Category Archives: Treatment

European Commission Approves Momelotinib for Myelofibrosis/Anemia

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Ariana Pelosci

The European Commission granted marketing authorization to momelotinib (Omjjara) for patients with primary myelofibrosis who have disease-related splenomegaly or moderate to severe anemia, according to a press release from GSK.1

This indication also covers patients with post polycythemia vera myelofibrosis or post essential thrombocythemia myelofibrosis who are JAK inhibitor naïve or received previous treatment with ruxolitinib (Jakafi). The authorization is based on results from the phase 3 MOMENTUM trial (NCT04173494), which analyzed the use of momelotinib and danazol in patients with symptomatic and anemic myelofibrosis.2

“The challenges of living with myelofibrosis can be burdensome, and symptomatic patients can experience spleen enlargement, fatigue, night sweats, and bone pain. Until now, there have been no options specifically indicated to treat these symptoms in patients who also experience anemia. The authorization of [momelotinib] brings a new treatment option with a differentiated mechanism of action to these patients in the European Union,” Nina Mojas, senior vice president of Oncology Global Product Strategy at GSK, said in the press release.

In the trial, the total symptom score response at week 24 was 24.6% (95% CI, 17.49%-32.94%) for patients receiving momelotinib vs 9.2% (95% CI, 3.46%-19.02%) in the danazol arm (P = .0095). Additionally, a reduction of splenic volume by 25% occurred in 40.0% (95% CI, 31.51%-48.95%) of patients in the momelotinib arm vs 6.2% (95% CI, 1.70%-15.01%; P <.0001) in the danazol arm. A 35% reduction in spleen volume was also observed in 23.1% (95% CI, 16.14%-31.28%) in the momelotinib arm and 3.1% (95% CI, 0.37%-10.68%; P = .0006) in the danazol arm.

In September 2023, the FDA approved momelotinib for patients with intermediate- or high-risk myelofibrosis, including primary and secondary myelofibrosis, who are experiencing anemia.3 In November 2023, the European Medicine’s Agency’s Committee for Medicinal Products for Human Use expressed a positive opinion for momelotinib.4 The positive opinion was one of the final steps leading to the approval of the drug in the European Union.

“I think [momelotinib] will make an immediate impact. There clearly are individuals now who are on JAK inhibitors like ruxolitinib or fedratinib [Inrebic] who have significant anemia who will immediately be potential candidates,” Ruben A. Mesa, MD, FACP, said in an interview with CancerNetwork® prior to the FDA approval. Mesa is the president of the Enterprise Cancer Service Line and senior vice president at Atrium Health; executive director of the National Cancer Institute-designated Atrium Health Wake Forest Baptist Comprehensive Cancer Center; and vice dean for Cancer Programs at Wake Forest University School of Medicine.

References

  1. European Commission authorises GSK’s Omjjara (momelotinib). News release. GSK. January 29, 2024. Accessed January 29, 2024. https://shorturl.at/ntuvy
  2. Mesa RA, Gerds AT, Vannucchi A, et al. MPN-478 MOMENTUM: phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. J Clin Oncol. 2022;40(suppl 16):7002. doi:10.1200/JCO.2022.40.16_suppl.7002
  3. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia, News release. GSK. September 15, 2023. Accessed January 29, 2024. https://shorturl.at/jnNQY
  4. GSK receives positive CHMP opinion recommending momelotinib for myelofibrosis patients with anaemia. News release. GSK. November 13, 2023. Accessed January 29, 2024. https://bit.ly/3MEYpOl

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New Developments in MPN Management Provide Additional Options for Patients

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Kyle Doherty

Although myeloproliferative neoplasms (MPNs), which are comprised of essential thrombocythemia, polycythemia vera (PV), and myelofibrosis, remain relatively rare— with estimated annual incidence rates of 1.03, 0.84, and 0.47 per 100,000 individuals, respectively—there remains an unmet need for effective treatment options for patients with these diseases who progress on standard of care therapies.1 However, significant progress has been made in terms of understanding this group of disorders and developing treatment strategies to combat them, with Naveen Pemmaraju, MD, saying the medical field has entered a “golden era” of MPN treatment.

During a recent OncLive Peer Exchange® video series titled “Expert Insights Into the Management of MPNs,” Jamile M. Shammo, MD, explained, “MPNs represent a heterogeneous group of hematopoietic stem cell neoplasms that share common features. Myeloid proliferation is certainly something that we see [in MPNs], as well as a propensity for thrombotic events, symptoms that are related either to constitutional symptoms or splenomegaly related. All 3 entities tend to progress to higher myeloid neoplasms; essential thrombocythemia [to] PV that goes to myelofibrosis and then myelofibrosis can evolve into acute leukemia. Of course, the rate of progression varies from one entity to the other, with essential thrombocythemia having the lowest risk [of progression].”

The development of MPNs is almost always associated with mutations in JAK2, making this family of genes an attractive treatment target. JAK2 mutations are observed in approximately 95% of patients with PV and approximately 50% of both patients with essential thrombocythemia and myelofibrosis. Notably, the emergence of additional treatment targets also has sparked the development of novel agents in recent years.1

During the discussion, expert oncologists reviewed updated findings from ongoing and completed clinical trials in the field. They primarily focused on studies evaluating emerging agents in PV and myelofibrosis.

MANAGING PV

Abdulraheem Yacoub, MD, began the discussion on PV by noting that the JAK1/2 inhibitor ruxolitinib (Jakafi) has been the standard-of-care agent in PV since 2015. Prior to this, PV was historically managed with phlebotomy, hydroxyurea, and/or interferons. Ruxolitinib became the first FDA-approved drug for the treatment of patients with PV in December 2014 when it received an indication from the agency for patients who had an inadequate response to or were intolerant of hydroxyurea.2

“The introduction of ruxolitinib to the treatment landscape of patients with myelofibrosis has truly been transformative,” Shammo commented. “We all remember the patients we had in the clinic [in the past] and how we had simply nothing but supportive care to offer. Ruxolitinib was approved based on the results of 2 phase 3 studies. COMFORT-I [NCT00952289] randomly assigned patients [with myelofibrosis] to receive ruxolitinib or placebo and examined [spleen] volume reduction and reduction in total symptom score from baseline at 24 weeks. COMFORT-II [NCT00934544], which ran mostly in Europe, randomly assigned patients to be treated with ruxolitinib or best available therapy [as selected by the investigator]. This study [also evaluated] spleen volume reduction, but at week 48. In either trial, ruxolitinib was statistically significantly more active in attaining the primary end point and for that reason it was approved. Some might say that the evidence is perhaps less compelling than what you would [typically] find in a phase 3 study, but when you have multiple studies showing the same thing, that treatment with ruxolitinib improves [outcomes] compared with placebo or best available therapy, I tend to feel like it’s reasonable enough to believe that actually is the case.”

Long-term data from 2 phase 3 trials, RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036), comparing the safety and efficacy of ruxolitinib with best available therapy in different patient populations with PV recently were published in The Lancet Haematology. RESPONSE enrolled adult patients with PV who were resistant to or intolerant of hydroxyurea and randomly assigned them 1:1 to receive either ruxolitinib (n = 110) or best available therapy (n = 112; hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide (Agrylin), approved immunomodulators, or observation without pharmacological treatment). RESPONSE-2 enrolled a higher-risk patient population; eligible patients had inadequately controlled PV without splenomegaly and were intolerant of or resistant to hydroxyurea with an ECOG performance status of 2 or less. They were randomly assigned to receive ruxolitinib (n = 74) or best available therapy (n = 75).3,4

Follow-up data from RESPONSE demonstrated that the 5-year overall survival (OS) rate was 91.9% (95% CI, 84.4%-95.9%) in the ruxolitinib group vs 91.0% (95% CI, 82.8%-95.4%) in the best available therapy arm. Most patients (88%) in the best available therapy arm crossed over to receive ruxolitinib, and no patients remained in this arm after week 80. There were 25 primary responders in the ruxolitinib arm, 6 of whom had progressed by the time of the final analysis. The 5-year probability of maintaining a primary composite response was 74% (95% CI, 51%-88%), the probability of maintaining complete hematological remission was 55% (95% CI, 32%-73%), and the probability of maintaining overall clinicohematological responses was 67% (range, 54%-77%).3

At a median follow-up of 67 months (IQR, 65-70), findings from RESPONSE-2 showed that the 5-year OS rate was 96% (95% CI, 87%-99%) in the ruxolitinib arm compared with 91% (95% CI, 80%-96%) in the best available therapy arm. In the ruxolitinib arm, 22% of patients (95% CI, 13%-33%) achieved durable hematocrit control with an estimated median duration of control not reached (NR) at week 260 (95% CI, 144-NR). Most patients in the best available therapy arm (77%) crossed over to ruxolitinib, no patients continued with best available therapy after week 80 per protocol, and the median duration of hematocrit control was not reported due to the small number of responders at week 80.4

In light of findings from RESPONSE and RESPONSE-2, investigators in both studies concluded that ruxolitinib is a safe and effective long-term treatment option for patients with PV for whom hydroxyurea proved ineffective.3,4

“Both studies have ong-term follow-up and have published 5-year data showing very durable responses,” Yacoub said. “There were very few late failures on ruxolitinib and no unexpected adverse effects were observed with longterm follow up. This has built a strong case for ruxolitinib as a standard treatment for patients [with PV] after hydroxyurea failure.”

Ropeginterferon Takes Center Stage

A more recent breakthrough for patients with PV was the emergence of the interferon ropeginterferon alfa-2b-njft (Besremi). In November 2021, ropeginterferon became the first agent to receive FDA approval for patients with PV regardless of their treatment history.5

Ropeginterferon was compared with hydroxyurea in the phase 3 PROUD-PV trial (NCT01949805) and its extension continuation study, CONTI-PV (NCT02218047). Eligible patients were 18 years or older and had earlystage PV with no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment. Patients could opt to enter CONTI-PV after 1 year of initial treatment in PROUD-PV.6

Findings from the studies revealed that at a median follow-up of 182.1 weeks (IQR, 166.3- 201.7) patients in PROUD-PV who received ropeginterferon (n = 122) achieved complete hematological response with normal spleen size at a rate of 21% compared with 28% of patients who received hydroxyurea (n = 123). However, in CONTI-PV, 53% of patients in the ropeginterferon arm (n = 95) had a complete hematological response with improved disease burden at 36 months vs 38% of patients in the hydroxyurea arm (n = 74; P = .044). Moreover, at 36 months in CONTI-PV, the complete hematological response rate regardless of spleen criterion was 71% vs 51% in the investigative and comparator arms, respectively (P = .012); at 12 months in PROUD-PV these rates were 43% vs 46%, respectively (P = .63).6

Study authors concluded that ropeginterferon was effective in inducing hematological responses. Although noninferiority to hydroxyurea in terms of hematological response and normal spleen size was not observed at 12 months, improved responses vs hydroxyurea were present at 36 months. Thus, the authors wrote that ropeginterferon offers an effective and “safe long-term avenue for treatment with distinct features from hydroxyurea.”6

“It’s wonderful to have options because we get patients with PV [who] could not be any more different,” Yacoub said. “They have different goals of care, and at the end of the day, we are treating individual patients, not diseases. For each patient, we have to define what we are trying to achieve. There are patients who are going to live with the disease a lot longer. They have more high-risk presentations and would benefit from the maximum data that we have with the application of the effective agents. There are patients who have relatively low-risk disease, and they’re likely going to live their natural lives with some medical management from our end. We have to individualize our choices.”

Looking ahead, the phase 3 VERIFY trial (NCT05210790) is underway with the aim of adding rusfertide (PTG-300), a novel and potent hepcidin mimetic, to the PV treatment landscape. Rusfertide previously demonstrated clinical activity in early-phase studies, characterized by good tolerability and consistent and durable hematocrit control, as well as improvements in iron deficiency among patients who required higher than normal amounts of phlebotomies even after standard-of-care therapy.7

VERIFY is enrolling patients with PV who have received at least 3 phlebotomies in the previous 6 months or at least 5 in the previous 12 months as a result of inadequate hematocrit control, with or without concurrent cytoreductive therapy. Eligible patients will be randomly assigned 1:1 to receive either placebo plus ongoing therapy or rusfertide plus ongoing therapy.

Part 1a of the trial is the double-blind, placebo- controlled, add-on phase that will enroll parallel groups and last 32 weeks. During part 1b, patients who complete part 1a will receive rusfertide for 20 weeks. Patients who successfully complete part 1b will enter the long term extension phase, part 2, and will continue to be treated with rusfertide for 104 weeks. The primary end point is the proportion of patients achieving a response in from week 20 to week 32 in part 1A. The study was initiated in January 2022 and has a target enrollment of 250 patients.7

Managing Myelofibrosis

Patients with myelofibrosis have more FDA-approved treatment options than those with PV. To date, 3 Janus kinase (JAK) inhibitors have been approved for the treatment of patients with myelofibrosis: ruxolitinib, fedratinib (Inrebic), and pacritinib (Vonjo).

Similar to PV, ruxolitinib became the first FDA-approved therapy for the treatment of patients with myelofibrosis, gaining an indication for patients with intermediate- and high-risk disease in November 2011. In August 2019, patients with intermediate- 2 or high-risk primary or secondary myelofibrosis gained fedratinib as an FDA-approved option. Finally, the FDA approved pacritinib in March 2022 for the treatment of adult patients with intermediate- or high-risk primary or secondary myelofibrosis with platelet levels below 50,000/μL.8-10

“The current NCCN [National Comprehensive Cancer Network] guidelines are really agnostic of the second-line therapy, which is interesting,” Raajit K. Rampal, MD, PhD, said. “You can start a patient who [at that time] has over 50,000 platelets on ruxolitinib or fedratinib. And if there is a need to change therapy, you could use any of these 3 agents. That’s an important message for our audience to remember, that the second line is not platelet restricted. We have an abundance of options.”

After summarizing updated data from pivotal trials of the already approved agents, the panelists shifted their focus to new findings from trials evaluating investigational therapies beyond JAK inhibitors in myelofibrosis. Updates from the studies were presented during the 2023 American Society of Clinical Oncology Annual Meeting in June.

Novel Agents Seek to Augment the Armamentarium

In the phase 2 ACE-536-MF-001 trial (NCT03194542), investigators examined the erythroid maturation agent luspatercept-aamt (Reblozyl) for the management of anemia in patients with myelofibrosis; it occurs in approximately 40% of patients. Investigators noted that luspatercept demonstrated anemia improvement across all cohorts of in the study, regardless of transfusion dependency and use of ruxolitinib. For example, 26.3% (95% CI, 13.4%- 43.1%) of patients who were red blood cell transfusion dependent and received prior ruxolitinib (n = 38) achieved transfusion independence following treatment with luspatercept.11

The phase 1/2 LIMBER study (NCT04455841) evaluated the safety and efficacy of the oral ALK2 inhibitor zilurgisertib alone and in combination with ruxolitinib in adult patients with intermediate 1 or 2 primary or secondary myelofibrosis. Among patients in the monotherapy group who were not transfusion dependent (n = 6), anemia improvement (hemoglobin increase of ≥ 1.5 g/ dL relative to baseline) occurred in 1 patient; this level of improvement was observed in 3 of 9 patients in the combination group. Zilurgisertib monotherapy or combination therapy with ruxolitinib was determined to be generally well tolerated and displayed the potential for therapeutic activity, the study authors concluded.12

Another phase 1/3 trial, XPORT-MF-034 (NCT04562389) evaluated a ruxolitinibcontaining combination, this time with the selective inhibitor of nuclear export selinexor (Xpovio) in patients with JAK inhibitor–naive myelofibrosis. At week 24, efficacy-evaluable patients (n = 22) achieved spleen volume reduction of at least 35% (SVR35) from baseline at a rate of 64%. Investigators noted that the combination displayed encouraging activity, and updated data will be made available at a future date.13

Finally, in a single-arm phase 2b study (NCT04217993) the oral, novel JAK/ACVR1 inhibitor jaktinib showed promising activity in patients with myelofibrosis who were intolerant to ruxolitinib. Efficacy-evaluable patients who received jaktinib (n = 44) achieved an SVR35 rate of 43% at 24 weeks, and the best spleen response rate was 55%. Notably, response was maintained for a minimum of 12 weeks in 80% of patients.14

“It’s exciting to have all these non-JAK inhibitors [in the pipeline],” Rampal said in conclusion. “Ultimately, hopefully, we can figure out what the best fit is for an individual patient. We’re not there yet, but with an abundance of data, we’ll get there. It’s also important to note that there are a number of agents that are earlier on [in development] that are moving along. Even beyond this next generation of non-JAK inhibitors already in the pipeline, there is a generation beyond that that is in clinical trial development.”

References

  1. McMullin MF, Anderson LA. Aetiology of myeloproliferative neoplasms. Cancers (Basel). 2020;12(7):1810. doi:10.3390/cancers12071810
  2. FDA approves ruxolitinib. News release. FDA. Updated February 22, 2016. Accessed October 18, 2023. bit.ly/3PVXObQ
  3. 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
  4. Passamonti F, Palandri F, Saydam G, et al. Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Haematol. 2022;9(7):e480-e492. doi:10.1016/ S2352-3026(22)00102-8
  5. FDA approves treatment for rare blood disease. News release. FDA. November 12, 2021. Accessed October 18, 2023. bit.ly/3rXAt1u
  6. Gisslinger H, Klade C, Georgiev P, et al; PROUD-PV Study Group. 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
  7. Verstovsek S, Kuykendall A, Hoffman R, et al. Verify: a phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera. Blood. 2022;140(suppl 1):3929-3931. doi:10.1182/ blood-2022-163755
  8. Mascarenhas J, Hoffman R. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. Clin Cancer Res. 2012;18(11):3008-3014. doi:10.1158/1078-0432.CCR-11-3145
  9. FDA approves fedratinib for myelofibrosis. News release. FDA. August 16, 2019. Accessed October 18, 2023. bit.ly/3s30OuX
  10. FDA approves drug for adults with rare form of bone marrow disorder. News release. FDA. March 1, 2022. Accessed October 18, 2023. bit.ly/3S0PVVj
  11. Gerds AT, Harrison C, Kiladjian JJ, et al. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis: results from the ACE-536-MF-001 study. J Clin Oncol.2023;41(suppl 16):7016.doi:10.1200/JCO.2023.41.16_suppl.7016
  12. Bose P, Mohan S, Oh S, et al. Phase 1/2 study of the activin receptor-like kinase (ALK)-2 inhibitor zilurgisertib (INCB000928,
    LIMBER-104) as monotherapy or with ruxolitinib (RUX) in patients (pts) with anemia due to myelofibrosis (MF). J Clin Oncol. 2023;41(suppl 16):7017. doi:10.1200/JCO.2023.41.16_suppl.7017
  13. Ali H, Kishtagari A, Maher KR, et al. Selinexor (SEL) plus ruxolitinib (RUX) in JAK inhibitor (JAKi) treatment-naïve patients with
    myelofibrosis: updated results from XPORT-MF-034. J Clin Oncol. 2023;41(suppl 16):7063. doi:10.1200/JCO.2023.41.16_suppl.7063
  14. Zhang Y, Zhou H, Xiao ZJ, et al. Jaktinib in patients (pts) with myelofibrosis (MF) who were intolerant to ruxolitinib (RUX): an open-label, single-arm phase 2b study. J Clin Oncol. 2023;41(suppl 16):7061.doi:10.1200/JCO.2023.41.16_suppl.7061

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CHMP Shares Positive Opinion of Momelotinib for Myelofibrosis/Anemia

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November 13, 2023

Hayley Virgil

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has expressed a positive opinion on momelotinib (Ojjaara) as a treatment for patients with moderate to severe anemia with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post-essential thrombocythemia, as well as disease-related splenomegaly according to a press release from GSK.1

Patients who are JAK inhibitor naïve or have previous treatment with ruxolitinib (Jakafi) can also receive treatment with momelotinib.

The positive opinion marks one of the final steps leading to the agent’s potential approval. If approved, momelotinib would be the only agent in Europe available for treating moderate to severe anemia in newly diagnosed and previously treated myelofibrosis, as well as potentially resolving splenomegaly and other symptoms.

“Momelotinib has a differentiated mechanism of action that may address the significant medical needs of [patients with] myelofibrosis, especially those with moderate to severe anemia,” Nina Mojas, senior vice president of Oncology Global Product Strategy at GSK, said in the press release. “The vast majority of [patients with] myelofibrosis will develop anemia, causing them to require transfusions and leading a notable proportion to discontinue treatment. This positive CHMP opinion is a significant step in bringing momelotinib to patients in the EU with this difficult-to-treat blood cancer.”

The positive opinion was supported by several clinical trials, including the phase 3 MOMENTEUM study (NCT04173494) and a patient subgroup from the phase 3 SIMPLIFY-1 study (NCT02101268) with moderate to severe anemia.2,3

Findings from the MOMENTEUM trial, which included 195 patients, showed a 24-week total symptom score response rate of 24.6% (95% CI, 17.49%-32.94%) among those treated with momelotinib compared with 9.2% (95% CI, 3.46%-19.02%) in those treated with danazol (P =

.0095). Additionally, a splenic volume reduction of 25% was observed in 40.0% (95% CI, 31.51%-48.95%) vs 6.2% (95% CI, 1.70%-15.01%), respectively, as well as a 35% reduction in 23.1% (95% CI, 16.14%-31.28%) vs 3.1% (95% CI, 0.37%-10.68%; P = .0006).

Additionally, in the SIMPLIFY-1 study, which included 432 patients, investigators reported a reduction in total symptom score of 50% or more in 28.4% of patients treated with momelotinib and 42.2% in those treated with ruxolitinib (P = .98).

Common adverse effects across both studies included diarrhea, thrombocytopenia, nausea, headache, dizziness, fatigue, asthenia, abdominal pain, and cough.

The FDA approved momelotinib for patients with myelofibrosis and anemia in September 2023.4

References

  1. GSK receives positive CHMP opinion recommending momelotinib for myelofibrosis patients with anaemia. News release. GSK. November 13, 2023. Accessed November 13, 2023. https://bit.ly/3MEYpOl
  2. Mesa RA, Gerds AT, Vannucchi A, et al. MPN-478 MOMENTUM: phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. J Clin Oncol. 2022;40(suppl 16):7002. doi:10.1200/JCO.2022.40.16_suppl.7002
  3. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;34(suppl 34):3844-3850. doi:10.1200/JCO.2017.73.4418
  4. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GSK. September 15, 2023. Accessed November 13, 2023. https://bit.ly/46eFscj

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Long-Acting Interferon: Pioneering Disease Modification of Myeloproliferative Neoplasms

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Seug Yun Yoon, Sung-Yong Kim

Abstract

Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells. The malignant clones produce cytokines that drive self-perpetuating inflammatory responses and tend to transform into more aggressive clones, leading to disease progression. The progression of MPNs follows a biological sequence from the early phases of malignancy, polycythemia vera, and essential thrombocythemia, to advanced myelofibrosis and leukemic transformation. To date, the treatment of MPNs has focused on preventing thrombosis by decreasing blood cell counts and relieving disease-related symptoms. However, interferon (IFN) has been used to treat MPNs because of its ability to attack cancer cells directly and modulate the immune system. IFN also has the potential to modulate diseases by inhibiting JAK2 mutations, and recent studies have demonstrated clinical and molecular improvements. Long-acting IFN is administered less frequently and has fewer adverse effects than conventional IFN. The current state of research on long-acting IFN in patients with MPNs is discussed, along with future directions.

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Advancing the Treatment Landscape for Patients With Myeloproliferative Neoplasms

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Pearl Steinzor

Despite recent advancements in treatments for patients with myeloproliferative neoplasms, a term encompassing several rare cancers, many challenges persist when it comes to these hematologic malignancies, primarily due to lack of uniform treatment plans for each of the classical subgroups.

These findings were presented in a landscape analysis by the Association of Community Cancer Centers (ACCC) at the 2023 National Oncology Conference from October 4-6, 2023, in Austin, Texas.

In 2008, the World Health Organization (WHO) reclassified myeloproliferative disease from a blood disorder to clonal hematopoietic stem cell malignancies, and in 2016, the WHO identified 4 classic types of myeloproliferative neoplasms: chronic myeloid leukemia (BCR-ABL1 positive), polycythemia vera (BCR-ABL1 negative), essential thrombocythemia (BCR-ABL1 negative), and primary myelofibrosis (ABCR-ABL1 negative).

Patients with myeloproliferative neoplasms report debilitating symptoms, including fevers, night sweats, fatigue, sleep disturbances, weight loss, bone pain, itchy skin, headaches, difficulty concentrating, anxiety, and depressive symptoms.

Although these patients are considered to have favorable life expectancy, with 60% of patients living up to 15 years after diagnosis, about 84% of these patients have reported a reduced quality of life directly due to these symptoms. Moreover, many low-risk patients are given a “watch-and-wait” treatment plan and receive no drug therapy despite experiencing a moderate to high symptom burden.

Gaps in care coordination also exist, and current standard-of-care pharmacological treatments are unable to fully relieve symptom burden. For example, approximately 84% of patients with myeloproliferative neoplasms reported reduced quality of life due to the effects of their current pharmacological interventions.

Moreover, patient and physicians perceptions regarding treatment are often misaligned, with patients reporting that their most important treatment goal was to slow or delay disease progression, whereas physicians reported the most important goal was symptom improvement and prevention of vascular or thrombotic events. Furthermore, an average of 30% of patients with myeloproliferative neoplasms did not believe their physician had a treatment plan, and an average of 35% of patients believed their physician was not providing updates on new treatments.

The researchers also identified health literacy as an important factor in understanding and managing symptom burdens, shared decision-making, and proper disease management. Additionally, a 2016 online survey of 904 adults found significant employment disruptions were common, with at least 1 employment change reported among 65.5% of patients with myelofibrosis, 48% of patients with polycythemia vera, and 38.8% of patients with essential thrombocythemia. Furthermore, respondents reported reduced working hours, medical disability leave, early retirement, dropping to part-time hours, and switching to a lower-paying job due to their disease.

For these reasons, myeloproliferative neoplasms have a significant disease burden and impact on patients, commonly due to anxieties about disease advancement and disruptive symptoms that affect a person’s quality of life.

Furthermore, lack of uniform treatment, risk diagnostic assessments, and care coordination can result in late diagnosis and rapid potential disease progression, which may also lead to a lack of transparency and patients feeling excluded in decision-making of their care.

Moreover, a lack of awareness surrounding available care guidelines, standardized symptom alleviation, and disease progression control plans are stressors that add to this disease burden, so further knowledge on the management of myeloproliferative neoplasms and related symptoms is necessary to improve patient outcomes.

Reference

Advancing care for patients with myeloproliferative neoplasms. Association of Community Cancer Centers. Accessed October 17, 2023. https://www.accc-cancer.org/home/learn/cancer-types/hematologic-malignancies/advancing-care-for-patients-with-myeloproliferative-neoplasms.

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Selinexor by Karyopharm Therapeutics for Chronic Idiopathic Myelofibrosis (Primary Myelofibrosis): Likelihood of Approval

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August 28, 2023

elinexor is under clinical development by Karyopharm Therapeutics and currently in Phase II for Chronic Idiopathic Myelofibrosis (Primary Myelofibrosis). According to GlobalData, Phase II drugs for Chronic Idiopathic Myelofibrosis (Primary Myelofibrosis) does not have sufficient historical data to build an indication benchmark PTSR for Phase II. GlobalData uses proprietary data and analytics to create drugs-specific PTSR and LoA in the Selinexor LoA Report. 

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

Selinexor overview

Selinexor (Xpovio, Nexpovio) is an antineoplastic agent. It is formulated as film coated tablets for oral route of administration. Xpovio in combination with dexamethasone is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. Xpovio is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Xpovio in combination with bortezomib and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. It is also under development for the treatment of soft tissue sarcoma, osteosarcoma, leiomyosarcoma, pleomorphic liposarcoma, synovial sarcoma, epithelial ovarian cancer.

Selinexor (KPT-330) is under development for the treatment of light chain amyloidosis, anaplastic astrocytoma, diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), newly diagnosed advanced hepatocellular carcinoma, metastatic urothelial carcinoma, relapsed or refractory peripheral T cell lymphoma and natural killer T cell lymphomas,  relapsed/refractory indolent non-Hodgkin lymphoma (R/R iHNL), malignant peripheral nerve sheath tumor (MPNST), leiomyosarcoma, endometrial stromal sarcoma, ovarian carcinoma, endometrial carcinoma, fallopian tube cancer, metastatic triple negative breast cancer, thymoma, non-small cell lung cancer, cervical carcinoma, non-Hodgkin lymphoma, melanoma, colon cancer, gastroenteropancreatic tumors, prolymphocytic leukemia, small lymphocytic lymphoma, recurrent glioblastoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), relapsed/refractory multiple myeloma (MM), relapsed and refractory acute myelogenous leukemia (AML), diffuse large B-cell lymphoma, chondrosarcoma, synovial sarcoma, liposarcoma, leiomyosarcoma, blast-crisis chronic myelogenous leukemia (bc-CML), relapsed and refractory acute lymphoblastic leukemia, rectal cancer, lung cancer, gynecological cancer, Penta-refractory multiple myeloma, recurrent/refractory high-grade gliomas, myelofibrosis, primary myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF), Ewing sarcoma and myelodysplastic syndrome, gastrointestinal stromal tumor (GIST), non-small cell lung cancer and recurrent glioma. The drug candidate is administered orally as a tablet and topically as a gel. It is a SINE compound that acts by targeting CRM1 (chromosome region maintenance 1 protein, exportin 1 or XPO1). It is being developed based on Selective Inhibitor of Nuclear Export (SINE) compound technology.

It was also under development for the treatment of coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), refractory or relapsed Richter’s transformation, metastatic castrate-resistant prostate cancer, advanced squamous cell carcinoma of head and neck, lung cancer and esophageal cancer, relapsed/refractory cutaneous T cell lymphoma, relapsed small cell lung cancer, rectal adenocarcinoma, gastric cancer, metastatic colorectal cancer and diabetic foot ulcers.

It was also under development for the treatment of recurrent glioblastoma multiforme.

Karyopharm Therapeutics overview

Karyopharm Therapeutics (Karyopharm) discovers and develops novel drugs for the treatment of cancer and other diseases. The company’s core technology harnesses the inhibition of nuclear export as a mechanism to treat patients suffering from cancer. Karyopharm’s lead product, Xpovio, is being developed for the treatment of multiple myeloma, and relapsed or refractory diffuse large B-cell lymphoma. Its pipeline drug candidates include selinexor, eltanexor, verdinexor, and KPT-9274. Karyopharm’s drug candidates are indicated for the treatment of various hematological and solid tumor malignancies including multiple myeloma, diffuse large B-cell lymphoma, liposarcoma, glioblastoma and endometrial cancer. The company has operations in the US, Israel and Germany. Karyopharm is headquartered in Newton, Massachusetts, the US.

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Know What Questions to Ask When Treating MPNs

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July 27, 2023

Brielle Benyon

Oncology nurses must know what to look for — and what questions to ask — when treating patients with myeloproliferative neoplasms (MPNs), as side effects and other patient characteristics can play a role in determining the best treatment regimen, according to Julie Huynh-Lu, PA-C, a physician assistant from The University of Texas MD Anderson Cancer Center.

MPN-Related Symptoms

“Whenever a patient comes to see us, they also fill out the MPN10 questionnaire, [which is] a list of all the 10 symptoms that frequently occur in our patients,” Huynh-Lu said in an interview with Oncology Nursing News. “Ideally, this should be occurring at every visit. On top of them filling that out, I obviously will ask them specific pointed questions as well just to tease out some more information. But this should occur at every visit.”

Symptoms can vary based on the subtype of MPN a patient has. Huynh-Lu said that patients with polycythemia vera and essential thrombocytosis are more likely to experience headaches, confusion or difficulty focusing, or pain and tingling in the fingertips. Meanwhile, common symptoms for patients with myelofibrosis include anemia and thrombocytopenia; shortness of breath and fatigue; bleeding; and complications from spleen enlargement, such as having a poor appetite.

Knowing about these symptoms is key, as they could indicate a physical issue that warrants a change in treatment, Huynh-Lu said. For example, if a patient is not experiencing splenomegaly (enlarged spleen), there may not need to be prescribed a JAK inhibitor. However, if the patient starts to experience a decreased appetite or feel full after eating only a small amount of food, that could indicate that their spleen is becoming enlarged, and that patient may benefit from being put on a JAK inhibitor.

“It can also change the trajectory on whether or not talking about splenectomy is an option. It’s not really our go-to [treatment] in our department at MD Anderson, but that could certainly lend to a conversation into if surgery is an option,” Huynh-Lu said.

Sometimes symptoms can lead to a change in treatment, while other times there may be an easy fix to manage the issue.

If a patient is currently taking a JAK inhibitor, nurses should be sure to ask them about worsening itching, diarrhea, and frequent infections (such as urinary tract infections or pneumonia). Secondary skin cancers can also occur, said Huynh-Lu, “so we always recommend that they get dermatology checks every 6 months.”

“If their [blood] counts are starting to drop, or if their spleen is starting to grow, well, maybe the medication they’re on right now, the dosage needs to be altered. But if we alter the dose to a higher medication dose, and the side effects are worse, maybe then it’s time to switch to a different class of drugs completely, or same class of drugs, just a different type of drug. There’s also, of course, clinical trials that are available, so that could be an option as well,” Huynh-Lu said.

Patient Characteristics and Comorbidities

Regarding patient characteristics and comorbidities, clinicians should know if patients have a history of cardiac, renal, or hepatic complications, as certain medications can affect these organs.

Additionally, interferons are commonly used to treat patients with polycythemia vera. However, according to the National Institutes of Health, these drugs can impact the synthesis of serotonin, dopamine, epinephrine, and norepinephrine, thereby increasing a patient’s risk for depression. That said, clinicians should know if patients have a history of depression or an autoimmune disease before they prescribe an interferon to a patient, Huynh-Lu said.

It also may be beneficial for oncology nurses to ask patients if they are experiencing financial struggles due to their cancer care.

“I know these drugs can be quite expensive. Financially, this can be a burden for some … Sometimes the local oncologists aren’t completely aware of financial assistance available for them. So maybe just ask and say, ‘Hey, I know this drug cost this much. Do you know of any financial assistance that you guys can provide for me?’ Because I know sometimes that’s not a question that gets asked,” Huynh-Lu said.

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A Caregiver’s Story: The Journey of a Spouse Through the Transplant Process

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In March, MPN Advocacy & Education International highlighted the story of a recent stem cell patient, Andrea (click here to view story). This month, Andrea’s wife, Denise, shares her story as a caregiver in an interview with us. 

Andrea and Denise

How did you feel about your spouse’s decision to have a transplant? Were you apprehensive? 

I have been a part of Andrea’s medical journey since her diagnosis from ET to myleofibrosis.  I recall it took me about a week to learn how to pronounce the name correctly, and it has been an education ever since.  Being present during doctor appointments and multiple clinical trials provided first-hand information in addition to our ongoing discussions.  Observing and experiencing her five years of transfusion independence was a gift.  We took advantage of the opportunity to cycle and travel together and separately. Knowing the clinical trial would either end or the drug would quit working was only a matter of time.  And knowing how she physically felt prior to and after this time period played a role in my ‘wrapping my head’ around a possible future transplant.  All the while, we adjusted and modified activities as needed in order to continue allowing her to live life to the fullest.

When medications were no longer yielding the same results, and Andrea’s blood transfusions became more frequent, the doctors felt the alternatives were to continue clinical trials and hope for the best or discuss a stem cell or bone marrow transplant. I felt she was strong enough physically to beat the odds. It was now or never. I never doubted our decision, and have had no regrets.

How did you prepare yourself as a caregiver? 

In order to prepare, I scoured MD Anderson’s educational resources to understand what a ‘typical’ transplant journey would entail.  I developed multiple spreadsheets to track medications, nutrition, recovery, therapy, etc. I left the online myleofibrosis forum readings to Andrea as she would report her findings from reading first-hand accounts.  She also talked to many individuals who had had transplants, pummeling them with questions.

Another important piece of this journey was my mindset.  I focused on the end goal – her successful transplant and healthy recovery.  I looked at the journey in three parts:

  1. Pre-transplant
  2. Transplant/hospital stay
  3. Post-transplant

My goal was to have as much of her daily care and needs become second nature to me prior to her hospital release. When she was released, the additional environmental interaction was familiar without the distraction of ‘everything new all at one time’.

What tools did you find useful as the caregiver and advocate?

I created a 3-ring notebook with tabs to manage spreadsheets, medical records/test,  and doctor questions, so I could access information easily and quickly. I created a spreadsheet to track her medication schedule.  The purpose was to help me identify what was needed, including dosage when refilling medications both inside and outside the hospital. Click here to view medication tracker template. (For an Excel spreadsheet version of the attached please email kmichael@mpnadvocacy.com).

I also knew there was a good possibility that after her hospital release and within the first 100 days, she would have a trip to the emergency room and be re-admitted to the hospital.  Therefore, medications and ‘the notebook’ were kept in one location and easily picked up and transported with us.  The notebook was with us each time we visited the care team.

I created additional spreadsheets to help track:

  • Food and water daily intake and output. This is useful for doctor & nutrition appointments.
  • Daily stats: blood pressure, temperature, pain levels, exercise, spirometer therapy.  This is useful for tracking blood pressure and temperature anomalies.  Because if her temperature rose to a specific number, she had to go to the emergency room immediately.
  • Signs of graft vs host disease (GVHD).
  • I choose to stay in the hospital 24/7 to understand how the nursing staff/care team handled her care. This experience helped me understand her routine.
  • I figured if I learned her hospital routine, it would be familiar when she was released.
  • I used my smartphone and set alarms with labels so I knew what drugs were due when. (Used upon hospital release.)
  • I utilized Caring Bridge (www.caringbridge.org) to communicate Andrea’s transplant journey to her friends and family. My intent with each post was to create an engaging story yet convey “a day in her life” so everyone could get a sense of being there.

What was the most challenging part of your role and why?

Coming home and changing environments automatically kicked us back to normal behaviors and patterns. I felt we had to be more careful and diligent in preventing infection.  Even though we were home, I had to be more watchful because familiarity brings about a relaxed state.  Her immune system was developing and the risk of infection was too great.  Andrea quickly tired of me saying “No, you can’t do that or touch that.”

Once home, Andrea’s friends visited.  This was a considerable risk to her because the natural tendency is to hug and touch. To reduce her risk, we asked people to use hand sanitizer when they were around her.  We developed a routine where I would greet her friends first with a hug and explain she couldn’t hug yet. Andrea stood back a few feet to reduce her availability.

What I learned :

Every recovery and journey is different.

While it’s tempting, don’t measure your progress against someone else.  It’s your journey.  That goes for both the patient and caregiver!

The “notebook” was a great tool.  It kept us on schedule for all medications and were able to provide information to the doctors as needed.

The hospital care team staff is a critical part of your recovery.  Don’t opt for staying close to home if you feel a facility’s care team is better in another location.

Deciding where to have the transplant included researching the number of myleofibrosis transplants, versus other blood disease transplants, and the success that facility had.

Participate in the journey. I chose to shave my head at the same time Andrea did.  It sure made showering quick and easy!

Take in the outdoors and/or change the scenery.

Exercise or go for walks.  Listen to music.  Visit a friend. Go to the grocery store.  Do something to clear your head and regain perspective.

Have a confidante. It’s normal to question, or become frustrated, and to second guess.  But remember – it’s temporary.

You are the coach, cheerleader, and guardian all at once.  Embrace the many hats you will wear!

Click here to read Andrea’s Transplant Story 

MPN Patient Daily Stats 06-10-18