Difference In Complete Remission Rate Research Articles

Therapeutic Response and Prognosis of Adult Acute Myeloid Leukemia with Chromosome Karyotype Abnormalities

To investigate the efficacy and prognosis of acute myeloid leukemia (AML) patients with chromosome karyotype abnormalities. The clinical features and treatment responses of 91 patients with AML were collected and analyzed retrospectively. The efficacy and survival rate of the AML patients with normal and abnormal chromosome karyotype were compared. Chromosome translocations and monosomal karyotypes were the main heterogeneity of AML. There was no significant difference in complete remission rate and overall response rate between the normal and abnormal karyotype groups, but the recurrence rate was higher in abnormal karyotype group. There was no significant difference in response of AML patients received the standard "3+7 regimen" and pre-excitation chemotherapy in the treatment of normal and abnormal karyotype groups. The relapse free survival time (RFS) was longer in the normal karyotype group, but there was no significant difference in overall survival time (OS). The abnormal karyotype of AML is an independent prognostic factor, monosomal karyotype shows a poor prognosis, and the recurrence rate in AML patients with monosomal karyotype is higher.

Analysis of Factors Predicting Treatment Response of 254 Patients Who Received CD19-Targeted CAR-T Cell Therapy for Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Backgrounds Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has demonstrated 80-90% complete remission (CR) rate in R/R B-ALL; however, 10% to 20% of patients have no response and the potential etiology and risk factors remain unclear. Patients and Methods From Apr. 2017 to Mar. 2019, 254 patients with R/R B-ALL received treatment at our single center with a second-generation CD 19 CAR-T from 5 companies (NCT03173417; ChiCTR-ONC-17012829; NCT02546739; ChiCTR1800016541; and NCT03671460). The targeted median infused CAR-T cell dose was 3x105/kg. For all patients, screening was undertaken for 58 types of B-ALL related gene mutations and 49 congenital immune deficiency gene mutations using next generation sequencing (NGS) method. The patient and CAR-T product characteristics were analyzed to see if any factors affected the initial CR rate. Univariate analysis comparing CR rates between subgroups were carried out using chi-squared tests. Logistic regression model was adopted for multivariate analysis. Results On D30, 90.6% (230/254) patients achieved CR, and minimal residual disease (MRD)-negative CR was 89.4% (227/254). Univariate analysis (Table 1&2) showed a statistical difference in CR rate between females and males (84.54% vs. 94.27%, p=0.011). The CR rate of patients who received prior either CAR-T or blinatumomab treatment was lower than those who had not (50% vs. 91.53%, p=0.01). For the characteristic fusion genes, the CR rate in patients with MLL-AF4 was 80%, which was inferior to those with other or no fusion genes (P=0.041). For gene mutations, a lower CR rate was observed in patients with TP53 mutation compared to those with other or no mutations (72.73% vs. 92.11% vs. 94.39%, P=0.004). Presence of congenital immune deficiency gene mutations did not affect CR rate. Patients with >20% bone marrow (BM) blasts had a worse outcome than those with BM blasts≤20% (79.17% vs. 97.47%, p<0.001). There were no differences in CR between patients age 1-14 yr and >14 yr, patients with or without extramedullary disease (EMD), or patients receiving different chemotherapies between enrollment and CAR-T cells infusion on top of fludarabine and cyclophosphamide (FC) conditioning regimen. Cytokine release syndrome (CRS) and neurotoxicity had no effect on CR rate.There was a trend towards a lower CR rate in patients who received donor-derived CAR-T versus patient-derived CAR-T products (61.54% vs. 92.12%, p = 0.081). A lower CR rate was observed in patients who received CD28 costimulatory domain versus 4-1BB CAR-T products (77.27% vs. 91.70%, p=0.053). There was no difference in CR rate between patients infused with cell dose ≥3x105/kg vs. cell dose <3x105/kg and >2x104/kg. No CR difference was observed from different manufacturing companies. Moreover, 125/254 cases had available data for analysis on subsets of CAR-T cells including central memory T cells (Tcm), naive T cells and T memory stem cells (Tscm). Each group was divided into high- or low-level groups based on the median level. The CR rate was 92.19% vs. 88.52% in high and low Tcm groups, 92.31% vs. 88.33% in high or low naive group, and 89.80% vs.90.24% in high and low Tscm groups, respectively. No difference in CR between the groups were observed. Multivariate analysis was performed to investigate factors affecting achievement of CR (Table 3). Female group had lower odds of achieving CR after CAR-T therapy compared to male group [OR=0.232(95%CI 0.082-0.652)]. Compared to patients without TP53 mutation or only with other gene mutations, patients with TP53 mutation were more likely to have a low CR rate after CAR-T treatment [OR=4.511(95%CI 1.295-16.895)]. Patients with BM blast >20% had lower odds of achieving CR compared to those with BM blast ≤20% [OR=0.095 (95%CI 0.022-0.260)]. Treatment with CAR-T with CD28 as a costimulatory domain resulted lower odds of CR compared to treatment with CAR-T with 4-1BB [OR=7.141 (95%CI 1.722-29.612)]. Patients who developed severe neurotoxicity (grade 2-4) post CAR-T had higher odds of achieving CR compared to patients with grade 0-1 neurotoxicity [OR=34.796(95%CI 3.232-374.659)]. Conclusions In this analysis, we have observed that significant risk factors for not achieving CR after CD-19 CAR-T therapy include female gender, BM blasts more than 20%, a positive TP53 mutation, treatment with CD28 co-stimulatory domain vs 4-1BB CAR-T product, and mild as opposed to severe CAR-T related neurotoxicity. Disclosures No relevant conflicts of interest to declare.

Comparison of Different Upfront Transplant Strategies in Multiple Myeloma - a Large Registry Study from Chronic Malignancies Working Party of EBMT

Comparison of Different Upfront Transplant Strategies in Multiple Myeloma - a Large Registry Study from Chronic Malignancies Working Party of EBMT

Coexisting mutations in NPM1-mutated elderly adults with acute myeloid leukemia

Objective: To explore the coexisting mutations in NPM1 mutated elderly patients with acute myeloid leukemia(AML). Methods: The clinical data of 152 elderly adults(aged≥60 years) and 49 young adults(aged 18-45 years) with AML between June 2013 and December 2018 in outpatient and hospitalized patients of Changzhou Second People's Hospital and Wuxi Second People's Hospital were retrospectively analyzed. A total of 51 gene mutations were detected using targeted next-generation sequencing (NGS) and sanger sequencing. The general clinical characteristics, the occurrence of coexistence gene mutations, the correlation between coexistence gene mutations and some clinical parameters, and the initial induction remission rate between elderly and young adult AML patients with NPM1 mutations were analyzed and compared. Results: NPM1 mutations were detected in 46 of 152 elderly AML patients. Thirty eight patients (82.6%) with NPM1 mutations carried other gene mutations at the same time, among whom 8 patients (17.4%) carried NPM1 mutations alone, while 14(30.4%) carried 2, 16 (34.8%) carried 3, and 8 (17.4%) carried ≥ 4 mutations. NPM1 mutations frequently co-occurred with FLT3-ITD15 cases (32.6%) , DNMT3A10 (21.7%) , TET26 (13.4%) and FLT3-TKD5 (10.9%) . Compared with young adults with NPM1 mutations, elderly patients had higher TP53, FLT3-TKD rates, lower incidence of DNMT3A, RAS mutation (all P<0.05) and lower coexistence rate of 4 gene mutations (P=0.002).The presence of ≥ 4 mutations was found to be significantly associated with higher white blood level than those in patients with single, double and 3 mutations coexisted in elderly adults AML patients(all P<0.05). With the increase of the amount of mutations, the complete remission(CR) rate decreased gradually after the initial induction. Patients who carried 3 or more mutations showed a lower CR rate than those with single gene mutations (all P<0.05) . Patients who carried>4 genes also showed a significantly lower CR rate than those with double gene mutations (P=0.031). Patients with FLT3-ITD mutations exhibited higher white blood level and lower CR rate than that in nonmutant type group (all P<0.05). The CR rate of patients with DNMT3A mutation was also significantly lower than that with nonmutant type (P=0.033). However, patients with FLT3-TKD mutations showed a higher platelet level than that with nonmutant type (P=0.019). There was no significant difference in CR rate and peripheral blood cell level between TET2 mutated and nonmutant type. Conclusion: NPM1 mutated elderly patients with AML commonly show additional mutations, and the amount and type of coexisting mutations have an influence on the clinical features and CR rate of elderly patients with AML.

Impact of FLT3-ITD allele ratio and ITD length on therapeutic outcome in cytogenetically normal AML patients without NPM1 mutation.

Mutations of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) contribute to poor prognosis in cytogenetically normal acute myeloid leukemia (CN-AML). Chemotherapy has limited effect, while allogeneic hematopoietic stem cell transplantation (allo-HSCT) plus sorafenib maintenance is a promising protocol to improve their therapeutic outcome. However, the prognostic significance of FLT3-ITD mutant status remains controversial. To investigate this, we detected FLT3-ITD mutant ratio (high and low) and length (long and short) in enrolled 184 CN-AML patients without NPM1 mutation, and evaluated their impact on complete remission (CR), overall survival (OS), relapse-free survival (RFS) and relapse risk (RR) after chemotherapy or allo-HSCT plus sorafenib maintenance. Our studies showed that FLT3-ITD mutation had negative impact on chemotherapeutic response, OS and RFS in CN-AML patients. There was no significant difference in CR rate between high and low ratio, or long and short length. Increasing ITD mutant ratio and length were associated with decreasing OS, and long length had shorter RFS and higher RR than the short after chemotherapy. Allo-HSCT plus sorafenib maintenance was an effective strategy to improve RFS and decrease relapse probability in FLT3-ITD AML patients, and benefited to these regardless of mutant ratio, and those with long length instead of the short.

Efficacy of Hyper-CVAD/MA and CHALL-01 regimens in the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia patients under 60 years old

目的比较传统Hyper-CVAD/MA方案及借鉴儿童急性淋巴细胞白血病（ALL）的新化疗方案CHALL-01在≤60岁成人Ph阳性ALL（Ph+ ALL）中的临床疗效。方法回顾性分析2007年1月至2017年12月第二军医大学附属长海医院及长征医院收治的158例Ph+ ALL患者（除外慢性髓性白血病急变期患者），其中Hyper-CVAD/MA组63例，CHALL-01组95例，诱导及巩固化疗期间联合酪氨酸激酶抑制剂（TKI）治疗，有合适供者的患者进行造血干细胞移植，并用TKI进行维持治疗。结果经过1~2个疗程的诱导治疗，91.1%（144/158）患者获得完全缓解（CR），其中Hyper-CVAD/MA组CR率为90.5%（57/63），CHALL-01组CR率为91.6%（87/95），两组间差异无统计学意义（χ2=0.057，P=0.811）。随访截止于2018年6月，共134例CR患者可进一步分析，其中Hyper-CVAD/MA组53例，CHALL-01组81例。CHALL-01组达到分子学缓解的比例显著高于Hyper-CVAD/MA组（完全分子学反应率：44.4%对22.6%，主要分子学反应率：9.9%对18.9%）（χ2=7.216，P=0.027）。Hyper-CVAD/MA组和CHALL-01组4年总生存率分别为44.81%（95%CI 30.80%~57.86%）和55.63%（95%CI 39.07%~69.36%）（P=0.037），4年无病生存率分别为37.95%（95%CI 24.87%~50.93%）和49.06%（95%CI 34.24%~62.29%）（P=0.015）。两组在4年累积复发率（P=0.328）及无复发死亡率（P=0.138）上差异无统计学意义。CHALL-01组肺部感染发生率较Hyper-CVAD/MA组明显减低（43.4%对67.9%，χ2=7.908，P=0.005）。结论CHALL-01方案治疗成人Ph+ ALL疗效优于Hyper-CVAD/MA方案，肺部感染发生率低，分子学缓解率高，可以提高Ph+ ALL患者的生存率。

Clinical and biological features of mixed-phenotype acute leukemia: an analysis of 24 cases

Objective To investigate the clinical and biological features of patients with mixed-phenotype acute leukemia (MPAL). Methods The clinical data of 24 de novo adult patients with MPAL who were admitted to Fujian Medical University Union Hospital from January 2012 to October 2018 were retrospectively analyzed. These patients were diagnosed according to the World Health Organization (WHO) 2016 criteria. The clinical and biological characteristics of the patients were analyzed by morphological and cytochemical staining, immunophenotyping, cytogenetics and molecular biology. Results Of the 24 patients, 16 were male and 8 were female, and the median age of the patients at diagnosis was 27 years old (5-66 years old). The average blasts of bone marrow were (57.41±23.20)%. Thirteen cases (54.2%) were diagnosed as MPAL morphologically, while 5 cases (20.8%) were diagnosed as acute myeloid leukemia (AML), 5 cases(20.8%) were diagnosed as acute lymphoblastic leukemia (ALL) and 1 case (4.2%) was inconclusive. Eighteen patients(75.0%) co-expressed B-lymphoid and myeloid markers, while 5 patients (20.8%) with T-lymphoid and myeloid markers and 1 patient (4.2%) with B-lymphoid and T-lymphoid markers, respectively. The positive rate [median (range)] of CD38, HLA-DR and CD34 was 90.5% (0.1%-99.7%), 90.1% (1.1%-98.8%) and 81.3% (0.1%-97.8%), respectively. Eighteen cases underwent chromosome examination, of which 5 cases carried with t(9;22)(q34;q11), 3 cases with t(v;11q23.3), 2 cases with complex karyotypes, and 2 cases with t(9;22)(q34;q11) and complex karyotypes, respectively. Twenty-one cases underwent genetic examination, of which 6 cases were positive for BCR-ABL, 3 cases were positive for MLL, 1 case was positive for MLL and BCR-ABL, 1 case was positive for BCR-ABL and TP53, and 1 case was positive for PHF6 and ASXL1 respectively. Of the 24 patients, 7 refused chemotherapy and 17 received induction chemotherapy. Of the patients receiving chemotherapy, 9 cases achieved complete remission (CR), 1 case was partial remission (PR), and 7 cases were not relieved (NR). In 11 patients treated by ALL-type induction regimen and 6 patients treated by ALL and AML-type induction regimen, 8 cases and 1 case achieved CR, the difference in CR rate was statistically significant (P < 0.05). In 6 patients with Philadelphia chromosome (Ph) positive and 11 patients with Ph negative, 1 case and 8 cases achieved CR, the difference in CR rate was statistically significant (P < 0.05). The median follow-up time was 5.5 months (0-36 months). The 3-year overall survival (OS) rate was 17.5% and the median OS time was 6 months. The 3-year OS rates in the allogeneic hematopoietic stem cell transplantation and non-transplanted groups were 75.2% and 0, respectively, and the median OS time was not reached and 4 months (P < 0.05). Conclusions MPAL is rare, it mostly co-expresses lymphoid and myeloid antigens and shows a much higher incidence of CD34, CD38 and HLA-DR. MPAL is often associated with Ph positive and complex karyotypes. MPAL has a low remission rate and poor prognosis, and a reasonable and effective treatment plan should be further explored. Key words: Leukemia, mixed-phenotype, acute; Immunophenotyping; Prognosis

Clinical analysis of expression of CD47 in patients with multiple myeloma

Objective To investigate the expression of CD47 in multiple myeloma (MM) and its clinical significance. Methods From September 2016 to May 2018, all of 25 cases of MM patients who were diagnosed and treated in Hongqi Hospital Affiliated to Mudanjiang Medical University were selected as research subjects, and enrolled in study group. In study group, there were 15 males and 10 females with the age of (58.5±4.2) years. Twelve MM patients were treated with CTD (cyclophosphamide+ thalidomide+ dexamethasone) regimen and the rest 13 cases with VAD (vincristine+ pirarubicin+ dexamethasone) regimen. Six cases of individuals who received physical examination in the same period and the same hospital were included in control group. In control group, there were 3 males and 3 females with the age of (56.3±4.1) years. CD47 expression levels of mononuclear cells in bone marrow from MM patients and peripheral blood from healthy individuals were detected by flow cytometry. Relationships between CD47 expression in MM patients and complete remission (CR), recurrence in study group were analyzed. The positive expression rate of CD47 of subjects in two groups, and CR rates of MM patients with different treatment regimens and CD47 expressions in study group were compared by Fisher′s exact probability method. The procedure of this study is accordance with the requirement of the revised World Medical Association Declaration of Helsinki in 2013. Informed consent was obtained from all participants. Results ① CD47 positive expression rate of MM patients in study group was 40.0% (10/25), and was significantly higher than that of 0(0/6) in control group, and the difference was statistically significant (P=0.018). ② In study group, CR rate of MM patients with positive CD47 expression was 20.0% (2/10), and was significantly lower than that of 73.3% (11/15) in patients with negative CD47 expression, and the difference was statistically significant (P=0.013). CR rate of MM patients receiving CTD regimen with positive CD47 expression was 16.7% (1/6), and was significantly lower than that of 83.3% (5/6) in pactients with negative CD47 expression, and the difference was statistically significant (P=0.040). CR rate of MM patients receiving VAD regimen with positive CD47 expression was 16.7% (1/6), and was significantly lower than that of 85.7%(6/7) in patients with negative CD47 expression, and the difference was also statistically significant (P=0.029). ③ There was no statistically significant difference in CR rate between patients with positive CD47 expression who were treated with VAD and these who were treated with CTD regimen (P=0.773). And there was no statistically significant difference in CR rate between patients with negative CD47 expression who were treated with VAD and these who were treated with CTD regimen (P=0.731). ④ All 2 MM patients with positive CD47 expression who obtained CR, and 2 of 11 MM patients with negative CD47 expression had relapsed. Conclusions The expression rate of CD47 on bone marrow mononuclear cells in MM patients was significantly higher and was related to curative effect and prognosis of MM patients. CD47 may be used as a potential auxiliary evaluation indicator for efficacy and prognosis in MM. This conclusion is limited to the clinical analysis of a small sample, and it requires large sample, multi-center, randomized controlled trials for further study and verification. Key words: Multiple myeloma; Antigens, CD47; Phagocytosis; Treatment outcome; Prognosis

Analysis of induction efficacy and prognostic factors in FLT3-ITD positive acute myeloid leukemia in the real world

目的探讨真实世界FLT3-ITD突变阳性急性髓系白血病（FLT3-ITD+AML）诱导治疗的疗效及预后影响因素。方法收集2013年1月至2016年12月收治的初发FLT3-ITD+AML患者114例，了解患者初诊时生物学特征，采用化疗方案进行诱导治疗，随访病例，并对其缓解率、预后等进行分析。结果114例FLT3-ITD+AML患者初诊时分子学检测发现伴随预后良好基因突变52例（NPM1突变46例，RUNX1-RUNX1T1 5例，CEBPA双突变1例）；其他类型FLT3-ITD+AML 62例。所有患者均至少完成1个疗程的诱导治疗并进行了疗效评估，1个疗程完全缓解（CR）率为50.0%（57/114），2个疗程CR率为72.5%（74/104）。52例伴随预后良好基因突变的FLT3-ITD+AML患者1个疗程CR率为67.3%（35/52），2个疗程CR率为83.3%（40/48）；62例其他类型FLT3-ITD+AML患者1个疗程CR率为35.5%（22/62），2个疗程CR率为64.8%（35/54）；两组CR率差异有统计学意义（P<0.05），显示FLT3-ITD伴随预后良好基因突变的AML患者治疗效果相对较好。对于其他类型FLT3-ITD+AML 1个疗程未缓解的患者，随后采用索拉非尼联合化疗的9例患者中6例达到CR，缓解率为66.7%；采用常规化疗方案的23例患者中7例达到CR，缓解率为30.4%，两者之间差异有统计学意义（χ2=4.47，P<0.05），显示索拉非尼联合化疗方案可以显著提高FLT3-ITD+AML不缓解患者的CR率。索拉非尼联合化疗与常规方案化疗患者总生存和无病生存比较，差异均无统计学意义（P值分别为0.641和0.517）。结论FLT3-ITD+AML患者整体预后不良，通过索拉非尼联合化疗的方案对不伴随预后良好基因突变的FLT3-ITD+AML进行分层治疗可以提高疗效。

Not type of induction therapy but consolidation with allogeneic hematopoietic cell transplantation determines outcome in older AML patients: A single center experience of 355 consecutive patients

Therapeutic decision making is often challenging in older AML patients. We collected retrospective data of 355 consecutive AML patients (≥60 years) who were treated with intensive chemotherapy (IC) (n = 155), hypomethylating agents (HMA) (n = 83), or best supportive care (BSC) (n = 117) between 2002 and 2017. Overall survival (OS) and response rates after therapy were analyzed. Multivariate Cox regression was performed to analyze the impact of different treatment strategies on survival. The median OS was not significantly different between patients treated with IC or HMA (14.9 vs 10.9 months; HR = 1.32, p = 0.076)), despite a difference in complete remission rate (59% after IC vs 35% after HMA). Patients who received a allogeneic hematopoietic cell transplantation (allo HCT) after treatment with IC or HMA had a significant survival benefit compared to patient who didn’t proceed to allo HCT (median OS 65 vs 8 months, respectively, p < 0.001). The type of induction therapy (i.e. IC or HMA) did not impact on survival after allo HCT (48 vs 65 months, respectively, p = 0.440). In conclusion, consolidation with an allo HCT provides a significant benefit for older AML patients independent of upfront treatment with IC or HMA. Our data suggest that more older patients should be considered for an allo HCT.

Human leukocyte antigen class II expression is a good prognostic factor in adult T-cell leukemia/lymphoma.

Attenuated human leukocyte antigen (HLA) class I expression is implicated as a major immune escape mechanism in several types of tumor. We previously reported that HLA class I/β2 microglobulin and programmed death ligand-1 expression are prognostic factors in adult T-cell leukemia/lymphoma. A recent report suggested that HLA class II expression is also an important prognostic factor for the clinical outcome of programmed death-1 blockade therapy in recurrent/refractory Hodgkin lymphoma. This prompted us to evaluate HLA class II expression in adult T-cell leukemia/lymphoma and to compare the findings with the patients’ clinicopathological features. Of the 132 biopsy specimens examined from newly diagnosed patients, lymphoma cells were positive for HLA class II expression in 44 patients (33.3%), whereas programmed death ligand-1 expression was observed on neoplastic cells from nine patients (6.9%) and on stromal cells in the tumor microenvironment in 83 cases (62.9%). HLA class II-positive cases showed a significantly better overall survival compared to the HLA class II-negative cases (P<0.0001). Patients positive for HLA class II and programmed death ligand-1 microenvironmental expression had significantly better prognosis than the other groups (P<0.0001). HLA class II-positive and HLA class II-negative groups also showed a significant difference in complete remission rate (P=0.0421), HLA class I/β2 microglobulin expression (P=0.0165), and the number of programmed death-1-positive tumor infiltrating cells (P=0.0020). HLA class II expression was a prognostic factor for overall survival both in univariate and multivariate analyses (P<0.0001 and P=0.0007, respectively). Our study reveals that HLA class II is a novel prognostic factor in adult T-cell leukemia/lymphoma.

Phase I Trial of Carfilzomib + R-CHOP (CarR-CHOP) for Frontline Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Phase I Trial of Carfilzomib + R-CHOP (CarR-CHOP) for Frontline Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Clinical and Molecular Characteristics of Acute Myeloid Leukemia (AML) Patients with TP53 Mutations and TP73 Mutations

Introduction: Patients (pts) with AML who harbor TP53 mutations (TP53m) have a poor prognosis, with complete remission (CR) rates of 20-30% with standard intensive cytarabine/daunorubicin induction regimens (7+3) and median disease-free survival (DFS) of 4-6 months. There is a high risk of relapse after allogeneic stem cell transplantation (allo SCT) with 3-year overall survival (OS) of 10-12%. Another member of the p53 family is TP73, expressed as multiple protein isoforms that range in function from tumor suppressive activity to promoting oncogenic activities through control of cell survival and cell renewal. The TP73 gene resides in the short arm of chromosome 1; although this region is frequently deleted in a broad range of tumors, TP73 is rarely mutated in cancer. In the era of next-generation sequencing (NGS), TP73 mutations (TP73m) have not yet been described in AML to our knowledge. Herein we describe AML pts with TP73m and compare their outcomes with those of pts with TP53m and pts without TP73m or TP53m.Methods: Mutational assessment of 81 leukemia- and/or cancer-associated genes using a customized NGS approach was performed on samples from 1165 pts (age ≥18 years) with newly diagnosed AML, treated with standard 7+3 followed by cytarabine +/- anthracycline based consolidation (Eisfeld et al., Leukemia 2017;31:2211-8).We identified 3 groups of pts: wild-type (wt) for both TP53 and TP73,TP53m (including 2 pts with TP73m), and TP73m/TP53wt (TP73m). We made statistical comparisons between groups regarding co-mutations, mutational functional groupings, and outcomes using Fisher's exact test, Kruskal Wallis test, Kaplan-Meier curves, and log rank test.Results: We identified 106 pts with TP53m and 11 pts with TP73m; 1048 pts were confirmed to be wt for both. TP73m pts were all found to have missense mutations, with the majority of variant allele frequencies (VAF) >20%, suggesting these mutations likely represent early mutational events similar to TP53m. Evaluation of mutations in other genes in TP73m pts revealed that most frequent were FLT3-ITD (27%) and mutations in ASXL1 (18%), DNMT3A (18%), IDH2 (18%), NPM1 (36%), RUNX1 (18%), STAG2 (18%), TET2 (27%), and U2AF1 (18%) genes. Frequencies of these mutations were similar to those seen in wt pts, except for higher frequencies of STAG2 (P=.05) and U2AF1 (P=.05) mutations in TP73m pts. No mutation occurred in TP53m pts with a significantly higher frequency than that found in wt pts. However, FLT3-ITD (P<.001), FLT3-TKD (P<.001), and mutations in DNMT3A (P<.001), GATA2 (P=.02), NPM1 (P<.001), SMC1A (P=.04), and WT1 (P<.001) were less frequent in TP53m pts than in wt pts. Compared with TP53m pts, TP73m pts carried NPM1 (P=.005) and U2AF1 (P=.02) mutations more often than TP53m pts.Pretreatment characteristics of pts with TP73m were similar to those of wt pts, except for lower white blood cell counts (WBC) in the former (P=.05). No differences were seen between TP73m and TP53m pts. In contrast, compared with wt pts, TP53m pts were older (P<.001) and presented with lower platelet count (P=.05), WBC (P<.001) and blast percentage of both blood and bone marrow (P<.001 for both), and had less frequent extramedullary involvement (P=.04). Assessment of mutational functional group involvement showed that mutations in chromatin remodeling (P=.004), methylation (P=<.001), and NPM1 (P<.001) were less frequent in TP53m pts than in both TP73m and wt pts. TP53m pts also had fewer mutations in the kinases (P<.001) and RAS pathway (P<.006) compared to wt pts. TP73m pts had more cohesion group mutations than either TP53m (P=.01) or wt pts (P=.04).There were no significant differences in CR, DFS or OS between TP73m and wt pts. However, compared to both TP73m and wt pts, TP53m pts had shorter DFS (P=.005 for TP73m and P<.001 for wt, respectively), event-free survival (EFS) (P=.001 for TP73m and P<.001 for wt, respectively) and OS (P<.001 for both). CR rates of TP53m pts were worse than those of wt pts (P<.001), but there was no significant difference in CR rates between TP53m and TP73m pts (P=.12).Conclusion:TP73m are recurrently found in adult AML pts, albeit with a lower frequency than TP53m. TP73m does not appear to portend the poor prognosis seen in TP53m pts in regards to DFS, EFS and OS and have outcomes that appear to be similar to wt pts.Support: U10CA180821, U10CA180882, U10CA180861, U24CA196171; ClinicalTrials.gov Ids: NCT00048958, NCT00900224 [Display omitted] DisclosuresMims:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Kolitz:Magellan Health: Consultancy, Honoraria.

Isocitrate dehydrogenase 1 and 2 mutations, 2-hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia.

Acute myeloid leukemia (AML) cells harboring mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) produce the oncometabolite 2-hydroxyglutarate (2HG). This study prospectively evaluated the 2HG levels, IDH1/2 mutational status, and outcomes of patients receiving standard chemotherapy for newly diagnosed AML. Serial samples of serum, urine, and bone marrow aspirates were collected from patients newly diagnosed with AML, and 2HG levels were measured with mass spectrometry. Patients with baseline serum 2HG levels greater than 1000 ng/mL or marrow pellet 2HG levels greater than 1000 ng/2 × 106 cells, which suggested the presence of an IDH1/2 mutation, underwent serial testing. IDH1/2 mutations and estimated variant allele frequencies were identified. AML characteristics were compared with the Wilcoxon test and Fisher's exact test. Disease-free survival and overall survival (OS) were evaluated with log-rank tests and Cox regression. Two hundred and two patients were treated for AML; 51 harbored IDH1/2 mutations. IDH1/2-mutated patients had significantly higher 2HG levels in serum, urine, bone marrow aspirates, and aspirate cell pellets than wild-type patients. A serum 2HG level greater than 534.5 ng/mL was 98.8% specific for the presence of an IDH1/2 mutation. Patients with IDH1/2-mutated AML treated with 7+3-based induction had a 2-year event-free survival (EFS) rate of 44% and a 2-year OS rate of 57%. There was no difference in complete remission rates, EFS, or OS between IDH1/2-mutated and wild-type patients. Decreased serum 2HG levels on day 14 as a proportion of the baseline were significantly associated with improvements in EFS (P = .047) and OS (P = .019) in a multivariate analysis. Among patients with IDH1/2-mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy.

TET2 expression is a potential prognostic and predictive biomarker in cytogenetically normal acute myeloid leukemia.

TET2 (Ten-Eleven Translocation 2) gene is a member of TET family that can modify DNA through catalyzing the conversion of 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC). Although TET2 mutation has been disclosed in a variety of hematopoietic malignancies, the prognostic implication of TET2 expression in acute myeloid leukemia (AML) remains largely elusive. In this study, real-time quantitative PCR was carried out to detect the level of TET2 transcript in 134 de novo AML patients and 35 healthy donors. TET2 mRNA level was significantly down-regulated in AML patients compared with controls (p = 0.010). Among the French-American-British (FAB) subtypes, the incidence of TET2 under-expression in M0/M1 subtypes was significantly higher than in the other subtypes M2/M3/M4/M5/M6 (p = 0.017), and also markedly higher than in the other granulocyte subtypes M2/M3 (p = 0.005). TET2 low-expressed patients showed a significantly higher frequency of NPM1 mutations than TET2 high-expressed patients. Although there was no significant difference in complete remission rate between two groups (low and high TET2 expression), patients with low TET2 expression had markedly shorter overall survival (OS) in both non-M3 and cytogenetically normal AML (CN-AML) (p = 0.016 and 0.044, respectively). Furthermore, multivariate analysis confirmed the prognostic value of TET2 expression on OS among CN-AML patients (p = 0.049). Importantly, TET2 expression in complete remission (CR) time was significantly higher than newly diagnosis time (p = 0.001), and was returned to lower level when in relapse time (p < 0.001). These findings indicated that down-regulation of TET2 expression was a common event and acted as a prognostic and predictive biomarker in CN-AML patients.

Analysis of Clinical Characteristics and Prognosis of Mantle Cell Lymphoma With Gastrointestinal Involvement

Introduction: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by rapid disease progression. Studies on gastrointestinal (GI) involvement of MCL are lacking. In this study, we investigated the clinical features and prognosis of MCL with GI involvement. Methods: We retrospectively analyzed 64 patients who diagnosed MCL from January 2009 to April 2017 consecutively. At the time of MCL diagnosis, patients who were identified to have GI involvement by endoscopy or radiologic examination were assigned to the GI-MCL group. And those who were confirmed to have no GI involvement were assigned to the non GI-MCL group. The clinical characteristics and the outcomes of both groups were compared. Results: The GI-MCL group included 29 patients (45.3%). There were no significant differences in age and gender between the GI and non GI-MCL group. The stage of GI-MCL group was higher compared to the non GI-MCL group and all of 29 patients were stage IV. The mean of International Prognostic Index (IPI) score was also significantly higher in GI-MCL (2.97 vs. 1.97, p=0.047). Bone marrow involvement in the GI-MCL group was much greater than non GI-MCL group (69.0% vs. 40.0%, p=0.021). R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone combined with rituximab) was the most abundant in 1st line chemotherapy (44/64, 69.8%). After 1st line chemotherapy, 56 of 64 patients showed complete remission (87.5%). Although there was no difference in complete remission rate between the two groups, recurrence rate was much higher in GI-MCL group (72.% vs. 41.2%, p=0.024). A total of 15 patients received bone marrow transplantation (15/64, 23.4%). The median follow up period was 37 months and 11 out of 64 patients died during this period (17.2%). There was no significant difference in mortality between the two groups. Conclusion: The patients with MCL invading GI tract tended to have advanced stage, higher IPI score, more bone marrow involvement and more recurrence than MCL not involving the GI tract. Endoscopic examination to rule out GI involvement in patients with MCL is warranted.

Daunorubicin 90 mg/m 2 in Acute Myeloid Leukemia Induction: Increased Toxicity in Young Patients

The combination of an anthracycline and cytosine arabinoside has been the standard induction therapy for acute myeloid leukemia for more than 3 decades. The clinical benefit of intensification of the daunorubicin dose to 90 mg/m2 has been supported by randomized trials. Based on these promising results, in 2010 we changed our induction protocol of acute myeloid leukemia, increasing the dose of daunorubicin. We retrospectively analyzed the treatment outcome of patients treated with high-dose daunorubicin (90 mg/m2 on days 1-3) and cytosine arabinoside (200 mg/m2/day continuous infusion on days 1-7) compared with patients receiving 45 to 60 mg/m2 of daunorubicin. Twenty-six previously untreated patients younger than 60 years of age were included. Twelve received high-dose daunorubicin (HD) and 14 the low-dose (LD). Seventeen patients were in complete remission after 1 induction cycle. There was no overall difference in complete remission rate between HD and LD (66% vs. 64%; P= 1.0). Thirty-day induction mortality was 15.3% overall, with a nonsignificant difference between groups (25% vs. 7.1%; P= .3). Relapses were observed in 9 (53%) patients: 3 (37.5%) in the HD group and in 6 (66.6%) in the LD group (P= .34). Invasive fungal disease (41.6% vs. 0%; P= .012), creatinine elevation (P= .001), abdominal pain (33% vs. 0%; P= .033), and need for intensive care unit admission (33.3% vs. 0%; P= .033) were more frequent in the HD group. Four patients in the HD group developed neutropenic enterocolitis (P= .033). These data indicate that 90 mg/m2 of daunorubicin increased the toxicity compared with lower doses.

Evaluation of insulin resistance improvement after laparoscopic sleeve gastrectomy or gastric bypass surgery with HOMA-IR.

Our purpose was to explore the remission of insulin resistance after bariatric surgery to discover the mechanism of diabetes remission excluding dietary factors. A retrospective case control study was conducted on patients with type 2 diabetes, who underwent laparoscopic sleeve gastrectomy (LSG) or laparoscopic gastric bypass surgery (LGB) in Beijing Shijitan Hospital from April 1, 2012 to April 1, 2013. The laboratory and anthropometric data was analyzed pre-surgery and during a 2-year follow-up. HOMA-IR was calculated and evaluated. The two surgical procedures were compared. No significant difference in complete remission rate was observed between the two groups (LGB group: 62.1%, LSG group: 60.0%, p = 0.892). HOMA-IR was reduced to a stable level at the 3rd month after surgery. The cut-off value of HOMA-IR was 2.38 (sensitivity: 0.938, specificity: 0.75) and 2.33 (sensitivity: 0.941, specificity: 0.778) respectively for complete remission after LSG or LGB surgery. Insulin resistance was improved while GLP-1 and Ghrelin was changed significantly in patients with type 2 diabetes prior to weight loss either in the LSG or LGB group. HOMA-IR decreased to less than the cut-off value at the 3rd month and was closely related to complete remission. The mechanism of bariatric surgery was not due just to simply dietary factors or body weight loss but also the remission of insulin resistance.

Analysis of Genetic Mutation of the Elderly Patients with Acute Myeloid Leukemia

Backgrounds: Acute myeloid leukemia (AML) is a heterogeneous disease whose onset involves a variety of chromosomal abnormalities and genetic mutations. To improve the outcome of AML treatment, it is very important to establish a prognosis from cytogenetic and genetic analysis and provide accordingly differentiated treatment. However, the treatment strategy has not been clear in elderly patients with AML due to intolerance of treatment and its adverse characteristics such as concomitant comorbidity and poor performance status. To clarify the prognostic impact of genetic abnormalities in elderly AML, we conducted a comprehensive analysis of recurrently mutated 28 genes in AML.Method: We retrospectively analyzed newly diagnosed 128 AML patients excluding M3 who were more than 65 years old at Nippon Medical School Hospital or its associated facilities between 1990 and 2014. Mutation analyses were performed by direct sequence analysis, Mutation Biased PCR, direct sequence analysis, and the next-generation sequencer Ion PGMTM.Results: Average age was 70.5 years (65-91years). The patients from 65 years old to 74 years old (early elderly) were 92 (71.9%)cases, the patients 75 years or older (late elderly) were 36 (28.1%)cases. Chromosomal analysis according to the prognostic risk classification of the Eastern Cooperative Oncology Group (ECOG) classified into 14 of the favorable cytogenetic risk group (10.9%), 80 of the intermediate cytogenetic risk group (62.5%), and 24 of the poor cytogenetic risk group (18.8%). Gene mutations were observed in 112 cases (87.5%). The most frequent gene mutations were NPM1 (89 cases/28.9%), FLT3/ITD (25 cases/19.5%), TET2 (20 cases/15.6%), and DNMT3A (19 cases/14.8%). CEBPA double mutation was detected at low frequency in elderly patients (younger patients: 15/311 (4.8%) vs elderly patients: 1/128 (0.8%)). There were no significant differences in gene mutations between early elderly and late elderly patients). Of 102 patients who received induction therapy, 52 patients (51.0%) achieved first hematological complete remission (CR), but primary refractory and early death were observed in 50 patients (49.0%). There was no significant difference in CR rate between the two groups in the early elderly patients and late elderly patients (early elderly: 53.8% vs late elderly: 41.7%. p= 0.354). In addition, there was no difference in CR rate in the standard chemotherapy and low dose chemotherapy group (standard chemotherapy: 48.7% vs low dose chemotherapy: 38.9%. p= 0.601). Median overall survival (OS) was 287days, OS at 3years was 35.9%. Prognostic stratification was possible for CR rate on the chromosomal classification (favorable cytogenetic risk 92.9%, intermediate cytogenetic risk 50.0%, poor cytogenetic risk 12.5%, p< 0.001). For total cohort of patients, rates of relapse free survival (RFS) at 3 years are significantly lower in patients with FLT3ITD (p=0.006) and TP53 abnormality (p< 0.001) compared to without it. Rates of overall survival (OS) at 3 years are significantly lower in patients with DNMT3A mutation (p=0.004), FLT3ITD (p=0.003), and TP53 abnormality compared to without it. Also late elderly patients (p=0.010) and high white blood cell count (≥ 20,000/μl) (p=0.023) were powerful factors for unfavorable prognosis. In stratified analysis of FLT3ITD-negative cases aged below 75 years with intermediate cytogenetic prognosis, TP53 abnormality was associated with unfavorable prognosis (RFS: p=0.062, OS: p< 0.001). Finally multivariate analysis demonstrated that FLT3ITD (p=0.014) and TP53 abnormality (p=0.015) were an independent poor prognostic factor for RFS, and poor cytogenetic risk (p=0.002), Flt3ITD (p=0.014), TP53 abnormality (p=0.015), and DNMT3A mutation (p=0.001) were an independent poor prognostic factor for OS.Conclusions: Our results suggest that the genetic abnormalities have a prognostic importance in elderly patients, as well as younger patients with AML. FLT3ITD mutation is an important factor for unfavorable prognosis, but going forward TP53 mutation may also serve as a clinically important gene mutation marker in elderly patients with AML. DisclosuresNo relevant conflicts of interest to declare.

Higher Incidence of Secondary AML and Adverse Molecular Markers, Together with Lower CR and Higher AML Related Death Rates in Elderly Compared to Younger Patients: Results from 2435 Patients Included in the Two German AML Intergroup Studies

Higher Incidence of Secondary AML and Adverse Molecular Markers, Together with Lower CR and Higher AML Related Death Rates in Elderly Compared to Younger Patients: Results from 2435 Patients Included in the Two German AML Intergroup Studies