Akira Hiraoka

Unification of Hematopoietic Stem Cell Transplantation Registries in Japan and Establishment of the TRUMP System

There are 4 registries of hematopoietic cell transplantation in Japan; the Japan Society for Hematopoietic Cell Transplantation (JSHCT), Japanese Society of Pediatric Hematology, Japan Marrow Donor Program, and Japan Cord Blood Bank Network; each play an important role in society by reporting the number and outcomes of transplantations and contributing new findings obtained from studies on individual topics. However, there have been a number of issues with the difficulty of analyzing data in overlapping registries and multiple databases at centers affiliated with each of the 4 registry organizations. JSHCT was pivotal in orchestrating the computerization and unification of hematopoietic stem cell transplantation registries for the purpose of resolving these issues and providing a more accurate awareness of hematopoietic stem cell transplantations being performed in Japan. JSHCT played a central role in developing the “Transplant Registry Unified Management Program (TRUMP)” to enable transplantation institutes to manage patient information with emphases on convenience to institutes, safety of patient information, and quality of data management. While enhancing domestic registries, the program seeks to coordinate with other hematopoietic cell transplantation registries around the world to contribute to the development of registries throughout Asia.

Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation.

We report the results of a phase III trial comparing tacrolimus (FK506) with cyclosporine for GVHD prophylaxis after allogeneic BMT. From February 1995 to July 1996, 136 patients were enrolled and followed up to September 1997. During the first 100 days post-transplant the incidence of grade II–IV acute GVHD (the primary end-point) was lower in the tacrolimus group (17.5%) compared with the cyclosporine group (48.0%, P < 0.0001). A significant difference was observed between the tacrolimus and cyclosporine groups when subset analyses were performed based on recipients from HLA-matched siblings (13.3% vs 41.3%, P = 0.015) or donors other than HLA-matched siblings (21.4% vs 53.8%, P = 0.0029). The incidence of chronic GVHD (47.3% and 47.8%) and Kaplan–Meier estimate of overall survival (62.9% and 65.2%) were similar between the tacrolimus and cyclosporine groups, respectively. The overall leukemia relapse rate was not significantly different between the tacrolimus and cyclosporine groups (19.6% and 11.4%, respectively). However, the relapse rate among recipients from HLA-matched siblings was significantly higher in the tacrolimus group (30.9%) compared with the cyclosporine group (3.6%, P = 0.013). These results suggest the merit of tacrolimus for the prophylaxis of acute GVHD, but a lack of merit for a graft-versus-leukemia effect among recipients from HLA-matched sibling donors. Bone Marrow Transplantation (2001) 28, 181–185.

Analysis of 500 bone marrow transplants from unrelated donors (UR-BMT) facilitated by the Japan Marrow Donor Program: Confirmation of UR-BMT as a standard therapy for patients with leukemia and aplastic anemia

In December 1991, the Japan Marrow Donor Program (JMDP) was established with the cooperation of the Japanese Red Cross and Japan Marrow Donor Foundation under the auspices of the Ministry of Health and Welfare in Japan. By December 1998, 122365 HLA-A,B typed volunteer marrow donors and 7207 patients had been cumulatively registered in the JMDP. The results of HLA-matching between donors and patients revealed that 5684 out of 7207 (78.9%) patients could have at least one HLA-A,B,DR serologically matched donor. Among these matched pairs, 1829 unrelated bone marrow transplants (UR-BMT) were performed. The initial 500 UR-BMT transplanted from January 1993 to October 1995 were analyzed as of July 1998. Engraftment was achieved in 95% of cases. Probability of the occurrence of grade III and IV acute GVHD was 18.4%. The rate of disease-free survival (DFS) of the patients who had standard-risk leukemia and did not suffer from grade III or IV acute GVHD (n = 154) was 60–71% and the rate of survival of patients with aplastic anemia was 56%. It can be stated that UR-BMT is a modality of treatment which is as effective as related BMT if the occurrence of grade III or IV acute GVHD is predicted and prevented.

Vidarabine therapy for virus-associated cystitis after allogeneic bone marrow transplantation

We describe a method of diagnosing virus-associated cystitis after allogeneic bone marrow transplantation (BMT) and treatment with vidarabine therapy. At 7–10 days post-BMT when cystitis was suspected, we observed urinary sediments by the Papanicolaou stain to detect virus inclusion bodies. When positive, we examined urinary sediments by transmission electron microscope and measured the diameter of viral particles to determine the families. This process needed only 4 days. Among 16 consecutive cases, adenovirus and polyomavirus were each detected in three. Adenovirus caused hemorrhagic cystitis in two cases and cystitis without macroscopic hematuria in one case. Polyomavirus caused cystitis without macroscopic hematuria in one case. Polyomavirus was also detected in two cases without any symptoms. Vidarabine (10 mg/kg/day i.v.) was administered for 5 days as one course. Soon after one course of vidarabine, most symptoms subsided and virus inclusion bodies disappeared in all cases except for one with severe hemorrhagic cystitis. From these experiences, vidarabine reduces excretion of adenovirus and polyomavirus in the urine of BMT recipients and improves clinical symptoms in some cases of cystitis associated with these viruses.

Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan.

Summary:Despite recent advances, graft-versus-host disease (GVHD) remains the main cause of treatment failure for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Tacrolimus (FK506) has been increasingly used in place of cyclosporine (CSP), and several studies have shown that FK506 reduces the incidence of acute GVHD more effectively than does CSP. However, no survival benefits have been demonstrated, and no established consensus exists on the choice of these immunosuppressive agents. To compare a CSP-based and an FK506-based regimen, we performed a large-scale retrospective study by using the data of 1935 patients who underwent HSCT from HLA-identical sibling donors (SIB-HSCT) and 777 patients who underwent HSCT from unrelated donors (UD-HSCT). For patients undergoing UD-HSCT, FK506 significantly reduced the risk of acute GVHD and treatment-related mortality (TRM) without an increase in relapse, thus improving overall survival (OS) (hazard ratio (HR): 2.20, 95% confidence interval (CI): 1.60–3.04, P<0.0001 for grade II–IV acute GVHD; HR: 1.81, 95% CI: 1.32–2.48, P=0.0003 for TRM; HR: 1.62, 95% CI: 1.23–2.14, P=0.0007 for OS). This superiority of FK506 was not observed in SIB-HSCT cases. These findings indicate that the use of FK506 instead of CSP for GVHD prophylaxis is beneficial for patients undergoing UD-HSCT.

Acute abdomen without cutaneous signs of varicella zoster virus infection as a late complication of allogeneic bone marrow transplantation: importance of empiric therapy with acyclovir

Two patients complained of severe abdominal pain as the first sign of varicella zoster virus infection about 1 year after allogeneic BMT. In case 1, eruptions, found on the face and chest on admission, became vesicular and dispersed on the third hospital day. Though acyclovir (ACV) was immediately started, he died on the fourth day. In case 2, skin rash was never observed during the clinical course. Laparotomy on the third hospital day revealed many hemorrhagic spots on the liver surface and mucous membrane of the upper GI tract, indicating disseminated visceral disease. Empiric therapy with ACV was successful. Bone Marrow Transplantation (2000) 25, 1003–1005.

Poor response to intensive chemotherapy in de novo acute myeloid leukaemia with trilineage myelodysplasia

Summary. The findings of morphologically dysplastic features in haemopoietic cells in de novo acute myeloid leukaemia (AML) has been named AML with trilineage myelodysplasia (AML/TMDS). We analysed the clinical data, karyotypes, and treatment outcomes of 230 de novo AML patients treated with the Japan Adult Leukaemia Study Group AML‐87 protocol. 40 (17%) patients had AML/TMDS. Platelet count was significantly higher (F=0·006) and bone marrow blasts were fewer (P=0·01) in the AML/TMDS group than in the AML without TMDS. Abnormal karyotype was shown in 12/30 patients (40%) analysed.

Fulminant septicemia of Bacillus cereus resistant to carbapenem in a patient with biphenotypic acute leukemia

We report a case of fulminant septicemia with Bacillus cereus resistant to carbapenem. A 33-year-old man was suffering from febrile neutropenia (FN) on day 15 after the start of remission-induction therapy for biphenotypic acute leukemia under gut decontamination with polymyxin B and nystatin. Meropenem, a carbapenem, was administered according to the guideline for FN. Two days later (on day 17), he complained of severe abdominal pain, lost consciousness, went into sudden cardiopulmonary arrest, and died. Autopsy showed multiple spots of hemorrhage and necrosis caused by bacterial plaque in the brain, lungs, and liver. B. cereus was isolated from a blood sample obtained in the morning on day 17 and it was after his death that the isolated B. cereus was revealed to be resistant to carbapenem. B. cereus obtained from blood samples has been reported to be usually sensitive to carbapenem and also to vancomycin, new quinolones, and clindamycin. If B. cereus resistant to carbapem increases, our method of gut decontamination with polymyxin B and nystatin may have to be changed to one containing a new quinolone for the prevention of septicemia. Careful watching to determine whether B. cereus resistant to carbapem increases may be also important for empiric therapy, because carbapenem is often selected as the initial therapy for FN in patients with severe neutropenia.

Effect of graft-versus-host disease on the outcome of bone marrow transplantation from an HLA-identical sibling donor using GVHD prophylaxis with cyclosporin A and methotrexate.

The effect of graft-versus-host disease (GVHD) on relapse incidence and survival has been analyzed in several studies, but previous studies included heterogeneous patients. Therefore, we analyzed the data of 2114 patients who received unmanipulated bone marrow graft from an HLA-identical sibling donor with a GVHD prophylaxis using cyclosporin A and methotrexate. Among the 1843 patients who survived without relapse at 60 days after transplantation, 435 (24%) developed grade II–IV acute GVHD. Among the 1566 patients who survived without relapse at 150 days after transplantation, 705 (47%) developed chronic GVHD. The incidence of relapse was significantly lower in patients who developed acute or chronic GVHD, but disease-free survival (DFS) was significantly inferior in patients who developed acute GVHD. A benefit of ‘mild’ GVHD was only seen in high-risk patients who developed grade I acute GVHD. The strongest association between GVHD and a decreased incidence of relapse was observed in patients with standard-risk acute myelogenous leukemia/myelodysplastic syndrome. In conclusion, the therapeutic window between decreased relapse and increased transplant-related mortality due to the development of GVHD appeared to be very narrow.

Prophylactic fresh frozen plasma may prevent development of hepatic VOD after stem cell transplantation via ADAMTS13-mediated restoration of von Willebrand factor plasma levels.

We initially conducted a multicenter, randomized trial (n=43), and subsequently a questionnaire study (n=209) of participating hospitals, to evaluate whether infused fresh frozen plasma (FFP) could prevent the occurrence of hepatic veno-occlusive disease (VOD) after stem cell transplantation (SCT). Forty-three patients were divided into two groups: 23 receiving FFP infusions and 20 not receiving it. VOD developed in three patients not receiving FFP. Plasma von Willebrand factor (VWF) antigen levels were lower at days 0, 7 and 28 after SCT in patients receiving FFP than in those not receiving it, whereas plasma ADAMTS13 activity (ADAMTS13:AC) did not differ between them. Plasma VWF multimer (VWFM) was demonstrated to be defective in the high∼intermediate VWFM during the early post-SCT phase, but there was a significant increase in high VWFM just before VOD onset. This suggests that a relative enzyme-to-substrate (ADAMTS13/high-VWFM) imbalance is involved in the pathogenesis of VOD. To strengthen this hypothesis, the incidence of VOD was apparently lower in patients receiving FFP infusions than in those not receiving it (0/23 vs 3/20) in the randomized trial. Further, the results combined with the subsequent questionnaire study (0/36 vs 11/173) clearly showed the incidence to be statistically significant (0/59 vs 14/193, P=0.033).