Eiji Kusumi

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.

Allogeneic haematopoietic stem cell transplantation as a promising treatment for natural killer-cell neoplasms

The efficacy of allogeneic haematopoietic stem‐cell transplantation (allo‐HSCT) for natural killer (NK)‐cell neoplasms is unknown. We investigated the results of allo‐HSCT for NK‐cell neoplasms between 1990 and 2003 through questionnaires. After reclassification by a haematopathologist, of 345 patients who underwent allo‐HSCT for malignant lymphoma, 28 had NK‐cell neoplasms (World Health Organization classification): extranodal NK/T‐cell lymphoma (n = 22), blastic NK‐cell lymphoma (n = 3), and aggressive NK‐cell leukaemia (n = 3). Twelve were chemosensitive and 16 chemorefractory. Twenty‐two had matched‐related donors. Stem‐cell source was bone marrow in eight and mobilised peripheral blood in 20. Conditioning regimens were myeloablative (n = 23) and non‐myeloablative (n = 5). Grade 2–4 acute graft‐versus‐host disease (GVHD) and chronic GVHD developed in 12 and 8 respectively. Eight died of disease progression, three of infection, two of acute GVHD, one of veno‐occlusive disease, one of interstitial pneumonitis, and one of thrombotic microangiopathy. Two‐year progression‐free and overall survivals were 34% and 40% respectively (median follow‐up, 34 months). All patients who did not relapse/progress within 10 months achieved progression‐free survival (PFS) during the follow‐up. In multivariate analysis, stem cell source (BM versus peripheral blood; relative risk 3·03), age (≥40 years vs. <40 years; relative risk 2·85), and diagnoses (extranodal NK/T‐cell lymphoma versus others; relative risk 3·94) significantly affected PFS. Allo‐HSCT is a promising treatment for NK‐cell neoplasms.

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.

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 hematopoietic stem-cell transplantation for malignant lymphoma : a retrospective survey of 112 adult patients in Japan

Summary:We conducted a nation-wide survey of 112 adult Japanese patients who underwent reduced-intensity stem cell transplantation (RIST) from 1999 to 2002. Underlying diseases included indolent (n=45), aggressive (n=58) and highly aggressive lymphomas (n=9). Median age of the patients was 49 years. A total of 40 patients (36%) had relapsed diseases after autologous stem cell transplantation and 36 patients (32%) had received radiotherapy. RIST regimens were fludarabine-based (n=95), low-dose total body irradiation-based (n=6) and others (n=11). Cumulative incidences of grade II–IV acute graft-versus-host disease (GVHD) and chronic GVHD were, respectively, 49 and 59%. Cumulative incidences of progression and progression-free mortality were 18 and 25%, respectively. With a median follow-up of 23.9 months, 3-year overall survival rates were 59%. A multivariate analysis identified three significant factors for progression, which are history of radiation (relative risk (RR) 3.45, confidential interval (CI) 1.12–10.0, P=0.03), central nervous system involvement (RR 6.25, CI 2.08–20.0, P=0.001) and development of GVHD (RR 0.28, CI 0.090–0.86, P=0.026). RIST may have decreased the rate of transplant-related mortality, and GVHD may have induced a graft-versus-lymphoma effect. However, whether or not these potential benefits can be directly translated into improved patient survival should be evaluated in further studies.

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.

Chronic graft-versus-host disease following umbilical cord blood transplantation: retrospective survey involving 1072 patients in Japan

We have little information on chronic graft-versus-host disease (GVHD) after cord blood transplantation (CBT). We investigated its clinical features in 1072 Japanese patients with hematologic malignancies who received a transplant through the Japan Cord Blood Bank Network. The primary end point was to investigate the incidence of any chronic GVHD. Median age of the patients was 33 years (range, 0-79 years). The cumulative incidence of chronic GVHD 2 years after transplantation was 28%. Chronic GVHD was fatal in 29 patients. Multivariate analysis demonstrated that development of chronic GVHD was favorably associated with both overall survival and event-free survival. Multivariate analysis identified risk factors of chronic GVHD: higher patient body weight, higher number of mismatched antigens for GVHD direction, myeloablative preparative regimen, use of mycophenolate mofetil in GVHD prophylaxis, and development of grades II to IV acute GVHD. Although chronic GVHD is a significant problem after CBT, it is associated with improved survival, perhaps due to graft-versus-malignancy effects.

Late hemorrhagic cystitis after reduced-intensity hematopoietic stem cell transplantation (RIST)

Summary:We reviewed medical records of 256 patients to investigate the frequency and characteristics of hemorrhagic cystitis (HC) associated with reduced-intensity stem cell transplantation (RIST) as opposed to conventional stem cell transplantation (CST); 137 patients underwent CST and 119 RIST. Diagnosis of HC was made based on two or more episodes of sterile, macroscopic hematuria with normal coagulation profiles, without any evidence of renal stones or genitourinary malignancy. Actuarial frequency of HC development in RIST group was 7.6% (9/119), which gave a cumulative annual incidence of 11.7%. In CST group, 13 of 137 patients (9.5%) developed HC, giving an estimated annual incidence of 9.7%. The probability of developing HC was similar between the two groups (P=0.77). The viral etiologies of HC, adenovirus (n=12) and BK virus (n=2), were documented in eight patients after RIST and in six after CST. HC was milder and of a shorter duration, with less blood transfusion requirements, in RIST group than in CST group. A multivariate analysis revealed that HC was associated with antiadenovirus antibody positivity in the recipients, total dose of busulfan, and chronic GVHD. Although HC following RIST is less severe than that following CST, it is still a significant problem.

Tacrolimus as prophylaxis for acute graft-versus-host disease in reduced intensity cord blood transplantation for adult patients with advanced hematologic diseases

Background. Myeloablative cord blood transplantation (CBT) for adult patients offers a 90% chance of engraftment with a 50% rate of transplant-related mortality, mostly attributable to infection. We have demonstrated the feasibility of reduced-intensity CBT (RI-CBT) for adult patients, in which cyclosporine was used for acute graft-versus-host disease (GVHD) prophylaxis. Transplantation-related mortality (TRM) was 27% within 100 days. Therefore our objective was to evaluate the feasibility of RI-CBT with tacrolimus as GVHD prophylaxis for adult patients with hematologic malignancies. Methods. Thirty-four patients with a median age of 56.5 years (range; 22–68) with hematologic diseases underwent RI-CBT at Toranomon Hospital between November 2003 and September 2004. Preparative regimen comprised 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. GVHD prophylaxis was continuous intravenous infusion of tacrolimus 0.03 mg/kg, starting on day –1. Results. Thirty-one patients achieved neutrophil engraftment at a median of day 20. Median infused total cell dose was 2.4×10E7/kg (range; 1.6–4.8). Thirty-two patients achieved complete donor chimerism at day 60. Grade II–IV acute GVHD occurred in 45% of patients, with a median onset of day 26. Primary disease recurred in five patients, and TRM within 100 days was 12%. Estimated 1-year overall survival was 70%. Conclusion. This study demonstrated the possible improvement in transplant-related mortality by tacrolimus as GVHD prophylaxis in adult RI-CBT recipients.