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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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Decitabine With or Without Ruxolitinib Shows Benefit in Advanced Phases of MPN

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Oncology Learning Network

When initiated early in the course of the disease, decitabine with or without ruxolitinib has shown clinical benefit in patients with advanced phases of myeloproliferative neoplasms (MPNs; Acta Haematol. 2021;144[1]:48-57).

“Treatment options are limited for patients with advanced forms of [MPN] including blast-phase disease (MPN-BP). Decitabine has frequently been deployed but its efficacy and safety profile are not well described in this population,” wrote Selena Zhou, MD, Icahn School of Medicine at Mount Sinai, New York, and colleagues.

Using data for 42 patients (16 with MPN-BP, 14 with MPN accelerated-phase [MPN-AP], and 12 with myelofibrosis with high-risk features [MF-HR]) treated with decitabine alone or in combination with ruxolitinib, Dr Zhou et al carried out a retrospective review.

According to the review, the median overall survival (OS) for patients with MPN-BP patients was 2.6 months, and 6.7 months for those given ≥2 cycles of decitabine. The patients with MPN-BP and a poor performance status who required hospitalization at the point of decitabine initiation had a dismal prognosis.

Dr Zhou et al reported that the median OS was not reached after a median follow-up of 12.4 months for patients with MPN-AP and 38.7 months for patients with MF-HR patients; 1 and 2 patients in these cohorts were alive at 60 months, respectively.

Furthermore, the likelihood of spleen length being reduced and transfusion independence within 12 months of decitabine initiation was 28.6 and 23.5%, respectively.

Compared with decitabine monotherapy, decitabine plus ruxolitinib improved OS (21 months and 12.9 months, respectively).

“Decitabine, alone or in combination with ruxolitinib, appears to have clinical benefit for patients with advanced phases of MPN when initiated early in the disease course prior to the development of MPN-BP,” Dr Zhou and co-investigators concluded.—Hina Porcelli

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Australian MPN Specialists

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Dr. Kate Burbury, MBBS(Hons) FRACP FRCPA DPhil
Peter MacCallum Cancer Centre, Victoria

Dr Burbury is a consultant haematologist; stream lead for myeloproliferative disorders (MPD)/chronic myeloid leukaemia (CML) and lead clinician for haemostasis, thrombosis and peri-operative optimisation, including pre-habilitation, for all major cancer surgery patients at the VCCC. Kate is a member of professional societies, scientific committees, council member for Haematology Society for Australia and New Zealand, and actively involved in the development of expert guidelines and governance structures for both the institution and external working parties, including European Leukaemia Network: flow cytometry in myelodysplastic syndromes (MDS).

Dr. Wendy Erber, FRCPA FRCPath FAHMS
The University of Western Australia

Professor Erber graduated in Medicine with 1st class honours from the University of Sydney. She undertook her Haematology training at the Royal North Shore Hospital of Sydney and the University of Oxford as a Rhodes Scholar. In Oxford her research led to Doctorate of Philosophy. She has held Consultant Haematologist posts in Western Australia and in Cambridge, UK. From Cambridge she returned to Australia in 2011 to take up the appointment as Chair and Head of the School of Pathology and Laboratory Medicine at the University of Western Australia. In December 2016 she was appointed Pro Vice-Chancellor and Executive Dean of the Faculty of Health and Medical Sciences. Professor Erber continues to be active in diagnostic and translational research in haematology.

Dr. Cecily Forsyth, MBBS FRACP FRCPA
Jarrett Street Specialist Centre, NSW

Dr Forsyth has worked as a clinical haematologist on the Central Coast of NSW for 20 years after training in haematology at Royal Prince Alfred Hospital. She is passionate about improving rural and regional patients’ access to disease information, education and clinical trials, and providing educational opportunities for haematology trainees and haematology nurses. Her main clinical and research interest is myeloproliferative neoplasms and she has collaborated on Australian and International studies in these disorders. She is a member of the ALLG CML and MPN Disease Group Committee and has established the Myeloproliferative Neoplasms Registry (MPN01) on behalf of the ALLG.

Dr. Steven Lane, MBBS, PhD FRACP FRCPA
Royal Brisbane and Women’s Hospital, QLD

Associate Professor Lane is a clinical haematologist interested in all aspects of benign and malignant haematology, with a particular focus on myeloid disorders such as acute myeloid leukaemia, myelodysplasia and myeloproliferative neoplasms. He achieved his medical degree from the University of Queensland and subsequently completed his clinical training at the Royal Brisbane and Women’s Hospital and Princess Alexandra Hospital. As a research head at QIMR Berghofer Medical Research Institute, his lab concentrates on basic science research to discover new treatments for myeloid disorders such as myeloproliferative neoplasm and acute myeloid leukaemia.

Dr. Andrew Lim, MBBS, FRACP, FRCPA
Austin Hospital, Victoria

Dr Andrew Lim is a clinical haematologist at Eastern Haematology Oncology Group and a staff specialist in the Department of Clinical Haematology at Austin Health. Andrew obtained his degree from the University of Melbourne and has trained in haematology at Austin Health, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital. He holds dual Fellowships from the Royal Australasian College of Physicians and the Royal College of Pathologists of Australasia. Andrew has held appointments at Western Health and Dorevitch Pathology.

Dr Lim has experience in all aspects of haematology including laboratory diagnosis of various haematologic conditions; management of haematologic cancers, blood clotting and disorders of iron; and dealing with abnormal blood test results. He also has expertise in bone marrow transplantation.

Dr. David M. Ross, MBBS PhD FRACP FRCPA
SA Pathology, South Australia

Dr Ross is a consultant haematologist at SA Pathology with clinical appointments at the Royal Adelaide Hospital and Flinders Medical Centre in Adelaide, Australia. His PhD was on the topic of minimal residual disease and treatment-free remission in chronic myeloid leukaemia (CML). He has been an investigator in numerous clinical trials, including the landmark COMFORT-1 study of ruxolitinib in myelofibrosis. He supervises the diagnostic haematology service at SA Pathology and is an examiner for the Royal College of Pathologists of Australasia. His clinical and research interests include CML and Ph-negative myeloproliferative neoplasms. He is a Senior Research Fellow in the South Australian Health & Medical Research Institute.

Nobody Wants Cancer. But a ‘Big C’ Label Has Surprising Upsides.

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Source: New York Times

Classifying a rare blood disorder as a cancer opened new doors for disease investigation, treatment and hope for a cure.

By Ruth Fein Revell

I have a rare blood disorder. When it was diagnosed 25 years ago, it was called an “orphan disease,” meaning the small number of people affected didn’t justify research investments by major pharmaceutical companies.

Enter the World Health Organization and its 2008 decision to classify the condition as a blood “cancer.” This opened new doors for disease investigation and understanding. It prompted a growing number of super specialist practitioners, and most important, hope for some 300,000 people living in the United States with what are now called myeloproliferative neoplasms, or MPNs.

Nobody likes to hear a cancer diagnosis, particularly for a disease they thought was benign. In fact, when I first saw my blood disorder referred to as a cancer, I wrote to the MPN Research Foundation, a nonprofit research and advocacy group, and suggested they remove the “Big C” word from their website. How, I thought, could they be so misleading?

That’s when I discovered I was behind the times. MPNs were indeed reclassified as a malignant condition of the bone marrow, affecting sometimes one, two or all three types of blood cells: white cells, red cells and platelets.

The average age people are diagnosed with an MPN is 60-something. My diagnosis came at age 38. For the next 15 years, I was treated for essential thrombocythemia, a type of MPN that caused my bone marrow to produce significantly higher than normal numbers of platelets. The proliferation of platelets put me at risk for dangerous clots and ultimately led to complete blockages of two important veins of the portal system, which carries blood to the liver.

The Big C label began to look like good news.

Once MPNs were classified as blood cancers — including essential thrombocythemia, polycythemia vera and myelofibrosis — interest grew from research laboratories, major medical centers, and small and mega pharmaceutical companies, which now saw these rare and poorly understood conditions as an opportunity. Perhaps pieces to the MPN puzzle could shed light on more common blood cancers, like leukemia and lymphoma. And perhaps treatments for those widely studied cancers could be used to treat MPNs.

“The cancer designation did open up significant new funding opportunities, for example from the National Cancer Institute,” said Barbara Van Husen, board chair of the MPN Research Foundation. “It has definitely accelerated research.” There are more than 200 clinical trials underway for various MPNs, as well as ongoing research into stem cell transplantation, currently the only potential cure for these rare cancers.

In my case, for reasons researchers are working to understand, my bone marrow flipped a switch. I was no longer making excessive platelets. Instead I was producing too many red cells and was given a revised diagnosis of polycythemia vera, a distinctly different MPN. I went for regular phlebotomies, the modern version of bloodletting in which pints of my blood were drained into a collection bag to reduce blood volume. Think blood transfusion, reversed.

Doctors increased the dose of the 30-year-old chemotherapy drug I had been taking since my blood clots first appeared. The drug is still considered standard of care “if well tolerated.” It effectively adjusted my red counts. Unlike newer, more targeted drugs, however, it does not discriminate, potentially killing off not just red cells but white cells and platelets as well. Read more

Ruth Fein Revell, a health and environment writer, serves on a patient advisory board of the MPN Research Foundation.