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Chronic Lymphocytic Leukemia
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1:22 PM|Current Cancer Drug Targets (Volume 16 - Issue 8)|Labels: PI3K, CLL
There have been significant advances in our understanding of the pathogenesis of chronic lymphocytic leukemia (CLL) over the last decade, which has been accompanied by a rapid increase in treatment options. Inhibitors of BCRsignaling such as ibrutinib and idelalisib, and pro-apoptotic agents such as ABT- 199 have shown great promise in initial clinical trials and have been at the forefront of recent developments. However, despite the encouraging early data, these agents do not appear to represent a “cure” for CLL and mechanisms of resistance to these agents have already been identified. In light of these considerations there remains a need for alternative treatment strategies. Lenalidomide, a second-generation derivative of thalidomide, has been demonstrated to have significant clinical activity in CLL. Its effect appears to be mediated by reduction of CLL-cell proliferation, improvement of anti-tumor immune responses and reduction of pro-tumoral factors in the CLL microenvironment. This review discusses our current understanding of the mechanism of action of lenalidomide on both healthy cells and in CLL. It also summarises the published clinical trial experience with this drug, and proposes an ongoing role for this agent in the CLL armamentarium.
1:22 PM|Current Cancer Drug Targets (Volume 16 - Issue 8)|Labels: CLL
Chronic lymphocytic leukemia (CLL), a clonal expansion of B CD5+ cells, is the most common type of adult leukemia in western countries. The accumulation of neoplastic B-cells is primarily caused by prolonged life-span of these cells due to deregulation of apoptosis, and only marginally due to a higher proliferation rate. In spite of numerous reports characterizing particular mechanisms of B-CLL cell apoptosis, still relatively little is known about the complex regulation of this process. Therefore, more detailed research is required to understand the complicated mechanisms and regulatory processes of apoptosis in neoplastic Blymphocytes.
1:22 PM|Current Cancer Drug Targets (Volume 16 - Issue 8)|Labels: Bcr-Abl, CLL
Various signal transduction pathways have been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL), which is characterized by the progressive accumulation of monoclonal CD5+ B cells in the blood. B cell receptor (BCR) signaling appears to have a crucial role in disease onset and is thought to be induced by self or non-self-antigen recognition leading to chronic stimulation. Several of the kinases functioning downstream of the BCR are aberrantly expressed or constitutively activated in CLL. Yet, these kinases have additional roles, particularly in chemokine receptor signaling, which is essential for homing and survival of CLL cells in lymphoid organs, or in toll-like receptor signaling. Recently, small molecule inhibitors of kinases in the BCR signaling pathway have shown impressive anti-tumor activity in clinical trials. Remarkably, the observed durable responses in CLL patients were accompanied by transient increases in blood lymphocyte numbers, indicating the importance of these kinases in chemokine receptor signaling. In this review, we therefore highlight the role of BCR signaling and the important other associated signal transduction cascades for CLL cells and give an overview of novel agents that target these specific pathways and were shown to be successful for CLL treatment in clinical trials.
1:22 PM|Current Cancer Drug Targets (Volume 16 - Issue 8)|Labels: INT, CLL
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of neoplastic cells with the morphological appearance of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. CD49d, the α chain of the α4β1 integrin heterodimer, is one of the main interactors between CLL cells and accessory cells in the microenvironmental sites and one of the main predictors of overall survival. In particular, CD49d is known to play a pivotal role in mediating both cell-cell and cell-matrix interactions in CLL-involved tissues eventually delivering prosurvival signals and protecting CLL cells from drug-induced damages. Treatment strategies targeting the α4β1 integrin could represent an interesting option in CLL. In this context, the recombinant anti-CD49d antibody natalizumab demonstrated the potential to overcome stromal cell-induced resistance of B cell lymphoma cells against cytotoxic drugs and rituximab in vitro. Moreover, a specific interest for the CD49d molecule raises from the clinical activity of the recently proposed inhibitors of kinases downstream the BCR that has been recently related with the inside-out activation of the α4β1 integrin. In the review, we addressed in detail the role of CD49d in CLL cells, including clinical impact, relationship with specific cytogenetic features, and CD49d-dependent interactions in lymph node and bone marrow microenvironment responsible for growth- and survival- supporting signals, eventually influencing CLL prognosis and therapeutic options.
Friday, September 16, 2016 4:27 PM|John Wiley & Sons|JournalTOCs API - Journal of Clinical Pharmacology (94 articles)|Labels: Bcl-2, CLL, clinical trial, NHL

Pharmacokinetics of Venetoclax, a Novel BCL‐2 Inhibitor, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Non‐Hodgkin's Lymphoma

Journal of Clinical Pharmacology, Vol. , No. () pp. -
Venetoclax is a selective BCL‐2 inhibitor that is now approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors as well as low and high fat meals on venetoclax pharmacokinetics. Patients received a once daily venetoclax dose of 20 mg to 1200 mg. Pharmacokinetic parameters were estimated using non‐compartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low fat conditions and the mean terminal phase elimination half‐life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady‐state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low‐fat and high‐fat meals increased venetoclax exposures by approximately 4‐fold, relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60% while weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp‐up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax. This article is protected by copyright. All rights reserved

Thursday, September 15, 2016 6:45 AM|Gatȷen, M., Brand, F., Grau, M., Gerlach, K., Kettritz, R., Westermann, J., Anagnostopoulos, I., Lenz, P., Lenz, G., Hopken, U. E., Rehm, A.|Cancer Research current issue|Labels: CLL
Recruitment of tumor-associated macrophages and neutrophils (TAM and TAN) to solid tumors contributes to immunosuppression in the tumor microenvironment; however, their contributions to lymphoid neoplasms are less clear. In human chronic lymphocytic leukemia (CLL), tumor B cells lodge in lymph nodes where interactions with the microenvironment occur. Tumor cell homing stimulates proliferation, such that engagement of the B-cell receptor is important for malignant progression. In the Eμ-Tcl1 murine model of CLL, we identified gene expression signatures indicative of a skewed polarization in the phenotype of monocytes and neutrophils. Selective ablation of either of these cell populations in mice delayed leukemia growth. Despite tumor infiltration of these immune cells, a systemic inflammation was not detected. Notably, in progressive CLL, splenic neutrophils were observed to differentiate toward a B-cell helper phenotype, a process promoted by the induction of leukemia-associated IL10 and TGFβ. Our results suggest that targeting aberrant neutrophil differentiation and restoring myeloid cell homeostasis could limit the formation of survival niches for CLL cells. Cancer Res; 76(18); 5253–65. ©2016 AACR.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: CLL, MM, clinical trial, NHL
This phase II trial studies autologous peripheral blood stem cell transplant followed by donor bone marrow transplant in treating patients with high-risk hodgkin lymphoma, non-hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Autologous stem cell transplantation uses the patient's stem cells and does not cause graft-versus-host disease (GVHD) and has a very low risk of death, while minimizing the number of cancer cells. Peripheral blood stem cell (PBSC) transplant uses stem cells from the patient or a donor and may be able to replace immune cells that were destroyed by chemotherapy. These donated stem cells may help destroy cancer cells. Bone marrow transplant known as a nonmyeloablative transplant uses steam cells from a haploidentical family donor. Autologous peripheral blood stem cell transplant followed by donor bone marrow transplant may work better in treating patients with high-risk hodgkin lymphoma, non-hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: PI3K, CLL, clinical trial, NHL
This phase II trial studies how well ibrutinib or idelalisib works in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or non-Hodgkin lymphoma that is persistent or has returned (relapsed) after donor stem cell transplant. Ibrutinib and idelalisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Wednesday, September 14, 2016 4:21 PM|Fred Hutchinson Cancer Research Center/UW Medicine Cancer Consortium - Clinical Trials|Labels: ALL, CLL, clinical trial, NHL
This phase I/II trial studies the side effects and best dose of laboratory treated T cells to see how well they work in treating patients with chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia that have come back or have not responded to treatment. T cells that are treated in the laboratory before being given back to the patient may make the body build an immune response to kill cancer cells.
This study is evaluating the efficacy of obinutuzumab in combination with chlorambucil compared with ACP-196 in combination with obinutuzumab (Arm B) for the treatment of previously untreated chronic lymphocytic leukemia (CLL).
Wednesday, September 14, 2016 7:55 AM|SCHMIDT-WOLF, I. G. H., PLASS, C., BYRD, J. C., FREVEL, K., PIETSCH, T., WAHA, A.|Anticancer Research current issue|Labels: CLL

Background: Chronic lymphocytic leukemia (CLL) is characterized by a clonal accumulation of neoplastic lymphocytes, indicating disruption of apoptosis. Patients and Methods: Differential methylation hybridization analysis was performed to identify novel target genes silenced by CpG island methylation in patients with CLL. Results: Patched (PTCH), a tumor-suppressor gene, was found to be frequently methylated in CLL samples compared to samples derived from healthy individuals. De novo methylation of a CpG island region located upstream of PTCH exon 1 was confirmed by pyrosequencing in 17/37 (46%) of peripheral blood mononuclear cells of patients with CLL, but in none isolated from seven healthy individuals. No association was found between PTCH hypermethylation and currently used prognostic CLL factors. Conclusion: Our investigation suggests that epigenetic silencing of PTCH is a mechanism contributing to CLL tumorigenesis.

Wednesday, August 31, 2016 10:05 PM|Amin, N. A., Seymour, E., Saiya-Cork, K., Parkin, B., Shedden, K., Malek, S. N.|Clinical Cancer Research current issue|Labels: CLL

Purpose: Chronic lymphocytic leukemia (CLL)-associated gene mutations that influence CLL cell fitness and chemotherapy resistance should increase in clonal representation when measured before therapy and at relapse.

Experimental Design: To uncover mutations associated with CLL relapse, we have performed whole-exome sequencing in a discovery cohort of 61 relapsed CLL patients identifying 86 recurrently mutated genes. The variant allele fractions (VAF) of 19 genes with mutations in ≥3 of 61 cases were measured in 53 paired pre- and posttreatment CLL samples sorted to purity using panel-based deep resequencing or by droplet digital PCR.

Results: We identify mutations in TP53 as the dominant subclonal gene driver of relapsed CLL often demonstrating substantial increases in VAFs. Subclonal mutations in SAMHD1 also recurrently demonstrated increased VAFs at relapse. Mutations in ATP10A, FAT3, FAM50A, and MGA, although infrequent, demonstrated enrichment in ≥2 cases each. In contrast, mutations in NOTCH1, SF3B1, POT1, FBXW7, MYD88, NXF1, XPO1, ZMYM3, or CHD2 were predominantly already clonal prior to therapy indicative of a pretreatment pathogenetic driver role in CLL. Quantitative analyses of clonal dynamics uncover rising, stable, and falling clones and subclones without clear evidence that gene mutations other than in TP53 and possibly SAMHD1 are frequently selected for at CLL relapse.

Conclusions: Data in aggregate support a provisional categorization of CLL-associated recurrently mutated genes into three classes (i) often subclonal before therapy and strongly enriched after therapy, or, (ii) mostly clonal before therapy or without further enrichments at relapse, or, (iii) subclonal before and after therapy and enriching only in sporadic cases. Clin Cancer Res; 22(17); 4525–35. ©2016 AACR.

Thursday, August 18, 2016 10:00 AM|Oppermann, S., Ylanko, J., Shi, Y., Hariharan, S., Oakes, C. C., Brauer, P. M., Zuniga-Pflucker, J. C., Leber, B., Spaner, D. E., Andrews, D. W.|Blood LYMPHOID NEOPLASIA|Labels: Bcl-2, PI3K, CLL

Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients. An in vitro microenvironment model was developed with primary CLL cells that could be incorporated into an automated high-content microscopy-based screen of kinase inhibitors (KIs) to identify agents that may improve venetoclax therapy in a personalized manner. Marked interpatient variability was noted for which KIs were effective; nevertheless, sunitinib was identified as the most common clinically available KI effective in overcoming venetoclax resistance. Examination of the underlying mechanisms indicated that venetoclax resistance may be induced by microenvironmental signals that upregulate antiapoptotic Bcl-xl, Mcl-1, and A1, which can be counteracted more efficiently by sunitinib than by ibrutinib or idelalisib. Although patient-specific drug responses are common, for many patients, combination therapy with sunitinib may significantly improve the therapeutic efficacy of venetoclax.

Wednesday, August 17, 2016 1:39 PM|Faitschuk, E., Hombach, A. A., Frenzel, L. P., Wendtner, C.-M., Abken, H.|BLOOD First Edition Papers|Labels: CLL

Adoptive cell therapy of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR)-modified T cells targeting CD19 induced lasting remission of this refractory disease in a number of patients. However, the treatment is associated with prolonged "on-target off-tumor" toxicities due to the targeted elimination of healthy B cells demanding more selectivity in targeting CLL cells. We identified the IgM Fc receptor (FcμR), also known as the Fas apoptotic inhibitory molecule-3 (FAIM3) or TOSO, as a target for a more selective treatment of CLL by CAR T cells. FcμR is highly and consistently expressed by CLL cells; only minor levels are detected on healthy B cells or other hematopoietic cells. T cells with a CAR specific for FcμR efficiently responded towards CLL cells, released a panel of pro-inflammatory cytokines and lytic factors, like soluble FasL and granzyme B, and eliminated the leukemic cells. In contrast to CD19 CAR T cells, anti-FcμR CAR T cells did not attack healthy B cells. T cells with anti-FcμR CAR delayed outgrowth of Mec-1 induced leukemia in a xenograft mouse model. T cells from CLL patients in various stages of the disease, modified by the anti-FcμR CAR, purged their autologous CLL cells in vitro without reducing the number of healthy B cells which is the case with anti-CD19 CAR T cells. Compared with the currently used therapies, the data strongly imply a superior therapeutic index of anti-FcμR CAR T cells for the treatment of CLL.

Monday, August 15, 2016 12:15 PM|Speedy, H. E., Kinnersley, B., Chubb, D., Broderick, P., Law, P. J., Litchfield, K., Jayne, S., Dyer, M. J. S., Dearden, C., Follows, G. A., Catovsky, D., Houlston, R. S.|BLOOD First Edition Papers|Labels: CLL

Chronic lymphocytic leukemia (CLL) can be familial, however thus far no rare germline disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying four families where loss-of-function mutations in POT1 co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and ACD, part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, TERF2IP (p.Ala104Pro and p.Arg133Gln), in three CLL families. In a complementary analysis of 1,083 cases and 5,854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P=0.009). This study further highlights telomere dysregulation as a key process in CLL development.

Friday, July 22, 2016 8:03 AM|Amin, N. A., Seymour, E., Saiya-Cork, K., Parkin, B., Shedden, K., Malek, S. N.|Clinical Cancer Research Online First Articles|Labels: CLL

Purpose: Chronic lymphocytic leukemia (CLL)-associated gene mutations that influence CLL cell fitness and chemotherapy resistance should increase in clonal representation when measured before therapy and at relapse.

Experimental Design: To uncover mutations associated with CLL relapse, we have performed whole-exome sequencing in a discovery cohort of 61 relapsed CLL patients identifying 86 recurrently mutated genes. The variant allele fractions (VAF) of 19 genes with mutations in ≥3 of 61 cases were measured in 53 paired pre- and posttreatment CLL samples sorted to purity using panel-based deep resequencing or by droplet digital PCR.

Results: We identify mutations in TP53 as the dominant subclonal gene driver of relapsed CLL often demonstrating substantial increases in VAFs. Subclonal mutations in SAMHD1 also recurrently demonstrated increased VAFs at relapse. Mutations in ATP10A, FAT3, FAM50A, and MGA, although infrequent, demonstrated enrichment in ≥2 cases each. In contrast, mutations in NOTCH1, SF3B1, POT1, FBXW7, MYD88, NXF1, XPO1, ZMYM3, or CHD2 were predominantly already clonal prior to therapy indicative of a pretreatment pathogenetic driver role in CLL. Quantitative analyses of clonal dynamics uncover rising, stable, and falling clones and subclones without clear evidence that gene mutations other than in TP53 and possibly SAMHD1 are frequently selected for at CLL relapse.

Conclusions: Data in aggregate support a provisional categorization of CLL-associated recurrently mutated genes into three classes (i) often subclonal before therapy and strongly enriched after therapy, or, (ii) mostly clonal before therapy or without further enrichments at relapse, or, (iii) subclonal before and after therapy and enriching only in sporadic cases. Clin Cancer Res; 1–11. ©2016 AACR.

Wednesday, June 15, 2016 10:56 AM|Almeida, A. R., Correia, D. V., Fernandes-Platzgummer, A., da Silva, C. L., Gomes da Silva, M., Anjos, D. R., Silva-Santos, B.|Clinical Cancer Research Online First Articles|Labels: TNF, CLL

Purpose: The V1+ subset of T lymphocytes is a promising candidate for cancer immunotherapy but the lack of suitable expansion/ differentiation methods has precluded therapeutic application. We set out to develop and test (preclinically) a V1+ T cell-based protocol that is GMP-compatible and devoid of feeder cells for prompt clinical translation. Experimental design: We tested multiple combinations of clinical-grade agonist antibodies and cytokines for their capacity to expand and differentiate (over 2-3 weeks) V1+ T cells from the peripheral blood of healthy donors and chronic lymphocytic leukemia (CLL) patients. We characterized the phenotype and functional potential of the final cellular product, termed Delta One T (DOT) cells, in vitro and in vivo (xenograft models of CLL). Results: We describe a very robust two-step protocol for the selective expansion (up to 2,000-fold in large clinical-grade cell culture bags) and differentiation of cytotoxic V1+ (DOT) cells. These expressed the Natural Cytotoxicity Receptors (NCRs), NKp30 and NKp44, which synergized with the T-cell receptor to mediate leukemia cell targeting in vitro. When transferred in vivo, DOT cells infiltrated tumors and peripheral organs, and persisted until the end of the analysis without showing signs of loss-of-function; indeed, DOT cells proliferated and produced abundant IFN- and TNF-α, but importantly no IL-17, in vivo. Critically, DOT cells were capable of inhibiting tumor growth and preventing dissemination in xenograft models of CLL. Conclusions: We provide a clinical-grade method and the preclinical proof-of-principle for application of a new cellular product, DOT cells, in adoptive immunotherapy of CLL.

Background: Treatment recommendations in chronic lymphocytic leukemia (CLL) are based upon selected, otherwise healthy study populations mostly under 72 years of age. The Project group Internistic Oncology (PIO) embarked on an analysis of the ‘real-world’ safety and efficacy of bendamustine with and without rituximab in unselected outpatients. Patients and Methods: A multicenter, open-label, prospectively stratified, retrospective study was conducted to determine routine feasibility, toxicity, and response rates obtained by bendamustine with and without rituximab in a random population of mostly elderly patients with CLL. Records were obtained from 775 patients with CLL from 60 private medical oncology practices. Informed consent was obtained prior to study participation. The median observation time was 28 months. Patients were stratified according to age, and treatment. Response criteria and statistics followed international guidelines adopted by the "German Chronic Lymphocytic Leukemia Study Group". Results: Overall, 57.5% of patients were over 70 (range=36-95) years old. Eastern Cooperative Oncology Group performance status and age influenced the total dose given, decreasing by 20% between ECOG 0 and 3, and by 15% above 80 years old. Response rates did not differ between the ages of 60 to 80 years, with an overall remission rate for bendamustine of 83%, and for the combination therapy of 89%, decreasing above the age of 80 years. Febrile neutropenia occurred in 25% of 775 patients, and grade 3 or 4 non-hematological adverse events in 9.55% (n=74), not interfering with the treatment. Conclusion: Bendamustine with and without rituximab was associated with high activity and tolerability, irrespective of age and risk factors. The median overall survival was 64 months with a 3-year survival rate of 72%; progression-free survival was 30.6 months, and the 3 year PFS was 43%. The good tolerability and feasibility of bendamustine with and without rituximab, in particular for the elderly population with CLL argues for it being a safe outpatient treatment.

NORTH CHICAGO, Ill., May 9, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) updated the IMBRUVICA® (ibrutinib) Prescribing Information (PI) to include new data from two Phase 3 trials supporting its expanded use in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).[1] The label now includes overall survival (OS) results in previously untreated CLL/SLL patients from the Phase 3 RESONATETM-2 (PCYC-1115) trial.

Tuesday, April 19, 2016 3:08 PM|Newsmax Health - FDA Approved Drugs (RSS 2.0)|Labels: CLL, regulatory
The FDA has approved a new drug, Venclexta, for the treatment of chronic lymphocytic leukemia (CLL).
Monday, February 8, 2016 4:00 PM|Seminars in Oncology|MedWorm: Cancer Therapy|Comments|Labels: CLL
Adoptive cell immunotherapy for the treatment of chronic lymphocytic leukemia (CLL) has heralded a new era of synthetic biology. The infusion of genetically-engineered, autologous chimeric antigen receptor (CAR) T cells directed against CD19 expressed by normal and malignant B cells represents a novel approach to cancer therapy. The results of recent clinical trials of CAR T cells in relapsed and refractory CLL have demonstrated long-term disease-free remissions, underscoring the power of harnessing and re-directing the immune system against cancer. (Source: Seminars in Oncology)