Prevalence and clinical outcomes of polycythemia vera and essential thrombocythemia with hydroxyurea resistance or intolerance

Figures & data

Table 1. Clinical characteristics and outcomes of PV and ET patients.

Clinical characteristics	Total (N = 260)	PV (N = 116)	ET (N = 144)	p-value
Age: mean ± SD	61.2 ± 14.7	60.7 ± 12.9	61.6 ± 16.0	0.641
Sex: N (%)				0.001
Male	134 (51.5)	73 (62.9)	61 (42.4)
Female	126 (48.5)	43 (37.1)	83 (57.6)
Comorbid diseases: N (%)
Hypertension	121 (46.5)	64 (55.2)	57 (39.6)	0.012
DM	27 (10.4)	11 (9.5)	16 (11.1)	0.669
Dyslipidemia	66 (25.4)	28 (24.1)	38 (26.4)	0.678
Symptoms and signs: N (%)
Asymptomatic	95 (36.8)	38 (33.0)	57 (39.9)	0.259
Hepatomegaly	15 (5.8)	8 (6.9)	7 (4.9)	0.484
Splenomegaly	37 (14.2)	21 (18.1)	16 (11.1)	0.109
Thrombotic events: N (%)	41 (15.8)	24 (20.7)	17 (11.8)	0.051
Bleeding events: N (%)	22 (8.5)	8 (6.9)	14 (9.7)	0.416
Conventional risk factor: N (%)				0.125
No	110 (42.3)	43 (37.1)	67 (46.5)
Yes	150 (57.7)	73 (62.9)	77 (53.5)
International Study of PV score (range)	-	3 (1.5, 5.5)	-	-
Risk: N (%)	-		-	-
High		67 (57.8)
Intermediate		40 (34.5)
Low		9 (7.8)
Clinical characteristics	Total (N = 260)	PV (N = 116)	ET (N = 144)	P-value
IPSET-Survival Score: mean (range)	-	-	2 (1, 3)	-
Risk: N (%)	-	-		-
High			61 (42.4)
Intermediate			68 (47.2)
Low			15 (10.4)
IPSET-Thrombosis Score: mean (range)	-	-	3(2, 4)	-
Risk: N (%)	-	-		-
High			83 (62.4)
Intermediate			21 (15.8)
Low			29 (21.8)
Hemoglobin (mean ± SD); g/dL)	14.3 ± 2.5	17.0 ± 3.9	12.1 ± 2.3	-
White Blood Cell (×10^9/L) (range)	14.4 (10.1,20.7)	16.4 (12.1,23.7)	12.4 (9.5,17.7)	<0.001
Platelet (×10^9/L) (range)	934 (626,1228)	669 (441,951)	1078 (883,1406)	<0.001
JAK2 Mutation: N (%)				<0.001
No	62 (25.6)	10 (9.2)	52 (39.1)
Yes	180 (74.4)	99 (90.8)	81 (60.9)
CALR Mutation: N (%)				<0.001
No	17 (54.8)	1 (100.0)	16 (53.3)
Yes	14 (45.2)	0 (0.0)	14 (46.7)
MPL Mutation: N (%)				1.000
Not Test	258 (99.2)	115 (99.1)	143 (99.3)
No	2 (0.8)	1 (0.9)	1 (0.7)
Yes	0 (0.0)	0 (0.0)	0 (0.0)
Response: N (%)				0.365
CR	137 (52.7)	59 (50.9)	78 (54.2)
PR	102 (39.2)	50 (43.1)	52 (36.1)
NR	21 (8.1)	7 (6.0)	14 (9.7)
HU Resistance/ intolerance: N (%)	31 (11.9)	10 (8.6)	21 (14.6)	0.140
Outcomes: N (%)
Myelofibrosis	5 (1.9)	2 (1.7)	3 (2.1)	1.000
AML Transformation	5 (1.9)	2 (1.7)	3 (2.1)	1.000
Thrombosis	10 (3.9)	6 (5.2)	4 (2.8)	0.349
Bleeding	28 (10.8)	12 (10.3)	16 (11.1)	0.843
Death	58 (22.3)	24 (20.7)	34 (23.6)	0.574

PV: Polycythemia vera; ET: Essential thrombocythemia; DM: Diabetes mellitus; CR: Complete response; NR: No response; PR: Partial response; HU: Hydroxyurea.

Table 2. Patients with hydroxyurea resistance and intolerance according to each criterion.

ELN^7 and Modified ELN^9,10 Criteria for PV (Total 116 Patients)	N = 10 (%)	Median Survival (Months) (IQR)
Need for phlebotomy to keep Hct <45% after 3 months of at least 2 g/day of HU (or MTD for modified ELN)	0 (0.00)	–
Uncontrolled myeloproliferation, i.e. platelet >400 × 10^9/L and WBC >10 × 10^9/L after 3 months of at least 2 g/day of HU (or MTD for modified ELN)	4 (3.45)	83.98 (67.45, 95.67)
Failure to reduce massive splenomegaly by more than 50% as measured by palpation, or failure to completely relieve symptoms related to splenomegaly, after 3 months of at least 2 g/day of HU (or MTD for modified ELN)	0 (0.00)	–
ANC < 1 × 10^9/L or platelet count <100 × 10^9/L or Hb <10 g/dL at the lowest dose of HU required to achieve a complete or partial clinico-haematological response	3 (2.59)	38.87 (33.12, 44.48)
Presence of leg ulcers or other unacceptable HU-related non-haematological toxicities at any dose of HU	3 (2.59)	54.37 (21.78, 95.67)
ELN Criteria for ET^8 (Total 144 Patients)	N = 21 (%)	Median Survival (Months) (IQR)
(1) Platelet count > 600 × 10^9/L after 3 months of at least 2 g/day of HU	-	-
(2) Platelet count > 400 × 10^9/L and WBC less than 2.5 × 10^9/L at any dose of HU	2 (1.39)	5.06 (5.06, 40.48)
(3) Platelet count > 400 × 10^9/L and Hb less than 10 g/dL at any dose of HU	12 (8.33)	52.04 (5.06, 70.78)
(4) Presence of leg ulcers or other unacceptable muco-cutaneous manifestations at any dose of HU or HU-related fever	7 (4.86)	53.62 (30.65, 83.22)

ELN: European LeukemiaNet; Hct: Hematocrit; HU: Hydroxyurea; MTD: Maximum tolerated dose; WBC: White blood cell count; ANC: Absolute neutrophil count; Hb: Hemoglobin.

Table 3. Univariate analysis of factors associated with hydroxyurea resistance or intolerance.

Factor	HR	95% CI	p-value
Disease, ET	2.07	0.97–4.41	0.058
Age > 60 years	2.48	1.17–5.26	0.018
Sex, male	1.29	0.63–2.61	0.485
Hypertension	1.28	0.63–2.59	0.497
Dyslipidemia	0.96	0.43–2.15	0.925
DM	0.61	0.14–2.54	0.493
Symptoms
Asymptomatic	0.46	0.19–1.12	0.087
Hepatomegaly	0.46	0.19–1.12	0.087
Splenomegaly	0.41	0.10–1.70	0.217
Thrombotic events at Presentation	1.18	0.48–2.88	0.715
Bleeding Events at Presentation	1.79	0.62–5.14	0.279
Clinical Risk Factor, High Risk	1.19	0.58–2.45	0.642
Laboratory
Hemoglobin at Baseline (g/dL)	0.86	0.77–0.96	0.007
White Blood Cell at Baseline
> 10 × 10^9/L	0.93	0.41–2.07	0.853
Platelet at Baseline > 1000 × 10^9/L	1.73	0.85–3.53	0.128
JAK2V617F mutation	1.77	0.37–8.40	0.473

PV: Polycythemia vera: ET: Essential thrombocythemia: DM; Diabetes mellitus.

Table 4. Clinical outcomes in patients with HU resistance or intolerance.

Clinical outcomes	All patients (N = 260)	HU resistant or intolerance (N = 31)
	Event, N (%)	Event, N (%)	HR	95% CI	P-value
Myelofibrosis	5 (1.9)	1 (3.2)^a	1.38	0.01–0.31	0.774
AML transformation	5 (1.9)	0 (0)	-	-	-
Thrombosis	10 (3.8)	1 (3.2)^b	0.66	0.08–5.32	0.696
Bleeding	28 (10.8)	9 (29.0)^c	2.64	1.19–5.85	0.017

^a Myelofibrosis: 1 ET.

^b Thrombosis: 1 Peripheral arterial disease (1 ET).

^c Bleeding: 7 Mucocutaneous bleeding (1 PV, 6 ET), 1 Gastrointestinal bleeding (1 PV), 1 Hemoptysis (1 ET).

HU: Hydroxyurea; AML: Acute myeloid leukemia.