Engraftment kinetics and graft failure after single umbilical cord blood transplantation using a myeloablative conditioning regimen

Abstract A high graft failure rate due to low stem cell dose and high treatment-related mortality have historically been the major pitfalls of myeloablative adult umbilical cord blood transplantation. The goal of this phase II clinical trial was to identify an approach that addresses both of these problems. There is compelling evidence that increasing the cell dose with the use of two partially matched UCB grafts reduces the graft failure rate. While non-myeloablative preparative regimens reduce treatment-related mortality, many patients with high-risk hematologic malignancies may be at increased risk for disease relapse following transplantation. Recently, myeloablative Bu/Flu has gained acceptance as an alternative to standard myeloablative regimens due to published treatment related mortality (TRM) rates as low as 3%. We recently reported an 80% graft failure rate when Bu 130mg/m2 daily × 4 and Flu 160mg/m2 is followed by dual UCB transplantation in adult recipients (Horwitz et al. BBMT 2008). We now report early results of a concurrent cohort of patients, treated on the same prospective clinical trial, who were prepared with myeloablative TBI (1350cGy)/Flu (160mg/m2). Methods: 16 patients with a median age of 35 (range 21–55) signed consent for the trial. All patients had high risk hematologic malignancies including AML(CR2) 7, ALL(CR1 or CR2) 4, MDS 2, NHL 3. The UCB grafts were at least 4 of 6 matched (antigen level class I, allele level class II) with the recipient and 3 of 6 matched with each other. Each graft contained a minimum cell dose of 1.5 × 107/kg providing a minimum combined total nucleated cell dose of 3 × 107/kg. Tacrolimus and mycophenolate mofetil were used for GvHD prophylaxis and G-CSF was administered until the neutrophil count exceeded 1000/mm3. Voriconazole, acyclovir and ciprofloxacin were used as anti-infective prophylaxis for at least 3 months post transplantation. Results: With a median follow-up of 15 months, the Kaplan-Meier event-free and overall survival is 61% and 56%, respectively. Three patients experienced graft failure. Hematopoiesis was restored in all three patients with either autologous (2) or allogeneic (1) hematopoietic stem cells. The remainder of patients evaluable for engraftment (competing risk; relapse) achieved >90% donor myeloid chimerism from a single dominant UCB graft. The cumulative incidence of neutrophil engraftment (ANC>500) and platelet engraftment (>50K) is 79% and 75%, respectively. The median time to neutrophil and platelet engraftment was 27 days and 47 days, respectively. Toxic death occurred in 2 patients, resulting in a treatment-related mortality at 6 months of only 9%. In summary, the combination of myeloablative TBI and fludarabine is superior to Bu/Flu in the setting of umbilical cord blood transplantation. This is likely attributable to more effective host immunosuppression provided by the TBI. Acute GvHD occurred in 4 of 9 patients at risk for this complication (Grade II-3, Grade III-1). Chronic GvHD occurred in 2 patients (limited-1, extensive-1). Like the Bu/Flu regimen, we find the TBI/Flu regimen to be well tolerated, resulting in a notably low treatment-related mortality rate compared to more conventional myeloablative drug combinations. Conclusion: We find the approach consisting of myeloablative TBI/Flu preparation followed by dual umbilical cord blood transplantation in adult patients to be promising and worthy of further investigation.

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Multiple Unit Umbilical Cord Blood Transplantation with Total Body Irradiation, Etoposide and Antithymocyte Globulin for Adult Hematologic Malignancy Patients.

Blood ◽

10.1182/blood.v114.22.4344.4344 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4344-4344

Author(s):

Ronald Sobecks ◽

Edward Copelan ◽

Matt Kalaycio ◽

Medhat Askar ◽

Lisa Rybicki ◽

...

Keyword(s):

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Hematologic Malignancy ◽

Cord Blood Transplantation ◽

Conditioning Regimen ◽

Umbilical Cord Blood Transplantation ◽

Blood Transplantation ◽

Multiple Unit ◽

Total Body

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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