Combination of Cytoreductive Therapies in Patients with Essential Thrombocythemia: A Preliminary Report From the E.X.E.L.S. Study.

As some patients (pts) with essential thrombocythemia (ET) may discontinue their cytoreductive treatment because of drug intolerance/inefficacy, combinations of drugs with different activity/tolerability patterns are being utilized in clinical practice.

To evaluate the clinical relevance and patterns of cytoreductive combination treatment in ET in Evaluation of Xagrid^™ Efficacy and Long-term Safety (EXELS), an observational study in 3643 European pts with high-risk ET.

Data on pts receiving cytoreductive treatments in combination for ≥30 days (COMB) were collected from a planned data cut in September 2011. This timepoint was 2.5 years after enrollment completed.

COMB was recorded in 347 pts (9.5%), the vast majority (87.6%) of whom received anagrelide + hydroxycarbamide (ANA+HC). Other combinations were anagrelide + interferon-α (ANA+IFN), anagrelide + pipobroman (ANA+PIPO; Table). Six patients also received anagrelide + other drugs (ANA+OTH).

In 333 pts, the initial drug was HC (n=167; 50.2%), ANA (n=138; 41.4%), IFN (n=14; 4.2%), PIPO (n=9; 2.7%), or OTH (n=5; 1.5%), while the added drug was ANA (n=195; 58.6%), HC (n=123; 36.9%), IFN (n=12; 3.6%), PIPO (n=2; 0.6%), or OTH (n=1; 0.3%). Fourteen pts started ANA+HC concomitantly. The median duration of monotherapy treatment before COMB start was 139 months for HC, 53 months for ANA, 71 months for IFN, and 237 months for PIPO.

In pts receiving ANA+HC, the median weekly dose of the initial drug, both before and during COMB, was 10.5 mg for ANA and 7.0 g for HC, while the median weekly dose of the added drug during COMB was 7.0 mg for ANA and 3.5 g for HC. In these pts, the median platelet count ≤6 months before COMB start, during COMB (first test), and during COMB (last test) was 581, 411, and 434 ×10⁹/L, respectively (with counts ≤600 ×10⁹/L in 52.9%, 79.2%, and 77% of cases, respectively); the median white blood cell count was 6.9, 6.8, and 6.8 ×10⁹/L, respectively; the median hematocrit was 38.0%, 36.3%, and 39.0%, respectively; and median hemoglobin was 11.9, 11.6, and 12.0 g/dL respectively. Similar laboratory results were obtained in pts receiving ANA+IFN or ANA+PIPO.

Before, during and after COMB, anti-aggregatory treatment, usually low-dose aspirin, was given in 66.3%, 71.8%, and 33.1% of pts, respectively. In the same time periods, thrombotic (3, 11, and 11 cases, respectively) and hemorrhagic events (1, 2, and 5 cases, respectively) occurred.

The COMB discontinuation rate was 54.5% globally (186/341 pts). COMB was discontinued by stopping ANA in 67 cases (36.0%), HC in 76 (40.9%), IFN in 8 (4.3%), PIPO in 4 (2.2%), both ANA and HC in 19 (10.2%), both ANA and IFN in 3 (1.6%), both ANA and PIPO in 3 (1.6%), or by adding a third drug in 6 cases (3.2%).

In the 158 pts who discontinued ANA+HC, reasons were: intolerance/side effects (n=79, 50.0%), lack of efficacy (n=35, 22.2%), investigator decision (n=34, 21.5%, mainly with switch to ANA monotherapy), patient preference (n=10, 6.3%), missing, other (including economic) or unknown (n=17, 10.2%). Similarly, intolerance/side effects was the most frequent reason for discontinuing ANA+IFN (12/20; 60.0%).

Overall, there were 63 patients with suspected severe adverse reactions (SSARs) and 45 with predefined events (PDEs) during COMB. The most frequent SSARs were myelofibrosis, palpitations, myocardial infarction and tachycardia. The most frequent PDEs included cardiovascular symptoms, myocardial infarction, stroke and transformation. Pts on COMB, the majority of whom received ANA+HC, accounted for 3.8% of all pts at registration and 5.0–5.8% of all pts in the following 5 years.

COMB was performed in almost 10% of the 3643 pts with ET in the EXELS study, mainly with use of ANA+HC (87.6%). COMB appears to be a useful approach to treating patients for whom monotherapy was not well tolerated or ineffective since platelet levels were reduced to <600 ×10⁹/L in almost 80% of pts, and a switch to monotherapy with the added drug, usually ANA, frequently followed.

Gugliotta:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Besses:Shire: Honoraria; Novartis: Honoraria. Griesshammer:Shire: Honoraria. Harrison:Novartis: Consultancy, Honoraria, Research Funding; YM Biosciences: Consultancy; S*Bio: Consultancy; Shire: Honoraria, Research Funding; Sanofi Avensis: Honoraria. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Coll:Shire Pharmaceuticals: Employment. Smith:Shire Pharmaceuticals: Employment. Abhyankar:Shire Pharmaceuticals: Employment. Birgegård:Shire Pharmaceuticals: Honoraria; Pharmacosmos: Research Funding; Shire Pharmaceuticals Sweden: Consultancy.