Risk Of Early Relapse Research Articles

AML-396 Venetoclax-Containing Regimens Improve Outcomes of Intensive Treatment and Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Extramedullary Acute Myeloid Leukemia

The optimal treatment strategy for patients with extramedullary acute myeloid leukemia (eAML) is questionable, especially as applied to extramedullary tumor persistence while bone marrow response is achieved. To determine whether venetoclax-containing regimens, intensive treatment, and allogeneic hematopoietic stem cell transplantation (alloHSCT) can improve outcomes in patients with eAML. Overall, 27 patients with verified eAML were included: 14 were male and 13 were female with a median age of 40 years (13-84). Standard ("7+3"), high-intensity ("HiDAC", "FLAG±Ida"), and low-intensity chemotherapy regimens were administered to all patients. Ten patients (37%) received venetoclax with 5-azacytidine (VEN-AZA) because of comorbidities or refractory disease. AlloHSCT was performed in 17 patients (63%). According to the 2017 ELN risk stratification system, 18.5% (5/27) were favorable risk, 25.9% (7/27) were intermediate risk, and 55.6% (15/27) were adverse risk. Patients with favorable genetic alterations achieved bone marrow remission more frequently (100% vs. 44%, P=0.044) but did not have advantages in the rate of complete extramedullary response (75% vs. 68%, P>0.05). Using HiDAC enabled eradication of extramedullary lesions in case of failure of standard and low-intensity regimens (85% vs. 0%, P=0.044) and decreased the rate of early (during the first 12 months) relapse (38% vs. 100%, P=0.019). The overall response rate to VEN-AZA was 70% (7/10). Five patients (50%) achieved complete eradication of extramedullary tumor after venetoclax; among them, 3 still had persistent extramedullary disease after HiDAC. Performing alloHSCT in first complete remission decreased the risk of early relapse (12% vs. 80%, P=0.015) and demonstrated better median overall survival (38.85 vs. 7.57 months, P=0.013) and relapse-free survival (38.85 vs. 3.78 months, P=0.0021) compared to alloHSCT performed in second and subsequent complete remissions. Favorable genetic aberrations do not increase the frequency of extramedullary response. Intensive treatment helps to achieve complete eradication of extramedullary tumor and reduces early relapse rate. Using VEN-AZA is effective among patients with eAML, including patients who were refractory to intensive treatment, and allows complete response achievement before alloHSCT. The best time to perform the alloHSCT among patients with eAML is the first complete remission.

Sequential rituximab therapy sustains remission of nephrotic syndrome but carries high risk of adverse effects.

Sequential rituximab (RTX) administration has emerged as an important strategy to sustain remission of disease in patients with difficult-to-treat nephrotic syndrome. We report the efficacy and safety of sequential therapy with two or more courses of intravenous RTX in 250 patients with difficult-to-treat steroid dependence (n=127) and calcineurin inhibitor (CNI)-dependent or CNI-refractory steroid resistance (n=123) managed at one center during 2015-2021. Subsets of patients were cross-sectionally tested for hypogammaglobulinemia, seroprotection against and hyporesponsiveness to vaccines for hepatitis B and tetanus, BK/JC viruria and human antichimeric antibodies (HACAs). Sequential RTX therapy, initiated at a median of 10years [interquartile range (IQR) 7.3-14.4], was administered for 1.8courses/person-year [95% confidence interval (CI) 1.7-2.0] over 2.0years (95% CI 1.2-3.0). Therapy was associated with postponement of relapses by a median of 3years in patients with steroid-sensitive disease and 2years in those with steroid resistance. Relapses were reduced by a mean of 2.0relapses/person-year (95% CI 1.8-2.2), enabling a reduction in prednisolone dose to 0.04mg/kg/day (95% CI 0.01-0.11) and withdrawal of additional immunosuppression in 154 (62%) patients. RTX-associated adverse events, occurring at 0.20events/person-year (95% CI 0.17-0.23), were chiefly comprised of infusion reactions (n=108) and infections (n=46); serious adverse events were observed in 10.8% patients, at 0.03events/person-year (95% CI 0.02-0.05). Hypogammaglobulinemia was observed in 35% of 177 patients and was moderate to severe in 8.5% of cases. Rates of seroprotection at baseline and response following vaccination were lower for hepatitis B [1.9% and 29.4% (n=52)] than tetanus [65.5% and 34.5% (n=58)]. BK/JC viruria, without viremia, was observed in 7.3% of 109 cases. A total of 19 of 107 patients (17.8%) had HACAs, which were associated with B cell nondepletion and serum sickness. Age at therapy of <9-10years was associated with a risk of early relapse, treatment failure and hypogammaglobulinemia following RTX therapy. Sequential therapy with RTX effectively reduces relapses in patients with difficult-to-treat steroid- and/or CNI-dependent or CNI-refractory nephrotic syndrome. Therapy is associated with high rates of hypogammaglobulinemia and infusion reactions.

P442: SPINK2 PROTEIN EXPRESSION QUANTIFIED BY IMMUNOHISTOCHEMISTRY REFINES RISK STRATIFICATION AND PREDICTS THERAPY OUTCOMES IN AML

Background: Suboptimal prognostication, therapy refractoriness and relapse contribute to the poor outcome of Acute Myeloid Leukemia (AML) patients. Leukemic stem cells (LSC) are considered crucial drivers of relapse and therapy resistance. Clinicopathological characterization of LSC-associated genes with convenient assessment tools such as immunohistochemistry (IHC) is needed. Our initial screening of AML datasets for LSC-associated genes identified Serine Protease Inhibitor Kazal type 2 (SPINK2) with high expression in AML, particularly in LSC fractions. However, in-depth analysis of its clinicopathological associations and prognostic utility in AML are lacking. Aims: To assess SPINK2 expression in adult AML with IHC, and determine its clinicopathological associations, prognostic impact and association with therapy response Methods: We studied the expression of SPINK2 by IHC in 172 non-M3 adult AML patients (median age:52yrs, range: 18-86yrs) treated at the Prince of Wales Hospital. The majority (90.8%) were de novo type and 72.3% had intermediate-risk(IR) cytogenetics, with 88.5% receiving Daunorubicin + Ara-C (DA 7 + 3) induction. SPINK2 expression was assessed by 3 hematopathologists in a double-blinded manner and quantified by a composite score (range: 0-16). Clinical data was collected for all cases. Results:SPINK2 staining in leukemic blasts was consistently cytoplasmic, and its protein expression strongly correlated with mRNA levels by qPCR in a subset of 128 patients (r=0.716, P<0.0001). The cohort was dichotomized at the median score 3, since this cut-off showed strongest association with poor event-free survival (EFS) and overall survival (OS). High SPINK2 (SPINK2hi) patients accounted for 77/172 (44.8%) cases, and low SPINK2 (SPINK2lo) patients for 95/172(55.2%). SPINK2hi associated with IR cytogenetics (P=0.014), normal karyotype (P=0.019) and NPM1 mutation (P<0.001), while SPINK2lo with t(8;21) and CEBPA double-mutation (both P<0.001). Survival and treatment-response analyses were performed on a subgroup of 137 patients who received DA 7 + 3 based induction. SPINK2hi patients had lower CR rates (73.8% vs 88.3%,P=0.028), higher 6-month relapse rates (31.8% vs 9.1%,P=0.004), lower 5-yr RFS (25.8% vs 46.8%,P=0.004), EFS (16.6% vs 37.2%,P<0.001) and OS (25.3% vs 51.2%,P<0.001). SPINK2 status also identified high risk patients of the IR cytogenetic subgroup. Of these, SPINK2hi patients had lower CR rates (68.6% vs 90.0%,P=0.013), higher 6-month relapse rates (31.4% vs 6.9%,P=0.018), lower 5-yr RFS(27.0% vs 44.6%,P=0.018), EFS(15.4% vs 38.3%,P<0.001) and OS(22.9% vs 51.5%,P=0.002). In this subgroup, median SPINK2 score was higher in patients requiring ≥2 inductions to achieve CR vs. patients requiring 1 course (7 vs 2,P=0.009). Multivariate analyses in whole and IR cytogenetics cohorts showed the poor prognostic effect of SPINK2hi on EFS and OS independent of age, cytogenetic risk, mutations and achievement of CR1, including stem cell transplantation given in CR (Table 1). In our NPM1mut subgroup (N=41), SPINK2hi status associated with poor EFS (HR:3.3,P=0.04) and OS (HR: 4.0,P=0.007) independent of age and FLT3-ITD with high allelic ratio. Incorporation of SPINK2 with FLT3 status refined ELN2017 risk definition, whereby 15/22 favorable-risk patients could be reclassified as intermediate-risk. Image:Summary/Conclusion: High SPINK2 protein expression by IHC predicted increased chemoresistance and early relapse risk in AML, and was an independent adverse prognostic biomarker, particularly in patients with intermediate-risk cytogenetics and NPM1 mutations.

T-cell lymphoblastic leukaemia: The Johannesburg state-sector experience

Background: T-cell lymphoblastic leukaemia (T-ALL) is a malignancy of immature T-cells which is reported to comprise 7% – 23% of cases of lymphoblastic leukaemia (ALL), making up a larger proportion of adult ALL than childhood cases. It is characterised by an increased risk for early relapse but reportedly has superior outcomes as compared to B-cell ALL amongst adult patients. The frequency and clinical behaviour of T-ALL in Africa are unknown.Aim: This study aimed to assess the prevalence and selected clinicopathological features of T-ALL in Johannesburg, South Africa (SA).Setting: The Johannesburg state sector.Methods: All cases of ALL diagnosed by flow cytometry in the state-sector hospitals of Johannesburg over 42 months between 2016 and 2019 were identified and pertinent data recorded from the laboratory information system.Results: One hundred and eighty-one cases of ALL were identified, of which 59 (32.6%) were of T-cell lineage. The proportion of adult and paediatric ALL made up by T-ALL was similar (19/54 [35.2%] vs 40/127 [31.5%] respectively). Crude survival rates were very poor, with 80.0% having demised at the time of data collection. The mortality rate was overall significantly poorer amongst patients with T-ALL (80.0%) as compared to those with B-ALL (53.8%; p = 0.005) but was similarly poor in adults with B-ALL (83.3%) vs T-ALL (86.7%) (p = 0.53). The mortality rate did not differ between those with low-risk versus high-risk clinical features (77.8% vs 80.6%; p = 1.00).Conclusion: T-cell lymphoblastic leukaemia makes up a larger proportion of ALL in Johannesburg than is reported elsewhere, and it is a high-risk disease that is not well stratified by conventional risk factors.

A single-arm, phase 2 study of perioperative ipilimumab, nivolumab, and cryoablation in women with hormone receptor-negative, HER2-negative, early-stage/resectable breast cancer.

TPS617 Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with checkpoint inhibition augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ipilimumab (ipi) +/- nivolumab (nivo) was not only safe in patients (pts) with operable, early stage breast cancer (ESBC) but also generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ipi/nivo/cryo in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible pts are ≥18y, with ER &lt; 10%, PR &lt; 10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Approximately 80 pts will be enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and will receive ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts will receive 3 additional doses of nivo at 240mg IV Q2 weeks. Adjuvant capecitabine is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Clinical trial information: NCT03546686.

A Clinical-Radiomics Nomogram Based on the Apparent Diffusion Coefficient (ADC) for Individualized Prediction of the Risk of Early Relapse in Advanced Sinonasal Squamous Cell Carcinoma: A 2-Year Follow-Up Study

PurposeTo develop and validate a nomogram model combining radiomic features and clinical characteristics to preoperatively predict the risk of early relapse (ER) in advanced sinonasal squamous cell carcinomas (SNSCCs).MethodsA total of 152 SNSCC patients (clinical stage III-IV) who underwent diffusion-weighted imaging (DWI) were included in this study. The training cohort included 106 patients assessed at the headquarters of our hospital using MR scanner 1. The testing cohort included 46 patients assessed at the branch of our hospital using MR scanner 2. Least absolute shrinkage and selection operator (LASSO) regression was applied for feature selection and radiomic signature (radscore) construction. Multivariable logistic regression analysis was applied to identify independent predictors. The performance of the model was evaluated using the area under the receiver operating characteristic curve (AUC), calibration curve and decision curve analysis (DCA). Furthermore, the patients were classified into high- or low-risk ER subgroups according to the optimal cutoff value of the nomogram using X-tile. The recurrence-free survival probability (RFS) of each subgroup was assessed.ResultsER was noted in 69 patients. The radscore included 8 selected radiomic features. The radscore, T stage and surgical margin were independent predictors. The nomogram showed better performance (AUC = 0.92) than either the radscore or the clinical factors in the training cohort (P < 0.050). In the testing cohort, the nomogram showed better performance (AUC = 0.92) than the clinical factors (P = 0.016) and tended to show better performance than the radscore (P = 0.177). The nomogram demonstrated good calibration and clinical utility. Kaplan-Meier analysis showed that the 2-year RFS rate for low-risk patients was significantly greater than that for high-risk patients in both the training and testing cohorts (P < 0.001).ConclusionsThe ADC-based radiomic nomogram model is potentially useful in predicting the risk of ER in advanced SNSCCs.

Validation of MiROvaR, a microRNA-based predictor of early relapse in early stage epithelial ovarian cancer as a new strategy to optimise patients' prognostic assessment

AimEarly-stage epithelial ovarian cancer (eEOC) patients have a generally favorable prognosis but unpredictable recurrence. Accurate prediction of risk of relapse is still a major concern, essentially to avoid overtreatment. Our robust tissue-based miRNA signature named MiROvaR, predicting early EOC recurrence in mostly advanced-stage EOC patients, is here challenged in an independent cohort to extend its classifying ability in the early-stage EOC setting. MethodsWe retrospectively selected patients who underwent comprehensive surgical staging at our institution including stages from IA to IIB. miRNA expression profile was analysed in 89 cases and MiROvaR algorithm was applied using the previously validated cut-off for patients' classification. The primary endpoint was progression-free survival (PFS) at 5 years. Complete follow-up time (median = 112 months) was also considered as secondary analysis. ResultsMiROvaR was assessable on 87 cases (19 events of disease progression) and classified 68 (78%) low-risk and 19 (22%) high-risk patients. Recurrence rate at primary end-point was 39% for high-risk patients as compared to 9.5% for low-risk ones. Accordingly, their Kaplan–Meier PFS curves were significantly different at both primary and secondary analysis (p = 0.0006 and p = 0.03, respectively). While none of the prominent clinical variables had prognostic relevance, MiROvaR significantly predicted disease recurrence at the 5-year assessment (primary endpoint analysis; HR:5.43, 95%CI:1.82–16.1, p = 0.0024; AUC = 0.78, 95%CI:0.53–0.82) and at complete follow-up time (HR:2.67, 95%CI:1.04–6.8, p = 0.041; AUC:0.68, 95%CI:0.52–0.82). ConclusionsWe validated MiROvaR performance in identifying at diagnosis eEOC patients' at higher risk of early relapse thus enabling selection of the most effective therapeutic approach.

Residual Monoclonal Free Light Chain Positivity By Mass Spectrometry Identifies Patients at Increased Risk of Early Relapse Following First-Line Anti-Myeloma Treatment

Residual Monoclonal Free Light Chain Positivity By Mass Spectrometry Identifies Patients at Increased Risk of Early Relapse Following First-Line Anti-Myeloma Treatment

Prognostic Factors for Early (5 years) Relapse in Multiple Myeloma- Pivotal Role of Cytogenetic Changes

Prognostic Factors for Early (<2 years) and Late (>5 years) Relapse in Multiple Myeloma- Pivotal Role of Cytogenetic Changes

Sustained Residual Disease Negativity Assessed By Diffusion-Weighted Whole-Body MRI (DW-MRI) Has Strong Predictive Relevance for Survival in Newly Diagnosed Multiple Myeloma Patients on Maintenance Therapy after Autologous Stem Cell Transplantation (ASCT)

Sustained Residual Disease Negativity Assessed By Diffusion-Weighted Whole-Body MRI (DW-MRI) Has Strong Predictive Relevance for Survival in Newly Diagnosed Multiple Myeloma Patients on Maintenance Therapy after Autologous Stem Cell Transplantation (ASCT)

A Novel Early Relapse Prediction Score Based on Age, ISS and Disease Status at the Time of Transplant in Patients with Newly Diagnosed Multiple Myeloma. a Study of the EBMT Chronic Malignancies Working Party

A Novel Early Relapse Prediction Score Based on Age, ISS and Disease Status at the Time of Transplant in Patients with Newly Diagnosed Multiple Myeloma. a Study of the EBMT Chronic Malignancies Working Party

Clinicopathologic predictors of early relapse in advanced epithelial ovarian cancer: development of prediction models using nationwide data

ObjectiveTo identify clinicopathologic factors predictive of early relapse (platinum-free interval (PFI) of ≤6 months) in advanced epithelial ovarian cancer (EOC) in first-line treatment, and to develop and internally validate risk prediction models for early relapse. MethodsAll consecutive patients diagnosed with advanced stage EOC between 01-01-2008 and 31-12-2015 were identified from the Netherlands Cancer Registry. Patients who underwent cytoreductive surgery and platinum-based chemotherapy as initial EOC treatment were selected. Two prediction models, i.e. pretreatment and postoperative, were developed. Candidate predictors of early relapse were fitted into multivariable logistic regression models. Model performance was assessed on calibration and discrimination. Internal validation was performed through bootstrapping to correct for model optimism. ResultsA total of 4,557 advanced EOC patients were identified, including 1,302 early relapsers and 3,171 late or non-relapsers. Early relapsers were more likely to have FIGO stage IV, mucinous or clear cell type EOC, ascites, >1 cm residual disease, and to have undergone NACT-ICS. The final pretreatment model demonstrated subpar model performance (AUC = 0.64 [95 %-CI 0.62−0.66]). The final postoperative model based on age, FIGO stage, pretreatment CA-125 level, histologic subtype, presence of ascites, treatment approach, and residual disease after debulking, demonstrated adequate model performance (AUC = 0.72 [95 %-CI 0.71−0.74]). Bootstrap validation revealed minimal optimism of the final postoperative model. ConclusionA (postoperative) discriminative model has been developed and presented online that predicts the risk of early relapse in advanced EOC patients. Although external validation is still required, this prediction model can support patient counselling in daily clinical practice.

AML-097: Impact of Genetic Alterations and Types of Chemotherapy on Outcomes of Patients with Extramedullary Acute Myeloid Leukemia and Myeloid Sarcoma: A Single-Center Experience

<h3>Context:</h3> Extramedullary acute myeloid leukemia (eAML) and myeloid sarcoma (MS) is a very rare condition characterized by the proliferation of immature blasts in extramedullary sites. Nowadays, such relevant questions as the prognostic impact of genetic alterations among patients, choosing the optimal treatment strategy, the role of radiation therapy (RT), and allogeneic bone marrow transplantation (alloBMT) are discussed. <h3>Objective:</h3> To identify the prognostic importance of genetic aberrations and different types of therapy among patients with eAML. <h3>Patients:</h3> The study included 23 eAML/MS patients: 12 males and 11 females, with an age range of 13 to 78 years (median 38 years). They were classified according to the WHO criteria. All patients received chemotherapy with standard ("7+3"), high ("HiDAC", "FLAG+/-Ida"), and low intensity, with or without RT. AlloBMT was performed in 17 patients (74%). <h3>Results:</h3> 20 patients (87%) had extramedullary lesions at the onset of the disease, and 3 patients had an extramedullary relapse of AML. Isolated MS was verified in 3 patients (17%). The most common sites were lymph nodes (21%), soft tissues (17%), bones (11%), and reproductive system (11%). 57% (13/23) of patients had multiorgan involvement. 17% (4/23), 26% (6/23), and 57% (13/23) of the patients were attributed to favorable, intermediate, and adverse risk categories, respectively. There were no significant correlations between ELN-2017 risk stratification and CR rates and frequency of early (during the first 12 months) relapse (p>0.05). Most of the patients with bone marrow involvement achieved CR (78%, 14/18), of whom 71% (10/14) achieved CR only after more than 2 cycles of chemotherapy, mostly because of persistent extramedullary disease (60%, 6/10). Using HiDAC in consolidation therapy significantly decreased the rate of early relapse (38% <i>vs</i> 100%, p=0.019). RT addition did not impact outcomes (p>0.05). The patients who received alloBMT at first CR had a lower risk of early relapse (12% <i>vs</i> 80%, p=0.015). <h3>Conclusion:</h3> The ELN-2017 stratification risk group does not influence the outcomes of patients with eAML/MS. Using HiDAC in consolidation therapy reduces the early relapse rate. The best time to perform the alloBMT among patients with eAML/MS is the first CR.

Early Relapse in First-Line Follicular Lymphoma: A Review of the Clinical Implications and Available Mitigation and Management Strategies.

Chemoimmunotherapy with rituximab (R-chemo) or obinutuzumab (G-chemo) is standard of care for patients with previously untreated symptomatic or high-tumor-burden follicular lymphoma. Median progression-free survival (PFS) with R-chemo plus R maintenance exceeds 10 years, and G-chemo plus G maintenance improves PFS relative to the corresponding R-containing regimen. Despite these positive results, a sizable proportion of patients continue to progress during or shortly after initial treatment. While no single definition of early relapse has been established, progression of disease within 24 months of initial treatment (POD24) is now widely accepted as a critical adverse prognostic factor. Multiple studies have shown increased mortality risk in patients with POD24 versus those without POD24. Unfortunately, tools for the assessment of POD24 risk are suboptimal, and it is not currently possible in clinical practice to identify individual patients who are at increased risk for early relapse. Treatment strategies for patients with POD24 are not well defined. G-chemo regimens appear to reduce the risk of POD24 relative to R-chemo regimens, although the impact on survival outcomes remains unclear. Beyond standard therapy, autologous stem cell transplant and emerging treatment modalities, such as bispecific antibodies and chimeric antigen receptor T-cells, may have a role in future management. Until standard treatments are defined, mitigating the risk of early relapse with effective up-front treatment remains the priority.

A tumor microenvironment-related mRNA-ncRNA signature for prediction early relapse and chemotherapeutic sensitivity in early-stage lung adenocarcinoma.

Postoperative early relapse of early-stage lung adenocarcinoma is implicated in poor prognosis. The purpose of our study was to develop an integrated mRNA and non-coding RNA (ncRNA) signature to identify patients at high risk of early relapse in stage I-II lung adenocarcinoma who underwent complete resection. Early-stage lung adenocarcinoma data from Gene Expression Omnibus database were divided into training set and testing set. Propensity score matching analysis was performed between patients in early relapse group and long-term nonrelapse group from training set. Transcriptome analysis, random survival forest and LASSO Cox regression model were used to build an early relapse-related multigene signature. The robustness of the signature was evaluated in testing set and RNA-Seq dataset from The Cancer Genome Atlas (TCGA). The chemotherapy sensitivity, tumor microenvironment and mutation landscape related to the signature were explored using bioinformatics analysis. Twelve mRNAs and one ncRNA were selected. The multigene signature achieved a strong power for early relapse prediction in training set (HR 3.19, 95% CI 2.16-4.72, P < 0.001) and testing set (HR 2.91, 95% CI 1.63-5.20, P = 0.002). Decision curve analyses revealed that the signature had a good clinical usefulness. Groups divided by the signature exhibited different chemotherapy sensitivity, tumor microenvironment characteristics and mutation landscapes. Our results indicated that the integrated mRNA-ncRNA signature may be an innovative biomarker to predict early relapse of early-stage lung adenocarcinoma, and may provide more effective treatment strategies.

Reproducibility of m7-FLIPI Risk Scores in Follicular Lymphoma Using Tumor Biopsies and Blood Specimens

Background: Follicular lymphoma (FL) is clinically and genetically heterogeneous. While most patients experience an indolent disease course, with median survival of over 15 years, a portion of patients experience early relapse and poor outcomes. The m7-FLIPI risk score has been described as a clinicogenetic method to accurately determine which patients are at highest risk for early relapse and poor outcomes (Pastore et al., Lancet Oncology 2015; Vindi et al., Blood 2015). However, molecular characterization of the m7 genes currently relies on tumor biopsies, which require an invasive procedure and may be unavailable. Furthermore, it is unclear whether the m7-FLIPI score is consistent over the course of disease. Circulating tumor DNA (ctDNA) is an emerging noninvasive biomarker for tumor detection in diverse lymphomas including FL. In this study, we evaluated the stability of m7-FLIPI status over multiple FL relapses as well as the utility of ctDNA for classification of patients with FL into high- and low-risk m7-FLIPI categories.Methods: We applied Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq), a capture-based method for ultra-deep sequencing (Newman et al., Nat Med 2014; Scherer et al., Sci Transl Med 2016 ) to identify risk via m7-FLIPI in pretreatment tumor and plasma samples of 29 FL patients. In addition, we retrospectively analyzed whole exome sequencing (WES) data of 37 patients from two FL cohorts (Green et al., PNAS 2015; Bouska et al., Leukemia 2017). We first validated in silico our capture-based method for identification of m7-FLIPI-relevant somatic alterations in 258 patients from the original publication (Pastore et al., Lancet Oncology 2015). We then identified non-synonymous mutations in CREBBP, EZH2, ARID1A, MEF2B, FOXO1, EP300, and CARD11 presentin each tumor and plasma sample. Using both CAPP-Seq and WES data (n = 66), we compared m7-FLIPI risk group concordance between paired diagnostic tumor biopsies, paired diagnostic and relapse tumor biopsies, paired FL and transformed FL (tFL) tumor biopsies, and paired diagnostic tumor and plasma samples. FLIPI was calculated at first FL time-point available.Results: We observed a 95% agreement in m7-FLIPI risk category between our capture-based method and methods utilizing full exon coverage. A 100% concordance of m7 gene profile and 100% concordance of m7-FLIPI risk category were seen when comparing paired FL tumor biopsy samples from two separate lymph nodes obtained at diagnosis (n = 5). In addition, a 75% agreement in m7 gene profile and 100% agreement of m7-FLIPI risk category were observed when comparing tumor biopsy samples obtained at FL diagnosis and first relapse (n = 36; median time to relapse of 547 days, range 55 - 4200 days). There was a low concordance in m7 genetic profile between tumor biopsy samples from time of initial diagnosis and transformation (48.4%, n = 31). Importantly, concordance of m7 gene profile and m7-FLIPI risk category was 64.3% and 78.6%, respectively, when assessed by paired tumor and plasma samples obtained at FL diagnosis (n = 14; Figure 1). Furthermore, non-concordant mutations could be present in either the tumor or the plasma sample. Across all FL samples, there was no significant difference in concordance based on individual m7 genes. When analyzing pairs in which mutations were observed, concordance between paired samples was lowest for EZH2 (p = 0.028).Conclusions: m7-FLIPI scores appear consistent between multiple FL tumor samples obtained at the time of diagnosis and across FL relapses. However, concordance in m7 gene profile between paired plasma and tumor samples is lower than between paired tumor biopsies, even at ultra-deep sequencing depths. Optimization of blood samples for assessing m7 gene profile should be performed to improve the reliability of ctDNA for determining m7-FLIPI risk status.Figure 1. Concordance of m7-FLIPI risk category. (A) Re-classification of m7-FLIPI risk category when using paired tumor biopsy and plasma samples from 14 patients. (B) Percentage of discordant samples when comparing diagnostic tumor pairs (n = 5), diagnostic versus relapse tumor pairs (n = 37), and diagnostic tumor versus plasma pairs (n = 14). Concordance was lowest for diagnostic tumor and diagnostic plasma pairs (p = 0.013). [Display omitted] DisclosuresDiehn:Varian Medical Systems: Research Funding; Quanticel Pharmaceuticals: Consultancy; Roche: Consultancy; Novartis: Consultancy. Alizadeh:Gilead: Consultancy; Roche: Consultancy; Genentech: Consultancy; Celgene: Consultancy; CiberMed: Consultancy.

Early Relapse Post Autologous Transplantation Is Associated with Very Poor Survival and Identifies an Ultra High Risk Group of Myeloma Patients

Treatment with high dose melphalan (HDM) and autologous stem cell transplantation (ASCT) improves progression free survival (PFS) and overall survival (OS) of myeloma patients and is a standard therapy for eligible patients. Furthermore, the use of maintenance therapy after ASCT is beneficial. However, a subset of patients relapses early after HDM, and there is a paucity of data about their outcomes and characteristics, especially regarding their identification at diagnosis or early in the course of the disease. The aim of the current study was to describe the characteristics, the management and outcomes of patients relapsing within 12 months from HDM.The study included 297 consecutive patients treated in the Department of Clinical Therapeutics, Athens, Greece, which received HDM-ASCT as part of first line therapy from 1995 until June 2016. Median age was 55 years (range 22-67); 38% were ISS-1, 31% ISS-2 and 30% ISS-3. Induction was bortezomib-based in 47%, thalidomide-based in 13%, lenalidomide-based in 6%, high dose dexamethasone-based in 25% and contained both bortezomib and an IMiD in 9%. After ASCT, 35% received consolidation and 30% maintenance.Median follow up for all patients is 5 years, 183 (62%) have relapsed, the median PFS post HDM was 36 months and 43 (13.5%) patients have progressed within <12 months post HDM. In univariate analysis, the baseline LDH ≥250 IU/L (37% vs 15%, p<0.001), eGFR <30 ml/min (22% vs 12%, p=0.055), hypercalcemia (26% vs 16%, p=0.069) and high-risk cytogenetics (available in 138 patients) (39% vs 23%, p=0.084) were associated with early relapse. Response to induction therapy was not predictive of early relapse but less than sCR/CR post HDM (day 100) was associated with early progression (p=0.1). The use of consolidation therapy post HDM was associated with lower rates of early relapses (4% vs 14% for maintenance and 26% for no post-HDM therapy, p<0.001). In multivariate analysis, LDH ≥250 IU/L (HR: 3.4, p=0.01) and hypercalcemia (HR: 3, p=0.006) at diagnosis increased while the use of consolidation reduced the risk of early relapse (HR: 0.23, p=0.012). Due to the limited number of patients with cytogenetics this parameter was not included in the multivariate model.Baseline characteristics that were associated with PFS post HDM included high-risk cytogenetics (HR: 2.1, p=0.003), ISS-3 (HR: 1.4, p=0.03), hemoglobin <10 g/dl (HR: 1.6, p=0.001), hypercalcemia (HR: 1.6, p=0.014) and achievement of sCR/CR after HDM (HR: 0.8 vs VGPR, p=0.18 and HR: 0.67 vs PR, p=0.06). The use of maintenance therapy (HR: 0.54, p=0.01) was also associated with better PFS. In multivariate analysis, the use of maintenance therapy (HR: 0.58, p=0.032) and sCR/CR post HDM (HR: 0.64 vs PR, p=0.06 and HR: 0.9 vs VGPR, p=0.17) were independently associated with PFS. In further analysis, PFS to 2nd line therapy was 14 months for all patients, but only 5 months for those with an early relapse vs 19 months for the other patients (P<0.001). Median PFS2 was 15.5 months for patients with a relapse <12 months post HDM vs 57% at 5 years for the other patients (p<0.001).The 5-years OS is 67%, but, median post HDM OS was 18 months for those with an early relapse vs 71% at 5 years for those with post HDM PFS ≥ 12 months (p<0.001; Figure). In univariate analysis prognostic factors for OS after HDM included high risk cytogenetics (HR: 3, p<0.001), ISS-3 (HR: 2.2, p<0.001), hypercalcemia (HR: 2.8, p<0.001), anemia (HR:1.9, p=0.001), LDH ≥250 IU/L (HR: 1.7, p=0.054) and sCR/CR after HDM (HR: 0.7, p=0.082), use of maintenance (HR: 0.5, p=0.014) or consolidation (HR: 0.61, p=0.017) after HDM. In multivariate analysis PFS post ASCT <12 months (HR: 14, p<0.001) was the most important prognostic factor; other factors included post-HDM sCR/CR (HR: 0.48 vs PR, p=0.021 and HR: 0.54 vs VGPR, p=0.054), hypercalcemia at diagnosis (HR:2.1, p=0.005) but not maintenance (p=0.1) or consolidation therapy (p=0.54) post ASCT.In conclusion, 13% of patients with newly diagnosed MM that receive HDM at first remission relapse within 12 months after ASCT and they have very poor outcomes. These patients should be considered as an ultra high-risk group that urgently needs more effective therapies and innovative approaches through targeted clinical trials. The use of consolidation in patients at high risk for early relapse, such as those with high LDH and hypercalcemia at diagnosis, may reduce early relapses, and maintenance may prolong PFS. [Display omitted] DisclosuresKastritis:Janssen: Honoraria, Research Funding; Gebesis/Celgene: Honoraria; Amgen: Honoraria, Research Funding; Takeda: Honoraria. Terpos:Abbvie: Honoraria; BMS: Honoraria; Amgen: Honoraria, Other: SC member, Research Funding; Janssen: Honoraria, Research Funding; Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; Takeda: Honoraria, Other: SC member; GSK: Honoraria. Dimopoulos:Novartis: Consultancy, Honoraria; Genesis Pharma: Research Funding; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology.

Scoring System for Predicting Risk of Relapse in Patients with Multiple Myeloma within Two Years after Stem Cell Transplantation

Novel drugs induction therapy followed with autologous stem cell transplantation (ASCT) is the first-line treatment for patients with multiple myeloma who suitable for ASCT, prolonging overall survival (OS) to approximately 7 years. However, some patients relapse within two years after transplantation and their prognosis is extremely poor. Identifying patients at high risk of early relapse might help clinicians propose alternative therapeutic strategies that improve outcomes. We retrospectively analyzed 641 multiple myeloma patients from 6 centers in China who received Bortezomib induction therapy followed by ASCT between June 1, 2006 and June 30, 2014. 181 patients (28.2%) progressed within two years after ASCT. Comparison of patients who progressed early [time to progression (TTP) < 2 year] and patients who did not (TTP ≥ 2 year) showed that those TTP < 2 yr had higher corrected calcium and lactate dehydrogenase (LDH) and more be in stage III of the International Staging System (ISS). 17p- was present in a significantly higher proportion of patients with TTP < 2 yr (P < 0.0001). Binary logistic regression identified the following four independent risk factors for TTP < 2 yr: ISS Ⅱ/Ⅲ, LDH > 240 U/L, presence of 17p- and HBsAg positivity. And these four independent risk factors were assigned scores using the regression coefficient β to predict relapse or progression within two years after ASCT, where LDH > 240 U/L was given a score of 2.0; 17p-, a score of 3.9; ISS II/III, a score of 3.8; and HBsAg positive, a score of 1.9. Based on total scores, patients were classified into three risk groups: the low-risk group (score < 4): 6.9% relapsed within two years of ASCT; the medium-risk group (score 4-8): 45.8% relapsed within two years; and the high-risk group (score > 8): 89.3% relapsed within two years. Based on this scoring system, TTP was analyzed for the 641 patients. TTP was not achieved in the low-risk group, while 25.6 months in the medium-risk group and 16.5 months in the high-risk group (Figure 1). The differences among the groups were significant. It is a useful scoring system for predicting risk of relapse within two years after ASCT in patients with multiple myeloma. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Differentiation Response to Quizartinib, a Potent 2nd Generation FLT3 Inhibitor, in Relapsed FLT3 -Mutant AML Patients Correlates with Specific DNA Methylation Signature Prior to Therapy

Activating mutations in Fms-like tyrosine kinase 3 receptor (FLT3 ) gene occur in 30% of AML patients, and are correlated with a high risk for early relapse. The second generation FLT3 inhibitor AC-220 (quizartinib), has shown significant responses in patients with relapsed and refractory FLT3 mutant AML. For those patients who respond, two different types of pathologic responses have been observed: a cytotoxic response or a differentiation response. Given these two different responses to therapy, we hypothesized that pre-existing epigenetic programs may be responsible for determining response type, and that DNA methylation analysis of AML blasts before and after treatment may help better understand the molecular underpinnings of the varied roles of FLT3 in AML pathogenesis. For this purpose, we analyzed a cohort of 13 FLT3 -ITD mutant AML patients relapsed after standard chemotherapy and treated with quizartinib as part of the Phase II ACE trial (NCT00989261). Patients were evaluated prior to therapy and after at time of maximal response and classified as having either cytotoxic (6 patients) or differentiation (7 patients) responses as previously described. Bone marrow or peripheral blood specimens were collected from 13 patients at baseline, prior to the administration of quizartinib, and 10 matched, post-treatment specimens were available for 9 patients. DNA was extracted from mononuclear cell fractions and analyzed using multiplexed Enhanced Reduced Representation Bisulfite Sequencing (mERRBS), which captures quantitative DNA methylation status at ~3 million CpG sites across the human genome. Supervised analysis between the different groups was performed using a beta binomial model as implemented in MethylSig, with significant differentially methylated regions (DMRs) being called with methylation differences ≥25% and false discovery rates (FDR) < 0.1. Notably, paired analysis of pre- and post-treatment samples revealed very little impact of quizartinib on the DNA methylation landscape of patients with cytotoxic responses, with only 21 DMRs detected. Similarly, those who exhibited a differentiation response, showed moderate methylation changes with 84 DMRs enriched at introns compared to whole coverage of mERRBS (Background [BG] 32% vs DMRs 56%; exact binomial test [EBT] p-value 5.053e-06). Thus, FLT3 inhibition did not appear to modify DNA methylation in these patients. However, and importantly, a direct comparison at baseline, prior to the administration of quizartinib, between patients who developed either differentiation or cytotoxic response, revealed robust epigenetic differences between these two groups of patients, with 580 DMRs. The majority of these (414 DMRs, 71%) were hypermethylated in patients with cytotoxic response. These DMRs were strongly depleted from promoter regions (BG 24% vs DMRs 9%; EBT p-value 2.2x10E-16) while they were enriched at intergenic regions (BG 35% vs DMRs 49%; EBT p-value = 1.064e-10). Given the preferential location of DMRs at these distal intergenic regions, we analyzed their relationship to enhancer elements. A total of 46.2% of DMRs (n=268) overlapped with ENCODE-defined enhancers (EBT p-value 3.57x10E-13 compared to 31.8% of BG). Pathway annotation of DMRs to the nearest genes revealed that they were associated with ion transmembrane transporter activity and extracellular matrix binding. In addition, amongst the DMRs were several annotated to HOX genes, including HOXB3 , HOXA7 and HOXD13 genes, which were hypomethylated in patients with a differentiation response. In summary, our analyses reveal that pre-existing epigenetic programs are encoded in FLT3 -mutant AML cells that correlate with the type of response they will undergo upon quizartinib treatment. The precise consequences of these epigenetic differences at the transcriptional level are still being explored and will be discussed at the meeting. We hypothesize that the pathologic role of FLT3 in AML may be modified by the epigenetic state of the transformed cells. DisclosuresPerl:Arog Pharmaceuticals: Consultancy; Actinium Pharmaceuticals: Other: Scientific Advisory Board; Pfizer: Other: Advisory Board; Astellas: Consultancy; Asana Biosciences: Other: Scientific advisory board; Daiichi Sankyo: Consultancy; Novartis: Other: Advisory Board; Seattle Genetics: Other: Advisory board. Carroll:Incyte Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding.

Outcomes of Vdpace with Immunomodulator Treatment in Initial and Relapsed/Refractory Multiple Myeloma in a Single Center

Background: High- risk multiple myeloma (MM) is considered challenging to treat because of the risk of early relapse and increased mortality. The main factors contributing to high risk myeloma are poor prognostic cytogenetic abnormalities that include 17p deletions, 1q21 gains, 1p deletion, t (4;14), t (14;16), and t (14;20). Other features of high risk MM include extramedullary disease (EMD) which is associated with an adverse prognosis in newly diagnosed and in relapsed MM patients with overall survival of less than 6 months. Another entity of high risk MM is primary plasma cell leukemia (pPCL) and has a very poor prognosis. Our institution performed a retrospective review that included induction/salvage therapy using multi-agent chemotherapy with novel agents such as a proteasome inhibitor and an immunomodulator agent (Imid) to achieve a better overall response rate.Patients & Methods: Thirty eight patients with MM, primary plasma cell leukemia, and myeloma with EMD between January 2012 and June 2017 at the University of Kansas Health System were reviewed These patients received VDPACE consisting of bortezomib 1 mg/m2 subcutaneous (SC) on days 1,4,8 and 11, doxorubicin 10 mg/m2 continuous infusion (CI) x 4 days, cisplatin 10 mg/m2 CI x 4 days, Cyclophosphamide 400 mg/m2 CI x 4 days, etoposide 40 mg/m2 CI x 4 days, an Imid either thalidomide 200 mg for 4 days or lenalidomide 25 mg for 14 days or pomalidomide 4 mg for 14 days every 28 days. Descriptive analyses were performed on available data for patient characteristics, disease course, and outcomes. Responses were evaluated using the IMWG criteria.Results: The median age was 59 years (40-77) for those who received VDPACE + Imid, 53% of patients had IgG isotype, 26% had ISS stage III at diagnosis, 61% had high risk cytogenetics, 55% had EMD and pPCL. Median number of cycles of VDPACE+ Imid received was 1 (1-4) cycles. Thirty patients (68%) received treatment for relapsed disease. In the relapsed group, the median prior lines of therapy were 2 (1-10), 100% had received proteasome inhibitor, 88% had received an Imid and 73% had received autologous stem cell transplant (ASCT), median number of ASCT prior to treatment was 1 (0-3). The ORR was 69%. Twelve patients (32%) received treatment as initial therapy with an ORR of 100%, 6 of these patients (16%) had pPCL. The response rates are summarized in table 2. The response rate for patients who had EMD+pPCL was 80% with 48% who achieved VGPR and better. Twenty-two patients (58%) proceeded with consolidation therapy with ASCT or allogenenic stem cell transplant (AlloSCT).Conclusion: Our single institution experience shows that patients with high risk MM, EMD and pCNS can achieve a significant response rate using VDPACE+Imid. This proves VDPACE+Imid can be utilized as salvage therapy in relapsed MM and as an initial therapy in pPCL and EMD. However, we believe that this treatment followed by high dose chemotherapy with ASCT should be further studied in terms of deeper response and OS to identify the long term clinical benefits of the treatment. [Display omitted] DisclosuresGanguly:Amgen: Other: Advisory Board; Seattle Genetics: Speakers Bureau.