Reduced Toxicity Conditioning (RTC) Compared to Myeloablative Conditioning (MAC) Prior to Unrelated Cord Blood Transplantation (UCBT) in Pediatric Recipients Was Associated with Similar but Also Delayed Time to Immune Reconstitution and a Concomitant Significant Decrease in Grade II-IV Agvhd.

Immune reconstitution in pediatric transplant recipients appears to take longer following myeloablative conditioning (MAC) and umbilical cord blood transplantation (UCBT) than following matched sibling allogeneic stem cell transplantation (AlloSCT) (Parkman et al., BBMT, 2006). Reduced toxicity conditioning (RTC) is associated with less transplant-related morbidity and mortality than MAC prior to AlloSCT although the effects of RTC on long-term immune reconstitution in UCBT recipients are unknown (Satwani, Cairo et al., BBMT, 2005). We previously demonstrated sustained donor chimerism following RTC and UCBT in pediatric recipients (Bradley, Cairo et al., BMT, 2007). Our group recently found no significant difference between MAC and RTC in time to engraftment or donor chimerism in pediatric UCBT recipients; RTC was associated with decreased transplant-related mortality (TRM) and improved overall survival (OS) (Cairo et al., ASBMT, 2009).

We analyzed time to immune reconstitution and associated risk factors in pediatric patients receiving RTC vs. MAC prior to UCBT.

We evaluated immune reconstitution in 88 consecutive pediatric UCBT recipients with transplant dates between March 2000 and October 2008. Absolute CD3, CD4, CD8, CD19, and CD56 cell counts and IgG, IgA, and IgM levels were assessed using FACS analysis and ELISA, respectively, at days 100, 180, and 365 post-transplant. Predictors of grade II-IV acute GVHD, lymphocyte recovery, and malignant recurrence were analyzed using chi-square or Fisher's exact tests and multivariable logistic regression models.

The median age of the 88 patients was 6.5 years (range 0.25-22); 59% male/41% female, 56% MAC/44% RTC, HLA match 19% 6/6, 28% 5/6, 52% 4/6, 93% unrelated/7% related, 66% malignant/34% non-malignant, median TNC x10⁷/kg 3.76 (range 0.9-22.61), and median CD34 ×10⁷/kg (range 0.34-9.57). Mean (±SD) absolute lymphocyte subset counts (cells/μL), immunoglobulin levels (mg/dL) and sample sizes at days 100, 180, and 365 post-transplant are shown in Tables 1 and 2, respectively.

At day 180, NK cell levels were slightly higher in the MAC group (310.0±212 vs. 171.3±83, p=0.05). Otherwise, MAC and RTC did not differ with respect to absolute lymphocyte subset counts or immunoglobulin levels. Other variables not associated with T-, B- and NK-cell reconstitution include grade II-IV acute GVHD, ATG/Campath conditioning, viral/fungal infection, and TNC/CD34 dose/kg. Lymphocyte subset counts and immunoglobulin levels were assessed as being normal or low according to age-specific reference ranges and did not differ significantly between MAC and RTC groups.

Of 88 subjects, 24 (27.3%) developed grade II-IV acute GVHD. In a logistic regression model that included conditioning regimen (MAC vs. RTC), risk (average vs. poor), HLA-matching (4/6 vs. 5-6/6), CMV status (donor/recipient -/- vs. other), and time period (before 2005 vs. after 2004) to analyze predictors of grade II-IV GVHD, MAC recipients had a significantly higher risk of grade II-IV acute GVHD (odds ratio 4.43, p=.01), and of viral infection (odds ratio 3.86, p=.02) than RTC recipients. Malignant relapse occurred in 12 of 34 MAC recipients (35%) and 11 of 24 RTC recipients (46%).

No significant differences between lymphocyte subset counts or immunoglobulin levels post-transplant were found with respect to MAC vs. RTC prior to UCBT. Children who received RTC had a significantly lower risk of grade II-IV acute GVHD than children who received MAC, when other risk factors were taken into account. These results support the continued use of RTC prior to UCBT for appropriate medical conditions.

Bradley:Bristol-Myers Squibb Company: Employment.