5-year EFS Research Articles

Busulfan/Fludarabine- or Treosulfan/Fludarabine-Based Conditioning Regimen for Patients with Wiskott-Aldrich Syndrome – an EBMT Inborn Errors Working Party and Scetide Study

Introduction Excellent survival rates have been reported after allogeneic haematopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome (WAS) patients. Recipient age >5 years in MUD HSCT as well as MMFD as donor were negative predictors for outcome. However, the vast majority of HSCTs in previously published studies were performed with (oral) busulfan/cyclophosphamide-based conditioning and in the early 2000 years or before. Objectives To compare OS and EFS after HSCT with either busulfan/fludarabine (BuFlu) ± thiotepa (TT) or treosulfan/fludarabine (TreoFlu) ± TT as recommended for primary immunodeficiencies since 2005 by the inborn errors working party (IEWP) of EBMT and ESID. Methods We performed a retrospective analysis via the EBMT and SCETIDE registries of WAS patients transplanted between 20006 and 2016 with these two regimens. At the time of this interim analysis, 174 patients were included, 92 (53%) with BuFlu±TT and 82 (47%) with TreoFlu±TT conditioning, with a median age of 1.6 years (0.2-30) at HSCT and a median follow-up of 32.9 months (1.5-128.9). Donors were MSD in 30, other MRD in 5, MUD (9/10 or 10/10) in 105, MMUD ( Results Two year overall survival (OS) of the entire cohort was 88.6% (95% c.i. 83.5%-93.6%). There was no significant difference in OS between BuFlu±TT or TreoFlu±TT conditioning (2-year OS 88.1% vs. 89.5%; p=0.7). Patients aged >5 years had a worse OS as compared to those 5 years or younger at HSCT (74.9% vs. 90.8%; p=0.005). The type of donor had no influence on OS: 96.4% for MSD/MFD, 86.8% for MUD/MMUD and 87.7% for MMFD (p=0.4). The rate of complete (≥90%) donor chimerism at last follow-up or before a secondary procedure (if a patient had one) was 41/42 (98%) in the BuFlu±TT group and 21/35 (60%) in the TreoFlu±TT group (p=0.0001). Twenty-six patients required a second procedure: stem cell boost in 4, donor lymphocyte infusion in 9, 2nd HSCT in 15 and splenectomy in 1. The 2-year cumulative incidence (CI) of second procedures was higher at 33.9% in the TreoFlu±TT versus 12.8% in the BuFlu±TT group (p=0.017), and 2-year EFS (events: second procedure or death) was 61.4% in the TreoFlu±TT and 75.0% in the BuFlu±TT group (p=0.2). Grade II-IV acute GVHD had the same incidence in both groups (24.4% vs. 26.3%; p=0.849) and chronic GVHD of any grade was borderline more frequent in the TreoFlu±TT group (17.2% vs 6.7%; p=0.054). Conclusion HSCT with either BuFlu±TT or TreoFlu±TT conditioning reliably cures almost 90% of patients with WAS regardless of donor type. Age >5 years at HSCT remains a negative risk factor. More patients were mixed chimeras and required second procedures after TreoFlu±TT than after BuFlu±TT conditioning. These data confirm the feasibility and efficacy of the regimens currently recommended by the IEWP.

Serum Soluble Interleukin-2 Receptor As a Surrogate Biomarker of Metabolic Tumor Volume Measured By 18F-FDG PET/CT in Diffuse Large B-Cell Lymphoma

Background. Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin lymphoma. High total metabolic tumor volume (TMTV) or total lesion glycolysis (TLG) calculated using 18F-FDG PET/CT images at diagnosis predicts poor prognosis of patients with DLBCL. However, high cost and poor access to the imaging facilities hamper wider use of 18F-FDG PET/CT.Methods. In order to explore a surrogate marker for TMTV/TLG, we evaluated the correlations between the serum levels of soluble interleukin-2 receptor (sIL-2R) and TMTV/TLG in 64 patients with DLBCL, and the results were verified in an independent validation cohort of 86 patients. The study procedures were in accordance with the Helsinki Declaration and institutional ethical guidelines, conducted under the auspices of the institutional ethics committee, and approved by the institutional review boards.Results. In the training cohort(n=64), OS and EFS were significantly lower in patients with TMTV≥150cm3 than in those with less than 150cm3 [5-year OS; 84.0% vs 29.1%, P=0.000194, 5-year EFS; 71.4% vs 28.7%, P=0.000384]. We also found that TLG≥1500cm3 at diagnosis predicted significantly inferior OS and EFS[5-year OS; 84.0% vs 31.7%; P=0.000477, 5-year EFS; 70.2% vs 30.6%, P=0.00107].Pearson's correlation tests demonstrated highly significant positive correlations between sIL-2R and TMTV[R2=0.490; P=0.00004] and between sIL-2R and TLG[R2=0.543; P=0.00000357]. Serum sIL-2R≥1300 U/ml was a strong prognostic factor both for worse OS and EFS[5-year OS; 85.2% vs 25.9%, P=0.000035, 5-year EFS; 72.0% vs 26.8%, P=0.000076].In a univariate analysis, B symptom, LDH, sIL-2R, TMTV and TLG were associated with poor 5-year OS; and B symptom, LDH, PS, sIL-2R, TMTV and TLG were identified as poor prognostic factors for 5-year EFS. We performed multivariate analysis that included sIL-2R and all factors in NCCN-IPI; age, LDH, clinical stage, ECOG PS and major organ involvement. In this multivariate analysis, age and sIL-2R were independently associated with poor 5-year OS(age; HR, 4.44; 95% CI, 1.05 to 18.7, P=0.0424, sIL-2R; HR, 4.45; 95% CI, 1.04 to 19.1, P=0.0444). Another multivariate analysis that included TMTV and all factors for NCCN-IPI demonstrated that TMTV was an only independent prognostic factor for 5-year OS(HR, 3.87; 95% CI, 1.08 to 13.8; log-rank, P=0.0373).Subgroup analyses included the patients with NCCN-IPI High-Int and High(n=49) demonstrated that the cut off value of TMTV 150cm3 stratified treatment outcomes in this poor prognostic group [5-year OS; 75.0% vs 27.7%, P=0.0355, 5-year EFS; 66.7% vs 29.7%, P=0.0493]. Similar results were obtained using the cut-off value of sIL-2R 1300U/mL [5-year OS; 75.0% vs 25.9%, P=0.0182, 5-year EFS; 58.3% vs 29.7%, P=0.0499].In the validation cohort(n=86), Kaplan-Meier curves showed that OS and EFS in patients with TMTV≥150cm3 was again lower than in those with TMTV<150cm3[5-year OS; 87.0% vs 59.5%, P=0.016, 5-year EFS; 72.8% vs 52.3%, P=0.0154]. We also found that TLG≥1500 cm3 at diagnosis predicted inferior OS and EFS as TMTV did[5-year OS; 84.8% vs 59.3%, P=0.0157; log-rank, 5-year EFS; 74.8% vs 45.8%, P=0.000604]. Kaplan-Meier curves showed that sIL-2R≥1300 U/ml was a strong prognostic factor both for worse OS and EFS[5-year OS; 86.3% vs 61.8%, P=0.0188, 5-year EFS; 85.0% vs 46.8%, P=0.000413]. Pearson's correlation tests gave similar results that there were positive correlations between sIL-2R and TMTV [R2=0.461; P=0.00000631], and between sIL-2R and TLG[R2=0.720; P=0.0000017987]. In a univariate analysis, TMTV and TLG were associated with poor 5-year OS, whereas sIL-2R, TMTV and TLG were identified as poor prognostic factors for EFS. In a multivariate analysis including sIL-2R, age and sIL-2R were associated with poor 5-year OS. In another multivariate analysis including TMTV showed that age, LDH and TMTV were independent prognostic factor for 5-year OS. Altogether, we could validate the prognostic significances of sIL-2R, TMTV, and TLG, and positive correlation between sIL-2R and metabolic values, such as TMTV and TLG, confirming that sIL-2R is a surrogate biomarker of these metabolic values.Conclusion. Serum level of sIL-2R represents a convenient surrogate marker to estimate metabolic tumor burden measured by 18F-FDG PET/CT that can predict treatment outcomes of patients with DLBCL.Disclosures. No relevant conflicts of interest to declare. [Display omitted]

Pediatric-Inspired Chemotherapy Incorporating Pegaspargase Is Safe and Results in High Rates of MRD Negativity in Adults Ages 18-60 with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Introduction: Among adolescents and young adults with (w/) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL), treatment using a pediatric (vs. adult) regimen appears to achieve superior event-free (EFS) and overall survival (OS); this observation has driven increased interest in adapting pediatric regimens for middle-aged adults w/ ALL/LBL. However, greater risk of toxicities associated w/ asparaginase complicates administration of pediatric-inspired regimens in adults. We therefore designed a pediatric-inspired chemotherapy regimen w/ doses of pegaspargase (PEG) rationally synchronized to limit overlapping toxicities w/ other chemotherapeutic agents.Methods: We conducted a phase II multi-center trial in adults ages 18-60 w/ newly-diagnosed Philadelphia chromosome-negative (Ph-) ALL/LBL (NCT01920737). Pts w/ Ph+ ALL or Burkitt-type ALL were ineligible. The treatment regimen consisted of 2-phase induction (I-1, I-2), followed by consolidation w/ 2 courses of alternating high-dose methotrexate-based intensification and reinduction, followed by 3 years of maintenance (Figure 1). PEG 2000 IU/m2 was administered in each of the 6 intensive courses of induction/consolidation at intervals of ≥4 weeks. Minimal residual disease (MRD) was assessed in bone marrow (BM) by multiparameter flow cytometry (FACS) on day (d) 15 of I1 and following I-1 and I-2. Any detectable MRD (even <0.01% of BM WBCs) was considered positive. Toxicities were assessed by CTCAE v4.0.Results: 39 pts were enrolled (30M, 9F), w/ B-ALL (n=28), T-ALL (n=7), B-LBL (n=3), and T-LBL (n=5). Median age at start of treatment was 38.3 years (range 20.2-60.4), w/ 18 pts age 40-60.Grade 3-4 toxicities associated w/ PEG are summarized in Table 1. Grade 3-4 hyperbilirubinemia was observed post-PEG in I-1 in 9 pts, but only recurred thereafter in 1/8 pts resuming PEG. Pts completing consolidation on protocol (n=16) received median of 6 doses of PEG (range, 2-6). Four pts developed hypersensitivity to PEG and subsequently received Erwinia asparaginase. PEG was discontinued in 4 additional pts due to hepatotoxicity (n=2), pancreatitis (n=1), and physician preference (n=1).Of pts w/ available response assessments, 35/36 (97%) achieved morphologic complete response (CR) or CR w/ incomplete hematologic recovery (CRi) following I-1 (n=34) or I-2 (n=1). Both pts not achieving CR/CRi after I-I had early T-precursor ALL; one of these pts was withdrawn from study, and the other (w/ M2 marrow after I-1) achieved CR after I-2.Of the pts w/ ALL (excluding LBL) w/ available BM MRD assessments, 11/28 (39%) achieved undetectable MRD by FACS following I-1; 18/22 (82%) achieved undetectable MRD by FACS following I-2. Of the pts w/ LBL w/ available BM MRD assessments, 7/7 (100%) achieved or maintained undetectable MRD by FACS following I-1 and I-2. Ten pts underwent allogeneic hematopoietic cell transplantation (alloHCT) in CR1. Seven pts experienced relapse at median 15.2 months from start of treatment (range, 5.4-30.4), of whom 6 subsequently underwent 1st (n=5) or 2nd (n=1) alloHCT. Of the 11 pts w/ ALL w/ undetectable MRD following I-1, only one has relapsed. Five patients have died, including 2 pts in CR1 (from sepsis and multi-organ system failure), and 3 pts in relapse.At median follow-up of 22.3 months among surviving pts (range, 1.0-48.1), median EFS and OS (Figure 2A&B) have not been reached (EFS not censored at alloHCT). 3-year EFS was 62.1% (95% CI: 38.4-78.9%) and 3-year OS was 80.0% (95% CI: 57.5-91.4%).Conclusions: PEG can be incorporated into pediatric-inspired chemotherapy regimens w/ manageable toxicity for appropriately selected adults up to age 60 w/ Ph- ALL/LBL. While PEG-related AEs are common, few pts require permanent discontinuation of asparaginase. Grade 3-4 hyperbilirubinemia was common, particularly post-I-1, but recurred infrequently when PEG was continued. Two induction courses resulted in a high rate of MRD negativity post-I-2 and translated to a low rate of relapse. Though further follow-up is required, 3-year EFS is encouraging. Data regarding asparaginase enzyme activity and silent inactivation w/ neutralizing anti-PEG antibody will be presented. Ongoing and future studies will additionally investigate whether incorporating novel therapies (e.g. blinatumomab, nelarabine) into frontline consolidation therapy may reduce risk of relapse among adults receiving PEG-containing regimens. [Display omitted] DisclosuresGeyer:Dava Oncology: Honoraria. Ritchie:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding. Rao:Kite, a Gilead Company: Employment. Tallman:Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Cellerant: Research Funding; AbbVie: Research Funding; BioSight: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding. Douer:Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Pfizer: Honoraria; Spectrum: Consultancy. Park:Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Adaptive Biotechnologies: Consultancy.

Fms-like Tyrosine Kinase 3 Ligand Concentration Kinetic Profile during Induction Is Strongly Predictive of Survivals in AML: Results of the FLAM/Flal Study

The cytokine Fms-like tyrosine kinase 3 ligand (FL) is a key regulator of hematopoiesis. In a previous Phase 1 study testing a radioimmunotherapy regimen for relapsed/refractory acute lymphoblastic leukemia (ALL), responders showed increased soluble FL serum concentration (sFLc) after salvage regimen (Chevallier, Lancet Haematol., 2015).This prospective monocentric study (ClinicalTrials.gov NCT02693899) aimed to assess the impact of sFLc in ALL and acute myeloid leukemia (AML) patients treated according to standard-of-care intensive first-line chemotherapy regimens. Serum samples were collected on days 1, 8, 15, 22 of induction, at days 1, 8, 15 of each intensive consolidation or day 1 of each non intensive consolidation when appropriate, frozen-stored then tested by ELISA (DY308, R&D Systems, Minneapolis, MN). The following outcomes were considered to assess the impact of sFLc: refractory status after induction (≥5% bone marrow blasts or persistent aplasia >45 days), morphologic, immunophenotypic, cytogenetic or molecular relapses, event-free (EFS) and overall survival (OS). All patients provided informed consent.Between May 2016 and January 2018, 80 patients were included. Data were ultimately available for 16 ALL and 62 AML patients. A total of 579 samples were assayed. Analysis of the results disclosed 3 sFLc kinetic profiles during induction i) sustained increase from days 1 to 22 (FLI group), ii) increase from days 1 to 15, then decrease at day 22 (FLD group) and iii) stagnation of low levels all along (<1000 pg/mL from days 1 to 22, FLL group).The 16 evaluable ALL patients were classified as FLI (n=2), FLD (n=7) and FLL (n=7). All reached a cytologic complete remission after induction and only 2 relapses have been documented so far in this group. No impact of sFLc kinetic profile was seen in this context.Conversely, a significant impact of sFLc during induction (but not during consolidation) was observed in AML patients. The median age in this group was 59 years old (range: 29-71, <60 years n=33). The median follow-up for alive patients was 541 days (range: 154-787). sFLc levels were assayed in 244 samples. Twenty-six patients were classified as FLI (42%), 22 as FLD (35%) and 14 as FLL (23%). Median sFLc at days 1, 8, 15, 22 were as follows for the three groups: FLI: 2, 724, 3673, 5753 pg/mL; FLD: 6, 1229, 6019, 684 pg/mL; and FLL: 0, 60, 124, 81 pg/mL. There was no significant difference between the 3 groups regarding age, ELN 2010 risk-stratification (ELNrs), OMS classification, WBC and bone marrow blasts percentages at diagnosis.When comparing the 3 sFLc groups, almost all refractory patients (n=6) were found in the FLL group (n=5, FLD n=1, FLI n=0, p=0.0007). Three cytologic relapses occurred in the FLI group, 7 in the FLD group (cytologic n=4, molecular n=2, immunophenotypic n=1) and 7 in the FLL group (cytologic n=4, molecular n=2, immunophenotypic n=1). There were more relapses in the FLL group (n=7/9 [78%] vs FLD n=7/21 [33%] vs FLI n=3/26 [11.5%], p=0.0009).In univariate analysis, 2-year EFS and OS were significantly better for the FLI group (79.1+-8 vs FLD 54.9%+-11 vs FLL 11.4%+-10,p<0.001; and 80.4%+-8 vs FLD 58.6%+-11 vs FLL 18.6%+-10, p=0.09,respectively). There was a trend for the association of 2-year EFS (but not OS) with ELNrs (favorable:70.9%+-11, vs Int-1+Int-2:57.1%+-10 vs adverse 33%+-13,p=0.06). Stratification of the patients according to the median sFLc level at day +15 (2952pg/mL) also showed significantly different 2 year EFS at 38.2%+-9 for low levels vs 71.8%+-8 for high levels (p=0.02). The same was true for day +22 median sFLc level (1390pg/mL) at 38.9%+-9 vs 73.6%+-8 (p=0.02). Age had no impact on EFS nor OS.In multivariate analysis considering age, ELNrs, sFLc at days 15 and 22 levels, and sFLc kinetic profile during induction, the latter remained the most powerful factor independently associated with EFS (HR: 3.62; 95%CI: 1,65-7,94, p=0,001; ELNrs: HR: 1.74; 95%CI: 0,98-3.10, p=0.05; sFLc at day+15 p=0,37; sFLc at day+22, p=0.24, age p=NS). sFLc kinetic profile was the sole factor that was also independently associated with OS (HR: 2.60; 95%CI: 1.12-6,07, p=0.02).In conclusion, sFLc kinetic profile during induction appears to be a new powerful early prognostic parameter in AML patients. These results need to be validated on a larger cohort of patients and the mechanism by which induction sFLc levels may impact AML outcome remains to be elucidated. [Display omitted] DisclosuresGastinne:Millennium/Takeda: Honoraria. Moreau:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Clinical Characteristics and Outcomes of 82 Patients with Mixed-Phenotype Acute Leukemia

Objectives: Mixed-phenotype acute leukemia(MPAL) is a rare disease and comprises 2% to 5% of all acute leukemia. Outcomes for MPAL are worse than both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).The complex phenotype exhibited by this type of leukemia resulted in a myriad of treatment approaches.In our study, we retrospective analysis 82 patients in clinical trail, treatment strategy and prognosis.Method: eighty-two patients diagnosed with MPAL at Nan fang hospital from 2006 to 2017 using either EGIL or 2008 WHO criteria were analyzed. Comparison the treatment effect and outcomes between different therapy types.Result: eighty-two patients, including 60 males and 22 females with a median age of 29 years (range, 2 months-72 years), were studied. 61 patients (77%) were older than 18years, 73patients met the criteria for MPAL via EGIL, 68via WHO2008, and 59of these were reported to satisfy both definitions. fifty one of these cases (62.2%) had a B/myeloid phenotype, Twenty four of these cases (29.3%) had a T/myeloid phenotype. The other cases (8.5%) showed immunophenotypic evidence of a B, T, and myeloid lineage in one blast population. Among the 82 cases, 57 cases with successful cytogenetic studies, 20(35.1%) had normal karyotypes and 37patients(64.9%) had abnormal karyotypes. Twelve patients (21.05%) translocation between chromosomes 9 and 22, five (8.8%) patients had 11q23/MLL translocations. Twelve patients (21.05%) had a complex karyotype and eight patients (14%) had other karyotype. The rarity of this disease and the fact that patients with MPAL are excluded from most AML and ALL clinical trials further complicates guidance about therapy. Of the 82 cases, 75 patients underwent the complete first course of treatment and complete remission rate was 49.8%. treatment approaches utilizing therapy for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and so-called “hybrid” therapy mixing elements of both are 51.9%, 16.7% and 66.7% respectively (P=0.003).OS and EFS with hybrid induction therapy and ALL like induction were not significantly different than those with AML induction by either definition (P>0.05). A total of 60 patients received consolidation treatment, 21 patients received the chemotherapy while 39 patients received stem cell transplant (HSC). The total Median EFS was 21months, in Chemotherapy group and HSC group, the Median EFS was 6 months and 40 months respectively, The 3-year EFS was 26.1% and 55.6% respectively (P=0.038). The total Median OS was 21 months, Median OS showed a significant survival benefit for starting with chemotherapy as compared to HSC( 12 months and 43 months respectively (P=0.001)), The 3-year OS was 19.1% and 57.7% respectively.Conclusion: In this study, ALL like induction therapy or “hybrid” therapy was associated with a more than three-fold greater CR rate than AML therapy. SCT therapy showed a trend for an association with higher OS and EFS for MPAL .Key words: MPAL, Immunophenotype,Treatment strategyFundingKey Sci-Tech Research Projects of Guangdong Province (2014A02021102). DisclosuresFan:National Natural Science Foundation of China (No. 81600141, No. 81770190) and Natural Science Foundation of Guangdong Province (No. 2016A030310390): Research Funding.

Treatment Patterns and Intensity Differ between Pediatric and Adult Centers in AYA with Hodgkin's Lymphoma but Result in Equivalent Outcomes: A Population-Based Study Using the IMPACT Cohort

Background: Hodgkin's lymphoma (HL) is one of the most common cancers in adolescents and young adults (AYA). Unlike acute lymphoblastic leukemia, few studies have compared AYA HL outcomes between pediatric and adult centers, or pediatric and adult protocols. Recently, a comparison of AYA (17-21 years) treated on a pediatric COG trial vs. an adult ECOG trial demonstrated superior survival in AYA treated on the pediatric trial, but other studies have not demonstrated a treatment center disparity. None of these studies were population-based. We therefore compared treatment patterns, intensity, and outcomes between AYA HL treated at pediatric vs. adult centers using a population-based clinical database.Methods: The IMPACT Cohort comprises all Ontario, Canada AYA aged 15-21 years diagnosed with one of six common cancers (including HL) between 1992-2012. Detailed demographic, disease, treatment, and outcome data were collected through chart abstraction and validated by content experts. Locus of cancer care (pediatric vs. adult cancer center vs. adult community hospital) was based on where the majority of therapy was delivered in the first three months after diagnosis. Linkage to population-based health administrative data identified additional cancer events (second cancers, relapse, death). The treatment modalities received [radiation vs. chemotherapy vs. combined modality treatment (CMT)] were compared by locus of care, as were cumulative doses of doxorubicin, bleomycin, and radiation. Predictors of CMT (vs. chemotherapy only) were examined using logistic regression. Event-free (EFS) and overall survival (OS) were determined using Kaplan-Meier methods. The impact of locus of care on EFS and OS was determined using multivariable Cox proportional hazard models, adjusting for demographic, disease, and treatment variables. Events included disease progression, relapse, death, and second malignancies.Results: Among 954 AYA with HL, 711 (74.5%) received therapy at an adult center (adult regional cancer center or community hospital). The proportion of AYA with limited stage disease did not vary between pediatric centers [90/221 (40.7%)] and adult centers [172/456 (37.7%); p=0.45]. While AYA treated at pediatric centers were more likely to receive radiation, radiation doses were higher at both adult cancer centers and adult community hospitals, as were cumulative doses of doxorubicin and bleomycin (Table 1). When adjusted for age, stage, and histology, AYA treated at pediatric centers were significantly more likely to receive CMT rather than chemotherapy alone as compared to AYA at adult cancer centers [odds ratio (OR) 5.0; 95% confidence interval (CI) 3.0-8.4; p<0.0001] or adult community hospitals (OR 3.9, CI 2.2-7.0; p<0.0001). 5-year EFS and OS for the cohort were 83.0%±1.2% and 94.9%±0.7%. 10-year EFS and OS were 81.1%±1.3% and 92.6%±7.4%. In multivariable analyses, CMT was associated with superior EFS as compared to chemotherapy alone [hazard ratio (HR) 0.68; CI 0.50-0.93; p=0.02] but was not significantly associated with OS. Despite the significant differences in treatment modality and treatment intensity between pediatric and adult centers, locus of care was not significantly associated with either EFS or OS in either univariate or multivariable analyses (Table 2).Conclusions: In this large, population-based cohort, survival outcomes did not differ between AYA treated at pediatric vs. adult centers. However, treatment intensity patterns varied, with AYA treated at a pediatric center more likely to receive radiation (though at lower doses) but exposed to lower cumulative chemotherapy doses. These results imply that acute toxicities and the types and cumulative burden of late effects may differ by locus of care. Given equivalent outcomes, these results also suggest that a proportion of AYA are being over-treated. Future analyses will study these hypotheses. DisclosuresNo relevant conflicts of interest to declare.

Outcome of Infants Younger Than 1 Year with Acute Lymphoblastic Leukemia Treated with the Interfant-06 Protocol; Results from an International Randomised Study

INTRODUCTIONInfant acute lymphoblastic leukemia is a high-risk subtype characterized by a very high incidence of KMT2A (MLL) gene rearrangements. In 1999, a large international consortium (Interfant) commenced; the first Interfant-99 protocol (Pieters et al, Lancet 2007) was used as baseline for the current Interfant-06 study, which run in 18 groups worldwide.AIMSTo determine:In a randomised study whether two AML-type courses ADE (araC, daunorubicin, etoposide) and MAE (mitoxantrone, araC, etoposide) after induction improved outcome compared to the consolidation IB course in KMT2A-rearranged cases (MR and HR risk group). With a target of 320 randomised cases, the study had 80% power to detect a DFS difference of 16% at 3 years (41% DFS in the control arm, α=0.05).The prognostic relevance of clinical and biological parameters.The outcome of Interfant-06 versus Interfant-99.The role of SCT in HR patients and in MR patients with MRD ≥ 10e-4 at the start of OCTADAD.As Interfant-99 showed outcome differences between the West-European/North-American groups who started Interfant (original countries) versus other countries that joined later, analyses were also performed separately in these groups.RISK GROUPS AND TREATMENTThree risk groups were defined: low risk (LR) - KMT2A germline; high risk (HR) - KMT2A rearrangement plus age < 6 months plus white blood cell count (WBC) >300 x 10e9/L or a poor prednisone response; medium risk (MR) - comprised all other KMT2A-rearranged cases.Treatment consisted of induction (prednisone prephase, dexamethasone, VCR, asparaginase, DNR), consolidation phase, either IB (araC, 6-MP, cyclofosfamide) or ADE/MAE in the experimental arm, MARMA (HD-araC, HD-MTX, 6-MP, asparaginase), OCTADAD (VCR, dexamethasone, asparaginase, DNR, 6-TG, araC, cyclofosfamide) and maintenance (6-MP, MTX) with intrathecal therapy in all courses. All HR patients were allocated to receive allogeneic stem cell transplantation (SCT). After June 2009, SCT was also undertaken in MR cases with MRD ≥ 10 e-4 at start of OCTADAD as the Interfant-99 update showed a very poor outcome for these patients.RESULTS651 infants were included (167 LR, 320 MR, 164 HR). In the original countries, 6-yr EFS (SE) and survival rates were 49.4 (2.5) and 62.1 (2.4) respectively, which were each 6% (not significantly) higher than in Interfant-99 study. In the other countries, the 6-yr EFS and survival rates were 39.0 (3.6) and 49.7 (3.7). The outcome of patients treated in the original countries was significantly better than in other countries due to lower rates of toxic death and resistant disease. The 6-year EFS and survival of all 651 cases were 46.1 (2.1) and 58.2 (2.0) respectively.330/407 eligible cases (81%) were randomised. The 6-yr cumulative incidence (CI) of relapse with ADE/MAE was 47.5 (4.0) which was not significantly (p = 0.11) lower than the 54.9 (4.1) with IB. The 6-yr CI of death in remission was 10.2 (2.4) with ADE/MAE versus 8.3 (2.2) with IB (p = 0.51). This resulted in no significant differences in 6-yr DFS rates of 39.3 (4.0) and 36.8 (3.9) respectively (the 3-yr DFS were 45.3 [3.9] versus 38.6 [3.9]).The 6-yr EFS rate of 164 HR patients was 20.9 (3.4) with the intention to use SCT in all HR patients; 76 of them received SCT as many HR patients had very early events. Out of 23 MR patients with MRD ≥ 10e-4 before OCTADAD, 16 received SCT; 4/23 are in CCR. In total, 14.4% of MR/HR patients receiving SCT died of transplant-related mortality.T(4;11) and t(11;19) translocated cases had a significantly lower EFS than other KMT2A-rearranged cases (p = 0.005). Multivariate analyses identified KMT2A rearrangement, age < 6 months, WBC ≥ 300 x 10e9/L, and poor prednisone response but not CD10, type of MLL translocation and sex as significant predictors of adverse DFS.CONCLUSIONSThe Interfant-06 study is by far the largest study performed in infant ALL. The 6-yr survival in West-European/North-American countries is 62%, which is 12% higher than in other participating countries. Two postinduction AML-type chemotherapy courses versus course IB did not lead to a significant better DFS. 6-yr survival rates are 6% higher than on Interfant-99, which is not a statistically significant improvement. Pilot studies by COG and Interfant are currently exploring the feasibility of adding azacytidine and blinatumomab to the Interfant backbone, which may lead to a worldwide randomised trial with these drugs in infant ALL. DisclosuresLocatelli:Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vora:Jazz: Other: Advisory board; Medac: Other: Advisory board; Pfizer: Other: Advisory board; Amgen: Other: Advisory board; Novartis: Other: Advisory board.

A Treatment Protocol with Imatinib and Intensive Chemotherapy for Pediatric Philadelphia Positive Acute Lymphoblastic Leukemia: A Single-Arm, Intergroup Study (Esphall 2010)

Background. EsPhALL2004 study showed a 10% advantage in DFS for short, discontinuous use of imatinib after induction in Ph ALL patients receiving BFM therapy and HSCT. Other contemporary studies showed an advantage from continuous protracted exposure to imatinib challenging the indications to transplant. Methods. Patients aged 1-17 years were enrolled in EsPhALL2010 trial and received imatinib 300/mg/m2 continuously from day 15 of induction, during chemotherapy. MRD was measured by IG/TR. Eligibility to HSCT depended on early morphological response and MRD. Imatinib was recommended throughout the first year after transplant. Findings. 155 evaluable patients were registered between 2010-2014. 151 (97%) achieved CR1 after induction and 4 after consolidation phase IB. 59 patients (38%) underwent HSCT in CR1. The 5-year EFS and OS were 57·0 (SE 4·1) and 71.8 (SE 3·8), respectively. The 5-year cumulative incidence of relapse was 26·9% (SE 3·7, 8 relapses in 59 transplanted patients and 32 relapses in 96 patients who received chemotherapy). In patients MRD negative at end of IB, there were no relapses in those transplanted (N=17) and 9 relapses in those (N=30) treated with chemotherapy. In patients with positive MRD at end of IB, 5 relapses each occurred in 15 transplanted and 12 not transplanted patients. WBC count at diagnosis ≥100x109/L was associated with a poor prognosis (HR 3·47, 95% CI 1·74-6·89, p=0·0004). Interpretation. Imatinib given since day 15 of induction markedly improved CR rates to 97% from 78% in EsPhALL2004. Though HSCT rates were significantly lower (38% versus 81%), outcomes were similar in the two studies: 5-year EFS and survival were 57·0% and 71·8% versus 60·3% and 71·6%, respectively. WBC ≥100x109/L was the most relevant independent prognostic factor. Funding. Projet Hospitalier de Recherche Clinique-Cancer and Novartis (France); Bloodwise and CRUK (UK). Wellcome-DBT Margdarshi fellowship (VS). MH CZ- DRO, 00064203 (Czech Republic). AIRC 5‰, Ref. 21147 (AB). AIRC2013, ID 14634 (MGV). Conflict of interest statements. No conflicts of interest have been declared by the authors. Ethics approval statement: EsPhALL2010 is a prospective, single arm trial derived from an amendment of the EsPhALL2004 protocol (EudraCT No. 2004-001647-30) which was approved by the ethics committee of each participating institution in ten national study groups (AIEOP, BFM-G/CH, COALL, French ALL-group, NOPHO, MRC, DCOG, CPH, PINDA, and HKPHOSG).

The prognostic potential of coilin in association with p27 expression in pediatric acute lymphoblastic leukemia for disease relapse

BackgroundCajal body (CB) is a nucleic organelle where small nuclear ribonucleoproteins undergo modification, maturation, splicing and/or assembly. Coilin is the marker structural protein of CBs. The expression level and cellular localization of coilin is sensitive to chemotherapeutic reagents, such as cisplatin. The gene of cyclin-dependent kinase inhibitor 1B (p27) is located with a high incidence translocation region of leukemic chromosomes, and its expression was of prognosis values in a variety of adult leukemia types. The exact profile and associated functions of coilin, as well as p27, in children’s acute lymphoblastic leukemia (ALL) is obscure.MethodsBone marrow samples from 144 patients with ALL were collected. The expression levels of coilin and p27 were detected by qRT-PCR. The patient cohort was divided into low and high groups of coilin and p27 respectively. The prognosis and clinicobiological characteristics of different groups were investigated, especially focused on the treatment outcome. Leukemia cells of Reh or RS4;11 were exposed to different concentrations of DNR, prior to the detection for morphological changes of coilin by immunofluorescence. In Reh cells, lentivirus sh-coilin was used to silence coilin expression. Western blotting was used to detect coilin and p27 expression; flow cytometry was used for cell cycle and apoptosis assay; MTS method was used for measuring cell viability to examine the drug sensitivity of DNR.ResultsIn this study, we found that daunorubicin was able to induce significant morphological changes of CBs in Reh and RS4;11 cells. Knockdown the expression of coilin increased the sensitivity to daunorubicin and inhibited the expression of p27 in Reh cells, and led to increased apoptosis. Importantly, not only the levels of coilin and p27 mRNA expression at initial diagnosis ALL children are markedly higher than those at complete remission (CR), but also both coilin and p27 expression in the relapsed patients was observed significantly higher comparing to the continuous CR patients. The 4-year EFS and RFS indicated that low levels of both coilin and p27 group favored better prognosis (p < 0.05).ConclusionsOur results indicated that consideration of coilin and p27 levels could be a prognostic reference for predicting the outcome of pediatric ALL patients, especially for disease recurrence. Reduction of coilin expression was sufficient to increase the sensitivity of leukemic cells to daunorubicin treatments, and during which possibly involved functions of p27 in cell cycle regulation and its effects on cell apoptosis.

Hodgkin lymphoma of the elderly patients: a retrospective multicenter analysis from the Polish Lymphoma Research Group*

We retrospectively analyzed long-term disease outcome of 350 elderly Hodgkin Lymphoma (eHL) patients treated with ABVD/ABVD-like regimen enrolled in the PLRG-R9 study between 2001 and 2013 in Poland. Complete remission was reported for 73% of early (ES) and 61% advanced stage (AS) patients. Nine (10%) ES and 56 (20%) AS patients have died. With the median follow-up of 36 (1–190) months, 3-year EFS and OS was 0.74 (95%CI: 0.63–0.85) and 0.90 (95%CI: 0.82–0.98) for ES; 0.51 (95%CI: 0.44–0.57), and 0.81 (95%CI: 0.75–0.86) for AS patients, respectively. For ES patients, Cox regression revealed ECOG <2 and age >70 as predictive for inferior OS and EFS. For AS patients, the most predictive for OS was the presence of cardiovascular disorders (CVD) (p = .00044), while for EFS four factors were significantly associated with a poor outcome: ECOG< 2, age >70 years, CVD and extranodal disease. In conclusion, CVD significantly impacts outcomes of ABVD-treated advanced eHL patients.

ICE Regimen for Relapsed/Refractory Bone and Soft Tissue Sarcomas in Children.

The outcome of bone and soft tissue sarcomas (BST) after relapse has very poor prognosis with survival rates less than 39%. Unfortunately there are not many treatment options, but promising responses have been reported with ifosfamide, etoposide and carboplatin (ICE). Therefore, we planned a study for children with recurrent/refractory BST treated with ICE regimen to evaluate their demographic features, responses to treatment and outcome. Patients with primary diagnosis of BST and treated with ICE regimen at the time of first or subsequent relapse, progression or unresponsive disease were selected for study. The files were retrospectively evaluated. Thirty of sixty-six patients had metastatic disease at relapse. Patients received median 5 cycles of ICE and were followed-up median 16.3 months. Overall survival rates were 83% and 62% at 1st and 2nd year. The ORR to the regimen was 43%. Survival rates were significantly higher in good responders (3-year EFS and OS rates: 50% vs. 8% and 78% vs. 14%; p<0.0001 and p<0.0001). Survival rates for non-metastatic disease were 42% and 75% for EFS and OS and higher than patients with metastases at relapse (p<0.001 and p<0.0001). EFS and OS rates of patients with rhabdomyosarcoma were 42% and 69%. No grade 3 or 4 renal toxicity was documented. ICE combination improves the outcome of relapsed or refractory sarcomas and it might serve as second line treatment. Patients with no metastases at relapse would benefit more than others with metastatic disease.

Outcome and Toxicity Patterns in Children and Adolescents with Non-Hodgkin Lymphoma: A Single Institution Experience.

BackgroundThe incidence and biology of non-Hodgkin lymphoma (NHL) vary according to age. Some data suggest that the impact of age in pediatric and adolescent NHL patients depends on the histological subtype. Objectives: We aimed to analyze the impact of age at diagnosis on clinical characteristics and treatment-related toxicity in children and adolescents with NHL.MethodsRetrospective review of medical records of children and adolescents diagnosed with NHL at the Hospital for Sick Children, Toronto, between January 1995 and December 2008.Results164 children were diagnosed with NHL during the study period, with a median age at diagnosis of 10 years. With a median follow-up of 6.2 years, 5-year OS in patients aged <15 and 15–18 years was 89± 2% vs 82% ± 6%, respectively (P = 0.30), and 5-year EFS was 84% ± 3% vs. 77% ± 7% (P= 0.37). In Burkitt’s lymphoma (BL) and lymphoblastic lymphoma (LL) there was a trend towards better outcomes in children compared to adolescents, with EFS of 91% ± 4% vs. 75% ± 15%, respectively in BL (P= 0.17), and 82% ± 7% vs. 51.4% ± 2% respectively in LL (P= 0.16). Late effects occurred in 21 patients (12.8%).ConclusionsChildren with NHL aged < 15 years tend to have better survival rates and similar long-term toxicity than adolescents aged 15–18 years.

Abstract GS3-08: Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL

Abstract Background: Pathological complete response (pCR) is accepted by FDA as a surrogate endpoint for accelerated approval of targeted agents in combination with chemotherapy based on better long-term outcomes compared to residual disease (Cortazar 2014). Methods: The multi-center, adaptively-randomized I-SPY2 platform trial uses pCR as the primary endpoint to identify investigational agents that will improve outcomes in women with stage 2/3 breast cancer with high risk of early recurrence, across all signatures, based on hormone receptor (HR), HER2, and 70-gene (MammaPrint) status. For patients with HR+ HER2- tumors, only 70-gene (Mammaprint) high-risk patients are enrolled. To date, 1200+ patients have been randomized to one of 14 arms: control (paclitaxel followed by AC); veliparib/carboplatin; neratinib; MK2206; trebananib; trastuzumab/pertuzumab; ado-trastuzumab emtansine/pertuzumab; pembrolizumabx4; ganitumab/metformin; ganetespib; PLX-3397. 7 agents graduated in at least one signature (&amp;gt; 85% probability of success in a 300-patient phase III confirmatory trial); 2 did not graduate; 1 stopped for toxicity, and 3 are enrolling (patritumab/trastuzumab, talazoparib/irinotecan, pembrolizumabx8). Local pathologists were centrally trained using the Residual Cancer Burden (RCB) assessment to ensure uniform evaluation and response classification; RCB 0 = pCR. Results: We evaluated the relationship between pCR and event free (EFS) and distant disease free survival (DDFS) in the first 522 pts (median follow-up:2.5 years). 180 pts achieved pCR (36%) while 338 did not (RCB=1-3). There were 82 EFS and 65 DRFS events. Over the entire group (including all arms), pCR was highly associated with 3-year EFS (p&amp;lt;0.001 for both). Pts achieving pCR had a 3% recurrence risk (RR) at 3 years; those with non-pCR had 24% RR over this time period. For distant recurrence, the 3-year RR with pCR was 2%, compared to 20% in pts with non-pCR. As expected, pCR rates varied by breast cancer subtype (HR+/HER2: 18% (35/196), HR+/HER2+: 40% (33/82), HR-/HER2+:68% (34/50), HR-/HER2-:41% (76/188)). The relationship between pCR and EFS was significant and clinically impactful within each subtype. 3-year survival (pCR group)Hazard Ratio OverallOverallHR+/HER2-HER2+TNBCEFS97%0.08 (0.03-0.23)0.14 (0.02-1.04)0 (NA)0.11 (0.03-0.37)DDFS98%0.08 (0.03-0.26)0.17 (0.01-1.23)0 (NA)0.09 (0.02-0.40) Conclusions: The first long-term efficacy results from the I-SPY2 TRIAL demonstrate that achieving pCR is a very strong surrogate endpoint for improved EFS and DDFS in a high-risk population, across all treatment arms, regardless of subtype. I-SPY2 shows substantially lower estimated EFS hazards for patients achieving pCR, compared to the 5 yr EFS hazard ratio for pCR vs not in Cortazar (hazard ratio 0.49), demonstrating important differences between a metaanalysis compared to a platform trial with uniform high-risk eligibility, standardized pathology assessment, and multiple targeted therapies. Our data support the use of pCR as a primary endpoint for accelerated approval of new drugs if EFS is evaluated in the same population. Based on these findings, the I-SPY2 TRIAL will test whether therapy can be deescalated or escalated for individual patients with the goal of achieving pCR for all. Citation Format: Yee D, DeMichele A, Isaacs C, Symmans F, Yau C, Albain KS, Hylton NM, Forero-Torres A, van't Veer LJ, Perlmutter J, Rugo HS, Melisko M, Chen Y-Y, Balassanian R, Krings G, Datnow B, Hasteh F, Tipps A, Weidner N, Zhang H, Tickman R, Thornton S, Ritter J, Amin K, Klein M, Chen B, Keeney G, Ocal T, Feldman M, Klipfel N, Sattar H, Mueller J, Gwin K, Baker G, Kallakury B, Zeck J, Duan X, Ersahin C, Gamez R, Troxell M, Mansoor A, Grasso LeBeau L, Sams S, Wisell J, Wei S, Harada S, Vinh T, Stamatakos MD, Tawfik O, Fan F, Adams A, Rendi M, Minton S, Magliocco A, Sahoo S, Fang Y, Hirst G, Singhrao R, Asare SM, Wallace AM, Chien AJ, Ellis ED, Han HS, Clark AS, Boughey JC, Elias AD, Nanda R, Korde L, Murthy R, Lang J, Northfelt D, Khan Q, Edmiston KK, Viscusi R, Haley B, Kemmer K, Zelnak A, Berry DA, Esserman LJ. Pathological complete response predicts event-free and distant disease-free survival in the I-SPY2 TRIAL [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-08.

Hepatoblastoma in Developing Countries; Eight Years of Single Centre Experience

Background and objectives: Although hepatoblastoma (HB) is a rare childhood tumor and constitutes only 0.9% of all pediatric cancers, there was an obvious improvement in risk stratification and prognosis over the last two decades. This study aimed to assess the outcome of HB patients treated in our center and to investigate the impact of different prognostic factors on the survival of these patients. Patients and methods: This was a retrospective study included newly diagnosed patients with HB presented to the Children Cancer Hospital Egypt (CCHE 57357), from July 2007 to June 2015. Patient’s data were analyzed for the clinical characteristics and survival outcome of the included patients. Results: One hundred twenty-four children were included during the study period with a median age of 14 months. The tumor was found occupying the entire liver in 25 patients (20%); while it was confined to one lobe in 80% of them, portal vein thrombosis was diagnosed in 10 patients, and there were 30 patients (24%) had metastatic disease at presentation. Only five patients (4%) underwent primary surgical excision, and all of them were grossly excised (stage I); 77/119 (64.7%) experienced delayed surgery after two to six courses (median, four courses) of C5VD and the overall resection rate was 66%. There were 42 patients (35.3%) failed to do surgical excision either because they still had evident metastatic disease with poor chemotherapy response, or because their tumor remained unresectable after six courses of chemotherapy. The 3-year event-free and overall survivals for the whole studied patients were 45.7% (95% CI, 36.9% - 56.7%), and 66.7% (95% CI, 57.1% - 77.8%) respectively. The 3-year EFS and OS were significantly better in those who underwent surgical excision (68.63% and 80.74% respectively, P-value 0.001). Also, the survival rates were significantly affected by the presence of metastatic disease at presentation, tumor stage and initial risk grouping of the studied patients. Conclusion: Surgical excision, tumor stage and COG risk grouping are the main prognostic variables affecting patients’ outcome. Efforts to achieve resectability of the tumor either by advanced surgical techniques or by developing effective preoperative treatment, especially for advanced and metastatic disease, are mandatory.

Efficacy of ALL Therapy for WHO2016-Defined Mixed Phenotype Acute Leukemia: A Report from the Children's Oncology Group

There remains uncertainty regarding the optimal treatment for mixed phenotype acute leukemia (MPAL), an uncommon leukemia that represents ~3% of de novo acuteleukemia. Because of the dearth of clinical trials, varying approaches are employed: acute lymphoblastic leukemia (ALL) regimens as well as more intensive acute myeloid leukemia (AML) and hybrid therapies. The evolution in the prevailing diagnostic criteria from the EGIL classification to the more narrowly defined WHO2008 and WHO2016 criteria has made the existing literature difficult to interpret. Increasing insight into the molecular heterogeneity of MPAL adds further complexity. Recently published studies (retrospective clinical case series), however, are beginning to suggest that ALL therapy may be the most appropriate form of initial therapy for MPAL.To further assess the efficacy of ALL therapy for pediatric MPAL, we reviewed the Children's Oncology Group (COG) experience. Possible MPAL cases were identified through the ALL biology studies (both AALL03B1 and AALL08B1 were open to MPAL) and from AAML0531, the phase 3 trial for de novo AML (patients enrolled on this trial subsequently found to have MPAL were taken off study). All identified cases were reviewed centrally. In cases where the original flow cytometry testing was inadequate to establish the diagnosis, flow cytometry was repeated with an expanded antibody panel using banked diagnostic specimens. Only cases meeting WHO2016 criteria were retained. Patients were treated per physician discretion and not on a therapeutic clinical trial. Supplemental data on treatment and outcomes were collected.From the study databases, 97 potential MPAL cases were identified; of these, 54 cases (56%) were confirmed to be MPAL via central review. Patients were diagnosed between 2003 and 2016. The majority of patients were <10 years of age and B/Myeloid MPAL (B/My) was the most common phenotype. Fewer than a third of patients presented with hyperleukocytosis, adverse recurrent cytogenetics, or central nervous system involvement (Table 1). In the cohort, 38 patients (70%) received ALL induction therapy, 12 (22%) AML induction, and 3 hybrid induction; 14 (28%) patients received hematopoietic stem cell transplantation (HSCT). The CR rate was 71.1% [27/38], 66.7% (8/12) and 100% (3/3) in patients receiving ALL, AML and hybrid induction, respectively (p=0.761). CR was achieved in 78.8% of B/My cases [26/33], 68.4% T/My cases [13/19], and no B/T cases (0/2, p=0.074). Treatment became more heterogeneous further into therapy due to varying incorporation of ALL, AML and hybrid elements and the varying use of HSCT. Three-year EFS was 65±17% in patients started on ALL therapy and 53±26% in patients started on AML therapy (p=0.169, Fig. 1A); 3-year OS was 79±15% and 60±27% respectively (p=0.510, Fig. 1B). SCT was not associated with a difference in EFS (p=0.935) or OS (p=0.726). In 20 patients receiving ALL therapy alone without SCT, 3-year EFS was 59±22% and OS 79±18%.This series represents a large cohort of centrally-reviewed pediatric MPAL cases diagnosed according to the most recent WHO2016 criteria and treated with COG-style chemotherapy. Our results add to the growing body of literature suggesting that ALL regimens may be effective for pediatric MPAL. It also suggests, however, that induction failure and relapse are still relatively common with ALL therapy and that alternative forms of treatment are necessary for some. The limited size of the sample and its heterogeneity preclude any conclusions regarding the relative efficacy of AML therapy and role for HSCT. Given the greater morbidity and mortality associated with these forms of therapy, consideration should be given to reserving their use for patients with a suboptimal response to ALL therapy. Continued variability in accurately diagnosing and treating MPAL as seen here also underscores the necessity of well-delineated clinical trials with integrated central review to advance MPAL therapy. Our results therefore further support the basis for the first-ever prospective evaluation of high risk ALL therapy for pediatric MPAL in a trial now being planned within the COG. In this trial, minimal residual disease testing with multiparameter flow cytometry will be employed to identify patients responding well to ALL therapy versus those who may benefit from more intensive AML therapy and transplantation. [Display omitted] DisclosuresMullighan:Loxo Oncology: Research Funding; Amgen: Consultancy. Hunger:Erytech Pharmaceuticals: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Honoraria; Amgen: Consultancy, Equity Ownership. Berman:AGADA Therapeutics: Research Funding. Zweidler-McKay:ImmunoGen: Employment.

Efficacy and safety of subcutaneous trastuzumab and intravenous trastuzumab as part of adjuvant therapy for HER2-positive early breast cancer: Final analysis of the randomised, two-cohort PrefHer study

AimTo assess efficacy (event-free survival, EFS) and safety in patients followed up for 3 years in the PrefHer study (NCT01401166). Patients and methodsPost surgery and post chemotherapy in the (neo)adjuvant setting, patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer were randomised to receive four cycles of the subcutaneous form of trastuzumab (Herceptin® SC [H SC] via single-use injection device [Cohort 1] or delivery via a hand-held syringe from an SC Vial [Cohort 2]; 600 mg fixed dose) followed by four of the intravenous form of trastuzumab (Herceptin® [H IV]; 8 mg/kg loading, 6 mg/kg maintenance doses) in the adjuvant setting or vice versa every 3 weeks. Patients could have received H before randomisation. H was then continued to complete a total of 18 cycles, including any cycles received before randomisation. ResultsA total of 488 patients were randomised across both cohorts. After median follow-up of 36.1 months, 3-year EFS across both groups in the evaluable intention-to-treat population (467 patients) was 90.6% overall, 89.9% in Cohort 1, and 91.1% in Cohort 2. No new safety signals were identified during long-term follow-up, with only one cardiac serious adverse event in the safety population (483 patients). ConclusionsThree-year EFS data following H SC and H IV treatment are consistent with those reported by previous trials for H in the adjuvant setting. The overall safety profile during adjuvant treatment was as expected.

FDG-PET–driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study

AbstractDose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2−/PET4− patients were assigned SIC, PET2+/PET4− patients were assigned ASCT, and PET4+ patients were treated with the investigator's choice. The primary end-point was the 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (ΔSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n = 109) or R-CHOP14 (n = 102). PET4−/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P = .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P = .08), leading to more salvage therapy (37% vs 26%; P = .07) and lower event-free survival (EFS; 4-year EFS, 31% vs 43%; P < .01), but progression-free survival (PFS) and overall survival (OS) were similar in both groups. PET2−/PET4− and PET2+/PET4− patients had similar outcomes. Using ΔSUVmax, 79% of the patients were PET2−/PET4−. ΔSUVmaxPET0-4 >70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing an alternative to SIC, including ASCT.

1019P - Evaluation of indoleamine 2,3-dioxygenase expression (IDO), transforming growth factor beta (TGF-β) and interleukin 13 (IL13) expression on clinical outcome in patients with Hodgkin’s lymphoma

Background: Nowadays, patients with Hodgkin’s lymphoma (HL) have a high cure rate. However, approximately 20% pts have relapse or progressive disease. The main histological feature in HL is presence by Hodgkin Reed-Sternberg (HRS) cells. HRS cells produce a diversity of cytokines and chemokines. There is still a limited information of prognostic role expression of cytokines in patients with HL. We assessed the impact on clinical outcome of the IDO, TGF- β and IL-13 expression in patients with HL. Methods: 79 patients (pts) with HL were included in this study (median age: 41, range: 18-65 years; males: 26, females: 53). Early stages of HL have 53.3% and 46.7% pts had advanced stages. Patients were treated with ABVD or BEACOPP (14/esc) and radiation therapy. CR/PR was achieved in 86.1% of patients. 13.9% of pts had relapse or disease progression during the therapy. mRNA expression levels of IDO, TGF-β, IL-13 were measured in fresh pre-treatment tumor tissue specimens from HL patients using real-time qPCR analysis. Results: 25 pts (31.6%) had IDO positive expression (IDO+) and 54 (65.4%) pts was IDO negative (IDO-). Multivariate analysis showed that IDO+ expression correlated with worser EFS rate with HRs of 10.7 [95% confidence interval(CI) 0.4–0.6, p = 0.01], especially in 3-years EFS in IDO+ males comparing to IDO+ females (61% vs 71%, p < 0,05). We did not find significant corellation between such signs as B-symptoms, stages, response reate and IDO expression (p = 0.14). Expression of IL13 and TGF was performed in 69 pts. We divided patients in two groups: IL13+ (high expression) vs. IL13- (low expression) and TGF-β+ (positive expression) vs TGF-β-(negative expression). Number of pts with IL13+ were 34 (49.3%) and 35 (50.7%) with IL13-, while 47 pts were TGF-β+ were (68.1%) and 22 pts (31.9) had TGF-β- expression. It was found, that patients with high IL13 expression had worse EFS and OS rate compared to pts with low IL13 expression. 5-year EFS in patients with IL13- was 98% vs 65% in IL13+ (p < 0,05), as well as 5 year OS in IL13- and IL13+ groups was 98% and 87%, respectively (p < 0,05). Patients with TGF-β- expression had better 5-years OS: 99% in pts with TGF-β- vs. 87% TGF-β+ pts (p < 0.05). We also analyzed two groups of double-positive (IDO+/TGF-β +) and double-negative(IDO-/TGF-β-) and three groups of pts with TGF+/IL13+ vs TGF-/IL13- vs TGF+/IL13 as potential prognosis biomarkers. ROC-analysis showed that response rate in pts with IDO-/TGF-β – was higher compared to IDO+/TGF-β + pts (p = 0.0001). 5-years EFS rate was lower in pts from TGF-β +/IL13+ group comparing to TGF-/IL13- and TGF+/IL13- groups and was 63% vs 99% vs 98% respectively (p < 0.05). Conclusions: Our data showed that IDO, TGF-β and IL13 expressions have a role in predicting clinical outcome in pts with HL. Positive expression of IDO, TGF-β and high expression level of IL13 could be considered as a negative prognostic marker. Significantly worser outcome had pts with positive expression of two cytokines comparing with patients, who had only one positive marker. Legal entity responsible for the study: T. Skrypets Funding: None Disclosure: All authors have declared no conflicts of interest.

Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial

AbstractChildren with myeloid leukemia associated with Down syndrome (ML-DS) have superior outcome compared with non-DS patients, but suffer from higher constitutional cytotoxic drug susceptibility. We analyzed the outcome of 170 pediatric patients with ML-DS enrolled in the prospective, multicenter, open-label, nonrandomized ML-DS 2006 trial by Nordic Society for Pediatric Hematology and Oncology (NOPHO), Dutch Childhood Oncology Group (DCOG), and Acute Myeloid Leukemia–Berlin-Frankfurt-Münster (AML-BFM) study group. Compared with the historical control arm (reduced-intensity protocol for ML-DS patients from the AML-BFM 98 trial), treatment intensity was reduced by lowering the cumulative dose of etoposide (950 to 450 mg/m2) and intrathecal central nervous system prophylaxis while omitting maintenance therapy. Still, 5-year overall survival (89% ± 3% vs 90% ± 4%; Plog-rank = .64), event-free survival (EFS; 87% ± 3% vs 89% ± 4%; Plog-rank = .71), and cumulative incidence of relapse/nonresponse (CIR/NR; 6% ± 3% vs 6% ± 2%; PGray = .03) did not significantly differ between the ML-DS 2006 trial and the historical control arm. Poor early treatment response (5-year EFS, 58% ± 16% vs 88% ± 3%; Plog rank = .0008) and gain of chromosome 8 (CIR/NR, 16% ± 7% vs 3% ± 2%, PGray = .02; 5-year EFS, 73% ± 8% vs 91% ± 4%, Plog rank = .018) were identified as independent prognostic factors predicting a worse EFS. Five of 7 relapsed patients (71%) with cytogenetic data had trisomy 8. Our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair excellent outcome. The trial was registered at EudraCT as #2007-006219-2.

Presentations, treatment complications and outcomes in HCV‐infected B‐cell lymphoma patients treated with immunochemotherapy: A single institute retrospective study

Numerous epidemiologic studies show an association between hepatitis C virus (HCV) and B-cell lymphomas. However, limited studies focused on hepatic consequences after immunochemotherapy, and the prognostic role of HCV is still a matter of debate. We retrospectively analyzed the clinical presentations, hepatic complications, and outcome of B-cell lymphoma patients who were HCV-infected and not HCV-infected. During 2008 to 2013, there were 230 newly diagnosed lymphoma patients who were negative for HBsAg received rituximab-containing chemotherapy as their first-line therapy in our institute. Thirty-six patients (15.7%) were positive for anti-HCV and 194 patients were negative. Most common lymphoma subtypes were DLBCL (73.5%) and follicular lymphoma (19.1%). DLBCL patients had a higher anti-HCV positive rate than FL (18.3% vs 5.6%, P = 0.015). Anti-HCV-positive patients had higher baseline AST and ALT levels (AST, 57.7 ± 46.5 U/L vs 31.1 ± 25.9 U/L, P < 0.001; ALT, 51.6 ± 51.0 U/L vs 25.6 ± 30.6 U/L, P < 0.001), and more liver cirrhosis before treatment (19.4% vs 2.2%, P < 0.001). However, spleen involvement (30.6% vs 21.2%, P = 0.227), extranodal involvements more than one site (27.8% vs 29.4%, P = 0.706), and other parameters are similar in both groups. The most common treatment regimens were R-CHOP like (65.7%) and R-COP (24.8%). After chemotherapy, the patients who were positive for anti-HCV developed more hepatitis (defined as ALT >40 U/L) (80.6% vs 59.8%, P = 0.018) and severe hepatitis (defined as ALT >200 U/L) (30.6% vs 7.7%, P < 0.001). One HCV-positive patient died of hepatic failure after salvage therapy (ESHAP), which was administered at 3 months after last cycle of R-CHOP. The reduction rate of chemotherapy dose (<90% of standard dose) due to hepatotoxicity occurred more often in HCV-infected patients (19.4% vs 2.4%, P = 0.001). Chemotherapy early stop is defined as patients received less cycles of chemotherapy than initial planning or guideline. Chemotherapy early stop rate for all causes was similar in both groups (38.9% vs 26.7%, P = 0.143), but early stop specifically due to hepatotoxicity was slightly higher in patients with HCV infection (3/36 (8.3%) vs 3/165 (1.8%), P = 0.072). The median follow-up time was 21.6 months (range, 1.3-92.8 months) for patients who were HCV-positive and 30.7 months (range, 0.7-78.1 months) for those who were HCV-negative. Complete remission rates were 58.3% and 55.2% in HCV-positive and HCV-negative patients, respectively. Partial response rates were 25.0% and 23.7% in HCV-positive and HCV-negative, respectively. No significant difference was observed in event free survival according to HCV infection (3-year EFS, 41.0% vs 42.8%, P = 0.989). The overall survival tended to be worse in patients who were positive for anti-HCV than those negative for anti-HCV (3-year OS, 47.6% vs 63.2%, P = 0.058). Keywords: B-cell lymphoma; hepatitis C; rituximab