Abbas Assesses the Use of Allogenic Transplant In MPNs

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Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Jonathan Abbas, MD, discussed with his fellow clinicians the use of allogeneic hematopoietic stem cell transplant in patients with myeloproliferative neoplasms and how ruxolitinib fits into their care.

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of mild fatigue, moderate night sweats and abdominal pain/fullness 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 she was negative for a JAK2 V617F or CALR mutation. Her karyotype was 46XX​ and a bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis.

A blood smear revealed leukoerythroblastosis and she was diagnosed with primary myelofibrosis​ with a DIPSS (Dynamic International Prognostic Scoring System) risk score of intermediate-2 and also had an intermediate MIPSS70 risk score.

DISCUSSION QUESTIONS

  • In your experience with myelofibrosis, which symptoms/presentations have the most negative impact on patients’ quality of life?​
  • What are the treatment goals for a patient like this? ​

In your practice:​

  • What is the trigger to initiate therapy for a patient with myelofibrosis?​
  • What is the timing to start JAK (Janus kinase) 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?​

JONATHAN ABBAS, MD: Is this a patient where from day 1 you’re talking about an allogeneic [hematopoietic stem cell] transplant [HSCT] referral? Is this a patient that a transplanter would want to see early in the disease course or is this something that you might want to hold off on a HSCT consult until something isn’t behaving as well as it could?

JEREMY PANTIN, MD: The [patient is] approaching the age limit where things are going to start getting [difficult] and not somebody that we’ll take straight to allogeneic HSCT transplant, but you probably want to consider therapy to reduce that spleen size. If the patient appears to not have comorbidities and may be a good candidate for HSCT, the intermediate-2 or greater risk will certainly allow them to move forward, in terms of the favorable risk-to-benefit ration, if everything is aligned.

MICHAEL T. BYRNE, MD: I think we used to argue about this, not argue [necessarily], but these were the hard patients because nobody knows what to do with them. She’s the right age for transplant, but also, transplant is not without risk. Quality of life is probably worse after an allogeneic HSCT than it could be without, so I don’t know. I think you plug her in then you see what her donor search looks like, and regardless of whether she goes to treatment, I think this is somebody that you probably treat if for no other reason than to try and improve her quality of life.

OLALEKAN O. OLUWOLE, MBBS, MD: I completely agree with what my colleague just said. We have several targeted therapies in this area, and we can just find 1 to give them to control their symptoms.1 If that fails, there will be another. There are many in development, so for those who are not keen on getting transplanted, there is a viable pathway to just keep treating them. Now for the patient who says, “I want to see what the odds are,” like what [Dr. Bryne] said, find out if they have a donor, talk about the risk-benefit, and go for it.

ABBAS: From my HSCT days, I would totally agree with you. I think this is a patient I would want to see early, to explain that you might not need me now, but you might need me one day. You’ve potentially got years left of transplant eligibility, and we don’t have a crystal ball about how your response to treatment is going to be and where this disease is going.

Then just to be the devil’s advocate for the case, this is a lucky one where we had intermediate risk with 1% blasts. If this [patient] had 6% or 7% of 8% blasts and we were now nudging closer to high risk, that might sway all of us to maybe think initially therapy might be more of a bridge to HSCT, because there might be a little bit less stable disease.

[This] is a symptomatic patient. Is there anybody out there who would watch and wait with this patient regardless of whether they are seeing the allogeneic HSCT team or not? Or does everyone feel this patient warrants some therapy?

RYAN CARR, MD: Yes, based on her symptoms, if you tried to watch and wait, so [the patient] might end up seeing somebody else.

ABBAS: I agree with you. She will certainly be finding another group in town if you said, “You have [myelofibrosis], but it’s not that big a deal. Let’s just see you back in 3 months.” I think it’s unanimous this is a [patient] who’s not a watch-and-wait case. They are out there, but this is not her.

CASE UPDATE

Additional lab values showed the following counts:

  1. Red blood cells: 3.40 × 1012/L
  2. Hemoglobin: 13.2 g/dL
  3. Hematocrit: 36%
  4. Mean corpuscular volume: 94 fL
  5. White blood cells: 23.0 × 109/L
  6. Platelets: 450 × 109/L
  7. Peripheral blood blasts: 1%

DISCUSSION QUESTIONS

  • How do you use platelet count?
  • What if a patient had thrombocytopenia at baseline? ​
  • How does age/frailty factor in?

ABBAS: [If there is] thrombocytopenia at baseline, I guess we have 2 options for this. One would be; are we comfortable still sticking with ruxolitinib [Jakafi], which we all agree on [in a patient case like this], but dose modifying potentially for thrombocytopenia or would just any thrombocytopenia necessarily make us think about another agent, if anybody wants to weigh in on it?

BRYNE: I think a thrombocytopenia of 140 × 109/L is different than thrombocytopenia of 30 × 109/L. That’s quite a difference [between the level where a patient should receive] ruxolitinib vs pacritinib [Vonjo].

ABBAS: Yes, I would agree with you. Without the specific measurements, it’s hard to say. Just also remember you certainly can, and we’ve been doing for years is dose decreasing the ruxolitinib with a lot of benefit.2 Unless you’re in that extreme situation like down below 50 × 109/L platelet count, I still think there’s a window to go with the tried and true [method here].

How about frailty? How about if this woman, let’s say she was extremely frail and it wasn’t necessarily a disease-related frailty, just other comorbidities? Would that sway us? Do we feel that JAK inhibitors are particularly tough on patients? Would this factor in at all if she were 78 years old or if she was 88 years old?

JACK ERTER, MD: No. I think this drug is, all things considered, quite on target and easy to take for most patients. I would certainly have no hesitation to give an 88-year-old a trial at a dose-modified start of ruxolitinib.

References

1. Li B, Rampal RK, Xiao Z. Targeted therapies for myeloproliferative neoplasms. Biomark Res. 2019 Jul 16;7:15. doi: 10.1186/s40364-019-0166-y

2. Mesa RA, Cortes J. Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. J Hematol Oncol. 2013 Oct 22;6:79. doi: 10.1186/1756-8722-6-79

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Patient Outcomes in the Myeloproliferative Neoplasm Treatment Landscape

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Prithviraj Bose, MD
Prithviraj Bose: The outcomes for patients with PV and ET overall are good. So, these are, of course, the indolent ones among the classic myeloproliferative neoplasms. And so when you compare to myelofibrosis, for example, the outcomes are much better. And for that reason, we’re not transplanting anybody with ET and PV, for example, because their median survival is fairly long. At least compared to myelofibrosis. So, in ET, we generally think that the median survival is not different from an age and gender matched population. In PV, it’s been reported to be between 14 and 19 years. And PV definitely is a worse disease than ET. That’s well known. Both of them can, of course, progress to myelofibrosis and rates have been published at 10 years, at 15 years, you definitely have a reasonable chance around 10% in PV, although there are ranges, of course, across different studies of progression to myelofibrosis and smaller risk, thankfully, of transformation to AML. So, generally, these are diseases that people live with for many years. And obviously, because of that, day to day symptoms become an issue. It’s not just about controlling the counts and preventing blood clots, which continues to be goal number one. But I think there’s a lot of other things that we need to pay attention to. In fact, there have been studies like the MPN landmark study, which have shown that there is some discordance between patients’ priorities and physicians’ priorities. So, for example, patients are very keen to modify their underlying biology to sort of stop or halt or slow this inexorable disease progression that may otherwise occur. So that is more important to them sometimes than preventing a blood clot. That’s not to say that a blood clot couldn’t be bad. It could be a stroke or a heart attack, but in patients with these chronic diseases, it’s really important to them to try and do something to the root cause, so to speak, and its natural course. So this is where I think the increasing interest in getting this allele burden of JAK2 down, regardless whether that’s with an interferon or with ruxolitinib, is gaining ground. And the hope is that that would translate to improved myelofibrosis-free survival, improved overall survival, and increased leukemia-free survival, all of that. Now, symptoms is another whole different and important domain. Symptoms, many studies have shown that MPN patients, PV, ET, MF, all of them, MF usually more symptomatic than PV, but PV more symptomatic than ET, have a wide range of symptoms. And they can be debilitating, disabling sometimes, or at least bad enough that they impair quality of life, work productivity, etc. There’s been many surveys of patients that have shown these. And so certainly, this is important to elicit from patients. As I said earlier, using that MPN SAFTSS form is very helpful, because it allows you to objectify it and follow it over time. And we do have drugs, for example, ruxolitinib that comes to mind first, as a drug that addresses symptoms really more effectively than any other drug right now with PV. And so, it certainly draws attention to the fact that we need to be cognizant of symptoms and always elicit those and see how well we’re doing with that aspect, beyond the more traditional aspects of treating patients with PV.

Researchers identify cell type that could be key to preventing marrow transplant complication

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March 24, 2023

A bone marrow transplant can be a lifesaving treatment for people with relapsed blood cancers, but a potentially lethal complication known as graft-versus-host disease put limitations on this procedure. New research from the University of Wisconsin–Madison is helping to change that by identifying the cell population that causes GVHD, a target that may make bone marrow transplants safer and more effective.

An allogenic (from a donor) bone marrow transplant is a common treatment for blood cancers and other diseases of the immune system. During the transplant, the patient’s immune cells are replaced with the donor’s healthy cells. While the donor cells can help cure the patient’s blood cancer, they can also cause GVHD—in which donor T cells, a specialized immune cell in the blood, attack the patient’s healthy cells. This causes complications similar to an autoimmune disease that can be lethal.

“Graft versus host disease is one of the most common complications after an allogeneic hematopoietic cell transplantation procedure, and the field knows quite well that the T cells from the donor are the ones mediating the disease,” says the study’s lead author Nicholas Hess, a scientist at UW–Madison’s Carbone Cancer Center. “Before this study, there was no finite T cell population that we’ve been able to identify as the cause of GVHD, so all our treatment regimens generally impacted the entire T cell population. But targeting all the T cells is not ideal, as they don’t just cause this detrimental disease, they also have a beneficial impact on the ability to prevent relapses.”

Today in Science Advances, Hess and collaborators including Stem Cell and Regenerative Medicine Center members Christian Capitini, professor of pediatrics, and Peiman Hematti, professor of medicine, published their findings, identifying cells called CD4/CD8 double positive T cells (DPT) causing GVHD in immunodeficient mice. To further confirm their findings, the researchers directly investigated human patient samples.

“We looked at over 400 clinical samples from 35 patients as a part of this study and found double positive T cells to be predictive of GVHD. We also found four other biomarkers which are predictive of not just GVHD, but also relapse in general,” says Hess. “Based on that, our next step is to merge the biomarkers into a machine learning algorithm that can output a risk prediction model. Clinicians could then use this model to understand a patient’s risk of relapse and GVHD.”

A team of physicians and scientists at UW–Madison is working on ways to address the problematic cells in patients while leaving healthy and helpful T cells to flourish. Hess says that while the team is very confident the double positive T cells are directly involved in GVHD, the key step in bringing this discovery to the clinic will be developing a targeted depletion strategy and this prediction model.

“When we can gain confidence in this biomarker research and our ability to identify patients at risk, then we will potentially be able to treat them before they have all the detrimental effects of this disease,” Hess says.

The study won a Best Abstracts Award from the American Society for Transplantation and Cellular Therapy and was presented at the American Association of Immunologists (AAI) and ECOG-ACRIN conferences, creating excitement based on the findings’ potential impact beyond blood cancer and transplantation.

“I’ve learned that DPTs have been found in a variety of chronic human inflammatory diseases, which goes to show that this is not a specific thing to graft-versus-host disease. It’s probably a wider phenomenon that these human T cells are doing that we’ve never really appreciated before,” says Hess. “It’s very exciting because it gives us something to study further. I’ve always been interested in taking something you discover in the lab and translating it to the clinic. I think it’s what gets me up every day. It is kind of the ultimate goal in my life to be able to say I participated in something that helped patients in some way.”

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Incyte Provides Regulatory Update On Ruxolitinib Extended-Release Tablets

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WILMINGTON, Del.–(BUSINESS WIRE)–Mar. 23, 2023– Incyte (Nasdaq:INCY) today announced that the U.S. Food and Drug Administration (FDA) has issued a complete response letter for ruxolitinib extended-release (XR) tablets, a JAK1/JAK2 inhibitor, for once-daily (QD) use in the treatment of certain types of myelofibrosis (MF), polycythemia vera (PV) and graft-versus-host disease (GVHD).

The complete response letter states that the FDA cannot approve the application in its present form. The FDA acknowledged that the study submitted in the New Drug Application (NDA) met its objective of bioequivalence based on area under the curve (AUC) parameters but identified additional requirements for approval. Incyte intends to meet with the FDA to determine appropriate next steps.

“While we are disappointed that the FDA issued a complete response letter for ruxolitinib extended-release tablets, we remain committed to advancing care for people with myeloproliferative neoplasms and GVHD,” said Hervé Hoppenot, Chief Executive Officer, Incyte. “We will work closely with the FDA on the appropriate next steps to address their comments.”

The NDA was based on two studies designed to show that ruxolitinib XR tablets are dosage strength proportional and bioequivalent to Jakafi® (ruxolitinib) tablets. The first study was designed to determine the relative bioavailability of ruxolitinib XR tablets to Jakafi tablets and to demonstrate that ruxolitinib XR tablets are dosage strength proportional to Jakafi tablets. The second study was an open-label, randomized, two-period, two-way crossover study in 63 healthy adults evaluating the bioequivalence of the highest strength of ruxolitinib XR tablets (50 mg) dosed once-daily (QD) to the highest strength of Jakafi tablets (25 mg) dosed twice-daily (BID), following a single dose and at steady-state. Study results demonstrated that ruxolitinib XR 50 mg tablets dosed QD is bioequivalent to Jakafi 25 mg tablets dosed BID, based on AUC parameters.

About Jakafi® (ruxolitinib)
Jakafi® (ruxolitinib) is a JAK1/JAK2 inhibitor approved by the U.S. FDA for treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea; intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults; steroid-refractory acute GVHD in adult and pediatric patients 12 years and older; and chronic GVHD after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older1.

Jakafi is a registered trademark of Incyte.

Important Safety Information

Jakafi can cause serious side effects, including:

Low blood counts: Jakafi® (ruxolitinib) may cause low platelet, red blood cell, and white blood cell counts. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will do a blood test to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you develop or have worsening symptoms such as unusual bleeding, bruising, tiredness, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.

Cancer: Some people have had certain types of non-melanoma skin cancers during treatment with Jakafi. Your healthcare provider will regularly check your skin during your treatment with Jakafi. Tell your healthcare provider if you develop any new or changing skin lesions during treatment with Jakafi.

Increases in cholesterol: You may have changes in your blood cholesterol levels during treatment with Jakafi. Your healthcare provider will do blood tests to check your cholesterol levels about every 8 to 12 weeks after you start taking Jakafi, and as needed.

Increased risk of major cardiovascular events such as heart attack, stroke or death in people who have cardiovascular risk factors and who are current or past smokers while using another JAK inhibitor to treat rheumatoid arthritis: Get emergency help right away if you have any symptoms of a heart attack or stroke while taking Jakafi, including: discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back, severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw, pain or discomfort in your arms, back, neck, jaw, or stomach, shortness of breath with or without chest discomfort, breaking out in a cold sweat, nausea or vomiting, feeling lightheaded, weakness in one part or on one side of your body, slurred speech

Increased risk of blood clots: Blood clots in the veins of your legs (deep vein thrombosis, DVT) or lungs (pulmonary embolism, PE) have happened in people taking another JAK inhibitor for rheumatoid arthritis and may be life-threatening. Tell your healthcare provider right away if you have any signs and symptoms of blood clots during treatment with Jakafi, including: swelling, pain, or tenderness in one or both legs, sudden, unexplained chest or upper back pain, shortness of breath or difficulty breathing

Possible increased risk of new (secondary) cancers: People who take another JAK inhibitor for rheumatoid arthritis have an increased risk of new (secondary) cancers, including lymphoma and other cancers. People who smoke or who smoked in the past have an added risk of new cancers.

The most common side effects of Jakafi include: for certain types of myelofibrosis (MF) and polycythemia vera (PV) – low platelet or red blood cell counts, bruising, dizziness, headache, and diarrhea; for acute GVHD – low platelet counts, low red or white blood cell counts, infections, and swelling; and for chronic GVHD – low red blood cell or platelet counts and infections including viral infections.

These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Call your doctor for medical advice about side effects.

Before taking Jakafi, tell your healthcare provider about: all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had low white or red blood cell counts, have or had tuberculosis (TB) or have been in close contact with someone who has TB, had shingles (herpes zoster), have or had hepatitis B, have or had liver or kidney problems, are on dialysis, have high cholesterol or triglycerides, had cancer, are a current or past smoker, had a blood clot, heart attack, other heart problems or stroke, or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change your dose or stop taking Jakafi without first talking to your healthcare provider.

Women should not take Jakafi while pregnant or planning to become pregnant. Do not breastfeed during treatment with Jakafi and for 2 weeks after the final dose.

Please see the Full Prescribing Information, which includes a more complete discussion of the risks associated with Jakafi.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

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Parsaclisib Myelofibrosis Trial Discontinues; Likely To Miss Primary End Point

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Nicholas Wrigley

The phase 3 LIMBER-304 trial examining parsaclisib with ruxolitinib vs matched placebo will be discontinued after an interim analysis concluded it would likely miss the primary end point.

Investigators will discontinue treatment with parsaclisib plus ruxolitinib (Jakafi) for patients with myelofibrosis after an interim analysis concluded the regimen was unlikely to meet its primary end point, according to a press release on the phase 3 LIMBER-304 trial (NCT04551053).

Investigators will present data from the phase 3 LIMBER-304 trial evaluating parsaclisib plus ruxolitinib in myelofibrosis at a future medical meeting.

LIMBER-304 examined the experimental regimen vs ruxolitinib monotherapy in patients with myelofibrosis who had an inadequate response to said monotherapy. In the interim analysis, an independent data monitoring committee assessed the intent-to-treat patient population.

Investigators will present data from this trial at a future medical meeting.

The randomized, double-blind phase 3 LIMBTER-304 study evaluated the combination regimen in an estimated 212 patients. Patients needed to be on stable doses of ruxolitinib ranging from 5 mg to 25 mg twice daily for at least 8 weeks prior to the first day of study treatment. They must also have received at least 3 months of prior ruxolitinib therapy overall.

Eligible patients were then randomly assigned 1:1 to receive either oral parsaclisib or matched placebo once daily in addition to continued ruxolitinib.

The primary end point was the incidence of targeted reductions in spleen volume as assessed by MRI or CT imaging. Secondary end points included the incidence of targeted reductions in total symptom score (TSS), overall changes in TSS, time to the first 50% or greater reduction in TSS, overall survival, the incidence of treatment-related adverse effects, the time of onset of spleen volume reductions, and the duration of maintenance of spleen volume reduction.

Stratification factors included platelet count and Dynamic International Prognostic Scoring System (DIPSS) risk category.

Patients needed to have disease which fell in the intermediate-1, intermediate-2, or high DIPSS risk categories to be included in the study. A palpable spleen of 5 cm or larger below the left costal margin on physical examination at the screening visit and an ECOG score no greater than 2 were also required for enrollment.

Available bone marrow biopsy specimens and pathology reports from 2 months prior or a bone marrow biopsy at screening were also required for inclusion. Patients also needed to have a life expectancy of at least 24 weeks.

Exclusion criteria included any prior therapy involving PI3K inhibition, as well as a recent history of inadequate bone marrow reserve or inadequate liver and renal function at screening. An active invasive malignancy in the preceding 2 years and splenic irradiation in the preceding 6 months before the first dose of the study drug were also grounds for exclusion.

Reference

Incyte provides update on interim analysis of phase 3 LIMBER-304 study of parsaclisib and ruxolitinib in patients with myelofibrosis. News Release. Incyte. March 3, 2023. Accessed March 6, 2023. https://bit.ly/3ydeqU7

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Update on Therapeutic Options for Myelofibrosis

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March 19, 2023

Sara M. Tinsley-Vance, PhD, APRN, AOCN

 

Myelofibrosis is a rare hematologic malignancy associated with abnormal blood counts, splenomegaly, symptoms of chronic inflammation, and scarring of the bone marrow. Prognosis varies, although in most cases is poor. Without hematopoietic stem cell transplant, cure is not possible.

Characteristics of the disease, goals of treatment, and new treatment strategies were discussed in an oral presentation at the 2023 ONA Summit Live Virtual Meeting.

Treatment is focused on alleviation of symptoms, management of cytopenias, and prevention of complications. Current care is focused on inhibition of altered signaling of the JAK/STAT pathway. Ruxolitinib, fedratinib, and pacritinib are FDA-approved for intermediate- and high-risk myelofibrosis. Ruxolitinib was the first in class, JAK 1 and 2 inhibitor, approved in 2011 based on spleen volume reduction and improvement in myelofibrosis-related symptoms.

Fedratinib was approved in 2019 and pacritinib in 2022. Both fedratinib and pacritinib have the potential for spleen volume reduction, and symptom improvement. Pacritinib provides a treatment option for patients with thrombocytopenia.

A new drug application for momelotinib, a JAK1/JAK2/ACVR1/ALK2 inhibitor, was recently accepted by the US FDA. In the MOMENTUM clinical trial (ClinicalTrials.gov Identifier: NCT04173494), momelotinib met all primary and secondary endpoints. Spleen volume response, improvement in symptoms, and transfusion independence were achieved with this new agent.

Nurses and other allied healthcare professionals can benefit from understanding myelofibrosis, potential treatments, adverse side effects, and recommendations for monitoring to educate patients and engage them in discussion for shared decision-making.

Sara Tinsley-Vance is a nurse practitioner and quality of life researcher in the Malignant Hematology Program at Moffitt Cancer Center in Tampa, Florida

Reference

Tinsley-Vance SM. Myelofibrosis: therapeutic options for a complex rare disease. Oral presentation at: 2023 ONA Summit Live Virtual Meeting; March 17-19, 2023.

 

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Earlier Jakafi Treatment Shows Encouraging Outcomes in Myelofibrosis

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Brielle Benyon

Earlier treatment with Jakafi showed promise in both improving survival and symptom burden in certain patients with myelofibrosis, though physicians often delay Jakafi treatment.

A higher percentage of patients with intermediate-2 and high-risk myelofibrosis who were introduced to Jakafi (ruxolitinib) within a year of being diagnosed saw improved survival and reduced symptom burden compared to those who were given the drug later or not at all,according to recent research that was published in the journal Cancer.

Researchers analyzed data from two clinical trials (COMFORT-I and COMFORT-II), which included 525 patients with myelofibrosis, a type of myeloproliferative neoplasm.

In this patient population, 84 patients received Jakafi within 12 months of being diagnosed, while 216 received the drug at or after 12 months from diagnosis. Additionally, 66 patients received placebo plus best available therapy within 12 months, and 159 patients received placebo plus best available therapy after 12 months.

Myelofibrosis causes a decrease in the number of normal cells that are produced in the bone marrow. As a result, the spleen starts to produce these types of cells, and often becomes inflamed — indicating potentially worsening disease and putting patients at risk for infections.

“Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue,” the researchers wrote.

Study findings showed that at week 48, patients who received Jakafi earlier had a higher rate of spleen volume response (meaning that their spleen shrunk) than those who were not exposed to the drug within a year of treatment (44% versus 26.9%, respectively).

Additionally, at a 240-week follow-up, 63% of patients who were given Jakafi early were still alive, compared with 57% of those who were given the drug a year or later after being diagnosed. At this time, 49.4% of patients who received placebo plus best available therapy within 12 months were alive, and 40.7% of those given placebo/best therapy at or after 12 months were alive.

The researchers also noted that on average, patients given Jakafi — regardless of whether it was within or after 12 months of diagnosis — tended to live longer than those prescribed placebo plus best available therapy.

The Food and Drug Administration approved Jakafi for intermediate- or high-risk myelofibrosis more than a decade ago, and it is recommended to be the first therapy offered for patients with the disease. However, as the study authors pointed out, Jakafi is often not the first drug given, or it is not given soon after diagnosis.

“The National Comprehensive Cancer Network guidelines for myeloproliferative neoplasms recommend (Jakafi) as a first-line treatment for patients with higher-risk (myelofibrosis),” study authors wrote. “There is a compelling rationale to treat patients with intermediate- or high-risk (myelofibrosis) with (Jakafi). Despite this, real-world treatment patterns indicate that many physicians delay or avoid (Jakafi) treatment, often in favor of hydroxyurea or watchful waiting.”

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Patient-specific comorbidities as prognostic variables for survival in myelofibrosis

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Andrew L. Sochacki, Cosmin Adrian Bejan, Shilin Zhao, Ameet Patel, Ashwin Kishtagari, Travis P. Spaulding, Alexander J. Silver, Shannon S. Stockton, Kelly Pugh, R. Dixon Dorand, Manasa Bhatta, 
Nicholas Strayer, Siwei Zhang, Christina A. Snider, Thomas Stricker, Aziz Nazha, Alexander G. Bick, Yaomin Xu, Michael R. Savona
Treatment decisions in primary myelofibrosis (PMF) are guided by numerous prognostic systems. Patient-specific comorbidities have influence on treatment-related survival and are considered in clinical contexts but have not been routinely incorporated into current prognostic models. We hypothesized that patient-specific comorbidities would inform prognosis and could be incorporated into a quantitative score. All patients with PMF or secondary myelofibrosis with available DNA and comprehensive electronic health record (EHR) data treated at Vanderbilt University Medical Center between 1995 and 2016 were identified within Vanderbilt’s Synthetic Derivative and BioVU Biobank. We recapitulated established PMF risk scores (eg, Dynamic International Prognostic Scoring System [DIPSS], DIPSS plus, Genetics-Based Prognostic Scoring System, Mutation-Enhanced International Prognostic Scoring System 70+) and comorbidities through EHR chart extraction and next-generation sequencing on biobanked peripheral blood DNA. The impact of comorbidities was assessed via DIPSS-adjusted overall survival using Bonferroni correction. Comorbidities associated with inferior survival include renal failure/dysfunction (hazard ratio [HR], 4.3; 95% confidence interval [95% CI], 2.1-8.9; P = .0001), intracranial hemorrhage (HR, 28.7; 95% CI, 7.0-116.8; P = 2.83e-06), invasive fungal infection (HR, 41.2; 95% CI, 7.2-235.2; P = 2.90e-05), and chronic encephalopathy (HR, 15.1; 95% CI, 3.8-59.4; P = .0001). The extended DIPSS model including all 4 significant comorbidities showed a significantly higher discriminating power (C-index 0.81; 95% CI, 0.78-0.84) than the original DIPSS model (C-index 0.73; 95% CI, 0.70-0.77). In summary, we repurposed an institutional biobank to identify and risk-classify an uncommon hematologic malignancy by established (eg, DIPSS) and other clinical and pathologic factors (eg, comorbidities) in an unbiased fashion. The inclusion of comorbidities into risk evaluation may augment prognostic capability of future genetics-based scoring systems.

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Protagonist Therapeutics Announces Highly Statistically Significant Results from the Randomized Withdrawal Portion of the REVIVE Study of Rusfertide in Polycythemia Vera

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Rusfertide met the study’s primary endpoint, with a statistically significant higher number of responders on rusfertide versus placebo (p=0.0003)

Rusfertide continues to be generally well tolerated with no new safety signals

NEWARK, CA / ACCESSWIRE / March 15, 2023 / Protagonist Therapeutics, Inc. (NASDAQ:PTGX) (“Protagonist” or “the Company”), today announced positive topline results from the blinded, placebo-controlled, randomized withdrawal portion of REVIVE, a study evaluating rusfertide, a subcutaneous injectable hepcidin mimetic, in patients with polycythemia vera (PV). Subjects receiving rusfertide achieved highly statistically significant improvements versus placebo in the primary endpoint.

The double-blind, placebo-controlled, 12-week randomized withdrawal phase was included as Part 2 of the REVIVE study to evaluate rusfertide in PV patients with frequent phlebotomy requirements. In the trial, study subjects were initially enrolled in the 28-week open label dose-titration and efficacy evaluation Part 1 of the study, followed by 1:1 randomization of 53 subjects to placebo versus rusfertide therapy for a subsequent duration of 12 weeks (“randomized withdrawal portion” or “Part 2”).

More subjects receiving rusfertide during the blinded randomized withdrawal portion of the REVIVE study were responders compared with placebo (69.2% versus 18.5%, p=0.0003). A study subject was defined as a responder if the subject completed 12 weeks of double-blind treatment while maintaining hematocrit control without phlebotomy eligibility and without phlebotomy. During the 12 weeks of the blinded randomized withdrawal, only 2 of 26 subjects on rusfertide were phlebotomized, keeping 92.3% patients phlebotomy free in the rusfertide arm (p=0.0003).

In patients with moderate or severe Myeloproliferative Neoplasm-Symptom Assessment Form (MPN-SAF) symptom scores at baseline, the change from baseline was statistically significant in fatigue, problems with concentration, inactivity and itching during the 28-week open label Part 1 of the study. Meaningful comparison of symptom assessments in Part 2 are not possible since a majority of subjects randomized to placebo discontinued prior to the 12-week assessment of MPN-SAF symptoms.

Rusfertide was well tolerated, with localized injection site reactions comprising the majority of reported adverse events. No new safety signals were observed in these data following presentation of safety data from the REVIVE study at the American Society of Hematology (ASH) December 2022 Annual Meeting.

Additional details on these data can be found in slides 25 through 31 of the Protagonist Corporate Presentation, available on the Company’s website at protagonist-inc.com.

“Participants in our studies who required frequent phlebotomy, with or without cytoreductives, have now been treated with rusfertide for more than two years, remaining largely phlebotomy free,” said Arturo Molina, M.D., M.S., Chief Medical Officer of Protagonist. “Data from the REVIVE study suggest that rusfertide treatment results in a highly statistically significant reduction in the need for therapeutic phlebotomy in phlebotomy-dependent patients, leading to rapid, sustained, and durable control of hematocrit levels below 45%. Part 2 of REVIVE, the randomized withdrawal study, yielded no new safety findings while confirming previously reported efficacy and safety findings observed in the open label portion of REVIVE (Part 1).”

“These randomized withdrawal data from the REVIVE study indicate a dramatic difference in the experience of the treatment group versus the placebo group,” noted Dr. Ronald Hoffman, M.D., the Albert A. and Vera G. List Professor of Medicine (Hematology and Oncology), Director of the Myeloproliferative Research Program at the Icahn School of Medicine at Mount Sinai, and principal investigator of the study. “With robust and strongly positive results observed across a diverse set of patients, we now have further confirmation of rusfertide’s potential to serve as an important future treatment option for patients with polycythemia vera.”

“All study subjects who participated in the REVIVE clinical trial had been previously unsuccessful in controlling their hematocrit using standard-of-care therapies alone,” said Andrew Kuykendall, M.D., Department of Malignant Hematology, Moffit Cancer Center. “These new data from REVIVE provide important insights into the role that rusfertide (PTG-300) can potentially have within a future PV treatment paradigm, supporting patients and their physicians in achieving the treatment goal of hematocrit below 45%, in step with current NCCN Clinical Practice Guidelines.”

“The new randomized withdrawal data confirm our previous efficacy and safety findings of rusfertide in PV and support our strong conviction that rusfertide can be a potentially transformational therapeutic option for polycythemia vera,” said Dinesh V. Patel, Ph.D., President and Chief Executive Officer of Protagonist. “With the completion of the REVIVE study, the Company’s topmost priority continues to be execution of the 250-patient global, pivotal, Phase 3 VERIFY study in PV. The Protagonist team continues to work with full dedication alongside investigators, site staff and other partners with the shared aim of bringing this important potential therapy to PV patients.”

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Novel Treatments Give Hope for a Transformed Transplant Community

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March 15, 2023

Improvements in graft-vs-host disease and transplant-related mortality have created a wave of hope for clinicians treating their patients with hematologic malignancies, stemming from the encouraging data seen with Orca-T and other novel therapeutics in the pipeline.

Improvements in graft-vs-host disease (GVHD) and transplant-related mortality have created a wave of hope for clinicians treating their patients with hematologic malignancies, stemming from the encouraging data seen with Orca-T and other novel therapeutics in the pipeline.

For example, at the 2023 Transplantation and Cellular Therapy Meetings, data from a single-center phase 2 trial showed that Orca-T, which is a high precision cell therapy, produced a 100% overall survival rate in 8 patients with acute leukemia, myeloproliferative neoplasms, chronic myeloid leukemia, and other hematologic cancers who underwent an allogeneic hematopoietic stem cell transplant with 7/8 non-permissive haploidentical mismatched donors.1

The immune reconstitution of Orca-T in 100 patients from an ongoing, multicenter phase 1b trial (NCT04013685) was also examined in findings presented at the 2022 ASH Annual Meeting. Investigators performed longitudinal measurements of immune reconstitution, showcasing the peripheral blood counts of platelets, white blood cells, neutrophils, lymphocytes, monocytes, T cells, B cells, and natural killer (NK) cells. Results showed that patients on Orca-T exhibited early immune reconstitution in each of the key leukocyte and lymphocyte subsets believed to manage relapse and infection.2 Researchers also observed elevated Treg frequencies. Overall, these immune reconstitution data may be correlated to the reduced occurrence and severity of acute and chronic GVHD.

In an interview with OncLive®, Lori Muffly, MD, an associate professor of medicine at Stanford University, discussed the updated findings with Orca-T in hematologic malignancies, spoke to the product’s immune reconstitution profile, and the next steps she hopes to see taken with this type of treatment and others in the pipeline.

OncLive: Orca-T has been an agent to watch for over the last few years. Updated findings were presented at the 2022 ASH Annual Meeting, as well as some at the 2023 Transplantation and Cellular Therapy Meetings. Could you highlight the topline data reported at both meetings?

Muffly: We are really excited about Orca-T in the transplant community. The data have been presented a few times now from the single-center phase 2 and multicenter phase 1b studies . In the matched setting, which has been presented multiple times, what has been shown is low rates of both acute and chronic GVHD, and incredibly low rates of transplant-related mortality.

For someone like me, who treats patients with typically adverse risk of acute leukemia, I think the most exciting part is seeing that the relapse rates appear to be not increased in any way compared with our historical tacrolimus/methotrexate GVHD prophylaxis. That is very exciting because having overall survival rates that are phenomenal, low relapse rates, and then particularly low GVHD and transplant-related mortality rates, is exactly what we’re looking for in the field of transplant.

There were some immune reconstitution data with Orca-T that were presented at the 2022 ASH Annual Meeting. What were the key takeaways from that?

One of the other nice things about the Orca-T platform, which is really a reduced T-cell dose, along with an administration of regulatory T cells, is that the infection rates are quite low, relative to historical control. One of the problems with more of a traditional T-cell depleted graft, either ex vivo or in vivo, is higher rates of infection, particularly viral infections. We have not seen that with Orca-T.

At this past year’s ASH Annual Meeting, there was a poster demonstrating in about 90 patients, at least with day 28 data, and then around 50 patients with 1 year of follow-up, the immune cell subset reconstitution. What we could see is that these patients reconstituted B cells, T cells, regulatory T cells and NK cells by 1 year, quite effectively. That probably has something to do with why we’re seeing lower rates of infection than as predicted in a T-cell deplete graft.

Putting it into context for the practicing clinician, why is immune reconstitution important and how do we use it to guide treatment decisions for patients?

With transplant, there are so many different factors that we think about—of course, a focus on the disease itself that we’re transplanting for. For example, if a patient has acute myeloid leukemia, trying to get a transplant that has the most potential for graft vs leukemia is important. We think about GVHD, because that is the adverse flip side of graft vs leukemia and identifying mechanisms of transplant that are associated with lower GVHD is important.

Then finally, the ability of the new graft to protect patients from infection and particularly opportunistic infection and viral reactivations [are what we think about]. Any 1 of those 3 components that’s missing is a big problem for our patients. If you have a transplant approach that really can take care of all 3 [components], that is really the holy grail of transplant: low relapse, low GVHD, and low infection.

Taking these data into context, what next steps would you like to see taken with this type of therapy?

I am really excited about the possibilities with Orca-T. Currently, as you probably know, there is a randomized phase 3 study, a registration trial, ongoing comparing Orca-T with historical control tacrolimus and methotrexate [and alloHSCT]. We have been very actively participating in that study. Obviously, we are hopeful to see the results and that this may lead to commercialization of this product.

We’re also really excited about Orca-T in the mismatched myeloablative setting. There was an oral abstract at the [2023 Transplantation and Cellular Therapy Meetings] presented with just under 10 patients with mismatched, unrelated donors. Those data look exciting, as well. There is a lot of opportunity for this program in the clinical space.

Now, the other thing that’s happening in the transplant community, which is very difficult to miss, is the evolution and uptake of posttransplant cyclophosphamide as GVHD prevention. We are really blessed right now that we have 2 exciting approaches going on at the same time: posttransplant cyclophosphamide and Orca-T. The field eventually will want to look at the 2 of them side by side, because they both seem to lead to low GVHD rates without an increase in disease relapse. As someone who offers these treatments to my patients, I have never been more excited about what we have going on in this field. I look forward to future studies as well.

Is there anything else that you think would be important for the practicing oncologist to know about these or any other therapies in the pipeline?

It is important for the practicing oncologist to know that as our therapeutics for blood cancers are improving, so are our approaches to bone marrow transplant. I no longer think about transplant-related mortalities of 20% to 30% when I’m talking to patients, and that’s how things started, at least when I started. I’m now hopeful that that sort of topline number is going to be more like a 5% risk [as more options become available]. While that’s still too high, it’s at least a bit more acceptable.

Also, the likelihood of developing GVHD with these newer approaches has substantially gone down. That is important for referring physicians to know because the darker days, scarier days, of transplant are behind us. This is a therapeutic that has curative potential for many, many adults out there. Many patients just are not referred. These data are important to get out there so that people in the community can realize transplant data are looking different than they used to look.

References

  1. Pavlova A, Lowsky R, Muffly L, et al. Orca-T, a high-precision cell therapy, for the treatment of hematologic malignancies in patients with 7/8 mismatch donors. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 30.
  2. Meyer EH, Killian MS, Pavlova A, et al. Rapid immune reconstitution and elevated regulatory T cell frequencies in patients treated with Orca-T. Blood. 2022;140(suppl 1):7656-7657. doi:10.1182/blood-2022-164468

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