Advanced Polycythemia Vera

A Subset of Patients May Experience Ineffective Disease Control

Polycythemia vera (PV) is a hematologic malignancy that may become advanced in a subset of patients despite treatment with hydroxyurea (HU) and phlebotomy, resulting in ineffective disease control.1-4

Actively Monitor for Hct+

Hematocrit (Hct) levels are an important clinical consideration when managing patients with PV.5

When it comes to advanced PV, think Hct+:

Hct+ means elevated Hct levels ≥45% plus one additional factor—either elevated white blood cell counts or burdensome symptoms despite treatment with HU and phlebotomy.5

These clinical characteristics are also included as part of the European LeukemiaNet (ELN) consensus criteria for HU resistance in patients with polycythemia vera.5

Hct = hematocrit WBC = white blood cell

Consider the Clinical Characteristics

It is important to proactively identify the subset of patients with clinical characteristics of advanced PV. Patients with clinical characteristics of advanced PV are at increased risk of thrombosis.

Elevated Hematocrit Levels ≥45%

Findings from the CYTO-PV study revealed a 4-fold higher rate of cardiovascular death and major thrombosis.8

Managing hematocrit (Hct) levels between 45% and 50% significantly increased the risk of cardiovascular death and major thrombosis compared with an Hct level managed <45% (hazard ratio, 3.91; 95% CI, 1.45-10.53; P=0.007).8*

Elevated Hct ≥45%:
4-fold higher rate of cardiovascular death and major thrombosis8

Image of chart showing the probability of remaining event free in the (CYTO-PV) study
Kaplan-Meier curves for primary composite end point. Adapted with permission from the Massachusetts Medical Society. CI = confidence interval Hct = hematocrit
* In the Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) study of 365 adult patients with PV treated with phlebotomy, hydroxyurea, or both, patients were randomized to 1 of 2 groups—either the low-Hct group (n = 182; with more intensive therapy to maintain a target Hct level <45%) or the high-Hct group (n = 183; with less intensive therapy to maintain a target Hct level of 45% to 50%). Baseline characteristics were balanced between the groups. Approximately 50% of patients had received an initial diagnosis of PV within 2 years prior to randomization. 67.1% of patients (n = 245) were at high risk because of age ≥65 years or previous thrombosis. The composite primary end point was the time until cardiovascular death or major thrombosis.8

Hct+ Elevated White Blood Cell Counts

Additional analysis from the CYTO-PV study associated elevated white blood cell (WBC) counts >11 x 109/L with increased risk of thrombosis (hazard ratio, 3.9; 95% CI, 1.24-12.3; P=0.02).6

There was a trend for increased risk of thrombosis with WBC count >7 x 109 (ie, hazard ratio >1) that became statistically significant in patients with WBC counts >11 × 109/L.6

These results are consistent with other literature that suggests leukocytosis may increase the risk of thrombosis.9,10

Elevated WBC counts >11 × 109/L increased the risk of thrombosis6

Time-Dependent Multivariable Analysis on the Risk of Major Thrombosis in CYTO-PV Study (N=365)6a
WBC Count (x109/L)
Events/Patients (%)
Hazard Ratio (95% CL), P
<7
4/100 (4%)
1.0
7-8.4
4/84 (4.8%)
1.58 (0.39-6.43), 0.52
8.5-11
8/88 (9.1%)
2.69 (0.80-9.05), 0.11
>11
12/93 (12.9%)
3.90 (1.24-12.3), 0.02
Adapted from Barbui T, et al. Blood. 2015;126(4):560-561.
aAdjusted for age, gender, cardiovascular risk factors, previous thrombosis, and Hct levels.
CI = confidence interval CYTO-PV = Cytoreductive Therapy in Polycythemia Vera WBC = white blood cell

Hct+ Burdensome Symptoms

Symptom burden in patients with PV is substantial and may not be adequately controlled with hydroxyurea.11

In a prospective study of 1334 patients with PV, a subset of patients with known hydroxyurea use (n = 499) on average experienced moderate to high symptom burden (TSS = 29.2).11

Image of chart showing MPN-10 Mean Symptom Scores in Patients with Know Hydroxyurea Use
MPN-10 = myeloproliferative neoplasm symptom assessment form a A prospective study of 1334 patients with PV was conducted to assess baseline symptoms with certain disease features (ie, known hydroxyurea use, known phlebotomy requirements, and splenomegaly). The patients had the following characteristics: known hydroxyurea use (n = 499), known phlebotomy (n = 646), palpable splenomegaly (n = 369), or all three features (n = 148). Assessment of myeloproliferative neoplasm (MPN) symptoms was performed by using the MPN-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS; MPN-10). All items were evaluated on a 0 (absent) to 10 (worst imaginable) scale. The MPN-10 TSS has a possible range of 0 to 100 with 100 representing the highest level of symptom severity. The TSS for each patient was analyzed to place the patient into the quartiles of low symptom burden (TSS, 0 to 7), intermediate symptom burden (TSS, 8 to 17), moderately high symptom burden (TSS, 18 to 31), or high symptom burden (TSS, ≥32).

Impact on Quality of Life

Findings from the MPN Landmark Survey suggest that patients experience a broad symptom burden, which may negatively affect quality of life, activities of daily living, and work productivity.12

Selected Survey Results in Patients With Polycythemia Vera
  • 66% reported that their symptoms diminish their quality of lifea
  • 73% reported fatigue as a symptomb
  • 52% reported that pain/discomfort limited their daily activitiesc
  • 63% reported that PV interfered with family or social lifec
The Myeloproliferative Neoplasm (MPN) Landmark Survey, funded by Incyte Corporation, was a web-based questionnaire composed of 65 multiple-choice questions intended to help evaluate the patient disease burden in the MPN disease setting. A total of 813 patients in the United States with a previous diagnosis of myelofibrosis (MF), PV, or essential thrombocythemia (ET) completed the survey (MF, n = 207; PV, n = 380; ET, n = 226).12 a Patients reported whether they strongly agreed, somewhat agreed, somewhat disagreed, or strongly disagreed with the following statement: PV symptoms reduce my quality of life.12 b Symptoms were evaluated using an adapted version of the MPN Symptom Assessment Form (MPN-SAF) and were rated on a scale of 0 (absent) to 10 (worst imaginable). The incidence is the percentage of those respondents who reported experiencing the symptom (ie, score ≥1) within the 12 months preceding the survey.12 c Patients reported impact on their activities of daily living on a scale that ranged from 1 (not at all) to 5 (a great deal). The patient was included as having interference with daily activities if they had ever experienced the issue and reported a score >1.12
References

1. Parasuraman S, DiBonaventura M, Reith K, Naim A, Concialdi K, Sarlis NJ. Exp Hematol Oncol. 2016;5:3. 2. Mascarenhas J. Clin Lymphoma Myeloma Leuk. 2016;16 suppl:S124-S129. 3. Rumi E, Cazzola M. Blood. 2017;129(6):680-692. 4. Spivak JL, Considine M, Williams DM, et al. N Engl J Med. 2014;371(9):808-817. 5. Barosi G, Birgegard G, Finazzi G, et al. Br J Haematol. 2010;148(6):961-963. 6. Barbui T, Masciulli A, Marfisi MR, et al. Blood. 2015;126(4):560-561. 7. Emanuel RM, Dueck AC, Geyer HL, et al. J Clin Oncol. 2012;30(33):4098-4103. 8. Marchioli R, Finazzi G, Specchia G, et al. N Eng J Med. 2013;368(1):22-33. 9. Gangat N, Strand J, Li CY, Wu W, Pardanani A, Tefferi A. Br J Haematol. 2007;138:354-358. 10. Landolfi R, Di Gennaro L, Barbui T, et al. Blood. 2007;109(6):2446-2452. 11. Geyer H, Scherber R, Kosiorek H, et al. J Clin Oncol. 2016;34(2):151-159. 12. Mesa R, Miller CB, Thyne M, et al. BMC Cancer. 2016;16:167.

 
Resources
The potential impact of a target hematocrit level of <45% on major thrombosis or cardiac death.
By: MPN Connect
An animated video highlighting PV pathophysiology and mechanisms of disease.