Increased apoptosis of bone marrow cells and preserved proliferative capacity of selected progenitors predict for clinical response to anti-inflammatory therapy in myelodysplastic syndromes

Objectives. To determine the relation of apoptosis and clonal proliferation in the hone marrow (BM) to the effectiveness of a therapeutic protocol des cribed to downmodulate monokine activity in patients with myelodysplastic s yndromes (MDS). Materials and Methods. Prior to protocol therapy, BM stroma was cultivated and selected CD34(+) cells were studied in stroma and cytokine-dependent cl onogenic assays. The TUNEL assay was used to establish the degree of apopto sis occurring in the marrow and CD34(+) population. the effectiveness of or al ciproloxacin 500 mg b.i.d., pentoxifylline 800 mg t.i.d., and dexamathas one 4 mg t,i.d. (CPD) antiinflammatory therapy was correlated with the inte nsity of cell apoptosis and proliferation of BM progenitor cells. Results. Seventeen patients were studied. Twelve patients (10 transfusion d ependent) received therapy for a median of 99 days (range 49-284). Toxicity caused four patients to discontinue the drug combination, Six patients ful filled 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 coun t remained unsupported in three patients, even at a median of 12 months aft er trial discontinuation. Apoptosis of marrow cells and selected CD34(+) pr ogenitors was detected in a median of 49.5% (range 3.6%-90%) and 10.6% (ran ge 3.6%-100%; p < 0.01), respectively. In patients who responded to therapy , the median apoptosis rate in the hone marrow population was 71%, in contr ast to the nonresponder's rate of 13% (p = 0.002), Overall clonogenic growt h of selected precursors corresponded significantly with response to CPD pr otocol (p = 0.004). Conclusions. In some patients with RIDS, ineffective hematopoiesis is relat ed to high apoptotic index despite proliferation of the CD34(+) precursors, These patients seem to benefit from CPD cytokine modulatory therapeutic st rategy. (C) 2000 International Society for Experimental Hematology, Publish ed by Elsevier Science Inc. Published by Elsevier Science Inc.