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An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4 years. The median age was 43 years (range, 16 to 59 years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42 days was 94.4% (95% confidence interval [CI]: 88.6–97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10 years were 26.0% (95% CI: 19.5–33.0%) and 16.9% (95% CI: 11.4–23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3–69.7%) at 10 years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT. more...

We herein describe a case of Sweet's syndrome (SS) in a patient being treated for pulmonary toxoplasmosis complicated with myelodysplastic syndrome (MDS). The patient's SS developed after the pulmonary toxoplasmosis improved following treatment. We searched his cytokine profiles comprehensively using a bead-based immunoassay. The results showed no elevation of interleukin (IL)-2, interferon (IFN)-γ or IL-17A, and IL-6 was only observed to have increased at the onset of SS, suggesting that the pulmonary toxoplasmosis had been well controlled and that chronic inflammation may have been the cause of SS. Pulmonary toxoplasmosis is an extremely rare occurrence. The cytokine profile can help to clarify the pathological condition of SS and MDS complicated with severely invasive infectious diseases. more...

This prospective randomized study compared the efficacy and toxicity of granisetron and dexamethasone to those of granisetron alone for antiemetic control in patients receiving high-dose chemotherapy with or without total body irradiation (TBI) for stem cell transplantation. Patients were divided randomly into 2 groups. Groups received granisetron twice daily at a dose of 40 microg/kg with or without 4 mg dexamethasone (GS group and G group, respectively), starting 30 minutes before each dose of chemotherapeutic agent or TBI, or 12 hours after the first dose if TBI or a drug was given once a day. Fifty patients were evaluated for the analysis. During the first 24 hours of conditioning, 23 of 25 patients (92.0%) in the GS group achieved complete control of emesis (no emetic episodes over the course of a day), compared with 72.0% in the G group (P = .06). For patients receiving TBI on the first day of conditioning, complete emetic control was achieved in all patients (100.0%) in the GS group, compared with 63.2% in the G group (P = .02). The same degree of emetic control was maintained throughout the conditioning period in 38.8% of the GS group and 29.9% of the G group (P = .10). Adverse reactions were observed more frequently in the GS group (68.0% versus 5.0% in the G group). These reactions included insomnia, headache, flushing, and hyperglycemia. None of the events were serious. We conclude that granisetron with dexamethasone seems superior to granisetron alone for the prevention of emesis resulting from the conditioning regimen; however, the more frequent side effects may limit the wide use of this combination. more...

Thirty patients with hematologic diseases received allogeneic hematopoietic stem cell transplants (HSCT) from related donors other than genotypically HLA-matched siblings. Their outcomes were compared with those of 102 patients who had received HSCT from genotypically HLA-matched siblings. All donors in the study group were HLA-haploidentical relatives. The degree of HLA mismatches in unshared haplotype was 0-locus (n = 6), 1-locus (n = 20), and 2-locus (n = 4). All patients in the study group achieved successful engraftment at a median of 17 days (range, 10-35 days). Grade II-IV and III-IV acute graft-versus-host disease (GVHD) occurred in 16 (53%) and 9 (30%) patients, respectively, in the study group, rates that were significantly higher than those of the control group, which were 33 (33%) and 12 (12%) patients, respectively (P = .034 and .022, respectively). The frequency of chronic GVHD was 85% (22 out of 26 evaluable patients) in the study group, a rate that was also significantly higher than that of the control group with 57% (52 of 91 patients) (P = .0078). The estimated probability of disease-free survival (DFS) for the study group was 56% at 5 years. When the 2 groups were compared according to the risk of disease, the probabilities of DFS at 5 years for patients with low risk in the study and for control groups were 100% and 84%, respectively, and those for patients with high risk were 43% and 42%, respectively.These results showed that the DFS for patients with both low and high risks in the study group was comparable to that of the control group. In conclusion, despite higher probabilities of acute and chronic GVHD, unmanipulated allogeneic HSCT from related donors other than genotypically HLA-matched siblings was considered to be a reasonable alternative for patients without genotypically HLA-matched sibling donors. Int J Hematol. 2002;76:354-359. ©2002 The Japanese Society of Hematology more...

To investigate the behavior of hematopoietic stem cells (HSCs) in cord blood (CB), we analyzed the expression and function of TIE2, a tyrosine kinase receptor. A subpopulation of Lineage (Lin)−/lowCD34+ cells in CB expressed TIE2 (18.8%). Assays for long-term culture-initiating cells (LTC-IC) and cobble-stone formation revealed that Lin−/lowCD34+TIE2+ cells showed to have a capacity of primitive hematopoietic precursor cells in vitro. When Lin−/lowCD34+TIE2+ cells were cultured on the stromal cells, they transmigrated under the stromal layers and kept an immature character for a few weeks. By contrast, Lin−/lowCD34+TIE2− cells differentiated immediately within a few weeks. Finally, we confirmed that 1×10 4 Lin −/ low CD34 + TIE2 + cells were engrafted in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, while 1×10 4 Lin −/ low CD34 + TIE2 − cells were not. Taken together, we conclude that TIE2 is a marker of HSCs in CB. A ligand for TIE2, Ang-1 promoted the adhesion of sorted primary Lin−/lowCD34+TIE2+ cells to fibronectin (FN), and this adhesion may play a critical role in keeping HSCs in an immature status under the stromal cells. more...

Although allogeneic transplantation is a curative therapy for chronic myelogenous leukemia (CML), treatment-related mortality is still a major cause of death after transplantation, especially in older patients. We investigated the safety and efficacy of reduced-intensity conditioning consisting of low-dose (600 cGy) total body irradiation and cytosine arabinoside (1 g/m2) together with a continuous infusion of granulocyte colony-stimulating factor and cyclophosphamide (120 mg/kg) in patients with CML in the chronic phase. Fractionated splenic irradiation (5 Gy) was also administered as part of the conditioning treatment. Eight patients older than 40 years underwent allogeneic bone marrow transplantation from an HLA-matched sibling following this conditioning. Regimen-related toxicities (equal to or greater than grade III) were not observed. Rapid restoration of 100% donor chimerism was confirmed by fluorescence in situ hybridization methods in 5 sex-mismatched transplant recipients. One patient died from severe acute graft-versus-host disease and another from Pneumocystis carinii pneumonia early in the course of transplantation. A sustained engraftment was achieved in 5 long-term survivors; in 1 case, the graft was rejected but the Philadelphia chromosome and BCR/ABL-negative autologous hemopoiesis were restored. After a minimum follow-up period of 60 months, 6 patients, including the patient with restored autologous hemopoiesis, were still alive and in remission with 100% donor chimerism. Six years after the transplantation, 1 patient experienced a cytogenetic relapse, which was successfully treated with donor lymphocyte infusions. In summary, this reduced-intensity conditioning resulted in a cure with markedly reduced regimen-related toxicities in this relatively older cohort of patients with CML. more...

Sixteen patients who underwent a second allogeneic hematopoietic stem cell transplantation (HSCT2) for leukemia relapse after the first allogeneic transplantation (HSCT1) were studied. The patients included 7 patients with acute myelogenous leukemia, 8 with acute lymphoblastic leukemia, and 1 with chronic myelogenous leukemia. The median patient age at HSCT2 was 22 years (range, 12 to 44 years). The median interval between HSCT1 and HSCT2 was 19 months (range, 2 to 46 months). At HSCT2, 7 patients were in complete remission (CR), 7 had relapsed, and 2 had bone marrow aplasia. In 14 patients, donors for HSCT2 were the same as those for HSCT1. Two donors were replaced, 1 for another HLA-matched sibling and 1 for an unrelated cord blood donor. Four patients (25%) died within 100 days after HSCT2 from veno-occlusive disease, sepsis, interstitial pneumonitis, or chronic graft-versus-host disease (GVHD), without leukemia relapse. Seven patients (44%) developed leukemia relapse and died between 4 and 20 months after HSCT2. Five patients (31%) survived beyond 4 years. One patient died from chronic GVHD without leukemia relapse 55 months after HSCT2. The 4 other patients were alive between 79 and 134 months after HSCT2 (median follow-up, 106 months). Factors that favorably influenced survival were age younger than 20 years and CR duration after HSCT1 longer than 12 months. HSCT2 is considered to be beneficial for select patients. Preparative regimens, GVHD prophylaxis, and donor choice for HSCT2 need to be studied to obtain a more successful outcome for HSCT2. more...

Leukemia relapse is a major cause of treatment failure after allogeneic bone marrow transplantation. We administered recombinant interleukin-2 (rIL-2) to a patient who relapsed after unrelated allogeneic bone marrow transplantation (uBMT). While the number of peripheral blood monoblastic leukemia cells increased after administration of rIL-2, the patient achieved durable remission for 5 months after low-dose chemotherapy followed by adoptive transfer of engrafted graft-derived lymphokine-activated killer (LAK) cells. Following the disappearance of the blast cells, however, both cutaneous and liver GVHD were exacerbated. Administration of rIL-2 and adoptive transfer of graft-derived LAK cells are considered to be possible choices for the treatment of acute leukemia relapsing after uBMT when donor leukocyte transfusion is not available. more...

Thyroid dysfunction is a common complication after allogeneic hematopoietic stem cell transplantation (SCT). However, thyrotoxicosis as defined by elevated serum-free thyroxine (FT4) or free triiodothyronine (FT3) levels together with low thyroid-stimulating hormone (TSH) levels is rare after SCT. Here we describe 2 patients who developed thyrotoxicosis within the first 50 days after unrelated cord blood transplantation (CBT). Patient 1 is a 32-year-old woman with acute myelogenous leukemia (AML)-M5a who underwent CBT. On day +41, she developed tachycardia. On day +48, FT4 increased to 2.2 ng/dL and TSH was suppressed to less than 0.1 microU/mL. Antithyroid peroxidase antibody was positive. On day +83, FT4 spontaneously decreased to 1.4 ng/dL. Patient 2 is a 42-year-old man with AML-M4 who underwent CBT. On day +42, he developed tachycardia. On day +48, FT3 increased to 4.75 pg/mL and TSH was suppressed to 0.02 microU/mL. Antithyroid peroxidase antibody was positive. Eight months after CBT, his thyroid function spontaneously returned to normal. The presence of antithyroid peroxidase antibody suggested that immune-mediated reactions might be associated with the development of thyrotoxicosis after CBT in our patients. The present study shows that thyrotoxicosis can occur during very early periods after CBT. more...

Objective The cause of delayed hematopoietic reconstitution after umbilical cord blood transplantation (UCBT) remains controversial. We hypothesized that hematopoietic stem/progenitor cells (HS/PCs) from UCB have some defects of the homing-related molecules responsible for their slow engraftment. Materials and methods A homing-related molecule repertoire expressed on HS/PCs from fresh and cryopreserved UCB, mobilized peripheral blood (mPB), and bone marrow (BM) were compared using sensitive, four-color fluorescence-activated cell sorting analysis. Purified CD34 + cells were subjected to ex vivo transmigration through double-coated transwell filter inserts, and an in vivo homing assay was performed in xenotransplanted NOD/SCID mice. Results UCB-derived CD34 bright cells expressed significantly lower levels of CD49e, CD49f, and CXCR-4 than their mPB and BM counterparts. CD34 + cells from UCB (and BM) exhibited significantly lower ex vivo transmigration than those from mPB, which were largely blocked by neutralizing antibodies to CD49e or CD49f. Recombinant human tumor necrosis factor-α treatment enhanced ex vivo transmigration of CD34 + cells from UCB and BM by inducing expression of the matrix metalloproteinases MMP-2/MMP-9. Short-term treatment of UCB-derived CD34 + cells with rHu-stem cell factor (rHuSCF) up-regulated levels of the homing-related molecules with their increased ex vivo transmigratory and in vivo homing potential. Conclusion Our results indicate that disadvantageous transmigratory behavior of HS/PCs from UCB, which might partly explain the delayed reconstitution after UCBT, can be reversed by ex vivo manipulation with rHuSCF. more...

Pulmonary alveolar proteinosis (PAP) is a heterogeneous disease that occasionally develops with hematological malignancy. However, PAP in association with hematopoietic stem cell transplantation is quite rare. Here we present the first report of a patient who developed PAP after cord blood transplantation (CBT). A 45-year-old female with AML underwent unrelated CBT. On day +2 after CBT she developed congestive heart failure with diffuse alveolar infiltrates in the bilateral lungs. Despite treatment, the alveolar infiltrates further increased with progression of multiple organ failure (MOF). She died from MOF before hematopoietic recovery on day +27. Post-mortem study revealed that massive amorphous materials positive for periodic acid-Schiff stain filled in the pulmonary alveoli. These findings led to a diagnosis of PAP. The bone marrow was hypocellular without the leukemic cells. The impaired immunity during the period of leukopenia as well as the impaired clearance of surfactant proteins might contribute to the development of PAP. more...

We performed a clinical comparison of unrelated cord blood transplantation (UCBT) and unrelated bone marrow transplantation in adult acute leukaemia patients in complete remission (CR) who received the same conditioning regimen, graft-versus-host disease (GvHD) prophylaxis and supportive treatment. The incidence of acute GvHD was almost the same between the two groups, but the haematopoietic recovery was delayed and the incidence of chronic GvHD was higher in the UCBT group. The probability of 2 year disease-free survival was similar between the two groups. These results suggest that adult acute leukaemia patients in CR without a suitable donor should be considered as candidates for UCBT. more...

Seven adult patients with myelodysplastic syndrome (MDS)-related secondary acute myeloid leukaemia (AML) were treated with total body irradiation (TBI), cytosine arabinoside (Ara-C) and cyclophosphamide (CY), followed by unrelated human leucocyte antigen (HLA)-mismatched cord blood transplantation (CBT). Granulocyte colony-stimulating factor (G-CSF) was infused continuously from 12 h before until the end of Ara-C therapy to enhance the antileukaemia effect of Ara-C. Five patients are alive and free of disease at 7-31 months after transplantation. These preliminary results suggest that adult MDS-related secondary AML patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT. more...

We have prospectively evaluated the efficacy of real-time PCR-guided preemptive therapy for CMV diseases in allogeneic hematopoietic stem cell transplant recipients with grades II-IV acute GVHD. The dose of ganciclovir was adjusted according to the viral load determined by real-time polymerase chain reaction (PCR). On detecting CMV reactivation in the plasma, ganciclovir was initiated at a dose of 5 mg/kg body weight once daily, and the dose was increased to twice daily if viral load continued to increase after initiating ganciclovir. In 39 evaluable patients, CMV reactivation assessed by real-time PCR became positive in 30 (77%). One developed CMV gastroenteritis before PCR became positive. Thus the remaining 29 patients were treated preemptively with ganciclovir. The dose of ganciclovir was increased in 12 patients (41%) of preemptively treated patients for increasing viral load. CMV diseases were diagnosed in two patients (one gastroenteritis and one retinitis), and late CMV disease was diagnosed in one patient (gastritis). The treatment was generally well-tolerated, but three patients (10%) developed neutropenia (neutrophil count less than 1.0 x 10(9)/l). In conclusion, real-time PCR-guided preemptive therapy with decreased dose of ganciclovir is feasible and does not increase the frequency of CMV diseases if the dose is adjusted according to the viral load. more...

Summary Dendritic cells (DCs) are highly effective antigen (Ag)-presenting cells (APCs) that are required for the initiation of the immune response. DCs derived from cancer patients have been shown to be defective in several phenotypic and functional properties. However, little is known about the capacity of monocytes derived from cancer patients to differentiate into DCs. Herein, we examined the differentiation of monocyte-derived DCs in cancer patients. Flow cytometric analysis revealed that monocytes derived from cancer patients cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin-4 (IL-4) exhibited lower levels of CD11c, CD40, CD86, and HLA-DR expression as compared with those of monocyte-derived DCs from healthy volunteers. Furthermore, the capacities of DCs derived from cancer patients' monocytes to stimulate allogeneic T cell responses and to migrate in response to regulated-on-activation normal T cells expressed and secreted (RANTES) were impaired in comparison with those of monocyte-derived DCs from healthy volunteers. However, the two cell types had similar pinocytotic capacities for fluorescein isothiocyanate labeled-dextran (FITC-DX) and lucifer yellow (LY). These results suggest that monocytes from cancer patients may be defective in the capacity to develop into DCs. more...

We transplanted 4.1x10(7) unrelated umbilical cord blood cells into a 27-year-old patient suffering from transformed acute myelocytic leukemia. The thawing method was the same as described by Rubinstein et al (Proc. Natl. Acad. Sci. USA 1995; 92: 10119-10122). ANC reached over 500x10(9)/l on day 19, and the patient was free from RBC and platelet transfusion on days 26 and 38, respectively. Cytogenetic and molecular analysis after transplant revealed complete chimerism. The CD3+CD4+ lymphocyte count became greater than 100x10(9)/l at 5 weeks after transplantation. The CD3+CD8+ count became greater than 500x10(9)/l at 7 weeks and thereafter progressively increased in spite of administration of CYA. This immunological reconstitution pattern after umbilical cord blood transplantation was different from that after bone marrow transplantation, and resistance of CD3+CD8+ lymphocytes to CYA was the distinguishing characteristic. The rapid hematological recovery and immunological reconstitution may be attributed to the high dose of transfused nucleated cells and umbilical cord blood transplantation may become a promising method for treatment for such cases. more...

We previously suggested that using a combined conditioning regimen including rhG-CSF with allogeneic BMT in refractory AML and CML in blast crisis might reduce the rate of relapse and improve disease-free survival, without any major side effects. In this study, we used the same protocol for 10 AML patients in complete remission (CR) and 6 CML patients in the chronic phase (CP). We compared disease-free survival as well as toxic side effects of the regimen with 6 AML patients in CR and 6 CML patients in CP treated with chemoradiotherapy without G-CSF. The conditioning regimen consisted of TBI and high-dose AraC. RhG-CSF was infused continuously at a dose of 5 microg/kg/day, starting 24 hr before the initial dose of total body irradiation (TBI) until the end of AraC therapy. In all 28 cases, there were no early stage deaths due to regimen-related toxicity (RRT). None of the 10 AML cases treated with the G-CSF combined regime relapsed. In 6 AML cases treated conventionally without G-CSF, one patient died of infection and another relapsed. There were no relapses in either CML group. In the combined G-CSF group, one patient died of interstitial pneumonitis 48 days after BMT, while the rest of the CML cases are still alive. There were no relapses with rhG-CSF and no serious adverse effects in terms of RRT, acute graft vs. host disease (GVHD), or leukocyte recovery. more...

We report a patient who underwent allogeneic bone marrow transplantation for ALL. The patient presented low grade fever, cough and dyspnea at day 3 after after bone marrow transplantation. Imaging studies showed bilateral patchy infiltrates on chest X-ray and chest CT. Though treated by antibiotics, chest auscultation recognized marked bilateral inspiratory crackles. Transbronchial lung biopsy performed on day 34 showed bronchiolitis obliterans and an organizing interstitial pneumonia. The patient was treated with methylprednisolone and follow up computed tomography findings improved. more...

We report a case of a 38-year-old female patient who developed facial cellulitis after cord-blood stem cell transplantation (CBT). The cellulitis was refractory to treatment with antibiotics and antifungal agents. Because facial cellulitis is rare after transplantation, its mechanism could not be determined exactly. On day 40 after CBT, a nurse with expertise in cosmetic surgery attended our rounds and correctly assumed that the patient had received cosmetic rhinoplasty. Although conventional x-rays of the head were normal, a computed tomographic (CT) scan of the brain disclosed the presence of a foreign body over the nasal dorsum. As a result, the patient's symptoms were diagnosed as facial cellulitis associated with foreign material that had been implanted at the time of cosmetic surgery. At a pretransplantation interview, the patient did not mention her history of rhinoplasty. Even after she was shown the head CT scans that revealed the presence of nasal implants, she denied that she had received rhinoplasty before CBT. Unless we realize that patients may have received cosmetic surgery before transplantation, it is difficult to make a diagnosis of infection associated with foreign implants. To our knowledge this is the first report after transplantation of infection associated with cosmetic surgery. Such infections should be included on the list of complications after bone marrow transplantation. more...

A 41-year-old female patient with AML, who relapsed after an allogeneic BMT from her HLA-identical sister, was treated by a donor leukocyte transfusion (DLT). Thereafter, bone marrow aplasia accompanied by the disappearance of leukemic blasts following the GVHD was observed. The patient died of chronic GVHD with respiratory muscle involvement 19 months after the DLT. Although the DLT was considered helpful in suppressing the proliferation of the leukemic cells, it might also have caused the severe GVHD observed in this case. Efforts to separate the lymphocyte clones responsible for GVL from those for the GVHD thus appear to be necessary for the further development of the therapeutic approach, so-called DLT. more...