Age-related macular degeneration and myeloproliferative neoplasms – A common pathway

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First published: 06 October 2022
https://doi.org/10.1111/aos.15247

This thesis has been submitted to the Graduate School of Health and Medical Sciences, University of Copenhagen, Denmark – January 31, 2022.

English summary

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss and blindness in high-income countries. It is a progressive retinal disease leading to damage of the cells responsible for central vision. The early stages of the disease are often asymptomatic, while late-stage AMD, which is divided into two entities, neovascular AMD and geographic atrophy (GA), both show vision loss, though generally with different progression rates. Drusen and pigmentary abnormalities in the retina characterise early AMD, while nAMD and GA show angiogenesis in and atrophy of the retina, respectively. The aetiology is multifactorial and, in addition to ageing, which is the most significant risk factor for developing AMD, environmental- and genetic risk factors are implicated in the pathogenesis. Research has focused on local changes in the eye where inflammation has been found to play an essential role, but studies also point to systemic alterations and especially systemic inflammation to be involved in the pathogenesis.

The Philadelphia-negative myeloproliferative neoplasms (MPN) are a group of haematological cancers with an acquired genetic defect of the pluripotent haematopoietic stem cell, characterised by excess haematopoiesis of the myeloid cell lineage. The diseases have been found to evolve in a biological continuum from early cancer state, essential thrombocythemia, over polycythaemia vera (PV), to the advanced myelofibrosis stage (PMF). The symptoms in these patients are often a result of the changes in the blood composition, hyperviscosity, microvascular disturbances, and reduced tissue perfusion. The major causes of morbidity and mortality are thromboembolic- and haemorrhagic events, and leukemic transformation. A group of mutations that drive the MPNs has been identified, e.g., the JAK2V617F mutation, which results in deregulation of the JAK/STAT signal transduction pathway important, for instance, in cell differentiation and survival. A previous large register study has shown that patients with MPNs have an increased risk of neovascular AMD, and a pilot study has shown an increased prevalence of intermediate AMD. We wish to study this further in a larger scale study. Several studies have also shown that systemic inflammation plays an essential role in both the initiation and progression of the malignant cell clone in MPNs. From this knowledge, a “Human inflammation model” has been developed. Since then, the MPNs has been used as model diseases for a similar inflammation model for the development of Alzheimer’s disease. In this PhD project, we would like to investigate systemic inflammation in relation to drusen presence. We will do this by comparing systemic immunological markers previously investigated in patients with AMD and compare with MPN. We are primarily interested in systemic immunological differences between patients with MPN and drusen (MPNd) and MPN with normal retinas (MPNn).

This thesis consists of two main studies. Study I investigated the prevalence of retinal changes associated with AMD and the prevalence of different AMD stages in 200 patients with MPN (paper I). Study II examined immunological similarities between AMD and MPNs. This study was divided into three substudies exploring systemic markers of inflammation, ageing and angiogenesis, respectively. This was done in four types of patients: nAMD, intermediate AMD (iAMD), MPNd and MPNn. Investigating, differences between MPNd and MPNn, will make it possible to identify changes in the immune system, relevant for AMD pathogenesis. Additionally, we will compare patients with MPNs with patients with iAMD and nAMD.

In study I (Paper I), we found that patients with MPNs have a significantly higher prevalence of large drusen and consequently AMD from an earlier age compared to the estimates from three large population-based studies. We also found that drusen prevalence was associated with a higher neutrophil-to-lymphocyte ratio indicating a higher level of chronic low-grade inflammation in patients with drusen compared to those without drusen.

In study II (papers II, III and IV), we found immunological differences between patients with MPNd and MPNn. When we investigated markers of inflammation, we found a higher level of systemic inflammation in MPNd than MPNn. This was indicated by a higher inflammation score (based on levels of pro-inflammatory markers), a higher neutrophil-to-lymphocyte ratio, and indications of a deregulated complement system. When examining markers of ageing, we found signs of accelerated immune ageing in MPNd compared to MPNn, shown by more senescent effector memory T cells.

Finally, when exploring a marker of angiogenesis, we found a lower CXCR3 expression on monocytes and T cells in nAMD compared to iAMD, MPNd and MPNn, in line with previous studies of nAMD compared to healthy controls. Further, we found decreasing CXCR3 expression over the MPN biological continuum. These studies indicate CXCR3 involvement in both nAMD and PMF, two disease stages characterised by angiogenesis and fibrosis.

From the results of this PhD project, we can conclude that the prevalence of drusen and AMD is increased in patients with MPN compared to the general population. Further, our results show that systemic inflammation may play a far more essential role in AMD pathogenesis than previously anticipated. We, therefore, propose an AMD model (Figure 18) where inflammation can initiate and accelerate the normal age-dependent accumulation of debris in the retina, which later evolve into drusen, resulting in increased local inflammation, and over time early- and intermediate AMD. This results in the increased risk of developing the late debilitating stages of AMD.

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Novel Interventions May Reduce Phlebotomy Use in Patients With Polycythemia Vera

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Brittany Lovely

Patients with polycythemia vera (PV), a myeloproliferative neoplasm associated with JAK2 mutations and overproduction of red blood cells, often require regular therapeutic phlebotomies to avoid thrombosis. The most common presentations of thrombosis in PV include stroke, myocardial infarction, peripheral arterial thrombosis, transient ischemic attack, peripheral vein thrombosis, pulmonary embolism, and thrombosis in unusual venous districts.1

To achieve acceptable disease control, patients with low-risk disease may need to undergo phlebotomy up to 5 times per year, which can lead to adverse effects (AEs) such as iron deficiency. Those with high-risk disease require cytoreduction and correction of cardiovascular risk factors with or without phlebotomy.1,2

Alternative interventional treatments to reduce the risk of thrombosis represent a significant unmet need in the community setting as phlebotomy and cytoreductive therapies including hydrea, ruxolitinib (Jakafi), and interferons have not demonstrated consistency in efficacy or tolerability.2

“Many patients who use pills, injections, [or] cytoreductive therapies, to minimize the need for phlebotomy. [However,] it seems that the achievement of the goal [to] control the hematocrit [levels] below 45% is not readily achieved in the community setting,” Srdan Verstovsek, MD, PhD, said in an interview with OncologyLive®. “Many times, we considered PV a benign condition, [but] when you dig in and analyze the results it’s not so. Individuals are unnecessarily exposed to uncontrolled blood cell counts, which leads to untimely death from the thrombotic events. To optimize care in a community setting for patients with PV, we should all engage in developing new drugs.” Verstovsek is the United Energy Resources Inc, professor of medicine, director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms, and chief of the Section for Myeloproliferative Neoplasms in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston.

Assessing the Unmet Need for Patients with PV

“Most patients with PV will get at least 1 phlebotomy during the course of their treatment,” Aaron Gerds, MD, said in an interview with OncologyLive®. “Even if they are going to [receive] alternative medication we may use phlebotomy early on to quickly get hematocrit down after diagnosis. Patients who are lower risk for thrombosis would be treated with phlebotomy alone and patients who are higher risk for thrombosis are treated with a medication, which can free them from the need for phlebotomy. But there are still a significant proportion of patients who require phlebotomy in addition to a medication to control counts. They’re really getting 2 treatments at once, which is complicated to manage, and can lead to multiple adverse effects.” Gerds is an assistant professor in medicine (hematology and medical oncology) at Cleveland Clinic Taussig Cancer Institute in Ohio.

A phase 3 study is underway to assess outcomes for patients with previously diagnosed PV who require phlebotomy on a regular basis. VERIFY (NCT05210790) will evaluate whether the addition of the novel hepcidin mimetic rusfertide to ongoing therapy for PV will eliminate the need for patients to receive or prolong time between phlebotomies.2,3

“The phase 3 study is built on the experience from the phase 2 study [REVIVE; NCT04057040],” Verstovsek said. “It includes patients from a variety of backgrounds. They don’t necessarily need to be on any therapy at all, if they fulfill the requirement of too many phlebotomies, which is certainly harmful for them. The patients would come often at the beginning to make sure that they are [treated] optimally with rusfertide, [and determining the] optimal dose without the adverse effects [may] require a few months of adjustments. [There is planned] long-term follow-up, almost a year and more, because PV is a lifelong condition.”

Rusfertide works by suppressing PV erythropoiesis. “Basically, it tricks the bone marrow into thinking it’s already iron deficient when it isn’t, thus slowing down the production of red blood cells keeping the hematocrit under 45%,” Gerds explained.

REVIVE assessed the ability of rusfertide to maintain hematocrit levels below 45%. All patients underwent phlebotomy to achieve hematocrit below 45% prior to prior to the first dose of rusfertide dose. Seventy patients received rusfertide at a median dose of 40 to 60 mg weekly via self-administered subcutaneous dosing.

Among 63 evaluable patients, during the first 28 weeks of treatment, 84% of patients did not require a phlebotomy. Of those who did proceed to phlebotomy, 14% required 1 and 2% required 2 phlebotomies.2 Rusfertide demonstrated similar efficacy in all categories of patients, independent of the PV patient risk category or concurrent therapy with hydroxyurea, interferon or ruxolitinib. In terms of safety, the most common AE was injection site reaction (33%) but no patients discontinued because of injection site reactions.

“Here is a drug that is effective, it is safe, it is self-administered, it is therefore simple, and it appears to be durable,” Verstovsek said of the phase 2 data.

VERIFY Aims to Extend Phlebotomy-Free Intervals

The double-blind, placebo-controlled trial will evaluate patients with PV randomly assigned 1:1 to ongoing therapy with either rusfertide or placebo. The primary efficacy will be evaluated during weeks 20 to 32, with primary end analysis reported at week 32. At that time the study will be unblinded. Durability of response will be assessed between weeks 32 to 52; all enrolled patients then will proceed with their ongoing therapy and rusfertide.2,3

At week 52, durability of response will be evaluated and patients will enter the long-term safety follow-up (weeks 52-156). Therapy administered during this portion of the trial will be PV therapy plus rusfertide. The end of treatment is week 156 with an additional safety follow-up period occurring for 4 weeks.2,3

Verstovsek noted that the aim of the trial is not to eliminate disease but control it. “We want to prove that rusfertide is effective, safe, simple, and long lasting. Studies such as [VERIFY] that cover [approximately] 1 year are the norm for PV and we are looking forward to this study to be open across the globe over the next couple of years. [We want to demonstrate] the value of eliminating the need for phlebotomy, improving the quality of life for these patients, and having it on the market for our patients in every practice,” he said.

Taking the Patient into Consideration

Gerds noted that patients may also benefit from the elimination of the multiple burdens associated with phlebotomy. “It leads to iron deficiency and [individuals] can be symptomatic from the iron deficiency—they can experience tiredness, achiness, changes in hair and nails, and the most famous adverse effect of iron deficiency being pica, the urge to eat dirt or ice. Additionally, [phlebotomy] takes time,” Gerds said noting that the scheduling and repeat tests are a “logistical hassle.”

Self-administration of the agent is also a key differentiator for patients with PV. “Patients [administer] the shot at home. Thinking about a systems-based approach to delivering of care, an infusion or injection room chair [remains free] in your cancer center,” Gerds said.

He added that there are several barriers to overcome, most of which rely on patient education. “When prescribing a medication such as rusfertide, you also have to prescribe the syringes and the needles, and you have to teach the patient how to do the injections,” he said.

At Cleveland Clinic, Gerds noted that they provide educational videos and offer nursing visits. “We also need to instruct them to on how to care for the medication at home—do not store it in extreme temperatures, how to draw from the vial, etc,” Gerds said.

In June 2021, the FDA granted breakthrough therapy designation to rusfertide as a potential therapeutic option for patients with PV to reduce erythrocytosis in those who do not require further treatment for thrombocytosis and/or leukocytosis.4

“I would envision, if we are successful in proving the value in eliminating phlebotomy and improving quality of life, that rusfertide would be a natural choice for individuals who are otherwise low risk, manage with phlebotomy alone, and have problems with it,” Verstovsek said. “Rusfertide appears to fulfill the purpose in patients who are low risk and for patients who are receiving some other cytoreductive therapy [such as] hydroxyurea in suboptimal responders. Adding rusfertide to optimize the care eliminates the need for phlebotomy and is a natural next step. I think there is a possibility of multiple different clinical scenarios where the drug may become valuable for low-risk to high-risk patients.”

Gerds noted that next steps for building on this research is improving the concurrent medications administered for this patient population as well as the identification of prognostic biomarkers. “We always want to [achieve] deep remissions and have [patients] live much longer than we would anticipate. And the truth is patients with PV often do very well…but we lack a lot of good biomarkers.”

References

  1. Vannucchi AM. How I treat polycythemia vera. Blood. 2014;124(22):3212-3220. doi:10.1182/blood-2014-07-551929
  2. Hoffman R, Ginzburg Y, Kremyanskaya M, et al. Rusfertide (PTG300) treatment in phlebotomy-dependent polycythemia vera patients. J Clin Oncol. 2022;40(suppl 16):7003. doi:10.1200/ JCO.2022.40.16_suppl.7003
  3. A phase 3 study of rusfertide in patients with polycythemia vera (VERIFY). ClinicalTrials.gov. Updated August 1, 2022. Accessed September 20, 2022. https://clinicaltrials.gov/ct2/show/ NCT05210790
  4. Protagonist Therapeutics receives FDA breakthrough therapy designation for rusfertide in polycythemia vera. News release. Protagonist Therapeutics. June 3, 2021. Accessed September 20, 2022. bit.ly/3R0Tir8

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Myelofibrosis Epidemiology Analysis and Forecast, 2021-2031

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ReportLinker

Summary Myelofibrosis (MF) belongs to a group of diseases called myeloproliferative disorders. MF is a serious bone marrow disorder that disrupts the body’s normal production of blood cells (MedlinePlus, 2020; Mayo Clinic, 2021).

New York, Sept. 22, 2022 (GLOBE NEWSWIRE) — Reportlinker.com announces the release of the report “Myelofibrosis Epidemiology Analysis and Forecast, 2021-2031” – https://www.reportlinker.com/p06317718/?utm_source=GNW

MF includes primary MF (PMF), which is idiopathic. At times, essential thrombocytosis (ET) or polycythemia vera (PV) could progress to MF, resulting in post-essential thrombocytosis MF (PET MF) and post-polycythemia vera MF (PPV MF), which are referred to as secondary MF (SMF).

MF not only shortens survival but also severely compromises quality of life due to marked splenomegaly and profound constitutional symptoms including fatigue, night sweats, fever or uncomfortable feeling of warmth, weight loss, peripheral edema, pruritus, bone pain, dyspnea, and intractable cough (Mesa et al., 2009; Canadian Cancer Society, 2022).

In the 8MM, diagnosed incident cases of MF (sum of the diagnosed incident cases of PMF and SMF) are expected to increase from 12,276 cases in 2021 to 15,009 cases in 2031, at an Annual Growth Rate (AGR) of 2.23%. In 2031, China will have the highest number of diagnosed incident cases of MF in the 8MM, with 9,302 cases, whereas Spain will have the fewest diagnosed incident cases of MF with 413 cases. In the 8MM, the diagnosed prevalent cases of MF (sum of the diagnosed prevalent cases of PMF and SMF) are expected to increase from 69,236 cases in 2021 to 84,311 cases in 2031, at an AGR of 2.18%Epidemiologists attribute the increase in the diagnosed incident cases and diagnosed prevalent cases of MF to changes in the diagnosed incidence and survival rates, and population dynamics in each market.

Scope
– This report provides an overview of the risk factors, comorbidities, and the global and historical trends for MF in the eight major markets (8MM: US, France, Germany, Italy, Spain, UK, Japan, and China).
– It includes a 10-year epidemiological forecast for the diagnosed incident and diagnosed prevalent cases of MF, PMF, PET MF, and PPV MF based on county-specific studies published in peer-reviewed journals. The diagnosed incident cases of PMF are further segmented by sex, age (40-49 years, 50-59 years, 60-69 years, 70-79 years, and 80 years), the mutation-enhanced international prognostic scoring system (MIPSS70+) version 2.0 [very low risk (0 points), low risk (1-2 points), intermediate risk (3-4 points), high risk (5-8 points), and very high risk (?9 points)], mutations (JAK2V617F, CALR, and MPL), and anemia (with or without). The diagnosed prevalent cases of PMF are segmented by sex and age (40-49 years, 50-59 years, 60-69 years, 70-79 years, and 80 years). Epidemiologists also provide sex-specific diagnosed incidents and diagnosed prevalent cases of PET MF and PPV MF in the 8MM for the forecast period.

– The myelofibrosis epidemiology report is written and developed by Masters- and PhD-level epidemiologists.
– The Epidemiology Report is in-depth, high quality, transparent and market-driven, providing expert analysis of disease trends in the 8MM.

Read the full report here

How the Name Change to Myeloproliferative Neoplasms Affected People With the Disease

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Leah Lawrence

CURE, CURE Fall 2022, Volume 21, Issue 03

A decision to rename myeloproliferative neoplasms led to a plethora of developments in a space where there was once little interest.

Name recognition. The term is often associated with Fortune 500 companies like Coca-Cola, famous celebrities and politicians running for office. But what about medicine and the subsequent treatment of diseases? What if a name — or rather, name change — could influence how the world views a particular disease and ultimately revolutionize the space?

To a greater extent, how would the evolution of the term myeloproliferative disorders (MPDs) — a group of diseases including polycythemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythemia (ET) — to myeloproliferative neoplasms (MPNs) affect the lives of thousands upon thousands of people living with a rare disease?

As it turns out, that decision would transform the trajectory of a cancer space where there was once very little interest.

What’s in a Name?

In 2008, the World Health Organization (WHO) in collaboration with the United States-based Society for Hematopathology and the European Association for Haematopathology published a revised classification of the diseases that made up MPDs and officially classified them as neoplasms.

“They were considered a ‘disorder’ and then a ‘neoplasm,’” says David Ricci, a long-time member of the MPN Research Foundation Board of Directors. “The diseases had not changed. There was nothing about these diseases that was different before the change versus after the change.”

Instead, the change of name was made largely to be more accurate, Ricci

David Ricci

David Ricci notes that until about 15 to 20 years ago, the incidence of MPNs was not well studied.

Photo provided by David Ricci

explains. The term MPDs dates back to a former president of the American Society of Hematology, Dr. Louis Wasserman, who coined the phrase to describe a range of diseases that had elevated blood counts, including chronic myeloid leukemia (CML), notes Dr. Ruben Mesa, executive director of Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center.

In PV, patients experience an increase in all blood cells, particularly red blood cells, which supply oxygen. Patients with ET have bone marrow that produces too many platelets, which can cause abnormal bleeding or blood clots. And in PMF, patients build up scar tissue in the bone marrow that produces blood cells, impairing the body’s ability to make normal blood cells.

“Over time we learned that all of these were neoplasms,” Mesa says. “All of the abnormal cells are related to one another, and that is a defining charac-teristic of a neoplasm.”

This characteristic is called clonality. Neoplasms are an abnormal growth of cells that can be either benign or malignant. MPNs start out as benign but may progress to being malignant.

“As science progressed and we learned this was a clonally driven disease, that sounded more like cancer,” says Dr. Michael R. Savona, head of hematology, cellular therapy and stem cell transplantation at Vanderbilt University Medical Center in Nashville, Tennessee.

“It would have been technically inaccu-rate to consider it otherwise.”

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CTI BioPharma Announces Presentation of New Anemia Benefit Data from Pacritinib Program at the Society of Hematologic Oncology (SOHO) Tenth Annual Meeting

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SEATTLE, Sept. 21, 2022 /PRNewswire/ — CTI BioPharma Corp. (NASDAQ: CTIC) today announced two poster presentations from the Company’s pacritinib program at the Society of Hematologic Oncology (SOHO) Tenth Annual Meeting, to be held in Houston, Texas and virtually September 28 – October 1, 2022.

A new data analysis from the Phase 3 PERSIST-2 trial and an in vitro analysis of pacritinib, a novel JAK2/IRAK1 inhibitor approved by the U.S. FDA for patients with myelofibrosis and a platelet count below 50 x 109/L, will highlight pacritinib’s impact on anemia and inhibition of Activin A receptor type 1 (ACVR1).

“Treatment with pacritinb at the approved dose of 200 mg twice daily (BID) led to improvements in transfusion independence and anemia when compared to best available therapy (BAT) in patients treated on the PERSIST-2 Phase 3 study,” said Dr. Stephen Oh, MD, PhD, Associate Professor of Medicine, Hematology Division at Washington University School of Medicine in St. Louis. “I am encouraged by these data, given the limited options to address anemia in myelofibrosis, especially high-risk patients with cytopenias who frequently require blood transfusions. I look forward to further investigation of pacritinib’s potential to alleviate anemia and related symptoms in this patient population.”

“We are pleased to report that pacritinib is a highly potent inhibitor of ACVR1. This inhibition is thought to lead to improvements in blood transfusion requirements and anemia in patients with cytopenic myelofibrosis,” said Adam Craig, MD, PhD, President and Chief Executive Officer of CTI BioPharma. “The data presented at SOHO 2022 support our belief that pacritinib is a simple, safe and effective JAK2 inhibitor. We plan to present additional data on pacritinib’s anemia benefit at a medical meeting later this year.”

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A Patient Story: My Journey to a Better Life

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By Mayra D.

My Primary Myelofibrosis journey started on a festive Cinco de Mayo in 2015 while I was at work. Without any warning, I started to feel sick to the point that I almost collapsed at my desk. I still remember this incident like it was yesterday. I was sweating and had an awful pain in my lower back that kept me out of my chair. I had very severe discomfort in my upper abdomen that was not an ordinary stomach pain. At that moment I knew I was struggling health-wise. I was feeling so weak and so out of balance, things I had never felt or experienced before in my life. After this scary episode, I was rushed to the ER. When I got to the hospital, I was not able to walk, and breathing was very difficult. Even holding my cell phone was a challenge. I was admitted right away due to the fact that my hemoglobin was very low among other things. After a bunch of blood transfusions, IV treatments, and everything in between, the doctors were able to stabilize my condition. After a week I was released from the hospital and started what I called ‘My Health Crisis Path’.


I started to see an Oncologist/Hematologist on a regular basis. One year later, I was rushed to the ER once again. At first the doctors thought I was pre-menopausal and that was the cause of the anemia.  No, it wasn’t!  The severe night sweats, the awful skin itching, especially after taking a shower, the painful feet, and leg cramps at night while in bed, and the severe anemia, were all part of a few of the new symptoms I was experiencing. Overall, my health was not improving, and I was feeling weaker every day. After a year and a half of trying new treatments with no diagnosis, the Oncologist/Hematologist team decided that the next step for me was a bone marrow biopsy. Everything became crystal clear with my ‘Jak 2 Mutation’ and the finding of Primary Myelofibrosis (MF).  

 

This health crisis of mine impacted me and my entire family.  My husband got so overwhelmed he even lost his job. I was forced to resign from my job and my husband losing his caused a great struggle financially. It was okay, and we managed together as a family, but having him by my side every step of the way was more important and something money can’t buy.

 

On the other hand, my daughter, who was only 14, felt like she was losing her mom. She reached rock bottom not only emotionally but academically.  Today I can say joyfully my daughter is now 21 years old and is a successful college student attending a State University. Through all of this, we saw a psychiatrist and had a few counseling sessions in order to help us individually and as a family cope with this unexpected health crisis. It has helped us with the healing and moving forward process.  Our daughter once said: “We are a family no one left behind.”

 

I used to donate blood and today I am on the other side of the chair. My driver’s license even says that I am an organ donor. Slowly but surely, I started to accept the fact that I suffered from a rare chronic blood disorder. I had two options in front of me, either feel sorry for myself and do nothing about it or go out there and make a difference. I chose the second option. It was not an easy task. In the beginning, I felt alone and confused, and I didn’t know where to go for help, support, and answers. When I heard the word ‘cancer’ for the first time it was a feeling I can’t explain. But this didn’t stop me. 

 

Being a former graphic designer, I was used to putting on a creative hat, so I knew what to do next. I began by researching about MPN in general. In the process, I came up with what I called ‘My 4 Daily Elements’: Chemo-Tablet Treatment, Anti-Inflammatory Nutritional Meal Plan, Routine of Exercise, and Mindfulness (I want to point out that when I started this health journey there was not much guidance like there is today). A few years ago, I received a couple of certificates in Modeling and Acting from a local school, so I decided to take advantage and use these tools. This knowledge and experience are my platform for cancer awareness. Today I’m proud to say I’m a member of a Cancer Support Community at the cancer institute in Orlando, FL. I’m also a member of MPN groups on social media. I was interviewed a couple of years ago and an article of my journey was published in Prevention Magazine. What an honor it was being able to speak about this rare and chronic blood disorder. We may be a small group, but our voices can make a big difference.


I am also the voice in the Latino community. I spoke on a local radio station where I was able to bring awareness to Central Florida. In my message I let the listeners understand that talking about cancer doesn’t make you a victim or a weak person, it makes us stronger by informing others. I even asked one of the CSC-Mental Health Therapist to join me for another live radio chat so we could talk about integrative medicine and what it offers the cancer community.

 

Next month, I’m going to attend my first meeting as part of the Patient and Family Advisory Council at Orlando Health. In December I’m also going to be participating in the Sea World 3 Mile Reindeer Run for pediatric cancer and bone marrow transplant programs at AdventHealth for the second year. Sharing my story is very important to me. If I can shed light, hope, and support to others then my mission is accomplished. “ME with a Purpose.”

 

Incyte Announces FDA Approval Of Pemazyre® (Pemigatinib) As The First And Only Targeted Treatment For Myeloid/Lymphoid Neoplasms (MLNs) With FGFR1 Rearrangement

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August 26, 2022 at 10:00am EDT

 

– This marks the second indication for Pemazyre, which received accelerated FDA approval in 2020 for adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement

– Pemazyre is the only FGFR inhibitor with multiple indications

WILMINGTON, Del.–(BUSINESS WIRE)–Aug. 26, 2022– Incyte (Nasdaq:INCY) today announced that the U.S. Food and Drug Administration (FDA) has approved Pemazyre® (pemigatinib), a selective fibroblast growth factor receptor (FGFR) inhibitor, for the treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement. MLNs with FGFR1 rearrangement are extremely rare and aggressive blood cancers that may impact less than 1 in 100,000 people in the United States1.

“The approval of Pemazyre represents an important treatment advancement for people living with MLNs with FGFR1 rearrangement who currently have limited treatment options,” said Hervé Hoppenot, Chief Executive Officer, Incyte. “These are complex hematologic malignancies with a range of presentations, and this approval highlights Incyte’s continued leadership and commitment to advancing care for patients with rare blood cancers.”

A patient with an MLN with FGFR1 rearrangement may present with bone marrow involvement with a chronic myeloid malignancy (such as myeloproliferative neoplasm [MPN], myelodysplastic syndrome/MPN) or a blast phase malignancy (such as B- or T-cell acute lymphoblastic leukemia/lymphoma, acute myeloid leukemia or mixed phenotype acute leukemia). Bone marrow involvement may or may not be accompanied by extramedullary disease (EMD); some patients may present with EMD only. MLNs with FGFR1 rearrangement are caused by chromosomal translocations involving the FGFR1 gene, with various partner genes resulting in constitutive activation of the FGFR1 receptor tyrosine kinase, impacting cell differentiation, proliferation and survival2. Patients often relapse because existing first-line therapies sometimes fail to induce durable clinical and cytogenetic responses.

The FDA approval was based on data from the Phase 2 FIGHT-203 study, a multicenter open-label, single-arm trial that evaluated the safety and efficacy of Pemazyre in 28 patients with relapsed or refractory MLNs with FGFR1 rearrangement. Patients could have relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or after a disease modifying therapy or were not a candidate for allo-HSCT or other disease modifying therapies.

  • Study participants included patients with documented MLNs with an 8p11 translocation on conventional cytogenetics and/or an FGFR1 rearrangement on break-apart FISH testing. (An FDA-approved test for detection of FGFR1 rearrangement in patients with relapsed or refractory MLNs is not available.)
  • In patients with chronic phase in the marrow with or without EMD (N = 18), the complete response (CR) rate was 78% (14/18; 95% CI 52, 94). The median time to response of CR was 104 days (range, 44 to 435 days). The median duration of CR was not reached (range, 1+ to 988+ days).
  • In patients with blast phase in the marrow with or without EMD (N = 4), two patients achieved a CR (duration: 1+ and 94 days).
  • In patients with EMD only (N = 3), one patient achieved a CR (duration: 64+ days).
  • For all patients (N = 28 including three patients without evidence of morphologic disease) the complete cytogenetic response rate was 79% (22/28; 95% CI: 59, 92).

The most common (≥ 20%) adverse reactions were hyperphosphatemia (74%), nail toxicity (62%), alopecia (59%), stomatitis (53%), diarrhea (50%), dry eye (50%), fatigue (44%), rash (35%), abdominal pain (35%), anemia (35%), constipation (32%), dry mouth (32%), epistaxis (29%), retinal pigment epithelial detachment (26%), extremity pain (26%), decreased appetite (24%), dry skin (24%), dyspepsia (24%), back pain (24%), nausea (21%), blurred vision (21%), peripheral edema (21%) and dizziness (21%).

“In patients with relapsed or refractory MLNs with FGFR1 rearrangement treated with Pemazyre in FIGHT-203, the high rate of complete response and complete cytogenetic response in patients with chronic phase disease and the high rate of complete cytogenetic response in patients with blast phase disease is clinically meaningful, especially in light of the lack of these specific responses with existing first-line treatments,” said Dr. Srdan Verstovsek, M.D., Ph.D., Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, and principal investigator for the FIGHT-203 study.

The supplemental New Drug Application (sNDA) for Pemazyre for the treatment of adults with relapsed or refractory MLNs with FGFR1 rearrangement was reviewed by the FDA under Priority Review. The FDA grants Priority Review to medicines that may offer a major advance in treatment where none currently exists. The designation shortens the review period to six months compared to 10 months for Standard Review.

Incyte established its leadership in rare blood cancers more than 10 years ago with the development of the first JAK inhibitor approved by the FDA for the treatment of certain patients with myelofibrosis and polycythemia vera. Incyte continues to research additional pathways to address rare blood cancers through its LIMBER (Leadership In MPNs Beyond Ruxolitinib) clinical development program, designed to evaluate multiple therapies and investigational strategies to improve and expand treatments for patients living with MPNs and other related hematologic malignancies and conditions.

Incyte is committed to supporting patients and removing barriers to access medicines. Eligible patients in the U.S. who are prescribed Pemazyre have access to IncyteCARES (Connecting to Access, Reimbursement, Education and Support), a comprehensive program offering personalized patient support, including financial assistance and ongoing education and additional resources. More information about IncyteCARES is available by visiting www.incytecares.com or calling 1-855-452-5234.

About FIGHT-203
FIGHT-203 is a Phase 2, multicenter trial that enrolled patients 18 years and older with myeloid/lymphoid neoplasms (MLNs) with a fibroblast growth factor receptor 1 (FGFR1) rearrangement. Sponsored by Incyte, the study evaluated the safety and efficacy of pemigatinib for the treatment of adults with MLNs with FGFR1 rearrangement. Patients received pemigatinib 13.5 mg once daily in 21-day cycles, either on a continuous schedule (the approved recommended starting dosage for use in patients with MLNs with FGFR1 rearrangement) or as an intermittent schedule (14 days on, 7 days off, an unapproved dosage regimen in MLN with FGFR1 rearrangement). Pemigatinib was administered until disease progression or unacceptable toxicity or until patients were able to receive allo-HSCT. For more information about the study, please visit https://clinicaltrials.gov/ct2/show/NCT03011372.

About Pemazyre® (pemigatinib)
Pemazyre, a fibroblast growth factor receptor (FGFR) inhibitor, is the first targeted treatment approved for use in the United States for treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with FGFR1 rearrangement.

Pemazyre is also indicated for the treatment of adults with relapsed or refractory previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement as detected by an FDA-approved test. This indication is approved under accelerated approval based on overall response rate and duration of response (DOR). Continued approval may be contingent on verification and description of clinical benefit in a confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

Ocular Toxicity
Retinal Pigment Epithelial Detachment (RPED): PEMAZYRE can cause RPED, which may cause symptoms such as blurred vision, visual floaters, or photopsia. Clinical trials of PEMAZYRE did not conduct routine monitoring including optical coherence tomography (OCT) to detect asymptomatic RPED; therefore, the incidence of asymptomatic RPED with PEMAZYRE is unknown.

Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, RPED occurred in 11% of patients, including Grade 3-4 RPED in 1.3%. The median time to first onset of RPED was 56 days. RPED led to dose interruption of PEMAZYRE in 3.1% of patients, and dose reduction and permanent discontinuation in 1.3% and in 0.2% of patients, respectively. RPED resolved or improved to Grade 1 levels in 76% of patients who required dosage modification of PEMAZYRE for RPED.

Perform a comprehensive ophthalmological examination including OCT prior to initiation of PEMAZYRE and every 2 months for the first 6 months and every 3 months thereafter during treatment. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of PEMAZYRE. Modify the dose or permanently discontinue PEMAZYRE as recommended in the prescribing information for PEMAZYRE.

Dry Eye: Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, dry eye occurred in 31% of patients, including Grade 3-4 in 1.6% of patients. Treat patients with ocular demulcents as needed.

Hyperphosphatemia and Soft Tissue Mineralization
PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Increases in phosphate levels are a pharmacodynamic effect of PEMAZYRE. Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, hyperphosphatemia was reported in 93% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 8 days (range 1-169). Phosphate lowering therapy was required in 33% of patients receiving PEMAZYRE.

Monitor for hyperphosphatemia and initiate a low phosphate diet when serum phosphate level is >5.5 mg/dL. For serum phosphate levels >7 mg/dL, initiate phosphate lowering therapy and withhold, reduce the dose, or permanently discontinue PEMAZYRE based on duration and severity of hyperphosphatemia as recommended in the prescribing information.

Embryo-Fetal Toxicity
Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm when administered to a pregnant woman. Oral administration of pemigatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 13.5 mg.

Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.

Adverse Reactions: Cholangiocarcinoma
Serious adverse reactions occurred in 45% of patients receiving PEMAZYRE (n=146). Serious adverse reactions in ≥2% of patients who received PEMAZYRE included abdominal pain, pyrexia, cholangitis, pleural effusion, acute kidney injury, cholangitis infective, failure to thrive, hypercalcemia, hyponatremia, small intestinal obstruction, and urinary tract infection. Fatal adverse reactions occurred in 4.1% of patients, including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received PEMAZYRE. Adverse reactions requiring permanent discontinuation in ≥1% of patients included intestinal obstruction and acute kidney injury.

Dosage interruptions due to an adverse reaction occurred in 43% of patients who received PEMAZYRE. Adverse reactions requiring dosage interruption in ≥1% of patients included stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, fatigue, abdominal pain, AST increased, asthenia, pyrexia, ALT increased, cholangitis, small intestinal obstruction, alkaline phosphatase increased, diarrhea, hyperbilirubinemia, electrocardiogram QT prolonged, decreased appetite, dehydration, hypercalcemia, hyperphosphatemia, hypophosphatemia, back pain, pain in extremity, syncope, acute kidney injury, onychomadesis, and hypotension.

Dose reductions due to an adverse reaction occurred in 14% of patients who received PEMAZYRE. Adverse reactions requiring dosage reductions in ≥1% of patients who received PEMAZYRE included stomatitis, arthralgia, palmar-plantar erythrodysesthesia syndrome, asthenia, and onychomadesis.

Clinically relevant adverse reactions occurring in ≤10% of patients included fractures (2.1%). In all patients treated with pemigatinib, 0.5% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N = 635]). Soft tissue mineralization, including cutaneous calcification, calcinosis, and non-uremic calciphylaxis associated with hyperphosphatemia were observed with PEMAZYRE treatment.

Within the first 21-day cycle of PEMAZYRE dosing, serum creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, and then decreased during the 7 days off therapy. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

In cholangiocarcinoma (n=146) the most common adverse reactions (incidence ≥20%) were hyperphosphatemia (60%), alopecia (49%), diarrhea (47%), nail toxicity (43%), fatigue (42%), dysgeusia (40%), nausea (40%), constipation (35%), stomatitis (35%), dry eye (35%), dry mouth (34%), decreased appetite (33%), vomiting (27%), arthralgia (25%), abdominal pain (23%), hypophosphatemia (23%), back pain (20%), and dry skin (20%).

Adverse Reactions: Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement

Serious adverse reactions occurred in 53% of patients receiving PEMAZYRE at all dosages (n=34). Serious adverse reactions in > 5% of patients included acute kidney injury. Fatal adverse reactions occurred in 9% of patients who received PEMAZYRE, including acute kidney injury, multiple organ dysfunction syndrome, and malignant neoplasm progression, occurring in one patient each.

Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received PEMAZYRE at all dosages. Adverse reactions requiring permanent discontinuation included cardiac failure, multiple organ dysfunction syndrome, blood alkaline phosphatase increase, and calciphylaxis. In patients who started treatment on the recommended dosage (n = 20), adverse reactions requiring dosage interruption of PEMAZYRE occurred in 80% of patients. Adverse reactions which required dosage interruption in > 2 patients treated at the recommended dosage included nail toxicities (20%) and hyperphosphatemia (15%).

Dose reductions of PEMAZYRE due to an adverse reaction occurred in 80% of patients who started treatment on the recommended dosage. Adverse reactions requiring dose reductions occurring in > 2 patients were nail toxicities (20%), hyperphosphatemia (20%), and alopecia (15%).

The most common (≥ 20%) adverse reactions were hyperphosphatemia (74%), nail toxicity (62%), alopecia (59%), stomatitis (53%), diarrhea (50%), dry eye (50%), fatigue (44%), rash (35%), abdominal pain (35%), anemia (35%), constipation (32%), dry mouth (32%), epistaxis (29%), retinal pigment epithelial detachment (26%), extremity pain (26%), decreased appetite (24%), dry skin (24%), dyspepsia (24%), back pain (24%), nausea (21%), blurred vision (21%), peripheral edema (21%), and dizziness (21%).

Drug Interactions

Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. Reduce the dose of PEMAZYRE if concomitant use with a strong or moderate CYP3A inhibitor cannot be avoided. Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE.

Special Populations
Advise lactating women not to breastfeed during treatment with PEMAZYRE and for 1 week after the last dose.

Reduce the recommended dose of PEMAZYRE for patients with severe renal impairment as described in the prescribing information.

Reduce the recommended dose of PEMAZYRE for patients with severe hepatic impairment as described in the prescribing information.

Please see Full Prescribing Information for PEMAZYRE.

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.

You may also report side effects to Incyte Medical Information at 1-855-463-3463.

 

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Paving the way to improve therapy for Myeloproliferative Neoplasms

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Megan Bywater & Steven W. Lane

Nature Communications 13, Article Number: 5052 (2022)

 

Long-acting IFNα induces durable molecular responses in myeloproliferative neoplasms. Emerging studies, including Saleiro et al. recently published in Nature Communications, have identified promising candidates that may synergise with IFNα by targeting stem cell function or feedback loops that mediate treatment resistance.

Clinical management in Myeloproliferative Neoplasms

The MyeloProliferative Neoplasms (MPN) are characterised by the excess production of phenotypically normal mature myeloid cells or cell products, specifically red blood cells in polycythemia vera (PV), megakaryocytes and platelets in essential thrombocythemia (ET) and additional cytokine driven fibro-cellular infiltration of the bone marrow in primary myelofibrosis (PMF)1. This expansion of mature myeloid cell populations is driven by the constitutive activation of the JAK-STAT signalling pathway in committed myeloid progenitors as a consequence of mutations in either JAK2, MPL or CALR1. However, although this disease is phenotypically driven from expanded committed myeloid progenitor cell compartments, these populations remain untransformed as they lack the capacity for long-term self-renewal. As a consequence, MPN-driving mutations must be maintained within the haematopoietic stem cell (HSC) compartment2.

MPNs are long-term chronic conditions and patient management is focussed on ameliorating the symptoms related to clinical pathologies1. Current approaches are limited by toxicity of long-term treatments that have little disease modifying activity and do not prevent transformation to more aggressive diseases such as leukaemia. Venesection leads to iron restricted erythropoiesis and is intended to reduce the expanded mature red blood cell population. To a similar end, hydroxycarbamide (also known as hydroxyurea) is frequently used for cytoreduction to control erythrocytosis and thrombocytosis with a concomitant effect on reducing thrombotic tendency. More recently, small molecule inhibitors of JAKs have been developed to target the signalling pathway hyperactivated in this disease. Unfortunately, current studies indicate that the MPN stem cell pool is not reliant on the constitutive activation of JAK2 for survival3. Consequently, JAK1/2 inhibitors like Ruxolitinib have proven effective at reducing the excess production of mature myeloid cells, inflammatory cytokine levels and the associated clinical symptoms in MPN, but have had limited efficacy in reducing the size of the MPN stem cell pool3. Therefore, long-term disease management via targeted JAK2 inhibition will most likely require chronic administration of these compounds, the practicality of which can be limited by significant side effects.

Disease progression to secondary myelofibrosis (sMF) or acute myeloid leukaemia (sAML) occurs in ~8–20% and 8–26% of patients with ET and PV respectively over a 20-year period1 and is related to an expanded mutational spectrum4. Importantly, clinical outcomes subsequent to disease progression are poor on account of limited effective treatment options. In the case of sMF and MPN-driver-positive sAML, it is assumed that transformation is driven by the selective pressure provided by the MPN-driving oncogene. Considering this, it would seem the most rational approach for the clinical management of MPN is the development of treatment options that selectively target the MPN stem cell pool to decrease both the burden of the chronic management of this disease and prevent the deleterious outcomes related to disease progression.

Long-acting IFNα induces durable responses in MPN

Recent years have seen a renaissance in the use of interferon alpha (IFNα) for the treatment of MPN, specifically PV and ET. Initially, the use of IFNα was rationalised on the basis of its known myelosuppressive effects with several groups also postulating an immunostimulatory role of these agents. The clinical uptake of IFNα therapy was initially hampered by low compliance related to a poor pharmacokinetic profile of unmodified recombinant forms. More recently, pegylated versions of IFNα have been found to be more persistent in vivo, extending the duration of response and allowing a longer interval between doses. Several studies have now compared long-acting pegylated IFNα with hydroxycarbamide in inducing durable long-term haematological responses5,6,7, including the normalisation of red blood cell counts and the prevention of thromboembolic events, with the advantage of also being non-leukemogenic. Importantly, IFNα therapy has also proven effective at targeting the MPN stem cell pool with durable molecular remissions also being observed across multiple studies5,6,7.

Mechanistically, IFNα drives cell cycle entry in HSCs with this mitogenic effect being more potent in Jak2-mutant HSCs3,8 supporting a prevailing hypothesis that molecular remissions observed in PV patients receiving IFNα are due to the preferential functional decline of the MPN stem cell pool. Despite its appreciable clinical success, it is clear that the selectivity of IFNα for mutant MPN stem cells over normal stem cells is mild. Consequently, there is an active field of interest looking to understand this selectivity and exploit it through combination therapies. Recently published in Nature Communications, Saleiro et al.9 further elucidates the ability of IFNα to activate a PKCd-ULK1-p38 MAPK signalling cascade that acts in parallel to STAT1 to drive transcription of interferon response genes (IRGs) and that genetic disruption of this pathway can attenuate the ability of IFNα to reduce self-renewal in malignant erythroid precursors. In demonstrating that ULK1 preferentially associates with the activated forms of ROCK1/2 and that IFNα also drives ROCK1/2 activation, they postulate whether modulating ROCK1/2 activity directly may also affect cellular responses to IFNα. In support of this, they demonstrate that both genetic and pharmacological inhibition of ROCK1/2 can enhance the ability of IFNα to reduce cell viability in JAK2-mutant cell lines and self-renewal in PV patient erythroid precursors9. It will be important to determine whether this combination will have enhanced selectivity in the targeting of MPN stem cells over normal stem cells.

Another intriguing combinatorial approach to enhance MPN stem cell selectivity exploits the higher basal levels of PML-nuclear bodies (NB) present in JAK2V617F HSCs10. Arsenic trioxide (ATO) is the standard of care in acute promyelocytic leukaemia and acts in part through degradation of the driving oncogene PML/RAR alpha. ATO can also drive PML-NB formation, which has been shown to be tumour suppressive. Notably, PML is also an IRG, with the combination of IFNα and ATO proving highly effective in preferentially increasing PML-NB formation in Jak2-mutant stem cells and reducing their capacity to transplant disease10. Perhaps counterintuitive is the combination of IFNα with the JAK1/2 inhibitor Ruxolitinib, which clearly has clinical activity, although trials have been limited by toxicity11. Although both agents have potent activity against JAK2V617F MPN, JAK1 kinase activity is required for IFNα-mediated phosphorylation and activation of STAT1. Interestingly, despite being able to robustly inhibit STAT1 phosphorylation in LT-HSCs in response to IFNα in vitro, Ruxolitinib effects only minimal attenuation of STAT1 phosphorylation and cell cycle entry of LT-HSCs in response to IFNα in vivo3. These data suggest this combination may be able to exploit the MPN stem cell-selective effects of IFNα in addition to the anti-proliferative and anti-inflammatory effects of Ruxolitinib on MPN myeloid precursors and committed cells.

Evolving resistance to IFNα mediated by alternate signalling pathways

Saleiro et al.9 also postulate the utility of identifying biomarkers of IFNα treatment response in the clinical management of MPN. They show that the hyperactivation of the PKCd-ULK1-p38 MAPK pathway may enhance the therapeutic response to IFNα treatment in MPN, in that increased expression of ULK1 and p38 MAPK mRNA correlates with haematological responses in a combined cohort of IFNα-treated PV and ET patients. Consistent with this, a number of genetic determinants of IFNα treatment response are emerging. Notably, despite the convergent mechanistic pathways of MPN-driver mutations, it appears that the ability of IFNα to deplete the MPN stem cell clone is largely restricted to patients with JAK2V617F mutations, and that CALR mutant MPN is less likely to achieve molecular remissions in response to pegylated IFNα therapy, despite achieving similar outcomes in terms of haematological responses12,13. Early studies also indicate that DNMT3A mutations are enriched after IFNα treatment, suggesting a possible association of this mutation with IFNα resistance in patients14. As such, we must consider how molecular responses to MPN therapies may be modified by the growing list of concomitant mutations in this disease4,15. To achieve this it is imperative that recent large cohort studies comparing the efficacy of IFNα therapy to standard of care should be combined with Next Generation Sequencing analysis of pathogenic loci, to determine what concomitant mutations are associated with IFNα treatment outcomes. This is important as, in the long-term, concomitant mutations in genes, including TP53, EZH2 and ASXL1, confer a higher risk of disease transformation to phenotypes with poor clinical outcomes, such as MF and AML1. Consequently, these studies are vital for determining the potential of IFN therapy to delay or prevent disease progression.

Conclusions

In summary, the clinical management of patients with MPN has been dominated by three main approaches: chemotherapy for cytoreduction, targeted JAK2 inhibition or long-acting IFNα analogues. Although all are highly effective, to date none have shown the sustained ability to modify the natural history of disease and prevent transformation to sAML or sMF. Long-acting pegylated IFNα is the only therapy to show reliable and deep molecular responses, but requires long-term treatment and is often limited by toxicity. Studies, like Saleiro et al., have identified promising candidates that may synergise with IFNα by targeting stem cell function or feedback loops that mediate treatment resistance. The next phase of clinical studies should address rational combinations and the contribution of concomitant mutations to treatment response, with ambitious clinical endpoints, including molecular remission, treatment free remission and prevention of disease transformation.

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Pelabresib and Ruxolitinib Combination Proves Durable in Patients With Myelofibrosis

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Targeted Therapies in Oncology, August 2022, Volume 11, Issue 11

Results from the MANIFEST study of pelabresib and ruxolitinib in myelfibrosis are positive. The phase MANIFEST-2 study continue to explored the combination in JAK inhibitor–naïve patients with myelofibrosis.

The combined use of pelabresib (CPI-0610) and ruxolitinib (Jakafi) demonstrated durable responses beyond week 24 in patients with myelofibrosis who experienced a suboptimal response to ruxolitinib and in those who were JAK inhibitor naïve, according to preliminary data from arms 2 and 3 of the phase 1/2 MANIFEST trial (NCT02158858).1

Findings, which were presented during the 2022 European Hematology Association Congress, showed that 68% (95% CI, 57%-78%) of patients with JAK inhibitor–naïve myelofibrosis (n = 84; arm 3) experienced a reduction in spleen volume of at least 35% (SVR35) at week 24 with the combination. Eighty percent of patients achieved this at any point in the study, and 69% of those with SVR35 maintained response at the time of data cutoff. Moreover, 56% (95% CI, 45%-67%) of patients in this arm experienced a 50% or greater reduction in total symptom score (TSS) from baseline at week 24, resulting in a median TSS change of –59% at this time point.

In patients with myelofibrosis who had previously experienced a suboptimal response to ruxolitinib (n = 81; arm 2), 20% experienced SVR35 at week 24; this was observed in 17% of those who were transfusion dependent (TD) and 26% of those who were non–transfusion dependent (NTD). Additionally, 30% of patients achieved SVR35 at any time point. A 25% or higher SVR from baseline by week 24 was noted in 27% of patients. The median SVR was –18%. The addition of pelabresib to ruxolitinib positively affected symptoms in these patients, as well. The TSS50 at week 24 was 37%; this rate was 36% in TD patients and 39% in NTD patients, with a median symptom burden reduction of –47%.

“The combination of pelabresib and ruxolitinib was generally well tolerated, and preliminary results showed durable improvements in splenomegaly and symptom burden, with associated biomarker results suggesting potential disease-modifying activity,” said Claire Harrison, MD, FRCP, FRCPath, lead study author and professor of myeloproliferative neoplasms at Guy’s and St. Thomas’ NHS Foundation Trust in London, England, during a presentation of the data.

Setting the Stage

The JAK inhibitor ruxolitinib serves as the current standard of care for patients with myelofibrosis who are not candidates for hematopoietic stem cell transplant. However, JAK inhibitors are associated with limited efficacy and high discontinuation rates due to toxicities. As such, a large unmet need remains for the treatment of these patients with this disease.

The BET inhibitor pelabresib downregulates the expression of genes that contribute to the heterogenous features of the pathology of myelofibrosis, including aberrant erythroid and megakaryocytic differentiation, according to Harrison. Preclinical data have suggested that the combination of BET and JAK inhibitors could have synergistic activity in this disease.

In the ongoing, global, open-label MANIFEST study, investigators sought to further evaluate pelabresib in patients with myelofibrosis and essential thrombocythemia. The trial was composed of 4 arms.

Arm 1 included patients with myelofibrosis who were no longer on ruxolitinib and who would receive pelabresib monotherapy in the second-line setting. Those in arm 4 had highrisk, essential thrombocythemia and were resistant to or intolerant of hydroxyurea (Hydrea).

Patients in arm 2 were given pelabresib as an “add on” to ruxolitinib; these patients had achieved a suboptimal response with ruxolitinib or experienced disease progression. Those in this arm were further divided into 2 cohorts: patients who were TD (n = 59; cohort 2A) and those who were NTD (n = 27; cohort 2B). The primary end point in cohort 2A was conversion of TD to transfusion independence (TI), and key secondary end points included SVR35 and TSS50. For cohort 2B, the primary end point was SVR35, and a key secondary end point was TSS50.

Patients enrolled in arm 3 did not previously receive a JAK inhibitor and were considered to have intermediate-2 or high-risk disease by the Dynamic International Prognostic Scoring System (DIPSS). These patients received the combination of pelabresib and ruxolitinib in the first-line setting. Here, the primary end point was SVR35 and the secondary end point was TSS50.

“Both these [groups of] patients have over 80 patients in them, and I just want to highlight that the vast majority were intermediate-2 or high-risk by DIPSS,” Harrison explained. “They represent a high-risk cohort, with more than 50% of patients—two-thirds on arm 3 and nearly 80% on arm 2—being anemic already. Spleen volumes were large and concerning and over half of patients in both arms had high molecular risk mutations.”

Delving Into the Data

Additional data showed that within arm 2, 16% of 38 patients in cohort 2A converted from TD to TI. Moreover, 22% of 27 patients in cohort 2B were found to experience a hemoglobin response, defined as a post-baseline mean increase of at least 1.5 g/dL, which is required for any 12 weeks’ red blood cell transfusion-free period.

Notably, durable SVR was observed over time in both arms 3 and 2. “In the JAK inhibitor–naïve patients, [we saw] progressive reduction in spleen volume,” Harrison noted. “Spleen volume reduction over time [was also observed] in the second-line [patients].”

For arm 3, the median treatment duration of pelabresib plus ruxolitinib was not yet reached (95% CI, 19.2-not reached), and the median follow-up time was 21.8 months (95% CI, 21.2-22.5). In arm 2, the median treatment duration with pelabresib add-on to ruxolitinib was 14.0 months (95% CI, 8.4- 20.6), and the median follow-up time was 24.4 months (95% CI, 23.0-30.7).

Additional analyses revealed improvements in bone marrow fibrosis grade following 24 weeks of treatment by central pathology review. Specifically, 28% of patients in arm 3 (n = 57) and 26% of those in arm 2 (n = 47) experienced an improvement of at least 1 grade at this time point. Notably, these responses proved to be durable, with 56% and 50% of patients, respectively, maintaining their bone marrow fibrosis improvement at the next available assessment or beyond. Overall, at any time in the study, 40% and 39% of patients, respectively, achieved at least a 1-grade improvement in bone marrow fibrosis.

Utilizing digital pathology, investigators further evaluated features of the bone marrow biopsy. Again, improvements in bone marrow fibrosis were observed, with an increase in erythrocytes and a decrease in megakaryocyte clusters.

“Clustering of megakaryocytes is a key pathological feature in this disease. We saw that over 40% of patients in arm 2 and over 50% of patients in arm 3 experienced a 15% reduction in clustering of megakaryocytes,” Harrison said. “Megakaryocyte ‘de-clustering’ in the bone marrow was correlated with SVR35 response.”

A cytokine analysis was performed on paired plasma samples, and investigators noted decreased plasma levels of myelofibrosis-associated or inflammation-related cytokines in patients enrolled in arms 2 and 3.

A reduction in JAK2 variant allele frequency (VAF) and bone marrow fibrosis observed with pelabresib plus ruxolitinib was seen in patients within arm 3. “[With regard to] JAK2 V617F VAF reduction, a 20% reduction was attained by over one-third of patients, at only week 24 in the study,” Harrison said. “Regardless of the baseline VAF, there was a reduction in JAK allele burden. [Bone marrow fibrosis grade change] occurred in patients regardless of whether they had a spleen volume response or not, but there seems to be a nice correlation across all these different dimensions of this disease.”

Safety Statistics

Regarding safety, in the JAK inhibitor–naïve patients, the most common hematologic treatment-emergent adverse effects (TEAEs) experienced with the combination were anemia (all grade, 42%; grade 3, 33%; grade 4, 1%) and thrombocytopenia (all grade, 52%; grade 3, 8%; grade 4, 4%). Gastrointestinal (GI) events were noted to be mostly low grade; they included diarrhea (all grade, 35%; grade 3, 1%), constipation (all grade, 25%), nausea (all grade, 24%), and abdominal pain (23%).

A total of 5 grade 5 TEAEs were reported, and they included COVID-19 (n = 1), multiorgan failure due to sepsis secondary to infections (n = 2), and acute respiratory distress syndrome because of ruxolitinib withdrawal (n = 2). The investigators determined that none were related to pelabresib except in the case of the patient who experienced multiorgan failure due to sepsis secondary to pneumonia.

Among those in arm 2 who had previously experienced a suboptimal response to ruxolitinib, serious AEs reported in 3 or more patients included anemia (n = 6), respiratory tract infections (n = 4), and urinary tract infections (n = 3). “Similar data were observed in this tougher cohort of patients in the second-line setting with thrombocytopenia and anemia representing grade 3 and 4 events,” Harrison said. Twenty patients experienced TEAEs that resulted in the discontinuation of pelabresib. “Grade 3 GI events are not common causes for discontinuation and are easily managed,” Harrison added. A total of 7 grade 5 TEAEs occurred in patients within this arm, and included acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage, disease progression, transformation to acute myeloid leukemia, congestive heart failure, and suspected lung cancer. All TEAEs, except for acute kidney injury, were determined to not be associated with pelabresib.

The double-blind, phase 3 MANIFEST-2 trial (NCT04603495), which is evaluating pelabresib plus ruxolitinib compared with placebo and ruxolitinib in JAK inhibitor–naïve patients with myelofibrosis, has been initiated and is open for enrollment.

 

REFERENCE:

1. Mascarenhas J, Kremyanskaya M, Patriarca A, et al. BET inhibitor pelabresib (CPI-0610) combined with ruxolitinib in patients with myelofibrosis––JAK inhibitor-naïve or with suboptimal response to ruxolitinib––preliminary data from the MANIFEST study. Presented at: European Hematology Association 2022 Congress; June 9-12, 2022; Vienna, Austria. Abstract S198.

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