Effect of Various Doses of Intravenous Polyclonal IgG on in vivo Levels of 12 Pneumococcal Antibodies in Patients with Chronic Lymphocytic Leukaemia and Multiple Myeloma

Oncology ◽  
1993 ◽  
Vol 50 (6) ◽  
pp. 466-477 ◽  
Author(s):  
I. Sklenar ◽  
G. Schiffman ◽  
V. Jønsson ◽  
G. Verhoef ◽  
H. Birgens ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Polyclonal Igg

scholarly journals Outcomes of patients with simultaneous diagnosis of chronic lymphocytic leukaemia/small lymphocytic lymphoma and multiple myeloma

2018 ◽  
Vol 185 (2) ◽  
pp. 347-350 ◽  
Author(s):  
Sikander Ailawadhi ◽  
Bhagirathbhai R. Dholaria ◽  
Sharad Khurana ◽  
Taimur Sher ◽  
Victoria Alegria ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Small Lymphocytic Lymphoma

Vaccine Measles Virus Has Therapeutic Potential In B Cell Malignancy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3757-3757
Author(s):  
Bella Patel ◽  
Dey Aditi ◽  
Ehsan Ghorani ◽  
Yogesh Malam ◽  
Steele Andy ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Intravenous Injection ◽  
Measles Virus ◽  
Lymphocytic Leukaemia ◽  
Intratumoral Injection ◽  
Scid Mice ◽  
Prolonged Survival ◽  
Tail Vein

Abstract Abstract 3757 Replicating viruses that selectively lyse transformed cells are attractive agents for cancer therapy. The vaccine strain of measles virus has proven oncolytic activity in various murine models of malignancy including myeloma and lymphoma. These pre-clinical reports of MV efficacy have led to advanced phase clinical trial. In the study here we investigate the anti-tumour potential of MV in 2 novel disease targets:- adult B lineage acute lymphoblastic leukaemia (ALL) and Chronic lymphocytic leukaemia (CLL) using in-vitro and in-vivo models. MV derived from the Edmonston strain genetically engineered to express GFP was used to infect primary ALL (n = 6) and chronic lymphocytic leukaemia (CLL, n = 7) cells. All CLL and ALL cells expressed the MV receptor CD46 and were efficiently infected by MV-GFP as indicated by quantitation of viral nucleocapsid mRNA by RQ-PCR and immunoblotting of viral proteins N and H. Large multinucleated syncytia, characteristic of MV- induced cytopathology, were found in all infected ALL cultures, by contrast syncitium formation was much less prominent in the infected CLL specimens. Despite this, both CLL and ALL cells were efficiently killed by MV-GFP, as characterised by viability assays and immunoblotting for PARP cleavage. To further probe the contribution of cell to cell fusion in MV induced oncolysis we used a relatively non-fusogenic strain of MV:- MV-Moraten to infect CLL and ALL specimens. As expected ALL and CLL cells infected with MV-Moraten lacked the typical features of MV induced cytopathology. Despite this cell viability was markedly reduced in both ALL and CLL cultures infected with MV-Moraten compared to uninfected controls suggesting that intracellular fusion might be dispensable for MV-induced oncolysis in our two models. To test whether MV had therapeutic efficacy in-vivo we established subcutaneous xenografts of pre-B ALL in CB17/SCID mice using the Nalm-6 cell line and administered 1 × 107 pfu of MV (n==12) or UV inactivated MV (n=12) intratumorally on 10 occasions. In vivo MV administration had striking antitumour activity resulting in complete resolution of 11/12 or regression (1/12) of established subcutaneous pre-B ALL tumours by week 4. In contrast, all UV-MV treated tumours progressed. The differences in tumour growth between the MV treated and UV-MV control groups was significantly different (p < 0.0001, Figure 1). To test for MV-induced oncolysis in a model more closely related to ALL in humans we used a disseminated pre-B ALL model established by tail vein injection of 1 × 106 Nalm-6 cells. 1 × 106 pfu of MV or UV-MV was administered by the intravenous route six times. Eleven of twelve mice receiving replication competent MV remain disease free whereas 6/7 mice receiving tail vein administered UV MV had become moribund by 67 days (Figure 2). Bone marrow examination of moribund mice revealed 52 – 99% of CD19+/CD10+ Nalm-6 cells present. Overall, our data suggest that both ALL and CLL are targets for MV-mediated lysis in vitro. The significant antineoplastic activity of MV against both subcutaneous and disseminated ALL xenografts holds great promise towards developing vaccine MV as a therapeutic tool in adult ALL. Figure 1 Regression of Nalm-6 subcutaneous xenografts in SCID mice after intratumoral injection of MV. Figure 1. Regression of Nalm-6 subcutaneous xenografts in SCID mice after intratumoral injection of MV. Figure 2 Prolonged survival of disseminated Nalm-6 SCID xenografts after intravenous injection of MV. Figure 2. Prolonged survival of disseminated Nalm-6 SCID xenografts after intravenous injection of MV. Regression of Nalm-6 subcutaneous xenografts in SCID mice after intratumoral injection of MV. Prolonged survival of disseminated Nalm-6 SCID xenografts after intravenous injection of MV. Disclosures: No relevant conflicts of interest to declare.

Novel Targeted Therapies and Their Impact on Survival from Multiple Myeloma (MM) and Chronic Lymphocytic Leukaemia (CLL) in the Real World

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3546-3546
Author(s):  
Alexandra G Smith ◽  
Timothy Bagguley ◽  
Eve Roman ◽  
Andy C Rawstron ◽  
James R Bailey ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukaemia ◽  
Combination Chemotherapy ◽  
Real World ◽  
Research Funding ◽  
Lymphocytic Leukaemia ◽  
Alkylating Agents ◽  
First Line ◽  
Time Periods ◽  
Line Chemotherapy

Abstract Introduction The treatment landscape for many mature B-cell malignancies is evolving rapidly, with patients and clinicians facing increasingly complex choices about therapeutic options that differ in efficacy, toxicity and cost. Accounting for around a quarter of all haematological cancer diagnoses, multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) are two conditions where increases in the number and combinations of potentially life-prolonging therapies has been particularly marked; ranging from the use of single alkylating agents to immunomodulatory drugs and proteasome inhibitors for MM, and combination chemotherapy, immuno-chemotherapy, novel monoclonal antibodies and tyrosine-kinase inhibitors (TKIs) for CLL. Contemporary data enabling the success of such therapeutic changes to be evaluated in the general patient population is, however, lacking. With centralized diagnostics and a unified clinical network covering a catchment population of 4 million, the UK's Haematological Malignancy Research Network (www.hmrn.org) was specifically established to provide timely real-world data to answer such questions; and findings from this unique population-based cohort are reported here. Methods Patients newly diagnosed 2004-13 with MM (n=2084) or CLL (n=1866) were followed-up until January 2016. Demographic, prognostic, first-line treatment and outcome data for the time-periods 2004-07, 2008-10 and 2011-15 were examined using standard statistical methods; relative survival (RS) was estimated using national life tables. Results The median age at diagnosis of MM was 73 years (17% <60 years); 39% of patients presented with an ISS score of III and 25% were asymptomatic (CRAB score 0). In total, 1514 (73%) patients received first-line chemotherapy either at diagnosis or as a consequence of disease progression. Regimens were classified by their main agent, and the therapy changes over the 11-year period are shown in Figure 1a; in 2004-07, 44% of treated patients received single-agent alkylating therapy, in 2008-10 76% were treated with combination immunomodulatory therapy and by 2011-15 this had increased to 92%. The 3-year overall survival (OS) and RS estimates for all patients combined were 45.9% (95% Confidence Interval 43.4-48.4) and 52.0% (49.1-54.8) respectively. Differences in outcome by treatment year are clearly evident (Figure 1b): 3-year RS 2004-07, 46.5% (41.8-51.2); 2008-10, 48.4% (43.5-53.2); and 2011-15, 62.1% (56.8-66.9). The improvement in survival for patients treated in 2011-15 compared to 2004-07 was confirmed by multivariate Cox regression (Hazard Ratio 0.65, 0.56-0.76). With a median diagnostic age of 71 years (18% <60 years); the majority of CLL patients had early-stage disease (BinetStage A, 78%). In total 547 patients were treated with first-line chemotherapy, with the regimen again changing over time (Figure 1c). Patients treated 2004-07 generally received single alkylating agents (56%) or combination chemotherapy (42%), by 2008-10 32% of patients had a monoclonal antibody added to chemotherapy (chemo-immunotherapy), increasing to 72% among those treated 2011-15. The 3-year OS and RS for all treated patients combined were 69.5% (65.3-73.3) and 80.3% (75.5-84.3) respectively. However, there was no incremental statistically significant change in 3-year RS (Figure 1d); 2004-07, 76.4% (65.2-84.4); 2008-10, 78.3% (69.8-84.6); and 2011-15 84% (76.3-89.4); and taking 2004-07 as the reference, the corresponding hazard ratios for the 3 time-periods were 1 (reference), 1.00 (0.78-1.37) and 0.79 (0.58-1.09). The cost implications of the changing treatment landscape are currently being examined, and by December 2016 the findings presented above will include more recently diagnosed patients (2014-15), which is particularly pertinent for CLL, where a step-change may have occurred due to the introduction of TKIs. Conclusions Our analyses confirm that first-line chemotherapy for MM and CLL is changing markedly; highlighting the importance of monitoring the impact of therapeutic change in a real-world setting. The improvement in MM survival currently contrasts with CLL, suggesting that encouraging results from clinical trials may not always translate directly into similar improvements at a population level. Clearly, additional analysis of data from patients diagnosed >2014 are required. Figure 1 Figure 1. Disclosures Smith: Novartis: Research Funding; Janssen-Cilag: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Cook:Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Glycomimetics: Consultancy. Patmore:Roche: Honoraria; Janssen Cilag: Honoraria.

Chronic Lymphocytic Leukaemia and Multiple Myeloma

2014 ◽  
Vol 17 (2) ◽  
pp. 135-139 ◽  
Author(s):  
N Pulenzas ◽  
◽  
A Porwit ◽  
KJ Craddock ◽  
N Thavarajah ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia

scholarly journals Derivatisation of Parthenolide to Address Chemoresistant Chronic Lymphocytic Leukaemia

2019 ◽  
Author(s):  
Xingjian Li ◽  
Daniel Payne ◽  
Badarinath Ampolu ◽  
Nicholas Bland ◽  
Jane T Brown ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Lymphocytic Leukaemia ◽  
Docking Studies ◽  
Secondary Amines ◽  
Drug Resistant ◽  
Resistant Disease ◽  
In Vivo Pharmacokinetics ◽  
Screening Cascade

A protocol for growing, extracting and derivatising parthenolide obtained from feverfew varieties is reported. Aminated parthenolide derivatives were prepared via 1,4-addition of primary or secondary amines utilising established and modified methods. The parthenolide derivatives’ drug-likeness properties were computed and they were screened for anti-leukaemic activity against the TP53-mutant, chemo-refractory, MEC1 chronic lymphocytic leukaemia (CLL) cell line. A screening cascade identified a small number of the most active compounds and their properties, including in vivo pharmacokinetics and in vitro hERG liability, were compared against DMAPT. This cascade culminated in the identification of a new compound with good anti CLL activity, with fewer drawbacks than some headline compounds from the literature and with utility against drug-resistant disease. Literature precedent and molecular docking studies support a multi-target-driven mode of action.<br>

scholarly journals EZN-2208 treatment suppresses chronic lymphocytic leukaemia by interfering with environmental protection and increases response to fludarabine

Open Biology ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 190262
Author(s):  
Roberta Valsecchi ◽  
Nadia Coltella ◽  
Daniela Magliulo ◽  
Lucia Bongiovanni ◽  
Lydia Scarfò ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chronic Lymphocytic Leukaemia ◽  
Environmental Protection ◽  
Lymphocytic Leukaemia ◽  
Therapeutic Approaches ◽  
Leukaemic Cells ◽  
Induced Apoptosis ◽  
Early Phases

The transcription factor HIF-1α is overexpressed in chronic lymphocytic leukaemia (CLL), where it promotes leukaemia progression by favouring the interaction of leukaemic cells with protective tissue microenvironments. Here, we tested the hypothesis that a pharmacological compound previously shown to inhibit HIF-1α may act as a chemosensitizer by interrupting protective microenvironmental interactions and exposing CLL cells to fludarabine-induced cytotoxicity. We found that the camptothecin-11 analogue EZN-2208 sensitizes CLL cells to fludarabine-induced apoptosis in cytoprotective in vitro cultures; in vivo EZN-2208 improves fludarabine responses, especially in early phases of leukaemia expansion, and exerts significant anti-leukaemia activity, thus suggesting that this or similar compounds may be considered as effective CLL therapeutic approaches.

The ATP-Competitive mTOR Inhibitor AZD8055 Reduces Cell Proliferation and Tumour Load in Chronic Lymphocytic Leukaemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5287-5287
Author(s):  
Emilio Cosimo ◽  
Anuradha Tarafdar ◽  
Ailsa Holroyd ◽  
Karen Dunn ◽  
Mark Catherwood ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mouse Model ◽  
Chronic Lymphocytic Leukaemia ◽  
Mtor Inhibitor ◽  
Lymphocytic Leukaemia ◽  
Lymphoid Organs ◽  
Tumour Burden ◽  
Drug Concentrations

Abstract Chronic lymphocytic leukaemia (CLL), often diagnosed in the elderly, is incurable with current therapeutic regimes. Recent studies demonstrate that the microenvironment within CLL patient lymphoid organs protects leukaemic cells from chemotherapy induced apoptosis. This highlights the need for novel therapies that can overcome such cytoprotective signals. Serine/threonine protein kinase mammalian target for rapamycin (mTOR) is a key regulator of cell survival and proliferation and is commonly deregulated in cancer. mTOR is active in two complexes mTORC1 and mTORC2. We demonstrate that mTORC1 and mTORC2 substrates, including S6 (pS6S235/236) and Akt (pAktS473) respectively, are active although differentially regulated, in CLL cells from distinct prognostic subsets ex vivo, which suggests that mTOR may represent a valid therapeutic target for CLL. Initial studies with everolimus, an analogue of rapamycin, showed only limited antitumor activity in recurrent/refractory CLL patients, possibly because mTORC1 inhibition releases the "brake" that normally active mTORC1 has on mTORC2, thus enabling mTORC2 mediated signalling. To test the impact of inhibiting both mTORC1 and mTORC2 on cell proliferation and survival, we treated primary CLL cells and an aggressive CLL mouse model with the novel ATP-competitive mTOR inhibitor AZD8055 in vitro and in vivo. CLL proliferation and mTORC1/2 activity were significantly reduced upon addition of AZD8055 to NTL-CD154/IL4 co-cultures, which mimic pro-proliferative conditions present in the microenvironment of lymphoid organs. However, in the same conditions use of AZD8055 did not induce apoptosis at clinically-achievable drug concentrations (<150 nM), likely due to ineffective inhibition of Mcl-1 upregulation mediated by the NTL-CD154/IL4 co-cultures. In contrast, B cell receptor (BCR)-mediated survival was inhibited by AZD8055 treatment, inducing significant levels of apoptosis, concomitant with a decreased Mcl-1 expression. These findings suggest that the BCR and CD154/IL4 mediated pathways regulate Mcl-1 expression by distinct mechanisms. In vivo studies using the PKCa-KR-induced CLL mouse model revealed that AZD8055 treatment efficiently reduced tumour burden in the organs (spleen and bone marrow) and blood of mice with established CLL. This was reflected by in vitro studies showing that use of AZD8055 increased apoptosis and reduced proliferation in mouse CLL cells. Overall these data indicate that AZD8055 inhibits CLL proliferation, in vitro and in vivo, and disrupts BCR mediated survival, by downregulating Mcl-1 protein levels. Therefore dual mTOR inhibitors through reduction of tumour burden, show promise as a future therapy for CLL. Disclosures No relevant conflicts of interest to declare.

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