bluuebunny/crossref_metadata_2025 huggingface dataset:
HIV-Associated NK/T-Cell Lymphomas: A Review of 93 Cases.
Authors: Castillo Jorge , Pantanowitz Liron
Published: October 2019

Introduction: NK/T-cell lymphomas (NKTCL) are being reported with increased frequency in HIV-infected patients in the HAART era. However, there has been no comprehensive review of these emerging HIV-associated lymphomas. We present, to our knowledge, the first comprehensive review of the epidemiology, clinical and pathologic features, therapeutic options, and outcome in HIV-associated NKTCL.

Methods: A total of 93 cases of NKTCL in HIV-infected individuals were identified in a literature review using PubMed and cited articles from 1996 until March 2007. Data regarding epidemiology (country), demographics (age, gender), clinical features (presentation, tumor location), HIV status (CD4, AIDS-defining illness, coinfections), lymphoma (WHO/EORTC subtype, immunophenotype, Ann Arbor stage), treatment, and outcome were extracted.

Results: Cases were reported worldwide (USA, Europe, South America, Asia), with a 15x increased incidence compared to the general population. Patients were of median age 38 years (range 1–63) at presentation, exhibited a 4:1 male predominance, and had a median CD4 count of 184 cells/mm3. Up to 54% had a prior AIDS-defining illness. The most common clinical findings were lymphadenopathy, B symptoms, erythroderma and pruritus. All subtypes were noted including Peripheral T-cell (n=36), Cutaneous T-cell including Mycosis fungoides (n=25), Anaplastic Large Cell (n=13), Adult T-cell Leukemia/Lymphoma (n=8), NK cell (n=4), and other lymphomas (2 AILD, 2 Enteropathy-associated, 1 PEL, 1 Intravascular). Most expressed CD45RO and CD3 antigens, CD4>CD8, CD30 in a subset (n=23), and EBV was detected in 20 cases (mainly extranodal PTCL, cutaneous ALCL, and NK cells). Most (74%) were extranodal (50% involving skin) and 26% nodal. Staging (60 patients) overall showed stage I (27%), II (3%), III (17%), and IV (53%).There was no standard therapeutic approach, with 46% given one modality, 17% multimodal treatment, and 12% were untreated in reported cases. HAART was rarely used. Death occurred in 55% of patients and median overall survival (83 patients) was 1.1 years from the time of diagnosis.

Conclusions: NKTCL afflicted HIV-infected persons are likely to be young males with AIDS who have a CD4 count under 200 cells/mm3 at presentation. They are also prone to present with extranodal disease, skin involvement, and at an advanced stage. Although a standard treatment approach is still required, the prognosis of HIV-associated NKTCL remains poor. The role of HAART needs to be further explored.
Pax5 Activates Oncogenic Transcription Factors of the Ets Family by Repressing the mir-15a/16-1 microRNA Cluster.
Authors: Chung Elaine Y. , Cozma Diana , Yu Duonan , Dews Michael , Wentzel Erik A. , Chang Tsung-Cheng , Mendell Joshua T. , Thomas-Tikhonenko Andrei
Published: October 2019

We have recently demonstrated that Pax5 promotes B-lymphomagenesis by upregulating key components of B-cell receptor signaling [Cozma et al, J Clin Inv, 117 (8), 2007]. Gene regulation by Pax5 often involves complex formation with other oncogenic transcription factors of the Ets family, namely Myb and Ets1. We determined that expression of these proteins themselves depends on the presence of Pax5, as seen in human diffuse large B-cell lymphomas with Pax5 knockdown and murine lymphomas with epigenetic silencing of Pax5 [Yu et al, Blood, 101:1950–1955, 2003; Johnson et al, Nat Immunol, 5:853–861, 2004]. Upon reconstitution with the Pax5 gene, Myb and Ets1 levels increase sharply. This occurs with little increase in steady-state mRNA levels, suggesting post-transcriptional regulation, possibly by microRNAs. To test this hypothesis, we compared miRNA profiles of Pax5-deficieint and sufficient cells and discovered that several miRNAs are indeed repressed by Pax5. Among them is the miR-15a/16-1 cluster whose predicted targets include both Myb and Ets1. Consistent with this prediction, forced expression of miR-15a/16 brings down Myb and Ets1 protein levels. This is accompanied by impaired Pax5 function and overall suppression of B-lymphomagenesis. Thus, Ets family members (along with previously identified bcl-2) are key targets of the miR-15a/16 locus, a tumor suppressor in chronic lymphocytic leukemia.

Interplay between Pax5, Myb/Ets1, and miR-15a/16-1. (A) Upregulation of Myb and Ets 1 in tumors over-expressing Pax5ER fusion, as compared to control GFP-only neoplasms. (B) Down-regulation of Myb and Ets1 in Pax5 tumors engineered to over-express the miR-15a/16-1 cluster. All panels depict Western blotting. Interplay between Pax5, Myb/Ets1, and miR-15a/16-1. (A) Upregulation of Myb and Ets 1 in tumors over-expressing Pax5ER fusion, as compared to control GFP-only neoplasms. (B) Down-regulation of Myb and Ets1 in Pax5 tumors engineered to over-express the miR-15a/16-1 cluster. All panels depict Western blotting.
FLT3-ITD but Not FLT3-TKD Mutations Have Major Prognostic Impact in Normal Karyotype AML.
Authors: Schneider Stephanie , Schneider Friederike , Dufour Annika , Mellert Gudrun , Zellmeier Evelyn , Braess Jan , Bohlander Stefan K. , Feuring-Buske Michaela , Buske Christian , Fritsch Susanne , Heinecke Achim , Sauerland Maria C. , Hoster Eva , Unterhalt Michael , Berdel Wolfgang E. , Wormann Bernhard J. , Buechner Thomas , Hiddemann Wolfgang , Spiekermann Karsten
Published: October 2019

Background: Approximately 45% of AML patients have a normal karyptype (NK-AML) and an intermediate clinical prognosis. As only 20–42% of these patients show long-term survival, it is important to identify prognostic markers to distinguish patients’ outcome more precisely. Mutations in the FLT3 gene such as internal tandem duplications (ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain (TKD) are the second most common abnormalties in AML patients. For FLT3-ITD it is well known that patients have an unfavourable prognosis. Up to now there are not enough reliable data to determine the prognostic impact of FLT3-TKD mutations.

Patients and Methods: We have investigated the prevalence of FLT3-TKD mutations in a cohort of 803 cytogenetically normal AML (NK-AML) patients and its possible prognostic significance. At diagnosis the mutation status of FLT3 (ITD and TKD) and the NPM1 gene were analyzed by routine molecular techniques.

Results: The median age of all patients was 60 years and the median observation time of survivors 23.2 months. Results of the mutation status’ of FLT3-ITD, FLT3-TKD and NPM1 were available in 757/803 (94.3%), 683/803 (85.1%) and 696/803 (86.7%) patients, respectively. FLT3-ITD, FLT3-TKD and NPM1 mutations were found in 222 (29.3%), 46 (6.7%) and 354 (50.9%) of all analyzed patients, respectively. We could not detect any influence of the FLT3-TKD mutation on OS (p= 0.753), RFS (p= 0.229), EFS (p= 0.835), CR (p= 0.168) and on d16 blast count (p= 0.696). In most patients FLT3-ITD and TKD mutations were mutually exclusive, although a minority of 8/674 patients (1.2%) carried both mutations. FLT3-TKD mutations were more frequently found in patients with NPM1 mutations compared to NPM1-negative patients (9.04% vs. 3.74%; p= 0.008). In contrast to FLT3-ITD mutations FLT3-TKD mutation had no prognostic impact in NPM1 positive AML cases.

Conclusions: In our study in a large cohort of 803 NK-AML patients we could not detect any prognostic impact of FLT3-TKD mutations. Although FLT3-ITD and TKD mutations have both transforming potential in vitro and in vivo mouse models, the clinical impact of both mutations shows striking differences. Further studies with FLT3-PTK inhibitors will clarify the pathogenetic relevance of these mutations in AML.
Prevalence and Prognostic Impact of KIT Mutations in Acute Myeloid Leukaemia with Inv(16). A Retrospective Study.
Authors: Cairoli Roberto , Beghini Alessandro , Ripamonti Carla B. , Grillo Giovanni , Nadali Gianpaolo , Di Bona Enrico , Colapietro Patrizia , Nichelatti Michele , Bertani Gianbattista , Ravelli Erika , Cuneo Antonio , Ottaviani Emanuela , Pioltelli Pietro , Ferrara Felicetto , Lazzarino Mario , Rossi Giuseppe , Rodeghiero Francesco , Pizzolo Giovanni , Martinelli Giovanni N. , Morra Enrica
Published: October 2019

Introduction Several studies have recently pointed out the adverse impact of KIT mutations (mutKIT) on relapse incidence (RI) and overall survival (OS) in AML pts with t(8;21). By contrast, the prognostic significance of mutKIT in pts with inv(16) remains unclear. Purpose of this study is to evaluate the prevalence and the prognostic impact of mutKIT in inv(16)(p13q22).

Patients and Methods Fifty adults with inv(16) AML at diagnosis (median age 46.6 yrs, range: 17–88; M/F: 30 /20), were centrally analyzed for mutKIT in exon 2, 8, 10, 11 and 17. Mutations were detected using sequencing and other sensitive assays such as ARMS (amplification refractory mutation system) PCR for D816Y and D816H and enzymatic digestion with HINFI for D816V and with Tsp509I for N822K.

Results Data showed a prevalence of KIT mutation of 34% (17/50 pts). Among the mutKIT cases, we detected mutations in exon 17 (n=12), exon 8 (n= 4) and exon 10 (n=1). There was no difference between the mutKIT vs the unmutated (KIT-) patients in the median of WBC count at presentation (WBC 13.9 x109/L, range 4.4 to 277.5 vs 19.4 x109/L, range 2.5 to 130; Mann-Whitney U test: p = 0.649). Of the 42 patients (age < 60 years) who received intensive chemotherapy, 13 resulted mutKIT upon mutational screening. Complete remission (CR) was achieved in 13/13 (100%) mutKIT vs 27/29 (93%) KIT- patients (Fisher’s exact test: p > 0.999). At a median follow-up of 26 months (range: 2–144), 9/13 (69%) mutKIT and 8/27 (29%)KIT- pts relapsed;the Kaplan-Meier plots revealed KIT mutations to be a significant factor adversely affecting RI (log-rank test: p = 0.017) but not OS (61% in mutKIT vs 75% in KIT-;log-rank test: p = 0.331).

Conclusion KIT mutations are associated with a greater probability of relapse following CR, without affecting OS, in AML pts with inv(16) aged <60 years.
The Prognostic Significance of Complex Karyotype in Philadelphia Chromosome-Negative (Ph−) Acute Lymphoblastic Leukemia (ALL) in Adults Is Related with Risk Group.
Authors: Granada Isabel , Sancho Juan-Manuel , Oriol Albert , Morgades Mireia , Bethencourt Concepción , Parody Ricardo , Hernández-Rivas Jesús-María , Moreno Maria-José , Del-Potro Eloy , Tormo Mar , Rivas Concepción , Sanz Miguel-Angel , Grande Carlos , Bueno Javier , Abella Eugenia , Ortega Juan-José , Ribera Josep-Maria
Published: October 2019

Different from acute myeloblastic leukemia, the prognostic significance of complex karyotype (CK) is not well known in adults with ALL. A recent study showed that CK (≥5 chromosomal abnormalities) confer an increased risk of treatment failure and poor survival (Moorman, 2007). The aim of study was to analyze the possible prognostic influence of CK in Ph- adult (≥15yr) ALL patients treated with risk-adapted protocols from the Spanish PETHEMA Group. The cytogenetic studies were reviewed following the ISCN criteria (2005). CK was defined as the finding of 3 or more structural chromosomal abnormalities. Patients were included in three different trials: ALL-96 for standard-risk (SR) ALL, and ALL-93 or ALL-AR03 for high-risk (HR) ALL. Patients with Burkitt’s ALL were not included in these trials. Patients included: 237. SR: n=44, 25 males, WBC count 12x109/L (SD: 14), 5 patients with CK (11.4%), 39 non-complex karyotype and normal karyotype (non- CK) (88.6%). HR: n= 193, 107 males, WBC count 58x109/L (SD: 77), 25 patients with CK (13%), 168 non- CK (87%). Complete remision (CR), disease free survival (DFS) and overall survival (OS) according to karyotype group and trial are showed in Table: When CK was defined as the finding of ≥ 5 structural chromosomal abnormalities (n=11, SR=3, HR=8), DFS and OS were also significantly shortened in patients with SR ALL and CK (p=0.007 and p=0.001, respectively), but not in patients with HR ALL. Complex karyotype (defined as ≥ 3 or ≥5 structural chromosomal abnormalities) did not have any prognostic relevance in adults with high-risk Ph- ALL, whereas a significant short survival observed in standard-risk patients with complex karyotype.
Regulation of the New CXCR7 Receptor in Plasma Cell Dyscrasias.
Authors: Moreau Anne-Sophie , Leleu Xavier , Jia Xiaoying , Runnels Judith , Pitsillides Costas , Carlson Alicia L. , Ngo Hai T. , Roccaro Aldo M. , Azab Abdelkareem , Azab Feda , Lin Charles P. , Ghobrial Irene M.
Published: October 2019

Background: Multiple Myeloma (MM) and Waldenstrom Macroglobulinemia (WM) are characterized by widespread involvement of the bone marrow (BM) as the result of successful homing, engraftment and growth of tumor cells at that site. The receptor for SDF-1, CXCR4 has already been implicated by us and others in the migration and homing of tumor cells to the bone marrow. Recently, a new receptor for the chemokine SDF-1 has been described, namely CXCR7. To date, it has been implicated in the migration of embryonic cells during neurogenesis in zebrafish. It has been reported to be expressed in cancer cells but its function remains unknown. We have previously shown that disruption of the CXCR4/SDF-1 axis interferes with homing of MM cells to the BM. To better understand the homing and migration of MM and WM tumor cells, we sought to study the expression and function of CXCR7.

Methods: MM (U266, MM1.S, RPMI, OPM2, OPM1, KMS12BM) and WM (BCWM.1 and WSU-WM) cell lines were used. CD19+ and CD138+ cells were extracted from patient bone marrow samples by microbeads selection after informed consent. To determine the expression of CXCR7 on MM and WM cell lines as well as primary samples, we used flow cytometry and RT-PCR analysis. The migration of tumor cells towards SDF-1 was studied using the transwell boyden chamber migration assay. The adhesion of tumor cells to fibronectin using a fluorometric assay. The CXCR7 inhibitor CCX-754 (ChemoCentryx Inc., Mountain View, CA) was used.

Results: CXCR7 was expressed in all cell lines tested except WSU-WM by flow cytometry and RT-PCR. Interestingly, U266 cell line did not express surface CXCR4 and expressed CXCR7 and therefore was used in further experiments to determine the differential role of CXCR7 in SDF-1 related function. Primary WM (n=14) and MM (n=7) cells expressed low intensity CXCR7 by flow cytometry. Use of the above cells in experiments utilizing small molecule antagonists of both CXCR4 and CXCR7 suggested that inhibiting the binding of SDF-1 to one receptor could impact the signaling functions of the other. Experiments are ongoing to clarify the nature of the interaction between these two SDF receptors. Furthermore, adhesion of U266 cells to fibronectin was increased in presence of SDF-1, and inhibited in the presence of CCX-7754. Further analysis to examine CXCR7 and CXCR4 antagonism in adhesion are ongoing.

Conclusion: we showed for the first time CXCR7 expression on MM and WM tumor cells. Our results lead us to conclude that through binding of a shared ligand, CXCR7 and CXCR4 may modulate the biological activity of the other.
Effects of Integrin-Linked Kinase (ILK) Inhibitor QLT0267 on Multiple Myeloma Cells and Evaluation of ILK as a Therapeutic Target in Multiple Myeloma.
Authors: Stühmer Thorsten , Steinbrunn Torsten , Grella Evelyn , Bargou Ralf C.
Published: October 2019

Multiple myeloma (MM) is a fatal plasma cell tumor that accounts for about 1% of cancers. A hallmark of the disease is its location in the bone marrow where the tumor cells receive prosurvival support from the microenvironment and cause extensive osteolytic damage. Novel drugs are currently being developed into a range of new treatment options. However, because the problems of cancer relapse and eventual selection of therapy-resistant offspring remain, additional therapeutic targets should still be investigated. ILK is a multifunctional protein that, as an adaptor and/or as a kinase, may relay adhesion- and growth factor receptor-mediated signals to downstream signaling cascades that promote growth and survival. We have analysed the expression of ILK in MM cells and have tested the effects of a novel small molecule ILK-inhibitor (QLT0267; QLT Inc., Vancouver, Canada) in MM cell lines, primary MM tumor cells and healthy cells, respectively. ILK expression at either cDNA or protein level was detectable in virtually every MM sample tested. Treatment with QLT0267 for up to 3 days resulted in extensive apoptotic death in MM cell lines (EC50 values below 10 microM in 8/9 MM cell lines tested) and in a majority of primary (anti-CD138-purified) MM samples (EC50 values below 10 microM in 8/14 primary MM samples tested). Drug treatment led to rapid decreases in the levels of phospho-STAT3, phospho-GSK3beta and total Akt protein, whereas levels of ILK and of phospho-ERK were unaffected or, in the latter case, showed a slight increase. Similar to other current pharmacologic approaches, targeting ILK may have several detrimental impacts on the signaling network that sustains MM cells. Such pleiotropic effects could prove valuable for combination treatments. The survival of peripheral blood mononuclear cells and of bone marrow stromal cells (BMSCs) at 20 microM QLT0267 was just slightly affected, indicating that the scope for establishment of a therapeutic window in MM might exist. High (20 microM) concentrations of QLT0267 gradually (and reversibly) promoted detachment of BMSCs from the culture dish, indicating that the drug might be useful to temporarily impair their effectiveness to support myeloma cells. Taken together, these experiments provide a rationale to further explore the utility of ILK-inhibition for the treatment of MM.
AT9283, a Potent Inhibitor of JAK2, Is Active in JAK2 V617F Myeloproliferative Disease Models.
Authors: Squires Matthew S. , Curry Jayne E. , Dawson Mark A. , Scott Mike A. , Barber Kelly , Reule Matthias , Smyth Tomoko , Wallis Nicola , Yule Murray , Thompson Neil T. , Lyons John F. , Green Anthony R.
Published: October 2019

AT9283 is a potent inhibitor of JAK2, JAK3, mutant Abl kinase (T315IAbl) and Aurora kinases A and B all of which have an IC50 <5nM. The compound is currently in early phase clinical development for hematological malignancies. Multitargeted kinase inhibitors may be of particular value as anti-proliferative agents as a consequence of their ability to inhibit several signalling pathways simultaneously. Many of the kinases targeted by AT9283 lie in signalling pathways activated by oncogenes and may contribute in a positive way to the anti-tumour action of the compound. Here we describe the characterisation of the anti-tumour effects of AT9283 in models of JAK2-dependent disease The JAK2 V617F mutation has been identified in more than 95% of patients with Polycythemia vera and in 50 to 60% of patients with Essential Thrombocythemia and myelofibrosis. JAK2 is a key modulator of cytokine signalling, transducing signals from cell surface receptors via the JAK/STAT pathway. The point mutation renders the kinase constitutively active and induces cytokine-independent proliferation of cell lines harboring mutated JAK2. AT9283 was profiled against two cell lines harboring JAK2 V617F (HEL, SET-2) as well as two lines with a dependence on cytokine signalling through wild type endogenous JAK2 for survival (BA/F3 wt, TF-1, stimulated with IL3). These lines were compared with two additional leukaemia cell lines not dependent upon JAK signalling for survival, K562 (Ph+CML) and HL60 (N-Ras PML). In each case the dominant effect of the compound is to inhibit cell growth through JAK inhibition where the survival of the cell line depends on signalling through the JAK2 pathway. In contrast the cell lines less dependent on JAK2 for survival show a polyploid phenotype indicative of Aurora kinase inhibition. In HEL cells AT9283 inhibits phosphorylation of JAK2 pathway markers such as phospho-STAT5 (Tyr694) at 100nM, a dose consistent with concentrations required to inhibit the proliferation of these cells. Consequently, the cell cycle profiles generated when either K562 or HL60 cells are treated with AT9283 suggest that endoreduplication derived from Aurora inhibition is the dominant phenotype. In a JAK driven system the dominant phenotype observed is induction of apoptosis via inhibition of JAK. In an in vivo model, administration of a single dose of AT9283 to the JAK-dependent HEL xenograft, inhibited phosphorylation of STAT5 indicating JAK2 inhibition in the tumour tissue and an efficacy study demonstrated growth inhibitory effects of 9283 in this model. Finally the activity of AT9283 was tested in primary assays using cells taken either from healthy volunteers or patients diagnosed with MPD. These data together support further clinical investigation of the compound in patients with a myeloproliferative disorder.
The Presence of the JAK2V617F Mutation in Primary Myelofibrosis and Its Allele Burden in Polycythemia Vera Predict Chemosensitivity to Hydroxyurea.
Authors: Sirhan Shireen , Huang Jocelin , Li Chin-Yang , Tefferi Ayalew
Published: October 2019

Background: Almost all cases of polycythemia vera (PV) and more than half of those with either essential thrombocythemia (ET) or primary myelofibrosis (PMF) harbor JAK2V617F. It has been previously shown that V617F-positive ET patients, as opposed to their mutation-negative counterparts, require lower doses of hydroxyurea (HU) for control of their platelet count. In the current study we looked for a similar scenario in PMF and PV.

Methods: Study patients were identified by database inquiry based on the presence of treatment history with HU and adequate follow-up. Qualitative (PMF) and quantitative (PV) analysis of JAK2V617F was performed according to previously published allele specific PCR-based methods. Mutation analysis was performed on bone marrow samples collected at time of initial diagnosis or within one year of diagnosis. HU treatment response assignment was according to criteria set by the International Working Group for Myelofibrosis Research and Treatment. In PV, a complete response (CR) required normalization of blood counts associated with a more than 50% benefit in both phlebotomy requirement and splenomegaly. Partial response (PR) required either becoming phlebotomy independent or normalization of blood counts or a greater than 50% improvement in splenomegaly.

Results: The study cohort consisted of 69 patients with PMF (median age 62 years; 36% females) and 56 patients with PV (median age 67 years; 45% females). In PMF, by univariate analysis, HU response was associated with a shorter disease duration (p=0.008), absence of previous therapy (p=0.01), older age at diagnosis (p=0.009), and presence of V617F (p=0.02). On multivariable analysis, only the latter retained its significance; HU response rate was 48% in V617F-positive patients (11/21 patients) and 8% in mutation-negative cases (1/12 patients). In PV, V617F allele burden correlated directly with HU response (p=0.05) and, in responding patients, inversely with HU dose (p=0.01; Figure). All 9 patients with upper quartile V617F allele burden responded (8 with CR) whereas 6 of the 11 (55%) HU non-responders displayed V617F allele burden in the lower quartile range. Among the 45 HU responders, the maximum daily dose of HU employed in all 9 patients in the upper quartile allele burden range and 4 of the 5 in the middle quartiles range was below 1500 mg. In contrast, 8 of the 31 patients (26%) in the lower allele burden quartile range required doses at 1.5 gm or more per day.

Conclusion: The current study suggests that response to HU therapy in both PMF and PV is more robust in the presence of JAK2V617F; the particular information is useful in identifying PMF patients who are likely to benefit from HU therapy and in individualizing HU starting dose in PV patients.

Figure Figure
Phase II Study of CEP701, an Orally Available JAK2 Inhibitor, in Patients with Primary Myelofibrosis and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis.
Authors: Verstovsek Srdan , Tefferi Ayalew , Kornblau Steven , Thomas Deborah , Cortes Jorge , Ravandi-Kashani Farhad , Garcia-Manero Guillermo , Kantarjian Hagop
Published: October 2019

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are myeloproliferative disorders (MPDs) associated with activating mutations of Janus tyrosine kinase 2 (JAK2) gene. The most common mutation, JAK2 V617F, has been reported in ∼97% of patients with PV, ∼50% with ET, and ∼50% with PMF. The resultant JAK2 protein is continuously autophosporylated and therefore always active. It is believed that this mutated tyrosine kinase contributes to the existence and progression of MPDs. CEP701 is an orally available potent low nanomolar inhibitor of wild type and mutated JAK2 tyrosine kinase in enzymatic and cellular assays. Significant inhibition (growth stasis) was observed following CEP-701 subcutaneous administration to V617F-mutated JAK2-dependent HEL.92 xenografts grown in immunocompromised mice. These results indicate that CEP-701 is an attractive candidate for clinical evaluation in patients with MPD carrying a mutated, constitutively activated JAK2. CEP701 is also a potent inhibitor of FLT3 and is being evaluated as FLT3 inhibitor in Phase II/III studies in patients with acute myeloid leukemia, at the starting dose of 80mg PO BID. We designed a Phase II study of CEP701, at the dose of 80 mg PO BID, in patients with PMF and post PV/ET MF, who harbor JAK2 V617F mutation. Eleven patients have been treated so far, seven males, median age 56 years (range, 38–69), median 3 prior therapies (range 0–6); 7 with abnormal cytogenetics; 8 with enlarged spleen (2 had splenectomy); 4 with enlarged liver; 5 transfusion dependent. Five patients have been followed for at least 1 month and have had stable disease. Response will be evaluated using International Working Group for MF Consensus Response Criteria. JAK2 V617F allele burden is being measured monthly. Except for Grade 2 nausea in one patient, no toxicities have been noted so far. Updated results will be presented at the meeting.
Comparison of Immunohystochemical (IHC) Expression Profile and Prognosis in 98 Patients with Diffuse Large B Cell Non-Hodgkin’s Lymphoma (DLBCL) with and without Human Immunodeficiency Virus (HIV) Infection.
Authors: Xicoy Blanca , Ribera Josep-Maria , Morgades Mireia , Mate Jose-Luis , Tapia Gustavo , Navarro Jose-Tomas , Ruiz Tatiana , Ariza Aurelio , Feliu Evarist
Published: October 2019

In some studies DLBCL germinal center (GC) phenotype has better prognosis than non-germinal center (non-GC) according to IHC expression profile by tissue microarrays (TMA), but the frequency and prognostic significance of ICH expression profile in HIV-related DLBCL is not well known. The objectives of this study were to characterize the IHC expression pattern in 98 pts with DLBCL, of which 34 were HIV positive, and to evaluate its prognostic significance. From August 1991 to February 2006, 98 consecutive pts with DLBCL from a single institution were retrospectively studied. Group A: HIV-negative DLBCL pts, n=64; group B: HIV-related DLBCL pts, n=34. TMA was constructed containing sections of paraffin-embedded tissue samples and cases were assessed for IHC study (expression of CD10, BCL-6, MUM-1). Patients were classified as CG pattern (CD10+ or CD10−/BCL-6+/MUM1−) and non-GC pattern (any other combination of these markers). Clinical and biological characteristics as well as overall survival (OS) and disease-free survival (DFS) were analyzed comparing: 1-GC vs non-GC pattern within groups A and B; 2-GC pattern from groups A vs B; 3-Non-GC pattern from groups A vs B; 4-non-GC pts from group A vs non-GC pts from group B, considering only the pts treated with highly active antiretroviral therapy (HAART) (n=13/32, 41%). There were no differences in clinico-biological parameters according to IHC pattern within each group. The only differences in OS and DFS between subgroups were observed in HIV-related DLBCL with non-GC pattern, whose survival was poorer than non-HIV related pts. Whithin the former group, only those pts not receiving HAART retained their bad prognosis. 5-year OS (95% CI) and 5-year DFS (95%CI) are summarized in the table. In our series the frequency of GC and non-GC subtypes was not significantly different in HIV positive and negative pts with DLBCL. Only those pts with HIV-related DLBCL with non-GC expression pattern not receiving HAART had a significantly inferior survival.
The Efficacy of R-ICE Therapy as a Salvage Treatment for Relapse and Refractory Diffuse Large B-Cell Lymphoma.
Authors: Kodaira Makoto , Yokoyama Masahiro , Asai Hiroaki , Yamada Shuhei , Ueda Kyoko , Myojo Tomohiro , Nishimura Tomoko , Mishima Yuko , Sakajiri Sakura , Takeuchi Kengo , Saotome Takashi , Terui Yasuhito , Takahashi Shunji , Hatake Kiyohiko
Published: October 2019

 Patients with relapsed and refractory diffuse large B-cell lymphoma are usually treated with platinum-based salvage chemotherapy. We retrospectively analyzed the efficacy of adding rituximab with ICE as a salvage treatment for relapsed and refractory diffuse large B-cell lymphoma.

From November 2003 to December 2006, patients with relapsed or refractory de novo diffuse large B-cell lymphoma represented CD20 positivty who received R-ICE (rituximab375mg/m2, Ifosfamide 1200mg/m2, calboplatin 400mg/m2 and etopside100mg/m2 ), were analyzed retrospectively.

23 patients (19 relapse and 4 reflactory) (M:F=14:9) (median age 69, 28–77) were included. At starting treatment, twelve patients received rituximab and 11 patients were rituximab naive. In all 23 patients, responses were 11 Complete remission (CR), and 6 partial response (PR), resulting in overall response (ORR) was 74.9%. With median follow up of 10.5 months, estimated 1yr-progression free survival (PFS) was 49% and 1yr-overall survival (OS) was 70%.In patients received rituximab, ORR was 66.7% and 5 patiets achieved CR (41.7%).In the without rituximab, ORR was 90.9% and 7 patiets achieved CR (63.6%). No statistical differences were observed in response even with retuximab pretreatment. Estimated 1yr-PFS was 23% and 70% (p=0.0752) and 1yr-OS was 59% and83% (P=0.0049),respectively. NCI-CTC grade 3/4 neutropenia and thrombocytopenia were reported 100% and 91%, For non-hematological adverse event, there were grade 3 liver dysfunction (2/23) and grade 3 arrythmia (1/23). No toxic death was reported in this study.

 R-ICE showed promising efficacy with tolelable toxicity. Available date suggested adding rituximab to ICE is more effective for patients not received rituximab in the pretreament.
R-COMP 21 (Prednisone, Cyclophosphamide, Vincristine, Myocettm and Rituximab) for Frail and Elderly Patients with Aggressive B-Cell Non-Hodgkin Lymphoma: A Pilot Study.
Authors: Isidori Alessandro , Ferrara Felicetto , Alesiani Francesco , Ronconi Sonia , Catarini Massimo , D’Adamo Francesca , Guiducci Barbara , Bernardi Daniele , Visani Giuseppe
Published: October 2019

CHOP chemotherapy is the gold standard treatment for patients with indolent and aggressive non-Hodgkin Lymphomas. However, CHOP is frequently poorly tolerated by frail and elderly patients resulting in dose reductions and consequently lower response and cure rates compared to younger patients. The toxicity and efficacy of nonpegylated liposomal doxorubicin (Myocet™) when substituted for conventional doxorubicin in the CHOP 21 regimen (Doxorubicin, Cyclophosphamide, Vincristine, Prednisone given every 3 weeks) were evaluated in the treatment of frail elderly patients with aggressive non-Hodgkin’s lymphoma. Twenty patients (median age: 73 years, range 61–82) with diffuse large B cell non-Hodgkin lymphoma, either at diagnosis (15 patients) or relapsing (5 patients), were enrolled in the study. At baseline 14/20 (72%) patients had stage III–IV disease. All patients had one or more comorbidity. Eighteen out of 20 patients (90%) had an intermediate or high risk International Prognostic Index score. The median left ventricular ejection fraction (LVEF) before starting chemotherapy was 62% (range 43–73). A total of 111 chemotherapy cycles were administered, with a median of 6 cycles (range 1–8). Of the cycles administered, 19 (17%) were delayed by haematological toxicity. The relative dose intensity for the regimen was 83%. Toxicity was mainly haematological with grade 3 or 4 neutropenia in 16% of cycles and febrile neutropenia in 5%. However, 3/20 patients presented a grade III–IV WHO toxicity (one fatal pulmonary embolism, one congestive heart failure, one ischemic heart failure) while receiving R-COMP chemotherapy. All but one patient were evaluable for response. 13 out of 19 (68%) had a complete response and an additional 5 patients (26%) achieved a partial response. Of the evaluable patients, only 1/19 (5%) did not respond at all to chemotherapy and rapidly died due to progressive disease. With a median follow-up of 14 months (range 7–18) as of July 2007, 15/18 responding patients (83%) are alive and disease free, as well as 3/18 are alive with active disease. In conclusion, the R-COMP 21 is a very effective regimen with promising response rates in frail and elderly patients with high risk aggressive non-Hodgkin lymphoma. Further studies with a larger cohort of patients are warranted to better define the impact of non pegylated liposomal doxorubicin on overall survival of this setting of elderly and particularly frail patients.
Development of Pulmonary Sarcoidosis during Lymphoma Treatment: A Diagnostic Dilemma.
Authors: Campos-Gines Angel F. , Antony Suresh J. , Arango Carmen P. , Landeros Mark M. , Herrada Juan
Published: October 2019

Background: Although the association of sarcoidosis and malignancy has long been described (Brincker, Br J Cancer 1972), so far only 3 patients (pts) have been documented to have developed sarcoidosis during or immediately after chemotherapy for non-Hodgkin lymphoma (NHL) (Kornacker et al. Ann Hematol 2002; Hollister et al. J Clin Oncol 2005).

Methods: Case report. Results: A 50 year-old male with 2-month history of back pain and 20 pound weight loss had a soft tissue mass in the lumbar area biopsied. The pathology revealed a diffuse large B-cell lymphoma. Bone marrow biopsy showed no abnormalities. Computed tomography (CT) and [18F] fluorodioxyglucose positron emission tomography (PET) revealed large bilateral pulmonary masses and extensive periaortic lymphadenopathy. Treatment consisted of chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab every 21 days. 11 days after completion of the 4th cycle, the pt was hospitalized with febrile neutropenia, and received intravenous cefepime and vancomycin with growth-factor support. Pt was released from the hospital on day 20th of the cycle with a white cell count of 15 thousand / uL, mostly neutrophils, and negative blood, sputum, and urine cultures. Because of persistent fever (38.5 °C) and non-productive cough 3 weeks after discharge, CT studies were obtained. In the chest there was no evidence of the previously noted lung masses, and there was the presence of new bilateral diffuse pulmonary infiltrates. Abdominal CT demonstrated near complete resolution of the periaortic lymphadenopathy. A transbronchial biopsy and a bronchoalveolar lavage were obtained, revealing the presence of non-caseating granulomas, and no evidence of malignancy, mycobacteria, or fungal micro-organisms. The serum level of angiotensin-converting enzyme was markedly elevated (112; normal range 9–67). At this point the pt was diagnosed with symptomatic pulmonary sarcoidosis and he was treated with oral prednisone. Follow-up CT evidenced a complete resolution of the pulmonary infiltrates. No further chemotherapy was administered. After a subsequent follow-up of 14 months, the pt remains in complete remission by clinical, serological, and radiographic (CT and PET) criteria.

Conclusions: The diagnosis of new radiographic changes in pts with NHL receiving chemotherapy needs to be histologically confirmed.
A Prospective Multivariate Analysis of Risk Factors Associated with Occurrence of Febrile Neutropenia in Any Cycle in NHL Patients Receiving Chemotherapy.
Authors: Pettengell Ruth , Bosly Andre , Szucs Thomas D. , Jackisch Christian , Leonard Robert , Paridaens Robert , Constenla Manuel , Schwenkglenks Matthias
Published: October 2019

Febrile neutropenia (FN) following chemotherapy often results in hospitalisation and chemotherapy dose delays or reductions in subsequent cycles. Although current guidelines highlight non-Hodgkin lymphoma (NHL) patients receiving standard regimens as having a significant risk of FN, the contribution of additional factors to the overall risk of FN is not fully understood. We present a logistic regression model describing the relationship of various clinical factors with FN occurrence in NHL. Predictors were chosen based on their clinical and statistical significance (5% level) and to allow comparison with other models. Data were obtained from the INC-EU Prospective Observational European Neutropenia Study, which aimed to assess the incidence and predictors of neutropenia, FN and chemotherapy dose limitations in breast cancer and lymphoma. 240 NHL patients were recruited from 37 centres in Belgium, France, Germany, Spain, and the UK. Ann Arbor stages were distributed: I 18%; II 26%; III 17%; IV 40%. Chemotherapy regimens received were 3-weekly CHOP-like (74%), 2-weekly CHOP-like (17%), ACVBP-like (4%) and other regimens (5%). Overall colony stimulating factor (CSF) prophylaxis in patients who had not previously experienced FN was 50%. FN incidence in any cycle was 22%. The resulting logistic regression model of any FN occurrence is shown in the table. Replacing GFR and height with the closely related parameters of age and weight slightly affected predictive ability but did not affect model stability. The area under the receiver operating characteristic curve was 0.84. Using the optimal probability cut-off, model test characteristics were 75% sensitivity and 76% specificity; corresponding to positive and negative predictive values of 48% and 91%, respectively. Low absolute neutrophil or white blood cell count (ANC, WBC), high baseline alkaline phosphatase, low GFR (or high age), low height (or low weight), cardiac comorbidity, recent infection, and high planned chemotherapy dose appeared to increase the risk of FN occurrence. Although chemotherapy dose reduction or delay protected against FN, these are associated with reduced survival in patients receiving CHOP-like regimens. CSF use was a protective factor. These results complement risk factors highlighted in current guidelines.
The Equal Activity of Azacytidine in 4 Risk Groups of IPSS in MDS.
Authors: Bang Soo-Mee , Kim In-Ho , Park Seonyang , Kim Byoung Kook , Lee Je-Hwan , Lee Jung-Hee , Lee Kyoo-Hyung , Kim Yeo-Kyeoung , Ahn Jae-Sook , Kim Hyeoung Joon , Bae Sung-Hwa , Ryoo Hun-Mo , Lee Mark , Shin Ho-Jin , Min Yoo-Hong , Lee Jae Hoon , Mun Yeung-Chul , Won Jong-Ho , Oh Doyeun ,   Korean AML/MDS Working Party
Published: October 2019

Introduction: The methylated proportion of the gene, turning on the cell cycle, increases with a progression of MDS. Newly introduced demethylaing agent, azacytidine (AZA) may be more active in advanced cases of MDS. Early data for the hematologic responses in several stages of MDS supported this. The powerful tool predicting the outcome of MDS is international prognostic scoring system (IPSS). Our study is to compare the response to AZA among the IPSS risk groups using international working group criteria.

Methods: One hundres five patients with MDS were treated with AZA from May 2006 till August 2007. Seven patients had insufficient data. Finally, 108 patients were enrolled.

Results: Their median age was 59 years-old (range; 20∼83), and male to female ratio was 2.09. The previous hematologic diseases documented in 8 patients; apalastic anemia (7), and megaloblstic anemia (1). The secondary MDS occurred in 3 patients; after the chemotherapy (2) and radiotherapy (1). A median time from the diagnosis to treatment was 3 months (0∼183). The previous treatment (percentage of patients given) was the transfusion of RBC (74%) and PLT (35%), oxymetholone (17%), steroid (13%), erythropoietin (7%), cyclosporine (7%), ATG (5%), valproic acid (5%), chemotherapy (3%), and allogeneic SCT (2%). Their ECOG performance scale was 0 (58 patients), 1 (45) and 2 (5), respectively. Their diagnoses just before the AZA were RA (20 patients), RARS (5), RCMD (27), RCMD-RS (6), RAEB-1 (27), RAEB-2 (20), MDS-U (1), MDS with isolated 5q− (1) and CMMoL (1). A number of patients with a LOW, INT-1, INT-2, and HIGH risk was 4 (4%). 70 (65%) 23 (21%) and 11 (10%), respectively. The rate of hematologic response (CR+PR+marrow CR+HI) and cytogenetic response (continued normal karyotype and CR) were similar; 100%/75%/93%/67% and 100%/59%/50%/50% in LOW/INT-1/INT-2/HIGH risk groups, respectively. There were 6 treat-related mortalities, and their causes of death were infection in 4 patients and bleeding in 2 patients. Two patients stopped after one cycle of treatment because of grade 4 hepatoxicity and pulmonary toxicity, respectively. During a median follow-up of 9 months, 4 patients were confirmed as transformation to AML and 1 patient suffered from persistent marrow aplasia. One-year expected overall and failure-free survival was 82 ± 5% and 79 ± 6%, respectively in 108 patients.

Conclusion: AZA showed the equal activity in 4 risk groups on IPSS in patients with MDS. Not only the hematologic response but the cytogenetic response was similar between 4 groups.
SDF-1 Is Responsible for the Constitutively High NF-kB Activity in Human Myeloma Cells.
Authors: Islam Abul , Otsuyama Ken-ichiro , Amin Jakia , Abroun Saeid , Shamsasenjan Karim , Iqbal Mohd S. , Kawano Michio M.
Published: October 2019

The chemokine, stromal cell-derived factor 1 (SDF-1; CXCL12) and its receptor, CXCR4 are considered to be essentially required for plasma cell homing to the bone marrow (BM). It is well known that plasma cells in the BM (long-lived plasma cells) survive for a long time and have the constitutively high NF-kB activity. Since human myeloma cells are considered to be derived from these committed long-lived plasma cells, we investigated the role of SDF-1 on the survival of primary myeloma cells from myeloma patients and the possible relationship with NF-kB activity. First, we confirmed that all primary myeloma cells expressed CXCR4 but not CCR9 or CCR10 receptors on their surface and the levels of CXCR4 expression apparently correlated with maturity of BM plasma cells; mature myeloma cells (MPC-1+) as well as polyclonal plasma cells expressed higher levels of CXCR4 than those on immature myeloma cells (MPC-1-). The production of SDF-1 was found strongly in BM stromal cells but not in primary myeloma cells as well as myeloma cell lines. On the other hand, high DNA binding activity of NF-kB was constitutively detected in primary myeloma cells as well as myeloma cell lines, and these NF-kB activities significantly correlated with the expression levels of CD54 on their surface, for CD54 gene is one of the strict NF-kB target genes. Based on the expression levels of CD54 protein, interestingly, primary myeloma cells showed weaker NF-kB activities than those in monoclonal plasma cells from MGUS and polyclonal plasma cells from polyclonal gammopathy. Plasma concentrations of SDF-1 were also significantly correlated to the expression levels of CD54 on primary myeloma cells significantly (P<0.01). Furthermore, it was confirmed that addition of SDF-1 significantly increased the expression levels of CD54 in the in vitro culture of primary myeloma cells. Therefore, these results indicate that SDF-1 is responsible for high expression levels of CD54 and possibly the constitutively high NF-kB activity in primary myeloma cells.
The Mechanism of Constitutive NF-kB Activity in Myeloma Cell Lines.
Authors: Amin Jakia , Otsuyama Ken-ichiro , Islam Abul , Shamsasenjan Karim , Iqbal Shamim Mohd , Kawano Michio M.
Published: October 2019

[Purpose] NF-kB has a key function in the transformation, proliferation and invasion of cancer cells as well as in resistance to radiotherapy and chemotherapy. Although constitutive NF-kB activation has been reported in many human tumors, the underlying factors and mechanisms responsible for constitutive NF-kB activation in myeloma cells has not been known. The purpose of this study was to determine the mechanism of constitutive NF-kB activity in myeloma cell lines and quantification of NF-kB activity in primary myeloma cells by expression of CD54 (a NF-kB target gene).

[Methods] We checked the constitutive expression of NF-kB family proteins by western blot analysis and possible dimer formation of different NF-kB family members by Immunoprecipitation-western blot reaction. Constitutive NF-kB DNA-binding activity and dimers that are responsible for NF-kB activity were analyzed by electrophoretic mobility shift assay (EMSA). Moreover, expression of different NF-kB target genes was done by RT-PCR.

[Results and discussion] Constitutive NF-kB activity was determined in myeloma cell lines and our results suggested that p50/RelB, p50/p50, p50/p52 dimers might be responsible for this. We also analyzed several NF-kB target gene expressions and found that the intensity of CD54 expression was positively correlated with total NF-kB DNA binding activity. Although there is no method to quantified NF-kB activity, it can be determine in terms of its target genes e.g. CD54. Therefore, this study provide the frame work for understanding the molecular mechanism of constitutive activation of NF-kB and would help to quantify NF-kB activation in primary myeloma cells.