Erba Explains the Significance of Mutational Markers in Patients with PMF and PV


Harry P. Erba, MD, PhD, recently talked about the treatment considerations and decisions he makes when treating patients with primary myelofibrosis and polycythemia vera. Erba explained his treatment decisions for patients with myeloproliferative neoplasms based on 2 case scenarios to a group during a <em>Targeted Oncology </em>live case-based peer perspectives presentation.

Harry P. Erba, MD, PhD

Harry P. Erba, MD, PhD, recently talked about the treatment considerations and decisions he makes when treating patients with primary myelofibrosis (PMF) and polycythemia vera (PV). Erba, a professor of medicine and director of the Leukemia Program at Duke University, explained his treatment decisions for patients with myeloproliferative neoplasms (MPNs) based on 2 case scenarios to a group during aTargeted Oncologylive case-based peer perspectives presentation.

Case 1

January 2016

A 59-year-old man presented to his physician with symptoms of fatigue and abdominal pain lasting 3 months; he also reported increased bruising. A physical exam showed his spleen was palpable, 6 cm below the left costal margin.

His genetic testing was positive for theJAK2V617F mutation. A bone marrow biopsy revealed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis and a blood smear also revealed leukoerythroblastosis.

Lab findings were notable for the following: red blood count (RBC), 3.20 x 1012/L; hemoglobin (Hb), 9.3 g/dL; hematocrit (HCT) blood test, 34%; mean corpuscular volume (MCV), 93.1 fL; white blood count (WBC), 12.1 x 109/L; platelet (PLT) count, 247 x 109/L; peripheral blood (PB) blasts, 0%.

What are your general impressions of this case?

This patient is a 59-year-old man who presents to his physician with symptoms of fatigue and abdominal pain lasting for the past 3 months. He also reported increased bruising. On physical exam, he had splenomegaly with a spleen palpable—6 cm below the left costal margin. His blood count showed an anemia with a Hb of 9.3 g/dL and his WBC was slightly elevated at 12.1 x 109/L. He had a normal PLT of 247 x 109/L. There were no PB blasts. He had peripheral blood sent for polymerase chain reaction (PCR) analysis, which showed that theJAK2V617F mutation was present.

A bone marrow biopsy was done, which showed megakaryocyte proliferation with atypia, and evidence of reticulin fibrosis. When looking at the blood smear, there was evidence of leukoerythroblastosis, which is dacrocytes or tear drop cells, nuclear red blood cells, and some giant platelets.

What are the diagnostic criteria for PMF?

According to the World Health Organization (WHO) 2016 diagnostic criteria, there are 3 major and 4 minor criteria for the diagnosis of PMF. The first is that the bone marrow should show megakaryocytic proliferation with atypia—which is typically large megakaryocytes with hyperlobated and hyperchromatic nuclei&mdash;and the presence of at least 2 reticulin fibrosis. At this point there is a pre-fibrotic or cellular stage of myelofibrosis where you do not need to see reticulin fibrosis. But, the megakaryocytic proliferation with atypical and granulocytic proliferations are important.

The second criteria is to rule out other causes of the patient's presentation with laboratory values and bone marrow, such as chronic myeloid leukemia and myeloid dysplastic syndrome. Additionally, I would like to remind people that autoimmune MF can cause significant marrow fibrosis in the setting of other autoimmune diseases. There is truly a whole list of things to rule out in terms of disease.

The third criteria is some evidence of clonality. This includes looking for theJAK2V617F mutation, found in about 50% to 60% of patients with PMF, theCALRmutation, which is found in about 20% to 30% of patients, orMPLmutations, which is found in about 10% of patients. There are about 10% of patients who don't have any of those mutations and some other form of clonality needs to be seen, such as cytogenetic changes or other mutations includingASXL1andIDH1/2. Of course, we also need to make sure that there are no causes of the reticulin fibrosis.

In terms of minor criteria, leukocytosis, anemia, the lymphoblastic picture, and elevated lactate dehydrogenase are all included. As I said before, we also need to rule out other disease, most commonly myelodysplastic syndrome and other MPNs that can cause the same picture. Also, keep in mind, if you are just looking at the fibrosis, there are many different things that infiltrate the marrow, such as Hodgkin disease, leukemia, other cancers, autoimmune fibrosis, and others.

How is risk assessed for PMF?

Until recently, the risk associated with PMF has been judged by clinical criteria. The first were called the International Prognostic Scoring System (IPPS), where 5 risk features were thought to carry a higher risk of death and progression in this disease. Those criteria include patients over the age of 65, constitutional symptoms, anemia with a Hb under 10, leukocytosis with a WBC of over 25,000, and circulating blasts of 1% or more.

The Dynamic International Prognostic Scoring System (DIPSS) could be used at any time along the disease course and was very similar to the IPSS criteria, except that the anemia was weighted twice. Finally, the DIPPS-Plus was published, where those 5 features were considered in addition to transfusion dependence, thrombocytopenia, and cytogenetic abnormalities. Most patients with PMF, such as this case, will present with intermediate- or high-risk disease. Only about 10% will have low-risk disease, and the rest will mostly be evenly divided between intermediate- and high-risk disease. Those patients with high-risk disease have the highest risk of transformation to acute myeloid leukemia. A 5-year-survival rate [for these patients] is only 39%.

We have been learning over the years that there are certain mutations that have been associated with outcome in patients with PMF, such as the presence of other high-risk mutational profiles, such asASXL1,SRSF2, and an unfavorable karyotype, which is almost any karyotype with a few exceptions. These have been added to the prognostic scoring system and can help us prognosticate further in this disease.

The reason why prognostication is so important is because patients with high-risk or very high-risk disease should be considered for allogeneic stem cell transplant (allo-SCT) if possible.

What is the trigger to initiate therapy for a patient with MF?

I would consider the initiation of therapy in any patients with intermediate- or high-risk disease, regardless of symptoms. In the COMFORT-I study, where patients were treated with either ruxolitinib (Jakafi) or placebo, patients who were randomly assigned to placebo had an inferior survival at 2 and 3 years, compared to those who were randomized to ruxolitinib.1What is amazing about this statement is that there was a crossover design in the study, and the majority of patients who were randomized to placebo actually crossed over at a median of 9 months after going on the study.

This has been interpreted to suggest that early intervention in appropriate patients with PMF is important in order to improve long-term—or at least short-term&mdash;survival. Having said that, all of the patients on this study had intermediate-2 and high-risk disease. They were quite symptomatic from their disease. Based on the COMFORT-I study, I think it is important to strongly consider beginning therapy for patients who have intermediate-2 and high-risk disease. They have a worse outcome without therapy and it appears that ruxolitinib may improve their survival. Of course, these patients, if appropriate, should be considered for allo-SCT. Many of these patients with intermediate-2 and high-risk disease will be symptomatic and can derive quite a bit of benefit from JAK1/2 inhibition with ruxolitinib. It is important to consider initiation of therapy in patients who may even have intermediate-1 risk disease, but who are symptomatic. The majority of patients&mdash;over 90%&mdash;will ultimately require therapy for their disease.

What are the risks associated with undertreatment?

Based on the results of the COMFORT-I study, the risk of undertreating these patients—not instituting a JAK1/2 inhibitor&mdash;is that the disease may progress to a point that, even with later intervention, you may not be able to impact the survival as much as if you had started treatment earlier on. The risk is missing the opportunity to improve their survival.

Secondly, in the appropriate patients, allo-SCT is the only curative option and it should be considered in patients who have progressive disease and intermediate- or high-risk disease. The tricky part in the management of these patients is to consider allo-SCT. This should not be done too early in the course, where the risk of a transplant may outweigh the benefit. But if there are signs of progression of disease, referral to a transplant center could be very important. If you miss the opportunity and refer patients too late for transplant, they may not be able to undergo the procedure. The complications may be greater in later stages of PMF, and many of these patients may be turned away.

Case 2

January 2015

A 39-year-old man presented with headache and palpable splenomegaly (2 cm below costal margin). He was a 1-pack-per-day smoker at the time, but had no thromboembolic event.

PCR analysis was positive for theJAK2 V617Fmutation and he was diagnosed with PV. The patient was started on phlebotomy as needed and daily low-dose aspirin.

January 2016

The patient had 3 phlebotomies in the last 3 months and complained of increasing dizziness, headaches, nausea, and abdominal fullness. He spleen length was 16 cm; spleen volume was 2847 cm3. His lab values were notable for the following: HCT, 48.5%; WBC 14.8 x 109/L; PLT, 709 x 109/L.

What are your general impressions of this case?

This patient is a 39-year-old man who presented with headaches and palpable splenomegaly. He is a smoker, but had no prior thromboembolic event. Therefore, by age and lack of thromboembolic events, he has low-risk disease, which turns out to be PV, as shown by his blood counts and a PCR analysis that was positive for aJAK2V617F mutation. This patient had leukocytosis, thrombocytosis, and PV presentation.

He was started on phlebotomy as needed and daily low-dose aspirin. This is an appropriate treatment because he is not at high risk for thrombotic events. He is not symptomatic from the spleen, which is only 2 cm down. The case does not mention any other symptoms related to PV, such as fever, weight loss, fatigue, or drenching night sweats. The headache was most likely due to PV, which can be managed.

He does have leukocytosis and thrombocytosis. Leukocytosis has been associated with a higher risk of thrombotic events, but it is not clear based on this risk factor alone that myelosuppressive chemotherapy should be used. Although, it would not be considered inappropriate. This patient was started on phlebotomy and low-dose daily aspirin. The reason for this is that maintaining the hematocrit less than 45% has been shown to decrease the risk of death due to thromboembolic events and arterial thrombosis in a study by Roberto Marchioli, MD, and colleges published in theNew England Journal of Medicine.2This was when compared with a slightly less stringent hematocrit control of 45% to 50%. The risk of those events decreased from 9.8% down to 2.7% at 3 years.

He goes on to receive 3 phlebotomies in the past 3 months and he is still complaining of dizziness and headaches. He also has some nausea and abdominal fullness, and his spleen is much bigger. We have progressive splenomegaly that is symptomatic. He is still requiring phlebotomies with a hematocrit of 48.5%, and he still has leukocytosis and thrombocytosis with a WBC of 14,800 and PLT of 709,000.

What are the treatment options?

At this point, phlebotomy alone is not reasonable. He has symptomatic splenomegaly and progressive leukocytosis, which may be associated with a higher risk of thrombotic events. So, I think it is appropriate now to consider cytoreductive therapy. It is also important to note here that this patient was reevaluated every 3 months, and this was over the first year that this developed.

For cytoreductive therapy, you have the choice of hydroxyurea (Hydrea) or interferon. Hydroxyurea is typically what we use based on its lower cost, tolerance by patients, and hematologic control. The concern of hydroxyurea is that some feel that this may be leukemogenic, particularly in a man who is under 40 years old, such as this one. Some may fear he might be at a higher risk of leukemia after decades of hydroxyurea therapy. Interferon can be used [as another option]. It does not carry the risk of leukemogenesis that we can perceive. However, it does have a number of other adverse events that make it very hard for patients to tolerate. Even though he was under 40 years old, I would personally have chosen hydroxyurea for this patient.

He continued on phlebotomy as needed and aspirin was continued. He was started on hydroxyurea 500 mg daily.

July 2016

The patient came back 6 months later. His spleen was a little smaller, and he had 2 phlebotomies. Lab values were notable for the following: HCT, 47.5%; WBC, 13.2 x 109/L; PCT, 650 x 109/L.

What are your impressions of this case after disease progression?

We continued to treat with phlebotomy and aspirin, and hydroxyurea was added at 500 mg a day. Six months later, the spleen was a little bit smaller, he was still requiring phlebotomy, and he still had leukocytosis and thrombocytosis, although they are better.

What are your treatment options after disease progression with hydroxyurea?

We started with hydroxyurea and he is only on 500 mg a day, so I think it is reasonable, since he has tolerated hydroxyurea, to push the dose to the maximum tolerated dose (MTD) in this patient before abandoning the therapy completely. I wouldn't just continue hydroxyurea, I would increase the dose to the MTD—hopefully to at least 2 g per day&mdash;and give him a 3-month trial.

I think that it is premature to switch to another myelosuppressive agent, such as interferon. We have not declared him intolerant or resistant to hydroxyurea, so I don't think that he is a good candidate for ruxolitinib. And in this case, that is what was done. Hydroxyurea was pushed to 2000 mg a day. I would advocate that the patient could take all 4 capsules at once to improve compliance, or you can split it into 2 times per day. Past that, you begin to decrease compliance with therapy. I try to dose hydroxyurea either once or twice a day.

Hydroxyurea was increased to 2000 mg/day over the next 3 months.

January 2017

The patient returned 6 months later with some abdominal fullness, pruritis, still requiring phlebotomy. He also had restless legs and complained of sore tongue and food tasting &ldquo;funny.&rdquo; Lab values revealed the following: HCT, 46.5%; WBC, 11.6 x 109/L; PCT, 580 x 109/L.

What are your impressions of this patient&rsquo;s response to therapy?

Despite the dose increase of hydroxyurea, he still has abdominal fullness. Now, he has pruritis. He is still requiring phlebotomy, which has led to iron deficiency with restless legs and food that tastes funny. So, it is symptomatic iron deficiency.

When you look at his blood counts, he still has leukocytosis and thrombocytosis. At this point, I feel comfortable saying that he is resistant to the effects of hydroxyurea. He has tolerated it—he hasn't had cytopenia, gastrointestinal toxicities, and there is no mention of leg ulcers or other unusual toxicities, such as squamous cell carcinomas, pulmonary toxicity, or fevers. However, he is clearly not having an optimal response. He is still symptomatic from splenomegaly. He now has a symptom directly from the PV, which is pruritis. And, although phlebotomy is being used, he is iron deficient and symptomatic. So, he is not tolerating that well. There are some retrospective data to suggest that more than 3 phlebotomies in a year may be associated with worse outcomes.

What are the treatment options at this point?

I think it is very appropriate to consider switching this patient to ruxolitinib at 10 mg twice daily because he has signs of having uncontrolled PV. He also has the persistent leukocytosis. In the Marchioli publication, a WBC over 11,000 was associated with a statistically higher chance of having a thrombotic event compared with patients with a WBC of 7000 or below.

Ruxolitinib has now been included as an option for patients with intolerance or resistance to hydroxyurea or interferon in the National Comprehensive Cancer Network (NCCN) guidelines. They also included if the patient is having persistent need for phlebotomy or poor tolerance, as in this patient, because of iron deficiency, progressive splenomegaly, as in this patient who has abdominal fullness, and symptomatic thrombocytosis. He did not have progressive leukocytosis but did have persistence of the leukocytosis despite a MTD of hydroxyurea. And he was having disease-related symptoms with pruritis. He met some of the criteria for the NCCN guidelines for switching to ruxolitinib. Keep in mind, as you start ruxolitinib, in the first months the PCT actually may go up but ultimately will come down.

What is the rationale for ruxolitinib in this group of patients?

The benefit of ruxolitinib in this group of patients was shown in the RESPONSE trial, with 60% of patients having hematocrit control and nearly 25% patients having a complete hematologic remission.


  1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis.N Engl J Med. 2012;366(9):799-807. doi: 10.1056/NEJMoa1110557.
  2. Marchioli R, Finazzi G, Specchia G, et al; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera.N Engl J Med. 2013;368(1):22-33. doi: 10.1056/NEJMoa1208500.
  3. Vannucchi AM, Kiladgian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera.N Engl J Med. 2015;372(5):426-435. doi: 10.1056NEJMoa1409002.
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