Research Publications – Page 20 – New Developments in Lymphoma

ASCO 2014: Promising Results with Lenalidomide Plus Rituximab for Patients with Previously Untreated Follicular Lymphoma

On May 30, 2014, at the 50^th annual meeting of the American Society of Clinical Oncology (ASCO) I had the pleasure of presenting updated, preliminary results from the multi-center, national cooperative group CALGB 50803 phase II trial of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma. This trial represents an important step as we move away from traditional cytotoxic chemotherapy towards a future with novel, better-tolerated regimens for treatment of patients with follicular lymphoma.

Patients in this trial received oral lenalidomide on days 1-21 of each 28-day cycle for a total of twelve cycles plus four weekly infusions of rituximab during cycle 1 followed by four additional infusions at the start of cycles 4, 6, 8, and 10. The primary objective was to measure the patient’s complete response rate. Overall, we found that the regimen was well tolerated, with very low rates of infection or other significant adverse events. Preliminary data from patients evaluable for complete response suggests that over 90% of patients responded, including roughly 70% complete responses. At two years, 89% of patients continued to respond. These efficacy data are consistent with what is typically seen with cytotoxic chemotherapy-based regimens and they support further evaluation of lenalidomide plus rituximab compared to chemotherapy in an ongoing phase III trial.

AACR 2014: MALT1 Inhibition has Potential for Rational Combinatorial Therapy of ABC-DLBCL

By Lorena Fontan Gabas, PHD

MALT 1 activity is a compelling therapeutic target for treatment of activated B-cell like diffuse large B-cell lymphoma (ABC-DLBCL), as the disease is biologically dependent on the protein. During, the 2014 meeting of the American Association for Cancer Research, the Melnick Lab, shared their recent findings regarding the potential of MALT1 as an ABC-DLBCL inhibitor. The MALT1 paracaspase plays a critical role in the proliferation and survival of ABC-DLBCL, the most chemo-resistant form of DLBCL. MALT1 mediates activation of the B-cell receptor (BCR) downstream of somatic mutations in signaling components such as: CD79, CARD11 or MYD88, leading to chronically activated NF-κB. MALT1 is the effector enzyme of the CARD11/Bcl10/MALT1 signalosome, a massive, high order structure that functions as an amplifier of BCR signaling to NF-κB.

Given that multiple pathways contribute to ABC-DLBCL pathogenesis we hypothesized that MALT1 inhibitors would be best utilized with combinatorial therapy regimens. Accordingly, MI-2 strongly enhanced the activity of CHOP chemotherapy drugs against ABC-DLBCL cells, especially those most resistant to doxorubicin. As BCR signaling forms a complex network of signaling molecules beyond NF-κB, MALT1 targeted therapy was strongly enhanced by small molecules that affect other branches of this pathway, such as PI3K inhibitors (e.g. BKM120), although this effect seemed to be obliterated by genetic lesions such us presence of CARD11 mutation. Finally MI-2 synergized with small molecules such as BH3 mimetics (most notably ABT-737) that target fundamental complementary survival pathways to BCR signaling in ABC-DLBCLs.

In summary, we were able to identify the first specific MALT1 inhibitor drug and demonstrated a promising role for MALT1 targeted therapy as an anchor of rational combinatorial therapy against ABC-DLBCL.

AACR 2014: How deregulation of histone methyltransferases drive malignant transformation of B-cells

By Wendy Béguelin, PhD

DLBCLs are a heterogeneous group of diseases initiating from germinal center (GC) B cells. GC B cells are uniquely specialized to tolerate rapid proliferation, and physiological genomic instability, thus generating a diverse set of clones of cells encoding high affinity antibodies. The GC phenotype poses a significant risk in the malignant transformation to B cells, with epigenetic regulatory complexes playing a critical role in lymphomagenesis. During a symposium session at the recent American Association for Cancer Research, the Melnick Lab, reported how the deregulation of histone methyltransferases causes the malignant transformation of B-cells.

EZH2, which epigenetically silences genes through histone 3 lysine 27 methylation is upregulated in normal and malignant GC B cells. EZH2 is often affected by gain of function mutations in lymphomas that alter its enzymatic specificity. EZH2 mediates GC formation by transiently suppressing checkpoint genes and terminal differentiation genes through formation of bivalent chromatin domains. EZH2 somatic mutations induce germinal center hyperplasia and malignant transformation, and cooperate with other oncogenes such as BCL2. EZH2 specific inhibitors can suppress the growth of GC derived lymphoma cells in vitro and in vivo, and are currently being evaluated in early phase clinical trials. DNA methyltransferase 1 (DNMT1) is required for B cells to form GC, and GC B cells display cytosine methylation redistribution as compared to resting or naïve B cells. DLBCL in turn exhibit prominent and heterogeneous disruption of cytosine methylation distribution, with specific and distinct DNA methylation profiles occurring in different lymphoma subtypes.

Epigenetic heterogeneity is associated with unfavorable outcomes in B-cell lymphoma. This suggests that epigenetic diversity may provide a survival advantage to lymphoma cell populations. DNA methyltransferase inhibitors can reprogram lymphoma cells to develop a form of incomplete senescence that allows for a more complete response to chemotherapy treatment. These DNA methyltransferase inhibitors can be safely combined with standard lymphoma therapies for first line treatment of patients with DLBCL. However, further research will be required to confirm this targeted therapy approach for clinical use in patients.

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