Reduced‐intensity cord blood transplantation without prior remission induction therapy induces durable remission in adult patients with relapsed acute leukemia after the first allogeneic transplantation

To the Editor: Leukemia relapse following allogeneic stem cell transplantation (allo-SCT) remains a major cause of treatment failure (1, 2). Among treatment options, second allo-SCT appears to increase disease-free survival compared with other interventions (3). The most important factors influencing outcomes of second allo-SCT may be the length of remission after the first transplantation and age (2). While disease status may also be an important factor, the probability of remission by re-induction therapy is generally low for relapsed acute leukemia after allo-SCT (4, 5). Limited data exist on other factors, such as conditioning regimens or use of different donors (2). Reducedintensity conditioning (RIC) regimens are now widely used in umbilical cord blood transplantation (CBT) (6). However, few reports exist on the use of RIC regimens in second allo-SCT with CB to treat relapsed patients after first allo-SCT (7). We report the outcomes of RIC CBT without prior reinduction chemotherapy for 11 consecutive adult patients from 2007 to 2009 at our institution (Table 1). Seven had acute myeloid leukemia (AML) and four had acute lymphoblastic leukemia (ALL). Median duration between first SCT and relapse was 6 months (3–24). All but one underwent conditioning with fludarabine (125 mg ⁄m), L-PAM (80 mg ⁄m), and total-body irradiation (TBI; 4 Gy). To achieve the maximum graft-versus-leukemia effect, a relatively low concentration of continuous tacrolimus was used as graft-versus-host disease (GVHD) prophylaxis (mean concentrations for each 10-d period spanning days 1 to 40 were 8.9, 8.9, 10.2, and 9.8 ng ⁄mL, respectively). Six patients received minimal cytoreductive chemotherapy prior to or during conditioning to control the rapid increase in leukemic cells in peripheral blood. Median duration between relapse to second SCT was 37 d (22–60). Four were in complete remission (CR) at the last follow-up (15–37 months). Except for three patients who died early after the second SCT, eight achieved longer CR after the second SCT than after the first. According to the definitions for pre-engraftment immune reaction (PIR) (8) and hemophagocytic syndrome (HPS) following SCT (9), PIR was observed in all cases and HPS in seven. In 10 cases, prednisolone (median dose, 1 mg ⁄kg, ranging 0.2–6.9) was introduced for a short period immediately following the diagnosis of PIR to avoid HPS, which may correlate with graft failure of CB. Graft failure was observed in three patients, two of whom underwent further CBTs as salvage treatment. Complications included severe infections (bacterial, n = 4; viral, n = 5). Other toxicities greater than grade 2 included mucositis (n = 3), sinusoidal obstruction syndrome (n = 2), and generalized skin pain (n = 2). While high grade acute GVHD (III or IV) was not observed in the four patients maintaining CR, all had chronic GVHD. To the best of our knowledge, the largest studies of second allo-SCTs using CB included seven relapsed adult leukemia patients (10) and 22 pediatric (11) leukemia patients; none of the adults and 10 of the pediatric patients received RIC regimens. Compared with these two studies, the interval from first SCT to relapse in the surviving four patients maintaining CR was extremely short in our cohort; in three of four patients, it was 5 months. Compared with the first SCT, an extremely high incidence of PIR was observed with the second SCT (one case vs. all cases), whereas no difference was seen in the incidence of acute GVHD (grade II–IV) and chronic GVHD. Although the biological mechanisms are unclear, PIR is assumed to reflect alloimmune reaction and is observed frequently in CBTs. (8). While the use of CB and a relatively low tacrolimus concentration may have caused the high incidence of PIR and HPS, PIR may have contributed to the suppression of leukemic cells that remained in the early phase after the RIC regimen. Graft failure was a devastating complication that has recently been reported to be closely correlated with HPS following CBT (9). As we previously reported, two of three patients who suffered from graft failure and sepsis underwent successful salvage therapy with a one-day regimen using CB (12). However, further studies are needed to clarify how PIR and HPS should be controlled. LETTER TO THE EDITOR doi:10.1111/j.1600-0609.2010. 01555.x European Journal of Haematology 86 (268–271)