bluuebunny/crossref_metadata_2025 huggingface dataset:
Micafungin As Antifungal Prophylaxis during Induction Phase of Chemotherapy in Pediatric Acute Lymphoblastic Leukemia
Authors: Khalil Sahar A , Mahmoud Afaf m , Shalaby Lobna m , el-Mahallawy Hadir A , Elhaddad Alaa M
Published: October 2019

Background:

Invasive fungal infection (IFI) comprises a major cause of infection related morbidity and mortality in neutropenic patients receiving chemotherapy or hematopoietic stem cell transplantation (HSCT). Micafungin exhibits broad antifungal activity against both Aspergillus and Candida species.

Objective :

We performed a prospective study to determine the efficacy, safety, and tolerability of prophylactic micafungin against IFI in pediatric neutropenic patients during induction chemotherapy for acute lymphoblastic leukemia (ALL). Patients and methods:

The study included 70 patients randomized in to two groups: Intervention group: 35 patients were given micafungin daily at a dose of (1 mg/kg/day) with maximum of 50mg/day from day one to the end of induction with close follow up for toxicity, tolerability, and efficacy. In case of failure of prophylaxis (defined as development of proven, probable, or possible fungal infection according to revised definitions of EORTC/MSG consensus group), we shifted to either voriconazole or liposomal ampho-B. Control group: 35 patients were treated according to empirical antifungal approach. Follow up of patients by clinical examination, routine work up, serum galactomannan, blood cultures, and CT chest together with paranasal sinuses. Results:

Treatment success rate, defined as absence of proven, probable, or possible IFIs was 75%; in the control group 8/35 (22.8%) developed IFIs, while in the intervention group 2/35 (5.7%). No adverse events were observed that could be related to micafungin prophylaxis. Conclusions:

These results suggest that prophylactic micafungin is well tolerated and may prevent IFIs in pediatric patients with neutropenia receiving chemotherapy.

Keywords: Pediatric, ALL, induction chemotherapy, IFI, micafungin prophylaxis.

Disclosures

No relevant conflicts of interest to declare.
Acute Promyelocytic Leukemia Relapse in a Large Medical Center of China over a 9-Year Period: Evolving Treatment Strategies and Lessons for This Highly Curable Disease
Authors: Wang Huaiyu , Zhang Huiyun , Li Dengzhe , Zhang Xinxin , Chen Limei
Published: October 2019

All-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combination based therapy has become recommended first line treatment for de novo diagnosed low- to intermediate-risk acute promyelocytic leukemia (APL) patients. Though highly curable, relapses of APL could happen due to various reasons. In this research, we retrospectively analyzed data from patients who were diagnosed and treated APL between 2007 and 2015 in a tertiary hospital in northwest China. 123 APL patients were included, among which, 13 patients experienced relapse despite intensive treatment of ATRA plus ATO or ATRA plus chemotherapy or ATRA plus ATO plus chemotherapy. Although they all achieved complete remission after first induction therapy, 2 patients relapsed during maintenance therapy, 3 patients discontinued treatment then relapsed, 6 patients relapsed during consolidation therapy. Relevant data were subsequently compared with guidelines and multi-centre clinical researches to find out possible reasons of relapse. The results showed, all 13 relapsed patients received less than recommended dose of ATRA and ATO. 6 patients had longer than 4 months' treatment intervals, 4 patients received more than 5 courses of chemotherapy as consolidation or maintenance therapy, among which 2 patients relapsed during maintenance therapy till received chemotherapy 12 and 16 courses respectively. Risk assessment: 5 patients with low-risk, 4 patients with intermediate-risk, 4 patients with high-risk. Conclusion: It is highly possible that the relapse of APL is related to insufficient prescription of ATRA and ATO, and too many courses of chemotherapy may exert negative effects on outcome.

Disclosures

Wang: National Natural Science Foundation of China: Research Funding. Zhang:National Natural Science Foundation of China: Research Funding. Li:National Natural Science Foundation of China: Research Funding. Zhang:National Natural Science Foundation of China: Research Funding. Chen:National Natural Science Foundation of China: Research Funding.
Acute Promyelocytic Leukemia with FLT3/ITD and RUNX1 Mutation Presenting As Extramedullary Soft Tissue Mass
Authors: Mori Shahram , Yuan Cai , Ahmed Wesam B. , Patel Rushang D.
Published: October 2019

Background: APL formerly known as AML M3 is a variant of myeloid malignancies characterized by recurrent cytogenetic abnormality of PML/RARA translocation, t(15;17). Myeloid sarcoma, also called granulocytic sarcoma or chloroma, is a very rare presentation of extramedullary APL. In rare cases seen, it presents mainly as CNS disease in relapsed or refractory patients. Extramedullary APL on initial presentation is even rarer. As a result no significant information exists on the prognosis of such patients.

Case report: A 50-year-old Caucasian female with no past medical history, presented with 6-month duration of chest pain, which was treated as costochondritis without any improvement. Three months later, a soft tissue mass was identified on her sternum. Complete blood count revealed pancytopenia with white blood cell 3.24 x 103/uL, hemoglobin 10.0 g/dL, platelets 58x 103/uL, absolute neutrophil count 1.13 x103/uL, and monocytes 0.13 x103/uL which indicated "low risk disease". A PET/CT scan revealed a 4.6 cm x 4 cm sternal soft tissue mass. The biopsy of the mass confirmed myeloid sarcoma. Bone marrow biopsy showed acute promyelocytic leukemia, approximately 20% blasts in a hypercellular marrow with 70-80% cellularity. Cytogenesis test was negative. FISH analysis subsequently showed a partial RARA transcript inserted at the PML locus suggestive of a cryptic PML/RARA. This was confirmed by PCR for the fusion transcript PML/RARA from the bone marrow. Next generation genome sequencing identified FLT3/ITD and RUNX1 mutation. The patient was treated as a high risk disease due to the presence of chloroma and immediately started on treatment with Daunorubicin, Arsenic Trioxide (ATO), and All-Trans-Retinoic Acid (ATRA).

Conclusion: We present an extremely rare case of APL initially presenting with concomitant extramedullary sternal soft tissue mass with cryptic t(15;17) and somatic mutations in FLT/ITD as well as RUNX1 mutations. To our knowledge this is the first reported case of extramedullary APL with FLT/ITD and RUNX1 mutations. Early recognition of this rare presentation with timely chemotherapy may improve the outcomes of these patients.

Disclosures

No relevant conflicts of interest to declare.
Chemotherapy Cannot Replace Transplantation in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia
Authors: Li Xiaoyu , Chen Baoan , Cheng Jian , Lin Min , Zhang Xiaoping , Ge Zheng
Published: October 2019

Abstract Text: Objective: The mortality rate of refractory/relapsed acute myeloid leukemia (AML) is very high with poor prognostic. Three are still no standard treatments for these patients nowadays. Our research compared the treatment effect between patients with chemotherapy and transplantation. Method: A retrospective research of 45 patients with refractory/relapsed AML was performed in our center. We analyzed the clinical features including gender, age, classification of AML, performance status (PS), complete remission (CR) duration, cytogenetic and molecular abnormities. Survival analyses were made by using the Kaplan Meier method and took the Log - rank test. Results: The mean survival time of the 45 patients with refractory/relapsed AML was (36.25¡À8.40) months and the median follow up was (9¡À2.58) months. The one year and two years overall survival rate was (40.6¡À7.5)% and (23.7¡À7.0)%. Univariate analysis results demonstrated that age¡Ý60 years and failing to undergo HSCT after relapse had poor influence on OS. Conclusion: Performance of HSCT after relapse can improve the prognosis through the single center study. HSCT is still the effective salvage therapy for patients with refractory/relapsed AML. Our research is benefit for individual therapy and can be applied to improve the survival.

Disclosures

No relevant conflicts of interest to declare.
The Experience in Treating Elders with AML Using High-Dose AraC.
Authors: Rodriguez Cesar , Herzig Roger , Herzig Geoffrey P.
Published: October 2019

Introduction

Cytarabine combined with an anthracycline has long been the basis of therapy for acute myeloid leukemia (AML). Complete remission (CR) with standard therapy in patients > 60 has been reported to be 30 - 50%. Studies to improve remission rates have suggested that induction treatment using high-dose cytarabine (HDAraC) in adults age < 60 is safe and may improve survival in some patients. The use of such an aggressive induction regimen in older (>60) patients has not been extensively studied. The objective of this study was to assess tolerability and efficacy of HDAraC in patients 60 years of age or older compared to those age < 60.

Methods

Chart review of all patients that received induction chemotherapy with HDAraC between 2007 and 2013 at University of Louisville was done evaluating for: disease status and performance status at time of diagnosis, adverse effects during induction treatment, and treatment outcomes. HDAraC treatment in patients > 50 involved cytarabine at 1.5 g/m2 every 12 hours for 12 doses; for patients < 50, the cytarabine dose was 3g/m2 every 12 hours for 12 doses. Cytarabine was combined with 3 daily doses of idarubicin (12 mg/m2) on days 2-4 in all patients. Response was assessed with bone marrow biopsy on day 30 of induction or until neutropenia resolved.

Results

Seventy-seven patients received HDAraC between 2007 and 2013 (42 patients age < 60 and 35 patients age > 60. One patient < 60 and 8 patients > 60 died before day 30 without remission; 35 (83%) patients < 60 achieved CR and 21 (60%) of patients > 60 achieved CR (p=0.038). Adverse events related to induction chemotherapy were statistically significant more common in patients > 60 for respiratory failure (p=0.01), septic shock (p=0.004), bleeding complications (p=0.029), and cardiac toxicity (p=0.001), but not for kidney failure (p=0.302), gastrointestinal complications (p=0.226), neurotoxicity (p=0.105), or neutropenic fever (p=0.205). Overall toxicities, especially death within 30 days, was increased in patients > 60.

Conclusions

HDAraC induction in patients > 60 had a favorable CR rate (60%) compared to reported CR with conventional therapy, but with more toxicity when compared to younger patients. Additional studies involving a larger study group and subset analysis of cytogenetic and molecular markers could identify a specific elder population that may benefit from high-dose treatment. Evaluation of tools like the Comprehensive Geriatric Assessment (CGA) or a modified HCT-CI in this setting are recommended.

Disclosures

No relevant conflicts of interest to declare.
γH2AX Foci Increase Across the Spectrum from Myelodysplastic Syndromes to Acute Myeloid Leukemias and Co-Localize with 53BP1 in Specific Patterns in the Context of an Impaired DNA Damage Response
Authors: Popp Henning D , Brendel Susanne , Naumann Nicole , Henzler Thomas , Hofmann Wolf-Karsten , Fabarius Alice
Published: October 2019

Purpose: Increased DNA damage and alteration of the DNA damage response (DDR) are critical features of genetic instability presumably implicated in pathogenesis of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML).

Materials and methods: We performed combined γH2AX/53BP1 immunofluorescent focus staining of DNA double-strand breaks (DSB) in MDS and AML cell lines, in CD34+ selected cells of normal and MDS bone marrow (including three cases of chronic myelomonocytic leukemias) and in blasts of AML bone marrow. In addition, we screened for activation of DDR by immunoblotting of p-ATM, p-ATR, p-CHK1, p-CHK2 and p-TP53.

Results: Compared to γH2AX foci levels in normal bone marrow samples (0.18 focus per CD34+ ± 0.6), increased levels of γH2AX foci were detected in 1/1 MDS cell line (6.4 foci per cell ± 0.0), 6/6 AML cell lines (12.0 foci per cell ± 0.6), 12/12 MDS bone marrow samples (2.8 foci per CD34+ ± 0.7) as well as 12/12 AML bone marrow samples (6.0 foci per blast ± 0.6). γH2AX and 53BP1 co-localized in all tested samples forming diffuse, clustered and marginal patterns. DDR proteins were expressed heterogeneously suggesting impairment of DDR.

Conclusions: Our results provide evidence for a continuous increase of constitutive DSB across the spectrum from MDS to AML in the context of an impaired DDR. γH2AX and 53BP1 co-localize in unique patterns in nuclei of MDS and AML presumably owing to a non-random spatial organization of the genome and foci formation implies promotion of ineffective nonhomologous end-joining repair mechanisms at sites of constitutive DSB.

Disclosures

No relevant conflicts of interest to declare.
BM-MSC Hhip Induced Microenvironment Protection from Chemotherapy in AML Via Ptch/Smo/Gli Pathwa
Authors: Jiang Xuejie , Xu Dan , Chen Fang , Jiang Ling , Yu Guopan , Meng Fanyi , Liu Xiaoli , Liu Qifa
Published: October 2019

Introduction. The mechanism of drug resistance is complicated in acute myeloid leukemia (AML), bone microenvironment provides protection niche for leukemia stem cells (LSC), and considered as an internal environment for AML cells to escape from chemotherapeutics cytotoxicity, but mechanism of drug resistance induced by microenvironment mesenchymal stem cell (MSC) isn't completely clear. In prophase study, it was found that Ptch/Smo/Glis pathway was the key in the network of AML drug resistance. Smo inhibition improved the survival of AML-bearing mice. Low expression of HHIP was found in refractory AML MSC and bone morrow liquid, overexpression of Smo and Gli-1 was verified in AML cells, and negatively correlated with prognosis in AML patients. Chemotherapeutic drug sensitivity was decreased in AML cells after co-cultured with AML MSC in vitro.

Methods. Bone morrow samples from AML patients and normal donors were collected to culture MSC cells. HL60/ADM and Kasumi-1 cells as well as HL60、KG-1cells were treated with daunomycin (DNR) or cytosine arabinoside (Ara-C) when cocultured with MSC. Cell cycle and apoptosis were determined by flow cytometry. The expression of HHIP was determined by confocal image and western blotting. Smo and Gli-1 activity was determined by western blotting.

Result. We took advantage of AML cells cocultured with MSC to imitate leukemic microenvironment in vitro. Co-culture with AML BM-MSC decreased the sensitivity to DNR or Ara-C compared with normal BM-MSC in HL60/ADM or Kasumi-1 cells. Flow cytometry analysis showed that cells in S phase and percentage of apoptosis cells were increased after co-culture with AML MSC. Western blotting also determined that low expression of HHIP was detected in refractory AML BM-MSC, Smo and Gli-1 expression were increased in HL60/ADM or Kasumi-1 cells after co-cultured with MSC. Confocal analysis also confirmed that the combination of HHIP and Ptch was decreased in AML MSC co-culture, Smo/Gli-1 pathway was activated through decreased inhibition of Shh in refractory AML cells co-cultured with MSC. Samples from AML patients also demonstrated that HHIP expression in AML BM-MSC was lower than that in normal BM-MSC, especially in refractory AML samples. HHIP expression in BM-MSC was negatively related to Smo and Gli-1 activity. Clinic data also showed that AML patients with overexpression of HHIP had a worse prognosis.

Conclusion. Our study demonstrated expression of BM-MSC HHIP was negatively related to activity of Ptch/Smo/Glis in AML. Low expression of BM-MSC HHIP resulted in activating Ptch/Smo/Gli pathway, and indicated drug resisitance and bad prognosis in AML. This project is connected with basic research and clinic, and provides support for diagnosis and targeted therapy in AML.

Disclosures

No relevant conflicts of interest to declare.
Association Analysis Between Oncogenic Genes and the Efficacy of Demethylation Drug
Authors: Wang Bianhong
Published: October 2019

Objectives:

In the present study, we investigated the relation between genetic mutations and complete remission (CR) in 78 leukemia patients treated with demethylation drug.

Methods:

One hundred and eleven leukemia-related genes were sequenced by ultra-deep targeted sequencing. Among these, 52 genes were found to be mutated, such as DNMT3A, TET2, IDH1, IDH2, etc., hotspot genes of demethylation drug treatment.

Results:

No DNMT3A nor TET2 mutations were found in 17 patients without significant remission after demethylation drug treatment, while 18% (11/61) patients with complete remission after demethylation drug treatment harbored DNMT3A mutations, and 10% (6/61) patients achieving complete remission after demethylation drug treatment harbored TET2mutations. The difference was statistically significant when compared with non-mutant group (P<0.05).

Conclusions:

Our study indicated a significant association between mutations of DNMT3A and TET2 and efficacyof demethylation drug-treated leukemia patients. Complete remission after demethylation drug treatment was achieved more frequently in the cohort harboring mutated DNMT3A or TET2, which is consistent with previous studies. Our findings suggest ultra-deep targeted sequencing is helpful for investigating the relation between mutated genes and the efficacy of drug. Moreover, it could be a way for screening more suitable patients for demethylation drug treatment in consideration of its extremely high expense.

Disclosures

No relevant conflicts of interest to declare.
Prognostic Genomic Biomarkers for Acute Myeloid Leukemia (AML) Based on French-American-British (FAB) Subtypes
Authors: Ping Zheng , McIntosh Eleanor R , Tao Guo , Shen Dejun , Reddy Vishnu
Published: October 2019

Background: The FAB classification system divides AML into eight subtypes, M0-M7, based on the blast cell morphology and its degree of myeloid maturation. It's an older system to classify AML, but is still used in some treatment protocols. Some prognostic factors related to patient and tumor characteristics have been previously described for AML, including age, Karnofsky score, and karyotype etc. However, the prognostic genomic biomarkers for detailed FAB subtypes of AML are not well defined.

Design: Whole genome sequencing data were analyzed in 197 cases of AML. Twenty-four mutation genes and 38 copy number altered genes were selected based on change rate >=2% as a cutoff. Kaplan Meier Survival analysis for these genes was performed in five FAB subtypes (M0-M5). M6 and M7 are excluded from this study because of small sample size (M6, n=3; M7, n=3). All sequencing data and corresponding pathology information were from The Cancer Genome Atlas (Acute Myeloid Leukemia, TCGA provisional) and were analyzed via cBioPortal bioinformatics tool.

Result: Total of seven mutation genes and two copy number altered genes show prognostic values. TP53 gene mutation is associated with worse overall survival in M0 (n=18). DNMT3A gene mutation is associated with worse overall survival in M1 (n=44). Gene mutations of NPM1, FLT3, IDH1 and gene amplification of KMT2A are associated with worse overall survival in M2 (n=44). BRINP3 gene mutation is associated with worse overall survival in M3 (n=21). TP53 gene mutation and gene amplification of KMT2A and ERG are associated with worse overall survival in M4 (n=39). KRAS mutation is associated with worse overall survival in M5 (n=22). (Log-rank test, p<0.05 for all tests)

Conclusion: These data suggest that different FAB subtypes of AML could have unique prognostic genomic biomarkers. Compared with whole exome sequencing, targeted gene sequencing for these biomarkers may save time and money for patients. Further studies are necessary to understand the biological effects of these gene mutations/amplifications and confirm the above associations.

Disclosures

No relevant conflicts of interest to declare.
Doublet Versus Triplet PET: Is END of Therapy PET Needed IF Interim PET Is Negative in Hodgkin'S or Diffuse Large B CELL Lymphoma?
Authors: Tailor Imran K , Btoosh Bilal , Hamdy Shaimaa , Raja Shanker , Alharbi Mohammed O , Motabi Ibraheem H , Alshehry Nawal Faiez , Qureshi Mohammed S , AlGhamdi Mubarak S. , Zaidi Syed Ziauddin A.
Published: October 2019

Introduction:

Baseline (PETb) and end of therapy (PETe) FDG PET is standard of care in the management of hodgkin's lymphoma (HL) and diffuse large B cell lymphoma (DLBCL). The role of interim PET (PETi) in HL is well established while its role in DLBCL is not well defined. We evaluated the utility of triPET (PETb, PETi and PETe ) in management of these two lymphomas.

Methods:

Retrospective review of PET archives revealed a total of 37 pts (HL=22, DLBCL=15). TriPET were acquired per accepted protocol. SUVmax and Deauville scores (DSc) were obtained from five target lesions, the average i.e. composite SUVmax & DSc were computed for each pt. Statistical analyses were performed with the composite maxSUV (cSUV) and Deauville scores (cDSc) (using EXCEL). Following statistics were performed (separately and combined in HL and DLBCL); mean+SD, PPV and NPV for complete response (CR) Vs. progressive disease (PD) on PETi using the following variables 1. cSUV and 2. cDSc and 3. delta change (DELT). Median progression free survival (PFS) was the clinical endpoint for response.

Results:

The mean PFS in our group was 17 and 15 months in HL and DLBCL respectively. Using cut off thresholds for intP to predict CR at cSUV<=2.0, , cDSC<=2.0 and DELT >=80%,. In HL: for cSUV- PPV 67%, NPV 95%; for DELT of cSUV PPV 100%, NPV 95%; for cDSC-PPV 30%, NPV 100%. In DLBCL: for cSUV- PPV 25%, NPV 100%; for DELT of cSUV PPV 33%, NPV 100%; for cDSC- PPV 50%, NPV 100%.

Conclusion:

The results from our series suggest that PETi has a role not only in HL but in DLBCL as well. Our modest cohort suggests that a negative PETi in DLBCL had a NPV of 100% across cSUV, cDSc and DELT, with regards to CR. Our data also suggests that PETe is not needed if PETi is -ve. While in HL subset, our results concur with results from other groups, this needs to be validated in a larger series.

Disclosures

No relevant conflicts of interest to declare.
Novel Bruton's Tyrosine Kinase Inhibitor Bgb-3111 Demonstrates Potent Activity in Mantle Cell Lymphoma
Authors: Li Carrie J , Liu Yang , Bell Taylor , Wang Jack , Guo Hui , Ahmed Makhdum , Zhang Hui , Lam Laura T , Nomie Krystle , Wang Lai , Zhang Liang , Wang Michael
Published: October 2019

Background:

Aberrant B-cell receptor signaling is an important contributor to lymphomagenesis in mantle cell lymphoma (MCL). Bruton's Tyrosine Kinase (BTK), a component of the BCR signaling axis, has been validated as a clinically relevant target, and BTK inhibitor ibrutinib received FDA approval for treatment of MCL in 2013. Growing concerns that single agent ibrutinib exerts off-target effects that interfere with other treatments such as rituximab-induced antibody-dependent cell cytotoxicity limit its utility in combination treatments. In this study, we assessed the in vitro and in vivo effects of BGB-3111in MCL models.

Methods:

We performed cell viability assays with BGB-3111 treated MCL cell lines to determine inhibition of cellular proliferation. The same assays were conducted on primary human MCL cells and patient-derived xenograft (PDX) tumor samples. Dose-dependent inhibition of BTK auto-phosphorylation and inhibition of downstream targets such as PLC-γ were determined by phospho-protein immunoblotting and immunoprecipitation. A reverse-phase protein assay (RPPA) was conducted on BGB-3111-treated Mino cells to evaluate changes in MCL oncogenic signaling. Induction of apoptosis in MCL cells treated with increasing doses of BGB-3111 was quantified using flow cytometry. For in vivo experiments, an ibrutinib-sensitive MCL PDX mouse model was treated with 50 mg/kg/day BGB-3111 and monitored for mean tumor burden and survival.

Results:

BGB-3111 potently inhibited cell viability in a panel of MCL cell lines, with an activity range of 1-10 uM, and induced apoptosis in a dose-dependent manner in several MCL cell lines.BGB-3111 treatment of MCL cells demonstrated a dose-dependent decrease in p-BTK (Y223) and inhibition of downstream effectors without impacting total protein levels, while RPPA revealed upregulation of the PI3K-Akt signaling axes. In addition, BGB-3111 treatment did not impact phosphorylation of off-target kinases affected by ibrutinib treatment. In vivo, BGB-3111 suppressed tumor growth and prolonged tumor survival in BGB-3111 treated mice.

Conclusion:

The second generation BTK inhibitor BGB-3111 demonstrates selectivity for BTK in vitro and BTK inhibition in vivo. BGB-3111-treated PDX mouse models examining survival, tumor growth, and other factors point to BGB-3111 as an effective single agent BGB-3111 is being investigated in Phase I clinical trials.

Disclosures

Wang: Beigene: Employment. Wang:Asana BioSciences: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; Acerta: Consultancy, Research Funding; Kite Pharma: Research Funding; BeiGene: Research Funding; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Juno Therapeutics: Research Funding.
NCCN-IPI in Patients with Diffuse Large B CELL Lymphoma Treated with DA-R-EPOCH. Retrospective Analysis
Authors: Bergua Burgues Juan Miguel , Lopez-Gomez Luis , Ibañez Fatima , Suarez-Varela Sara , Prieto-Fernandez Julio , Carnicero Fernando , Casas Ignacio , Martín-Mateos Maria Luisa , Cabrera Carmen , Arcos-Carmona María José , Bañas M Helena , Bermejo Nuria , Sanz Miguel A. , Bobillo-Varela Sara , Lopez Andres
Published: October 2019

We analyzed the value of new NCCN-IPI index in patients affected of Large B cell lymphoma (LBCL) treated with DA-EPOCH-R in order to assess the validity of this index in patients treated homogenously with dose adjusted R-EPOCH.

Patients and protocol: We analyzed the use of NCCN-IPI (Zhou et al, 2014) index in a retrospective cohort of 98 DLBCL patients treated with -EPOCH. These patients were included in DA-EPOCH using IPI(Shipp M.A., 1993) as criteria of inclusion, including only patients (95 patients, 96%)with suspected bad prognosis based in IPI (2-5) and 3 patients with primary mediastinal large B cell lymphoma (PMLBCL). R-EPOCH was administered as reported previously(Wilson et al, 2013). Only 10 patients (10%) were Ann Arbor stage I or II.

Results: The median age of the cohort was 57,13(15-82), 47 woman, 75 patients alived. The median follow-up of the patients alive is 6,7 years (1,3-11). Ann Arbor stage was IVB in 44 patients, and IVA in 21. Responses during treatment: Complete response (CR): 81 (82%), refractory during treatment: 7 (7%), death during treatment: 7 (7%). The number of patients who relapsed after treatment was 19 (20%). The median overall (OS) survival of all patients was not reached, (at 5 years, 0.669, CI: 0.562-0.798). The progression free survival (PFS) at 5 years is 0.62, CI: 0.483-0.795. We classify by the new NCCN-IPI the patients in Low-Intermediate risk (L-I)(3 patients, 3%), High-Intermediate risk (H-I)(38, 44%) and High risk (HR) (45, 52%). The OS at 5 years in H-I is 0.839 (CI: 0.73-0.96) and HR was 0.56 (CI: 0.421-0.754), p=0.025. The PFS at 5 years in H-I is 0.65 (CI: 0.518-0.826) and HR is 0.57 (CI: 0.43-0.755), p=0.4.

Conclusions: NCCN-IPI discriminates well prognosis between HR/H-I patients with DLBCNHL treated with DA-EPOCH-R. The results of this retrospective analysis of high and intermediate high-risk patients compares better than the published in patients treated with R-CHOP. PFS were similar in H-I and HR; differences in OS could be explain by differences in outcome after salvage treatment with autologous stem cell

Disclosures

No relevant conflicts of interest to declare.
Ponatinib Facilitates Treatment-Free Remission By Inducing Deep Molecular Responses
Authors: Wisniowski Brendan , Mapp Sally , Knop Louise , Morton James , Eliadis Paul , Mills Anthony K.
Published: October 2019

Multiple trials now demonstrate the potential for treatment-free remission (TFR) in patients with sustained deep molecular response to tyrosine kinase inhibitors (TKIs). We describe two patients who remain in treatment-free remission after achieving undetectable BCR-ABL with ponatinib on the phase II PACE trial, despite being multiply resistant/intolerant to other agents or carrying the T315I mutation.

Patient 1 previously had a suboptimal response to imatinib (BCRABL >10% at 15mo) and then was intolerant of nilotinib and dasatinib due to grade 3 liver enzyme abnormalities. He achieved undetectable BCR-ABL (Molecular MD laboratories) by six months on ponatinib. His ponatinib dose was gradually reduced from 45mg/d to 15mg/d due to vascular events (myocardial infarction requiring stenting, carotid stenosis requiring endarterectomy, recurrent ischaemic colitis). At the time of his last episode of colitis, his BCR-ABL had been undetectable for 47 months and hence a decision to attempt TFR was made. He remains in TFR 11 months post-cessation.

Patient 2 progressed on imatinib and was found to carry the T315I mutation. He achieved undetectable BCR-ABL by nine months on ponatinib. His ponatinib dose was also gradually reduced from 45mg/d to 15mg/d due to vascular events (popliteal stenosis requiring stenting, embolic stroke, coronary artery disease requiring stenting). At the time of his last event, his BCR-ABL had been undetectable for 30 months and hence a decision to attempt TFR was made. He remains in TFR 17 months post-cessation.

This series adds to the one prior case report of ponatinib facilitating treatment-free remission (Engel NW et al. J Oncol Pract 2016. 12(6);592-4) and these remissions are notable because they occur in patients not considered for other TFR studies because of refractoriness to other agents or known T315I mutations. This is an alternative avenue to dose reduction to reduce the risk of vascular events in ponatinib-treated patients.

Disclosures

Mills: Ariad: Other: This clinical study funded by Ariad.
Incidence of Elevated Expression of wt1 in Primary Myelofibrosis (pmf) and Postpv-, Postet Myelofibrosis and Its Dynamics during Ruxolitinib Treatmeny
Authors: Siordiya Nadiya , Lisina Ekaterina , Butylin Pavel , Matuhina Natalia , Bogdanov Konstantin , Silutina Anna , Lomaia Elza , Zaritskiy Andrey , Konopleva Marina
Published: October 2019

Background. Wt1 expression is thoroughly studied in acute myeloblastic leukemia and widely used for disease response monitoring.Its role in MPN is less known.

Aim. The aim of the study was to reveal the incidence of elevated Wt1 expression in PMF and secondary MF, as well as to find out clinical significance during ruxolitinib therapy.

Patients and methods. 38 pts were included ( Primary Mf-31, post PV- and post ET Mf- 8, males - 12, females- 26). Wt1 expression in peripheral blood was studied by qPCR at diagnosis and during ruxolitinib treatment using Quiagen kit. Dynamics of Wt1 expression was studied in 20 pts treated by ruxolininib. Spleen size was measured in cm below costal margin.

Results.

Wt1 increased expression was found in 35/38 pts. Correlation of Wt1 expression and DIPSS was not found. The relation between blast cell and Wt1 expression was studied by dividing pts in 3 subgroups according to the number of blast cells in peripheral blood- 0, 1-2, >2. Wt1 expression was lowest in the 1st group, and the highest in the 3rd group((p<.05). Ruxolitinib treatment resulted in the decrease of spleen size and parallel decrease of Wt1 level( p<.05 -Fig1).Pts with transformation to acute leukemia(5) had higher level of Wt1 than before transformation.

Conclusion.

Wt1 expression is elevated in the majority of pts with PMF as well as in secondary MF. Correlation was found with blast level and spleen size. Wt1 could be used for monitoring efficacy of ruxolitinib therapy

Disclosures

Konopleva: Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.
Ribosomal Protein L23 Negatively Regulates Cell Apoptosis Via Its Suppression of Miz1 and Activation c-Myc in Higher-Risk Myelodysplastic Syndromes
Authors: Qi Yuekun , Wu Lingyun , Chang Chunkang , Xu Feng , He Qi , Li Xiao
Published: October 2019

Ribosomal protein (RP) L23 has been suggested to be a negative regulator of cell apoptosis. Previously, we reported that RPL23 is over-expressed in higher -risk myelodysplastic syndromes (MDS), which is negatively correlated with apoptosis of bone marrow CD34+ cells and predicts poor prognosis. However, the mechanism of the negative regulation of cell apoptosis by RPL23 in higher- risk MDS remains unclear. In the present study, lentiviral transfection of a RPL23-RNAi vector led to generate RPL23-knockdown (KD) in MDS cell line (SKM-1). Gene microarray was performed in RPL23-KD and control (NC) cells. We employed Gene Set Enrichment Analysis (GSEA) to identify functional gene sets and pathways differentially expressed between the two groups. The results showed that RPL23 knockdown induced remarkable proliferation inhibition, distinct pro-apoptosis and cell cycle arrest when compared with NC. Global gene expression profile showed, by comparison to NC samples, 306 genes upregulated while 448 genes downregulated. Among genes varying wildly, increased expression of Miz-1 (FC = 3.79, p=1.19E-20) and lowered expression of c-Myc (FC= -2.613, p=1.49E-05) were identified in RPL23-KD cell, which were verified both by qRT-PCR and western-blot. mRNA and protein levels of p15and p21significantly increased in RPL23-KD cells. In bone marrow sample from 46 patients with higher risk MDS, the mRNA level of Miz1 was remarkably lower than normal controls, which was negatively correlated to RPL23 expression level (r= -0.252, p = 0.048). The mRNA expression level of c-Myc in higher-risk MDS was significantly higher than normal control, which is positively correlated to the RPL23 expression level (r = 0.70, p = 0.004). IHC showed equidirectionally increased c-Myc and RPL23 and lowered expression of Miz1 in patients with higher-risk MDS compared to normal control. In conclusion, the negative regulation of cell apoptosis by RPL23 in higher-risk MDS might be through its suppression of Miz1 and activation of c-Myc.

Disclosures

No relevant conflicts of interest to declare.
Efficacy of First-Line CLL Treatments in Comparison to Chlorambucil: A Network Meta-Analysis
Authors: Firwana Belal , Sonbol Mohamad Bassam , Atrash Shebli , Ravilla Rahul , Raval Mihir , Hao Lin , Jethava Yogesh , Veeraputhiran Muthu , Makhoul Issam , Sasapu Appalanaidu
Published: October 2019

Background: In the past several years, biology of CLL is being unleashed which had led to discovery of novel treatments, including ofatumumab and obinutuzumab, CD20 monoclonal antibodies (mAb), and ibrutinib, a Bruton tyrosine kinase inhibitor, which exhibited a paradigm shift in CLL. Available clinical trials provided direct comparison with chlorambucil, with no head-to-head trials to compare them. We conducted a network meta-analysis (NMA) to summarize the evidence on first-line treatments of CLL.

Methods: We included randomized controlled trials (RCTs) that evaluated the efficacy of ofatumumab, obinutuzumab, ibrutinib, rituximab, bendamustin or alemtuzumab, in patients with previously untreated CLL. Efficacy outcome measures included progression-free survival (PFS) at 18 months and best overall response rate (ORR), which consists of both complete and partial response rates. Bayesian NMA method was used to conduct this NMA that pools evidence from direct and indirect comparisons to facilitate simultaneous inference regarding all treatments used.

Results: Five trials were identified, enrolling 2,113 newly diagnosed CLL patients with a median age ranging from 60 to 73. NMA demonstrated superiority of obinutuzumab plus chlorambucil over other mAb combinations and ibrutinib, and had the highest probability of achieving PFS at 18 months when compared to ibrutinib with risk ratio (RR) of 2.41 (credible interval [CrI] 0.89 to 5.29) and ofatumumab plus chlorambucil with RR of 7.11 (CrI 3.31 to 13.8). Table-1 depicts the results of NMA for PFS at 18 months. It also had the highest probability of achieving ORR, followed by ibrutinib ranking the second.

Conclusion: Obinutuzumab plus chlorambucil has higher probability of achieving efficacy compared to other mAb combinations or ibrutinib, in terms of better ORR and better PFS rates, followed by ibrutinib. The certainty in the evidence is low because of indirectness, which is a limitation in this NMA, however our results parallel the evidence based practice. Although no head to head clinical trials compared first-line treatments for CLL, our NMA showed that obinutuzumab plus chlorambucil and ibrutinib had better efficacy profile. NMA is not a substitute for well conducted RCTs investigating direct comparisons.

Abbreviations: CrI, credible intervals; PFS, progression free survival. *Treatments are ranked according to their probability of achieving comparative effectiveness.

Disclosures

No relevant conflicts of interest to declare.
Ibrutinib for Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Meta-Analysis of Randomized Controlled Trials
Authors: Zhang Shijia , Sanchez Larysa , Liu Jieqi , Chang Victor , Goldberg Stuart L.
Published: October 2019

Background: Ibrutinib, a Bruton's tyrosine kinase inhibitor, was approved by FDA for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). This study aims to evaluate the efficacy and safety data from randomized controlled trials (RCT) of ibrutinib-based therapy in patients with CLL or SLL.

Methods: PubMed, ASH, and ASCO databases (2008-2016) were searched for randomized control trials of ibrutinib therapy (either single-agent or combination) for chronic lymphocytic leukemia or small lymphocytic lymphoma through June 30, 2016. Study endpoints included overall survival (OS), progression-free survival (PFS), and adverse events (AE). Pooled hazard ratios (HR) for survival outcomes and relative risks (RR) for dichotomous data with 95% confidence interval (CI) were calculated with a random effect model using MedCalc.

Results: Four randomized controlled trials (RESONATE-1, RESONATE-2, HELIOS, and CLL12) were identified, but CLL12 trial was excluded from this study since the efficacy data were not available at the time of this meta-analysis. Pooled data from the 3 RCTs (1238 patients) showed that ibrutinib-based therapy improved overall survival (HR 0.419; 95% CI 0.242-0.725, P = 0.002) and progression-free survival (HR 0.201; 95% CI 0.162-0.251, P < 0.001) compared to regimens without ibrutinib. Subgroup analysis showed that the PFS benefits were independent of sex (male: HR 0.188, 95% CI 0.143-0.249, P < 0.001; female: HR 0.225, 95% CI 0.154-0.331, P < 0.001), Rai stage (0-II: HR 0.154, 95% CI 0.109-0.217, P < 0.001; III-IV: HR 0.235, 95% CI 0.167-0.333, P < 0.001), bulky disease (<5 cm: HR 0.219, 95% CI 0.155-0.309, P < 0.001; ≥5 cm: HR 0.179, 95% CI 0.135-0.238, P < 0.001) or chromosome 11q deletion (positive: HR 0.099, 95% CI 0.060-0.163, P < 0.001; negative: HR 0.261, 95% CI 0.212-0.322, P < 0.001). Ibrutinib-based therapy significantly increased the risk of developing all-grade diarrhea (RR = 2.135, 95% CI = 1.437-3.174, p < 0.001), pyrexia (RR = 1.265, 95% CI = 1.011-1.583, p = 0.040), and arthralgia (RR = 1.863, 95% CI = 1.101-3.152, p = 0.020), but not anemia (RR = 0.955, 95% CI = 0.694-1.313, p = 0.777), neutropenia (RR = 1.048, 95% CI = 0.760-1.446, p = 0.774), fatigue (RR = 0.897, 95% CI = 0.746-1.078, p = 0.247), or nausea (RR = 0.951, 95% CI = 0.600-1.506, p = 0.829).

Conclusions: Ibrutinib-based therapy significantly improves OS and PFS (independent of sex, Rai stage, bulky disease or chromosome 11q deletion) in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, but increases the risks of all-grade adverse events including diarrhea, pyrexia, and arthralgia.

Disclosures

Chang: Johnson and Johnson: Other: Stock; Amgen: Other: Research; Boehringer Ingelheim: Other: Research. Goldberg:Neostem: Equity Ownership; Bristol Myers Squibb, Novartis: Speakers Bureau; COTA Inc: Employment; Pfizer: Honoraria; Novartis: Consultancy.
Preliminary Detection of Leukemia with Blood By a Novel Electrochemical Method
Authors: Wang Yujie , Chen Baoan , Ge Zheng
Published: October 2019

Information

A simple, novel and fast electrochemical method was applied for clinical diagnosis of leukemia. Blood samples of leukemia patients were identified by screen-printed electrodes with potassium ferricyanide (III) probes. Our study successfully developed and raised the possibility of utilizing the electrodes in the identification and diagnosis of leukemia.

Background

Accurate preliminary detection of leukemia is vital for timely and suitable chemotherapy and clinical outcomes of patients. Electrochemical methods have been widely used in cytobiology, including identification of leukemia cells. In the present study, we creatively applied the use of an electrochemical method to the analysis of human blood samples. The aim of this study was to identify leukemia, breast cancer, respiratory infection and healthy individuals by detecting the electrochemical characteristics of leukocytes in the peripheral blood of patients with a screen-printed electrode. This method might be effectively used in the preliminary screening of leukemia.

Methods

A total of 99 blood samples obtained from Zhongda hospital in China (May 2016 - July 2016) were divided into four groups: healthy individuals (n = 25), respiratory infection (n=23), leukemia (n = 29) and breast cancer (n = 22). We used probes to distinguish leukocytes of people's blood from different samples immediately due to the different electrochemical behaviors of leukocytes. A screen-printed electrode was used to measure differential pulse voltammetry by a potassium ferricyanide (III) probe combined with a simple bio-sensor system. Then, one-way analysis of variance (ANOVA) method was applied to analyze the scanning curves and peak potential and peak shifts were compared (ΔEp).

Results

The scanning curves demonstrated the specific electrochemical behaviors of the blank potassium ferricyanide solution and which mixed with different samples in different groups. Significant differences in mean peak potentials were observed over the four groups (P< = 0.001). 105.00±8.02mV, 111.84±9.53mV, 120.90±11.18mV, 132.84±11.53mV for Group healthy, Group respiratory infection, Group leukemia, and Group breast cancer, respectively. Meanwhile, there were 4.67±3.14mV, 10.91±5.81mV,20.42±8.50mV, 33.42±10.05mV in peak shifts for above four groups respectively.

Conclusions

Using the screen-printed electrode to identify cancer was a novel method with good sensitivity and specificity. It might be effective and had a potential utility in the preliminary screening of leukemia.

Disclosures

No relevant conflicts of interest to declare.
Global Increase in Replication Fork Speed during a p57KIP2-Regulated Erythroid Cell Fate Switch
Authors: Hwang Yung , Futran Melinda , Hidalgo Daniel , Ramalingam Iyer Divya , Rhind Nicholas , Socolovsky Merav
Published: October 2019

Cell cycle regulators are increasingly implicated in cell fate decisions such as the acquisition or loss of pluripotency and self-renewal potential. The cell cycle mechanisms that regulate these cell fate decisions are largely unknown. Here we studied an S phase- dependent cell fate switch in the erythroid fetal liver, in which murine early erythroid progenitors transition in vivo from a self-renewal state into a phase of active erythroid gene transcription and concurrent maturational cell divisions. In the fetal liver, this transition corresponds to the transition from subset S0 (CD71-low, Ter119-negative) to subset S1 (CD71-high, Ter119-negative). We found that the S0 to S1 transition takes place during an S phase that is abruptly shorter (decreasing from 7 hours to 4 hours). Further, self-renewing S0 cells uniquely express the cyclin-dependent kinase (CDK) inhibitor p57KIP2 during S phase. To investigate its potential role, we studied DNA replication in vitro and in vivo in p57KIP2 -deficient fetal liver progenitors, employing a variety of techniques, including DNA combing. We found that S0 erythroid progenitors are dependent on p57KIP2-mediated slowing of replication forks for self-renewal, either in vivo, or in dexamethasone-dependent expansion cultures in vitro. The switch from self-renewal in S0 to differentiation in wild-type S1 progenitors entails rapid downregulation of p57KIP2 with a consequent global increase in replication fork speed and an abruptly shorter S phase. In the absence of p57KIP2, replication fork processivity increases prematurely in self-renewing S0 cells, prior to the activation of the erythroid transcriptional program (Figure 1), resulting in replicative stress and cell death.

It is well established that differentiation leads to reprogramming of DNA replication, reflected by changes to origin usage and to the timing of replication of chromatin domains. Here we find that the replication program is fundamentally altered in additional key respects: the global processivity of replication forks, regulated by CDK activity, increases abruptly with the switch from self-renewal to differentiation, affecting DNA synthesis rates and S phase duration. Our results are also of interest since the regulation of replication kinetics was thought to be primarily via the regulation of origin firing efficiency, rather than via fork processivity. Here we found no difference in the former (there was no significant change in inter-origin distances, Figure 1). While the full significance of faster forks to the activation of the erythroid transcriptional program is yet to be understood, a recent report found that T cell help leads to faster forks and a shorter S phase in B cells (Gitlin et al., Science 349, 643-646 2015). Regulation of global fork speed may therefore be an intrinsic part of physiological developmental programs.

Disclosures

No relevant conflicts of interest to declare.