Yrs Overall Survival Research Articles

Prognostic value of the end of induction PET in patients with follicular lymphoma: results from the analysis of FOLL 12 trial

Aim: To assess the prognostic value of the PET metabolic response using the Deauville Score at the end of induction (EoI) therapy. Methods: FOLL12 trial (NCT02063685) is a multicenter, phase III, randomized study with the primary objective to evaluate whether a FDG-PET (PET) and MRD (molecular residual disease) response-based maintenance therapy (experimental arm) is more effective in terms of Progression-Free Survival (PFS) than a standard maintenance therapy with Rituximab (standard arm) in patients with follicular lymphoma. Adult patients with untreated grade 1–3a FL and stage II-IV were randomized to receive standard immunochemotherapy followed by rituximab maintenance versus standard immunochemotherapy followed by a response adapted post-induction management (i.e. non-maintenance for patients in CMR and with MRD negative, short rituximab therapy for CMR (complete metabolic response) and MRD +ve cases and radioimmunotherapy followed by rituximab maintenance for non-CMR patients). EoI-PET was mandatory. All PET scans were centralized on WIDEN® platform and classified according to Deauville score (DS) in a blind independent central review. DS1-3 was considered negative (CMR), whereas DS4-5 was considered positive (not CMR). The primary endpoint was PFS. Main secondary endpoint was Overall Survival (OS) Results: Overall, 729 follicular lymphoma patients, 52% women, 89% stage III-IV disease and 40% with a high-risk FLIPI-2 score, were included in the analysis. DS at the EoI-PET resulted 1,2,3,4, and 5 in 361(49.5%), 168(23.1%), 112(15.4%), 49(6.7%) and 39(5.3%) patients, respectively. EoI-PET resulted positive in 88/729 (12%). Among the reviewers, the overall agreement (OA) on PET pos/neg result was 0.92, while agreement on positive and negative cases were 0.77 and 0.94, respectively. In the whole population of 729 patients, 5 yrs PFS (95% CI) for DS1-3 and DS4-5 was 69%(65–73) and 35%(25–46) with HR3.32(2.45–4.50), p < 0.001, respectively. The 5 yrs OS (95% CI) in DS1-3 and DS4-5 was 94%(92–96) and 81%(71–88), HR4.72(2.69–8.32), p < 0.001. The prognostic role of CMR was confirmed both in the standard and in the experimental arm of the study. In the whole population, the 5 yrs PFS (95% CI) in DS1-2, DS 3 ad DS4-5 was 74% (69–78), 55% (44–65; HR1.90 (1.36–2.66) p < 0.001) and 37%(26–48; HR 4.01 (2.90–5.54) p < 0.001); DS3 patients had an intermediate 5 yrs PFS rates between those of DS1-2 and DS4-5 patients. OS in DS3 patients had similar values to those with DS1-2. Applying a different definition of CMR (i.e., DS1-2 only) the rate of positive EoI-PET rose to 27%. Conclusion: In FOLL12 trial, EoI-PET according DS criteria was a reliable tool to stratify PFS and OS in advanced follicular lymphoma patients treated with immunochemotherapy; in addition, these data showed DS3 patients as a new category with an intermediate prognosis in terms of PFS. Keywords: Diagnostic and Prognostic Biomarkers, PET-CT No conflicts of interests pertinent to the abstract.

Prospective Validation of CD34+CD38- Leukemic Stem Cell Frequency in the HOVON-SAKK 132 Trial: Perspectives for Future Improvements

Clinical implementation of measurable residual disease (MRD) requires accurate MRD detection to assess relapse risk for acute myeloid leukemia (AML) patients. One possibility to further improve the prognostic ability of the current MRD assay is to include the quantification of relapse initiating cells such as the CD34+CD38- leukemic stem cells (LSC) in the assay. In the HOVON-SAKK 102 trial, detection of LSC by multiparameter (MFC) flow MRD at diagnosis and after 2nd chemotherapy cycle (C2) has shown prognostic value (Zeijlemaker et al. Leukemia 2019). In addition, together with MRD detection, LSC could identify a category of patients with very high risk of relapse. Based on those data, improvements for LSC assessment measurements have been suggested, such as measuring more white blood cells (WBC) with the purpose of enhancing the sensitivity for the low frequency of CD34+CD38- cells. In the HOVON-SAKK 132 trial (Lowenberg et al. Blood Adv 2021), the one tube LSC assay was used that included LSC markers CD45RA, CD123, CD33, CD44, CLL-1, TIM-3, CD56, CD7, CD22 and CD11b (Zeijlemaker et al. Leukemia 2016). The one tube approach allows acquiring the suggested 4 million WBC for LSC-load estimation. In the current study, we prospectively validated the prognostic value of LSC burden at the following time points, i.e. at diagnosis (764/905 patients) and after two cycles of chemotherapy (C2; 357/706 patients). The median WBC acquired was 2x106 (range: 3x104- 6x106) at diagnosis and 3x106 (range: 4x105-5x106) after C2. Median percentages of LSC at diagnosis and after C2 were respectively 0.004% (range: 0.0000%-26.85%) and 0.00002% (range: 0.0000%-1.36%). Similar to the HOVON-SAKK102 study, three prognostic groups based on the presence or absence of CD34 and/or LSC, showed significant associations between LSC burden at diagnosis and overall survival (OS) or relapse- free survival (RFS) (Figure 1A): 1. CD34negative patients without any measurable LSCs and Leukemia Associated Immunophenotypes on the CD34+ blasts fraction (CD34negLSC=0 3 years (yrs) OS: 76.4% standard error (SE) 5; median OS not reached). 2. Patients with low percentages of CD34+CD38-LSCs < 0.03% (LSClow; 3 yrs OS 62.8% SE 2; median OS not reached) 3. Patients with high percentages of CD34+CD38-LSCs ≥0.03% (LSChigh, 3 yrs OS 44.5% SE 3; median 25.6 months; 95% confidence interval (CI): 18.7-49.1). Multivariate analysis adjusted for age, WBC at diagnosis, AML type, ELN2017 risk group and -only for RFS- the number of chemotherapy cycles to attain complete remission, showed that LSC burden at diagnosis is a strong independent prognostic factor for OS and RFS (Figure 1B). After C2, before the consolidation treatment, a cut-off value of 0.000075% of LSC showed the best prognostic value of LSC (univariate, LSCneg versus LSCpos: OS, HR 1.79 95% CI: 1.25-2.56, P < 0.01; RFS, HR 1.55, 95% CI: 1.12-2.13, P < 0.01). This cut-off appeared also highly significant as a prognostic factor in former trials (Terwijn et al. PLoS One 2014; Zeijlemaker et al. Leukemia 2018). Multivariate analysis showed that also LSC status after C2 was an independent prognostic factor for OS and RFS (Figure 1B). By combining the LSC status after C2 (≥0.000075%) together with the MRD status as used in the HOVON-SAKK 132 (based on ≥0.1% MFC-MRD and/or NPM1-MRD), MRDpos patients who are LSCpos have worse prognosis in OS and RFS (univariate: MRDnegLSCneg vs MRDposLSCpos; OS HR 3.2, 95% CI: 1.94-5.28, P < 0.01, RFS: HR 2.61 95% CI: 1.65-4.12, P < 0.01, multivariate: Figure 1B). Further analyses of the data are now directed towards potential influences of the cell amount of acquisition, ELN risk groups and MRD guidance in this trial. In conclusion, this prospective validation confirmed that assessing LSC burden, at diagnosis and after C2, remains to have additional prognostic value to MRD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Proteomics-Based Strategy for the Recommendation of Conventional Chemotherapy Vs Venetoclax Plus Hypomethylating Agents in Adult Acute Myeloid Leukemia (AML)

INTRODUCTION: Newer AML therapies with Hypomethylating Agents & Venetoclax (HV) provide an alternative to Conventional Chemotherapy (CC), with anthracycline and cytosine arabinoside, but criteria to select which to use are lacking. We investigated whether proteomic classification could provide guidance. METHODS: Using Reverse Phase Protein Array (RPPA) methodology, the level of 405 proteins (327 total; 78 post-translational modified) were measured in 818 samples from newly diagnosed adult AML patients and normalized to normal CD34+ cells. Patients treated with HV (N=85) or CC (N=335) were analyzed. Overall Survival (OS) and Complete Remission Duration (RD) analysis was performed with pairwise LogRank tests (p < 0.05), adjusted for False Discovery Rate (FDR), to identify individual proteins predictive of outcome. Patients were clustered based on protein expression. Categorical clinical variables were compared with Fisher's Exact test with simulated p-values (10000 replicates), and continuous ones with Kruskal-Wallis test. Univariate (UV) and Multivariate (MV) models were built with Cox proportional hazards model (CoxPH). Deep neural network analysis using random forest was performed to create a Protein Classifier for treatment recommendation. RESULTS: Individual protein analysis found 55 prognostic proteins (Protein Selector 1 - PS1), which clustered patients into 3 groups. A preferred therapy for cluster 2 was not identified with PS1, so a second Protein Selector 2 (PS2) was generated, identifying 45 predictive proteins in this subset. From the PS1/2 analysis, the 95 proteins formed 4 distinct expression profiles (C1=red, C2=gold, C3=magenta, C4=green) which were stratified by treatment (HV or CC), as shown in Fig. 1. Patients in C2 were enriched for secondary AML (57% vs C1=41%, C3=33%, C4=32%; p<0.001) and unfavorable cytogenetics (41% vs C1=32%, C3=39%, C4=35%; p<0.001), and were older (60yo vs C1=61yo, C3=54yo, C4=56yo; p<0.001). Mutations in CEBPA, GATA2, FLT3 and NPM1 were more common in C4 (22%, 13%, 35%, 35% vs C1=12%, 1.7%, 5.7%, 6%; C2=7.8%, 6.2%, 18%, 15%; C3=9.3%; 1.4%, 29%, 21%; p=0.037, p=0.013, p<0.001, p<0.001, respectively), highlighting the heterogeneity between groups. We evaluated OS and RD (Fig. 2) in each cluster (C1=red, C2=gold, C3=magenta, C4=green), considering each treatment (HV= solid line, CC=dashed line). Patients in C1 and C2 treated with HV had a diametrically different and superior response compared to those treated with CC (C1-HV: Median OS (MS)>65mo, Median RD (MRD)>60mo; C2-HV: MS=15mo, MRD=24mo vs C1-CC: MS=20mo, MRD=39mo; C2-CC: MS=10mo, MRD=17mo). C3 showed the opposite, with CC outperforming HV (MS=19mo, MRD>102mo vs MS=7mo, MRD=9mo). Similarly, in C4, CC patients did dramatically better, (MS=40mo, MRD>96mo vs MS=9mo, MRD=7mo). In the UV CoxPH model, we included variables for PS cluster and treatment and all groups predicted OS, except for C3-CC and C4-CC, as did age, secondary AML, complex karyotype, and CEBPA, FLT3, KIT, MLL, NPM1, PTPN11 and TP53 mutations. In the MV model, all clusters were predictive for OS, together with age, secondary AML, complex karyotype and NPM1 mutation. Regarding RD, in the UV model, only C2-HV, C2-CC, and C4-HV predicted RD, as did age, secondary AML, complex karyotype, unfavorable cytogenetics, and FLT3, RUNX1 and TP53 mutations. In the MV model of RD, all clusters, except for C3-HV were predictors, together with age. Importantly, optimized treatment triaging based on PS1/2 would have reassigned 52% (218/420) of cases, and is estimated to increase the 3yrs OS of the whole cohort from 35.6% to 48.8%, a 37.2% increase. Moreover, the 2yrs Relapse Free Survival would increase from 57,9% to 63,9%, a 10.39% increment. Furthermore, our Protein Classifier identified a set of 3 proteins (SPI1, NOTCH1.cle, and TGM2) whose expression can be used to rapidly classify patients and recommend either HV or CC. This classifier has a very high c-index (a measure of individual patient discriminatory power) of 0.93 (>0.7 is considered predictive, 1 would indicate perfection) demonstrating that it robustly predicts optimal therapy choice. CONCLUSION: Protein profiling identified protein expression patterns which had diametrically different responses according to treatment (HV or CC). Given the US annual incidence of 20000 newly diagnosed AML cases, proteomic triaging could result in ~2600 more cures using existing therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dose Reduced Chemotherapy in Sequence with Blinatumomab for Newly Diagnosed Older Patients with B-Precursor Adult Lymphoblastic Leukemia (ALL): Results of the Ongoing GMALL Bold Trial

Dose Reduced Chemotherapy in Sequence with Blinatumomab for Newly Diagnosed Older Patients with B-Precursor Adult Lymphoblastic Leukemia (ALL): Results of the Ongoing GMALL Bold Trial

1042P Anti-PD1 (PD1) monotherapy or in combination with ipilimumab (IPI) after BRAF/MEK inhibitors (BRAF/MEKi) in BRAF mutant metastatic melanoma (MM) patients (pts)

Pts with V600BRAF mutant MM have numerically higher rates of progression-free survival (PFS) and overall survival (OS) with 1st line IPI+PD1 vs PD1. Whether this is also true after BRAF/MEKi therapy is yet to be determined. We aimed to: (1) determine the efficacy and safety of PD1 vs IPI+PD1 after BRAF/MEKi; and (2) identify the subgroup of pts with >3 yrs OS with PD1+/-IPI after BRAF/MEKi.

The Effect and the Cost of Tandem Transplantation in Multiple Myeloma Patients with Adverse Cytogenetics

Introduction:Autologous stem cell transplantation (ASCT) plays a major role in the treatment of multiple myeloma. However, the result of STaMINA trial showed no extra benefit of second transplantation or consolidation therapy in addition to single ASCT; there is still argue about the optimal intensity of the treatment in patients with high-risk cytogenetic abnormalities. We analyzed retrospectively, the effect of the tandem ASCT and the cost.Methods:We analyzed multiple myeloma patients with Adverse Cytogenetics who were treated with ASCT in National Center for Global Health and Medicine Hospital from January 2010 to the end of March 2017. Most patients were treated with bortezomib based induction therapy. Patients who failed to achieve very good partial remission or better after the first ASCT proceeded to the second ASCT. Most patients received consolidation therapy and/or maintenance therapy. Overall Survival (OS) and progression free survival (PFS) was analyzed using the Kaplan-Meier methods, and the log-rank test. Also, cumulative cost for the treatment was evaluated. Adverse cytogenetics were defined as hypodiploidy, del(17p), t(4;14), and t(14;16).Results:Ten patients were treated with tandem ASCT, and fifteen patients were treated with single ASCT. Twenty-one patients were treated with BD regimen, two patients with CyBorD regimen, and two patients with VAD regimen. The median number of induction therapy was 4 cycles (4-6). The PFS of the tandem ASCT group (3yrs PFS was 87.5%) was superior to the single ASCT group (3yrs PFS was 37.2%) (P = 0.0038). The OS of the tandem ASCT group (3yrs PFS was 100%) was superior to the single ASCT group (3yrs OS was 49.5%) without statistical significance (P = 0.057). We compared cumulative costs of tandem ASCT patients with single ASCT patients. We plotted the average cumulative cost of every 3 months in each group. The first 21 months and beyond 54 months, the rate of cost increment was apparently higher in the single ASCT group than tandem ASCT group. A regression line was calculated for the average cumulative cost of single ASCT group and tandem ASCT group. Regression analysis revealed that overall inclination of the regression line of the cost in single ASCT was significantly larger than that of the cost in tandem ASCT (P = 0.0024).Conclusion:The outcome of tandem ASCT was superior to single ASCT in patients with adverse cytogenetics. Also, the total cost in patients with tandem ASCT was lower than that with single ASCT. Tandem ASCT may reduce the rate of relapse and the cost for salvage treatment. Therefore, tandem ASCT should be considered for multiple myeloma patients with adverse cytogenetics from a cost-benefit point of view. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High Intratumoral Galectin-1 Is Associated with Adverse Outcome in ALK-Negative, CD30-Positive Peripheral T-Cell Lymphomas

Galectin-1 (Gal-1) has been associated with prognosis in several cancers including lymphomas. CD30-dependent cell signaling mediated by Gal-1 has been proposed in CD30-positive lymphomas and cell lines. Still, Gal-1 expression has not been systematically assessed as a possible prognosticator in nodal peripheral T-cell lymphomas (PTCL).Tissue micro arrays with pre-therapeutic tumor specimens from 169 patients with nodal PTCL (n=29 AITL, n=37 ALK-negative ALCL, n=14 ALK-positive ALCL, and n=83 PTCL-NOS) were assessed for intratumoral Gal-1 expression by immunohistochemistry and quantified using digital image analysis. For outcome analysis Gal-1 expression in tumors was categorized in two groups i.e. i) the quartile of patients with highest expression values (Gal-1 high) and ii) the lower three quartiles taken as one group (Gal-1 low). Overall survival (OS) in high and low Gal-1 groups was compared in the entire cohort and in CD30-positive subsets of PTCL.Gal-1 stains were evaluable in 163 cases (96%). The Gal-1 expression level was significantly different between PTCL subtypes (P<0.001) with ALK-positive and ALK-negative ALCL having the highest levels. Moreover, CD30-positive PTCLs showed higher expression compared with CD30-negative ones (P=0.001). No significant difference in OS according to Gal-1 expression was seen in the PTCL cohort as a whole or in the CD30-positive subgroup when including ALK-positive ALCL. Due to the superior survival and very few events among ALK-positive ALCL patients (P<0.001), a CD30-positive cohort without ALK-positive ALCL was analyzed separately. This cohort consisted of ALK-negative ALCL (n=37), PTCL-NOS (n=5), and AITL (n=1). Within this cohort, patients with ‘Gal-1 high’ had significantly poorer outcome (5 yrs OS 10%, 95% confidence interval (CI): 0.1-36) than their ‘Gal-1 low’ counterparts (5 yrs OS 48%, 95%CI: 30-64, P=0.025). Risk factors were evenly distributed between the groups. In univariate analyses age≤60, normal LDH, and performance score <2 correlated with superior survival, whereas high Gal-1 expression significantly predicted adverse outcome at both univariate (HR 2.4, 95%CI: 1,1-5.5, P=0.030) and multivariate level (HR 2.9, 95%CI: 1.1-7.8, P=0.027). We conclude that high intratumoral Gal-1 expression correlates with inferior survival in nodal ALK-negative, CD30-positive PTCL patients. Disclosuresd'Amore:Nordic Nanovector: Other: Advisory Board; Sanofi: Research Funding; Les Laboratoires Servier: Honoraria, Other: Advisory Board; Takeda Pharma: Honoraria, Other: Advisory Board, Research Funding.

TREATMENT AND OUTCOMES OF PATIENTS WITH POST‐TRANSPLANT LYMPHOPROLIFERATIVE DISORDER: A SINGLE CENTRE EXPERIENCE

Background: Post-transplant lymphoproliferative disorder (PTLD) is a potentially severe complication that takes place after solid (SOT) or allogeneic hematopoietic stem cell transplant (HSCT). To date, its treatment is not standardised, and choice of therapy depends on histology and clinical presentation. We report the results of a 10 years (yrs) single-centre retrospective study assessing presentation, treatment patterns and outcomes of patients with PTLD. Methods: Patients ≥18 yrs diagnosed with a PTLD between 2011 and 2020 were identified in our medical records database. Primary endpoints were 2 yrs progression-free survival (PFS), overall survival (OS), and relapse incidence (RI) estimated with Kaplan-Meier and comparison between HSCT and SOT group. Secondary endpoints were the overall response rate (ORR) and complete response rate (CRR) at the end of first line treatment. Exploratory univariate analysis for OS, PFS were investigated using Cox regression model. Results: A total of 38 patients were included. Patient's characteristics and treatment strategies are presented in Table 1. HCST patients present a significantly higher prevalence of early onset PTLD (90% in HCST group vs 0% in SOT group), positive EBER immunostaining (100% vs 22%) and detectable Epstein Bar Virus (EBV) viremia (100% vs 28%), higher LDH (95% vs 66%), IPI score 3-5 (50% vs 33%), with a remarkable higher use of single agent Rituximab as first line therapy in HSCT patients (65% vs 11%). 2 yrs PFS was 54% (95%CI 36-73%) for the entire cohort, 42% (95%CI 16-67%) for HSCT and 67% (95%CI 41-92) for SOT; p-value 0.23. 2 yrs OS was 53% (95%CI 41-66%) for the entire cohort, 42% (95% CI 16-67%) for HSCT and 65% (95% CI 39-91) for SOT; p-value 0.22. 2 yrs RI was 9% (95% CI: 0-21%) for the entire cohort, 0% for HSCT and 14% (95% CI 0-33%) for SOT; p-value 0.26. ORR and CRR were similar with 82% (75% for HSCT, 89% for SOT, p-value 0.41) at the end of first line treatment. High IPI score (3-5) demonstrated worse outcome for PFS (HR: 2.5, 95%CI 0.95-6.65, p-value 0.063) and OS (HR: 2.4, 95%CI 0.92-6.48, p-value 0.07). A total of 17 patients died during follow-up: 7 during first line treatment of PTLD complication and multiorgan failure (5 in the HSCT group, 2 in the SOT group; p-value 0.41); 2 following PTLD relapse after first CR (0 in the HSCT group, 2 in the SOT group; p-value 0.22). Conclusion: This study highlights the clinical and therapeutic heterogeneity of PTLD. We observe a worse 2 yrs PFS and OS in patients with high IPI score. CRR after first line treatment is almost 90% in the SOT group, with a 2 yrs OS of 53%, consistent with previous studies (Trappe et al, JCO 2017). The higher mortality observed in the HSCT group suggests that serious treatment-related toxicities remain main challenges in this fragile patient population. New tools to guide therapeutic approaches in PTLD patients are warranted. Keywords: Lymphoid Cancers - Other No conflicts of interests pertinent to the abstract.

Metastatic osteosarcoma at diagnosis: Analysis of 92 cases from a single institution.

e23506 Background: Metastatic osteosarcoma (MOS) with synchronous metastases accounts for 20-25% of all new cases of osteosarcoma. Lungs are the most common site of metastases at presentation (80%) followed by Bone (10%). 5- years Overall Survival (OS) of MOS ranges from 11 to 40%. In a previous study from our institution (Bacci G 2006) on 57 pts &lt; 40 years old (1995-2000) the 2- and 5-year OS were 55% and 18%. Methods: Data of patients with pathologic and radiologic confirmed MOS with adequate follow up were reviewed (EC Approval N 916/2020/Oss/IOR). Time-to-event outcomes were estimate with Kaplan-Meier method and compared between groups with log-rank test and Cox model. Results: From August 2000 to October 2018, 92 patients had a diagnosis of MOS: median age 16.5 yrs (6-73, twelve pts &gt; 40 ), gender rate was M 51/F 41, axial primary tumor in 15 cases, extremity in 77. Lung only metastases were described in 66 (71.7%). In 75/90 cases primary tumor was surgically removed, 43 (46%) cases had at least one surgical metastasectomy. All patients received chemotherapy: preoperative only in 6 cases, postoperative in 6, and pre and postoperative in 66 patients. The 1st line chemotherapy was a combination of drugs: Adriamycin in 91/92 pts, Cisplatin in 89/92, Ifosfamide in 88/92, Methotrexate in 83/92; 59 patients received a 2nd line chemotherapy, 34 pts received a 3rd line; most employed regimen were Gemcitabine-Docetaxel, Ifosfamide 15 gr/m2, Cyclophosphamyde-Etoposide, TKI (Pazopanib, Sorafenib), and a few received experimental drugs. Complete remission (CR) was obtained in 26/92 (28%), in 19 cases after surgical metastasectomy.In 30 pts the information of PGP (P- glycoprotein) was available; patients with positive PGP (19/30) had a worst overall survival as compared to those PGP negative (P = 0.038). Of those in Complete Remission 14/26 relapsed. At December 2020 with a median follow-up of 95 ms (IQR 34-159): 65/92 (70%) died , 12 are alive and free from disease , 6 are alive with disease, 9 were lost . The 2-yrs OS for all 92 pts from diagnosis was 66% (95%CI 55-75) and 5-yrs OS was 26% (95% CI 16-37). From the end of treatment, for those who reached a CR the 5-year OS was 57% vs 9% for those who did not (P &lt; 0.001). At univariate analysis, primary tumor site (2-y OS 48% axial vs 72% extremity, P &lt; 0.001), site of metastases (2-y OS 74% only lung vs 48% other, P = 0.004) and number of lung nodules (P = 0.007), were significantly associated to OS. At multivariate analysis, only site of metastases (other vs. only lung HR = 2.26, 95%CI: 1.21-4.22) and number of lung nodules (≥10 nodules vs ≤3 HR = 2.44, 95%CI: 1.24-4.81) were confirmed as significant for OS. Conclusions: Compared to our previous report from 20 yrs ago, 2-years and 5 yrs OS of MOS has improved but it remain unsatisfactory (66% vs 55% and 26% vs 18%).

Fludarabine, High Dose Cytarabine and Idarubicin-Based Induction Is Highly Effective in Young AML Patients with Concomitant NPM1 and FLT3-ITD Mutation Irrespectively of FLT3-ITD Allelic Burden

Background: The presence of FLT3 "internal tandem duplication" (FLT3-ITD) mutation is associated with poor prognosis in acute myeloid leukemia (AML). However, the concomitant presence of NPM1 mutation (NPM1-mut) partially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild-type allelic ratio. NPM1 and FLT3 mutational status assessment is strongly recommended for risk stratificationat diagnosis by the last European Leukemia Net (ELN) guidelines. Aims: To investigate the efficacy of an intensive fludarabine-containing induction regimen (FLAI) for fit, de novo AML patients according to NPM1 and FLT3-ITD mutational status. Methods: One-hundred and sixteen consecutive AML patients, treated in 3 Hematology Italian centers from January 2008 to January 2018, were included in this analysis. Twenty five patients showed isolated FLT3-ITD, 39 concomitant FLT3-ITD and NPM1-mutation and 52 isolated NPM-1-mutation.Median age was 52 yrs (range: 18-65 years). All patients received fludarabine, high dose cytarabine-based induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm ondays 1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5). For patients achieving CR fludarabine was omitted on II induction course and idarubicin dose was increased to 12 mg/sqm. Before2017 patients with isolated FLT3-ITD mutation were scheduled to receive allogeneic bone marrow transplantation (BMT) in first complete remission regardless of allelic burden whereas after 2017 only patients with high allelic burden received BMT in 1st CR. Minimal residual disease was evaluated on marrow samples using multicolor flow-cytometry (MFC)or NPM1 expression levels. Negative MFC-MRD wasdefined by the presence of less than 25 clustered leukemic cells/105 total events (threshold of 0.025% residual leukemic cells, Minetto et. al, BJH 2019). NPM1mutation (NPM1-A, B and D) was measured using Muta Quant Kit Ipsogen from Qiagen. FLT3-ITD allelic burden was available in31/64 of FLT3-ITD patients. Results: Overall 60-days mortality was 4%. After two induction cycles, 101 patients achieved CR (87%). Thirty-three/101 (33%) CR patients underwent BMT in first CR. After a median follow up of 61 months, 3-year overall survival (OS) was 56.8% (median not reached). In univariate analysis OS duration was favorably affected by age &lt;55 yrs (p&lt;0.05), MRD-negative status after induction (both MFC and NPM1 based MRD) (p&lt;0.001) and wild-type FLT3(p&lt;0.05). However, in multivariate analysis only MRD status significantly affected OS (p&lt;0.003). The probability of achieving a molecular MRD negative CR after first cycle among NPM1-mut patients was similar between patients with or without concomitant FLT3-ITD mutation (61% and 66%, respectively, p=n.s.). Interestingly, in younger patients (&lt; 55yrs) OS was comparable in case of isolated NPM1 mutation or concomitant NPM1/FLT3-ITD mutation (3-year OS 68.4% and 62.3%, respectively, p= n.s, Figure 1), regardless of FLT3-ITD allelic burden.Patients with isolated FLT3-ITD mutation had a significantly worse prognosis (3-year OS 34.4%, p&lt;0.05). Again, multivariate analysis showed that persistence of MRD (by any method, p &lt;0.05) was the strongest predictor of outcome. Moreover, performing BMT infirst CR did not impact OS neither in univariate or multivariate analysis. Conclusion: Despite the potential bias due to the retrospective nature of the analysis, our data indicate that intensive fludarabine-high dose cytarabine-based induction exerts a strong anti-leukemic efficacy in younger AML patients carrying NPM1 mutation irrespectively of FLT3 mutational status.Thus, the synergism of fludarabine and cytarabine seems to affect the intrinsic chemosensitivity of NPM1-mut leukemic cells, overcoming the negative impact of FLT3-ITD. Moreover, our data suggest the strong prognostic impact on survival of MRD clearance and question the role of BMT in I CR in this setting of patients. Figure 1 Disclosures Candoni: Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Merck SD: Honoraria, Speakers Bureau. Bocchia:Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria.

Abstract P3-08-01: Characteristics, outcomes and prognostic factors of luminal androgen receptor (LAR) triple-negative breast cancer (TNBC)

Abstract Background: The LAR subtype is a genomically distinct subset of TNBC. Using a large cohort of non-metastatic TNBC patients (pts) with long term follow-up, we sought to further characterize the clinicopathologic features and outcomes of LAR vs non-LAR TNBC. Methods: From a cohort of 9982 women with surgically-treated non-metastatic breast cancer, 605 met criteria for TNBC (ER/PR&amp;lt;1% and HER2-negative) by central pathology. RNA extracted from 304 FFPE tumor specimens using the HighPure RNA extraction kit was subjected to TruSeq RNA Access library preparation and sequencing on a HiSeq2500. Adequate RNA was available for 283 pts. Tumors were classified as LAR or non-LAR using a shrunken centroid model, CABAL (Clustering Among BAsal and Luminal androgen receptor). In addition to previously described analyses [Leon-Ferre et al, Breast Cancer Res Treat 2017], immunohistochemical (IHC) androgen receptor (AR) staining was performed and the impact of various parameters on invasive disease-free survival (IDFS) and overall survival (OS) was assessed using Cox proportional hazards models. Results: 58 (20%) tumors were classified as LAR and 225 (80%) as non-LAR. Compared to non-LAR, LAR pts were older (mean age 65 vs 54) and more often postmenopausal (79%vs53%), both p=0.01. Apocrine histology was more common among LAR tumors (21%vs0%), which were also lower grade (grade3: 69%vs95%) and had lower Ki-67 (Ki-67&amp;gt;15%: 64%vs82%), all p&amp;lt;0.01. Additionally, LAR tumors had lower median stromal tumor infiltrating lymphocytes (TILs, 20%vs25%) and were less frequently lymphocyte-predominant [≥50% stromal or intratumoral TILs (19%vs32%)], although neither reached statistical significance. AR IHC was available for 223 of 283 tumors. Median AR IHC score in LAR was 65% (range 0-100%) vs 0% (range 0-90%) in non-LAR. T/N stage, surgery type, and receipt of adjuvant chemotherapy (AdjCT) or radiotherapy were similar between LAR and non-LAR. LAR pts had shorter IDFS and OS compared to non-LAR (5.6 vs 11.8 yrs and 10.8 vs 20.8 yrs, respectively), although this did not reach statistical significance. Test of proportional hazard assumption was not significant for IDFS or OS (p = 0.30 and 0.09). IDFS estimates were numerically higher in LAR vs non-LAR (80.2%vs70.5%,p = 0.92) at 3yrs post-diagnosis; whereas the opposite was true (40.9%vs55.6%,p = 0.07) after 10yrs. OS estimates at 3 and 5yrs were similar between LAR and non-LAR, but at 10yrs OS was inferior in LAR (40.9%vs66.4%,p = 0.24). In a univariate analysis including both LAR and non-LAR, older age, higher N stage, lower TILs and absence of AdjCT were associated with poorer IDFS and OS. In a multivariate analysis, higher N stage and absence of AdjCT remained associated with both poorer IDFS and OS; while lower stromal TILs were associated with poorer IDFS (p=0.01), and with a trend towards poorer OS (p=0.07). Conclusions: LAR TNBCs occurred in older women, were lower grade, and had lower TIL density than nonLAR tumors. While significant differences in IDFS or OS were not demonstrated, LAR pts exhibited a numerically lower risk of a disease event at 3yrs, but higher risk by 10yrs compared to nonLAR pts. In the entire cohort, higher N stage, absence of AdjCT and lower TILs were independently associated with poorer outcomes. Citation Format: Leon-Ferre RA, Polley M-Y, Liu H, Kalari KR, Boughey JC, Liu MC, Cafourek V, Negron V, Ingle JN, Thompson KJ, Tang X, Barman P, Carlson E, Visscher DW, Carter JC, Couch FJ, Goetz MP. Characteristics, outcomes and prognostic factors of luminal androgen receptor (LAR) triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-01.

CXCR4 expression varies significantly among different subtypes of glioblastoma multiforme (GBM) and its low expression or hypermethylation might predict favorable overall survival

ABSTRACTBackground: CXCR4 is an oncogene in glioblastoma multiforme (GBM) but the mechanism of its dysregulation and its prognostic value in GBM have not been fully understood.Research design and methods: Bioinformatic analysis was performed by using R2 and the UCSC Xena browser based on data from GSE16011 in GEO datasets and in GBM cohort in TCGA database (TCGA-GBM). Kaplan Meier curves of overall survival (OS) were generated to assess the association between CXCR4 expression/methylation and OS in patients with GBM.Results: GBM patients with high CXCR4 expression had significantly worse 5 and 10 yrs OS (p < 0.05). Across different GBM subtypes, there was an inverse relationship between overall DNA methylation and CXCR4 expression. CXCR4 expression was significantly lower in CpG island methylation phenotype (CIMP) group than in non CIMP group. Log rank test results showed that patients with high CXCR4 methylation (first tertile) had significantly better 5 yrs OS (p = 0.038).Conclusion: CXCR4 expression is regulated by DNA methylation in GBM and its low expression or hypermethylation might indicate favorable OS in GBM patients.

Abstract 3283: Adjuvant therapy associated with improved survival in gall bladder cancer: A single institution retrospective study

Abstract Introduction: The survival outcome of resected gallbladder carcinoma remains poor. We conducted a retrospective study to examine factors affecting patient outcomes in resectable gallbladder carcinoma. Methods: We retrospectively collected data on patients treated at our institution between January 2005 and June 2015 from the electronic medical record using a standardized data collection tool. The univariate Cox proportional hazard model was used for evaluating predictors of overall survival. Kaplan-Meier method was used to compare time-to-events among subgroups and the p values were calculated by the log-rank method. Overall survival (OS) was defined as the time between surgery and death, or censored at the last follow-up date. Progression-free survival (PFS) was defined as the time to recurrence or death. Results: Of 67 evaluable patients, 65.7% were female. While clinical staging determined 51% to be stage 2 or less, interval portal lymphadenectomy and hepatic resection upstaged 20% to stage 3 or 4. Adjuvant chemotherapy (CT) was given to 18% and adjuvant chemoradiation (CRT) to 15%. About 46% did not receive any post-operative treatment and data was not available in 21%. On multivariate analysis, albumin &amp;lt; 3.5g/dl, LN involvement and pathological (p)Stage &amp;gt;2 were independent predictors of OS and PFS. Median 5 yrs OS and PFS of pstage &amp;lt; 2 was 54% and 54% respectively. Median 5 yr OS and PFS of stage ≥3 was 10.9% and 5.8% respectively. Adjuvant therapy was administered commonly for stage 3 and 4 (20 patients) compared to stage 1 and 2 (2 patients). In stage ≥3, adjuvant therapy improved OS (17.5% vs 8.9% for surgery alone) and PFS (12% vs 0%). Adjuvant chemoradiation for stage 3/4 had better median OS advantage compared to chemotherapy alone (54 m vs 15m, p=0.0008). Conclusion: The use of adjuvant treatment may improve long-term disease control in patients with node positive tumors. A significant difference between CRT and CT was demonstrated in our series and needs further validation in a larger cohort. Overall survial (OS) and progression-free survival (PFS) among various subgroupsGroup (n)Median OS (months)5 year OSMedian PFS (months)5 year PFSstage 1&amp;2 (21)NA54%NA54%stage 3&amp;4 (46)13.410.9%9.45.8%Surgery + Adjuvant treatment (22)25.115.9%16.910.9%Surgery alone (31)26.134.4%21.331.8%Surgery + CRT (10)54.235%45.724%Surgery + CT (12)14.90%13.40%Stage 3 and 4- Surgery + Adjuvant treatment (20)27.317.5%22.512%Stage 3 and 4- Surgery alone (15)2.78.9%2.10% Citation Format: Lakshminarayanan Nandagopal, Martin J. Heslin, John R. Porterfield, Rojymon Jacob, Peng Li, James Posey, Ravikumar Paluri. Adjuvant therapy associated with improved survival in gall bladder cancer: A single institution retrospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3283. doi:10.1158/1538-7445.AM2017-3283

Long term follow up of patients with locally advanced triple negative breast cancer treated with adjuvant high dose chemotherapy and autologous stem cell transplantation: A single center experience.

e12590 Background: Adjuvant high dose chemotherapy (HDC) with Autologous Hematopoietic Stem Cell Transplantation (AuSCT) as part treatment of high risk locally advanced breast cancer has remained controversial. Multiple trials reported disease free survival (DFS) without Overall survival (OS) resulting in its abandonment in early 2000s. However, post hoc analysis of these trials consistently reported DFS and OS benefit in young and triple negative breast cancer (TNBC) subgroups. This has not been re-evaluated till date. Recent European registry reports coupled with improved transplant related mortality (TRM) and still poor out-come of standard of care in TNBC subgroup has generated renewed interest. We report long term out-come of locally advanced high risk TNBC treated with HDC and AuSCT treated in Karmanos Cancer Institute from 1995 to 2001 Methods: Majority of the patients were treated with Adriamycin and Taxane based induction chemotherapy. Patients without evidence of metastatic disease proceeded to HDC and AuSCT using Carmustine 600mg/sqm Cyclophosphamide 5.6gm/sqm and Cisplatin 165mg/sqm (STAMP 1 regimen). This is followed with loco- regional radiation per protocol. Results: 72 hormone negative patients with Lymph Node(LN) &gt; 4 or inflammatory breast cancers were selected from 576 treated for advanced or metastatic breast cancer. 33 patients were TNB with HER2 status of 39 patients unknown. Median time from diagnosis to stem cell transplantation was 6 months. Median age at diagnosis was 47yrs. Mean LN involvement was 9 with 90% having (4-20) LN positivity. With median follow up of 16 years,10yrs DFS and OS were both 62.5%. Median follow up for DFS and OS was not reached.TRM was 9% mostly from pulmonary toxicity. Conclusions: This study of locally advanced high risk TNBC treated with adjuvant HDC and AuSCT have high 10yr OS of 62.5% compared to current standard of care. With the current improvement in TRM, reevaluation of this strategy through clinical trials in this subgroup whose outcome remain poor is reasonable.

Abstract P1-07-24: Increased risk of contralateral breast cancer after diagnosis of microscopically invasive breast cancer: SEER 1998-2012

Abstract Node negative microscopically invasive breast cancer (BC) is frequently associated with ductal carcinoma in situ (DCIS) and considered to have a similar prognosis. We evaluated women with T1micN0M0 (T1mic), DCIS and Stage I BC and report clinical characteristics, risk for subsequent contralateral breast cancer (CBC) and overall survival (OS). Methods: The study cohort included women diagnosed 1998-2012 and reported to Surveillance, Epidemiology, and End Result (SEER) data with DCIS, T1mic, or Stage I BC (not including T1mic). Subsequent CBCs were identified in patients with known laterality without contralateral mastectomy. Kaplan Meier models were used to estimate survival and time to CBC. Log-rank tests assessed differences in survival across groups Results: During the study period, 9,785 women were diagnosed with T1mic. Clinical features and risk of CBC are shown in the Table 1. Women with DCIS and T1mic were younger than those with Stage I BC. T1mic was more likely to be hormone receptor (HR) negative. Women with T1mic underwent mastectomy significantly more often than women with DCIS or Stage 1 BC. T1mic occurred more frequently in non-white women. Women with T1mic were significantly more likely to develop subsequent CBC than women with Stage 1 BC with a trend for increased CBC compared to women presenting initially with DCIS. Of those who develop CBCs 5.9% (DCIS), 11.2% (T1mic), and 14.6% (Stage 1) developed within 1 year (YR) of diagnosis of the index cancer. At 10 YRS these numbers were 73.7%(DCIS), 82.7%(T1mic) and 83.2% (Stage 1) (DCIS vs T1mic, p&amp;lt;0.001 T1mic vs Stage 1, P= 0.048). At 10 YRS OS for women with CBC after initial BC was 89.5%(DCIS), 86.6%(T1mic) and 84.3%(Stage1) (DCIS vs T1mic, p=0.077, T1mic vs Stage1 p=0.293), Table 2. Table 1 DCIS, T1mic, Stage I BC: Clinical Features and Contralateral Breast Cancer DCIST1micStage 1 (excluding T1mic) %%%p ^p ^^N49,6829,785248,307 Median Age5858620.719&amp;lt;0.001HR positive85.0%72.8%86.5%&amp;lt;0.001&amp;lt;0.001Grade Well-moderately differentiated56.3%61.1%76.6% Poorly-undifferentiated43.7%38.9%23.4%&amp;lt;0.001&amp;lt;0.001Mastectomy22.7%36.7%24.1%&amp;lt;0.001&amp;lt;0.001Race White79.7%77.3%84.2% Black10.8%11.0%7.9%&amp;lt;0.001&amp;lt;0.001Other9.4%11.6%7.9% CBC*4.1%4.3%3.4%0.317&amp;lt;0.001CBC**57.9%72.9%77.0%&amp;lt;0.0010.021* Portion of full sample, **Of those who had a subsequent BC (ipsilateral or contralateral),^ DCIS vs T1mic,^^ stage I vs T1mic Table 2 OS by Initial Stage and with CBC 5 YR10 YRp* OSOS DCISall97.3%88.4% develop CBC97.8%89.5%0.037T1micall96.3%88.9% develop CBC95.0%86.6%0.036Stage1 (excluding T1mic)all95.9%85.0% develop CBC86.9%84.3%0.001*Comparing survival of the stage cohort (all) with women diagnosed with that stage who develop CBC Conclusion: Women with T1mic were at increased risk for subsequent CBC relative to women with Stage I BC. When subsequent CBC occurred it developed earlier in women with T1mic than those with DCIS. Time course for this second event and survival with CBC at 10 years matched more closely with women diagnosed with Stage 1 BC. These findings offer suggestions about the biology of T1mic and may have implications for counseling these women on risk reducing strategies. Citation Format: Thomas A, Weigel RJ, Leone JP, Spanheimer PM, Schroeder MC. Increased risk of contralateral breast cancer after diagnosis of microscopically invasive breast cancer: SEER 1998-2012. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-24.

Autologous Hematopoietic Stem Cell Transplantation (AHSCT) in Severe Auto-Immune Disease Adult Patients: Analysis of Outcomes from the French Society for Bone Marrow Transplantation and Cellular Therapy (SFGMT-TC) in Light of the European Society for Blood and Marrow Transplantation (EBMT) Activity

IntroductionAutologous Hematopoietic Stem Cell transplantation (AHSCT) is used since 1994 worldwide to treat severe autoimmune disease (AD) refractory to standard therapy. Despite early release and regular update of the European Society for Blood and Marrow Transplantation (EBMT) practice guidelines (Snowden JA et al BMT 2012, Alexander T et al BMT 2014) along with 3 randomised Clinical trials (CTs) for Systemic Sclerosis (SSc) ASTIS, Crohn's Disease (CD) ASTIC and Multiple sclerosis (MS) ASTIMS, the uptake of this approach varies according to each ADs and between countries. We therefore design this retrospective study to evaluate patients (pts) outcomes as reported to the French Bone Marrow Transplantation Society registry (SFGMT-TC) in light of the other States activity published or reported to the EBMTregistry.Materials and methodsAll AHSCT for adult AD pts (> 18 years (yrs)) reported in France from 1997 to 2013 with at least one yr follow-up after AHSCT were included in the study. Primary data were derived from the EBMT registry (MED-A/B forms) with additional data obtained through a specific questionnaire (MED-C) for the study. Primary end point is overall survival (OS), defined as time since the day of transplant to death, irrespective of the cause. Secondary end points are Progression Free Survival (PFS), 100 day treatment related mortality (100-day TRM) and non-relapse related mortality (NRM). The probabilities were estimated using the Kaplan-Meier estimator for OS and PFS, cumulative incidence for NRM, relapse/progression being the competing event. All tests were two-sided. Statistical analyses were performed with IBM SPSS Statistics 22.0 and R version 3.1.2 (R Development Core Team, Vienna, Austria) software packages.Results96 adult pts (55% Female), median age 45 yrs [20-71], underwent a first AHSCT for ADs in 19 HSCT Units. Most of the ADs were rheumatological(72%) with 55 SSc, 7 polymyositis-dermatomyositis, 3 polychondritis, 2 Lupus Erythematosus, 1 Rheumatoid Arthritis (RA), 1 Ankylosing Spondylitis, or neurological (15%) with 14 MS, whereas the others were 5 CDs, 5 immune thrombocytopenic purpura, 1 hemolytic autoimmune anemia, 1 IgM neuropathy and 1 POEMS syndrome. Two pts had 2 simultaneous ADs (1 SSc and RA, 1 CD and RA). Median duration between AD diagnosis and AHSCT was 3.5 yrs [1-33]. With a median follow-up of 7 yrs [<1- 17], 5 yrs OS and PFS were 79.4% [95% CI: 70.8-88] and 49.3% [95% CI: 38.7-59.9] while 10 yrs OS and PFS were 70.2% [95% CI: 58.9-81.7] and 41.9 % [95% CI: 30.6-53.2], respectively. The 100 days NRM was 7.4% [95% CI: 3.2-13.9]. 5 and 10 yrs NRM was 9.6% [95% CI: 4.7-16.6] and 13.6% [95% CI: 6.9-22.7] respectively. At the end of follow-up, 28 pts (29%) had died, for whom the causes of death were: relapse or progression (n=12), AHSCT related cause (n=7 with 3 infections, 2 cardiac toxicity, 1 renal toxicity, 1 respiratory failure), secondary malignancies (n=3), aspiration pneumonia in polychondritis (n=1) or unknown causes (n= 5).ConclusionAHSCT for severe ADs, has progressively developed in France, allowing 5y OS equal to 79.4%, similar to UK (Snowden JA et al, BJH 2012) and EBMT data. In rapidly progressive severe SSc, where the proof of efficacy of AHSCT was obtained (Van Laar J and Farge D et al, JAMA 2014) and in MS (Pasquini MC et al BBMT 2010) where long-term responses are confirmed worldwide, the French and the EBMT registry activities have increased over the past 14 years, with sustained positive clinical results despite non negligible NMR, which remains lower than spontaneous AD evolution. Meanwhile, AHSCT activity has become exceptional in RA due to the availability of safe and effective biological therapies, and other indications remain rare, such as for CD or SLE where the risk of AHSCT in highly immunosuppressed patients has to be balanced with ADs severity. More than half of French pts were treated on an individual basis, outside CTs, underlying the need to evaluate national activity and to promote education of HSCT Unit members. At each French or other European state levels, like in the US, the indications for AHSCT in ADs remain low due to other competing therapies. Combined study using European and American data registry will allow analysis of a larger number of AD pts treated by AHSCT and would offer more clues to better understand the determinants of the response and to refine indications for each AD type. DisclosuresLeblond:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Mundipharma: Honoraria. Snowden:MSD: Consultancy, Other: Educational support, Speakers Bureau; Janssen: Other: Educational support, Speakers Bureau; Celgene: Other: Educational support, Speakers Bureau; Sanofi: Consultancy.

Long-Term Overall and Event-Free Survival after RIC Allogeneic Transplantation in Acute Leukemias in a Single Centre - Impact of Age and Donor Type?

BACKGROUND: Between January 2007 and December 2014, we transplanted 143 patients (Pts) using RIC- conditioning allogeneic transplant. 71 were transplanted for acute leukemias (AML and ALL) and high risk myelodysplastic syndromes (MDS) not eligible for myeloablative transplantation. Clinicians are usually scared to transplant older patients with MUD because of the higher risk of Treatment-related mortality (TRM). We thus reviewed retrospectively the impact of donor / recipient ages and donor-choice (familial related donor (RD) versus matched unrelated donors (MUD)) on the post-transplant outcome of the pts.POPULATION AND METHODS: We retrospectively studied in our cohort of 71 leukemia pts evaluable after RIC transplant, the overall survival (OS) and event-free survival (EFS), according to recipient ages (≤ 54yo vs ≥55yo) and donor types (RD vs MUD).Conditioning consisted of combinations of Busulfan-Fludarabin-ATG or Endoxan-Fludarabine-ATG. Immunosuppression was a combination of cyclosporine (CSA)/mycofenolate mofetil (MMF), Tacrolimus (TAC)/ MMF or TAC/ Sirolimus. Chimerism analyses were performed on d30, d90 and d180. Both study-groups were well balanced concerning transplant conditioning regimens, (ATG or not) RD vs MUD donors, type of leukemia and status of the disease at transplant. Our local EBMT database was the source for this analysis.RESULTS: 34 de novo AML (20 ≤54 yr and 14 ≥55 yr), 30 secondary AML and MDS (15 ≤54 yr and 15 ≥55 yr) and 7 ALL (5 ≤54 yr and 2 ≥55 yr) were enrolled in our trial. 24 pts received HLA identical RD in the group ≤54yr and 14 pts in the group ≥55 yr. The others pts received MUD transplant from HLA 9 or 10/10 donors (16 in the group ≤ 54yr and 17 in the group ≥ 55yr). The median follow-up was 22 (3-93) months. Engraftment rate was 100% in the studied cohort. TRM before d100 was 18,3% (15% ≤54 yo and 22,6% ≥ 55yo). Grade II-IV Acute GVHD (aGVHD) at d90 (16,6%) and Chronic GVHD rates (24%) were similar in both age populations. 5 yrs OS was not different according to the age of the recipient (≤54 yr versus ≥55 yr)(p = 0.9). However, there is a clear, difference in 5years OS when stratifying the two age groups according to donor-types, especially for older patients (≥55 yr) with MUD transplant. (pts ≤ 54yr : OS: RD: 31,6%; and MUD: 38%; pts ≥ 55yr : OS: RD: 27,8% and MUD 44,2%). This trend in a better OS in older MUD pts could be explained partially by a lower relapse-rate in the group ≥ 55 yr with a MUD as shown by EFS/5yrs (pts ≤ 54 yr : RD: 32%; ≤ 54yr MUD: 19%; pts ≥ 55yr RD: 21% and ≥ 55yr MUD 38,5 %). As reported already in transplanted CLL patients, this suggests a greater GVHD/GVL-effect in the MUD transplantation. We then further investigated the age of the donors and its correlation with aGVHD and cGVHD. In the RD RIC transplant group, median age of the donors was 49 yrs (range 35-69 years) with 37.5% of aGVHD and 42% of cGVHD. In the MUD RIC transplant cohort, donor median age was 31 yrs (20-55 years) with 12% of aGVHD and 32% of cGVHD. We previously reported that the number of CD8+ T cells and naïve CD4+ T cells decreases with the age of the donor, also supporting a better control of the disease with younger donors. This combination of younger donor age, lower aGVHD and a similar rate of cGVHD clearly explains the better outcome in pts transplanted with MUD. Our data requires confirmation in a larger series of patients.CONCLUSION: our observations confirm that: 1) RIC transplantation is a curative approach in acute leukemia whatever the age when the pts are fit enough to tolerate the transplant. 2) despite a higher TRM compared to younger patients, older patients seem to particularly benefit from MUD in terms of OS. 3) an increased EFS is observed in older pts transplanted with MUD (also younger) donors more likely due to a greater GVHD/GvL effect in the MUD setting. DisclosuresNo relevant conflicts of interest to declare.

IGHV Mutation Status Does Not Add Prognostic Information In The Background Of Mutations In TP53 and SF3B1, and Deletions Of 17p and 11q, Which Are Independent Adverse Prognostic Parameters In CLL

BackgroundIn CLL, the IGHV mutation status is an established prognostic marker. However, associations between the IGHV mutation status and other genetic markers have been reported. Based on genome sequencing data, novel recurrent mutations have been identified in CLL and first data on their prognostic impact is also available. AimsIn this study we addressed the following questions in a large cohort of 934 CLL patients: 1. Associations of IGHV mutation status with cytogenetic and molecular genetic markers 2. Age dependency of IGHV mutation status, cytogenetic and molecular mutations 3. Impact on survival. Patients and MethodsIn total, in 934 CLL patients the IGHV mutation status was determined. Median age was 66.8 years (range: 29.6 - 90.5 years). Further, all patients were analyzed by DNA sequencing for mutations in TP53, SF3B1, MYD88, XPO1, NOTCH1 and FBXW7 and by FISH for TP53 deletion status as well as for del(13q), del(11q) and +12. ResultsIn the entire cohort 550/934 (58.9%) patients showed a mutated and 384 (41.1%) an unmutated IGHV status. Molecular mutations were observed in the following frequencies: NOTCH1: 12.6%, SF3B1: 11.9%, TP53: 9.2%, XPO1: 4.0%, FBXW7: 2.6%, and MYD88: 1.7%. Patients showed deletions 13q in 58.7% (13q as the sole abnormality in 45.5%), trisomy 12 in 15.6%, 11q in 12.1%, and 17p in 5.8%, respectively. The following genetic aberrations were more frequent in CLL with unmutated vs mutated IGHV status: TP53mut (14.8% vs 5.3%), SF3B1mut (19.0% vs 6.9%), XPO1mut (9.1% vs 0.4%), NOTCH1mut (24.2% vs 4.5%), del(17p) (10.7% vs 2.4%), del(11q) (24.2% vs 3.6%), +12 (21.4% vs 11.6%) (for all p<0.001). In contrast, del(13q) (45.8% vs 67.6%), del(13q) sole (26.3% vs 58.9%) (for all p<0.001), and MYD88mut (0.3% vs 2.7%, p=0.004) were less frequent in CLL with unmutated IGHV status. No association between age and IGHV status was observed. With respect to all other analyzed markers only the frequency of TP53mut and del(17p) increased significantly with age. In univariate analysis the following parameters were significantly associated with shorter overall survival (OS): IGHV unmutated (HR: 2.0), age (≤70 vs >70 yrs: HR:3.4), TP53mut (HR: 3.8), SF3B1mut (HR: 2.3), del(17p) (HR: 6.2), del(11q) (HR: 2.3) (for all p<0.001), and NOTCH1mut (HR: 1.5, p=0.05), while del(13q) sole was associated with longer OS (HR: 0.6; p=0.003). In multivariate analysis the following parameters were independently associated with shorter OS: age (≤70 vs >70 yrs: HR: 3.1; p<0.001), TP53mut (HR: 2.0; p=0.018), SF3B1mut (HR: 2.1; p=0.001), del(17p) (HR: 3.6, p<0.001), del(11q) (HR: 2.1; p=0.005), while IGHV mutation status surprisingly did not show an independent impact on OS. Next we separated the cohort according to the number of adverse prognostic markers TP53mut, SF3B1mut, del(11q), and del(17p) (group A: 0 marker (n=658), group B: 1 marker (n=197), group C: 2 or more markers with alterations (n=78)). Kaplan-Meier-analysis revealed a 5 yrs OS of 89.5% in group A, of 71.3% in group B and of 37.4% in group C (for all comparisons p<0.001). Neither within groups A, B nor within group C did the IGHV mutation status have an impact on OS. On the other hand, OS at 5 yrs differed significantly according to the group within patients with either mutated IGHV or unmutated IGHV status (mutated IGHV status: group A (n=467) 90.6%, group B (n=67) 73.7% and group C (n=16) 47.2%; A vs B: p=0.031; B vs C: p=0.022; unmutated IGHV status: group A (n=191) 86.8%, group B (n=130) 69.6% and group C (n=62) 35.8%; A vs B: p=0.006; B vs C: p<0.001). Interestingly, a significant association between a higher number of adverse prognostic markers and age was observed (p=0.019). Further we performed multivariate analysis with the number of adverse prognostic factors (TP53mut, SF3B1mut, del(11q), del(17p): 0 markers to 4 markers positive) and age per decade. Both parameters were independently associated with OS (HR: 2.3 per adverse marker positive and HR: 1.7 per decade, for both p<0.001). Conclusions1. Several adverse prognostic markers (TP53mut, SF3B1mut, NOTCH1, del(17p), del(11q)) were associated with an unmutated IGHV status. 2. However, in the background of the genetic markers TP53mut, SF3B1mut, del(11q), or del(17p) IGHV status lost its independent prognostic impact. 3. An accumulation of adverse prognostic markers worsens prognosis in CLL. Disclosures:Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Jeromin:MLL Munich Leukemia Laboratory: Employment. Weissmann:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Results of upfront therapy for marginal zone lymphoma (MZL).

e19510 Background: MZL is an indolent NHL composed of 3 subtypes: extranodal (MALT), splenic marginal zone (SMZL) and nodal marginal zone (NML). While MALT usually presents with early stage, the others frequently present with advanced disease. Early stage MALT is usually treated with XRT or antibiotics with ~85-90% failure free survival (FFS) and overall survival (OS), while for SMZL watch and wait or splenectomy (Spl) have been the mainstay of therapy. Spl leads to improvement but rarely to CR. 5 yr FFS and OS with Spl have been 45% and 80%. At 10 yrs FFS and OS are 22% and 62%. NML is usually managed with watch and wait. The 5 yr FFS and OS for NML have been 30% and 60%. Watch and wait and Spl are used in part because advanced MZL is considered incurable. Rituximab (R) as well fludarabine (F) are active in this disorder but traditionally are given after relapse. Methods: Instead of watch and wait or Spl, we have used upfront chemo with curative intent for SMZL and NML as well as for advanced MALT. For early stage MALT we used either XRT alone or antibiotics. We hereby report on 44 pts with MZL of which 31 were MALT, 9 SMZL, 4 NMZL. For the purpose of analysis we divided the pts in 2 groups. Group 1 consists of 22 early stage MALT who were all treated with either XRT (N=17) or antibiotics +/- surgery (N=5). Group 2 consists of 22 cases who were treated with chemo alone. This group is made up of 9 MALT (4 advanced stage, 3 early stage but with transformation, 2 early stage but in whom XRT was contraindicated), 9 advanced stage SMZL, 4 NML. Chemo for group 2 consisted of F, mitoxantrone, dexamethasone, rituximab (FND-R) (N=14) or R-CHOP (N=8). Maintenance R was used in 70% of group 2. Results: Of the whole group, 100% were CR and only 2 relapsed at 70 and 75 months; both relapses were stage I MALT and had received XRT only. Both were salvaged with FND-R and remain NED 27 and 39 months from relapse. At 10 yrs, FFS was 80% and OS=100%. None of the 22 in group 2 have relapsed. The long-term toxicity has been acceptable. Conclusions: The excellent FFS and OS using upfront chemotherapy in group 2, suggests that this disorder is curable and our results should be confirmed in a prospective trial. For those with early stage MALT, XRT alone +/- antibiotics and when necessary salvage with FND-R, should be tested.

Serum Soluble Interleukin-2 Level Determines Clinical Outcome In Patients with Follicular Lymphoma In Rituximab Era

AbstractAbstract 3106 Introduction:Follicular Lymphoma (FL) is usually characterized by an indolent clinical course with a median overall survival (OS) ranging between 7 and 8 years before Rituximab (R) era. However, a minority of patients(pts) has rapidly progressive disease and in some cases histological transformation to high-grade lymphoma may occur. Recent large cohort studies suggested improved outcomes for pts treated in the last decade, First-line chemotherapy including R may produce excellent responses in pts with advanced FL, but most of pts invariably relapse even in R era. Early recognition of pts with poor prognosis is necessary to decide management and treatment of patients with FL. Some investigators have suggested that serum levels of cytokines and their soluble receptors might reflect tumor growth and host tumor responses. We have previously that soluble interleukin-2 receptor (sIL2-R) is a strong prognostic factor in aggressive lymphoma pts who received CHOP. In addition, we reported that sIL2R was a powerful tool which can discriminate favorable group from unfavorable group in diffuse large B-cell lymphoma pts who received R-CHOP. SIL-2R is a soluble form of interleukin-2 receptor (IL-2R). IL-2R is expressed on the cell membrane of lymphocytes and plays important roles in their activation and proliferation. The sIL-2Ra chain is induced and expressed only after mononuclear cell (T cell, B cell, monocyte, and natural killer cell) activation. Therefore, activated T and B cells have elevated levels of sIL-2R. Purpose:The aim of the present study is to assess the prognostic significance of serum sIL2-R in follicular lymphoma, especially in R era. Patients:We enrolled total 94 pts with FL (including FL grade 1, 2, 3a). Twenty-three of 94 pts enrolled between Septenber1986 and November 2001 (group A: without R), and 71 between July 1999 and June 2009 (group B: with R). The group A pts received 6 cycles of CHOP and the group B pts six cycles of R-CHOP. Results:The median serum sIL2-R levels were 1320 (range 475– 8120) U/ml and 2407 (range 320–1690) U/ml in groups A and B, respectively. In group B pts who treated with R-CHOP, various poor prognostic features such as elevated LDH (p = 0.0001), Hb <12g/L (p=0.0009), advanced clinical stage (p = 0.0005) and involved nodal areas > 4 (p = 0.0385) were significantly associated with a high serum sIL2-R level. In group B, the median (range) serum sIL2-R levels of each FLIPI risk group were 651 (320–8120) U/ml in low risk group, 2677 (538– 5305) in intermediate risk group, 2935 (419–16900) in high risk group (p < 0.0001). The 10-years (yrs) OS rates for patients in group A with sIL2-R < 2000 U/ml and ≥ 2000 U/ml were 75.0% and 29.2%, respectively (p < 0.002). The 10-yrs PFS rates for pts in group A with sIL2-R < 2000 U/ml and ≥ 2000 U/ml were 22.9% and 15.2%, respectively (p < 0.05). The 5-yrs OS rates for pts with sIL2-R < 2000 U/ml and ≥ 2000 U/ml were 100 and 73.4%, respectively (p < 0.05) in group B. The 5-yrs PFS rates for pts in group B with sIL2-R < 2000 U/ml and ≥ 2000 U/ml were 80.3% and 44.3%, respectively (p < 0.001). Multivariate analysis in group B employing sIL2-R and some conventional prognostic factors demonstrated that sIL2-R for OS and for PFS was an only independent poor prognostic factor (OS; p=0.016, PFS p=0.0002, respetively). The results suggest that a high serum sIL2-R level predicts a poor prognosis in FL and may be a useful biomarker for selecting appropriate treatment. Conclusion:Serum sIL2-R might be a powerful tool which can discriminate the prognosis for pts with FL. Long term follow up with many pts should be considered to confirm clinical usefulness of sIL2-R in pts with FL of R era. Disclosures:No relevant conflicts of interest to declare.