Biol Blood Marrow Transplant 19 (2013) 1387e1392
Impact of Graft-versus-Host Disease Prophylaxis on Outcomes after Myeloablative Single-Unit Umbilical Cord Blood Transplantation
ASBMT
American Society for Blood and Marrow Transplantation
Jaime Sanz 1, *, Alessandra Picardi 2, Juan C. Hernández Boluda 3, Carmen Martín 4, Christelle Ferrá 5, Chiara Nozzoli 6, Marta Gonzalez-Vicent 7, Alessandro Rambaldi 8, David Valcarcel 9, Amparo Verdeguer 10, David Serrano 11, Cristina Díaz de Heredia 12, María Jesús Pascual 13, Raquel de Paz 14, Pau Montesinos 1, Benedetta Bartolozzi 6, Alessandra Algarotti 8, Miguel A. Sanz 1, William Arcese 2, Guillermo F. Sanz 1, on behalf of GETH and GITMO 1
Department of Hematology, Hospital Universitario La Fe, Valencia, Spain UOC Trapianto di Cellule Staminali, Università di Roma Tor Vergata, Italy 3 Hospital Clínico Universitario, Valencia, Spain 4 Hospital Reina Sofía, Córdoba, Spain 5 Hospital Universitari Germans Trias I Pujol, Barcelona, Spain 6 Azienda Ospedaliera Universitaria Careggi, Firenze, Italy 7 Hospital Niño Jesús, Madrid, Spain 8 Ospedali Riuniti di Bergamo, Italy 9 Hospital Universitari Vall D’Hebron, Barcelona, Spain 10 Department of Pediatrics, Hospital Universitario La Fe, Valencia, Spain 11 Servicio de Hematologia Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain 12 Department of Pediatrics, Hospital Universitari Vall D’Hebron, Barcelona, Spain 13 Hospital Carlos Haya, Málaga, Spain 14 Hospital La Paz, Madrid, Spain 2
Article history: Received 9 April 2013 Accepted 1 July 2013 Key Words: Umbilical cord blood GVHD prophylaxis Engraftment
a b s t r a c t
Myeloablative single-unit umbilical cord blood transplantation (sUCBT) using busulfan, thiotepa, fludarabine, and antithymocyte globulin (Grupo Español de Trasplante Hematopoyético [GETH]-2005 protocol) resulted in high rates of engraftment and high antitumor activity. We designed a new graft-versus-host disease prophylaxis, substituting long-term steroids with mycophenolate mofetil together with a slight reduction of antithymocyte globulin (GETH/Gruppo Italiano Trapianto Midollo Osseo [GITMO]-2008 protocol). The results in 145 consecutive patients were compared with those obtained in 88 patients from the previous GETH-2005 trial. The cumulative incidence (CI) of myeloid engraftment at 60 days for patients in the GETH-2005 and GETH/GITMO-2008 trials was 94% and 88%, respectively, at a median time to neutrophil recovery of 19 and 23 days, respectively (P < .0001). In the multivariable analyses, platelet engraftment, acute and chronic graftversus-host disease, nonrelapse mortality, relapse, and event-free survival were not significantly different. The 3-year event-free survival rate in the GETH/GITMO-2008 trial was 66%, 31%, and 25% for patients transplanted in early, intermediate, and advanced stages of the disease, respectively (P < .0001). This study confirms that myeloablative sUCBT using busulfan-based conditioning is a valuable strategy for patients with hematological malignancies. The use of mycophenolate mofetil apparently had an adverse effect on myeloid engraftment, and therefore a cautious use of this agent is warranted in the UCBT setting. Ó 2013 American Society for Blood and Marrow Transplantation.
INTRODUCTION Single-unit umbilical cord blood transplantation (UCBT) from an unrelated donor using busulfan, thiotepa, fludarabine, and antithymocyte globulin (ATG) as the myeloablative conditioning regimen (UCBT-GETH-2005 protocol) has previously reported high rates of engraftment with fast neutrophil recovery and high antitumor activity in patients with high-risk hematologic malignancies [1]. This strategy designed by the cooperative Grupo Español de Trasplante
Financial disclosure: See Acknowledgments on page 1392. * Correspondence and reprint requests: Jaime Sanz, MD, Servicio de Hematología, Hospital Universitari i politècnic La Fe, Bulevar Sur s/n, 46026 Valencia, Spain. E-mail address:
[email protected] (J. Sanz).
Hematopoyético (GETH) was, however, associated with substantial morbidity and mortality, mainly due to opportunistic infections. To improve the outcome of the previous strategy, a new trial (UCBT-GETH/Gruppo Italiano Trapianto Midollo Osseo [GITMO]-2008) was designed to decrease infection-related mortality rate. With this objective in mind, the long-term steroid therapy previously used for graft-versus-host disease (GVHD) prophylaxis was substituted by a short course of mycophenolate mofetil (MMF) and a slightly reduced dose of ATG. In addition, the minimum cell dose threshold in the GETH/GITMO-2008 protocol did not take into account the recipient’s body weight but only the total dose of the unit, with total nucleated cells (TNCs) >150 107 and CD34þ cells >70 105 being the minimum required.
1083-8791/$ e see front matter Ó 2013 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2013.07.004
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J. Sanz et al. / Biol Blood Marrow Transplant 19 (2013) 1387e1392
This study compares the results obtained in 2 consecutive cohorts of patients with hematological malignancies with 2 different protocols (GETH-2005 and GETH/GITMO-2008) that differed only in the above-mentioned changes in GVHD prophylaxis after single-unit UCBT from an unrelated donor using a chemotherapy-based myeloablative conditioning regimen. METHODS Eligibility Criteria Patients with high-risk hematological malignancy requiring urgent hematopoietic cell transplantation and lacking a suitable related donor (HLA identical or 1-antigen mismatched) were eligible for enrollment. The institutional review board approved the protocol, and written informed consent was obtained from all patients according to the Declaration of Helsinki. Protocol was registered on the EudraCT with code 2008-000927-24. Cord Blood Unit Selection Graft selection required UCB 4/6 HLA matched with the recipient (HLA class I antigens [A and B] at antigen level and class II antigens [DRB1] at allele level resolution DNA typing). Cell dose was considered the most important criteria for unit selection. In the GETH-2005 protocol, TNCs > 2 107/kg and CD34þ cells > .6 105/kg or TNCs > 1.5 107/kg and CD34þ cells > 1 105/ kg were required. For adults included in the GETH/GITMO-2008 protocol, the cell dose did not take into account the recipient’s body weight but only the total dose of the unit, with TNC > 150 107 and CD34þ cells > 70 105 being the minimum required. When the UCB units had a similar cell dose, a higher degree of HLA match was preferred. Conditioning Regimen and GVHD Prophylaxis All patients received myeloablative conditioning regimen with thiotepa 5 mg/kg/day on days e7 and e6, i.v. busulfan 3.2 mg/kg/day as a single daily dose on days e5 to e3, and fludarabine 50 mg/m2/day on days e5 to e3.The busulfan dose was adjusted in patients weighing < 34 kg to achieve a total dose of 12 mg/kg, 14.4 mg/kg, 13.2 mg/kg, and 11.4 mg/kg in patients weighing
