IFN vs HU — what the MPN specialists think.
Dr. Ruben Mesa (Mayo Clinic, Scottsdale)
First I would say that there is a difference as to the decision on what to choose for front line for the patient who has not tried anything yet versus the patient who has been on hydroxyurea and is doing well (decision of front line, versus switching). As front line I discuss HU and INF with all high risk ET and PV patients needing cytoreduction and feel patient input is important given the sometimes significant insurance hassle needed for INF. Factors in selecting INF, at this juncture, are those most concerned with risk of progression. Factors in selecting HU would be for those at greatest risk of recurrent blood clots, ease of use, expense, and for some a better tolerated medication.
Dr. John Mascarenhas (Mt. Sinai)
ET and PV remain a challenge to adequately treat on multiple levels. As physicians we aim to provide a therapy that is risk adapted (risk of toxicity of therapy is commensurate with inherent risk of the disease and potential benefit of a therapy is outweighed by potential risk of the therapy) and will serve in the case of ET and PV to accomplish two goals.
The first is a short term goal of thrombotic risk reduction and the longer term goal is disease course modification of an illness that is both chronic and progressive (and sometimes in an unpredictable fashion). After multiple prospective and retrospective studies we are left with the following: 1) Aspirin appears to be warranted; 2) reduction of hematocrit <45% in PV is accepted; 3) The use of cytoreductive agents in “high risk” individuals further reduces the thrombotic risk.
How to clearly define high risk remains vague as age >60 is somewhat arbitrary and thrombosis risk may not sufficiently capture all those at risk for a clotting or bleeding event. HU has emerged as first line therapy for the purpose of thrombosis risk reduction as it was shown to be superior to other chemotherapies and anagrelide (in one study). Interferon-alpha has also emerged more recently as an alternative therapy that may in fact provide a benefit beyond thrombotic risk reduction in the form of disease course modification. This is based on relatively small phase II trials demonstrating not only hematologic remissions (normalization of counts and reduction in spleen) but also molecular responses in a subset of individuals over prolonged administration. This has been exciting but remains unclear as to the true clinical impact. Interferon clearly has activity in this disease type and that is supported by extensive preclinical study and growing clinical data.
Ongoing Phase III trials will shortly begin to result in data and provide prospective evidence comparing both efficacy and tolerability of each agent and hopefully will confirm early phase trial results in larger populations over long periods with clear comparison between arms. What we will need to pay close attention to will be: 1. Is there a difference in hematologic response rates between the two agents 2. Is there a difference between thrombotic rates between the two agents; 3. Are these two agents tolerable with toxicity profiles that are amenable to long term administration and can we identify subgroups upfront that are more likely to have intolerance to these agents; 4. Do molecular responses correlate with bone marrow histomorphologic response and most importantly do patients in a molecular response enjoy a life with less risk of thrombosis, progression of disease, and premature death.
As to whether combining JAK1/ 2 inhibitors with interferon or statins or other “immunomodulatory” agents will improve upon the outcomes for our patients will need to be demonstrated in rigorous clinical trials. This is an exciting time to be a clinician/investigator in MPN and we owe it to our patients to fully investigate each therapeutic option and confirm our current suppositions. I remain confident that the insights derived from the current interferon clinical trials will help us better tailor this therapy to the appropriate patients thereby limiting unnecessary toxicity and increasing success rate.
Dr. Jerry Spivak (Johns Hopkins)
The context for the discussion
“As a cytoreductive agent hydroxyurea has amply demonstrated its ability to lessen the likelihood of hemorrhagic and thrombotic events in high risk ET. Despite its association with serious side effects, suspected leukemogenicity and lack of efficacy in reducing symptoms or increasing QOL for these patients, HU remains frontline treatment for ET patients.
One primary reason for the pre-eminence of hydroxyurea is simply its historic precedence over other agents, notably anagrelide and interferon, as described in a recent retrospective study by members of the MPD Research Consortium.”
“Those who cannot remember the past are condemned to repeat it” (1), and nowhere is this more relevant in clinical medicine than in the MPN (2).
Recurrent and interrelated themes in the MPN dating back over 60 years include the value of phlebotomy therapy to prevent thrombosis in PV and the role of chemotherapy or radiotherapy in the management of PV and ET. Powerful voices espoused each; for PV, Louis Wasserman favored chemotherapy or radiotherapy, while William Dameshek preferred phlebotomy.
With regard to chemotherapy, Dameshek stated “There is a tendency in medical practice ─ by no means limited to hematologists ─ to treat almost any condition as vigorously as possible. In hematology, this consists in attempting to change an abnormal number – whether this number is the hematocrit, white cell count or platelet count to get normal values, whether the patient needs it or not!” (3)
Interestingly, there was strong sentiment to exclude a phlebotomy arm in the seminal Polycythemia Vera Study Group clinical trial, PVSG-01; fortunately, wiser heads prevailed. PVSG-01 demonstrated that neither chemotherapy nor radiotherapy prolonged survival in PV compared to phlebotomy alone but increased the incidence of leukemia > 10 fold. There was an “apparent” benefit of chemotherapy over phlebotomy with respect to thrombosis but the phlebotomy hematocrit target in PVSG-01 was initially 50 %, which is much too high to prevent thrombosis in any PV patient. Part way through the trial, the hematocrit target was lowered to 45 %, which is still too high for women patients. Yet, PVSG-01 continues to be cited as proof of the efficacy of chemotherapy over phlebotomy and hydroxyurea is currently widely employed to reduce the hematocrit in PV patients.
Prescient clinicians as early as 1950 had warned of the leukemogenic effects of chemotherapy and radiotherapy in the MPN but were ignored, although we now know from prospective clinical trials such as PVSG-01 and the French PV hydroxyurea vs pipobroman trial as well as large epidemiologic and observational studies, that every chemotherapeutic agent employed to treat PV and ET, including hydroxyurea, is leukemogenic. Yet, this information has been ignored for hydroxyurea as an inconvenient truth, largely because of the false belief that hydroxyurea has anticoagulant activity. This belief was fostered by several prospective clinical trials in ET. Yet in these trials, hydroxyurea only prevented transient ischemic attacks because it is a nitric oxide donor and prevents platelets from adhering to vessel walls; it did not prevent arterial or venous thrombosis. In fact, anagrelide was more effective in the prevention of venous thrombosis than hydroxyurea in the high risk ET PT-1 trial. Nevertheless, hydroxyurea became a standard of care in PV as well as in ET, even though subsequent studies aimed at normalizing the blood counts in PV and ET patients with hydroxyurea demonstrated no improvement in survival or relief from thrombotic events. As an aside, some physicians still adhere to the initial PVSG-01 phlebotomy hematocrit target of 50 % and do not distinguish between men and women patients, even though women normally have smaller blood volumes than men.
Granted that phlebotomy therapy in PV does not prevent splenomegaly but for PV, a disease whose clinical course extends for decades in most patients, thrombosis is the major threat with respect to morbidity and mortality. Symptomatic splenomegaly is also not a feature in all PV patients, and Richard Silver demonstrated that splenomegaly could be effectively managed with interferon, a nonmyelotoxic agent, while we now have a second agent, ruxolitinib for this purpose as well. Since there is excellent evidence that neither the platelet count or the leukocyte count is involved in promoting thrombosis in the MPN, despite continued unproven claims to the contrary, Dameshek’s sage advice is still worth heeding. Chemotherapy still has a role in MPN management but an extremely limited one and certainly not as “a first line agent or the standard of care”.
In this regard, so-called expert opinion also supports the use of chemotherapy in PV and ET patients older than 60 years, since they are considered at high risk of thrombosis. However, the complications of PV in this age group do not differ from younger PV patients with the exception that older patients are more prone to developing acute leukemia. Thus, there is good reason to avoid myelotoxic agents in these patients and to employ nonmyelotoxic therapy if there are signs or symptoms of disease acceleration. We now have two excellent agents, ruxolitinib and pegylated interferon, for this purpose which should essentially eliminate the need for chemotherapy in the MPN, but we still need to learn how to use these agents. Clinical trials comparing these agents with hydroxyurea represent a false equivalency and have only served to hinder understanding how to use ruxolitinib and pegylated interferon effectively alone or together.
Finally, attempts to manage the MPN will continue to prove frustrating despite new remedies because, with the introduction of the WHO MPN diagnostic criteria in 2008, the ability to accurately distinguish PV from ET or PMF has been lost (4). PV is the most common MPN and the one with the most immediate threats to longevity, arterial and venous thrombosis. Therefore, distinguishing PV from the other MPN, which share the same driver mutations, as well as from benign causes of erythrocytosis is of paramount importance. The PVSG recognized this and in 1971 established diagnostic criteria for PV that did not rely on marrow histology or even a serum erythropoietin level.
Now, despite the identification of driver mutations in ~90 % of MPN patients, uncritical acceptance of WHO MPN diagnostic criteria, which eschewed the PVSG diagnostic criteria, and have never been prospectively validated, has led to a striking failure to distinguish PV from ET or PMF. Attempts by the WHO to revise their diagnostic criteria have not been an improvement, particularly since a clinical diagnosis is left in the hands of pathologists, who do not see patients, based on the unproven assumption that MPN marrow histology is disease-specific when it is not.
Yet, despite repeated published demonstrations of the unacceptable reliability of the WHO MPN diagnostic criteria, they continue to be employed. A predictable result has been the conflation of PV with JAK2 V617F-positive ET, an increase in thrombosis in so-called ET patients, and false clinical comparisons of JAK2 V617F-positive ET with CALR-mutant ET. A simple review of any clinical publication comparing the three MPN will illustrate the constant conflation of JAK2 V617F-positive PV and ET, about which both the authors and their journal reviewers appear oblivious. MPN patients deserve better.
- George Santayana.
- Blood 100:4272, 2002
- Blood 32:483, 1968
- Blood 112:231, 2008
Brady Stein, MD, Northwestern Medicine
Like others, I primarily use cytoreduction as a means of reducing the risk of vascular complications, which is a primary goal in managing patients with ET. Like others, I assess vascular risk based on age and thrombosis history. I do incorporate other aspects including cardiovascular risk factors (hypertension, diabetes, high cholesterol, smoking status) and the type of mutation that an ET pt has (all this in keeping with the IPSET-Thrombosis score). The latter is important as those with JAK2 V617F mutations have higher risk of thrombosis compared to those with other mutations, such as those involving CALR.
Since vascular risk is what mainly guides ET management, an accurate prediction of risk is very important. I hope to see recognition or incorporation of more personalized/sophisticated variables that would allow us to better identify at risk patients. Though consistently identified, age and thrombosis history are more generic risk factors for thrombosis. There are many more contributing factors to MPN-associated thrombosis, including gender, inflammatory stress, leukocytes, mutational burden, and novel markers, including microparticles, and markers that reflect platelet, endothelial (blood vessel lining), and leukocyte activation.
I typically do not treat based on the platelet count alone, unless extreme (1.5 million or more), or clearly associating with symptoms that impact quality of life. The platelet count itself better correlates with bleeding risk rather than thrombosis risk. I often see treatment initiated based on the platelet count alone, even in traditionally lower risk, asymptomatic patients.
While reducing vascular risk is a major goal, of course, there are other instances where cytoreduction may be started, even in lower risk patients. If there are uncontrolled symptoms, perhaps small vessel disturbances (migraine headaches, vision changes, burning hands/feet) unrelieved by aspirin, like others, I will start additional therapy. In those with bleeding symptoms, due to an increased platelet count, or acquired bleeding tendencies due to Von Willebrand disease, I will often start cytoreduction. Finally, there are lower risk patients that have a preference to start an agent—it is in these patients that watchful waiting does not fit their personal philosophy.
It is with this background that I choose between hydroxyurea and pegylated-interferon. While US based guidelines are in development, the European Leukemia Net offers some guidance on use of these agents—both are considered as first-line therapies. However, in the US, the overwhelming majority of practicing physicians will use hydroxyurea over pegylated interferon. In ET, there is data to support use in higher-risk patients, but widespread use has a lot to do with ease of administration and tolerability of HU.
In my own academic practice, I consider age, comorbid illness, symptom profile, patient preference, and goals of therapy when deciding between HU and interferon. First, if the pt is solely higher risk because of advanced age and presence of a JAK2 mutation, for example, I would typically start on hydroxyurea. Similarly, in those with significant comorbid illness, particularly a history of autoimmune disease or mood disturbance, hydroxyurea is likely to be better tolerated than pegylated interferon.
With regard to symptoms, in those with prominent fatigue, I caution that fatigue is often seen in the first several months of peg-IFN therapy. I explain that the likelihood for side effects is higher with peg-IFN, compared to HU. Certainly, there are patients that have preferences for one agent over the other. The individual goals of therapy have to be taken into account. In my own experience, those patients who have pursued pegylated-interferon have been traditionally lower risk; while careful observation is acceptable, for some, this does not fit with their philosophy of care. I see such patients pursuing peg-IFN due to reports of reduction in mutational burden (reported for those with JAK2 mutations and CALR mutations). Such pts see peg-IFN as a more proactive approach.
We are intrigued by the data, but it is only with careful discussion, weighing risks and benefits, that I initiate peg-IFN. I temper expectations about this drug. As I am sure that it is well described in this issue, there are definitely patients who have had excellent tolerance and response, and others with poor tolerability and/or marginal response. The whole spectrum has to be discussed. I do explain that pivotal trials are underway, as conducted by the MPD-RC. Such trials may better define the role of peg-IFN, but will not yet determine long-term benefits, and whether or not this is a truly proactive approach that can modify MPN natural history. One hopes this will be the case.