Correlating leukocytosis with risk of progression and thrombosis in PV

Polycythemia vera (PV) is a type of chronic myeloproliferative neoplasm characterized by erythrocytosis, specific histological features in the bone marrow and commonly the presence of either V617F or exon 12 mutations in Janus Kinase 2 in myeloid cells.¹ In some patients it may also result in high white blood cell counts (WBC), platelet counts, and erythrocytes.² In addition, patients are susceptible to thrombotic events and the disease progression eventually evolving to myelofibrosis, myelodysplastic syndrome or acute myeloid leukemia (AML).³

Previous studies have investigated the association of leukocytosis with thrombotic events or disease evolution with discordant results, however mostly at a single time point (usually at diagnosis) rather than using a longitudinal analysis looking at leukocyte count evolution overtime.

This study used retrospective data from 520 patients to investigate the association of leukocyte level, hematocrit value and platelet count with thrombosis or disease evolution using group-based trajectory modeling (GBTM).⁴ Latent clusters of patients whose leukocyte, hematocrit or platelet count follow distinct trajectories over time were analyzed to evaluate the prognostic significance of blood cell counts over a 1-year period as biomarker.

Methods⁴

• Records of 520 patients from 10 participating academic institutions in the US were analyzed
• Inclusion criteria: ≥ 18 years old at time of diagnosis, three recorded appointments with hematologist at participating institution and at least one appointment within January 2009 to January 2019
• Statistical analysis: GBTM was used to identify clusters of patients with similar patterns of hematological laboratory values within 12 months of index visit
• Multinomial modeling strategy was employed to identify homogenous groups with distinct trajectories
• 377 patients were analyzed in all thrombosis hazard models while 378 patients were analyzed in disease evolution hazard models
• For thrombotic events all models were adjusted for age at diagnosis, sex, duration of disease, history of prior thrombotic event, the number of relevant cardiovascular risk factors, and cytoreductive therapy at any time during the trajectory period
• For disease evolution all models were adjusted for age at diagnosis, duration of disease, and cytoreductive therapy during the trajectory period

Results⁴

• 4 leukocyte trajectories (WBC5=stable at 5 ×10⁹/L, WBC10=10 ×10⁹/L, WBC15=15 x10⁹/L, and WBC35=oscillating at 35 ×10⁹/L), 3 hematocrit trajectories (hematocrit roughly at 35, 43, and 47%) and 3 stable platelet trajectories (125, 300, and 600 ×10⁹/L) were identified
• No significant association was found between leukocyte trajectory and thrombosis (p = 0.4163)
• However, there was a significant, stepwise association between leukocyte trajectory and disease evolution (p = 0.0002)
• While WBC10 did not significantly increase the probability of disease evolution (p = 0.1418), the risk of transformation increased by 5.51-fold for WBC15 (p = 0.0083) and by 24.23-fold for WBC35 (p < 0.0001)
• Cox proportional hazards model showed no significant associations between hematocrit trajectory and thrombosis (p = 0.1849) or hematocrit and disease evolution (p= 0.5407)
• Platelet trajectory results were similar with no significant association with thrombosis (p = 0.9501) or disease evolution (p = 0.1670)

Study limitations⁴

• Significant proportion of patients were excluded either for lacking the necessary frequency of compete blood count assessments within landmark period (≥ 3 within a 12-month time frame) or having experienced censorship or an event of interest (thrombosis or disease evolution)
• Older and sicker patients may have been more likely to maintain stable long-term follow-up at a particular center and may be enriched in this study
• Excluded patients who experienced an event of interest during the 1-year model plotting period may represent the most significantly at-risk population
• The event rate after these exclusions was low, 9% for thrombosis and 10% for evolution, therefore, small but significant associations may have been missed
• Data on medication use such as anticoagulants and statins were not collected

Study advantages⁴

• Multicenter focus with 48-month follow-up
• Use of GBTM algorithm which
  • identifies latent properties of retrospective data and prevents arbitrary categorization
  • prevents adjustment of categorization rules post hoc to discover grouping
• No correction for time-based bias required

Representation of cumulative “exposure” to an elevated leukocyte count, hematocrit, or platelet count accounting for the fact that events may result from cumulative damage

Conclusions⁴

This longitudinal trial of 520 patients, retrospectively pooled and analyzed using GBTM, found that persistent leukocytosis was significantly associated with disease evolution to myelofibrosis, myelodysplastic syndrome or AML (p = 0.0002) but not with thrombosis.

No association with thrombosis or disease progression was found for long-term increases in hematocrit and thrombocyte counts.

A prospective trial of leukocyte control in otherwise uncontrolled patients with the endpoint being primary disease evolution may be warranted.