Инфо для профессионалов: рисковые факторы в развитии МДС/ОЛ в исходе эритремии

[Dr.Vad]

Инфо для профессионалов: рисковые факторы в развитии МДС/ОЛ в исходе эритремии:

Blood. 2004 Dec 7;

Acute leukemia in polycythemia vera. An analysis of 1,638 patients enrolled in a prospective observational study.

Finazzi G, Caruso V, Marchioli R, Capnist G, Chisesi T, Finelli C, Gugliotta L, Landolfi R, Kutti J, Gisslinger H, Marilus R, Patrono C, Pogliani EM, Randi ML, Villegas A, Tognoni G, Barbui T.

Ospedali Riuniti, Bergamo, Italy.

Progression to acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) is a possible evolution of polycythemia vera (PV), but whether some subjects have an increased natural risk to develop this complication and how much the contribution of pharmacological cytoreduction can affect the natural course of the disease remain uncertain. The European Collaboration on Low dose Aspirin in Polycythemia Vera (ECLAP) prospective project included 1,638 patients with PV. Twenty-two cases of AML/MDS were diagnosed after a median time of 2.5 years from the recruitment in the study and 8.4 years from the diagnosis of PV. Variables associated with progression to AML/MDS were assessed using different models of multivariate analysis. Older age was confirmed as the main independent risk factor (HR 4.30, 95% CI 1.16-15.94; P = 0.0294), while overall disease duration failed to reach statistical significance (> 10 years: HR 1.91, 95% CI 0.64-5.69; P = 0.2466). The associations between development of AML/MDS and high count of WBC and low cholesterol levels suggest that these parameters could represent early markers of progression. Exposure to P32, busulphan and pipobroman (HR 5.46, 95% CI 1.84-16.25; P = 0.0023), but not to hydroxyurea (HU) alone (HR 0.86, 95% CI 0.26-2.88; P = 0.8021) had an independent role in producing an excess risk of progression to AML/MDS as compared to patients treated only with phlebotomy or interferon.

[Hematolog]

Очень интересная статья.
Попутно хочу задать давно терзающий меня вопрос о препаратах снижающих уровень холестерина:

Сообщение от Dr. Vad

The associations between development of AML/MDS and high count of WBC and low cholesterol levels suggest that these parameters could represent early markers of progression.

Какие есть мнения?

[Dr.Vad]

Уважаемый Hematolog!

По Вашему вопросу приведу фрагмент статьи:

We found that low levels of total blood cholesterol at recruitment were strongly associated to the development of AML/MDS. Some small studies have found low levels of cholesterol in patients affected by hematological malignancies (34-37), and some of these reports include patients with PV. It has been observed that the lowest levels of blood cholesterol are observed in advanced stages of proliferative diseases, and some have suggested to use this parameter as a marker of disease activity (33-35). Since the average total blood cholesterol in a Mediterranean population like Italy, aged from 35 to 75 years, is 206 mg/dl (38), the average cholesterol level of the ECLAP population (187.4 mg/dl) is surprisingly low and indicative of the proliferative nature of the disease. In addition to patients progressing to AML/MDS, those who developed myelofibrosis also had a more noticeable hypocholesterolemia. These findings also resemble the increased risk of death from cancer observed in subjects with very low cholesterol levels and suggest that low-cholesterol could be a precocious marker of neoplastic diseases in otherwise normal subjects with no cholesterol-lowering treatment (39).

34. Marini A, Carulli G, Azzara A, Grassi B, Ambrogi F. Serum cholesterol and triglycerides in hematological
malignancies. Acta Haematol. 1989;81:75-9.
35. Pandolfino J, Hakimian D, Rademaker AW, Tallman MS. Hypocholesterolemia in hairy cell leukemia: a
marker for proliferative activity. Am J Hematol. 1997 ;55:129-33.
36. Gilbert HS, Ginsberg H, Fagerstrom R, Brown WV. Characterization of hypocholesterolemia in
myeloproliferative disease. Relation to disease manifestations and activity. Am J Med. 1981;71:595-602.
37. Aixala M, Sarandria CN, Speroni JG. Hypocholesterolemia in hematologic neoplasms. Sangre (Barc).
1997;42:7-10.
38. The Italian Cardiovascular Epidemiological Observatory. Ital Heart J. 2004;5 (Suppl 3): 49S-92S.
39. Sherwin RW, Wentworth DN, Cutler JA, Hulley SB, Kuller LH, Stamler J. Serum cholesterol levels and
cancer mortality in 361,662 men screened for the Multiple Risk Factor Intervention Trial. JAMA.
1987;257: 943-8.

где приводятся собственные и литературные данные, что низкий уровень холестерина коррелирует с опухолевыми заболеваниями и может быть с их прогрессией.

Не следует считать, что снижение холестерина фармакопутем (статинами) тем самым может увеличить заболеваемость от опухолей - похоже, что статины наоборот оказывают и противоопухолевое действие:

The total number of cancer deaths was 68 (3.1%) in the placebo group and 52 (2.3%) in the simvastatin group (relative risk 0.73, 95% confidence interval 0.51 to 0.05, p = 0. 087), and the numbers of noncardiovascular and other deaths were similar in both groups.

Из Pedersen TR et al.Follow-up study of patients randomized in the Scandinavian simvastatin survival study (4S) of cholesterol lowering. Am J Cardiol. 2000 Aug 1;86(3):257-62.


А также

Semin Thromb Hemost. 2003 Jun;29(3):259-74.
The statins: multifunctional antithrombotic and antineoplastic drugs.
Splichal JE, Stamm JA, Ornstein DL.
Department of Hematology and Oncology, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, Texas, USA.
...Most statins appear to have antithrombotic activity that is unrelated to the ability to reduce cholesterol levels, and several have significant antitumor effects. This article reviews the laboratory and clinical evidence that statins have antithrombotic and anticancer activity, discusses the ways in which these two activities intersect, and proposes novel uses for statins for the treatment of conditions other than hypercholesterolemia...

Drucker L, Afensiev F, Radnay J, Shapira H, Lishner M.
Co-administration of simvastatin and cytotoxic drugs is advantageous in myeloma cell lines.
Anticancer Drugs. 2004 Jan;15(1):79-84.

Gronich N, Drucker L, Shapiro H, Radnay J, Yarkoni S, Lishner M.
Simvastatin induces death of multiple myeloma cell lines.
J Investig Med. 2004 Jul;52(5):335-44.

[3458] A Phase I Trial of Dose Escalating Simvastatin Combined with Chemotherapy in End-Stage Myeloma and Lymphoma.

Henk M. Lokhorst, Niels van de Donk, Ellen van de Spek, Okke de Weerdt, Rene van de Griend, Shulamiet Wittebol, Leo F. Verdonck, Andries C. Bloem. University Medical Center Utrecht, Dept Hematology, Utrecht, Netherlands; University Medical Center Utrecht, Dept Immunology, Utrecht, Netherlands; Mesos Medical Center, Dept Internal medicine, Nieuwegein, Netherlands; Meander Medical Center, Dept Internal Medicine, Amersfoort, Netherlands; Diakonessen Ziekenhuis, Dept Internal Medicine, Utrecht, Netherlands

We recently described that simvastatin effectively induced apoptosis in myeloma and lymphoma tumor cells by inhibition of proteingeranylgeranylation resulting in the reduction of the anti-apoptosis protein Mcl-1. In addition low concentrations of simvastatin had a chemosensitizing effect in combination with dexamethasone or doxorubicin. Based on these observations we initiated a Phase I study of dose escalating simvastatin combined with chemotherapy in patients with end-stage Myeloma and Lymphoma. Starting dose level of simvastatin was 5 mg/kg/day for 7 days, divided in 2 doses orally, followed by VAD chemotherapy in patients with myeloma and CHOP in patients with lymphoma. Three patients were included per dose level. In the absence of side effects WHO grade III/IV in 3 patients the dose of simvastatin was escalated with 2.5 mg/kg. Twenty-one heavily pretreated patients all refractory to at least 3 lines of chemotherapy (14 myeloma patients and 7 lymphoma patients) were included. No toxicity beyond WHO 2 was recorded with dose level 1-4 (5 mg-12.5mg/kg/day/7days). One patient treated at dose level 5 (15 mg simva/kg/day/7 days) became severely depressed and performed an unsuccessful suicide attempt. Two patients treated at dose level 6 (17.5 mg/kg/day/7 days had severe gastro-intestinal side effects (WHO 3; vomiting, diarrhoea, dehydration), necessitating interrupting simvastatin after 3 and 4 day respectively. The third patient treated at dose level 6 had moderate gastro-intestinal complaints but died on day 13 (2 days after VAD, deeply neutropenic) from overwhelming Gram-Septicaemia although prophylactic antibiotics had been prescribed. Three additional patients were then treated at dose level 5 again without side effects beyond WHO 2. None of the patients complained about muscle pain. No signs of rhabdomyolysis were registered.
Although response was not the primary endpoint of the study, it could be evaluated in 16 patients who completed at least 2 cycles of simvastatin with chemotherapy. Six patients (4 myeloma and 1 transformed low grade lymphoma) responded (32 %) including 5 patients with a Partial Response (> 50 tumor reduction) and 1 patient with a minor response. Four of 8 evaluable (myeloma) patients treated at dose level 4 and 5 responded. Due to toxicity all 3 patients at dose level 6 were not evaluable for response. In patients treated at dose level 4 and 5, in vivo down regulation of Mcl-1 (> 50 %) was observed in PBMC collected after 7 days of simvastatin treatment. These data show that in vivo downregulation of Mcl-1 by high dose (simva) statin in combination with chemotherpy may be a promising new modality for patients with drug resistant myeloma and lymphoma.
Abstract #3458 appears in Blood, Volume 104, issue 11, November 16, 2004