Science & Medicine

Spivak – How I treat PV

Spivak on PV

“How I Treat Polycythemia Vera”
Jerry Spivak (Johns Hopkins University School of Medicine)  Blood First Edition Paper, prepublished online May 31, 2019; DOI 10.1182/blood.2018834044

— Reviewed  Zhenya Senyak

Few if any hematologists have immersed themselves as deeply in the history, diagnosis and treatment of polycythemia vera as Johns Hopkins professor Jerry L. Spivak, MD.

Jerry L. Spivak, MD

In this well-written paper, he shares his thoughts on the options open to hematologists and weighs in on his preferrences using  a clinical and patient-based approach. Along the way the reader is treated to snippets of history, observations from medical icons and a wealth of graphic and reference data.  And he does it all in a mere eight pages.

The paper itself — along with its figures, graphics and list of  fully annotated 138 references – outlines a thorough experienced-based approach to PV treatment in accordance with precision medicine for physicians and patients alike

(Spivak’s main points about diagnosis and treatment options are presented here in an interview format focused on treatment.)

From the abstract:

“Since its discovery, polycythemia vera (PV) has challenged clinicians responsible for its diagnosis and management and scientists investigating its pathogenesis. As a clonal hematopoietic stem cell (HSC) disorder, PV is a neoplasm but its driver mutations result in overproduction of morphologically and functionally normal blood cells. PV arises in an HSC but it can present initially as isolated erythrocytosis, leukocytosis, thrombocytosis, or any combination of these together with splenomegaly or myelofibrosis, and it can take years for a true panmyelopathy to appear.

First recognized in 1892, PV has been studied for 125 years and despite its infrequency, it has captured the imagination of physicians in every generation

Spivak goes on to describe the current intense scientific exploration of PV. Since Alessandro Vannucchi’s publication in  Blood of “How I treat PV” five years ago, Spivak points out there have been 585 papers published on or about PV diagnosis and 655 on its management. all without consensus on definitions, diagnosis or treatment.  His paper, employing historical perspectives and patient case studies sets out to clarify the best practices for each based on his direct experience.

And those best practices have developed in the course of a stormy history. The issues of phlebotomy-only versus treatment with various drugs. the diagnosis of PV itself, the hematocrit levels at which venesection is indicated, the choice of drugs in the post-JAK2 era are  just some of the heated disagreements that have bedeviled physicians and patients alike.  With clarity and assurance, Spivak lays out his own approach to the treatment of PV

Forum:  What’s the first step?

Spivak:  My evaluation begins with a medical history form, sent to patients in advance for completion at their leisure in a familiar environment  Created before the MPN patient symptom score, the form was designed to capture MPN-associated symptoms. An inquiry about pain with respect to location and intensity on an analog scale is conducted at the visit

On physical examination, I focus on the skin and mucous membranes for acne rosacea, plethora, glossitis and cheilosis and, if there is a history of urticaria, Darier’s sign to search for concomitant mastocytosis; sternal tenderness as a sign of disease activity, and liver and spleen size. Unless a patient is obese, I do not use ultrasound to detect or follow splenomegaly. The initial laboratory evaluation includes a complete blood count and blood smear and a JAK2V617F assay.

Do you also start with a bone marrow biopsy to set a benchmark?

Spivak: I do not obtain a marrow specimen for diagnostic purposes or to screen for myelofibrosis in the absence of splenomegaly, a leukoerythroblastic reaction, unexplained anemia or thrombocytopenia. I also obtain SNP and NGS assays under these circumstances. I always obtain a quantitative JAK2V617F VAF [Ed. Note: VAF= Variant Allele Frequency] because MPN driver mutations are not mutually exclusive and the VAF permits assessment of disease burden and clonal dominance, it cannot be used prognostically but if greater than 50 %, ET is excluded

 In general, do you follow the current therapeutic recommendations summarized by Tefferi et al (“Polycythemia vera treatment algorithm” 2018, Blood Cancer)

Spivak: Current therapeutic recommendations for chronic phase PV stratify risk according to age and thrombosis history, recommending phlebotomy and aspirin, and in patients ≥65 years, and hydroxyurea for cytoreduction to prevent thrombosis, even though PV thrombosis is provoked and no study has proved that hydroxyurea prevents either arterial or venous thrombosis; at best, it is a nitric oxide (NO) donor that inhibits platelet aggregation and prevents TIA uncontrolled by aspirin.

The recommendations make no reference to control of splenomegaly, nor acknowledge that the impact of age on survival with PV is independent of the disease or the very high risk of thrombosis in patients <60 years old,  Furthermore, the recommendations are based on observational data involving patients with inadequate hematocrit control, and fail to specify that men and women patients have different target hematocrits.

What is your position on phlebotomy?

For readers unfamiliar with PV history, there has always been prejudice against phlebotomy therapy.The Polycythemia Vera Study Group (PVSG) had three debates before including, at Dameshek’s insistence, a phlebotomy therapy-only control arm in PVSG-01, the first randomized, controlled, PV clinical trial (RCT) 39; no PV RCT since has had a phlebotomyonly control arm.

PVSG-01 sought to determine whether chemotherapy or 32P supplemented by phlebotomy caused AML in therapy-naïve patients but was flawed because the initial hematocrit target was 52 %, changed to 45%  four years after full enrollment; so phlebotomy-only patients were essentially untreated until then Despite this, thrombosis frequency, though initially higher in the phlebotomy arm, was eventually equal in all three arms; survival was superior in the phlebotomy-only arm, while the AML incidence was greater in the chemotherapy (13.5%) and 32P arms (10.2 %) compared to phlebotomyonly (1.5%). Furthermore, there was an increase in skin cancer and GI tumors, lymphomas and nonhematologic  malignancies in the chemotherapy and 32P arms; observations confirming these results have been reported continuously.

Isn’t hydroxyurea the front line drug for PV?
These results notwithstanding, the PVSG adopted hydroxyurea, a non-alkylating agent as the therapy of choice based on an observational study using the flawed PVSG-01 phlebotomy-only arm as a control.  Hydroxyurea is similar to other drugs that impair DNA synthesis; all cause tAML because they facilitate clonal expansion of HSC bearing harmful mutations  Hydroxyurea is a skin tumor promoter, causes tAML in association with 32P or alkylating agents , del17p 42, and inhibits TP53 activation. Importantly, in a PV RTC, with long term follow up, 24 % of hydroxyurea-treated patients developed AML by 20 years .

What do you see as the goals of PV therapy…and how do you approach them?

PV treatment has two goals: alleviation of symptoms and prolonging survival through prevention of thrombosis, intractable splenomegaly and leukemic transformation. Adequate phlebotomy therapy alleviates symptoms due to hyperviscosity but not severe migraine, aquagenic pruritus or erythromelalgia. Control of thrombocytosis may benecessary for migraine relief or TIA, for which I prefer pegIFN to anagrelide; aquagenic pruritus has many therapeuticoptions depending on its severity: ruxolitinib, pegIFN, PUVA  [psoralen photochemotherapy] and hydroxyurea. Erythromelalgia classically responds to aspirin

What is the greatest danger faced by PV patients?

Thrombosis is the most immediate threat to health in PV. Phlebotomy is the cornerstone of therapy; it completely addresses Virchow’s triad  [Ed. note: Virchow’s triad:  The three broad categories of factors contributing to thrombosis:Hypercoagulability. Hemodynamic changes   and  Endothelial injury] reducing the RCM and expanding the plasma volume. In newly-diagnosed patients, this can be accomplished by daily or every other day procedures or all at once by erythrocytapheresis. The ultimate aim is to induce a state of chronic iron deficiency, which reduces phlebotomy frequency.

Why iron deficiency?

PV patients absorb iron maximally; an increased phlebotomy requirement is a sign of excess body iron, not disease acceleration. Phlebotomy does not cause myelofibrosis , provoke thrombosis or stimulate hematopoiesis because PV hematopoiesis is autonomous. Compliance is improved by giving patients a monthly phlebotomy appointment schedule for hematocrits ≥45% for men 103 or ≥42% in women To those arguing that the latter target needs formal proof, men have 10-fold higher testosterone levels than women and at every body weight, a woman’s normal red cell mass is ~600 mL lower  Thus at a hematocrit of 45 %, a woman PV patient has at least an excess of ~600 mL of blood and much more with hepatic vein thrombosis (HVT)12, which frequently occurs with a normal hematocrit due to pv [plasma volume] expansion. Symptoms or thrombosis recurrence are the best evidence for inadequate phlebotomy therapy. This is not a trivial issue since HVT is a unique and catastrophic feature of PV, primarily affecting young women.

Do you also prescribe aspirin?

Aspirin was recommended for primary thrombosis prevention in all PV patients without a contraindication based on a RCT 113 involving patients with hematocrits > 45% but this recommendation has been challenged because of the bleeding risk, especially in patients older than 60. I do not use aspirin in asymptomatic PV patients < age 50 without cardiovascular risk factors unless they smoke or have diabetes, nor in patients ≥ age 60 because of the bleeding risk.

Recently, Jakafi was FDA approved for PV application. What are your thoughts?

The discovery of JAK2 V617F and, as result, ruxolitinib, a JAK1/2 inhibitor, opened a new MPN therapeutic era. Together with pegIFN, which targets the involved HSC  we have two nonmyelotoxic, target-specific agents to treat PV. Ruxolitinib, unlike pegIFN, does not kill HSC making it unlikely to produce molecular remissions, and both drugs are not without significant side-effects but we are dealing with a neoplasm and controlling splenomegaly and achieving molecular remissions while avoiding tAML are worthwhile goals. Ruxolitinib proved to be effective in PPMF [post polycythemic myelofibrosis] and chronic phase PV  providing durable symptom relief, blood count control and reduction in splenomegaly and was superior to hydroxyurea. We have no information, however, about its role in chronic phase PV, in particular, its effectiveness compared to phlebotomy for hematocrit control and prevention of thrombosis, which insurers will want to know, as well as its long term safety with respect to immunosuppression in this patient population.
Ruxolitinib produces durable effects but fatigue, weight gain, immunosuppression, herpes zoster, opportunistic infections, skin cancer and, rarely lymphomas are drawbacks. Patients should receive pneumococcal and zoster vaccines Taking a drug holiday due to toxicity does not preclude a response on rechallenge.

We are also faced with the problem of how and when to use pegIFN; comparing it to hydroxyurea will not provide the answer because hydroxyurea does not affect the involved HSC. Furthermore…, most PV patients with an indolent phenotype can enjoy substantial longevity with phlebotomy alone but we also know that molecular remission is a 20 % possibility

And combination therapies?

In advanced PPMF with anemia, thrombocytopenia and intractable splenomegaly, in addition to ruxolitinib or in place of it, I will use daily low dose (50-100 mg) thalidomide and prednisone (40 mg daily with tapering over one month), which can improve blood counts, reduce circulating blasts and splenomegaly, though not uniformly 136. Combined therapy with ruxolitinib and azacytidine has proved useful in advanced PPMF

What are your conclusions?

…  PV is the diagnosis of exclusion because PV is a hypercoagulable disorder. Thrombosis due to blood hyperviscosity is the immediate risk to health, and phlebotomy, not chemotherapy, to a sexspecific target hematocrit or red cell count, is the initial therapy of choice. PV is a chronic illness with the potential for substantial longevity. The current therapeutic challenge is how to integrate the two available nonmyelotoxic target specific drugs, ruxolitinib and pegIFN, to control PV symptoms and prevent the development of JAK2V617F-positive HSC clonal dominance and extramedullary hematopoiesis in those patients most at risk in accordance with the dictates of precision medicine.

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Comments on: "Spivak – How I treat PV" (3)

  1. I have been on PEG for 5 years (started 3 months post-diagnosis) doses never exceeding 70 mcg however mostly 50 mcg over this period of time. I have had 3 bone marrow biopsies. The first at diagnosis showed classical PV with MF-1, 2nd showed an improvement in hypercellularity and still MF-1, my last one showed normalization of my bone marrow to an age-appropriate level and no fibrosis. My AB was 25% on diagnosis and statistically has stayed at that level for 5 years. Is there an explanation on why my bone marrow as returned to normal but my AB remains unchanged?

  2. From Dr. Spivak in response to an e-mailed question:

    “I suspect that the durability of ruxolitinib is both disease and patient-specific. It is probably more durable in PV than PMF but there is still patient variability on top of that. MPN patients do not fit into neat categories and JAK2 inhibition is far from the whole story of disease pathogenesis. Ruxolitinib does not attack the involved stem cells and is thus not going to cure anyone. However, it is still a mile stone achievement and has made a profound difference in controlling splenomegaly. We should feel very lucky considering how many JAK2 inhibitors have failed to reach the clinic and that we don’t have to resort to marrow and patient-toxic chemotherapy, which has always been a therapeutic dead end. What is needed now is some imaginative drug trials with ruxolitinib and Pegasys instead of searching for the next bright shiny object.”

  3. C. Brogan said:

    Dr. Slovak, I enjoyed your “How I Treat Polycythemia Vera” article. However one of my concerns is boxing women into the obligation to keep their hematocrit at or less than 42%. With all the complaints of fatigue with PV patients, one cause with women could be reducing their hct lower than optimum for them.

    Looking at healthy people’s hct, women average 3% less than men. If you set a goal of 45% for PV patients for reducing thrombosis risk, than the average women would then be 42%. However since women AVERAGE 3% less than men, some may be naturally higher and some may be naturally lower than 42%.

    Since the predominant evidence based research sets the hct at less than 45% for both men and women for reduction of thrombosis risk, well, that is or should be the standard. Theorizing testosterone or anything else changing the safe hct simply is not evidence based.

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