Blood consult: resistant and progressive essential thrombocythemia

A 40-year-old man presented in 1992 to his local hospital and was found to have chest discomfort, blue discoloration of his extremities, and a platelet count in excess of 1000 × 10⁹/L. He was started on aspirin and platelet pheresis with a marked improvement to the duskiness of his toe. Concurrently, he had evaluation for a pulmonary embolism, which was unremarkable, and his chest discomfort subsided with conservative management. He underwent a diagnostic bone marrow, which demonstrated essential thrombocythemia with megakaryocyte clustering, a slightly hypercellular marrow, no significant increase in fibrosis, and no karyotypic abnormalities. He was placed on hydroxyurea and aspirin therapy from 1992 through 2002. During that interval, he never had optimal control of his platelet count, which vacillated between 500 × 10⁹/L and 800 × 10⁹/L and at times spiked to in excess of 1500 × 10⁹/L, with dosing of hydroxyurea limited by periods of neutropenia with dose escalation. In 1998, because of difficulty in control of his counts, he received 2 mg of melphalan daily (in addition to hydroxyurea) for 1 year without significant additional control of his counts. Because of difficulty controlling his platelets, he received in 2001 an injection of radioactive phosphorus (P-32), but this was ineffectual in improving his counts. In 2002, because of resistance to hydroxyurea and issues of neutropenia he was started on anagrelide. He eventually became intolerant to the anagrelide because of palpitations and headaches.

He presented to our institution, now age 58, with a platelet count of 850 × 10⁹/L, an untransfused hemoglobin of 10.1 g/dL, and a leukocyte count of 18 × 10⁹/L (with a leukoerythroblastic blood film without circulating blasts). The bone marrow aspiration and biopsy was repeated and now demonstrates 3+ reticulin fibrosis, a hypercellular marrow of 80%, and normal karyotypic analysis. He has the JAK2-V617F mutation as assessed by the peripheral blood. His physical examination is remarkable for palpable splenomegaly at 11 cm below the costal margin. In addition, he had night sweats and had 10 pounds of weight loss. He is diagnosed as having post–essential thrombocythemia myelofibrosis (post-ET MF) but has continued thrombocytosis and risk of thrombotic events. He is enrolled in a JAK2 inhibitor trial and he and his siblings are HLA-typed for a possible future allogeneic stem cell transplantation.

First, our patient clearly had his initial presentation with essential thrombocythemia (ET) and on the basis of his vascular event he is correctly identified as high risk. Major identified risk factors for thrombosis/hemorrhage in ET are age > 60 years and incidence of a previous thrombotic event, with possible risk factors being the presence of the JAK2-V617F mutation, strong cardiovascular risk factors, or leukocytosis (> 15 × 10⁹/L) at baseline. Therefore his management was correct from the beginning, that is, he required both antiplatelet therapy (aspirin) and cytoreduction with hydroxyurea. The challenge he encountered was a common one: resistance or intolerance to hydroxyurea. How do we define hydroxyurea or intolerance, and what are our options when this arises (Table 1)?

Hydroxyurea is the lead agent for control of thrombocytosis in high-risk ET patients on the basis of both a randomized trial compared with placebo¹  and a subsequent randomized trial compared with anagrelide.²  The challenge, as seen in our patient, is that the dose of hydroxyurea required to control the thrombocytosis (ie, to normalize the platelet count) cannot administered because of neutropenia, anemia, or nonhematologic toxicity. The European LeukemiaNet (ELN) drafted a consensus set of criteria to address what constitutes hydroxyurea failure.³  These helpful criteria indicate failure if the dose required to control thrombocytosis leads to a leukocyte count less than 2.5 × 10⁹/L, a hemoglobin level less than 10 g/dL, or an unacceptable nonhematologic toxicity such as mucocutaneous ulcerations, leg ulcers, or hydroxyurea-induced fevers.

So this patient was clearly resistant/intolerant by the ELN criteria; what about the second-line therapies he received? He received anagrelide, which, although inferior to hydroxyurea in the randomized trial, is still a valid second-line agent.²  Unfortunately, our patient failed second-line therapy with anagrelide because of palpitations and headaches, both well-recognized toxicities of this agent. For subsequent treatment he received both alkylator therapy and P-32. As third-line therapy, these latter therapies are probably less than ideal, as they can certainly have the unintended consequence of acceleration of ET toward acute myeloid leukemia and should be used only in patients with limited life expectancy.

What should third-line therapy for thrombocytosis in ET patients entail, and perhaps occur even earlier in the therapeutic lineup? Pegylated interferon α-2a has been shown to be able to control thrombocytosis and leukocytosis and prevent vascular event in both high-risk polycythemia vera and essential thrombocythemia.⁴  In addition, pegylated interferon α-2a has led to reductions in the JAK2-V617F mutant allele burden and might have the ability to alter the natural history of the disease, and is the subject of an ongoing trial.

The issue of progression in ET is a complex one, with inadequately understood pathogenetic underpinnings. Our patient had post-ET MF, having fulfilled the International Working Group for Myelofibrosis Research and Therapy Criteria for this entity with the presence of (1) a clear ≥ 2-grade increase in intramedullary fibrosis and (2) development of several supportive features unique to the MF end of the spectrum including splenomegaly, constitutional symptoms, and leukoerythroblastic blood film.⁵  A key point in making this assessment for this patient is that the initial marrow on review did not demonstrate the cellular phase of primary myelofibrosis, according to the 2008 WHO diagnostic criteria, which has both a high likelihood of progression and the absence of significant fibrosis at diagnosis.⁶ 

Our patient is now 58 years old, which, in the absence of overwhelming comorbidities, makes him a candidate for allogeneic stem cell transplantation. The question is, given his post-ET MF, is his survival with his illness poor enough to mandate such an intervention? All of our current prognostic criteria for MF have been derived from retrospective analysis of patients with only primary myelofibrosis, and all except 2 sets have been measured at the time of diagnosis. Because we recognize that we are extrapolating PMF prognostic criteria to a post-ET MF patient, the recently published Dynamic International Prognostic Scoring System Plus is the most helpful system to apply to his case.⁷  This system builds on previous PMF prognostic criteria, and this patient's survival accurately estimated would be 78 months based on the presence of constitutional symptoms. However, a hemoglobin level just slightly lower (ie, less than 10 g/dL) would drop his estimated survival to 35 months, highlighting that prognostic groups exist on a spectrum. Regardless, we recognize that his MPN is now in a stage where, given his youth and barring a disease-altering therapy, the post-ET MF will take his life at some point in the next 3-7 years.

The patient was HLA-typed as were his siblings. Current estimates of survival for allogeneic stem cell transplantation come to us from a variety of trials. The recent prospective trial from the European Bone Marrow Transplantation Registry would suggest a 67% survival at 5 years, with a 16% 1-year nonrelapse mortality (27% and 43% rates of acute and chronic GVHD, respectively⁸ ). The availability of a sibling match, the quality of an unrelated donor match, the stability of the patient's disease, and his wishes for treatment are all key factors in deciding whether he will in fact proceed with the allogeneic stem cell transplantation as soon as possible or delay the treatment until evidence of further disease progression emerges.

We decided to place this patient on a JAK2 inhibitor trial, leaving allogeneic stem cell transplantation as a back-up option, in an attempt to both assist his illness and control his thrombocytosis. Current medical options have not been shown to alter the natural history of the disease and largely palliate only anemia or splenomegaly. JAK2 inhibitors have, as a class, been shown to decrease symptomatic splenomegaly and significantly improve constitutional symptoms.⁹  In patients with hydroxyurea-resistant or -intolerant ET and PV, the JAK2 inhibitor INCB18424¹⁰  has been helpful in controlling thrombocytosis and erythrocytosis (and has been previously recognized to improve MPN-associated symptoms and splenomegaly). What remains unclear, given that only single-arm phase 2 trials have been published, is whether JAK2 inhibition will lead to an alteration in the natural history of the disease (namely, improved survival or progression-free survival).

Soon we may have at least one if not several JAK2 inhibitors commercially available to add to our panel of options for post-ET MF patients. As with the patient discussed in this case, we must cautiously weigh each of our options in an attempt to control or overcome the disease in a therapeutic sequence that we hope benefits the patient in the most favorable manner.

Contribution: R.T. and R.M. wrote the paper.

Conflict-of-interest disclosure: R.M. has received research support from Incyte, S*BIO, Novartis, Genentech, and Telik. R.T. declares no competing financial interests.

Correspondence: Ruben A. Mesa, MD, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259; e-mail: Mesa.ruben@mayo.edu.