Reduced Intensity Conditioning (RIC) is Associated with a Significant Decrease In Day +100 Non-Relapse Mortality (NRM), Grade II-IV AGVHD and Overall Survival (OS) In Pediatric Recipients Following Cord Blood Transplantation (CBT)

We and others have demonstrated that myeloablative conditioning (MAC) and CBT results in a high engraftment rate and lower severe AGVHD rate but a 20–40% incidence of Day +100 NRM (Cairo et al BBMT, 2008). RIC and AlloSCT in adults have been associated with a decrease in acute toxicity and NRM (Satwani/Cairo et al BBMT, 2005). Our group recently demonstrated the safety and sustained high donor chimerism following RIC and UCBT in pediatric recipients (Bradley/Cairo et al BMT, 2007). In this study we investigated the risk factors associated with Day +100 NRM, Grade II-IV AGVHD and OS in 101 consecutive CBT pediatric recipients. Probability of Day +100 NRM and OS were calculated by Kaplan Meier estimates. Continuous variables are summarized as mean ± SD and categorical variables as %. Risk factors for Grade II-IV AGVHD and Day +100 NRM was assessed by logistic regression and and OS was assessed by Cox proportional hazards; variables <0.2 in univariate were included in multivariate analyses. Risk factors: RIC vs MAC, average vs poor risk, malignant/non, HLA 4/6 vs ≥4/6, CMV donor/recipient, CD34 <2.3 vs ≥2.3 × 105 CD34/kg, TNC 3, ≥3 <5, ≥5 × 107 TNC/kg, Grade II-IV AGVHD, chronic GVHD. 101 pts, age 7.6 ± 6.5 yrs; M/F 60/40%; MAC/RIC 55/45%; average/poor risk 74/26%; CMV -/- 26%; HLA 4/6 52%; malignant/non 66/34%. Median time to ANC and platelet recovery was similar between RIC and MAC CBT (24 vs 24) and (59 vs 64) d, respectively. Day 180 and 365 chimerism was also similar (84 vs 89%) and (89 vs 92%), respectively. However, the probability of Grade II-IV AGVHD was significantly less following RIC 20% (CI95 8.3%–31.7%) vs 42.9% (CI95 29.9%–55.8%%) (p< 0.015). Multivariate analysis demonstrated the following independent risk factors in Grade II-IV AGVHD: High CD34 hazard ratio (HR): 3.1, p<0.02; HLA 4/6 HR: 4.2, p<0.007 and MAC HR: 4.1, p<0.005. Day +100 NRM was significantly less following RIC 2.3% (CI95 0–6.7%) vs. 26.1% (CI95 14.3%–37.8%), p<0.002. The only significant factor in Day +100 NRM was MAC HR: 27.2, p<0.005. Lastly, 3yr OS was significantly improved following RIC 56% (CI95 37–70) vs MAC 28% (CI95 16–40) and the following risk factors: Low vs High CD34 HR: 1.0 vs 0.38, p<0.004; and MAC HR: 2.9, p<0.001 were associated with a significant improvement in OS. In summary, RIC was the single most important risk factor associated with a significant reduction in Grade II-IV AGVHD, Day 100 NRM and OS in pediatric recipients following CBT. We and others have demonstrated that myeloablative conditioning (MAC) and CBT results in a high engraftment rate and lower severe AGVHD rate but a 20–40% incidence of Day +100 NRM (Cairo et al BBMT, 2008). RIC and AlloSCT in adults have been associated with a decrease in acute toxicity and NRM (Satwani/Cairo et al BBMT, 2005). Our group recently demonstrated the safety and sustained high donor chimerism following RIC and UCBT in pediatric recipients (Bradley/Cairo et al BMT, 2007). In this study we investigated the risk factors associated with Day +100 NRM, Grade II-IV AGVHD and OS in 101 consecutive CBT pediatric recipients. Probability of Day +100 NRM and OS were calculated by Kaplan Meier estimates. Continuous variables are summarized as mean ± SD and categorical variables as %. Risk factors for Grade II-IV AGVHD and Day +100 NRM was assessed by logistic regression and and OS was assessed by Cox proportional hazards; variables <0.2 in univariate were included in multivariate analyses. Risk factors: RIC vs MAC, average vs poor risk, malignant/non, HLA 4/6 vs ≥4/6, CMV donor/recipient, CD34 <2.3 vs ≥2.3 × 105 CD34/kg, TNC 3, ≥3 <5, ≥5 × 107 TNC/kg, Grade II-IV AGVHD, chronic GVHD. 101 pts, age 7.6 ± 6.5 yrs; M/F 60/40%; MAC/RIC 55/45%; average/poor risk 74/26%; CMV -/- 26%; HLA 4/6 52%; malignant/non 66/34%. Median time to ANC and platelet recovery was similar between RIC and MAC CBT (24 vs 24) and (59 vs 64) d, respectively. Day 180 and 365 chimerism was also similar (84 vs 89%) and (89 vs 92%), respectively. However, the probability of Grade II-IV AGVHD was significantly less following RIC 20% (CI95 8.3%–31.7%) vs 42.9% (CI95 29.9%–55.8%%) (p< 0.015). Multivariate analysis demonstrated the following independent risk factors in Grade II-IV AGVHD: High CD34 hazard ratio (HR): 3.1, p<0.02; HLA 4/6 HR: 4.2, p<0.007 and MAC HR: 4.1, p<0.005. Day +100 NRM was significantly less following RIC 2.3% (CI95 0–6.7%) vs. 26.1% (CI95 14.3%–37.8%), p<0.002. The only significant factor in Day +100 NRM was MAC HR: 27.2, p<0.005. Lastly, 3yr OS was significantly improved following RIC 56% (CI95 37–70) vs MAC 28% (CI95 16–40) and the following risk factors: Low vs High CD34 HR: 1.0 vs 0.38, p<0.004; and MAC HR: 2.9, p<0.001 were associated with a significant improvement in OS. In summary, RIC was the single most important risk factor associated with a significant reduction in Grade II-IV AGVHD, Day 100 NRM and OS in pediatric recipients following CBT.