Cord Blood Transplantation in Adolescents and Young Adults with Acute Leukemia: On Behalf of Eurocord, Ctiwp and PDWP of EBMT
Authors: Hayashi Hiromi , Volt Fernanda , Sanz Jaime , Petersen Eefke J. , Boissel Nicolas , Hough Rachael , Milpied Noel , Angelucci Emanuele , Yakoub-Agha Ibrahim , Michallet Mauricette , Michel Gerard , Aljurf Mahmoud , Kenzey Chantal , Rocha Vanderson , Dalle Jean-Hugues , Bader Peter , Gluckman Eliane , Ruggeri Annalisa 
Published: October 2019

Abstract

Outcomes for adolescents and young adults (AYA) might be considerably different from children and older adults with acute leukemia (AL). Patients in this transitory period tend to be considered at higher risk for poorer outcomes. However, AYA is still underrepresented in most hematopoietic stem cell transplant (HSCT) studies. Recent evidence shows superior outcomes for AYA with acute lymphoblastic leukemia (ALL) using pediatric rather than adult first line chemotherapy regimens. The aim of this study is to analyze outcomes of umbilical cord blood transplant (UCBT) in AYA patients with ALL or acute myeloid leukemia (AML) after myeloablative conditioning regimen (MAC).
Eligibility criteria included patients with AL aged 15-25 (median 19) years, transplanted between 2004 and 2016 in EBMT centers, with single or double UCBT as first allogenic transplantation after MAC regimen and reported to Eurocord. A total of 504 patients were included. Primary endpoint was overall survival (OS).
Median follow-up for survivors was 38 months (1 month-11 years). Median time from diagnosis to UCBT was 11 months (1 month-17 years) (interquartile range 5-29 months). Diagnosis was ALL in 59% (n=297) and AML in 41% (n=207); 64% of patients were male. Disease status at UCBT were 42% in 1st complete remission (CR) (n=203), 2nd CR in 38% (n=183), and advanced disease in 20% (n=96).
Fifty eight percent of patients (n=293) received single and 42% (n=211) double UCBT. Cyclophosphamide + TBI ± fludarabine (45%) was the most frequently used conditioning regimen. Anti-thymoglobulin (ATG) was used in 54% and GVHD prophylaxis was cyclosporine A + mycophenolate mofetil in 44% of patients. Median nucleated cell dose at collection was 3.63 (range 0.9-9.0) X107/Kg for single and 5.25 (range 2.3-10.6) X107/Kg for double UCBT.
The 3-year OS was 45±2%; 3-year leukemia free survival (LFS) was 41±2% and refined GVHD free/relapse free survival (rGRFS) was 32±2%.
OS was similar in ALL and AML (45±3% vs 45±4%, p-value=0.69). According to disease status at UCBT, 3-year OS was 54±4% for patients in CR1, 48±4% for CR2 and 20±4% for advanced disease (p-value<0.001).
Cumulative incidence function (CIF) for neutrophil engraftment at day-60 was 88% [95% confidential interval (CI) 85-90] in a median time of 24 days. CIF of acute GVHD grade II-IV at day-100 was 28% (95%CI 24-32) and out of the 233 patients with aGVHD, 73 (21%) had grade III-IV.
The 1-year CIF of chronic GVHD was also 28% (95%CI 24-33) and out of the 124 patients with cGVHD, 52 (42%) had the extensive form.
The 3-year CIF of transplant related mortality (TRM) was 31% (95%CI 24-33). The 3-year CIF of relapse was 28% (95%CI 24-32), and according to disease status at UCBT, relapse was 28% (95%CI 21-34) for patients in CR1, 24% (95%CI 18-31) for those in CR2 and 37% (95%CI 27-47) for advanced disease.
Main causes of death were relapse (41%) and TRM (57%, mainly infections and GVHD).
In multivariate analysis, disease remission at UCBT (HR 0.46, 95%CI 0.32-0.66, p-value<0.001) and transplant performed in more recent years (HR 0.75, 95%CI 0.62-0.90, p-value=0.002) were independently associated with increased OS. A similar effect was observed for LFS (recent transplantation: HR 0.80, 95%CI 0.66-0.95, p-value =0.01 and disease remission: HR 0.51, 95%CI 0.36-0.72, p-value <0.001). On the other hand, negative CMV serology (HR 0.77, 95%CI 0.61-0.99, p-value =0.042), recent transplantation (HR 0.85, 95%CI 0.73-0.99, p-value=0.49) and disease remission (HR 0.61, 95%CI 0.44-0.84, p-value =0.002) were significantly associated with increased rGRFS. For grade II-VI aGVHD, ATG use (HR 0.52, 95%CI 0.32-0.82, p-value=0.005), single UCBT (HR 0.63, 95%CI 0.42-0.96, p-value=0.03), and recent transplant (HR 0.76, 95%CI 0.59-0.98, p-value=0.034) reduced the risk. However, no factor was associated to cGVHD.
This large series of AYA patients with AL provides detailed information on UCBT for this particular cohort with results comparable with other sources of HSCT.
Due to the lack of information on pre-transplant chemotherapy (pediatric versus adult protocols), we were unable to evaluate its effect on outcomes. Nevertheless, this study contributes to a better understanding of HSCT for an age group that is not thoroughly described in most publications. Demonstrating the feasibility of UCBT in AYA patients is important to facilitate the decision of stem cell source selection when a more standard donor is not available.

Disclosures
Hough: University College London Hospital's NHS Foundation Trust: Employment. Angelucci:Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Roche Italy: Other: Local (national) advisory board. Bader:Medac: Patents & Royalties, Research Funding; Neovii: Research Funding; Riemser: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau.