bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous Inhibition of Mcl-1 and Induction of DNA Damage Accumulation By Chidamide, a Novel Selective HDACi, Potentiates the Cytotoxicity of ABT-199 in Acute Myeloid Leukemia
Authors: Xu Bing , Chen Kai , Yang Qianying , Zha Jie , Zhao Haijun , Feng Liying , Chen Xiaolei , Fu Guo , Young Ken H.
Published: November 2019

Acute myeloid leukemia is a heterogeneous hematopoietic neoplasia with a poor clinical outcome despite its treatment have made great progress in recent years. Strategies for targeting Bcl-2 using ABT-199 attract increasing attentions. however, most treatment failure strongly correlates with acquired up-regulation of MCL-1, which become the Achilles's heel of ABT-199 in clinical use. Here we describe low-cytotoxicity dosage of Chidamide (CS055), a novel selective HDACi designed in China, potentiated the cytotoxicity of ABT-199 towards diverse AML cell lines in vitro and primary samples obtained from patients with AML ex vivo, especially those carrying hyperleukocytosis, as well as highly active in vivo in a AML patient-derived xenograft murine model, while sparing normal peripheral blood mononuclear cells. Mechanistically, ABT-199/CS055-induced cytotoxicity was closely associated with inactivation of Mcl-1 and simultaneous induction of DNA damage accumulation. Of note, we also find a superior resensitization activity of CS055 in contrast with Romidepsin. In summary, our findings suggest that CS055 enhance the eliminating activity of ABT-199 towards AML cells, thus implying a highly promising and potent strategy for treatment of relapsed and refractory AML.

Disclosures

No relevant conflicts of interest to declare.
Outcome of Atypical Presentations of Hairy Cell Leukemia
Authors: Moustafa Afraa , Shwaylia Hawraa M , Aldapt Mahmood , Yassin Mohamed A
Published: November 2019

Hairy cell leukemia (HCL) is a distinctchronic lymphoproliferative disorder that accounts for 2% of all adult leukemias. The median age at the time of diagnosis is 52 years with a male to female ratio of 4:1.

Hairy cell leukemia predominantlycharacterized by infiltration of peripheral blood, bone marrow, and spleen by malignant cells with prominent irregular cytoplasmic projections, namely, "hairy cells". HCL patients may be asymptomatic or develop symptoms of cytopenia, particularly infections .

The exact prevalence of atypical presentation of HCL is difficult to be determined because most cases were published as incidental reports.

The classical presentation of Hairy cell leukaemia includes splenomegaly (80-90%), pancytopenia (60-80%) and hepatomegaly (40-50%), however, the same may not be true in the clinical settings.

As hairy cell leukemia may present with a wide range of atypical organ involvements which could result in a diagnostic dilemma.

The aim of this literature review is to highlight non- classical presentations of HCL and the importance to have high index of suspicion to consider a diagnosis of HCL based on histomorphological features even in the absence of classical clinical features.

Method:

We searched the medline database (PubMed), GoogleScholar from1985 until 2018 with the following search terms: atypical presentation of hairy cell leukemia ,unusual cases of hairy cell leukemia,unique hairy cell leukemia presentation.

Result:

A total of 21 cases were found, with age range from (29-88),5 cases were female and the rest were males.

Skeletal involvement was the most common presentation with osteolytic bone lesion.

Majority of the patients were treated with Cladribine,13/21 showed complete remission.

Discussion:

HCL is an indolent disorder of B-cell origin that accounts for 2% of all forms of leukemia and 8% of lymphoproliferative diseases.

In our literature review we looked up the unique presentations, which

Most of the reported cases we found involved the skeleton in the form of pathological fracture and osteolytic lesion.

Serositis, in the form of massive ascites and pleural effusion has been reported. Additionally, Cases of central nervous system involvement and presentation at young age were observed.

Due to rarity of the disease and no established treatment modality for unusual organ involvement, standard treatment with Cladribine result in complete remission in 61% of the observed cases.

Conclusion:

While Classical presentation of hairy cell leukemia is well described in the literature.

atypical presentation is still rare but with diverse presentation.

most of the cases reviewed in the literature were middle age males, majority had good response to treatment, while the rest had disease progression .

rare pretension of Hairy cell leukemia despite being rare should always be considered ,particularly in cases of pathological fractures or unexplained serositis.

Table

Disclosures

No relevant conflicts of interest to declare.
Development of Exosome-Capturing Antibody-Conjugated Nucleic Acid Medicines Targeting Multiple Myeloma Cells
Authors: Soma Emi , Toda Yuki , Hosogi Shigekuni , Yamayoshi Asako , Ashihara Eishi
Published: November 2019

Nucleic acid medicines including small interfering RNAs (siRNAs) are expected to be next-generation therapies. However, targeted delivery of siRNAs into cancer cells, especially hematological cancer cells, via systemic administration is limited by the lack of efficient and cell-specific delivery systems. We previously demonstrated that cancer cell-derived exosomes are preferentially transfer into their parental cancer cells. Based on this observation, we hypothesized that monoclonal antibody (mAb)-conjugated siRNAs that capture exosomes can efficiently deliver siRNAs into hematological cancer cells (Figure 1). To test this hypothesis, we developed a noncovalent Ab-conjugated siRNA system and confirmed the efficient delivery into multiple myeloma (MM) cells. We selected the surface antigen CD63 to capture MM cell-derived exosomes. An anti-CD63 mAb was thiolated using Traut's reagent and then modified with a linear (D-arginine (Arg))9 (9r) or branched (Arg)18 (9+9r) peptide (vehicle). The anti-CD63 mAb-Arg:siRNA complex was obtained by mixing anti-CD63 mAb-Arg and siRNA in phosphate-buffered saline and incubating the mixture.

A gel shift assay showed that the anti-CD63 mAb-linear Arg construct bound to siRNAs in a construct concentration-dependent manner and the optimal vehicle-to-siRNA ratio was 5:1. By contrast, the anti-CD63 mAb-branched Arg construct bound to siRNAs at lower concentrations, and the optimal vehicle-to-siRNA ratio was 1:1-2.5:1. We next examined uptake of fluorescence-labeled siRNAs by OPM-2 MM cells using a confocal microscope. A higher level of siRNAs was delivered using the anti-CD63 mAb-branched Arg construct than using the anti-CD63 mAb-linear Arg construct; therefore, we used the former construct for further experiments. We investigated the knockdown effects of the CD63 mAb-branched Arg construct conjugated with luc siRNA in luciferase-expressing OPM-2 cells (OPM-2-luc cells). Luciferase activity decreased to 55.9% in OPM-2-luc cells following uptake of this construct. We next examined the mRNA transcript levels of MYC and CTNNB1 (β-catenin) mRNA transcript levels by RT-PCR in OPM-2 cells treated with the anti-CD63 mAb-branched Arg construct conjugated with MYC and CTNNB1 siRNAs. Treatment with mAb-conjugated siRNAs at a vehicle-to-siRNA ratio of 1:1 decreased the mRNA transcript levels of MYC and CTNNB1 to 52.5% and 55.3%, respectively (Figure 2).

In conclusion, exosome-capturing antibody-conjugated siRNAs are effectively delivered into MM cells via uptake of exosomes by parental cells. We are currently investigating their delivery into other hematological cancer cells. This technology might lead to a breakthrough in drug delivery systems for hematological cancers.

Disclosures

No relevant conflicts of interest to declare.
The Impact of a Mandatory Prescription Drug Monitoring Program (PDMP) on Opioid Prescription Among Sickle Cell Disease Patients By Emergency Medicine Physicians in Community Teaching Hospitals in Philadelphia
Authors: Shikdar Sufana , Edlukudige Keshava Vinay Edlukudige , Lambert Peter , Gudipally Sindusha , Esposito Anthony , Bendesky Brad , Green Eric
Published: November 2019

Introduction:

Although opioids are the recommended treatment for acute pain management in sickle cell disease (SCD) patients, the opioid epidemic may have negatively affected the care of these patients in the emergency care settings. Literature suggested that ED physicians routinely overestimate opioid misuse in patients with SCD. Pennsylvania mandated Prescription drug monitoring programs (PDMP) in August 2016 which may affect ED opioid prescription among SCD patients. We evaluated the impact of that PDMP on opioid prescription in the management of acute pain for patients with SCD.

Method:

The data collection took place in the two community hospitals (Mercy Fitzgerald and Mercy Philadelphia Hospital) in Philadelphia. Participants were adults (aged ≥18 years) diagnosed with SCD who triaged for pain in the ED was included in the study. We grouped the encounter by year of PDMP implementation: prior to September 2016 (January 2016-August 2016), and after September 2016 (January 2017-August 2017) to collect patient records of a 6-month period and analyzed the data on number of visits, treatment types, opioid dispensing and total morphine milligram equivalents (MMEs) drug prescriptions during the ED visit. Paired t-test and chi square test were used to compare pre- and post-intervention results. Repeat encounters within 7 days period were excluded in the study.

Result:

The study included 180 qualifying ED visits (92 pre-intervention; 88 post-intervention). PDMP intervention was not significantly associated with reductions in the with opioid prescribing or the amount of prescribed MMEs. The mean age is 32.7 and 58% were male; and all were of African American race/ethnicity. However, prescriptions for non-opioid analgesics increased significantly during the same periods (p<0.012).

Conclusion:

During January 2017-August 2017, PDMP implementation was not associated with a change in opioid prescription among SCD patients in our community teaching hospitals in Philadelphia. The use of the PDMP would be expected to increase narcotic use by correctly identifying SCD patients as not having opioid misuse. The failure to increase narcotics suggests that the use of PDMP data to adjust prescribing for SCD patients is not adequate. As PDMP is crucial for addressing the opioid crisis, clinicians should also use PDMP data for more tailored care in SCD patients. Integration of palliative care could be more pragmatic approach in balancing opioid abuse and access to opioids for pain management among SCD patients.

Disclosures

No relevant conflicts of interest to declare.
Observation on the Efficacy of Consolidation Chemotherapy Combined with Allogeneic Natural Killer Cell Infusion in the Treatment of Low and Moderate Risk AML
Authors: Jiang Hao , Huang Xiaojun , Wang Chunjian , Gong Lizhong , Jia Jinsong , Liu Xiaohong , Wang Yu , Yan Chenhua , Chang Yingjun , Zhao Xiaosu , Shi Hongxia
Published: November 2019

Objective To evaluate the efficacy of consolidation chemotherapy combined with allogeneic natural killer (NK) cell infusion in the treatment of low or intermediate-risk(LIR) AML. Methods 23 cases of LIR AML patients with hematologic complete remission (CR) were enrolled from January 2014 to June 2019 and treated with mIL-21/4-1BBL actived NK cell transfusion combined with consolidation chemotherapy after 3 consolidation courses. Control group were concurrent patients from Department of Hematology and their gender, age, diagnosis, risk stratification of prognosis, CR and the number of courses of consolidate chemotherapy before NK cell transfusion were matched with LIR AML patients. Results A total of 45 times of NK cells were injected into 23 LIR AML patients during 4 to 7 courses of chemotherapy. The median NK cell infusion quantity was 7.5 (6.6~8.64) x 109/L, and the median survival rate of NK cells was 95.4 (93.9~96.9) %. Among them, the median CD3-CD56 + cell number is 5.0(1.4 ~ 6.4) × 109/L, which accounts for 76.8(30.8 ~ 82.9) %; The number of CD3+CD56+ cells was 0.55 (0.24~1.74) x 109/L, accounting for 8.8 (4.9~20.9) %. Before NK cell infusion, the number of patients with positive MRD in the treatment group was 9/23 (39.1%), and the control group was 19/46 (41.3%) (X2=0.03, P=0.862). After NK cell infusion, There was no significant difference in MRD that went from negative to positive between the treatment group and the control group(14.3%vs 22.2%, X2=0.037, P=0.847). In the treatment group, 66.7% (6/9) of the MRD were converted from positive to negative, which was significantly higher than that in the control group10.5% (2/19) (X2=6.811, P=0.009). Morphological recurrence occurred in 1 case of MRD negative in the treatment group and 2 cases of MRD positive in the control group. By the end of the follow-up, the median follow-up was 35 (10~59) months, the number of patients with morphological recurrence in the treatment group was 30.4% (7/23), which is significantly lower than that in the control group (50.2%, 24/46)(X2=2.929, P=0.087),although there was no statistically significant difference between the two groups. There was no significant difference on MRD-negative between the treatment group and the control group(43.5% vs 43.5%, X2=1.045, P=0.307).The 3-year leukemia -free survival were better in the treatment group(65.1±11.1)% than that in the control group (50.0±7.4)%(P=0.047). The 3year overall survival in the treatment and chemotherapy groups were(78.1±10.2)%and (65.8±8.0)%(P=0.212), respectively. Conclusion The consolidation of chemotherapy combined with allogeneic NK cell infusion contributes to the further remission of patients with LMR AML and the reduction of long-term recurrence.

Figure

Disclosures

No relevant conflicts of interest to declare.
Seven Cases of JAK2 Mutation Negative Chronic Polycythemia Patients with Elevated IGF-1R
Authors: Shi Guanfang , Morcus Rewais , Liaukovich Maksim , Wong Ching , Gotlieb Vladimir , Wang Jen-Chin
Published: November 2019

We previously reported that assaying blood MNC (Mononuclear cells) IGF-1 levels by Flow cytometry, will be helpful in differentiating Polycythemia vera (PV) from secondarypolycythemia (1). Patients with chronic polycythemia who are negative for JAK2 V617F or exon 12 mutation and who lack the typical bone marrow findings of polycythemia vera will remain a diagnostic enigma. We collected 7 cases of patients who had persistent chronic erythrocytosis ranging from 1-15 years with negative driver mutations, lacking the typical PV bone marrow findings and absence of secondary causes such as smoking or malignancies. Blood mononuclear cells (MNC ) were collected as well as blood DNA extracted for 237 genes including EPO-R, PHD2, VHL or HIF-1-alpha (Familial erythrocytosis genes)with Next generation sequence, performed by Genoptyx lab (Carisbad, CA) and assayed for IGF-1R by flow cytometry as described previously (1). The results are shown in Table 1.

Conclusion. All these 7 patients with elevated IGF-1R who had no evidence of familial erythrocytosis gene mutation nor had any secondary cause for erythrocytosis, likely carried the diagnosis of PV. It was shown that EEC formation in PV is due to IGF-1 hypersensitivity (2), andsecondary polycythemia do not show significantly elevated IGF -1R (1). Hence the elevated IGF-1R in these 7 patients strongly suggests the diagnosis of PV, re-affirming our proposal that simple procedures to assay blood MNC cells for IGF-1R by flow cytometry will be helpful in the diagnosis of PV and to be added as one of the minor criteria in the diagnosis of PV.

References

1. Wang JC, et al . Quantification of IGF-1 Receptor May Be Useful in Diagnosing Polycythemia Vera-Suggestion to Be Added to Be One of the Minor Criterion.PLoS One. 2016 Nov 3;11(11):e0165299. doi: 10.1371/journal.pone.0165299.

2. Correa PN, Eskinazi, D and Axelrad AA .Circulating Erythroid Progenitors in Polycythemia Vera Are Hypersensitive to Insulin-like Growth Factor-l In Vitro: Studies in an Improved Serum-Free Medium Blood, Vol83, No 1 (January l), 1994: pp 99-1

Disclosures

Wang: Incyt: Research Funding.
Updated Meta-Analysis of Randomized Controlled Trials on Primary Ambulatory Thromboprophylaxis (PATP) in Patients with Locally Advanced or Metastatic Lung Cancer Receiving Chemotherapy
Authors: Thein Kyaw Zin , Tijani Lukman , Oo Thein H.
Published: November 2019

Introduction: Lung cancer (LC) is the second most common cancer in both sexes and is the leading cause of cancer mortality in the United States. Thrombosis is the second leading cause of death in cancer patients and PATP in solid cancer patients were performed in research trials to decrease venous thromboembolism (VTE) rates with ultimate aim to improve survival. We undertook an updated meta- analysis of RCTs to determine the benefit and risk of PATP with low-molecular weight heparins (LMWHs) and direct oral anticoagulants (DOAC) in patients with locally advanced or metastatic LC receiving chemotherapy.

Methods: We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2019. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied.

Results: A total of 5,375 patients with LC from five RCTs and a subgroup of another four RCTs were included in our meta-analysis. The prophylactic doses of bemiparin, certoparin, dalteparin, nadroparin, semuloparin and tinzaparin, intermediate dose of enoxaparin and prophylactic dose of rivaroxaban were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I2statistic for heterogeneity was 0, suggesting homogeneity among RCTs. The VTE incidence was 114 (4.16%) in PATP group and 207 (7.85%) in control group with a RR of 0.53 (95% CI: 0.43 to 0.67, P < 0.001). The absolute RD in VTE was -0.04 (95% CI: -0.05 to -0.02, P < 0.001) with an estimate of the number needed to treat (NNT) of 28 to prevent one VTE event. MB events were reported in 26 (1.37%) patients in PATP group compared to 15 (0.84%) in control group according to an analysis of 6 RCTs. The pooled relative risk for MB was statistically non-significant at 1.57 (95% CI: 0.85 to 2.88, P = 0.15).

Conclusions: Our analysis showed that the relative risk reduction is 46% with a NNT of 28 to prevent one VTE without increasing MB events in ambulatory patients with locally advanced or metastatic LC. Selection of appropriate patients who are high risk for VTE is crucial and further studies are required to define high risk subsets of LC patients receiving chemotherapy who may benefit from PATP.

Disclosures

Oo: Janssen and Janssen: Other: Research: site co-investigator ; Medical Education Speakers Network: Honoraria.
Efficacy of Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Combined Analysis of Three Phase III Randomized Controlled Trials
Authors: Swarup Sriman , Quick Donald P. , Sultan Anita , D'Cunha Nicholas , Htut Thura Win , Hlaing Pwint Phyu , Sharma Upama , Adhikari Nimesh , Aung Ye , Han Myat Min , Myat Yin Mon , Hardwicke Fred , Tijani Lukman , Thein Kyaw Zin
Published: November 2019

Introduction:

The B-cell receptor signaling pathway involves in the pathogenesis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/ SLL), the most common adult lymphoproliferative disorder in western countries. Ibrutinib, a novel Bruton's tyrosine kinase (BTK) inhibitor, has shown great efficacy in the treatment of hematological malignancies via inhibition of BTK, a kinase involved in cellular signaling downstream of the B-cell receptor. However, treatment becomes more challenging upon progression after initial treatment. We performed a combined analysis of currently available randomized controlled trials (RCTs) to evaluate the efficacy of ibrutinib in relapsed or refractory CLL/SLL.

Methods:

We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing ibrutinib in patients with previously treated, relapsed or refractory CLL/SLL were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied.

Results:

Three phase III RCTs (HELIOS, RESONATE and Huang et al. studies) with a total of 1,129 patients with relapsed or refractory CLL/SLL were eligible. Studies compared ibrutinib vs ofatumumab, ibrutinib vs rituximab, and ibrutinib+ bendamustine+ rituximab vs bendamustine+ rituximab were included in the analysis. The randomization ratio was 2:1 in Huang et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCT. The pooled HR for PFS was statistically significant at 0.17 (95% CI: 0.12-0.22; P < 0.0001). The PFS benefit was observed in all Rai stages, either del11q or del17p status and bulky disease (≥ 5cm); Rai stage ≤ 2 cohort (HR, 0.14; 95% CI: 0.09- 0.22; P < 0.0001), Rai stage >2 cohort (HR, 0.26; 95% CI: 0.19- 0.36; P < 0.0001), del11q group (HR, 0.10; 95% CI: 0.06- 0.17; P < 0.0001), del17p group (HR, 0.24; 95% CI: 0.14- 0.39; P < 0.0001), and bulky disease cohort (HR, 0.19; 95% CI: 0.15- 0.25; P < 0.0001).

Conclusions:

Our study depicted that ibrutinib maintains activity in previously treated, relapsed or refractory CLL/SLL, across all Rai stages, in bulky disease and in del11q or del17p. Thus, the use of ibrutinib is likely beneficial to patients with relapsed or refractory CLL/SLL, regardless of disease stage, bulkiness or del11q/del 17p status.

Disclosures

No relevant conflicts of interest to declare.
Histologic and Molecular Correlates in Patients with AL Amyloidosis in Remission but with Persistent Renal Disease
Authors: Varga Cindy , Nair Viji , Fogo Agnes , Nasr Samih , Godfrey Bradley , Eichinge Felix , Toskic Denis , Kretzler Matthias , Comenzo Raymond L
Published: November 2019

Background: Seventy percent of patients with light chain (AL) amyloidosis present with renal involvement. The phases of the disease include asymptomatic seeding, increasing proteinuria, and progression to end stage renal disease. In an attempt to identify genes relevant to renal reprogramming due to persistent disease,renal biopsies from treated AL patients were obtained for systematic histologic evaluation and transcriptional profiling. Correlates were sought between these two approaches. Methods: Renal biopsies from 10 patients with persistent proteinuria (>500mg/day) following hematologic responses to anti-plasma cell therapy were scored independently by 2 expert renal pathologists employing a novel histologic tool that assessed scarring, fibrosis and the distribution of amyloid, and were successfully evaluated by transcriptional profiling in the Michigan Kidney Translational Medicine Core lab. Clinical data and histologic scores (CSIC = composite scarring injury score, AS = amyloid score) were correlated to the expression profiles of specific tubular and glomerular gene sets. Results: Baseline characteristics and histologic scores are in Table 1. Using a false discovery rate corrected P-value of < 0.10, numerous genes of interest were identified (Table 2). Transcriptional profiling revealed 2 distinct patient clusters (G1 and G2) within the tubular and glomerular gene expression sets. The histopathologic features were different between G1 and G2; the amyloid score was significantly higher in G2 in both the tubular (7.0 vs. 4.25; p=0.03) and the glomerular (6.92 vs. 4.38; p= 0.04) compartments. The differential expression for the genes of interest between G1 and G2 were also determined (Table 2). Conclusion: This effort has generated multiple genes of interest. ICQD and PODXL, in particular, correlated with the distribution of amyloid in the capillaries and mesangium. We are currently comparing these expression profiles to those of other nephropathies to identify genes whose expression levels may be specific to AL nephropathy, hopefully leading to further novel histologic and protein-based investigations.

Disclosures

Comenzo: Takeda: Research Funding; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966.
Post-Induction Minimal Residual Disease Measured By Flow Cytometry and Deep Sequencing of Mutant GATA1 Are Both Significant Prognostic Factors for Children with Myeloid Leukemia and Down Syndrome: A Nationwide Prospective Study of the Japanese Pediatric Leukemia/Lymphoma Study Group
Authors: Taga Takashi , Tanaka Shiro , Terui Kiminori , Iwamoto Shotaro , Hiramatsu Hidefumi , Miyamura Takako , Hashii Yoshiko , Hasegawa Daisuke , Moritake Hiroshi , Nakayama Hideki , Takahashi Hiroyuki , Shimada Akira , Taki Tomohiko , Toki Tsutomu , Ito Etsuro , Koh Katsuyoshi , Hasegawa Daiichiro , Hama Asahito , Saito Akiko M , Adachi Souichi , Tomizawa Daisuke
Published: November 2019

Background: Myeloid leukemia in Down syndrome (ML-DS) is associated with good response to chemotherapy thus results in a favorable outcome. However, relapsed and refractory cases are rarely salvageable, regardless of receiving hematopoietic stem cell transplantation. Several factors such as certain chromosomal abnormalities and age at diagnosis are somewhat prognostic, but no universal prognostic factor has been found to date. In order to identify a subgroup with high risk of treatment failure, the role of minimal residual disease (MRD) with three methods were explored in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) trial AML-D11.

Procedure: AML-D11 is a nationwide single-arm clinical trial for children (4 months to 17 years old) with ML-DS. All patients received an identical chemotherapy to the previous AML-D05 study (Taga T. Pediatr Blood Cancer 2016). MRD was evaluated at two time points, one after the induction therapy and another at the end of whole chemotherapy, using 3 different methods; flow cytometric MRD (FCM-MRD), deep sequencing MRD of mutant GATA1 (GATA1-MRD) and PCR MRD of WT1 mRNA expression (WT1-MRD). WT1-MRD was measured in both bone marrow (BM) and peripheral blood (PB) samples, while FCM- and GATA1-MRD were measured only in BM samples.

Results: A total of 78 patients were eligible and followed-up with a median of 47.6 months (range, 8 to 68.8 months). Seventy-six patients were stratified to the standard risk (SR) and one patient to the high risk (HR) group by morphological response. One patient died of sepsis during initial induction therapy. Three-year event-free survival (EFS) and overall survival (OS) rates were 87.2% (95%CI, 77.5 to 92.9%) and 89.7% (95%CI, 80.5 to 94.7%), respectively. FCM-MRD and GATA1-MRD after initial induction therapy were positive in 5/65 and 7/59 patients, respectively, which were both significantly prognostic (Fig.1). Prognostic significance of WT1-MRD could not be evaluated due to a limited number of collected samples.

Conclusions: MRD detections by FCM and targeted deep sequencing of GATA1 after initial induction therapy are both significant prognostic factors for predicting relapse. Risk stratification using FCM-MRD is currently incorporated in the on-going Japan Children's Cancer Group ML-DS trial (AML-D16; jrct.niph.go.jp, jRCTs041190047).

Figure 1

Disclosures

No relevant conflicts of interest to declare.
Metabolic Reprogramming of Human Mitochondrial NAD(P)+-Dependent-Malic Enzyme 2 in Acute Myeloid Leukemia
Authors: Peng Ching-Tien
Published: November 2019

Yu-Nan Huang1, Kang-Hsi Wu4, Te-fu Weng4, Su-Ching Liu4, Hui-Chih Hung1*, Ching-Tien Peng4,5*

FLT3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukemia (AML) are usually associated with other mutations resulting in unfavorable outcome. Tyrosine kinase inhibitors (TKI) have shown promising responses, however, these responses are almost transient in therapy-resistant AML. Here, we show that human mitochondrial NAD(P)+-dependent-malic enzyme 2 (ME2) have significantly increased in CD34+ cell of patients with AML. To determine how ME2 establish metabolic reprogramming of leukemogenesis, we performed a comprehensive analysis of metabolism in CRISPR-mediated ME2 knockout leukemic cells (THP-1 and MV4-11) and purified leukemic blast cells (CD34+) derived from patients with AML. We demonstrate that disrupting ME2 signaling exerts potent activities against proliferation, reduced oxidative metabolism and lactate metabolism. We also show that genetic inhibition of RUNX1/FLT3/ME2 markedly repressed AML cell leukemogenesis.

In conclusion, our findings provide a rationale for clinical development of this strategy for treating RUNX1 and FLT3-mutated leukemic patients.

Disclosures

No relevant conflicts of interest to declare.
Suppression of CXCL-1 Could Restore Necroptotic Pathway in Chronic Lymphocytic Leukemia
Authors: Xu Zhao , Sun Yifeng , Wei Zheng , Liu Peng
Published: November 2019

The defective necroptotic pathway and cytokines were important in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). On the other hand, selenite could induce necroptosis in various sold malignancies by generating reactive oxygen species. However, the relationship between necroptosis and cytokines still remains unclear. Here, we managed to clarify the role of different cytokines and selenite in the defective necroptotic pathway of CLL.

We first screened the expression of different cytokines related to malignancies between CLL patients and controls using Realtime RT-PCR. Only the expression of CXCL-1, MCP-1, IL-6 and GM-CSF was significantly higher in CLL patients than that of controls. (Figure A, B) In normal B lymphocytes, TNF-α and z-VAD could induce necroptosis and also downregulated the expression of CXCL-1 and MCP-1, which indicated that CXCL-1 and MCP-1 might have correlation with necroptosis. (Figure C) After knockdown of CXCL-1 rather than MCP-1 by siRNA, CLL cells restored the TNF-α/z-VAD induced necroptosis measured by flow cytometry. (Figure D, E)

To assess the association between CXCL-1 and lymphoid enhancer-binding factor 1 (LEF-1), which has already been confirmed as the key protein in the necroptotic pathway of CLL, we first performed flow cytometry to verify that CLL cells restored TNF-α/z-VAD induced necroptosis after inhibition of either CXCL-1 or LEF-1. (Figure F) Then, we used Realtime RT-PCR, Western Blot and ELISA to confirm that the expression of LEF-1 was downregulated after inhibiting the expression of CXCL-1 by siRNA, however, the expression of CXCL-1 did not change significantly after knockdown of LEF-1. (Figure G, H, I) This results demonstrated that CXCL-1 located the upstream of LEF-1.

To figure out the relationship between cytokines, necroptosis and selenite, we first construct the selenite concentration gradient and selenite with different concentrations was added into CLL cells together with TNF-α and z-VAD. We found that selenite could downregulate the expression of CXCL-1 but had little influence on LEF-1 measured by Realtime RT-PCR. (Figure J) Then, flow cytometry was performed to calculate the percentage of survival CLL cells and only 3.2μM selenite could significantly induce necroptosis of CLL cells. (p = 0.0102, Figure K) Finally, both Western Blot and ELISA showed the similar result that 3.2μM sodium selenite downregulated the translational expression of CXCL-1 but had little impact on LEF-1. (Figure L)

Figure

Disclosures

No relevant conflicts of interest to declare.
Decitabine As Part of a Modified Bu-Cy Conditioning Regimen Significantly Improved the Outcome of High-Risk AML Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Tang Xiaowen , Valdez Benigno C. , Zhang Qianqian , Ma Yunju , Dai Haiping , Yin Jia , Li Zheng , Xu Ting , Xu Yang , Chen Jia , Zhu Xiaming , Wu Depei , Andersson Borje S
Published: November 2019

Background :Relapse remains a major cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially in patients with high-risk acute myeloid leukemia (AML). Therefore, how to eradicate the minimal residual disease and prevent of relapse are of great importance to improve the outcome of allo-HSCT for these high risk AML patients.

M ethods :We retrospectively investigated decitabine (DAC) as part of a modified Bu-Cy regimen for high-risk AML patientsundergoing allo-HSCT. Fifty-nine patients received DAC (20 mg/m2/d,i.v.) for 5 days, followed by modified Bu-Cy (DAC group). A control (CON) of 177 patients (pair-matched 1:3) received modified Bu-Cy only.

Results:Median follow-up was 402 (85-1504) days. There was no difference in graft versus-host disease occurrence. Treatment-related mortality (day 100) was 0% (DAC) and 6.2% (CON). The DAC group had better 2-year overall survival (OS, 77% versus 64%, P=0.018) and leukemia-free survival (LFS, 73% versus 56%, P=0.007). The differences were more substantial among patients with active disease: OS, 83% (DAC) versus 47% (CON), P=0.01 and LFS, 77% (DAC) versus 34% (CON), P=0.002. Median time to relapse was 187 days (DAC) versus 86 days (CON) and two-year relapse rates were 10% (DAC) and 49% (CON) for patients with active disease. Patients with cytogenetic monosomy 7 or 7q- abnormality responded better.

Conclusions: Our data indicate that novel conditioning regimen containing DAC may be an effective and well-tolerated strategy and confer a subgroup-specific survival advantage in high-risk AML patients undergoing allo-HSCT.

Disclosures

No relevant conflicts of interest to declare.
Population Pharmacokinetics of Ruxolitinib in Patients with aGVHD Who Had an Inadequate Response to Corticosteroids
Authors: Chen Xuejun , Liu Xiang , Wang Phillip , Yeleswaram Swamy
Published: November 2019

Background: Jakafi® (ruxolitinib) is currently approved for the treatment of adult patients with intermediate- and high-risk myelofibrosis (MF) and for the treatment of adult patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant to hydroxyurea. A prospective, open-label, single-cohort, Phase 2 study (REACH1) was conducted to evaluate the safety and efficacy of Jakafi® (ruxolitinib) in patients with acute graft versus host disease (aGVHD) who have had an inadequate response to corticosteroids. A population PK analysis was employed to characterize the PK of ruxolitinib in this patient population.

Patients and Methods: REACH1, Study INCB 18424-251, and COMFORT-I are the 3 studies supporting the population PK of ruxolitinib; the first study is in participants with aGVHD who have had an inadequate response to corticosteroids, and the other 2 studies are in participants with MF. First, the final PK model for ruxolitinib in patients with MF was applied to the data in patients with MF and aGVHD. When significant biases were observed in this validation process, new population PK models were developed based on the pooled data. The accuracy and robustness of the final population PK model were assessed using a predictive check method.

Results: An under-prediction bias was observed at the population level when existing PK model in MF was applied to pooled data in patients with MF and aGVHD. A new model was developed to account for the under prediction bias at the population level. The final population PK model for ruxolitinib was a 2 compartment disposition model with first order absorption, absorption lag time, and linear elimination. Body weight and gender were significant predictors of the volume of distribution of the central compartment and oral clearance, respectively. Patients with aGVHD showed lower oral clearance (66.7%) and slower rate of absorption (~28%) than that in patients with MF. The stage of liver involvement in GVHD and use of moderate or potent CYP3A4 inhibitors were identified as covariates for ruxolitinib CL.

Conclusion: The population PK analysis supports the proposed dose regimen in patients with aGVHD who had an inadequate response to corticosteroids as well as dose recommendations for DDI and subjects with organ dysfunction.

Disclosures

Chen: Incyte Research Institute: Employment. Liu:Incyte Research Institute: Employment. Wang:Incyte Research Institute: Employment. Yeleswaram:Incyte Research Institute: Employment.
Maintenance Therapy with Decitabine after Allogeneic Hematopoietic Stem Cell Transplantation to Prevent Relapse of High Risk Acute Myeloid Leukemia
Authors: Ma Yunju , Qu Changju , Dai Haiping , Yin Jia , Li Zheng , Chen Jia , Qiu Huiying , Sun Aining , Miao Miao , Fu Chengcheng , Jin Zhengming , Zhu Xiaming , Wu Depei , Tang Xiaowen
Published: November 2019

Background: Relapse remains the main cause of treatment failure post transplantation. Relapse prevention is an important strategy for acute myeloid leukemia (AML) patients.

M ethods: We retrospectively analyzed the results of21 high risk AML patients who received a median number of 3 courses (range, 2 - 8) of decitabine (DAC) maintenance treatment (20mg/m2/d ×5d every 3 months for 1 year). Meanwhile, another 63 high risk AML patients without any prophylactic treatment after transplantation were included as a control group for 1:3 pair matched study.

Results: With median follow-up of 23 months, 20 out of 21 (95.2%) patients maintained complete molecular remission (CMR) in DAC group, while 35 out of 63 (55.6%) patients maintained CMR in control group. Comparing with control group, the patients of DAC group had higher 3-year overall survival (OS) rates and 3-year leukemia free survival (LFS) rates (92.9% vs 51.8%, P =0.003; 94.1% vs 54.7%, P=0.002 respectively). Moreover, DAC maintenance was well tolerated in all patients and grade 3/4 or 4/4 hematological toxicities were observed in 11 of 21 (52.4%) patients.

Conclusion: Our results suggested that DAC maintenance therapy was an effective and safe treatment option to prevent relapse after transplantation for high risk AML patients.

Disclosures

No relevant conflicts of interest to declare.
Long-Term Follow-up of Hematopoietic Stem Cell Transplantation with the Modified Peking Regimen for the Treatment of Acute Leukemia
Authors: Yang Xi , Li Chenglong , Zhang Rong , Zheng Hong , Wei Qing , Wang Chunsen , Dai Jingying , Huang Xiaobing , Tang Ningning
Published: November 2019

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment strategy for patients with acute leukemia. The ATG-based transplantation system initiated by Peking University people's hospital, known as the Peking regimen, has become a mainstream transplant system worldwide. Here, based on the Peking regimen, we report a modified protocol:(1)add Fludarabine and replace ATG with ATG-F in the conditioning regimen; (2)transfuse higher-dose cell collections from granulocyte-colony stimulating factor(G-CSF) primed bone marrow and peripheral blood samples; (3) add Basiliximab (a CD25-antibody) on day +3 for acute GVHD prophylaxis. In this study, 265 patients (158 patients with haplo-SCT and 107 patients with sibling-SCT) underwent allo-HSCT with our modified protocols. All patients achieved sustained full-donor chimerism. The incidence of grade II-IV and III-IV acute GVHD in haplo-SCT comparing with sibling-SCT was 36.1%(57/158) vs 17.8%(19/107)(P=0.001) and 13.3% (21/158) vs 9.3%(10/107)(P>0.05) respectively. The 2-year cumulative incidence of total chronic GVHD and extensive chronic GVHD in haplo-SCT was 41% (65/158) and 15% (24/158) respectively. The 3-year cumulative incidence of non-relapse mortality (NRM) in haplo-SCT and sibling-SCT was 6.3% (10/158) and 4.7%(5/107) respectively(P>0.05). The 100-day cumulative incidence of CMV viremia in haplo-SCT and sibling-SCT was 35.5% (56/158) and 23.4%(25/107) respectively(P=0.036). A total of 36 patients in haplo-SCT group and 24 patients in haplo-SCT group had recurrent disease, reaching a cumulative incidence of relapse of 20.8% in haplo-SCT and 23.4% in sibling-SCT at 3 years respectively(P>0.05). The relapse ratio of haplo-SCT and sibing-SCT in the 1st year, between the 1st and the 2nd year and after 2 years was 21.5% vs 14.1%(P>0.05), 1.3%(2/158) vs 0%(P>0.05) and 0% vs 6.5%(P=0.009) respectively. The 3-year overall survival(OS) and leukemia-free survival(LFS) rates in haplo-SCT and sibling-SCT was 78.8% vs 74.2% and 76.8% vs 75.04% respectively(P>0.05) by the Kaplan-Meier estimate. The 3-year GVHD-free and leukemia-free survival rates (GRFS) in haplo-SCT and sibling-SCT were 43.4% vs 69.5%(P=0.045) respectively. Lower OS in haplo-SCT was associated with III-IV aucte GVHD and lower MNC(<19×10^8/L) in grafts by Cox regression analysis. In a word, the results from our experience showed that the modified protocol based on the Peking Regimen is safe and reliable for acute leukemia patients and brings on a long-stage survival post transplantation.

Disclosures

Zheng: Pfizer: Research Funding.
Venous Thromboembolism Prophylaxis in Acute Medically Ill Patients: A Retrospective Cohort Study
Authors: Gafter-Gvili Anat , Drozdinsky Genady , Zusman Oren , Kushnir Shiri , Leibovici Leonard
Published: November 2019

Background and Aims

Venous thromboembolism (VTE) is considered as a preventable cause of death for hospitalized patients. Current guidelines recommend pharmacologic prophylaxis for medical patients considered high risk for VTE, despite failure of studies to show reduction in mortality. We aimed to assess the benefit and safety of VTE prophylaxis in acutely ill medical patients hospitalized in internal medicine wards.

Methods

Retrospective cohort study of all patients admitted to the internal medicine and acute geriatric departments, with an admission lasting more than 48 hours, during 2012-2018. Patients who received pharmacologic prophylaxis were compared to those who did not. The primary outcome was 30-day mortality. Secondary outcomes were the 90 day incidence of pulmonary embolism (PE), symptomatic deep vein thrombosis (DVT), and major bleeding. Propensity-weighted logistic multivariable analysis was performed.

Results

A total of 18890 patient-unique episodes were included in the analysis. Of them 3206 (17%) received prophylaxis. A total of 1309 (6.9%) died. 540/1309 (41.3%) of those who received VTE prophylaxis died and 769/1309 (58.7%) of those who did not receive prophylaxis died. VTE Prophylaxis was not associated with a reduction in mortality, multivariate-adjusted OR 0.99 (95% CI 0.84-1.14). One hundred and forty two patients (0.7%) developed VTE. The frequency of VTE among patients who received VTE prophylaxis was 31% (44/142) compared with 69% (98/142) in patients who did not receive prophylaxis. The frequency of VTE in patients who had a Padua score ≥4 and received VTE prophylaxis, was 1.9% (30/1573) compared with 1.6% (44/2797) in those with a Padua score ≥4 who did not receive prophylaxis. 74/142 (52.1%) of patients with VTE had a Padua score ≥4, 44/1309 (1.4%) of those who received VTE prophylaxis and 98/15864 (0.6%) of those who did not. VTE Prophylaxis was not associated with reduction in VTE in the whole cohort, multivariable-adjusted OR 1.09 (95% CI 0.52-2.29). VTE prophylaxis was associated with an increase in major bleeding (multivariable-adjusted OR 1.24, 95% CI 1.04-1.48)

Conclusion

The current practice of routinely administering VTE prophylaxis to medically ill patients considered at high risk for VTE, resulted in a high risk for bleeding a without clear clinical benefit, and should be reassessed.

Disclosures

No relevant conflicts of interest to declare.
An Evaluation of Major Comorbidities and Treatment Patterns of Newly Diagnosed Acute Myeloid Leukemia Patients: A Retrospective Analysis of Electronic Medical Records from US
Authors: Tu Nora , Islam Zahidul , Fliss Albert E , Salas Maribel
Published: November 2019

Background: There is limited data available on patient characteristics and treatment patterns for patients diagnosed with acute myeloid leukemia (AML) particularly from electronic medical record (EMR) database in US.

Objective: Our goal was to examine comorbidities and treatment patterns among newly diagnosed AML patients in US.

Methods: We conducted a retrospective cohort study using fully adjudicated data provided by IQVIA from the EMR database including patient data from January 2012-July 2018 across the US. ICD-9/10-CM codes were used to identify newly diagnosed AML (excluding APL) patients. Initial AML diagnosis codes which indicated relapse or remission were excluded from the newly diagnosed population. Demographics and comorbidities at baseline as well as AML

treatments received after initial diagnosis were examined.

Results: A total of 3387 patients who had an AML diagnosis were retrieved. 2879 were newly diagnosed with mean age of 65.9 and median age at 70 (ranged from 17 to 85) and 54.8 % were male. Prior to the first AML diagnosis record (i.e. index date), 18.7% had other prior malignant solid tumors and 13.5% had antecedent Myelodysplastic Syndrome (MDS), while 71.2% were AML de novo.

Cardiovascular diseases (18.7%) and diabetes (4.6%) were the most common comorbidities occurred before or after initial AML diagnosis. After index date, 38.2% of the newly diagnosed patients received FDA approved drugs for AML and 18% received supportive care only. 2.3 % received hematopoietic cell transplant. Among the FDA approved drugs for AML, hypomethylating agents (37.4% Decitabine and 35.3% Azacitidine), cytarabine based treatments (21.8%) were the most commonly used first line treatment. 25% switched to other AML drugs later in the treatment. Filgrastim (49.6%) and Azoles (37.4%) were the most frequently used supportive care.

Conclusions: Among newly diagnosed AML patients, most had AML de novo. Cardiovascular disease and diabetes are the most common comorbidities and monotherapy was predominantly used as first line therapy. Low percentage of hematopoietic cell transplant observed in this population needs further investigation.

Disclosures

Tu: Daiichi Sankyo, Inc.: Employment. Islam:Daiichi Sankyo, Inc.: Employment. Fliss:Daiichi Sankyo, Inc.: Employment. Salas:Daiichi Sankyo, Inc.: Employment.