ALBERT

Description: Abstract 1976 Background: Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in the first step of heme degradation to biliverdin, free iron, and carbon monoxide. Aside from heme degradation, HO-1 has been attributed several regulatory functions in tissue inflammation and protection against stress-induced apoptosis. Inducibility of HO-1 is moderated by a single nucleotide polymorphism (SNP) A -413 T in the promoter. It has been reported that the A-allele of this SNP is associated with higher promoter activity than T-allele. Additionally, there have been several reports on the involvement of polymorphism within the promoter region of the human HO-1 gene in various diseases of the vascular systems. Recently, the polymorphism in the HO-1 gene has been reportedly associated with the graft survival after liver transplantation. In this study we analyzed the impact of HO-1 polymorphism on transplant outcomes in patients undergoing unrelated HLA-fully-matched bone marrow transplantation (BMT) through the Japan Marrow Donation Program. Methods and Results: The SNP A -413 T was analyzed using the TaqMan system (Applied Biosystems). The HO-1 polymorphisms were retrospectively analyzed in a cohort of 259 pairs of patients with hematologic malignancies and their unrelated donors. The genotype frequencies of A/A, A/T and T/T were 22%, 48% and 38% in recipients and 20%, 53% and 27% in donors (P=0.41). The donor A/A or A/T genotype, a genotype expected to induce higher activity of the HO-1 gene, was associated with a better overall survival (OS) than the donor T/T genotype (55% vs. 38% @5-yr, P=0.002; Fig 1A) as well as trend toward reduced transplant-related mortality (TRM; 18% vs. 27% @5-yr, P=0.08; Fig 1B), while no significant differences between the A/A genotype and A/T genotype were noted. The beneficial effects of the donor A/A or A/T genotype were also found to be consistent on the multivariate analysis for OS (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.44 to 0.93; P=0.02) and TRM (HR, 0.59; 95% CI, 0.32 to 1.06; P=0.08). Furthermore, in the multivariate analysis the donor A/A or A/T genotype showed a tendency to a lower incidence of grades II-IV acute graft-versus-host disease (GVHD; HR, 0.68; 95% CI, 0.43 to 1.06; P=0.09). The recipient HO-1 genotypes did not significantly influence the transplant outcomes. Conclusions: These results suggest an association of the donor HO-1 genotype with overall survival after unrelated BMT, and may substantiate that the higher HO-1 activity by donors with the HO-1 A allele likely accounts for a reduced risk for TRM and acute GVHD in their recipients. These could therefore be useful in selecting the donor and creating therapeutic strategies for improving the final outcome of allogeneic BMT. Disclosures: No relevant conflicts of interest to declare.

Description: Prognosis of patients with AML varies widely reflecting the heterogeneity of AML and the background of each patient. It is important for both physicians and patients to predict the response to chemotherapy to correctly select the therapeutic options. In the JALSG-AML97 study, patients were stratified using JALSG scoring system, and those who were categorized into the intermediate or adverse prognosis group were assigned to allo-HSCT during CR1 if they had an HLA-matched sibling. JALSG scoring contains several factors that have 1 or 2 points: 2 points, age 〈 50 years, WBC 50%; 1 point, PS

Description: The FcγRllla (FCGR3A) 158V/V allotype displays a higher antibody-dependent cellular cytotoxicity compared to the FCGR3A-158V/F or 158F/F allotype, leading to susceptibility to rheumatoid arthritis, better clinical response to rituximab in NHL, and lower risk of periodontitis. We tested the hypothesis that FCGR3A polymorphism influences the development of GVHD and GVL, and TRM. The FCGR3A-158V/F genotype was determined in 49 recipient and donor pairs who underwent HLA-matched SCT in our institute. Subjects with the recipient FCGR3A-158V/V allotype and the donor FCGRA-158V/V allotype were almost one-third and twice as likely to develop chronic GVHD respectively (Table 1). The recipients with the FCGR3A-158V/V allotype had a 60% increase in probability of 3-year TRM. Multivariate analysis showed that the recipient FCGR3A-158V/V allotype and the donor FCGRA-158V/V allotype were independent risk factors for chronic GVHD (HR = 0.8 and 1.2, respectively), as well as the unrelated donor BMT (HR = 1.6) and the related donor PBSCT (HR = 2.4). The recipient FCGR3A-158V/V was an independent predictor for 3-year TRM (HR = 4.0) with the high risk disease (HR = 3.0) and the cord blood transplantation (HR = 5.0). We conclude that the recipient and donor FCGR3A polymorphism is associated with the development of chronic GVHD and TRM after HLA-matched SCT. These findings could therefore be useful in selecting the donor and creating therapeutic strategies for improving the final outcome of allogeneic SCT. Besides, these raise the question of whether the genetic risk factor in a recipient might also be involved in the mechanisms of chronic GVHD. Table 1 FCGR3A allotype 2–4 acute GVHD(HR) Chronic GVHD (HR) 3 YR TRM (HR) *P

Description: A randomized study had been performed between December 2001 and December 2005 to assess the optimal post remission therapy for adult AML in the first CR. The updated results are here presented, after a median follow-up of 48 months. JALSG AML201 enrolled 1064 previously untreated AML patients (pts) aged 15–64 yrs. The induction therapy consisted of cytarabine (Ara-C 100 mg/m2 day1–7) and idarubicin (IDR 12 mg/m2 day1–3) (arm A) or cytarabine (100 mg/m2 day1–7) and daunorubicin (DNR 50 mg/m2 day1–5) (arm B). If the patients did not achieve remission after the first induction therapy, then the same therapy was given once more. Pts were categorized into good, intermediate or poor risk groups by risk factors based on the criteria established in previous JALSG AML studies (Miyawaki et al. Cancer 2005). All CR pts were stratified according to the induction, the number of courses of induction, age and karyotype and were randomly assigned to the high dose Ara-C (HDAC) post remission regimen (arm C) or the conventional JALSG post remission regimen (arm D). Arm C: the three courses of HDAC which consisted of Ara-C 2.0 g/m2 q12h day1–5, arm D: the first course consisted of Ara-C 200 mg/m2 day1–5+ mitoxantrone (MIT) 7 mg/m2 day1–3, 2) Ara-C 200 mg/m2 day1–5+ DNR 50 mg/m2 day1–3, 3) Ara-C 200 mg/m2 day1–5+ aclarubicin (ACR) 20 mg/m2 day15, 4) Ara-C 200 mg/m2 day1–5+ etoposide (ETP) 100 mg/m2 day1–5 + vincristine (VCR) 0.8 mg/m2 day 8 + vindesine (VDS) 2 mg/m2 day10. Results: Of the 1064 pts registered, 1057 pts (median age: 47 years) were evaluable. 823 pts (78%) achieved CR after one or two courses of induction therapy. Of the 823 pts in CR, 781 pts were assigned to arm C (n=389) or arm D (n=392). The 5-year OS rate of arm C was 57.8% while that of arm D was 55.9% (p=0.96). The 5-year RFS rate of the CR pts was 42.7% in arm C and 38.9% in arm D (p=0.73). Among the good risk group (n=155), the 5-year OS rate of arm C was 69.9% while that of arm D was 80.5 % (p=0.11), and the 5-year RFS rate of arm C was 54.5% while that of arm D was 55.7% (p=0.53). Among the intermediate risk group (n=439), the 5-year OS rate of arm C was 50.9% while that of arm D was 48.5% (p=0.59), and the 5-year RFS rate of arm C was 41.5% while that of arm D was 36.5% (p=0.50). Among the poor risk group (n=49), the 5-year OS rate of arm C was 12.9% while that of arm D was 17.2% (p=0.58), and the 5-year RFS rate of arm C was 14.3% while that of arm D was 15.5% (p=0.78). In the CBF leukemia group (n=218), the 5-year OS rate of arm C was 75.0% while that of arm D was 65.8% (p=0.17), and the 5-year RFS rate of arm C was 56.5% while that of arm D was 38.7% (p=0.05). Among the young group (=50 yrs) (n=314), the 5-year OS rate of arm C was 51.3% while that of arm D was 40.1% (p=0.16), and the 5-year RFS rate of arm C was 40.0% while that of arm D was 28.1% (p=0.23). After all of consolidation, the lowest WBC count and the duration of neutropenia in arm C were significantly lower and longer than those in arm D. There was a higher rate of documented infection in arm C (20.9%) than in arm D (14.5%) (p〈 0.001). Conclusion: The conventional post remission therapeutic regimen established by JALSG consisting of 4 courses of consolidation was found to be as effective as the three courses of HDAC therapy. HDAC therapy produced a slightly positive effect on RFS in only the CBF leukemia group.

Description: The outcome of elderly patients with acute myeloid leukemia (AML) has not been improved for these three decades, although the incidence is getting increased with the aging of the population in Japan. In the JALSG GML200 study, we prospectively registered all elderly patients with AML during this study irrespective of the eligible criteria,. Since elderly patients are less able to tolerate to intensive cyottoxic intensive chemotherapy, we conducted a randomized study to assess an individualized induction treatment. After consolidation chemotherapy, we evaluated the adjuvant effect of ubenimex (UBX), an anti-leukemia immunomodulator. Method: From April 2000 to August 2005, the JALSG GML200 study registered all newly diagnosed AML patients aged 65 years and over. Patients who satisfied the eligibility criteria were randomized to receive either the individualized therapy (arm B) or non-individualized therapy (arm A). Patients who were not eligible were classified in arm C. Induction therapy of Arm A: enocitabine (BH-AC) 200 mg/m2 on days 1–8, 3 h infusion + daunorubicin (DNR) 40 mg/m2 on days 1–3, 30 min infusion. Arm B: BH-AC 200 mg/m2 on days 1–8, with extension to day 12 according to the results of bone marrow examination on days 7 and 10, + DNR 40 mg/m2 on days 1–3, with extension on day 12 depending on the results of bone marrow examination on days 7 and 10. Patients who achieved a complete response (CR) were randomized again to receive immuno-therapy with ubenimex (group UY) or without ubenimex (group UN). Consolidation therapy consisted of three courses: BH-AC 200 mg/m2 on days 1–5 + Mitoxantrone (MIT) 7 mg/m2 on days 1–3, BH-AC 200 mg/m2 on days 1–5 + DNR 30 mg/m2 on days 1–2, ETP 100 mg/m2 on days 1–3, BH-AC 200 mg/m2 on days 1–5 + ACR 14 mg/m2 on days 1–5. Result: Of the 374 patients registered, 244 patients were eligible for randomization to arms A and B, and 235 patients were evaluable. The median patients’ age of arms A, B and C were 70 (range, 65–79), 71 (range, 65–79), and 74 years (range, 65–92), respectively. CR rate of arm A was 63.2% and that of arm B was 65.3% (p = 0.75). CR rates of male and female patients significantly differed in each arm (arm A: male 55.4% vs. female 76.3%, p=0.053, arm B: male 53.1% vs. female 80.0%, p=0.008). Overall survival rates at 3 years of arms A and B were 25.5% and 21.5% (p = 0.56), respectively. With reference to survival with or without ubenimex in patients who achieved CR, the overall survival rate at 3 years was 43.1% for arm UY and 26.9% for arm UN (p=0.073). The number of patients in arm C was 130, and most patients in this arm received similar induction chemotherapy using DNR and BH-AC. The survival rate of this group at 3 years was unexpectedly high at 29.4%. Conclusion: Induction chemotherapy using DNR and BH-AC is one of the superior methods to achieve CR in elderly AML patients. However, individualized treatment has little advantage over non-individualized therapy. The remission rate of the female patients is higher than male patients, and it may have relations with a long life span of the Japanese female. Long-term survival rate is still unfavorable and search for a better post-remission therapy is warranted. Immunomodulator therapy using ubenimex provides a possible benefit for longer survival in elderly AML patients at CR.

Description: The Philadelphia chromosome, which constitutes BCR-ABL fusion gene, is the most frequent cytogenetic abnormality in adult acute lymphoblastic leukemia (ALL). Although complete remission (CR) is achieved in 50–80% of patients, most of them suffer a relapse, resulting in overall survival (OS) of approximately 10% by standard chemotherapy. Recently, the Japan Adult Leukemia Study Group (JALSG) has started a phase 2 trial for newly diagnosed BCR-ABL positive ALL patients, and 60 patients have been enrolled at this time. We present here the results for the first 41 patients. After screening for BCR-ABL at presentation, those with positive BCR-ABL were treated with IDEAMOP regimen. For remission induction therapy, intensive chemotherapy comprising daunorubicin, cyclophosphamide, vincristine (VCR) and predonisolone (PSL) was combined with imatinib at a dose of 600 mg/day administered from day 8 to day 63. Consolidation therapy consisted of the odd courses with high-dose methotrexate and high-dose cytarabine and the even courses with 600 mg/day of imatinib alone for 28 days, which were repeated alternatively for 4 cycles. Thereafter, patients received maintenance therapy with VCR, PSL and imatinib until 2 years from the date they had attained CR. If an HLA-identical sibling donor was available, allogeneic hematopoietic stem cell transplantation (HSCT) was recommended. HSCT from an alternative donor was used at the discretion of the institution. Between September 2002 and March 2004, a total of 41 patients with newly diagnosed BCR-ABL positive ALL were treated with IDEAMOP. All patients except two cases of early death (95%) attained CR. PCR negativity in bone marrow was achieved in 25% of the patients on day 28, in 57% on day 63, and in up to 73% during the follow-up period. Toxicity of the remission induction therapy was almost similar to that observed for chemotherapy alone. The median time of WBC recovery to at least 1,000/mL was 19 days (range, 14 to 29 days), and the median time of platelet recovery to at least 100,000/mL was 22 days (range, 14 to 30 days). Death occurred in two patients, one for pulmonary bleeding on day 10, and the other for pneumonia on day 32. Interruption of imatinib was implemented for 11 patients (27%) for the following reasons; nausea in 4, GPT elevation in 3, pulmonary bleeding, pneumonia, fluid retention, ileus, amylase elevation in one patient, respectively; however, none of the 39 surviving patients dropped out the protocol due to intolerance of treatment. Four patients had a relapse during consolidation therapy after 4.0, 4.5, 4.9 and 10.3 months of CR. Allogeneic HSCT was performed for 20 patients (9 from a sibling donor, 8 from an unrelated donor, and 3 from unrelated cord blood) during their first CR. The 1-year event-free survival (EFS) and OS rates were estimated at 78% and 88%. Outcomes were superior to those in ALL93 study, where patients were treated with chemotherapy alone, in terms of CR rate, EFS, and OS (P 〈 0.0001, P 〈 0.0001, and P = 0.0118, respectively). In summary, our study demonstrated that IDEAMOP produces high-quality CR for a majority of patients with newly diagnosed BCR-ABL positive ALL without an increase in toxicity. This is especially useful for providing patients with a better chance to receive allogeneic HSCT. Long-term efficacy will be addressed in the final analysis of this study.

Description: Between 2001 and 2005, JALSG conducted a randomized study to assess the optimal post remission therapy for adult AML in the first CR. JALSG AML201 enrolled 1064 previously untreated AML patients (pts) aged 15–64 yrs. The induction therapy consisted of cytarabine (Ara-C 100mg/m2 day1–7) and idarubicin (IDR 12mg/m2 day1– 3) (arm A) or cytarabine (100mg/m2 day1–7) and daunorubicin (DNR 50mg/m2 day1– 5) (arm B). If the patients did not achieve remission after the first induction therapy, then the same therapy was given once more. Pts were categorized into good, intermediate or poor risk groups by risk factors based on the criteria established in previous JALSG AML studies. All CR pts were stratified according to the induction, the number of courses of induction, age and karyotype and were randomly assigned to the high dose Ara-C (HDAC) post remission regimen (arm C) or the conventional JALSG post remission regimen (arm D). Arm C: the three courses of HDAC which consisted of Ara-C 2.0g/m2 q12h day1–5, arm D: the first course consisted of Ara-C 200mg/m2 day1–5+ mitoxantrone (MIT) 7mg/m2 day1–3, 2) Ara-C 200mg/m2 day1–5+ DNR 50mg/m2 day1–3, 3) Ara-C 200mg/m2 day1–5+ aclarubicin (ACR) 20mg/m2 day1–5, 4) Ara-C 200mg/m2 day1–5+ etoposide (ETP) 100mg/m2 day1–5 + vincristine (VCR) 0.8mg/m2 day 8 + vindesine (VDS) 2 mg/m2 day10. Results: Of the 1064 pts registered, 1057 pts (median age: 47 years) were evaluable. 825 pts (78%) achieved CR after one or two courses of induction therapy. Of the 825 pts in CR, 781 pts were assigned to arm C or arm D. The 4-year OS rate of arm C was 61.6% while that of arm D was 62.8% (p=0.58). The 4-year RFS rate of the CR patients was 42.8% in arm C and 40.8% in arm D (p=0.65). Among the good risk group, the 4-year OS rate of arm C was 77.0% while that of arm D was 75.8 % (p=0.40), and the 4-year RFS rate of arm C was 54.6% while that of arm D was 53.1% (p=0.71). Among the intermediate risk group, the 4-year OS rate of arm C was 63.2% while that of arm D was 65.7% (p=0.78), and the 4-year RFS rate of arm C was 38.7% while that of arm D was 42.2% (p=0.63). Among the poor risk group, the 4-year OS rate of arm C was 36.3% while that of arm D was 34.1% (p=0.71), and the 4-year RFS rate of arm C was 25.9% while that of arm D was 6.6% (p=0.17). In the CBF leukemia group, the 4-year OS rate of arm C was 79.4% while that of arm D was 66.5% (p=0.09), and the 4-year RFS rate of arm C was 57.7% while that of arm D was 43.7% (p=0.14). Among the young group (=50 yrs), the 4-year OS rate of arm C was 53.4% while that of arm D was 57.7% (p=0.90), and the 4-year RFS rate of arm C was 39.1% while that of arm D was 33.8% (p=0.67). Conclusion: The conventional post remission therapeutic regimen established by JALSG consisting of 4 courses of consolidation was thus found to be as effective as the three courses of HDAC therapy. To further confirm these results, a longer follow-up is therefore needed.

Description: Background: The dose of imatinib 400 mg is considered to be standard for chronic-phase chronic myeloid leukemia (CML) based on the IRIS study. However, the optimal dose of imatinib is not yet settled and the response of lower dose imatinib has not been investigated. Lower dose of imatinib might be enough in Asian patients since the results of PK in IRIS study showed weak correlation between imatinib trough level and body weight. We showed the results of the interim analysis of JALSG CML202 study and analyzed the efficacy of imatinib according to the mean daily dose level. Methods: The objectives of CML202 study are to determine the efficacy of imatinib monotherapy in patients with newly diagnosed chronic-phase CML, and to test whether combining imatinib with IFN or cytarabine ocfosfate overcome the resistance of imatinib and to estimate the frequency and severity of toxicities. Primary end point of imatinib monotherapy was overall survival, and that of combination therapy was cytogenetic response after 9 months. Newly diagnosed patients with chronic phase CML will receive imatinib at a dose of 400mg daily. At 9 months, if patients don’t achieve major cytogenetic response (MCR), they were randomized to the combination therapies, imatinib plus conventional IFN or imatinib plus cytarabine ocfosfate. Results: From 2002 to 2006, 489 patients were enrolled to this study. On July 2007, 36 months median follow-up data were analyzed. Only 2 patients were enrolled to the combination therapy because a majority of patients achieved good response. 13 patients underwent HSCT. The estimated cumulative rates of complete hematologic response (CHR), MCR and complete cytogenetic response (CCR) were 97%, 97% and 91%, respectively. The estimated major molecular response (MMR) rate at 24 months was 55%. The estimated survival without AP/BC progression rate at 60 months was 94%. The overall estimated survival at 60 months was 94%. 95% of low risk patients achieved CCR significantly as compared with intermediate and high-risk patients according to Sokal risk. The mean daily dose of imatinib for the first 2 years was 400mg or more in 54% patients (400mg group), 300–399mg in 27% (300mg group), 200–299mg (200mg group) in 11%, and 100–199mg in 9% (100mg group), respectively. The cumulative rate of MCR and CCR at 60 months was 99% and 97% in 400mg group, 99% and 98% in 300mg group, 92% and 85% in 200mg group, and 81% and 48% in 100mg group, respectively (p=0.003 and p