ALBERT

Description: BACKGROUND Limited information is available on incidences and clinical features of acute graft-versus host disease (GVHD) after cord blood transplantation and large-sized researches have been awaited. METHODS We investigated the incidences and clinical features of acute GVHD in 2,015 patients reported to the Japan Cord Blood Bank Network, who underwent cord blood transplantation between June 1997 and August 2006. RESULTS Of 2,015 patients, 1481 patients (73%) achieved neutrophil engraftment at a median of day 22 (range, 6–81). Cumulative incidence of neutrophil recovery at day 100 was 0.74 (95%CI, 0.73–0.76). Of 2015 patients, 708 patients developed grade II-IV acute GVHD: grade II (n=423), grade III (n=237), and grade IV (n=48). The median onset was day 19 (range, 4–190). The cumulative incidences of grade II-IV and III-IV acute GVHD at day 100 were 0.35 (95% CI, 0.33–0.37) and 0.14 (95% CI, 0.12–0.15), respectively. Skin and gastrointestinal acute GVHD was documented in 1,006 and 405 patients, respectively, whereas liver GVHD was diagnosed in 149 patients. Multivariate analysis identified the following predictors of grade II-IV acute GVHD: the number of infused nucleated cells, transplantation from female donors to female recipients, TBI-containing preparative regimens, methotrexate-containing GVHD prophylaxis, and tacrolimus-based GVHD prophylaxis. Overall survival rates at three years of patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer were 0.58 (95%CI, 0.53–0.63), 0.61 (95% CI, 0.54–0.67) and 0.40 (95%CI, 0.31–0.49), respectively. CONCLUSIONS Acute GVHD following cord blood transplantation is mild and has graft-versus malignancy effects. Probability of event free survival after cord blood tranplantation in the patients with grade 0-I, II and III-IV who survived 100 days or longer Event - free survival of the patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer was 0.54 (95% CI, 0.49–0.59), 0.58 (95%CI, 0.52–0.65) and 0.41 (95%CI, 0.32–0.49),respectively,3 years after transplantation. Probability of event free survival after cord blood tranplantation in the patients with grade 0-I, II and III-IV who survived 100 days or longer Event - free survival of the patients with grade 0-I, II and III-IV GVHD who survived 100 days or longer was 0.54 (95% CI, 0.49–0.59), 0.58 (95%CI, 0.52–0.65) and 0.41 (95%CI, 0.32–0.49),respectively,3 years after transplantation.

Description: Delayed engraftment or graft failure is one of the major complications after cord blood transplantation (CBT). To investigate factors impacting engraftment, we conducted a retrospective analysis of adult patients who underwent reduced-intensity CBT at our institute, in which preparative regimens mainly consisted of fludarabine, melphalan, and total body irradiation with graft-versus-host (GVH) disease prophylaxis using single calcineurin inhibitors. Among 152 evaluable patients, the cumulative incidence of neutrophil engraftment was 89%. High total nucleated cell and CD34+ cell dose were associated with the faster speed and higher probability of engraftment. In addition, the degree of human leukocyte antigen (HLA) mismatch in the GVH direction was inversely associated with engraftment kinetics, whereas no statistically significant association was observed with the degree of HLA mismatch in the host-versus-graft direction. Similarly, the number of HLA class I antigens mismatched in the GVH direction, but not in the host-versus-graft direction, showed a negative correlation with engraftment kinetics. HLA disparity did not have significant impact on the development of GVH disease or survival. This result indicates the significant role of HLA disparity in the GVH direction in the successful engraftment, raising the novel mechanism responsible for graft failure in CBT.

Description: Despite the fact that the majority of cord blood grafts were human leukocyte antigen (HLA) disparate at one to two antigens, acute graft-versus-host disease (GVHD) was less severe after cord blood transplantation (CBT) compared to unrelated bone marrow transplantation. On the other hand, engraftment failure is a serious problem after CBT. We retrospectively analyzed the influence of HLA compatibility on engraftment after reduced-intensity umbilical cord blood transplantation (RI-CBT). We analyzed the clinical outcome of patients who underwent first RI-CBT at Toranomon hospital between January 2002 and December 2005. Those who had died within 28 days from the day of transplant were excluded from these analyses. All 156 patients had hematological malignancies including 41 with AML, 21 with ALL, 6 with CML, 19 with MDS, 31 with malignant lymphoma, 14 with adult T-cell leukemia/lymphoma, 6 with other diseases. Median age was 54 years (range, 17–79 years). All of them were considered to be inappropriate for conventional stem cell transplantation due to the lack of an HLA-identical related donor, age 〉50 years old and/or organ dysfunction. The preparative regimens were mainly composed of fludarabine 125 mg/m2, melphalan 80 mg/m2, and 4 Gy total body irradiation. GVHD prophylaxis was composed of cyclosporine or tacrolimus alone. Eight, 46, 98 and 4 patients received 6 of 6, 5 of 6, 4 of 6 and 3 of 6 HLA antigen matched cord blood in graft-versus-host (GVH) direction. Primary engraftment failure was diagnosed in 18 patients (11.5%). Median time to engraftment was 19 days (range, 11–55 days) for the total patient group. In GVH direction, the cumulative incidence of engraftment at day 100 were 94.4% in 5 to 6 of 6 antigen matched cord blood and 85.3% in 3 to 4 of 6 antigen matched cord blood (p=0.001). Median time to engraftment was 17 days (range, 11–36 days) in 5 to 6 antigen matched cord blood and 20 days (range, 11–55 days) in 3 to 4 antigen matched cord blood. In host-versus-graft direction, the cumulative incidence of engraftment at day 100 were 90.9% in 5 to 6 antigen matched cord blood and 87.5% in 3 to 4 antigen matched cord blood (p=0.5895). Median time to engraftment was 18.5 days (range, 11–55 days) in 5 to 6 antigen matched cord blood and 19 days (range, 11–49 days) in 3 to 4 antigen matched cord blood. In univariate analysis, both total cell dose (〉3 x 107/kg) and CD34 positive cell dose (〉1 x105/kg) were significantly associated with the engraftment (p=0.0009 and p=0.0005). Age, gender, risk, GVHD prophylaxis, blood type mismatch and early immune reaction were not associated with the engraftment kinetics. Multivariate analysis revealed 5 to 6 antigen mismatch in GVH direction was a significant independent factor for engraftment (p=0.0073), as well as CD34 positive cell dose. In conclusion, HLA disparities in GVH direction are associated with engraftment in adult patients receiving reduced-intensity umbilical cord blood transplantation using calcineurin inhibitor alone for GVHD prophylaxis.

Description: Backgrounds: Although cytomegalovirus (CMV) infection is one of the major complication after allogeneic haematopoietic stem-cell transplantation, there is little information on the incidence and clinical features of CMV infection after reduced-intensity cord blood transplantation (RI-CBT) for Adult Patients. Patients/methods: We reviewed medical records of 166 patients who received RI-CBT at Toranomon Hospital between January 2002 and December 2005. Fifty Patients were excluded due to early death before engraftment, primary graft failure, and those who CMV antigenemia was not properly monitored. The remaining 116 patients were included in the analysis. Median age of the patients was 52 years (range 17–79). Underlying diseases were AML (n=34), ALL (n=13), MDS(n=15), ATL (n=13), CML (n=5), NHL (n=20), and others (n=16). Ninety-four of those were chemo-refractory, and the other were chemo-sensitive. Conditioning regimens comprised of fludarabine 125 mg/m2, melphalan 80 mg/m2 and total body irradiation (TBI) of (2–4 Gy)(n=107) and others(n=9). Graft-versus-host disease (GVHD) prophylaxis was cyclosporine (n=59) or tacrolimus (n=57). Median number of total nucleated cells and CD34+ cells was 2.6×106 cells/kg (range, 1.8–4.8), and 0.72×105 cells/kg (range, 0.1–4.4) respectively. HLA disparity was 6/6 (n=2), 5/6 (n=17), 4/6 (n=95), and 3/6 (n=2). All the patients were monitored weekly for CMV-antigenemia and received pre-emptive ganciclovir or foscarnet therapy. Results: Positive antigenemia was observed in 81 patients (70%) at a median of 34 days (range, 0–87) after RI-CBT. Median of maximal numbers of CMV antigen positive cell was 15 per 50,000 leukocytes (range, 1–848). CMV diseases developed in 22 patients (19%) at a median of 45 days (range, 20–350); enterocolitis (n=20), pneumonia (n=2), and adrenalitis (n=1). CMV-antigenemia remained negative in five patients with enterocolitis, even when CMV disease was diagnosed. Twenty of the 22 patients were improved using ganciclovir or foscarnet with only one recurrence. The other two had fatal outcome from CMV disease. Despite improvement of CMV disease, thirteen of the remaining 20 patients died due to infection (n=6 bacterial sepsis: 4, bacterial pneumonia: 1, gas gangrene:1), GVHD (n=2), disease progression (n=3), and others (n=2). Multivariate analysis revealed that grade II–IV acute GVHD were associated with on increased risk and developing CMV disease (p

Description: Backgrounds: For more than 10 years, umbilical cord blood has become an alternative stem cell source for the patients with hematological malignancies requiring allogeneic stem cell transplantation. Cord blood transplantation (CBT) can be performed more quickly than other stem cell transplantation, since cord blood units are preserved in the deep freeze and 1–3 HLA mismatched donors are acceptable. Considering these advantage, we examined the feasibility of cord blood transplantation using reduced-intensity regimens (RI-CBT) for adult relapsed patients after allogeneic tranplantation. Patients/methods: We reviewed medical records of 26 patients who received RI-CBT at Toranomon Hospital between November 2003 and June 2006. Median age of the patients was 36 years (range, 20–66). Underlying diseases were acute leukemia (n=17), myelodysplastic syndrome (n=4) and lymphoma (n=5). The stem cell source of the first transplantation were bone marrow from sibling donor (n=2), bone marrow from unrelated (n=5) donor, peripheral blood stem cell from sibling donor (n=5) and unrelated cord blood (n=14). Conditioning regimens comprised fludarabine 125–180 mg/m2 in several combination with melphalan 80–140 mg/m2, Busulfan 8–16mg/kg and total body irradiation (TBI) (4–8 Gy). Graft-versus-host disease (GVHD) prophylaxis was cyclosporine (n=5) or tacrolimus (n=21). Median number of total nucleated cells and CD34+ cells was 2.56×106 cells/kg (1.91–5.94), and 0.86×105 cells/kg (0.57–1.77) respectively. HLA disparities were 5/6 (n=2), 4/6 (n=22), and 3/6 (n=2). Results: Median observation period was 58 days (range, 32–380). Overall survival for 1 year was 15% and 16 patients were died of disease progression (n=5) and infection (n=11). The infection in 4 patients was considered to be caused by regimen related toxicity (RRT). No grade IV toxicities (NCI-CTC Ver.3.0) were observed. The duration between two transplantations was longer in surviving patients compared to dead patients (98 days (range, 39–2108) and 262 days (range, 95–901), respectively), although significant difference was not detected. The stage of the disease in the second transplantation, conditioning regimens and HLA disparities did not influence to the outcome. Discussion: We demonstrated that RI-CBT could be an available and feasible treatment for the relapsed patients after stem cell transplantation. Moreover, the RRT is acceptable even in the patients with an advanced disease.

Description: Background: Therapeutic outcomes for hematological diseases have recently been markedly improved due to the introduction of hematopoietic stem cell transplantation (HSCT), improvement of therapeutic regimens, and advancement of support therapy. Although invasive fungal infections have been one of the major causes of morbidity and mortality after cord blood transplantation(CBT), proper prophylactic and therapeutic approach to them has not been clearly established yet. To address this, we performed retrospective analysis to assess the effectiveness and safety of various antifungal agents for prevention and treatment of invasive fungal infections. Patients and Methods: Medical records of a total of 188 patients who underwent umbilical CBT at Toranomon hospital between March 2002 and December 2005 were reviewed. The diagnosis included AML (n=53), ML (n=32), MDS (n=25), ALL (n=24), ATL (n=22), CML (n=7), AA (n=5), MM (n=3), and others (n=17). The median age was 54 (range; 17–79). The conditioning regimen consisted of fludarabine (125mg/m2), melphalan (80 mg/m2) and 4 Gy TBI for most of the patients. The incidence of breakthrough invasive fungal infection within 50 days after transplant was analysed. Results: Forty-eight of the 188 were administered prophylactic anti-fungal agents other than fluconazole (FLCZ) due to prior mold infection, intorelant to FLCZ, and so on, were excluded. Remaining 140 patients who received FLCZ categolized into 2 groups; those who had empirically switched FLCZ to micafungin (MCFG) and/or amphotericin B (AMPH) and/or itraconazole (ITCZ) capsule at the first sign of infection (group A, n=69), and those who had continued FLCZ (group B, n=71). Four breakthrough invasive fungal infections were observed, 3 of them were invasive pulmonary aspergillosis (IPA), and 1 of them was tricosporon sepsis. Interestingly, all of these 4 were in group B, whereas no breakthrough infections were observed in those who were in group A. All 3 diagnosed IPA died of its exacerbation despite MCFG and/or AMPH treatment. Conclusion: Proper administration of prophylactic anti-fungal agents can reduce the incidence of invasive fungal infection early after CBT. Although FLCZ has less activity to aspergillus, prophylactic FLCZ is effective enough to prevent breakthrough fungal infection. Immediate switch to other agents at the first sign of infection, such as MCFG, AMPH, ITCZ which are active against aspergillus could be recommended to prevent breakthrough infections.

Description: Bortezomib is a novel proteasome inhibitor with significant antimyeloma activity. Its frequent adverse effects are manageable, including gastrointestinal symptoms, peripheral neuropathy, and thrombocytopenia. Severe lung toxicity has not previously been reported. Between June 2004 and September 2005, 13 Japanese patients with multiple myeloma were treated with bortezomib in Toranomon Hospital, Juntendo University School of Medicine, and Jichi Medical School. Four of them developed severe pulmonary complications, and 2 died of respiratory failure without progression of underlying disease. To our knowledge, this is the first report on life-threatening pulmonary adverse effects after bortezomib therapy. Previous clinical studies on bortezomib, mostly in the United States and Europe, have shown low incidences of pulmonary adverse effects. Our study suggests that bortezomib can cause serious lung injury, and that its incidence might vary among different ethnicities. Clinicians need to be alert to the possibility.

Description: 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.

Description: Background: The optimal regimen for allogeneic stem cell transplantation with a reduced-intensity conditioning regimen (RIST) needs to be established. Therefore, we retrospectively reviewed data of 84 patients who underwent RIST using 180 mg/sqm fludarabine and 8 mg/kg busulfan (Flu/Bu8). All patients received mobilized blood stem cells from a related donor between Nov. 2000 and Jun. 2005. Patients and Methods: The median age of the patients was 53 years (range, 25–65). The diagnosis included 42 AML/MDS, 34 lymphoma and 8 others. Sixty-nine patients (82%) had high-risk diseases, including 56 (81%) in non-remission status before RIST. All were serologically 6/6 matched pairs, except for one who had a 5/6 match. For GVHD prophylaxis, 61 used cyclosporine A (CSP) alone, 21 used CSP + methotrexate (MTX), and 2 used some other compounds. Results: The engraftment kinetics were remarkable since all of the patients successfully engrafted at a median of 11 days (5–24 days), with no late graft rejection. Toxicities of grade 2 or 3 according to CTCAE v.3 were observed at minimal frequencies, i.e. 38 mucosal, 35 hepatic, 13 GI tract, 12 renal, 2 cardiac, 1 pulmonary, 19 febrile neutropenia, and 9 documented infections, and there were no grade 4 toxicities. The administration of MTX increased the incidence and severity of stomatitis (P=0.05). The cumulative incidences of grade II–IV and III–IV acute GVHD were, respectively, 50% and 29%, and 76% experienced chronic GVHD. Seventy-three patients (87%), including 38 of the 56 patients who were not in CR at the time of transplant, achieved partial or complete remission. The median follow-up of surviving patients was 1349 days (34–1981 days), and the day-100 mortality was 11% (disease progression 6% and non-relapse mortality [NRM] 5%). The 5-year overall and progression-free survival rates were 36% and 30%, respectively. Among 46 total deaths, 27 were from disease progression and 19 were from NRM primarily related to GVHD. The patients in remission at transplant showed better overall survival than those who were not in remission (85 % vs 34 % at 5 years post-transplant, respectively, P

Description: [Back ground] HTLV-1 known as the 1st recognized human retrovirus infection described 1979 is endemic to some regions of the world, especially southwest Japan, Caribbean and others. Acute ATL type among the HTLV-1 associated leukemia/lymphoma has the poorest prognosis after various chemotherapies that are easily mutated chemo-resistantly. We hereby present 2 acute ATL cases receiving stem cell transplantation. [Case 1] The patient was a 21 years-old female. Induction therapy like ALL setting and then CHOP 14 for acute ATL induced to CR. The patient had HTLV-1 negative full matched 31 years-old brother. We performed bone marrow transplantation at day 90 from the beginning of initial chemotherapy. Typical conditioning regimens and immunotherapies consisted of CY (60mg/kg×3) +TBI (12Gy) and tacrolimus+steroid respectively. The engraftment was day 14 with no aGVHD of grade 2 to 4 observed till day 100. HTLV-1 viral load by RT -PCR was not detected at day 40 after BMT although HTLV-1 antibody and Western blotting analysis were still positive. [Case 2] The patient was a 32 years-old male. He was admitted our emergency room due to hypercalcemia (Ca 26.5mg/dl). CHOP and other chemotherapies were performed for a critical life saving situation. However, the control of his hypercalcemia was difficult even under intensive chemotherapy with steroid, elcatonin and bisphosphonates. His metastatic pulmonary calcification and arthralgia due to hypercalcemia were progressive on bone scintigram and CAT scan. The Japan Marrow Donor Program failed to provide an adequate donor. We decided to initiate peripheral stem cell transplantation (PBSCT) from his haplo-identical (3 locus mis-matched) HTLV-1 positive 68 years-old mother with informed consent from the patient and his family, as there was no life expectancy from usual chemotherapeutic treatment only. We performed PBSCT at day 90. The conditioning regimen and immunotherapy consisted of fludarabine phosphate (25mg×5) +L-PAM (240mg) +TBI (4Gy) and tacrolimus +steroid +short term MTX from the beginning of initial chemotherapy. At day 16 from PBSCT, Hypercalcemia and metastatic calcification as well as leukemic status improved dramatically. Engraftment and complete chimera were observed on day 11 and day 26 respectively with no aGVHD till day100. Although immunotherapy induced CMV infection was severe, the infection improved by using ganciclovir and foscarnet. [Results] The former case showed positive for results the successful eradication of HTLV-1. The latter case is still positive for HTLV-1 on PCR. However, this case showed CR in acute ATL with neither hypercalcemia nor its related complications. [Conclusion] In our limited studies, the modality for stem cell transplantation in acute ATL to cure or control leukemic cells in young patients has strong potential, even in a haplo-identical setting.