Abstract 5177

BACKGROUND:

Hydroxyurea and anagrelide are therapeutic options for essential thrombocythemia (ET) with distinct mechanism of actions and side effect profiles. However, therapeutic goals may not be achieveable due to drug intolerance or disease resistance. Here we report our successful clinical experience with combination treatment with hydroxyurea and anagrelide.

METHODS:

Medical records of six patients who were on the combination treatment for the ET were retrospectively reviewed. All had history of unsuccessful monotherapy with either hydroxyurea or anagrelide.

RESULTS:

All patients were female with median age of 59.5 years. All were positive for the V617_ jak2 mutation. Two had prior major thromboses (portal vein; ischemic stroke), and one had Raynaud's disease. Reasons for failure of hydroxyurea monotherapy were leukopenia and/or inadequate platelet reduction, while reasons for anagrelide failure were palpitations and orthostasis. Rather than discontinue the primary drug, doses were lowered to a tolerable level and the second agent was added. These patients have been treated with the combination of hydroxyurea and anagrelide for a mean duration of 4.89+ years. Combination regimen achieved 64% reduction of platelet counts (mean best platelet counts during treatment 328×109/L), while maintaining adequate leukocyte counts (range 3.64–7.88 × 109/L). Relatively low daily doses of hydroxyurea (mean 684mg/day) and anagrelide (1.7mg/day) were required. Adverse events noted during the combination therapy were one case with rectal bleeding and two cases of myelofibrosis. One patient returned to monotherapy due to persistent headache to low-dose anagrelide. No arterial or venous thromboses bleeding events have occurred.

CONCLUSION:

This is the longest follow-up experience of hydroxyurea and anagrelide combination therapy in ET that has been resistant to monotherapy or where high monotherapy doses could not be tolerated. The low-dose combination regimen was able to achieve clinical and laboratory response in all patients with a low incidence of medication side effects. This strategy is made more attractive by data that hydroxyurea may be more effective in prevent arterial events while anagrelide was found more effective in preventing venous clots, but conclusions on superior efficacy of the combination would require formal study. We recommend that rather than substitute for an agent that has had partial success or is causing dose-related side-effects, the dose can be adjusted and a second agent added.

AgeSexJAK2 mutationPrevious HU mean daily dose (mg)Previous AG mean daily dose (mg)Combination HU mean daily dose (mg)Combination AG mean daily dose (mg)Combination Rx duration (mo)% dose reductionCriteria for combined Rx
1 56 F + NA NA 500 1.5 60  Uncontrolled platelet 
2 65 F + 0 2 500 1 90 50 Palpitation 
3 63 F + NA 1 392.50 0.75 54 25 Headache 
4 63 F + 500 0 214.29 1 52 57 Uncontrolled platelet 
5 43 F NA NA NA 1500 4 36  Neutropenia 
6 47 F NA 1500 3 1000 2 60 33.33 Palpitation 
MEAN 56.2     684.47 1.71 58.67 41.33  
MEDIAN 59.5       57   
AgeSexJAK2 mutationPrevious HU mean daily dose (mg)Previous AG mean daily dose (mg)Combination HU mean daily dose (mg)Combination AG mean daily dose (mg)Combination Rx duration (mo)% dose reductionCriteria for combined Rx
1 56 F + NA NA 500 1.5 60  Uncontrolled platelet 
2 65 F + 0 2 500 1 90 50 Palpitation 
3 63 F + NA 1 392.50 0.75 54 25 Headache 
4 63 F + 500 0 214.29 1 52 57 Uncontrolled platelet 
5 43 F NA NA NA 1500 4 36  Neutropenia 
6 47 F NA 1500 3 1000 2 60 33.33 Palpitation 
MEAN 56.2     684.47 1.71 58.67 41.33  
MEDIAN 59.5       57   
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Previous WBC (×10̂9/L)Previous Hg (g/dL)Previous HTC (%)Previous Plt count (×10̂9/L)WBC at best PLT (×10̂9/L)Hg at best Plt (g/dL)HTC at best Plt (5)Best Plt during combination (×10̂9/L)
1 NA NA NA NA 5.37 11.5 35.4 295 
2 7.47 13.8 42.1 1015 7.60 13.4 42.0 590 
3 13.76 13.9 40.7 1162 5.38 12.0 35.9 269 
4 7.53 14.5 42.6 725 7.88 14.7 42.3 355 
5 NA NA NA NA 3.64 9.2 29.3 217 
6 5.10 12.0 35.1 777 6.00 12.4 38.2 242 
Previous WBC (×10̂9/L)Previous Hg (g/dL)Previous HTC (%)Previous Plt count (×10̂9/L)WBC at best PLT (×10̂9/L)Hg at best Plt (g/dL)HTC at best Plt (5)Best Plt during combination (×10̂9/L)
1 NA NA NA NA 5.37 11.5 35.4 295 
2 7.47 13.8 42.1 1015 7.60 13.4 42.0 590 
3 13.76 13.9 40.7 1162 5.38 12.0 35.9 269 
4 7.53 14.5 42.6 725 7.88 14.7 42.3 355 
5 NA NA NA NA 3.64 9.2 29.3 217 
6 5.10 12.0 35.1 777 6.00 12.4 38.2 242 
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Disclosures:

No relevant conflicts of interest to declare.

Topics:
anagrelide, hydroxyurea, thrombocythemia, hemorrhagic, palpitations, adverse effects, combined modality therapy, headache, prescriptions, drug, adverse effects of medication, adverse event
© 2011 by The American Society of Hematology
2011
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