bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-1 Receptor Antagonist and Interleukin-1 beta: Different Roles in Patients with Chronic Lymphocytic Leukemia.
Authors: Zhang Zhong , O’Brien Susan , Keating Michael , Jilani Iman , Kantarjian Hagop , Estrov Zeev , Ferrajoli Alessandra , Giles Francis , Albitar Maher 
Published: April 2020

Abstract
Interleukin-1 receptor antagonist (IL-1Ra) is a 23-KDa soluble glycoprotein that blocks the activity of IL-1α and IL-1β by competing with type I and type II IL-1 receptors without initiating signal transduction. IL-1Ra is anti-inflammatory, while IL-1β is a proinflammatory molecule. IL-1β enhances the immunological and hemopoietic systems and IL-1Ra acts as an inhibitor. IL-1β induces the cell surface expression of cytokine receptors on lymphoid and hemopoietic cells, whereas IL-1Ra suppresses this activity. IL-1β augments lymphoid and hemopoietic cell growth, whereas IL-1Ra suppresses this growth. We evaluated the clinical relevance of IL-1Ra and IL-1β levels in the plasma of 92 patients with chronic lymphocytic leukemia (CLL). IL-1Ra levels were significantly higher in CLL patients (median, 389, range 52–3667 pg/mL) than in 31 normal control subjects (median, 217; range, 94–868 pg/mL) (P &lt;0.001). In contrast, IL-1B levels were significantly lower in CLL patients (median, 2.23; range, 1.89–12 pg/mL) than in normal controls (median, 2.68; range, 2.08–5.5) (P &lt;0.01). Overall, neither IL-1Ra nor IL-1B correlated significantly with WBC count, β2-microglobulin (β2-M) level, Rai stage, platelet count, mutation status, or treatment history. Only age correlated with IL-1Ra (R = 0.39, P &lt;0.001). Using a univariate Cox proportional hazards model, we found direct correlation with survival when IL-1Ra was used as a continuous variable (P &lt;0.001). This association was independent of Rai stage, β-2M, and IgVH mutation status. However, in a multivariate analysis incorporating a combination of IgVH, β2-M, and IL-1Ra, IL-1Ra was no longer a predictor of survival. When patients were dichotomized according to the median IL-1Ra level, those with higher levels had longer survival (P = 0.057). In contrast, IL-1B did not correlate with survival (P = 0.14). These data suggest that IL-1Ra, but not IL-1B, plays a role in the biology of CLL and that the stronger the anti-inflammatory process in CLL, the more aggressive the disease.
Chronic Lymphocytic Leukaemia Has a More Aggressive Phenotype in Asians Compared to Caucasians.
Authors: Austen Belinda , Gunawardana Chaminda , Pratt Guy , Wandroo Farooq , Jacobs Abe , Powell Judith , Moss Paul 
Published: April 2020

Abstract
Chronic lymphocytic leukaemia (CLL) is the commonest leukaemia in the western world with an incidence of 3 per 100,000. The precise aetiology remains obscure but there is clear evidence for a genetic predisposition. CLL has a seven-fold increased incidence amongst relatives of index cases compared to controls and the disease is also more common in males. These genetic subgroups can also determine phenotype as familial CLL has a younger age of onset and increased association with second malignancies compared to sporadic cases. Similarly, CLL is more aggressive and more frequently requires treatment in males in comparison to female patients. The incidence of CLL also varies according to racial origin and has been found to be up to 20-fold less common in Japanese and Asian populations compared to Caucasian populations. However, it is not known whether or not there is also phenotypic variation in CLL patients according to racial origin.
We studied 29 Asian patients with a diagnosis of CLL and compared disease characteristics with a control group of 277 Caucasians. We found that CLL in Asians was diagnosed at a younger age (median age 62yr in Asians vs 70yr Caucasians, p=0.001) and was also more common in males (M:F Asians 3.1:1; Caucasians 1.3:1, p=0.023). No association was seen between racial origin and either IGVH status or CD38 status.
Interestingly, we also found that the Asian population had a more aggressive clinical phenotype as indicated by a shorter time to the requirement of first treatment (TTFT) (p=0.019). This observation was independent of both age and gender. Although no difference was seen in overall survival between the two groups, ‘non-leukaemia related’ deaths were more common in the older Caucasian population. 27.5% of Caucasian deaths occurred in patients who had never required treatment for CLL whereas no deaths occurred among untreated Asian patients, for whom the primary cause of death was progressive leukaemia. The failure to observe a difference in overall survival was therefore partly accounted for by an increase in non-leukaemia related deaths in Caucasians.
In conclusion, we have shown that there are phenotypic differences in CLL patients according to the racial origin. CLL in Asian patients occurs at a younger age and is associated with a more aggressive phenotype. The mechanisms underlying these observations are unknown but warrant further investigation.
Impaired Peripheral Blood Dendritic Cell Counts in B-Chronic Lymphocytic Leukaemia.
Authors: Horvath Rudolf , Budinsky Vit , Pytlik Robert , Klener Pavel , Trneny Marek , Spisek Radek , Bartunkova Jana 
Published: April 2020

Abstract
B-cell chronic lymphocytic leukaemia (B-CLL) is the most common leukaemia of adults in Western worls accounting for about 40% of leukemias in adults over the age of 65 years. Although, B-CLL cells can, under certain conditions, act as antigen presenting cell (APCs) they fail to generate an efficient anti-leukemic immune response. Dendritic cells (DCs) represent the most potent APCs and they are the only cell type capable of initiating a primary immune response. To asses a potential role of DCs compartment in insufficient anti-leukemic and anti-infectious immunity in B-CLL, we have analysed peripheral blood DCs subsets in 17 patients with an early stage B-CLL and 8 age matched controls by multi colour flow cytometry. Dendritic cells were identified by lack of B, T, NK and monocyte markers, HLA-DR expression and expression of CD11c and CD123 for myeloid and plasmacytoid DCs, respectively. We found a significant reduction of absolute plasmacytoid DCs counts in patients with B-CLL (average count = 49,4×106/L) when compared to healthy donors (average count = 111,3 ×106/L, p&lt;0,05). Myeloid DCs counts were not different from healthy controls (average count = 192,7×106/L vs. 196,7×106/L p=NS). Number of plasmacytoid DCs decreased with B-CLL cells number. DC counts did not depend on CD38 or ZAP70 expression or immunoglobulin mutational status. Phenotypic analysis of circulating plasmacytoid and myeloid DCs showed low co-stimulation profile comparing to isotype controls. Thus, the depletion of pDCs in B-CLL could represent a mechanism contributing to the poor anti-leukemic immune responses in B-CLL and/or to immune deficiency in CLL patients.
An International Multicentric Trial with Fludarabine Plus Cyclosphosphamide in B-Cell Chronic Lymphocytic Leukemia (CLL) “Up Front”: Second Interim Analysis.
Authors: Bezares Fernando , Jait Cecilio , Caviglia Daniel , Bhar Daniel , Rodriguez Andrea , Pilnik Norma , Prates Virginia , Lastiri Francisco , Carpio D. del , Carrasco-Yalan Antonio A. , Giralt Sergio 
Published: April 2020

Abstract
Introduction: On August 2002 an international multicentric trial on Fludarabine monophosphate (FAMP) plus Cyclophsphamyde (Cy) among previously untreated B-cell CLL, was activated. Our aim is to evaluate efficacy and toxicity of FAMP plus Cy in previously untreated B-cell CLL patients (pts). This is the second interim analysis after a fourth-year period.
Material and Methods: Treatment consists in three consecutive days of oral FAMP 40 mg/m2 (n=84) or i.v. FAMP 25 mg/m2 (n=13) plus i.v. Cy 600 mg/m2 on day 1 or Cy 250 mg/m2 from day 1 to 3, every 28 days × 6 cycles. Responses were assessed according to the National Cancer Institute working group criteria after cycle 3 and again after cycle 6. Since August 2002 to March 2006, 109 CLL pts from Argentina (n=95), Perú (n=11) and Uruguay (n=3) were enrolled for this protocol; eighty-nine were evaluated for response and toxicity. Median age: 64 years old (range: 44–81); male = 47, female = 42; Binet staging: A=14, B=45, C=30; median beta-2 microglobuline = 4.00 mg/dL (range: 1.3–9.2); median LDH = 341 UI/L (range: 101–762); among patients with available data the CD 38 expression more than 10% was 38% (22 of 58 pts). Blood counts at inclusion: median values (range); Lymphocytes: 32 ×109/L (2,7–137), Hb: 120 g/L (50–164), platelets: 175×109/L (10–364). Renal and hepatic parameters within normal range limits. Cytogenetic by banding was available in 27 cases: no alterations (n=17), +12 (n=1), del (6), del (12) (n=1), lost Y (n=1).
Results: At the time of this second interim analysis (March 2006), 56.2% (50 pts) had completed 6 cycles and 97.8% (87 pts) had undergone at least 3 cycles.
Overall responses: 92% = 81 pts (CR: 39% = 35 pts; PR: 52% = 46 pts); treatment failure: 9% = 7 pts. Evaluation for toxicity: 89 episodes of haematological toxicity and 7 episodes of infection grade 3–4 were reported after 436 cycles. Thirteen pts died: seven due infectious complications because of prolonged hematologic toxicity; one due to tumoral lysis syndrome, one due hemoptysis associated with lung cancer and the remaining four due disease progression. At 24 months, estimated DFS was 70% (figure 1, SE 7.6%) and estimated Overall Survival was 76% (figure 2, SE 7.4%). The median survival was not achieved in responders (PR and CR).
Conclusion: FAMP plus Cy combination as front-line treatment is effective in B-cell CLL. Haematologic toxicity is the most severe adverse events. The response rates to this therapy is quite similar to those reported for other multicentric trials and better than others GATLA protocols.
Figure 1 Figure 1. Figure 2 Figure 2.
Combination Therapy with Alemtuzumab and Pentostatin Is Effective and Has Acceptable Toxicity in Patients with T-Lymphoid Neoplasms.
Authors: Ravandi-Kashani Farhad , Kantarjian Hagop , Faderl Stefan , Verstovsek Srdan , Koller Charles , Odinga Shirley , Wierda William , Borthakur Gautam , Jones Dan , Giles Francis , O’Brien Susan , Keating Michael 
Published: April 2020

Abstract
The development of effective therapeutic strategies for T-lymphoid neoplasms has been difficult partly due to their rarity and paucity of clinical trials. These neoplasms are generally refractory to traditional chemotherapy regimens and novel therapeutic strategies are needed. Alemtuzumab and pentostatin have response rates of 50% to 65% when used individually to treat various T-cell leukemias and lymphomas. However, most responses are partial and of limited duration. Immunosuppression and risk of opportunistic infections are their principal overlapping toxicities. We have treated 17 patients with T-lymphoid malignancies (10 T-PLL, 1 ATL, 2 T-ALL, 2 γδ-T cell hepatosplenic lymphoma, 2 T-LGL) with a combination of alemtuzumab 30 mg IV, 3 times weekly for up to 3 months and pentostatin 4 mg/m2 weekly × 4 followed by alternate weekly administration for up to 6 months. Prophylactic antibiotics including valacyclovir, fluconazole, and trimethoprim/sulfamethoxazole (or equivalents) were administered during the treatment and for 2 months after its completion. The median age of patients was 57 years (range 22 – 79 years), median white blood count was 54.1 × 109/L (range 0.6 – 279.5 ×109/L), and median serum β2M was 4.0 mg/L (range, 1.7 – 10.8 mg/L). Four patients had splenomegaly (1 to 5 cm), and 5 lymphadenopathy. Eleven had prior therapy (median 2, range 1 to 6 regimens). Eleven patients have responded (8 CR, 3 PR) for an overall response rate of 65% (including 8 of 10 T-PLL, 1 of 1 ATL, 0 of 2 T-ALL, 1 of 2 γδ-T cell hepatosplenic lymphoma and 1 of 2 T-LGL). Monoclonal T-cell receptor chain gene rearrangements were detected by PCR in 16 patients and became negative in 5 of 7 evaluable patients in CR. Median response duration has not been reached (range 0 to 78 weeks). Three patients have proceeded to allogeneic stem cell transplant, 4 (1 with ATL, 2 with T-PLL, and 1 with T-LGL) have died from disease progression after a response, and 6 were refractory to therapy. Opportunistic infections included reactivation of CMV in 6 patients (no disease), reactivation of HSV in 1 patient, recurrence of pre-existing Serratia pneumonia in 1 patient and Aspergillus pneumonia in 2 patients. Unexplained, marked and sustained pancytopenia occurred in 2 patients, 1 with T-LGL and 1 with T-PLL. Other toxicities were mainly grade 1 and 2 and included nausea, fever, fatigue, infusion reactions, edema, and shortness of breath. The combination of alemtuzumab and pentostatin is feasible and effective in T-cell neoplasms. Although infections including CMV reactivation are a concern, they may be minimized with adequate prophylactic antibiotic therapy.
Remission duration for patients in CR Remission duration for patients in CR
The Effect of Initial Therapy Choice in Determining Long Term Survival in Patients with Chronic Lymphocytic Leukemia (CLL).
Authors: Tam Constantine S. , Wen Sijin , Do Kim-Anh , Lerner Susan , Wierda William G. , O’Brien Susan , Keating Michael J. 
Published: April 2020

Abstract
Successive advances in CLL therapy have led to significant gains in response quality and remission duration but have not yet shown improved survival. An inherent limitation of randomised trials is the long followup required to demonstrate survival benefit in indolent diseases. In order to examine the effect of initial therapy on survival, we retrospectively analyzed the outcomes of patients treated on frontline protocols at the MD Anderson Cancer Center. Between 10/86 to 01/04, 616 patients received initial therapy with one of three fludarabine-based chemotherapy regimens. Patients in Cohort 1 (F; n=190) received fludarabine±prednisone, Cohort 2 (FC/M; n=140) fludarabine & cyclophosphamide or mitoxantrone, and Cohort 3 (FCR; n=286) FC & rituximab. Therapy indication and response assessment were as per the NCI 1996 Guidelines.
Patient characteristics: median age 57 years; male 67%; Rai intermediate/high risk, 60%/36%; performance status 2 or more, 3.5%; abnormal cytogenetics 27%; B2m 4mg/L or greater, 38%. Median followup was 176, 108 and 56 months for F, FC/M and FCR respectively. Excluding the effect of therapy, univariate predictors of survival were (p-value all &lt;0.05): age, hemoglobin, B2m, abnormal cytogenetics, performance status, Rai stage, albumin and absolute lymphocyte count; only age, B2m and abnormal cytogenetics remained significant following Cox multivariate analysis. Incorporating the therapeutic regimen (F v FC v FCR) into the model, significant predictors for survival were: age (RR 1.05 per year; p&lt;0.0001), FCR regimen (RR 0.42 vs F, 0.41 vs FC/M; p&lt;0.001), high B2m (RR 1.13 per mg/L, p=0.001) and abnormal cytogenetics (RR 1.48, p=0.05). FCR significantly improved survival in the following adverse prognostic groups: age 60 or older (p=0.03), high-risk Rai stage (p=0.002), B2m 4mg/L or greater (p=0.005), performance status 2 or more (P=0.03) and abnormal cytogenetics not involving chromosome 17 (p=0.003). Patients with deletion or abnormality of the chromosome 17 had median survival of &lt;24 months irrespective of treatment regimen. Our analysis underscores the importance of initial therapy choice in determining the survival of patients with CLL. Novel therapeutic strategies are required for patients with chromosome 17 deletion or abnormality.
Survival By Initial Regimen Survival By Initial Regimen
In Vitro Cytotoxicity of Alemtuzumab on B-CLL Cells: Differential Effect on B and T Lymphocytes.
Authors: Berretta Salvatore , Chiarenza Annalisa , Adamo Luana , Parrinello Laura , Buglio Daniela , Stagno Fabio , Tibullo Daniele , Conticello Concetta , Palumbo Giuseppe A. , Di Raimondo Francesco 
Published: April 2020

Abstract
Alemtuzumab, a monoclonal anti-CD52 antibody, has shown high efficacy against lymphoproliferative disorders such as B-cell chronic lymphocytic leukemia (B-CLL). However, its use results in a profound immunosuppression with decrease of T lymphocytes leading to increased susceptibility to infections. The aim of our study was to assess the in vitro cytotoxic effect of alemtuzumab on normal T and neoplastic B lymphocytes obtained from B-CLL patients.
Peripheral blood mononuclear cells (PBMC) from 12 B-CLL patients (5 at diagnosis and 7 previously treated) were collected and treated in vitro with alemtuzumab (10 μg/ml) and autologous serum in the culture as complement source. Spontaneous and alemtuzumab-induced apoptosis were quantified in T (CD3+) and B (CD20+) lymphocytes after 24 hours using an annexin-V flow cytometry based asssay.
Alemtuzumab was able to induce apoptosis on both B and T lymphocytes of CLL patients. However, the cytotoxic activity on neoplastic B cells was comparable in all cases analyzed, irrespective of stage or previous treatments. Spontaneous apoptosis of B CLL cells was also comparable in all studied samples.
On the contrary, the activity of alemtuzumab on normal T lymphocytes varied according to stage of disease and previous treatment. In early stages (0–I) alemtuzumab induced apoptosis in 19 % of T cells vs 60% of advanced stages (II–IV) (p=0,009). Differences were also relevant when patients were split by treatment: in fact, alemtuzumab induced apoptosis in 15% of T cells of untreated patients vs 52% of T cells of previously treated patients (p=0,005). Moreover, spontaneous apoptosis of T cells was more pronounced in treated vs. untreated patients (15% vs 2%, p=0.03) while the difference was not statistically significant in early vs advanced stage (p=0.06).Our in vitro data confirm that alemtuzumab is active against B-CLL cells in all stage of disease. However, in advanced stages and in previously treated patients, T cell compartment seems to be more fragile and susceptible to both spontaneous and alemtuzumab-induced apoptosis. This observation supports the hypothesis that using Alemtuzumab earlier in the treatment of B-CLL might result in less immunosuppression. The study is still ongoing with accrual of more patients samples.
Low-Dose Prednisone Decreases the Severity but Not the Frequency of Lenalidomide Associated Tumor Flare Feaction (TFR) in Chronic Lymphocytic Leukemia (CLL) Patients.
Authors: Musial Laurie , Miller Kena C. , Tonelli Amy , Manochakian Rami , Padmanabhan Swaminathan , Lawrence David , DePaolo Dawn , Coignet Jean-Gabriel , Chanan-Khan Asher Alban 
Published: April 2020

Abstract
Introduction: Lenalidomide (L) is clinically active in pts with CLL. TFR is a common side effect of L, unique to CLL pts and is characterized by tender enlargement of lymph nodes (LN), spleen and/or liver with low-grade fever, rash and/or increase in white blood cell count. Onset is usually with 24 hours of first dose and it is rarely seen after the 1st cycle. The underlying etiology of TFR remains undetermined though clinical presentation is suggestive of an immune activation phenomenon. Diagnosis, management and effective prophylaxis of TFR is crucial for the pt care as it is associated with considerable morbidity and mimics disease progression. We investigated the effectiveness of low-dose prednisone prophylaxis in CLL pts treated with L.
Method & Results: Forty five pts (36 male, 9 female), median age 64 years (range 42–75) with rel/ref CLL were enrolled on a phase II clinical trial. Single agent L (max. dose 25mg/day) was given to all pts enrolled. No prophylaxis was given to the first 29 pts (group A). Subsequently 16 pts (group B) were treated with prednisone 20mg PO QD × 5 days followed by 10mg PO QD × 5 days, starting day 1 of treatment. Median age was 64 years (range 42–75) with 36M and 9F. Stage III/IV disease was noted in 64% (n=18) of the pts. Twenty four (83%) pts in group A and 13 (81%) in group B developed TFR with &gt; grade II TFR was seen in 31% and 6%, respectively. Among pts with TFR, 4 achieved complete remission (CR) and had grade &gt; 2 reaction vs. 19 pts with a &lt; partial remission who had a median of grade 1 (range 1–2) TFR.
Conclusion: Although the sample size investigated is small, we observed that use of oral prednisone prophylaxis decreased the severity but not the overall incidence of TFR. We therefore recommend that low-dose prednisone be considered for lenalidomide associated TFR in patients with CLL.
Pleiotropic Role of GSK3 Kinase in Myeloma Cell Biology.
Authors: Piazza Francesco A. , Gurrieri Carmela , Chioetto Gino , Bonanni Luca , Montini Barbara , Carraro Samuela , Cabrelle Anna , Zambello Renato , Trentin Livio , Adami Fausto , Semenzato Gianpietro 
Published: April 2020

Abstract
GSK3 is a cellular serine-threonine kinase discovered because of its involvement in insulin, growth factor and Wnt signalling, downstream of which it is inhibited through the action of the PI3K/AKT cell survival pathway or through other Wnt signalling-dependent mechanisms. GSK3, therefore, has been included in the group of “tumor suppressors”, as it can antagonize cell proliferation triggered by these cascades. Recent findings, however, have challenged this notion in that GSK3β has been found central for cell survival and NF-κB signalling. Since growth factor, Wnt and cytokine-dependent signalling pathways have been implicated in MM pathogenesis, we decided to investigate the role of GSK3 in multiple myeloma cell biology. GSK3 kinase activity was found slightly higher in malignant plasma cells as compared to normal resting B-lymphocytes and normal in vitro generated plasmablasts. GSK3 enzymatic activity was hampered by stimulation of MM cells with IL-6 and IGF-I but, remarkably, not with TNFα. IL-6 and IGF-I driven MM cell proliferation was significantly increased by GSK3 blockade as it was MM cell survival upon serum starvation or contact with bone marrow stromal cells (BMSC). At molecular level, IL-6-dependent STAT3 phosphorylation was unaffected by GSK3 inhibition, however, ERK1, 2 phosphorylation was increased. Importantly, NF-κB activation and transcriptional activity downstream from TNFα were only slightly affected when GSK3 function was inhibited in MM cells. However, when GSK3 inhibitors were added to MM cell cultured with BMSC, IL-6 secretion in the medium was reduced and the expression of NF-κB-dependent antiapoptotic genes was altered. Lastly, the addition of GSK3 inhibitors in MM cells-BMSC cultures led to an increased expression of Wnt/β-catenin-dependent genes both in MM and in BMSC cells. Our data indicate a different involvement of GSK3 downstream from growth factors or TNFα-induced signalling pathways in MM cells; the observed effects of GSK3 inhibition on the Wnt-signalling pathway indicate that, whereas they would be desirable in the BMSC compartment (i.e. antagonisms of Wnt-inhibitors released in the MM bone marrow, such as Dikkopf-1 (DKK1) or secreted Frizzled-Related Protein (sFRP)-2 and favouring of the osteoblast maturation) on the other hand they could lead, together with the loss of a brake downstream from growth factor signals, to uncontrolled and enhanced MM cell proliferation; thus, the inhibition of this kinase for therapeutic purposes in MM is likely to be accompanied by dangerous and unwanted side effects that may promote the progression of this disease.