A non-randomised dose-escalating phase II study of thalidomide for the treatment of patients with low-risk myelodysplastic syndromes: the Thal-SMD-2000 trial of the Groupe Français des Myélodysplasies.
Patients (n=47) with low-risk myelodysplastic syndrome were treated with thalidomide [200 mg/d, increased by 200 mg/d/4 weeks up to week 16]. Responses were evaluated according to the International Working Group criteria at week 16 for 39 patients who received at least 8 weeks of treatment. Twenty-three (59%) patients showed haematological improvement (HI): four major erythroid response (HI-EM), 15 minor erythroid response, six major neutrophil response, two major platelet response. Side effects caused 22/39 to stop thalidomide before week 16. Nine of 23 responders continued thalidomide after week 16 [19% of trial patients] with sustained response in eight of nine. Six reached week 56, including the four HI-EM patients [13% of trial patients]. Nineteen of 36 red blood cell transfusion-dependent patients (53%) showed erythroid response, but only four became transfusion-independent. Among the 23 responders, the median duration of response was 260 d (range 30-650). Responses were sustained in all patients except one, and were observed between week 4 and week 8 in 85% of patients, at doses ranging from 200 to 400 mg. Only two patients responded at 600 mg/d and none at 800 mg/d. No clinical characteristics of responding versus non-responding patients were identified. The erythroid response rate was identical in all cytogenetic subgroups, including 5q31.1 deletions. Pretreatment vascular endothelial growth factor levels were lower in responders compared with non-responders (P=0.004). Microvessel density (MVD) increased and apoptosis decreased in four of six and in all six responders studied respectively whereas MVD and apoptosis were unchanged in three non-responders.
Bouscary
Didier
D
Service d'Hématologie, Hôpital Cochin, Paris, France. bouscary@cochin.inserm.fr
Legros
Laurence
L
Tulliez
Micheline
M
Dubois
Stéphanie
S
Mahe
Béatrice
B
Beyne-Rauzy
Odile
O
Quarre
Marie C
MC
Vassilief
Dominique
D
Varet
Bruno
B
Aouba
Achille
A
Gardembas
Martine
M
Giraudier
Stéphane
S
Guerci
Agnès
A
Rousselot
Philippe
P
Gaillard
Fanny
F
Moreau
Anne
A
Rousselet
Marie C
MC
Ifrah
Norbert
N
Fenaux
Pierre
P
Dreyfus
François
F
D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D001854:Bone Marrow Cells / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic; D012306:Risk; D018709:Statistics, Nonparametric; D013792:Thalidomide / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide