GvHD prophylaxis after single-unit reduced intensity conditioning cord blood transplantation in adults with acute leukemia.

To investigate better GVHD prophylaxis in reduced intensity conditioning umbilical cord blood transplantation (RIC-UCBT), we compared transplant outcomes after UCBT among GvHD prophylaxes using the registry data. We selected patients transplanted for AML or ALL with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 748 first RIC-UCBT between 2000 and 2012 (MTX+ group, 446, MMF+ group, 302) were included. The cumulative incidence of neutrophil and platelet counts higher than 50 000/µL was significantly better in the MMF+ group (relative risk (RR), 1.55; P<0.001: RR, 1.34; P=0.003, respectively). In multivariate analyses, the risk of grade II-IV and III-IV acute GvHD was significantly higher in the MMF+ group than in the MTX+ group (RR, 1.75; P<0.001: RR, 1.97; P=0.004, respectively). In disease-specific analyses of AML, the risk of relapse of high-risk disease was significantly lower in the MMF+ group (RR, 0.69; P=0.009), whereas no significant difference was observed in the risk of relapse-free and overall survival in high-risk disease. In patients with standard-risk disease, no significant differences were noted in the risk of relapse or survival between the MTX+ and MMF+ groups. Collectively, these results suggest that MMF-containing prophylaxis may be preferable in RIC-UCBT, particularly for high-risk disease.

Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation.

The effect of graft-versus-host disease (GVHD) on transplant outcomes after unrelated cord blood transplantation (UCBT) has not been fully elucidated. We analyzed the impact of acute and chronic GVHD on outcomes in adult patients with acute leukemia or myelodysplastic syndrome who underwent their first UCBT (n=2558). The effect of GVHD on outcomes was analyzed after adjusting for other significant variables. The occurrence of GVHD was treated as a time-dependent covariate. The occurrence of grade 1-2 or 3-4 acute GVHD was significantly associated with a lower relapse rate. Grade 3-4 acute GVHD was associated with a higher risk of non-relapse and overall mortality than no acute GVHD, whereas grade 1-2 acute GVHD was associated with a lower risk of non-relapse and overall mortality than no acute GVHD. Limited or extensive chronic GVHD was significantly associated with a lower relapse rate. Limited chronic GVHD was associated with a lower overall and non-relapse mortality than no chronic GVHD. In conclusion, mild acute or chronic GVHD was associated not only with a low risk of relapse but also with a low risk of non-relapse mortality, and provides a survival benefit in UCBT.

Favorable survival after allogeneic stem cell transplantation with reduced-intensity conditioning regimens for relapsed/refractory follicular lymphoma.

Allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with relapsed follicular lymphoma (FL). Prospective studies of reduced-intensity conditioning (RIC) have revealed that chemosensitivity at allo-SCT is the most reliable predictor of outcome; however, limited data are available for progressive/refractory disease. We report here a retrospective analysis of RIC allo-SCT for patients with FL. The purpose of this study was to elucidate the role of allo-SCT for patients with relapsed/refractory FL. We analyzed 46 patients-11 (24%) transplanted in CR, 6 (13%) transplanted in PR and 29 (63%) with progressive/refractory disease. The estimated 5-year overall survival rate was 71.6% (95% confidence interval (CI), 51.5-84.5%). According to the disease status at transplantation, the 5-year survival rate was 80.7% (95% CI, 37.7-95.4%) in the patients with CR or PR and 66.1% (95% CI, 41.5-82.3%) in those with progressive/refractory disease (P=0.29). There were no differences in relapse/progression and non-relapse mortality between the patients with chemosensitive disease and progressive/refractory disease. Allo-SCT may be a valuable treatment option, even for patients with progressive/refractory FL.

Clinical significance of pretransplant serum ferritin on the outcome of allogeneic hematopoietic SCT: a prospective cohort study by the Kanto Study Group for Cell Therapy.

This prospective study aimed to investigate the influence of pretransplant serum ferritin levels on the outcomes of allogeneic hematopoietic SCT (HSCT). In total, 190 patients with acute leukemia or myelodysplastic syndrome were consecutively enrolled. The patients were divided into two groups: low-ferritin group (<1000 ng/mL) and high-ferritin group (⩾1000 ng/mL). The primary end point was the cumulative incidence of infection within 100 days after HSCT, which was similar between the two groups: bloodstream infection, 35 vs 38%, P=0.65; bacterial infection, 44 vs 41%, P=0.68; and fungal infection, 6 vs 8%, P=0.71. The 1-year adjusted probability of OS of the high-ferritin group was significantly lower than that of the low-ferritin group (76 vs 63%, P=0.017). Using receiver operating characteristic curve, the threshold of pretransplant serum ferritin levels for bloodstream infection was 1400 ng/mL; the threshold for OS, EFS and non-relapse mortality was 1349 ng/mL. In conclusion, pretransplant serum ferritin levels of ⩾1000 ng/mL did not influence the incidence of infection but adversely affected OS after HSCT. A higher threshold of pretransplant serum ferritin levels may predict HSCT outcomes.

Effects of KIR ligand incompatibility on clinical outcomes of umbilical cord blood transplantation without ATG for acute leukemia in complete remission.

To clarify the effect of killer cell immunoglobulin-like receptor (KIR) ligand incompatibility on outcomes of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients in complete remission after single cord blood transplantation (CBT), we assessed the outcomes of CBT registered in the Japan Society for Hematopoietic Cell Transplantation (JSHCT) database. A total of 643 acute leukemia (357 AML and 286 ALL) patient and donor pairs were categorized according to their KIR ligand incompatibility by determining whether or not they expressed HLA-C, Bw4 or A3/A11 by DNA typing. A total of 128 patient-donor pairs were KIR ligand-incompatible in the graft-versus-host (GVH) direction and 139 patient-donor pairs were incompatible in the host-versus-graft (HVG) direction. Univariate and multivariate analyses showed no significant differences between the KIR ligand-incompatible and compatible groups in the GVH direction for both AML and ALL patients of overall survival, disease-free survival, relapse incidence, non-relapse mortality and acute GVH disease. However, KIR incompatibility in the HVG direction ameliorated engraftment in ALL patients (hazard ratio 0.66, 95% confidence interval 0.47-0.91, P=0.013). Therefore, there were no effects of KIR ligand incompatibility in the GVH direction on single CBT outcomes for acute leukemia patients without anti-thymocyte globulin use. However, it is necessary to pay attention to KIR incompatibility in the HVG direction for engraftment.

Secondary solid tumors after allogeneic hematopoietic SCT in Japan.

To evaluate the incidence and risk factors for secondary solid tumors in Japan after allogeneic hematopoietic SCT (allo-HSCT), 2062 patients who had received allo-HSCT between 1984 and 2005 were retrospectively analyzed. Twenty-eight patients who developed 30 solid tumors were identified a median of 5.6 years after transplantation. The risk for developing tumors was 2.16-fold higher than that of the age- and sex-adjusted general population. The cumulative incidence of solid tumors at 10 years after allo-HSCT was 2.4%. The risk was significantly higher for tumors of the skin, oral cavity and esophagus (standard incidental ratio 40.23, 35.25 and 10.73, respectively). No increase in gastric, colon or lung cancer, despite being the most prevalent neoplasm in the Japanese, was observed. In multivariate analysis, occurrence of chronic GVHD and malignant lymphoma as a primary disease was associated with a higher risk for developing solid tumors. Eighteen patients are still alive, and their 5-year probability of survival since diagnosis of solid tumors is 59.7%. Our data suggest that the incidence and risk factors of secondary solid tumors in Japanese allo-HSCT recipients are comparable to those reported in Western countries and emphasize that the early detection of solid tumors has a crucial role in improving OS.

[Feasibility of early tapering and discontinuation of cyclosporine to intensify the graft-versus-leukemia effect in patients with advanced hematologic neoplasms].

Twenty patients with advanced hematological malignancies at high risk of relapse who had each received a bone marrow transplant from a matched sibling were registered between October 1996 and January 2000. Cyclosporine (CSP) was tapered on day 40 and stopped on day 50 in 10 patients without prior grade II-IV acute graft-versus-host disease (GVHD), relapse or active infection. These patients were eligible for early tapering of CSP. Although grade II/III acute GVHD was observed in three patients and chronic GVHD in eight patients after CSP tapering, no patients died of GVHD. Three patients died due to disease relapse and one patient died of idiopathic interstitial pneumonia while in remission. The probability of event-free survival at 2 years was 60%. These result indicate that early tapering and withdrawal of CSP is feasible and may provide a graft-versus-leukemia effect in patients with advanced leukemia.

Fulminant Mycoplasma pneumoniae pneumonia.

A 64-year-old woman, who was previously in good health was admitted because of progressive respiratory distress. Her chest radiograph revealed bilateral widespread alveolar infiltrates. She was given a diagnosis of pneumonia caused by Mycoplasma pneumoniae serologically, acute respiratory distress syndrome, and disseminated intravascular coagulation. She died of multiple organ failure despite intensive therapy with mechanical ventilation, intravenous erythromycin and corticosteroids, continuous hemodiafiltration, and plasma exchange. Although Mycoplasma pneumoniae infection is usually a benign self-limited disease, this case emphasizes its potentially serious nature even in normal healthy individuals.

The Japanese multicenter open randomized trial of ursodeoxycholic acid prophylaxis for hepatic veno-occlusive disease after stem cell transplantation.

Hepatic veno-occlusive disease (VOD) is a common transplant-related complication of stem cell transplantation. There is no safe and proven therapy for established VOD, and attempts have focused on its prevention. Limited studies have suggested that prophylactic use of ursodeoxycholic acid (UDCA) reduced the incidence of VOD. To confirm the preventive effect of UDCA on VOD, we conducted a prospective, unblinded randomized, multicenter study of UDCA involving 132 patients who underwent stem cell transplantation for a variety of disorders. Sixty-seven patients were assigned to the UDCA-treated group, and 65 patients were assigned to the control group. The clinical characteristics of the two groups were similar with respect to primary diagnosis, age, sex, and baseline organ function. The preparative regimen and GVHD prophylaxis did not differ significantly between the two groups. UDCA was highly effective in preventing VOD, which occurred in only 3.0% in the UDCA-treated group, as opposed to 18.5% in the control group (P = 0.0043). There were no adverse effects attributable to UDCA. The initial promising report of a prophylactic effect of UDCA on VOD after stem cell transplantation was confirmed in this prospective study.

Bilateral pleuritis caused by Legionella micdadei.

A 58-year-old woman was hospitalized because of progressive respiratory distress. She had a history of myasthenia gravis and invasive thymoma. After thymectomy, she had been administered oral prednisolone and intrathoracic anti-cancer drugs postoperatively. Her chest radiograph revealed bilateral pleural effusions. Legionella micdadei (L. micdadei) was isolated from the pleural effusions, and she was diagnosed as pleuritis caused by L. micdadei. She died despite intensive therapy with mechanical ventilation, drainage tube in the chest and intravenous erythromycin. Although only two cases of Legionellosis caused by L. micdadei have been reported in Japan, clinicians should be aware of L. micdadei as one of the candidates for infection in immunosuppressed hosts.

[Nationwide survey of allogeneic peripheral blood stem cell transplantation from related donors in Japan: current trends and issues].

In December 1997, we conducted a nationwide survey of cases of primary allogeneic peripheral blood stem cell transplantation (allo-PBSCT) performed in Japan between December 1994 and November 1997 Data was collected on 103 patients with hematologic malignancies, aplastic anemia, or solid tumors. Eighty-seven patients received transplants from HLA-identical siblings, and 16 from HLA-mismatched related donors. Granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSC) were collected from donors by 1 to 3 aphereses. Apheresis products contained a median 5.4 (1.0-30.4) x 10(6) CD34 + cells/kg. Most patients were given cyclosporine and methotrexate for graft-versus-host disease (GVHD) prophylaxis. Median days to ANC > 500/microliter and platelets > 50,000/microliter were 13 (7-49) and 16 (10-94), respectively. Grade II-IV acute GVHD developed in 37/99 (37.4%) and chronic GVHD in 59/86 (68.6%) patients. The incidence of treatment-related mortality within 100 days after transplant was 16.1%. Fifty-five patients (59.6%) were alive after a median follow-up of 794 days. More patients and longer follow-up periods will be required to assess the efficacy of allo-PBSCT and evaluate graft-versus-leukemia effect along with the incidence of acute and chronic GVHD.

Allogeneic peripheral blood stem cell transplantation for standard-risk leukemia. A multicenter pilot study: Japanese experience. Japan Blood Cell Transplantation Study Group.

A multicenter phase II study of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) was conducted. Twenty-two patients (median age, 36 years) with standard-risk leukemia were transplanted with G-CSF-mobilized PBSC from an HLA-identical sibling donor, and received cyclosporine and methotrexate for GVHD prevention. Median days to ANC >500/microl and platelets >50,000/microl were 12 (9-20) and 16 (11-32), respectively. Grade II-IV acute GVHD developed in 6/21 (29%) and extensive chronic GVHD in 12/20 (60%). These observations indicate that allo-PBSCT is characterized by rapid hematologic engraftment, no increase of acute GVHD and an increased risk of chronic GVHD, and can be used as an alternative to allogeneic bone marrow transplantation.

[Treatment of acute lymphoblastic leukemia of young adults (15-22 years of age): results of co-operative study with internal medicine and pediatrics].

Ten young adults (15-22 years of age) with acute lymphoblastic leukemia were treated with the protocol of internal medicine and pediatrics co-operative study group since 1989. All patients had complete remission within 5 weeks. Four of 6 patients of low risk group (less than 30,000/microliter of WBC count at diagnosis) and 1 of 4 patients of high risk group have continued the complete remission. Three patients relapsed in bone marrow (BM), and 2 patients in both BM and central nervous system (CNS). All patients could be treated without serious complications except for infection. We obtained the good results of treatment for the low risk group, but did not for the high risk group in this study. Little is known about acute lymphoblastic leukemia in young adults because these individuals are at the borderline age between internal medicine and pediatrics. Taken together with the psychologically distinct age of these patients, it is necessary to establish a closer relationship between internal medicine and pediatrics.

Interleukin-2 does not overcome suppression of graft rejection by cyclosporin A: effect of cyclosporin A on T cell properties in vivo.

The most evident immunosuppressive effect of cyclosporin A (CsA) on T cells is suppression of interleukin-2 (IL-2) production through the suppression of type-2B serine/threonine-specific phosphatase, calcineurin. To test whether suppression of IL-2 production is a major mechanism of CsA-mediated suppression of allograft rejection, we treated allogeneic skin-grafted mice with CsA and IL-2, and observed that IL-2 did not override the suppressive effect of CsA. Specific cytotoxic T lymphocyte (CTL) activity and natural killer (NK) activity of the spleens were increased by treatment with IL-2, and CsA significantly suppressed the killing activity. We also found that CsA-treatment decreased the expression of lck kinase of T cells and the production of IL-2 in response to concanavalin A (ConA), with minimum effect on IL-4 production. These results suggest that T cell dysfunctions other than decreased production of IL-2 are essential for suppressive effect of CsA on skin allograft rejection.

Lymphocyte subset reconstitution following human allogeneic bone marrow transplantation: differences between engrafted patients and graft failure patients.

To define the relationship between hematopoietic reconstitution and lymphocyte subset analysis in human allogeneic bone marrow transplantation (BMT), we compared lymphocyte subset reconstitution during the first 4 weeks after BMT in nine engrafted patients with that in three graft failure patients using flow cytometry. Marked differences were observed between the two groups. In graft failure patients, the percentage of CD3+ lymphocytes had increased 2 weeks after BMT by over 90% (p less than 0.05). The percentage of CD16+ lymphocytes and CD16+ CD57- lymphocytes did not increase (CD16+ at 3 and 4 weeks: p less than 0.05, CD16+ CD57- at 3 weeks; p less than 0.05, at 4 weeks: p less than 0.01), nor did the percentage of CD8+ 11b+ lymphocytes. The percentage of CD8+ 11b- lymphocytes had increased markedly 2 weeks after BMT (at 2 weeks: p less than 0.05, at 3 and 4 weeks: p less than 0.01). Of particular interest is the difference in the percentage of CD3+, CD16+, and CD8+ CD11b- T cells between the two groups. These cells may play a role in allogeneic bone marrow cell engraftment.

[Transient B lymphocytosis associated to hepatitis B after allogeneic bone marrow transplantation].

A 42-year-old male suffered from AML (M2) and achieved remission with chemotherapy. After that, he was successfully treated with allogeneic bone marrow transplantation. About eight months later, jaundice and general malaise developed and diagnosis of acute hepatitis B type was made based on laboratory findings. After 3 months of a conservative therapy, he recovered from the disease. During the clinical course of the hepatitis, B lymphocytes were increased to about 70% of peripheral blood lymphocytes (PBLs) transiently, and furthermore CD5 positive B lymphocytes occupied 12% of the PBLs at that time. This B lymphocytosis disappeared gradually along with the improvement of the hepatitis. The remarkable increase of B lymphocytes in PBLs was considered to be an abnormal reaction induced by HB virus infection, when his immune system was in the recovering phase after bone marrow transplantation.

Hepatic veno-occlusive disease in a patient with lupus anticoagulant after allogeneic bone marrow transplantation.

A 37-year-old man with acute myeloblastic leukemia (FAB M2) in first remission underwent a bone marrow transplant (BMT) following conditioning with high-dose cytarabine and total body irradiation. The donor was an HLA-identical brother. Graft rejection occurred and a second BMT was performed from the same donor following conditioning with cyclophosphamide. Engraftment was achieved, but the patient developed severe jaundice and died of respiratory failure on day +46 after the second BMT. Liver biopsy revealed luminal narrowing of the central veins and a diagnosis of hepatic veno-occlusive disease (VOD) was made. The coagulation studies showed a prolonged kaolin clotting time which was not corrected by 1:1 mixture with normal plasma, and the platelet neutralization test was positive. Dilute tissue thromboplastin time and dilute Russell viper venom time were also prolonged. These results fulfilled the criteria for lupus anticoagulant, which may have contributed to VOD in this patient.

[Lymphocyte subset reconstitution following human allogeneic bone marrow transplantation].

We analysed the reconstitution of lymphocyte subset during the first 4 weeks after human allogeneic bone marrow transplantation (BMT) in relation to the recovery of hematopoiesis. Lymphocyte subset analysis was performed with flow cytometry. We performed allogeneic BMT from HLA matched sibling donor in 9 patients. We analysed the positive percentage of each surface antigen and analysed data prior to conditioning therapy and weekly during the first 4 weeks after BMT. Results were as follows: Two or 3 weeks after BMT, percentages of CD8+ (CD8+ CD11b+) lymphocyte and CD16+ (CD16+ CD57-) lymphocyte (NK cell) were increased, and those of CD3+ lymphocyte and CD4+ (CD4+ Leu8+) lymphocyte decreased. And the ratio of CD4+ lymphocytes to CD8+ lymphocytes decreased below 1.0 at 2 or 3 weeks after BMT and remained low. In relation to the recovery of hematopoiesis, CD16+ lymphocyte (especially CD16+ CD57- lymphocyte) percentages at the third weeks correlated significantly to the recovery of granulocyte, reticulocyte, and platelet. It seems that CD16+ lymphocytes may play a role in bone marrow cell engraftment and the recovery of hematopoiesis.