A Patient Story: A Physician Shares his MPN Diagnosis

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By Dr. Howard S.
The biggest burden I experience with my diagnosis of secondary (post PV) myelofibrosis, 21 months ago, is anxiety for my future. I am a family physician, so I knew what it meant when I no longer needed to phlebotomize after a
20-year run with polycythemia vera. For the last 10 years I injected Pegasys weekly at the top dose without any side effects and excellent control of my platelet and white blood cell count. I still required phlebotomies four times a year, but I was always saying that I am grateful to still be “proliferating!” Unlike many who struggle with myelofibrosis, I am physically asymptomatic, if you consider an hour of strenuous exercise every day (swim a mile, run 5 miles or bike 26 miles) as asymptomatic. I experience no itching and I continue to work full-time. But the question is always, “when will the other shoe drop?”

My counts are stable, no anemia, no thrombocytopenia (low platelets) and I am a “rare bird” with a diagnosis of chronic lymphocytic leukemia, also stable requiring no therapy at this time.  I did have one significant physical finding and that is an enlarged spleen known as splenomegaly. I can feel it and yet it does not interfere with my appetite or activities. I say “did” because after many months of visiting numerous East Coast MPN specialists, I decided to begin a Jak2 inhibitor at a moderate dose of 10 mg twice daily. Almost immediately my spleen decreased in size and again I am fortunate to not experience any untoward side effects. I am, of course, aware of the literature that suggests that Jak2 inhibitors may predispose to an increased number of unfavorable mutational changes but my MPN specialist does not support that viewpoint.

I have also been advised that someday in this Jak2 inhibitor may lose its beneficial effect for me and at that time (barring new advancements) I will likely need to proceed with an allogeneic stem cell transplant. Father time is not in my favor. Transplants for those over 70 years old are risky at best and in 3 months I turn 65. Even now, the data suggest a 20 percent mortality in the first year, that means one ini five people die. So pulling the trigger on a transplant is a monumental decision. Oh well…

For now, I feel well and try really hard to believe that my future will work out well for me. Because really, in the final analysis, what other choice do I have?

 

 

 

FDA approves ruxolitinib for chronic graft-versus-host disease

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On September 22, 2021, the Food and Drug Administration approved ruxolitinib (Jakafi, Incyte Corp.) for chronic graft-versus-host disease (cGVHD) after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older.

Efficacy was evaluated in REACH-3 (NCT03112603), a randomized, open-label, multicenter clinical trial of ruxolitinib compared to best available therapy (BAT) for corticosteroid-refractory cGVHD after allogeneic stem cell transplantation. The trial randomized 329 patients (1:1) to receive either ruxolitinib 10 mg twice daily or BAT.

The major efficacy outcome used to support approval was overall response rate (ORR) (2014 NIH Response Criteria) through cycle 7 day 1. The ORR was 70% (95% CI 63%, 77%) for the ruxolitinib arm and 57% (95% CI 49%, 65%) for the BAT arm with a difference in response rate of 13% (95% CI 3%, 23%). The median durations of response, calculated from first response to progression, death, or new systemic therapies for chronic GVHD, were 4.2 months (95% CI 3.2, 6.7) and 2.1 months (95% CI 1.6, 3.2) for the ruxolitinib and BAT arms, respectively. The median times from first response to death or new systemic therapies for cGVHD were 25 months (95% CI 16.8, NE)  and 5.6 months (95% CI 4.1, 7.8) for the ruxolitinib and BAT arms, respectively.

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Protagonist Therapeutics Reports FDA Clinical Hold on Rusfertide Clinical Development Program

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NEWARK, Calif., Sept. 17, 2021 /PRNewswire/ — Protagonist Therapeutics, Inc. (Nasdaq: PTGX) (“Protagonist” or “the Company”) today announced the receipt of a verbal communication from the U.S. Food and Drug Administration (FDA) that Protagonist’s clinical studies for rusfertide, an investigational product candidate currently in development, have been placed on a clinical hold.

The clinical hold follows Protagonist’s notification to the FDA of a recent non-clinical finding in a 26-week rasH2 transgenic mouse model study. The rasH2 model is designed to detect signals related to tumorigenicity, and benign and malignant subcutaneous skin tumors were observed in this study.

The Company is working with the FDA and will be prepared to make all appropriate updates to clinical study documents and determine the next steps in consultation with the FDA. In particular, we will provide additional clinical safety reports, update the investigator brochures and patient informed consent forms, and make necessary modifications to study protocols. Dosing of patients in all ongoing clinical trials with rusfertide will be put on hold, and study investigators have been contacted to facilitate patient notification.

“Patient safety is our absolute top priority,” said Dinesh Patel, President and Chief Executive Officer of Protagonist. “We are fully committed to working closely with the FDA in understanding and evaluating potential clinical risks and determining next steps for the development of rusfertide.”

Genomic Profiling of a Randomized Trial of Interferon-a versus Hydroxyurea in MPN Reveals Mutation-Specific Responses

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Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPN) comprise essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), including prefibrotic myelofibrosis (Pre-MF). MPNs are clonal hematopoietic neoplasms characterized by excessive proliferation of mature hematopoietic cells from one or more of the myeloid lineages. The diseases are associated with an increased risk of thrombohemorrhagic events and reduced life expectancy compared with the general population. ET and PV may progress into post-ET and post-PV myelofibrosis, and all disease entities may transform into secondary acute myeloid leukemia (sAML), which has a dismal prognosis.

The majority of MPNs are driven by somatic mutations in JAK2, CALR, or MPL that arise in the hematopoietic stem cell compartment (ie MPN phenotypic driver mutations). All three MPN phenotypic driver mutations lead to uncontrolled myeloproliferation by constitutive activation of the JAK-STAT signal transduction pathway through ligand-independent activation and hypersensitivity of type I cytokine receptors. Approximately 95-97% of patients with PV and 50-60% of patients with ET or PMF harbor a point-mutation in exon 14 of the JAK2 gene. The remaining 2-3% of PV patients carry mutations in JAK2 exon 12. CALR or MPL mutations are present in the majority of JAK2-negative ET and PMF patients. Approximately 10% of patients with MPN carry none of the three phenotypic driver mutations and are referred to as “triplenegative”.

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Selecting Therapy to Treat MF

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OncLive

Pankit Vachhani, MD: Fedratinib is a JAK2 inhibitor that was recently FDA approved for treatment of patients with myelofibrosis, intermediate-2 and high risk. We consider using this drug either in the frontline space or in a setting where ruxolitinib has previously been used and failed the patient in giving them a long-term benefit.

When a patient is newly diagnosed with myelofibrosis, if their platelet count is higher than 50 x 109 per liter and they happen to be intermediate-2 or high risk in terms of their risk stratification, one could either use ruxolitinib or fedratinib in that setting. A key thing to consider here is the need for an assessment for stem cell transplant. Should a patient progress after using the first JAK2 inhibitor, they could use the alternative JAK2 inhibitor, or consider clinical trials at that point as well.

If, on the other hand, a patient has lower-risk myelofibrosis, the key thing to identify is whether they are symptomatic. For patients who are symptomatic, one could use ruxolitinib to alleviate the patient’s symptoms despite the disease being lower risk in nature. If one should need to use alternative agents, these would include drugs like hydroxyurea or interferon. In the event that the patients have lower-risk myelofibrosis and are asymptomatic, one may choose to monitor the patients every few months to assess their symptomatology, spleen volume or length, and assess their platelet counts.

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Sierra Oncology Signs Exclusive Global In-Licensing Agreement with AstraZeneca for Novel BET Inhibitor to Expand Myelofibrosis Pipeline

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Sierra Oncology Signs Exclusive Global In-Licensing Agreement with AstraZeneca for
Novel BET Inhibitor to Expand Myelofibrosis Pipeline

—Combination study to build upon momelotinib’s differentiated potential as a cornerstone
myelofibrosis therapy-—

SAN MATEO, CA, August 4, 2021 – Sierra Oncology, Inc. (NASDAQ: SRRA), a late-stage biopharmaceutical company on a mission to deliver targeted therapies that treat rare forms of cancer, today announced it has acquired an exclusive global license from AstraZeneca (LSE/STO/NASDAQ: AZN) for AZD5153, a potent and selective BRD4 BET inhibitor with a novel bivalent binding mode. Sierra plans to initiate a Phase 2 study examining momelotinib in combination with AZD5153 in myelofibrosis patients in the first half of 2022.

“This global in-licensing deal is of two-fold importance to Sierra’s long-term strategy. First, it brings another novel compound into the Sierra development pipeline, expanding our opportunity to deliver transformative therapies for patients with rare cancers. Second, it may allow us to enhance and extend our ability to treat myelofibrosis patients, building on momelotinib’s potential as a cornerstone therapy,” said Stephen Dilly, MBBS, PhD, President and Chief Executive Officer at Sierra Oncology.

Inhibitors of the Bromodomain and Extra-terminal Domain (BET protein family consisting of BRD2, BRD3, BRD4 and BRDT) can modify a range of pathological cellular processes, including the initiation and continuation of transcription and cell cycle control. BET inhibition can lead to decreased inflammatory cytokine release, anti-fibrotic activity and reduced mutant cell proliferation, all of which are indicative of disease-modifying effects. Several BET inhibitors are under clinical investigation in multiple solid tumor and hematologic indications, including myelofibrosis.

AZD5153 is a selective BRD4 inhibitor with a novel bivalent binding mode that inhibits both protein bromodomains, resulting in improved potency. Unlike currently available JAK inhibitors, momelotinib is not myelosuppressive, therefore the combination of momelotinib and AZD5153 may provide an efficacy and safety advantage over other JAK inhibitor plus BET inhibitor combinations and allow for prolonged dose intensity and treatment duration. This trial will be designed to provide preliminary proof of concept for a future confirmatory study and support potential additional studies of momelotinib with other novel agents in development for myelofibrosis. Trial initiation is anticipated to begin in the first half of 2022.

Mark Kowalski, MD, PhD, Chief, Early Research and Development at Sierra added, “The combination of JAK inhibition and BET inhibition has been identified as a promising emergent approach for the treatment of myelofibrosis. However, currently available JAK inhibitors are
myelosuppressive, leaving a critical unmet need for patients with anemia or those at risk of developing treatment-emergent anemia. Given momelotinib’s unique mechanism as an inhibitor of ACVR1 / ALK2 in addition to JAK1 and JAK2, we are excited by the potential for improved outcomes for myelofibrosis patients with this promising combination.”

Impaired response to first SARS-CoV-2 dose vaccination in myeloproliferative neoplasm patients receiving ruxolitinib

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American Journal of Hematology

 

Published July 31, 2021

COVID–19, the disease caused by pandemic SARS–CoV–2 infection, had significant impact on patients with hematologic conditions; a meta–analysis involving 3,377 patients with hematologic malignancies who were affected by COVID–19 reported a mortality rate of 34%. A similarly dismal outcome was documented among 175 patients with chronic myeloproliferative neoplasms (MPN), collected in a European observational study, where mortality rate was 30% for the entire cohort, reaching 48% in primary overt myelofibrosis (MF). COVID–19 was also associated with higher incidence of thrombosis in patients with essential thrombocythemia (ET), compared to MF and polycythemia vera (PV) (20% versus 5% for both, respectively). Finally, MPN patients surviving the acute phase may suffer from additional long–term sequelae from COVID-19, that furtherly increase mortality and morbidity.
The JAK1 and JAK2 inhibitor (JAKi) ruxolitinib is approved for the treatment of patients with MF and hydroxyurea resistant/refractory PV. By inhibiting JAK–STAT signaling, ruxolitinib has profound effects on different cell compartments of the immune system, including T cells, natural killer, and dendritic cells, in addition to potently dampening inflammatory cytokine production. These properties have been mechanistically linked to the increased rate of infections in MPN patients receiving ruxolitinib, and, conversely, were explored successfully in the setting of steroid-refractory acute graft versus host disease following allogeneic stem cell transplantation. In the above cited European study in MPN, rapid discontinuation of the drug was implicated in 75% of deaths occurring in the ruxolitinib–treated cohort; these were ascribed to a previously described “discontinuation syndrome”, a potentially fatal complication due to a cytokine storm that follows the abrupt suspension of ruxolitinib. In fact, observational studies support the effectiveness of ruxolitinib to quench the hyperflammatory reaction accompanying COVID–19 in the general population. Due to the immunomodulatory properties of ruxolitinib, the question arises
whether response to vaccination for SARS–CoV–2 in patients under stable ruxolitinib therapy might be impaired.

A Patient Story: The decision to get a Stem Cell Transplant

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Parachuting from a Crippled Plane

 

By Dave D.

My daughter came to Ohio to provide support to me and my wife during my recent stem cell transplant (SCT). In explaining the process to her I used the analogy of parachuting from a crippled airplane and she found it very helpful. I hope that this analogy might also help others understand my experience. Like with parachuting, there are risks there are steps to take. Each step is a small victory, but the ultimate victory is landing safely.

When I was diagnosed with Primary Myelofibrosis in 2013, it became clear that my high-flying airplane (my body) had a problem. It was still possible that it could fly on for years with relatively few problems, but we needed to keep an eye on it. Medications like Jakafi and Inrebic made the flight a bit more pleasant, but blood counts and bone marrow biopsies indicated that we were losing altitude.

This December I realized through consultation with Dr. Aaron Gerds from the Cleveland Clinic that the plane’s problems were becoming unmanageable. I was now High Risk and I was headed for a fatal crash sooner rather than later. It was difficult to say just how long it would take – but our calculator (MIPPS70) predicted about 5 years – give or take.

At that point I needed to decide whether I would take the risks involved in jumping out of the plane or choose to die in the crash. In consultation with my dear wife and my medical team and with the prayers of my friends and family we considered my options. I decided to make the jump.

View Our Recent Stem Cell Transplant Webinar 

Some people cannot find a good donor match – or they have physical problems that would make SCT pointless. But in my case, everything appeared promising. The team at the Cleveland Clinic put me through tests that showed I was relatively fit. They found multiple 10/10 unrelated donor matches for me. We received necessary insurance approvals. We received logistical support from our family, church family and friends for help throughout the process.

Finally everything was in place. I was giving up on the old airplane that was certainly failing and entrusting myself to the parachute for a safe descent and landing.

  1. I got my final approval to go ahead (negative COVID test. 2/16)
  2. I got the notification that the parachute was in hand (the donor cells had been collected and received by Cleveland Clinic. 2/17)
  3. I prepared myself with the equipment make the jump (my Hickman port was installed through my chest up to my heart. 2/18)
  4. I jumped out the door of the plane (I received chemotherapy to kill my defective bone marrow. from 2/19-2/22)
  5. I put on my parachute and pulled the ripcord (The donor cells were infused into my body. Day Zero – 2/24.

The free fall is not very much fun. The chemo continued to kill off my bone marrow and other fast-growing cells and I didn’t feel well. I had some nausea. I felt very tired. My mouth got sore to the point that I could barely swallow and needed to get most meds through my port. Eventually I needed transfusions of whole blood almost every day and platelets every other day.

And there is always the nagging question of whether or not that parachute would actually open! I was very happy when my fall turned around on day +14. That day my WBC finally went up from 0.050 to 0.090. And it continued to gradually climb so that by day +19 I was able to leave the hospital. At that point I had not needed a transfusion in three days, and they canceled my first outpatient transfusion day.

I am now at day +69 and I have not needed any transfusions for 7 weeks! I feel well. I’m able to exercise. I’m down to one Cleveland Clinic visit each week. Every week they tweak my meds – add one, change the dose of another. We keep watch for any sign of infection or of Graft versus Host Disease. (I’m happy to report there’s nothing much to report so far.)

I am doing well and I am very grateful. I am grateful to God who is the source of my life and my salvation. I am grateful to my beloved friends and family for their prayers and their constant encouragement. I am grateful to the all the people at Cleveland Clinic for their expertise and good care for me. And I am very grateful to the donor who provided me with my parachute – I don’t know him but I do know that he is 25 years old, lives somewhere in the USA and goes out of his way to help strangers!

 

Assessing Best Practices in Managing Pregnancy, Myeloproliferative Neuroplasms

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American Journal of Managed Care


Published April 24, 2021
By Matthew Gavidia

Researchers discuss the unique fetal and maternal challenges for pregnant women with myeloproliferative neoplasms, with insight and recommendations provided on the potential benefit of aspirin therapy, cytoreductive therapy, and systemic anticoagulation.

In women with myeloproliferative neoplasms (MPN), pregnancy events have been reported most frequently in those with essential thrombocythemia (ET), followed by polycythemia vera (PV) and primary myelofibrosis (PMF).

As researchers noted in a critical review published in the American Journal of Hematology, MPNs pose unique fetal and maternal challenges, particularly risk of fetal loss. For ET, live birth rate is estimated at 70% with first trimester loss serving as the major complication in these populations, affecting 30%.

“Both pregnancy and MPN impart a hypercoagulable milieu, conferring a heightened risk for thrombosis,” said the authors. “In addition, bleeding diathesis may escalate at the time of delivery and in the postpartum phase, especially in the context of treatment with aspirin and/or low molecular weight heparin.”

With hematological and obstetrical challenges becoming increasingly prevalent for patients with MPNs during pregnancy, researchers sought to review these issues, as well as provide their systematic approach to management.

As they highlighted, it is now well established that patients with PV or ET experience a higher rate of both arterial and venous thrombotic events. However, current thrombotic risk stratification models in MPN have limited applicability in determining pregnancy complications, with risk suggested to be relatively low in those without prior thrombotic events and high if otherwise.

“In regards to thrombotic events, risk of venous thromboembolism is increased 4-fold to 6-fold during pregnancy, with the greatest risk in the post-partum phase,” they wrote.

“Both pregnancy and MPN impart a hypercoagulable milieu, conferring a heightened risk for thrombosis,” said the authors. “In addition, bleeding diathesis may escalate at the time of delivery and in the postpartum phase, especially in the context of treatment with aspirin and/or low molecular weight heparin.”

With hematological and obstetrical challenges becoming increasingly prevalent for patients with MPNs during pregnancy, researchers sought to review these issues, as well as provide their systematic approach to management.

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