Shigesaburo Miyakoshi

Successful Engraftment After Reduced-Intensity Umbilical Cord Blood Transplantation for Adult Patients with Advanced Hematological Diseases

Purpose: The purpose of this research was to evaluate the feasibility of reduced-intensity unrelated cord-blood transplantation (RI-UCBT) in adult patients with advanced hematological diseases. Experimental Design: Thirty patients (median age, 58.5 years; range, 20–70 years) with advanced hematological diseases underwent RI-UCBT at Toranomon Hospital between September 2002 and August 2003. Preparative regimen composed of fludarabine 25 mg/m2 on days −7 to −3, melphalan 80 mg/m2 on day −2, and 4 Gy total body irradiation on day −1. Graft-versus-host disease prophylaxis was composed of cyclosporin alone. Results: Twenty-six patients achieved primary neutrophil engraftment after a median of 17.5 days. Median infused total cell dose was 3.1 × 107/kg (range, 2.0–4.3 × 107/kg). Two transplant-related mortalities occurred within 28 days of transplant, and another 2 patients displayed primary graft failure. Cumulative incidence of complete donor chimerism at day 60 was 93%. Grade II-IV acute graft-versus-host disease occurred in 27% of patients, with median onset 36 days. Primary disease recurred in 3 patients, and transplant-related mortality within 100 days was 27%. Estimated 1-year overall survival was 32.7%. Excluding 7 patients with documented infection, 19 patients displayed noninfectious fever before engraftment (median onset, day 9). Manifestations included high-grade fever, eruption, and diarrhea. The symptoms responded well to corticosteroid treatments in 7 of 13 treated patients. Conclusion: This study demonstrated the feasibility of RI-UCBT in adults.

Early Immune Reaction after Reduced-intensity Cord-blood Transplantation for Adult Patients

Background. To investigate immune reactions after reduced-intensity cord-blood transplantation (RI-CBT). Materials and Methods. We reviewed medical records of 57 adult RI-CBT recipients. Preparative regimen comprised fludarabine, total-body irradiation, and either melphalan (n=51) or busulfan (n=6). Graft-versus-host disease (GvHD) prophylaxis was cyclosporine. PostRI-CBT immune reactions were classified according to time course: pre-engraftment immune reactions (PIR), engraftment syndrome (ES), and GvHD. Results. Forty-five patients achieved engraftment at a median of day 19. PIR was characterized by high-grade fever and weight gain and developed on a median of day 9 in 35 of the 45 evaluable patients, including 3 who did not achieve engraftment. PIR subsided spontaneously in 12 patients, whereas corticosteroids were required in the other 23. ES and grade I to IV acute GvHD developed in 36 and 29 patients, respectively. GvHD could not be distinguished from preceding PIR or ES in 10 patients. Causes of the 32 nonrelapse mortalities included GvHD (n=5) and PIR (n=1). There were no significant differences in relapse and nonrelapse deaths between patients with PIR and those without it (18% vs. 5%, and 60% vs. 65%, respectively). Conclusions. Immune reactions after RI-CBT can be categorized into three distinct subtypes.

Allogeneic haematopoietic stem cell transplantation for the treatment of adult T‐cell leukaemia/lymphoma

Summary. The feasibility of allogeneic haematopoietic stem‐cell transplantation (allo‐HSCT) in 11 patients with adult T‐cell leukaemia/lymphoma (ATL) (6 acute, 4 lymphoma, 1 chronic type) was evaluated. The preparative regimens (9 conventional, 2 reduced‐intensity) were tolerable. Five patients developed acute graft‐versus‐host disease (GVHD), and three, extensive chronic GVHD. All 10 patients who survived > 30 d achieved complete remission. Estimated 1‐year overall and disease‐free survival rates were 53 ± 30% and 45 ± 29% respectively. Four patients remain alive and disease‐free at a median follow‐up of 25 months. The others died of transplantation‐related complications. This pilot study suggests that allo‐HSCT in ATL should be evaluated further.

Umbilical Cord Blood Transplantation after Reduced-Intensity Conditioning for Elderly Patients with Hematologic Diseases

Although allogeneic hematopoietic stem cell transplantation is a potentially curative approach for advanced hematologic diseases, its application to elderly people is limited because of their comorbid physical conditions and lower chance of finding suitable related donors. Umbilical cord blood transplantation with reduced-intensity pretransplant conditioning (RI-UCBT) is 1 way to avoid these obstacles. We analyzed elderly patients aged 55 years and older with hematologic diseases who underwent RI-UCBT at our institute to assess feasibility and effectiveness of this treatment approach. Among the 70 patients included, 50 died, 74% of them from nonrelapse causes. Infection was the primary cause of death. Estimated overall survival and progression-free survival at 2 years were both 23%. In multivariate analyses, standard-risk diseases, age younger than 61 years, grade 0-II acute graft-versus-host disease, and the absence of preengraftment immune reaction were significantly associated with better overall survival. RI-UCBT is a potentially curative and applicable approach for elderly patients. Higher mortality, especially from nonrelapse causes, is the biggest problem to be solved to increase the feasibility of this approach.

High incidence of haemophagocytic syndrome following umbilical cord blood transplantation for adults

Umbilical cord blood transplantation (CBT) is widely accepted, but one critical issue for adult patients is a low engraftment rate, of which one cause is haemophagocytic syndrome (HPS). We aimed to identify the contribution of HPS to engraftment failure after CBT, following preparative regimens containing fludarabine phosphate, in 119 patients (median age, 55 years; range; 17–69 years) with haematological diseases. Graft‐versus‐host disease prophylaxis comprised continuous infusion of a calcineurin inhibitor with or without mycophenolate mofetil. Of the 119 patients, 20 developed HPS within a median of 15 d (cumulative incidence; 16·8%) and 17 of them did so before engraftment. Donor‐dominant chimaerism was confirmed in 16 of 18 evaluable patients with HPS. Despite aggressive interventions including corticosteroid, ciclosporin, high‐dose immunoglobulin and/or etoposide, engraftment failed in 14 of 18 patients. Of these 14 patients, four received second rescue transplantation and all resulted in successful engraftment. Overall survival rates significantly differed between patients with and without HPS (15·0% vs. 35·4%; P < 0·01). Univariate and multivariate analysis identified having fewer infused CD34+ cells as a significant risk factor for the development of HPS (P = 0·01 and 0·006, respectively). We concluded that engraftment failure closely correlated with HPS in our cohort, which negatively impacted overall survival after CBT.

Reduced-intensity stem-cell transplantation for adult acute lymphoblastic leukemia: a retrospective study of 33 patients.

Summary:Efficacy of reduced-intensity stem-cell transplantation (RIST) for acute lymphoblastic leukemia (ALL) was investigated in 33 patients (median age, 55 years). RIST sources comprised 20 HLA-identical related donors, five HLA-mismatched related, and eight unrelated donors. Six patients had undergone previous transplantation. Disease status at RIST was first remission (n=13), second remission (n=6), and induction failure or relapse (n=14). All patients tolerated preparatory regimens and achieved neutrophil engraftment (median, day 12.5). Acute and chronic graft-versus-host disease (GVHD) developed in 45 and 64%, respectively. Six patients received donor lymphocyte infusion (DLI), for prophylaxis (n=1) or treatment of recurrent ALL (n=5). Nine patients died of transplant-related mortality, with six deaths due to GVHD. The median follow-up of surviving patients was 11.6 months (range, 3.5–37.3 months). The 1-year relapse-free and overall survival rates were 29.8 and 39.6%, respectively. Of the 14 patients transplanted in relapse, five remained relapse free for longer than 6 months. Cumulative rates of progression and progression-free mortality at 3 years were 50.9 and 30.4%, respectively. These findings suggest the presence of a graft-versus-leukemia effect for ALL. RIST for ALL is worth considering for further evaluation.

Monitoring cytomegalovirus infection by antigenemia assay and two distinct plasma real-time PCR methods after hematopoietic stem cell transplantation.

We compared a CMV virus load determined by real-time PCR with an antigenemia value to analyze the correlation between these two methods. We also compared the values for virus load determined by the two distinct real-time PCR methods, which amplify the US17 region and immediate–early (IE) gene of CMV, respectively, to evaluate the reliability of these methods. Two hundred and sixty-five samples were obtained weekly from 29 patients, who had engraftment after unrelated bone marrow transplantation or HLA-mismatched related blood stem cell transplantation. CMV infection was detected in 115 samples from 22 patients by US17-PCR and 69 samples from 20 patients by the antigenemia assay. Fifty-eight samples were positive for both assays, but 57 and 11 samples were positive only for US17-PCR and antigenemia, respectively. A good correlation of the results of US17-PCR and antigenemia was demonstrated (r = 0.61). All antigenemia-positive samples and randomly selected antigenemia-negative samples were subjected to IE-PCR. The results of IE-PCR showed a good correlation with those of antigenemia (r = 0.64). Furthermore, the best correlation was observed between US17-PCR and IE-PCR (r = 0.83). In conclusion, both real-time PCR methods showed a good correlation with the antigenemia assay, and could be used to monitor CMV infection after hematopoietic stem cell transplantation.

Impact of HLA disparity in the graft-versus-host direction on engraftment in adult patients receiving reduced-intensity cord blood transplantation

Delayed engraftment or graft failure is one of the major complications after cord blood transplantation (CBT). To investigate factors impacting engraftment, we conducted a retrospective analysis of adult patients who underwent reduced-intensity CBT at our institute, in which preparative regimens mainly consisted of fludarabine, melphalan, and total body irradiation with graft-versus-host (GVH) disease prophylaxis using single calcineurin inhibitors. Among 152 evaluable patients, the cumulative incidence of neutrophil engraftment was 89%. High total nucleated cell and CD34(+) cell dose were associated with the faster speed and higher probability of engraftment. In addition, the degree of human leukocyte antigen (HLA) mismatch in the GVH direction was inversely associated with engraftment kinetics, whereas no statistically significant association was observed with the degree of HLA mismatch in the host-versus-graft direction. Similarly, the number of HLA class I antigens mismatched in the GVH direction, but not in the host-versus-graft direction, showed a negative correlation with engraftment kinetics. HLA disparity did not have significant impact on the development of GVH disease or survival. This result indicates the significant role of HLA disparity in the GVH direction in the successful engraftment, raising the novel mechanism responsible for graft failure in CBT.

False-positive results of Aspergillus enzyme-linked immunosorbent assay in a patient with chronic graft-versus-host disease after allogeneic bone marrow transplantation

False-positive results of Aspergillus enzyme-linked immunosorbent assay in a patient with chronic graft-versus-host disease after allogeneic bone marrow transplantation

Graft failure following reduced‐intensity cord blood transplantation for adult patients

We reviewed the medical records of 123 adult reduced‐intensity cord blood transplantation (RI‐CBT) recipients to investigate the clinical features of graft failure after RI‐CBT. Nine (7·3%) had graft failure, and were classified as graft rejection rather than primary graft failure; they showed peripheral cytopenia with complete loss of donor‐type haematopoiesis, implying destruction of donor cells by immunological mechanisms rather than poor graft function. Three of them died of bacterial or fungal infection during neutropenia. Two recovered autologous haematopoiesis. The remaining four patients underwent a second RI‐CBT and developed severe regimen‐related toxicities. One died of pneumonia on day 8, and the other three achieved engraftment. Two of them died of transplant‐related mortality, and the other survived without disease progression for 9·0 months after the second RI‐CBT. In total, seven of the nine patients with graft failure died. The median survival of those with graft failure was 3·8 months (range, 0·9–15·4). Graft failure is a serious complication of RI‐CBT. As host T cells cannot completely be eliminated by reduced‐intensity preparative regimens, we need to be aware of the difficulty in differentiating graft rejection from other causes of graft failure following RI‐CBT. Further studies are warranted to establish optimal diagnostic and treatment strategies.