Increased apoptosis of bone marrow cells and preserved proliferative capacity of selected progenitors predict for clinical response to anti-inflammatory therapy in myelodysplastic syndromes.
To determine the relation of apoptosis and clonal proliferation in the bone marrow (BM) to the effectiveness of a therapeutic protocol described to downmodulate monokine activity in patients with myelodysplastic syndromes (MDS). Prior to protocol therapy, BM stroma was cultivated and selected CD34(+) cells were studied in stroma and cytokine-dependent clonogenic assays. The TUNEL assay was used to establish the degree of apoptosis occurring in the marrow and CD34(+) population. The effectiveness of oral ciproloxacin 500 mg b. i.d., pentoxifylline 800 mg t.i.d., and dexamathasone 4 mg t.i.d. (CPD) antiinflammatory therapy was correlated with the intensity of cell apoptosis and proliferation of BM progenitor cells. Seventeen patients were studied. Twelve patients (10 transfusion dependent) received therapy for a median of 99 days (range 49-284). Toxicity caused four patients to discontinue the drug combination. Six patients fulfilled response criteria. Four patients became transfusion independent, and 50% reduction in the need for blood transfusions was noted in one patient. Blood parameters of one untransfused patient increased by >30%. Blood count remained unsupported in three patients, even at a median of 12 months after trial discontinuation. Apoptosis of marrow cells and selected CD34(+) progenitors was detected in a median of 49.5% (range 3. 6%-90%) and 10.6% (range 3.6%-100%; p < 0.01), respectively. In patients who responded to therapy, the median apoptosis rate in the bone marrow population was 71%, in contrast to the nonresponder's rate of 13% (p = 0.002). Overall clonogenic growth of selected precursors corresponded significantly with response to CPD protocol (p = 0.004). In some patients with MDS, ineffective hematopoiesis is related to high apoptotic index despite proliferation of the CD34(+) precursors. These patients seem to benefit from CPD cytokine modulatory therapeutic strategy.
Novitzky
N
N
The University of Cape Town Leukemia Centre and the Department of Haematology, Groote Schuur Hospital, Observatory, Cape Town, South Africa. novitzky@samiot.uct.ac.za
Mohamed
R
R
Finlayson
J
J
du Toit
C
C
D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018952:Antigens, CD34 / Q000032:analysis; D017209:Apoptosis; D001803:Blood Transfusion; D001854:Bone Marrow Cells / Q000473:pathology*; D002455:Cell Division; D002939:Ciprofloxacin / Q000009:adverse effects / Q000627:therapeutic use; D003907:Dexamethasone / Q000009:adverse effects / Q000627:therapeutic use; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D020287:In Situ Nick-End Labeling; D007958:Leukocyte Count; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000473:pathology*; D010431:Pentoxifylline / Q000009:adverse effects / Q000627:therapeutic use; D013234:Stem Cells / Q000473:pathology*; D017154:Stromal Cells / Q000473:pathology
D000893:Anti-Inflammatory Agents; D018952:Antigens, CD34; D005938:Glucocorticoids; D002939:Ciprofloxacin; D003907:Dexamethasone; D010431:Pentoxifylline