Favorable Risk Group Research Articles

Retrospective Analysis of Turkish AML Registry Database, on Behalf of AML Working Group of Turkish Society of Hematology

Introduction: To investigate the demographics and treatment details of the acute myeloid leukemia (AML) patients who were diagnosed and followed up in Turkey. Methods: Patients who were recorded on the database of Turkish AML Registry project were included in this study retrospectively if they were diagnosed before 1st of Jan 2022. Demographics, patient, and disease related parameters both at the time of diagnosis and at the follow up and treatment outcomes were presented. Results: A total of 519 patients were included in the study, median follow-up period was 14.0 (SD:25.6) months and 44.5% of the patients were female. Median age at the time of diagnosis was 54 (18-89). According to the FAB classification most common subtypes were M4 (24.9%), M2 (24.6%), M5 (16.8%) and M1 (14.2%) and AML, NOS (60.2%) was the most common type according to the WHO classification. Of the patients 64.7%, 24.7%, 14.7%, was intermediate, favorable and poor respectively considering AML risk stratification (ELN 2017) by genetics. Only 4.6% of the patients had extramedullary involvement at the time of diagnosis. For the first induction therapy, 89.0% of the patients had received intensive regimens composing anthracyclines and ARA-C, the rate of intensive therapies declined to 41.2% at the time of first relapse. ARA-C (69.6%) backbone and Azacitidine alone (6.9%) were the most commonly used regimens and 13.2% underwent allo-HCT at first remission. Response rates obtained by the induction therapies were as follows; 68.9% CR (including 11.9% MLFS), 11.9% PR, 8.1% SD, 11.1% PD, the ratio was 24.7% for CR2. Median overall survival was not reached for the favorable risk group, were 22.8 months for the intermediate risk and 14.3 months for the poor risk group (p:0.002) and 22.5 months for the entire population. Median progression free survival were 21.5 months for the favorable risk group, 11.9 months for the intermediate risk and 8.6 months for the poor risk group (p:0.003) and 11.5 months for the entire population (Figure 1). Conclusion: Progression free survival obtained after induction therapy and overall survival were relatively shorter than the ones which were presented by other real-world registries. Lack of early access to the targeted and novel agents, like Flt3 inhibitors, Venetoclax, IDH1 and 2 inhibitors, CPX351 and Glasdegib should be a potential explanation to this relatively short PFS and OS. We have also been aware of un-ideal access to well established and nation wide cytogenetic laboratory service to induce early integration of targeted agents to the treatment and better risk stratification to determine the patients who should obtain the best prolonged survival via allo-HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Analysis According to European Leukemianet 2022 Risk Stratification for Elderly Patients with Acute Myeloid Leukemia Treated with Decitabine

The European LeukemiaNet (ELN) recently published the revised risk stratification system for AML in 2022 (ELN-2022). The risk stratification of ELN-2017 is generally focused on younger patients who are fit on standard induction treatment. Prognostic impact of the ELN risk stratification for elderly patients who treating low intensity chemotherapy is well not established. This retrospective cohort aimed to evaluate the prognostic significance of the revised ELN-2022 risk stratification in elderly patients treated decitabine chemotherapy. Total 123 patients with elderly AML were eligible. Based on 2022 ELN risk stratification, 14 (11.4%) patients were classified as favorable, 53 (43.1%) as intermediate risk, and 56 (45.5%) as the high risk, respectively. The ELN-2022 classification re-assigned 27 (21.2%) of patients into more adverse-risk group, and 2 (2.4%) of patients into more favorable-risk group compared with the ELN-2017 recommendations. This difference was largely due to the FLT3-ITD allelic ratio which is no longer considered in the ELN 2022 risk classification. Moreover, myelodysplasia-related gene mutations including EZH2, SF3B1, SRSF2, STAG2, U2AF1 genes is now indicated as adverse risk which was another important change compared to previous ELN risk stratification. Because elderly patients highly associated with AML following prior MDS or MDS/MPN, the revised ELN-2022 is well presented an adverse prognosis in elderly AML patients. The rate of CR and CRi was 16.3% (20/123, CR = 8 patients, CRi =12 patients). There was no difference in overall response rate by ELN-2017 and ELN-2022 risk stratification. According to the ELN-2017 classification, the difference of 2-year overall survival (OS) between each risk group was not significant in 123 elderly patients treated decitabine (median OS of ELN-2017 favorable (n = 22), 7.2 months; intermediate-risk (n = 62), 8.0 months; Adverse-risk (n=39), 5.2 months; P = 0.081). In the revised 2022-ELN, the 2-year OS of each risk group was more distinct in elderly patients, compared to ELN-2017(median OS of ELN-2022 favorable (n = 14), 10.4 months; intermediate-risk (n = 53), 7.6 months; Adverse-risk (n=56), 5.5 months; P = 0.053). The study presents the prognostic significance of revised 2022-ELN risk stratification in elderly AML patients receiving decitabine. This study suggests the possibility that the 2022-ELN classification could be predict survival in patients with AML for whom intensive induction therapy is not candidate. Figure legendsFigure 1. Kaplan-Meier curves in patients with elderly AML according to (a) 2017-ELN (b) 2022-ELN. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Measurable residual disease by flow cytometry in acute myeloid leukemia is prognostic, independent of genomic profiling

Measurable residual disease (MRD) assessment provides a potent indicator of the efficacy of anti-leukemic therapy. It is unknown, however, whether integrating MRD with molecular profiling better identifies patients at risk of relapse. To investigate the clinical relevance of MRD in relation to a molecular-based prognostic schema, we measured MRD by flow cytometry in 189 AML patients enrolled in ECOG-ACRIN E1900 trial (NCT00049517) in morphologic complete remission (CR) (28.8 % of the original cohort) representing 44.4 % of CR patients. MRD positivity was defined as ≥ 0.1 % of leukemic bone marrow cells. Risk classification was based on standard cytogenetics, fluorescence-in-situ-hybridization, somatic gene analysis, and sparse whole genome sequencing for copy number ascertainment. At 84.6 months median follow-up of patients still alive at the time of analysis (range 47.0–120 months), multivariate analysis demonstrated that MRD status at CR (p = 0.001) and integrated molecular risk (p = 0.0004) independently predicted overall survival (OS). Among risk classes, MRD status significantly affected OS only in the favorable risk group (p = 0.002). Expression of CD25 (α-chain of the interleukin-2 receptor) by leukemic myeloblasts at diagnosis negatively affected OS independent of post-treatment MRD levels. These data suggest that integrating MRD with genetic profiling and pre-treatment CD25 expression may improve prognostication in AML.

Clinical Outcomes and Prognostic Factors of Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Refractory/Relapsed Acute Myeloid Leukemia

To investigate the clinical outcomes and prognostic factors of refractory/relapsed acute myeloid leukemia (AML) patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical data of 80 refractory/relapsed AML patients who received allo-HSCT from December 2013 to June 2020 were retrospectively analyzed, including the overall survival (OS) rate, disease-free survival (DFS) rate, relapse rate, incidence of transplant-related mortality (TRM), and the related risk factors were explored. Hematopoietic reconstitution was obtained in all 80 patients after transplantation, the 3-year OS and DFS rates were (48.8±6.3)% and (40.8±6.7)%, respectively. The 3-year cumulative incidence of relapse and TRM were 33.8% (95%CI: 0.254-0.449) and 15.0%(95%CI: 0.114-0.198), respectively. Univariate analysis showed that non-remission (NR) status before transplantation, DNMT3A R882 mutations and grade II-IV acute graft-versus-host disease (aGVHD) had negative effects on OS and DFS. Multivariate analysis indicated that the DNMT3A R882 mutations and grade II-IV aGVHD were independent risk factors for OS (HR=0.253, 95%CI: 0.092-0.695, P=0.008; HR=5.681, 95%CI: 2.101-15.361, P=0.001) and DFS (HR=0.200, 95%CI: 0.071-0.569, P=0.003; HR=7.117, 95%CI: 2.556-19.818, P<0.001). The 3-year cumulative incidence of relapse was 71.4%(95%CI: 0.610-0.836) in genetic high-risk group, which was higher than 23.3%(95%CI: 0.147-0.370) in intermediate-risk group and 23.5%(95%CI: 0.127-0.437) in favorable-risk group (P=0.006). Allo-HSCT is an effective and safe choice for refractory/relapsed AML patients. DNMT3A R882 mutations and grade II-IV aGVHD are negative prognostic factors of allo-HSCT for refractory/relapsed AML patients.

Impact of modified Glasgow prognostic score on predicting prognosis and modification of risk model for patients with metastatic renal cell carcinoma treated with first line tyrosine kinase inhibitor.

Intermediate risk group of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria is thought to consist of patients with different prognoses. This study investigated the impact of a pretreated modified Glasgow prognostic score (mGPS), which is defined on the basis of the pretreated serum albumin and C-reactive protein level, on predicting the prognosis of patients with metastatic renal cell carcinoma (mRCC) and its usefulness for the re-stratification of patients into a more improved risk model. One hundred ninety-six mRCC patients treated with first-line tyrosine kinase inhibitor (TKI) were retrospectively investigated. All patients were classified into either a high-mGPS or a low-mGPS group on the basis of mGPS score upon starting systemic therapy, the overall survival (OS) and cancer specific survival (CSS) rates in each group were compared. We use decision curve analysis and calculate C-index based on OS and CSS to compare IMDC+mGPS model and IMDC model. The categories of favorable, intermediate, and poor risk groups in the IMDC model were assessed in 32, 113, and 51 cases, respectively. The low- and high-mGPS groups consisted of 149 and 47 cases. The median OS in the high- and low-mGPS groups were 38.4 months and 5.6 months, and their median CSSs were 41.0 months and 5.6 months, respectively (P < 0.0001). Multivariate analysis showed that a high mGPS, multiple metastatic organs, and hypercalcemia were independent predictive factors for a worse OS (P = 0.0260). Next, we divided the intermediate risk group into two subgroups using the mGPS score. The OS and CSS for the high-mGPS subgroup were significantly worse than those for the low-mGPS one (P = 0.0024, median OS: 21.0 months and 33.7 months, P = 0.0007, median CSS: 21.0 months and 39.8 months), and there was no significant difference in OS between the high-mGPS subgroup in the intermediate risk group and poor risk group (P = 0.2250). The value of C-index based on OS at IMDC and IMDC+mGPS model were 0.6771 and 0.6967, and those based on CSS were 0.6850 and 0.7080, respectively. In decision curve analysis to evaluate the clinical net benefit using the IMDC+mGPS model compared to the IMDC model, there was no significant difference between the two groups. mGPS is useful for establishing a more improved prognostic model that is able to stratify mRCC patients treated with first-line TKI.

AML-440 Prognosis of Molecularly-Defined Secondary Acute Myeloid Leukemia Patients

Mutations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 were proposed as secondary AML (sAML) defining mutations independent from the patients' history. We evaluated the prognostic impact of molecularly-defined sAML (msAML) patients in the context of the European LeukemiaNet (ELN) risk categories. 459 adult newly-diagnosed AML patients (median age 54) with available genetic and follow-up data were included. Patients received standard induction and consolidation chemotherapy or underwent allogeneic hematopoietic cell transplantation (alloHCT). Patients were classified as de-novo AML (dnAML), msAML carrying ≥ 1 sAML-defining mutations, and clinically-defined secondary AML (csAML) based on previous medical history and cytogenetics. 208 (45%) patients had dnAML, 155 (34%) msAML, and 96 (21%) csAML. 62 msAML patients overlapped with csAML. Of msAML patients, 104 (67%) had 1, 39 (25%) 2, and 12 (8%) 3 or more msAML-defining mutations. The most frequently mutated msAML-defining genes were ASXL1 (n=48, 31%) and SRSF2 (n=44, 28%). The likelihood to reach complete remission (CR) was higher for dnAML compared to msAML patients (92% vs 79%, P =.003), but there was no difference between csAML and msAML patients. The median follow-up of all patients was 5.56 years. The transplantation rate in first CR was similar in dnAML, msAML and csAML patients (33%, 37%, 44%, respectively). Overall survival (OS) was significantly worse in msAML compared to dnAML patients (median OS 3.3 years vs not reached, HR = 1.7, 95%CI 1.2-2.2, P<.001), also when ASXL1 mutated patients were excluded (HR = 1.7, 95%CI 1.2-2.4, P<.001). OS was similar in csAML vs dnAML and in msAML vs csAML patients. In the ELN favorable and intermediate risk groups msAML patients (n=19 and n=52) had a significantly worse OS compared to dnAML patients (n=66 and n=80) (HR=3.1 95%CI 1.5-6.3, P=.001 and HR=2, 95%CI 1.2-3.2, P=.008, respectively). OS was similar in the ELN adverse risk group between msAML (n=79) and dnAML patients (n=31). Accordingly, the ELN risk groups did not stratify OS in msAML patients. msAML-defining mutations identify a subgroup of dnAML patients with poor prognosis and reclassify 10% of all patients in our cohort from favorable/intermediate to the adverse risk group.

Development of a Simple and Objective Prognostication Model for Patients with Advanced Solid Malignant Tumors Treated with Immune Checkpoint Inhibitors: A Pan-Cancer Analysis

Systemic therapy using immune checkpoint inhibitors (ICIs) has recently become prevalent in the treatment of patients with various types of advanced cancers; however, difficulties are still associated with predicting the outcomes of patients receiving ICIs due to heterogenous responses to these agents. To develop a prognostic model for advanced cancer patients treated with ICIs. This study retrospectively analyzed the impact of clinical parameters on overall survival (OS) in 329 patients with several advanced solid malignant tumors who received systemic therapy using ICIs. The primary tumors of 329 patients were as follows: lung (n = 89), kidney (n = 70), urinary tract (n = 52), skin (n = 50), stomach (n = 30), esophagus (n = 21), and head and neck (n = 17). Median OS after the introduction of ICIs was 17.3 months. Among the factors that correlated with OS in a univariate analysis, body mass index, C-reactive protein, hemoglobin, lymphocytes, and platelets were identified as independent predictors of OS in a multivariate analysis. Following the classification of patients into 3 groups based on positive numbers of these independent risk factors, median OS was not reached in the favorable risk group with 0 or 1 risk factor (n = 76), 19.5 months in the intermediate-risk group with 2 or 3 risk factors (n = 182), and 7.2 months in the poor risk group (n = 71) with 4 or 5 risk factors. Although this is a simple and objective model, it may be used as a reliable tool to predict the outcomes of advanced cancer patients receiving ICIs across multiple tumor types.

Molecular-targeted Therapy for Metastatic Renal Cell Carcinoma As First-line Therapy: A Single Institution 13-year Experience.

We aimed to identify the role of first-line monotherapy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) in patients with metastatic RCC. Eligible patients were categorized into three groups (favorable, intermediate, and poor risk) according to the International Metastatic RCC Database Consortium risk criteria. Overall survival (OS) was the primary endpoint. Survival was compared using the log-rank test. A total of 108 patients were retrospectively analyzed. The numbers of patients in the favorable-, intermediate-, and poor-risk groups were 32 (30%), 66 (61%), and 10 (9%), repestively. The median OS values in the entire cohort was 36 months (95% confidence interval [CI] 29-53). The median OS in the favorable, intermediate, and poor risk groups were 94 months (95% CI: 43-Not reached), 30 months (95% CI: 20-38), and 8 months (95% CI: 0-Not reached), respectively (p<0.05). Prior nephrectomy, clear cell histology, clinical T stage ≤2, no metastasis at the time of diagnosis, nivolumab beyond first-line therapy, and objective response to VEGFR-TKIs were factors significantly prolonging OS on univariate analysis. VEGFR-TKI monotherapy as first-line therapy was an effective treatment option for patients with metastatic clear cell RCC with favorable risk.

P443: IMPACT OF PHARMACOGENETIC VARIANTS ON CYTARABINE AND ANTHRACYCLINE EFFECT ON OUTCOMES IN ADULT AML PATIENTS

Background: Acute myeloid leukaemia (AML) is primarily treated with combination of cytarabine and anthracyclines. Despite high remission rates, the 5-year overall survival (OS) is <50% and <20% for<60-year-old a ≥60-year-old patients, respectively. This grim clinical outcome could be partly explained by the patients’ genetic variability of proteins involved in metabolic paths of cytarabine and anthracyclines. Pharmacogenetic variants of the main cytarabine membrane transporter SLC29A1 (solute carrier family 29 member 1), DCK (Deoxycytidine kinase) the first enzyme in cytarabine stepwise activation process, genes coding main anthracycline efflux pump ABCB1 (ATP binding cassette) and genes coding glutathione S-transferases GSTM1 and GSTT1, main cytosolic detoxifiers od anthracycline-induced oxidative stress, are shown to influence clinical outcome in AML patients. Aims: to evaluate: 1) the effects of variants in pharmacogenes SLC29A1, DCK, ABCB1, GSTM1 and GSTT1, on complete remission (CR) and relapse rate (RR), disease free survival (DFS) and overall survival (OS), 2) the influence of demographic, laboratory and AML-related parameters on CR, RR, DFS and OS. Methods: 100 newly-diagnosed consenting adults (18-62 years old) diagnosed with AML, except acute promyelocytic leukaemia in Clinic of Haematology UCCS from January 2015 to January 2018, were included in retrospective cohort. Patients received one or two inductions ‘’3 + 7’’ cycles. In patients achieving CR either three consolidation cycles with high/intermediate doses of cytarabine or allogenic SCT in selected patients were performed. Demographic, standard laboratory and AML-related parameters (blood/bone marrow blast percentage, cytologic, flow cytometry and genetic markers enabling ELN risk stratification were collected from patients’ health records. Variants SLC29A1 rs9394992, DCK rs12648166, ABCB1 rs2032582 and GSTM1 and GSTT1 gene deletions were detected by methodology based on PCR, fragment analysis and direct sequencing. The study was approved by the Ethics Committee of the UCCS. The methods of descriptive and analytic statistics were used, while survival analysis was done by the Kaplan-Meier method using the Log-Rank test. Results: 100 patients (53 males) were included in the study, with the median age of 51 (range 18-62). Median laboratory parameters were: WBC 15.5x109/L (range 1-348.8), Hgb 97g/L (range 20-166), Plt 53.5 (range 1-422), LDH 249U/L (1-4169). CD34 was positive in 56% patients. According to ELN 15, 55 and 30 patients were classified in favorable, intermediate and adverse risk group, respectively. CR was achieved in 57 patients (41 after the first and 16 after the second induction cycle). A total of 34% of patients relapsed. Median DFS was 5.3 months (range 0.25-61.5), while median OS was 6 months (range 0.3-75). There was a significant difference in median DFS between CC, CT and TT genotype of SLC29A1: 13, 8 and 1.75 months, respectively (p=0.00037). Median DFS was significantly decreased in null genotype of GSTM1 (9.5 (null) vs 18 months (non-null); p=0.028). Significant difference in OS within ABCB1 genotypes TT, GG, GT and AG+AT was registered: 13, 7, 6.5 and 3 months, respectively (p=0.0036). Other parameters did not differ significantly. Summary/Conclusion: Our results, regarding impact of variants of SLC29A1, GSTM1 on DFS and impact of variant ABCB1 on OS in AML patients, are in line with previous studies. Although further studies, with larger cohorts, are needed, these pharmacogenetic variants show a potential to become prognostic markers in AML.

P508: REAL LIFE EXPERIENCE USING FRONT-LINE CPX-351 FOR THERAPY-RELATED AND AML-MRC: RESULTS FROM THE SPANISH PETHEMA REGISTRY.

Background: Acute Myeloid Leukemias arising after cytotoxic therapy (t-AML) or with myelodysplasia-related changes (AML-MRC) share adverse risk features and poor outcomes after standard 3 + 7 chemotherapy. In a randomized clinical trial, CPX-351 has shown superior overall survival (OS) compared to standard anthracycline-cytarabine schedule in these AML subtypes. Aims: to evaluate the effectiveness of CPX-351 treatment in a real-world setting. Methods: adult t-AML and AML-MRC patients who have been treated upfront with CPX-351 in 35 Spanish centers between 2018 and 2021. All patients were included in the PETHEMA registry (NCT02606825). Primary end-point was OS. Secondary end points were complete remission with or without hematological recovery (CR/CRi), proportion of minimal residual negativity (MRD), rate of allogeneic hematopoietic stem cell transplant (HSCT) and safety. Results: CPX-351 was administered to 74 patients as first induction chemotherapy. Median age was 67 (63-71) years, with 40% (30/74) of female patients. ECOG performance status score was 0-1 in 85% (53/62) patients. A diagnosis of t-AML was present in 30% (22/74) patients. Hypomethylating agents were used for MDS or CMML phase in 15%. Hematopoietic Transplant Comorbidity Index was low, intermediate and high in 14% (10/74), 43% (32/74) and 43% (32/74) patients. ELN17 risk classification was favourable, intermediate, adverse and indeterminate in 9% (7/74), 38% (28/74), 46% (34/74) and 5% (4/74). CR/CRi was obtained in 43% (32/74) patients after first cycle with CPX-351. Three additional patients achieved Morphological Leukemia Free Status. A second induction with CPX-351 was administered in 5 patients with 100% CR (CR/CRi after 2 cycles 37/74, 50%). MRD was evaluated in 97% (36/37) of CR/CRi patients, being low (<0.1%) in 47% (17/36) of them. In univariate analysis, no factor was associated with response. However, 71% (5/7) response rate was observed in the favourable ELN17 genetic risk group compared to 48% (32/67) in the non-favourable. HSCT was performed in 27% (20/74) patients, in 1st CR/CRi in 70% (14/20), MLFS in 15% (3/20) and active disease in 10% (2/20). With median follow up of 11.9 months (7.2-23.6) from HSCT, median OS was not reached (95% CI 9.5-NR months (Figure). In univariate analysis no factors were significantly associated with OS after HSCT. Median time to absolute neutrophil count ≥0.5 x109/L and platelets ≥50 x109/L were 30.5 (25-35) and 30 (26-39) days, respectively. Deaths within the first 30 days after induction occurred in 12% (9/74) patients. Causes of early death: infection in 5 patients, haemorrhage in 3 and respiratory failure in 1. With 6.1 (1.8-14) months of median follow up, median OS was 10.5 (6.9-NR) months, with significant differences between HSCT and non-HSCT patients [NR, (95% CI: 12.7-NR), vs. 6 months, (95% CI: 4-NR), P<0.001]. In univariate analysis, factors associated with lower OS were non-favourable ELN17 [8.9 vs 23.5, P=0.04]; ECOG≥2 [0.7 vs 12., P=0.002]; age ≥65 [7.9 vs NR, P=0.007] and male [6.6 vs NR, P= 0.007]. In multivariate analysis, age above 65 years [HR 1.6, P<0.001], male [HR -0.9, P=0.02] and ECOG≥2 [HR 1.9, P<0.001] were associated with OS. Image:Summary/Conclusion: Our real-life cohort was comparable to the target population of the pivotal trial including patients diagnosed with sAML (t-AML, AML-MRC and ELN17 high risk AML), obtaining similar outcomes than the CPX-351 phase 3 trial arm. To optimize treatment outcomes CPX-351 should be preferably offered to t-AML and AML-MRC patients who are suitable for HSCT.

MEDB-71. Molecular characterisation of group 4 medulloblastoma improves risk-stratification and its biological understanding

Group 4 (MBGrp4) accounts for ~40% of medulloblastoma and the majority of non-WNT/non-SHH cases, yet its underpinning biology is poorly understood, and survival outcomes are not sufficiently explained by established clinico-pathological risk factors. We investigated the clinical and molecular correlates of MBGrp4, including second-generation methylation non-WNT/non-SHH subtypes (I-VIII) and whole chromosome aberration (WCA) subtypes (defined by chromosome 7 gain, 8 loss, and 11 loss; WCA-favourable risk [WCA-FR] ≥2 features, WCA-high risk [WCA-HR] ≤1 feature). A clinically-annotated MBGrp4 discovery cohort (n=378) was assembled from UK CCLG institutions, collaborating centres and SIOP-UKCCSG-PNET3/HIT-SIOP-PNET4 clinical trials. Contemporary molecular profiling integrating methylation/WCA subtypes and next-generation sequencing was performed. Survival modelling was carried out with patients >3 years old who received craniospinal irradiation (n=336). Association analysis confirmed relationships between methylation and WCA subtypes. Subtypes VI and VII were enriched for WCA-FR (p<0.0001) and aneuploidy, whereas subtype VIII was defined solely by i17q (p<0.0001). Whilst we observed an overall low mutational burden, WCA-HR harboured recurrent mutations in genes involved in chromatin remodelling (p=0.007). No gene-specific events were associated with disease risk, however integration of both methylation subtype and WCA groups enabled improved risk-stratification survival models that outperformed current schemes. The optimal MBGrp4-specific model stratified patients into: favourable-risk (local disease, subtype VII or subtype VI with WCA-FR; 39/194 [20%], 97% 5-year PFS), very-high-risk (metastatic disease with WCA-HR; 71/194 [37%], 50% 5-year PFS) and high-risk (remaining patients; 84/194 [43%], 67% 5-year PFS). Findings were validated in independent cohorts. Comprehensive clinico-molecular assessment of MBGrp4 provides important understanding of its clinical and biological heterogeneity. Our novel MBGrp4 stratification scheme removes standard risk disease and identifies a favourable risk group (20% of MBGrp4) with potential for therapy de-escalation. Current therapeutic strategies are insufficient for the very-high risk group (encompassing 37% of MBGrp4), for whom novel therapies are urgently required.

Predictors for metastatic renal cell carcinoma in IMDC favorable risk group treated with a single agent first line systemic therapy.

e16518 Background: With the induction of molecular targeted agents, which interfere with proteins that play critical roles in tumor growth and progression, and immune checkpoint inhibitors, the scenario of systemic treatment of metastatic renal cell carcinoma (mRCC) have dramatically been changed with improved survival. Prognostic risk assessment is essential for choosing the most appropriate first line treatment option, with selection based on International Metastatic RCC Database Consortium (IMDC) Risk Category. This study was designed to evaluate the actual efficacy of a single agent systemic therapy in the IMDC favorable risk group patients with mRCC. Methods: A total of 240 patients with mRCC who received systemic therapy were retrospectively reviewed (Institutional review board approval No 2013-0425). Among them, 55 patients were classified as favorable risk group based on the IMDC Risk Category and received a single agent systemic therapy. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each marker on overall survival (OS) was investigated with univariate and multivariate Cox’s proportional hazards regression models. Results: After a median follow-up of 46 months after first-line treatment initiation, the median progression free survival (PFS) for first line treatment and OS of patients in favorable risk group were 29 months (95% CI 21–34)) and not reached, respectively. The estimated percentage of patients who were alive at 12 and 24 months were 96 and 94%, respectively. Multivariate analysis revealed that the long-term duration of first-line treatment (hazard ratio [HR]: 0.97, 95% confidence interval [CI]: 0.94–0.99, p = 0.0299) and the metastases limited to lung (HR: 3.85, 95% CI: 1.08–24.50, p = 0.0361) were independent predictors for longer OS in favorable risk mRCC patients. Conclusions: First-line systemic therapy for favorable risk mRCC patients with a single agent resulted in relatively longer PFS and OS. A longer duration of first-line treatment and lung only metastases are correlated with longer OS.

5 - Benefits and harms of stratification of intermediate-risk prostate cancer into favorable and unfavorable risk groups.

5 - Benefits and harms of stratification of intermediate-risk prostate cancer into favorable and unfavorable risk groups.

Real-world data on the efficacy and safety of pazopanib in IMDC favorable- and intermediate-risk metastatic renal cell carcinoma: a multicenter retrospective cohort study of Chinese patients.

BackgroundPazopanib was recommended as first-line treatment option for Metastatic renal cell carcinoma (mRCC), while evidence from strictly selected patients has poor external validity and clinical characteristics are complex in real-world clinical practice. This study aimed to illustrate the survival benefits and safety of pazopanib monotherapy using real-world data of mRCC patients.MethodsThis was a retrospective, multicenter, cohort study. We recruited adult patients with International Metastatic renal cell carcinoma Database Consortium (IMDC) favorable- and intermediate-risk mRCC receiving first-line pazopanib from May 2017 to February 2020. Patients were treated with pazopanib 800 mg or 600 mg orally once daily. Treatment efficacy, and drug safety were analyzed. Response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Drug safety was assessed according to the grade of treatment-related adverse reactions.ResultsBased on IMDC risk stratification, there were 46 (32.2%) patients in the favorable-risk group and 97 (67.8%) patients in the intermediate-risk group. The median progression-free survival (PFS) of the entire cohort, favorable- and intermediate risk groups was 21.2, 27.1 and 17.2 months, respectively. In the intermediate-risk group, PFS was much longer in patients with 1 risk factor than in patients with 2 risk factors, with a median of 25.9 months versus 11.2 months (P<0.0001). Patients with lung metastasis only had longer PFS than those with bone metastasis only, with a median PFS of 25.9 vs. 21.2 months, respectively. Furthermore, local therapy for the metastatic site appeared to benefit patients in the IMDC favorable-risk group but not those in the IMDC intermediate-risk group. The best response was 40/140 (29%) partial response (PR), 86/140 (61%) stable disease (SD), and 14/140 (10%) progressive disease (PD). The most common adverse drug reactions (ADRs) were change in hair color (47.7%), hypertension (40.0%), diarrhea (40.0%), proteinuria (38.5%), elevation of transaminase (35.4%), and hand–foot skin reaction (32.3%).ConclusionsThis real-world data analysis recommended that patients in intermediate-risk group need to be further stratified according to the number of risk factors. Pazopanib was most suitable for patients with lung metastasis only. Local treatment for metastatic lesions should only be recommended in IMDC favorable patients.

GRade, Age, Nodes, and Tumor (GRANT) compared with Leibovich score to predict survival in localized renal cell carcinoma: A nationwide study.

ObjectiveTo examine the performance of Leibovich score versus GRade, Age, Nodes, and Tumor score in predicting disease recurrence in renal cell carcinoma.MethodsIn total, 7653 patients diagnosed with renal cell carcinoma from 2010 to 2018 were captured in the nationwide DaRenCa database; 2652 underwent radical or partial nephrectomy and had full datasets regarding the GRade, Age, Nodes, and Tumor score and Leibovich score. Discrimination was assessed with a Cox regression model. The results were evaluated with concordance index analysis.ResultsMedian follow‐up was 40 months (interquartile range 24–56). Recurrence occurred in 17%, and 15% died. A significant proportion of patients (36%) had missing data for the calculation of the Leibovich score. Among 1957 clear cell renal cell carcinoma patients the distribution of GRade, Age, Nodes, and Tumor score of 0, 1, 2, or 3/4 was 21%, 56%, 21% and 1.4%, respectively, and for Leibovich score of low/intermediate/high this was 47%, 36% and 18%, respectively. A similar distribution was seen in 655 non‐clear cell patients. Both Leibovich and GRade, Age, Nodes, and Tumor scores performed well in predicting outcomes for the favorable patient risk groups. The Leibovich score was better at predicting recurrence‐free survival (concordance index 0.736 versus 0.643), but not overall survival (concordance index 0.657 versus 0.648). Similar results were obtained in non‐clear cell renal cell carcinoma.ConclusionGRade, Age, Nodes, and Tumor and Leibovich scores were validated in clear cell and non‐clear cell renal cell carcinoma. Leibovich score outperformed the GRade, Age, Nodes, and Tumor score in predicting recurrence‐free survival and should remain the standard approach to risk stratify patients during follow‐up when all data are available.

Liver Imaging-Reporting and Data System treatment response algorithm predicts postsurgical recurrence in locoregional therapy-treated hepatocellular carcinoma.

In HCC, locoregional therapy (LRT) is performed as a bridging or downstaging treatment before curative surgery. The impact of the LI-RADS Treatment Response (LR-TR) algorithm on surgical outcomes remains unknown. We aimed to evaluate radiologic and clinical factors predicting recurrence-free survival (RFS) and overall survival (OS) after curative surgery for LRT-treated HCC. Consecutive HCC patients who underwent liver transplantation or curative resection after LRT from 2010 to 2016 and had baseline and follow-up post-LRT CT/MRI up to the point of surgery were included. The LR-TR category at the time of surgery and other features were assessed using Cox proportional hazard models. RFS was estimated and compared using the Kaplan-Meier method with log-rank tests. We evaluated 73 patients with 115 lesions. The LR-TR viable category at the time of surgery (hazard ratio [HR], 3.84; 95% confidence interval [CI]: 1.04, 14.16), preoperative AFP > 200 ng/mL (HR, 3.63; 95% CI: 1.63, 8.10), LRT sessions > 3 (HR, 4.99; 95% CI: 1.73, 14.38), and resection (HR, 3.35; 95% CI: 1.39, 8.09) independently predicted recurrence. The risk score categorized the patients into poor, intermediate, and favorable-risk groups with 1-year RFS rates of 35.0%, 78.3%, and 97.0%, respectively (p < 0.001). Outside Milan at the time of surgery (HR, 5.79; 95% CI: 1.94, 17.07) and recurrence within the first postoperative year (HR, 17.66; 95% CI: 6.42, 48.56) predicted death. In LRT-treated HCC, non-LR-TR viable disease achieved within fewer LRT sessions and removed by liver transplantation recurred less. • The Liver Imaging Reporting and Data System treatment response (LR-TR) viable disease (hazard ratio [HR], 3.84; p = 0.043), preoperative serum AFP level > 200 ng/mL (HR, 3.63; p = 0.002), more than three locoregional treatment (LRT) sessions (HR, 4.99; p = 0.003), and resection compared to liver transplantation (HR, 3.35; p = 0.001) were the independent predictors for postsurgical recurrence in LRT-treated HCCs. • A scoring system combining LR-TR categories and key clinical factors stratifies the patients into poor, intermediate, and favorable recurrence risk groups, with 1-year RFS rates of 35.0%, 78.3%, and 97.0%, respectively (p < 0.001). • Outside Milan at the time of surgery (HR, 5.79; p = 0.001) and recurrence within the first postoperative year (HR, 17.66; p < 0.001) were associated with poor overall survival.

Early Serum and Hematological Responses to Pembrolizumab Therapy as Predictors of Survival in Metastatic Urothelial Cancer.

In order to search for predictive biomarkers of efficacy of pembrolizumab therapy for metastatic urothelial cancer (UC), we investigated the relationship between treatment outcomes and early neutrophil-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and C-reactive protein (CRP) responses. Medical records of 101 patients with metastatic UC who started pembrolizumab as a second-line or later treatment were reviewed. NLR, LDH, and CRP were recorded after 3 weeks of therapy. In addition, we investigated whether these factors had an association with prolonged progression-free (PFS) or overall (OS) survival. The objective response rate, median PFS, and median OS were 25.7%, 6.3 months, and 15.2 months, respectively. PFS and OS were significantly shorter in patients with NLR>3, LDH>upper limit of normal (ULN), and CRP>0.5 mg/dl after 3 weeks of pembrolizumab treatment (p<0.05). A predictive model comprising these factors (favorable risk group: 0 risk factors; intermediate-risk group: 1-2 risk factors; poor-risk group: 3 risk factors) revealed distinct PFS and OS curves (p<0.001). In the favorable risk group, 12-month OS was 79.6%; in the poor-risk group, it was 12.8%. Harrell's C-indices for NLR >3, LDH >ULN, CRP >0.5 mg/dl, and all three combined for predicting OS were 0.656, 0.625, 0.633 and 0.678, respectively. Early responses were also non-significantly associated with ORR (p=0.37). Pembrolizumab treatment outcomes are associated with early NLR, LDH, and CRP responses in metastatic urothelial cancer.

Real-World Outcomes of Hodgkin Lymphoma: A Multi-Centric Registry From India.

BackgroundHodgkin’s lymphoma (HL) is one of the most curable malignancies with a 5-year survival of over 80%. Most published literature from low-middle income countries comes from single institute experience.MethodologyThe OncoCollect Lymphoma group registry was set up in 2017 and has 9 major participating sites across India. Data of newly diagnosed classical HL (CHL) patients, treated between 2011 and 2017, were collected using OncoCollect software. The clinical features, subtypes, prognostic stratification, treatment patterns, response to first-line treatment, and 5-year outcomes were analyzed. All statistical analysis was done using Microsoft R Open statistical software linked to OncoCollect software.ResultsThere were 939 newly diagnosed CHL patients with a median age of 38 (range, 18–99) years at presentation. The male-to-female ratio was 2.07:1. Histological subtypes included mixed cellularity, CHL (MC, CHL), nodular sclerosis, CHL (NS, CHL), lymphocyte-rich, CHL (LR, CHL), and lymphocyte-depleted, CHL (LD, CHL), in 60.60%, 26.94%, 9.80%, and 2.66%, respectively. At presentation, 50.43% had B symptoms and 53.35% had advanced disease. 29.71% of advanced-stage patients had high Hodgkin IPI score. 79% and 21% of patients received 1st-line treatment with chemotherapy alone or combined modality treatment with chemotherapy and radiotherapy. The most common first-line chemotherapy was ABVD-based regimen (94.68%). The overall response rate was 93.48%. Complete response rates among early-stage favorable and unfavorable risk groups were 92.73% and 86.79%, and those among advanced-stage low- and high-risk groups were 76.64% and 69.78%, respectively. The median relapse-free follow-up duration was 51 months (IQR 22–69). A significant difference was found in 5-year EFS between the early- and advanced-stage disease 83.53% and 73.55% (p = 0.00087), respectively. Similarly, significant difference was found in EFS among early-stage patients treated with a combination of 4-cycle chemotherapy and radiotherapy vs. chemotherapy alone 88.57% and 66.33% (p = 0.0042), respectively.ConclusionsIn this large cohort from India, survival of patients with HL was comparable to the developed world. With a median follow-up of 51 months, the 5-year EFS and OS of all patients were 78.24% and 83.63%, respectively.

Predictors of Survival in Favorable Risk Patients with Metastatic Renal Cell Carcinoma Treated with a Single-Agent First-Line Therapy

Introduction: The aim of this retrospective study was to elucidate predictors of survival in metastatic renal cell carcinoma (mRCC) patients in an International Metastatic Renal Cell Carcinoma Database Consortium favorable risk group treated with frontline therapy without immune checkpoint inhibitors. Methods: A total of 238 patients with mRCC were reviewed. Among them, 55 patients in favorable risk group treated with single-agent systemic therapy were retrospectively analyzed. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each marker on overall survival (OS) was investigated with univariate and multivariate Cox’s proportional hazards regression models. Results: After a median follow-up of 46.2 months after first-line treatment initiation, the median progression-free survival (PFS) was 29.3 months, and the median OS has not been reached. The estimated percentage of patients who were alive at 12 and 24 months were 96.1 and 94.1%, respectively. Multivariate analysis revealed that the long-term duration of first-line treatment (hazard ratio [HR]: 0.972, 95% confidence interval [CI]: 0.944–0.997, p = 0.0299) and the metastases limited to lung (HR: 3.852, 95% CI: 1.080–24.502, p = 0.0361) were independent predictors for longer OS in favorable risk mRCC patients. Conclusion: First-line systemic therapy for favorable risk mRCC patients with a single agent resulted in relatively longer PFS and OS. A longer duration of first-line treatment and lung only metastases are correlated with longer OS.

Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience

目的探究维奈克拉联合阿扎胞苷（Ven+AZA）在初治不适合强化疗（unfit）及难治（≥1次强化诱导化疗未缓解）/复发（R/R）急性髓系白血病（AML）患者中的近期疗效。方法回顾性分析北京大学血液病研究所2019年6月1日至2021年5月31日接受Ven+AZA治疗（Ven 100 mg第1天、200 mg 第2天、400 mg第3～28天；阿扎胞苷75 mg/m2第1～7天）的初治unfit及R/R AML患者60例。分析各组完全缓解/血细胞计数未完全恢复的完全缓解（CR/CRi）率、微小残留病（MRD）转阴率及总体反应率（ORR）。结果60例初治 unfit及R/R AML患者，中位年龄54（18～77）岁，男性33例（55.0％），中位随访时间4.8（1.4～26.3）个月。其中初治unfit患者24例（40.0％），R/R患者36例（60.0％）。初治unfit组及R/R组中位治疗疗程均为1（1～5）个。24例初治unfit患者（依据NCCN预后分层：低危8例、中危2例、高危14例）经第1疗程Ven+AZA治疗后，17例（70.8％）达CR/CRi，3例（12.5％）达部分缓解（PR），ORR为83.3％。其中9例患者接受第2疗程治疗，2例接受第3疗程治疗。17例CR/CRi患者中8例（47.1％）经2个疗程治疗后MRD转阴。36例R/R患者经第1疗程诱导治疗后，21例（58.3％）达CR/CRi（其中7例MRD转阴，占33.3％），3例（8.3％）PR，ORR为66.7％。R/R患者中12例治疗≥2个疗程，第2疗程治疗后无新增缓解患者，累计MRD转阴14例（66.7％）。R/R患者中低危组（CR至血液学复发≥18个月）12例，其余24例为高危组。低危R/R组1个疗程后10例（83.3％）达CR/CRi，CR/CRi率显著高于高危R/R组［45.8％（11/24），P＝0.031］。在60例患者中，13例伴IDH1/2突变及4例TP53阳性患者经1个疗程治疗后均达CR/CRi，18例NPM1突变阳性患者1个疗程CR/CRi率为77.8％，5例RUNX1-RUNX1T1伴c-kit D816患者（2例初诊，3例复发）均未获缓解。Ven+AZA作为诱导及再诱导治疗总体耐受性好。结论Ven+AZA在初治unfit及R/R AML患者中均获得较高的治疗反应率，部分缓解患者可快速获得MRD转阴。其在伴NPM1、IDH1/2、TP53等基因突变的AML患者中疗效显著。