Impactos de las inundaciones extremas en la vida comunitaria

As outlined previously the anaemia in PMF is multifactorial and deficiency of iron, vitamin B12 and folate should always be excluded before adding other therapies. The hemoglobin level nessecitating therapy should be determined in the individual patient. As a general guideline, treatment of anemia should be considered at Hb levels < 110g/L in symptomatic patients and in patients with a reduced functional capacity.

Androgens

Androgens stimulate bone marrow function and have been an important treatment option for the anaemia, which has been shown to improve in about 40% of the patients, in particular in those patients with only moderate splenomegaly and normal cytogenetics (191). Danazol – a

semisynthetic androgen - has much fewer side effects than conventional androgens (nandrolone, fluoxymesterolone, oxymethalone) and accordingly has virtually substituted these agents. Danazol has proved to be very effective with responses in about 40% of the patients. In general, the

treatment is well tolerated with only moderate toxicity and most frequently a slight increase in liver enzymes (191). However, androgenic side effects can be seen in female patients. Danazol is

administered at a dose of 200mg x 3/day. Monitoring of liver function is recommended regularily (once/monthly). Most patients respond within the first 2-3 months but a subgroup of patients have a late response occurring about 6-8(-9) months after starting therapy (191). A synergistic effect between human recombinant erythropoietin and danazol has been recorded (160). However, at the present time danazol is only available with special license in Finland, Norway and Sweden (from Sanofi/Aventis or affiliated companies).

Recommendations: Danazol is , if available, recommended as one first-line therapy in the treatment of anaemia in PMF .

Glucocorticoids

Treatment with glucocorticoids is indicated in those patients with Coombs positive immune haemolysis, but may also be effective in patients without overt haemolytic activity.

Recommendations: Prednisolone is recommended as the drug of choice in the treatment of Coombs positive anaemia in PMF. Prednisolone may also be useful in occasional patients without biochemical evidence of immune haemolysis.

Grade B recommendations, evidence level III.

Erythropoietin

In recent years several studies have shown that human recombinant erythropoietin effectively increases the Hb-concentration in about 40-50 % of the patients. The required dose is about 10.000 U three times per week. Darbepoietin-alpha administered once a week is equally effective – the recommended dose is in the range 150-300ug/week. A goal of EPO therapy of hemoglobin around 120 g/L has been advocated by the FDA and ASH/ASCO when EPO is used in patients with other hematological malignancies in order to minimize the risk of thrombosis. It seems reasonable to suggest this also in PMF. A plasma erythropoietin below 125 U/l has been clearly associated with a higher probability of response (160-161). However, higher S-EPO levels do not preclude patients from responding. In the first reports on Epo-treatment of PMF enlargement of the spleen was recorded in some patients. However, this has not been observed in subsequent studies. A single study has found that a few non-responsive patients may be Epo-responsive when adding

thalidomide, possibly being explained by the immunomodulating effects of thalidomide therapy (192). A similar syngergistic effect has been seen in a single patient treated with erythropoietin and danazol (160).

Recommendations : Erythropoietin is recommended in the treatment of anaemia in PMF in patients not responding to danazol, or in patients in whom danazol therapy is considered inappropriate/not available.

Grade B recommendations, evidence level III.

Thalidomide and thalidomide analogues

As outlined above some patients with PMF may benefit from treatment with thalidomide as

evidenced by an increase in the Hb-concentration and a decrease in spleen size (193,194). However, in a few studies no benefit of thalidomide was recorded and treatment was associated with

significant side effects and a high drop out rate (195,196). Low-dose thalidomide (50mg/day) in combination with prednisolone appears to be highly effective with an increase in the Hb-

concentration in about 60% of the patients (197). However, there is still a need to minimize non- haematologic toxicity associated with thalidomide therapy. In this context the novel thalidomide analoges seem very promising. CC-5013 (Lenalidomide; Revlimid) is an immunomodulatory analog of thalidomide that is substantially more potent than the parent drug in terms of both anti- angiogenic and anti-TNF-alpha activity. The compound has also significantly fewer non-

myelodysplastic syndrome as well as in PMF (198, 260-263). A study included three consecutive patients with del(5q)-associated PMF or post-PV MF (all three patients JAK2V617F-positive, 263). One of these patients had been previously reported (262). A very impressive effect of lenalidomide therapy was recorded and screening for del(5)(q) was recommended in all patients with PMF or post-PV MF. If found, lenalidomide therapy should be offered and continued indefinitely, if tolerated (263).

Recommendations: Low-dose thalidomide (50mg/day) + prednisolone (1mg/kg for 2 weeks and afterwards tapering to the lowest dose maintaining an adequate Hb-concentration) is recommended for patients not responding to danazol monotherapy or erythropoietin. In the rare patient harbouring del(5)(q) lenalidomide should be considered.

Grade B recommendations, evidence level III. JAK2 inhibitors

No clinical recommendations can be given at this time, since therapy with JAK2 inhibitors is a strictly experimental treatment modality at the moment. They are not available outside of clinical trials. Preliminary data with different JAK2 inhibitors presented at major meetings suggest that these agents have profound effects on splenomegaly and constitual symptoms, but have very limited or no effects on blood counts.