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FAQ: MPNs
Experts Answer Frequently Asked Questions on the Management of Myeloproliferative Neoplasms

Released: January 16, 2020

Expiration: January 14, 2021

Raajit K. Rampal
Raajit K. Rampal, MD, PhD
Alessandro M. Vannucchi
Alessandro M. Vannucchi, MD
Srdan Verstovsek
Srdan Verstovsek, MD, PhD
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This ClinicalThought features a selection of questions asked by participants during an ASH 2019 satellite symposium focused on the optimal management of patients with myeloproliferative neoplasms (MPNs), with responses provided by members of the program faculty.

Prognosis and Risk Assessment

How does a CALR mutation affect prognosis and treatment for patients with essential thrombocythemia (ET)?
Traditionally, patients with ET have been classified as high risk for thrombosis if they are older than 60 years of age and/or have a history of thrombosis. More recently, the revised IPSET-Thrombosis model was developed. This model takes into account cardiovascular risk factors and JAK2 V617F mutations to stratify patients as very low, low, intermediate, or high risk for thrombosis. Per larger retrospective studies of patients with ET, the presence of the CALR mutation is generally found in patients at lower risk for thrombosis; however, addition of the CALR mutation as a variable to IPSET scoring did not increase the predictive power of this system, owing to the more powerful adverse impact of JAK2 V617F mutation. Furthermore, data from a retrospective analysis suggested that aspirin did not reduce thrombosis rate in CALR mutated patients and actually increased their risk of thrombosis.

Can MIPSS70 be used to assess prognosis at any time during the course of myelofibrosis (MF) (like DIPSS or DIPSS Plus) or is it best used at the times of diagnosis (like IPSS)?
MIPSS70 (Mutation-Enhanced International Prognostic Scoring System), MIPSS70+, and MIPSS70+ v2.0 are newer prognostic systems that take into account clinical risk variables as well as key mutations (MIPSS70) and karyotype (MIPSS70+ and MIPSS70+ v2.0). Although these have not been assessed as dynamic scoring systems, it should be noted that mutations present at diagnosis generally do not change over time unless the disease transforms to acute leukemia. As such, the variables that have been shown to be dynamic according to DIPSS (Dynamic International Prognostic Scoring System) continue to be informative with MIPSS70, although there are no data to support dynamic use yet with these newer systems.

Contemporary Management of MF

Can fedratinib be used for patients who exhibit an inadequate response or intolerance with ruxolitinib?
The JAK1/2 inhibitor ruxolitinib is now a standard first-line therapy for patients with symptomatic and/or higher-risk MF based on findings from the randomized phase III COMFORT-I and -II studies, which showed significant improvements in spleen responses, symptom reduction, and survival with ruxolitinib vs placebo and/or best available therapy. Despite this, for many patients, the response to ruxolitinib is finite, with the median duration of spleen response being approximately 3 years. Many patients who lose response or experience intolerance to ruxolitinib proceed to second-line treatment with immunomodulatory drugs, chemotherapy, or hypomethylation agents, with which outcomes are poor; quality of life suffers due to spleen and liver enlargement, anemia, and thrombocytopenia, and median survival is limited to approximately 14-23 months after ruxolitinib discontinuation.

In August 2019, the FDA approved fedratinib—a JAK2-specific inhibitor that also targets FLT3—as a treatment option for patients with intermediate 2–risk and high-risk MF. This approval was based on the randomized phase III JAKARTA trial, which demonstrated a significantly higher rate of spleen volume reduction with fedratinib vs placebo for patients with MF who were naive to JAK2 inhibitors.

The single-arm phase II JAKARTA-2 trial assessed fedratinib treatment specifically in patients with MF who were intolerant or resistant to ruxolitinib. Data presented at ASCO 2019 indicated that fedratinib is active in this setting, with a spleen volume response rate of 31% and a symptom response rate of 27%. Although these rates are not overwhelming—many patients may not derive the optimal benefit with this agent in this setting—they are higher than those observed with other available treatment options. Although the JAKARTA-2 data were noncomparative, the ongoing randomized FREEDOM2 trial is comparing fedratinib vs best available therapy for patients with MF who were previously treated with ruxolitinib. At this time, it is reasonable to consider fedratinib for patients in the second-line setting after ruxolitinib.

What are some of the agents that are currently in later-stage clinical development for treating patients with MF who have challenging clinical features (eg, ruxolitinib failure, low platelet counts)?
Numerous agents are now in various stages of clinical development for managing patients with MF. For example, the JAK2/IRAK1 inhibitor pacritinib showed promise in treating patients with previous ruxolitinib experience in the phase III PERSIST-2 trial and is currently undergoing further evaluation in patients with intolerance or resistance to ruxolitinib in the phase II PAC203 trial, with the phase III PACIFICA trial also ongoing. This latter trial will assess pacritinib vs physician’s choice of treatment for patients with limited/no previous JAK inhibitor treatment and intermediate-risk or high-risk MF and platelet count < 50,000/µL. In addition, momelotinib, a JAK1/2 inhibitor, was found to be active in patients previously treated with ruxolitinib in the phase III SIMPLIFY 2 trial, with benefits seen in spleen response and anemia improvement. This agent will continue to undergo evaluation in the phase III MOMENTUM trial in the second-line setting for patients with symptomatic MF who are anemic. The management of anemia in patients with MF is an area of clinical need. Preliminary results presented at ASH 2019 from an ongoing, open-label phase II study of luspatercept (an erythroid maturation agent) for the management in patients with MF-associated anemia (either those not receiving ruxolitinib or red blood cell RBC transfusions, those not receiving ruxolitinib but with RBC transfusion–dependent anemia, or those with anemia and on a stable dose of ruxolitinib) were very encouraging. Of note, luspatercept was recently approved for treating anemia in adult patients with β-thalassemia who require regular RBC transfusions.

Various additional agents are also in clinical development, including the telomerase inhibitor imetelstat—with which promising survival was observed in the phase II IMBark trial in patients who were relapsed/refractory after ruxolitinib treatment. Another area of active research involves evaluating combinations with ruxolitinib for patients who have had suboptimal spleen and symptom responses or have significant anemia despite treatment with this agent. Combinations currently under investigation include ruxolitinib plus azacytidine, decitabine, interferon, lenalidomide, thalidomide, or the PI3K inhibitor INCB050465.

How should a patient with MF and progressive anemia (eg, hemoglobin 8 g/dL) be managed in the absence of constitutional symptoms or splenomegaly?
Although it depends on the clinical context, for a patient without symptomatic anemia, it would be reasonable to watch and observe. If the patient were symptomatic, one could check the erythropoietin level; if it is < 250 mU/mL, it would be reasonable to consider an erythropoietin-stimulating agent. If that does not resolve the patient’s anemia (or becomes ineffective after a time), danazol could be considered.

What are current options for patients with constitutional symptoms and/or splenomegaly with platelet counts < 50,000/µL?
Treatment for patients with symptoms/splenomegaly and low platelet counts is currently an area of clinical need. Presently, the labels for both ruxolitinib and fedratinib recommend use in patients with platelet counts > 50,000/µL; however, an off-label trial on a low starting dose of a JAK inhibitor could be considered for such a patient. The challenge would be to start very slowly and then titrate the dose up as the platelets allow. Platelet and spleen responses may also be observed with immunomodulatory drugs or thalidomide, among other agents. As mentioned earlier, pacritinib is currently being assessed for managing patients with platelet counts < 50,000/µL. If available, clinical trials should be considered for these patients.

After a patient is deemed intolerant of ruxolitinib, how should he or she be moved off this therapy?
This partly depends on the dose that the patient is receiving. It would be reasonable to dose reduce ruxolitinib if a patient is experiencing adverse events to attempt to find a dose that the patient can tolerate. If the drug does need to be stopped, it should not be discontinued abruptly, as exacerbation of symptoms or additional adverse events may occur, but rather tapered over several days per the package insert.

Polycythemia Vera (PV) in Focus

Should high platelet counts be specifically managed in patients with PV?
A significant proportion of patients with PV have high platelets, but there is no evidence that elevated platelet counts are associated with a higher risk of thrombosis in patients with PV. Despite this, extreme thrombocytosis is an independent risk factor for hemorrhage, so cytoreductive therapy may be considered when platelet counts exceed 1.5 million due to an increased bleeding risk. In these patients, aspirin should be used with caution and stopped in the presence of laboratory evidence of an acquired von Willebrand disease. It should be noted that elevated platelet counts can occur following intensive phlebotomies, which may be related to rapid decreases in iron. In these cases, it may be reasonable to observe the patient since this thrombocytosis is clinically not relevant; persistent increase in platelet counts should be regarded as a feature of the disease more than as a side effect of phlebotomies.

If a complete hematologic response is achieved with interferon in a patient with PV, can the agent be discontinued?
Interferon treatment has been associated with reduction in JAK2 allele burden and complete hematologic response.

Dr. Kiladjian: Currently, guidelines at my institution state that after a complete hematologic response is achieved, interferon dose can be slowly reduced by approximately 25% every 6 months if the response is maintained. At minimal doses, a trial stoppage may be attempted with monitoring. If the patient relapses, the treatment may always be restarted. In my experience, approximately one third of those patients can stop treatment for a considerable length of time.

Dr. Verstovsek: I would say that it is not common practice in my institution to stop interferon for patients who have complete hematologic response.

Dr. Vannucchi: Due to the fact that interferon is not approved for use in PV in Italy, I have little experience regarding this point, but in general, I would say that in the few ongoing cases I have seen it is not common practice to stop interferon if the patient is doing well.

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