Showing papers by "Jan A. Burger published in 2009"
TL;DR: A paradigm shift in the treatment of selected B-cell malignancies is anticipated, moving from targeting primarily the malignant cells toward combining cytotoxic drugs with agents that interfere with the microenvironment's proactive role.
543 citations
TL;DR: Because CXCR4 plays a key role in cross-talk between leukemia cells (and a variety of other tumor cells) and their microenvironment, cancer treatment may become the ultimate application of CX CR4 antagonists.
Abstract: Hematopoietic and epithelial cancer cells express CXCR4, a seven-transmembrane G-protein-coupled chemokine receptor. Stromal cells within the bone marrow microenvironment constitutively secrete stromal cell-derived factor-1 (SDF-1/CXCL12), the ligand for CXCR4. Activation of CXCR4 induces leukemia cell trafficking and homing to the marrow microenvironment, where CXCL12 retains leukemia cells in close contact with marrow stromal cells that provide growth and drug resistance signals. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogs, can disrupt adhesive tumor-stroma interactions and mobilize leukemia cells from their protective stromal microenvironment, making them more accessible to conventional drugs. Therefore, targeting the CXCR4-CXCL12 axis is a novel, attractive therapeutic approach that is explored in ongoing clinical trials in leukemia patients. Initially, CXCR4 antagonists were developed for the treatment of HIV, where CXCR4 functions as a co-receptor for virus entry into T cells. Subsequently, CXCR4 antagonists were noticed to induce leukocytosis, and are currently used clinically for mobilization of hematopoietic stem cells. However, because CXCR4 plays a key role in cross-talk between leukemia cells (and a variety of other tumor cells) and their microenvironment, cancer treatment may become the ultimate application of CXCR4 antagonists. Here, we summarize the development of CXCR4 antagonists and their preclinical and clinical activities, focusing on leukemia and other cancers.
453 citations
TL;DR: Common denominators for CLL cocultures with MSCs are defined to provide a reliable, validated tool for future investigations into the mechanism of MSC-CLL cross talk and for drug testing in a more relevant fashion than the commonly used suspension cultures.
341 citations
TL;DR: It is suggested that BCR activation favors CLL cell homing, retention, and survival in tissue microenvironments, providing an explanation for the activity of R406 in patients with CLL.
255 citations
TL;DR: It is demonstrated that MCL cells adhere and spontaneously migrate beneath MSCs in a CXCR4- and VLA-4-dependent fashion (pseudoemperipolesis).
174 citations
TL;DR: It is demonstrated that AT-101 induces apoptosis in CLL B cells and overcomes microenvironment-mediated resistance while sparing normal stromal cells.
152 citations
TL;DR: The data demonstrate that p110alpha inhibitors antagonize stromal cell-derived migration, survival, and drug-resistance signals and therefore provide a rational to explore the therapeutic activity of these promising agents in CLL.
146 citations
TL;DR: Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TKIs and can help in therapy selection, and more complex prognostic models will be required for advanced stages of disease.
133 citations
TL;DR: In conclusion, CFAR is an active frontline regimen for high-risk CLL and may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation.
101 citations
TL;DR: The European LeukemiaNet recommendations for chronic myeloid leukemia (CML) defined a group of patients with suboptimal response to imatinib as a group, but the significance of this response was not well defined.
Abstract: Imatinib is currently standard therapy for patients with chronic myeloid leukemia (CML) in early chronic phase. The most recent update of the International Randomized Study of Interferon and STI571 (IRIS) trial demonstrated that 82% of patients achieve a complete cytogenetic response (CCyR), with most responses being durable.1 After 6 years of follow-up, the event-free survival rate is 83%, and that for survival free from transformation is 93%. Despite these favorable results, there is a subset of patients who do not achieve the optimal response and may eventually require additional therapy. A panel of experts, on behalf of the European LeukemiaNet (ELN), recently proposed definitions for the criteria of what is considered failure to therapy.2 These definitions became particularly relevant as new tyrosine kinase inhibitors were developed for the treatment of patients with resistance or intolerance to imatinib therapy. Two of these agents, nilotinib and dasatinib, have demonstrated efficacy in the management of patients who meet these definitions of failure after imatinib therapy.3,4 In addition, the ELN recognized the presence of a group of patients with a response that the group considered suboptimal. Similar to the definition for failure, the definition for suboptimal response was based on the level of response achieved at different time points. Patients with suboptimal response were described as a group of patients who could still derive substantial benefit from continuing therapy with imatinib, but it was noted that the long-term outcome of such treatment was not likely to be as favorable as in responders at the same time point.2 However, the long-term outcome of patients who meet these definitions of suboptimal response is not yet well known.
Thus, we conducted an analysis of patients receiving imatinib as initial therapy for early chronic-phase CML to determine the frequency with which suboptimal response occurs and the long-term outcome of patients with such response.
94 citations
TL;DR: Identifying pretreatment patient characteristics associated with CR, TTF, and OS establishes a baseline to compare and incorporate new prognostic factors and may help patients and clinicians in decision making as well as facilitate clinical research through design and analyses of clinical trials.
Abstract: Purpose Response to front-line treatment and subsequent clinical course for patients with chronic lymphocytic leukemia (CLL) are heterogeneous. Identifying pretreatment patient characteristics or prognostic factors associated with clinical outcomes is important for counseling patients, conducting clinical research, and evaluating trial results. Patients and Methods We evaluated the pretreatment characteristics of 595 previously untreated patients who had National Cancer Institute Working Group indications to initiate front-line therapy for predictors of complete response (CR), time to treatment failure (TTF), and overall survival (OS). Multivariable models were developed for all three end points. Results CR is an important treatment end point correlated with longer TTF and OS. In this retrospective analysis, front-line treatment regimen was a significant independent predictive factor for all three end points; chemoimmunotherapy was the superior treatment regimen. Considering front-line treatment regimen, ...
TL;DR: Targeting the CXCR4–CXCL12 axis is a novel, attractive therapeutic approach in SCLC and the current status of the preclinical and clinical development of CX CR4 antagonists is summarized.
Abstract: Small-cell lung cancer (SCLC) is a particularly aggressive form of lung cancer characterized by early and widespread metastases and the ability to rapidly develop resistance against chemotherapeuti...
TL;DR: On March 20, 2008, bendamustine HCl (Treanda, Cephalon, Inc.) was approved by the U.S. Food and Drug Administration for treatment of chronic lymphocytic leukemia (CLL).
Abstract: On March 20, 2008, bendamustine HCl (Treanda, Cephalon, Inc.) was approved by the U.S. Food and Drug Administration (FDA) for treatment of chronic lymphocytic leukemia (CLL). This approval was based on a randomized, multicenter trial comparing the test drug ( n = 162) to chlorambucil ( n = 157) as a
TL;DR: To the editor: Despite major improvements of treatments, chronic lymphocytic leukemia (CLL) remains an incurable disease and one of the reasons is survival signals from the microenvironment.
TL;DR: Twenty patients with newly diagnosed Ph+ ALL receive dasatinib for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate, and 22 have achieved complete molecular remission (CMR) and another 8 have achieved a major (but not complete) molecular response (MMR).
TL;DR: A long-term follow-up of 80 pts who received CFAR as salvage therapy demonstrated favorable responses in pts younger than 70 years with F-sensitive disease who had 5 or fewer prior therapies and CFAR is a good salvage regimen for pts who have received prior FC or FN based regimen.
TL;DR: A phase II study of vorinostat followed by Ida and ara-C in pts with AML or MDS, designed to stop early based on a composite endpoint and predefined stopping rules of progression free survival (PFS), toxicity and response rates compared to standard IdA and Ara-C (IA) combination at MD Anderson.
TL;DR: The efficacy and safety of the combination of GO with decitabine, another hypomethylating agent in AML and myelodysplastic sydromes (MDS) is investigated, with 33 patients with previously untreated AML or MDS enrolled in the trial.
TL;DR: Evidence is provided that an “adhesive” phenotype of the eukemia cells, characterized by higher surface expression of CXCR4 hemokine receptors, VLA-4 integrins, and the focal adhesion inase (FAK) is associated with poor outcome in patients with AML.
TL;DR: In conclusion, INCB018424 has significant activity in sAML and CMML associated with JAK2 V617F mutation and clinical studies combining it with chemotherapy in s AML are warranted.
TL;DR: The maintenance phase was extended to 30 months with additional intensifications owing to late relapses after completion of POMP therapy, and rituximab improved outcome compared to historical experience with hyper-CVAD alone.
TL;DR: Adhesion of chronic lymphocytic leukemia (CLL) cells to stromal cells in the marrow and secondary lymphoid tissues confers drug resistance and may account for survival and maintenance of residual CLL cells after conventional treatments, paving the way to relapses.
Journal Article•
TL;DR: A review of the current understanding of the molecular interactions that underlie CLL cell trafficking and some of the promising approaches underway to target these pathways therapeutically in CLL is presented in this paper.
Abstract: Chronic lymphocytic leukemia (CLL) is an indolent lymphoproliferative disorder characterized by both circulating peripheral disease as well as involvement of the lymph nodes and bone marrow. Increasing evidence suggests that the stromal microenvironment provides anti-apoptotic and pro-survival signals to CLL cells, and may contribute significantly to resistance to a wide variety of treatments. Our understanding of the complex interactions involved in CLL cell trafficking continues to grow. Chemokines and corresponding chemokine receptors are key factors for organizing CLL cell trafficking and homing and the complex cellular interactions between CLL and accessory cells. Important chemokines include CCL3, CCL4, and CCL22, which are released by CLL cells, and CXCL12, CXCL13, CXCL9, 10, 11, CCL 19, and CCL21, which are constitutively secreted by various stromal cells. Integrins such as VLA-4 (CD49d) as well as selectins and CD44 also likely play a role in directing CLL cell migration within the tissue microenvironments. Data are also emerging that other molecules such as MMP-9 and cytoskeletal proteins also contribute to CLL cell trafficking. Though this interplay is complex, it is critical that we improve our understanding of CLL cell trafficking to facilitate the development of novel therapies that target these pathways. Several drugs in clinical development, such as CXCR4 antagonists and PI3K, Btk, and Syk inhibitors appear to modulate CLL cell trafficking and CLL-stroma interactions. Here, we review the current understanding of the molecular interactions that underlie CLL cell trafficking and we highlight some of the promising approaches underway to target these pathways therapeutically in CLL.
TL;DR: Previously treated patients with 17p del have extremely poor prognosis and outcomes based on low response rate to salvage treatment, short time to treatment failure and overall survival, including with alemtuzumab-containing treatment.
TL;DR: A limited multivariate analysis identified the independent prognostic influence of B2M on survival and confirmed the prior observations in a larger more homogenous population of de novo ALL treated with intensive chemotherapy.
TL;DR: It is found that MSC can induce and regulate TCL1 expression in CLL, suggesting that the microenvironment plays an even greater role in the pathogenesis of this disease than previously recognized.