Successful Engraftment in Reduced-Intensity Cord Blood Transplantation (CBT) as a Salvage Therapy for Graft Failure After Primary CBT in Adults

Abstract

Accumulating evidence strongly supports the efficacy of umbilical cord blood transplantation (CBT) in adults (1, 2). This now becomes a standard alternative to bone marrow or peripheral blood stem cell transplantation for patients who lack a human leukocyte antigen (HLA)-matched donor. However, surprisingly high incidence of graft failure (GF) after CBT (7–40%) has been reported (2–4). The second CBT could be a therapeutic strategy to rescue patients with GF, but very few cases of successful engraftment by the second CBT for patients with GF after primary CBT have been reported (4–6). In the past few years, we performed the second CBT in four cases with primary GF after CBT and all cases successfully achieved engraftment as summarized in Table 1. In these salvage CBTs, we paid attention to following three points. First, we tried to make a confirmation of GF and decision to perform the salvage CBT as quickly as possible. The confirmation of GF was made by no donor chimerism in bone marrow cells on day 28 or by no sign of hematopoietic recovery until day 35 (week 5) after primary CBT. Finally, the salvage CBT was performed before day 42 (week 6). The earlier application of salvage CBT while patients still have better performance status without infection or organ toxicities may improve the engraftment and survival.TABLE 1: Patient characteristicsSecond, considering toxicities of conditioning regimen used for primary CBT, reduced-intensity CBT was chosen for the second transplant to avoid regimen-related toxicity and mortality. Because strong immunosuppression has a clear advantage over engraftment, we used fludarabine-based preparative regimen. Subsequent conditioning therapy including fludarabine within a short duration after primary transplant and strong graft-versus-host disease (GVHD) prophylaxis could cause a high risk of infection, particularly cytomegalovirus (CMV) in CBT. However, only subclinical CMV infection occurred, which was well controllable with preemptive administration of ganciclovir. Acute GVHD was also mild. Third, to intensify the immunosuppression in combination with a key drug tacrolimus, we utilized mycophenolate mofetil (MMF) instead of methotrexate (MTX) which was used in the first CBT in cases 1, 2 and 3 for the following two reasons. MMF has been reported to cause lower incidence of mucositis compared with MTX (7). Although mechanism has not been elucidated, several reports have suggested that a GVHD prophylaxis regimen containing MMF after allogeneic transplantation is associated with faster engraftment (7–10). Our retrospective observation also shows the promotional effect of MMF in hematopoietic engraftment (data not shown), but further studies are necessary to decide the optimal dose of MMF for stem cell transplantation. We all have to recognize the fact that GF can possibly occur in approximately one third of adult CBT, particularly in the case of low transplant cell numbers. It would be important to make sure of a cord blood unit for salvage transplant as early as possible, and not to lose a chance to make a decision of the salvage CBT to avoid life-threatening complications. Further clinical studies are necessary to establish reduced-intensity CBT as a salvage therapy for primary GF. Yuriko Kawamori Kimikazu Yakushijin Atsuo Okamura Shinichiro Nishikawa Kentaro Minagawa Manabu Shimoyama Katsuya Yamamoto Yoshio Katayama Toshimitsu Matsui Hematology/Oncology Department of Medicine Kobe University Graduate School of Medicine Kobe, Japan