bluuebunny/crossref_metadata_2025 huggingface dataset:
Findings of Feasibility Assessment From Multicenter Clinical Trials of Antithrombotic Therapy in Pediatric Venous Thromboembolism
Authors: Wallace Amy E , Young Guy , Manco-Johnson Marilyn J. , Goldenberg Neil A.
Published: October 2019

Abstract 4323

BACKGROUND:Two major multicenter pediatric randomized controlled clinical trials (RCTs) in pediatric venous thromboembolism (VTE) have been conducted in the last decade, and each was closed early due to poor accrual. With the recent trend in reduced federal grant support for clinical trials, an emphasis on demonstration of feasibility is critical.OBJECTIVE: In order to inform the design and execution of future RCTs in pediatric VTE, we sought to report findings of feasibility assessment from two ongoing and one proposed clinical trials in the field. METHODS: In the UNBLOCK study (ongoing phase 1 trial of bivalirudin in acute DVT; clinicaltrials.gov registration #NCT00812370), feasibility was assessed informally in 2008/9 during grant development teleconferences and early investigator meetings. In the Kids-DOTT trial (ongoing phase 3 RCT of shortened vs. conventional duration of therapy in acute VTE associated with a transient/reversible clinical risk factor; NCT00687882), feasibility was assessed in 2005 and updated in 2011 using standardized questionnaires, with response data summarized via descriptive statistics. The latter approached was also used in 2011 for the PHLO trial (proposed phase II/III RCT of catheter-directed thrombolysis followed by therapeutic anticoagulation vs. anticoagulation alone in completely veno-occlusive acute DVT of the proximal leg). RESULTS: Response rate (Kids-DOTT and PHLO questionnaires) was 100%. Number of investigative sites/principal investigators assessed and geographical distribution, by trial, were as follows: UNBLOCK: n=6 (all USA); Kids-DOTT: n=26 (25 USA, 1 Canada); PHLO: n=7 (all USA). Of the 26 site PIs in Kids-DOTT, 84% reported past experience with 5 or more trials, with a median experience of 20 per PI. Across all 3 trial feasibility assessments, all but one site used electronic health records in clinical care, and all but one investigative team had trial experience in using electronic data capture systems. With regard to size of the screening population for pediatric VTE trials, Figure 1 shows the reported average annual volume of new pediatric VTE cases managed by each Kids-DOTT investigator/site, using data from the prior 2 years. All sites reported use of inpatient/consult lists in screening efforts. CONCLUSIONS: These findings indicate appropriate site experience and capacity to execute multicenter clinical trials in pediatric VTE. Therefore, feasibility of ongoing and future trials in the field is more likely related to such issues as: suitability of funding and number of sites to targeted enrollment; experience/capabilities of the clinical coordinating and data coordinating centers; and pragmatic protocol design, particularly eligibility criteria, enrollment/randomization windows, and frequency, timing, and invasiveness of follow-up and endpoint determinations.

Disclosures:

No relevant conflicts of interest to declare.
Use of Emergency-Release, Uncrossmatched O Negative Red Blood Cells (RBCs) in a Tertiary Care Children’s Hospital
Authors: Andrews Jennifer C. , Viele Maurene , Goodnough Lawrence T
Published: October 2019

Abstract 4341

Background:

Transfusion services must offer means of issuing blood products quickly for emergent transfusions. At Lucile Packard Children’s Hospital (LPCH), off-site refrigerators were installed in the Neonatal Intensive Care Unit (NICU), the LPCH operating room (OR) and the Cardiovascular Intensive Care Unit (CVICU) inventoried with uncrossmatched O negative RBCs for immediate emergency use. Uncrossmatched O negative RBCs are also provided to children undergoing cardiac catheterization at the discretion of the Pediatric Cardiologist, since these patients commonly do not have type and screen samples drawn until large vessel venous cannulation via insertion of the catheter. Uncrossmatched blood products are also provided for children per our massive transfusion protocol (MTP). The purpose of this study was to assess the utilization of these uncrossmatched blood products in children and its impact on transfusion service (TS) inventory of O negative RBCs.

Methods:

Orders received for emergency-release uncrossmatched RBCs for patients ages 0 days to 18 years including MTPs from January 1 2011 to March 31 2011 were evaluated retrospectively. Variables collected include: patient demographic information and diagnosis; blood products ordered, released and transfused; location of the patient and location from where blood was dispensed (off-site refrigerator versus [vs] TS).

Results:

Median patient age was 3.46 years (range 0 days to 15.62 years), and 82% of the patients had congenital heart disease. Sixty four RBCs were issued to 33 patients during the 3-month study period. Of those, 32 RBCs were transfused, 8 RBCs were wasted because temperature parameters were exceeded before return to the TS, and 24 RBCs (38%) were not transfused and returned to TS inventory. Nineteen of the 32 RBCs were transfused, representing 2% of the total 964 O negative RBC units transfused at our institution for that time period. Nineteen (58%) units were for children in the cardiac catheterization suite. Seven patients were in the CVICU, five children were in the NICU, and two were in the Pediatric Intensive Care Unit. Two units of O negative RBCs were dispensed from the emergency off-site refrigerator in the CVICU.

Discussion:

The majority of children (79%) who received emergency-release uncrossmatched O negative RBCs at LPCH were those with congenital heart disease undergoing cardiac catheterization or being cared for post-operatively in the CVICU. There were 2 instances of children requiring RBCs from off-site refrigerators for an emergent transfusion. Emergency-release, uncrossmatched O negative RBCs at LPCH either from the TS or from three off-site refrigerators caused no undue strain on our supply and inventory of donor O negative RBCs.

Disclosures:

No relevant conflicts of interest to declare.
Successful Mobilization with the Combination of Plerixafor and G-CSF in Korean Pediatric Patients Who Failed in Previous Chemomobilization with G-CSF Alone
Authors: Kang Hyoung Jin , Hong Kyung Taek , Kim Nam Hee , Kim Min Sun , Lee Ji Won , Kim Hyery , Park Kyung Duk , Shin Hee Young , Ahn Hyo Seop
Published: October 2019

Abstract 4397

Introduction:

The classical peripheral blood stem cell mobilization (PBSCM) relies on granulocyte colony-stimulating factor (G-CSF) either as a single agent or in conjunction with chemotherapeutic agents (chemomobilization). This method however, sometimes fails in patients who have previously been heavily treated with chemotherapy or radiotherapy. PBSCM with plerixafor (AMD3100), a newly developed specific inhibitor of the CXCR4 receptor, in combination with G-CSF has been shown to enhance stem cell mobilization in adult patients, but pediatric data is scarce. We document our experiences with this drug in five pediatric patients.

Patients & Methods:

Five patients (three males, two females) with a median age of 9.6 years (range 6–11 years) who have failed in chemomobilization with G-CSF alone, received plerixafor. The diagnosis of patients was medulloblastoma in 2, osteosarcoma in 2, and neuroblastoma in 1. All the patients had previously been heavily treated with chemotherapy (median 15.4 months) and two of them with medulloblastoma underwent craniospinal irradiation. Patients received G-CSF (10mcg/kg) for 4 days at 10 AM before the first plerixafor (240ug/kg) administration, which was given subcutaneously 10 hours before apheresis. Apheresis was performed thereafter on the fifth day of G-CSF administration. Patients received G-CSF at 8AM and apheresis was started at 10AM. Each apheresis was performed with plerixafor and G-CSF in the same manner.

Results:

All the patients mobilized targeted numbers of CD34+ cells (median 12.86×10^6/kg, range 6.34–28.97×10^6/kg) successfully with two to three cycles of apheresis, without complications (Per each apheresis: median 3.8×10^6/kg, range 1.55–14.49×10^6/kg). A total of four autologous transplantations were performed in 3 patients including one tandem transplantation in a neuroblastoma patient. Neutrophil and platelet were successfully engrafted in four transplantations within a median of 9.7 days (range 9–10 days) and 68.3 days (range 15–197 days), respectively.

Conclusion:

Our study suggests that mobilization with plerixafor is safe and effective in Korean pediatric patients who have previously been heavily treated and have failed PBSC mobilization with classical chemomobilization with G-CSF. This is the first results of PBSCM with plerixafor in Asian pediatric patients.

Disclosures:

No relevant conflicts of interest to declare.
Single-Agent Bruton's Tyrosine Kinase (Btk) Inhibitor and Single-Agent Carfilzomib Induce Cell Apoptosis, Arrest Cell Growth and Downregulate NF-Kb Activity In Mantle Cell Lymphoma
Authors: Ou Zhishuo , Pham Lan V , Zhang Liang , Tamayo Archito T. , Lee John , Zhang Kejie , Wang Jacqueline , Phan James , Li Changping , Sun Luhong , Ford Richard J. , Wang Michael
Published: October 2019

Abstract 4971

Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma with poor prognoses. Discovery of less-toxic and better therapeutic agents is an ongoing challenge. Bruton tyrosine kinase (BTK), is identified as an essential kinase for B-cell survival, activated through the B-cell receptor (BCR) pathway. Recent studies have indicated that BTK mediates NF-kB activation. The potential therapeutic agent PCI-32765, a novel BTK inhibitor (Pharmacyclics, Sunnyvale, CA) have shown effective preliminary targeting of these pathways in MCL. Carfilzomib, a 2nd generation proteasome inhibitor (Onyx Pharm. Inc., Emeryville, CA) proven effective in myeloma in clinical trial is also effective in MCL in vitro and in vivo in pre-clinical studies. The objective of our study was to evaluate the therapeutic efficacy of PCI-32765 and carfilzomib in MCL, and elucidate the mechanisms of their actions. We initially screened 12 MCL cell lines and discovered that Btk is constitutively phosphorylated in all MCL cells. Representative MCL cell lines, both classic and blastoid variant, were utilized for in vitro studies. PCI-32765 effectively inhibited phospho-BTK, leading to reduced MCL cell growth with IC:50 values range from 10–50 uM. PCI-32765 also induced MCL cell apoptosis in both dose- and time-dependent manner as well as carfilzomib. Using luciferase pGL3 reporter plasmid (6xNF-kB-CD40L/TKm), we demonstrated that both PCI-32765 and carfilzomib down-regulated the reporter with a dosage dependent manner. Our data suggest that strategic targeting of growth/survival pathways with novel therapeutic agents PCI-32765 and carfilzomib should provide a novel therapy regimen for patients with relapsed/refractory MCL.

Disclosures:

Wang: Onyx Pharmaceuticals: Research Funding.
Adeno-Associated Viral Vector Mediated Gene Transfer for Hemophilia B
Authors: Nathwani Amit C , Tuddenham Edward GD , Rangarajan Savita , Rosales Cecilia , McIntosh Jenny H , Linch David C , Chowdary Pratima , Griffioen Anja , Riddell Anne , Pie Jun , Harrington Chris , O’Beirne James , Smith Keith , Pasi John , Glader Bertil , Rustagi Pradip , Ng Catherine , Kay Mark , Zhou Junfang , Spence Yunyu , Morton Christopher , Allay James , Coleman John , Sleep Susan , Cunningham John M , Basner-Tschakarjan Etiena , Mingozzi Federico , High Katherine A. , Gray John T. , Reiss Ulrike M. , Nienhuis Arthur W. , Davidoff Andrew
Published: October 2019

Abstract 5

Background:

Hemophilia B (HB), an X-linked bleeding disorder, is ideally suited for gene therapy. We investigated a novel approach using peripheral vein infusion of a single dose of a serotype-8 pseudotyped self-complementary adeno-associated virus (AAV) vector expressing a codon-optimized coagulation factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco).

Methods:

Six severe HB subjects (FIX ≤1%) were enrolled sequentially into one of three dose cohorts with two subjects in each group. Vector was administered without immunosuppression. The subjects were followed for 6–16 months post treatment.

Results:

AAV-mediated expression of FIX at 2–11% of normal was observed in all subjects. Four of the six have discontinued prophylaxis and remain free of spontaneous hemorrhage. The other two have increased the interval between FIX prophylaxes. A high-dose subject developed asymptomatic, transient elevation of serum transaminases associated with detection of AAV8 capsid specific T cells in peripheral blood. The second high-dose subject experienced a slight increase of liver enzymes, of less clear etiology. Treatment of each with a short course of steroids led to rapid normalization of the transaminases and maintenance of FIX levels in the 3–11% range.

Conclusion:

Peripheral vein administration of scAAV2/8-LP1-hFIXco was well tolerated and resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype. Immune-mediated clearance of AAV-transduced hepatocytes remains a concern but our data suggest that this process may be controlled with a short course of steroids without loss of transgene expression. Hence, our novel approach shows promise for gene therapy of HB and other protein deficiencies. (ClinicalTrials.gov number, NCT00979238)

Disclosures:

Nathwani: Amsterdam Molecular Therapeutics: Patents & Royalties. Gray:Amsterdam Molecular Therapeutics: Patents & Royalties. Davidoff:Amsterdam Molecular Therapeutics: Patents & Royalties.
Rescue of Doxorubicin-Induced Chemoresistance by API 31510 in Chloroleukemia
Authors: Narain Niven R , Wu Shuohan , McCook John P , Sarangajan Rangaprasad R , Alshaji Jasem M , Castillo Maite , Mauro Lucia M , Jimenez Joaquin J
Published: October 2019

Abstract 5016

Cancer resistance to single or multiple chemotherapy regimens continues to be a major problem in achieving complete remission. Fundamental knowledge of the mechanistic aspects underlying chemoresistance has yet to yield a practice changing answer to the problem. Thus, models of chemoresistance are necessary to shed light into molecular pathways and translational aspects of chemotherapy induced resistance. A classical example of chemotherapy to which resistance is developed is with use of doxorubicin. Several molecular and cellular aspects of doxorubicin resistance have been elucidated; however overcoming resistance remains elusive, thereby rendering animal models of doxorubicin to test novel drugs vital in solving this problem. In the present study we have used a well-established model of rat chloroleukemia (Science. 1987; 238:1278-80) to study resistance to doxorubicin. As an extension of this study, we derived a novel clone of the parent chloroleukemic cell resistant to doxorubicin. We proceeded to test this clone on the development of chloroleukemia in rats and to compare the cure rates of the parent (doxorubicin sensitive) cell line versus the doxorubicin resistant clone. Animals injected with the parent clone were treated with 1 mg/kg doxorubicin for 3 days. This regimen resulted in a cure rate of 35 percent. In sharp contrast, 100% of the animals injected with the doxorubicin resistant clone did not respond to doxorubicin therapy. Conversely, treatment of animals injected with the parent and doxorubicin-resistant clones exhibited a 50% cure rate when treated with ubidecarenone (API31510) (p<0.01). In vitro investigations revealed that API 31510 induced apoptosis in both chloroleukemic cell lines. The molecular pathways regulating API 31510- induced reversal of doxorubicin resistance were characterized, and shown to be independent from doxorubicin effect on the induction of resistance. The data herein strongly demonstrate that resistance to doxorubicin can be overcome by co-administration with API 31510.

Disclosures:

Narain: Berg Biosystems, LLC: Director, stock ownership, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Berg Therapeutics, LLC: Director, stock ownership, Equity Ownership. McCook:Berg Therapeutics, LLC: Director, stock ownership. Sarangajan:Berg Therapeutics, LLC: Director, stock ownership; Berg Biosystems, LLC: Director, stock ownership.
A Phase I Study of the Combination of Decitabine with Lenalidomide for Patients with High Risk (IPSS Int-2 or High) Myelodysplastic Syndrome
Authors: de Castro Carlos Manuel , Adams Donna , Rao Arati V , Moore Joseph O. , Gockerman Jon P. , Diehl Louis F. , Beaven Anne W , Warzecho Julie , Rizzieri David A.
Published: October 2019

Abstract 5029

Background:

Decitabine and lenalidomide have demonstrated single agent activity in patients with myelodysplastic syndromes (MDS). The addition of lenalidomide to decitabine in patients with high risk MDS may improve responses through distinct mechanisms. A phase I study of azacytidine and lenalidomide has previously demonstrated the feasibility of the combination of a hypomethylating agent with lenalidomide and did suggest higher response rates. (Sekeres M, et al. JCO 2010)

Methods:

We conducted a 3×3 cohort design. Patients with high risk MDS who had received prior hypomethylating agent were eligible for the study. Patients were treated with decitabine 20mg/m2 IV over 1 hour daily on days 1–5. Lenalidomide was escalated in each cohort using a dose of 5 mg po daily for 21 days in cohort 1 and 10 mg po daily for 21 days in cohort 2. Additional cohorts using 15 mg and 25 mg of lenalidomide are planned but have not yet been entered. Cycles were repeated every 28 days if count recovery was adequate. Toxicity was assessed by NCI CTCAE v3.0 criteria. Responses (a secondary objective) were assessed using IWSG criteria.

Results:

Seven patients have been entered into this study and are evaluable for toxicity and response. Median age is 74 years (69–77). Because of 1 death in cohort 1 (felt to be due to respiratory failure in a patient with severe COPD and not related to study drugs), the cohort was expanded to 6 patients. No other deaths occurred on study. One patient has been entered on cohort 2. No grade 3 or 4 toxicities were seen in the other 6 patients. Myelosuppression is common but does not appear to be worse than decitabine alone. In the 6 patients in which response could be assessed, there were 2 complete responses (CRs) and 3 partial responses (PRs). One patient progressed to AML after one cycle. Responses were seen in the 3 patients that had received prior treatment with hypomethylating agents (1 CR, 2 PR). Duration of responses ranged from 4 months to 16 months.

Conclusion:

The combination of decitabine and lenalidomide has been well tolerated in patients with high-risk MDS. The maximum tolerate dose has not been reached, although myelosupression is common. Good responses have been seen even in patients with prior treatment with a hypomethylating agent.

Disclosures:

Off Label Use: Decitabine in combination with lenalidomide for high risk myelodysplastic syndrome. Rizzieri:Celgene: Speakers Bureau.
Registry of Patiens with Myelodysplastic Syndrome (MyDyS) in Slovakia
Authors: Mistrik Martin , Richterova Katarina , Tothova Elena , Markuljak Imrich , Valekova L'ubica , Palasthy Stanislav , Brabec Petr
Published: October 2019

Abstract 5051

While clinical studies and guidelines provide important data regarding the safety and efficacy of new drugs, their application to daily practice can be limited by the inclusion of selected patient populations. Population-based studies can provide additional insight into the complex process of implementing treatment guidelines in daily practice. The objective of the MyDyS registry was to collect and analyze data regarding the diagnosis and management of patients with myelodysplastic syndrome (MDS) in Slovakia.

Material and methods:

five clinical centers collected data regarding demographics, staging, history and cytopathology from newly diagnosed patients (pts) with MDS from 2009 to 2011. Patients were classified according to the French American British (FAB) and World Health Organization (WHO) systems and the International Prognostic Scoring System (IPSS). The database allowed online pts registration.

Results:

one hundred thirty pts were registered to MyDyS in the yrs 2009–2011 and data from 128 pts were analyzed. Male/ female: 53,1%/ 46.9%; average age 64,8 yrs (range 22–89 yrs). The most frequent diagnosis according to FAB classification was RA (53.9%) and RAEB (21.9%), and according to WHO classification RCMD (27,3%) and RAEB II (22,7%). IPSS Low risk was in 16,4% pts, INT-1 in 43%, INT-2 in 19,5% and High risk in 11,7%. The majority of pts were de novo (89,8%). Patients with secondary MDS (10,2%) had a history of malignancy (breast cancer, 23,1%; hematologic malignancy, 2,6% only) and history of combination chemo and radiation therapy in 61,5%. In these pts, bone marrow (BM) was hypercellular in 49,2%, hypocellular in 24,2% of patients. Number of blasts less than 5% in 60,2% patients. Erythroid dysplasia was observed in 88,3%, myeloid dysplasia in 56,3% and dysplasia of megakaryocytes in 71,9% of patients. BM biopsy was performed at diagnosis in 87,5% and reported as hypercellular in 56,6%, with fibrosis in 62,8% and abnormal localization of precursors (ALIP) in 8%. Peripheral cytopenia in 2–3 lineages was observed in 67,2% pts. Growth factor therapy was given to 63 pts and red blood cell transfusions (average 20,7; range 2–80 RBC units) were given to 35 patients. Deferasirox (mostly 1500mg/ d) was given to 25 patients, and serum ferritin level decreased after 8 months in 27,3% pts, after 12 months in 57,4% pts. Chelation therapy was associated with gastrointestinal intolerance in 1 case, and skin reaction in 2 patients.

Conclusion:

The presented data document the first steps in the complex process of improvement of management of MDS in daily clinical practice in Slovakia. Expansion of the registry is necessary for determination of best practices for discussion with health care authorities and health insurance institutions.

Disclosures:

No relevant conflicts of interest to declare.
Decitabine Treatment in Higher Risk MDS, CMML and AML Post-MDS Who Failed Azacitidine
Authors: Sanna Alessandro , Gozzini Antonella , Sassolini Francesca , Bosi Alberto , Santini Valeria
Published: October 2019

Abstract 5052

Background:

5-azacytidine (Vidaza, AZA) and 5-aza-2'-deoxycytidine (Decitabine, DAC) are active in therapy of myelodysplastic syndromes (MDS) probably with different mechanisms of action. Azacitidine is approved by FDA and EMEA and is routinely used in therapy of higher risk MDS in Europe and in the US. Decitabine is a demethylating agent approved for treatment of IPSS INT-2 and high risk MDS by FDA but not yet from EMEA and it seems particularly active in Chronic myelomonocytic leukemia (CMML) and AML of the elderly. Difference in mechanisms of action of these 2 agents have been determined in vitro, involving nuclear acid incorporation, cell cycle and apoptosis, gene and protein expression.

Patients:

Nine patients (4 RAEB 2, 4 AML, 1 CMML-1) were treated with decitabine 20mg/m2 × 5 days every 28 days as single agent or in association with Gemtuzumab ozogamicin 3 mg/m2 in day 5 and 9. IPSS score at diagnosis was: 1 low, 4 intermediate 1, 4 intermediate 2. All patients received at least 4 cycles of azacitidine 75 mg/mq per seven days every 28, 44% of them reached at least Hematological improvement and received DAC as second line after relapse. Median age was 70 (62–84) and 8/9 were male.

Methods:

Medical records of 14 patients who received decitabine treatment were reviewed and survival was calculated by the Kaplan Meier method and differences in survival calculated by the log-rank test using SPSS software. Complete remission was defined by normo-cellular bone marrow with <5% blasts and normal Hgb, WBC, and platelet counts, and PR required 50% decrease in blast count, increases in Hgb by >1.5 mmol/L, WBC count by >1000, and platelet count by >50,000. Results: Median overall survival (OS) was 121 days, range 27–586 days. Overall response rate (CR+PR+HI) was 33.3% with mean duration of response was 3.33 months. Mean number of cycles was 4 (range 1–20). Median OS of responder patients was 12 months vs 1 month of non responder patients. OS of patients treated with DAC after AZA-resistance was 2 months vs 4 months of patients relapsed, but who reached at least HI with AZA (p>0.05). Longer history of MDS disease seemed not relevant for outcome. Therapy was well tolerated and only two patients required a long hospitalization (42 and 77 days) for sepsis due to relevant myelosuppression.

Conclusions:

Decitabine treatment has some activity in MDS, CMML and AML patients refractory to AZA or who relapsed after initial response to AZA, suggesting that the two supposed hypomethylating agents act via partially different molecular mechanisms.

Disclosures:

No relevant conflicts of interest to declare.
Incidence of Bone Marrow (BM) Fibrosis in Multiple Myeloma (MM) Patients and Its Relationship to Cytogenetic (CG) Abnormalities in a Minority Population
Authors: Sidhu Gurinder , Latif Rabia , Liu Jinli , Axiotis Constantine , Khillan Ratesh , Braverman Albert S.
Published: October 2019

Abstract 5077

Background:

The incidence of BM fibrosis in MM is low and uncertain, and its causes are not known. Cytogenetic and fluorescence in situ hybridization (FISH) in some MM patients reveals prognostically significant anomalies.

Methods:

Records of patients with MM seen at Kings County Hospital from 2004 through 2010 were reviewed, the histological sections of patients reported to have fibrosis we re-examined. The degree of fibrosis was graded according to the World Health Organization system.

Results:

Records of 113 patients were reviewed, 110 (97%) were African American (AA). Of these, 62 (55%) were female and 51 (45%) male. Their age ranged (median 65) from 38 to 89 years. Cytogenetic data (CGD) was available in 46 patients; and abnormal in 10 (22%) and normal in 36 (78%) of those. All patients with abnormalities of chromosomal number were hyperdiploid.

Of 113 patients, 62 (55%) were female, 110 were African American. Ages ranged from 38–89 (median 65) years. Cytogenetic data was available for 46 patients and abnormal in 10 (22%). All patients with abnormal chromosome numbers were hyperdiploid. FISH studies to detect abnormalities in chromosomes 13, 14 and 17 were available in 25 and abnormal in 2 (8%).

BM fibrosis had been initially noted in 27 of 113 patients (24%), and confirmed by another hematopathologist; 17 (63%) were women. The ages of the patients with fibrosis ranged from 4–79 years: median age was 67, 67 for the women and 62 for the men. Focal and grades 1, 2 and 3 fibrosis were noted in 2 (7%), 12 (44%), 7 (26%) and 6 (22%) of patients. Grade 3 fibrosis was found in 24% of the women and 20% of the men with fibrosis.

CG data was available for 17 fibrosis patients and abnormal (hyperdipliod) in 2 (18%). FISH studies for chromosomes 13, 14 and 17 were normal in the 7 patients studied. CGD for all 8 of the female fibrosis patients studied were normal, and abnormal in 2 of the 9 men (22%).

Conclusions:

Of our 113 AA myeloma patients 25% had detectable BM fibrosis, but it was grade 3 in only 5%. Female preponderance was more marked in the patients with fibrosis than in the whole MM group. CG and FISH data did not distinguish patients with and without fibrosis.

Disclosures:

No relevant conflicts of interest to declare.
IgD Amyloidosis: An Unrecognized Entity
Authors: Gertz Morie Abraham , Buadi Francis K , Hayman Suzanne R , Dingli David , Dispenzieri Angela , Greipp Philip R. , Kumar Shaji , Lacy Martha Q , Lust John A , Leung Nelson , Rajkumar S. Vincent , Russell Stephen J. , Zeldenrust Steven R , Mikhael Joseph R. , Roy Vivek , Kyle Robert A
Published: October 2019

Abstract 5079

Introduction:

IgD monoclonal proteins are rare. They are not seen as a MGUS and are present in 1% to 2% of patients with myeloma. In light chain amyloidosis (AL), IgD monoclonal proteins are rare. When an IgD protein is found, amyloidosis is often omitted from the differential diagnosis. An IgD protein in amyloidosis has been reported in single cases but never as a patient series. We report IgD AL in 53.

Patients & Methods:

Clinical and demographic data for patients were retrieved from the patient records. Factors of interest were compared between patients who did and did not have an IgD protein.

Results:

Among 3,955 patients with AL amyloidosis seen, 53 patients (1.3%) had a serum IgD monoclonal protein. (Table 1) A serum monoclonal protein peak was visible on SPE in only 14, and only 5 had an M spike greater than 1 g/dL. On immunofixation of the serum, the IgD light chain was k in 11, λ in 35, and uncertain in 6; 1 patient had a biclonal D λ and G k protein. A urine monoclonal protein was detected in 43 of 51 patients; urinary immunofixation detected a λ light chain in 33 and a k light chain in 10. Biopsy of tissues showed amyloid deposits in the bone marrow in 47% and in the fat aspirate in 73%.

Six patients (age 47–63 years) underwent autologous SCT. Four had renal & two had cardiac AL. All 6 had hematologic PR, 4 CR, and 4 had organ response. One patient had relapse of disease and is now on dialysis, and another had relapse and is alive with salvage chemotherapy. One patient had disease relapse and died of progressive GI amyloidosis at 22 months. The other 5 are alive at a median of 68 months (range, 7.5–83.5 months). We compared the 53 patients with IgD amyloidosis with 144 patients with non-IgD amyloidosis. (Table 2) Findings that were significantly different between groups included a lower frequency of renal amyloidosis (P=.005) and a lower prevalence of cardiac amyloidosis (P=.047). There was a higher serum albumin level (P=.04) related to the lower level of proteinuria. No difference in survival was seen between the groups. (Figure). Variables that might affect survival—liver size, performance status, septal thickness, serum creatinine level, and β2-microglobulin level—were not different between groups.

Conclusions:

IgD AL patients have a lower frequency of renal involvement and possibly also of cardiac involvement. The overall survival of these patients does not appear to be different from that of patients who have AL associated with another monoclonal protein. IgD monoclonal proteins are so closely linked to the diagnosis of multiple myeloma in the mind of a clinician that the possibility of amyloidosis may be overlooked.

Disclosures:

No relevant conflicts of interest to declare.
The Human CD38 Monoclonal Antibody Daratumumab Improves the Anti-Myeloma Effect of Lenalidomide with Dexamethasone in Vitro
Authors: Weers Michel de , Veer Michael van der , van Kessel Berris , Bakker Joost M , Wittebol Shulamiet , Parren Paul WHI , Lokhorst Henk M. , Mutis Tuna
Published: October 2019

Abstract 5106

Multiple myeloma (MM) represents an incurable malignancy of antibody-producing clonal plasma cells. Over the past decade significant progress has been made in MM treatment using novel immunomodulating agents such as lenalidomide (LEN) and bortezomib (BORT). Daratumumab (DARA) is a human CD38 antibody with broad spectrum killing activity. DARA mediates MM cell death via ADCC (antibody dependent cellular cytotoxicity), CDC (complement dependent cytotoxicity) and apoptosis. We are currently exploring the possibility to further improve MM therapy by combining novel MM therapeutics with DARA. Our initial in vitro work already showed significantly improved MM cell killing by combining DARA with LEN and BORT treatment, especially in patient samples which showed poor responses to the LEN-BORT combination. We now investigated whether DARA can also further improve therapy of lenalidomide or bortezomib in combination with corticosteroids. In ex vivo assays, which allow us to address MM cell lysis directly in BM-MNC isolated from MM patients, DARA significantly enhanced killing of MM cells that were treated with LEN or dexamethasone (DEX). Importantly, DARA was also able to enhance lysis of MM cells that were poor responders to the LEN-DEX combination. This suggests that patients might benefit from a DARA-LEN-DEX combination therapy. Experiments showing effects of DARA on killing of BORT-DEX treated cells are currently underway. The results of this study extend our previous results with LEN-BORT-DARA, showing that MM cells lysis is enhanced by DARA, especially in in samples from patients that are refractory or poorly responding to existing and novel emerging combination therapies. These results support the hypothesis that powerful and complementary effects may be achieved when DARA is combined with LEN and cortocosteroids in clinical MM studies.

Disclosures:

Weers: Genmab: Employment, Equity Ownership, Patents & Royalties. Veer:Genmab: Research Funding. van Kessel:Genmab: Research Funding. Bakker:Genmab: Employment, Equity Ownership. Parren:Genmab: Employment, Equity Ownership, Patents & Royalties. Lokhorst:Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mutis:Genmab: Research Funding.
Long Term Efficacy of Percutaneous Vertebroplasty in Multiple Myeloma (MM) Patients: Experience of the “Gruppo Ematologico Di Romagna” (GER)
Authors: Tosi Patrizia , Molinari Annalia , Sintini Michele , Merli Anna , Ceccolini Michela , Imola Manuela , Savini Paolo , Pasini Silvana , Mianulli Anna M , Castagnari Barbara , Fattori Pier P , Martinelli Giovanni , Zaccaria Alfonso
Published: October 2019

Abstract 5123

Vertebral compression fractures occur in approximately 60% of MM patients and can cause pain, persistent disability and dismail quality of life. Appropriate therapy of MM or radiotherapy can lead to improvement of symptoms in a significant percentage of patients, but these positive effects can take time to be perceived. Vertebral agumentation techniques have been recently proposed as suitable options to relieve bone pain from vertebral compression fractures in patients with benign osteoporosis or neoplastic diseases such as MM. Aim of this study was to analyze the clinical course and outcome of 40 consecutive MM patients (23M, 17F, median age = 67.6yrs) treated in the Centers referring to GER, who underwent percutaneous vertebroplasty from 2006 to 2010. Seventeen patients (43%) were newly diagnosed while 23 patients were relapsed or refractory after 1–3 lines of therapy. All the patients were treated because of severe pain, the extent of vertebral fractures was assessed by nuclear magnetic resonance imaging. Sixty-nine procedures were performed at C2-L5 levels, 51% of the patients were treated at a single level, a maximum of three levels were treated in 6 patients, 13 procedures (32%) were performed at L1 level. Thirty seven patients (92%) experienced reduction of pain, with 55% showing complete disapperance of symptoms prior to any further treatment, 3 patients reported no or little improvement. Responses were durable, after a median follow-up of 14 months no further collapse of the treated vertebrae was observed. After vertebroplasty, first line or salvage therapy was administered to 35 patients, 10 newly diagnosed patients were scheduled to receive autologous stem cell transplant, and peripheral blood stem cell collection was not affected by the procedure.

In conclusion, percutaneous vertebroplasty appears to be useful in MM patients with painful vertebral fractures as it allows rapid and durable achievement of pain control, without interfering with further therapeutic programs

Work supported in part by RiminiAIL

Disclosures:

No relevant conflicts of interest to declare.
Development of a Splenic Marginal Zone Lymphoma Associated with Active Chronic Visceral Leishmaniasis
Authors: Vase Maja Ølholm , Hellberg Ylva Kristina , Larsen Carsten Schade , Petersen Jørgen Eskild , Schaumburg Henrik , Bendix Knud , Ravel Christophe , Bastien Patrick , Christensen Mariann , Nyvold Charlotte Guldborg , d'Amore Francesco
Published: October 2019

Abstract 5202

We here report the observation of the development of a splenic marginal zone lymphoma (SMZL) after years of active chronic visceral Leishmania (VL) infection, implying a possible pathogenic link between these two conditions, where the neoplastic process is preceded by a prolonged period of chronic antigen stimulation.

In 2004, a 60-year old male developed attack-like episodes of septic fever with chills, rigor and subsequent profound fatigue. He had a 4 years previous medical history of severe asthma-like symptoms and hypereosinophilia. A bone marrow (BM) and liver biopsy were inconclusive. A whole-body computed tomography showed a moderately enlarged spleen. No evidence of bacterial, fungal or viral infection was found; the symptoms persisted, although mitigated, with occasional exacerbations over the following 3 years.

By 2007 the patient was admitted again and a new BM biopsy was taken, still showing reactive changes. Due to increased splenomegaly, a diagnostic splenectomy was performed. Examination of the spleen revealed a primary splenic marginal zone lymphoma (SMZL).

In 2010 the patient was admitted with septicaemia and constitutional symptoms. A BM biopsy showed the presence of numerous Leishmania amastigotes and a retrospective review of all previous biopsies (since 2004) identified Leishmania amastigotes in all of them.

In fact, a thorough travel history covering the previous two decades revealed several visits, often twice a year, to the Mediterranean basin, e.g. Greece and Malta, areas endemic for Leishmania infantum (L. infantum).

Visceral Leishmaniasis is a frequent opportunistic infection in HIV-infected immunodeficient individuals but uncommon in cancer patients, and only a few cases of VL in patients with already well-established malignant lymphoma have been reported.

Chronic antigenic stimulation by microbial pathogens has been proposed as a pathogenetic factor in a variety of marginal zone lymphomas. Tissue specific immune responses toward Leishmania parasites have been shown in rodents, and the spleen is a ‘safe harbor’ for the long-term persistence of visceralizing Leishmania. Sustained antigenic stimulation with upregulation of critical signaling pathways may result in prolonged polyclonal B-cell proliferation, and a subsequent increased risk of malignant transformation.

This case is the first to provide evidence for a possible link between chronic antigen stimulation by long-lasting L. infantum infection and the development of a SMZL.

Disclosures:

No relevant conflicts of interest to declare.
Subcutaneous Panniculitis-Like T-Cell Lymphoma: A Study of 12 Cases
Authors: Chen Xiaochen , Depei Wu , Sun Aining , Qiu Huiying , Wu Xiaojin , Shi Xiaolan
Published: October 2019

Abstract 5217

Objective:

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare and distinct type of T-cell lymphoma. The objective of this study was to explore the clinical presentation, treatment, and prognosis of patients with SPTCL.

Methods:

Twelve cases of SCPTCL, treated in our hospital between June 2005 and June 2010, were included in this study. Their clinicopathological data were reviewed and analyzed retrospectively.

Results:

The median age at diagnosis was 41 years (range 25–69 years) and 7 (58%) were women. 9 cases had a CD3+, CD4-, CD8- phenotype; 2 cases, a CD3+, CD4-, CD8+ phenotype; and 1 case, a CD3+, CD4+, CD8- T-cell phenotype. In all cases, strong expression of cytotoxic proteins (granzyme B, TIA-1, perforin) was observed. CD56 was expressed in 8 of 12 cases.

4 patients had presented with solitary or localized skin lesions. Ulceration was observed in 3 patients. B symptoms, such as fever, chills, night sweats, and weight loss, had been recorded in 7 of 12 patients. Laboratory abnormalities, mainly anemia, leucopenia, thrombocytopenia or combined cytopenias, and elevated liver function tests and lactate dehydrogenase, were reported in 4 patients. Bone marrow examination showed histiocytic hyperplasia, hemophagocytosis, or decreased cellularity in 3 cases, but no evidence of lymphoma. A HPS was diagnosed in 4 of 12 patients (33%), and was fatal in 2 of them.

Four patients presenting with solitary or localized skin lesions had been treated with radiotherapy (2 cases) or surgery (2 cases). All 4 patients reached complete remission and only 1 of them showed a skin relapse, which was treated successfully with radiotherapy again. Eight patients with diffused lesions were treated with chemotherapy (CHOP or CHOP-like courses). After initial treatment 5 (63%) of 8 patients had developed new skin lesions, and 2 of them had developed extracutaneous localizations. Then the 3 of the relapsed patients were treated with autologous stem cell transplantation, all of whom obtained complete remission. At the time of last follow-up (median follow-up: 34 months; range: 10–60 months), 5 patients are in complete remission, 4 patients have ongoing skin disease, while 3 patients have died, 2 of the complications of HPS or therapy-related side effects and 1 of unrelated disease. The 3-year OS and DSS of the patients were 75% and 42%, respectively. Patients without HPS had a significantly better 3-year OS (88%) than patients with HPS (50%; P <.001).

Conclusion:

SPTCL seems to be a kind of heterogeneity disease. The factors associated with an unfavorable disease course were: diffuse lesions, a low white blood cell count, elevated lactate dehydrogenase, and combine with HPS. Autologous stem cell transplantation may improve the overall survival of high risk patients.

Disclosures:

No relevant conflicts of interest to declare.
ProatherogenIc Inflamatory mRNAs Have structural Features for Being Regulated by MicroRNAs
Authors: Yang Xiao-Feng , Virtue Anthony , Mai Jietang , Yin Ying , Jiang Xiaohua , Wang Hong
Published: October 2019

Abstract 5316

The current literature focusing on miRNAs has failed to adequately address two important questions - how miRNAs modulate atherogenic inflammatory genes from a panoramic viewpoint and whether the augmented expression of the atherogenic inflammatory genes is the result of miRNAs suppression. To resolve these knowledge gaps, we have employed a novel database mining technique in conjunction with statistical analysis criteria established from experimentally verified miRNAs. Utilizing this strategy we were able to conclude that the expression of 33 inflammatory genes is upregulated in atherosclerotic lesions and that these genes contain structural features in the 3'UTR of their mRNA for potential miRNAs regulation. Additionally, the binding features governing the interactions between the miRNAs and the inflammatory genes were statistically identical to the features of experimentally verified miRNAs. It was also determined that 21 (64%) of the 33 inflammatory genes were targeted by highly expressed miRNAs while the remaining 12 genes (36%) were targeted by normally expressed miRNAs. In addition, 10 of the 21 highly expressed miRNA-targeted inflammatory genes (48%) were targeted by a single miRNA, suggesting miRNA regulation specificity. Furthermore, 12 (48%) out of the 25 miRNAs found to meet our criteria targeted individual inflammatory genes while the other 13 miRNAs targeted multiple inflammatory genes. These results indicate a critical role of miRNAs in regulating proatherogenic inflammatory gene expression.

Disclosures:

No relevant conflicts of interest to declare.
“Rolling Recruitment” of Endothelial Cell (EC) Activation in the Prothrombotic Nature of Heparin-Induced Thrombocytopenia (HIT)
Authors: Hayes Vincent M , Cines Douglas B. , Poncz Mortimer , Rauova Lubica
Published: October 2019

Abstract 536

HIT is an iatrogenic, prothrombotic, immune-mediated disorder associated with antibodies directed against platelet factor 4 (PF4) and heparin complexes. Once these pathogenic anti-PF4/heparin antibodies develop, they recognize and bind to antigenic complexes formed on cell surfaces composed of PF4 released from platelets bound to cell membrane glycosaminoglycans (GAGs). Unlike platelets, which have only chondroitin sulfate on their surface, endothelial cells express mainly heparan sulfate resulting in a very high capacity to form PF4/GAG complexes and become targets for HIT antibodies. In fact, activation of endothelial cells by HIT antibodies was recognized almost 25 years ago (Cines et. al., 1987). We now show direct interaction of the HIT-like monoclonal antibody KKO with perithrombus endothelial cells, which propagates thrombosis following laser induced cremaster vessel injury in a passive immunization murine model of HIT. PF4 released from activated platelets at the site of laser injury binds rapidly and predominantly to the adjacent endothelium and is recognized by KKO in both transgenic mice expressing only human PF4 (hPF4+) and mice expressing hPF4 and human FcgRIIA on platelets (hPF4+/FcgRIIA+). These studies show that HIT-like antigenic complexes are present within thrombi prior to antibody exposure, predominantly localized to endothelial cells, which is consistent with their surface GAGs having higher affinity for PF4 than platelets. These endothelial cell surface PF4/GAG complexes, and with it KKO binding, are dissociated by high concentrations of intravenous heparin. Infusion of KKO in hPF4+/FcgRIIA+ mice but not in control mice, reinitiates growth of previously stable thrombi at sites of laser injury, leading to a significant increase in vascular occlusion (24/33 injuries, 73%, compared to 0/30 in control mice; P<0.0001). Clot extension is followed by dissemination of endothelial activation, demarcated by binding of annexin V and Factor Xa, and extension of the endothelial surface that binds KKO. Based on these studies, we propose a model of feed-forward rolling recruitment to explain how the endothelial lining contributes to the prothrombotic state in HIT: PF4 released from activated platelets at a site of injury or disease binds to the surface of perithrombus endothelial cells, which then binds HIT antibodies followed by endothelial cell activation. These activated endothelial cells then bind and activate additional platelets, leading to the next round of PF4 release, more extensive endothelial cell activation and platelet recruitment into thrombi.

Disclosures:

No relevant conflicts of interest to declare.