bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcome Of Dose-Adjusted Decitabine Regimen Compared With FLAG Regimen In The Treatment Of Relapsed/Refractory Acute Myeloid Leukemia
Authors: Wu Qian , He Guangsheng , Depei Wu , Sun Aining , Qiu Huiying , Jin Zhengming , Miao Miao , Tang XiaoWen , Han Yue , Shen Yiming , Chen Feng , Hu Xiaohui , Jin Song , Zhang Xuhui
Published: October 2019

Background

The salvage therapy in patients with relapsed/refractory acute myeloid leukemia still poses a highly unmet clinical need. Given the established activity and toxicity profiles of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) in patients with untreated acute myeloid leukemia (AML), we explored the therapeutic effects of dose adjusted DAC in patients with relapsed / refractory AML, and compared treatment outcome with the conventional FLAG regimen.

Patients and Methods

27 patients with relapsed/refractory AML were included in this analysis. Twelve patients were treated with DAC 20 mg/m2 per day as 1-hour intravenous infusion for consecutive five days, with additional  1-3 doses of DAC added based on response and tolerability (Table 1). Another group of 15 patients received a course of FLAG regimen as controls.

Results

Although the overall response rates (ORR) were similar in DAC group (5/12) and FLAG group (9/15)£¨41.7 % versus 60 %, P=0.449£©, the complete remission (CR) rate plus CRi was lower in DAC group (2/12) than in FLAG group(10/15)£¨16.7 %versus 66.7 %, P=0.047£©. Induction mortality was 0 (0% at 8 weeks) and toxicities were manageable in both groups. Toxicities were predominantly hematologic. The most common drug-related adverse events (AEs£© were grade 4 myelosuppression which were comparable for DAC and FLAG., DAC group hadfewer infections£¨DAC, 6/12£»FLAG£€n=14/15, P=0.024£©. The 2-year survival rate was similar in the two groups: 25.0% in the DAC versus 26.7% in the FLAG group£¨P=0.574£©, while median survival times of the two groups were 4 and 12 months, respectively.

Conclusion

Dose-adjusted DAC achieved similar overall response rate with lower infection risk compared to FLAG regimen in patients with relapsed / refractory AML.

Disclosures:

No relevant conflicts of interest to declare.
Acute Myeloid Leukemia In Patient Over 90 Years Old: Where Do We Go From Here? Case Report
Authors: Bellesso Marcelo , Dias Daniela Ferreira , Centrone Renato , Santucci Rodrigo , Nicodemo Izabel Pernambuco
Published: October 2019

Introduction

Acute Myeloid Leukemia (AML) widely affects elderly patients, with disappointing survival rates with increasing age. Although chronological age is an independent prognostic risk, it is really important to understand that this group is heterogeneous, so a geriatric assessment may be helpful before making decisions regarding therapy. We describe a 91 year-old patient with AML treated with decitabine, achieving a complete response and good quality of life for 10 months.

Case Report

In May 2012, a 91 year-old woman with myelodysplastic syndrome was admitted at the emergency department presenting asthenia, pallor, pain and edema of the left inferior limb. Her blood count showed: hemoglobin 10.7g/dL, leukocytes 81.800/mm³ with 95% blast cells, and platelets 45.000/mm³. In addition, a Doppler ultrasound evidenced deep venous thrombosis in her left leg. A bone marrow aspirate confirmed AML with myelodysplasia-related alterations, with 95% blast cells, with positive expression of CD45, CD33, MPO, and CD117 (CD45+; CD33+; MPO+; CD117+). Her karyotype was 46,XX [20 cells analyzed]. She was first treated with hydroxyurea. Afterwards, as her performance status improved and in spite of her age, we decided to treat her with Decitabine 20mg/m²/day for 5 days, because she had no severe comorbidity or any severe impairment of every-day-life instrumental activities. After a first cycle with grade 4 neutropenia and thrombocytopenia, she was discharged. After 40 days, complete hematologic recovery was observed. She received seven treatment cycles, and the most important symptom of toxicity was febrile grade 3 neutropenia in the 3rd cycle, with the only inpatient treatment. After this intercurrence, the doses were reduced by 25%. The patient achieved complete remission, spent eleven months without needing blood transfusions and with an acceptable quality of life, but then she relapsed, presenting persistent neutropenia and 44% of blasts in a bone marrow aspirate (05/27/2013). She died on 07/02/2013 due to the progression of the disease.

Conclusion

This case shows that, despite her advanced chronological age, our patient, affected by a fatal disease, lived approximately 13 months with optimal response to treatment (with Decitabine) and enjoying an acceptable quality of life for ten months. Considering this patient profile, could we conclude that this outcome is the best our treatment can aim to achieve?

Disclosures:

No relevant conflicts of interest to declare.
Disulfiram, an clinically used anti-alcoholism drug has the potential to target acute myeloid leukemia cells in a copper-dependent manner in vivo
Authors: Xu Bing , Li Rongwei , Dong Huijuan , Chen Feili , Liu Yuejian , Wang Shiyun , Zhou Shuyun
Published: October 2019

Background

Disulfiram(DS), an old drug clinically used for alcoholism, was reported to have antitumor effects, recent studies have found that Copper(Cu) can significantly enhance the DS-induced cell death in vitro in a variety of tumor cells. Our previous studies also demonstrated that disulfiram/copper (DS/Cu) couldtarget human leukemia cell lines(like KG1α,Molt4) through the activation of JNK, in vitro. However, there is few report about the ability of DS/Cu in killing cancer cells in vivo.

Aims

This study aims to explore the effect of DS/Cu on acute myeloid leukemia cell line KG1αin vivo and clarify the underlining mechanism.

Methods

6-8 week old female NOD/SCID mice were sublethally irradiated with 2Gy X-ray the day before transplantation, followed by intravenous injection of KG1α cells (1×107 cells) suspended in 0.2 mL of PBS. 5 weeks after transplantation mice were randomly divided into three treatment groups: vehicle (0.9% saline), a combination of DS and Cu daily for 2 weeks, Ara-C alone twice before killing. Mice were sacrificed after 2 weeks treatment with tissues of spleen, liver, bone marrow being observed using histopathology method to detect the invasion of leukemia. The DS/Cu-induced p-c-jun activation was also examined by western blot using tissues of spleen, liver, bone marrow. Statistical analysis was carried out with one-way ANOVA to assess statistical significance (*p < 0.05).

Results

4 weeks after transplantation, mice were dispirited with low appetite, down-bent gait, wrinkled fur, slow move, just like suffered from leukemia. What’s more, immature blasts like morphology similar to KG1α were found in the peripheral blood of the mice(11%±3.41). All the mice were sacrificed after 2 weeks treatment, mice in control group were observed with slightly larger spleen and liver with the morphology of invasion of leukemia such as a granular appearance than the other two groups. Histopathology examination showed that leukemia cells infiltrate liver, spleen and bone marrow, and the immunohistochemistry examination found that the leukemia cells in spleen, liver and bone marrow expressed human specific antigen CD45 with the highest expression level in the control group. Moreover, solid tumor could be observed in the peritoneal cavity of two mice in the control group with expression of human specific antigen CD45detected by immunohistochemistry examination. Western blot in this study showed DS/Cu complex induced phosphorylation of c-Jun expression in the spleen, liver and bone marrow.

Conclusion

DS/Cu complex could effectively target the acute myeloid leukemia cells in the acute leukemia NOD/SCID mice while inhibiting the invasion of leukemia to some extent, and the activation of JNK might play a functional role in DS/Cu mediated antileukemic effects.

Disclosures:

No relevant conflicts of interest to declare.
PET Scan Negativity Post Treatment In DLBCL May Not Indicate A Cure
Authors: Atherton David , Lachica Mila , Kuo Yen-Hong , Topilow Arthur A.
Published: October 2019

Background

Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive Non-Hodgkin’s lymphoma. Previous work has suggested that a negative FDG-PET/CT scan, following chemotherapy with curative intent, indicated a cure. However, the understanding that a negative PET post-treatment indicates that no further PET scans are needed, has not yet been accepted as a standard of care. We reviewed the medical records of DLBCL patients with negative post-treatment PET scans in order to evaluate if further PET scanning is superfluous and that the treatment has effected a cure.

Methods

A list of DLBCL patients diagnosed and treated at JSUMC from 2000 to 2010 was obtained from the Tumor Registry. Patient health information was reviewed using electronic as well as paper records.

Results

A total of 133 DLBCL patient charts were reviewed and only 40 had complete PET scan records available at the time of study. Thirteen of the 40 fit the criteria of a negative post-treatment PET scan. Sixty-nine percent (9/13) were males and 31% (4/13) were females. The average age at diagnosis was 61 years. Seventy-seven percent (10/13) had a complete response and did not relapse based on their subsequent PET scan reports. Twenty-three percent relapsed after 14, 22, and 25 months, respectively (3/13, 95% confidence interval: [5%, 54%]). The mean (standard deviation) annual number of PET scans was 1.65 (0.68). The frequency ranged from 0.55/year to 2.67/year.

Conclusions

Three of 13 DLBCL patients eventually relapsed after a negative post-treatment PET scan. This study suggests that careful monitoring of DLBCL patients who have negative PET scans is needed after treatment. Further studies need to be done to confirm the time period a PET scan may be most effective in restaging the disease.

Disclosures:

No relevant conflicts of interest to declare.
The Research Of TCR Vβ Clonality Distribution In Patients With Diffuse Large B-Cell Lymphoma and Its Clinical Significance
Authors: Wang Chunyan , Tan Huo , He Ganlin , Li Yangqiu
Published: October 2019

Background

This study investigated the gene expression of TCR Vβ subfamily T cells and clonality in peripheral blood from patients with DLBCL and discussed the relation between TCR VB subfamily and clinical characters, prognosis, T Cell Subgroup, et al. this study include 14 patients with DLBCL, to analyzed TCR Vβclonality of their blood samples and to comprehend the CDR3 sequence.

Methods

The complementarity determining region 3(CDR3)of TCR Vβ subfamily genes in peripheral blood mononuclear cels(PBMCs) from 14 DLBCL patients were amplified using RT-PCR, and the products of PCR were further analyzed by genescan technique for detection of the CDR3 size,to evaluate clonality of TCR Vβ T cells.

After that, analyzing the data with statistics software SPSS 17.0, to find out the relationshop between clonality of TCR Vβ(oligoclon, oligoclone trendenc, monoclonal bioclone or polyclon ) and laboratory features, immunophenotype, period, efficacy of chemotherapy, prognosis, et al.

Result

This study magnified samples and comprehensively analized characteristics of TCR Vβ subfamily in patients with DLBCL patients, confirming the unbalance distribution and clonal expansion of TCR Vβ subfamily. Several cases showed clonal proliferation in Vβ3, Vβ6, Vβ7, Vβ9, Vβ14, Vβ15 and Vβ22, especially in Vβ15 and Vβ22.These clonal proliferation and deletion of Vβ16, Vβ18, Vβ24 may be considered DLBCL related. Several TCR Vβ subfamily appeared 3-polyclonal. Through number of clonal proliferation, gender, age, time since diagnosis, LDH, germinal center type or nongerminal center type, period, autologous transplantation or not, initial treatment / relapse of 14 cases were analized using two independent samples t-test. initial treatment / relapse was statistically significant (p = 0.027): number of clonal proliferation in patients with relapse-DLBCL compared to the number of untreated patients is high than patients with initial treatment. Pearson correlation analysis illustrated the number of clonal proliferation and ki-67 was negatively correlated, while CD3+ CD8+ lymphocytes showed a positive correlation. for the first time discriminant analysis was applied to gene scan results in the patients with DLBCL.

Conclusion

This study confirmed the unbalance distribution and clonal expansion of TCR Vβ subfamily in patients with DLBCL. Further studies may pay attention to Vβ15, Vβ22 and 3-polyclonal which may relate to DLBCL. Several indicators of TCR Vβ subfamily are closely linked with clinical data, that TCR Vβ may be considered to use in clinical diagnosis and prognosis. It’s the first time that Discriminant analysis was applied to gene scan results, so discriminant analysis may be considered to clinical application after perfecting.

Disclosures:

No relevant conflicts of interest to declare.
Bortezomib plus Dexamethasone versus Fludarabine plus Cyclophosphamide in initial treatment of patients with Waldenström macroglobulinemia
Authors: Zhang Yaping , Lin Zenghua , Wang Xinfeng , Cao Xin , Song Guoqi , Liu Hong
Published: October 2019

Purpose

We examined the efficacy of bortezomib plus dexamethasone(BD) versus fludarabine plus cyclophosphamide(FC) in patients with symptomatic, untreated Waldenström macroglobulinemia(WM). Furthermore, to evaluate the toxicity of BD regimen in WM. Patients and methods: 17 untreated WM patients received either bortezomib and dexamethasone(n=7) or fludarabine and cyclophosphamide(n=10). BD group: A cycle of therapy consisted of bortezomib 1.3 mg/m2 intravenously; dexamethasone 40 mg on days 1, 4, 8, and 11. Patients received 4 cycles at least. FC group: A cycle of therapy consisted of fludarabine 25 mg/m2 on days 1-3; cyclophosphamide 250mg/m2 on days 1-3. Patients received 4-6 consecutive cycles for induction therapy. Responses were based on paraprotein levels. Herpes zoster prophylaxis was instituted with using oral valacyclovir. Results: In BD and FC groups, the overall response rates(PR+MR) were 86% versus 70% respectively. There was not complete response in two groups. In BD and FC groups, minor and partial responses occurred at a median of 25 vs. 54 days and 55 vs. 94 days respectively(P<0.05, respectively). The median progression-free survival(PFS) was 27 months, and a median follow-up of 62 months the actuarial 5-year overall survival(OS) rate was 80% in FC group. Because of a short following time, there were not PFS and OS that can be observed in BD group. Hemoglobin and platelet levels increased normally in 83% vs. 50% and 100% vs. 66% patients in BD and FC groups respectively(P<0.05, respectively). In BD group, peripheral neuropathy was the most common toxicity(57% grade 1- 2, no grade 3- 4). Hematologic toxicities included grade 3 to 4 thrombocytopenia in 2/7(28%) and neutropenia in 1/7(14%). 42% patients developed herpes zoster. Conclusions: The results demonstrate that BD produces rapid responses, along with high rates of response in WM, and it was generally well-tolerated in our study. Herpes zoster prophylaxis is necessary with BD, and peripheral neuropathy was the most common toxicity, but not leading to discontinuance of BD. This retrospective analysis confirms that BD therapy is an effective initial treatment in WM.

Disclosures:

No relevant conflicts of interest to declare.
Concomitant Radiochemotherapy In The Treatment Of Refractory Or Locally Relapsed Diffuse Large B-Cell Lymphoma: A Single Center Retrospective Study
Authors: Gyan Emmanuel , Villate Alban , Lissandre Severine , Benboubker Lotfi , Delain Martine , Colombat Philippe
Published: October 2019

Introduction

Primary refractory Diffuse Large B-Cell Lymphoma (DLBCL) as well as relapse after salvage therapy displays a poor prognosis. Salvage radiation therapy alone does not provide sufficient disease control on locally chemoresistant DLBCL. Autologous stem cell transplantation (ASCT) provides the best progression-free survival when salvaged patients are transplanted in Complete Response (CR). The objective of this study was to assess the effectiveness of CCR in locally relapsed or refractory DLBCL, followed by ASCT in responding patients.

Material and methods

We report the outcome of consecutive patients with locally relapsed or refractory lymphoma for which a decision of CRC was taken in a single institution. Each patient has been assessed by CT or PET-scan. The CRC regimen consisted in 3 cycles of Rituximab (375 mg/m² day 1), CDDP (30 mg/m² 3 days 1-3) and VP16 (120 mg/m² days 1-3) at 21 days intervals, with concomitant radiotherapy delivered to the residual disease sites, administrated in 2 Gy fractions per day to a total dose of 30 Gy, starting on day 1 of the second cycle. Responding patients received ASCT with a BEAM conditioning at the end of the procedure. Extra-hematological toxicity was ranked according to the Common Terminology Criteria for Adverse Events. Tumor response was evaluated according to IWG 1999 at 1 month after the last cycle of CRC, three months after ASCT if performed and during a quarterly follow-up.

Results

We identified 13 patients with localized chemoresistant DLBCL from January 2002 to April 2011 including 12 primary refractory forms. The median age was 56 years (20-76), 12 of 13 patients had received at least two lines of chemotherapy before inclusion with anthracycline and cisplatin. 11 patients achieved a partial response (85%) and 4 of them (31%) a complete response after the CRC. 8 (61.5%) patients were transplanted 1 month after the last cycle of CRC. 7 patients have relapsed within 6 months after the end of treatment. After a median follow-up of 37 months (range 21-125) for the surviving patients, 7 patients are alive and free of disease. The overall survival is 54%, and all surviving patients had been transplanted. No severe toxicity was reported.

Conclusion

CRC should be considered as an option in the therapeutic arsenal in refractory or locally relapsed DLBCL, especially in patients eligible for ASCT. Further research on CRC is warranted.

Disclosures:

No relevant conflicts of interest to declare.
Phase II Trial Of Bortezomib In Combination With Fractionated Cyclophosphamide and Rituximab (BCR) For Relapsed/Refractory Mantle Cell Lymphoma (MCL)
Authors: Romaguera Jorge E , Fanale Michelle A. , Samaniego Felipe , Fayad Luis E , Hagemeister Fredrick B , McLaughlin Peter , Rodriguez Maria Alma , Weaver Pam , Hartig Kim , Badillo Maria , Kwak Larry W. , Younes Anas , Pro Barbara , Wang Michael
Published: October 2019

Background

MCL is incurable. Bortezomib has shown single agent activity of 33% in relapsed MCL. Pre-clinical published data shows additive/synergistic activity of BCR.

Materials and methods

  MCL pts  ages 18 through 85, with adequate organ function unless due to lymphoma, and without HIV-1 infection or any significant medical/mental condition, were treated under an IRB-approved study, consisting of Bortezomib  1.3 mg/m2 IV given on days 1, 4, 8, and 11 (dose on day 11 omitted early on study); fractionated cyclophosphamide 300 mg/m2 q 12 hrs days 1, 2, and 3, and rituximab 375 mg/m2 day 1. Cycles were repeated every 21 days for a total of 6 or less if a response was achieved and patient qualified for SCT.

Results

From  9/2009 to 8/2012, twenty-one patients were entered in the study. Their clinical characteristics are as follows:

Overall response (OR)/CR rates:  71%/53%.

One patient had stable disease and 4 patients progressed. With a Median follow-up of 31 months, the median TTP was 15.8 months and the median OS was 36.4 months.

Toxicity was mainly hematologic. With 77 cycles given, grade 3 anemia was 5%, grade 3 / 4 neutropenia was 16%/9%, and grade 3 / 4 thrombocytopenia was 19%/8%. Early in the study, day 11 dose of bortezomib was omitted because of low counts by day 11 of cycle. Non-hematologic toxicity included grade 3 neutropenic fever (1%), and grade 3 fatigue (3%). No patient developed sensory neuropathy grade ¾.

Conclusion

Bortezomib can be safely combined with cyclophosphamide and rituximab and results in high rates of overall/complete responses in patients with relapsed/refractory MCL.

Disclosures:

Off Label Use: Gemcitabine, fludarabine and melphalan for transplant conditioning. Younes:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel expenses Other.
Can Polymorphisms In Oxidative Stress Related Genes Be a Risk Factor For CML?
Authors: Gonçalves Ana Cristina , Alves Raquel , Freitas-Tavares Paulo , Teixeira Adriana , Mota-Vieira Luísa , Nascimento-Costa José Manuel , Sarmento-Ribeiro Ana Bela
Published: October 2019

Oxidative stress (OS) is recognized to be a evident feature in cancer development and progression. Indirect evidences suggest a role for oxidative stress (OS) in Chronic Myelogenous Leukemia (CML) etiology and pathogenesis. OS, resulting from an imbalance between Reactive Oxygen Species (ROS) production and antioxidant defenses, contributes to cell damage, apoptosis and ineffective hematopoiesis. The antioxidant enzymes superoxide dismutases (SOD) and catalase (CAT) are important components of cell defense against OS, and polymorphisms in the genes may contribute to differences in susceptibility of individuals to oxidative damage since it can lead to reduced protection against OS.

In the present study we set to investigate the influence of polymorphisms of oxidative stress related genes, namely SOD1 (A251G), SOD2 (Ala16Val), COX2 (G-765C), CAT (C-262T) and NADPH oxidase p22 phox (C242T), as a risk factor for CML development and also as a prognostic risk marker in CML patients.

Our study population consisted of 48 patients diagnosed with CML and the same number of healthy controls. Diagnosis was set according to international criteria. The genetic polymorphisms of SOD1 (A251G), SOD2 (Ala16Val), COX2 (G-765C), CAT (C-262T) and NADPH oxidase p22 phox (C242T) were assessed by RFLP-PCR. The patient group median age was 51 years (18-86), gender M/F=27/21. The strength of association between polymorphisms and CML risk was assessed by odds ratio (OR) with the corresponding 95% confidence interval (CI95%) and Kaplan-Meier survival analysis will be assessed to investigate the prognostic importance of these polymorphisms.

Our preliminary results show a higher wild type allelic frequency of SOD1 (94%), COX2 (80%), CAT (82%) and NADPH oxidase p22 phox (67%) polymorphism and a higher variant allelic frequency SOD2 (52%) in CML patients, compared to controls. In these patients the predominant genotype was AA (88%), CG (52%), GG (67%), CC (73%) and CT (46%), respectively for SOD1, SOD2, COX2, CAT and NADPH oxidase p22 phox. Besides that, individuals with CC genotype of NADPH oxidase p22 phox and with TT genotype of CAT have an increase risk for CML about 2,3636-fold (CI95% 1,0346-5,3997; p=0,032) and 12,368-fold (CI95% 1,5151-100,9687; p=0,0076), respectively.

These preliminary results show that CAT (C-262T) and NADPH oxidase p22 phox (C242T) genetic polymorphisms might be related with CML development and may be a novel genetic markers for CML susceptibility.

Disclosures:

No relevant conflicts of interest to declare.
Megakariocytic Hypoplasia Due To TKIs In a CML Patient Can Be Overcome By TPO Receptor Agonist Eltrombopag
Authors: Dolata, MD Wojciech K.
Published: October 2019

Background

Patients who develop severe thrombocytopenia while treated with TK inhibitors may be forced to stop them, face a worse prognosis, and eventually require a treatment with a bone marrow transplant.

Eltrombopag is a TPO receptor agonist that stimulates megakaryocytic proliferation.

Case

62-year-old man presented in October 2008 with splenomegaly and leukocytosis. The bone marrow biopsy was diagnostic of CML. Imatinib was started at 400 mg daily resulting in hematological response and resolution of splenomegaly, but severe thrombocytopenia necessitated 50 % dose reduction. Thrombocytopenia was not responsive to Prednisone, and a trial of platelets transfusions with the standard dose of Imatinib had to be stopped because of thrombocytopenia below 10 K and the risk of bleeding – reducing the dose of the TKI was improving the platelet count.

Treatment with Dasatinib and with Nilotinib also necessitated 50 % dose reductions because of thrombocytopenia.

These reduced TKI dosing resulted in the best Quantitative RT-PCR for bcr/abl product reduction level at – 1.01. Bone marrow biopsy in December 2010 showed no morphologic evidence of CML, and no dysplasia; it was normocellular marrow with erythroid hyperplasia and megakaryocytic hypoplasia. Cytogenetic analysis and FISH showed presence of the Philadelphia chromosome rearrangement. The patient declined the treatment with a Bone marrow transplant.

In April 2011 a TPO agonist Eltrombopag 50 mg daily was started, given on two weeks on two weeks off schedule. As platelets remained adequate since then, the Nilotinib was escalated to the full dose of 400 mg twice daily. The patient tolerated the treatment well.

Results

The patient required about half-a-year support with Eltrombopag; after that it was discontinued as the platelet count remained above 40 K. No dose reduction of Nilotinib was necessary. In January 2012 the patient reached the milestone of Complete Cytogentic Response with the level of bcr/abl transcript minus 2 or less, which continued to decrease and now the patient is achieving a Major Molecular Response.

Conclusion

Treatment of CML with Tyrosine Kinase Inhibitors – Imatinib, Dasatinib, or Nilotinib in our patient – can be complicated by severe thrombocytopenia. These patients’ next treatment option may be a Bone marrow transplant.

Limited use of Eltrombopag can improve thrombocytopenia, and allow these patients to continue TKIs with attainment of the treatment milestons.

Disclosures:

Off Label Use: Eltrombopag. It is used in thrombocytopenia, in ITP. In this presentation it was used to treat thrombocytopenia secondary to Thyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia.
Interferon-Alpha (IFN-a) Is Able To Maintain Complete Molecular Response (CMR) In Chronic Myeloid Leukemia (CML) Patients Who Maintain Undetectable disease After Imatinib (IM) Discontinuation
Authors: Carella Angelo Michele , Beltrami Germana , Ghiggi Chiara
Published: October 2019

Cytotoxic lymphocytes (CTLs) which recognize distinct antigenic peptides on CML cells, contributed greatly to the eradication of leukemic cells after allografting. Previously, BCR-ABL specific peptides and the PR1 non-apeptide, were found to elicit a CML-specific CTL response. PR1 is a peptide derived from myeloblastin (MBN), also known as proteinase 3. MBN is abundantly expressed in azurophil granules of normal myeloid cells and is substantially overexpressed in certain immature myeloid leukemia cells where it may be important for the maintenance of a leukemic phenotype. PR1-specific CTLs (PR1-CTLs) lyses and inhibits the proliferation of CML cells but not of normal myeloid precursors. The association between the emergence of PR1-CTLs and the response to IFN-a in vivo strongly implied that IFN-a can induce remissions via induction of a CML-specific PR1-CTLs response. Therefore IFN-a, given to CML patient with undetectable disease achieved with IM, might enable its discontinuation.

Ten consecutive CML patients, who were in stable CMR for at least one year after IM therapy, discontinued IM and received IFN-a. This drug was given at the dose of 3M/U/m2 weekly. The median duration of IM therapy before discontinuation was 60 (range, 31-76) months. At a median follow-up of 40 months (range, 26-58 months), five patients still have undetectable level of BCR-ABL transcript. Five patients relapsed at a median of 8 months (range, 3 – 11 months) but all except one, achieved a new CMR after reintroduction of IM. Grade 2 intolerance (muscle pain, fever) to IFN-a developed in 6/10 patients. The details of patients characteristics will be discussed during the presentation. These preliminary results demonstrate that treatment with low dose IFN-a offered to CML patients with undetectable disease is feasible and this approach may become an attractive alternative to TKI discontinuation alone.

Disclosures:

No relevant conflicts of interest to declare.
Is EUTOS Score Predictive Of Outcome In Patients With Early Chronic Phase Chronic Myeloid Leukemia Treated With Imatinib? Preliminary Data From The National Protocol Of The Chilean Cooperative Group Panda
Authors: Zelada Javier , Aida Capurro Marisa Pia , Rojas Bernardita , Pilleux Lilian M , Aspillaga Augusto , Intriago Marvila , Rosas Jeanette , Graver Diego , Undurraga Soledad S.
Published: October 2019

Background

Before the Tirosine Kinase Inhibitors (TKI) era, the SOKAL and HASFORD scores have been used to predict outcome in chronic myeloid leukemia (CML) patients. The recently reported European Treatment and Outcome Study (EUTOS) score is a simple formula created to identify patients with significantly lower probabilities of responding to therapy and survival. The MD Anderson group didn´t validate this score.

Aims

To validate the EUTOS score in our population treated in the public health hospitals in Chile with a single protocol of the cooperative group PANDA.

Methods

Patients were selected from the data base of the CML 2007 PANDA protocol. All patients were adults (>15 years old) in early chronic phase and received first-line treatment with imatinib-based regimes and had a minimal follow up of twelve months. Event was defined as not reaching complete cytogenetic response in the first year of treatment, death from any cause at any time, loss of complete hematologic response, loss of major cytogenetic response, or progression to accelerated or blast phase. Overall survival (OS) was defined as death of any cause at any time. Event free survival (EFS) was defined as time from diagnosis to any event.

Results

A total of 78 patients were selected from the 330 patients of the data base. The rest had incomplete data. The median age was 48 (range 16 to 79 years old), 47 men and 31 women. Patients with low EUTOS score were 49 (63%) and 29 (37%) were high. The sensitivity of EUTOS was 46% , the specificity was 71% and the negative predictive value was 68%. There was no significative difference in EFS and OS in both EUTOS groups.

Conclusions

EUTOS score was not predictive of outcome in our patient population. Nevertheless it showed a good negative predictive value meaning that it can only identify low risk patients. This could be used in developing countries to select patients that could use lower cost TKI in first line treatment.

Disclosures:

No relevant conflicts of interest to declare.
Improved Prognostic Assessment Of Patients With MDS By IPSS-R and MDS-CI
Authors: van Spronsen Margot , van Spronsen Margot , de Loosdrecht Arjan van , Chamuleau Martine ED
Published: October 2019

Purpose

Myelodysplastic syndrome (MDS) is a broad spectrum of bone marrow failure syndromes characterized by diversity concerning clinical behavior, influence on patient’s outcome and risk for leukemic evolution. For more accurate prognostic assessment, the International Prognostic Scoring System (IPSS) has been recently revised. The purpose of this single-center study was to validate the r-IPSS and to compare this model with the MD Anderson Risk Model Score (MDAS), the IPSS and the (revised) WHO classification-based Prognostic Scoring System (WPSS(-R)). Furthermore, the predictive value of the MDS-Specific Co-morbidity Index (MDS-CI) as several other prognostic factors were analyzed.

Methods

Data were retrospectively collected from 222 MDS patients diagnosed at the VUmc between January 2000 and 2013. Selection was based on informative cytogenetics and the availability of peripheral blood and bone marrow counts. The MDAS, (r-)IPSS, (r-)WPSS and MDS-CI were applied and the impact of individual prognostic factors on patients’ outcome was investigated. Kaplan-Meier method was used for estimating survival and the value of prognostic models was determined by Cox’s multivariate regression method.

Results

Of our study population, 25 (11%), 83 (38%), 51 (23%), 37 (17%) and 25 (11%) patients were classified according to the IPSS-R as very low, low, intermediate, high and very high risk with, respectively, median overall survival (OS) of 129 (95%CI 96-161), 89 (95%CI 73-105), 43 (95%CI 30-57-61), 31 (95%CI 20-42) and 19 (95%CI 7-31) months (P < 0.000). Compared to the MDAS, IPSS, WPSS(-R) and MDAS, the IPSS-R had a higher predictive power for OS. The MDS-CI was of significant predictive value additional to IPSS-R (P < 0.003). Low risk MDS-CI patients who underwent stem cell transplantation (SCT) had a significantly higher mean overall survival (OS), respectively 104 versus 43 months (P < 0.038). However, mean OS of intermediate and high risk MDS patients who received SCT was not better.

Conclusion

Our data confirm the predictive value of the IPSS-R and show the additional value of the MDS-CI. Combined application of these models refines the prognostic assessment and identifies co-morbidity among MDS patients, which may assist and influence clinical decision making.

Disclosures:

No relevant conflicts of interest to declare.
Rhodiola Rosea Extract Reduces Autophagy In Acute Myeloid Leukemia Transformed From Myelodysplastic Syndromes Tumor Xenograft Model
Authors: Torello Cristiane Okuda , Machado-Neto Joao , Veira Karla P. , Maso Victor , Calgarotto Andrana , Franchi-Junior Gilberto Carlos , Lazarini Mariana , Queiroz Mary L. S. , Saad Sara Teresinha
Published: October 2019

Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by ineffective hematopoiesis and a tendency to progress towards acute myeloid leukemia (AML). The autophagy process has been implicated in the pathophysiology of both disorders. MDS treatment usually focuses on reducing or preventing complications, and single-target drugs are ineffective. The identification of novel compounds with anti-leukemia activity, as well as understanding the molecular and cellular basis of the disease may provide new therapeutic opportunities for MDS. In this concern, natural compounds such as Rhodiola rosea are considered interesting for the development of drugs against various molecular targets. Phytochemicals analyses of R. rosea extracts (RRE) revealed the presence of several components including polyphenols. The aim of this study was to study RRE effects using human tumor xenograft model. A total of 2x106 P39 cells (AML transformed from MDS), were subcutaneously injected in dorsal region of NOD.CB17-Prkdcscid/J mice. Tumor volume was measured once every 7 days and RRE treatment initiated when tumors reached 100-200 mm3 (n=6). The dose of 250mg/Kg body was given once every day by oral route (gavage). Control group received vehicle only (n=6). After 14 days, mice were sacrificed; tumors were removed and autophagy-related protein expression was evaluated by Western blot. After 14 days treatment, there was reduction of approximately 30% in tumor volume compared to controls. We found increased expression of beclin-1 and STSQM1/p62, and also Bcl-2 expression. In conclusion, Rhodiola rosea extract treatment in AML transformed from MDS tumor xenograft model reduces tumor growth, with pronounced inhibition of autophagy process.

Disclosures:

No relevant conflicts of interest to declare.
FANCA Controls Mitotic Phosphosignaling Networks To Ensure Genome Stability During Cell Division
Authors: Enzor Rikki , Sater Zahi Abdul , Cerabona Donna , Sun Zejin , Park Su-jung , Hanenberg Helmut , Clapp D. Wade , Nalepa Grzegorz
Published: October 2019

Fanconi anemia (FA) is a heterogenous genome instability syndrome with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair. However, it is incompletely understood why FA-deficient cells also develop gross aneuploidy and multinucleation, which are symptoms of error-prone chromosome segregation. Emerging evidence indicates that the FA signaling network functions as a guardian of the genome throughout the cell cycle, including chromosome segregation during mitosis. However, the mechanistic aspects of the critical role of the FA signaling in mitosis remain poorly understood.

We have recently shown that the FA signaling network localizes to the mitotic apparatus to control the spindle assembly checkpoint and centrosome maintenance (J Clin Invest 2013, in press). The spindle assembly checkpoint (SAC) is a complex tumor suppressor signaling network that prevents premature separation of sister chromatids by delaying the metaphase-to-anaphase transition until all the kinetochores are properly attached to the mitotic spindle. Since weakened SAC promotes stochastic chromosome segregation, mutagenesis and cancer, these findings shed new light on the role of FA signaling in maintenance of genomic stability. We found the subcellular localization of FA proteins to the mitotic apparatus is spatiotemporally regulated as cells divide.

Our new data revealed the pathways connecting the FANCA protein with canonical mitotic phosphosignaling networks. We have employed unbiased kinome-wide phospho-mass spectrometry to compare the landscape of abnormalities of mitotic signaling pathways in primary FANCA-/- patient cells and gene-corrected isogenic cells. These experiments led us to identify and quantify a wide range of phosphorylation abnormalities of multiple FANCA-dependent centrosome-, kinetochore- and chromosome-associated regulators of mitosis. Our data illuminated the role for FA signaling in three critical stages of cell division: (1) the spindle assembly checkpoint, (2) anaphase and (3) cytokinesis. Thus, we employed live phase-contrast imaging of primary FANCA-/- patient cells in comparison to gene-corrected cells to separately quantify aberrations in (1) chromosome congression and metaphase-anaphase transition (SAC malfunction), (2) execution of anaphase and (3) completion of cytokinesis.

Our findings further our understanding of human cell cycle control and provide new insights into the origins of genomic instability in Fanconi anemia by establishing mechanistic connection between the FANCA protein and key mitotic signaling networks. The identification of cell division pathways regulated by FANCA has implications for future targeted drug development in Fanconi anemia and FA-deficient malignancies in the general population.

Disclosures:

No relevant conflicts of interest to declare.
Incidence and Predictors Of Venous Thromboembolism Among Lymphoma Patients In Denmark: A Nationwide Population-Based Cohort Study
Authors: Lund Jennifer L , Ostgard Lene Sofie Granfeldt , Prandoni Paolo , Sorensen Henrik Toft , Brown Peter de Nully
Published: October 2019

Background

Prior studies examining the incidence of venous thromboembolism (VTE) in lymphoma patients have been limited by small sample size and restriction to specific lymphoma subtypes, leading to a wide range of estimates (1.5%-59.5%). Incidence of VTE in lymphoma patients may be influenced by a variety of patient, clinical, and treatment-related factors. These factors also can influence risk of death, a nuance ignored in prior work. We examined the incidence and predictors of VTE among lymphoma patients in Denmark, considering death as a competing risk.

Methods

Our nationwide cohort study identified all newly diagnosed lymphoma patients in Denmark from 2000-2010 using a population-based lymphoma registry (n=10,759), which prospectively collects clinical, pathological, treatment, and relapse and progression data. These data were linked to the Danish National Registry of Patients to identify selected comorbid conditions, treatments, incident VTE (excluding patients with a VTE registered before the year preceding lymphoma diagnosis, n=256), and vital status. VTE incidence rates per 1,000 person-years and 95% confidence intervals (CIs) were computed for pre-specified time intervals from 1 year before through 2 years following lymphoma diagnosis. After excluding patients diagnosed with a VTE during the year before lymphoma diagnosis (n=128), we estimated the 2-year cumulative incidence of VTE overall and by lymphoma subtype, accounting for death as a competing risk. Using the Fine and Gray model, we estimated subdistribution hazard ratios (sHRs) and 95% CIs to identify patient, clinical, and time-dependent treatment predictors of VTE.

Results

The VTE incidence rate varied over time (Figure 1), with a peak immediately following diagnosis.

Excluding patients with a VTE prior to lymphoma diagnosis, the 2-year cumulative incidence was 3.5% and was highest among peripheral T-cell (5.2%) and diffuse large B-cell (4.5%) lymphoma patients. The overall 2-year cumulative incidence of death was 24.7%.

CNS involvement, elevated lactate dehydrogenase count, central venous catheter placement, and chemotherapy were the strongest predictors of VTE, after accounting for risk of death. Patients with low-risk or mantle cell lymphomas were at decreased risk of VTE compared with diffuse large B-cell lymphoma patients. Risks were similar for all other lymphoma subtypes.

Conclusions

Although the incidence of VTE was high among lymphoma patients in Denmark, this risk was substantially lower than the risk of death. In order to mitigate VTE risk while continuing to treat patients with lymphoma, prophylactic approaches should be targeted towards patient subgroups at highest risk.

Disclosures:

No relevant conflicts of interest to declare.
From B-Cell Tolerance to Autoimmunity
Authors: Marshak-Rothstein Ann
Published: October 2019

Despite numerous mechanisms that exist to purge the B-cell repertoire of potentially dangerous autoreactive cells, it is now clear that numerous cells with the capability of binding self determinants survive negative selection and persist peripherally as anergic or ignorant cells. Exactly how these B cells are normally constrained, and then aberrantly activated in the context of autoimmunity, are two major questions in B-cell biology. A better understanding of the mechanisms involved in these processes could provide important insights to the regulation of alloreactivity. One clue to our understanding of autoimmunity comes from the nature of the autoantigens commonly targeted in systemic autoimmune diseases. Autoantigens often consist of macromolecular complexes that incorporate self-nucleic acids, and numerous in vitro studies have now shown that many of these canonical autoantigens are essentially potent endogenous autoadjuvants. Mice expressing a low affinity BCR specific for autologous IgG2a can be potently activated by DNA or RNA-associated immune complexes through a mechanism dependent on both the BCR and either TLR9 or TLR7, and serve as a useful prototype for autoreactive B cells in general. A number of groups have now tested this BCR/TLR paradigm in vivo. As expected, Tlr9-/- autoimmune-prone mice fail to produce autoantibodies directed against chromatin, while Tlr7-/- mice fail to produce autoantibodies directed against numerous RNA-associated proteins. However, the Tlr9-/- mice develop accelerated clinical disease, while the Tlr7-/- mice exhibit remarkably prolonged survival. We have now shown that BCR/TLR9 and BCR/TLR7 induce inherently different functional outcomes in B cells. Quite remarkably, both in vitro and in vivo, BCR/TLR7-dependent activation of autoreactive B cells leads to a more prolonged response and increased numbers of antibody producing cells. This response can be defined by a unique gene-expression profile and associated with proteins known to promote plasmablast differentiation. By contrast, BCR/TLR9 activation appears to initially limit autoreactive B-cell expansion; although in the context of systemic autoimmunity TLR9 is required for the production of DNA-reactive autoantibodies. Together these data indicate that the outcome BCR/TLR9 engagement of autoreactive B cells is highly dependent on environmental cues, and suggest that BCR/TLR7 B-cell activation is a key factor in the initiation of systemic lupus erythematosus and other systemic disorders.

Disclosures:

Marshak-Rothstein: Idera Pharmaceuticals: Consultancy; Abbvie: Consultancy; Genentech: Honoraria.
Gene Regulation: A Genomic Perspective
Authors: Stamatoyannopoulos John
Published: October 2019

Regulatory elements control the anatomic and cellular contexts, timing, and magnitude of gene expression patterns. Under the ENCODE and Roadmap Epigenomics Projects, human regulatory DNA has been mapped using a variety of approaches in over 300 cell and tissue types and developmental states. Collectively, the human genome encodes several million regulatory elements, most of which are located at some distance from promoters. The vast majority of these elements exhibit exquisite cell-and lineage-selective activation patterns, providing novel insights into the coordination of gene expression patterns. Genomic footprinting is a new and powerful technology that enables simultaneous profiling of the occupancy of hundreds of sequence-specific transcription factors within regulatory regions. These profiles in turn enable construction of transcription factor regulatory networks that are providing new insights into how cell-and lineage-specific gene expression programs arise. Hundreds of genetic variants associated with a wide range of hematological traits and disorders localize within regulatory regions. Many such variants disrupt specific transcription factor-DNA interactions, exposing pathophysiologically relevant transcriptional regulatory pathways.

Disclosures:

No relevant conflicts of interest to declare.
Genomic Evolution and Clinical Correlates
Authors: Campbell Peter J.
Published: October 2019

Multiple myeloma (MM) is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. It is classically subdivided into a subtype with rearrangements involving the IGH locus and the hyperdiploid subtype, which harbors multiple trisomies involving odd-numbered chromosomes. These chromosomal abnormalities are nevertheless insufficient for malignant transformation because they are also observed in monoclonal gammopathy of unknown significance, a pre-malignant syndrome that precedes MM. Malignant progression is associated with additional events such as somatic mutations, aberrant methylation, and chromosomal copy-number changes. This implies that the genetic landscape of MM changes over time, driving its symptomatic emergence and progression. Furthermore, evidence suggests that the molecular events necessary for myeloma progression are not attained in a linear fashion but rather through branching, nonlinear pathways. Through whole exome and genome sequencing, copy number profiling and cytogenetics, it has been possible to identify new candidate genes, define diverse mutational processes contributing to the genomic landscape, and study patterns of disease evolution. In particular, the overwhelming majority of MM patients have at least one cluster of subclonal variants, including subclonal driver mutations, implying ongoing tumor evolution. Serial samples reveal diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. These new findings reveal the myeloma genome to be heterogeneous across patients and within individual patients and that it can exhibit diversity in clonal admixture and dynamics in response to therapy. As modern genomics technologies will increasingly become available in routine diagnostic laboratories, it will be critical to develop an understanding of myeloma as a restless and dynamic disease, with multiple subclones exploring the genomic landscape seeking fitter states. This understanding should, in turn, be used to shape our therapeutic approach to the disease.

Disclosures:

No relevant conflicts of interest to declare.