad behaviors, it does, however, contribute to one’s demeanor at times. The question you must ask yourself is are you receiving the quality care, direction, and treatment you need, despite the differences in your personalities? That does not mean you should continue to see someone you don’t like, it is something you should weigh in your decision to make a change.

One of the best strategies I learned as a younger person to deal with difficult people was to empathize. It was the hardest thing to do but it did work most of the time. When it comes to a health provider, the last thing any of us needs is the extra stress of not wanting to go to our physician when we need to because we do not like them.

Things to consider:

  • If you’re able, interview physicians –schedule a consultation. Very often, you will learn from that visit if there is a good fit.
  • For MPN patients, the relationship with health providers is critical because it will last for years, therefore it is even more important to develop a great foundation at the onset of your care.
  • A mutual respect and understanding should evolve during your long-term care. If it doesn’t, consider the pros and cons of changing physicians.
  • Try to be prepared for each visit with any changes you’re experiencing and anything you’d like to discuss with your physician.
  • If the care you receive outweighs the personality differences with a physician, carefully think about what’s important to you before making a change.
  • Many of us do not have the luxury of changing doctors whether it is financial or geographical. If these are the issues you face, perhaps a conversation with a nurse or Physician’s Assistant may help. They can offer insights and ways to deal more effectively with the physician’s personality.

Finally, the MPN Community has some of the best specialists I’ve ever seen in my career. They are dedicated, considerate, kind, available, and willing to go above and beyond for the sake of their patient’s care. If you need to make a change and require some direction, let us know and we can direct you accordingly.

Diagnosing Myelofibrosis: What to Expect From a Bone Marrow Biopsy

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Bone Marrow Biopsies for Myelofibrosis

  • Bone marrow biopsies are one of the tests used to confirm a diagnosis of myelofibrosis, a rare type of bone marrow cancer.
  • During the biopsy, a needle is inserted into center of the bone in order to extract marrow for testing.
  • The procedure can be painful and patients may be given a mild sedative, pain medication, and a local anesthetic to help manage the pain. Typically, pain is only felt during the procedure and patients do not have side effects afterwards.
  • In some cases, patients may opt to be fully or partially sedated for the biopsy.

Several tests are often used to diagnose myelofibrosis, a rare type of bone marrow cancer. This may include a bone marrow biopsy, an assessment of symptoms, blood work, genetic testing, and/or imaging tests (like an MRI).

Bone marrow biopsies are helpful to diagnose the disease — which is part of a group of disorders known as myeloproliferative neoplasms — because these samples taken from the marrow can be studied in a lab and used to confirm a myelofibrosis diagnosis.

While this is a necessary test, patients should be aware that the biopsy itself can be uncomfortable and they will likely deal with some pain.

What Happens During a Bone Marrow Biopsy?

During the biopsy, bone marrow will be extracted through a needle so doctors can run tests on it in a lab.“Unfortunately, a bone marrow biopsy is a painful procedure,” Dr. Abdulraheem Yacoub, a hematologist at University of Kansas Medical Center, tells SurvivorNet. “It will require inserting a needle through the thick part of the bone in order to go to the center of the bone and extract some of the bone marrow for examination.”

Is a Bone Marrow Biopsy Painful?

The process of inserting a needle into the bone can be painful, as can the process of removing the marrow, Dr. Yacoub says.

Typically, a bone marrow biopsy will be performed in a clinic, and patients will be given some sort of sedative and other medications to help them cope with the pain from the procedure.

“Most of the time we perform this in the clinic with mild sedation and some pain medicines, as well as local anesthetic,” Dr. Yacoub says. “With the combination of all of this, most patients can tolerate that with some sensation of pressure rather than pain.”

In certain cases, patients may opt to be partially or completely sedated. It’s important to discuss these options with your doctor to ensure you feel as comfortable as possible during the bone marrow biopsy.

The good news is that patients don’t typically have issues with pain or other side effects after the procedure.

Possible Complications of a Bone Marrow Biopsy

With any procedure, there is the potential for complications — and bone marrow biopsies are no different.

“The pain is usually only during the actual active part of the procedure,” Dr. Yacoub says. “It is very unlikely that the patient will have any symptoms after the biopsy. But, of course, some procedures have complications such as bleeding or other issues that could occur.”

If you experience any of the following symptoms in the days after a biopsy, contact your healthcare provider immediately:

  • Bleeding
  • Fever
  • Worsening pain or discomfort
  • Swelling at procedure site
  • Increasing redness or drainage at procedure site

“Patients should contact their physicians immediately if they are having pain after the procedure — [since] it’s not an expectation,” Dr. Yacoub adds.

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Imetelstat Displays Early Efficacy in Myelofibrosis; Phase 3 Trial Is Underway

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Kyle Doherty

Patients with myelofibrosis have limited effective treatment options and a poor prognosis. However, the first-in-class telomerase inhibitor imetelstat is poised to expand the treatment armamentarium should it prove safe and effective in the newly initiated phase 3 IMpactMF trial (NCT04576156).1,2

Three FDA-approved treatment options are available for myelofibrosis: ruxolitinib (Jakafi), pacritinib (Vonjo), and fedratinib (Inrebic).1,3 However, a significant portion of patients discontinue treatment with 1 or more of these JAK inhibitors and the median overall survival (OS) with these agents ranges from 11 to 16 months, underscoring the need for more effective alternatives.1,3

“Not a lot of the therapies that we give are clearly anticlonal or antistem cell; [imetelstat] is a stem cell–directed therapy,” John O. Mascarenhas, MD, director of the Center of Excellence for Blood Cancers and Myeloid Disorders and professor of medicine at the Icahn School of Medicine at Mount Sinai in New York, New York, said in an interview with OncologyLive®. “Telomerase is a great target because it is overexpressed constitutively in the myelofibrosis stem cells and only transiently in the normal stem cells. It adds these telomere repeats to chromosomes; every time cells divide you lose a certain amount of these caps, then the cells go into a quiescent state or undergo apoptosis. This is a way of leveling the playing field so that you no longer allow this sort of mechanism of immortality to the malignant stem cells.”

Imetelstat Shows Early-Stage Activity

Imetelstat was evaluated in patients with relapsed or refractory intermediate-2 or high-risk myelofibrosis at 2 dose levels in the phase 2 IMbark trial (NCT02426086). IMbark enrolled patients previously treated with a JAK inhibitor who had disease progression and an ECOG performance status of 2 or less, among other enrollment criteria. Those who were intolerant to a JAK inhibitor were not enrolled unless they satisfied the relapsed- or refractory-related criteria.3

Patients were randomly assigned to receive the active dose of imetelstat, which was determined in a pilot study to be 9.4 mg/kg (n = 59) or the minimally active dose with telomerase target engagement of 4.7 mg/kg (n = 48). The agent was given via a 2-hour intravenous infusion once every 3 weeks until disease progression, unacceptable toxicity, consent withdrawal, or lack of response.

The coprimary end points of the trial were 24-week spleen and symptom response rates. Secondary end points included OS, safety, and clinical improvement. Molecular response and changes in telomerase activity and human telomerase reverse transcriptase levels served as exploratory end points.

Findings showed that the 24-week spleen response rate was 10.2% and the 24-week symptom response rate was 32.2% among patients who received the 9.4 mg/kg dose. In the 4.7-mg/kg cohort, the 24-week rates were 0% and 6.3%, respectively. At a median follow-up of 27.4 months, the median OS was 29.9 months (95% CI, 22.8-not estimable [NE]) and 19.9 months (95% CI, 17.1-NE) in the 9.4-mg/kg and 4.- mg/kg cohorts, respectively. The 12-month survival rate was 84.0% (95% CI, 71.6%-91.4%) vs 78.6% (95% CI, 63.9%-87.9%), respectively. The 24-month survival rate was 57.5% (95% CI, 43.2%-69.5%) vs 41.8% (95% CI, 27.1%-55.8%), respectively.3

Patients treated at either dose level experienced benefit with imetelstat if they displayed at least 1 grade or higher improvement in bone marrow fibrosis. Patients who showed improvement (n = 19) experienced a median OS of 31.6 months (95% CI, 23.6-NE) compared with 24.6 months (95% CI, 18.4-NE) among 38 patients who showed no improvement (HR, 0.54; 95% CI, 0.23-1.29).

The study authors noted that imetelstat displayed an acceptable safety profile for this patient population. The most common treatment-emergent adverse events (TEAEs) of any grade in the lowerdose arm included diarrhea (38%), anemia (31%), nausea (31%), and peripheral edema (27%). In the 9.4-mg/kg arm, common any-grade TEAEs included thrombocytopenia (49%), anemia (44%), neutropenia (36%), and nausea (34%).3

TEAEs of grade 3 or worse severity in the 4.7-mg/kg arm included anemia (31%), thrombocytopenia (23%), and dyspnea (13%); in the higher-dose arm, grade 3 or higher TEAEs were thrombocytopenia (41%) anemia (39%), and neutropenia (32%).3

“The myelosuppression that’s there is manageable,” Mascarenhas said. “Other than that, [imetelstat] doesn’t have a significant signal of toxicity from nonhematologic aspects. We didn’t see real concerns from the pattern of toxicity, which was originally a concern for the drug. Sometimes you get some low-grade gastrointestinal toxicity, but I have to say it’s very rarely a reason for concern or discontinuation. From a nonhematologic standpoint, it seems well tolerated.”

The study authors concluded that imetelstat displayed clinical benefits with potential disease-modifying activity at the 9.4-mg/kg dose level and that the novel telomerase mechanism of action offers a new treatment option for patients with myelofibrosis that may alter the course of their disease.3

Notably, imetelstat also has shown activity in myelodysplastic syndrome (MDS), a cousin of myelofibrosis, according to Mascarenhas. Patients with low- or intermediate-1–risk MDS achieved significant and durable transfusion independence when treated with imetelstat compared with placebo, according to topline findings from the phase 3 IMerge trial (NCT02598661).4

Data from the primary analysis of IMerge showed that patients treated with imetelstat (n = 118) achieved a transfusion independence rate of 39.8% (95% CI, 30.9%-49.3%) at 8 weeks compared with 15.0% (95% CI, 7.1%-26.6%) among patients (n = 60) who received placebo (P < .001). Moreover, the 24-week transfusion independence rates were 28.0% (95% CI, 20.1%-37.0%) and 3.3% (95% CI, 0.4%-11.5%), respectively (P < .001).

Additionally, the median transfusion- independence duration reported with imetelstat was approximately 1 year vs approximately 13 weeks with placebo via Kaplan-Meier estimates, indicating statistically significant durable transfusion independence for 8-week transfusion-independent responders (HR, 0.23). In the 24-week transfusion-independent responders who received imetelstat, the median transfusion independence duration was approximately 1.5 years.

These findings met the trial’s primary end point of percentage of patients without any red blood cell (RBC) transfusions during any consecutive 8-week period; the key secondary end point of percentage of patients without RBC transfusions in a 24-week period also was met.

“Durable transfusion independence [was observed] across the spectrum of patients,” Mascarenhas said. “That opens up the potential pathway for approval in MDS with a goal of addressing anemia. It’s interesting because in myelofibrosis we’re really [administering] it as a therapy to try to prolong survival in this very advanced sick patient population; MDS is sort of the other way around, [where it’s given] to patients and the goal is [management of] anemia, but even in that study they saw molecular responses.”

IMpactMF Looks to Solidify Imetelstat’s Place in Myelofibrosis

Following the positive findings from IMbark, investigators initiated the phase 3 randomized, open label, multicenter IMpactMF trial comparing the efficacy and safety of imetelstat with that of best available therapy (Figure1,5).

Figure. IMpactMF Phase 3 Trial Design1,5

The study aims to enroll a total of approximately 320 adult patients with intermediate-2 or high-risk myelofibrosis that is relapsed or refractory to treatment with a JAK inhibitor. Patients are eligible for enrollment if they have an ECOG performance status of 2 or less, have active myelofibrosis symptoms with a symptom score of at least 5 points according to the Myelofibrosis Symptom Assessment Form version 4.0, and have hematology and biochemical test values within the protocol defined limits. Patients with a peripheral blood blast count or a bone marrow blast count of 10% or more, with prior treatment with imetelstat, or who have undergone major surgery within 28 days prior to randomization will be excluded from enrollment.1,5

Eligible patients will be randomly assigned 2:1 to receive either imetelstat or best available therapy, which will consist of an investigator-selected nonJAK inhibitor treatment. Imetelstat at 9.4 mg/kg or best available therapy will be given every 3 weeks until disease progression or unacceptable toxicity, treatment discontinuation, or study end. Patients in the control arm will have the option to cross over to receive imetelstat if they meet the protocol-defined criteria for progressive disease.

The primary end point is OS, and secondary end points include symptom response rate, progression-free survival, and spleen response rate. The trial is recruiting patients and is estimated to be completed in August 2025.

“This is [enrolling] patients who have really bad disease—it’s an unmet need; they don’t have excellent choices at that point [when they] are refractory to ruxolitinib,” Mascarenhas said. “I’m not aware of [other] studies in myelofibrosis where survival is an end point; usually it’s spleen and symptom benefit.

“We are in desperate need of therapies that can prolong survival in this patient population. For some patients, it might be a bridge to transplant, which is definitive and potentially curative. For other patients, it may simply be to improve survival, maybe improve their disease process default, [or] their malignant stem cell population. Maybe [other patients would] move on to other combination therapies—there are a lot of combination therapies moving forward in this space.”

References

  1. Mascarenhas J, Harrison C, Kiladjian JJ, et al. MYF3001: a randomized open label, phase 3 study to evaluate imetelstat versus best available therapy in patients with intermediate-2 or high-risk myelofibrosis relapsed/refractory to janus kinase inhibitor. Blood. 2022;140(suppl 1):6826-6829. doi:10.1182/blood-2022-160364
  2. Imetelstat. Geron. 2023. Accessed February 28, 2023. https://www.geron.com/research-and-development/imetelstat/
  3. Mascarenhas J, Komrokji RS, Palandri F, et al. Randomized, single-blind, multicenter phase II study of two doses of imetelstat in relapsed or refractory myelofibrosis. J Clin Oncol. 2021;39(26):28812892. doi:10.1200/JCO.20.02864
  4. Geron announces positive top-line results from IMerge phase 3 trial of imetelstat in lower risk MDS. News release. Geron. January 4, 2023. Accessed March 1, 2023. https://ir.geron.com/investors/press-releases/press-release-details
  5. A study comparing imetelstat versus best available therapy for the treatment of intermediate-2 or high-risk myelofibrosis (MF) who have not responded to janus kinase (JAK)-inhibitor treatment. ClinicalTrials.gov. Updated January 13, 2023. Accessed March 1, 2023. https://clinicaltrials.gov/ct2/show/NCT04576156

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