Courses Of Consolidation Chemotherapy Research Articles

A Novel Risk Stratification Model for Cytogenetically Normal Acute Myeloid Leukemia with FLT3-ITD Mutation

Introduction Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations are observed in about 30 % of patients with newly diagnosed cytogenetically normal acute myeloid leukemia (CN-AML) and has now been acknowledged to be associated with a poor survival. However, long-term follow-up revealed a high degree of heterogeneity in the clinical prognosis of these patients. Further risk stratification to identify high-risk patients is urgently needed. Methods A total of 106 patients with CN-AML and FLT3-ITD mutations who visited the People's Hospital of Peking University from 2007-2019 were included, and target region sequencing was performed by 266 gene panel. Patients were randomly divided into training and validation cohort according to the ratio of 7:3. Molecular and clinical data in training cohort were incorporated to construct a nomogram model. Cumulative incidence of relapse (CIR), Relapse-free survival (RFS) and survival by allogenic hematopoietic stem cell transplantation (allo-HSCT) and consolidation chemotherapy were compared. Results Clinical variables, genes, and genetic groups with mutations occurring in more than 10 patients were enrolled for univariate analysis of RFS (allo-HSCT was recorded as a censored event). And to avoid bias patients with RFS ≤ 4.57 months (median interval from complete remission to allo-HSCT) would be excluded from the subsequent analyses unless receiving an allo-HSCT was treated as a censored event. Three variables were eventually entered into the nomogram analysis: DNMT3A mutation (+ vs. -), minimal residual disease detected by multiparameter flow cytometry (MPFC-MRD) at the end of the 2nd course of consolidation chemotherapy (CON2) (+ vs. -, represents ≥ vs. ＜0.01%), typical ITDs (+ vs. -, represents ITDs have insertion sequences that exactly match wild-type FLT3 gene vs. ITDs have insertion sequences containing other exogenous nucleotides). And the model demonstrated good discrimination in both the training and validation cohort with C-index value of 0.82 (95% confidence interval, 0.7-0.86), 0.86 (95% confidence interval, 0.76-0.95), respectively. The Nomogram model was constructed as: Score = 1.44×DNMT3A mutation+2.16×MFPC-MRD-0.94×typical ITDs (Figure 1, A). According to the variables in nomogram model, patients with risk scores ≤ 0 were assigned to the low-risk subgroup (N = 39) and the rest were assigned to the high-risk subgroup (N = 67). The 5-year RFS was significantly higher in the low-risk group than in the high-risk group (training cohort, HR 3.68 [1.16-11.66], P = 0.002; validation group, HR 4.45 [1.52-13.00], P = 0.03) (Figure 1, B-C). We then interrogated the effect of consolidation chemotherapy and allo-HSCT as post-remission therapies in the two risk subgroups. Allo-HSCT did not further improve the prognosis of patients in the low-risk group (allo-HSCT vs. chemotherapy, 5-year CIR, HR 0.46 [0.11-1.93], P = 0.29; 5-year RFS, HR 0.41 [0.09-1.86], P = 0.24; 5-year survival, HR 0.91 [0.18-4.68], P = 0.91) (Figure 2, A-D). In contrast, in the high-risk group of patients, transplantation showed a significant survival benefit (5-year CIR, HR 0.21 [0.06-0.74], P = 0.01; 5-year RFS, HR 0.23 [0.06-0.80], P = 0.01; 5-year survival, HR 0.25 [0.06-1.11], P = 0.05) (Figure 2, E-H). Conclusion Our study suggests that risk stratification by our novel nomogram scoring system can identify patients at high risk of relapse in CN-AML with FLT3-ITD mutations and allo-HSCT further benefits their prognosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interferon-α-2b As a Maintenance Therapy Gain a High Rate of MRD Negative Conversion and Improve RFS in Patients with Favorable-Risk Acute Myeloid Leukemia----a Prospective, Single-Arm Study

Background: Maintenance therapy in favorable-risk is still controversial, so the maintenance therapy of AML is of great concern. Interferon-α (IFN-α), a type Ⅰ IFN, is a well-known antitumor agent, which has an immunoregulatory function. Several studies have shown that IFN has a definite therapeutic effect on AML. Indeed, studies have reported that IFN-α as maintenance therapy in patients with AML can prevent leukemic relapse. However, the only randomized controlled trial (RCT) that explored the role of IFN-α as maintenance therapy in AML found no difference between the comparison groups in remission duration, overall survival (OS), disease-free survival (DFS) or relapse-free survival (RFS). In our previous respective studies, IFN-α-2b as a maintenance therapy may reduce the relapse rate in patients with favorable-risk AML after consolidation chemotherapy. Moreover, IFN-α-2b could effectively control minimal residual disease (MRD) in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the efficacy and safety of IFN-α-2b in the maintenance of favorable-risk AML. Method: This is an interim analysis of an ongoing clinical prospective study (trial registration number: ChiCTR2000035310) of a planned 31 favorable-risk (NCCN Guideline) AML patients with MRD positive who underwent 1-2 therapeutic induction chemotherapy for complete hematologic remission (CR) and completed 4-6 courses of consolidation chemotherapy. MRD positive was defined as detectable MFC-MRD >0.1% or fusion genes level decreased by >3 log. 22 patients were recruited in our study to date. Patients were administered with 3 million U of IFN-α-2b three times a week for 18 months. Bone marrow assessments were performed on the 2nd, 5th, 8th, 11st, 14th, 18th month since IFN-α-2b therapy. The primary objective is to determine the cumulative rates of MRD negative conversion, 3-year RFS and adverse reactions. Results: Patients were classified as favorable-risk category according to cytogenetics and molecular biology. 22 participants with favorable-risk AML were enrolled in this study, and 2 of them received IFN-α-2b less than 3 months, who were not evaluated in this report. The molecular biological characteristics of this study were AML-ETO+/c-KIT- 11 cases; AML-ETO+/c-KIT+ 2 cases (T417_D419delinsIP); CBFβ-MYH11+/C-KIT- 5 cases; CBFβ-MYH11+/C-KIT+ 2 cases (Y418_D419insFF, D816Y); NPM1+/FLT3-ITD- 3 cases; and CEBPA double mutation 1 case. The median age of the 22 participants was 47.5 (18.0-66.0) years old. Outcome data were updated as of July 2022, for a median follow-up 13.5 (6.6-24.0) months of the 20 patients received IFN-α-2b more than 3 months, and the median duration of treatment was 13.5 (5.2-18.0) months. Among 20 evaluated patients, the cumulative rates of MRD negative conversion is 66.7±11.0% after the median time of 4.4 (1.1-8.1) months IFN-α-2b treatment (Figure 1). As for recurrence, 2 patients had hematologic recurrence, with the estimated rate of 2-year RFS was 86.1±9.4% (Figure 2). Meanwhile, there are 5 persistent MRD positive participants, 3 of them got decreased MRD level for 1 log-fold, 1 case got increased MRD level for 2 log-fold, and MRD level did not decline in 1 case. The regimen was well tolerated. In terms of safety, the most frequent nonhematologic adverse events were fever (11/20, 55.0%) after IFN-α-2b therapy. 4/20 (20.0%) developed hematologic toxicity which were thrombocytopenia, 1/20 (5.0%) had muscle pain, 1/20 (5.0%) elevated hepatic transaminases, 1/20 (5.0%) developed rash. Conclusion: IFN-α-2b as maintenance therapy for CR1 patients with favorable-risk AML gain a high rate of MRD negative conversion and high rate of 2-year RFS Interferon therapy is safe and well-tolerated. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

More than two courses of pre-transplant consolidation therapy benefits patients with acute myeloid leukemia in the first complete remission who underwent human leukocyte antigen-matched sibling allografts: a multicenter study.

Although the need for consolidation chemotherapy after successful induction therapy is well established in patients with acute myeloid leukemia (AML) in first complete remission (CR1), the value of consolidation chemotherapy before allogeneic hematopoietic stem cell transplantation remains controversial. We retrospectively compared the effect of the number of pre-transplant consolidation chemotherapies on outcomes of human leukocyte antigen-matched sibling stem cell transplantation (MSDT) for patients with AML in CR1 in multicenters across China. In our study, we analyzed data of 373 AML patients in CR1 from three centers across China. With a median follow-up of 969 days, patients with ≥ 3 courses of consolidation chemotherapy had higher probabilities of leukemia-free survival (LFS) (85.6% vs . 67.0%, P < 0.001) and overall survival (89.2% vs . 78.5%, P = 0.007), and better cumulative incidences of relapse (10.5% vs . 19.6%, P = 0.020) and non-relapse mortality (4.2% vs . 14.9%, P = 0.001) than those with ≤ 2 courses of consolidation chemotherapy. Pre-transplantation minimal residual disease-negative patients with AML in CR1 who received MSDT with ≥ 3 courses of consolidation chemotherapy had a higher probability of LFS (85.9% vs . 67.7%, P = 0.003) and a lower cumulative incidence of relapse (9.6% vs . 23.3%, P = 0.013) than those with ≤ 2 courses. Our results indicate that patients with AML in CR1 who received MSDT might benefit from pre-transplant consolidation chemotherapy.

Umbilical Cord Blood Microtransplantation in Newly Diagnosed, Elderly Patients with Acute Myeloid Leukemia

Objective: We observed the efficacy and safety of umbilical cord blood microtransplantation (UCBMT) in the treatment of newly diagnosed with acute myeloid leukemia (AML) in the elderly.Methods: Prospective one-arm phase I clinical study. The patients should meet the following criteria: 60-80-year-old; newly diagnosed AML; receive the treatment of chemotherapy combined with UCBMT.Result: In total, 11 patients newly diagnosed with AML received chemotherapy in combination with UCBMT, from November, 2019 to January, 2021, including 7 males and 4 females. The average age was 71 (60-80). For the patients, 7 cases with normal chromosome karyotype, and 2 cases with +8 chromosome, 1 case with 7q- chromosome, and 1 case with karyotype of monomer. In the 7 patients with normal chromosome karyotype, 3 cases were FMS-liketyrosine kinease 3 (FLT3) positive (2 of them in combination with nucleophosmin 1 (NPM1) mutation); in addition, in 4 patients of the 7, one showed double mutation of CEBPA, one showed NPM1 mutation, one showed IDH1 mutation, and one showed IDH2 mutation. In 4 patients with chromosomal abnormalities, one patient showed no special gene, one patient showed ASXL1 mutation, one patient was IDH1 mutation, and one patient was TP53 mutation. All of the patients were treated with IA (IDA 8-10 mg/ m 2/day x 3 days, cytarabine 100 mg/ m 2/day x 7 days) for inducing chemotherapy. For the patients with 60-70-year-old, they were treated with IDA (8 mg/ m 2/day); and for the patients with 70-80-year-old, they were treated with darubicin (10 mg/ m 2/day). In the consolidation phase, the patients were treated with cytarabine (1 g/ m 2, q12h) for 3 consecutive days. There were 3 courses of consolidation chemotherapy. Next, patients received single unrelated cord blood transplantation (UCBT) from China's public umbilical cord blood bank, HLA matching was performed for all patients before treatment. A total of 4 units of UCB with HLA 0-3/6（HLA-A,-B,-DR）matching and the ABO blood type matched with the patient were transfused after induction and consolidation chemotherapy for 24-48 hours, then with follow-up. At the same time, the immunological characteristics of these patients were fully analyzed. We demonstrated that, 8 of 11 patients received one course of induction chemotherapy, and achieved a complete response. The complete response rate was 72.7%. What's more, the median time for neutrophils ≥ 0.5 x 10 9/L and platelete ≥ 20 x 10 9/L was 12 days. There were no treatment-related deaths during induction therapy. The median follow-up was 14 (7-31) months. 1 patient showed monomer karyotype with P53 gene mutation, and got complete remission after one course of induction chemotherapy with IA. However, the patient died for AML recurred. For the other 10 patients, they were alive, and the OS of 1 year was 89.8%. Moreover, we found the expression of PD-1 on CD8 +T cells decreased, while the expression of CD38 increased after therapy. Besides, the proportion of NKp30 +NK cells, as well as the IFN-γ +TFN-α +NK cells increased significantly.Conclusion: UCBMT therapy for newly diagnosed elderly AML patients could accelerate the recovery of hematopoietic function and improve the safety of chemotherapy. This method is effective and worthy of further promotion. DisclosuresNo relevant conflicts of interest to declare.

#15: Risk Factors of Infection related mortality in Pediatric Acute Myeloid Leukemia- Single Institute Experience: 2016–2018

Abstract Children with acute myeloid leukemia (AML) are at a particularly high risk for infectious complications related to the highly intensive chemotherapy. Infections leads to mortality and prolong hospitalization. The aim of the study is to evaluate the risk factors, infectious complications and assess outcome of febrile episodes during induction and consolidation chemotherapy courses in children with AML at the Pediatric Oncology Department, National Cancer Institute, Cairo University from January 2016 to December 2018. Infectious complications were evaluated retrospectively in 621 febrile episodes. Mortality from gram negative bacteremia was 29.9%, in febrile episodes with multidrug resistant gram negative bacteremia: Mortality was 39.2 % in febrile episodes with multidrug resistant gram negative bacteremia and septic shock. Mortality was 71.8 % (p value &amp;lt;0.001). Mortality was high in early chemotherapy phase (intensive timing). Infection related mortality was 39%. In our institute there is epidemiological shift towards gram negative organisms. Sepsis and septic shock are major causes of mortality during chemotherapy-induced neutropenia. Thus, awareness of the presenting characteristics and prompt management is most important. Improved management of sepsis during neutropenia may reduce the mortality of pediatric Acute myeloid leukemia. It is Important to trace the risk factors that may affect the outcome of febrile episodes. Summary of Significant laboratory and clinical predictors of mortality Risk Factor Mortality p value Septic shock 55% &amp;lt;0.001 Septic shock with MDRO 72% Cardiac impairment/inotropic support 65.60% Presence Of Central venous line 18.30% Episode duration &amp;gt;18 days 20.50% Start of antimicrobial in relation to start of chemotherapy &amp;lt; 16 days 33% Episodes: Not in remission 15.60% Risk factor Mortality p value CRP more than or equals 90 mg/l 24.4% Not significant ANC LESS THAN 500 29.9% 0.003 Hgb less than or equals to 7 g/dl 19.9% 0.633 Platelets less than 20000/cc 29.9% 0.299 Liver impairment (grades 3 and 4) 42.2% 0.025 Electrolyte imbalance (grades 3 and 4) 24.1% 0.003 Renal impairment 56.8% 0.025 Coagulopathy 41% &amp;lt;0.001

Durable Remission after Salvage Chemotherapy with Combining Bortezomib and Vorinostat Followed By CD19 CAR-T Therapy in a Patient with MLL-Rearranged ALL after Early Relapse Post Allogeneic Hematopoietic Stem Cell Transplantation

Durable Remission after Salvage Chemotherapy with Combining Bortezomib and Vorinostat Followed By CD19 CAR-T Therapy in a Patient with MLL-Rearranged ALL after Early Relapse Post Allogeneic Hematopoietic Stem Cell Transplantation

Determinants of Early Death and Outcomes for Acute Promyelocytic Leukemia in the Arsenic Era: A Real World Study

ObjectiveEarly death (ED) persists as the main obstacle to cure all the patients with acute promyelocytic leukemia (APL) in all-trans retinoic acid (ATRA) era. Uncertainty remains as to whether ED rate can reduce and which markers are independent predictors for ED and outcomes in arsenic era. We conducted a real world study of APL patients to assess ED, outcomes and predictors in arsenic era.MethodsThis study includes consecutive 309 APL patients in our center between 2005 and 2013. Three treatment protocols using arsenic and ATRA as first-line treatment were adopted in our center. Protocol A was used from 2005 to 2007.Patients received oral tetra-arsenic tetra-sulfide (As4S4) (60mg/kg/day) or intravenous ATO (10 mg/day) daily with ATRA (25 mg/m2/day), until complete remission (CR) for induction therapy, whereas additional minimal chemotherapy was administered to control hyperleukocytosis (mitoxantrone 1.4 mg/m2/day for 5-10 days or daunorubicin 40 mg/m2/day for 2-3 days was added if peripheral WBC was greater than 10 × 109/L or on the second day in patients with high risk). After achieving CR, most patients were administered 3 courses of consolidation chemotherapy including mitoxantrone (6-8 mg/m2/day for 3 days), daunorubicin (40mg/m2 for 3 days) ,idarubicin (6-8 mg/m2 for 3 days). Maintenance treatment included inter-mittent oral As4S4 and ATRA for 2-3 years. Protocol B was used from 2008 to 2012, which is described in our previous report (Zhu HH, et al. JCO 2013; 31:4215-4221 ).Protocol C was used since 2013, which only included non high-risk patients and was described in our previous report (Zhu HH, et al. NEJM 2014; 371:2239-41).ResultsThe ED (death within 30 days of diagnosis) rate was 4.8% (n=15) and showed a trend of decrease after 2008 (3.8% vs, 8.5% p=0.053). Using multivariate Cox proportional hazards regression, the hazard ratio of ED was 19.89 (95% CI, 4.49-88) for white blood cell (WBC) count of >10×109/L vs ≤10×109/L (P<0.0001) and 8.70 (95% CI, 1.15-66.67) for platelet count of ≤40×109/L vs >40×109/L(P=0.037). Estimated 10 year cumulative incidence of relapse (CIR), disease-free survival and overall survival (OS) was 6.32% (95% CI: 3.03%-9.61%), 93.0% (95% CI: 88.7%-95.7%) and 92.0% (95% CI: 88.3%-94.6%). WBC count was only independent predictor for OS (HR 5.34, 95% CI, 2.36-12 for >10×109/L vs ≤10×109/L, P<0.0001) in multivariate analysis.ConclusionsIn this large cohort of APL patients under a ‘real world’ setting, a relative low ED and high OS could be achieved and high WBC count emerged as an independent predictor of ED and OS in arsenic era. DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation Improved Survival for Adult Core Binding Factor Acute Myelogenous Leukemia Patients with Intermediate- and Adverse-Risk Genetics in the 2017 European LeukemiaNet

The use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for consolidation therapy in patients with core binding factor (CBF) acute myelogenous leukemia (AML) with intermediate- and adverse-risk genetics remains controversial. We retrospectively analyzed the clinical outcomes of 286 CBF-AML patients with intermediate- and adverse-risk genetics in first complete remission following consolidation with chemotherapy (n=122), auto-HSCT (n=27), or allo-HSCT (n=137) between January 2009 and December 2018 at our center. Patients with allo-HSCT showed superior 5-year overall survival (OS; 74% versus 38% or 49%; P < .001) and progression-free survival (PFS; 74% versus 26% or 49%; P < .001) and lower cumulative incidence of relapse (CIR; 9% versus 69% or 31%; P < .001) compared with chemotherapy alone or auto-HSCT. In the allo-HSCT group, minimal residual disease (MRD) at the second and third months after allo-HSCT could predict relapse in t(8;21) patients (2 months: PCIR=.002; 3 months: PCIR < .001) but not in inv(16) patients. Moreover, positive MRD after 2 courses of consolidation chemotherapy before allo-HSCT was an independent risk factor for survival in CBF-AML patients with intermediate- and adverse-risk genetics, whereas haploidentical donor (haplo-) HSCT could overcome the adverse prognosis (5-year OS, 87%; 5-year PFS, 81%; 5-year CIR, 7%). Allo-HSCT could be the optimal first-line consolidation therapy for patients with intermediate- and adverse-risk genetics, and haplo-HSCT could improve survival for patients with positive MRD after 2 courses of consolidation chemotherapy.

Circulating miR-451a levels as a potential biomarker to predict the prognosis of patients with multiple myeloma.

The natural course of multiple myeloma (MM) varies greatly between patients. The Revised MM International Staging System (R-ISS) identifies high-risk patients, but it is unsuitable for assessing minimal residual disease (MRD). Furthermore, the focal location of myeloma cells and clonal evolution often produce false negative results in flow cytometry. Extracellular microRNA (miRNA/miR) expression levels are stable in bodily fluids, and are retrievable and measurable from fresh or archived serum or plasma samples. Therefore, the present study aimed to investigate the clinical utility of circulating miRNA levels in patients with MM, particularly miR-451a, which is commonly downregulated in MM, and whether it could predict the prognosis and relapse of patients with MM. In total, 66 patients with MM, stratified using the R-ISS criteria, were recruited, while 10 healthy subjects (transplantation donors) were enrolled as controls. Reverse transcription-quantitative PCR was used to evaluate miR-451a expression in bone marrow (BM) and in the circulation. IL-6 levels were measured using ELISA, while western blotting was conducted to analyze the protein expression levels of the IL-6 receptor (IL-6R). During follow-up, MRD was assessed via multiparameter flow cytometry (MFC). miR-451a was identified to target IL-6R using a dual-luciferase reporter assay. Circulating miR-451a levels were low in patients with MM, and was found to be 0.39 times that of the control group (U=4.00; P<0.001). Among the 66 patients with MM, the median level of miR-451a was 0.73 and 0.41 times that of the control group in R-ISS stage I MM (15 patients) and R-ISS stage II stage (17 patients), respectively; patients with R-ISS stage III MM (34 patients) had the lowest level, at 0.24 times the value of the control group. Circulating miR-451a levels had a strong positive correlation with miR-451a levels in BM, but negatively correlated with IL-6 and IL-6R levels. After two courses of consolidation chemotherapy, 19 patients achieved complete remission, 10 of whom presented steady circulating miR-451a levels during follow-up; the other nine patients had an abrupt decrease in circulating miR-451a levels. The turning points in the trend appeared 4–8 weeks before positive results were obtained via MFC, and 4–16 weeks before clinical relapse. Moreover, miR-451a overexpression notably downregulated the expression of the IL-6R mRNA and protein. Collectively, circulating miR-451a levels potentially represent a novel biomarker to monitor MRD and predict relapse.

Genomic Landscape and Risk-Stratification for De Novo Acute Myeloid Leukemia with Normal Cytogenetics and No NPM1 or FLT3-itd Mutation

Introduction-About 25% of persons with new-diagnosed acute myeloid leukemia (AML) have normal cytogenetics and no NPM1 or FLT3-ITD mutation. The prognosis and best therapy of these persons is controversial. Methods-We evaluated 809 consecutive newly diagnosed adult with normal cytogenetics and 231 of whom had no NPM1 or FLT3-ITD mutation identified by targeted regional sequencing. 158 achieved a complete remission within 2 cycles of induction therapy and were assigned to 2 different post-remission strategies: (1) 6 courses of consolidation chemotherapy (N=95); or (2) 2-4 courses of consolidation chemotherapy and an allotransplant (N=63). Results-In multi-variable analyses a WBC ≥13·6×10E+9/L, mutated IDH2, not having a bi-allelic CEBPA mutation at diagnosis, a positive measurable residual disease (MRD)-test during consolidation and not receiving an allotransplant were independently associated with a higher cumulative incidence of relapse (CIR) and worse event-free survival (EFS). Amongst subjects with IDH2 mutations, non-bi-allelic CEBPA mutations or a positive MRD-test, subjects receiving an allotransplant had a lower 5-year CIR (16% [95% confidence interval, 6, 26%]; vs. 83% [72, 95%]; hazard ratio, HR=8·77 [4·05, 13·49]; P &amp;lt; 0·001) and better 5-year EFS (74% [60, 88%] vs. 15% [5, 25%]; HR=0·16 [0·09, 0·29]; P &amp;lt; 0·001). In contrast, in subjects with none of these adverse predictive variables there was no difference in CIR and EFS between those receiving an allotransplant and those who did not. Conclusions-Our data suggest a strategy to identify which persons with AML with normal cytogenetics and no NPM1 or FLT3-ITD mutation benefit from an allotransplant. Trial Registration: Registered in the www.clinicaltrials.gov, NCT01455272 and NCT02185261. Keywords: Acute myeloid leukemia, mutations, prognosis, targeted regional sequencing, measurable residual disease, risk stratification. *Correspondence Profs. Guo-Rui Ruan and Xiao-Jun Huang Peking University Peoples Hospital and Institute of Hematology No.11 Xi-Zhi-Men South Street, Beijing 100044, China T 86-10-88324672 F 86-10-88324672 Disclosures No relevant conflicts of interest to declare.

A Multicenter Nonrandom Clinical Study Using Induction Regimen of FLAG-IDA or Dae in Treatment of 101 Children with Newly Diagnosed CBF-AML in South of China: Clinical Responses and the Midterm Report of Survival

OBJECTIVE: Patients with core binding factor (CBF) AML generally have a favorable prognosis, but the appropriate intensity of chemotherapy and number of courses are still key points for further exploration by the different leukemic group. Our prospective multicenter clinical study was designed to use high intensity, 4-courses of chemotherapy (backbone of MRC AML 15 protocol) to treat childhood CBF-AML and to observe the feasibility and effectiveness in China. METHODS: Total of 101 children with CBF-AML from 9 centers of south of China were enrolled on the C-HUANAN Children AML 2015 protocol from 2015.1 to 2018.11, accounting for 30.6% of total AML (non-APL) cases. There were 59 boys and 42 girls, aged between 2- 14 years old. The diagnosis of CBF-AML was established by PCR-based detection of RUNX1-RUNX1T1 and CBFβ-MYH11 fusion gene transcripts or by FISH based detection of t(8;21) and inv(16) aberration, respectively. Nine cases were combined with FTL3-ITD. Eleven cases were combined with ASXL1 mutation, and 23 cases were combined with c-KIT mutation. The induction regimen were non-randomized to DAE group and FLAG-IDA group. The induction regimen of DAE group including coures 1 (DAE 3+5+10), course 2 (DAE 3+5+8) . The induction regimen of FLAG-IDA including two courses of FLAG-IDA. Consolidation treatment was same and consisted of 2 courses: 1.HAE or MACE; 2.MidAC. Follow-up observation was then started after 4 courses of treatment. All of patients were followed-up to 06/30/2019, median follow-up time was 25 months. RESULTS: The overall complete remission rate was 93.1% after two courses of induction, 93.8% in the DAE group and 92.8% in the FLAG-IDA group. There was no statistical difference between the two groups. The MRD negative rate (&lt;0.1%) detected by the flow cytometry after first course was 57/87 (65.5%) and 67/77 (87.0%) after second course respectively. The RUNX1-RUNX1T1 or CBFβ-MYH11 gene negative rate was 28/60 (46.7%) and 25/43 (58.1%) after first course and second course of treatment respectively .The overall survival rate (OS) was 83.2%, and the leukemia-free survival rate was 81.1%.Among them, the OS and LFS of the DAE group were 76.4% and 73.2%, respectively, and the OS and LFS of the FLAG-IDA group were 86.3% and 84.6%, respectively( P= 0.331 and 0.241).The OS and LFS of the RUNX1-RUNX1T1 group were 81.8% and 79.2%, respectively.The OS and LFS of the CBFβ/MYH11 group were both 88.9%( P= 0.542 and 0.403). The OS and LFS in CBF-AML with FLT3-ITD positive were both 62.2%. The OS and LFS in CBF-AML without FLT3-ITD were 85.3% and 82.9%, respectively (P=0.045 and 0.081),there was significantly inferior OS in CBF-AML with FLT3-ITD subgroup. Among them, the OS was 60.0% and 85.9% in RUNX1-RUNX1T1 with or without FLT3-ITD group respectively( P=0.041), there was significantly inferior OS in RUNX1-RUNX1T1 with FLT3-ITD subgroup. There were no significant differences in OS and LFS between the CBF with or without C-kit and ASXL1 genes. The overall relapse was 10.9%, and treatment related mortality was 6.9%. Conclusion: The childhood CBF-AML accounted for 30.6% of children's newly diagnosed AML in the South China Children's AML Group. The complete remission rate reached to 93.1% by using 2 courses of intensive induction regimen of DAE or FLAG-IDA. Only 2 courses of consolidation chemotherapy were administered. Two years OS and LFS were higher than 80%.There were significant difference in OS of CBF-AML with FLT3-ITD, and RUNX1-RUNX1T1 AML with FLT3-ITD. There were no significant differences in that of LFS. The overall LFS was close to the outcome of the MRC AML 15 protocol, but there was a gap in OS. The main reason was that the most of relapsed patients abandoned treatment. On other hand the treatment related mortality need to be further reduced. Figure Disclosures No relevant conflicts of interest to declare.

Effectiveness and Survival of 4 Courses of Chemotheray in 321 Children with Acute Myeloid Leukemia in China: A Multicenter, Nonrandomized Clinical Study

Objectives Increasing the intensity of chemotherapy can improve long-term survival in young patients with acute myeloid leukemia, but the number of appropriate courses is still worth exploring. We prospectively used MRC-AML 15 protocol as backbone to designed the C-HUANAN-AML15 protocol, which including 2 courses of inductions and 2 courses of consolidation to treat new diagnosed acute myeloid leukemia children in order to adapt to China's actual situation. The midterm outcome of effectiveness and survival was analyzed in the multicenter of south of China. Patients and methods Total of 321 newly diagnosed childhood AML patients from 9 centers of south of China from November 2014 to December 2018 were included in the study. 194 boys and 127 girls, with median age 6 (0.5-14) years old were enrolled. The median follow-up period was 16 (4 to 73) months up to July 2019. Risk stratifications were based on genetic abnormalities and response to induction chemotherapy . One hundred and seven patients (33.3%),146 patients (45.5%),68 patients (21.2%) were classified as low-risk group (LR), intermediate-risk group (IR) and high-risk group (HR) respectively. The protocol C-HUANAN-AML15 protocol including tandem 2 courses of FLAG-IDA regimen (marked as group A, n=225) , or sequential DAE(3+5+10) and DAE(3+5+8) regimen (marked as group B, n=96) were applied to induction chemotherapy. One course of Homoharringtonine (substitution of Amsacrine in MRC-AML 15 protocol)/ Cytarabine/ Etoposide and one course of Mitoxantrone/ Cytarabine in consolidation chemotherapy were uniform in both groups. 57 patients (39 patients in group A and 18 patients in group B, P=0.752) selected hematopoietic stem cell transplantation (HSCT) after 2-3 courses of chemotherapy. In the 264 patients who only underwent chemotherapy, the LR/IR/HR ratio in the A and B group was 65(34.9%),82(44.1%),39(21.0%) and 34(43.6%),37(47.4%),7(9.0%) respectively (P=0.056). The similarity of clinical data was analyzed by the chi square test and COX proportional hazard function model. Complete remission (CR) rates, treatment related mortalities (TRM), event-free survival (EFS) and overall survival (OS) were compared by Log-Rank chi square test. Results The CR rates in A and B group were 87.6% and 83.3% after 1st course induction regimen, and 92.4% and 89.2% after 2nd course induction regimen, which were not significantly different (P=0.375, 0.337). The 3-year EFS and OS of all patients were 65.8±3.2% and 70.3±3.4% respectively. The 3-year EFS and OS of 264 patients who only received chemotherapy was 65.4±7.4% and 71.7±3.4%. The 3-year EFS of HR, IR and LR in patients who received only chemotherapy were 40.3±8.8%, 62.0±5.2% and 83.5±4.3% respectively (P=0.000). The 3-year OS of HR, IR and LR in patients who received only chemotherapy were 46.9±9.0%, 69.1±5.1% and 86.1±4.0% respectively (P=0.000). The 3-year EFS of A and B group in patients who received only chemotherapy was 70.8±4.0% and 56.7±6.3% (P=0.059); The 3-year OS of A and B group in patients who received only chemotherapy was 78.7±3.6% and 58.6±6.4% (P=0.005). The 3-year EFS and OS of 57 patients who received HSCT was 60.2±8.9% and 65.4±7.4%(P=0.477, 0.821). The EFS of IR and HR patients who received HSCT were superior than that of who received only chemotherapy, but they were not significantly different (78.6±8.6%vs62.4±5.1%, P=0.121; 44.4±12.9%vs38.9±8.8%, P=0.208). Univariate analysis showed that initial white blood cell count (≥50×109/L), RUNX1-RUNX1T1 fusion gene, EVI1 gene positive, FLT3-ITD mutation, no CR after 1st course and 2nd course induction affected 3-year EFS (all P&lt;0.05). Multivariate prognostic analysis with COX proportional hazard function model for EFS showed that EVI1 gene (HR0.397, 95%CI 0.201-0.785, P=0.008) and no CR after 2nd course induction (HR0.319, 95%CI 0.134-0.763, P=0.010) were independent risk factors. Conclusion This prospectively clinical study indicated that intensive induction with FLAG-IDA or DAE followed only 2 courses of consolidation chemotherapy was effective in the LR and IR group, and could be utilized as first line treatment in childhood AML. EVI1 gene positive and no CR after 2nd induction course were independent risk factors for EFS. More effective strategies are needed to be explored for HR group patients, EVI1 gene positive patients and those who cannot achieve CR after 2nd course induction. Figure Disclosures No relevant conflicts of interest to declare.

Interferon-a-2b As a Maintenance Therapy Significantly Improves Disease-Free Survival in Patients with Low-Risk Acute Myeloid Leukemia

Background: Interferon-𝜶has a world-widely acknowledged anti-tumor activity and immunoregulatory function. Rare of the previous study reported significant efficacy of IFN-𝜶in AML (high, medium and low risk) patients. Although cytotoxic chemotherapy significantly improved the survival of low-risk AML, the reported low-risk AML 5-year OS was only 34-65%.Whether Interferon-𝜶-2b(IFN-𝜶-2b) could reduce recurrence and improve DFS in the maintenance therapy of low-risk AML subtypes has not been verified. The aim of this study was to evaluate the efficacy and safety of IFN-𝜶-2b in the maintenance of low-risk acute myeloid leukemia, in order to provide suggestions for clinical practice. Method: This study retrospectively analyzed 31 patients with low-risk AML who were treated with IFN-𝜶-2b maintenance therapy from March 2015 to March 2018 at the Peking University Institute of Hematology. The control group consisted of 1:1 matched 31 patients with low-risk AML. The pairing factors were age, gender, diagnostic time and subtype, induction and consolidation courses, and minimal residual disease (MRD) at the end of chemotherapy. Both groups of patients were AML patients who underwent 1-2 therapeutic induction chemotherapy for complete hematologic remission (CR) and completed 5-7 courses of consolidation chemotherapy. The interferon group was administered with 3 million U ofIFN-𝜶-2b three times a week; the control group was only observed and followed up after consolidation chemotherapy. We compared the treatment efficacy and prognostic improvement in low-risk AML by comparing MRD, disease-free survival (DFS), event-free survival (EFS), and overall survival (OS). Results: The median age of the 31 patients in the interferon group was 50 (21-67) years. Themolecular biological characteristicsof the interferon group were NPM1+/FLT3-ITD-8 cases; CEBPA double mutation 9 cases; CBFβ-MYH11+/C-KIT-5 cases; and ETO+/C-KIT- 9 cases. The median age of the control group was 44 (26-70) years old, and the molecular biological characteristics were paired with the interferon group. The median follow-up time of the 31 patients with low-risk AML in the interferon group and the control group was 14.5 (4-34) months and 16 (5.5-35) months, respectively. The median duration of treatment in the interferon group was 10(1-24) months. In interferongroup, patients with negative or positive MRD status were 16 and 15, respectively. Whereas, in control group, patients with negative or positive MRD status were 20 and 11, respectively. In interferon group, patients with original MRD, 10/15 (66.67%) showed MRD conversion after the median time of 5 (1-14.5) months IFN-𝜶-2b treatment, while in control group 3/11 (27.3%) of the patients showed MRD negative-positive conversion. There was a statistically significant difference in the rate of MRD conversion between the two groups (X2=3.939, P=0.047). The interferon group significantly decreased the rate of MRD compared with the control group. The conversion rate of the interferon group and the control group was (66.67%) vs (27.3%). In addition, the 2-year EFS of the interferon group was significantly higher than that of the control group (81.6±7.5) % vs (50.0±10.9) %, P=0.041(Figure 1.A). With refer to recurrence, 3 patients had hematologic recurrence in the interferon group, compared with 10 in the control group. Each group has 2 persistent MRD positive patients and MRD level increased more than 2 log-fold. 1 patient in control group had negative MRD converted to positive. The 2-year DFS of the interferon group was significantly higher than that of the control group (81.2±8.8)% vs (56.7±9.9)%, P=0.042 (Figure 1.B). There was no significant difference between the interferon group and the control group at 2 years of OS, which was (91.4±5.8)% vs (78.7±10.8)% (P=0.587) (Figure 1.C).In terms of safety, 24/31 (77.4%) had grade 1-2 fever after IFN-𝜶-2b therapy. 4/31 patients (12.9%) developed grade 3-4 hematologic toxicity, all of which were thrombocytopenia. Conclusion:IFN-𝜶-2b as maintenance therapyfor CR1 patients with low-risk AML significantly improved the rate of MRD conversion compared with patients without it. DFS and EFS were higher than those without it. Patients receiving interferon therapy have a low incidence of adverse reactions. Interferon therapy is safe and well-tolerated. Disclosures No relevant conflicts of interest to declare.

Outcome and Genomic Characteristics of Non-Down Syndrome Acute Megakaryoblastic Leukemia in Children Treated with Low-Dose Chemotherapy for Induction Remission

Background: Acute megakaryocytic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML) with a dismal outcome in children without Down syndrome. Refractory or relapsed disease accounts for treatment failure in most cases. Hematopoietic stem cell transplantation (HSCT) is recommended as post-remission therapy, although some patients have been cured with intensive chemotherapy alone. Genetic and genomic abnormalities are common in AMKL, but their prognostic significance is not known. In this study, we analyzed AMKL using high-throughput sequencing in addition to conventional morphology, immunophenotype, cytogenetic, and molecular (MICM) approaches. Methods: From February 2015 to April 2019, 19 cases of AMKL in non-Down syndrome patients were diagnosed according to conventional methods in our center. All patients, except one, were treated using a low-dose chemotherapy (LDC) regimen (cytarabine 10 mg/m2, subcutaneously every 12 h, 20 doses; mitoxantrone 5 mg/m2 days 1, 3 and 5, and G-CSF 5µ/kg subcutaneous, daily, 10 doses) for induction remission followed by four courses of intensive chemotherapy or hematopoietic stem cell transplantation (HSCT) as post-remission consolidation[1]. Patients were treated with consolidation chemotherapy if parents refused HSCT. High-throughput mutational sequencing of leukemia cells obtained at diagnosis was performed. The average sequencing depth was 500-1000× and analyses were performed using mGATK, SAMTools, SIFT, PolyPhen2, LRT, and MutatioinTaster methods. Results: The average age at diagnosis of AMKL of the nine boys and 10 girls was 19.7 months (7-53 months). Eighty-four percent of the cases were younger than 2 years of age. The 19 patients with AMKL represent 10% of cases diagnosed with AML during the study period. The median initial white blood cell (WBC) count was 13×109/L(2.38-126×109/L)and the average blasts at initial bone marrow (BM) was 54.5% (13-85%). In all cases of AMKL, more than 25% of cells were positive for CD41. Sixty-three percent of patients had recurrent fusion genes, including NUP98-KDM5A, HOXA11-AS/ANGPT1, CBFA2T3-GLIS2, KMT2A-MLLT3, RBM15-MKL1. Also, we identified PICALM-MLL10, TNIP1-CSF1R, NUP98-TAF3, and CBFA2T3-GLIS1 fusion genes which had not been previously reported in AMKL. EVI-1 expression was evaluated in all cases and was overexpressed in two cases. Forty-seven percent of patients showed at least single-gene mutations, including JAK2, MPL, KRAS, NRAS, TP53, NTRK3, MYO16, PDGFB, FLT3, and others. The response rate after remission induction I (IND-I) were 84.2% with 63.1% (12/19) attaining complete remission (CR) and 21.1% (4/19) partial remission (PR). After IND-II, the CR, PR, and no response (NR) rates was 68.4%, 10.5%, and 21.1%, respectively. Four patients (21.1%) were refractory to induction chemotherapy. Seven patients (36.8%) relapsed, three during consolidation chemotherapy courses, and four after transplantation (Table 1). Currently, 75% (6/8) patients who received chemotherapy only for consolidation were alive (median follow-up time 27 months). Eleven patients underwent allo-HSCT, and 8 patients are alive, including 6 cases living without evidence of disease. Four patients relapsed after allo-HSCT, and two of them have died. One additional patient died of transplantation related mortality. The 4-year OS, RFS, and EFS in this cohort were 62.4%±13.9%, 54.1±13.0% and 40.5±11.5%, respectively (Figure 1).Conclusion: Non-Down syndrome AMKL is genetically heterogeneous with recurrent and new fusion genes. Patients treated with LDC for induction followed by intensive chemotherapy or HSCT for consolidation have outcome comparable to those treated with intensive induction regimens. New treatment strategies are needed to improve the outcome of pediatric AMKL. Figure 1 Disclosures No relevant conflicts of interest to declare.

Genomic Landscape and Risk-Stratification for &lt;i&gt;De Novo &lt;/i&gt;Acute Myeloid Leukemia with Normal Cytogenetics and No &lt;i&gt;NPM1&lt;/i&gt; or &lt;i&gt;FLT3&lt;/i&gt;-ITD Mutation

Background: About 25% of persons with new-diagnosed acute myeloid leukemia (AML) have normal cytogenetics and no NPM1 or FLT3-ITD mutation. The prognosis and best therapy of these persons is controversial. Methods: We evaluated 809 consecutive newly diagnosed adult with normal cytogenetics and 231 of whom had no NPM1 or FLT3-ITD mutation identified by targeted regional sequencing. 158 achieved a complete remission within 2 cycles of induction therapy and were assigned to 2 different postremission strategies: (1) 6 courses of consolidation chemotherapy (N=95); or (2) 2-4 courses of consolidation chemotherapy and an allotransplant (N=63). Findings: In multi-variable analyses a WBC ≥13·6×10E+9/L, mutated IDH2, not having a bi-allelic CEBPA mutation at diagnosis, a positive measurable residual disease (MRD)-test during consolidation and not receiving an allotransplant were independently associated with a higher cumulative incidence of relapse (CIR) and worse event-free survival (EFS). Amongst subjects with IDH2 mutations, non-bi-allelic CEBPA mutations or a positive MRD-test, subjects receiving an allotransplant had a lower 5-year CIR (16% [95% confidence interval, 6, 26%]; vs. 83% [72, 95%]; hazard ratio, HR=8·77 [4·05, 13·49]; P < 0·001) and better 5- year EFS (74% [60, 88%] vs. 15% [5, 25%]; HR=0·16 [0·09, 0·29]; P < 0·001). In contrast, in subjects with none of these adverse predictive variables there was no difference in CIR and EFS between those receiving an allotransplant and those who did not. Interpretation: Our data suggest a strategy to identify which persons with AML with normal cytogenetics and no NPM1 or FLT3-ITD mutation benefit from an allotransplant. Trial Registration: Registered in the www.clinicaltrials.gov, NCT01455272 and NCT02185261. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China [Grant 81570182 and Grant 81770156], the Peking University People’s Hospital Research and Development Funds [Grant RDF2018-02], the Beijing Municipal Science and Technology Commission [Z18111000960000], the Peking University Clinical Scientist Program[BMU2019LCKXJ003] and the Fundamental Research Funds for the Central Universities Declaration of Interests: RPG is a part-time employee of Celgene Corp. Ethics Approval Statement: The study was approved by the Ethics Committee of Peking University Peoples Hospital and written informed consent obtained from all study participants according to tenets of the Declaration of Helsinki.

Analysis of Molecular Minimal Residual Disease in Patients with Acute Leukemia during Complete Remission

Introduction: Acute leukemia is a group of clonal heterogeneous diseases with high recurrence rate. The monitoring of minimal residual disease (MRD) after treatment mainly relies on flow cytometric immunophenotyping. Genetic abnormalities as the basis of the development of leukemia, the prognosis value of gene mutations in complete remission (CR) has yet to be established except for NPM1 and FLT3-ITD mutations. Recent studies have reported that persistent mutations in non-DNMT3A, TET2, and ASXL1 (DTA) mutations during CR had significant independent prognostic value with respect to relapse and survival rates, but the detection of persistent DTA mutations did not have such prognostic value (Jongen-Lavrencic M et al., N Eng J Med 2018). In this study, we analyzed the molecular MRD of mutations in 58 genes during CR in patients with acute leukemia and explored its impact on prognosis.Methods: Amplicon-targeted, next-generation sequencing (IonTorrent PGM platform, Thermo Fisher Scientific) of 58 genes that are frequently mutated in hematological malignancies was performed retrospectively on 202 patients of acute leukemia, including 117 cases of AML (median age, 23 years; rang, 1-65 years), 66 cases of B-ALL (median age, 13.5 years; rang, 1-45 years) and 19 cases of T-ALL (median age, 11 years; rang, 1-42 years). The average sequencing depth was 1000x. A minimum coverage of 100x and a variant allele frequency >5% were used as thresholds for calling variants.Results: Mutations presented in 8.5% (10/17) of AML patients during CR and the variant allele frequency (VAF) ranged from 5.0% to 25.5% (median VAF, 12%), of which 80% (8/10) were epigenetic regulator gene mutations (DNMT3A, TET2, and IDH1/2). DNMT3A mutation (R882 locus) were detected in five cases, IDH2 mutation (R140Q) were detected in two cases, IDH1 (R132C), TET2 (C1211Y), KIT (D816H), NPM1 (W288Cfs*12), and U2AF1 (S34F) mutation were each presented in one case. There were four cases with DTA and non-DTA mutations respectively and two cases concomitant with DTA and non-DTA mutations (one with DNMT3A and IDH1 mutations and another one with DNMT3A and NPM1 mutations). The median age of four patients with DTA mutations was 45 years (rang, 22-54 years), and the median follow-up time was 15 months (rang, 10-19 months). Among them, three cases were relapsed, two of the three patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) were relapsed. The median age of four patients with non-DTA mutations was 24.5 years (rang, 12-64 years), and the median follow-up time was 25.5 months (rang, 12-35 months). All the patients with non-DTA mutations underwent allo-HSCT and were in continuous CR. One of the two patients who concomitant with DTA and non-DTA mutations (mutation in DNMT3A and IDH1) relapsed after allo-HSCT.Mutations presented in two cases of B-ALL patients during CR, of which PTPN11 (H520Y, VAF 5.9%) mutation was identified in one case who achieved MRD-negative after one course of induction and three courses of consolidation chemotherapy and in a state of sustained remission for two years after allo-HSCT at the time of reporting. KRAS (G12S, VAF 6.3%) mutation was identified in another case whose MRD persists positively after multiple courses of chemotherapy and relapsed in the third years after chemotherapy. At the time of reporting, the bone marrow is in a state of sustained remission for eight months after allo-HSCT. No mutations were detected in all T-ALL patient during CR.Conclusion: Mutations in the epigenetic regulators DNMT3A, TET2, and IDH1/2 are most common in patients with AML during complete remission and the majority of mutations in genes related to the RTK/RAS pathway were cleared. DTA mutations are more common in older patients. The recurrence rate after allo-HSCT is higher in patients with DTA mutation than that of patients with non-DTA mutation and which need to be further verified in the expanded cohort due to the limited number of cases in this study. In contrast to AML, mutations detected in B-ALL during complete remission were mainly RAS pathway and its prognostic significance needs to be further studied. DisclosuresNo relevant conflicts of interest to declare.

Tamibarotene maintenance improved relapse-free survival of acute promyelocytic leukemia: a final result of prospective, randomized, JALSG-APL204 study.

Between April 2004 and December 2010, we conducted a prospective randomized controlled study comparing tamibarotene with all-trans retinoic acid (ATRA) in the maintenance therapy of newly diagnosed acute promyelocytic leukemia (APL), and here report the final results of this study with a median follow-up of 7.3 years. Of 344 eligible patients who had received ATRA and chemotherapy, 319 (93%) achieved complete remission (CR). After completion of three courses of consolidation chemotherapy, 269 patients in molecular remission underwent maintenance randomization, 135 to ATRA (45 mg/m2 daily), and 134 to tamibarotene (6 mg/m2 daily) for 14 days every 3 months for 2 years. The primary endpoint was relapse-free survival (RFS). The 7-year RFS was 84% in the ATRA arm and 93% in the tamibarotene arm (p = 0.027, HR = 0.44, 95% CI, 0.21 to 0.93). The difference was prominent in high-risk patients with initial leukocytes ≥ 10.0 × 109/L (62% vs. 89%; p = 0.034). Tamibarotene was significantly superior to ATRA by decreasing relapse in high-risk patients. Overall survival after randomization did not differ (96% vs. 97%; p = 0.520). Secondary hematopoietic disorders developed in nine patients, secondary malignancies in 11, and grade 3 or more late cardiac comorbidities in three. These late complications did not differ between the two arms.

Induction Chemoradiotherapy (50 Gy), Followed by Resection, for Stage IIIA-N2 Non-Small Cell Lung Cancer

The optimal therapeutic strategy for potentially resectable clinical (c-) stage IIIA-N2 non-small cell lung cancer (NSCLC) remains controversial. This phase II multiinstitutional study (West Japan Oncology Group 5308L) was designed to evaluate the feasibility of induction chemotherapy with concurrent thoracic radiotherapy (50 Gy), followed by resection and postoperative consolidation chemotherapy, in IIIA-N2 NSCLC. Patients with resectable c-stage IIIA-N2 were eligible, and pathologic confirmation of N2 disease was mandatory. Patients received chemotherapy consisting of weekly carboplatin plus paclitaxel with concurrent radiotherapy (50 Gy in 25 fractions). Unless disease progression was documented, patients underwent surgical resection, and thereafter received two courses of consolidation chemotherapy with carboplatin plus paclitaxel. The primary end point was the proportion of patients who achieved complete resection after induction chemoradiotherapy (R0 rate). From December 2011 to November 2013, 40 eligible patients were enrolled. All patients completed induction chemoradiotherapy with an overall response rate of 58%, and 32 patients achieved complete resection (R0 rate, 80%) mostly with lobectomy (n= 27). Twenty patients (50%) completed the study treatment, including postoperative chemotherapy. After the median follow-up period of 38 months, the progression-free survival, overall survival, and recurrence-free survival rates at 2 years were 63%, 75%, and 62%, respectively. The 30-day and 90-day mortality were 0%. Induction chemotherapy with concurrent radiotherapy (50 Gy), followed by resection, was a feasible and promising treatment option for resectable c-stage IIIA-N2 NSCLC.

A pilot study of daunorubicin-augmented hyper-CVAD induction chemotherapy for adults with acute lymphoblastic leukemia.

Induction of complete remission (CR) is imperative for long-term survival in adult acute lymphoblastic leukemia (ALL) patients regardless of transplantation eligibility. Hyper-CVAD chemotherapy is a widely-used frontline remission induction regimen for these patients. We conducted a pilot trial of frontline remission induction using daunorubicin-augmented hyper-CVAD regimen (hyper-CVDD) in adult ALL patients (n = 15). The CR rate after this modified regimen was 100% (n = 15). Twelve patients were able to proceed to allogeneic hematopoietic cell transplantation, two patients died before transplantation due to infection, and the remaining one who was ineligible for transplant due to her age received an additional five courses of consolidation chemotherapy. Overall survival (OS) and event-free survival (EFS) of the study patients was 61.0 and 47.5% at 3 years. OS and relapse-free survival of transplanted patients was 66.8 and 55.0% at 3 years. This pilot trial demonstrates the favorable efficacy of the hyper-CVDD chemotherapy as a frontline remission induction regimen. Further clinical trials using this regimen are warranted.

The number of CD34+CD38+CD117+HLA-DR+CD13+CD33+ cells indicates post-chemotherapy hematopoietic recovery in patients with acute myeloid leukemia.

Hematopoietic recovery is considered to be associated with the number of multipotent hematopoietic stem cells in the bone marrow, as observed in functional assays involving stem cell transplantation. However, there is little evidence related to hematopoietic recovery in non-transplantation settings, which is accomplished by endogenous hematopoietic cells. A recent study suggested that progenitors are the main contributors during this steady-state hematopoiesis, which differs from exogenous transplantation. We hypothesized that endogenous progenitor support post-chemotherapy hematopoietic recovery. To investigate the potential impact of these progenitor cell percentage on hematopoietic recovery, we retrospectively analyzed the percentage of CD34+CD38+CD117+HLA-DR+CD13+CD33+ cells (P cells) and hematopoietic recovery in 223 newly diagnosed acute myeloid leukemia patients during two courses of consolidation chemotherapy after complete remission. We found that a lower P cell percentage was significantly associated with prolonged neutropenia recovery time after the first and second courses of consolidation chemotherapy (p = 0.001; p = 0.045, respectively). We also observed similar results with regard to platelet recovery time after the first course of consolidation chemotherapy (p = 0.000). Univariate analysis showed that P cell percentage and consolidation chemotherapy regimens, and not gender, age, induction chemotherapy regimens, infection grade, WHO classification and NCCN risk category, were associated with neutrophil recovery after chemotherapy. Multivariate analysis demonstrated that P cell percentage is an independent factor affecting neutrophil recovery capacity for both the first and second courses (p = 0.008; p = 0.032, respectively). Our results indicate that CD34+CD38+CD117+HLA-DR+CD13+CD33+ cells before each course of chemotherapy is independently associated with chemotherapy-related hematopoietic reconstitution capacity. These findings may help modify future chemotherapy regimens based on progenitor cell percentages.