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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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Overview of Myelofibrosis and Risk Stratification

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Abdulraheem Yacoub, MD

Myelofibrosis, as a myeloproliferative neoplasm, is defined and characterized by JAK-STAT activation. Myeloproliferative neoplasms—particularly myelofibrosis—are dependent on JAK-STAT activation in the pathogenesis and clinical features, including proliferation, constitutional symptoms, and risk of transformation to higher-risk myeloid neoplasms. JAK-STAT activation can be the result of an acquired somatic JAK2 mutation, an acquired MPL mutation, an acquired CALR [calreticulin] mutation, or other unknown mutations that continue to be discovered as we go on.

[Regardless of] the driver mutation, it will result in the downstream STAT activation and uncontrolled proliferation and constitutional symptoms. Although the common pathway of pathogenesis is the same in the majority of patients with myelofibrosis, patients present with different clinical vignettes or subtypes. Classically, we’ve recognized the proliferative vs the cytopenic myelofibrosis, especially as the treatment pathways have diverged for these clinical subtypes. Cytopenic myelofibrosis has recently been recognized, particularly in patients who present with a uniquely low white blood cell count, severe-to-moderate thrombocytopenia, and severe-to-moderate anemia, including transfusion requirements.

Most patients who are cytopenic meet many of those cytopenic features, and this relates to the pathogens of these diseases. Because those patients are often primary vs secondary myelofibrosis, they’re often JAK2 mutated or triple negative. And they often have higher-risk karyotype, higher-risk mutations, and generally worse prognosis and high-risk transformation. Cytopenic myelofibrosis has been recognized because it carries a worse clinical presentation, more restrictions to the standard therapies for myelofibrosis, and worse prognosis in general. We’re fortunate that we have dedicated therapeutic options available commercially for those patients. That’s why we try to recognize them early, so we can address their diseases differently and more effectively.

Because many oncologists are very familiar with the staging of cancers, we often [give] a solid tumor a stage so we can describe it to patients, prescribe therapy, and provide prognosis for patients. In myelofibrosis, we use a calculator for risk assessment to define the prognostic risk for those patients, which serves the same purposes. One is for providing prognostic information for our patients. A second is for choosing the appropriate therapy. And third is also for clinical trial enrollment, to better define inclusion and exclusion criteria for those studies.

Prognostic models have evolved over time, from simple clinical prognostic models to more sophisticated, integrated models that include clinical, cytogenetic, and molecular data. We often use multiple prognostic calculators in each patient to serve different purposes. For example, our patient has an advanced age, which by all prognostic models adds a relatively negative prognostic value to these patients. She has circulating blasts. On the other hand, she’s not anemic or thrombocytopenic, which is favorable. She has symptoms that seem to be adverse in all prognostic models. She has a favorable cytogenic and molecular profile. By integrating all these variables, she has an intermediate-2 prognostic risk on the clinical features and an intermediate risk on the molecular-inspired prognostic scores. These prognostic scores provide a relative estimate of life expectancy of under 5 years on a clinical prognostic model without therapy. Of course, with modern therapy, patients do much better than they did in historical reports.

This creates a different therapeutic approach to these patients. Patients with relatively higher-risk disease, such as this patient, will advance into a more immediate intervention path. They should be advancing into earlier evaluation for curative-intent therapy. This will put heightened clinical attention on immediate intervention rather than a watch-and-wait approach, where you would implement that in patients with relatively lower-risk disease. This is an integrated and very essential step in every new case of myelofibrosis as we make that diagnosis and provide staging and prognostic value for our patients. In addition, these are dynamic scores, meaning that as patients live longer with their disease, they can potentially be reassessed for their prognosis. At different time intervals, they probably will transform, or advance into a high-risk category. Then we have to adapt to their new score and treat them differently. This is a dynamic tool that we need to apply every time the patient has a disease event or worsening of their clinical features.

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MorphoSys Completes Enrollment of Phase 3 MANIFEST-2 Study of Pelabresib in Myelofibrosis with Topline Results Expected by End of 2023

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MorphoSys Completes Enrollment of Phase 3 MANIFEST-2 Study of Pelabresib in Myelofibrosis with Topline Results Expected by End of 2023

Enrollment of Phase 3 frontMIND study of tafasitamab in first-line diffuse large B-cell lymphoma is also complete

MorphoSys AG (FSE: MOR; NASDAQ: MOR) announced today that enrollment is complete for MANIFEST-2, the ongoing Phase 3 study exploring the efficacy and safety of pelabresib, an investigational BET inhibitor, in combination with ruxolitinib versus ruxolitinib alone in patients with myelofibrosis who have not previously been treated with a JAK inhibitor (JAK inhibitor-naïve). The topline data are now expected by the end of 2023, earlier than previously anticipated.

Myelofibrosis – which belongs to a group of diseases called myeloproliferative disorders – is a difficult-to-treat form of blood cancer with limited treatment options. JAK inhibitors are a current standard of care treatment for myelofibrosis, which focus on relieving symptoms of the disease rather than treating its cause. But, with this treatment strategy, only about half of patients attain adequate disease control, and durability of response is often limited. Clinical data suggest synergistic effects between BET inhibition and JAK inhibition in myelofibrosis, supporting the potential of this combination therapy.

“With so many patients left behind by current treatment options for myelofibrosis, there is a critical need for regimens that elevate the standard of care for patients suffering from this debilitating disease,” said Tim Demuth, M.D., Ph.D., Chief Research and Development Officer, MorphoSys. “Now that MANIFEST-2 has completed enrollment earlier than anticipated, we look forward to the coming insights into the therapeutic potential of pelabresib in combination with ruxolitinib for JAK inhibitor-naïve patients with myelofibrosis. MANIFEST-2 is the latest milestone in our efforts to improve outcomes for blood cancer patients and is a testament to our continued commitment to the myelofibrosis community.”

MANIFEST-2 is a global, multicenter, double-blind, Phase 3 study of more than 400 patients who were naïve to JAK inhibitors. Patients were randomized 1:1 to pelabresib in combination with ruxolitinib or placebo plus ruxolitinib. The primary endpoint of the trial is the proportion of patients who achieve a 35% or greater reduction in spleen volume at week 24 (known as SVR35). Reduction in spleen size is an important clinical endpoint in myelofibrosis because spleen enlargement reflects disease activity and can cause significant pain and discomfort.

The key secondary endpoint is the proportion of patients achieving a 50% or greater improvement in total symptom score, as measured by the Myelofibrosis Symptom Assessment Form v4.0, at week 24. Patients with myelofibrosis experience a severely diminished quality of life due to symptoms such as severe fatigue, fever and weight loss. The Myelofibrosis Symptom Assessment Form is a validated self-assessment tool designed specifically for myelofibrosis patients that can track changes in these symptoms.

The MANIFEST-2 trial is supported by findings from the Phase 2 MANIFEST trial of pelabresib in combination with ruxolitinib in patients with myelofibrosis, including those who were JAK inhibitor-naïve. Updated results from MANIFEST presented at the American Society of Hematology 2022 Annual Meeting and Exposition suggest that pelabresib in combination with ruxolitinib provided prolonged improvement in both spleen size and symptom severity at and beyond 24 weeks.

Enrollment of the Phase 3 frontMIND study is also complete, with more than 880 patients enrolled in the trial. frontMIND is a global, multicenter, randomized, double-blind, placebo-controlled trial exploring tafasitamab, marketed in the U.S. as Monjuvi® and outside the U.S. by Incyte as Minjuvi®, plus lenalidomide in addition to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) versus R-CHOP alone as a first-line treatment for high-intermediate and high-risk patients with diffuse large B-cell lymphoma. The topline data from this study are expected in the second half of 2025.
About Pelabresib

Pelabresib (CPI-0610) is an investigational selective small molecule designed to promote anti-tumor activity by inhibiting the function of bromodomain and extra-terminal domain (BET) proteins to decrease the expression of abnormally expressed genes in cancer. Pelabresib is being investigated as a treatment for myelofibrosis and has not yet been evaluated or approved by any regulatory authorities.

About Myelofibrosis

Myelofibrosis – one of a group of diseases called myeloproliferative disorders – is a difficult-to-treat form of blood cancer that’s characterized by bone marrow fibrosis (a buildup of scar tissue in the bone marrow), spleen enlargement and anemia (low red blood cell counts) often requiring periodic blood transfusions. Patients with myelofibrosis can also suffer from a range of physical symptoms, including severe fatigue, night sweats, itching, increased bleeding and significant pain caused by their enlarged spleen. For many living with myelofibrosis, the combination of symptoms often severely impacts their quality of life. At diagnosis, several factors, such as age, genetics and bloodwork, help determine a patient’s long-term prognosis. About 90% of newly diagnosed patients have intermediate- to high-risk disease, which has a worse prognosis and a higher likelihood of disease-associated symptoms. Today, myelofibrosis treatments revolve around the use of medications called JAK inhibitors, which focus on relieving symptoms of myelofibrosis rather than treating its cause. But with this strategy, only about 50% of patients achieve adequate symptom control, and, unfortunately, that relief fades with time for many. Patients suffering from myelofibrosis are in critical need of treatment options that not only address their symptoms but also change the overall course of their disease.

About MANIFEST-2

MANIFEST-2 (NCT04603495) is a global, double-blind, randomized Phase 3 clinical trial with pelabresib in combination with ruxolitinib versus placebo plus ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis. The primary endpoint of the study is a 35% or greater reduction in spleen volume (SVR35) from baseline at 24 weeks. The key secondary endpoint of the study is a 50% or greater improvement in total symptom score (TSS50) from baseline at 24 weeks. Constellation Pharmaceuticals, Inc., a MorphoSys company, is the MANIFEST-2 trial sponsor.

About MANIFEST

MANIFEST (NCT02158858) is an open-label Phase 2 clinical trial of pelabresib in patients with myelofibrosis. The MANIFEST trial is evaluating pelabresib in combination with ruxolitinib in JAK-inhibitor-naïve myelofibrosis patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. The trial is also evaluating pelabresib either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1) or as add-on therapy in combination with ruxolitinib in patients with a suboptimal response to ruxolitinib or myelofibrosis progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on transfusion-dependent (TD) status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment. Constellation Pharmaceuticals, Inc., a MorphoSys company, is the MANIFEST trial sponsor.

About Monjuvi® (tafasitamab-cxix)

Tafasitamab is a humanized Fc-modified CD19 targeting immunotherapy. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb® engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP).

In the United States, Monjuvi® (tafasitamab-cxix) is approved by the U.S. Food and Drug Administration in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT). This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

In Europe, Minjuvi® (tafasitamab) received conditional marketing authorization in combination with lenalidomide, followed by Minjuvi monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT).

Tafasitamab is being clinically investigated as a therapeutic option in B-cell malignancies in several ongoing combination trials.

Monjuvi® and Minjuvi® are registered trademarks of MorphoSys AG. Tafasitamab is co-marketed by Incyte and MorphoSys under the brand name Monjuvi® in the U.S., and marketed by Incyte under the brand name Minjuvi® in Europe and Canada.

XmAb® is a registered trademark of Xencor, Inc.

Important Safety Information

What are the possible side effects of MONJUVI?
MONJUVI may cause serious side effects, including:

– Infusion reactions. Your healthcare provider will monitor you for infusion reactions during your infusion of MONJUVI. Tell your healthcare provider right away if you get fever, chills, rash, flushing, headache, or shortness of breath during an infusion of MONJUVI.

– Low blood cell counts (platelets, red blood cells, and white blood cells). Low blood cell counts are common with MONJUVI, but can also be serious or severe. Your healthcare provider will monitor your blood counts during treatment with MONJUVI. Tell your healthcare provider right away if you get a fever of 100.4 F (38 C) or above, or any bruising or bleeding.

– Infections. Serious infections, including infections that can cause death, have happened in people during treatments with MONJUVI and after the last dose. Tell your healthcare provider right away if you get a fever of 100.4 F (38 C) or above, or develop any signs and symptoms of an infection.

The most common side effects of MONJUVI include:

– Feeling tired or weak

– Diarrhea

– Cough

– Fever

– Swelling of lower legs or hands

– Respiratory tract infection

– Decreased appetite

These are not all the possible side effects of MONJUVI.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Before you receive MONJUVI, tell your healthcare provider about all your medical conditions, including if you:

– Have an active infection or have had one recently.

– Are pregnant or plan to become pregnant. MONJUVI may harm your unborn baby. You should not become pregnant during treatment with MONJUVI. Do not receive treatment with MONJUVI in combination with lenalidomide if you are pregnant because lenalidomide can cause birth defects and death of your unborn baby.

– You should use an effective method of birth control (contraception) during treatment and for at least 3 months after your final dose of MONJUVI.

– Tell your healthcare provider right away if you become pregnant or think that you may be pregnant during treatment with MONJUVI.

– Are breastfeeding or plan to breastfeed. It is not known if MONJUVI passes into your breastmilk. Do not breastfeed during treatment for at least 3 months after your last dose of MONJUVI.

You should also read the lenalidomide Medication Guide for important information about pregnancy, contraception, and blood and sperm donation.

Tell your healthcare provider about all the medications you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to MORPHOSYS US INC. at (844) 667-1992.

Please see the full Prescribing Information for MONJUVI, including Patient Information, for additional Important Safety Information.

About Diffuse Large B-cell Lymphoma (DLBCL)

DLBCL is the most common type of non-Hodgkin lymphoma in adults worldwide, characterized by rapidly growing masses of malignant B-cells in the lymph nodes, spleen, liver, bone marrow or other organs. It is an aggressive disease with about 40% of patients not responding to initial therapy or relapsing thereafter, leading to a high medical need for new, effective therapies, especially for patients who are not eligible for an autologous stem cell transplant in this setting.

About frontMIND

The frontMIND (NCT04824092) trial is a randomized, double-blind, placebo-controlled, global Phase 3 clinical study in previously untreated high-intermediate and high-risk DLBCL patients that is conducted in partnership with the German Lymphoma Association (GLA), the Italian Lymphoma study group and the US Oncology Network. The study enrolled more than 880 DLBCL patients to receive either tafasitamab plus lenalidomide in addition to rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or R-CHOP alone. The primary endpoint is investigator-assessed progression-free survival, according to Lugano 2014 criteria, and key secondary endpoints include event-free survival by investigator, overall survival, metabolic complete response rate by a Blinded Independent Review Committee, and overall response rate.

About MorphoSys

At MorphoSys, we are driven by our mission: More life for people with cancer. As a global commercial-stage biopharmaceutical company, we develop and deliver innovative medicines to patients, aspiring to redefine how cancer is treated. MorphoSys is headquartered in Planegg, Germany, and has its U.S. operations anchored in Boston, Massachusetts. To learn more, visit us at www.morphosys.com and follow us on Twitter and LinkedIn.

Forward Looking Statements

This communication contains certain forward-looking statements concerning the MorphoSys group of companies. The forward-looking statements contained herein represent the judgment of MorphoSys as of the date of this release and involve known and unknown risks and uncertainties, which might cause the actual results, financial condition and liquidity, performance or achievements of MorphoSys, or industry results, to be materially different from any historic or future results, financial conditions and liquidity, performance or achievements expressed or implied by such forward-looking statements. In addition, even if MorphoSys’ results, performance, financial condition and liquidity, and the development of the industry in which it operates are consistent with such forward-looking statements, they may not be predictive of results or developments in future periods. Among the factors that may result in differences are that MorphoSys’ expectations may be incorrect, the inherent uncertainties associated with competitive developments, clinical trial and product development activities and regulatory approval requirements, MorphoSys’ reliance on collaborations with third parties, estimating the commercial potential of its development programs and other risks indicated in the risk factors included in MorphoSys’ Annual Report on Form 20-F and other filings with the U.S. Securities and Exchange Commission. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements. These forward-looking statements speak only as of the date of publication of this document. MorphoSys expressly disclaims any obligation to update any such forward-looking statements in this document to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statement is based or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements, unless specifically required by law or regulation.

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Clonal architecture evolution in Myeloproliferative Neoplasms: from a driver mutation to a complex heterogeneous mutational and phenotypic landscape

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  • Nabih Maslah, Lina Benajiba, Stephane Giraudier, Jean-Jacques Kiladjian & Bruno Cassinat

Leukemia (2023)

Abstract

Myeloproliferative neoplasms are characterized by the acquisition at the hematopoietic stem cell level of driver mutations targeting the JAK/STAT pathway. In addition, they also often exhibit additional mutations targeting various pathways such as intracellular signalling, epigenetics, mRNA splicing or transcription. The natural history of myeloproliferative neoplasms is usually marked by a chronic phase of variable duration depending on the disease subtype, which can be followed by an accelerated phase or transformation towards more aggressive diseases such as myelofibrosis or acute leukemia. Besides, recent studies revealed important new information about the rates and mechanisms of sequential acquisition and selection of mutations in hematopoietic cells of myeloproliferative neoplasms. Better understanding of these events has been made possible in large part with the help of novel techniques that are now available to precisely decipher at the single cell level both the clonal architecture and the mutation-induced cell modifications. In this review, we will summarize the most recent knowledge about the mechanisms leading to clonal selection, how clonal architecture complexity can explain disease heterogeneity, and the impact of clonal evolution on clinical evolution.

Introduction

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). In these chronic hematological malignancies, the main short-term risk is the occurrence of thrombosis but a subset of patients may also evolve into secondary myelofibrosis, myelodysplastic syndrome or acute myeloid leukemia in the long run. However, the risk of long term evolution is heterogeneous between MPN subtypes: recent retrospective studies suggest that a high proportion of PV patients (up to 75% in 13 years) may experience progression to secondary myelofibrosis or AML [1], while in ET only a minority of patients experience clonal evolution and deterioration of MPN. The clinical course of MPNs is therefore characterized by a hitherto not fully understood nor accurately predicted inter-patient heterogeneity.

In the recent years, disease heterogeneity has been mainly linked to the diversity of genetic lesions found in patients’ hematopoietic stem cells (HSC). Indeed, MPNs represent a model of sequential acquisition of genetic abnormalities over time, allowing the study of the influence of environmental and intrinsic factors on tumor shape. Numerous studies have shown that precise genetic characterization of the disease can help to evaluate its prognosis [2] as the number and type of mutations are the main criteria considered to predict the outcome of patients. Indeed, recent prognostic scoring systems include the mutational pattern [3,4,5]. Dissecting the prognostic impact of diverse molecular markers allows a better understanding of the heterogeneity of tumor cells and demonstrates its predominant role in MPN evolution. Furthermore, implementation of new sequencing techniques at the single-cell level allows more precise characterization of complex molecular patterns associated with disease heterogeneity. Despite an improved understanding of the clonal architecture of MPNs over the past years, the mechanisms leading to clonal selection once the mutations are acquired remain poorly understood. In several types of cancers, a clear role of the microenvironment has been demonstrated in the selection of mutations. Specific clones harboring particular mutations may be selected due to inter-clone competition for nutrients or to the presence of an inflammatory environment. The drugs received during the chronic phase of the disease can also participate in clonal selection, which may be of particular importance in MPN patients who often require lifelong treatments. The aims of this review are to recapitulate the current knowledge of the different molecular lesions acquired in MPNs, highlight their impact on disease evolution and discuss the processes influencing their selection and expansion over time.

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