Clinico-Molecular Features and Treatment Outcomes in Primary Myelofibrosis Phenotypes with Protracted Disease Dynamics
Authors: Aguirre Luis E. , Jain Akriti G , Ball Somedeb , Al Ali Najla , Tinsley-Vance Sara Marie , Sallman David A. , Sweet Kendra , Lancet Jeffrey E. , Padron Eric , Kuykendall Andrew T. , Komrokji Rami S. 
Published: November 2021

Abstract

Background
Primary myelofibrosis (PMF) is the most aggressive subtype among classical BCR-ABL1 negative myeloproliferative neoplasms (MPN). Driven by constitutive activation of the JAK/STAT pathway, its prognosis is defined by cardinal clinical, cytogenetic and molecular features. While most patients require therapy for symptomatic splenomegaly, disease-related symptoms, or cytopenias, asymptomatic lower-risk patients may be appropriately monitored with active surveillance. The aim of this study was to explore disease characteristics and outcomes among pts who remained on prolonged active surveillance compared to those who received early treatment.
Methods
We identified patients with confirmed MF (inclusive of primary MF and MF occurring after essential thrombocythemia or polycythemia vera) treated at Moffitt Cancer Center between 2003-2021. Patients were stratified into two cohorts: those remaining on active surveillance for ≥ 36 months following diagnosis and those who received within 36 months of diagnosis.
Results
Between August 2000 and March 2021, we identified 626 patients with a diagnosis of MF. Among these, 48 (8%) did not receive treatment for at least 3 years. Table 1 summarizes the baseline characteristics comparing those pts who remained on active surveillance for ≥ 36 months (LTO-MF) to those who received treatment within 36 months of diagnosis (ET-MF). The LTO cohort presented at a younger age (median age 63 vs 68; p = 0.001), but otherwise demographic variables were balanced between the two cohorts.
LTO patients were more likely to have primary MF (85.4% vs 60.9%, p=0.003). LTO patients were less likely to have leukocytosis (28.2% vs 49.9%, p=0.01), and constitutional symptoms (29.8% vs 44.6%, p=0.05), while having a higher reticulocyte percentage (81.4% vs 64.1%, p=0.02). LTO patients also had lower platelet counts (mean: 274k vs 359k, p=0.006), lower percentage of circulating blasts (0.4% vs 1.2%, p&lt;0.001), and lower percentage of marrow myeloblasts (1.3% vs 1.9%, p&lt;0.001) at baseline. Cohorts had comparable rates of anemia, thrombocytopenia, transfusion dependence, LDH levels and splenomegaly at baseline.
Interestingly, the cohorts were well-balanced in terms of risk score based across all major prognostic scoring systems: IPSS (p=0.356), DIPSS (p=0.764), DIPSS+ (p=0.148), GIPSS (p=0.125), MIPSS70 (p=0.924) and MIPSS70+ (p=0.407). There was no association between GPSS karyotype risk and need to start treatment earlier (p=0.481) (Table 1).
LTO patients were less likely to harbor JAK2 mutations (58.3% vs 72.4%, p=0.04). No significant differences were seen regarding CALR (p=0.144), MPL (p= 0.271), or triple-negative disease (p=0.521) (Table 2).
The median OS (mOS) for the entire population was 82.5 months (95%CI 69.4-95.5). LTO patients had longer OS (mOS 170.3 mo vs 63.9 mo; (p&lt;0.001). Rates of transformation to blast phase were comparable (6.2% vs 9.7%;p=0.441), but median time to blast phase transformation was longer for LTO MF: 66.3 mo vs 29 mo, p=0.011).
Expectedly, time to first treatment longer for LTO patients (62.1 mo vs 0.9 mo; (p&lt;0.001). No differences were noted between cohorts in terms of response to ruxolitinib, duration of response to ruxolitinib or response to lenalidomide/thalidomide (p = 0.91, 0.90, 0.83, respectively)
Conclusion
In this single-center study of patients seen at a tertiary referral center, the vast majority of MF patient required treatment within 36 months of diagnosis. Those monitored with active surveillance were younger, had less proliferative signs/symptoms, were less likely to have JAK2 mutations, and more favorable outcomes.
Figure 1 Figure 1.

Disclosures
Tinsley-Vance: Fresenius Kabi: Consultancy; Novartis: Consultancy; Incyte: Consultancy, Speakers Bureau; Abbvie: Honoraria; Jazz: Consultancy, Speakers Bureau; Taiho: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Astellas: Speakers Bureau. Sallman: Magenta: Consultancy; Takeda: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; BerGenBio: Consultancy; ElevateBio Management: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; Jazz: Consultancy. Padron: Incyte: Research Funding; BMS: Research Funding; Taiho: Honoraria; Kura: Research Funding; Blueprint: Honoraria; Stemline: Honoraria. Kuykendall: Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; BluePrint Medicines: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; PharmaEssentia: Honoraria; Abbvie: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria. Komrokji: AbbVie: Consultancy; Geron: Consultancy; Acceleron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees.