bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Humanized Anti-CD40 Antibody SGN-40 Inhibits Tumor Growth in LAGκ-1A, a CD40+ Mouse Model of Human Multiple Myeloma.
Authors: Campbell Richard A. , Gordon Melinda S. , Sanchez Eric , Chen Haiming , Turker Lauren , Trac Olivia , Li Mingjie , Pang Shen , Bonavida Benjamin , Said Jonathan , Drachman Jonathan G. , Berenson James R. 
Published: October 2019

Abstract
CD40 is a TNF receptor found on the cell surface of mature B cells (B lymphocytes) and most B-cell malignancies including multiple myeloma (MM). SGN-40 is a high-affinity, humanized monoclonal antibody that targets the CD40 antigen. Recently, it has been shown that SGN-40 decreases the proliferation of malignant B cells by partial agonistic signaling and effector functions in vitro. In this study, we examined the anti-MM effects of SGN-40 in vivo using a CD40+ SCID-hu murine model of human myeloma, LAGκ-1A. Each immunodeficient (SCID) mouse was implanted with a 2.0 – 4.0 mm3 LAGκ-1A tumor fragment into the left hind limb muscle. The tumor was allowed to grow for 14 days at which time human IgG levels were detectable in the mouse serum. Mice were then randomly assigned to one of four SGN-40 treatment groups (6 mice per treatment group). SGN-40 was administered via intraperitoneal injection twice per week at doses of 0.1, 0.3, 1, and 3 mg/kg. Control mice were given a control IgG antibody (3 mg/kg) using the same schedule. Mice receiving the higher doses of SGN-40 showed marked inhibition of tumor growth (0.3 mg/kg, P < 0.02; 1 mg/kg, P < 0.03; and 3 mg/kg, P < 0.04) and reduction of paraprotein levels (1 mg/kg, P < 0.05; and 3 mg/kg, P < 0.03) compared to mice receiving control antibody. At the lowest dose of SGN-40 evaluated (0.1 mg/kg) a slight inhibition of tumor growth was observable, but there was no effect on human paraprotein. Treatment with SGN-40 was not associated with any observed toxicity. Based on these data with SGN-40 monotherapy, we are currently investigating the antitumor activity of SGN-40 plus bortezomib as well as other available anti-MM agents using our in vivo SCID-hu myeloma murine model. These data for single-agent SGN-40 are encouraging and support testing SGN-40 both alone and in combination regimens to treat MM patients.
Pharmacokinetic (PK) and Pharmacodynamics (PD) Study of Two Doses of Bortezomib (Btz) in Patients with Relapsed Multiple Myeloma (MM).
Authors: Stewart A. Keith , Sullivan Dan , Lonial Sagar , Mohrbacher Ann F. , Chatta Gurkamal , Shustik Chaim , Burris Howard , Karol Michael , Zannikos Peter , Reece Donna E. 
Published: October 2019

Abstract
Btz (VELCADE®) is approved for patients (pts) with relapsed MM. This study characterized PK/PD of btz at 2 doses (1.0, 1.3mg/m2) after single- and multiple-dose administration, and evaluated their relationship. 24 pts with relapsed MM and creatinine clearance ≥50mL/min were randomized to btz 1.0 (n=12) or 1.3mg/m2 (n=12) on D 1, 4, 8 and 11 of a 21-D cycle (C). Pts could continue therapy for ≥8 Cs if beneficial. PK/PD samples were drawn at multiple time points on D1 and D11 of C1 and C3 over 48h. Plasma concentrations of btz were similar following administration of 1.0 and 1.3mg/m2; differences in mean plasma Cmax and AUC values were within the degree of intersubject variability (Table). There was a decrease in clearance and an increase in terminal half-life of btz on D11 vs D1 of C1.The volume of distribution of btz suggests extensive peripheral tissue distribution. After single or repeat administration, mean maximum percent inhibition of 20S proteasome activity (vs baseline) in whole blood was 70–84% and 73–83% for the 1.0 and 1.3mg/m2 doses, respectively. The percentage of pts who had >90% inhibition was greater in subsequent doses vs first dose. Reversibility of 20S proteasome inhibition in whole blood was demonstrated. PK/PD modeling revealed an exposure-response relationship, with Emax and EC50 values consistent across study days. These results confirm btz is a potent inhibitor of the 20S proteasome. The efficacy of single-agent btz has been explored and validated in the pivotal phase 2 SUMMIT and phase 3 APEX trials at 1.3mg/m2, and explored in the phase 2 CREST trial at 1.0mg/m2. Complete safety and efficacy data by dose will be presented.
Mean±SD PK parameters of btz in plasma 1.0mg/m2 1.3mg/m2 1.0mg/m2 1.3mg/m2 D1/C1 (n=11) D11/C1 (n=12) an=5;bn=11;cn=10;dn=7;en=11;fn=9 Tmax (h) 0.13±0.13 0.11±0.06 0.07±0.03 0.20±0.29 Cmax (ng/mL) 56.7±36.3 112±122 106.2±46.7 88.6±47.6 AUC48h(ng·h/mL) 26.5±12.4 34.6±19.8 82.8±35.9b 82.4±28.6b AUClast (ng·h/mL) 22.6±12.6 31.5±18.6 137±106 122.2±67.4 CL (L/h) 102.1±48.1 111.6±73.6 23.2±17.8 28.0±19.8 Vβ (L) 1976±2498a 2015±2974d 1659±752c 2415±1711 t1/2λz(h) 30.7±44.8a 11.5±12.7d 78.9±50.9c 75.6±49.9 D1/C3 (n=12) D11/C3 (n=12) Tmax (h) 0.12±0.12 0.10±0.05 0.16±0.17 0.10±0.05 Cmax (ng/mL) 66.5±42.6 120.3±70.7 83.9±69.3 114.9±98.3 AUC48h(ng·h/mL) 66.4±24.1 79.4±24.5b 101.6±58.2b 85.2±18.7f AUClast (ng·h/mL) 74.8±35.8 86.0±27.6 227±181 160.7±67.1 CL (L/h) 32.2±19.0 32.1±15.4 15.1±13.9 18.2±9.2 Vβ (L) 1852±951d 2059±1231 3294±2993e 2505±1641 t1/2λz (h) 39.9±14.4d 49.1±34.6 193±169e 108.6±64.8
Final Results of a Phase II Study of Bortezomib (Velcade) in Combination with Liposomal Doxorubicin (Doxil) and Thalidomide (VDT) Demonstrate a Sustained High Response Rates in Patients (pts) with Relapsed (rel) or Refactory (ref) Multiple Myeloma.
Authors: Chanan-khan Asher Alban , Padmanabhan Swaminathan , Miller Kena C. , Musiel Laurie , Yu Jihnhee , Bernstein Zale P. , Manochakian Rami , Czuczman Myron S. 
Published: October 2019

Abstract
Background: Tumor microenvironment (ME) plays an important role in MM. It is associated with disease progression, metastasis, and resistance to therapy. Therefore, targeting the ME and the tumor cell simultaneously may be an effective way to overcome resistance in pts with rel/ref MM.
Aim: Orlowski et al reported improved anti-tumor responses when bortezomib (V) was combined with doxil (D) in pts with hematologic malignancies. We investigated clinically, this approach i.e., targeting the MM cell as well as its ME, using a combination of V, D and low-dose thalidomide (T) as salvage therapy for pts with rel/ref MM. Here we report the final results along with survival data of this phase II study.
Methods: All pts with rel/ref disease were eligible for this study. V was given at 1.3mg/m2 (D1,4,15,18) and D at 20mg/m2 (D1,15) every 4 weeks with daily T (200 mg) for 4–6 cycles. SWOG criterion was used to assess response. Low-dose coumadin (1–2 mg po qd) was used for prevention of venous thromboembolism (VTE).
Results: Twenty three pts (9M, 14F; median age −57 , range 43–79 yrs; 21MM, 2 WM) have been enrolled. All pts had Stage III disease, median b2M was 4.2 and median number of prior therapies were 5(range 1–6). Prior therapies included stem cell transplant(SCT) in (41%), T (41%), adriamycin(A) (65%) steroids (82%) and velcade (12%). 74% had refractory disease. Seventeen pts have completed at least 1 cyc and are available for toxicity and response evaluation. One pt died of sepsis prior to completing 1 cyc and 1 pt with PR was taken off study for non-compliance after 1 cyc. ORR was with 65%(CR+PR) with 23% CR all of whom were IFE negative. The Median Progression Free survival was 10.9 months with an median overall survival of 15.7 months. Toxicity: 2 pts developed Gr. II plantar-palmar erythrodysthesia (PPE) and 1 had Gr. III cellulitis. No VTE was noted. No significant non-hematologic Gr. III/IV toxicity were seen. Despite prior exposure to anthracycle, we did not noted any cardiotoxicity with D.No significant neuropathy was noted.
Conclusions: Pt with rel/ref MM usually have aggressive disease with paucity of effective regimens. VDT is an effective salvage regimen. Final results show high response rates with 22% of the patients achieving complete (IFE−) remissions. Responses were noted regardless of type of prior therapy. VDT could be safely given in patients with renal failure/insufficiency. Venous Thromboembolism (VTE) does not appear to be a problem with low dose coumadin prophylaxis. Final results of this phase II study will be presented at the 48 th annual ASH meeting.
Treatment with Bendamustine, Thalidomide and Prednisolone (BPT) in Patients with Refractory or Relapsed Multiple Myeloma after Autologous Stem Cell Transplantation or Conventional Chemotherapy: Results of a Phase I Clinical Trial.
Authors: Poenisch Wolfram , Rozanski Marta , Goldschmidt Hartmut , Hoffmann Franz-Albert , Boldt Thomas , Schwarzer Andreas , Ruffert Ute , Rohrberg Robert , Schwalbe Elke , Uhlig Jens , Zehrfeld Thomas , Schirmer Veronika , Haas Antje , Kreibich Ute , Niederwieser Dietger 
Published: October 2019

Abstract
Thalidomide is an active single agent in advanced relapsed or refractory multiple myeloma (MM). The combination of low dose thalidomide with bendamustine and prednisolone might maintain or increase efficacy of the drug while avoiding dose limiting toxicity (DLT).
Patients and Methods: The treatment consists of a fixed dose of bendamustine (60mg/qm) day 1, 8, and 15 with prednisolone (100 mg) day 1, 8, 15, and 22. In addition, thalidomide is given in three escalating doses, starting with 50 mg to a maximum of 200 mg daily. At each dose level 8 to 12 relapsed or refractory patients, half of them after conventional chemotherapy and half after high dose therapy with stem cell support, were enrolled. Cycles were repeated every 28 days for a minimum of 2 and a maximum of 10 cycles either until a maximal response was achieved, or until a DLT or a disease progression were observed. Between March 2004 and May 2006, 28 patients were enrolled: 8 in the first dose level with 50 mg thalidomide; 8 in the second dose level with 100 mg and 12 in the third dose level with 200 mg. All patients had received a minimum of 2 prior treatment regimens. Seven patients had been refractory to the last treatment. Median age was 67 years (range: 40 – 78). All patients completed 2 cycles of BPT-treatment and are therefore evaluable. Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR).
Results: Twentyfive of 28 patients responded after at least 2 cycles of chemotherapy with 3 CR, 1 nCR, 5 VGPR, 15 PR and 1 MR. Two patients had stable disease and one patient was refractory. With a median follow up of 15 months, EFS and OS at twelve months were 34 % and 92 %, respectively. The most common side effects were constipation (11 patients WHO grade 1, 8 patients WHO grade 2), polyneuropathy (15 patients WHO grade 1, 3 patients WHO grade 2) and somnolence (4 patients WHO grade 1). None of the 28 patients developed dose-limiting hematoxicity as defined by an ANC < 1,0 Gpt/l for > 7 days or an ANC < 0,5 Gpt/l for > 3 days or platelet count < 25 Gpt/l. Transient neutropenia was reported in 9 patients (WHO grade 3 and 4) but no thrombocytopenia was observed.
Conclusion: BPT with a dose between 50 and 200 mg thalidomide daily is well tolerated in patients with relapsed or refractory MM.
Rituximab in CD20 Positive Multiple Myeloma: A Prospective Study from the IFM Group.
Authors: Moreau Philippe , Voillat Laurent , Benboubker Lotfi , Dumontet Charles , Mathiot Claire , Hulin Cyrille , Robillard Nelly , Loiseau Herve Avet , Herault Olivier , Garnache Francine , Varoqueaux Nathalie , Harousseau Jean-luc , Bataille Regis 
Published: October 2019

Abstract
Multiple myeloma (MM) is a heterogenous disease. A strong association between small mature plasma cell morphology, t(11;14) and CD20 expression has been described in approximately 10% of the patients with MM (Robillard et al, Blood 2003). In this subgroup of patients with MM expressing CD20, rituximab (anti-CD20 chimeric monoclonal antibody) could target the antigen and could have a clinical impact. Thus we conducted a prospective phase II trial of 4 weekly IV infusions of 375 mg/m2 rituximab in patients with MM expressing CD20 on at least 33% of tumor cells. From 07/2004 to 02/2006, 14 consecutive patients, median age 65 years, with either stage I MM never pretreated (n = 7) or stage III MM in relapse or refractory after a median of 2 lines of therapy (n= 7) were treated. Immunophenotype using flow cytometry revealed that a median of 75% of tumor cells were expressing CD20 (range, 33–100%) at the onset of therapy. Responses were evaluated 3 months after therapy according to EBMT criteria. At the reference date of June 1st, 2006, a single patient, who had relapsed 8 months after a double autologous SCT, experienced a minor response, ongoing 18 months after rituximab therapy. At the time of rituximab therapy, 100% of its plasma cells were expressing CD20, and 3 months after treatment, bone marrow examination showed 0.6% of plasma cells, none of them expressing CD20. Five patients (1 with relapsed MM and 4 with stage I MM) experienced stable disease, ongoing for 3, 4, 4, 11 and 12 months, respectively. Three patients with stage I MM had stable disease but subsequently progressed 10, 11, and 15 months after therapy, respectively. The last 5 patients with relapsed MM did not respond to anti-CD20 therapy, despite partial clearance of CD20+ plasma cells in the bone marrow in 2 cases. Conversely in the 3 latter cases, the percentage of CD20+ plasma cells did not decrease despite rituximab therapy.
Several factors have been described to explain resistance against rituximab in a variety of B-cell malignancies such as the level of CD20 expression, dissociated action of complement-dependent cytotoxicity and antibody-dependant cellular cytotoxicity, polymorphism in FcgammaRIIIA receptor, and may be inadequate dose schedule. These mechanisms could explain the marginal activity of rituximab as single-agent in CD20+ MM.
The CALM-AF10 Fusion Gene Expressed in Transgenic Mice Produces Acute Leukemia.
Authors: Caudell David L. , Zhang Zhenhau , Chung Yangjo , Aplan Peter D. 
Published: October 2019

Abstract
The rare but recurring translocation [t(10;11)(p13;q21)] occurs in patients with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML); a more recent analysis of clinical cases showed that of the T-ALL cases, t(10;11) are restricted to the TCRγδ lineage. This translocation was initially described in immature T-cells; subsequently the molecular features were characterized in the U937 cell line and shown to result in the production of a CALM-AF10 fusion gene. In order to study the leukemic effects of a CALM-AF10 fusion in mice as a model of human disease, a CALM-AF10 fusion cDNA was cloned from the U937 cell line and inserted into an expression vector that utilized Vav 5′ and 3′ regulatory elements. The Vav gene is expressed in all hematopoietic tissues and is essential for lymphocyte development; Vav regulatory elements have been used by a number of groups to direct transgene expression to the hematopoietic compartment. We generated transgenic Vav-CALM-AF10 mice by pronuclear injection, and followed offspring from two founder mice that were shown to express the CALM-AF10 transgene in hematopoietic tissues for 18 months. Mice were clinically healthy for the first 9 months of life, but had T and B cell developmental abnormalities, including decreased CD4+/CD8+ cells and increased CD4−/CD8− cells in the thymus. In addition, CALM-AF10 mice had decreased B220+/IgM+ cells in the spleen, as well as an unusual Mac1+/B220+ population of cells in the spleen. Eight of 20 offspring from founder C10, and 7 of 16 from founder E6 developed acute leukemia between 9 and 18 months-of-age. Additionally, 5 of 20 mice from the C10 founder and 3 of 16 mice from the E6 founder were found dead unexpectedly but were too necrotic for analysis. Animals that developed acute leukemia were either found dead without premonitory symptoms or presented with ruffled fur, hunched posture and dyspnea. Gross findings included splenomegaly and hepatomegaly. CBC analysis indicated a leukocytosis and anemia and peripheral blood and bone marrow contained increased numbers of blasts and immature forms. Spleens from leukemic mice were effaced by leukemic blasts, which also invaded peripheral tissues including liver, lung, and kidney. Tissue sections from most of the leukemias were myeloperoxidase (MPO) positive and negative for CD3, F4/80, and B220, and immunophenotype was typically Mac1+, Gr+/−, CD4−, CD8−, and B220−. Spleen and/or liver from animals with leukemia were evaluated for clonal T-cell receptor (TCR) β or δ rearrangements. Two of 11 had clonal TCR β rearrangements, one of which also had a clonal TCR δ rearrangement. These findings suggest that CALM-AF10 produces a predominately myeloid leukemia in mice, some of which also have T-cell features. The long latency period and incomplete penetrance suggests that collaborative events may be needed to initiate leukemogenesis.
AML1/MDS1/EVI1 Induces Essential Thrombocythemia in Mice Independently of Jak2 Mutations.
Authors: Senyuk Vitalyi , Li Donglan , Fazzina Raffaella , Cattaneo Francesca , Rinaldi Ciro R. , Dickstein Jerome , Nucifora Giuseppina 
Published: October 2019

Abstract
The molecular etiology of subgroups of essential thrombocythemia (ET), as well as some other myeloproliferative disorders (MPDs) has been recently better understood by the identification of an activating somatic point mutation (Valine 617 to Phenylalanine) in Jak2 detected in patients with MPDs. Approximately 23%–57% of ET patients harbor this mutation, which is thought to be one of the dominant factors contributing to the disease. However, the pathways disrupted in at least half of ET patients who have wild type Jak2 are not known. The fusion gene AML1/MDS1/EVI1 (AME), a product of the t(3;21)(q26;q22) translocation, is associated with several hematopoietic disorders, primarily chronic myelogenous leukemia and acute myeloid leukemia, and to a lesser extent with ET. We have investigated the role of AME by generating C57BL/6J mice that express this fusion oncogene in their bone marrow after bone marrow infection and transplantation. After a latency of 12 ± 1.8 months, all the reconstituted mice invariably developed an ET-like disease. The disease was fatal and the animals died of anemia probably caused by bleeding. Until 1–2 weeks before death, at which time the mice were severely cytopenic, the peripheral blood hemoglobin and leukocyte counts of the reconstituted AME mice were normal. The only striking difference was the platelet counts, which were consistently above the normal range (1456–3153 and 940–1608 K/ml for AME and control mice, respectively, p=0.00029). Platelets appeared dysplastic with anisocytosis, various degrees of degranulation, and giant size. The bone core biopsies of AME mice were especially remarkable for large and giant megakaryocytes with a tendency for clustering. Touch preparations of the biopsies showed progressive maturation in the granulocytic and erythroid precursor cell lines, a normal myeloid to erythroid ratio and no evidence of dyshematopoiesis. These finding coupled with markedly increased levels of TPO but normal concentrations of c-Mpl and Epo-R are concordant with the morphologic and laboratory features of patients with ET. The sequence analysis of exon 12 of Jak2 demonstrated no guanine-to-thymine transversion at nucleotide 1849 in all AME mice tested. These data are valuable because they provide a novel mouse model for understanding the deregulated pathways in ET patients with wild-type Jak2.
Correlation of JAK2 V617F Mutation Status and Cytogenetic Findings in Myeloproliferative Disorders.
Authors: Sun Guoxian , Buccini Frank , Fuentes Elizabeth , Weisberger James 
Published: October 2019

Abstract
Detection of JAK2 V617F mutation is quickly becoming a front-line screening test for suspected myeloproliferative disorders (MPDs), as the mutation shows high frequency and specificity in non-CML MPDs, PV, ET or CIMF. Routine cytogenetics can detect chromosome abnormalities in approximately 20% of MPDs and is very helpful in establishing or confirming the presence of aberrant clonality, although chromosome changes are often numerical gains and losses, deemed non-specific. To see if there is correlation between JAK2 mutation and karyotypes, we studied 57 consecutive patients with clinically and morphologically confirmed diagnosis of non-CML MPDs. JAK2 V617F mutation performed using allele-specific PCR (sensitive to 10% using pyrosequencing) was found in 72% of patients (41/57), whereas clonal chromosome abnormalities were observed in 15.8% (9/57). There was no correlation between JAK2 mutational status and karyotypes. In 41 patients positive for the JAK2 mutation, 6 were cytogenetically abnormal and 35 normal. In 16 patients negative for the mutation, 3 showed abnormal karyotypes and 13 had normal karyotypes (X2 test, p>0.5). Among 6 patients with both JAK2 mutation and an abnormal karyotype, JAK2 mutation was seen in >50% of each sample in 4 patients, consistent with a homozygous mutation. Interestingly, in two cases, one with PV and trisomy 9 and another with MPD unclassifiable and trisomy 9p resulting from an unbalanced translocation between chromosomes 9p and 13, JAK2 mutation was present in >65% of each sample. Trisomy 9 and trisomy 9p are common abnormalities in MPDs, particularly in PV, seen in over 20% of cytogenetically abnormal cases. JAK2 gene is located on 9p24. Mitotic recombination is considered the most likely cause of loss of heterozygosity (LOH) and thus mutant homozygosity which is undetectable at the cytogenetic level. However, in cases with trisomy 9 or 9p, the JAK2 allele genotypes may be G/T/T and/or T/T/T as well as the usual G/T and/or T/T. Our observations suggest that trisomy 9 or 9p should be taken into consideration when interpreting JAK2 mutation status and that further molecular studies are needed to delineate the implication of trisomy 9 or 9p in potential mutant allele selective advantage and clonal evolution in JAK2 mutation positive MPDs.