ALBERT

Description: Abstract 3687 Background: Prednisolone at a dose of 1 mg/kg/day (PRD) for 2 to 4 weeks is administered as front-line therapy to most adult patients with immune thrombocytopenia (ITP) who need to be treated. Recent results from 2 large single arm studies suggest high dose dexamethasone (DEX) as first-line treatment may produce a high sustained response rate. Therefore, we conducted prospective randomized trial comparing DEX with PRD as initial treatment of adult patients with newly diagnosed ITP. Methods: We did a randomized multicentre trial based on a 1:1 design. We enrolled treatment-naïve patients, 16 years or older, with a diagnosis of ITP according to the practice guidelines of the American Society of Hematology and a platelet count of 30×109/L or less. Patients with ITP were randomly assigned to receive either DEX 40 mg/day on day 1–4 (If the platelet count dropped below 3×109/L within the first six months, another four-day course of DEX was given) or PRD 1mg/kg/day for 4 weeks. The primary object of this study was the sustained response (platelet count〉30×109/L after 6 months) rate. Second objectives are response rate at 4 weeks, predictors of steroid response, and toxicity. This study is registered at http://clinicaltrials.gov as NCT00451594. Results: From September 2005 to December 2009, 151 adults with ITP were randomly assigned (76 patients in the DEX arm, 75 patients in the PRD arm). Overall demographics were balanced between arms; Median age 44 years old (DEX:PRD 44 years old:44 years old); 69.5% female (DEX:PRD 73.7%:65.3%); median initial platelet count 17×109/L (DEX:PRD 16×109/L:17×109/L). Of 151 enrolled patients, 117 patients (57 patients in the DEX arm, 60 patients in the PRD arm) were evaluable in terms of sustained response. Sustained response rate by intention-to-treat (ITT) and per protocol were 25.0% and 33.3% in the DEX arm, 36.0% and 45.0% in the PRD arm, respectively (p=0.33 by ITT). Eight patients in the DEX arm and 17 patients in the PRD arm had a sustained platelet counts more than100×109/L. Fifteen patients had a sustained response after a single course of DEX and 6 patients among them required no further treatment during two to four year follow up. Median time to relapse in patients who had a sustained response was 1320 days and 1140 days, respectively. The response rate at day 28 was 68.2% in the DEX arm and 81.2% in the PRD arm. Pre-treatment platelet count was higher in patients who achieved sustained response (responder vs. non-responder: 17.1±7.8×109/L vs. 15.9±8.9×109/L). Eleven patients in the DEX arm and 8 patients in the PRD arm received splenectomy. Both treatments were well tolerated. Three patients represented side effects that were severe enough to discontinue the treatment in the PRD arm, including pneumonia (1), hyperglycemia (1), and myalgia (1). Six patients receiving DEX and 5 patients receiving PRD had G3 or more hyperglycemia. Conclusion: One or two courses of DEX were not more effective than PRD in adults with ITP. However, 19.7% of adult ITP had a sustained response with a single course of DEX. Initial treatment with DEX could be useful for identifying patients who may not require prolonged steroid treatment. Disclosures: No relevant conflicts of interest to declare.

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: Allogeneic hematopoeitic cell transplantation (alloHCT) is a curative therapy for severe/very severe aplastic anemia (sAA) in adult. alloHCT from haplo-identical family donor (HD) is an alternative approach while alloHCT from matched sibling donor (MSD) is the choice of therapy. Our previous study suggested that alloHCT from matched unrelated donor (MUD) were comparable with MSD when pre-transplantation conditions were well-matched. It means poor outcome of MUD might come from poor pre-transplantation clinical factors such as delayed alloHCT. Same will be applied to HD. In this study we compared HD with alternative donors (AD; MUD or mismatched family donor) by matched case study. We selected AD cases from KSBMT2007-01 study population who had comparable pre-transplantation clinical factors with HD by propensity-score matching. Pre-tranplatation clinical factors such as age, ATG conditioning or ABO-compatibility were matched. Therefore 48 AD cases were selected for the comparison with 16 HD cases. Male (p=0.009) and female to male transplantation (p=0.002) were more frequent in HD. AD received prior immune suppression therapy (IST) frequently (p=0.092). Cyclophosphamide (p

Description: Background In a randomized study of single-agent eltrombopag (EPAG; n=64) versus placebo (PBO; n=34) in thrombocytopenic patients with advanced myelodysplastic syndromes or acute myeloid leukemia (AML), median overall survival (OS) was 27 weeks for EPAG versus 15.7 weeks for PBO (hazard ratio [HR]: 0.73). In addition to standard supportive care, disease-modifying treatments were generally permitted at any time at the investigator's discretion. To explore the role of concomitant anticancer therapy in this study population, a post hoc subgroup analysis was conducted in patients in each treatment group who received anticancer treatment. Methods Anticancer treatment was grouped post hoc into the following categories: palliative treatment (eg, hydroxyurea, low-dose cytarabine), hypomethylating agents (HMAs; eg, azacitidine and decitabine), induction chemotherapy (eg, 7 + 3; mitoxantrone, etoposide, and cytarabine, etc), and other (eg, lenalidomide). Baseline characteristics and safety/efficacy parameters were examined in this subgroup of patients. Results While on study treatment, a similar proportion of patients in both treatment arms of the trial received anticancer therapy (EPAG, n=28 [44%]; PBO, n=13 [38%]). The majority of patients receiving anticancer therapy in both the EPAG (64%) and PBO (54%) arms received palliative treatments (primarily hydroxyurea and low-dose cytarabine) followed by HMAs (Table). Induction chemotherapy was received by 11% of patients in the EPAG subgroup, compared with no patients in the PBO subgroup. For the subgroup of patients who received anticancer therapy, EPAG patients had higher baseline median platelet counts and absolute neutrophil counts, and a lower incidence of poor prognosis karyotype (Table). The percentage of patients with AML and those who were platelet transfusion dependent were similar between treatment arms at baseline (Table). All patients in both treatment groups experienced ≥1 adverse event (AE) while on study treatment. A lower proportion of EPAG patients experienced a serious AE (SAE) on therapy compared with PBO patients, and proportionately fewer infection-related SAEs were reported in EPAG versus PBO patients (Table). Pyrexia SAEs were higher in the EPAG (5 [18%]) arm versus the PBO (1 [8%]) arm. In the subgroup of patients receiving anticancer therapy, a similar proportion of EPAG and PBO patients experienced Grade ≥3 hepatobiliary events (3 [11%] vs 1 [8%]). Three (11%) EPAG patients experienced Grade ≥3 renal and 2 (7%) thromboembolic events on study drug, whereas no PBO patients experienced these events. A lower proportion of patients on EPAG (18%) experienced AEs that led to discontinuation of study treatment compared with those on PBO (46%). A lower proportion of EPAG patients (32%) died on therapy compared with PBO (69%); the primary cause of death in both arms was the underlying disease. Median platelet counts for EPAG patients receiving anticancer treatment increased above baseline, whereas median platelet counts remained stable at baseline levels for PBO patients. A higher proportion of EPAG patients than PBO patients achieved platelet (50% vs 31%) and red blood cell (RBC; 29% vs 8%) transfusion independence for ≥8 weeks (Table). Bleeding events (Grade ≥3) were reported in fewer EPAG patients (11%) versus PBO patients (38%). When censoring patients at the start of anticancer treatment, no apparent difference in OS was observed between treatment arms (HR: 0.97). Summary/conclusion In the subgroup who received anticancer therapy, EPAG patients had higher incidences of platelet and RBC transfusion independence, higher median platelet counts, and lower incidences of bleeding and infectious complications compared with PBO patients, with selected SAEs occurring at higher rates. These results support the safety profile of EPAG in combination with a variety of anticancer agents. In addition, these data suggest a possible beneficial supportive care effect in patients receiving concomitant therapy with EPAG and anticancer treatment. Further studies of EPAG in combination with anticancer therapy are warranted to confirm these hypotheses. Disclosures: Platzbecker: GlaxoSmithKline: Honoraria. Off Label Use: Eltrombopag is a TPO receptor agonist that is used for the treatment of thrombocytopenia due to various diseases. It is approved in cITP and now being evaluated for the correction of thrombocytopenia in subjects with MDS/AML. Wong:GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau. Verma:GlaxoSmithKline: Research Funding. Abboud:Alexion: Honoraria; Ariad: Honoraria; Novartis: Honoraria; Teva: Speakers Bureau. Greenberg:Amgen: Research Funding; GlaxoSmithKline: Research Funding; KaloBios: Research Funding; Novartis: Research Funding; Onconova: Research Funding. Lyons:Novartis: Research Funding; GlaxoSmithKline: Research Funding; Amgen: Honoraria, Research Funding. Santini:Novartis: Honoraria; Janssen: Honoraria; GlaxoSmithKline: Honoraria; Celgene: Honoraria. Cheng:GlaxoSmithKline: Speakers Bureau. Dougherty: GlaxoSmithKline: Employment. Mannino:GlaxoSmithKline: Employment. Mostafa Kamel:GlaxoSmithKline: Employment, Equity Ownership. Chan:GlaxoSmithKline: Employment. Stone:GlaxoSmithKline: Employment. Giagounidis:GlaxoSmithKline: Honoraria.

Description: Recent studies have shown that mesenchymal stem cells (MSCs) have profound immunomodulatory function, both in vitro and in vivo. There are several reports to treat effectively therapy-resistant graft-versus-host disease (GVHD) using ex vivo expanded MSCs. We performed a pilot clinical trial to treat intractable GVHD with bone marrow derived MSCs. All of 5 patients, 3 males and 2 females, with steroid-refractory GVHD were included in this study. Age range was 27 to 48 years old. Diagnosis of underlying disease was CML in 2, AML in 1, ALL in 1, and MDS in 1. Hematopoietic stem cell (HSC) donor was a sibling in 2 and an unrelated volunteer in 3. The donor of MSCs was a sibling in all patients: two donors were the same to HSC donors, but other three were not. About 20 mL of bone marrow was aspirated from donors and MSCs were cultured ex vivo. After about 3 weeks, MSCs were harvested for the first infusion, and 4 more weeks’ culture was done for the planned second infusion. The infused doses of MSCs were 5.3 to 6.9 x 106/kg for the first infusion and 1.8 to 7.0 x 106/kg for the second infusion. The onset of GVHD was post-transplant day 24 to 191 and the times from the onset of GVHD to the infusion of MSCs were 73 to 2469 days. There were no adverse events related to the infusion of MSCs. Three patients did not show any response to the treatment of MSCs for GVHD and two showed minimal response: transient improvement of jaundice and diarrhea without improvement of skin GVHD lesions in one patient, and improvement of performance status without significant increase of pulmonary function test parameters in another patient with lung involvement of GVHD. There were no significant changes in hemoglobin, and peripheral blood counts of platelets, leukocytes, lymphocytes, CD3+ cells, CD4+ cells, CD8+ cells, NK cells and B cells over 6 months’ period after the infusion of MSCs. Results of our pilot study suggest that the treatment effects of MSCs may be limited in patients with chronic established GVHD. Further studies on MSCs for GVHD should be focused on acute or exacerbated GVHD.

Description: High-dose cytarabine (HDAC)-based postremission therapy has been generally considered to be more beneficial than allogeneic stem cell transplantation (alloSCT) for AML patients with core binding factor (CBF). However, advancements in methods and supportive care in SCT over decades have led to gradual improvement in the treatment-related mortality rate after alloSCT. Therefore, it could be considered that alloSCT after the first CR in AML with CBF patients may show better results than HDAC chemotherapy alone compared with past. We conducted a retrospective study in 169 patients with CBF AML aged less than 60 years collected in 18 institutions in Korea between 1994 and 2006, with comparing alloSCT (n= 60), autoSCT (n= 31) and HDAC chemotherapy (n= 78) as postremission therapy during first remission. With a median follow-up of 46 months, the probability of disease-free survival (DFS) and overall survival (OS) rates at 5 years were 67.8% and 66.6%, retrospectively. AlloSCT (83.1% ± 5.2%) shows a significantly improved 5-year probability of DFS over autoSCT (59.9% ± 9.6%) or HDAC (60.8% ± 6.2%; p=0.048). There was no differences in 5-year probability of OS from complete remission (CR) between 3 treatment arms. In comparison of DFS and OS according to period of enrollment of patients, 4-year probability of DFS or OS of the three groups prior to 2003 was not different, nonetheless, after 2003, 4-year probability of DFS was better in the group underwent alloSCT in comparison with the group without performing it (86.8% vs 70.0%; p=0.035), and in the group underwent SCT (alloSCT plus autoSCT) in comparison with the group without performing it (89.0% vs 67.3%; p=0.047). 4-year probability of OS has a tendency to be improved slightly in the group underwent SCT than the group without performing it (89.0% vs 67.3%; p=0.08). In comparison with prior to 2003, cumulative treatment-related mortality and relapse risk of alloSCT after 2003 was decreased to 13.5% vs 6.7% and 26.2% vs 6.9%, respectively, and depending on the result, 4-year probability of DFS and OS of the alloSCT showed the improvement from 73.9% and 63.3% prior to 2003 to 93.1% and 90.0% after 2003, respectively. This study has the limitation of retrospective study, nonetheless, it could suggest the possibility that alloSCT as a postremission therapy in AML with CBF patients after the first CR may be appropriate if a HLA matched sibling donor were available.

Description: Most preparative regimens in alternative donor BMT for SAA have included TBI to overcome high incidence of graft rejection, which is the major problem in this setting. With routine use of irradiated leukocyte-poor blood products, however, the incidence of graft rejection due to pre-transplant allo-sensitization has decreased. Recently, efforts to reduce dose intensity of the preparative regimen for alternative donor transplants have been made with promising results. Using non-TBI containing preparative regimens, 13 patients with SAA were transplanted from alternative donors in our center and we report on the results of BMT in these patients. Median age of the patients, 6 males and 7 females, was 22 years (range, 15-34). Twelve donors were unrelated volunteers and one was an HLA one-locus mismatched sibling. Median time from diagnosis of SAA to BMT was 304 days (range, 49–5,403). Nine patients had received one cycle of immunosuppressive treatment with ATG (± cyclosporine) before BMT, while 4 had not. All patients except one had been transfused before BMT. Preparative regimens consisted of cyclophosphamide (50 mg/kg x 4) plus ATG (Atgam® 30 mg/kg x 3) in 9 patients, cyclophosphamide (50 mg/kg x 4) plus fludarabine (30 mg/m2 x 3) in 2 patients, and cyclophosphamide (50 mg/kg x 2) plus fludarabine (30 mg/m2 x 5) plus ATG (Atgam® 30 mg/kg x 3 or Thymoglobuline® 3 mg/kg x 3) in 2 patients. All patients received non-T-cell depleted bone marrow graft form the donor. Cyclosporine plus methotrexate were given for GVHD prophylaxis. All patients engrafted on a median of day 21 (range, 15–27) with complete donor chimerism. Grade III-IV acute GVHD developed in 3 (23%) of 13 patients and extensive chronic GVHD in 4 (31%) of 12 evaluable patients. With a median follow-up duration of 1,138 days (range, 118–1,553), 10 patients are alive with durable engraftment showing 75% of survival rate. Causes of death were chronic GVHD in 2 and CNS bleeding in 1. In conclusion, non-TBI containing preparative regimen could ensure durable engraftment in alternative donor BMT for SAA and showed promising results.