Blast Phase Not Stalled With Ruxolitinib Treatment in Myelofibrosis, Study Shows


A new analysis of nearly 600 patients with myelofibrosis found patients who take ruxolitinib progress to blast phase at approximately the same rates as those who are ruxolitinib-naïve.

Ruxolitinib (Jakafi) neither promotes nor prevents blast phase (BP) evolution in patients with myelofibrosis (MF), according to a new study of close to 600 patients treated with the JAK1/2 inhibitor. The results, published in the journal Hematological Oncology,1shed important light on what has become the standard therapy for MF. They also underscore the importance of screening high-risk patients for allogeneic transplantation eligibility.

Myelofibrosis is a type of myeloproliferative neoplasm (MPN) that can be categorized as either primary or secondary. In the latter case, it follows polycythemia vera or essential thrombocythemia. Corresponding author Francesca Palandri, MD, PhD, of the University of Bologna, and colleagues, noted that the outlook for patients diagnosed with MF can vary significantly, with survival ranging anywhere from 2 years to 2 decades. As with other MPNs, MF eventually transitions to BP, at which point the median survival is a mere 5 months.

Investigators have sought ways to avoid these poor prognoses by attempting to predict or avoid the transition to BP. A number of theories of risk factors have been put forward, including a predictive model consisting of mutations of the IDH1, SRSF2, or ASXL1 genes; age of 70 or greater; and at least 3% circulating blasts. However, the model has not been tested in patients treated with ruxolitinib.

Palandri and colleagues wrote that ruxolitinib has been shown to decrease cachexia, but it is not known whether and to what extent it affects evolution to BP.

In an effort to answer that question, Palandri and colleagues conducted a multicenter, observational, retrospective study at 20 hematology centers in Europe. The authors analyzed records of patients who had been treated for chronic-phase MF with ruxolitinib beginning in the year 2011 and ending in June 2019. A total of 589 patients were included in the data set, including 51.6% with primary MF, and the median follow-up was 2.95 years.

The cohort’s median age at start of ruxolitinib was 68 years (range, 24-88). The median time from diagnosis to initiation of ruxolitinib was 1.3 years (range, 0.1-32.8). Prior to ruxolitinib initiation, 206 patients (34.9%) had received no therapy or supportive therapy only. About half of patients (n = 297were previously treated with hydroxyurea alone or in combination, 37 patients were given alkylating agents, and 29 patients received interferon-alpha (IFN-α) alone or in sequential therapy with anagrelide and/or hydroxyurea (Hydrea).

The patients in the cohort were categorized by risk based on the Dynamic International Prognostic Score System (DIPSS) for those with primary MF and the Myelofibrosis Secondary to Polycythemia Vera and Essential Thrombocythemia Collaboration Prognostic Model (MYSEC-PM) for those with secondary MF. A large majority of patients were categorized as intermediate-1 or -2 risk in both groups.

At the close of the observation period, 65 patients (11%) had developed myeloid BP. None of the patients developed lymphoid BP. The median time from diagnosis to BP evolution was 3.5 years (range, 0.2-18.9), and the median age at evolution was 71 (range, 44-89). Among those 65 who developed BP, 61 stopped ruxolitinib upon diagnosis of BP, which occurred at a median period of 1.2 years (range, 0.1-6.8) after starting the therapy. The remaining 4 patients had stopped taking ruxolitinib prior to BP, with an average discontinuation period of 2.4 years (range, 2.2-3.3) before BP. Five patients evolved to BP following splenectomy.

Palandri and colleagues said the data suggest incidence of BP was generally comparable to previously reported studies of ruxolitinib-naïve patients.2That held true even when patients were initiated on ruxolitinib quickly after diagnosis.

“Taken together, these observations may indirectly suggest that ruxolitinib does not significantly modify the probability of BP transformation or delay its occurrence,” the authors wrote; though they noted that the findings could only be conclusively confirmed in a study that matched a ruxolitinib cohort against a ruxolitinib-naïve cohort.

In further analysis, the investigators said the only statistically significant risk factor for progression to BP among patients with primary MF was risk category. Among patients with secondary MF, however, a couple of predictors were found on univariate analysis: platelet count (<150x109/L), circulating blasts of greater than 3% at the start of ruxolitinib therapy, grade 3 marrow fibrosis, and duration of the primary MPN of at least 10 years.

“Both parameters reflect a greater disease severity and are included among risk factors for inferior survival in the MYSEC-PM score, which is dedicated to SMF,” Palandri and colleagues wrote.

On the other hand, the authors noted that in both primary and secondary MF, a history of IFN-α use resulted in a lower likelihood of evolving to BP, regardless of risk category. That could mean IFN-α has a disease-modifying effect in MF, though the authors noted that the number of patients in the study who received IFN-α was too small to draw broad conclusions (n = 29).

As with studies of ruxolitinib-naïve patients, the survival rates of patients who progressed to BP remained small. Of the 65 patients in the study who entered BP, 54 (81.8%) died, with a median survival of just 0.2 years (95% CI, 0.1-0.3). Thus, the data suggest ruxolitinib does not affect survival once a patient progresses to BP.

Palandri and colleagues said their findings support the use of risk assessment tools as a valid means of evaluating patients, which in turn will allow clinicians to closely track patients in the high-risk category. Such patients should be immediately evaluated for allogeneic transplant eligibility, the authors concluded, as this study suggests transplantation remains the primary avenue by which to achieve long-term responses.


1. Palandri F, Breccia M, Tiribelli M, et al. Risk factors for progression to blast phase and outcome in 589 patients with myelofibrosis treated with ruxolitinib: Real‐world data. Hematol Oncol. 2020;1-9. doi:10.1002/hon.2737

2. Tefferi A, Guglielmelli P, Larson DR, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;124(16):2507-2513. doi:10.1182/blood-2014-05-579136

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