Small Number of Myelofibrosis Patients Develop Aggressive Lymphoma from JAK Inhibition

 
BY Brielle Urciuoli
PUBLISHED June 25, 2018

While JAK inhibitors have proven to be an effective treatment for patients with myelofibrosis, a type of myeloproliferative neoplasm (MPN), they may come with a severe downside – in particular, a 16-fold increase in the chance of developing a B-cell lymphoma, according to recent research published in the journal Blood.

“Many patients profit from this treatment and survive with good quality of life. Therefore, it is important to study potential long-term side effects of this therapy,” study author Ulrich Jager, M.D., head of the Division of Hematology and Haemostaseology at the Medical University of Vienna in Austria, said in an interview with CURE.

Researchers examined 626 patients with MPNs who were diagnosed and treated at the Medical University of Vienna between the years of 1997 and 2016. Of these patients, 69 with myelofibrosis were treated with a JAK1/2 inhibitor for lymphoma development, which included Jakafi (ruxolitinib), gandotinib, fedratinib or momelotinib.

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Learn more about Myelofibrosis

 

From Cleveland to Pittsburgh: A Busy Travel Schedule Worth Every Minute

Pittsburgh

Top left, Dr. James Rossetti, Pittsburgh Support Group Coordinator, Jean Diesch, with Ann Brazeau, Dr. Salman Fazal with Dr. John Mascarenhas and Dr. Raajit Rampal.

On June 7, MPN Advocacy & Education International held its first MPN Patient/Caregiver program in Pittsburgh. Support Group Coordinator, Jean Diesch, invited us many times and we were finally able to make it happen. Two local hematologists, Drs. Fazal and Rossetti joined Drs. Rampal and Mascarenhas for this program.

Dr. Rampal, Memorial Sloan Kettering, presented on new therapies in MPNs, The good news is the development of new JAK inhibitor therapies on the horizon for MPN patients. Click here to view new clinical trials.

Dr. John Mascarenhas, Mount Sinai, discussed new polycythemia vera therapies. Comparing the goals of PV patients to feel better, and the goal of investigators to take what they are doing in the lab and bring it to the patient. Dr. Mascarenhas believes clinical trial participation is the pathway to a cure. This resulted in an excellent discussion with the patients on what they can do to help. Dr. Mascarenhas urged patients to consider donating to a tissue bank. Mount Sinai has a donation program in place, click here to learn more.

Dr. James Rossetti, UPMC Hillman Cancer Center, gave an overview of bone marrow biopsies and aspirations, including how they are done, what is extracted and why, and what they can learn. Many patients have multiple biopsies over the course of their disease.  Biopsies are helpful in creating a baseline for assessing the progression of the disease. (There is a new method being researched to produce non-invasive biopsies, click here to learn more.)

Dr. Salman Fazal, Temple University School of Medicine, reviewed the findings from the MPN Landmark Study. This study highlighted the differences in treatment goals and perception of symptom burden between patients and the hematologists/oncologists who treat MPN patients. While patients listed slowing the progression of the disease as their top priority, physicians listed the reduction in symptom burden, thrombotic events, as their primary goal. For many physicians, this offered unique insights into a patient’s mindset. To learn more about the outcomes of this study click here.

From Cleveland to Pittsburgh: A Busy Travel Schedule Worth Every Minute

Cleveland

MPN Advocacy and Education International hosted its 3rd MPN Patient/Caregiver program at the Cleveland Clinic on May 31. Dr. Aaron Gerds presented information on two MPN topics, Symptom Burden and MPNs 101.

Dr. Gerds helped explain the biology of MPNs and likened the JAK2 mutation to a broken thermostat. In this case, constantly triggering the body to turn up the heat (see slide). His discussion on symptom burden provided a keen insight into why patients endure extreme fatigue, itching and other constitutional issues. Dr. Gerds recommended reviewing the yoga study. The majority of patients who participated found some level of relief and improvements in their quality of life. (read more about the yoga study)

 

Dr. Betty Hamilton, Cleveland Clinic, presented on bone marrow transplants for MPN patients and how to determine the optimal time to proceed. Are the current treatments reducing the symptom burden? Is the patient healthy enough to recover? It is a matter of finding that point at which it will maximize survival and improve the patient’s quality of life. It isn’t age as much as the overall fitness of the patient. One of the most common issues for patient’s recovering from transplant is graft vs host disease, which affects more than half of transplant patients.

Dr. Kristen Pettit, University of Michigan, gave an overview of clinical trials and the benefits of participation. Patients who participate receive quality care from MPN experts.  The protocols in place are designed to ensure the utmost safety of the patient. Participating in a clinical trial is a big commitment. Patients should be aware of all the necessary requirement.

Click here for a list of questions to consider before participating in a trial

Click here for a list of current mpn clinical trials

 

Dr. Naveen Pemmaraju, MD Anderson, discussed what is on the horizon for MPN patients. He encouraged physicians to pay attention to what patient’s are dealing with beyond the visible symptoms. “No one understands the war going on inside your body.” MD Anderson is currently working on several clinical trials for MF patients:

Evaluation of Ruxolitinib in Combination With PU-H71 for Treatment of Myelofibrosis.

Testing of SL-401 in Advanced, High Risk MPN Patients

 

From left, Dr. Aaron Gerds, Dr. Naveen Pemmaraju, Dr. Kristen Pettit and Dr. Betty Hamilton

Structure of protein pair provides blueprint for future drugs

Walter and Eliza Hall Institute researchers have visualised for the first time how the protein SOCS1 ‘switches off’ cell signalling to dampen immune responses and block cancer growth.

The atomic-level structure of SOCS1 binding to its partner protein JAK could guide the development of drugs that alter disease-causing cell signalling pathways, and may have applications for treating some blood cancers, including leukaemias.

The research, led by Dr Nick Liau, Dr Nadia Kershaw, Associate Professor Jeff Babon and Professor Nick Nicola, was published in the journal Nature Communications.

AT A GLANCE

– The SOCS1 protein binds to JAK proteins to ‘switch off’ cell signalling, which dampens processes including immune responses and cancer growth.

– Our researchers have used structural biology to visualise how SOCS1 binds to JAK proteins in never-before seen detail.

– The detailed structure may guide the development of new drugs that modify JAK activity, amplifying or dampening cell responses, with potential applications in cancer therapies.

Learn more about clinical trials

 

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Effect of MPN Diagnosis on Work, Employment Status

Many patients experience a negative impact on work productivity and employment status after a diagnosis of myeloproliferative neoplasm (MPN), according to a study published in BMC Cancer.

The clinical adverse effects of MPNs (eg, polycythemia vera [PV], essential thrombocytopenia [ET], myelofibrosis [MF]) are well known; risks for cardiovascular and thrombotic events and various other symptoms are increased. The impact of illness on the workplace and careers, however, have yet to be explored.

For this study, researchers sent the cross-sectional online survey “Living with MPNs” to patients with a myeloproliferative neoplasm. The survey consisted of approximately 100 questions related to MPN, focusing on factors such as diagnosis, symptoms, and changes in employment, work productivity, and daily activities. The Work Productivity and Activity Impairment Specific Health Problem questionnaire (WPAI-SHP) was used to evaluate the effects of MPN on work productivity and activity for currently employed respondents, and the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) was used to measure symptom burden.

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Learn About MPN Study

Potential Combos With Ruxolitinib in Myelofibrosis

To date, the JAK inhibitor ruxolitinib (Jakafi) is the only FDA-approved therapy for the treatment of patients with myelofibrosis (MF); however, novel agents and combination regimens are in development to address some of the unmet needs in MF, including treating cases of anemia associated with MF and treatment with ruxolitinib, as well as increasing responses to the targeted therapy.

In an interview with Targeted Therapies in Oncology™ (TTO), at the meeting, Prithviraj Bose, MD, assistant professor, The University of Texas MD Anderson Cancer Center, discussed the findings of 2 combination trials with ruxolitinib to optimize outcomes for patients with MF.

TTO: What are the unmet needs that still exist in MF that you would like to see be resolved?

BOSE: Ruxolitinib is a very well-established choice for JAK1/2 inhibition, but we also have some limitations. It is great at shrinking the spleen and improving symptoms, and it extends overall survival [OS], but certain things don’t get that much better. For example, ruxolitinib causes anemia, which can make it hard for patients to stay on or go up to the optimal dose.

The unmet needs are (1) to have a drug that could circumvent the anemia with ruxolitinib, and maybe even the thrombocytopenia, so that patients can stay on ruxolitinib at an optimal dose for an extended period of time, and (2) the fact that ruxolitinib is not a cure. Even though it extends OS, MF is still not curable without allogeneic transplant. We need disease-modifying drugs, which, in combination with ruxolitinib, for example, will hopefully give us more biology-altering benefits.

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Prognostication in MF: Integrating genetics into routine practice

Dr. Gabriela Hobbs

One of the most exciting aspects of clinical research is translating lab-based discoveries into tests and treatments that can be used in daily clinical practice.

The last 2 decades have yielded an explosive amount of information about the genetics of hematologic malignancies, as well as targeted therapies based on this information Myeloproliferative neoplasms (MPNs) are no exception.

Dr. Hobbs will be joining us in Chicago for the 4th Annual Women & MPN Conference Learn More

Prior to the 2005 discovery of the JAK2 V617F mutation in most patients, MPNs were classified as diseases rather than neoplasms.

This semantic difference may seem trivial, but it has tremendous implications on how patients are cared for. It is quite different to tell a patient he or she has a “disorder” than it is to say the person has a malignant neoplasm.

Understanding that patients with MPNs have a genetic marker of disease was the springboard that led to the discovery of additional genetic mutations, primarily in calreticulin (CALR) and MPL among most patients without JAK2 mutations.Read more

 

Pacritinib Can Fill Unmet Need in Myelofibrosis

The investigational agent pacritinib (CTI BioPharma) holds promise as a treatment option for patients with myelofibrosis and baseline thrombocytopenia, and previous concerns that led to a hold on clinical trials have now been dispelled.

In a pivotal trial, PERSIST-2, pacritinib was significantly more effective than the best available therapy, including ruxolitinib (Jakafi, Incyte), in reducing splenomegaly and trended toward a reduction in total symptom score in patients with myelofibrosis and thrombocytopenia.

The study was published online March 8 in JAMA Oncology. Ruxolitinib, which was approved in 2011 and the first drug ever approved for myelofibrosis, is not safe for patients with low platelet counts.

“The label on ruxolitinib states it is for patients with platelet counts above 50,000, so it isn’t a viable option for those with thrombocytopenia,” said lead author, John Mascarenhas, MD, associate professor of medicine, hematology and medical oncology, at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York.

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View Dr. Mascarenhas’ presentation at MPN Advocacy’s San Antonio Patient Program

Recruiting: New Phase 2 Clinical Trial for MF Patients on Ruxolitinib

People with myelofibrosis who are currently receiving ruxolitinib therapy may be eligible for a new phase II clinical trial led by Dr. Ellen Ritchie.

Navitoclax is an investigational agent that inhibits a family of BCL proteins. These proteins block some of the enzymes that keep cancer cells from dying and by inhibiting these proteins, navitoclax may cause the cancer cells to die.  Ruxolitinib is approved by the FDA for the treatment of myelofibrosis. Ruxolitinib blocks a protein called Janus-associated kinases (JAK) which may help keep abnormal blood cells or cancer cells from growing.

The purpose of this study is to evaluate the addition of navitoclax to ruxolitinib in patients who have been receiving ruxolitinib alone. Ruxolitinib treatment alone has not been fully controlling disease which is evident by an enlarged spleen. Preclinical data suggest that the combination of navitoclax with ruxolitinib are synergistic and that navitoclax may help to overcome disease resistance to ruxolitinib.

The study will help to determine the effect of the combination of navitoclax plus ruxolitinib on your cancer. The study will evaluate how the efficacy and safety of the drug.

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View MF Clinical Trials

 

 

Imago BioSciences Receives FDA Approval of IND Application for the Treatment of Myeloid Malignancies

SAN CARLOS, Calif., Feb. 1, 2018 /PRNewswire/ — Imago BioSciences, a clinical-stage pharmaceutical company developing novel therapies for hematological and inflammatory diseases, announced that the U.S. Food and Drug Administration (FDA) has accepted their Investigational New Drug (IND) application providing clearance to proceed with the clinical development of IMG-7289 in the U.S. The IND supports the company’s ongoing Phase 1/2 clinical trial of IMG-7289 for myelofibrosis (MF).

“There is a pressing need for novel approaches to the treatment of myeloproliferative disorders including myelofibrosis,” said Hugh Young Rienhoff, Jr. M.D., Imago’s Chief Executive Officer.  “We are pleased to have received FDA acceptance of our clinical trial protocol and look forward to the imminent expansion of this study into the United States.”

This Phase 1/2 open-label clinical trial is designed to assess the pharmacodynamics of IMG-7289, an oral inhibitor of the epigenetic enzyme lysine-specific demethylase 1 (LSD1) in high-risk myelofibrosis patients aged 18 or older (www.clinicaltrials.gov Identifier NCT03136185).  Assessments include measuring changes in spleen volume, patient reported total symptom scores, mutant allele burden, inflammatory cytokines and bone marrow fibrosis over the course of the treatment period.  The trial commenced in Australia in 2017 and will add multiple sites in the United States in 2018.

This is the second clinical trial of IMG-7289 sponsored by Imago BioSciences, Inc.  The first, evaluating IMG-7289 for the treatment of high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), was initiated in 2016 (www.clinicaltrials.gov Identifier NCT02842827) and continues to enroll patients.

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 Go to MPN Clinical Trials