ALBERT

Description: BACKGROUND: The prognosis of chronic myeloid leukemia (CML) in advanced stages (accelerated phase, AP or blast crisis, BC) is still extremely poor even with tyrosine kinase inhibitors (TKIs) and allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for them. METHOD: Using our database, we retrospectively collected CML patients transplanted at Toranomon Hospital between June 2004 and March 2014, after the introduction of TKIs in Japan. RESULT: Twenty-nine consecutive patients were extracted. The median age was 52 years (range; 16-70). The disease status at diagnosis was chronic phase (CP, n=11), accelerated phase (AP, n=5) and blast crisis (BC, n=13). All the patients were treated with TKIs before transplantation, including imatinib (n=15), nilotinib (n=1), dasatinib (n=6), imatinib/dasatinib (n=4), nilotinib/dasatinib (n=1) and imatinib/nilotinib/dasatinib (n=2). All the 11 patients in CP at diagnosis progressed into AP/BC in their course and only 3 patients achieved second CP (MinorCyR, n=1; PCyR, n=1; MMR, n=1) at transplantation. On the other hand, 11 of 18 patients in AP/BC at diagnosis achieved CP (MinorCyR, n=1; PCyR, n=4; CCyR, n=3; MMR, n=3) at transplantation and the remaining 7 patients did not achieve CHR (Fig. 1). The median HCT-CI and EBMT score at transplantation was 2 (range, 0-5) and 5 (range, 0-7), respectively. Additional cytogenetic abnormalities developed until transplantation in 8 of 11 patients (73%) in CP at diagnosis and in 11 of 18 (61%) in AP/BC at diagnosis. Point mutations in ABL gene were detected in 9 of 20 patients (45%) in their course. Four of 7 patients (57%) in CP at diagnosis had ABL mutations, including T315I (n=1), E255K (n=2) and L359C (n=1). Five of 13 (38%) in AP/BC at diagnosis had ABL mutations, including T315I (n=4) and V299L (n=1). Overall, 14 of 29 (48%) patients underwent transplantation in CP stage (MinorCyR, n=2; PCyR, n=5; CCyR, n=3; MMR, n=4). The donors were related PBSC (n=6), unrelated BM (n=4) or unrelated CB (n=19). The conditioning regimens were myeloablative in 20 patients and reduced-intensity in 9. Twenty-seven patients achieved neutrophil engraftment at a median day of 19 (range, 10-34). The cumulative incidence of neutrophil engraftment was 93.1% at day 42 (patients engrafted, n=27; dead before day 19, n=2). At 3 years, the cumulative incidence of relapse and non-relapse mortality was 32.3% and 14.0%, respectively. In 15 patients who did not achieve CP before transplantation, 11 patients (73.3%) achieved CR after transplantation. With a median follow-up of survivors of 1144 days (range, 127-3705), overall survival (OS) and event free survival (EFS) at 3 years was 63.2% and 56.3%, respectively. In univariate analysis, age (

Description: Abstract 2284 Poster Board II-261 Background: To evaluate the role of autologous and allogeneic SCT in the treatment of PTCLs, Japan Study Group for Cell Therapy and Transplantation conducted a multicenter retrospective survey in Japan and Korea. Methods: After excluding patients with adult T-cell leukemia/lymphoma and NK-cell tumors, patient data were newly collected from 330 patients (222 male and 108 female) with a median age of 49 years (range, 13–71) who underwent SCT between 9/1991 and 12/2008 (196 autologous and 134 allogeneic including 31 patients with previous autograft). Allogeneic SCT (53 BM, 54 PB, 1 BM+PB, 26 CB) was performed using a reduced-intensity conditioning (RIC) in 84 patients (63%). While a pathologic central review will be performed, currently there were 159 (48%) patients with PTCL, not otherwise specified, 63 (19%) with angioimmunoblastic T-cell lymphoma, 47(14%) with anaplastic large cell lymphoma (23 ALK-negative, 14 ALK-positive and 10 unknown), 12 (4%) with enteropathy-associated T-cell lymphoma, and others. The disease status at transplant in the allo-group was significantly worse than that in the auto-group (Table 1). The median number of chemotherapy regimens was 2 (range, 1–7), and the median duration between diagnosis and transplant was 267 days (range, 120-4889 days). Results: The median follow-up for surviving patients was 45 mo (range, 2.3–141 mo). There was no significant difference in overall survival among different groups, including histological subtypes, RIC and myeloablative conditioning in the allo-group and high-dose chemotherapy regimens in the auto-group. Early survival rate after transplant was significantly better for auto-group than allo-group (Wilcoxon P=0.001), but the difference was marginal in the total course (Logrank P=0.06) (Figure). The non-relapse mortality (NRM) in the auto-group was significantly lower than that in the allo-group (P1), cell source (CB/BM+PB), and performance status (PS; 〉1), stage, chemorefractory disease, international prognostic index (IPI; H-I/H risk) and prognostic index for PTCL, unspecified (PIT; group 3/4) at transplant. The risk factors in the allo-group were bulky mass at diagnosis, age (〉50 years), cell source, and PS, stage, IPI and PIT at transplant, while those in the auto-group were age (〉40 years), recurrence after frontline therapy, number of chemotherapy regimens, and stage, chemorefractory disease, IPI and PIT at transplant. Conclusions: Despite a worse disease status at transplant in the allo-group, the overall survival was comparable to that in the auto-group. This supports the notion that early allogeneic SCT is a valuable treatment option for PTCLs, although a large-scale randomized trial to identify a suitable upfront-transplant type for chemosensitive patients with PTCLs is warranted. Disclosures: No relevant conflicts of interest to declare.

Description: Adult T-cell leukemia (ATL) is characterized by massive infiltration of circulating ATL cells into a variety of tissues, a finding often associated with poor prognosis. Leukocyte migration from circulation into tissue depends on integrin-mediated adhesion to endothelium, and integrins are tightly regulated by several stimuli, such as inflammatory chemokines. However, the exact mechanisms that enhance adherence of leukemic cells to the endothelium and infiltration into tissues remain to be fully understood. We investigated the mechanisms of extravasation of leukemic cells using ATL cells and report the following novel features of endogenous chemokine-induced adhesion of ATL cells to the endothelium. ATL cells spontaneously adhered to endothelial cells without exogenous stimulation. Integrin leukocyte function-associated antigen-1 (LFA-1) on ATL cells was spontaneously activated. ATL cells produced high amounts of chemokines, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β. Adhesion of ATL cells to endothelial cells and the expression of activated form of LFA-1 were reduced by pretreatment with pertussis toxin, wortmannin, or anti–MIP-1α and MIP-1β antibodies or transfection with antisense of MIP-1α or MIP-1β. Spontaneous polymerization of cytoskeletal F-actin was observed in ATL cells, which was also inhibited by pertussis toxin and wortmannin. We propose that ATL cells adhere to endothelial cells through an adhesion cascade similar to normal leukocytes and that the chemokines produced by ATL cells are involved in triggering integrin LFA-1 through cytoskeletal rearrangement induced by G-protein–dependent activation of phosphoinositide 3-kinases in an autocrine manner. These events result in a strong adhesion of ATL cells to the endothelium and spontaneous transendothelial migration.

Description: Delayed immune reconstitution after allogeneic transplantation increases the risk of treatment-related mortality, and chronic GVHD. Previous reports showed that absolute lymphocyte count at day 30 (ALC30) was a significant prognostic factor of transplantation, and lower numbers of total CD4+ T cells and naïve CD4+ T cells in particular were associated significantly with higher mortality. However, there is little knowledge about the factors associated with low lymphocyte recovery, especially in cord blood transplantation (CBT). The cut-off value of lymphocyte recovery for statistical significance has not been determined yet. We retrospectively analyzed the outcome of 579 consecutive patients who underwent single cord blood transplantation (CBT) for the first time at Toranomon Hospital between January 2011 and 2018. Patients with active infection at transplantation (n=40), in poor ECOG PS (3 or more) (n=36), or lacked information about CT before CBT (n=1) were excluded from this study. Five hundred and two patients (n=317 male; n=185 female) were included in this study. The median age at transplantation was 57 years (range, 16-77), with a median HCT-CI score of 2 (0-10). Underlying diseases were AML (307), MDS (43), MPN (20), ALL (50), mature lymphoid malignancies (54), and others (28). Median spleen index (SI) before transplantation was 60.2 (16.5-319.7). Three hundred and ninety eight patients (79%) were not in remission at transplant. MAC regimens were selected in 400 (80%). TAC alone was used in 132 (26%) as GVHD prophylaxis. Median number of TNC and CD34+ cells infused were 2.62 (1.57-6.85) x 107/kg and 0.86 (0.29-3.77) x 105/kg, respectively. 194 (39%) were positive for anti-HLA antibodies, but none had donor-specific. With a median follow-up of 32 (range, 3-99) months, cumulative incidence of neutrophil engraftment (NE), the 3-year probabilities of overall survival (OS), relapse rate (RR) and non-relapse mortality (NRM) for entire population were 92.8%, 40.6%, 23.5%, and 35.3%, respectively. Underlying disease (myeloid malignancy), disease status at SCT (non-CR), poor PS (PS=2), GVHD prophylaxis (TAC+MMF), low CD34-positive cell dose (

Description: Blood stream infection (BSI) is a major problem after cord blood transplantation (CBT). However we have little information on it after reduced-intensity cord blood transplantation (RICBT). This study aims to investigate clinical characteristics of BSI within 100 days of RICBT, and to identify its risk factors in the patient who received RICBT between January 2002 and March 2004 in Toranomon hospital. We reviewed medical records of 77 patients with advanced hematologic diseases who underwent RICBT at Toranomon Hospital between January 2002 and June 2004. Median age of the patients was 55 years (17-79). Median number of infused cells and CD34+ cells were 0.86 x 10E7 (range; 1.73–4.31) and 0.8x10E7/kg (range; 0.01–46.1), respectively. Conditioning regimen consisted of fludarabine (125–150 mg/m2), melphalan (80–140 mg/m2), and TBI 2–8 Gy. GVHD prophylaxis was cyclosporine or tacrolimus. BSI must have met at least one of the following criteria previously described. (O’Grady, NP et al., Infect Control Hosp Epidemiol 2002) Mortality was considered to be directly attributable to a bloodstream pathogen if the patient died within 7 day after the last positive blood culture without any other probable cause of death, The patient’s characteristics were compared between those with or without BSI by univariate analysis. 149 episodes of BSI were observed in 31 patients. Cumulative incidence within 100 days was 0.40. Median onset was day 13 (1–98) after RICBT. The causative organisms were P. aeruginosa (47), S. epidermidis (44), E. faecium (13), T. beigelii (6), S. maltophilia (6), E. faecalis (5), E. coli (3), A. xylosoxidans (3) and others (22). 8 patients died of septicemia directly associated with BSI. A mortality rate was 26%. The causative organism included P. aeruginosa, A. xylosoxidans, S. maltophilia, S, aureus and gram-positive rod. Use of corticosteroid (p=0.012) and time to engraftment (p=0.003) were associated with the development of BSI. BSI is a major complication in our series of RICBT. Use of corticosteroid and prolonged neutropenia might have increased the risk of incidence of BSI.

Description: Background: Graft failure, graft rejection, or disease relapse post allogeneic hematopoietic stem cell transplantation(HSCT) is life-threatening and serious complication that necessitate consideration for a second transplantation. Graft failure has been more frequently reported in patients with aplastic anemia with T-cell depletion of the graft, in cord blood transplants, or when unrelated or HLA-mismatched related donors were used. In second allogeneic stem cell transplant setting, current questions include suitable stem cell source, additional conditioning, immunosuppression, and the use of a different donor, still remain unknown. We performed a feasibility study of reduced intensity umbilical cord blood transplantation (RI-UCBT) in adult patients with graft failure or disease relapse after first allogeneic transplantation. Patients and Methods: Nine patients (median age, 53 years; range 17–68) with advanced hematological diseases [AML (n=4), ALL (n=2), MDS (n=2), ATL (n=1)] who showed relapse or graft failure after first allogeneic transplantation underwent RI-UCBT with single cord blood unit at Toranomon Hospital between May 2003 and February 2004. Eight cases were in non-CR at transplant. A median time from first to second transplant was 226 days (range 31–475). The median number of mononuclear cells transfused was 2.3 x 107 /kg (range 1.8–3.5). HLA disparities were as follows; 5/6 in two cases, 4/6 in seven cases. Conditioning regimen mainly consisted of fludarabine 25 mg/m2 on days -7 to −3, melphalan 40mg/m2 (n=8) or busulfan 4mg/kg(n=1) day −3 to −2, and 4 Gy total body irradiation on day −1. Graft-versus-host disease (GVHD) prophylaxis was composed of ciclosporin alone (n=6) and tacrolimus alone (n=3). Results: All of them achieved primary neutrophil engraftment (〉500/μL) after a median of 22 days (range, 15–32) and achievement of donor T-cell chimerism was confirmed. Four cases developed grade II-IV GVHD, and one case developed limited chronic GVHD. Of all the nine cases received RI-UCBT, seven died from relapse (n=4), sepsis (n=2), and TMA (n=1). Two survived without relapse for +232 and +81 days, respectively. Discussion: Although the number of patients is small and the follow-up period is short, our results corroborate that RI-UCBT for graft failure or relapse post first transplant is tolerated and may be worth considering for further evaluation. Neutrophil engraftment was achieved, however, disease relapse rate and treatment-related mortality is high. The management of disease status and development of ideal conditioning regimen will be the focus of future investigation.

Description: Backgrounds: Cytomegalovirus (CMV) infection is a major complication after allogeneic transplantation; however clinical significance of CMV reactivation after cord blood transplantation remains unclear. Objective: We retrospectively investigated the incidence of CMV antigenemia, and CMV diseases, and its prognosis in adult patients who underwent reduced-intensity cord blood transplantation (RI-CBT) Patients/ Methods: We reviewed medical records of 77 patients who received RICBT at Toranomon Hospital between January 2002 and March 2004. Median age of the patients was 55 years (range 17–79). Underlying diseases were chemorefractory hematologic diseases (n=76) and severe aplastic anemia (n=4). Conditioning regimen comprised fludarabine (125 mg/m2), melphalan (80 mg/m2), and TBI 4-8Gy. GVHD prophylaxis was cyclosporine (n=69) or tacrolimus (n=11). Median total nucleated cells and CD34+ cells was 2.4×106 cells/kg (0.39–4.3), and 0.81×105 cells/kg (0.05–5.7) respectively. HLA disparity was 6/6 (n=3), 5/6 (n=12), 4/6 (n=63), and 3/6 (n=2). All patients were monitored CMV-antigenemia weekly and received pre-emptive gancyclovir or foscarnet. Results CMV antigenemia tested positive in 47 patients on a median of day 32 (range, 12–55) after RICBT. The cumulative incidence of CMV reactivation at day 100 was 0.70. Seven and 29 patients were treated with preemptive ganciclovir and foscarnet, respectively. Adverse events of them were myelosuppression in 3 patients given ganciclovir, and mild hyponatremia in a patient given foscarnet. CMV diseases developed in 15 patients on a median of day 39 (range 15–92); enterocolitis (n=13), pneumonia (n=1), and encephalitis (n=1). Seven of 15 patients were resolved with antiviral treatment, and the other patients were fatal with CMV infection. Univariate analysis showed any risk factors for CMV reactivation. Discussion CMV reactivation and diseases develop early after cord blood transplantation. Opitimal strategy for preventing CMV disease should be established in RICBT.

Description: Objective: Cord blood is widely used as a third possible stem cell source for allogeneic transplantation following bone marrow and peripheral blood. CBT has unique characteristics such as allowing 2 loci mismatch and emergency use or ready to use transplantation. Reduced-intensity transplantation also has been widely accepted to offer opportunities for allogeneic transplant for older and poor overall status patients. We previously showed the feasibility of reduced-intensity cord blood transplantation (RI-CBT) in 30 patients with advanced hematological diseases. Then performed more than 300 time RI-CBT to those whom needed urgent transplantation without suitable HLA matched donors. Methods: We retrospectively analyzed medical records of 318 times and 287 cases of RI-CBT from 1/1/2004 to 5/7/2008 in Toranomon Hospital. Disease distribution of 287 studied patients was as follows; acute myeloblastic leukemia/myelodysplastic syndrome was 136 cases, malignant lymphoma 58, acute lymphoblastic leukemia 42, adult T cell leukemia/lymphoma 25, severe aplastic anemia 8 and others 18. A mean age was 56 ranging from 19 to 79 years old. The number of high risk and standard status patients were 243 and 44, respectively. High risk disease status is defined as residual uncontrolable tumor cells despite of chemotherapy such as primary refractory and beyond CR1 and standard risk is as in remission in a meaning of tumor control. MDS and SAA patients who need frequent transfusions and intensive care for infection are defined as standard risk. Preparative regimen mainly 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. Some patients were contiditioned with iv-busulfan without TBI. Graft-versus- host disease prophylaxis was composed of cyclosporine or tacrolimus alone. Results: We analyzed the association of various factors on engraftment in possible 158 patients. Eighty eight % (95% CI, 83%–93%) of patients were engrafted on a median days of 20 (range, 11–55 days) after transplant. Multivariate analysis revealed 5 to 6 antigen match in GVH direction was a significant independent factor for engraftment as well as CD34 dose, while HLA in HVG direction did not significantly influence on engraftment. Three-year estimated overall survival (OS) in total 287 cases was 39.6% (95% CI: 33.5–45.8%). Standard risk patients (n=44) showed 3-year OS of 53.8% (95% CI: 38.3–69.2%) and high risk (n=243) was 26.3% (95% CI:20.2–32.5%). Tacrolimus GVHD prophylaxis group (n=159) had superior 3y-OS of 33.8%(95% CI: 25.9–41.8) to cyclosporine alone with 3yOS of 22.4 % (95% CI: 14.2–30.7). We previously reported pre-engraftment immune reaction characterized by high-grade fever and weight gain and developed on a median of day 9. More intensive immune suppression after RI-CBT using tacrolimus decreased the incidence and severity of PIR and increased OS. Conclusion: RI-CBT is a feasible approach even for relatively aged patient population (Mean age=56) with advanced hematological malignancies.

Description: Introduction Cord blood is an alternative stem cell source, and RICBT is investigated as a clinical trial. High incidence of infection is an obstacle to the spread of RICBT; however, the detail of infectious complication is not described. We retrospectively investigated the incidence and risk factor of IFI after RICBT. Patient and method A total of 102 patients received RICBT at Toranomon Hospital from March 2002 to May 2004. The median age of the patients was 57 years (range, 20–79). Underlying diseases included acute myeloid leukemia or myelodysplastic syndrome (n = 43), malignant lymphoma (n = 38), acute lymphoblastic leukemia (n = 12), multiple myeloma (n = 4), severe aplastic anemia (n = 3), chronic myeloid leukemia (n = 1) and idiopathic myelofibrosis (n = 1), and 90 (88%) patients had advanced or chemorefractory diseases. Preparative regimen comprised fludarabine 125mg/m2, melphalan 80 mg/m2 and 400 cGy total body irradiation. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine (n = 80) or tacrolimus (n = 22). The median number of infused nucleated cell was 2.8 (range, 2.0 – 4.6) x 10E7 cells / kg, and HLA disparity was 0 (n = 1), 1 (n = 15) and 2 (n = 86). Patients were managed in laminar airflow-equipped rooms. All patients received fluconazole 200 mg/day for the prophylaxis of fungal infection. Proven or probable invasive fungal infections were defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC / MSG) criteria. Patients with possible IFI were not included in this analysis. The day of diagnosis of the fungal infection was the day on which the first positive diagnostic test was performed. For patients whose diagnosis was established after death, the date of death was considered to be the day of diagnosis. Result The median follow-up after RICBT was 8.5 months (range, 0.9–28). Eighty patients achieved primary engraftment, and the median time to engraftment was 20 days (range, 9–55). Nine (9%) patients developed IFI (Aspergillosis 8, Trichosporosis 1). Two patients had a history of IFI prior to transplant. The median time of diagnosis was 15 (range, 2–179) days after transplant. Six of the nine IFI developed during neutropenia. Four patients responded to treatment with amphotericin B and micafungin, and five patients died of IFI. No risk factor was identified in univariate and multivariate analysis. Discussion Different from recent reports on IFI after nonmyeloablative transplantation from adult donor, IFI develops early after RICBT. Because most of patients received multiple courses of myelosuppressive chemotherapy, patients possibly had latent IFI. In fact, two patients with history of IFI recurred after RICBT. Moreover, most of patients developed IFI in laminar-airflow equipped room. These facts suggest that early onset IFI might be an activation of latent fungal infection. On the other hand, increased incidence of bacterial and viral infection suggests the possibility that profound immunosuppression after RICBT causes early onset IFI. Conclusion IFI develops during neutropenia in RICBT. Prospective study to evaluate the risk factor of IFI and the effective fungal prophylaxis for RICBT is warranted.