–          Navitoclax is being studied in myelofibrosis, a rare, difficult-to-treat blood cancer
–          Results are from an exploratory analysis of 34 myelofibrosis patients who received at least one dose of navitoclax in combination with ruxolitinib after suboptimal response or disease progression with ruxolitinib monotherapy
–          Median overall survival was not reached for patients who had a ≥ 1 grade improvement in bone marrow fibrosis or ≥ 20% variant  allele frequency reduction
–          At the time of analysis with > 2 year follow up the survival estimate was 100% in patients who had improvements in bone marrow fibrosis or variant allele frequency
–          Results were presented at the American Association for Cancer Research annual meeting

NORTH CHICAGO, Ill., April 12, 2022 /PRNewswire/ — AbbVie (NYSE: ABBV) today announced new data from a Phase 2 trial of navitoclax in combination with ruxolitinib in patients with myelofibrosis. The results were presented at the American Association for Cancer Research annual meeting (AACR 2022, abstract #LB108). Navitoclax is an investigational, first-in-class, oral BCL-X_L/BCL-2 inhibitor that is designed to activate programmed cell death (apoptosis) in cancer cells. Navitoclax and its safety and efficacy are under evaluation as part of ongoing Phase 2 and registrational Phase 3 studies.

“Myelofibrosis is a cancer that originates in the bone marrow, leading to fibrosis. Currently, available therapies do not address the underlying disease biology and have not shown a consistent effect on both biomarkers of disease modification and overall survival. Disease control with reversal of bone marrow fibrosis is a key objective for improving patient outcomes,” said Mohamed Zaki, M.D., Ph.D., vice president and global head of oncology clinical development at AbbVie. “That’s why we are especially pleased about these early results of navitoclax in combination with ruxolitinib that indicate its novel mechanism of action of inducing cell death may cause reversal of bone marrow fibrosis and extend survival for patients who respond to treatment.”

Myelofibrosis is a rare, difficult-to-treat blood cancer that results in excessive scar tissue formation (fibrosis) in the bone marrow. Anti-fibrosis activity, measured by reversal of bone marrow fibrosis (BMF) and reduction in driver gene variant allele frequency (VAF) have been suggested as potential biomarkers to measure disease modification in myelofibrosis, but their association with a survival benefit have not been widely described.¹ These data build on AbbVie’s history of transforming standards of care in blood cancers with significant unmet needs.

The results presented at AACR 2022 were from REFINE (NCT03222609) – a Phase 2 trial evaluating navitoclax in combination with ruxolitinib (a JAK1/2 inhibitor), which included patients with myelofibrosis who had progressed on or had a suboptimal response to at least 12 weeks of ruxolitinib monotherapy. Median exposure to prior ruxolitinib was 91 weeks (range: 19 weeks – 391 weeks) in the first 34 patients enrolled earlier in the trial.

In the exploratory analysis of 32 patients who were evaluable for improvements in BMF, 12 (38%) had a ≥1 grade improvement during any time point in the study. For driver gene VAF reduction, 26 patients were evaluable and 6 (23%) achieved a ≥20% reduction at week 24. Five patients achieved both BMF and VAF responses.

Median overall survival (OS) for all patients was not reached as presented previously by Harrison² et al. For patients who had a ≥1 grade improvement BMF median OS was not reached compared with 28.5 months for patients who did not experience an improvement. Similarly, median OS was also not reached for patients who achieved a ≥20% driver gene VAF reduction versus 28.5 months for patients who did not.

All 34 patients (100%) experienced at least one adverse event (AE), and 15 (44%) experienced a serious adverse event (SAE).² The most common AEs of any grade were thrombocytopenia  (n= 30, 88%), diarrhea (n= 24, 71%), fatigue (n= 21, 62%), and nausea (n= 13, 38%). The most common SAEs were pneumonia (n= 4, 12%) and splenic infarction (n= 2, 6%).² There were no SAEs of bleeding and thrombocytopenia was manageable and reversible with dose reduction/interruption of navitoclax and/or ruxolitinib.² REFINE was a dose-finding study and the target dose of navitoclax was reduced subsequent to these findings.

“Data obtained from this exploratory analysis holds promise for potential future clinical research,” said Jacqueline S. Garcia, M.D., Dana-Farber Cancer Institute, assistant professor of medicine at Harvard Medical School. “What is most notable in this analysis is the overall survival among patients who demonstrate VAF and BMF responses and all patients were alive at time of analysis. Patients in this Phase 2 trial had suboptimal response to ruxolitinib at time of study entry and then had navitoclax added to ruxolitinib on the trial. VAF and BMF responses occurred despite the presence of high molecular risk mutations, which suggests the potential efficacy of combination navitoclax and ruxolitinib could be independent of underlying risk factors.”

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Dr Jamile Shammo  is a Professor of Medicine and Pathology in the Department of Internal Medicine, Division of Hematology, Oncology and Cell Therapy, at Rush Medical College.

How did you become interested in hematology versus other areas of medicine?

As a medical student ( a very very long time ago!)  , I was fascinated and intrigued by the complexity and highly specialized role of each component of  what makes our blood. I remember thinking, how can red cells shed their nucleus and continue to function? The more I learned about blood, the more interesting it got! Furthermore, The growing body of science surrounding the field of hematology has grown and continues to do so in an exponential manner which keeps me challenged and I find it very satisfying to my scientific curiosity and interests in general. Finally, I find the concepts in hematology to be more abstract and “less palpable” than in any other field.  It is for all those reasons that I collectively chose hematology as a field of study and practice. I have never looked back!

What have been the highlights in your career, specifically in the area of MPNs?

Being a clinician and a pathologist granted me a much deeper understanding of  MPN’s as a disease entity and helped sharpen my diagnostic skills. I have participated in trials and witnessed the emergence of various effective therapies that I could now offer my patients which is greatly satisfying. I know we need to do more, but seeing the science in that area explode with the discovery of multiple disease-associated mutations, and the plethora of available clinical trials aiming to improve the response rate and duration in this disease, I know that we are coming on better times for our patients. 

As a female in this area of medicine, what advice would you give women grappling with career choices in hematology and medical research?

Know thyself! Identify an area of interest preferably early on in you academic career.  Identify a mentor who can support you through the process of establishing yourself as an investigator. Collaborate with your like-minded peers and never give up!

Dr. Linda Resar, is a Professor of Medicine at Johns Hopkins Medicine, where she studies molecular mechanisms leading to cancer, blood diseases, sickle cell anemia, hemophilia and other coagulopathies.

How did you become interested in hematology versus other areas of medicine?

  I first became interested in hematology during my pediatrics training at Hopkins as our institution serves a large community of children and young adults with sickle cell anemia and many other blood diseases.  I found it rewarding to care for these patients who face many challenges and are in great need of excellent hematologic care.  I fell in love with hematology because blood is essential for every organ in the body to function, and physicians caring for these patients must consider the effects of blood diseases on the entire body, making hematology a challenging but particularly rewarding field.  Moreover, blood diseases such as MPN involve blood stem cells which are fascinating from a scientific perspective since these remarkable stem cells must generate 200 billion red cells each day for many decades.  The opportunity to modulate stem cell function to improve outcomes for our MPN patients is particularly exciting.

What have been the highlights in your career, specifically in the area of MPNs?

My laboratory focuses on a  gene, called HMGA1, which is important regulator for normal stem cell function and becomes abnormally activated in cancer.  We recently discovered that HMGA1 plays a critical role in blood stem cell function in MPN, particularly when patients progress to more advanced disease.  We are currently searching for approaches to modulate HMGA1 in blood stem cells as therapy to treat, or even better, to prevent, progression in MPN.

As a female in this area of medicine, what advice would you give women grappling with career choices in hematology and medical research?

Please do not ever let anyone convince you that you are not suited for medicine, hematology, or research.  Unfortunately, women and others who are under-represented in medicine continue to confront unconscious bias, or even more blatant signals, that they do not belong since the field has been dominated by men.  However, it is clear that diversity in medicine, not only benefits our patients, but also scientific discovery.  Let any hurdles, failed experiments, and critiques serve to further ignite your passion for medicine, hematology, and research and work to foster the careers of other women in medicine, hematology, and MPN.

Dr. Angela Fleischman is an Associate Professor of Medicine in the Division of Hematology/Oncology at the University of California, Irvine. The Fleischman Lab is known nationwide for its research on the role of nutrition in MPN.

How did you become interested in hematology versus other areas of medicine?

 I started as a PhD student before going to medical school. I was very interested in hematopoiesis (blood cell development) and so went to medical school for the purpose of caring for people with blood conditions.

What have been the highlights in your career, specifically in the area of MPNs?

I would say getting to know people with MPN is the most rewarding part of what I do.

As a female in this area of medicine, what advice would you give women grappling with career choices in hematology and medical research?

Identify what is important to you and what you are passionate about, as long as you keep your eye on that everything else is just details.

By Ethan Rix by abc net Australia

Posted Thu 24 Mar 2022 at 8:20pm

When Bruce Glover was diagnosed with a rare blood cancer, he quickly realised life would not be the same.

“My doctor put her hand on my shoulder and said, ‘I’m your friend for life,’ and I realised at this stage it wasn’t going to be cured,” he said.

The 69-year-old runs his own business on the Gold Coast but has found it harder to stay on top of his game since being diagnosed with myelofibrosis in 2018.

“I used to be like the Energiser battery — I could outrun anyone in business, work and so forth,” he said.

“I can’t do the things I used to do, which gets extremely frustrating.”

But a recent stroke of luck for a team of Adelaide researchers could lead to the first possible effective treatment for the rare and crippling blood cancer.

Myelofibrosis, a type of bone marrow cancer, affects about one in 100,000 people in Australia and can often lead to complete marrow failure or even acute leukaemia.

Daniel Thomas, leader of the Myeloid Metabolism Lab at the South Australian Health and Medical Research Institute (SAHMRI), has been searching for better therapies for primary myelofibrosis for three years.

“It progresses over a period of three to five years, resulting in severe fibrosis of the marrow, and it can sometimes change into acute leukaemia where patients get sick extremely quickly,” he said.

Dr Thomas and his team of Adelaide researchers were trying to create a tool to help understand how the disease impacted the human body, but what they ended up discovering was much more extraordinary.

“As we were making an antibody to try and understand how calreticulin protein worked inside stem cells … we were completely shocked to find out that it actually stopped their (cancer cells’) growth,” he said.

Dr Thomas first assumed the results were a mistake.

“I said, ‘We have to repeat this. This is too good to be true,'” he said.

But after multiple tests, he was convinced they had found a treatment for what is often considered an “undruggable mutation”.

“And low and behold, the antibody actually stopped these [cancer cells] growing out but did not stop a single normal healthy stem cell growing,” Dr Thomas said.

The new antibody is currently being prepared for early-phase clinical trials set to run in South Australia later this year.

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Dr. Catriona Jamieson is Professor of Medicine in the Division of Hematology-Oncology, Deputy Director of UC San Diego Moores Cancer Center, Co-Lear of Hematologic Malignancies Program, and Director of Stem Cell Research at UC San Diego Moores Cancer Center.

How did you become interested in hematology versus other areas of medicine?

My father’s mother died of leukemia when he was 18 and it had a profound impact on his life.

What have been the highlights in your career, specifically in the area of MPNs?

The capacity to translate discoveries to the clinic for the benefit of patients with MPNs, including fedratinib ® and glasdegib ®, has been the most important aspect of my career together with the recent discovery and development of our splicing modulator that inhibits splicing-mediated activation of both MCL1 and ADAR1.

As a female in this area of medicine, what advice would you give women grappling with career choices in hematology and medical research?

Persevere and surround yourself with supporters.

Dr. Nicole Kucine is an Associate Professor of Clinical Pediatrics at Weill Cornell Medicine and Associate Pediatrician at NewYork-Presbyterian/Weill Cornell Medical Center. She is an advisor of our Pediatric & Young Adult MPNs focus.

Join our Pediatric & Young Adult Webinar with Dr. Kucine, March 24, 2022

How did you become interested in hematology versus other areas of medicine?

I always knew I wanted to be a pediatrician and found hematology/oncology most interesting, but during my residency and fellowship, I realized my heart was really in hematology. The variety of illnesses, the ability to see a mix of patients for both short-term and long-term follow-up, and the detective work involved in making a diagnosis appealed to me more than oncology.

What have been the highlights in your career, specifically in the area of MPNs?

I think working with children with MPNs and their families has been so rewarding. The fact that so many families want to partner with me and work as a team, and how dedicated families are to ensure we can learn more about these diseases has been so important and inspiring.

As a female in this area of medicine, what advice would you give women grappling with career choices in hematology and medical research?

Women still deal with gender discrimination in medicine. I would encourage any woman interested in a career in hematology and research to go for it. Don’t let anyone tell you that you can’t!

Ann Mullally, MD is an Associate Professor, Medicine, Harvard Medical School, an Attending Physician, Leukemia Program, Medical Oncology, Dana-Farber Cancer Institute and an Associate Physician, Hematology, Brigham And Women’s Hospital. She is a translational cancer researcher in the field of myeloid malignancies, with a focus on myeloproliferative neoplasms (MPN).

How did you become interested in hematology versus other areas of medicine?

I became really interested in hematology during residency training at Johns Hopkins where I became fascinated by acute leukemia.I became interested in lab-based research in hematology during fellowship at Brigham/Dana-Farber and I joined the lab of Dr. Gary Gilliland, who co-discovered the JAK2V617F mutation. That set me on path studying MPN.

What have been the highlights in your career, specifically in the area of MPNs?

I am very proud of our work deciphering the mechanism by which mutations in calreticulin cause MPN. I hope this work and that of others in the field will ultimately result in curative therapies for patients with CALR-mutant MPN.

I also feel privileged to have a MPN clinic and witness firsthand the challenges faced by our patients and the deficiencies of our treatments, which both provide huge motivation for researchers like myself to do better.

As a female in this area of medicine, what advice would you give women grappling with career choices in hematology and medical research?

Still in 2022, women face many challenges in academic medicine including the gender pay gap, under-representation in senior faculty and leadership positions and gender inequity in recruitment, promotion and retention to name but a few.

In order to overcome these challenges medicine needs to be remodeled and this is an active and ongoing process. My advice would be that the best way to have your voice heard is to be in the room, so come join us!

03-14-2022 11:27 AM CET

Press release from Orion Market Research

The global post polycythemia vera myelofibrosis (PPV-MF) market is anticipated to grow at a significant CAGR during the forecast period (2021-2027). Post-polycythemia vera myelofibrosis is a form of the myeloproliferative neoplasm and is also called chronic idiopathic myelofibrosis. It is a rare chronic blood cancer. People with myelofibrosis (MF) have a defect in their bone marrow that results in an abnormal production of blood cells which causes scar tissue to form. The major factor driving the growth of the market is the increasing prevalence of polycythemia vera (PV) across the globe.

According to the Leukemia & Lymphoma Society, PV is more prevalent among Jews of Eastern European descent than other Europeans or Asians. However, the incidence of PV is about 2.8 per 100,000 population of men and about 1.3 per 100,000 population of women of all races. Additionally, an estimated number of people in a population with PV is about 22 cases per 100,000 people. Furthermore, PV is mostly diagnosed at the average age of 60 to 65 years and it is uncommon in individuals younger than 30 years. Hence, the increasing prevalence of PV is driving the growth of the global post polycythemia vera myelofibrosis (PPV-MF) market.

To Request a Sample of our Report on Post Polycythemia Vera Myelofibrosis (PPV-MF) Market: https://www.omrglobal.com/request-sample/post-polycythemia-vera-myelofibrosis-ppv-mf-market

Researchers led by Christopher Garcia of the Ludwig Center at Stanford University have solved the long-sought structure of a large signaling protein involved in responses to infection, inflammation, the generation of immune cells, and when dysregulated by mutation-; the emergence of blood cancers known as myeloproliferative neoplasms. Published in the journal Science, the structure reveals the mechanism by which this protein, Janus kinase (JAK), transmits signals sent by immune cell growth factors called cytokines.

That structural information has direct implications for the development of new drugs for myeloproliferative neoplasms, which are currently treated with drugs often referred to as “jakinibs” that target all JAK proteins, not just the mutants that drive cancer. This broad targeting of JAK proteins causes side effects that include anemia and thrombocytopenia, a blood clotting disorder.

“Our model of JAK structure gives us an atomic blueprint for how one could make mutant-selective medicines to treat these cancers,” said Garcia. “This is the essence of basic discovery biology leading to translational insights.”

Cytokines signal through receptors found on the cell surface that thread through the cell’s outer membrane into its cytoplasm. Each receptor has attached to its cytoplasmic tail, a single JAK protein in an inactive state. Each cytokine protein binds two of these receptors, drawing their attached JAKs together.

“When the JAKs are brought close together, they activate one another,” Garcia explained. “That’s the activated complex that gets the signaling engine running.”

Each JAK phosphorylates-; or adds a phosphate molecule-; to a specific spot on its partner. So activated, the JAKs then phosphorylate the cytokine receptor to which they’re attached, drawing a protein known as STAT to the complex. It is this complex that transmits the cytokine’s growth-promoting signal.

The structure solved by Garcia’s lab, which has pursued this prize for more than two decades, is of the JAKs in their juxtaposed and activated state.

“Small pieces of the JAK structure had been published over the years-; a toe here, a finger there, an ear there-; but nobody had seen what the whole body looked like, so to speak,” said Garcia.

The full structure shows that when drawn together by the cytokine, the JAKs meet at a roughly flattened region in their middle. The change induced by the oncogenic JAK mutation-; swapping the smaller amino acid valine for the much larger phenylalanine-; falls in the middle of this region. The mutation alters the flat interface between the JAKs, creating a sort of ball and socket connection between the two that makes them adhere far more firmly to one another.

“When people have this mutation-; the most classical mutation in blood cancers-; the JAKs come together and start working all the time because there’s like a little dab of glue in there that’s bringing them together even when there’s no cytokine around,” Garcia said. They thus continuously transmit growth signals, driving cell proliferation.

The finding opens the door to developing small molecules that disrupt the ball-and-socket connection of the mutant JAKs. Such drugs would not affect normal JAK proteins and would, therefore, be less likely to have toxic side effects.

Garcia and his colleagues solved the structure of the mouse JAK-1 protein. The “V617F” mutation that drives myeloproliferative neoplasms is, however, found in its cousin, JAK-2. But, Garcia says, the two are sufficiently alike to share the same signaling mechanism.

Garcia’s group is now working on developing drugs to target V617F mutant JAKs and capturing the structure of the larger JAK-STAT complex and that of the complexes formed between different types of JAKs, which are also involved in cytokine signaling.

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