Delayed Platelet Engraftment after Umbilical Cord Blood Transplant: Relationship to Circulating Levels of Thrombopoietin

Delayed platelet engraftment is an important contributor to the increased morbidity, poor quality of life, and cost after umbilical cord blood transplant (UCBT). Thrombopoietin (TPO) receptor agonists have played an important role in immune thrombocytopenic purpura (ITP) and other disorders of low platelets. Therefore, we investigated thrombopoietin levels after UCBT, to determine if treatment with TPO receptor agonists after UCBT might be warranted. Twenty-two consecutive patients with hematologic malignancies who underwent reduced intensity double UCBT were included in the analysis. The conditioning regimen was fludarabine, 30mg/m2/days -7, -6, -5, -4, -3, -2, melphalan 100mg/m2 on day -1, and total body radiation 200 cGy on Day 0. Graft vs host disease (GVHD) prophylaxis was tacrolimus and sirolimus. TPO levels (Quest Diagnostics) were measured pre-conditioning, on days 0, 14, 30, 60, and 100, and at 6, 9, 12 and 24 months post transplant. Additional TPO levels were measured in association with platelet transfusion, prior to, 30 minutes, 6 hours, and 24 hours post transfusion. The median age was 55 years (range 21 to 68).Nine patients had AML, 4 had MDS, 4 had NHL, 2 had ALL, 2 had MPD, 1 had HD. Median days to neutrophil engraftment (ANC > 500) were 24 days (range 13-54); median days to platelet engraftment >20,000 were 50 days (range 25-89), and; median days to platelet engraftment >50,000 were 53 days (range 31-132). 100 day treatment related mortality was 5.3%. At one year, overall survival was 48%. Normal TPO levels in our lab are 39 pg/ml (range 7-99): Median TPO levels after UCBT were as follows: Pre-conditioning: 205 pg/ml (range 9 to 2389), Day 0: 222 pg/ml (range 107 to 2501), Day 14: 2880 pg/ml (range 973 to >4000), Day 30: 2372 pg/ml (range 208 to >4000), Day 60: 781 pg/ml (range 319 to 2242), Day 100: 609 pg/ml (range 109.3 to 1653), Month 6: 380 pg/ml (range 121 to 3126), Month 12: 239 pg/ml (n=4; range 122 to 843). TPO levels fell 6 hours after platelet transfusion in 86% of patients, (decrease 8% to 49%). At 24 hours after platelet transfusion, TPO levels started to rise to baseline, with a decrease from baseline of 4-22%. In summary, 1) TPO levels are markedly elevated in the first month after UCBT, and fall after platelet recovery, returning to baseline at one year post transplant. 2) TPO levels fall 6 hours after platelet transfusion and start to rebound within 24 hours. 3) These data suggest that high levels of endogenous TPO do not alleviate the thrombocytopenia after UCBT and suggest that other modalities should considered. Further studies using other agents are planned.