Efficacy and Safety of Pegylated Interferon Alpha-2a in Patients with Essential Thrombocythemia and Polycythemia Vera: Results after a Median 7-Year Follow-up of a Phase 2 Study

Introduction: It has been previously reported that pegylated interferon alpha-2a can induce hematologic and molecular responses in patients with essential thrombocythemia “ET” and polycythemia vera “PV”, but the follow up in these studies were relatively short.

Objective: We present longer-term efficacy and safety results of a prospective phase II study of pegylated interferon alpha-2a in patients with ET and PV after a median follow up of 82.5 months (range, 8-107).

Methods: Patients with a diagnosis of ET or PV, in a need of therapy, either newly diagnosed or previously treated, were eligible for this study.  Median interferon starting dose of 180 mcg/week SQ (range, 450-90; 39% started on 90mcg/week) was modified in majority of the patients based on toxicity or lack of efficacy. Clinical and molecular responses were assessed every 3 to 6 months.

Results: Among 83 enrolled patients (43 PV, 40 ET), 32 patients (39%) are still on study (but in 8 therapy is on hold: 5 due to toxicity, and 3 for financial reasons). Median age was 53 years (range, 19-78). Overall 37% of patients did not receive prior cytoreductive treatment. The overall median exposure to therapy was 87 months (range, 58-107) and was no different for patients still enrolled on the study and those who stopped study participation. Nine (28%) patients still on study are currently on a dose equal or higher than 90 mcg/week and 15 (47%) are on dose equal or smaller than 45mcg/week. JAK2 status or allele burden had no impact on achievement of response (clinical or molecular), time to response or duration of therapy. 55 of 59 (71%) JAK2V617F positive patients were evaluable for molecular response (Figure); 8 patients carried CARL mutation, 3 carried MPL and in 13 were triple negative. Median duration of hematologic and molecular response was 66 and 53 months, respectively; and directly correlated with treatment length and type of response (CMR had the longest duration of response). Overall yearly discontinuation rate were gradually decreasing for first 5 years, from 17% to 5%, and slowly increasing afterward to 10%. Of the 51 patients not on the study anymore, 27 (35% of the total) discontinued therapy primarily due to treatment toxicity. New late (≥24 months from start of therapy) G3/4 toxicity occurred in 17% of patients. Among patients in complete hematologic response treatment failure due to vascular adverse event or disease transformation was seen in 5 patients each. Three patients died on study (not related to therapy or disease), and 8 after stopping participation. Mean changes in allele burden over time in JAK2 positive patients are depicted in figure.   

Conclusions: Although pegylated interferon alpha-2a can induce significant hematologic and molecular responses; toxicity still limits its use over longer period of time and loss of response or transformation is encountered.

Response	Characteristics	First response	Last response
Hem Resp, N. of patients (No), (%)	CHR	62 (76)	25 (40)a
	PHR	4 (5)	1 (25)
	ORR	66 (79)	26 (39)a
Mol Resp, No, (%)	CMR	10 (18)	9 (90)
	PMR	20 (36)	5 (25)*
	mMR	5 (9)	2 (40)
	ORR	35 (74)	16 (46)
Safety		Any grade	Grade ≥3
Overall Adverse Events (AE), No, (%)	any AE	83 (100)	57 (67)
	recurrent AE	74 (89)	13 (16)
AE subtypes, No, (%)	musculoskeletal	73 (88)	6 (8)
	neurological	53 (64)	2 (4)
	psychiatric	38 (46)	4 (11)
	gastrointestinal	54 (65)	11 (20)
	LFT elevation	27 (33)	5 (18)
	skin	18 (22)	2 (11)
	infection/fever	26 (31)	3 (12)
	respiratory	23 (28)	2 (9)
	cardiovascular	13 (16)	3 (23)
	metabolic	16 (19)	2 (13)
	neutropenia	37 (45)	21 (57)
	thrombocytopenia	18 (22)a	1 (6)
	anemia	36 (43)	1 (3)
Autoimmune toxicity, No, (%)	hepatitis	1 (2.5)
	CNS vasculitis	1 (2.5)
	lupus nephritis	1 (2.3)
	Sjogren sy & dermatitis	1 (2.5)
Vascular AE (TEE/bleeding),	Unprovoked	6 (7)	5 (83)
No, (%)	Provoked	4 (5)	3 (75)
Disease transformation, No, (%)	Myelofibrosis	6 (7)
	AML	1 (1)
Safety over ≥24 months **		Any grade	Grade ≥3
New AE, No (%)	3th year	10 (17)	4 (40)
	4th year	6 (11)	4 (67)
	5th year	5 (10)	1 (20)
	≥ 6th year	10 (24)	1 (10)

** Effective sample size for patients on therapy/year: Initial number of patients at risk at the beginning of period minus half of patients censored during that period

* % calculated from 19 patients

^a statistically significant differences by Fisher's exact test

 

Abbr. CMR= complete molecular remission (undetectable JAK2 allele burden), PMR= partial molecular remission (>50% decrease in allele burden), mMR= minor molecular remission (20-49% decrease in allele burden)