Senior Member, Vice Chair
Leukemia and MDS
H. Lee Moffitt Cancer Center & Research Institute
Department of Oncologic Sciences
University of South Florida
Rami S. Komrokji, MD, has disclosed that he has received consulting fees from Celgene, Daiichi Sankyo, Inc., Jazz, Novartis, and Pfizer and fees for non-CME/CE services from Jazz and Novartis.
The management of myeloproliferative neoplasms (MPNs) continues to evolve at a rapid pace. In this commentary, I address key clinical questions in the diagnosis and treatment of polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF).
What are key considerations in the diagnosis of the MPNs?
For all MPNs, diagnosis should follow the algorithms outlined in the WHO 2016 diagnostic criteria. It should be noted that the updated 2016 versions of these criteria included important changes vs earlier versions. For example, with PV, a major criterion for diagnosis is elevated hemoglobin. In the 2016 update, the hemoglobin threshold required to satisfy a major criterion for a PV diagnosis was lowered to 16.5 g/dL (hematocrit > 49%) in men and 16.0 g/dL (hematocrit > 48%) in women.
Regarding ET and MF, clinicians need to be careful to not confuse ET with a new WHO diagnostic entity called prefibrotic MF; although management is similar for these 2 conditions, prefibrotic MF has different outcomes and a greater likelihood of progression to overt MF. To distinguish between these MPNs, it is important to assess bone marrow biopsy findings—prefibrotic MF is associated with a pronounced proliferation of granulopoiesis and medium to giant megakaryocytes with hypolobulated or irregular nuclei, whereas ET is associated with large/giant mature megakaryocytes with hyperlobulated or deeply folded nuclei and no significant increase in granulopoiesis.
How do you decide on a course of treatment for patients with PV, ET, and MF?
Treatment is tailored to the risk of thrombosis for PV and ET. Patients are considered high risk if they are older than 60 years of age and/or experienced previous thromboembolic events. Leukocytosis has also been identified as an important risk factor for thrombosis. High-risk patients are managed with phlebotomy, low‑dose aspirin, and cytoreductive therapy. First-line cytoreductive therapy commonly consists of hydroxyurea. Although treatment with this agent does not alter the natural history of the disease, it can reduce the risk of thrombosis and reduce the need for phlebotomies. Despite this, adverse events such as cytopenias, pneumonitis, vasculitis, ulcers, and gastrointestinal intolerance are common with higher doses of hydroxyurea, and intolerance or resistance to hydroxyurea occurs in up to 25% of patients. Second-line options include the JAK1 and JAK2 inhibitor ruxolitinib for those with PV or peginterferon for either PV or ET. Ruxolitinib has been shown to significantly improve hematocrit and symptom control and reduce spleen volume (vs standard therapy) for patients with PV in this setting. Peginterferon use is discussed in more detail below.
Lower-risk patients can be managed with phlebotomy and low‑dose aspirin. As stated above, for patients with ET who have a high risk of thrombosis, I would recommend cytoreductive therapy; however, I would consider a patient who is older than 60 years of age yet has no JAK2 mutation, no previous thromboembolic event, and/or a CALR mutation to be at intermediate risk and manage the patient without cytoreductive therapy.
There are several clinical risk stratification models in MF based on clinical and hematologic parameters. These include the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS‑Plus. Other models incorporate mutations (eg, MIPSS [mutation-enhanced IPSS] or GIPSS [genetically inspired prognostic scoring system]). MF treatment is based on risk findings from these systems and symptom burden. Those with higher‑risk disease should be considered for allogeneic hematopoietic stem cell transplant (AHSCT); note that MIPSS 70+ is a risk assessment model designed to determine candidacy for AHSCT. If patients are ineligible for transplant or have lower-risk disease, then treatment is based on symptoms. For those with constitutional symptoms and splenomegaly, ruxolitinib has emerged as standard of care, with treatment having been shown to improve symptoms, reduce splenomegaly, and prolong survival.
When and how should interferon be used for PV and ET?
Cytoreductive therapy with peginterferon may be considered in the first-line or second-line settings for patients with PV or ET. Data from small studies have suggested that interferon can potentially alter the natural history of disease and lead to molecular responses in a small subset of patients, at the potential cost of considerable toxicity. A larger phase III study, MPD‑RC 112, randomized high‑risk patients with PV or ET to hydroxyurea or peginterferon and found similar CR rates between the 2 groups. A recent 3-year analysis of the phase III PROUD and CONTI-PV trials—which assessed a newer interferon formulation, ropeginterferon, for treating patients with PV or ET who required cytoreductive therapy—reported superiority of ropeginterferon vs hydroxyurea in terms of hematologic CR rate.
Given the safety challenges associated with interferon, whom would I consider for this approach? In the settings of PV and ET, I would consider interferon-based cytoreductive therapy for younger patients, women considering pregnancy, individuals with no major comorbidities (ie, no major depression, normal liver function tests), and those motivated to achieve molecular response.
How should ruxolitinib be dosed in patients with MF, including those with myelosuppression?
Ruxolitinib is dosed up to 20 mg twice daily for patients with MF. The starting dose is determined by baseline platelet count, with patients who have a platelet count of > 200 x 109/L receiving 20 mg twice daily and those with a lower platelet count receiving a lesser daily dose. The challenge with ruxolitinib is that myelosuppression commonly occurs within the first 8-12 weeks of treatment and can necessitate dose adjustment. Despite this, ruxolitinib can still provide substantial clinical benefit for patients with myelosuppression—even if they must be supported early in treatment with blood transfusions—as MF symptom improvement can be seen at doses of 5-10 mg twice daily. It should be noted, however, that spleen responses with ruxolitinib are dose dependent and typically achieved with higher doses. Thus, when starting at a lower dose of ruxolitinib, the dose should escalate faster within the first month or two based on blood counts. Ruxolitinib-associated anemia can be treated with erythropoiesis-stimulating agents.
For those patients who are predominantly anemic and/or cytopenic and lack both major splenomegaly and constitutional symptoms, ruxolitinib is not the optimal initial treatment of choice. Danazol, thalidomide, and lenalidomide are all used to manage anemia, with response rates ranging from 20% to 30%. Ongoing studies are evaluating the TGF‑β inhibitor luspatercept in patients with MF and anemia, as well as combinations like ruxolitinib plus thalidomide.
How should ruxolitinib failure be managed?
This is a challenging area representing an unmet need. After ruxolitinib discontinuation, a median survival of 14 months was reported in patients with MF in a clinical trial, with similar findings noted in a real-world study. Management depends on the type of failure—whether is it mostly due to cytopenias, progressive splenomegaly, and/or constitutional symptoms. In practice, there are few options outside of a clinical trial. For cytopenia, we sometimes consider either thalidomide or lenalidomide plus prednisone. Clinical trials are currently exploring combining ruxolitinib with new agents such as TGF‑β inhibitors or antiapoptotic agents targeting BCL‑2.
In the realm of investigational monotherapy, the selective JAK2 inhibitor fedratinib was associated with activity in patients with ruxolitinib failure in the open-label phase II JAKARTA-2 study. There was some earlier concern about Wernicke encephalopathy with this agent, but further review indicated that some cases were misdiagnosed and that events were mostly related to thiamine deficiency in those with severe nausea and vomiting or preexisting malnutrition. Fedratinib has been submitted for FDA review as a second‑line treatment option. In addition, pacritinib is a JAK2/FLT3 inhibitor that seems to be active in patients with baseline thrombocytopenia; there is an ongoing dose‑finding study of pacritinib that will provide additional data on this agent. Finally, the JAK inhibitor momelotinib will continue to undergo evaluation a phase III trial in the second-line setting for symptomatic patients with MF who are anemic.
What are your most pressing clinical questions about the diagnosis and treatment of PV, ET, and MF? Please answer the polling question and share your thoughts in the comments box.
To see what 5 experts would recommend for patients with MF and PV in different clinical scenarios, visit the Interactive Decision Support Tool: Treatment of Myelofibrosis and Polycythemia Vera.