bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final Report on Tandem Autologous Stem Cell Transplantation for Patients with Primary Progressive or Poor Risk Recurrent Hodgkin Lymphoma - A Two Institution Study.
Authors: Fung Henry C. , Stiff Patrick , Nademanee A. , Smith E. , Cutrone C. , Parthasarathy M. , Krishnan A. , Klein J. , Molina A. , Ruel C. , Smith D. , Rodriquez T. , Falk P. , Toor A. , Schriber J. , Rosenthal J. , Ivers B. , Somlo G. , Kogut N. , Vora N. , Margolin K. , Spielberger R. , Forman Stephen J. 
Published: October 2019

Abstract
Background: While autologous stem cell transplantation (ASCT) for patients with relapsed/refractory Hodgkin lymphoma (HL) appears to offer a survival advantage over conventional therapy, only approximately 25–35% of patients with primary progressive or poor risk recurrent Hodgkin Lymphoma achieve durable remission after ASCT with disease progression after transplant accounted for most of the treatment failures. We (a collaboration between City of Hope Comprehensive Cancer Center and Loyola University Medical Center) conducted a pilot study to evaluate the toxicities and efficacy of a tandem transplant approach in this subgroup of patients.
Methods: Between 4/98 and 3/00, 46 patients (median age: 37 [range 17–65]) were enrolled in the study.
Eligibility criteria: primary progressive (n=28) or recurrent HL (n=18) with at least one of the following poor prognostic factors: first CR < 12 months (n=15) or extra-nodal disease (n=4) or B symptoms at relapse (n=4). The 1st cycle consisted of melphalan (150mg/m2) alone. The 2nd cycle consisted of Fractionated total body irradiation (1200cGy) or BCNU (450mg/m2) in combination with etoposide (60mg/kg) and cytoxan (100mg/kg). A minimum of 2 x 106 CD 34/kg autologous stem cells were re-infused after each cycle of therapy.
Results: Of the 46 pts, 41 (89%) patients completed the planned tandem transplants. Five (11%) did not receive the planned tandem transplants because of inadequate stem cells collection for 2nd ASCT. After a median of 64 days (25–105), 41 patients received the 2 transplants. With a median follow up of 5 years (1.6–6.4), 24 patients are alive and progression-free at last follow up. Of the 41 patients who received both cycles of high dose therapy, 21 are alive and disease-free; 17 developed disease progression at a median of 4 months (range 1–61) post-ASCT. There were 2 early deaths secondary to regimen related toxicities. Both of them died of interstitial pneumonitis. The Day100 mortality was 4%. One patient developed secondary MDS 28 months post-ASCT after receiving further chemotherapy for relapsed disease. Using an intent-to-treat analysis for all 46 patients included in the study, the 5-year K-M estimate of overall survival, progression free survival and event free survival were 73% (95%CI 60,87), 61% (95% CI 46, 76) and 50% (95% CI 35, 64) respectively.
Conclusion: Our mature results from this study suggest that in patients with primary progressive or poor risk recurrent Hodgkin Lymphoma, this tandem ASCT program is effective and well tolerated and compares favorably with the conventional single transplant without increase in transplant related toxicities.
Prolonged Survival in Patients with Angioimmunoblastic T-Cell Lymphoma (AIL) after High-Dose Chemotherapy and Autologous Stem Cell Transplantation (ASCT). The GELTAMO Experience.
Authors: Rodriguez Jose , Caballero Maria Dolores , Gutierrez Antonio , Gandarillas Marco , Leon Angel , Ojanguren Jesus , Sureda Ana , Lopez-Guillermo Armando , Carrera Dolores , Bendandi Mauricio , Arranz Reyes , Moraleda Jose , Ribera Jose Maria , Albo Carmen , Morales Alfonso , Garcia Juan Carlos , Fernandez Pascual , Cañigral Guillermo , Bergua Juan , Conde Eulogio 
Published: October 2019

Abstract
Conventional treatment of patients with AIL offers poor results with a median survival ranging from 15 to 24 months. No standard treatment for this disease has been established. Thus, our aim in this report is to provide our experience within a cooperative group in patients with this type of lymphoma who underwent ASCT. Nineteen patients were transplanted in the GELTAMO cooperative group in the last 12 years. Median age at transplant was 46 years. Fifteen patients (79%) underwent the procedure as front line therapy, 8 out of these 15 pts as consolidation of first CR, 5 in first PR and 2 in induction failure condition. Four patients who relapse received the procedure as salvage therapy. Most patients (90%) received peripheral stem cell product and the conditioning regimen was based in BEAM or BEAC in 79% of patients. Seventy-nine percent of patients achieved a CR with the transplant, 5% a PR and 16% of patients failed the transplant. With a median follow up of 25 months for alive patients, 11 patients are alive and free of disease at present. The OS at 5 years is 60% and the PFS, 55%. Eight patients died, 7 of them of disease and 1 patient of a second neoplasia. Prognostic factors associated with a poor outcome were the presence of extranodal disease at transplant, bone marrow involvement, the presence of more than 1 factor of the age-adjusted-IPI (a-IPI) and be transplanted in refractory disease. Patients with AIL who underwent ASCT in chemosensitive disease have 60% of probability to be alive at 5 years, most of them free of disease. Patients who received the procedure as consolidation either as first CR or in first PR have similar outcome. However patients in refractory disease do not benefit of this therapeutic modality. The presence of extranodal disease at transplant predicts an unfavourable outcome.
Prognostic Factors in the UK LRF CLL4 Trial.
Authors: Oscier David Graham , Richards Sue , Orchard Jenny , Davis Zadie , Best Giles , Morilla Alison , Brito-Bapapulle Vasantha , Matutes Estella , Pettitt Andrew , Catovsky Daniel 
Published: October 2019

Abstract
The CLL4 trial randomised 777 previously untreated patients between Chlorambucil (Chlor), Fludarabine (Fluda) and Fludarabine with Cyclophosphamide (FC). The median follow-up is 21 months. VH gene mutation status using a 98% cut off, CD38 expression using a 7% cut off, ZAP70 expression (Orchard et al Lancet 2004) and interphase FISH were measured on samples taken at randomisation. In an interim analysis 253/397 patients had unmutated VH genes. 32 patients utilised the VH3-21 gene, of whom 27 showed restricted HCDR3 usage. 343/535 were CD38 positive and 131/261 were ZAP70 positive. 10/24 VH 3-21 cases were ZAP 70 positive, of whom 7 were unmutated. There was no significant association between VH genes and age, sex or a positive DAT. There were significant correlations between VH gene mutations and CD38, ZAP70 and FISH results.
Association of VH genes with CD38, ZAP70 and FISH results. CD38+ ZAP 70+ p53 loss Del 11q Del 6q21 Del 13q Trisomy 12 % = % of all cases with known VH mutation status VH Unmutated 119 (58%) 110 (72%) 21 (9%) 48 (22%) 18 (10%) 109 (45%) 50 (21%) VH Mutated 30 (25%) 17 (16%) 3 (2%) 13 (11%) 6 (6%) 97 (73%) 13 (10%) p= <0.0001 <0.0001 0.02 <0.009 0.2 <0.0001 0.008
Logistic regression including age, stage, gender, VH mutations and genetic factors shows that stage (p=0.002), VH genes (p=0.05), p53 loss (p=0.02) and del 11q (p=0.01) affect response. Response rates by VH gene mutation status and treatment arm are given in table 2.
Response rates according to VH mutation status and treatment arm Chlor Unmut Chlor Mut Fluda Unmut Fluda Mut F/C Unmut F/C Mut %=% of all unmutated or mutated cases receiving a particular treatment CR/NPR 24 (25%) 23 (42%) 25 (43%) 18 (55%) 37 (58%) 23 (70%) PR 43 (45%) 19 (34%) 21 (36%) 10 (30%) 21 (33%) 10 (30%) NR/PD 29 (30%) 13 (24%) 12 (21%) 5 (15%) 6 (9%) 0 (0%) p (trend) 0.07 0.3 0.1
Analysis of variance shows that both VH genes (p=0.01) and treatment (p<0.0001) have an effect on response with no significant interaction. Among 104 patients with unmutated VH genes and both ZAP 70 expression and response data available, there was no significant difference in response rates between ZAP positive and negative cases. In univariate analysis p53 loss (p<0.00005), unmutated VH genes (p=0.003), CD38 positivity (p=0.06) but not ZAP70 positivity correlate with poor overall survival. In multivariate Cox regression analyses, age (p<0.0001) stage (p=0.01) and p53 loss (p<0.0001) are significant for survival. When patients with p53 loss are excluded unmutated VH genes (p=0.007) but not CD38 or ZAP70 positivity are significant. In conclusion p53 loss identifies a small group of patients with both poor response to treatment and short survival. In the remaining cases, unmutated VH genes are associated with a relatively poor response independent of treatment arm, and with a shorter survival.
Transcriptosome Profiling of B-CLL Identifies WNT-3A and ROR-1 as an Autocrine Mechanism in Cell Survival.
Authors: Choi James , Simons B. , Riley Chris , Klinkhammer T. , Cooke Laurence , Spier Catherine , Sud R. , Hehn Sean , Garewal Harinder , Mahadevan Daruka 
Published: October 2019

Abstract
Background: B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia afflicting the Western world. B-CLL accounts for 25% of all newly diagnosed leukemias. Despite many new therapeutic advances, B-CLL is still not a curable malignancy. The hallmark feature is the presence of an elevated number of circulating clonal leukemic B cells that typically express CD 5, CD 19, CD 23, and low levels of surface immunoglobulins.
Methods: Mononuclear cells from 5 patients were analyzed utilizing the HG-U133A 2.0 Affymetrix array (~18,400 transcripts, 22,000 probe sets) after isolating and purifying total RNA (Qiagen, RNAeasy). The control RNA samples were isolated from normal peripheral blood (PB) B-cell (AllCell, CA). Immunohistochemistry (IHC) confirmed tumor lineage and quantitative real time RT-PCR was performed on selected genes to validate the microarray study. The GEP data was processed and analyzed utilizing Affymetrix MAS 5.0 and GeneSpring 5.0 software. Our data was analyzed in the light of published GEP of B-cell CLL. Fifteen B-CLL patients (retrospectively) were evaluated by RT-PCR for ROR-1 and WNT-3A with gene specific probes. As a potential therapy, thalidomide was evaluated on B-CLL cells grown in cell culture for 24 hours. GEP of the thalidomide treated B-CLL from the initial 5 patients was performed to look for gene expression changes that could drive the B-CLL toward apoptosis. A homology model of ROR-1 tyrosine kinase was built, ATP docked and in silico databases screened for potential lead molecules.
Results: Data are represented as “robust” increases or decreases of relative gene expression common in the 5 patients. However, ROR-1 and WNT-3A were consistently over-expressed together in these 5 patients. The average increase was 25-fold for ROR-1 and 7-fold by WNT-3A when compared to normal B-cell RNA. Of the 15 patients we evaluated for ROR-1 and WNT-3A with gene specific probes, the increase in gene expression correlated well with our initial gene expression profiling study. Thalidomide specific gene changes included several molecules involved in apoptosis. Of these gene changes, Bcl-G, p35, and Cdk-5 were up-regulated several fold. Data will be presented on the influence of the stage of disease on ROR-1 and WNT-3A expression.
Conclusions: GEP of B-CLL in combination with quantitative real time RT-PCR has identified several novel therapeutic targets for therapy based on a comparison to normal (B-cell) RNA. GEP has identified ROR-1 as a key component in an autocrine pathway that helps B-CLL elude apoptosis. The identification of this novel tyrosine kinase-like protein has led to the development of a molecular target for future therapeutic applications. Several lead compounds have been identified and are being evaluated as potential therapeutics in B-CLL.
Development of Forodesine Hydrochloride (FH), an Inhibitor of Purine Nucleoside Phosphorylase, for Patients with Chronic Lymphocytic Leukemia (CLL).
Authors: Balakrishnan Kumudha , Ravandi Farhad , Keating Michael J. , Gandhi Varsha 
Published: October 2019

Abstract
Mammalian purine nucleoside phosphorylase (PNP) catalyzes the cleavage of inosine, deoxyinosine, guanosine, and deoxyguanosine (dGuo) to their corresponding base and sugar 1-phosphate by phosphorolysis. PNP deficiency in humans produces a relatively selective depletion of T cells without much effect on normal B cells. FH, a potent inhibitor of PNP, was designed based on the transition-state analog structure stabilized by the enzyme. Previous studies demonstrated that FH in the presence of dGuo inhibits the proliferation of T-lymphocytes (Kicska et al. PNAS 2001). Based on these observations, we conducted a phase I clinical trial of FH in patients with advanced T-cell malignancies. Significant antileukemic activity was correlated with an increase in plasma FH (median 5 μM) and dGuo (median 14 μM), and an accumulation of intracellular dGuo triphosphate (dGTP) (Gandhi et al, Blood, in press, 2005). High accumulation of dGTP in T-cells may be dependant on activity of deoxynucleoside kinases. Because B-CLL cells have high activity of deoxycytidine kinase, we hypothesized that they would be sensitive to FH. This postulate was tested in primary CLL lymphocytes during in vitro investigations. Lymphocytes from patients with CLL were incubated in vitro with FH (2 μM) in the presence of 10 μM dGuo. Lymphocytes from 3 of 4 patients showed an elevation in the intracellular dGTP levels to a median 30-fold at 8 hr, without any effect on other deoxynucleotides. This increase in dGTP was associated with phosphorylation of p53 at ser15, stabilization of p53, and an increase in p21 protein. The dGTP accumulation was related to induction of apoptosis measured by activation of caspase 8, 9, and 3 and cleavage of PARP. Incubation with either FH or dGuo alone did not result in dGTP accumulation or cell death suggesting that PNP inhibition by FH and phosphorylation of dGuo to dGTP are essential for CLL cell death. Based on these encouraging results, availability of oral formulation and to validate these in vitro data during clinical trial, a phase II study of FH in patients with advanced, fludarabine-refractory CLL has been initiated. FH is administered orally at a dose of 200 mg/day for 7 days each week for 4 weeks (cycle 1). Patients are evaluated after 1 full cycle of therapy and in the absence of serious side effects, or disease progression, they continue the treatment for up to 5 more cycles. Laboratory endpoints such as level of FH and dGuo in plasma, PNP activity, dGTP levels in cells, will be measured and correlated with cytoreduction. It is postulated that a high kinase/low nucleotidase activity leading to the accumulation of intracellular dGTP in target CLL cells and apoptosis (akin to what has been seen in T-cells) will result in response to therapy. This is the first trial of a PNP inhibitor for treatment of B-CLL.
Polymorphisms in the Promoter Region of the IL-10 Gene Is Associated with Inhibitor Development in Hemophilia A.
Authors: Astermark Jan , Oldenburg Johannes , Pavlova Anna , Berntorp Erik , Lefvert Ann-Kari ,   MIBS Study Group
Published: October 2019

Abstract
The development of inhibitory antibodies is a severe and costly complication to replacement therapy occurring in 10–15% of patients with hemophilia A, and the aim of the Malmo International Brother Study (MIBS) is to evaluate host genetic factors associated with this adverse effect of treatment. In the present study, factor VIII mutations, HLA genotypes and polymorphisms of the interleukin IL-1beta, IL-4 and IL-10 genes known to influence antibody production in autoimmune diseases, were analyzed in 164 patients with hemophilia A (120 severe, 30 moderate and 14 mild) belonging to 78 unrelated families. Seventy-seven (47.0%) of the subjects had a history of inhibitors (57 high-responding, 20 low-responding) in 54 unrelated families (34 discordant, 20 concordant siblings). In 24 families, no inhibitor was reported in any of the siblings. Seventy-five patients (45.7%) in 36 families had an inversion. In this group, 40 patients (53.3%) in 28 families had inhibitors (17 concordant, 11 discordant). Weak associations between inhibitor development and the HLA alleles A26 and B44 were found. No association was found with the IL-1beta Taq 1 RFLP alleles in exon 5, and the −590 C/T SNP in the promoter region of IL-4. There was however, a strong association between an allele with 134 bp in one of the CA repeat microsatellites, IL-10G, located in the promoter region of the IL-10 gene, and development of inhibitor. Allele 134 was found in 32 (41.6%) of the patients with inhibitors compared with 12 (13.8%) of the inhibitor negative patients (p<0.001), corresponding to an odds ratio of 4.4 (95% CI 2.1–9.5, p<0.001). The association was consistent in the subgroup of families with severe hemophilia and an inversion of the factor VIII gene (p=0.002). Only one discordant inhibitor family was identified in which the subject without allele 134 developed an inhibitor, and the allele 134 positive brother did not. IL-10 is the first gene located outside the causative factor VIII gene mutation to be associated with inhibitor development in hemophilia and our data indicate this gene to be an important determinant for this side-effect of replacement therapy.
Fludarabine Versus Fludarabine Plus Epirubicin in the Treatment of Chronic Lymphocytic Leukemia - Final Results of a German Randomized Phase-III Study.
Authors: Rummel Mathias J. , Stilgenbauer Stephan , Gamm Heinold , Rost Andreas , Hartmut Doehner , Hoelzer Dieter , Bergmann Lothar 
Published: October 2019

Abstract
Based on promising results from our previous phase-II study demonstrating an overall response rate (ORR) of 92% and a high rate of complete remissions (CR) of 40% we initiated a multicenter randomized phase-III study to compare efficacy and toxicity of the combination fludarabine plus epirubicin (FluEpi) versus monotherapy with fludarabine (Flu) as first-line therapy or therapy of first relapse. In addition, cytogenetic aberrations were investigated in all patients to evaluate, if special chromosomal abnormalities are associated with prognosis and response to fludarabine. Treatment schedule: Fludarabine 25 mg/qm day 1–5, epirubicin 25 mg/qm day 4+5 for a maximum of 6 cycles every four weeks. Results: 150 patients (pts) are evaluable for response (77 pts with Flu, 73 pts with FluEpi). Median age of the patients is 62 years. All pts were in need of treatment with 86 pts being in stage Binet B and 64 pts in Binet C. Cytogenetic aberrations were well balanced between both groups. The ORR for the total group of 150 pts was 79% with a CR-rate of 19%. The ORR for patients treated with FluEpi was 88% compared to patients treated with Flu monotherapy reaching an ORR of 73%. This difference is statistical different with a p-value of 0.0255. CR are different in favor for combined treatment modality (29% CR for FluEpi vs 9% for Flu) with a significance level of 0.0029. Patients treated with FluEpi have a longer median duration of progression free survival with 26 months in comparison to 20 months for patients treated with fludarabine alone (p=0.085). There is a trend for a longer median overall survival time, which is 76 months for patients with FluEpi compared to the median survival time of 63 months for the Flu monotherapy group, however this difference is not statistical different (p=0.10). The event free survival (EFS), which was defined as not achieving any remission, progression/relpase of disease or death for any cause, was superior for pts treated with FluEpi (30 months) in comparison to the pts treated with Flu monotherapy (19 months) with a significance level of 0.048. Conclusions: The combination therapy of fludarabine plus epirubicin achieves statistically higher response rates and a longer duration of event free survival, however this does not translate in an statistical significant overall survival benefit.
Phase 2 Study of Talabostat and Rituximab in Patients with Advanced Chronic Lymphoctyic Leukemia (CLL) Previously Treated with a Rituximab/Fludarabine Regimen.
Authors: Khan Khuda D. , O’Brien Susan , Rai Kanti R. , Brown Jennifer R. , Cook Perry , Maddox Anne Marie , Duarte Alison M. , Haltom Eric J. , Uprichard Margaret J. 
Published: October 2019

Abstract
Background: Talabostat (T) is an orally available inhibitor of dipeptidyl peptidases (DPP) such as fibroblast activation protein (FAP). FAP is expressed in bone marrow, lymph nodes, and the stroma of solid tumors. T induces the production of cytokines and chemokines in lymph nodes and spleen, stimulating both adaptive and innate immune responses. T was shown to enhance the activity of rituximab (RTX) in a Phase 1 study in previously treated patients with B-cell malignancies, most likely by enhancing the antibody-dependent cytotoxicity of RTX. This study was conducted to evaluate the activity of T and RTX in patients with CLL who had previously failed a fludarabine/RTX (FR)-based regimen.
Methods: This is a single-arm, open-label study in up to 54 patients using the Simon 2-stage design. The 28-day treatment course consists of RTX 375mg/m2 on Days 1, 8, 15, and 22, with T 300mcg BID tablets for 6 days following each RTX infusion; additional courses are permitted at the discretion of the investigator depending on response. Eligibility criteria include: CD20(+) B-CLL; Rai Stage III or IV, or Stages I and II with lymphadenopathy or hepatosplenomegaly; ECOG 0-2; primary resistance or PD following a FR-regimen; no CNS metastases. The primary endpoint is disease response (evaluated per NCI-WG criteria); secondary endpoints include response duration, progression-free survival, and survival.
Results: Of 20 patients treated to date, 19 patients (17 men, 2 women; median age 62, range 44 to 80) have completed at least 1 course of treatment and are considered evaluable for response:17 patients failed prior FR and 2 patients failed prior F (RTX naive). A partial response (PR) is reported in 4/19 patients (21%); 3 who had failed FR and one who had falied F. In 3 patients, the PR was reported at Day 29. One patient who failed FR was noted to be a PR after multiple courses. At Day 29, stable disease was reported in 12 patients and 4 had progressive disease. Most patients have received 1 course of treatment; 2 have received 2 courses and one PR has received 5 courses. The most frequent adverse events (AEs) include: edema (47%), pyrexia (35%), fatigue (24%), and dyspnea (24%). Grade 3 dyspnea has been reported in 2 patients. Grade 4 events include decreased platelets in one patient and hypoglycemia in one patient with a PR who was taking antidiabetic medications. Hypoglycemia is consistent with the inhibition of DPP-IV by T.
Conclusion: The addition of T to RTX shows promising activity in advanced CLL, with clinical responses reported in patients who failed an FR-based regimen. Edema was the most frequent AE, and other AEs are consistent with the safety profile of RTX. Updated results will be presented at the Annual Meeting.