CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of fatigue and abdominal pain lasting 4 months. She also reported increased bruising and unexplained weight loss. Her spleen was palpable 8 cm below the left costal margin. Genetic testing showed a JAK2 V617F mutation. A bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis. Blood smear revealed leukoerythroblastosis.

DISCUSSION QUESTIONS

• Given the multiple risk-assessment tools for myelofibrosis (MF), how do you choose between them?
• Based on your experience, what are the survival outcomes for patients with low-, intermediate-, and high-risk disease?
  • What percentage of your patients are high risk?

PANKIT VACHHANI, MD: [Would you] pick the Dynamic International Prognostic Scoring System [DIPSS] for one patient but some other tool for another patient?

KHALEEL K. ASHRAF, MD, MBBS, DMRD: I’ve been using the DIPSS Plus. It helps us decide when to [send] patients to referral centers for transplant and so on and also when to start treatment.

In community practice, this is not a very common disease. You stick with one [risk-assessment tool]. I don’t use all of them. I have not used the Mutation-Enhanced [International Prognostic Scoring System in Adults 70 and Younger (MIPSS70)], even though I’m sure it must have its place. I have been using DIPSS Plus for a good while.

KEVIN M. GALLAGHER, MD: I use the DIPSS Plus [because] this is what I have used historically, so I’m comfortable with it. I stick with the same method for each patient. [As to] the question of how [often the patients are] high risk, the numbers are very small, maybe 1 per year.

VACHHANI: The IPSS risk-stratification schema was the first schema that came out in modern times. The IPSS incorporates 5 different points: age, hemoglobin level, white blood cell count, peripheral blood blast count, and constitutional symptoms.¹

I don’t use IPSS anymore. That system was only supposed to be used at the time of diagnosis. I don’t think it’s wrong to use it, but I think that there are better risk-stratification schemas that you could use. This brings us to the DIPSS.²

The difference [between DIPSS and IPSS] is that with DIPSS, more weight is given to anemia.^1,2 For example, a hemoglobin level of less than 10 g/dL gets 2 points with the DIPSS and only 1 with the IPSS. [Additionally,] the D in DIPSS, which stands for “dynamic,” means that you can use this risk-stratification schema at any time [during] a patient’s journey.²

The DIPSS Plus includes 3 additional things. [This schema] incorporates karyotype information. It also gives additional weight to anemia; [not only does] anemia feature in the risk calculation, but also, if the patient is transfusion dependent, they get an extra point. [Finally,] with the DIPSS Plus, a platelet count of less than 100 × 10⁹/L is recognized as a prognostic factor.³

[There are some circumstances in which] you would not use the DIPSS Plus. If you don’t have the karyotype information for some reason—if a prior physician saw the patient and bone marrow [biopsy] was never done, or [if the biopsy] was done, but you couldn’t get the karyotype information—DIPSS Plus won’t be [very] helpful. In those scenarios, DIPSS would be the better thing to use.

[For patients stratified according to the DIPSS, an analysis showed] the median survival of low-risk patients [was not reached]. The median survival of intermediate-1–risk patients was approximately 14 years, and the median survival of intermediate-2–risk patients was approximately 4 years. The high-risk patients’ median survival, which was the worst, was 1.5 years.²

All these schemas were made for patients who had primary MF. If your patient has secondary MF, you could use one of these schemas. We did it for a long time, and we still do it [occasionally]. But there is another risk-stratification schema: the MF Secondary to PV and Essential Thrombocythemia [ET]–Prognostic Model [MYSEC-PM], which was made specifically for those patients.⁴

According to the latest version of the National Comprehensive Cancer Network guidelines, if you have a patient with primary MF, [the preferred options are] the MIPSS70 or MIPSS70 Plus [version 2.0] schemas, which incorporate some additional molecular results like U2AF1 and ASXL1.^5-7

In routine practice, if you were not seeing many different patients with MF and you had to pick just one [schema] that could be applied to almost every patient without knowing the patient’s karyotype or genetic mutation profile beyond JAK2, MPL, and CALR, maybe the single schema to remember would be DIPSS. The key here is that we should risk stratify every patient if possible.

DISCUSSION QUESTIONS

• What is the trigger to initiate therapy for a patient with MF?
  • What is the timing to start Janus kinase (JAK) inhibitor therapy, and how do you choose?
  • How does the nature and burden of symptoms influence your decision to initiate JAK inhibitor therapy?
• How important is it to initiate therapy early?
• When do you consider clinical trial enrollment?

JOSÉ L. MENDOZA, MD: Typically, these patients with MF are symptomatic, and they need a diagnosis in order to be able to treat the symptoms. I would say that as soon as you have a diagnosis, if the patient is symptomatic [with] splenomegaly, cytopenias, or both, that is an indication to initiate therapy in most cases.

ASHRAF: I agree. Most patients, by the time I see them, have symptoms, and JAK inhibition quickly improves their symptoms.

VACHHANI: Is there anyone who [uses a JAK inhibitor] for patients whose risk status is high or intermediate-2 but not intermediate-1? Does that [factor into your decision], or is [your decision based] purely on symptoms and spleen?

DAVID YOUNG KAHN, MD: Often if the patient has splenomegaly, I like to start JAK inhibitor therapy. In terms of what to choose, [although] I hate to say it, it often depends on cost, insurance, and what’s on the patient’s formulary.

MENDOZA: My response was a general [one] but was applicable to higher-risk patients. But in the lower-risk situation, it’s more likely that you [will find yourself diagnosing] an asymptomatic patient, [so] you will have more time to plan your strategy. I would probably wait [to treat] unless there were issues like cytopenias or organomegaly. If a low-risk patient does develop high-bulk disease, I still treat, but the treatment [might] be a little different. [In this situation,] I think you might have a chance to try treatments that you wouldn’t use in a higher-risk population.

VACHHANI: The pivotal studies that led to the approval [of JAK inhibitor therapy] were done with intermediate-2 and high-risk patients, although there are data for intermediate-1–risk patients as well.⁸ In fact, recent data have shown that starting patients [on treatment] earlier led to better outcomes.⁹

DISCUSSION QUESTIONS

• Have you used fedratinib (Inrebic)? If so, what line have you used it in?
• How does it compare with your use of ruxolitinib (Jakafi)?

CANDICE BALDEO, MD: I haven’t had the chance [to use] fedratinib yet. My patients have been doing well on ruxolitinib.

VACHHANI: Is there a reason that you would not use fedratinib? Does anything concern you?

BALDEO: I think the risk of encephalopathy scares my patients.

QUILLAN HUANG, MD: I haven’t [used fedratinib]. I’ve seen my colleagues use it in the second-line setting after ruxolitinib failure.

VACHHANI: Is that because you just haven’t [found yourself in] that scenario, or is there any other reason?

HUANG: I think fedratinib is a very reasonable choice in the second line. I just haven’t had that situation yet.

VACHHANI: Personally, I restrict fedratinib use to the second-line setting or beyond if I cannot get someone on a clinical trial.

Read more

Selinexor, a first-in-class, oral XPO1 inhibitor, previously received an orphan drug designation for the treatment of myelofibrosis from the FDA in May 2022.

“We are very pleased to receive orphan medicinal product designation from the EC for selinexor for the treatment of myelofibrosis,” Reshma Rangwala, MD, PhD, chief medical officer of Karyopharm, stated in a press release. “Building on our recent orphan drug designation from the FDA, this recognition continues to reinforce the significant unmet need for a drug with a novel mechanism of action like selinexor for this devastating disease. Our clinical plans remain on track, and we look forward to the continued development of selinexor in myelofibrosis.”

Selinexor is under investigation in 3 ongoing clinical trials for patients with myelofibrosis.

A phase 2 trial (NCT04562870) in evaluating selinexor monotherapy vs physician’s choice of therapy in patients with previously treated myelofibrosis.² The trial is enrolling patients with a diagnosis of primary myelofibrosis, post-essential thrombocythemia, or post-polycythemia myelofibrosis, according to the 2016 WHO classification of myeloproliferative neoplasms, who received prior treatment with JAK inhibitors for at least 6 months.

Patients are being randomly assigned to receive selinexor at 80 mg per week in the first two 28-day cycles, followed by 60 mg of selinexor per week in subsequent cycles, or physician’s choice of treatment. The primary end point of the trial is spleen volume reduction of at least 35% from baseline up to week 48. Secondary end points include symptom score reduction, overall survival (OS), overall response rate (ORR), anemia response, and safety.

The phase 2 ESSENTIAL trial (NCT03627403) is also evaluating single-agent selinexor for patients with primary myelofibrosis, post-essential thrombocytosis, or post-polycythemia vera who received prior treatment with ruxolitinib (Jakafi) or any experimental JAK inhibitor.³

Prior to protocol version 7 of the trial, patients were administered 80 mg or 60 mg of selinexor once weekly until disease progression, unacceptable toxicity, or no sign of clinical benefit. Patients enrolled after protocol version 7 will receive 40 mg of selinexor per week.

Change in spleen volume is the primary end point of the trial. Secondary end points are comprised of change in symptom score, ORR, OS, and safety.

Finally, a phase 1/2 trial (NCT04562389) is investigating the combination of selinexor and ruxolitinib in patients with intermediate-1–, intermediate-2–, or high-risk myelofibrosis.⁴

The dose-escalation phase 1a portion of the study will determine the maximum tolerated dose, establish the recommended phase 2 dose (RP2D), and evaluate the safety and preliminary efficacy of the combination in a standard 3+3 trial design. The dose-expansion phase 1b portion of the study will further assess the RP2D for safety and preliminary efficacy.

Phase 2 will randomly assign treatment-naïve patients with myelofibrosis to receive the combination of selinexor and ruxolitinib or ruxolitinib monotherapy.

“Myelofibrosis is a difficult-to-treat and complex disorder of the bone marrow with limited therapeutic options and we are committed to bringing novel treatments to patients through our collaboration with Karyopharm,” Olivia del Puerto, MD, LMS, head of Medical Affairs Oncology at EMEA of Menarini, said. “We are excited about the potential to bring selinexor to myelofibrosis patients in Europe, pending positive study read-outs and regulatory approval.”

In July 2022, the EC approved selinexor in combination with once-weekly bortezomib (Velcade) and low-dose dexamethasone for the treatment of adults with multiple myeloma who have received at least 1 previous therapy.⁵

Additionally, in March 2021, the EC approved selinexor for use in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have previously received at least 4 therapies and whose disease is refractory to at least 2 proteasome inhibitors, 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody, and have experienced progressive disease on their last therapy.⁶

References

1. Karyopharm and Menarini Group announce orphan medicinal product designation from the European Commission for selinexor for the treatment of myelofibrosis. News release. Karyopharm Therapeutics, Inc. October 31, 2022. Accessed November 1, 2022. https://bit.ly/3h2hfC3
2. A study to evaluate safety and efficacy of selinexor versus treatment of physician’s choice in participants with previously treated myelofibrosis. ClinicalTrials.gov. Updated October 10, 2022. Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04562870
3. Selinexor in myelofibrosis refractory or intolerant to JAK1/2 inhibitors (ESSENTIAL). ClinicalTrials.gov. Updated May 9, 2022. Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT03627403
4. A study to evaluate safety and efficacy of selinexor in combination with ruxolitinib in participants with myelofibrosis. ClinicalTrials.gov. Updated May 3, 2022. Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT04562389
5. Karyopharm and Menarini Group receive full marketing authorization from the European Commission for Nexpovio (selinexor) for the treatment of patients with multiple myeloma after at least one prior therapy. News release. Karyopharm Therapeutics, Inc. July 21, 2022. Accessed November 1, 2022. https://bit.ly/3PNvWFk
6. Karyopharm receives conditional marketing authorization from the European Commission for NEXPOVIO (selinexor) in combination with dexamethasone for the treatment of adult patients with relapsed and or refractory multiple myeloma. News release. Karyopharm Therapeutics, Inc. March 29, 2021. Accessed November 1, 2022. https://bit.ly/3sz2t6P

Read more