Controlling Hematocrit in Polycythemia Vera

Jamile M. Shammo, MD: I think the dose that this patient has received—being 500 mg initially, 1 tablet—that’s really remarkable that it did result in symptom control. So, in a way, I’m not surprised that the dose had to be taken up to 1000 mg, and frankly, if you wanted to exactly assess or categorize the response of the 1000 mg of Hydrea, even if it were to suboptimal, you can argue that it may be because the dose wasn’t sufficient. Because again, let’s remember, the guidelines for Hydrea resistance demand that the patient needs to be taking at least 2 g of Hydrea for at least 3 months, without any optimization of the hematological parameters. In which case, you can say that, “Well, maybe you had a patient who has actually developed Hydrea-resistance.” But if she hasn’t even taken 1000 mg, or even 1500 mg, then it would hard to argue or make a case for resistance to Hydrea.

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Agent Orange and Hematologic Malignancies: The Fog of War Still Hovers

More than 40 years after the Vietnam War, the fog of Agent Orange hangs thick over veterans and those providing their medical care. Aging veterans suffer from an extensive list of diseases, including several hematologic malignancies, deemed related, or possibly related, to exposure to Agent Orange.

Many cases we see may resonate back to historic events that we don’t pay much attention to, in part because it is difficult to dissect the details.”
—C. Ola Landgren, MD, PhD

The number of affected veterans will likely increase as new conditions are added to the official list of “presumptive diseases” and as controversies are resolved regarding which veterans were affected (and how the U.S. government should compensate and care for them). Although the science connecting Agent Orange exposure and certain hematologic malignancies is sound, the story of Agent Orange is far from clear-cut. It is covered with a sticky mist of politics, controversy, blame, and denial.

“Many cases we see in our clinics may resonate back to historic events that we don’t pay much attention to, in part because it is difficult to dissect the details,” said C. Ola Landgren, MD, PhD, chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York, who has extensively studied the link between environmental exposures and multiple myeloma (MM).

To help unravel the story, ASH Clinical News spoke with Dr. Landgren and ASH Clinical News Associate Editor David Steensma, MD, about the science behind Agent Orange, the clinical considerations of exposure, and the task of caring for ill veterans.

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Tips for Caregivers

Suggestions for being an effective caregiver

Caring for a person with cancer may seem complex and like too much to cope with at first. Depending on the person’s needs, you may provide different types of support, such as:

  • Emotional support
  • Help with medical care
  • Assist with financial and insurance issues
  • Serve as the communicator between the patient and the health care team

You may find the following tips can help you become a successful caregiver:

Remember that caregiving is a team effort. A caregiver is a member of an important team of family members, friends, volunteers, and the health care team. Each member of the team offers different skills and strengths to provide effective care.

If you are the main caregiver, help each team member express concerns, opinions, and emotions. Also, make sure that the person with cancer has a central role in all discussions and decisions, if possible. It is very important for the person with cancer to feel like an active member in their care.

CancerCare provides a special website for caregivers called My Cancer Circle.  This website can help caregivers organize the family and friends who want to help. Find other online communities for support.

Create a list of tasks. Caregiving, like any responsibility, involves tasks of varying importance. Start by making a list of all of your caregiving tasks. Then, use it to decide how to divide the tasks between friends, family, professionals, and other volunteers.

Be proactive. Being proactive means taking charge and planning as much as possible to prevent last-minute emergencies. This can also help provide a sense of control and order. Create schedules that list which relative, friend, or other volunteer is available when and for what tasks. Make sure that all of the caregivers involved have some time to be away without feeling guilty or concerned. Long-distance caregiving takes even more planning. Find out more about how to be an effective long-distance caregiver.

 

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Notes from MPN Physician Meeting

Thursday, 27 April 2017

Dr. Ruben Mesa

MPN patients still have significant unmet needs — particularly those with myelofibrosis.

Anemia is a multi=factorial problem due to several influencers: red cell production, red cell destruction, spleen activity, low EPO, iron, vitamin D, vitamin B, medication side effects. Hemoglobin can be limited by iron.

Treatments: how are they viewed by regulators? Insurance companies vary in the limits of treatment options.

Molecular features are important in determining the course of action.

Treatments:

What is the therapy?

Dosage: what is minimally effective dose by patient type? Variances by time of day or BID?

What are the expected benefits?

How long will benefits last?

What are known risks and side effects

How is therapy viewed by regulators?

What limits are placed on treatments by insurance?

 

Dr. Cecily Forsyth

Bone Marrow Biopsies: Yes? No? When?

She conducts a BMB on every MPN patient upon diagnosis along with a thrombophilia screen. The BMB identifies the MPN sub-classification and identifies known mutations at diagnosis. This forms baseline data for a chronic blood cancer that can evolve over many years.

Some MPN patients who are not JAK2+ at diagnosis go on to develop the JAK2 mutation.

Learning more about signaling mutations and epigenetic mutations that occur over time. The order in which the mutations occur may affect rate of progression and eventually therapy options.

Splachnic vein and portal vein thrombosis are typically caused by MPN. When the mesentery vein system is also affected, survival rate is very low (around 10%).

Is there an inflammatory response that triggers MPN or does MPN trigger inflammation? We know the JAK2 affects the endothelium.

Most people diagnosed with a myeloproliferative neoplasm receive the diagnosis over one year after symptoms begin.

 

Dr. Laura Michaelis

Risk assessment models for myelofibrosis (IPSS, DIPSS, DIPSS+) are based on historical data. The mean survival rates are imprecise and scare patients.

Other tests: MIPSS

GPSS shows molecular risk

“These tools have huge confidence limits.”

  • Do not include use of ruxolitinib
  • Do not adequately predict AML transformation
  • Too dull for stem cell transplant decisions
  • Not portable

MPNs are not linear diseases. Patients can be stable and quickly progress to AML. We don’t know why yet.

The panel of somatic mutations is still a work in progress, and is retrospective in development.

Still do not know all the gateways to progression.

The sensitivity of the assay is still an issue.

Most insurance companies will not pay for the testing.

Sometimes more information is simply confusion.

Patients are concerned about how the information may be used against them in insurance availability and pricing (health care and life insurance) and in employment decisions.

 

Dr. David Ross

The quality of pathology reporting varies wildly.

Descriptive reports are more useful than a diagnosis without specific description of what is seen to draw that conclusion.

The order of mutation acquisition and identification of cooperating mutations will help future diagnoses.

The mutation of JAK2C168 can mask the JAK2V617 mutation.

Complete Molecular Response: the allele burden of a mutation is below 1%

Signaling Somatic Mutations:

JAK2           CALR Type 1                  CALR Type 2                  MPLW515x

JAK2 & UPD9:

Triple Negative (JAK2, CALR, MPL):

10% have germline mutations that appear to be inherited, not somatic. Occur further down the gene than typical for somatic mutations.

Megakaryocytes:

 

Dr. Wendy Erber

Megakaryocytes

Wrote paper published 2017 American Journal of Pathology, Guo, BB, et al.

Dr. Erber does not use the term “pre-fibrotic MF” because there is evidence to show transformation.

The megakaryocytes are larger than normal. They proliferate at 2-3 times normal rate and they don’t die.

She looked at genomes of the megakaryocytes.

The platelets may be the signal of changes in megs.

 

Dr. Kate Burbury

MPN Mutational Landscape:

MPN Myeloid Panel – includes exons and targeted locations of mutations

The number of somatic mutations strongly correlates with OS and transformation. There are some (5) known to be high risk mutations.

Can we use the mutational profile to treat and reduce the risk of progression?

This is likely possible as new targeted treatments are developed.

Known mutations in three types of proteins:

Cytokine (signaling)

Epigenetic:

Splicing:

CALR mutations: CALR Type 1 and CALR Type 2 are different in ET and MF.

Type 2 is mostly in ET

CALR mutants bine and activate MPL. The mutation may be deletion or insertion.

The microenvironment affects the proteins and the mutations affect the microenvironment.

Extra information doesn’t always tell you what to do. And we don’t always know what it mea

Dr. Raajit Rampal

Geneticist

JAK2 inhibitors (Ruxolitinib)

Its efficacy decreases over time.

They don’t inhibit heterodimeric JAK-2

PIM kinases

The mutations in de novo AML are different from post-MPN AML.

They are different diseases.

Ruxo and decitabine combined has additive value.

 

Dr. Andrew Grigg

Allografting for Myelofibrosis

There is a disconnect between primary myelofibrosis and secondary myelofibrosis.

TRM – Transplant Mortality

Risk of relapse post transplant is 40%

Selecting patients: TIMING is everything.

CALR patients tend to do better than JAK2

Decision to transplant is complicated and individualized.

= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =

 

 

 

Australian MPN Specialists

aussie doc

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.

Registration-Cleveland Patient Education Program June 9. 2016

Thank you for registering for the MPN Patient/Caregiver Education Program on June, 9 in Cleveland, Ohio.  We look forward to seeing you.  To complete the registration you can use the link below to pay the registration fee.  Follow the brief instructions to link to the PayPal account.


NOTE:
You do not need a PayPal account to make this payment, you can select the “Pay with Debit or Credit Card” option.

 If you are registering for you and a guest or 2 guests please use “Select Registration Option” from the drop down menu provided on the registration page.

Select Registration Option



FDA Marketing Approval for PV Test Kit

The U.S. Food and Drug Administration (FDA) has granted marketing approval to the ipsogen JAK2 RGQ PCR Kit – the first FDA-authorized in vitro test for the evaluation of suspected polycythemia vera (PV). The testing kit detects mutations in the JAK2 gene in patients with suspected PV by sequencing data from DNA extracted from EDTA whole blood.

The marketing authorization was based on data from a clinical study of 216 patients with suspected PV, which compared results from the ipsogen JAK2 RGQ PCR Kit with those obtained from Sanger sequencing. The kit detected PV with a 94.6 percent sensitivity and 98.1 percent specificity.

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18F-FLT (PET/CT) in Pediatrics With MPNs

The Main purpose of this project to study the uptake pattern of FLT-PET and it is value in assessing the malignant hematopoiesis in MPN within the pediatric age group, in terms of diagnosis, staging and monitoring response to therapy. As well as, evaluating FLT-PET as a novel non-invasive technique in cases with MPN and its role in comparison to the standard bone marrow biopsy with regard to disease diagnosis, assessment of disease activity, detection of transformation, monitoring of treatment response and grading of fibrosis.Furthermore, we aim to study the association of FLT-PET uptake patterns with different genetic makeup (JAK2, CALR positive, MPL, or Triple negative disease) or allele burden in cases of Pre-PMF with the ability of FLT-PET to differentiate between Pre-PMF and ET.

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Costs of MPN Clinical Trials May Hinder Enrollment

While clinical trials are paving the way for new treatments to treat hematologic malignancies, but many patients are apprehensive to participate in them after considering the costs.
Clinical trials are leading the way in developing new treatments for hematologic malignancies, but the cost associated with them may be holding many patients back from participating, according to a recent international study that was published in the European Journal of Hematology.

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