Real-World Survival Outcomes for Elderly Patients With Myelofibrosis Show Correlation With FDA Approval of Ruxolitinib

Srdan Verstovsek, MD, PhD

Improvements were observed in the 1-year overall survival of elderly patients with intermediate- or high-risk myelofibrosis (MF) who had never received ruxolitinib (Jakafi) following the agent’s FDA approval, according to a real-world analysis presented during the 25th European Hematology Association Virtual Annual Congress.

Ruxolitinib received its FDA approval in November 2011 for the treatment of adult patients with intermediate- or high-risk MF. The JAK1/2 inhibitor was also approved in August 2012 by the European Medicines Agency for the treatment of disease-related splenomegaly or symptoms in adult patients with MF. The approval of ruxolitinib may have generated an increased awareness around this disease, ultimately improving the overall management of this patient population, according to lead author Srdan Verstovsek, MD, PhD.

“Ruxolitinib was associated with significant improvements in survival compared with placebo in the phase 3 clinical trials or compared to best available therapy,” said Verstovsek, medical oncologist and professor, Department of Leukemia, University of Texas MD Anderson Cancer Center, during the presentation. “However, understanding the clinical benefit of ruxolitinib in the real-world practice requires an understanding of changes in patient outcomes before and after ruxolitinib approval, independent of ruxolitinib treatment.”

The purpose of this study was to compare the overall survival benefit in patients with newly diagnosed, intermediate- to high-risk MF who had not received prior ruxolitinib, both pre- and post-approval of ruxolitinib in the United States.

“Following the approval of ruxolitinib, European Leukemia and National Comprehensive Cancer Network consensus guidelines were revised, which may have led to improved overall management of patients with MF, irrespective of ruxolitinib treatment,” Verstovsek added.

A total of 119 patients out of 278 (42.8%) in the pre-approval arm had a valid death date compared with 262 of the 1127 patients (23.3%) in the post-approval arm during a mean follow-up of 25.7 months and 15.8 months, respectively. The 1-year survival rate for the pre-approval arm was 55.6% (95% CI, 49.4%-61.3%) and 73.6% in the post-approval arm (95% CI, 70.7%-76.3%).

A higher risk of mortality was observed in the pre-approval arm compared with the post-approval arm, with an adjusted hazard ratio (HR) of 1.41 (95% CI< 1.11-1.78; P =.0043).

Survival also appeared to improve over time in the post-approval arm. The 1-year survival rate was 62.1% (95% CI, 60.0%-66.8%) in the 2012-2014 group and 81.2% (95% CI< 77.9%-84.1%) in the 2015-2017 group. Patients in the 2015-2017 group also had a lower risk of mortality compared with the 2012-2014 group, with an adjusted HR of 0.54 (95% CI, 0.39-0.75; P =.0002).

The 1-year survival rates generally improved in the post-approval versus pre-approval cohorts. When patients were excluded with pre-index myelodysplastic syndrome (MDS), the 1-year survival rate was 64.2% in the pre-approval arm (95% CI, 61.5%-66.7%) versus 67.2% (95% CI, 65.8%-68.7%) in the post-approval arm (adjusted HR, 0.99; 95% CI, 0.89-1.11). When patients were excluded for pre- and post-MDS, the 1-year survival rate was 59.5% (95% CI, 55.8%-63.0%) in the pre-approval arm and 69.4% (95% CI< 67.5%-71.1%) in the post-approval arm (adjusted HR, 1.13; 95% CI, 0.98-1.3).

With the exclusion of patients with MDS or other hematologic malignancies pre- and post-index, the 1-year survival rate was 60.1% (95% CI, 55.7%-64.2%) for the pre-approval arm and 72.0% (95% CI< 69.7%-74.1%) in the post-approval arm (adjusted HR, 1.14; 95% CI, 0.96-1.36). With exclusion of patients with MDS, other hematologic malignancies, or solid tumors pre- and post-index, the 1-year survival rate was 55.6% (95% CI, 49.2%-61.3%) in the pre-approval arm and 73.4% (95% CI, 70.5%-76.1%) in the post-approval arm (adjusted HR, 1.41; 95% CI, 1.12-1.78).

With exclusion of patients with MDS, other hematologic malignancies, or solid tumors pre- and post-index or AML pre-index, the 1-year survival rate was 55.6% (95% CI, 49.4%-61.3%) in the pre-approval arm and 73.6% (95% CI, 70.7%-76.3%) in the post-approval arm (adjusted HR, 1.41; 95% CI, 1.12-1.78). With the exclusion of patients with MDS, other hematologic malignancies, solid tumors, or AML pre- and post-index, the 1-year survival rate was 55.6% (95% CI, 49.4%-61.3%) in the pre-approval arm and 73.6% (95% CI, 70.7%-76.3%) in the post-approval arm (adjusted HR, 1.41; 95% CI, 1.11-1.78).

Investigators noted that many factors contributed to the survival improvement, including an increased awareness of the disease and improved patient management. However, there may have been some limitations in this real-world analysis.

“The study was a retrospective analysis of unadjusted claims and therefore may be limited by sampling bias, medical errors, and incomplete records,” Verstovsek said. “The evaluable dataset did not include clinical variables and the MF risk classification was based solely on age.”

Study investigators used a 100% sample of the Medicare Free-for-Service claims database (Parts A/B/D) from January 2010 to December 2017 to identify patients who were at least 65 years old with at least 1 inpatient or 2 outpatient treatment claims with a diagnosis of MF. To be included in the analysis, patients had to have a minimum of 12 months of pre-index continuous medical and pharmacy enrollment. Patients were separated into 2 groups for the study, which included pre-ruxolitinib approval with an index year 2010 to 2011 and post-ruxolitinib approval with an index year of 2012 to 2017. Patients were also subdivided in the post-approval cohort into 2012 to 2014 and 2015 to 2017.

Any patients who had evidence of a diagnosis at least 12 months prior to the index date or who had been treated with ruxolitinib were excluded from the study. Those with MDS; hematologic malignancies besides acute myeloid leukemia, multiple myeloma, and lymphomas; solid tumors of acute myeloid leukemia either ≤ 12 months before, on, or any time after the index date were also excluded from the study.

Overall, 1405 patients met the study inclusion criteria, which included 278 patients in the pre-approval arm, 387 in the post-approval 2012-2014 arm, and 740 in the post-approval 2015-2017 arm. The median age of all patients was 78.9 years (range, 65-105), and 39.0% were male while 83.3% were Caucasian. Overall, 7.9% of patients had a history of polycythemia vera and 15.7% had a history of essential thrombocytopenia.

In the pre-approval arm, the median age was 80.7 years (range, 65-102) compared with 80.0 years in the 2012-2014 arm (range, 65-105) and 77.7 years in the 2015-2017 arm (range, 65-101). In the pre-approval arm, 29.9% were male, 84.9% were Caucasian, 8.6% African American, and 6.5% were other or unknown, compared with the 2012-2014 and 2015-2017 arms, which were 34.9% and 44.6% male, 82.7% and 83.0% Caucasian, 10.6% and 10.0% African American, and 6.7% and 7.0% other or unknown.

_Reference

_{Verstovsek S, Parasuraman S, Yu J, et al. Real-world survival in elderly patient with myelofibrosis in the United States: pre- vs post-ruxolitinib approval. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract EP1120.}