Prospective Analysis Highlights Patterns of Progression to Myelofibrosis Following Essential Thrombocythemia Diagnosis

Most patients with essential thrombocythemia (95.7%; 1184/1237) included in an analysis of the prospective, observational MOST study (NCT02953704) did not experience disease progression to myelofibrosis, but those who did were found to have had longer duration of disease, higher white blood cell counts, and lower hemoglobin levels at enrollment, according to findings presented at the 2024 EHA Congress.¹

Of the 4.3% (n = 53) of patients who progressed to myelofibrosis, a pathologic diagnosis of the disease or grade 2 or greater fibrosis was the most common indicator (49.1%; n = 26) of disease progression, followed by new or worsening splenomegaly coupled with a combination of high white blood cell counts and low hemoglobin levels and platelet counts (22.6%; n = 12). Additional indicators were death from myelofibrosis, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML; 11.3%; n = 6) and circulating blasts above 1% with new or worsening splenomegaly (5.7%; n = 3); patients also met at least 2 progression criteria (11.3%; n = 6).

“These findings and further analyses of MOST data will add insight into disease progression in patients with essential thrombocythemia and facilitate clinical management of this patient population,” lead study author Ruben A. Mesa, MD, FACP, president and executive director of Atrium Health Levine Cancer Institute and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, and vice dean of cancer programs at Wake Forest University School of Medicine in Charlotte, North Carolina, and coauthors wrote in the poster.

Essential thrombocythemia is a myeloproliferative neoplasm characterized by clonal blood cell growth, constitutional symptoms, excessive platelet production, and increased risk of vascular symptoms. There is potential for disease transformation to myelofibrosis, however most documented cases of disease progression have been pulled from retrospective series. For this reason, investigators launched the longitudinal, noninterventional, observational MOST study allowing for prospective study of patients with essential thrombocythemia throughout the United States.

The study enrolled adult patients who received a clinical diagnosis of essential thrombocythemia and patients either were at least 60 years old; had a history of thromboembolic events; or were receiving essential thrombocythemia–directed therapy excluding aspirin monotherapy. Criteria for enrollment were confirmed through central and local assessment. Enrollment then began in November 2016 after which patients entered an observation period where physician-level data were collected during routine visits for at least 3 years. March 2022 marked the end of the study and observation period at which point investigators evaluated disease progression to myelofibrosis.

Patients were considered to have disease progression to myelofibrosis if they experienced any of the following criteria during the study period: bone marrow biopsy with fibrosis of grade 2 or greater or a pathologic diagnosis of myelofibrosis; death because of myelofibrosis, MDS, or AML; circulating blasts above 1% and new or worsening splenomegaly; and new or worsening splenomegaly. For new or worsening splenomegaly, patients also needed to have 2 of the following: white blood cell count above 11 × 10⁹/L, hemoglobin level below 10 g/dL, and platelet count below 100 × 10⁹/L.

A total of 1,237 patients with essential thrombocythemia were enrolled in MOST, all of whom were included in the present analysis. Only 14.2% (n = 176) and 76.0% (n = 940) of patients had bone marrow data and spleen records available, respectively. Regarding patient characteristics, the median time from essential thrombocythemia diagnosis to enrollment was 4.2 years (range, 0-42) and the median duration of enrollment was 4.8 years (range, 3.5-5.8).

“Compared with patients without progression, those with progression had longer duration of disease, higher white blood cell counts [10.4 × 10⁹/L vs 7.4 × 10⁹/L; P <.001], and lower hemoglobin [levels 12.5 g/dL vs 13.1 g/dL; P =.026] at enrollment. Mean platelet count was not significantly different [418.6 × 10⁹/L vs 455.0 × 10⁹/L; P =.466 and] symptom burden at enrollment [based on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score] was similar between the 2 groups [with progression: mean, 17.2, standard deviation (SD), 13.4; without progression: mean, 16.9, SD, 15.6],” the authors wrote.

Patients with progression also had a prolonged time from essential thrombocythemia diagnosis to enrollment vs those without, at 7.9 years (range, 0-41) vs 4.2 years (range, 0-42), respectively (P =.001).

Additionally, 94.8% of patients with progression and 94.3% of patients without progression were receiving essential thrombocythemia–directed therapy at enrollment; more patients without progression (91.1%) were receiving single-agent therapy vs those with progression (81.1%; P =.0142). However, there were some variations in the types of therapy received between the 2 groups, most notably for ruxolitinib (Jakafi; with progression, 11.3%; without progression, 3.0%; P =.0011), hydroxyurea (45.3% vs 66.4%; P =.0016), and anagrelide (17.0% vs 7.9%; P =.0198). Other types of therapy included interferon (1.9% vs 2.9%; P =.6723), aspirin monotherapy (5.7% vs 10.5%; P =.2588), busulfan (0% vs 0.4%; P =.6355), and no therapy (5.7% vs 5.2%; P =.8924).

Notably, disease duration at enrollment was prolonged in patients receiving ruxolitinib at 13.2 years (range, 4-41) compared with those receiving hydroxyurea at 8.7 years (range, 4-47; P <.001).

In addition to evaluating treatment at enrollment investigators performed mutational testing in 950 patients. Among patients with progression, 71.7% (n = 38) had at least 1 positive mutation test; common mutations included JAK2 (80.6%; n = 29/36), JAK2p.V617F (87.5%; n = 28/32), CALR (33.3%; n = 2/6), and MPL (28.6%; n = 2/7); 2 of 4 patients were triple negative for the 3 aforementioned mutations and 5 (13.2%) had unknown status. Among patients without progression, 77.0% (n = 912) had at least 1 positive mutation test; common mutations included JAK2 (69.7%; n = 598/858), JAK2p.V617F (71.0%; n = 516/727), CALR (62.3%; n = 101/162), and MPL (17.7%; n = 22/124). Further, 31.1% of patients (n = 14/45) were triple negative for the 3 aforementioned mutations and 274 (30.0%) had unknown status.

Study authors also noted that hemorrhagic events were slightly increased in patients with progression although thrombotic and hemorrhagic events were overall infrequent. The rates of thrombotic events, hemorrhagic events, and death from thrombotic or hemorrhagic events were 1.9% (n = 1), 7.5% (n = 4), and 0% in patients with progression, respectively, vs 3.7% (n = 44), 1.3% (n = 15), and 0.3% (n = 4) in patients without progression, respectively.

“One limitation of this study is the lack of bone marrow data for the majority of patients, which likely contributed to an underestimation of the rate of progression to myelofibrosis,” the authors noted.

Disclosures: Dr Mesa reported consulting or advisory roles with Constellation Pharmaceuticals, La Jolla Pharmaceutical, Novartis, and Sierra Oncology. He also noted receiving institutional research funding from AbbVie, Celgene, Constellation Pharmaceuticals, CTI BioPharma, Genentech, Incyte Corporation, Mays Cancer Center, National Cancer Institute, Promedior, and Samus Therapeutics.

Reference

Mesa RA, Lyons RM, Braunstein EM, et al. Progression to myelofibrosis in patients with essential thrombocythemia: a real world analysis from the prospective MOST study. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P1030.