Primary Graft Failure (GF) after Unrelated Donor Cord Blood Transplants (UCBT): Risk Factors and Management.

Primary GF is recognized as a major risk in UCBT. Both graft (cell dose and quality of the cord blood unit) and recipient (diagnosis of aplastic anemia, prior chemotherapy exposure) characteristics have been reported as being associated with non-engraftment. Here we present a large series of UCBT patients from a single institution and analyze the risk factors and management of this complication. Between 3/2001 and 7/2006, 106 consecutive patients (pts), of median age 5.3 (range 0.1–18.4) years and weight median 22 (range 4–85) kg, received UCBT at Texas Transplant Institute. 13 did not achieve donor engraftment as documented by recovery of ANC< 500/μl by day + 42, and lack of donor cells on ≥2 RFLP analysis of the bone marrow. Failure to attain engraftment occurred in 5/27 with a non-malignant disorders, and 8/79 with hematologic malignancies (p< 033). Non-engraftment was less common in better HLA matched transplants (≥5/6 HLA match: 1/45 vs ≤ 4/6 HLA : 12/61; p< 0.02). Preliminary analysis showed no difference in cord blood TNC/kg, CD34/kg and pre thaw CFU/kg in pts who had primary GF compared to the rest of the cohort. A post thaw CFU/pre-freeze ratio of <20% was more common in primary GF. Among the 79 pts with hematologic malignancies (HM), 8 did not engraft. 4 died early; 1 from persistent leukemia, and 3 from transplant-related complications (TRM). Of the remaining 4 pts with HM, 2 were ALL children in CR1. The other primary GF occurred in 2/5 children with HLH (both with active disease at UCBT), 2/8 the children transplanted for aplastic anemia, and one pt with CD40L deficiency who had primary GF. The 9 pts who had not relapsed or died of TRM went on to second (2^nd) UCBT 33 to 95 (median 55) days after first transplant (1^st UCBT). Conditioning regimen for 2^nd UCBT was fludarabine 175mg/m², cyclophosphamide 50mg/kg, TBI 2 Gy, ± ATG in 7/9 patients. Median cell dose for 2^nd UCBT were 3.6 × 10⁷/kg. HLA matching was similar to 1^st UCBT. There was one TRM (respiratory failure) but the rest (8/8) engrafted; with ANC >500/μl at a median of 15 (range 5–64) days, and platelets > 20000/μl at a median of 92 (range 24 to 137) days. All became transfusion-independent, and as of 8/1/2006, 7 of 9 pts are alive. All have complete donor chimerism 164–1616 (median 672) days after 2^nd UDCBT. EBV-lymphoproliferatve disorders developed in 2 patients and it was fatal in one. Other viral infections encountered were BKV(1), HHV-6(1), CMV(3) in the blood; adenovirus(1) and enterovirus(1) in the stool; and BKV (1) in the urine. Acute graft-versus-host disease (GVHD) was diagnosed in 2/8 pts. 7/8 pts surviving >100 days had chronic GVHD, and it was extensive in 5 pts. It is important that primary GF be recognized as a risk of UDCBT and a back-up donor source be identified prior to transplant. Children with intact/active immune systems prior to transplant are at greater risk. Early 2^nd UCBT, before patient’s condition deteriorates, is a feasible treatment alternative. This immunosuppressive preparative regimen is well tolerated early post first UCBT and can result in reliable engraftment, albeit a greater risk of chronic GVHD and viral reactivation post transplant.