Combined differentiation therapy in myelodysplastic syndrome with retinoid acid, 1 alpha,25 dihydroxyvitamin D3, and prednisone.
The myelodysplastic syndrome (MDPS) provides an opportunity for identifying host factors (genetic, endocrine, immune) involved in initiation and progression of preleukemia into frank acute myeloid leukemia. The aim of this study was to identify bone marrow (BM) cellular and humoral dysfunctions central to the development of MDPS and useful in therapeutic follow-up studies. Our preclinical studies have shown that (1) the characteristic stromal cell composition of the normal BM microenvironment was impaired in MDPS and in AML in 67 and 86% of the cases, respectively; (2) the 1 alpha,25(OH)2D3 concentration in BM plasma was abnormal in 50% of MDPS and 30% of AML; and (3) an inverse correlation existed in MDPS between the 1 alpha,25(OH)2D3 concentration and the frequency of F-CFU, (r = 0.41, p < 0.02), suggestive of a regulatory interaction between this secosteroid hormone and BM stromal cells. The analysis of clonal extinction of BM blast cells in response to all trans retinoic acid (RA), 1 alpha,25(OH)2D3, and colony stimulating factors (PHA-LCM), either alone or in various combinations, revealed individual patterns of responses in the cases of MDPS or AML. The results indicate the necessity for preclinical studies to select patients for combined differentiation therapy. Our ongoing clinical trials suggest that RA (Roaccutan, 20 mg/day continuously) as induction therapy, followed at weeks 6 to 8 by prednisone (40 mg/day for 15 days) and 1 alpha,25(OH)2D3 (Rocaltrol, 3 x 0.25 micrograms/day for 3 months) may induce a long-lasting hematological remission in MDPS.
Blazsek
I
I
Institut du Cancer et d'Immunogénétique, Association Claude Bernard, Université Paris-Sud, Paris, France.
Musset
M
M
Boulé
D
D
Labat
M L
ML
Bringuier
M F
MF
Comisso
M
M
Le Maignan
C
C
Ribaud
P
P
Mathé
G
G
Misset
J L
JL
D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002117:Calcitriol / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011241:Prednisone / Q000627:therapeutic use*; D014212:Tretinoin / Q000627:therapeutic use*
D014212:Tretinoin; D002117:Calcitriol; D011241:Prednisone