EFFECTS OF RECOMBINANT HUMAN INTERLEUKIN-11 (NEUMEGA(TM) RHIL-11 GROWTH-FACTOR) ON MEGAKARYOCYTOPOIESIS IN HUMAN BONE-MARROW

We examined the effects of recombinant human interleukin 11 (rhIL-11) on in vivo human hematopoiesis. Twelve women with advanced breast canc er and no evidence of bone marrow (BM) involvement were treated with 1 0, 25, 50, or 75 mu g/kg/day of rhIL-11 administered subcutaneously fo r 14 consecutive days. Examination of bone marrow trephine biopsies ob tained before and after rhIL-11 treatment revealed unchanged BM cellul arity at all doses, and a statistically significant increase in megaka ryocyte (MK) frequencies (from 0.5 +/- 0.1% to 1.0 +/- 0.3%) following administration of the two highest doses (p < 0.001). The BM biopsies also showed an increased proportion of immature myeloid and erythroid precursors following 14 days of treatment in all cases. The mean propo rtion of marrow cells stained with PC10, a monoclonal antibody (mAb) t hat recognizes the proliferating cell nuclear antigen (PCNA), increase d from 16.3 +/- 5.7% to 45.8 +/- 17.1% (p < 0.001) following the two h ighest treatment doses. Most of the PC10(+) cells were promyelocytes a nd proerythroblasts. In this same group, the proportion of PC10(+) MKs increased from 28.3 +/- 11.5% to 56.8 +/- 24.3% (p < 0.01) after trea tment, while megakaryocyte ploidy analysis revealed a greater number o f higher ploidy (64N) megakaryocytes following rhIL-11 treatment (p < 0.012). Numbers of BM and peripheral blood (PB) CD34(+) CD34(+)DR(+), and CD34(+)DR(-) cells did not change following rhIL-11 treatment. Fol lowing rhIL-11 therapy at the highest dose studied, a 3- and 10-fold i ncrease in the number of committed BM MK progenitor cells (CFU-MK) was observed in two of three patients, while no change was seen in the nu mber of the other BM or PB progenitor cells examined. rhIL-11 administ ration was also associated with an increase in BM reticulin content (f ibrosis grade 1-2) in 7 patients. These results indicate that the admi nistration of rhIL-11 to patients with normal hematopoiesis stimulates MK endoreduplication, PCNA expression and, at high doses, increases M K and CFU-MK progenitor cell numbers. In addition, rhIL-11 was able to stimulate precursor cells of different marrow lineages without affect ing the number of assayable progenitor cells.