Duration Of Relapse-free Survival Research Articles

Myelodysplastic Syndrome Hematopoietic Stem Cells Can Undergo Differentiation Trajectory Rewiring to Escape Venetoclax Vulnerability

Myelodysplastic syndromes (MDS) are incurable neoplasms that arise from early hematopoietic stem cells (HSCs). The standard of care for MDS is hypomethylating agent (HMA) therapy. However, the disease invariably fails these agents, resulting in fatal cytopenias or progression to acute myeloid leukemia (AML) with a dismal prognosis. We previously showed that the cellular hierarchy of MDS HSCs predicts the mechanisms of progression after HMA failure and can guide the design or choice of specific therapeutic approaches targeting these cells (Ganan-Gomez et al., Nature Medicine 2022). MDS HSCs in one of two differentiation states, long-term HSCs or lymphoid-primed multipotent progenitors, have a “common myeloid progenitor (CMP) pattern” or “granulocytic-monocytic progenitor (GMP) pattern” of differentiation. HSCs in these 2 differentiation states persist throughout the disease course and, driven by the recurrent activation of BCL2- or NF-κB-mediated survival pathways, respectively, expand at disease progression. In our preclinical studies, pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden, which suggests that only patients with “CMP pattern” MDS may benefit from venetoclax-based therapies. Accordingly, patients with “CMP pattern” MDS, whose disease progressed after frontline HMA failure, enrolled in clinical trials of venetoclax-based therapy (NCT04160052, NCT04550442, or NCT04655755; n=28: 12 “CMP pattern” MDS and 16 “GMP pattern” MDS) had a shorter cumulative time to complete remission (P=0.012) and a longer relapse-free survival duration (14.0 months vs 5.2 months) than those with “GMP pattern” MDS did. Consistent with the hypothesis that venetoclax-based therapy selectively targets different HSC populations after HMA therapy failure, bone marrow (BM) HSC frequencies were significantly decreased at the time of remission after venetoclax-based therapy in “CMP pattern” MDS patients, but not in those with “GMP pattern” MDS. These results explain why “GMP pattern” MDS are resistant to venetoclax therapy. However, 8 of the 12 patients with “CMP pattern” MDS relapsed during venetoclax treatment and/or progressed to AML after an initial remission. In 2 patients with “CMP pattern” MDS, sequential flow cytometry and next generation sequencing analyses showed that the HSC hierarchy switched to “GMP pattern” MDS before venetoclax failure. This immunophenotypic hierarchical change was associated with the detection or expansion of STAG2- or RUNX1-mutant clones with isolated trisomy 8. To evaluate whether the immunophenotypic switch resulted from the distinct differentiation potential of early HSCs or from the aberrant expression of cell surface markers, we performed sequential single-cell RNA sequencing analyses of BM mononuclear cells isolated from the 2 “CMP pattern” MDS patients whose disease changed hierarchy before venetoclax failure. Our analyses revealed that after undergoing significant depletion during disease remission, HSCs expanded at therapy failure. Differential expression analysis showed that the expansion of STAG2- or RUNX1-mutant clones in the HSC compartment not only rewired MDS HSCs' differentiation state towards a granulo-monocytic-biased trajectory but also changed HSCs' survival dependency from BCL2-mediated anti-apoptotic pathways to TNFa-induced pro-survival NF-κB signaling, thus enabling HSCs to evade the cytotoxic effects of venetoclax (Fig. 1). The anti-apoptotic gene MCL1, a direct transcriptional target of NF-κB, was also significantly upregulated in HSCs at the time of progression, which suggests that the combination of venetoclax with an MCL1 inhibitor can overcome secondary failure to venetoclax. Together, these results reveal a novel mechanism of venetoclax resistance. HSCs under venetoclax therapy undergo survival pressure, which results in the expansion or acquisition of clones carrying specific mutations that change HSCs' survival dependencies (Fig. 2). Our study suggests that MDS patients receiving venetoclax-based therapy should be monitored at the molecular level and enrolled in clinical trials of other targeted agents before their disease undergoes clonal evolution and HSC hierarchical rewiring.

Tumor-informed circulating tumor DNA (TI-ctDNA) based molecular residual disease (MRD) detection and relapse risk for patients with stage II-IV melanoma in surgical remission: A single center experience.

9572 Background: Melanoma is associated with significant risk of relapse after surgery. While the odds of relapse increase with advancing stage, long term relapse free survival (RFS) is possible without adjuvant therapy in a significant subset of patients as shown by AJCC v8 staging long term survival data. TI-ctDNA (Signatera™) is a non-invasive biomarker for MRD detection and functions by sequencing the patient’s own tumor for the creation of a customized panel of PCR probes based upon a tumor’s unique mutational profile. Positive TI-ctDNA testing is significantly associated with relapse after surgical resection in colorectal cancer and may help inform treatment decision-making, allowing for intensification or de-intensification of patient management. This study describes the operating characteristics of TI-ctDNA in monitoring for relapse in patients with resected melanoma. Methods: This is a single center retrospective analysis of patients with stage IIb-IV melanoma in surgical remission. Between January 2021 and January 2023, male and female patients presenting in surgical remission were monitored with TI-ctDNA at 6- or 12-week intervals. Surveillance imaging for relapse was performed according to standard of care guidelines appropriate for tumor stage. Patients were treated with immunotherapy, targeted therapy, or melanoma specific anti-tumor vaccine. Duration of RFS from surgery to detectable TI-ctDNA was recorded, along with duration of RFS from surgery to confirmed melanoma relapse. Results: 45 eligible patients were included in the analysis. 10 patients had detectable TI-ctDNA during the study period. 7 patients had confirmed relapse, 6 of whom were TI-ctDNA positive and 1 who was TI-ctDNA negative. The total relapse rate in TI-ctDNA positive patients (6/10) was significantly higher than the relapse rate in TI-ctDNA negative patients (1/35) [p = 0.0002]. Time to detection of positive TI-ctDNA was variable and ranged from 0 to 664 days (median 73 days). Conclusions: TI-ctDNA testing demonstrated preliminary ability to differentiate melanoma patients at the highest risk of relapse. Prospective evaluation of TI-ctDNA monitoring for determination of patients at high versus low risk of relapse is warranted and may help to inform future clinical trial designs by allowing for patient stratification to low risk (undetectable TI-ctDNA) and high risk (detectable TI-ctDNA) disease states.

Conversion Surgery for Unresectable Pancreatic Cancer Treated With FOLFIRINOX or Gemcitabine Plus Nab-paclitaxel.

Recent advances in chemotherapy have made significant progress in conversion surgery (CS) for unresectable pancreatic cancer (uPC). However, the success rate and efficacy of CS have not been fully demonstrated in patients with uPC treated with FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP). We retrospectively reviewed the records of 318 patients with uPC who received FFX or GnP as first-line chemotherapy. The efficacy in the CS group, defined as undergoing complete resection after chemotherapy, was analyzed, and compared with the non-CS group; then, contributing factors to achieving CS were extracted. We also analyzed differences in the efficacy of CS between locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC). Overall, CS was achieved in 4.3% of cases, eight patients (13.3%) with LAPC and five (2.1%) with MPC. Contributing factors to CS were LAPC, no liver metastasis, CA19-9 ≤37, and chemotherapy response. After adjusting for these, overall survival was significantly better in the CS group than in the non-CS group [median of 32.9 vs. 11.3 months; adjusted hazard ratio (HR)=0.32; 95% confidence interval (CI)=0.14-0.70; p<0.01]. Median relapse-free survival duration after CS was 19.1 and 18.1 months in the LAPC-CS and MPC-CS group, respectively (p=0.84). The median post-conversion survival was 27.6 months in the entire CS group, 43.8 months in the LAPC-CS group and 21.3 months in the MPC-CS group. CS was achieved in 13.3% of LAPC and 2.1% of MPC cases. If possible, CS can markedly improve prognosis, even in MPC.

Outcomes of PD-1 Inhibitors Treatment of Chronic Active Epstein Barr Virus Infection : A Single Center Retrospective Analysis

INTRODUCTION Chronic active Epstein-Barr virus (CAEBV) disease is a high-mortality disease, which is characterized by persistent infectious mononucleosis-like symptoms. There is no standard treatment of CAEBV and allogeneic hematopoietic stem cell transplantation (HSCT) was considered as an only potentially therapeutic approach. PD-1 inhibitors have achieved high response in many Epstein-Barr virus-related diseases. In this single-center retrospective analysis, we report the outcomes of PD-1 inhibitors treatment of CAEBV. METHODS Sixteen CAEBV patients were treated with PD-1 inhibitors between 6/1/2017 and 12/31/2021. Hemophagocytic lymphohistiocytosis (HLH) was excluded. Patients received Nivolumab or Sindilizumab therapy every 3 to 4 weeks, 100 to 200 mg intravenously. Clinical and laboratory assessments were performed on patients before each infusion during treatment. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. RESULTS Among the sixteen patients with a median age at onset of 33 years (range, 11-67 years), twelve patients responded to PD-1 inhibitors, and their median duration of relapse-free survival (RFS) was 10.3 months (range, 1.0-54.8 months). Three of them achieved clinical complete response (clinical CR), as well as molecular CR, and nine patients achieved partial response (PR) (Figure 1). Four of the nine PR patients converted from PR to no response (NR), and five remained in PR. The remaining four patients did not respond to PD-1 inhibitor therapy. One patient eventually died from a severe lung infection and one patient died of severe liver failure. The median time and cycles from the first application of PD-1 inhibitor to clinical CR in three patients with clinical CR were 43 days (range, 30-72 days) and 3 cycles (range, 2-4 cycles). Patient 14 suffered immune-related pancreatitis (Grade 2, CTCAE 5.0) after 6 cycles of PD-1 inhibitor therapy. Four patients developed persistent or intermittent high fever after the first infusion of PD-1 inhibitors. Other than that, no treatment-related adverse events have been observed. There was no correlation of treatment outcome with blood count, aspartate aminotransferase (AST) level, alanine aminotransferase (ALT) level, LDH level, cytokine level or ferritin level. Comparing the NK cell function of responders and non-responders, the test results showed higher numbers of patients with defective NK cell function among non-responders. The immunohistochemical analysis showed that patients with high PD-L1 expression in tumor tissue may have a more significant response to PD-1 inhibitors. Genetic testing indicated that, except for 1 patient without gene sequencing and 8 patients with no related gene mutation detected, the other 7 patients were detected with potentially pathogenic or susceptibility mutations. CONCLUSION In patients with CAEBV, PD-1 inhibitors have tolerable toxicity and comparable outcomes while improving quality of life and financial toxicity. Larger prospective studies and longer follow-up time is needed to be conducted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Use of High Dose Cytarabine (HiDAC) for Post-Remission or Re-Induction Therapy Is Safe and Effective in Select Older AML Patients

IntroductionA standard therapy for fit older adults (≥60 years) with acute myeloid leukemia (AML) being treated with curative intent consists of induction chemotherapy with cytarabine and an anthracycline followed by 1-4 cycles of shorter course post-remission therapy with cytarabine +/- anthracycline. Historically, HiDAC has been reserved for younger patients due to the high incidence of cytarabine-induced neurotoxicity, febrile neutropenia, and hospital re-admissions in older patients (Mayer et al. 1994). In select older adults (e.g., those with good-risk cytogenetic/molecular abnormalities, or requiring reinduction for persistent AML), the risk/benefit for HiDAC may favor its use. Real world evidence is lacking on the safety of full dose HiDAC (total 18 grams/cycle) in fit older adults in the 60-75 age range.MethodsWe performed a retrospective analysis of AML patients ≥60 years who received at least one cycle of HiDAC, defined as 3g/m2 every 12 hours for 6 doses, either days 1-3 or days 1, 3, 5, as post-remission therapy or primary re-induction (i.e., after failure of primary induction with 7+3 or CPX-351) between July 1, 2014 and May 28, 2021. AML risk was defined by European LeukemiaNet (ELN) guidelines. All patients had daily neurologic exams including prior to each dose of HiDAC and at the beginning of each nursing shift.The primary endpoint was tolerability, defined as average dose per cycle, rate of dose reductions, incidence of febrile neutropenia, cerebellar toxicity, and rate of hospital re-admissions. Secondary endpoints were overall survival (OS), composite complete remission (CCR) for patients treated with HiDAC re-induction, and duration of relapse-free survival (RFS) (from day 1 of treatment) in all patients.ResultsFrom July 2014 to May 2021, 34 patients ≥60-years-old were treated with HiDAC at our center. Median age at HiDAC administration was 64 (60-73) [Table 1]. Approximately half the patients were Hispanic and male and almost all (97%) had ECOG performance scores of 0-1. HiDAC was used as post-remission therapy (following 7+3-type induction in 80%) in 25 patients and as re-induction in 14. Eleven patients (32%) were ELN favorable risk, 8 (25%) were intermediate, and 15 (44%) were poor risk.For post-remission therapy, the average total dose of cytarabine per cycle was 16.6 gm/m2 (6-18 gm/m2) and the median number of cycles was 4 (1-4) [Table 2]; 6 patients (24%) required dose reductions, the most common reason being upcoming allogeneic stem cell transplant (n=4). No cerebellar toxicity was observed. Duration of neutropenia was on average 15 days (7-53) in the re-induction group and 7.5 days (1-29) in the post-remission group, with 23 post-remission patients (92%) receiving granulocyte colony stimulating factors (G-CSF). Eleven hospital readmissions occurred, most commonly (73%) for febrile neutropenia. Early mortality rates were low, with one patient on the post-remission arm and one patient on the re-induction arm dying within 30 and 60 days, respectively, both due to sepsis. Median OS was 15.8 months (95% CI 0-31.8) in patients who received post-remission HiDAC, with 44% of patients still alive with a median follow up of 17.2 months (95% CI 7.2-55.8). Favorable risk patients (n=11) receiving post-remission HiDAC had median OS of 15.8 months (95% CI 0-43.1), while intermediate/poor risk patients (n=14) had median OS of 11.3 months (95% CI 9.3-13.2) [p=0.53]. Median OS was 9.8 months (95% CI 2.5-17.1) in patients who received HiDAC re-induction, with 29% of patients still alive with a median follow up of 28.6 months (95% CI 16.6-39.9) [Table 3]. Five patients (36%) achieved CCR after HiDAC re-induction, all of whom went on to receive post-remission HiDAC. Median RFS was 8.5 months for re-induction and 8.8 months for post-remission patients [Table 3].ConclusionsHiDAC (18 grams) can be safely given to select patients over age 60. Critical to tolerability is rigorous screening of “fitness,” limiting the upper age receiving HiDAC to 75, ensuring adequate renal function and euvolemia, and advances in supportive care. Encouraging survival outcomes were observed in older adults receiving post-remission or re-induction HiDAC, independent of ELN risk. [Display omitted] DisclosuresBradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding.

Phase II Trial of Eprenetapopt (APR-246) in Combination with Azacitidine (AZA) As Maintenance Therapy for TP53 Mutated AML or MDS Following Allogeneic Stem Cell Transplantation (SCT)

Phase II Trial of Eprenetapopt (APR-246) in Combination with Azacitidine (AZA) As Maintenance Therapy for TP53 Mutated AML or MDS Following Allogeneic Stem Cell Transplantation (SCT)

ALL-175: High CD38 and CD58 Expression on Leukemia Cells, Forming MRD Population, Dramatically Decreases Relapse-Free Survival in B-ALL Patients Enrolled in RALL-2016 Study

<h3>Context:</h3> It is well known that measurable residual disease (MRD) has a significant prognostic impact in patients with acute leukemia. However, the effect of the immunophenotype of MRD cells has not been studied yet. <h3>Objective:</h3> The aim of the study was to assess the significance of CD38 and CD58 expression for relapse-free survival (RFS) in B-ALL patients. <h3>Design:</h3> This study included data from 2016 to 2020 for patients enrolled in the Russian multicenter study RALL-2016 (NCT03462095). MRD was assessed in the bone marrow at the end of induction (day +70) in patients who achieved a complete remission. <h3>Patients and Methods:</h3> The RALL-2016 study included 207 adult patients. The MRD was assessed in 150 patients (80 B-ALL patients and 70 T-ALL patients). Analysis of MRD was performed by 6- or 10-color flow cytometry. The sensitivity was at least 0.01%. CD19, CD34, CD10, CD20, CD38, CD45, and CD58 were analyzed to detect MRD. The main immunophenotypic features of B-ALL blasts are low CD38 expression and high CD58 expression. CD38 expression in MRD cells was considered low if it was lower than that on normal B-cell progenitors. CD58 expression was considered high if it was equal to or higher than that on plasma cells. The RFS was estimated with the Kaplan–Meier method, and comparisons were assessed using the log-rank test. <h3>Results:</h3> Among B-ALL patients, 48 (60%) patients were MRD-negative, and 32 (40%) patients remained MRD-positive at the end of induction. The duration of RFS was lower in MRD-positive patients (median 29.5 months <i>vs</i> median undefined, p=0.004). Among MRD cells, high CD38 expression was found in 8 patients, and 7 (87.5%) of these relapsed or died. RFS was shorter in CD38-high-MRD patients than in CD38-low-MRD (median 5.2 months <i>vs</i> median undefined, p<0.001). RFS in CD58-high-MRD was also shorter (medians 9.7 <i>vs</i> 34.7 months, p<0.001). <h3>Conclusion:</h3> MRD at the end of induction was confirmed as an important prognostic factor in the RALL-2016 study. However, immunophenotyping residual blasts could improve the prognostic impact of MRD. High expression of CD58 and CD38 on MRD cells dramatically decreases the duration of RFS in B-ALL patients.

Second Autologous Transplantation in Multiple Myeloma with Renal Dysfunction

Introduction Autologous stem cell transplant (ASCT) as a salvage option in patients (pts) with late relapse (≥18 months after upfront ASCT) represents an effective therapy and can prolong response in Multiple Myeloma (MM). Presence of comorbidities such as renal dysfunction can limit treatment options and impact ASCT eligibility. Efficacy and safety data supporting a second ASCT in pts with renal dysfunction for relapsed disease are limited. Methods All adult pts with MM with renal dysfunction undergoing a non-tandem second ASCT at our institution between January 2006 and January 2019 were identified. Renal dysfunction was defined as pre-transplant creatinine clearance ≤ 60 ml/min. Demographics, disease characteristics, and treatment history were compiled. Relapse free survival (RFS), overall survival (OS), relapse rate, and non-relapse mortality (NRM) outcomes were assessed. RFS durations after both the first and second ASCTs for each pt were compared using a paired log-rank test and corresponding hazard ratios (HR) was estimated using a paired cox proportional hazards regression model through mixed-effects models. Results Thirty six pts with renal dysfunction underwent a second ASCT at our institution. Fourteen pts (39%) had progressive disease (PD) and 9 pts (25%) had very good partial response or better. Median time between first and second ASCT was 57.05 months (18.98-103.25). Conditioning regimens included: ≤140 mg/m2 Melphalan (MEL) (61%; n=22), >140 mg/m2 MEL (28%; n=10) and BEAM (8.3%; n=3). Median length of hospitalization during second ASCT was 18 days (Range, 11-74). Median time to granulocyte and platelet engraftment was 12 (9-16) and 19 (0-61) days, respectively. In hospital events included: treatment-requiring infections in 15 pts (41.7%) and cardiac complications in 5 pts (13.9%). Four pts (11.1%) required intensive/critical care admission. By day 100 (d100) assessment, 30 of 34 surviving pts (83% by ITT) had stable disease or better, and 4 pts (11%) had PD. Twenty pts (58.8%) had an improvement in disease status compared to their pre-ASCT status, while 8 pts (23.5%) maintained their pre-ASCT disease status. Five pts (14%) were readmitted by d100, with 2 pts requiring intensive care. One of 2 pts on dialysis pre-second ASCT became dialysis independent. From second ASCT, median RFS was 1.04 yrs (95% CI, 0.74 to 1.67) and median OS was 3.34 yrs (95% CI, 3.30 to 7.99; median follow up 4.31 yrs); respectively. The cumulative incidence rates for relapse and NRM at 1 yr after second ASCT were 37.1% and 5.6%, respectively. By MVA, light chain MM was associated with higher relapse rate (p=0.03) and lower NRM (p=0.01). Conclusion Our data suggests that second ASCT is well tolerated with low complication /readmission rates in patients with renal dysfunction. Second ASCT as salvage can provide disease control for more than a year for these patients who may have limited treatment options.

Predictive biomarkers of platinum and taxane resistance using the transcriptomic data of 1816 ovarian cancer patients

ObjectiveThe first-line chemotherapy for ovarian cancer is based on a combination of platinum and taxane. To date, no reliable predictive biomarker has been recognized that is capable of identifying patients with pre-existing resistance to these agents. Here, we have established an integrated database and identified the most significant biomarker candidates for chemotherapy resistance in serous ovarian cancer. MethodsGene arrays were collected from the GEO and TCGA repositories. Treatment response was defined based on pathological response or duration of relapse-free survival. The responder and nonresponder cohorts were compared using the Mann-Whitney and receiver operating characteristic tests. An independent validation set was established to investigate the correlation between chemotherapy response for the top 8 genes. Statistical significance was set at p < 0.05. ResultsThe entire database included 1816 tumor samples from 12 independent datasets. From analyzing all the genes for platinum + taxane response, we identified the eight strongest genes correlated to chemotherapy resistance: AKIP1 (p = 1.60E-08, AUC = 0.728), MARVELD1 (p = 2.70E-07, AUC = 0.712), AKIRIN2 (p = 2.60E-07, AUC = 0.704), CFL1 (p = 8.10E-08, AUC = 0.694), SERBP1 (p = 8.10E-07, AUC = 0.684), PDXK (p = 1.30E-04, AUC = 0.634), TFE3 (p = 7.90E-05, AUC = 0.631) and NCOR2 (p = 1.90E-03, AUC = 0.611). Of these, the independent validation confirmed TFE3 (p = 0.012, AUC = 0.718), NCOR2 (p = 0.048, AUC = 0.671), PDXK (p = 0.019, AUC = 0.702), AKIP1 (p = 0.002, AUC = 0.773), MARVELD1 (p = 0.044, AUC = 0.675) and AKIRIN2 (p = 0.042, AUC = 0.676). An online interface was set up to enable future validation and ranking of new biomarker candidates in an automated manner (www.rocplot.org/ovar). ConclusionsWe compiled a large integrated database with available treatment and response information and used this to uncover new biomarkers of chemotherapy response in serous ovarian cancer.

Knockdown of LINC01116 inhibits cell migration and invasion in head and neck squamous cell carcinoma through epithelial-mesenchymal transition pathway.

Long noncoding RNAs (lncRNAs) are linked to tumor development and progression. The aim of this study was to determine the prognostic significance and biological role of LINC01116 in head and neck squamous cell carcinoma (HNSCC). We identified 21 aberrantly expressed lncRNAs specific to HNSCC that were common in two microarray datasets. LINC01116 was highly overexpressed in HNSCC tissues and was correlated to shorter overall survival and relapse-free survival duration, as analyzed by the online Gene Expression Profiling Interactive Analysis platform. LINC01116 was also overexpressed in oral squamous cell carcinoma and nasopharyngeal carcinoma tissues, and LINC01116 silencing significantly inhibited the migration and invasion capacities of both cell lines by blocking the epithelial-mesenchymal transition process. In addition, 125 coexpressing genes were identified by circlncRNAnet, and were mainly located on human autosomes and enriched in transforming growth factor-β signaling pathway. These findings indicate that LINC01116 might be a potential therapeutic target for HNSCC.

A Phase 1 Trial of CNDO-109–Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia

Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell–resistant cell lines. To translate this finding to the clinic, CNDO-109–activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 105 (n = 3), 1 × 106 (n = 3), and 3 × 106 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3 × 105), 156 (1 × 106), and 337 (3 × 106) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.

Reirradiation of gliomas under stereotactic conditions: Prognostic factors for survival without relapse or side effects, a retrospective study at Tours regional university hospital (France)

PurposeTo search for factors correlated with relapse-free survival following stereotactic reirradiation in patients with recurrent glioma following radiochemotherapy and evaluate tolerance to this treatment. Patients and methodsInitial radiotherapy was given according to the protocol of Stupp and al. Reirradiation was performed using the CyberKnife® system. Patients could have had surgical resection initially and at the time of recurrence. We analysed 13 patients treated between July 2010 and September 2014. The median age was 55 years. The doses delivered ranged from 20 to 36Gy, in one to ten fractions. ResultsMedian survival after stereotactic radiotherapy was 14 months. Survival without relapse was 3.7 months. Factors significantly influencing duration of relapse-free survival were: age (P=0.04), total dose (P=0.02), dose per fraction (P=0.04) and number of fractions (P=0.01). We found no correlation between gross tumour volume, clinical target volume, grade of tumour or prescription isodose and relapse-free survival following radiochemotherapy. Three patients developed radionecrosis. ConclusionReirradiation under stereotactic conditions is well tolerated. A dose of more than 30Gy delivered in 5 or more fractions seems to prolong relapse-free survival.

RADIATION THERAPY OF MENINGEAL HEMANGIOPERICYTOMAS (LITERATURE REVIEW AND CLINICAL OBSERVATION)

Meningeal hemangiopericytomas are rare tumors of the meninges developing from pericytes. The main method of their treatment is surgery aimed at total removal of the tumor. Analysis of the literature studies shows high potential of post-operative distant radiation therapy to increase duration of relapse-free survival of these patients. The recommended total radiation dose varies from 50 to 60 Gy (and in some publications, it exceeds 60 Gy). Radiation is applied as classic fractionation and hypofractionation, and different types of radiosurgery and stereotaxic radiotherapy are suitable approaches to treatment of recurrent meningeal hemangiopericytomas in patients with a history of radiation therapy.

The Role of Intraperitoneal Carboplatin as Consalidation Chemotherapy in Women with Ovarian Carcinoma: Report of Our Experience and Systematic Review

Background: Epithelial ovarian cancer is the leading cause of death from gynecology malignancy. The aim of this study was to assess the role of intraperitoneal chemotherapy with carboplatin, as a consolidative treatment, in reducing relapse and increasing survival of patients in advanced epithelial ovarian cancers, as well as evaluation of its toxicity. Methods: This clinical trial was conducted on 30 patients with epithelial ovarian cancer in stages II-IV in Gynecology oncology department in Valiasr University Hospital, Tehran during 2005-2010. They were enrolled through non-random sequential selection. They divided into 18 cases as the intervention group (receiving intraperitoneal chemotherapy) and 12 patients as the control group (with only retrospective follow-up). The cases received 3 cycles of 400 mg/m2 intraperitoneal carboplatin every 21 days following intravenous chemotherapy. Mean survival of two and five years, progression-free interval, overall survival, relapse, demographic parameters, drug toxicities and pathologic types of cancers were coded in the two groups and compared using SPSS 14. Results: The mean ages of cases and controls were 52.4 ± 8.6 and 55.1 ± 11.5 years. The mean duration of relapse-free survival was 13 ± 8.6 months for the cases and 9.5 ± 4.3 months for the control patients (not statistically different, P&gt;0.05). The mean overall survival for cases and controls were 39 ± 16.5 and 30.8 ± 16.2 months, respectively (no significant difference, P&gt;0.05). The frequency of drug toxicities in the cases was 5.6%, and consisted of mild-to-moderate abdominal pain, nausea and vomiting. Conclusion: consolidation therapy with intraperitoneal carboplatin may not increase overall survival, reduce relapse rate or decrease mortality, though it does not induce considerable side effects.

Minimal Residual Disease Assessment May Drive Post Remission Therapy in Acute Myeloid Leukemia. It's Time for MRD-Driven Therapy

IntroductionWith standard intensive induction regimens, up to 80% of Acute Myeloid leukemia (AML) patients can achieve complete remission (CR). Several evidences demonstrated that the persistence of detectable disease (MRD) assessed with highly sensitive techniques such as Multicolor-Flow-Cytometry (MFC) and PCR based molecular analysis, retains a prognostic value among patients achieving morphological remission (Walter RB, 2015; Araki D et al, 2016, Zhou Y et al, 2016).The aim of the present study was to retrospectively evaluate the prognostic impact of MRD in a cohort of uniformly treated AML patients.One hundred and ten consecutive AML patients who had been treated in our center between January 2004 and December 2014 were retrospectively analyzed. All patients had received a fludarabine-containing induction (FLAI-5) and received second cycle and further consolidation therapy according to our published strategy (Guolo F, 2016). Median age was 47 years (range 17-61). Median follow up was 59 months. Patients features are summarized in Table I.MRD assessment was performed through 4-colour MFC analysis (MFC-MRD)and through WT1-gene expression analysis, as previously described (Guolo F, 2016). Three different MRD time-points (TP)were considered: TP1, after induction I; TP2, after induction II; TP3, after consolidation therapy for patients who did not undergo HSCT and at HSCT for patients who underwent HSCT. Relapse-free survival (RFS) was calculated from the time of diagnosis until last follow-up or documented leukemic relapse.CR rate after 1st and 2ndinduction was 82.7 and 85.5%, respectively, whereas 30 and 60 days mortality was 6.4% and 8.2%, respectively.Overall, patients showed MRD reduction from TP1 to TP2. Detailed MRD negativity rates are provided in table II. MRD clearance probability was significantly influenced only by ELN risk group and Karyotype (p <0.05 for both).In the whole cohort, 2 years RFS was 62.4% (median not reached). RFS duration was significantly influenced by secondary disease (p <0.001), NPM mutation (p <0.05), ELN risk group (p <0.001), WT1 expression level at diagnosis (p<0.03) and MFC MRD positivity, at any time-point with both <0.025% and <0.1% as cut-off for positivity (p<0.03 and 0.05, respectively, for MRD TP1 and p<0.05 and <0.005, respectively, for MRD TP2, Figure 1), WT1 MRD at TP1 (p<0.05). Multivariate Cox-Proportional Hazard model showed that MFC MRD <0.1% at TP2 was the strongest predictor of DFS.Overall survival (OS) analysis led to similar results.However, at TP1, when performing MFC-MRD evaluation with a "Leukemia-associated immunophenotype" (LAP) approach, the choice of the deeper 0.025% cut-off for positivity identified patients at lower risk of relapse (2-year RFS of 88.9%) whereas patients with MFC MRD >0.1% had an high probability of relapse, with a 2-year RFS of only 21.5%.Moreover, the combination of MFC and WT1- MRD assessment identified three subgroups of patients with significantly different outcome (2-years OS 100, 64.4 and 46.7%, respectively, for MFC-neg/WT1 neg, MFC-pos/WT1 neg, MFC-pos/WT1 pos), as we previously described (Marani C, 2013).Consolidation chemotherapy with High Dose Ara-C was able to improve prognosis and increase MRD TP3 negativity rate only in patients not scheduled for HSCT in 1st CR and only if at least 2cycles were administered. The positive impact was higher if MFC MRD at TP2 was <0.1%.ConclusionsOur data clearly show that the quantification of MFC-MRD assessment at different time-points during treatment retains a strong prognostic impact in AML and can improve patients-risk stratification.In our experience the established threshold of 0.1% to define MFC negativity is confirmed as the most useful in post induction program setting. However, performing a MFC-MRD evaluation with LAP approach, choosing a deeper cut-off value can discriminate patients with a significantly lower risk of relapse. Prospective randomized trials evaluating the prognostic impact of MRD-driven therapeutic decisions are strongly needed. [Display omitted] [Display omitted] [Display omitted] DisclosuresGobbi:Takeda: Consultancy; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Celgene: Consultancy; Roche: Honoraria; Novartis: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding.

E2A-PBX1 exhibited a promising prognosis in pediatric acute lymphoblastic leukemia treated with the CCLG-ALL2008 protocol.

ObjectiveThe objective of this study was to observe the prognosis of pediatric patients with E2A-PBX1-positive acute lymphoblastic leukemia (ALL) from the treatment with the CCLG-ALL2008 protocol.Design and methodsThree hundred and forty-nine Chinese pediatric patients with pre-B-cell ALL were enrolled in this study from December 2008 to September 2013. Of these, 20 patients with E2A-PBX1 expression and 223 without the gene expression were stratified into two cohorts. Clinical and biological characteristics and 5-year event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS) were analyzed and compared between these two groups.ResultsThe E2A-PBX1 fusion transcript was detected in 20 of 349 (5.7%) patients. Compared with the gene-negative subgroup, patients with E2A-PBX1 were younger in age but did not show significant differences in white blood cell (WBC) count or gender distribution at primary diagnosis. Moreover, there were more inferior karyotypes detected in the E2A-PBX1 subgroup (P=0.035). With the CCLG-ALL2008 treatment protocol, patients with E2A-PBX1 showed a favorable treatment response with lower minimal residual disease (MRD) levels (<10−4) at time point 1 (TP1, P=0.039) but no superior steroid response or histological remission. We also observed a promising survival outcome, with a 5-year EFS reaching 95.0%±4.9% versus 66.3%±3.9% in the gene-negative group (P=0.039). However, we did not find significant differences in RFS (P=0.061) and OS (P=0.113).ConclusionOur data provided clinical observation of Chinese pediatric patients. Patients with E2A-PBX1-positive ALL benefited well from the CCLG-ALL2008 protocol, a risk-based intensified treatment trial, with lower levels of MRD and longer RFS duration though they had no favorable characteristics at primary diagnosis.

Mitoxantrone and Etoposide for the Treatment of Acute Myeloid Leukemia Patients in First Relapse

Relapsed acute myeloid leukemia (AML) represents a major therapeutic challenge. Achieving complete remission (CR) with salvage chemotherapy is the first goal of therapy for relapsed AML. However, there is no standard salvage chemotherapy. The current study evaluated outcomes and prognostic factors for achievement of CR in 91 AML patients in first relapse who were treated with the mitoxantrone–etoposide combination regimen. The overall response rate (CR and CRi) was 25%. Factors that were associated with a lower rate of CR included older age, shorter duration of first CR, low hemoglobin, and low platelet count. The median overall survival for all patients was 7.4 months. The survival of patients who achieved CR and underwent allogeneic hematopoietic cell transplantation (allo-HCT) was higher than those who achieved CR and did not undergo allo-HCT (35.3 months vs. 16.8 months, p = 0.057). The median duration of relapse-free survival was 12.7 months in the patients achieving CR. Older age at the time of AML relapse was associated with worse overall survival. The all-cause 4-week mortality rate was 4%, and the all-cause 8-week mortality rate was 13%. The findings of this study underscore the need for newer therapies, especially those that will improve the ability for patients with relapsed AML to achieve CR and to allow them to receive additional therapies.

European experience with methotrexate treatment in Crohn's disease: a multicenter retrospective analysis.

Methotrexate (MTX) has been utilized for the treatment of Crohn's disease (CD) for decades. Nevertheless, current data provide equivocal evidence on the efficacy of MTX in CD.The aims of this study were to describe the efficacy of MTX for maintenance of remission in CD and to identify the factors associated with the probability of steroid-free clinical remission in a multicenter European referral center cohort. This was a retrospective cohort analysis. Consecutive patients treated with MTX for CD were included from 11 referral centers. Patients receiving concomitant treatment with tumor necrosis factor inhibitors or thiopurines were excluded. The main outcome was steroid-free clinical remission; the secondary outcomes included the rate of complications leading to MTX discontinuation and duration of relapse-free survival in patients achieving the main outcome. Between July 1992 and January 2012, 118 patients were identified for inclusion. MTX administration route was oral for induction in 31.4% and for maintenance in 49.1% of the patients. Steroid-free remission was achieved in 44/118 (37.2%) patients and was maintained relapse free by 28/44 (63.6%) for a median of 12 (3.5-18.5) months. At least one adverse effect was reported by 28.9% of the patients. No clinical or demographic factors were associated with either likelihood of achieving a clinical response or duration of relapse-free survival. MTX treatment induced steroid-free clinical remission in over a third of CD patients and maintained it for a year in almost two-thirds of the responders. MTX should be considered a viable therapeutic option in CD patients refractory to other therapies.

Krüppel-like Factor 4 Blocks Hepatocellular Carcinoma Dedifferentiation and Progression through Activation of Hepatocyte Nuclear Factor-6.

Tumor differentiation is a behavioral index for hepatocellular carcinoma (HCC) and a prognostic factor for patients with HCC who undergo orthotopic liver transplantation (OLT). However, the molecular basis for HCC differentiation and prognostic value of the underlying molecules that regulate HCC differentiation are unclear. In this study, we defined a potential driver pathway for HCC differentiation and prognostication. The regulation and function of Krüppel-like factor 4 (KLF4) and hepatocyte nuclear factor-6 (HNF-6) in HCC differentiation was evaluated using human tissues, molecular and cell biology, and animal models, and its prognostic significance was determined according to its impact on patient survival. There was a direct relationship between the expression levels of KLF4 and HNF6 in HCC. Reduced KLF4 or HNF6 expression correlated with high HCC grade. Poorly differentiated HCC cells had lower expression of KLF4 or HNF6 and differentiation-associated markers than did well-differentiated cells. Elevated KLF4 of HNF6 expression induced differentiation of poorly differentiated hepatoma cells. Mechanistically, KLF4 trans-activated HNF-6 expression. Restored HNF-6 expression upregulated expression of differentiation-associated markers and inhibited HCC cell migration and invasion, whereas HNF-6 knockdown did the opposite. Loss of KLF4 expression in primary HCC correlated with reduced overall survival and shortened relapse-free survival durations after OLT. Combination of KLF4 expression and the Milan criteria improved prognostication for HCC after OLT. The dysregulated KLF4/HNF-6 pathway drives dedifferentition and progression of HCC, and KLF4 is a biomarker for accurate prognostication of patients with HCC treated by OLT when integrated with the Milan Criteria.

Undetectable anti-TNF drug levels in patients with long-term remission predict successful drug withdrawal.

Low drug levels are associated with emerging loss of response to anti-TNF. However, this may not be the case in patients with long-term remission. To investigate the outcome of anti-TNF discontinuation in patients with long-term remission and incidental undetectable drug levels. A retrospective cohort study examining the duration of relapse-free survival in IBD patients in remission who discontinued infliximab or adalimumab having undetectable drug levels. Forty eight patients who discontinued anti-TNF while in remission and had available drug levels were identified in two centres in France and Israel (infliximab-treated 35, adalimumab-13, Crohn's disease 30, ulcerative colitis 18, mean treatment duration of 22.7 ± 12.4 months). Endoscopy/MRE before stopping showed absence of active inflammation in 40/42 (95%) of evaluated patients, while inflammatory biomarkers (CRP and/or Calprotectin) were completely normal in only 31/48 (65%) of patients. During 12 months median follow-up, relapse occurred in 16/20 (80%) of patients who stopped anti-TNF while having measurable drug levels compared with 9/28 (32%) of patients who had undetectable drug levels (OR: 8.4, 95% CI: 2.2-32, P = 0.002). Relapse-free survival after anti-TNF cessation was significantly longer in patients with absent drug compared to those with detectable drug (P < 0.001, log rank test). On multivariate analysis, a patient's decision to stop therapy was weakly associated and abnormal inflammatory biomarkers and detectable drug levels were both strongly and independently associated with a higher risk of relapse after drug discontinuation. Incidental finding of undetectable anti-TNF drug levels in patients with stable long-term deep remission may identify a subset of patients whose clinical remission is no longer dependent on anti-TNF treatment.