While younger matched donors and older matched sibling donors provide similar outcomes, matched sibling donors are the optimal donor type for patients with cancer in need of a stem cell transplant, according to Salman Fazal, MD.

According to previous research, 3 to 5-year survival rates and outcomes between these donors are similar. However, a study published in Blood revealed that the average 3-year overall survival for patients with a matched sibling donor was 46% while it was 43% for unrelated donors. Having a matched sibling donor also lowered the risk of acute graft-versus-host-disease (GVHD).

“[A]t this point in time, even if we have a matched sibling, probably even above the age of 50, we would prefer using that matched sibling over a younger matched unrelated donor,” Fazal, director of the cell transplantation program in the division of hematology & cellular therapy at the Allegheny Health Network, told Targeted Oncology^TM.

In the interview, Fazal discussed the differences between older matched sibling donors vs younger unrelated donors in stem cell transplants and donor preferences at his institution for patients with cancer.

Targeted Oncology: What is the difference between younger, matched, unrelated donors and donor matched sibling donors? According to research, which achieves the better results?

Fazal: For each patient, we sometimes do not have the option of choosing between matched sibling [donor] vs an unrelated donor. So, if we have a match on an unrelated donor, we take that match from the unrelated donor for allogeneic stem cell transplant. However, in a situation where we have the options between an older matched sibling vs a younger matched unrelated donor the clinical study that was published in Blood, roughly about 8 to 10 years ago, looked at this comparison.

[They] found that using a matched sibling has resulted in a better outcome in terms of lowering the risk of acute and chronic graft versus host disease, and other complications related to transplant. So, at this point in time, even if we have a matched sibling, probably even above the age of 50, we would prefer using that matched sibling over a younger matched unrelated donor.

Can you discuss what kind of disease-free survival we’re seeing with young matched unrelated donors?

It is very relevant in terms of disease-free survival. It depends upon the type of disease the patient has, whether we’re dealing with acute leukemia or myelodysplastic syndrome, and we’re also dependent upon their status of the disease moving into the transplantation. In general, for different types of acute leukemia, depending upon the intensity of the conditioning, the disease-free survival rates vary between 50% to 70%, depending upon the status of the disease and the intensity of the conditioning chemotherapy. We do try to improve the disease-free survival with maintenance therapies which are used in conjunction with reducing the immunosuppression following the stem cell transplant to improve the disease-free survival.

Can you talk about acute and chronic GVHD occurring and younger match unrelated donor transplant?

Over the last few years, there has been a lot of interest in terms of using different modalities to lower the risk of acute and chronic graft-versus-host disease. I always feel that we would be performing more allogeneic stem cell transplantation for different diseases if there was no significant risk of acute or chronic graft-versus-host disease. In general, the matched donors prefer per cell transplantation, there have been different modalities or methods have been used to lower the risk of acute and chronic graft-versus-host disease. Historically, we have used strategies, which include calcineurin inhibitors and methotrexate to lower the risk of graft-versus-host disease.

More recently, there was a study which compared tacrolimus and methotrexate with post-transplant cyclophosphamide to further lower the risk of graft-versus-host disease. We found that using post-transplant cyclophosphamide, even in matched related donors, led to lowering the risk of acute and chronic graft-versus-host disease. However, that study did not have the comparator arm with antithymocyte globulin, which is 1 of the other modalities that has been used to lower the risk of acute and chronic graft-versus-host disease. But as we all know, post-transplant cyclophosphamide came into the scene with the haploidentical transplantation, and now it is making its way in other types of transplantation, including measuring later donor transplantation. It has shown that it is an effective strategy in terms of both acute and chronic efforts. However, we do still see significant risk of both acute and chronic, although I believe that chronic graft-versus-host disease remains a challenge in terms of allogeneic stem cell transplantation.

What is the donor preference in your institution and what studies support that choice?

It all depends upon each individual patient, which options we have at our institution, and we do always consider matched siblings and over a matched unrelated donor. However, unfortunately, because of health conditions and other exceptions, matches are not sometimes available in those circumstances. We do prefer using a match on a later donor for transplantation. However, in situations where we do not have a match and later donor, then we are posed with the question whether we choose a mismatched, unrelated donor vs a haploidentical transplantation?

Currently, that trial is ongoing in terms of trying to figure out which is a better strategy in that type of situation. Is a mismatched unrelated donor transplantation a better option than a haploidentical transplantation? At this time, at our institution, because of the reliability of haploidentical transplantation and immediate availability of the donor, we do usually prefer to proceed with the haploidentical transplantation.

I think clinical trials have to show that if using a haploidentical transplantation is associated with better outcomes as compared with mismatched unrelated donors, I think the use of post-transplant cyclophosphamide in haploidentical transplantation has now made its way of using post-transplant cyclophosphamide following mismatched unrelated donor transplantation as well. I think in that context, the outcomes probably could be similar between the 2 strategies. However, because of the reliability of availability of the donor with the haploidentical transplant and with the unrelated donor, we always are concerned about the possibility of a situation where an unrelated donor is unavailable. In that situation, the patient may be left with delay in transplantation. We like to proceed with haploidentical transplantation because of its reliability of availability. I think that is also stems from the time when we were doing transplantation during the COVID pandemic because during the COVID pandemic, it was much more practical to use a haploidentical transplant donor where we don’t have to cryopreserve the cells and use the the or the fresh stem cells from the haploidentical donor.

Can you discuss haploidentical donors and their overall survival and relapse-free survival data?

In general, with haploidentical transplantation, there is overall improvement in the outcomes. However, we still prefer to do unrelated donor vs haploidentical transplantation. There are certain institutions across the country that do prefer haploidentical transplant over unrelated donors. However, now, at least at our institution, we prefer to do match unrelated donor transplantation. In terms of the outcomes of the haploidentical transplantation, it is dependent on different diseases. In terms of acute leukemia, depending upon the intensity of conditioning, chemotherapy, and the status of the disease, the outcomes vary. Again, in terms of acute leukemia, as I mentioned earlier, the disease-free survival rates vary between 50% to 70%. Outcomes with chronic graft-versus-host disease vary somewhere between 30% to 50%. Up to 50% can develop graft-versus-host disease, however, the majority of these graft-versus-host diseases are mild to moderate.

How would you advise other doctors on deciding on which donor to select in deciding when to do a transplant?

In terms of the other dissenters, I would prefer that we continue to use the match unrelated donor. However, I think, for mismatch vs the haploidentical transplant, we certainly have to look at the data. I do like the idea that the haploidentical has the bigger liability. So, I think in those situations, taking a haploidentical donor is preferable over a mismatched unrelated donor.

In terms of the difference for transplantation, we hope that the transplant physician is involved with the care of the patient from the beginning. There are situations in acute leukemia, where the choice of initial therapy impacts the post-transplant outcome. There are situations even with the availability of immunotherapy where use of certain agents can increase the risk of graft-versus-host disease and such complications after transplantation. I think incorporating the transplant physician in terms of choice of initial therapy, and then getting them to the transplant physician in a timely fashion is important.

Data that was presented in terms of comparing post-transplant cyclophosphamide vs tacrolimus and methotrexate confirmed that post-transplant cyclophosphamide does improve the outcomes following the transplantation. I think using these during this phase 2 clinical trials are a way to improve patient outcomes following the transplantation.

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Although literature, guidelines, and laboratory data are available to guide treatment decisions for patients with myeloproliferative neoplasms (MPNs), most decisions in clinical practice stem from individual presentations, according to onco-nursing experts.¹

During a Medical Crossfire^® at the 48th Annual Oncology Nursing Society Congress, specialists highlighted the best practices and latest treatment regimens for patients presenting with the 3 most common MPNs: myelofibrosis, polycythemia vera (PV), and essential thrombocythemia (ET).

The crossfire was chaired by Jill Brennan-Cook, DNP, RN, GERO-BC, an associate professor in the ABSN program and a member of the Healthcare in Adult Populations Division at Duke University School of Nursing.

Brennan-Cook was joined by Abdulraheem Yacoub, MD, an associate professor of medicine and clinical director of ambulatory clinics at the University of Kansas Cancer Center, Ilene Galinsky, BSN, MSN, ANP-C, a research nurse practitioner at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and Brandi Ligon, MS, BSN, RN, AGPCNP-BC, a hematology and oncology nurse practitioner at AdventHealth.

Myelofibrosis

Clinical, laboratory, and pathologic analyses are needed to make a diagnosis of myelofibrosis, Yacoub explained in an overview of the disease. Updated major criteria include megakaryocytic proliferation and atypia with reticulin and/or collagen fibrosis of grade 2 or 3; presence of a JAK2, CALR, or MPL mutation or other clonal markers such as ASXL1, EZH2, TET2, IDH1/2, among others, or the absence of reactive myelofibrosis; and not meeting other World Health Organization criteria for myeloid malignancies.2 In addition to these 3 criteria, patients must also present with 1 minor criteria which can include the following: anemia not related to a comorbid condition; leukocytosis at least 11 × 109/L; palpable splenomegaly, lactate dehydrogenase increased above the upper limit of normal; and leukoerythroblastosis.²

“Patients with myelofibrosis have unique presentations and each patient has unique therapeutic needs that requires collaboration between the physician, the nurse, the nurse practitioner, that pharmacist the whole health care system to try to provide better care,” Yacoub said. “There is also a significant education need for practitioners, as well as the patients and their caregivers to teach them more about myelofibrosis, how to approach the disease, and [identify] the unmet needs so that we can work as a team to advance the field.”

Despite MPNs entering clinical discussions nearly a century ago, most of the knowledge and treatments have been generated in the past 15 years, Yacoub explained. As overactive JAK signaling presents as a hallmark of myelofibrosis agents targeting the signaling mechanism have come into use. When JAK/STAT signaling increases, myeloproliferation and abnormal levels of cytokines can trigger presentations of myelofibrosis such as abnormal cell counts, bone marrow fibrosis (which prevents normal hematopoiesis), and splenomegaly, a common occurrence in up to 90% of patients with myelofibrosis.³

The best avenue for the management of patients with myelofibrosis can evolve over time, Yacoub said, but noted that 3 goals are common—reduce splenomegaly, improve symptoms, and improve survival. For example, splenomegaly, chronic inflammation, fatigue, among other symptoms have resulted in reductions in quality of life. “This is a unique feature of MPNs which requires extra attention and examination by providers,” Yacoub said. “There have been tools developed to quantify patients’ symptoms and address them appropriately.”

Finally, Yacoub noted that patients are treated based on symptom burden and risk. Based on the National Comprehensive Cancer Network (NCCN) guidelines, low-risk and intermediate-1 patients should undergo observation if asymptomatic, or ruxolitinib (Jakafi) if symptomatic. They may also be treated for cytopenias and select patients may qualify for transplant.

For those who are high-risk or intermediate-2, transplant, ruxolitinib (platelet count >50), fedratinib (Inrebic; platelet count >50), or pacritinib (Vonjo; platelet count <50) should be considered. Anemia and thrombocytopenia should also be managed appropriately. Alternatively, clinical trial enrollment are options for all-risk patients.⁴

Despite guidelines for these treatments, the time to progression in myelofibrosis varies with most experiencing progression in the first 10 years of a diagnosis. Long-term, progressive complications such as cytopenias, constitutional symptoms, organomegaly and extramedullary hematopoiesis have been reported, as well as short-term vascular events.¹

There is also the potential for evolution to leukemia, which Yacoub noted makes the unmet need for patients who progress on JAK inhibitors of importance.

“We are lucky that the research has identified many targets,” Yacoub said, noting that there is a long way to go.

In a case study of a patient with myelofibrosis, Galinsky, noted that a 75-year-old woman presented with progressive disease that was ultimately defined as post-ET myelofibrosis, along with a prognosis of approximately 8 years after using scoring systems who was about to undergo treatment for symptom management.

“It’s important that, in addition to your clinical lab studies, symptoms are subjective and objective and it’s always important to communicate with your patients,” Galinsky said. “How do you treat these patients? You want to think about where they are in their life. [The case study patient] happens to be older, so she is not a transplant candidate, but at [Dana-Farber] up to 75 years are referred for transplant consult just to get her HLA typing. That’s important to do for all patients. What needs to be done in regard to her symptoms? You want to fix their anemia and splenomegaly, and the JAK inhibitor is the way to go—so we started at low-dose ruxolitinib.”

Galinsky noted it is important to rule out other causes of symptoms prior to starting therapy. “Always in these patients, it’s not always what it looks like. Just because a patient has myelofibrosis, you cannot blame everything on myelofibrosis.”

“My take-home message is always, always look at the patient. Always look at their labs, but always talk to the patient—what are they reporting that their symptoms are?” Galinsky added. “If their numbers are changing and they’re not feeling well, always ask if they are taking their drug. If they are not taking their drug—why? If they are having adverse effects [AEs], it’s our job to help them [manage the symptoms].”

PV

“PV is the most common of the 3 MPNs and shares many characteristics with myelofibrosis…but the hallmark of PV is the excessive production of red [blood] cells, white [blood] cells, and platelets,” Yacoub said. Fortunately, Yacoub said, patients have normal life expectancy with PV and therefore management goals focus on achieving cytoreduction, improving symptoms, and avoiding treatment-related toxicities.

Cytoreductive agents are reserved for patients with high-risk disease and for those with uncontrolled disease manifestations with phlebotomy, which is the immediately available tool to reduce blood counts, Yacoub explained. Aspirin is essential for all patients. In a study of therapies used for PV, it was noted that most physicians were using hydroxyurea either with aspirin or phlebotomy. Even though hydroxyurea is the most common and up to 70% of patients respond to therapy, Yacoub said that for the 30% who do not respond or have resistance, alternative options are needed.⁵

“Interferons, which are becoming a standard first-line therapy, are still underused,” Yacoub noted. For example, ropeginterferon-alfa-2b-njft (Besremi) was approved for first- and second-line treatment of patients with PV and has shown far superior long-term outcomes compared with hydroxyurea in the PROUD-PV study (NCT01949805).⁶

“It’s not uncommon for a person to [receive a diagnosis of] PV randomly, just going for blood work and [they] have elevated hemoglobin and hematocrit and sometimes white blood cells and sometimes platelets,” Brennan-Cook said in a case discussion of a patient with PV. “Approximately 30% of patients who are newly diagnosed come in after they’ve had a thrombotic event. So, they find out as they are admitted to the hospital for a [blood] clot that they have PV.”

Brennan-Cook said that any patient with an MPN should be seen by a specialist. “For those of us who work at large academic medical centers that is easy, but a lot of our patients have the travel quite a distance to be seen by an MPN specialist. That confounds a lot of the care that they get and it complicated the treatment because sometimes they have to spend a whole day at the center and they have to drive several hours and that [can] impact adherence.”

Although management of symptoms sounds simple—prevention of thrombotic events being paramount—Brennan-Cook said that maintaining quality of life is also a consideration in nursing interactions. Health literacy has a role in adherence, she noted, and understanding what knowledge patients have at baseline can guide how nurses can best communicate with them regarding treatments. She cited NCCN guidelines as a resource for patients.

Nurses should consider symptom burden, especially fatigue, which is present in approximately 80% of patients with PV. Brennan-Cook said that this can play a role in whether they make it to not only social events but appointments as well. She recommends yoga and motivational conversations that bring the patient into the treatment decision-making, rather than the nurse providing recommendations without patient buy in.

“The symptoms for PV can change,” Brennan-Cook said, highlighting that symptoms such as pruritus may evolve over time and necessitate concurrent treatments. Tobacco use has also been associated with the increased symptom burden.

Finally, Brennan-Cook noted that patients with PV can appear healthy, but the unknown of their disease afflicts them like other oncologic diagnoses. “They know it’s progressive, they don’t know if [their PV] is going to progress to myelofibrosis because approximately 20% progress to myelofibrosis and a small amount to acute myeloid leukemia, but they don’t know when or if it is going to happen,” she said. “So, every month when they are going for their labs that thought is with them. Whatever you can do to work with them, thinking about quality of life, thinking about activity levels, and staying healthy on their own, it’s important to have those conversations.”

ET

The lowest-risk MPN, ET manifests as isolated thrombocytosis, with a high risk of thrombosis and bleeding. Half of patients present with a JAK2 mutation, thrombocytosis, and megakaryocyte proliferation. Additionally, the disease has a high symptom burden.⁷

“ET is a bunch of megakaryocytes and platelets that take over the bone marrow,” Ligon said in a presentation on clinical observations with ET. Symptoms can present as headaches, dizziness, fainting, and vision changes, which are the most common. Patients may also experience chest pain, numbness, burning sensation in the hands, and bleeding events.

Patients are divided into risk categories based on age, mutational status, and thrombosis history.4 Despite the division based on cardiovascular risk, Yacoub explained that patients should be treated if they are symptomatic regardless of risk status. “For patients who are not high-risk, we treat them based on symptoms,” he said. “This can include cytoreductive agents or observation only or any of the other options that we have.”

Hydroxyurea is a mainstay in treatment for this population, and ruxolitinib is also used in certain cases, but Yacoub added that ropeginterferon alfa-2b is under investigation in the phase 3 SURPASS ET trial (NCT04285086). “Hopefully if these studies are successful the same drug that is used in PV will be approved and an option for patients with ET.” Another agent is bomedemstat, which is an LSD1 inhibitor that targets megakaryocytes, which has demonstrated normalization of platelet counts.⁸

“What is our role as oncology nurses? The biggest thing is symptom management for these patients, reductions of complications, reducing the risk of thrombus,” Ligon said. “[We also must] make sure that these patients know that when they take hydroxyurea that they are wearing gloves when they administer the medication because they can cause toxicities through the skin.”

Ligon noted that there is an MPN symptom management app available for patients.⁹

What’s Next?

As for the future of MPNs, the panel noted that as more medicines are introduced and diagnoses are made earlier through educational efforts, a new wave of treatment may emerge.

“We’re making major progress at all aspects of MPNs,” Yacoub said. “We’re a lot better at making a diagnosis now, we have better tools, we are doing whole genome sequencing or next-generation sequencing, so we are learning a lot more about disease biology and are describing it better. We have a much more informed discussion with patients about their futures now.”

“Being able to target some of these mutations with the drugs that are coming down the pipeline, would allow these patients to have more control and have more personalized medicine when it comes to treating these diagnoses,” Ligon said. “I also like that some of our community physicians can be an asset to the physicians at the bigger centers. A lot of times, they can work in conjunction together so that patients do not have to travel as far, maybe only every 3 months, or so.”

“Communication and collaboration make a big difference,” Brennan-Cook concluded.

References

1. Brennan-Cook J, Galinsky I, Ligon B, Yacoub A. Medical Crossfire®: exchange between onco-nursing experts on MPN treatment and symptom management along the care continuum. Presented at: 48th Annual Oncology Nursing Society Congress; April 26, 2023; San Antonio, TX.
2. Arber DA, et al. Kvasnicka HM, Orazi A, et al. The international consensus classification of myeloid neoplasms and acute leukemias: myeloproliferative neoplasms. Am J Hematol. 2023;98(3):544-545. doi:10.1002/ajh.26821
3. Spivak JL. Myeloproliferative neoplasms. N Engl J Med. 2017;376(22):2168-2181. doi:10.1056/NEJMra1406186
4. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 3.2022. Accessed April 26, 2023. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf
5. Grunwalk MR, Kuter DJ, Altomare I, et al. Treatment patterns and blood counts in patients with polycythemia vera treated with hydroxyurea in the United States: an analysis from the REVEAL study. Clin Lymphoma Myeloma Leuk. 2020;20(4):219-225. doi:10.1016/j.clml.2019.09.601
6. Kiladjian JJ, Klade C, Georgiev P, et al; PROUD-PV Study Group. Long-term outcomes of polycythemia vera patients treated with ropeginterferon alfa-2b. Leukemia. 2022;36(5):1408-1411. doi:10.1038/s41375-022-01528-x
7. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-405. doi:10.1182/blood-2016-03-643544
8. Gill H, Palandri F, Ross DM, et al. A phase 2 study of the LSD1 inhibitor bomedemstat (IMG-7289) for the treatment of essential thrombocythemia (ET). Blood. 2022;140(suppl 1):1784-1787. doi:10.1182/blood-2022-159047
9. The MPN Genie. Canadian Research Foundation. Accessed April 26, 2023. https://www.cmpnrf.ca/genieapp

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The first patients have been dosed in the phase 3b ECLIPSE PV trial (NCT05481151), which is evaluating an accelerated dosing schedule of ropeginterferon alfa-2b-njft (Besremi) using a prefilled syringe for the treatment of patients with polycythemia vera (PV).¹

“This therapy represents an important addition to the treatment arsenal for PV in the U.S., and clinical data support its use across a broad range of patients regardless of their treatment history,” John Mascarenhas, MD, professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai in New York, stated in a news release. “This new study is addressing an important therapeutic and clinical question regarding whether treatment utilizing accelerated dosing leads to a more rapid hematologic and molecular response, indicating potential disease modifying activity and long-term disease control.”

In November 2021, the FDA approved ropeginterferon alfa-2b for the treatment of patients with PV.² The agent is a novel monopegylated, long-acting interferon that can be administered once every 2 weeks, or every 4 weeks with hematological stability, for at least 1 year. The agent has the potential to produce durable activity through its pegylation technology.¹

The phase 3b study will evaluate an accelerated dosing schedule for ropeginterferon alfa-2b compared with the current labeled dosing.³ The primary end point of the study is the proportion of patients achieving a complete hematologic response at 24 weeks of treatment, defined as hematocrit below 45% for at least 3 months since last phlebotomy, platelets not exceeding 400 x 10⁹/L, and leukocytes of 10 x 10⁹/L or below.

The study, which will enroll approximately 100 patients with PV in the United States and Canada, will randomly assign patients to receive either the accelerated dosing or the current labeled dosing of 50 µg or 100 µg with 50 mcg titration every 2 weeks. Patients assigned to the accelerated dosing arm will receive a starting dose of 250 µg, then 350 µg at week 2, with a target optimal dose of 500 µg at week 4. Subsequent dosing will remain fixed at the highest tolerated dose for the rest of treatment.

The study will run for 48 weeks and will be followed by a 28-day period of safety follow-up. Patients who respond to treatment will be eligible to participate in a long-term extension phase of the study.

Topline data from the trial are expected by 2024.

“Our goal with this study is to deliver evidence on the potentially enhanced benefits of treating patients with ropeginterferon alfa-2b through this accelerated dosing schedule and to bring additional confidence to clinicians and patients in the utility of the treatment to manage this chronic cancer,” Raymond Urbanski, MD, PhD, U.S. head of Clinical Development and Medical Affairs, said in a news release. “We believe this study will deliver further insight into the potential of ropeginterferon alfa-2b to meet the needs of PV patients.”

References

1. PharmaEssentia initiates phase 3b trial of ropeginterferon alfa-2b-njft investigatng new dosing regimen for patients with polycythemia vera (PV). News release. May 3, 2023. Accessed May 15, 2023. https://us.pharmaessentia.com/wp-content/uploads/2023/05/ECLIPSE-PV_Initiation_Press_Release_May-3-2023-1.pdf
2. US FDA approves BESREMI (ropeginterferon alfa-2b-njft) as the only interferon for adults with polycythemia vera. News release. PharmaEssentia Corporation. November 12, 2021. Accessed May 15, 2023. https://us.pharmaessentia.com/wp-content/uploads/2021/11/BESREMi-FDA-Approval-November-12-2021.pdf
3. A study to assess efficacy, safety, and tolerability of P1101 in adult patients with PV. ClinicalTrials.gov. Updated March 27, 2023. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT05481151

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JAK inhibitors have paved the way and improved clinical outcomes for patients with myeloproliferative neoplasms over the past decade. Not only have these agents shown significant improvements in efficacy outcomes, but they have demonstrated favorable safety profiles in this patient population.

Currently, 3 JAK inhibitors are approved for patients with myelofibrosis. The first was ruxolitinib (Jakafi), which was approved by the FDA in 2015 and continues to be the main therapy for patients with myelofibrosis. Patients treated with ruxolitinib have had improved splenomegaly and constitutional symptoms, as well as an observed survival benefit.

Following the approval of ruxolitinib came 2 more, including the JAK2 inhibitor fedratinib (Inrebic) which was approved in 2019, and pacritinib (Vonjo) in 2022. Studies of fedratinib have confirmed that the agent is a beneficial second-line treatment option for patients who are ruxolitinib-resistant. Pacritinib also continues to serve as a good treatment option for patients with myelofibrosis and severe thrombocytopenia.

Now, another JAK1/2 inhibitor is in clinical development, known as momelotinib, and is being evaluated in the phase 3 MOMENTUM trial (NCT04173494) for patients who are symptomatic and anemic with advanced myelofibrosis. Those enrolled in MOMENTUM must have previously been treated with a JAK inhibitor, and findings from the study already have revealed clinically significant improvements with momelotinib vs danazol in this patient population.

Data from the MOMENTUM study revealed that 25% of patients treated with momelotinib (n = 130) had a 50%, or more, reduction in patient’s Myelofibrosis Symptom Assessment Form Total Symptom Score (TSS) vs 9% of patients treated with danazol (n = 65), making a proportion difference of 16%. Researchers confirmed this difference to be statistically significant (95% CI, 6–26; P =.0095).

Now, the United States has assigned a Prescription Drug User Fee Act (PDUFA) action date of June 16, 2023.

“We are in an unprecedented period of excitement around new therapies for myeloproliferative neoplasms. Each response and benefit with JAK inhibitors showed a lot of great updated data, [including] momelotinib, which may be approved in 2023,” Ruben Mesa, MD, told Targeted Oncology^TM, in an interview.

In the interview, Mesa, director of the UT Health San Antonio MD Anderson Cancer Center, discussed the currently available JAK inhibitors for patients with myelofibrosis, and what is in store for the field.

Targeted Oncology: Can you discuss some of the approved JAK inhibitors in the myelofibrosis space?

Mesa: For myelofibrosis, we are excited to have 3 FDA-approved therapies, ruxolitinib, pacritinib, and fedratinib, that are all inhibitors of JAK2. Ruxolitinib is from 2011, fedratinib is from 2019, and pacritinib which [was approved in 2022]. Ruxolitinib and fedratinib are both approved in the frontline setting as well as fedratinib in the second-line setting. Now pacritinib is approved in the front and second-line settings for patients who have a platelet count of less than 50,000, and certainly, is a consideration for platelet counts under 100,000 or as a third-line in any patient. These have been a great help.

We have momelotinib coming up on the heels. That might become an approved therapy in 2023. We anticipate all these agents will hopefully improve spleen and symptoms. I think in responding patients, probably all will have a beneficial impact in terms of survival, and we’re excited to have these to build from in this space.

Can you explain the purpose behind the MANIFEST trial and the SIMPLIFY-1 study?

What the MANIFEST study was looking at was pelabresib [CPI-0610] in combination with ruxolitinib, either in the frontline or second-line setting. That was the goal, and we’ve been excited by the data that shows a good depth of response as a single agent with JAK inhibition, as well as potentially extending further the types of benefits that might be seen. That’s helped us to set up the MANIFEST-2 that is ongoing.

The MOMENTUM study, a different study, is [looking at] second-line therapy, symptomatic myelofibrosis with anemia, and showed that momelotinib is clearly superior compared with danazol. These data provide further study updates showing the durability of response screaming symptoms anemia. We are excited about this data.

What is the most new, exciting, and practice changing data in the myeloproliferative neoplasm space?

We are in an unprecedented period of excitement around new therapies for myeloproliferative neoplasms. Each response and benefit with JAK inhibitors showed a lot of great updated data, [including] momelotinib, which may be approved in 2023, as well as pacritinib and validating data with fedratinib. Combinations and phase 2 studies, whether with parsaclisib, venetoclax [Venclexta], pelabresib, or other combinations that may be coming, these combination therapies are truly the way of the future, so it is an exciting time.

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