MANAGEMENT OF MYELOPROLIFERATIVE NEOPLASMS

LINDSEY      

Welcome to this expert round table on the management of myeloproliferative neoplasms, a case-based discussion; this is a part of JADPRO’s MPN updates.  My name is Lindsey Lyle, I’m a Physician Assistant at the University of Colorado in the Blood Disorder Center.  Joining me today are three experts in the field.  We have Dr. Srdan Verstovsek who works at the University of Texas MD Anderson Cancer Center.  Welcome, Serg.

DR. VERSTOVSEK            

My pleasure; thank you.

LINDSEY      

Next, we have Dr. Stephanie Chase, who is a Clinical Pharmacist at the University of Colorado in the Blood Disorder Center.  Welcome, Stephanie.

DR. CHASE 

Thank you.

LINDSEY      

And we have Sandra Allen-Bard, who is a Nurse Practitioner at Cornell Medical Center in the Department of Leukemia.

SANDY         

Thanks, Lindsey.

LINDSEY      

Thank you for all being here.  So, the goal of this program is to broaden the knowledge base of and offer practical strategies to advanced practitioners, including advanced practice nurses, physician assistants, and pharmacists, as well as physicians who are involved in the care of patients with myeloproliferative neoplasms in order to optimize patient outcomes.

A brief overview of MPNs:  Myeloproliferative neoplasms, otherwise known as MPNs, are a heterogenous group of chronic myeloid malignancies associated with somatic hematopoietic stem cell mutations leading to overaction of JAK/STAT signaling, resulting in hyperproliferation of one or more hematological cell lines.  Classic BCR/ABL-negative MPNs is a subcategory that includes polycythemia vera, essential thrombocythemia, primary myelofibrosis, and pre-fibrotic myelofibrosis.  These subsets of diseases are characterized by stem cell–derived clonal myeloproliferation with mutually exclusive JAK2, calreticulin, or thrombopoietin receptor gene mutation, otherwise known as MPL.  Diagnosis is based on a composite assessment of clinical and laboratory features. 

Let’s talk about some cases that will highlight real world challenges as we care for patients with MPNs.  The first case is an 87-year-old male with a past medical history significant for hypertension, hyperlipidemia, and a symptomatic inguinal hernia.  He presents for a pre-surgical evaluation and a CBC is performed showing a platelet count of 700,000.  His white blood cell count and red blood cells are reportedly within the normal range and the surgeon feels that he should put off surgery and have the patient evaluated by a hematologist.  So, Dr. Verstovsek, how would you proceed with the workup of a patient presenting with an elevated platelet count?

DR. VERSTOVEK   

First of all, I would make sure that this is a correct finding by repeating the blood cell count, making sure, also, that other blood findings in the repeat testing are normal, like red blood cells and white cells.  And look beyond just the obvious; looking at the types of white cells, looking at the size, shapes, and colors of the red blood cells that will, perhaps, indicate different abnormalities in the item, for example, or look at the elevation in lactate dehydrogenase, or LDH. 

So, it suggests the complexity of looking at everything that is available to you when you get the full blood cell count, not just the one part of it, but looking beyond just the platelet number, and confirming and then extending your observations from the obvious.

LINDSEY      

And, Sandy, how would you go about ruling out reactive thrombocytosis?  Because we know that --

SANDY         

Right.

LINDSEY      

-- is a possibility.

SANDY         

So, basically, how Dr. Verstovsek says, we would look at other findings, so looking for iron deficiency.  Although the hemoglobin and hematocrit are normal or MCV size are normal, we would rule out iron deficiency because that can give you thrombocytosis, as well as inflammatory processes or infections.  So, we want to work the gentleman up prior to surgery to make sure there are no active infections, as well as any chronic inflammatory processes going on.

LINDSEY      

And, Dr. Verstovsek, in this patient once you’ve ruled out a reactive cause for the platelet elevation, would you be okay with just performing peripheral blood mutation testing?  Would you think that this patient needs a bone marrow biopsy?

DR. VERSTOVEK   

Well, typically, the first approach is just to send the sample for molecular testing for the driver mutations if it’s suspected this is part of the bone marrow disease.  And here, obviously, we’re talking about myeloproliferative neoplasms and I would suspect possibly essential thrombocythemia, but you cannot make a diagnosis based only on the blood findings.  I would send the blood for a JAK2 mutation, which is present in about 50 to 60 percent of the patients with ET, essential thrombocythemia.  And then you can extend the molecular testing to calreticulin testing or MPL mutation testing.  But, the real diagnosis will come from the bone marrow biopsy.

LINDSEY      

And, also, within that molecular testing, too, making sure to check a BCR/ABL because sometimes those patients can have the elevated platelets.

DR. VERSTOVEK   

Absolutely.  I think you are right. That would be, in fact, given because chronic myeloid leukemia, which is defined by BCR/ABL, can present as just the high platelets, so that’s completely true.  I think that’s a very good point.

LINDSEY      

Okay, great.  Well, so, this patient was sent for a bone marrow biopsy and we found that he had megakaryocytic proliferation, no evidence of fibrosis in the marrow, and the pathologist stated morphologically this was consistent with essential thrombocythemia.  A molecular panel was run and he was positive for MPL mutation and he had diploid karyotype. 

So, when we think about a patient with ET, then the next step once we have a diagnosis is stratifying their risk for thrombotic or bleeding complications.  And so, currently, right now looking at patients who are high risk, these would be patients over the age of 60 or with a prior history of thrombosis and this really helps guide the need for therapy or lack thereof.  And so, this patient, because of his age, is at higher risk and, additionally, taking into account his cardiovascular risk factors, which include pretty significant hypertension and hyperlipidemia, which are important to consider, of course, as well.

Serg, thinking about treatment for this gentleman, what factors go into how you choose a treatment for an ET patient?

DR. VERSTOVEK   

So, based on the discussion - that was a very nice summary - this is a patient who at high risk for thrombotic event and the start of that therapy is indicated.  First-line therapy is typically hydroxyurea.  And the goal of therapy would be to control the blood cell count, meaning platelets in this situation.  And if there would be any other problem in terms of possibly in about ten percent of patients elevation in the white cells, or in some patients with elevation or enlargement of the spleen or symptoms, you would like to control it.  In this case, control of the platelets is paramount.  I would start the patient on the first-line therapy hydroxyurea. 

Alternative options in the younger people, for example, might be involvement of interferon preparations; there are several of them.  Long-acting interferons in particular are useful in younger people with ET to counteract the possible long-term side effects of hydroxyurea.  After taking it for three or four decades, one may have, for example, increased risk of squamous cell carcinoma of the skin.  So, in this particular case, hydroxyurea is the first choice.

LINDSEY      

Okay, great.  And, Sandy, although this patient - this was an incidental finding and he doesn’t have symptoms of the disease - in patients with ET, what are some common symptoms you may expect?

SANDY         

Right.  Well, we normally will see some patients who have migraines or headaches and don’t even relate it to high platelet counts.  Sometimes they would get some peripheral vascular thrombotic - little thromboses; microcirculatory problems are big.  We usually put patients on aspirin, along with hydroxyurea, to prevent any of those types of little thrombotic events from happening, paresthesias. 

But, a lot of the times patients may have some abnormal bruising or bleeding because of the platelet counts being so high, so definitely starting somebody on some type of therapy to lower the platelets would be recommended.

LINDSEY      

So, Sandy, are there any contraindications that you can think of of why you would not place somebody on aspirin?

SANDY         

So, patients who would not be placed on aspirin - one can think about if they’ve had a history of GI bleeding or are they on warfarin or clopidogrel already, so that these blood thinners where the patients really don’t need an aspirin to prevent thrombotic events would be contraindicated in using a low-dose aspirin.

LINDSEY      

Okay, great.  And, Serg, what about in patients who have a very elevated platelet count, is this something that you worry about?

DR. VERSTOVEK   

That’s a very good point.  When we reach a platelet number of a million and a half or higher, like two million, three million, then we know that because of the number of platelets that is acquired, one will have a refractory deficiency.  Basically, platelets chew up the protein from the blood and that makes people prone to bleeding.  In that case, as the guidelines usually indicate, there is the indication to site reduce the patients, meaning, prescribe a medication that will lower the platelets below a million to eliminate the risk of bleeding.

If that risk of bleeding is there and I test for 1 mg factor activity if it’s less than 30 percent - that’s the sign of the tendency to bleed - then I would not give the aspirin until the platelets are below the million.  And so, there would be a combination then of, let’s say, hydroxyurea and aspirin.  But, platelets should need to be below the million.

LINDSEY      

Okay, great.  That makes a lot of sense.  So, this patient is started on hydroxyurea and we started him at a dose of 500 mg twice daily and an aspirin 81 mg.  So, after three weeks of therapy, this patient’s platelets were still elevated - 600,000.  And so, the decision was made to increase the dose of the hydroxyurea to 1 gm twice a day. 

And, Sandy, now that his counts are more stable, the surgeons are thinking about doing this repair because he is symptomatic from this hernia.  And so, how do you collaborate with the surgeons to try to make them feel more comfortable about doing a safe procedure?

SANDY         

Well, we would check Von Willebrand factor, I guess, just to appease the surgeons and make sure that there would be no bleeding complications.  And as Dr. Verstovsek has stated, that really with higher platelets we are worried about risk of bleeding, where surgeons are usually worried about after surgery having thrombotic events.

LINDSEY      

Right, right.

SANDY         

So, bringing the platelets down below 500 usually is a safe area to have surgery and they should do okay.  But, we would monitor and work with them closely.

LINDSEY      

Okay, great.  And so, fortunately, this patient had a successful surgery and there were no complications.  And his labs were stable enough that he was just getting once monthly lab checks in the clinic continuing on 1 gm twice a day of hydroxyurea.  And he also, per our recommendations, is following up with his cardiologist to make sure that his cardiovascular disease is well controlled to eliminate further possible complications with these two processes.

And six months after starting therapy, however, the patient was admitted to the hospital for pneumonia and when he was admitted, his platelets were now 400,000, which is excellent.  That’s our goal, right?  But, his ANC had dropped to about 500.  There were no other lab findings that would make one concerned about transformation to, let’s say, myelofibrosis or leukemia, but now that the patient has been admitted for an infection with a pretty low neutrophil count - and we assume that it’s from the hydroxyurea - Serg, how would you approach this scenario?

DR. VERSTOVEK   

In every practice actually it’s very uncommon to have a patient on such a high dose.  We are talking about 2 gm total dose per day.  There are a number of retrospective chart review papers that were published over the last couple of years saying that that is uncommon for up to 10 percent of patients really require that much.  And this patient required that much, so this is the minimum effective dose for this patient to benefit in terms of controlling the platelet number.  That’s what you aim for.

LINDSEY      

Right.

DR. VERSTOVEK  

And that level, unfortunately, now he has a low white cell count, so cytopenia is a side effect.  He is now hospitalized, he has pneumonia; that’s not a good sign for continuation of this therapy.  And one needs to think about replacing the hydroxyurea with something else, which would provide a good control of platelets without any side effects.

LINDSEY      

Sure, okay.  So, if we decided to proceed with second-line therapy, we would consider a pegylated interferon or anagrelide.  Stephanie, can you talk to us about, you know, for this patient specifically, which would you favor and the reasoning behind that?

DR. CHASE

Sure.  There are very specific and distinct side effect profiles associated with both anagrelide and the interferon products.  Specifically, interferon products we want to counsel the patient on potential flu-like symptoms that occur immediately after each dose of the interferon, as well as patients can complain of significant fatigue with long-term use, as well as a very clinically significant side effect is mood disturbances.  And for patients that have a history of significant or profound depression or anxiety, there is a very increased risk of even suicidality in these patients. 

And then on the flip side, we have anagrelide, and anagrelide should be used with extreme caution in patients with a history of cardiovascular diseases.  And there was actually a statement released by the American Heart Association that anagrelide can directly induce myocardial toxicity such that it usually manifests as palpitations, arrhythmias, which usually originate from QTc prolongation, and they can even lead to torsades, and then you can also see arrhythmias. 

So, in this patient who already presents with several risk factors that already increase his risk for developing cardiovascular disease, we would potentially want to avoid anagrelide specifically because we have alternative options.

LINDSEY      

Okay, great.  So, then we’re going to go with an interferon.  So, Sandy, how does this work in your practice in getting somebody started and monitoring?

SANDY         

So, once we prescribe the peginterferon, we then have to go through a process of getting it approved through the insurance company.  It is a subcutaneous injection weekly, so an 87-year-old gentleman, he may be a little bit challenging to teach.  But, we normally start at 45 mcg subcutaneous weekly.  We teach the patent how to give the injection; it’s just like a little insulin injection, very small needle, pick a day.  They can take Tylenol prior to or right after taking it.  We explain to them taking it at bedtime is usually best so that if they do experience any of the flu-like symptoms, it’s better tolerated.

We do monitor, again, in the patients as they come into the office do they feel any depression or any fatigue, things like that.  Because it can also cause hypothyroidism, so that we do have to monitor their thyroids on a regular basis, as well.  So, they all come with side effects and --

DR. CHASE 

Yes.

SANDY         

Although it’s very tolerated.

LINDSEY      

Okay.  Well, great.  So, this patient actually is started and he has very good control of his disease within eight weeks of starting therapy.  And he’s tolerating it well; he is taking the Tylenol before the injection to try and avoid some of these flu-like symptoms.  And so, within eight weeks of therapy, his white blood cell count is 3.5, so we’ve had an increase in the neutrophils to 1.4; the hemoglobin is 13; and the platelets are 455.  And so, now he’s continuing every two months just following up in the clinic and doing pretty well.

LINDSEY      

So, the next case is a young patient.  This is a 30-year-old female with a past medical history significant for depression that’s well managed on Lexapro.  And she presented to the ED with three days of abdominal pain and bloating that has become progressively worse.  She does have an abdominal Doppler ultrasound in the emergency department and they have identified mild hepatomegaly with a hepatic vein thrombosis.  There’s no family history of a hypercoagulable condition or inheritable hypercoagulable diseases and the patient is not currently on birth control; the only thing she’s taking is Lexapro.

So, she is admitted overnight for pain control, anticoagulation initiation, and then further investigation, so the HEM/ONC team is consulted.  And Sandy, if you were consulted on this case, how would you go about teasing through this?

SANDY         

We would look at the CBC, obviously, look at the differential, see what the cells are made up of.  Her hematocrit being quite high would lead us to does she have a myeloproliferative neoplasm or does she have something else going on?  Checking her thyroid, making sure her thyroid is functioning properly.  We would rule out any sleep apnea, anything that would cause her to have a high hematocrit hemoglobin that could be like a secondary erythrocytosis, as far as any lung disorders, things like that.

Especially in a young woman of 30, if she’s menstruating, she should be pretty much self-phlebotomizing, so she should have a lower hemoglobin/hematocrit.  And the thrombotic complications also would steer us into working that whole system up, right?  So, CBC, LDH, erythropoietin level is important in working up if she does truly have polycythemia vera.  We would also look at a JAK2 status, so we would send off blood for mutation analysis.  As we discussed in the prior case, 95 percent of patients with polycythemia vera will have a JAK2 mutation

LINDSEY      

Right.  Okay, excellent.  Serg, what do --

DR. VERSTOVEK   

I think it’s standard practice now for an unexplained, out of the blue serious condition like that --

SANDY         

Right.

DR. VERSTOVEK   

-- where you have an unexplained thrombotic episode.  In addition to screening for all the other normal benign condition reasons, you should also screen - and half of the patients will be found to have a JAK2 mutation, JAK2 V617F, in unexplained situations like that.  And that would indicate possibly a presence of myeloproliferative neoplasms.  In many of these cases, that’s the case, up to 20, 25 percent of the patients with JAK2 positivity actually do have a disease if you do the bone marrow. 

So, paying attention to other blood cell count is key to find that disease and pursue for workup, including the bone marrow again, to make sure that you know that the disease is there.  It’s not just a risk factor of having a mutation, but having a disease there makes a difference for overall outcome of the patients.

LINDSEY      

Right.  Absolutely.

SANDY         

Right.  I mean, one always says do we need to do a bone marrow biopsy, right, on these patients?  Because we can do blood and just --

LINDSEY      

Sure.

SANDY         

-- get the JAK2 mutation.

LINDSEY      

Sure.

SANDY         

But, it is important to do a bone marrow biopsy, especially because of the NCCN Guidelines now or the WHO criteria stating the diagnostic factors that we need to meet in order to give the diagnosis of polycythemia vera.

LINDSEY      

Right, absolutely.  It just updated.  You know, that --

SANDY         

Yes, exactly.

LINDSEY      

-- diagnostic criteria just updated in the last year, so - right, very important - or the last two years.

SANDY         

Yeah.

LINDSEY      

So, this patient did have a hematocrit of 49 percent and, also, her white blood cell count was elevated at about 15,000, then with normal platelets on admission; they were 322,000.  So, Stephanie, a part of managing this patient is, of course, starting anticoagulation for this intraabdominal thrombosis.  And so, can you talk to me about starting anticoagulation in these patients and how to counsel patients?

DR. CHASE 

Sure.  So, of course, the first step is to select the most appropriate anticoagulant that we’re going to use for the patient.  And for these high-risk patients that have a history of a thrombotic event or an existing current thrombosis, there really are no stringent or well-established recommendations for which agent is actually preferred and so, we can actually break it up into the different classes of anticoagulants.  And because there are no strict recommendations for the preferred agent, it helps to take a deep dive and look at the patient’s comorbidities, as well as their current medications, because there are various drug interactions with the anticoagulants.

And then, of course, looking at organ functionalities, so hepatic and renal function.  And so, these factors will definitely help guide therapeutic decisions as far as which anticoagulant to use.  And so, looking at the different classes of anticoagulants - the DOACs, for example, or the direct oral anticoagulants - they all require renal dose adjustments.  And because they are all either substrates or metabolized through CYP3A4 enzymes and can be substrates of peak lacO protein, there are various drug interactions that, of course, come into play with patients that are on various medications.

And then looking at warfarin, for example.  Warfarin is a well-established agent - it’s been used for years and years and years - it carries the advantage of easy reversibility in the presence of supratherapeutic INR levels.  Therapeutic drug monitoring is very easy - it’s easily accessible - however, there are dietary restrictions.  So, for patients that have a transient diet, they have appetite changes, Warfarin likely isn’t the best agent to use.  And we also want to consider social habits; alcohol consumption can also alter how well we’re targeting the therapeutic range with warfarin.

And then, lastly, looking at the low molecular weight heparins, these are usually the agents utilized in the most acute setting because we can achieve immediate anticoagulant effects, rare drug interactions.  And as far as long-term use because you have to counsel the patients and make sure that they realize that their anticoagulation is going to be for at least a duration of three months.  And so, whether or not we decide to proceed with a low molecular weight heparin in the long term for that three-month duration is highly dependent on the patient’s compliance and their willingness to endure the discomfort of injecting a subcutaneous medication up to twice daily, as well as the inconvenience of the administration.

LINDSEY      

Sandy, now, you mentioned that the hematocrit being high can place patients at higher risk for thrombotic complications - and this patient does have a thrombosis, right?  So, can you talk about the utility of phlebotomy in patients with polycythemia vera and goals of the phlebotomy?

SANDY         

Yes.  So, that usually is the first line of therapy, is where we phlebotomize the patients - take out blood - because they are making too much red blood cells or their hematocrits are too high.  In the clinical practice, the magic number - hematocrit - we want to keep it under 45 percent.  And where that came from was clinicians in Italy.  Marchioli actually had a clinical trial and which published in the New England Journal of Medicine that came up with patients who were randomized to 45 percent and under compared to those that were kept 45 percent and higher to 50 percent showed a four-fold decrease in cardiovascular death and thrombotic events, major thrombotic events.

So, we as healthcare practitioners, have now adopted the under 45 percentage hematocrits.  We even use 42 in women because we’re smaller framed, right?  So, that’s quite important.  And if we’re not keeping those patients under 45 percent, they are at that much higher risk of major thrombotic events or even cardiovascular death, according to Marchioli’s data.

LINDSEY      

Sure.  Sure.  And so, then along with the phlebotomy at the very beginning of everything and starting the low molecular weight heparin for acute treatment or prevention of furthering of the thrombosis, the patient then does require cytoreductive therapy because although she’s not over the age of 60, now she has manifested herself as somebody who’s had a blood clot.  So, Serg, how do you approach initiating therapy in this type of a patient?

DR. VERSTOVEK   

Now, we would typically - not in this case - in the younger people consider the biological agent interferon.  Now, one of the side effects that is very well described and mentioned is depression.  And this patient is already diagnosed with depression and is already on therapy for depression.

LINDSEY      

Right.

DR. VERSTOVEK   

So, that is one of the contraindications to using the interferon; therefore, in this case, one would consider pills, and that would be hydroxyurea as front-line.  Although the patient is younger, but the necessity is there to use cytoreductive therapy, that will be standard practice to prevent another clotting.  And one is to normalize the red blood cells and white cells and eliminate any enlargement of the organs and look at the quality of life for that patient, as well.  So, cytoreductive is mandatory and hydroxyurea would be first-line.

LINDSEY      

Okay.  When she presented she had an elevation in her white blood cells - they were about 15,000 - does that affect your decision of how she’s responding to therapy or does that play a role?

DR. VERSTOVEK   

The abnormality that we can see is polycythemia vera comes in different flavors.  We always look at the red blood cells; it is mandatory to control hematocrit below 45 percent.  Now, we would like to have normal white cells, white platelets, normal spleen, not palpable spleen, and no symptoms from the disease, so the goals of therapy go around those five factors.  Not every patient has all the five factors.  In this case, she does have a high white cell count and with hydroxyurea you are likely to decrease that.

There are a number of papers, scientific reports, that in retrospect of a chart review setting indicate that the patients should have normalization of the white cell count because the high white cell count has been connected with the increased risk of thrombosis.  So, in my own practice, I am sensitive to the control of the white cells; first, would be the control of the red blood cells, then would be the white cells.  Platelets are the least worry because apart from the case of very high platelets that are associated with the bleeding, where the patient has 500, 700, 800, or 900 platelets, that platelet number has not been so far associated with the progressive risk or increased risk of thrombosis.  So, red blood cells first, white cells count second, platelets probably the least.

LINDSEY      

Okay.

DR. VERSTOVEK   

And then organs and symptoms.  That’s quality of life, so we look at the person altogether.

LINDSEY      

So, she is started on hydroxyurea and, additionally, with the phlebotomies - and she required the phlebotomies weekly for two weeks and that was it.  And then her hematocrit was controlled under 45 with hydroxyurea.  And she did start on 1500 mg a day, which was a pretty big dose, right?  And for many years she did well on hydroxyurea at a decreased dose, about 1000 mg a day.  But, the phlebotomy frequency started to increase actually over time despite being on this maximum tolerated dose of hydroxyurea.  And the white blood cell count actually started coming up again over time with the increased need of phlebotomy.

And so, Serg, can you describe how you determine if somebody is resistant to or intolerant of hydroxyurea in this setting?

DR. VERSTOVEK   

If you go by the five factors, they should be controlled, and in this particular case it is control of white cells and control of the red blood cells.  The first question is how do we describe the optimal control?  That would be normalization of the white cells, right?  And if the platelets were high, normal original platelets.  For the red blood cells, one would say elimination of the need for phlebotomy.  The guidelines usually clearly spell out elimination, that would be the goal. 

Now, there is sometimes the inability to control the red blood cells and you do utilize on top of the cytoreductive therapy a phlebotomy occasionally.  So, the practical question for everyday use is how many phlebotomies should you allow to happen while you are using cytoreductive therapy?  So, this discussion is very heated in the field where our Spanish colleagues published a year and a half ago that if you have three or more phlebotomies a year while you are on hydroxyurea, that’s not good enough.  You a decreasing the thrombotic risk somewhat, but not completely or not a satisfactory decrease and you should aim for better.  Other interesting entries are not sure, but the guidelines suggest to normalize hematocrit without the use of phlebotomy anymore. 

So, in this particular case, she did require occasional phlebotomy - that’s fine - but, now the phlebotomy requirement is increasing, the white count is increasing, so that goes under the loss of a response.  So, resistance, how do we define resistance?  Uncontrolled white cell platelets, progressive need for phlebotomy, progressive splenomegaly, progressive control of symptoms.  And there will be a need for discussion about if we cannot increase the dose of hydroxyurea - which we can’t; that’s the maximum tolerated dose - then alternative options.

LINDSEY      

Okay, great.  So, Sandy, what are some second-line options for this patient?  You know, we talked about that the interferons are not good for her because of her history of depression and so, what would you consider as the next step?

SANDY         

So, that’s a great question.  Again, interferon low doses -  now it’s mostly contraindicated being that she is well-controlled - one can argue can we monitor her very closely on low doses and see how she does?  If not, the only FDA approved drug that we do have to date now for hydroxyurea resistant or intolerant patients is ruxolitinib.  So, ruxolitinib - which is the new JAK inhibitor - would be something that we would start, as indicated.  So, it’s usually a 10 mg twice a day dosing. Again, it’s oral pills, again, 30-year-old and compliance issues with oral meds, but that would be the choice; ruxolitinib 10 mg twice a day.

LINDSEY      

Okay, great.  And, Stephanie, if we are going to choose this for our patient, then how would you go about ordering the ruxolitinib and what has been your experience in getting ruxolitinib for polycythemia vera patients who are resistant or intolerant to hydroxyurea?

DR. CHASE 

Sure.  Most insurance companies do consider ruxolitinib a specialty medication, so it makes the acquisition of the medication a little more tricky and may require a little extra TLC to ensure that the patient gets the medication in hand.  So, for larger institutions that have increased access to additional resources for medication access, they are lucky enough such that the time that lapses between the medication is actually prescribed to when the medication is in the patient’s hand can be significantly abbreviated.

At the University of Colorado, we have the luxury of working with the MARC PAR Team, which is our medication access renewal center and prior authorization request team.  It is a team made up of pharmacists and pharmacy technicians and they help the individual clinics in coordinating the different various moving parts that may be required to actually dispense and prescribe these specialty medications.

And so, we have found success in our specific clinic in which in conjunction with the Mark Team, the clinical pharmacists are primarily responsible for medication acquisition, as well as assessing the patient for any financial assistance needs if their resulting co-pay tends to be a little higher than they can afford.

So, we’ve developed a very stepwise approach to kind of simplify it and make it a lot easier in that first, we need to prescribe the medication and get it to the pharmacy.  And because it’s a specialty medication, many insurance companies will require that the medication be dispensed from a specific mail order specialty pharmacy, so getting it to the appropriate pharmacy first and then processing that prescription to assess whether or not it requires a prior authorization.  If so, it’s usually just a very simple submission of some signatures by the provider or additional clinical notes or maybe a little of evidence.  It’s rare that the prior authorization gets denied.  If so, we would send an appeal, which is simply submitting a letter of medical necessity on behalf of the physician.

Once all that is approved, we can see the resulting co-pay.  If that is cost prohibitive for the patient, we can actually apply them for various foundational support, as well as - luckily, for ruxolitinib for patients who are either commercially or privately insured, they actually are eligible for a co-pay or co-insurance card, which is available through Incyte - the program is called IncyteCARES.  And through this program, patients pay a maximum of $25 a month for their co-pay, which is wonderful.

LINDSEY      

That’s great.

DR. CHASE 

However, for patients who are not eligible for this co-pay card, as I mentioned, there are various foundational organizations for which patients can be approved for grants.  And some of these include NeedyMeds.org, there’s the HealthWell Foundation, Cancer Care Alliance, the PANF or Patient Access Network Foundation, as well as the Patient Advocate Foundation, so there are many resources out there.  And so, it does seem like a daunting process, but once you do it a few times and you actually establish that stepwise approach, it becomes very seamless and we can expedite and allow the patient to have a favorable medication access experience.

LINDSEY      

Absolutely.  Wow, great.  Well, with --

SANDY         

That’s so far - yeah.

LINDSEY      

It is very nice to have that entity to take care of those details and get the medication for the patients.  So, we were successful in getting it for this patient and she started on ruxolitinib 10 mg twice daily, like Sandy said.  That is the starting dose for polycythemia vera patients - it’s around the board - as opposed to in myelofibrosis where it’s based on different counts, which we’ll get into in a little bit.  So, she is started and we do labs weekly just to make sure that we’re controlling her counts.  And within four weeks, we are able to get her hematocrit to a place about 41 percent and her white blood cell count is about 8,000 and her platelets are about 200,000.  So, she’s tolerating it well and now we can kind of space her out to about every two weeks to once a month down the line.

SANDY         

Yep.

LINDSEY      

Yeah. 

SANDY         

Great.

DR. VERSTOVEK   

So, I want to ask if there is a need for overlap between hydroxyurea and ruxolitinib. 

LINDSEY      

Oh, excellent, yes.

DR. VERSTOVEK   

Which is quite often the case where I get a question from the community doctor do you just stop hydroxyurea or you --

LINDSEY      

Right.

DR. VERSTOVEK   

-- introduce - and if there is any benefit from hydroxyurea, I would say usually let it be in place.  The patients should continue for a few weeks, two or three weeks, while we are introducing ruxolitinib to have overlap and not to lose that partial benefit --

LINDSEY      

Absolutely.

DR. VERSTOVEK   

-- from hydroxyurea while we are waiting for ruxolitinib to kick in.

LINDSEY      

Okay.

DR. VERSTOVEK   

And the other aspect is what is the expectation of the dose adjustments of ruxolitinib?  So, 10 mg twice a day starting dose for everybody, only about 10 percent of the patients will need less, which you usually see within a month.  And about 66 percent of the patients will need more.  So, every month as you get the medications through the system and that’s automatically released to the patient’s home; usually you just call in another dose to be shipped when it’s necessary. 

So, I see patients usually about every three weeks at the beginning, just before the next shipment to see whether there is a next dose adjustment necessary.  And, again, the expectation is that you will need more.  Once you are stable and the disease is under control - signs and symptoms are under control - you can really space those follow-ups to every two or three months.

LINDSEY      

Okay, excellent.  Thanks for talking about that overlap; yeah, that should definitely happen.

SANDY         

Yes.

LINDSEY      

Okay.  Well, we’re moving on to our last case, which is a case about a myelofibrosis patient.  And so, this is a 72-year-old male with a past medical history of COPD, a history of an MI with stent placement ten years ago, and he presented to his primary care physician with increasing fatigue and dyspnea at night when he was lying flat.  And so, they did a pretty big workup given his cardiovascular diseases.  A CBC was included in that.  He was found to have a white blood cell count of 24,000 with three percent circulating blasts, a hemoglobin of 10.7, and platelets of 100,000.  And in his physical exam he had some wheezing in the bilateral lung fields and he had a very large abdomen full of fluid, so he had ascites and a palpable spleen on exam.  He really had not been going to his primary care physician very often for the physicals and this had just kind of happened over time.

He was sent for an echocardiogram and that did show some increased pulmonary arterial pressure concerning for pulmonary hypertension.  There was no evidence of overt heart failure for this patient.  So, then this patient was, of course, referred to one of us and so, Serg, again, we’ll talk a little bit about the workup in the office and I’ll give you a little bit of information first.  He did have a bone marrow biopsy and he had four percent blasts in the bone marrow, grade two to three reticulum fibrosis with atypical megakaryocytes, and diploid cytogenetics.  He did not have the JAK2, CALR, or MPL mutation, but he did have an ASXL1 mutation and a DNMT3A mutation.

The Doppler ultrasound of the abdomen revealed massive splenomegaly and evidence of portal hypertension.  And he did meet diagnosis for myelofibrosis looking at the bone marrow biopsy, symptoms of the disease, and then different laboratory features.  They did not do an LDH, but I’m assuming that we’ll add that to the panel once he gets to you.  So, Sandy, can you discuss prognostic scoring systems for patients who have met criteria for diagnosis with myelofibrosis?

SANDY         

So, there are a couple now that have come out.  IPSS scoring was the original and that is usually at time of diagnosis.  So, there’s one point for each of the five criteria, being age is constitutional symptoms, anemia, peripheral blasts, and leukocytosis.  So, that would give each a point depending on what criteria they have.  So, he is 70, so he’s over 65, he gets a point; he has peripheral blasts, he’s got another point; and he’s got constitutional symptoms - fatigue and we’ll say dyspnea, however.  He doesn’t meet for criteria because his hemoglobin isn’t under ten and his white count isn’t over 20, I think, or 25.

LINDSEY      

25.  He’s right on the cusp.

SANDY         

So, he’s right on the cusp, so even given the three points.  So, that’s International Prognostic Scoring Systems.  We then, also, have the DIP Scoring System and there are multiple different DIPSS; MD Anderson has their DIPSS scoring, we have a DIPSS scoring.  But, the major differences with the DIPSS is DIPSS can be used at any time at the patient’s - if he diagnosed in 2017 and we want to know what his scoring system is now, we can use the DIP Scoring System.  And it’s a little bit different - they just get two points for anemia under ten - but, again, the same point system.  We add up the points and what it gives us are the low-risk, intermediate, intermediate-2, or high-risk patient population, and it just gives us a little bit more information about their disease.

LINDSEY      

Okay, excellent.  And I think, too, the DIPs plus, yet another, the addition of thrombocytopenia --

SANDY         

Thromb - right.

LINDSEY      

-- with the platelets less than 100,000 --

SANDY         

Right.

LINDSEY      

-- and like you said, the transfusion requirements.  And then, also, the complex cytogenetics on the --

SANDY         

Right.

LINDSEY      

-- bone marrow biopsy --

SANDY         

Right.

LINDSEY      

-- can increase the patient’s risk.  Now, he did have diploid cytogenetics, --

SANDY         

Right.

LINDSEY      

-- so we don’t have to worry about that for now.  But, Dr. Verstovsek, so this patient with high-risk myelofibrosis with a lot of complications from the disease, would you send this patient for a stem cell transplant consult?  And when thinking about the possibility of sending somebody, what are important factors that you consider before you refer?

DR. VERSTOVEK   

So, why do we prognosticate?  The only reason why to prognosticate is not to utilize any specific medication.  Medications are given to counteract big spleen or symptoms of anemia, thrombocytopenia, something clinically irrelevant that needs to be controlled.  The reason is to send patients to the transplant and that is just based on IPSS, DIPSS, DIPSS Plus; there are variations.  And people use different scoring systems to identify patients that have a life expectancy of less than five years; usually, these are intermediate-2 or high-risk patients among these four. 

Regardless of the scoring system that they use, these are usual ones and this patient by that definition is the candidate.  However, he is sick otherwise; he has other medical problems, his performance status is not good.  He should probably be optimized what we say by giving him medications that will decrease his spleen, improve his ascites, that would improve pulmonary hypertension, that would improve his body composition.  And that would possibly make him a transplant candidate because we do transplant up to age of 75 if you get the patient in a proper physical condition and medical care is provided beforehand.

LINDSEY    

Okay, excellent. 

DR. VERSTOVEK   

Now, the other aspect here is presence of the molecular findings.  Some of these prognostic scoring systems that recently were published is MIPSS70 - just published in December of last year and presented in the American Society of Hematology Meeting - tries to incorporate not just the clinical findings and the symptoms and the cytogenetics, but also the molecular findings.  Among the driver mutations, which everybody usually can test for and they’re exclusive of each other like you said, JAK2 V617F, MPL, or calreticulin.  The calreticulin is the one that has a good prognosis.  The other ones, the MPL would be intermediate and the JAK2 would be intermediate, but the triple negative ones - and this patient has none of the three - is the worst.  So, by that feature he is not going to do well.  He’s already by the conventional ways in intermediate-2 or high-risk, plus he has a bad driver mutation profile, none of the three.

And you also brought to our attention the additional nondriver mutations that we can test for in many academic centers that we’re testing at MD Anderson 82 different genes - some other centers are up to 400 different genes - these are genes that make proteins that are not attached to the JAKs at part way, which is the underlying biological problem in these diseases.  These are mutations seen - and you mentioned one - NSX01, for example, is a known bad prognostic practice.  So, this unfortunate gentleman has many abnormalities that are going to affect him.

LINDSEY      

So, because he isn’t transplant eligible at this point in time, outside of a clinical trial - which, of course, you’d consider for these patients - what would be the best options for conventional therapy to start, Serg?

DR. VERSTOVEK   

So, if you look through his case you would say that his performance status is bad, he has organomegaly, he has a poor quality of life.  His anemia is not that bad; it’s above ten.  His white cell count is high, platelets are reasonable - it’s 100 - so, what are the main reasons to treat him?  Performance status, organomegaly, you would probably prescribe the ruxolitinib to counteract these two factors.  And the starting dose would be - as is usually the practice - determined based on the platelet number.  

His platelets are 100,000, so the judgement call is here what the dose would be because between 100 and 200, the start dose usually is 15 mg twice a day.  He is on a lower spectrum than 100, maybe use 5 twice a day or 10 twice a day for a starting dose in this case.  But, bear in mind that the maximum benefit of the ruxolitinib - in particular in the spleen to shrink it to the most it can - is directly related to the dose.  So, I would probably start cautiously with 5 twice a day or 10 twice a day and go higher as much as they can in monthly increments, not less frequent, in monthly increments to get him to benefit the most with the highest possible said dose.

LINDSEY      

Okay.  Okay, great.  Now, Stephanie, when these patients who do have portal hypertension secondary to organomegaly, are there any supportive medications that may be helpful for symptom control and even to kind of offload the portal pressures?

DR. CHASE 

Sure.  The American Association for the Study of Liver Diseases actually publishes really great and comprehensive guidelines for the management of complications associated with hepatic diseases particularly.  And for like ascites control they have very specific recommendations and it is to initiate a combination of diuretics.  And these are spironolactone at 100 mg once a day, plus furosemide 40 mg once a day in the morning.  And the once daily administration in the morning is recommended to improve compliance, as well as prevent nocturia because when patients are up in the middle of the night using the restroom multiple times, we run the risk of them just stopping the medications cold turkey.

LINDSEY      

Right.

DR. CHASE 

And these doses can be escalated every three to five days based on patient tolerance and efficacy and we always want to maintain that ratio of the 100 mg to 40 mg.  However, as we know, there are side effects with all medications and what’s nice about the combination is that we can maintain normal potassium levels because spironolactone is actually a potassium-sparing diuretic and then the loop diuretics, like furosemide make the body waste potassium.  So, we can kind of maintain normal potassium levels a little easier that way.  And the combination products have been found to be more effective than monotherapy with either agent alone.

LINDSEY      

Okay.

DR. CHASE 

And then another unfortunate side effect of spironolactone is the development of tender gynecomastia.  There are alternative agents, such as amiloride; however, it is not as effective as spironolactone, and it can be very expensive.  Eplerenone is a newer aldosterone antagonist that has been developed.  It’s well-studied in heart failure patients, but unfortunately, it hasn’t been studied in patients with ascites, so --

LINDSEY      

Okay.  Okay, excellent.  Yeah, so we start this patient then on ruxolitinib monotherapy and, Sandy, we know that cytopenias are a dose dependent side effect of ruxolitinib because of its mechanism of action.  And so, if this patient does develop the need for blood transfusions, how do you manage that?

SANDY         

We will give them a blood transfusion as needed.  Ruxolitinib will drop their counts about a gram to two grams of hemoglobin when starting, but it will then eventually come up, so you just have to be patient.  So, we do support them with blood transfusions through the low periods of their blood counts.

LINDSEY      

Okay, yeah.  So, not a reason to just --

SANDY         

Not a reason to stop, no.

LINDSEY      

-- all of a sudden, stop?

SANDY         

No. 

LINDSEY      

Okay.

SANDY         

But, they may require diuretics --

LINDSEY      

Sure.

SANDY         

-- with the transfusions so we don’t fluid overload them.

LINDSEY      

Absolutely.  Absolutely.

SANDY         

That would be the one.

LINDSEY      

Okay, great.  So, this patient - because of his platelets being right at 100,000 - he was started on the 15 mg twice a day of the ruxolitinib.  And he had improvement in his splenomegaly, white blood cell count also improved.  And he did receive a blood transfusion two weeks after starting for symptomatic anemia and hemoglobin was less than 8.  He had fatigue and shortness of breath, which resolved a little bit with the blood transfusion.  So, at four weeks lab assessment shows worsening thrombocytopenia; about 75,000 for the last couple of weeks.  And so, Stephanie, can you talk to us a little bit about dose reductions in ruxolitinib in relation to platelet count?

DR. CHASE 

Sure.  Similarly, to how we select the initial dose of ruxolitinib, dose reductions are based on platelet count if patients are developing any hematologic toxicities.  So, specifically for our patient - whose platelet count dropped between the range of 75,000 and less than 100,000 - it is recommended to decrease the current ruxolitinib dose by 5 mg twice a day below the current ruxolitinib dose or the dose at which the treatment interruption occurred.  So, if he was initiated on 15 mg twice a day, the resulting new reduced dose would be 10 mg twice a day.

LINDSEY      

Okay, great.  So, then after we make this change, then, Sandy, how frequently are you monitoring this patient after dose adjustments?

SANDY         

Yeah, we would bring him in weekly --

LINDSEY      

Okay.

SANDY         

-- for several weeks just to make sure that his counts are still holding on --

LINDSEY      

Okay.

SANDY         

-- and that he doesn’t require any more transfusions.

LINDSEY      

Sure.  Absolutely.  Yes?

DR. VERSTOVEK   

Now, for anemia one can consider adding another agent.

SANDY         

Right.

LINDSEY      

Sure.

SANDY         

Yes.

DR. VERSTOVEK   

And that would be usually - if there is no contraindication we would look at danazol, --

SANDY         

Right.  Oh, danazol.

DR. VERSTOVEK   

-- 200 mg twice a day.  Or we would also measure the erythropoietin level and if it’s less than 125 - some even say less than 500 according to NCCN Guidelines - there possibly would be candidate for adding EPO --

SANDY         

Right.

LINDSEY      

Okay.

DR. VERSTOVEK   

-- to the regimen.  And that is being officially studied, but in every practice one can consider that already.

LINDSEY      

Okay. 

SANDY         

This is a side note, but do you see using darbepoetin or erythropoietin spleen sizes increasing?

DR. VERSTOVEK   

No, I haven’t seen that.

SANDY        

No?

DR. VERSTOVEK   

That’s a concern.  The clinical experience so far that was published didn’t show that, but the question is is that a real benefit to giving patients that darbepoetin, which is being studied in Europe in an official study?  But, occasionally patients can actually benefit.  There are not too many choices, as you know, for anemia, so --

SANDY         

Right.

DR. VERSTOVEK   

-- giving it or giving danazol, it’s usually a way to go to trying to help patients at least to some extent.

SANDY         

Right.  Because then we have to face iron overload with --

DR. VERSTOVEK   

That’s right.

SANDY         

-- these patients, yeah.

LINDSEY      

Right, absolutely.  So, on routine follow-up a few months later, he’s doing well on this dose of ruxolitinib without furthering cytpopenias.  But, unfortunately, a few months later he comes back and his white blood cell count is now 43,000 and he’s got peripheral blasts at 10 percent now in the blood.  His platelets have dropped slightly, but not terribly so; they’re 65,000.  And he’s still requiring the transfusions about every two weeks now.  And when he comes into the office he also notes that he has some tender nodules on his leg that are fairly new in the right thigh and they’re growing fairly rapidly it seems to him. 

So, Dr. Verstovsek, what is your approach now with a patient like this in developing some increased peripheral blasts and some concerning nodules?

DR. VERSTOVEK   

So, this is something that actually is expected because the patient had a very good molecular profile.  SXL1 mutation is one that leads to rapid progression in short order.  He had other bad prognostic factors, so one needs to follow this patient, optimize his care as much as possible, and maybe consider transplant.  But, he didn’t make it and now we have a complication.  That’s a progression of the disease, elevation in the blast, progression in the blood cell count, that means lowering of the platelets.  These are usually silent signs of a progression; increase in white cells, lowering the platelets, sometimes worsening anemia and progressive splenomegaly; basically, loss of response with the JAK inhibitors.

And in this sense, we separate the patients with them all in three groups; one would be chronic phase up to 10 percent of the blast; then 10 to 20 percent of the blast would be patient with accelerated phase myelofibrosis; of course, after 20 percent and above, that would be blastic phase, acute myeloid leukemia.  And this patient has accelerated phase myelofibrosis.  The outcome is not very good because of tendencies for progression to acute myeloid leukemia where your life is very short.  So, the standard approach would be adding a hypomethylation agent - and this is even by NCCN Guidelines - to a regimen that the patient is already on. 

If there is a benefit, for example, in this patient, in controlling spleen and symptoms with ruxolitinib, but you have a new development, which is not related to the ruxolitinib, not a side effect of ruxolitinib, all the numbers are different, you would be able to continue on the ruxolitinib and add another medication to counteract new development.  And that would be one of the hypomethylation agents.  And then control those blasts, optimize his care again, and try again to get him to transplant, if possible.

LINDSEY      

Okay, great.  And in these patients - you know, he’s an accelerated phase, but let’s say we were to do a bone marrow biopsy and he had 30 percent blasts, making him transform to acute myeloid leukemia - and the subcutaneous nodules, right.  Yeah, they were biopsied and consistent with a myeloid sarcoma - which unfortunately, can happen - outside of transplant thinking about hypomethylating agents with the ruxolitinib versus standard chemotherapy - how do you think about those sort of decisions, Dr. Verstovsek?

DR. VERSTOVEK   

Yeah.  So, the acute myeloid leukemia after myeloproliferative neoplasm is a very bad condition.  Among different types of acute myeloid leukemia, this would be the worst outcome and there are no effective therapies.  We know that the complete response rate with standard intensive chemotherapy is achievable in about 30 percent of the patients, but the survival from many studies is about five to six months.   You can usually sustain that response, patients are too sick or it doesn’t work anymore, disease comes back. 

Studies in hypomethylation agents either in accelerated or blastic phase have shown that the response rate is about the same and yet, you keep the patient in an outpatient setting, it’s not hospitalization, it’s not intensive chemotherapy.  Therefore, the new NCCN Guidelines suggest that for accelerated or blastic phase AML after MPN you should consider hypomethylation agents, clinical study, or a low intensity chemotherapy.  Unless there is a situation where you have a donor, you need to eliminate disease or minimize it as much as possible, then you would do intensive chemotherapy followed immediately by the transplant, which unfortunately, is not very common.

So, standard practice in elderly patients like this one would be hypomethylation agents for accelerated or blastic phase with or without ruxolitinib for the symptoms control.

LINDSEY      

Okay.  All right.  So, Stephanie, we’ve decided then that hypomethylating therapy is the way we’re going to go and so, it’s decided to use decitabine therapy.  And so, when you’re talking to a patient about starting decitabine, what are some of the things that you tell them about possible side effects?  And then kind of a follow-up question, too, is that in these patients who have developed more aggressive disease - as you would probably say, cytopenias are a possible risk of the decitabine therapy and the patient is still on ruxolitinib - how do you navigate if they need, let’s say, antifungal prophylaxis or these sorts of things to protect them?

DR. CHASE 

Sure.  Anytime we’re initiating a patient on an antineoplastic therapy, they usually voice two concerns; am I going to lose my hair and is it going to make me vomit? 

SANDY         

Right.

DR. CHASE 

So, we can rest assured that decitabine and the hypomethylating agents have a very, very low, if no, risk of causing alopecia.  With respect to nausea and vomiting, the hypomethylating agents, azacitidine and decitabine, fall into a category of very minimal emetic risk, such that less than 10 percent of patients will experience chemotherapy-induced nausea and vomiting without any intervention.  Thus, the use of prophylactic antiemetics in this case really isn’t warranted; however, it is important to assess a patient’s past medical history and look for risk factors that increase the risk of developing chemotherapy-induced nausea and vomiting.  Some of these include younger age; female gender; patients that have a significant history of motion sickness; women who throughout their pregnancies have a significant history pregnancy-induced morning sickness; and then depression is also another risk factor.

SANDY         

Anxiety, I think, too, right?

LINDSEY      

Yes.

DR. CHASE 

Yes.  So, if patients are presenting with various risk factors, I would say it’s not going to hurt to initiate a prophylactic antiemetic regimen and monotherapy is very sufficient.  At our institution, we usually utilize ondansetron, a serotonin receptor antagonist, 8 mg orally 30 to 60 minutes prior to each decitabine dose, and this is going to help prevent any acute nausea and vomiting associated within 24 hours after each dose.

LINDSEY      

Okay.

DR. CHASE 

Other side effects that we look out for, the hypomethylating agents can cause some GI distress; the incidence of constipation versus diarrhea is actually quite similar, so assessing a patient’s baseline bowel movement habits.  And sometimes patients tend to have a little more constipation.  And especially if patients are already on opioids or we anticipate that they’re going to be utilizing the serotonin receptor antagonist pretty heavily, they’re going to be at increased risk of constipation.  And then, so counseling them about maintaining a healthy bowel movement regimen and potentially initiating or introducing a stool softener or some laxatives into their regimens.

Other side effects include some fatigue - a lot of patients will complain of fatigue - decreased appetite, sometimes a headache, and then, of course, pancytopenia.  So, it’s important to counsel patients on watching out for signs and symptoms of bleeding if their platelet count tends to dip lower, making sure that they are reporting any shortness of breath if - you know, consistent with anemia, and then, of course, making sure that we’re counseling on neutropenic precautions if patients are going to be neutropenic.

And in the setting of profound and prolonged neutropenia, most patients are going to be initiated on prophylactic anti-infective, which include an antiviral, an antibiotic, and an antifungal.  So, our gold standard outpatient antifungal class is the use of azole antifungals.  And as we know, the azole antifungals carry the risk of significant drug interactions. 

And in the case of our patient, if we’re going to maintain him on the ruxolitinib therapy, the ruxolitinib is a substrate of CYP3A4 enzymes and the azole antifungals are going to inhibit the metabolism of ruxolitinib, thereby potentially increasing toxicities of the ruxolitinib itself.  And so, there are some recommendations as far as when to dose reduce or looking at the package insert for ruxolitinib.  The recommendations are actually quite vague; it says avoid the combination when possible or even disrupt the ruxolitinib therapy for the duration of the strong CYP3A4 inhibitor, which in our patient population doesn’t make sense because we’re using ruxolitinib as symptomatic control.  And we’re always driving the importance of compliance because missing just a couple doses, we can have the rebound symptoms associated with their disease.

And so, from my perspective for agents such as fluconazole and isavuconazole - the azole antifungals - if we’re utilizing those as prophylaxis, they’re more moderate CYP3A4 inhibitors.  So, I would argue if the patient has really good symptomatic control at this point and they’ve been on a stable dose for quite some time, that I would maintain that dose of ruxolitinib and not initiate any dose reductions at this time because we can always increase the frequency of how often we’re monitoring and watching out for hematologic toxicities specifically.

However, for the other azole antifungals, such as voriconazole, posaconazole, itraconazole, and ketoconazole, those are very potent CYP3A4 inhibitors.  So, you can argue that for patients that probably don’t have a symptomatic control or they have a history of various dose modifications and reductions of the ruxolitinib secondary to toxicities, then it would be warranted to decrease the dose of ruxolitinib empirically by at least 25 to 50 percent.

LINDSEY      

Okay, excellent.  Thank you.  So, Sandy, what does a follow-up look like?  Like as Stephanie’s talking, if we’re needing to add these different agents and monitoring their counts a little bit more closely, especially patients on decitabine, what does follow-up looking like for these types --

SANDY         

These patients?  So, --

LINDSEY      

-- of patients, right?  Because now we’re out of the chronic phase, myelofibrosis and into a more acute situation, of course.

SANDY         

So, we would be bringing them back twice a week - Mondays/Thursdays - checking their CBCs, transfusing as needed, making sure they’re not having any of the symptoms of ruxolitinib or decitabine -  neutropenia - make sure they’re not having neutropenic fevers or any mouth sores or diarrhea or any of those types of symptoms.  So, we monitor them very closely and throughout the cycles.

Now, decitabine - we may need to treat them again with a second cycle of decitabine.  So, depending on counts and recovery and if they do recover and whatnot, it’s just very close follow-up.

LINDSEY      

Okay, excellent.  And, Serg, when would you repeat a bone marrow biopsy to see if we’ve had good response or --

DR. VERSTOVEK   

Yep.  So, usually you have an effect between the two or three cycles; usually, by two cycles you have optimum response.  But, typically, we would do this after three cycles not to miss the benefit.  And if there is any benefit - and benefit not only includes the complete resolution of the disease, but a decrease in the blasts - that will be beneficial for the patients because you are preventing progression and all the signs and symptoms of the disease with uncontrolled blood cell count and organomegaly.  So, it’s not absolutely necessary to fulfil a strict definition cell response for you to see a clinical benefit.

And so, after three months, you assess the response by looking at physical exam, blood cell count, bone marrow, and then you decide whether to continue.  And my practice is usually if there is any benefit for the patients - because the situation is extraordinarily difficult for the patient - even any benefit of an improvements that you see, I would continue therapy as long as possible for possible prolongation of life.  Some studies show that with continuous therapy even without CR you can make people live longer for a few months with a good control of the disease in an outpatient setting.

LINDSEY      

So, that kind of talks about a lot of points in these very high-risk patients with unfortunate progression.  And being at an academic institution, all of us are fortunate to have access to clinical trials, as well.  And so, I would just kind of - this is kind of an open forum, but are there any specific trials that are exciting or particularly promising right now going on at anyone’s institution?

DR. VERSTOVEK   

Now, to learn from this particular case, one would realize that ruxolitinib or JAK inhibitors do not prevent progression.  They are controlling the signs and symptoms of the disease very well in many patients for very long and they may extend the life for some years, but the therapy does not work forever.  Our approach is to optimize the care as much as possible and then try to get the patients to transplant, which would be a curative potential.

Otherwise, adding a medication to prevent progression, for example, is one.  We have studies with hypomethylation agents and two types of studies with both of the hypomethylation agents for patients that are increasing their blasts after 20 percent or when they’re all in acute myeloid leukemia phase to see which dose and schedule is optimum for the two agents to work together the best because we already realize then intensive chemotherapy doesn’t work well.

The other aspect that we talked about is the anemia problem.  So, we have medications in our live studies across the globe that are appearing to improve the anemia; these are called sotatercet or luspatercept.  These are investigational agents that are being tested even in the combination with ruxolitinib in patients if they’re anemic.  Because anemia is a problem, so antianemia medications, hypomethylating agents for accelerated blastic phase, and the medications that are being developed as a second-line after ruxolitinib where patients lose response.  We have pancytopenia, we have progressive spleen, something else needs to be done; other JAK inhibitors or new agents that have a completely different ballgame here to try to counteract some other problems that arise during therapy with the JAK inhibitors.  Because one of the main problems of failing therapy is clonal evolution. 

You talk about the known driver mutations that may be present in patients, they are actually acquired during the life of the patients, acquired during therapy with whatever you use, either interferon or ruxolitinib in this case.  So, that is one of the many reasons of failing therapy.  Disease changes, basically.

LINDSEY      

Well, it’s good to know that there are many clinical trial options available to these patients.  Thank you all for being here.  It’s been a really great discussion and I’m really, really thankful for all your valuable input.        

DR. VERSTOVEK   

It was great, thank you.

SANDY         

Thank you.  Thank you.

LINDSEY      

So, in conclusion, the management of MPN patients requires a multidisciplinary approach and can be quite complex.  In ET and PV, proper medical management of cardiovascular risk factors is key for reducing cardiovascular events.  Presentation of myelofibrosis patients is heterogenous and can quickly progress to high-risk disease with subsequent transformation to acute myeloid leukemia.  And close monitoring of higher risk patients will help ensure a change in therapy or additional therapy is started in a timely manner.

Clinical trials should be considered for MPN patients, as current therapies are not necessarily disease modifying, but rather, aimed at controlling the disease and associated signs and symptoms. 

Thank you so much for watching this video.  I hope you’ve gained valuable insights that will affect your practice.

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