5-year EFS Research Articles

Idarubicin and cytarabine with clofarabine or fludarabine in adults with newly diagnosed acute myeloid leukemia: Updated results of a randomized phase II study.

7037 Background: The purine nucleoside analogues fludarabine and clofarabine are effective agents in the treatment of acute myeloid leukemia (AML). This study evaluated the efficacy and safety of combining idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Methods: Using a Bayesian adaptive design, patients (pts) deemed suitable for intensive chemotherapy were randomized to receive CIA (n = 106) or FIA (n = 76). All pts received idarubicin 10 mg/m2 IV daily on Days 1-3 and cytarabine 1 g/m2 IV daily on Days 1-5. Clofarabine and fludarabine were given at 15 mg/m2 and 30 mg/m2, respectively, IV daily on Days 1-5. Pts with FLT3 mutations could receive sorafenib. Up to 6 cycles of consolidation were allowed for responding pts. Results: Baseline characteristics were similar comparing CIA to FIA with a median age of 53 years (range, 20-66) vs 49 years (range, 18-66) respectively and ELN risk intermediate-2/adverse of 57% and 58% respectively. With a median follow-up of 27 months (range, 1-58), the CIA and FIA arms had a similar CR/CRp rate (80% and 82%, respectively). MRD negativity rate by multiparameter flow cytometry at the time of CR/CRp was higher comparing CIA to FIA (80% vs. 65%, respectively, P = 0.07). The median EFS were 13 months and 12 months, respectively (P = 0.91), and the median OS were 24 months and not reached, respectively (P = 0.23). There were more adverse events (all grades) associated with CIA, particularly AST/ALT elevation (29% vs 4%), hyperbilirubinemia (26% vs 9%) and rash (31% vs 9%). Early mortality was similar in the 2 arms (60-day mortality: 4% for CIA vs 1% for FIA; P = 0.32). Comparing the 2 arms to a historical cohort of pts treated with IA showed similar response rates, EFS and OS excluding pts with FLT3 mutations from this analysis. However, in pts < 50 years of age, FIA was associated with improved survival compared with IA (2-year EFS rate: 58% vs 30%, P = 0.05; 2-year OS rate: 72% vs 36%; P = 0.009). Conclusions: CIA and FIA have similar efficacy in younger pts with newly diagnosed AML. FIA is associated with a better toxicity profile and may improve survival compared to IA in pts < 50 years of age. Clinical trial information: NCT01289457.

Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia.

High-dose methotrexate (HDMTX) plays an important role in the treatment of acute lymphoblastic leukemia (ALL) although there is great inter-patient variability in the efficacy and toxicity of MTX. The relationship between polymorphisms in genes encoding MTX transporters and MTX response is controversial. In the present study, 322 Chinese children with standard- and intermediate-risk ALL were genotyped for 12 polymorphisms. SLCO1B1 rs10841753 showed a significant association with plasma MTX levels at 48 h (P = 0.017). Patients who had the ABCB1 rs1128503 C allele had longer duration of hospitalization than did those with the TT genotype (P = 0.006). No association was found between oral mucositis and any polymorphism. Long-term outcome was worse in patients with the SLCO1B1 rs4149056 CC genotype than in patients with TT or TC (5-year event-free survival [EFS] 33.3 ± 19.2% vs. 90.5 ± 1.7%, P < 0.001), and was worse in patients with the SCL19A1 rs2838958 AA genotype than in patients with AG or GG (5-year EFS 78.5 ± 4.6% vs. 92.2 ± 1.8%, P = 0.008). Multiple Cox regression analyses revealed associations of minimal residual disease (MRD) at day 33 (hazard ratio 3.458; P = 0.002), MRD at day 78 (hazard ratio 6.330; P = 0.001), SLCO1B1 rs4149056 (hazard ratio 12.242; P < 0.001), and SCL19A1 rs2838958 (hazard ratio 2.324; P = 0.019) with EFS. Our findings show that polymorphisms in genes encoding MTX transporters substantially influence the kinetics and response to HDMTX therapy in childhood ALL.

OS02.4 Long-term Outcome of Infants and Young Children with Newly Diagnosed Nodular Desmoplastic Medulloblastoma Treated on “Head Start” III Protocol

Background: High-dose chemotherapy with autologous hematopoietic cell rescue (AuHCR) is a potentially curative approach used in the management young children with medulloblastoma), with the additional benefit of avoiding the late-effects of craniospinal irradiation (CSI). Nodular desmoplastic medulloblastoma (NDMB) patients have been shown to have a favorable outcome in most contemporary infant clinical trials. We report the outcome of young children with NDMB treated on “Head Start” III, a ­prospective, multi-national clinical trial. Methods: Between April 2003 and December 2009, 92 children with newly-diagnosed medulloblastoma were enrolled amongst 29 participating institutions, of whom 27 patients had NDMB. All children were to receive 5 induction cycles (vincristine, cisplatin, cyclophosphamide, etoposide, high dose methotrexate - cycles 1, 3, 5), and vincristine, cyclophosphamide, oral VP-16 and temozolomide (cycles 2, 4), followed by 1 consolidation cycle of myeloablative chemotherapy (thiotepa, carboplatin, etoposide) and AuHCR. Only children between 6 -10 years old or with residual tumor pre-consolidation, were to receive irradiation after consolidation. Results: The 2-year event-free (EFS) and overall survival (OS) rates (+/- SE) for patients with ND medulloblastoma enrolled on HS III (primary objective of the study) were 89 ± 6% and 93 ± 5%, respectively. The 5-year EFS and OS rates were 89 ± 6% and 89 ± 6%, respectively. For 15 patients with localized NDMB (M0), the 5-year EFS and OS rates were 93 ± 6% and 93 ± 6%, respectively. Only one patient died, from CNS hemorrhage related to an accidental fall while undergoing induction. The remaining 14 patients are surviving without having received any irradiation. For 11 patients with disseminated NDMB (M+), the 5-year EFS and OS rates were 82 ± 12% and 81 ± 12%, respectively. One patient died from progressive disease post-transplant and one patient died of toxicity (6 months of age at diagnosis) from veno-occlussive disease and multi-organ failure post-transplant. Only 3 of remaining 9 surviving patients with M+ disease received CSI (2340cGy, 2160cGy, and 2700cGy, respectively, along with posterior fossa boost to a total dose of 5400cGy) according to protocol guidelines. One patient did not have staging work-up performed. Multi-variate Cox regression analyses of the entire cohort revealed ND medulloblastoma histology to be the only significant independent predictor of EFS after adjusting for metastatic status, initial extent of resection of the primary tumor, regimen, age and sex (p<0.001). The 5-year irradiation-free EFS rate for Desmoplastic patients was 88+/-6%. Conclusion: These are among the best survival data published so far on young children with ND medulloblastoma, while avoiding CSI in most patients, including 6 of 9 patients with disseminated disease.

P11.02 Long-term Outcome of Infants and Young Children with Newly Diagnosed Non-Nodular/Desmoplastic Medulloblastoma Treated on “Head Start” III Protocol

Abstract Background: High-dose chemotherapy with autologous hematopoietic cell rescue (AuHCR) is a potentially curative approach used in the management young children with medulloblastoma), with the additional benefit of avoiding the late effects of craniospinal irradiation (CSI). We report the outcome of infants and young children with classic and large cell/anaplastic (LCA) medulloblastoma treated on “Head Start (HS)” III, a prospective, multi-national clinical trial. Methods: Between April 2003 and December 2009, 92 children with newly-diagnosed medulloblastoma were enrolled amongst 29 participating institutions. All children were to receive 5 induction cycles (vincristine, cisplatin, cyclophosphamide, etoposide, high dose methotrexate - cycles 1, 3, 5), and vincristine, cyclophosphamide, oral VP-16 and temozolomide (cycles 2, 4), followed by 1 consolidation cycle of myeloablative chemotherapy (thiotepa, carboplatin, etoposide) and AuHCR. Only children between 6-10 years old or with residual tumor pre-consolidation, were to receive irradiation after consolidation. Results: Of 92 children with medulloblastoma enrolled on HSIII, 52 patients had classic and 13 had LCA medulloblastoma. Eighteen patients with classic and 6 with LCA medulloblastoma had localized disease (M0) whereas 33 patients with classic and 7 patients with LCA medulloblastoma had evidence of dissemination (M+). The 2-year event-free (EFS) and overall survival (OS) rates (+/- SE) for patients with classic medulloblastoma (primary objective of the study) were 37 ± 7% and 62 ± 7%, and for patients with LCA medulloblastoma were 54 ± 14% and 62 ± 13%, respectively. The 5-year EFS and OS rates were 26 ± 6% and 53 ± 7% for classic medulloblastoma and 38 ± 13% and 46 ± 14% for LCA medulloblastoma patients, respectively. For patients with M0 medulloblastoma, the 5-year EFS and OS rates were 38 ± 12% and 66 ± 11% for patients with classic histology and 50 ± 20% and 67 ± 19% for patients with LCA histology. Similarly, for patients with M+ medulloblastoma, the 5-year EFS and OS rates were 21 ± 7% and 48 ± 9% for patients with classic histology and 29 ± 17% and 29 ± 17% for patients with LCA histology. In multivariate Cox regression analyses, no significant difference in EFS was found between classic and LCA tumors. 5-year irradiation free-EFS for non-nodular/desmoplastic patients was 29 +/- 6%. Conclusion: Encouraging survival figures are reported for patients with classic medulloblastoma, similar to other contemporary infant protocols, whereas patients with LCA medulloblastoma had equivalent survival when compared to patients with classic medulloblastoma when treated with high-dose chemotherapy with AuHCR. These are among the best survival data published so far on infants and young children with LCA medulloblastoma. Approximately third of the survivors were able to avoid irradiation.

MYCN amplification predicts poor prognosis based on interphase fluorescence in situ hybridization analysis of bone marrow cells in bone marrow metastases of neuroblastoma

BackgroundMYCN gene amplification is related to risk stratification. Therefore it is important to identify accurately the level of the MYCN gene as early as possible in neuroblastoma (NB); however, for patients with bone marrow (BM) metastasis who need chemotherapy before surgery, timely detection of the MYCN gene is not possible due to the unavailability of primary tumors.MethodsMYCN gene status was evaluated in 81 BM metastases of NB by interphase fluorescence in situ hybridization (FISH) analysis of BM cells. The clinicobiological characteristics and prognostic impact of MYCN amplification in NB metastatic to BM were analyzed.ResultsMYCN amplification was found in 16% of patients with metastases, and the results were consistent with the primary tumors detected by pathological tissue FISH. MYCN amplification was associated with age, lactate dehydrogenase (LDH) levels and prognosis (P = 0.038, P < 0.001, P = 0.026). Clinical outcome was poorer in patients with MYCN amplification than in those without amplification (3-year EFS 28.8 ± 13.1 vs. 69.7 ± 5.7%, P = 0.005; 3-year OS 41.5 ± 14.7 vs. 76.7 ± 5.5%, P = 0.005).ConclusionsMYCN amplification predicts a poor outcome in NB metastatic to BM, and interphase FISH of bone marrow cells provides a timely direct and valid method to evaluate the MYCN gene status.

Inferior vena cava involvement in children with Wilms tumor.

Retrospective review of children with WT thrombus involving the IVC. We reviewed the charts of 123 patients with WT diagnosed between January 2006 and December 2015. Patients with caval tumor thrombus were identified, demographic data, radiological images, extent of thrombus, chemo- and radiotherapy, surgical approach, pathology reports and outcomes were analyzed. IVC involvement was identified in 11 patients (9%). Left-sided tumors were more common (55%). Sensitivity of CT scan in thrombus identification was 64%. Neoadjuvant chemotherapy was the primary mode of treatment with 19% reduction of primary tumor size, thrombus resolution in four and regression in six patients. No thrombus progression was observed. Delayed surgical treatment was either nephro-ureterectomy (nine patients) or partial nephrectomy in patients with bilateral WT (two patients). During surgery, thrombectomy and intimal stripping achieved local control in patients with persistent caval tumor. Cardiopulmonary bypass was not needed in patients with initial atrial involvement (five patients). Despite adherence and invasion of tumor thrombus to IVC wall, only one patient required segmental vein resection. All patients eventually achieved CR, none had local relapse. One patient had lung relapse treated to complete remission. The 3-year EFS is 85.7±13.2% and the 3-year OS is 100%. IVC tumor thrombus in patients with WT was managed successfully using preoperative chemotherapy followed by surgery with minimal aggressive approach. Luminal thrombus removal and intimal stripping supplanted by local radio boost when indicated seem to be adequate tools for local control with documented good overall outcomes.

Long-term outcome of diffuse large B-cell lymphoma: Impact of biosimilar rituximab and radiation.

Rituximab (R)-CHOP improves survival over CHOP in diffuse large B-cell lymphoma (DLBCL). The availability of biosimilar rituximab in India has increased access of this drug. We report on the impact of treatment on outcomes with special emphasis on the impact of biosimilar rituximab and radiation. Outcomes of adults (age 15-60 years) treated with CHOP+/- Rituximab radiation were analyzed retrospectively to look at baseline features, treatment, and event-free and overall survival (EFS and OS). In the period 2000-2013, 444 patients (median age 47 years: 15-60; males: 288 [65%]; Stage III/IV: 224 [50%]; age-adjusted international prognostic index [aaIPI] Score 2 or 3 in 50%) received either CHOP (n = 325 [73%]) or RCHOP (n = 119 [27%]) therapy. Biosimilar rituximab and the original were used in 95 (80%) and 24 (20%) patients, respectively. Radiation was given in 134 (30%) patients (Stages I and II, 100/220 [45%] and Stages III and IV, 34/224 [15%]). After a median follow-up of 46 (0.2-126) months, the 5-year EFS and OS were 59% and 68%, respectively. The factors predicting inferior EFS and OS were age> 40 years, performance status 2-4, Stage III/IV, hemoglobin <12 g/dL, the aaIPI Score 2 or 3, and nonuse of rituximab and radiation. Radiation used in early stage disease benefitted all subgroups regardless of bulky disease, use of rituximab, or the number of cycles of chemotherapy. Addition of rituximab improved survival across all categories of aaIPI. Availability of biosimilar rituximab has increased access and survival of patients with DLBCL in India. Radiotherapy improved outcomes in early stages.

Acute Myeloblastic Leukemia and Myelodysplastic Syndrome: Azacitidine for Prophylactic and Preventive Purposes after Allogeneic Hematopoietic Stem Cell Transplantation

Aim. To evaluate the effectiveness of preventive and prophylactic post-transplantation therapy using azacitidine (5-AZA) in patients at high risk of post-transplantation relapse. Methods. 136 patients were included in the study performed by the pairwise comparison: 68 of them received 5-AZA after allo-HSCT and 68 patients were included in the historical control group. 5-AZA was prescribed for prophylactic or preventive purposes. The results were assessed according to the OS, RR, EFS, DUM, and relapse-free and GVHR-free survival. Results. 1-year OS was 76 % in the 5-AZA group (95% CI 60-84 %) and 44 % in the reference group (95% CI 33-55 %) (р = 0.001); 2-year OS was 63 % (95% CI 39-67 %) and 37 % (95% CI 26-48 %) (р = 0.007), respectively. The relapse rate (RR) in the 5-AZA group was 34 % (95% CI 22-46 %) during 1 year and 51 % (95% CI 38-64 %) in the reference group (р = 0.02). 1- and 2-year disease unrelated mortality (DUM) was similar: 5 % in the 5-AZA group (95% CI 0.1-14.0 %) and 25 % (95% CI 13-37 %) in the reference group (р = 0.005). 1-year EFS was 76 % in the 5-AZA group (95% CI 61-85 %) and 44 % in the reference group (95% CI 33-55 %) (р = 0.001); 2-year EFS was 63 % (95% CI 39-67 %) and 37 % (95% CI 2648 %) (р = 0.01), respectively. 1-year relapse-free and GVHR-free survival was 55 % in the 5-AZA group (95% CI 41-69 %) and 28 % in the reference group (95% CI 17-39 %) (р = 0.001); 2-year relapse-free and GVHR-free survival was 47 % (95% CI 32-62 %) and 27 % (95% CI 17-37 %) (р = 0.002), respectively. Conclusion. The use of 5-AZA for prophylactic and preventive purposes after allo-HSCT does not increase the risk of GVHR and DUM, does not suppress the GVL effect and can be used in combination with the donor lymphocyte infusion (DLI). The therapy with 5-AZA is safe during the early period after allo-HSCT. The drug does not suppress the GVL effect and can be used in high risk patients to prevent early post-transplantation relapse. The use of 5-AZA in combination with DLI does not increase the incidence of severe GVHR.

Age and Gemtuzumab Ozogamicin Influence the Prognostic Impact of TET2 Expression and Splicing in Intensively Treated Patients with Acute Myeloid Leukemia

Background. In AML, the frequency of TET2 mutations increases with age ranging from 1-5% in children to 6-27% in adults. These mutations have both been reported to exert unfavorable or neutral effects on patient outcomes. Besides mutations, fluctuation in TET2 expression has been evidenced in AML while we recently found that TET2 exon 2 skipping (TET2E2S) is associated with favorable outcome in adult AML (Mint-Mohamed et al., ASH 2014 and submitted). Here we investigated the effect TET2 expression and TET2E2S in homogeneously treated adult and pediatric AML patients with intensive chemotherapy (IC).Methods. Samples derived from 341 patients with available high-quality RNA and enrolled in the ELAM2 protocol (n=120) and the ALFA-0701 protocol (n=221).qRTPCR amplification of 2 conserved TET2 mRNA sequences was performed with GUS and ABL as reference genes. TET2 exon 2 skipping was quantified throughexon(E)-specific qRTPCR (qESPCR) amplification of E1E3 (spliced) and E2E3 (unspliced) TET2 isoforms. TET2E2S was quantified by calculating the ratio E1E3/E2E3. Patients were classified according to their standardized cytogenetic and molecular (NPM1 mutations, FLT3-ITD, CEBPA double mutations) risk subgroups. In children, treatment consisted in 1 induction course (AraC and mitoxantrone) and 3 consolidation courses (course 1 and 3 with high dose AraC); children with either intermediate or high-risk disease were candidates for hematopoietic stem cell transplant (HSCT) in complete remission (CR) after 1 to 2 consolidation courses. Adult patients were given a 3+7 induction course without (control group, n=110) or with fractionated intravenousgemetuzumab ozogamicin (GO) (n=111) as already described (Castaigne S, Lancet 2012; 379:1508-1516).Results. In pediatric AML, median age, median WBC, CR rate, relapse rate, median follow-up, 3-years EFS, DFS, and OS were 9.4 years, 19 G/L, 95%, 29%, 48 months, 60±5%, 63±6%, and 72±5%, respectively. Lower TET2 expression was associated with inferior EFS (3-years: 44±10%vs 69±6%, log-rank p = 0.01), DFS (51±8%vs 64±5% p=0.02), and OS (60±8%vs 83±3%, p=0,0003) while TET2E2S was associated with inferior EFS (44±8%vs 70±7%, p = 0.006) and OS (61±7%vs 81±4%, p=0.01). For TET2 expression, multivariate analysis identified WBC, age, risk group, and TET2 expression as independent prognostic factors for EFS and OS, and age, WBC, and TET2 expression for DFS (Table 1). For TET2 splicing, WBC and TET2E2S independently predicted EFS while TET2E2S alone independently predicted DFS (Table 1). In the low- (n=29) and intermediate-risk (n=62) groups, lower TET2 expression remained associated with shorter 3-years EFS. There was no significant correlation between TET2 expression and TET2E2S and TET2E2S retained its negative prognostic impact in the 85 patients with higher TET2 expression (3-years EFS 48±8vs 84±6%, p=0.004). In adult AML, median age, median WBC, CR rate, relapse rate, median follow-up, 3-years EFS, DFS, and OS were 62 years, 8 G/L, 76%, 59%, 47 months, 26±3%, 30±4%, and 44±4%, respectively. In the entire population, TET2 expression and splicing had no significant effect on outcome. In the 110 patients treated with IC alone, TET2 expression was associated with inferior OS (25±9vs 29±9%, p=0.02) while TET2E2S was associated with better EFS (17±5vs 7±6%, p=0.008), DFS (28±8vs 8±6%, p=0.02), and OS (46±8vs 29±8%, p=0.05). TET2E2S, age, and disease risk represented independent prognostic factors for EFS (Table 1). In the GO arm, TET2 expression had no significant effect on outcome whereas TET2E2S was associated with inferior EFS (27±5vs 60±12%, p=0.01), DFS (31±6vs 63±12%, p=0.05), and OS (39vs 72±11%, p=0.04).Conclusion. Inchildren, higher TET2 expression confers a favorable outcome whereas TET2E2S represents an independent unfavorable prognostic factor. In adult treated with IC alone, present results confirm the favorable prognostic impact of TET2E2S and the weak prognostic effect of TET2 expression. In contrast, in patients fulfilling the same inclusion criteria, TET2E2S loses its favorable prognostic effect and is even associated with unfavorable outcome when GO is associated to IC. While TET2 expression and splicing might represent useful biomarkers, the data highlight the strong difference in tumor biology between adult and pediatric AML and suggest distinct relationships between TET2E2S and the cytotoxic effect of GO plus IC versus IC alone. [Display omitted] DisclosuresThomas:Pfizer: Consultancy.

A microRNA Expression-Based Model Predicts Event Free Survival in Pediatric Acute Myeloid Leukemia

INTRODUCTIONAcute myeloid leukemia (AML) is a hematopoietic malignancy that comprises almost 25% of pediatricleukemiasand is characterized by genetic and epigenetic alterations that lead to impairment of differentiation and clonal expansion. Despite intensive chemotherapy, more than half of children with AML either fail to achieve a complete remission (CR) or relapse after initial response.As such, the availability of a predictor of treatment failure at diagnosis may allow early institution of alternative therapies to improve outcome. MicroRNAs (miRNAs), a class of small non-coding RNAs that regulate the translation of their target mRNAs, are frequentlydysregulatedin cancers, and thus may serve as robust biomarkers of patient outcome.METHODSTo identifymiRNAbiomarkers associated with treatment failure and candidate therapeutic targets, we performed a comprehensive sequence-based characterization of the pediatric AMLmiRNAexpression landscape usingmiRNA-seqdata from 637 primary samples. AmiRNAexpression-based model for EFS separating patients into low, intermediate, andhigh riskgroups was produced using penalized Cox regression. The model was designed usingmiRNAexpression data obtained from a training cohort, which consisted of two-thirds of our study cohort (n=425), and then tested on the remaining one-third of our study cohort (n=212). The training and test cohorts were derived by random selection.RESULTSA 36-miRNA EFS predictive model was generated. This model was comprised of16miRNAsthat were over-expressed and 20 that were under-expressed in patients who experienced an event (death, relapse or IF). Among the 36miRNAtranscripts were miR-155, miR-335, miR-139 and miR-375, which have been previously individually associated with survival in pediatric AML.To demonstrate the potential clinical utility of the model, we determined 2 miRNAmodel score thresholds in the training cohort to separate patients into low, intermediate and high miRNAmodel score risk groups. The miRNAmodel score groupings were significantly associated with EFS in both the training cohort and test cohort (Figure 1A; P<0.001). Specifically, within the training cohort, the model identified 108 (25%) patients as high risk (5-year EFS: 7.36%; HR: 2.83, P<0.001), and 106 (25%) patients as low risk (5-year EFS: 81.4%; HR: 0.32, P<0.001). The training and test cohorts were combined for further subclass evaluation. In the combined cohort, multi-variate Cox regression analysis, which includedmiRNA expression risk status and conventional cytogenetic and molecular (CM) risk groups, demonstrated that themiRNA risk classification remains an independent predictor of high risk (HR: 2.44, P<0.001) and low risk (HR: 0.34, P<0.001).Furthermore, to demonstrate the strength of our predictive model, we evaluated the clinical significance of the model in each of the low, standard and high CM risk cohorts. In this analysis, our model was capable of further stratifying patients in each of the 3 CM risk cohorts into 3 distinct miRNAmodel score-based risk categories (Figure 1B, P<0.001). Of particular interest is the ability of the model to identify patients with poorer outcomes in the CM low risk cohort and those with more favorable outcomes in the CMhigh risk cohort.CONCLUSIONSWe present amiRNAexpression-based predictor of outcome in pediatric AML, comprised of 36miRNAtranscripts. Our predictive model was developed and tested on a large cohort of primary patient samples (n=637), and demonstrated that diagnosticmiRNAexpression profiles can identify risk groups in patients independent of other CM risk factors. Moreover, this model is applicable to RNA from samples that are routinely obtained for diagnosis, and thus has the potential to impact clinical practice. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Characteristics and Outcomes of Newly Diagnosed Patients with Adult T-Cell Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LL) with Hypercvad Based Regimens

Introduction: T-cell ALL and T-LL are considered as different spectra of the same neoplastic clone. In various clinical trials of adult ALL, patients with T-ALL and T-LL were combined when analyzing treatment responses and survival outcomes. We have previously reported the results with HCVAD-based regimens in patients with adult ALL. In this study we addressed whether the initial presentation, treatment response, and survival outcomes of adults with T-LL and T-ALL differed when patients were uniformly treated with frontline HCVAD-based regimens at a single institution.Methods: One hundred and fifty previously untreated patients with T-LL (n=54) and T-ALL (n=96) who were treated with HCVAD-based regimens (1992-2016) were included in this analysis. Patient charts were reviewed for initial characteristics, treatment responses including minimal residual disease (MRD) status and survival outcomes; event free (EFS) and overall survival (OS) were analysed.Results: Among 150 patients with previously untreated adult T-ALL/LL, we identified 54 patients (36%) with T-LL and 96 (64 %) with T-ALL. Among patients with available immunophenotype data (n=104), early T precursor (ETP) phenotype was significantly more frequent among patients with T-ALL compared to patients with T-LL (44% vs 19%; p=0.006). The proportion of early, cortical and mature immunophenotype were 2% vs 6%, 31% vs 49% and 16% vs 12% in T-ALL versus T-LL, respectively. The clinical characteristics, response to therapy and outcomes of patients in T-LL versus T-ALL were compared (Table 1 and Figure-1).Patients with T-ALL were slightly older at presentation (median age 37 years [18-67] versus 31 years [17-78]; p=0.07). Patients with T-ALL had significantly higher white blood cell counts, peripheral blood blasts %, bone marrow blasts %, and serum LDH as compared to patients with T-LL. Distribution of chromosomal aberrations was significantly different among the two groups: Diploid karyotype was more commonly encountered in patients with T-LL while patients with T-ALL had more hyperdiploidy and hypodiploidy. Among patients evaluable for response, complete remission (CR) rates were 85% and 95% (p=0.002) in T-LL and T-ALL, respectively. Overall the median follow up times were 72 months (range, 5-243) and 61 months (range, 1-267). Thirty nine (72%) patients with T-LL and 43 (45%) with T-ALL were alive at the time of last follow-up. Patients with T-LL had better outcomes than patients with T-ALL. The 3-year EFS and OS rates were 78% and 74% in patients with T-LLand 53% (p=0.005) and 50% (p=0.001) in patients with T-ALL (Figure 1).Conclusions: In summary, adult patients with T-LL have better outcomes than patient with T-ALL after treatment with HCVAD-based regimens. Additional studies to characterize the genomic profile in tumoral tissues, as well as the pattern of relapses in patients with adult T-LL and T-ALL are ongoing. [Display omitted] [Display omitted] DisclosuresKonopleva:Calithera: Research Funding; Cellectis: Research Funding. Jain:Incyte: Research Funding; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Infinity: Research Funding; Novimmune: Consultancy, Honoraria; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Genentech: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Wierda:Acerta: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

ABCA3 Expression Predicts Response to Gemtuzumab Ozogamicin in AML

Background. The ATP binding cassette transporter 3 (ABCA3) has been recently found to induce a significant reduction in cytotoxicity following exposure to anthracyclines, mitoxantrone, etoposide, Ara-C, vincristine, and rituximab. ABCA3 acts through the modulation of multivesicular bodies (MVB) and contributes to drug sequestration in late endosomal organelles, i.e. MVB and lysosomes. Studies having investigated the prognostic impact of ABCA3 expression in AML have yielded conflicting results as ABCA3 expression has both been reported to exert unfavorable or neutral effects on patient outcomes. In addition, the small sample size of these studies precluded the use of multivariate analyses.Methods. Our goal was to investigate the prognostic impact of ABCA3 expression in adult patients with AML treated with IC with or without gemtuzumab ozogamicin (GO). To this end we investigated the relationship between ABCA3 expression and EFS in a representative series of 221 AML homogeneously treated in the ALFA-0701 trial. qRTPCR amplification of conserved ABCA3 mRNA sequences, as identified with FasterDB database, was performed with GUS and ABL as reference genes. Primer sets were complementary to conserved ABCA3 exons 6-7 and exon 19-20 junctions. Patients were given a 3+7 induction course without (control group, n=110) or with fractionated intravenous GO (n=111) (Castaigne S, Lancet 2012; 379:1508-1516).Results. Among the 278 randomized patients, 221 had available bone-marrow diagnostic samples with high-quality RNA. The same benefits associated with GO were observed in the 221 patients from the present study as in the entire trial population. Overall, median age, CR rate, relapse rate, median follow-up, 3-years EFS were 62.1 years, 76.5%, 66%, 47.45 months, 28±3%, respectively. There was no significant difference in the level of ABCA3 expression between responders and non-responders. In the 169 responders, ABCA3 expression at diagnosis was more than 3-fold higher in the 111 remitters who subsequently relapsed than in the 58 patients who remained in persistent CR (p=0.033). The level of ABCA3 expression was significantly lower in ELN favorable group than in intermediate and adverse risk AML (p= 0.004) and negatively correlated with CD33 expression (R=-0.272, p<10-4). Through univariate analysis, higher ABCA3 expression was associated with shorter EFS (3-years: 22±3 vs 45±7 % p=0.002). Multivariate analysis identified age, treatment arm, and ELN risk group as independent prognostic factors for EFS. In the control group, there was no significant association between ABCA3 expression and CR rate, relapse rate, and EFS. In the 111 patients within the GO arm, there was no significant difference in the level of ABCA3 expression between responders and non-responder whereas in the 89 responders, ABCA3 expression at diagnosis was more than 7-fold higher in the 53 remitters who subsequently relapsed than in the 36 patients who remained in persistent CR (p=0.006). Through univariate analysis, higher ABCA3 expression was associated with shorter EFS (3-years: 22±5 vs 64±9 % p=0.0002). Multivariate analysis identified ABCA3 expression, cytogenetics, CD33 expression, and ECOG as independent prognostic factors for EFS (Figure 1).Conclusion. WhileABCB1 has been previously found to attenuate GO-induced cytotoxicity in AML cells (Walter RB, Blood 2003; 102:1466-1473), present results indicate that higher ABCA3 expression independently predicts poor outcome in AML patients treated with fractionated GO and intensive chemotherapy (IC). GO is an anti-CD33 antibody carrying a toxic calicheamicin derivative that, after hydrolytic release within lysosomal vesicles, induces DNA strand breaks, apoptosis, and cell death. Whether the clinical effect of ABCA3 expression relies on the modulation of CD33 internalization, calicheamicin release or combination thereof is under investigation. Finally our results encourage inhibiting ABCA3, such as with indomethacin, in order to overcome drug resistance in AML treated with GO-IC. [Display omitted] DisclosuresThomas:Pfizer: Consultancy.

The Prognosis of PR Patients after Induction Therapy Was Not Inferior to CR in ASCT-Eligible NDMM Patient.

Introduction:Autologous stem cell transplantation (ASCT) is standard therapy for newly diagnosed multiple myeloma (NDMM) patients who are younger than 70 years old. In the IFM 90 trial, 5-year OS was 52% in the ASCT group compared to 12% in the initial chemotherapy group (p=0.03). 5-year EFS was 28% in the ASCT group compared to 10% in the chemotherapy only group (p=0.01). MRC IV trial also showed a higher rate of OS (p=0.04) and PFS (p<0.001) in the ASCT group. However, there was no result about the differences of the prognosis between CR and PR before ASCT. In this study, we studied the response level before ASCT to understand if it is related to the prognosis after ASCT.Methods:We studied 25 NDMM patients who received ASCT in our hospital from 2005 to 2015. Induction therapies were VRD, VCD, VAD, VD, Rd or VTD-PACE. Stem cells were collected using G-CSF or cyclophosphamide plus G-CSF. After stem cell harvest, all patients underwent high dose melpharan (200mg/m2) before ASCT. The responses according to the IMWG guidelines were performed at the point of 4-6 weeks after ASCT. Statistical analyses were performed using a software, EZR version 1.Results:The total number of NDMM patients was 25. The median age was 55 years (range 33-62), the median follow-up period was 1,375 days (range 340-3,763). Male were 16 (64%), 11 patients (44%) were ISS II or more and 20 (80%) were D&S stage II or more. ECOG PS 2 was 4 patients (8%) and one (4%) is ECOG PS 3. Before ASCT, 21 patients (84%) received 1 regimen and 4 (16%) received 2 regimens. In the 1 regimen group, 9 patients (43%) were treated by VCD with 2-4 cycles, 9 received VD with 4-5 cycles and 5 (24%) were received VAD with 3 cycles before ASCT. In the 2 regimens group, details of induction therapy were VD with BCD, VCD with Rd, VCD with VRD and VCD with VTD-PACE. In all patients, 3-year OS was 91.6% (95% CI, 70-98%) and 3-year PFS was 56% (95% CI, 34-74%). After induction therapy, CR was achieved in 11 (44%), VGPR was 2 (8%), PR was 11 (44%) and MR was 1 (4%). After ASCT, CR was achieved in 18 (72%), VGPR was 2 (8%), PR was 4 (16%) and PD was 1 (4%). 4 patients (16%) died for progression of multiple myeloma.There were no statistical differences in 3-year OS and PFS between CR group and VGPR + PR group after induction therapy (3-year OS; 100% vs 92%, p=0.11, 3-year PFS; 70% vs 50%, p=0.26). There were also no differences between the two groups CR group and PR without VGPR group (3-year OS; 100% vs 90%, p=0.18a, 3-year PFS; 70% vs 60%, p=0.4). As sub-analysis, the achievement time until normalization of FLC and disappearance of serum or urine M-protein in IFE did not affect 3-year OS and PFS.Discussion and Conclusions:When MM patients having residual disease did the stem-cell harvest, it has been possible to contaminate of myeloma cells in their collected stem cells. Several literatures described the contamination of myeloma cells in the stem cells induced inferior prognosis after ASCT. However our limited data suggested that the prognosis of patients who had residual disease after induction therapy, if they had achieved better than PR, were not inferior to CR group. This is reasonable data for recommendation of ASCT to MM patients getting PR after induction therapy. DisclosuresMishima:Chugai: Consultancy. Nishimura:Chugai: Consultancy. Yokoyama:Chugai: Consultancy. Terui:Yanssen: Honoraria. Hatake:Chugai: Research Funding; Otsuka: Consultancy; Kyowa Kirin: Honoraria, Research Funding; Meiji-Seika: Consultancy.

Outcomes of Patients with Myeloproliferative Neoplasms (MPN) after Interferon-Alpha (IFN) Therapy Discontinuation

▪Background:We and others have shown that IFN therapy provides several benefits to MPN patients (pts) including molecular responses and possible long-term remissions off cytoreductive therapy (CRT). However, little is known about outcomes after IFN discontinuation, and the clinical relevance of achievement of molecular response is disputed.Methods:We collected all cases of MPN pts followed in our institution who received IFN therapy since 2000, and who discontinued treatment. Cumulative incidences of relapse, hematological transformation and thrombosis were based on competing risks estimator. Survival curves and event free survival (EFS, i.e. time to first event including transformation, thrombosis and death) curves from IFN start were plotted based on the Kaplan Meier method. Univariate logistic models were used to predict complete hematological response (CHR) without any CRT; Cox models were used to predict EFS, and cause-specific hazard of relapse. Multivariable models were then fitted, with a stepwise selection procedure. All tests were two-sided with p-values ≤0.05 denoting statistical significance.Results:A total of 149 out of 333 IFN treated MPN pts had discontinued therapy at time of analysis. 78 had polycythemia vera (PV), 61 essential thrombocythemia (ET), and 10 myelofibrosis (MF). Reasons for choosing IFN in these 149 pts were young age in 75 (50%), resistance / intolerance to previous therapies in 40 (27%), pregnancy in 4 and other in 30. Median age at IFN start was 49.5 years [interquartile range, IQR: 39-60] and median [IQR] time since diagnosis of MPN was 2 years [0.6-6.8]. 64 pts had a history of vascular event.123 pts were JAK2V617F+, 15 had CALR, 5 MPL and 1 JAK2 exon 12 mutations, and 5 were triple-neg. Among 47 pts tested by NGS, 15 had additional mutations.Best response to IFN was CHR in 123 (83%), partial response (PR) in 16, and failure in 10 pts. Reasons for IFN discontinuation were toxicity in 79 (53%), prolonged hematological CHR in 52 (35%), and other in 18. Median IFN treatment duration was 28.3 months (mos) [10-45]. At discontinuation, 114 (77%) pts were in CHR, 17 (11%) in PR, and IFN failed in 18 (12%).At IFN start, median mutant allele burdenwere 25% [IQR: 15-48] and 38% [34-43] for JAK2 and CALR resp. At IFN discontinuation, median %JAK2 and %CALR had decreased to 10% [3-25], and 13.5% [6-43], resp.At last follow up, 109 (73%) pts were alive in CHR for a median time after IFN discontinuation of 42 mos [23-58], including 46 (42%) without CRT after 33 mos [19-53]. Based on a multivariable logistic model, the CHR without CRT was associated with mutant allele burden at IFN discontinuation (OR=0.95, 95%CI, 0.95-0.96, P=0.034), stopping for toxicity reason (OR= 0.82, 95%CI, 0.75-0.89, P= 0.009), and cumulative dose of IFN (OR=1.01/mg, 95%CI, 1.003-1.02, P= 0.012).Hematological relapse occurred in 49 pts. IFN was restarted in 25 of them and all achieved hematological response, including 72% CHR. Based on a multivariable Cox model, the cause-specific hazard of relapse was decreased in ET (HR= 0.4, 95%CI, 0.2-0.8; P= 0.013) while increased with the baseline WBC count (HR= 1.07, 95%CI, 1.02-1.14, P= 0.011).Ten pts had a thrombotic event after IFN, with a 5 year cumulative incidence of 10% (95%CI, 4-16%). A total of 11 pts transformed to MF, 3 to MDS / AML, and 2 from ET to PV; the 5-year cumulative incidence of transformation was 3.8% (95%CI, 0.4-7.2%). Six patients had died (4 after transformation). Overall, 25 patients developed a thrombosis, transformation or death. The 5- and 10-year EFS were 92% (95%CI, 87-97) and 72% (95%CI, 62-84), resp. In multivariate model, only time between diagnosis and IFN start (HR=1., 95%CI, 1.002-1.016, P=0.011) and mutant allele burden at IFN discontinuation (HR=1.03, 95%CI, 1.016-1.048, P<0.0001) remained jointly associated with the outcome. Pts with an allele burden ≥ 25% at discontinuation had a higher hazard of event (HR= 3.4, 95%CI, 1.3-9.3, P=0.0145).Conclusion: This study allowed for the first time identification or several parameters associated with major outcomes after IFN therapy. In particular, a lower mutant allele burden at IFN discontinuation was associated with persistent complete hematologic response without therapy and longer event-free survival, indicating a clinical relevance in obtaining a deeper molecular response. Our results also show that late onset of IFN therapy after MPN diagnosis is associated with poorer outcome. DisclosuresKiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Prognostic Impact of ABCA3 Expression in Pediatric Acute Myeloid Leukemia

Abstract Background. Despite progress in the molecular and genetic classification of pediatric acute myeloid leukemia (AML), the prognosis remains heterogeneous. The ATP-binding cassette transporter A3 (ABCA3) seems specifically involved in the resistance of pediatric AML to intensive chemotherapy. However, studies having investigated the prognostic impact of ABCA3 expression have yielded conflicting results with respect to patient outcomes while the small sample size of these studies precluded the use of multivariate analysis. Here we investigated the prognostic impact of ABCA3 expression in a representative series of homogeneously treated pediatric AML. Methods. Samples derived from 233 patients with available high-quality RNA and enrolled in the ELAM2 protocol (NCT00149162). qRTPCR amplification of 2 conserved ABCA3 mRNA sequences was performed with GUS and ABL as reference genes. Primer sets were complementary to exons 6-7 and exons 19-20 junctions. Patients were classified according to their standardized cytogenetic and molecular (NPM1 mutations, FLT3-ITD, CEBPA double mutations) risk subgroups (Rubnitz JE, Blood 2012;119:5980-5988, Creutzig U, Blood 2012;120:3187-3205). Treatment consisted of 1 induction course (AraC and mitoxantrone) and 3 consolidation courses (course 1 and 3 with high dose AraC); all children with either intermediate or high-risk disease were candidates for hematopoietic stem cell transplant (HSCT) in complete remission (CR) after 1 to 2 consolidation courses. Results. The discovery cohort included 120 patients. Median age, median WBC, CR rate, relapse rate, median follow-up, 5-years EFS, DFS, and OS were 9.4 years, 19.3 G/L, 95%, 29%, 60 months, 58±6%, 61±6%, and 71±5 months, respectively. The two primer sets yielded consistent results (R=0.9, p&lt;10-4, Spearman Rank Correlation). Lower ABCA3 expression was positively associated with CBFB-MYH11 AML (p=0.002) and thereby with favorable cytogenetics (p=0.036) and low-risk AML (p=0.027). Higher ABCA3 expression was associated with higher relapse rate (p=0.006), shorter EFS (5-years, 34±9 vs 61±6 % p=0.0005), DFS (36±9 vs 62±6% p=0.0028), and OS (49±12 vs 79.5±5% p=0.0007). Multivariate analyses identified age, WBC, risk group, and ABCA3 expression as independent prognostic factors for EFS, DFS, and OS (Table 1). The validation cohort included 113 patients in whom the proportions of AML1-ETO- and MLL-positive AML were significantly higher than in the discovery cohort: 26,5% vs 6,7% (p&lt;10-4) and 24.8 vs 14.2% (p=0.03). There was no significant difference in patients' outcome between the 2 cohorts. Using the same cutoff value in the validation cohort, higher ABCA3 expression remained significantly associated with shorter 5-years EFS: 63±7% vs 43±9% (p=0.025) with a trend for shorter DFS: 45±9 vs 53±11% (p=0.065). Multivariate analyses identified ABCA3 expression as an independent negative prognostic factor for EFS and DFS (Table 1). In the entire patients population, ABCA3 expression independently predicted EFS, DFS, and OS (not shown). In the low- (n=74) and adverse-risk (n=59) groups, higher ABCA3 expression remained associated with shorter 5-years EFS (low: 46±12 vs 75±7%, p=0.006; adverse: 12±10 vs 44±16%, p=0.018), DFS (low: 49±13 vs 75±7%; high: 12±11 vs 45±16%, p=0.016), and OS (low: 76±10 vs 94±4%; adverse: 32±14 vs 57±18%, p=0.046). Conclusion. ABCA3 expression represents an independent prognostic factor in pediatric AML. As they indicate that the level of ABCA3 expression is significantly associated with survival for currently accepted cytogenetic and molecular prognostic categories, our findings suggest that assessing ABCA3 expression will permit a better assessment of disease risk. Finally our results suggest that inhibiting ABCA3 expression, such as with indomethacin, could be beneficial in order to overcome drug resistance in pediatric AML. Disclosures No relevant conflicts of interest to declare.

Is Arsenic Trioxide (ATO) Required in the Treatment of High Risk Newly Diagnosed APL? Analysis of a Randomized Trial (APL2006) By the French Belgian Swiss APL Group

▪Background:In standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + anthracycline based chemotherapy (CT) while being less myelosuppressive (Lo Coco, NEJM 2014, Burnett, Lancet Oncol, 2015). In high risk APL (WBC> 10G/l), it is still unclear if CT can be avoided or greatly reduced, but addition of ATO to ATRA + CT reduces relapses (Powell, Blood 2010). In a randomized trial (APL2006 trial) in high-risk APL patients (pts) who received ATRA + CT induction treatment, we evaluated the addition of ATO to CT during consolidation.Methods: Between 2006 and 2015, newly diagnosed APL pts <70 years with WBC> 10 G/L, after an induction of ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7, were randomized for consolidation between CT and CT+ATO. The CT group (standard group) received a first consolidation with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7, a second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d, and 2-year maintenance with intermittent ATRA and continuous 6 MP + MTX. The CT+ATO group received the same treatment except that ATO 0.15 mg/Kg/d d1 -25 was added during both consolidation courses. After a first interim analysis in Sept 2010, based on 81 pts, AraC was deleted from consolidation cycles of the CT+ ATO group. The primary endpoint was EFS from CR achievement.Results: 211 pts <70 years with WBC> 10 G/L were included (after the exclusion of 8 diagnostic errors) in 58 centers. 95.7% achieved CR, 3.3% had early death and 1% resistant leukemia. 193 pts were randomized for consolidation, 97 in the CT and 96 the CT+ ATO groups. Pre-treatment characteristics were well balanced between the 2 groups. 7 pts (3 CT vs 4 CT+ATO) had relapsed (5-year cumulative incidence of relapse (CIR) of 2.5% vs 3.9%; p= 0.39) and 9 pts had died in CR :7 (7.8%), 2 (5.1%), 0 (0%) in the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively (p=0.04). Causes of death in CR were bleeding (n=5), infection (n=2), previous cancer relapse (n=2). One patient in the CT+ATO arm developed AML/MDS.5-year OS was 93% vs 94% (p=0.56) and 5-year EFS was 89% vs 93% (p=0.47) in the CT and CT+ATO groups, respectively. Omission of AraC (after the amendment) in the CT+ATO group did not increase CIR (5 year CIR 5.3% with and 3.3% without AraC, p=0.57). In the CT, CT (with AraC) + ATO, CT (without AraC) + ATO groups respectively, median time to ANC>1 G/L after consolidation 2 was 22, 25 and 19 days (p<0.0001), and median time to platelets>50G/l was 24, 26 and 20 days (p<0.0001). Similarly, median duration of hospitalization after the first and the second consolidation courses were 33, 34, 29 d (p<0.0001) and 31, 32, 28 d (p=0.0005), respectively.Conclusion: Very high CR rates and very few relapses are now obtained in high risk APL on a large multicenter basis using classical ATRA and CT (including AraC) for induction and consolidation, and maintenance treatment, but at the expense of 5 to 7% deaths in CR. Addition of ATO to this regimen did not further reduce relapses, and added some myelosuppression if CT contained AraC. However, if ATO was added and AraC omitted from consolidation cycles, relapses were not increased, while myelosuppression and deaths in CR were reduced. ATO therefore appears useful in high risk APL. We are currently comparing, in the international APOLLO trial, the "classical" ATRA-CT approach and a prolonged ATO-ATRA regimen with only 2 days of Ida during induction treatment, hoping to further reduce myelosuppression and possibly relapses. DisclosuresAdes:Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Fenaux:Celgene, Novartis, Teva: Honoraria; Celgene, Janssen, Novartis, Astex, Teva: Research Funding.

Primary mediastinal large B-cell lymphoma in Japanese children and adolescents.

This is the first case series to describe primary mediastinal large B-cell lymphoma (PMLBL) patients in children and adolescents in Asia. We retrospectively identified 17 PMLBL patients diagnosed between 1991 and 2014; in seven of these cases, the diagnosis was confirmed by central review, representing 1.0% of all NHL and 2.2% of all B-NHL cases registered. All patients were teenagers, including seven adolescents, with a median age of 14years (range 12-18years). Ten patients were male, and seven were female. The 5-year EFS and OS rates were 81.9 and 84.4%, respectively. All seven recent cases remain alive, of which three received rituximab combination therapy. Incidence, characteristics, and outcome varied considerably from those of Western populations. Further studies, including molecular analysis, are warranted.

The clinical characteristics and outcomes of 16 Burkitt' s lymphoma with testicular involvement

目的总结伴有睾丸侵犯的儿童伯基特淋巴瘤的临床特征，以及应用大剂量甲氨蝶呤（HD-MDX，5~8 g/m2）等联合化疗取代睾丸放疗的临床疗效及预后。方法收集16例伴有睾丸侵犯的伯基特淋巴瘤患儿资料，分析其临床特征，按前瞻性方案设计及分层。全部患儿进入高危组分层治疗，并定期追踪随访。方案采用北京儿童医院淋巴瘤治疗方案中的NHL-BCH-2009-成熟B细胞淋巴瘤方案（来自改良的LMB-89方案联合利妥昔单抗治疗）。结果137例伯基特淋巴瘤患儿中伴睾丸侵犯的患儿16例（11.7%）。16例患儿均为Ⅳ期，中位发病年龄为6.5（2.25~13.5）岁。16例患儿中8例存在骨髓侵犯（其中5例已达白血病期），9例存在中枢神经系统受累（其中5例为中枢神经系统白血病，4例为颅内或脊髓占位）；5例为双侧睾丸侵犯，11例为单侧睾丸侵犯；1例病初存在近期EBV感染（EBV-IgM+）。中位随访时间为31.8(0.5~79.0）个月，16例患儿中死亡2例（1例因早期化疗合并症放弃治疗死亡，1例于早期停药后复发死亡）；1例停药2年8个月后出现膀胱部位肿瘤复发，经治疗目前处于完全缓解；13例无事件生存，无睾丸复发。3年总生存率为87.5%，3年无事件生存率为72.9%。追踪其中>10岁患儿（3例）的睾酮水平，均在正常范围。结论对于伴有睾丸侵犯的伯基特淋巴瘤患儿，为减少放疗的远期不良反应、保留睾丸功能，应用HD-MTX等联合化疗取代睾丸放疗，疗效好，不增加睾丸复发率，性腺功能正常，但远期不良反应及睾丸功能仍有待观察。

MGMT and CALCA promoter methylation are associated with poor prognosis in testicular germ cell tumor patients

Testicular germ cell tumors (TGCT) represent the second main cause of cancer-related death in young men. Despite high cure rates, refractory disease results in poor prognosis. Epigenetic reprogramming occurs during the development of seminomas and non-seminomas. Understanding the molecular and genetic basis of these tumors would represent an important advance in the search for new TGCT molecular markers. Hence the frequency of methylation of a gene panel (VGF, MGMT, ADAMTS1, CALCA, HOXA9, CDKN2B, CDO1 and NANOG) was evaluated in 72 primary TGCT by quantitative methylation specific PCR. A high frequency of MGMT (90.9%, 20/22; p=0.019) and CALCA (90.5%, 19/21; p<0.026) methylation was associated with non-seminomatous tumors while CALCA methylation was also associated with refractory disease (47.4%, 09/19; p=0.005). Moreover, promoter methylation of both genes predicts poor clinical outcome for TGCT patients (5-year EFS: 50.5% vs 77.1%; p=0.032 for MGMT and 51.3% vs 77.0%; p=0.029 for CALCA). The findings of this study indicate that methylation of MGMT and CALCA are frequent and could be used as new molecular markers of prognosis in TGCT.

Prognostic Significance of Forkhead Box M1 (FOXM1) Expression and Antitumor Effect of FOXM1 Inhibition in Angiosarcoma.

Background: The prognosis of angiosarcoma is poor and a novel treatment option for the disease is desired. The aim of this study was to investigate the prognostic significance of Forkhead box M1 (FOXM1), a transcription factor that regulates cell-cycle progression and various crucial processes in tumor progression, and its potential as a new therapeutic target.Methods: We investigated 125 angiosarcoma clinical samples (94 primary lesions and 31 metastatic lesions in 94 patients) and a human angiosarcoma cell line (HAMON) using immunohistochemical staining and molecular biological approaches. FOXM1 expression in angiosarcoma samples was also compared with that in Kaposi's sarcomas (n = 13), epithelioid hemangioendotheliomas (n = 13) and benign hemangiomas (n = 10).Results: Patients with FOXM1-overexpressing angiosarcoma had significantly shorter survival (both for disease-specific survival [DSS] and event-free survival [EFS]) than other patients (5-year DSS, 23.5% vs. 47.1%, P = 0.013; and 5-year EFS, 5.5% vs. 28.7%, P = 0.004). FOXM1 overexpression was also an independent prognostic factor for both DSS and EFS in Cox multivariate analyses (hazard ratio [HR] 2.84, 95% confidence interval [CI] 1.10-5.81, P = 0.039; and HR 4.16, 95%CI 2.03-8.67, P = 0.0001, respectively). FOXM1 inhibition using both small interfering RNA and a specific inhibitor (thiostrepton) suppressed cell proliferation of the angiosarcoma cell line. Furthermore, FOXM1 inhibition improved the chemosensitivity to docetaxel in vitro.Conclusions: FOXM1 inhibition may be a potential therapeutic option for angiosarcoma.