bluuebunny/crossref_metadata_2025 huggingface dataset:
Matched Cohort Analysis of Allogeneic Hematopoietic Cell Transplantation (HCT) with Total Marrow Irradiation/Fludarabine/Melphalan (TFM) Versus Fludarabine/Melphalan (FM) Conditioning for Acute Leukemia
Authors: Rosenthal Joseph , Wong Jefrrey , Stein Anthony Selwyn , Stiller Tracy , Palmer Joycelynne , Forman Stephen J.
Published: October 2019

Abstract 222

We have previously reported the feasibility and safety of augmenting the reduced-intensity regimen (RIC) of FM by addition of total marrow irradiation, a targeted form of TBI, using a helical tomotherapy (HT) device (Rosenthal, Blood. 2011;117(1):309–315). In this study we compared outcomes in patients with acute leukemia undergoing HCT receiving either TFM or FM.

Patients and Methods:

We analyzed 72 patients with acute leukemia or MDS who received either FM (N=36) or TFM (N=36) HCT. Eligibility criteria for TFM were age > 50 years of age or compromised organ function (COF); high-risk remission or marrow blasts ≤10%. TFM patients were matched to a set of FM patients based on age, gender, diagnosis and disease risk (low, intermediate, high). All patients received FM with fludarabine 25 mg/m2/d × 5 days and melphalan140 mg/m2/d × 1 day, and TMI was delivered at 150cGy/fraction in 8 fractions over 4 days in the TFM group. Supportive care and treatment for prevention of GVHD were given according to our institution standard guidelines for both groups.

Results:

Demographic characteristics were similar, including gender (20 females, 55.6%) and age (median 58 years, range: 22–68 in TFM and 20–68 in FM). The proportions of patients by diagnoses were similar: AML (n=27), ALL (n=7), MDS (n=2). Disease risk assignments in both groups were: Low risk (n=15), intermediate (n=6), high (n=15). There were 15 and 13 pts with active disease in FM and TFM, respectively. HLA-identical siblings (n=16, 44.4%) or matched unrelated donor (n=20, 55.6%) were used in each group. Outcomes are reported for the TFM and FM recipients, respectively as follows: myeloid recovery was documented on day 13.5 (9–24) and 15 (8–20). Transplant-related toxicities were limited to grade 3 or less in both groups. The most common grade 3 toxicities were: mucositis, n=9 and n=7 and bacterial infection, n=10 and n=11, respectively. Acute GvHD grade II-IV occurred in 20 pts (55%) and 19 (53%). Extensive chronic GVHD was documented in 24 (67%) and 20 (56%) pts. Twenty-one and 18 patients are alive at a median of 30.2 months and 35.3 months in the TFM and FM, respectively. The relapse cumulative incidence at 2 years post HCT was 11.1% (TFM) compared to 30.6% (FM) (p=0.06) (insert ). With a median follow-up of 31.7 months (4.1 – 62.5) for alive patients, the 2-year overall and progression-free survival estimates are 57.2 % (95% CI, 46.6–66.4) -TFM, and 62.8% (95% CI, 51.8–72.0) -FM, and 57.7% (95% CI, 47.2–67.0) -TFM, and 48.5% (95% CI, 40.2–56.3) -FM, respectively.

Conclusion:

The addition of TMI at a dose of 1200 cGy to FM is safe and tolerable and may decrease the risk of relapse related mortality.

Disclosures:

No relevant conflicts of interest to declare.
Recombinant B-Domain Deleted Porcine Factor VIII (OBI-1) Safety and Efficacy in the Treatment of Acquired Hemophilia A: Interim Results.
Authors: Louis Jean St. , Kruse-Jarres Rebecca , Greist Anne , Shapiro Amy D. , Smith Hedy , Drebes Anja B , Lozier Jay N. , Gomperts Edward D.
Published: October 2019

Abstract 2224

Introduction

OBI-1 is an investigational B-domain deleted recombinant porcine factor VIII (FVIII) with low cross-reactivity to anti-human FVIII antibodies. Acquired hemophilia A (AHA) is caused by autoantibodies (inhibitors) against human FVIII. Patients are predominantly elderly and have co-morbidities. Current pharmacologic treatment of bleeds is guided by clinical assessment alone as there is no laboratory surrogate for efficacy. Importantly, OBI-1 efficacy can be monitored by FVIII levels in addition to clinical assessment.

Methods

Accur8 Auto-antibody trial (NCT01178294) is a prospective, open label, Phase 2/3 study. The primary objective is to evaluate efficacy of OBI-1 treatment for serious (life- or limb-threatening) bleeds in patients ≥18 years with AHA. FVIII levels are obtained before and within 10–20 min following initial OBI-1 dose (200U/kg) and at 2–3 h. Additional OBI-1 doses (≤400U/kg every 2–3 h) are administered to achieve target FVIII levels. The primary efficacy outcome is the control of bleeding 24 h after starting OBI-1.

Results

As of July, 2012, fifteen patients with severe bleeds were entered into the trial along with one individual treated under compassionate use and all had successful control of hemorrhage at 24 h and subsequent resolution of the bleed. Therapeutic FVIII activity levels were achieved and maintained with intermittent

OBI-1 administration based on FVIII levels. Six serious adverse events were reported including four deaths after treatment was discontinued, all being unrelated to OBI-1 as determined by the investigators. Antibodies to OBI-1 developed in two subjects indicated with an * in the table below. However, both responded toOBI-1.

Conclusions

These interim results provide support for the safety and efficacy of OBI-1 in the treatment of serious bleeding episodes in AHA. Additional confirming data could establish OBI-1 as a useful treatment option for AHA.

Disclosures:

St. Louis: Inspiration Biopharmaceuticals Inc: Research Funding. Kruse-Jarres:Inspiration Biopharmaceiticals Inc: Research Funding. Greist:Inspiration Biopharmaceuticals Inc: Research Funding. Shapiro:Inspiration Biopharmaceuticals Inc: Research Funding. Smith:Inspiration Biopharmaceuticals Inc: Research Funding. Drebes:Inspiration Biopharmaceuticals Inc: Research Funding. Gomperts:Inspiration Biopharmaceuticals Inc: Consultancy.
Recombinant Human Soluble Thrombomodulin Safely and Effectively Rescues Acute Promyelocytic Leukemia Patients From Disseminated Intravascular Coagulation.
Authors: Ikezoe Takayuki , Takeuchi Asako , Kim Tsukie , Akabuki Kazuki , Sakai Mizu , Taniguchi Ayuko , Togitani Tazuto , Yokoyama Akihito
Published: October 2019

Abstract 2226

Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia (AML) with a high mortality rate, mostly attributable to intracranial hemorrhage caused by disseminated intravascular coagulation (DIC). Almost all patients with APL develop DIC. The introduction of all-trans retinoic acid (ATRA) into the induction chemotherapy regimen has revolutionized the treatment of individuals with APL, with nearly 90% of newly diagnosed APL patients achieving complete remission and over 70% of patients surviving longer than 5 years. However, population-based studies have shown that the early death-rate during induction chemotherapy remains extremely high with nearly 30% incidence and the most common cause of death is associated with hemorrhage. Thus, development of a novel treatment strategy to alleviate abnormal coagulation in APL patients is urgently required.

Recombinant human soluble thrombomodulin (rTM) comprises the active, extracellular domain of TM, and inactivates coagulation. A phase III trial comparing efficacy and safety between rTM and low-dose heparin showed that rTM significantly improved DIC associated with hematological malignancies or infections. This clinical trial excluded almost all patients with APL, because concomitant use of ATRA was prohibited. The use of rTM for the treatment of DIC was approved in Japan in be 2008.

In this study, we treated individuals for DIC caused by APL (n=9) using rTM in combination with ATRA and chemotherapy, and compared the clinical outcomes with historical control patients (n=8) treated with ATRA and/or chemotherapy. Two control patients developed intracranial vascular incidents. On the other hand, no bleeding related mortality was noted in rTM-treated patients. Percentage change of FDP and change of fibrinogen were significantly higher in the rTM group than the control group (repeated measures ANOVA, p=0.041 and p=0.045, respectively). Interestingly, treatment with rTM significantly reduced the transfusion units of FFP required to maintain plasma levels of fibrinogen above 150 mg/dl (0.63 ± 0.93 U/d vs. 4.3 ± 1.6 U/d, p=0.001). Notably, treatment with rTM rescued patients from DIC earlier than historical controls (log rank test, p=0.019). These results suggest that administration of rTM should be considered for the treatment of individuals with DIC associated with APL.

Disclosures:

No relevant conflicts of interest to declare.
Surgery with Turoctocog Alfa: Efficacy and Safety in Bleeding Prevention During Surgical Procedures - Results From the guardian™ Trials.
Authors: Santagostino Elena , Lentz Steven R. , Misgav Mudi , Brand Brigitte , Chowdary Pratima , Savic Aleksander , Kilinc Yurdanur , Tuddenham Edward GD , Lindblom Anders
Published: October 2019

Abstract 2228

Introduction:

Novo Nordisk is developing turoctocog alfa, a human third generation recombinant FVIII for treatment of hemophilia A. During the pivotal trial in adult and adolescent previously treated patients with severe hemophilia A (guardian™1), subjects in need of surgery were able to participate in a subtrial to document efficacy and safety of turoctocog alfa in prevention of surgical bleeding. Pediatric (<12 years of age) previously treated patients in the guardian™3 trial were allowed to undergo minor surgery if needed during the trial. In addition, after completing these initial trials subjects were allowed to continue treatment with turoctocog alfa in the extension trial (guardian™2) which also includes a subtrial to document efficacy and safety of turoctocog alfa in prevention of surgical bleeding.

Methods:

We here describe surgeries performed within the guardian trials. For the ongoing guardian™2 extension trial, only cases included in the interim analysis (data cut-off 21NOV2011) are included.

Results:

In all, results from 10 major and 3 minor surgeries are included. Surgery indication was related to hemophilia joint disease in 8/13 cases. The hemostatic efficacy during and after surgery was rated on a 4-point scale (excellent, good, moderate and none) by the Investigator and/or Surgeon. Details and outcome of the individual surgeries performed are presented in Table 1. In addition, there were no safety concerns.

Discussion:

Prevention of surgical bleeding is an important aspect of hemophilia treatment. In the present 13 surgeries, including all surgeries performed with turoctocog alfa in the phase 3 guardian™ trials, hemostatic efficacy during and after was rated as either excellent or good in each case. The results support that turoctocog alfa has an excellent safety and efficacy profile for use in hemophilia A.

Disclosures:

Santagostino: Novo Nordisk and Pfizer: Research Funding; Pfizer, Baxter, Bayer, CSL Behring, Kedrion, Grifols and Novo Nordisk: Consultancy; Bayer, Baxter, Pfizer, CSL Behring, Novo Nordisk, Biotest, Kedrion and Grifols: Speakers Bureau. Lentz:Novo Nordisk: Consultancy, Research Funding. Brand:Bayer: Travel support, Travel support Other; Novo Nordisk, Baxter, Pfizer: Advisory Boards, Advisory Boards Other; Novo Nordisk: Honoraria. Chowdary:Novo Nordisk: Consultancy. Savic:Novo Nordisk: Speakers Bureau. Lindblom:Novo Nordisk A/S: Employment.
Influence of Factor V G1691A or Prothrombin G20210A Mutation On Inhibitor Development in Patients with Severe Hemophilia A - an Israeli-German Database Study.
Authors: Kenet Gili , Bidlingmaier Christoph , Ettingshausen Carmen Escuriola , Gutsche Sven , Halimeh Susan , Janssen Verena , Kurnik Karin , Nowak-Gottl Ulrike
Published: October 2019

Abstract 2234

It has been reported that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V (FV) G1691A mutation and that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors, namely the FV or the factor II (FII) G20210A variant, is significantly later in life than in non-carriers. Until today many factors, such as a positive family history, the use of recombinant FVIII [rFVIII] concentrates, or high dose FVIII administration, are included as potential risk factors for inhibitor development. The present non-concurrent Israeli-German database study was performed to investigate the impact of FV and FII mutations on clinical meaningful inhibitor development (outcome variable) in patients with severe HA. 272 patients with HA < 1% consecutively ascertained from Israel (n=88) and four different German catchment areas (n=184) born between 1980 and 2011 were followed after initial HA diagnosis over the first 200 exposure days. To avoid family cluster effects [inhibitor; IT] in both countries only the first HA patient who presented for diagnosis at the treatment center was included in the present study. From the entire cohort 80% were tested for thrombophilia [IT]. 32 of 216 children (14.8%) carried either the FV or the FII variant. During the follow-up period of 200 exposure days 54 of 216 (26%) developed a clinical meaningful inhibitor: 14 out of 32 carriers of IT (44%) compared with 40 of 184 (22%) without IT [Hazard ratio [HR]/95% confidence intervals [CIs] 2.1/1.16–3.9]. In addition, univariate Cox regression analysis for patients treated with rFVIII products compared with plasma-derived [pdFVIII] showed a significant increased risk for inhibitor development [HR/CI: 2.1/1.3–3.6]. Multivariate analysis adjusted for patient's individual median single FVIII dose, administered during the first three months, first-line use of pdFVIII (n=82) versus rFVIII concentrations (n=134) and treatment periods [1980–2011] revealed that the presence of IT independently increases the risk of inhibitor development to a hazard of 2.5 [CI: 1.1–5.8]. In addition, the increase of FVIII per one IU/kgbw was significantly associated with the risk to develop a high responding inhibitor [HR/CI: 1.2/1.04–1.1]. In multivariate analysis neither rFVIII products, nor treatment periods showed a statistically significant influence on clinical important inhibitor development. Data presented here suggest that clinical meaningful inhibitor development is of multifactorial origin and that apart from a positive family history also FV and FII mutations should be included in the aetiology research.

Disclosures:

No relevant conflicts of interest to declare.
Increased Relapse Associated with Mixed Donor-Donor Chimerism Following Double Umbilical Cord Blood Transplantation (dUCBT)
Authors: Verneris Michael R. , Turcotte Lucie M. , Cao Qing , MacMillan Margaret L. , Miller Jeffrey S. , Weisdorf Daniel , Brunstein Claudio G , Wagner John E.
Published: October 2019

Abstract 358

We previously showed lower rates of relapse in recipients of dUCBT, compared to patients treated with single UCBT (Verneris, Blood, 2009). One unit predominates by D+100 in ∼90% of patients and recent studies show that single unit dominance is associated with T cell recognition of the rejected unit (Gutman, Blood, 2010). In addition, higher rates of acute graft-vs-host disease (aGVHD) have been observed after dUCBT compared to single UCBT, regardless of age (MacMillian, Blood, 2009). Thus, we hypothesized that graft vs. graft interactions that occur during dUCBT may drive both GVL and GVHD reactions. To test this hypothesis, we reviewed the records of patients with hematological malignancies transplanted with a dUCBT from 2000 to 2011 at the University of Minnesota. Myeloablative (MA) conditioning was with cyclophosphamide (Cy 120 mg/kg), fludarabine (Flu 75 mg/m2) and total body irradiation (TBI 13.2 Gy) (n=178) and non-MA conditioning was with Cy (50 mg/kg), Flu (200 mg/m2) and TBI (2 Gy) (n=282). Acute GVHD prophylaxis consisted of cyclosporine and mycophenolic acid. At D+100 316 patients were evaluable and had either BM (n=273) and/or PB (n=178) donor engraftment data. Engraftment was assessed using short tandem repeat analysis. “Mixed donor-recipient chimerism” was defined as >5% host cells and “dual chimerism” was defined as complete donor chimerism (donor 1 + donor 2), with a minimum contribution of 5% by each unit (5% is the lower limit of detection for this clinical test). As expected, patients with evidence of mixed donor-recipient chimerism in the blood or marrow at D+100 (n=35) had high rates of relapse (69% [95% CI, 49–89%] at 2 years) and were excluded from further analysis. Of the patients with evaluable peripheral blood chimerism data, 90.4% (n=161) had hematopoiesis derived from a single unit, while 9.6% (n=17) showed dual chimerism after dUCBT. In multivariate analysis, dual chimerism at D+100 was associated with higher relapse (HR=1.97 [95% CI, 1.08–3.59], p=0.01), less grade II-IV aGVHD (HR=0.36 [95% CI, 0.17–0.78], p=0.01) and a trend toward worse DFS (HR=1.68 [95% CI, 0.9–3.13], p=0.1). Dual chimerism was not associated with age (p=0.32), nor non-MA conditioning (p=0.15). Recipients of two HLA 6/6 matched units (with each other and the recipient), were more likely to have dual chimerism (p<0.01). Nearly identical results were obtained in a separate model examining BM engraftment (single (n=247) and dual chimerism (n=26)) and transplant outcomes. While these findings should be confirmed in a separate dataset, they suggest that an unexpected consequence of selecting well matched units for dUCBT is higher mixed donor-donor chimerim, less aGVHD and more relapse. Further study of dUCBT and GVL is needed.

Disclosures:

No relevant conflicts of interest to declare.
Targeting B-Cell Lymphoma with Idiotype-Specific Peptibodies: Toward a Personalized and Tumor-Specific Therapy
Authors: Torchia James A , Ng Patrick P , Chen Homer , Kohrt Holbrook E , Marabelle Aurelien , Alizadeh Ash A. , Levy Ronald
Published: October 2019

Abstract 3713

Background:

The complementarity determining region, or idiotype, of the surface immunoglobulin receptor is a tumor-specific marker on B-cell lymphomas that is unique to each patient. Antibodies against idiotype can induce complete regression of lymphoma in patients, but since this therapeutic approach requires the generation of a custom monoclonal antibody for each patient, it has not been practical.

Objective:

Here we describe a method for targeting the idiotype on the surface of a B-cell lymphoma by using synthetic idiotype-ligands covalently linked to a recombinant IgG Fc domain (Figure 1A). These peptide idiotype-ligands can be identified through oligopeptide library screens and produced inexpensively by automated solid-phase synthesis. Linkage of idiotype-ligands to the Fc domain serves two purposes: to enhance their pharmacokinetics and to augment their anti-tumor effect by activating immune effector functions. Since each patient-specific peptide can be chemically linked to a common IgG Fc domain, this modular construct design yields a patient-specific therapeutic that does not require the production of a custom biologic macromolecule for each patient.

Results:

Idiotype peptide-ligands were produced by solid-phase synthesis and covalently linked to the amino-terminus of a recombinant mouse IgG2a Fc domain by native chemical ligation, a method for site-selective polypeptide ligation. The resulting peptibody demonstrated targeted killing of a human lymphoma cell line in vitro by crosslinking surface immunoglobulin and triggering activation-induced death. Additionally, the peptibody triggered complement-mediated cytotoxicity of opsonized lymphoma cells in vitro and activated natural killer cells co-cultured with opsonized lymphoma cells. The peptibody exhibited a favorable pharmacokinetic profile and peptibody treatment was sufficient to clear tumor in SCID mice challenged intravenously with a luciferase-labeled human lymphoma cell line (p = 0.0018; Figure 1B-D).

Conclusions:

Idiotype-specific peptibodies demonstrate multimodal activity against lymphoma cells in vitro and clear human lymphoma in a disseminated xenograft model. The modular design of this therapeutic may enable a personalized and targeted therapy that is feasible to produce for patients with B-cell lymphoma.

Disclosures:

No relevant conflicts of interest to declare.
Targeting the Genetic Resistance of JAK2 and BCR/ABL by TG101348
Authors: Kesarwani Meenu , Azam Mohammad
Published: October 2019

Abstract 3765

The inherent preponderance of genetic resistance against tyrosine kinase inhibitor (TKI) therapy poses significant challenge for effective treatments. Recent approval of Janus kinase 2 (JAK2) inhibitor INCB018424 (Jakafi, ruxolitinib) for the treatment of myeloproliferative neoplasms (MPNs) prompted us to identify resistant mutations that may pose clinical challenge. In vitro drug selection screening against two leading JAK2 inhibitors (INCB018424 and TG101348) were performed. Here we show that like other kinase inhibitors, INCB018424 is prone to genetic resistance while TG101348 is recalcitrant to develop in vitro resistance. Sequencing of INCB018424 resistant clones identified 211 amino acid substitutions spanning across FERM, SH2, JH2 and the kinase domain. Biochemical and structural modeling studies of these mutants demonstrate that mutations within the active site confer resistance either by direct steric hindrance or destabilizing the architecture of the active site. And mutations from the allosteric sites destabilize the intermediary state of the active and inactive conformations of JAK2 to which INCB018424 preferentially binds. Furthermore, these resistant variants are cross resistant to other JAK2 inhbitors (Lestaurtinib, CYT-387 and AZD1480). In contrast, these resistant variants are fully sensitive to TG101348 supporting the lack of resistance against this compound as observed during in vitro screening. Structural modeling studies revealed that TG101348 stabilizes the active conformation of the kinase and binds to the substrate-binding pocket. Mutations affecting the substrate-binding pocket may either alter substrate binding/phosphorylation or encode an incompetent kinase that blocks the emergence of resistance. Because JAK2 and BCR/ABL share a common substrate, STAT5, they might have similar architecture of the substrate-binding pocket, which may allow the inhibition of BCR/ABL by TG101348. Indeed, TG101348 can inhibit both native and gatekeeper variants of BCR/ABL and in vitro drug resistant screening failed to develop emergence of resistant clones. These studies provide evidence that the patients developing resistant variants of JAK2 and BCR/ABL can be treated with TG101348 and support for future drug design geared towards targeting the substrate binding sites in other oncogenic kinases for better and sustained therapeutic response.

Disclosures:

No relevant conflicts of interest to declare.
Development of Inhibitory Antibodies to Therapeutic Factor VIII in Severe Hemophilia A Is Associated with Microsatellite Polymorphism in the HMOX1 promoter
Authors: Repesse Yohann , Peyron Ivan , Dimitrov Jordan , Dasgupta Suryasarathi , Moshai Elika Farrokhi , Borel-Derlon Annie , Costa Catherine , Guillet Benoist , d'Oiron Roseline , Aouba Achille , Rothschild Chantal , Oldenburg Johannes , Pavlova Ana , Kaveri Srinivas , Lacroix-Desmazes Sebastien
Published: October 2019

Abstract 38

The occurrence of inhibitory anti-factor VIII (FVIII) antibodies is the major complication of replacement therapy in patients with hemophilia A. Heme oxygenase-1 (HO-1) is a stress inducible enzyme with anti-inflammatory activity. Induction of HO-1 in hemophilic mice reduces the immunogenicity of therapeutic FVIII. Interestingly, polymorphisms in the promoter of the HO-1-encoding gene (HMOX1) modulate the expression of HO-1.

We investigated the relationship between polymorphisms in the promoter of HMOX1 in severe hemophilia A patients and the development of FVIII inhibitors.

We analyzed 362 patients with severe hemophilia A involving 99 patients with FVIII inhibitors and 263 patients who did not develop inhibitor within the first 150 cumulative exposure days to therapeutic FVIII. Direct sequencing and DNA fragment analysis were used to study the variable (GT)n polymorphism and single nucleotide polymorphisms located at −1135 and −413 in the promoter of HMOX1. We assessed associations between the individual allele frequencies and genotypes, and the development of inhibitors.

Our results demonstrate a higher frequency of alleles with large (GT)n repeat (n≥30, L, associated with a lesser expression of HO-1) in inhibitor-positive patients [odds ratio (OR) 2.31; 95% CI 1.46–3.66, p<0.001]. Six genotypes (L/L, L/M, L/S, M/M, M/S and S/S) of (GT)n repeats were identified (S: n<21; M: 21≤n<30). The genotype group including L alleles (L/L, L/M and L/S) was statistically more frequent among inhibitor-positive than inhibitor-negative patients, as compared to the other genotypes (33.3% vs 17.1%) [OR 2.21, 95% CI 1.30–3.76, p<0.01].

To our knowledge, this is the first association between HMOX1 promoter polymorphism and development of anti-drug antibodies. Modulating the endogenous anti-inflammatory machinery of hemophilia A patients appears as a plausible therapeutic option for reducing the risk of inhibitor development.

Disclosures:

No relevant conflicts of interest to declare.
Clinical Utility of PET/CT Scanning in Patients with Chronic Lymphocytic Leukemia
Authors: Conte Michael J. , Bowen Deborah , Rabe Kari G. , Schwager Susan , Slager Susan L , Zent Clive S.
Published: October 2019

Abstract 3903

The clinical utility of 2-deoxy-2-[18F] fluoro-D-glucose (FDG) positron emission tomography-computed tomography (PET-CT) scans in the management of patients with chronic lymphocytic leukemia (CLL) has not been clearly defined. CLL cells typically have low FDG avidity and the addition of the PET component has not been shown to improve the utility of CT scans in the management of patients with CLL. However, patients with CLL are at increased risk of developing FDG avid complications including more aggressive lymphomas, other second malignancies, and infections for which FDG PET-CT scans are a useful imaging modality. We hypothesized that FDG PET-CT scans are sensitive tests for evaluation of these complications in patients with CLL.

Patients and Methods:

This observational study was performed with IRB approval. We studied all 4030 CLL patients seen at least once in the Division of Hematology at Mayo Clinic Rochester between January 1, 2006 and December 31, 2011 using data prospectively collected into the Mayo Clinic CLL database. We reviewed the clinical and radiological records of the 272 (7%) patients who underwent 526 FDG PET-CT scans of the trunk during this time period to determine the indication for PET-CT scan, results of imaging, and the effects of the use of PET/CT scan on management.

Results:

Four hundred and seventy two (90%) of the 526 PET-CT scans were reported as abnormal. Of these, 78 (17%) scans were useful in directing a tissue biopsy of high FDG avidity lesions. Of the 37 (8%) positive PET-CT scans that facilitated the diagnosis of new complications of CLL, 21 (4%) scans led to a diagnosis of diffuse large B cell lymphoma and 9 (2%) scans led to a diagnosis of a solid malignancy. The FDG component of 22 PET-CT scans done because of clinical suspicion of complications of CLL were negative, and thus useful in management of these patients. PET-CT scans showed progressive CLL in 138 (29%) studies but in these patients, the PET component of the scan did not provide additional information about the status of the patients' CLL compared to the CT component alone.

Conclusions:

FDG PET-CT scans are not of proven value in staging CLL or determining response to treatment. However, our data suggest that they could be of considerable value in evaluation for complications, especially more aggressive lymphomas, other cancers, and infections that complicate the course of CLL.

Disclosures:

Off Label Use: Phase I study using PGG beta glucan in CLL. Zent:Biothera: Research Funding; Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding.
The Myeloma Genome in Drug Refractory Extra-Medullary Disease Identifies Mutations in Proteasome, Cereblon and Glucocorticoid Pathways
Authors: Egan Jan , Kortuem Klaus Martin , Shi Chang-Xin , Schmidt Jessica , Craig David , Carpten John , Stewart Keith
Published: October 2019

Abstract 3968

To better understand the genetic events associated with extra-medullary multiple myeloma (MM) we completed whole exome, long-insert whole genome and RNA sequencing on a patient with t(14;16) and neck adenopathy, as well as whole genome sequencing on two additional patients with respectively: t(4;14) and plasma cell leukemia, and del 17 with chest wall mass. All patients had multi-drug resistant disease and del 13. The frequency of somatic non-synonymous single nucleotide variants (SNV) ranged from 119 to 498, including an average of 15 truncating SNV, as well an average of 75 structural variants (range 2–147). Importantly, in one patient a truncating mutation, Q99*, on one allele and minor clone point mutation, R283K, on the second allele was observed in CRBN, a gene whose expression is required for effective lenalidomide and pomalidomide anti-myeloma activity. In the same patient a non-synonymous mutation, E171K, was also observed in PSMG2, a proteasome assembly protein, and a non-synonymous mutation, G369A, in NR3C1, a glucocorticoid receptor. Subsequently we have sequenced CRBN in 27 patients and 7 cell lines and have found no further examples of mutation in CRBN but have previously reported a bi-alleleic focal deletion in the MM.1Sres cell line. Mutations in NR3C1 have not previously been described in other MM genomes. Other, potentially clinically relevant mutations in the three patients were observed in FGFR3, PRDM1, STAT5B, NRAS, KRAS, PIK3CA, NF1, ATM, NFKB2, CKS1B and ERBB4. Although the three patients did not share a unifying event, a number of mutated genes observed were shared with other published myeloma genomes including RB1, TP53, MLL3, JAG2, VAV3 and SETD2. We also looked at pathway activation across the three genomes with the most statistically mutated pathways including VEGF signaling and activation, cell adhesion and chemokines, cytoskeleton remodeling, integrins in carcinoma progression, TP53 signaling and NOTCH signaling. In conclusion, we have identified, for the first time, the presence of a mutation in CRBN in a myeloma patient as well as mutations in PSMG2 and NR3C1, likely associated with drug resistance.

Disclosures:

Schmidt: Karyopharm: Research Funding. Carpten:Life Technologies: Research Funding. Stewart:Millenium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.
Mutational Profiling of Multiple Myeloma Bone Marrow Aspirates As a Clinical Tool for Personalized Treatment of Myeloma
Authors: Mahindra Anuj , Dias-Santagata Dora , Borger Darrell , Santo Loredana , Scullen Tyler A. , Yee Andrew , Eda Homare , Cirstea Diana , Iafrate Anthony John , Raje Noopur
Published: October 2019

Abstract 3990

Introduction:

Multiple Myeloma (MM) is increasingly being recognized as a heterogeneous disease. Previous studies have reported various oncogenic mutations in myeloma. Recent genome sequencing studies have revealed activating mutations of BRAF kinase in 4% of patients, a potentially druggable target, underscoring the importance of identifying these and other potential oncogenic mutations. However, a validated methodology for clinical assessment of mutation profiles is lacking. Applying such technologies will be increasingly important to accelerate development of targeted therapies toward tumor-specific oncogenic pathways. Utilizing a high-throughput genotyping platform we evaluated the commonly described somatic mutations in bone marrow aspirates in patients diagnosed with MM.

Methods:

We developed a CLIA (Clinical Laboratory Improvement Amendments) validated, highly sensitive multiplexed PCR-based assay (SNaPshot) to simultaneously identify 70 genetic loci frequently mutated in 15 cancer genes. This assay has been used at our institution for over 3 years for tumor genotyping and to help guide therapeutic decisions for patients with solid malignancies. To test the value of this approach in patients with MM, we first validated the methodology on MM cell lines followed by testing patient derived bone marrow samples.

Results:

The detectable mutations in the 8 MM cell lines tested include: MMIR: KRAS 35G>C, G12A mutation; MMIS: KRAS 35G>C, G12A mutation; H929: NRAS 38G>A, G13D mutation; LR5: KRAS 35G>C, G12A mutation; RPMI8226: TP53 743G>A, R248Q mutation;U266: no mutations identified; OPM2: NRAS 182A>T, Q61L mutation; OPM1: TP53 524G>A, R175H mutation.

Thirty six bone marrow aspirates from patients with MM have been analyzed to date. Tweny five percent of patients had a detectable mutation, with KRAS mutation in 17%, NRAS in 5% and TP53 in 3%. Additional data in a larger cohort is currently being analyzed and will be presented.

Conclusion:

Oncogenic driver mutations can be detected by SNaPshot from routinely-collected bone marrow aspirate samples. Experience from lung and breast cancer studies indicates that while the type and frequency of mutation varies somewhat by tumor phenotype, the common oncogenic mutations are often found in isolation. Broad tumor mutational analysis will be helpful to efficiently tailor personalized therapies based on individual tumor genetic profiles.

Disclosures:

Dias-Santagata: Bio-Reference Laboratories, Inc.: Consultancy. Borger:Bio-Reference Laboratories, Inc: Consultancy. Iafrate:Bio-Reference Laboratories, Inc: Consultancy. Raje:Eli-Lilly: Research Funding; Amgen: Research Funding; Acetylon: Research Funding; Millennium: Consultancy; Celgene: Consultancy; Onyx: Consultancy.
Disulfiram, an Clinically Used Anti-Alcoholism Drug Has the Potential to Target Leukemia Stem and Progenitor Cells in a Copper-Dependent Manner
Authors: Xu Bing , Wang Shiyun , Chen Feili , Shi Pengcheng , Zha Jie , Zhang Yanyan , Guo Xutao , Wang Weiguang
Published: October 2019

Abstract 4088

Backgrounds

Acute myeloid leukemia(AML) is a hierarchical disease initiating from a rare population of cells known as leukemia stem cells (LSCs), which are typically enriched in CD34+CD38- cells and presumed responsible for the relapse and refractory of AML. Moreover, current regimens may not effectively discriminate between normal and malignant cells. For this reason, it is important to identify therapies that can specifically target the LSC population without affecting normal cells. Disulfiram (DS) is an anti-alcoholism drug that has recently been indicated to show cytotoxic to multiple cancers including acute myeloid leukemia (AML) and the antineoplastic activity was enhanced in the present of copper (Cu). In the present study, we investigated the effect of DS/Cu on LSCs and further explored its mechanism.

Methods and Results

CD34+CD38- leukemia stem cell (LSC) enriched subpopulations were sorted from both KG1a cell lines and primary AML bone marrow or peripheral blood mononuclear cells (n=6) by fluoresce-activated cell sorting (FACS) analysis. Using MTT cell proliferation assay and Annexin-V/PI staining assay, We demonstrated that DS/Cu inhibited proliferation and induced apoptosis in CD34+CD38−KG1a cells (IC50= 0.788± 0.451 μM at 24h). With the increasing concentrations of DS (DS=0.05, 0.5, 5, 50μM), the apoptotic proportion increased from 7.2% to 89.5% at 24h. Apoptosis was also observed in CD34+CD38- primary AML cells and the exposure to DS/Cu (DS=0.01, 0.1, 1μM;Cu=0.5μM clearly inhibited the growth of AML-colony-forming units (CFUs) for both CD34+CD38-LSC enriched subpopulations (AML-CFUs decreased from 34.2% to 0% in KG1a cells), but was relatively sparing to normal hematopoietic progenitors. Further more, using flow cytometric analysis, western blot and RT-PCR, we identified that the change in redox status and redox-dependent signaling events play a crucial role in DS/Cu-induced apoptosis. We showed that DS/Cu(DS= 0.625,1.25,2.5,5μM, Cu=1μM) increased reactive oxygen species (ROS) and activated its downstream apoptosis-related SAPK/JNK pathway in association with blockade translocation of Nrf2 and expression of Nrf2-regulated genes in CD34+CD38−KG1a cells. Notably, blockade of ROS by glutathione precursor N-acetylcysteine (NAC)(10mM) strongly diminished DS/Cu mediated lethality and restored Nrf2 nuclear translocation and blocked JNK activation. Additionally, consistent with the ROS accumulation, we also seen that translocation of RelA/p65 and the expression of NF-κb-related gene, associated with abnormal apoptotic response of LSCs, were significantly inhibited by DS/Cu.

Conclusion

Taken together, we concluded that DS/Cu might selectively eradicate LSCs by induction of oxidatibe stress and blockade the NF-κb pathway and offers a potential therapeutic option in AML.

Disclosures:

No relevant conflicts of interest to declare.
Use of the Immunoproteasome Subunit LMP7 Inhibitor to Ameliorate Gvhd in an MHC-Matched miHA-Disparate Murine Model
Authors: Zilberberg Jenny , Dziopa Eugenia , Kirk Christopher J , Korngold Robert
Published: October 2019

Abstract 4106

Background:

Therapeutic targeting of the ubiquitin-proteasome pathway is currently used for the treatment of multiple myeloma. The immunoproteasome however, is a distinct class of proteasome found predominantly in monocytes and lymphocytes, and it is known to regulate antigen presentation on class I major histocompatibility complexes (MHC-I). ONX 0914 is a LMP7-selective peptide-epoxyketone proteasome inhibitor that is currently in pre-clinical development for the treatment of inflammatory diseases. In the current study, we evaluated the feasibility of using ONX 0914 in the B10.BR→CBA MHC-matched (H2k), minor histocompatibility antigen (miHA)-disparate bone marrow transplantation (BMT) model to decrease the incidence of GVHD. This well established allogeneic BMT model is relevant to the MHC-matched sibling donor or completely matched unrelated donor clinical situation.

Methods:

To evaluate the effects of ONX 0914 on GVHD, we tested different compound regimens in the model. CBA recipient mice were lethally irradiated (11 Gy, split dose, 4 h apart) and transplanted with 2×106 anti-T cell depleted B10.BR bone marrow cells (ATBM) alone, or in combination with 1×107 enriched B10.BR T cells (GVHD control and ONX 0914 treated groups). ONX 0914 was administrated in full (s.c., once/day at 8 mg/kg) or as a split dose (half dose, twice/day approximately 6 hr apart).

Results:

Treatment with the ONX 0914 compound significantly improved the survival of mice compared to control GVHD recipients when dosing was performed once/day for three consecutive days (0,1,2 post-BMT) [p = 0.02]. Alternating dosage (days 0,2,4) or daily drug treatment (days 0–4) provided comparable amelioration of GVHD in this model.

Conclusion:

Our preclinical findings suggest that the immunoproteasome subunit LMP7 is potentially a novel therapeutic target in GVHD as demonstrated by the improved survival rate of recipient mice treated with ONX 0914 in the B10.BR→CBA BMT murine model.

Disclosures:

Zilberberg: Onyx Pharmaceuticals: Research Funding. Dziopa:Onyx Pharmaceuticals: Research Funding. Korngold:Onyx Pharmaceuticals: Research Funding.
Effectiveness of Ursodeoxycholic Acid As Prophylactic Agent Against Hepatic Sinusoidal Obstruction Syndrome in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Treatment of Hematological Malignancies
Authors: Ng Hong Yen HY , Chong Mui Fong MF , Song Jielin JL , Hwang William YK , Linn Yeh Ching , Loh Yvonne SM , Ho Aloysius YL , Goh Yeow-Tee YT
Published: October 2019

Abstract 4165

Introduction:

Hepatic sinusoidal obstruction syndrome (SOS) is a major and potentially fatal complication of hematopoietic cell transplantation (HCT). In May 2008, a risk-adapted SOS prophylaxis guideline was implemented for patients undergoing allogeneic HCT in Singapore General Hospital. Patients were stratified into 3 risk categories according to conditioning regimen and risk factors including preexisting hepatitis/cirrhosis or hepatic dysfunction. Low risk patients did not receive routine prophylaxis, and patients at moderate or high risk received oral ursodeoxycholic acid 250 mg TDS starting before conditioning till D+21 of HCT.

Objective:

This study aimed to evaluate the efficacy of ursodeoxycholic acid in preventing hepatic SOS in patients undergoing allogeneic HCT. In addition, additional risk factors associated with SOS were also identified.

Method:

A retrospective study of patients who underwent allogeneic HSCT between Jan 2005 and May 2012 was carried out where medical records were reviewed. Outcomes were compared between patients who received ursodeoxycholic acid as prophylaxis (from May 2008 to May 2012) against historical controls (from Jan 2005 to Apr 2008). The primary outcome was the incidence of SOS. Secondary outcomes included SOS-related mortality, and liver function post HCT.

Results:

A total of 202 patients were included with 129 patients in the study group and 73 historical controls. The incidence of SOS was 14% in the study group vs 23.3% in historical controls (p=0.121). In the moderate risk category, a statistically significant reduction of 12.7% in SOS occurrence was associated with routine prophylaxis (12.7% vs 25.4%, p=0.039). Among high risk patients, the incidence was 27.3% in the study group and 10% in controls, p=0.586. SOS-related mortality was comparable between the 2 groups. Elevation in liver function tests (including bilirubilin, ALT, AST, ALP, and GGT) post HCT was significantly lower in patients receiving ursodeoxycholic acid as prophylaxis. Prior HCT was identified as risk factor associated with SOS (OR, 9.082; 95% CI, 2.57 – 32.089; p=0.01).

Conclusion:

The use of ursodeoxycholic acid as prophylaxis resulted in a significant reduction in SOS occurrence in patients at moderate risk for this complication. However, the high incidence of VOD among high risk patients underscores the need for more effective prophylactic strategies in this population.

Disclosures:

No relevant conflicts of interest to declare.
Single-Infusion of Donor Early Apoptotic Cells (ApoCell) As Prophylaxis of Graft-Versus-Host Disease in Myeloablative HLA-Matched Allogeneic Bone Marrow Transplantati
Authors: Mevorach Dror , Reiner Inna , Or Reuven
Published: October 2019

Abstract 4176

Because of its potent immunomodulatory effect together with presumably high safety profile, apoptotic cells infusion (ApoCell) was tested in addition to cyclosporine and methotrexate, as prophylaxis of graft-versus-host disease (GVHD) in HLA-matched myeloablative allogeneic bone marrow transplantation (alloBMT) from a related donor. We conducted a phase I//IIa clinical trial where we treated 13 patients (median age, 37 years; range, 20–59 years) with advanced hematologic malignancies (7 patients with ALL, 5 patients with AML (4 patients with MDS that transformed to AML and one patient with AML de novo), and 1 patient with CML that received conventional myeloablation with 35, or 70, or 140, or 210×106 cell/kg of donor ApoCell, on day -1 of transplantation. Ten serious adverse effects were reported with all being not related (seven) or unlikely to be related (3) to ApoCell infusion. Out of hundreds adverse effects, only three were reported as possibly related to ApoCell infusion (with no definite or probable adverse effects). The non-relapse mortality at day 100 and 180 after transplantation was the same, 7.7%. The overall survival at 100 and 180 days after transplantation was 92% and 85%, respectively. The incidences of acute grades II through IV GVHD for all 13 patients and for the two higher doses were 23% and 0% (six patients), respectively. Biomarker ratio levels including tumor necrosis factor receptor I (TNFR1), hepatocyte growth factor (HGF), interleukin 2 receptor alpha (IL-2Ra), and interleukin 7 (IL-7), supported the clinical data. These results suggest that single-infusion high-dose donor early apoptotic cells in HLA-matched myeloablative alloBMT is a safe and potentially effective single-agent prophylaxis of acute GVHD occurring after myeloablative conditioning (clinicaltrials.gov no. NCT00524784).

Disclosures:

Mevorach: Enlivex: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Reiner:Enlivex: Employment.
SOCS1 Mutation Subtypes Predict Divergent Outcomes in DLBCL Patients
Authors: Lennerz Jochen K , Schif Birgit , Kohler Christian W , Bentink Stefan , Kreuz Markus , Melzner Ingo , Trümper Lorenz , Löffler Markus , Spang Rainer , Moeller Peter
Published: October 2019

Abstract 419

Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in Hodgkin, primary mediastinal and diffuse large B-cell lymphomas (DLBCL). In the primary mediastinal B-cell lymphoma line MedB-1, mutated SOCS1 abnormally stabilizes phospho-JAK2, thereby enhances STAT signaling leading to continuous proliferation. Here, we evaluated the prognostic value of SOCS1 mutations by full-length gene sequencing of SOCS1 in 154 comprehensively characterized DLBCL cases. By sequence analysis, we identified 90 SOCS1 mutations in 16% of lymphomas. We defined two distinct subtypes with respect to putative mutational consequences: those predicting the full-length (minor) and a truncated protein (major), respectively. Neither the SOCS1 mutation group, nor minor/major subgroups can be distinguished by clinical phenotype; however, assignment of four established expression-based classifiers revealed significant associations of SOCS1 major cases with germinal center- and specific pathway activation pattern signatures. Above all, SOCS1 major cases had an excellent overall survival, even better than the GCB-like subgroup (see Figure). SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group (see Figure). SOCS1 mutation subsets retain prognostic significance in uni- and multivariate analyses. Thus, if a SOCS1 mutation is present, the mutation type is an important single gene prognostic biomarker in DLBCL.

Disclosures:

No relevant conflicts of interest to declare.