BackgroundRecently, maintaining higher relative dose intensity (RDI) of chemotherapeutic drugs has become a widespread practice in an attempt to achieve better outcomes in the treatment of aggressive lymphoma. The addition of rituximab to chemotherapy regimens has significantly improved outcome in diffuse large B-cell lymphoma (DLBL). However, it is unknown if higher RDI in chemotherapy when combined with rituximab leads to a better outcome in aggressive B-cell lymphoma.MethodsWe retrospectively evaluated the impact of the RDI of initial chemotherapy (consisting of cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) on outcome in 100 newly diagnosed DLBL patients.ResultsA multivariate Cox regression model showed that RDI trended towards a significant association with mortality [hazard ratio per 0.1 of RDI = 0.8; 95% confidence interval 0.6–1.0; P = 0.08]. Additionally, on multivariate logistic analysis, advanced age was a significant factor for reduced RDI.ConclusionOur data suggest that in DLBL patients, mortality was affected by RDI of R-CHOP as the initial treatment, and the retention of a high RDI could therefore be crucial.

A 59-year-old man with lymphoma-type adult T-cell leukemia/lymphoma was admitted to hospital for treatment of a skin relapse on day 398 after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To induce a graft-versus-adult T-cell leukemia/lymphoma effect, we discontinued methylprednisolone and tacrolimus. About a month after the discontinuation, he developed grade II acute graft-versus-host disease (GVHD) with a high fever. Soon after the development of GVHD, all the skin lesions regressed in size and finally vanished. However, he developed diffuse alveolar hemorrhage (DAH), which was resistant to high-dose corticosteroid therapy. He was intubated for respiratory insufficiency on day 451. Cyclophosphamide pulse therapy was administered at a dose of 1 g per day for 2 days and his oxygen saturation then improved, and ventilatory support was released on day 465. On analysis of cytokine profiles at the onset of DAH, we found elevated serum levels of T-helper 2 cytokines as well as T-helper 1 cytokines, suggesting that both T-helper 1 and T-helper 2 cytokines might play a role in the occurrence of DAH following allo-HSCT. Pulse cyclophosphamide treatment might be very effective in suppressing the exaggerated allogeneic immune response in DAH.

In reduced intensity, allogeneic stem cell transplantation from unrelated donors (u-RIST), graft-versus-host disease (GVHD), graft failure, and non-relapse mortality (NRM) are persistent problems. Although anti-thymocyte globulin, alemtuzumab, and total body irradiation (TBI) have been explored as conditioning modalities for u-RIST, the necessity for T-cell depletion or TBI to prevent GVHD or facilitate engraftment in u-RIST has not been determined. We here report the use of u-RIST with bone marrow grafting, following a simple conditioning regimen of 180 mg/m(2) fludarabine and 8 mg/kg of oral or intravenous busulfan without TBI or T-cell depletion. The study population was exclusively Japanese patients with a history of prior chemotherapy. We retrospectively analyzed 31 consecutive patients (median age 53 years). Twenty-five patients (81%) were transplanted from HLA-A, -B, and -DRB1 allele-matched donors. In all patients, neutrophil engraftment was achieved. The cumulative incidence of grade II-IV acute GVHD was 42%. However, 77% of patients with acute GVHD improved with, and could be managed by, initial, systemic, high-dose steroid treatment alone. Two-year overall and event-free survival was 62 and 53%, respectively. The NRM of 10% at 2 years was relatively low. Our results suggest that u-RIST without TBI or T-cell depletion may improve the prognosis after u-RIST in certain patient populations.

3551 Background: Allogeneic hematopoietic cell transplantation (HCT) may even cure leukemia following relapse or primary induction failure. Several pre-transplant variables including age, duration of remission, poor-risk cytogenetics, tumor burden at HCT, type of donor, and performance status reportedly affected the post-HCT prognosis of leukemia that is not in remission. However, there has been insufficient examination of the factors required to achieve long-term survival or cure of leukemia that is not in remission at HCT. We might consider long-term survival without relapse, particularly for more than 5 years, as ‘likely cure' of leukemia. Therefore, we evaluated the factors that contribute to long-term survival (for more than 5 years) in patients with active leukemia at HCT. Method: We retrospectively performed an analysis of leukemia not in remission at HCT performed at our single institute between January 1999 and July 2009. Forty-two patients aged from 15 to 67 years (median age: 39 years) received intensified myeloablative (n=9), myeloablative (n=11) or reduced-intensity conditioning (n=22) for HCT. Twelve patients received individual chemotherapy for cytoreduction within the three weeks before reduced-intensity conditioning for HCT. Diagnoses included de novo AML (n=17), ALL (n=12), CML-AP (n=2), MDS/AML (n=10) and plasma cell leukemia (n=1). In those with acute leukemia, cytogenetic abnormalities were intermediate (n=17, 44%)or poor (n=22, 56%). Seven patients were primarily refractory to induction chemotherapy. The other patients relapsed after conventional chemotherapy or the first HCT. The median number of blast cells in bone marrow (BM) was 26.0% (range; 0.2–100) before the start of chemotherapy for HCT. Six patients had leukemic involvement of the central nerve system. Stem cell sources were related BM (n=3, 7%), related peripheral blood (n=13, 31%) unrelated BM (n=20, 48%) and unrelated cord blood (CB) (n=6, 14%). Thirty-one pairs were matched for HLA-A, B and DRB1 antigens. Three patients were mismatched for one HLA antigen (two at HLA-A, one at HLA-B), and seven were mismatched for two (two at HLA-A and B, five (all CB) at HLA-B and DRB1). The remaining patient was mismatched for all three antigens. Prophylaxis for acute GVHD consisted of calcineurin alone (n=5), calcineurin combined with short-term methotrexate (n=32), calcineurin combined with mycophenolate mofetil (n=2) or none (n=3). In this study, we defined long-term survival as survival without relapse for more than 5 years. Results: Engraftment was achieved in 33 (79%) of 42 patients. Median time to engraftment was 17 days (range: 9–32). Five patients died early after HCT (range 4–20 days). Twenty four (65%) of 37 evaluable patients developed acute GVHD (eight grade I, nine grade II, five grade III, two grade IV), and 12 (50%) of 24 evaluable patients developed chronic GVHD (1 limited, 11 extensive). With a median follow up of 85 months for surviving patients, the five-year Kaplan-Meier estimates of leukemia-free survival rate and overall survival (OS) were 17% and 19%, respectively. At five years, the cumulative probability of non-relapse mortality was 38%. In the univariate analyses of impact of pre-transplant variables on OS, poor-risk cytogenetics, number of BM blasts (>26%), MDS/AML and CB as stem cell source were significantly associated with worse prognosis (p=.03, p=.01, p=.02 and p<.001, respectively). In addition, the five-year Kaplan-Meier estimates of OS in patients with and without cGVHD were 66.7% and 0% (p<.001) respectively. Conclusion: Graft-versus-leukemia effects mediated by cGVHD may have played a crucial role in long-term survival in, or cure of active leukemia. We speculate that effective cytoreduction by individual chemotherapy and/or conditioning for HCT to control disease until cGVHD subsequently occurred might be also important, particularly in leukemia with rapid proliferation. However, intensive conditioning for HCT did not appear to be indispensable in relatively indolent leukemia, even with non-remission status at HCT. In addition, based on our results, CB might be unsuitable as a source of stem cells for leukemia that is active at the time of HCT. Disclosures: No relevant conflicts of interest to declare.

BackgroundThere has been insufficient examination of the factors affecting long-term survival of more than 5 years in patients with leukemia that is not in remission at transplantation.MethodWe retrospectively analyzed leukemia not in remission at allogeneic hematopoietic cell transplantation (allo-HCT) performed at our institution between January 1999 and July 2009. Forty-two patients with a median age of 39 years received intensified conditioning (n = 9), standard (n = 12) or reduced-intensity conditioning (n = 21) for allo-HCT. Fourteen patients received individual chemotherapy for cytoreduction during the three weeks prior to reduced-intensity conditioning. Diagnoses comprised acute leukemia (n = 29), chronic myeloid leukemia-accelerated phase (n = 2), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (n = 10) and plasma cell leukemia (n = 1). In those with acute leukemia, cytogenetic abnormalities were intermediate (44%) or poor (56%). The median number of blast cells in bone marrow (BM) was 26.0% (range; 0.2-100) before the start of chemotherapy for allo-HCT. Six patients had leukemic involvement of the central nervous system. Stem cell sources were related BM (7%), related peripheral blood (31%), unrelated BM (48%) and unrelated cord blood (CB) (14%).ResultsEngraftment was achieved in 33 (79%) of 42 patients. Median time to engraftment was 17 days (range: 9-32). At five years, the cumulative probabilities of acute graft-versus-host disease (GVHD) and chronic GVHD were 63% and 37%, respectively. With a median follow-up of 85 months for surviving patients, the five-year Kaplan-Meier estimates of leukemia-free survival rate and overall survival (OS) were 17% and 19%, respectively. At five years, the cumulative probability of non-relapse mortality was 38%. In the univariable analyses of the influence of pre-transplant variables on OS, poor-risk cytogenetics, number of BM blasts (>26%), MDS overt AML and CB as stem cell source were significantly associated with worse prognosis (p = .03, p = .01, p = .02 and p < .001, respectively). In addition, based on a landmark analysis at 6 months post-transplant, the five-year Kaplan-Meier estimates of OS in patients with and without prior history of chronic GVHD were 64% and 17% (p = .022), respectively.ConclusionGraft-versus-leukemia effects possibly mediated by chronic GVHD may have played a crucial role in long-term survival in, or cure of active leukemia.