Unrelated Umbilical Cord Blood Transplantation Using a TBI/FLAG Conditioning Regimen for Adults with Hematologic Malignancies

Abstract Abstract 4344 Multiple unit umbilical cord blood transplantation (MU-UCBT) has become an acceptable alternative donor transplant approach for adult hematologic malignancy patients without a bone marrow or peripheral blood stem cell donor. Total body irradiation (TBI) and etoposide (VP16) is an effective conditioning regimen for allogeneic hematopoietic stem cell transplantation, but its utility in MU-UCBT has not been well described. From 10/03-2/09 16 adult hematologic malignancy patients were enrolled on a clinical trial at our institution using this regimen prior to MU-UCBT. Patients were eligible if they did not have an HLA matched related or unrelated donor. They also were required to have at least a 4/6 HLA matched UCB unit with at least 0.5 × 107 nucleated cells/kg and a second UCB unit that was at least a 4/6 HLA match with the first UCB unit. The minimum required cryopreserved total nucleated cell (TNC) dose for the combined units was 1 × 107/kg or an infused CD34+ cell dose of 1.5 × 105/kg. Patients received TBI 1,320 cGy (fractionated over days -7 through -4), VP16 60 mg/kg (day -3) and antithymocyte globulin (ATG) 30 mg/kg (days -3 through +1). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. The median age was 47 yrs (range, 18-60) and diagnoses included: 8 AML, 3 CML-accelerated/blast phase, 2 MDS, 1 ALL, 1 CLL 1 NHL. Comorbidity index scores were 9 low, 6 intermediate and 1 high. The median time from diagnosis to UCBT was 8 mos (range, 1-89). HLA match results of the 1st UCB unit infused (UCB1) with the recipient included five 4/6, ten 5/6 and one 6/6 matches, and for the 2nd UCB unit (UCB2) with recipient there were one 3/6, five 4/6, and ten 5/6 matches. The median thawed TNC doses infused for UCB1 and UCB2 were 1.6 × 107/kg (range, 1.0-2.4 × 107/kg) and 1.2 × 107/kg (range, 0.8-2.4 × 107/kg), respectively; the thawed CD34+ cell doses were 0.6 × 105/kg (range, 0.01-2.4 × 105/kg) and 0.6 × 105/kg (range, 0.2-3.1 × 105/kg), respectively. Twelve were evaluable for engraftment analyses; 3 others had early deaths and 1 had graft failure and was rescued with infusion of cryopreserved remission autologous bone marrow. Sustained engraftment in the 12 was observed from a single UCB unit in all cases and the winning unit was UCB1 in 5 (42%). The winning unit had larger median CD8 (p=0.009) and thawed CD34+ cell (p=0.006) doses infused. The median time to achievement of T-cell complete donor chimerism was 30 days (range, 13-139). Median times to neutrophil and platelet engraftment were 20 days (range, 14-48) and 46 days (range, 29-86), respectively. Median time hospitalized was 39 days (range, 20-74). Grade 2-4 and 3-4 acute GVHD developed in 3 pts (19%) and 1 pt (6%), respectively. Chronic GVHD developed in 5 pts (31%) and 4 (25%) were extensive. Graft failure occurred in 2 pts. Six developed CMV infection and 15 developed other infections. There have been 2 (13%) relapses (1 MDS, 1 AML). Eight pts (50%) remain alive at a median follow-up of 15 mos (range, 5-35). Causes of death include 4 infections, 1 graft failure, 1 pulmonary toxicity, 1 CNS bleed, 1 relapse (AML). Incidence of death at 1 and 2 years are 45% (6% relapse, 39% non-relapse) and 59% (6% relapse, 53% non-relapse), respectively. We conclude that the TBI, VP16 and ATG conditioning regimen for MU-UCBT is effective in adult hematologic malignancy patients. Further strategies to enhance immune reconstitution and prevent infections post-transplant are clearly warranted. Disclosures: Off Label Use: Etoposide (VP16) may be considered off-label. Total body irradiation (TBI) and etoposide (VP16) is an effective conditioning regimen for allogeneic hematopoietic stem cell transplantation, but its utility in multiple unit umbilical cord blood transplantation has not been well described. This abstract shares results of a novel trial with TBI/VP/ATG for multiple unit umbilical cord blood transplantation.

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Higher Risk Of HHV6 Reactivation Among Patients Undergoing Umbilical Cord Blood Transplantation

Blood ◽

10.1182/blood.v122.21.s4649.s4649 ◽

2013 ◽

Vol 122 (21) ◽

pp. s4649-s4649

Author(s):

Paulo Guilherme Alvarenga Gomes de Oliveira ◽

Miriam Ueda ◽

Juliana Monte Real ◽

Eloisa de Sá Moreira ◽

Ana Paula Vaz Carvalho ◽

...

Keyword(s):

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Primary Infection ◽

Cord Blood Transplantation ◽

Conditioning Regimen ◽

Umbilical Cord Blood Transplantation ◽

Blood Transplantation ◽

Human Herpesviruses ◽

Cmv Reactivation

Introduction Human herpesviruses may cause severe complications after allogeneic hematopoietic stem cell transplantation (HSCT) such as interstitial pneumonia, encephalitis, delayed engraftment and post-transplant lymphoproliferative disease. A prospective survey on the incidence of primary infection or reactivation and clinical features of the eight human herpesviruses after HSCT has not yet been performed in Brazilian patients. Additionally, the impact of most of these infections on the transplant outcome is still unclear. Methods Between August 2010 and December 2012, peripheral blood samples from 99 allogeneic HSCT recipients were collected weekly after transplant until day +100, totalizing 824 samples. Median age was 15 years (range: 2-72), 60% were male, and acute leukemias were the most frequent diagnosis (54%). Stem cell sources were bone marrow in 62%, umbilical cord blood in 22% and mobilized peripheral blood in 16%. Fifty–one percent of donors were related. In a semi-automated workflow, the DNA was extracted from plasma in the QIAcube robot. A test based on quantitative real-time PCR (Taqman®) was optimized to screen and quantify all known human herpesviruses (CMV, EBV, HSV1, HSV2, VZV, HHV6, HHV7 and HHV8). The PCR reactions were set up using QIAgility robot for high-precision pipetting, and have been performed in a 7900HT (Life Technologies). Infected cell cultures and plasma specimens with a known viral load/amplicon copy number have been used as controls. The limit of detection of the qPCR was 5 copies per reaction, representing 250 copies/mL of plasma for all of the viruses. Results The incidences of primary infection or reactivation of herpesviruses were as follows: CMV=41%, HHV6=11%, HHV8=5.5%, EBV=3%, HSV1=3%, VZV=3%, HHV7=2%, and HSV2=1%. CMV reactivation was significantly more frequent in adults (72% vs. 27% for children, p<0.0001), and in those or receiving fludarabine (60% vs. 29%, p=0.03) and TBI (68% vs. 32%, p=0.01) in the conditioning regimen, but in a multivariate analysis, only age greater than 18 years remained significant (HR 3.4, 95%CI 1.7-6.7). HHV6 reactivation was significantly more frequent after umbilical cord blood transplant than after transplant from other sources (41% vs. 6%, respectively, p<0.0001) and in those receiving TBI in the conditioning regimen (19% vs. 3%, p=0.01) and in those receiving mycophenolate mofetil as GVHD prophylaxis (22% vs. 2%, p=0.004). In a multivariate analysis, only the use of cord blood remained significantly associated with the risk of HHV6 reactivation (HR 5.7, 95%CI 1.2-26.2). CMV reactivation was associated with a higher risk of acute graft-versus-host disease (GVHD), with a cumulative incidence at 100 days of 37% vs. 17% (p=0.02), but had no impact on the other outcomes. HHV6 reactivation had no significant impact on outcomes. HHV8 reactivation was associated with an increased risk of chronic GVHD (83% vs. 49%, p=0.001). Conclusion HHV6 primary infection or reactivation is more frequent after umbilical cord blood transplantation. CMV and HHV6 primary infection or reactivation are frequent after HSCT, but had no significantly impact on the transplant outcomes, possibly due to monitoring and preemptive measures. Monitoring these viruses constitute an essential measure to improve outcomes. Disclosures: No relevant conflicts of interest to declare.

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