ALBERT

Description: Background: Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm developing in a minority of individuals infected with human T-cell leukemia virus type I (HTLV-I). Although the results of conventional chemotherapy remain unsatisfactory for the management of ATL, allogeneic hematopoietic stem-cell transplantation (allo-SCT) is emerging as a promising alternative which can provide long-term remission in selected patients. Methods: To evaluate the efficacy of allo-SCT for the treatment of ATL, data on 397 patients (pts) with ATL who had received allo-SCT between 01/1996 and 12/2005 were collected through JSHCT, JMDP and JCBBN. We analyzed pts who did not have a history of previous stem-cell transplantation; who received a T-cell-replete graft; who had data on age at transplantation, sex, donor type, stem-cell source, conditioning regimen, and graft-versus-host disease (GVHD) prophylaxis. A total of 363 pts, with a median age of 51 yrs (range, 18–79), 201 males and 162 females, fulfilled these criteria: 175 received bone marrow and/or peripheral blood from a related donor; 188 received marrow or cord blood from an unrelated donor. At the time of transplantation, 91 pts were in complete remission (CR) and 226 were not in CR. Risk factors which potentially affect the survival outcomes were analyzed using proportional-hazards models. Results: The median follow-up was 21.6 months (range, 1.5–102). The unadjusted 3-year overall survival, disease-associated mortality, and treatment-related mortality (95% confidence interval [CI]) for pts in CR at transplantation were 48% (35–59%), 16% (8–27%), and 35% (24–45%), respectively, while those for pts not in CR were 22% (16–29%), 35% (28–42%), and 41% (34–48%), respectively. Multivariable analyses revealed four significant factors which adversely affected survival: older recipient age (〉50 yrs)(adjusted hazard ratio [HR] 1.71; 95% CI, 1.24–2.38; P=0.001), male recipient (HR 1.46; 95% CI, 1.10–1.93; P=0.009), disease status other than CR (HR 2.21; 95% CI, 1.57–3.12; P

Description: The addition of rituximab to CHOP (CHOP-R) chemotherapy has resulted in an improved outcome for patients with DLBCL and has recently been shown to diminish the prognostic impact of several recognized biomarkers. S-phase kinase-associated protein 2 (Skp2) is a proto-oncogene that has been shown to be expressed in a number of tumors. We have reported that Skp2 expression in tumor cells is an unfavorable prognostic factor in DLBCL. In the present study, we investigated the significance of Skp2 expression in the patients with DLBCL treated with CHOP or CHOP-R. DLBCL patients (333 cases) were entered into this study, based on the availability of paraffin blocks for interpretable immunohistochemistry for all antigens (CD10, Bcl-6, MUM1, Bcl-2, Skp2). All patients were treated with either CHOP (201) or CHOP-R (132) from 1996 to 2005, and were diagnosed as having DLBCL at the twenty different hospitals. All specimens were histopathologically reviewed before entering into this study. Their clinical characteristics, including either the IPI or R-IPI factors, were evenly matched. The median follow-up of living patients was 3.7 and 2.1 y for CHOP vs CHOP-R, respectively. DLBCL were assigned to GCB subtype (40.8%: 136/333) or non-GCB subtype (59.2%: 197/333) based on the method of Hans et al., Blood 103: 275–82 (2004), with similar distribution in both treatment groups. Expression of bcl-6 (p

Description: AML1-MTG8 generated by t(8;21)(q22;q22) contributes to leukemic transformation but additional events are required for full leukemogenesis. We examined whether mutations in the receptor tyrosine kinase (RTK) pathway could be the genetic events that cause acute myeloblastic leukemia (AML) harboring t(8;21). Mutations in the second tyrosine kinase domain, juxtamembrane domain and exon 8 of the C-KIT gene were observed in 7, 1 and 3 of 37 AML patients with t(8;21), respectively. Three patients showed an internal tandem duplication in the juxtamembrane domain of the FLT3 gene. One patient had a mutation in the K-Ras gene at codon 12. As the occurrence of these mutations was mutually exclusive, a total of 15 (41%) patients showed mutations in the RTK pathway. These results suggest that AML1-MTG8 predisposes cells to the acquisition of activating mutations in the RTK pathway as an additional event leading to the development of AML. Ten of 15 patients with mutations in the RTK pathway relapsed, compared with only 3 of 19 patients lacking such mutations (p=0.0042). Furthermore, the 6-year disease-free survival (DFS) in patients with mutations was 12% compared to 55% in those without mutations (p=0.0344). When patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) were censored at the date of the HSCT, patients with mutations had a 6-year DFS of 0% versus 60% for the patients without mutations (p=0.0096) These observations indicate that RTK mutations are associated with the clinical outcome in t(8;21) AML.

Description: Background Rituximab has dramatically improved the clinical outcomes of mature B cell lymphoma. It has been reported that women show more favorable survival than men with rituximab-containing treatment. A multicenter, retrospective study was conducted to assess the role of sex in survival with rituximab treatment. Patients and Methods Patients with newly diagnosed mature B cell lymphoma treated at 20 National Hospital Organization hospitals in Japan from January 2000 to December 2004 were consecutively registered. Rituximab was approved in September 2002 for indolent B cell lymphoma and in September 2003 for aggressive B cell lymphoma in Japan. The patients were divided into two groups depending on whether they received induction therapy containing rituximab. The target population of this study was all mature B cell lymphoma patients who received first remission induction therapy containing rituximab. The patients treated without rituximab were used as controls. The endpoint was to compare 2-year progression-free survival (PFS) and overall survival (OS) between men and women. Survivals were assessed using the Kaplan-Meier method, and the groups were compared using the log-rank test. Results A total of 1126 patients received systemic chemotherapies during this study period. Of these, 348 (men 185, women 163), including 184 diffuse large B cell lymphomas (DLBCLs) and 111 follicular lymphomas (FLs), were treated by rituximab-containing regimens as front-line therapy. The 2-year PFS was better in women than in men (75.8% vs. 64.2%, p=0.048). This difference was not seen in the control group (men 396, women 382), which was treated by chemotherapeutic regimens without rituximab (48.7% vs. 50.6%, p=0.994). The 2-year OS was not statistically different between men and women (81.9% vs. 88.6%, p=0.115). When this population was broken down into DLBCL and FL, the women’s benefit in 2 year PFS was not statistically significant in both subtypes. Multivariate analysis both with forced entry and stepwise method could not show that sex was an independent prognostic factor in mature B cell lymphoma treated by rituximab containing induction regimen. Conclusions In mature B cell lymphoma, women would have better PFS than men when treated with rituximab containing therapy. These data suggest that the sex-based rituximab dose modification might be considered. Disclosures: No relevant conflicts of interest to declare.

Description: Background: The outcome of patients who suffer from GF after allogeneic transplantation is poor, primarily due to an increased risk of infectious complications and toxicities. We evaluated whether rescue with RICBT could improve survival after GF. Patients and Methods: We retrospectively surveyed the data of 63 patients (median age, 51 years: range, 17–68 years) with hematological disorders who received RICBT within 3 months of GF between Jan, 2000, and Apr, 2006. The diagnosis included AML (n=28), MDS (12), CML (2), ALL (13), lymphoma (4), and AA (4), and 28 patients were not in remission before the preceding allogeneic HCT, which had been performed with either myeloablative (29) or reduced-intensity conditioning regimens (34). Twelve patients (19%) had received unrelated BM, while 46 (73%) received CB. Fifty-one patients had developed primary GF (failure of the ANC to surpass 500/mm3 or

Description: Abstract 881 Background. The Japan Clinical Oncology Group (JCOG)-Lymphoma Study Group (LSG) conducted 3 clinical trials in the 1990s for aggressive ATL, i.e. acute, lymphoma, and unfavorable chronic types, associated with human T-lymphotropic virus type-I. The prognosis of aggressive ATL patients (pts) is still poor, but the 5-year survival rate was improved from 5% in the 1980s to 15% in a JCOG study in late 1990s. To characterize long-term survivors and to develop a new predictive model for aggressive ATL, we performed a combined analysis of enrolled pts in the 3 JCOG studies. Methods. A total 276 pts with aggressive ATL were registered in 3 consecutive JCOG-LSG trials exclusively against aggressive ATL, i.e. JCOG9109, a phase II (pII) study of LSG11 consisting of pentostatin, VCR, ETP, PSL and DOX; JCOG9303, a pII study of LSG15 consisting of VCAP-AMP-VECP; and JCOG9801, a pIII study comparing modified (m) LSG15 with CHOP-14. The pts were analyzed for their prognosis, the effects of central nervous system (CNS) prophylaxis in the protocol treatment and allogeneic hematopoietic cell transplantation (allo-HCT) after the protocol treatment, and the outcome of long-term survivors with a follow-up survey. To build a predictive index, multivariate analyses with a Cox proportional hazard model were conducted using the test sample of 193 pts without missing covariate data from the entire cohort of 276 pts. Validation was carried out using external data for 136 pts, who were independent from those included in the JCOG studies. Results. The MST, 5- and 8-yesr OS rates of the entire cohort of 276 pts were 10.9 months, 13.6% and 10.0%, respectively. The median and longest follow-up periods were 10.9 months and 17.5 years, respectively. The differences of CNS prophylaxis by each regimen did not significantly affect the CNS relapse rate. We analyzed 269 eligible pts (acute 170, lymphoma 78, chronic 21). In 67 pts who survived for more than 2 years, there were 38 (22%) pts with acute type, 21 (28%) with lymphoma type and 5 (24%) with chronic type. The major proportion of relapse in pts with acute type occurred within 2 years after initiating chemotherapy, and occurred earlier than in pts with other types. In 37 pts who survived for more than 5 years (acute 22 (13%), lymphoma 8 (10%), chronic 7 (33%)), there were no disease-related deaths among lymphoma type pts, which was in contrast to the 10 disease-related deaths that occurred in pts with acute or chronic type during the follow-up period. The numbers of pts achieving CR and the other response category at the end of the protocol treatment were 24 and 13 in the 37 pts who survived for more than 5 years, respectively, and 11 and 1 in the 12 who survived for more than 10 years, respectively. Six of the 37 pts who survived for more than 5 years and 2 of 12 who survived for more than 10 years had received allo-HCT. In a test sample of 193 pts, two unfavorable factors associated with OS, high calcium (Ca) level and ECOG performance status (PS) of 2 to 4, were identified. The hazard ratio (HR) [95% confidence interval (CI)] of Ca and PS were 1.574 [1.09–2.28] and 1.554 [1.12–2.16], respectively. Considering the potential for clinical usage, four categories using these two factors were combined into a predictive index with 2 strata, thus resulting in pts with both Ca=5.5 mEq/l and/or PS 2 to 4, respectively (Fig 1). The HR [95% CI] was 1.926 [1.42–2.61]. The predictive model was reproducible in the validation set. Conclusion. There were no disease-related deaths in 8 lymphoma type pts who survived for more than 5 years, suggesting that about 10% of pts with lymphoma type may be curable. We developed a predictive model for aggressive ATL based on Ca and PS, however, the MST was only 14.3 months even in the better prognostic group. To further improve the outcome, a pII trial of VCAP-AMP-VECP followed by allo-HCT (JCOG0907) and a randomized pII study of VCAP-AMP-VECP with or without anti-CCR4 antibody are underway. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Many clinical trials have documented the efficacy of rituximab in B-cell lymphomas. However, it remains unclear whether rituximab will improve long-term prognosis of the patients. This multicenter retrospective cohort study was conducted to evaluate the clinical impact of the drug in the treatment of B-cell lymphomas. Study design: We retrospectively analyzed clinical characteristics, 2-year progression-free survival(2y PFS) and 2-year overall survival(2y OS) of all B-cell lymphoma patients who were newly diagnosed and initially treated with either CHOP-like regimen alone (R(−) group) or in combination with rituximab (R(+) group) between 2000 and 2004 at our 20 hospitals belonging to the National Hospital Organization. Since rituximab was approved in 2002 for indolent B-cell lymphomas and in 2003 for aggressive B-cell lymphomas in Japan, the patients were almost automatically divided into the 2 groups dependent on the year they underwent treatment. Results: Of the 1,072 patients enrolled, 335 were given rituximab, while 737 did not receive it for the initial induction therapy. 2y PFS was 74.3% and 61.2% for R(+) group and R(−) group, respectively(P

Description: Allogeneic hematopoietic cell transplantation (HCT) is an effective treatment for adult T-cell leukemia (ATL), raising the question about the role of graft-versus-leukemia effect against ATL. In this study, we retrospectively analyzed the effects of acute and chronic graft-versus-host disease (GVHD) on overall survival, disease-associated mortality, and treatment-related mortality among 294 ATL patients who received allogeneic HCT and survived at least 30 days posttransplant with sustained engraftment. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated that the development of grade 1-2 acute GVHD was significantly associated with higher overall survival (hazard ratio [HR] for death, 0.65; P = .018) compared with the absence of acute GVHD. Occurrence of either grade 1-2 or grade 3-4 acute GVHD was associated with lower disease-associated mortality compared with the absence of acute GVHD, whereas grade 3-4 acute GVHD was associated with a higher risk for treatment-related mortality (HR, 3.50; P 〈 .001). The development of extensive chronic GVHD was associated with higher treatment-related mortality (HR, 2.75; P = .006) compared with the absence of chronic GVHD. Collectively, these results indicate that the development of mild-to-moderate acute GVHD confers a lower risk of disease progression and a beneficial influence on survival of allografted patients with ATL.

Description: Pure red cell aplasia (PRCA) has been reported in association with lymphoma as one of the autoimmune diseases seen during the course of lymphoid malignancies. However, the relation of PRCA with the underlying lymphomas remains unclear. The aim of this study was to clarify the histologic subtypes of lymphomas, the chronological sequence of anemia and lymphoma, and the response to treatment, and eventually to establish the treatment guideline for lymphoma-associated PRCA. We conducted a nationwide survey in Japan. From a cohort of 185 patients with PRCA, 8 patients with lymphoma were evaluated. Complete response (CR), partial response (PR) and no response (NR) were defined as the achievement of normal hemoglobin levels without transfusion, the presence of anemia but without transfusion dependence, and the continued presence of transfusion-dependence, respectively. Patient age at the onset of PRCA ranged from 48 to 82 years (median age, 68 years) with an equal male to female ratio. Histologic subtypes varied and the lymphoma was of the B-cell type in four cases and of the T-cell type in four. Four patients had coexisting anemia and lymphoma. One patient developed PRCA before the onset of lymphoma. Three other patients developed PRCA following lymphoma, two of whom developed anemia during remission. Anemia responded to chemotherapy and/or immunosuppressive therapy in seven of eight patients. In four responding patients, PRCA remained in durable remission without maintenance immunosuppressive therapy (27, 76, 97 and 127 months), which is a different feature from that of idiopathic PRCA (Sawada K, et al. Haematologica2007;92:1021). Four patients were alive, and two of these four remained in remission for both lymphoma and PRCA. Effective chemotherapy was associated with remission of anemia in patients with concurrent lymphoma and PRCA. In patients with PRCA presenting before or after the onset of lymphoma, immunosuppressive therapy was effective for improving anemia. In conclusion, chemotherapy should be introduced for patients with coexisting lymphoma and PRCA. Additional immunosuppressive therapy may be necessary for PRCA that has failed to respond to chemotherapy. Durable maintenance-free remission of anemia may be obtained in lymphoma-associated PRCA. Table 1. Patient characteristics and induction therapy for PRCA Age/Sex Histologic subtypes Days from lymphoma to PRCA Disease status of lymphoma Induction therapy for PRCA * Response of PRCA Response of lymphoma *(/), in sequential administration; (-), in combination. 76/F DLBCL −114 - Steroid CR - 75/M DLBCL −13 On disease R-CHOP/CsA NR/CR PR 62/M ATLL 0 On disease CHOP-CsA CR PD 82/F MZL 0 On disease Steroid NR NR 58/F AILT 35 On disease CHOP CR CR 48/M Follicular 720 On disease Steroid/CHOP NR/CR CR 64/M T-LBL 205 CR Steroid PR - 71/F AILT 801 CR Steroid/CsA PR/PR -

Description: BACKGROUND: Despite recent increase of reduced intensity conditioning (RIC) transplantation, mortality rates after RIC and myeloabrative conditioning (MAC) HSCT remain high and hepatic veno-occlusive disease (VOD) cannot accurately predicted. OBJECTIVE: To determine the value of risk factors associated with the development of VOD after allergenic HSCT with RIC and MAC. Estimating VOD based on clinical factors may further improve results of allogenic HSCT. PATIENTS AND METHODS: A retrospective review of 415 consecutive allogenic HSCT was performed with attention to VOD, pre-transplant factors and laboratory data in five hematopoietic cell transplantation centers between 2000 and 2005. Patients underwent transplantation with MAC (n=247) or RIC (n=168). Main outcomes and risk factors were analyzed in multivariable analyses (a logistic regression model) with RIC and MAC. Three kind of laboratory data set, pre-transplant (day −10), post-transplant (day 20) and differences from pre-transplant to post-transplantation were analyzed. RESULTS: VOD occurred in 65 of 415(15.7%) transplant recipients; 40 of 247(16.1%) with MAC and 25 of 168(14.9%) with RIC. Multivariate analyses identified risk factors with the development of VOD with MAC (albumin level, creatinine level) and with RIC (HCT-CI, number of prior chemotherapy regimen, ALT) in pre-transplant laboratory data set. The risk factors of VOD were identified in post-transplant and differences (Table). The Akaike’s information criterion (AIC) of risk factors with differences was better than with the post-transplant. CONCLUSION: Our results provided risk factors of VOD with MAC and RIC. The estimation of VOD before transplantation may be useful for the selection of conditioning regimens. Differences of laboratory data with the time course of transplant may be useful for the early diagnosis of VOD. MAC Pre-transpant data Post-transplant data Differences data OR P-Value OR P-Value OR P-Value Age - - 0.945 0.0090 - - Alb 0.290 0.0125 - - - - Cr 10.204 0.0307 1.786 0.0039 1.984 0.0139 TPro - - 0 358 0.0019 - - TBi I - - 1.385 0.0027 1.314 0.0037 Ara-C - - 5.000 0.0139 goodness of fit AIC 106.727 126.499 86.931 RIC Pre-transpant data Post-transplant data Differences data OR P-Value OR P-Value OR P-Value Sex - - 3.401 0.0446 - - HCTCI 3.922 0.0050 2.000 0.0123 - - ImpScore 2.000 0.0314 - - - - TPro - - 0.366 0.0091 - - TBi I - - 1.675 0.0042 2.273 0.0004 ALT 0.969 0.0432 - - - - CY - - - - 5.682 0.0447 goodness of fit AIC 61.552 91.09 52.808