ALBERT

Description: Backgroud: Allogeneic marrow transplantation remains the only proven curative therapy for CML, but many patients have no suitably HLA matched related donor. Recently, we developed a new method for HLA-mismatched /haploidentical transplantation without in vitro T cell depletion. Conditioning including antithymocyte globulin followed by un-manipulated HLA-mismatched/haploidentical blood and marrow achieved comparable outcomes to HLA identical sibling transplantation. So good outcomes of HSCT from mismatched family donor for CML patients could be expected. Methods: 81 consecutive patients received mismatche family donor HSCT for CML were analyzed. There are 40 cases in CP1, 10 cases in CP2 after BC or AP, 14 cases in AP and 17 cases in BC pre-HSCT. Patients received the modified BuCy2 regimen consisting of cytarabine, busulfan, cyclophosphamide, Me-CCNU and ATG. Both of donor G-BM (G-CSF immobilize ) and G-PB were harvested and infused to recipients. All patients were given CsA/MTX and MMF for prophylaxis of GVHD. Results All patients achieved full donor chimerism. The cumulative incidence of aGVHD is 62.71% (CI 57.3– %−68.2%), grade III–IV is 24.69% (CI 28.7 %−30.7 %). 2 yrs cumulative incidence of cGVHD was 56.48 % (CI 49.6 %–−53.4%). 2 years OS is 71.33%(CI 66%–−76.7%), 2-year LFS were 61.23% (CI 54.66%–−67.8 %). The cumulative incidence of relapse is 17.74% (CI 11.3%–−14.2 %). The incidence of relapse in CML-CP1, CP2, AP and BC group pre-HSCT were 10.8% (CI 2.67%–18.95%), 0%, 9.2% (CI 0.5%–− 17.9%) and 42.71% (28.47%–56.95%%), with P=0.0150. The OS in CML-CP1, CP2, AP and BC group pre-HSCT were 67.66% (59.93%–75.39%), 83.33% (68.12%±098.54%), 77.38% (65.88%±88.90%), 69.68 % (58.32%±81.04 ) with p=0.7876. Conclusion For patients with CML without an HLA identical sibling donor, haploidentical family members can be an alternative donor for HSCT. In our HSCT protocol, survival of HSCT for CML in advanced stage was no worse than that in stable stage. The optimal time of HSCT for CML patients from MM-family donors need to be further studied.

Description: Abstract 3853 Background With the incorporation of more aggressive therapies such as hematopoietic stem cell transplantation (HSCT), more myelodysplastic syndromes (MDS) patients fall into a status of minimal residual disease (MRD). The sensitive molecular markers are required to monitor MRD and predict relapse. The Wilms' tumor gene (WT1) is now a widely accepted molecular marker of MDS. However, WT1 itself could not fully meet the demands because a subset of MDS patients does not overexpress WT1, and the increase of WT1 expression compared with the normal control of MDS patients was mainly within 2-log. We wondered if the preferentially expressed antigen of melanoma (PRAME) gene could supplement WT1. Methods The PRAME and WT1 transcript levels were simultaneously measured in 312 bone marrow samples collected from newly diagnosed MDS patients and 27 samples from non-malignant cytopenia patients. Bone marrow samples from 14 MDS patients after their disease progression were also detected. To evaluate the value of combined detection of WT1 and PRAME transcripts, one hundred and eleven BM samples collected from 17 MDS patients during their treatment were tested them simultaneously (chemotherapy alone: 1 patient; HSCT:16 patients). Bone marrow samples from six MDS patients and five normal controls were sorted into the blasts (CD34+), nucleated erythrocytes (CD71+), immature myeloid cells (CD33+CD34-), and lymphocyte (CD45+high, low SSC) fractions by flow cytometry and measured the PRAME and WT1 transcript levels, respectively. We had previously established that the upper limits of the PRAME and WT1 transcript levels tested in normal bone marrow samples were 0.28% and 0.50%, respectively. Results None of the 27 non-malignant cytopenia patients overexpressed PRAME (median 0.085%, range 0.01%-0.28%) and WT1 (median 0.095%, range 0.0089%-0.36%). Both WT1 and PRAME were commonly overexpressed in MDS. Both the overexpression frequency and the 〉1-log increase expression frequency of PRAME were similar to those of WT1 (74.4 % vs 77.6%; 51.6% vs 49.0%; p〉0.05), and 88.1% of the patients overexpressed at least one marker. Moreover, the frequencies of PRAME expression with higher degrees of increase were significantly higher compared with those of WT1 expression (〉2-log increase: 30.8% vs 3.8%; 〉3-log increase: 9.0% vs 0%; all p

Description: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukemia (CML).Many patients have deep molecular responses(DMR), a prerequisite for TKIs therapy discontinuation. Many clinical studies have been done in discontinuation of TKIs worldwide. We aimed to explore the appropriate criteria for failure of TKIs discontinuation; and to observe the effect of interferon on patients with continuous low level positive BCR-ABL1 after TKIs discontinuation. Therefore, we analyzed the clinical data of 40 CML patients with DMR who have withdrawn TKIs from Match 2013 to January 2018. Eligible CML patients had received any TKI for at least 3 years, and had a confirmed deep molecular response for at least 2 year. The molecular relapse(MR) was defined as loss of major molecular response (MMR; BCR-ABL1 〉0.1% on the International Scale). The patients with MR would be prescribed TKI, and patients with 0.0032% 〈 BCR-ABL1IS

Description: Introduction CBF-acute myeloid leukemia (AML) is a heterogeneous disease that requires prognostic factors for patient differentiation. c-KIT mutations are predominantly detected in CBF-AML among AML cases, and reported frequencies vary significantly. To date, the clinical significance of c-KIT mutations in CBF-AML has been intensively studied; however, the results are controversial and a final conclusion has not been reached. Large-scale studies with subgroup analysis should be performed to elucidate the clinical effects of c-KIT mutations in CBF-AML. Methods A total of 351 patients with CBF-AML [t(8;21) (n = 253) or inv(16) (n = 98)] were included in this study. Overall, 250 patients [42 pediatric t(8;21);146 adult t(8;21); 11 pediatric inv (16) and 51 adult inv (16)] received standard treatment and underwent follow up. Induction therapy consisted of one or two cycles of combined anthracycline and cytarabine for adult patients, whereas cytarabine, idarubicin, and etoposide were used for pediatric patients. 131, 17, and 93 of the patients further received intermediate-dose cytarabine-based chemotherapy, chemotherapy with auto-hematopoietic stem cell transplantation (HSCT), and chemotherapy with allogeneic (allo)-HSCT for consolidation, respectively. c-KIT mutations in exon 8 and 17 were screened by direct sequencing. Patients who received allo-HSCT were censored at the time of transplantation for relapse and survival analysis to exclude the effects of allo-HSCT on outcome. The median follow up time was 10 months (3 to 93 months) for the 211 living patients. Results Overall, 36.5% (128/351) of the patients were found to have a c-KIT mutation. The frequencies of c-KIT mutations were similar between pediatric and adult patients with t(8;21) AML (41.7% vs. 38.5%, P 〉 0.05), whereas pediatric patients tended to have higher frequency of c-KIT mutations than the adult patients with inv(16) AML (53.8% vs 25.9%, P = 0.053). In adults, the frequency of c-KIT mutations was significantly higher in patients with t (8;21) than those with inv(16) (P = 0.043). In adults, the frequency of mutations in exon 17 was significantly higher in t(8;21) than inv(16) AML (P 〈 0.0001). In pediatric group, the frequencies of mutations in exon 17 and exon 8 were similar for t(8;21) and inv(16) AML (P 〉 0.05). The low PLT count (¡Ü 30∙109/L) in pediatric t(8;21) AML tended to be associated with the presence of c-KIT mutations ( P = 0.063). High white blood cell (WBC) count (〉10∙109/L), WBC index, and AML1-ETO transcript levels in adult t(8;21) AML patients were significantly correlated with the presence of c-KIT mutations (P = 0.015, 0.0051, and 0.030, respectively). Moreover, low CBF¦Â-MYH11 transcript levels in adult inv(16) AML tended to be significantly related to c-KIT mutations (P = 0.059). No difference was observed in CR rates between patients with and without c-KIT mutations (P 〉 0.05). c-KIT mutations were significantly associated with less reduction in fusion transcript levels after the first induction therapy in adult inv(16) patients (P = 0.021). c-KIT mutations in adult t(8;21) AML patients (n = 137) significantly correlated with higher CIR rates at 2 years and low 2-year DFS and OS rates (73.2% vs. 46.2%, P = 0.0070; 26.8% vs. 49.1%, P = 0.013; 48.9% vs. 65.7%, P = 0.0055, respectively. Figure 1). In contrast, c-KIT mutations had no impact on CIR, DFS, and OS rates in pediatric t(8; 21)(n = 42), as well as in adult inv (16) (n = 51; all P 〉 0.05. Figure 1). Multivariate analysis demonstrated that c-KIT mutation was the only independent prognostic factor for relapse (hazard ratio (HR) = 2.47, 95% CI = 1.25 to 4.86, P = 0.009) and DFS (HR = 2.23, 95% CI = 1.17 to 4.41, P = 0.016). Moreover, c-KIT mutation and PLT count were independent prognostic factors for OS (HR = 3.68, 95% CI = 1.57 to 8.63, P = 0.003; HR = 0.37, 95% CI = 0.16 to 0.87, P = 0.023). Conclusion CBF-AML is a heterogeneous disease with regard to c-KIT mutations. c-KIT mutations have a strong adverse impact on relapse and survival in adult t(8;21) AML. Grant support Nature Science Foundation of China (81170483 and 81370639) and Beijing Municipal Science & Technology Commission£¨Z141100000214011). Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3755 Objective: Assess the outcome of imatinib- and/or nilotinib-failure chronic myelogenous leukemia (CML) patients with pre-existing, highly nilotinib-resistant mutations (Y253H, E255K/V and F359V/C), during dasatinib therapy. Methods: Sixty-one CML patients who failed imatinib (n=44) or imatinib and nilotinib (n=17), including 20 in chronic phase (CP), 16 in accelerated phase (AP) and 25 in blast phase (BP), were switched to dasatinib, except for patients with highly dasatinib-resistant mutations (T315I/A, F317L/V/I/C and V299L). Patients were grouped into 3 cohorts: no mutation (n=22), no-specific mutation (any mutation except highly nilotinib-resistant mutations; n=15), or specific mutation (Y253H, E255K/V or F359V/C; n=24), according to baseline BCR-ABL mutation status. Cumulative incidence frequencies of hematological response (HR), complete hematological response (CHR), major cytogenetic response (MCR), complete cytogenetic response (CCR) and major molecular response (MMR) were compared. Probabilities of clinical resistance to dasatinib (according to European LeukemiaNet recommendations), progression-free survival (PFS) and overall survival (OS), and dynamics of BCR-ABL mutations during dasatinib therapy were also assessed. Results: Prior nilotinib was associated with a higher proportion of specific mutation versus no mutation (50.0% vs 13.6%, P=0.001) and non-specific mutation (50.0% vs 13.3%, P=0.02). Patients harboring specific mutation also had a higher frequency of advanced phase CML before dasatinib treatment than patients with no mutation (83.3% vs 50.0%, P=0.008), and a similar frequency to those with non-specific mutation (83.3% vs 66.7%, P=0.266). Response, PFS and OS rates, and follow-up duration were similar among the 3 cohorts by baseline mutation status, as shown in Table. Probability of clinical resistance to dasatinib in patients with specific mutation was not significantly different to those with no mutation (54.2% vs 77.3%, P=0.100) or non-specific mutation (54.2% vs 33.3%, P=0.204) despite that there was a significant difference between the cohort with no mutation and non-specific mutation (77.3% vs 33.3%, P=0.008). Among 32 patients who developed clinical resistance to dasatinib and were assessed for BCR-ABL mutation status, newly detectable mutations were identified in 14 patients and most frequently occurred in those already harboring specific mutation versus those with no mutation (76.9% vs 26.7%, P=0.008) and non-specific mutation (76.9% vs 0%, P=0.015) at baseline. T315I (9/14, 64.3%) was the most common newly acquired BCR-ABL mutation. Harboring specific mutation compared with other mutation states at baseline (76.9% vs 16.7%, P=0.001), and developing hematological resistance rather than cytogenetic resistance during dasatinib therapy (65.0% vs 8.1%, P=0.002), were identified as risk factors associated with the development of new mutations. Conclusions: Imatinib- and/or nilotinib-failure patients with highly nilotinib-resistant BCR-ABL mutations demonstrate similar efficacy to dasatinib as those with no or any other mutation. However, patients with highly nilotinib-resistant mutations had a higher likelihood of developing new mutations at the time of clinical resistance. More extensive studies are needed to assess the significance of various BCR-ABL mutations prior to and during tyrosine kinase inhibitor therapy for CML. Disclosures: No relevant conflicts of interest to declare.

Description: Background In China, the incidence of aplastic anemia (AA) is about 0.74/105, with 0.14/105 of severe aplastic anemia (SAA). Most of these SAA patients are treated in big medical centers or traditional Chinese medicine (TCM) hospitals, which could stand for the current practices in China. Despite the China Aplastic Anemia Consensus, published in 2010, recommended that the immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT) were the standard treatment for SAA, very severe aplastic anemia (VSAA) and transfusion-dependent non-severe aplastic anemia (TD-NSAA), the current treatment options for patients with these diseases are diverse, including antithymocyte globulin (ATG)/antilymphocyte globulin (ALG) + cyclosporin A (CsA), CSA + androgen, CSA or androgen alone, only supportive care, TCM, etc. This national disease registry study aimed to describe the current clinical practice and treatment patterns for SAA, VSAA and TD-NSAA patients in China and understand their IST patterns as well as the supportive care measures. Methods In this prospective, multi-center, observational study, adult or pediatric patients diagnosed as acquired aplastic anemia within 3 months and met the guideline criteria of SAA, VSAA or TD-NSAA were enrolled from October 2012 to April 2014. All enrolled patients will be followed at least for one year. Each subject will be visited every 3 months in the first year and every 6 months from the second year until the patients withdraw the ICF or study close. The main evaluation criteria is the treatment patterns of SAA, VSAA and TD-NSAA which will be specified as: IST (ATG + CsA, CsA + androgen, CsA and others), HSCT, TCM, androgen, supportive care and others. The response of SAA/VSAA and TD-NSAA after each treatment, and serious adverse events, will also be evaluated by the investigators. An interim analysis is planned when all patients have been enrolled (target N=350) and will focus on their baseline characteristics and first treatment choice. This study was sponsored by Sanofi. Results A total of 352 patients were enrolled at 29 sites in China (SAA 221 pts; VSAA 84 pts; TD-NSAA 47 pts). The median age was 21 years (range, 0-84) and 65.1% were adults. 51.7% were male and 71.6% had ECOG PS

Description: Abstract 162 Background and Aims. The relative merits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia (CML) in the first chronic phase (CP) in the imatinib era have not previously been evaluated. This prospective cohort study was designed to compare the medical outcomes and quality of life (QOL), with imatinib versus allo-HSCT from an HLA-matched sibling donor for CML in the first CP including the early CP (ECP; a CML duration 〈 12 months) and the late CP (LCP; a CML duration ' 12 months). Patients and methods. From April 2001 to April 2010, patients treated consecutively at the Peking University People's Hospital, Peking University Institute of Hematology were nonrandomly assigned to treatment with imatinib or allo-HSCT according to whether the patient had an HLA-matched sibling donor; those with an HLA-identical sibling donor were assigned to the allo-HSCT group, and the others were assigned to the imatinib group. QOL of surviving patients still in the imatinib and allo-HSCT groups was measured by the Medical Outcomes Survey Short Form 36 (MOS SF-36) at the end of the study evaluation period in April 2011. Results. In total, 463 patients were recruited, 209 patients were assigned to the allo-HSCT group and 254 patients were assigned to the imatinib group, respectively.Based on a ten-year follow-up period, a multivariate analysis revealed that allo-HSCT was an independent adverse prognostic factor for event-free survival (EFS; estimated HR=2.4, P=0.002 and estimated HR=0.31, P