INSIGHT IN THIS ISSUE. Thomas Kipps, MD, PhD receives the iwcll Binet-Rai Medal for Outstanding Contribution to CLL Research

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1 INSIGHT WINTER 2013 Developing a cure for blood-related cancers through human innovation. IN THIS ISSUE PAGE 2 LLS SCOR Grant Funded to Dr. Thomas Kipps to Continue Research in CLL UC San Diego Cancer Researchers Receive $4M CIRM Disease-Team Grant PAGE 3 Clinical Trials Update PAGE 4 New Weapons In The Fight Against CLL PAGE 7 The Mechanism of Action of Lenalidomide in CLL Richter s Syndrome Research Fund Thomas Kipps, MD, PhD receives the iwcll Binet-Rai Medal for Outstanding Contribution to CLL Research Thomas Kipps, MD, PhD, UC San Diego, Moores Cancer Center deputy director for research, was honored as one of two recipients of this year s Binet-Rai Medal for Outstanding Contribution to CLL Research. The award was presented at the annual biennial international workshop on chronic lymphocytic leukemia (iwcll) in Cologne, Germany in September. The Binet-Rai Medal was first given in 1999 to Kanti R. Rai, MD, and Jaques-Louis Binet for their description of the earliest CLL staging systems. Dr. Kipps has an international reputation for his work in cancer research, immunology and gene therapy. His laboratory research focuses on the immunobiology and genetics of human B-cell malignancies, with emphasis on CLL.

2 LLS SCOR Grant Funded to Dr. Thomas Kipps to Continue Research in CLL* Clinical Trials Update The UC San Diego Moores Cancer Center is leading the way for breakthroughs in therapeutic treatments for CLL. by Yadira Galindo The Leukemia & Lymphoma Society has awarded the Marshall A. Lichtman Specialized Center of Research (SCOR) grant to Thomas J. Kipps, MD, PhD, from the UC San Diego Moores Cancer Center, with a 5-year, $6.25-million grant. Kipps, Evelyn and Edwin Tasch Chair in Cancer Research and UC San Diego Moores Cancer Center deputy director for research, is one of four recipients of the Leukemia & Lymphoma Society s grant for the Specific Targets for Therapy of Patients with Chronic Lymphocytic Leukemia, a four-part project. The LLS recognizes but a few centers in the US that have an integrated research program leading to the potential development of new therapies for patients with blood cancers. Although the research proposal is directed toward improving therapy for patients with CLL, the research may impact other leukemias, lymphomas and cancers in general, said Kipps. The Leukemia & Lymphoma Society s Specialized Center of Research grant plays an important part in moving this research forward. Kipps and colleagues will work on developing new technologies that may lead to new therapies for patient with CLL. Two members of the National Academy of Science, Dr. Dennis Carson and Dr. Michael Karin, will lead projects. Dr. Kipps will also be working with Dr. William Wierda from MD Anderson Cancer Center to develop a chimeric antigen receptor (CAR) therapy for patients with CLL that will be able to activate T-cells to eradicate and attack CLL cells. *Originally published on the UC San Diego Health System Website UC San Diego Cancer Researchers Receive $4M CIRM Disease-Team Grant by Scott LaFee Researcher Thomas J. Kipps, MD, PhD, professor of medicine and deputy director of research operations at UC San Diego Moores Cancer Center, is principal investigator for one of six Disease Team awards approved December 12 by the governing board of the California Institute for Regenerative Medicine (CIRM). The grant, for $4.18 million, is part of a total $61 million awarded to fund work which promises to move therapies out of the lab and into clinical trials in patients. The funding was approved by the stem cell agency s governing board, the Independent Citizen s Oversight Committee (ICOC), at a two-day meeting in Los Angeles. The UC San Diego research team s goal is to develop new therapies that specifically target a protein found only on the surface of cancer stem cells. The protein, called Receptortyrosine-kinase-like Orphan Receptor 1 or ROR1, is produced in great amounts during embryogenesis, when it helps regulate early muscle and skeletal development. Later, ROR1 is turned off. Normal cells and tissues in adults do not typically express ROR1. But multiple types of cancer stem cells do, co-opting ROR1 to promote their growth and survival. In fact, Kipps and colleagues have found that exploitation of ROR1 by cancer cells is critical to the disease s spread or metastasis, estimated to be responsible for 90 percent of cancer-related deaths. With earlier CIRM funding, Kipps, fellow researcher Catriona Jamieson, MD, PhD associate professor of medicine and director of the stem cell research program at Moores Cancer Center and colleagues developed a humanized monoclonal antibody that specifically targets and inhibits the functioning of ROR1. Because this antibody does not bind to normal cells, it can serve as the magic bullet to deliver a specific hit to cancer stem cells, the researchers said in their CIRM proposal. They plan to conduct clinical trials with the antibody, first in patients with chronic lymphocytic leukemia, the most common type of blood cancer in the United States, to determine appropriate dose levels and safety protocols, followed by clinical trials involving patients with other types of cancer, including solid tumor types like breast and lung. We will investigate the potential for using this antibody to deliver toxins selectively to cancer stem cells, the researchers wrote. This selective delivery could be very active in killing cancer stem cells without harming normal cells in the body because they lack expression of ROR1. With this antibody, we can develop curative stem-cell-directed therapy for patients with any one of many different types of currently intractable cancers. The CIRM Disease Team awards are designed to encourage multidisciplinary teams of researchers from academic institutions, medical centers and industry to work together and to develop new treatments for a broad range of therapies. The recipients were selected from 14 applications, all of which were reviewed by an independent group of internationally renowned scientists. The grant brings the total CIRM funding for stem cell research at UC San Diego to bring UC San Diego s total to more than $ 137 million in CIRM funding since the first awards in *Originally published on the UC San Diego Health System Website Gilead GS-US Millennium C14012 A Phase 3, Randomized, Controlled Study Evaluating the Efficacy and Safety of GS-1101 (CAL-101) in Combination with Ofatumumab A Phase 3, Randomized, Two-Arm, Open-Label, Multicenter, International Trial of Alisertib (MLN8237) or Investigator s Choice (Selected Single Agent) Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma Infinity IPI A Phase 3 Study of IPI-145 versus Ofatumumab Patients with Relapsed or Refractory CLL or SLL Infinity IPI A Study of IPI-145 and Ofatumumab Patients with Relapsed or Refractory CLL or SLL perviously enrolled in Study IPI Angstrom A6-005 Genentech GO28667 Genentech ML29060 Gilead GS-US Gilead GS-US A Phase 2 Trial to Determine the Safety, Tolerability, and Efficacy of Å6, a CD44 Binding Peptide A Multicenter, Phase III, Open-Label, Randomized Study to Evaluate the Benefit of the Investigational Drug Plus Rituximab Compared with Bendamustine Plus Rituximab. A Phase Ib/II Study of GA101 in Combination with High-dose Methylprednisolone (HDMP) Disease or Unable/ Unwilling to Receive Chemotherapy A Phase 3, Randomized, Double-blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination with Either Rituximab or Chlorambucil A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS 1101) in Combination with Bendamustine and Rituximab Patients with CLL these trials can be found at as well as at UPCOMING TRIALS CURRENT New targeted therapies are being developed in CLL and other cancers. As we learn more about what makes CLL cells grow, we are better able to specifically target the tumor cells, killing the cancer, and sparing normal, healthy cells. Here at the UC San Diego Moores Cancer Center, we strive to bring the most promising agents and the most effective treatments to our patients on clinical trials. The following is a list of the current and upcoming clinical trials available to patients with CLL, and related blood cancers, at the UC San Diego Moores Cancer Center: TRIAL NAME DESCRIPTION ELIGIBILITY AbbVie M AbbVie M AbbVie M AstraZeneca AZD6738 Phase I study to evaluate the safety, pharmacokinetics, and preliminary efficacy of ABT-199 A Phase 1b Study Evaluating the Safety and Tolerability of ABT-199 in Combination with Rituximab A Phase 2 Open-Label Study of the Efficacy of ABT-199 in Subjects with Relasped or Refractory CLL Harboring the 17p Deletion A two-part Phase I, Open-label, Multi-center Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumour Activity of Multiple Ascending Doses of AZD6738 Patients with Relapsed CLL Patients with 17p deletion Relapsed or Refractory CLL with 11q deletion CRC022 A Two-Arm, Multi-Center trial of Revlimid(R) and Rituximab Genentech GP28331 Genentech GO28440 Gilead-GS-US Gilead GS-US MedImmune 1019 Pharmacyclics PCYC-1115-CA Pharmacyclics PCYC-1116-CA A Phase IB, Multicenter, Dose-Finding, and Safety Study of GDC-0199 (ABT-199) and GA101 A Phase 1B, Open-Label Study Evaluating the Safety and Pharmacokinetics of GDC-0199 (ABT-199) in Combination with Bendamustine/Rituximab (BR A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, Tolerability, and Pharmacodynamics of GS-9973 in Combination with Idelalisib A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of Two Different Dose Levels of Single-Agent GS-1101 (CAL-101) A Phase 2 Randomized Open-label Study of MEDI-551 and Bendamustine vs Rituximab and Bendamustine A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton s Tyrosine Kinase Inhibitor PCI versus Chlorambucil in Patients 65 Years or Older An Open-label Extension Study in Patients 65 Years or Older with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Who Participated in Study PCYC-1115-CA Patients with Relapsed or Refractory or Previously Untreated CLL or Previously Untreated CLL Patients with Relapsed or Refractory Hematologic Malignancies Patients with Previously Untreated CLL or SLL SBI Biotech G A Phase I Study of GNKG168 Administered by Intravenous Infusion UCSD A Phase II Pilot Translational Study of Sorafenib for the Treatment of Chronic Lymphocytic Leukemia Patients Celgene Connect CLL Registry The Chronic Lymphocytic Leukemia Disease Registry All Patients with CLL To find out more about leukemia/lymphoma clinical trials available at the UC San Diego Moores Cancer Center, please call (858) Additional information on all of

3 New Weapons In The Fight Against CLL 4 The UC San Diego Moores Cancer Center CLL program, under the leadership of Dr. Thomas Kipps, has been at the forefront of leading or conducting trials evaluating the clinical activity of novel drugs, such as obinutuzumab (Gazyva), ABT-199, ibrutinib (Imbruvica), idelalisib, sorafenib, AV-292, or Medi-551. Some of these new drugs are making news, as the data have shown promising clinical activity, allowing for their registration by the Federal Food and Drug Administration (FDA) as an agent that can be used in treating patients with CLL. This is providing us with an increased number of weapons with which to fight this disease, offering treatment alternatives to patients who either do not respond well or cannot tolerate currently approved treatments. These treatments can be divided into several categories; we will describe in this article some new treatments involving monoclonal antibodies, bcl-2 inhibitors, or kinase inhibitors. Monoclonal Antibodies Obinutuzumab (Gazyva ) Anti-CD20 Antibody Binding To CLL Cell We are happy to announce that obinutuzumab (Gazyva, formerly called GA101) was approved last month by the FDA for treatment of patients with CLL. Approval largely was based on the results from a clinical trial of patients over age 65 who had CLL along with other medical problems, which precluded them from even considering treatment with multi-drug chemotherapy regimens, such as fludarabine, cyclophosphamide, and rituximab (FCR). Patients were randomly assigned to take chlorambucil alone or chlorambucil plus either rituximab or obinutuzumab. Chlorambucil is an oral chemotherapy drug that is widely used in Europe, whereas the latter two drugs are monoclonal antibodies that target the protein CD20, which is found on leukemia cells. The results of this study showed that patients taking either monoclonal antibody plus chlorambucil fared significantly better than patients taking chlorambucil alone. Not only did patients taking the combined therapy have higher remission rates, but they also had longer intervals after completion of therapy before having to take additional treatments for CLL. Furthermore, patients treated with obinutuzumab (Gazyva ) and chlorambucil fared even better than patients treated with rituximab and chlorambucil. Moreover, roughly 20% of the patients treated with obinutuzumab (Gazyva ) and chlorambucil achieved a complete remission and lacked evidence for detectable leukemia cells in the marrow. Although follow-up period is limited, already there appears to be a significant increase in the time between completion of therapy and the requirement for additional therapy in the group that received obinutuzumab (Gazyva ) compared to the group that received rituximab. We know that obinutuzumab (Gazyva ) packs a punch. We have conducted some of the earliest trials of this antibody in the U.S., either as a single agent or combined with chemotherapy. In one study presented at the meeting of the American Society of Hematology (ASH meeting) held in December 2013, we found that 90% of patients treated with obinutuzumab (Gazyva ) and the drug bendamustine (Treanda ) had a favorable response to therapy, many patients achieving complete responses. In another study soon-to-be released, we found that patients treated with obinutuzumab (Gazyva ) alone also had good responses to therapy, outrivaling those we have observed with another anti- CD20 monoclonal antibody, ofatumumab. Antibody therapy generally is very well tolerated. The most notable side-effects that we have observed with either of these monoclonal antibodies are seen during the first infusion. During the first infusion of these monoclonal antibodies, patients can experience so called infusion reactions, which can involve chills, shortness of breath, changes in blood pressure, anxiety, or other reactions. We found that the intensity of these infusion-reactions can be mitigated by giving the patient pre-medications, such as anti-histamines, acetomenophen, and methylprednisolone. We also give the first infusion very slowly and with close supervision by our infusion nurses, who have been trained to spot such infusion reactions early and to stop the infusion and, if necessary, give some additional medicines that can treat the type of reaction observed. Once the patient has had one or two doses of the antibody, it is uncommon to see such reactions. Because obinutuzumab (Gazyva ) can kill leukemia cells quickly, we also have to remain vigilant for so-called tumor lysis, which can be potentially dangerous in patients with a high tumor burden. Some of the risks of tumor lysis can be mitigated by taking medicines, such as allopurinol, and by maintaining ample hydration prior to therapy. These side effects of obinutuzumab (Gazyva ) are similar to those seen with either rituximab or ofatumumab, although obinutuzumab appears most capable of lowering the leukemia cell counts quickly and thus might pose a higher risk for tumor lysis. Finally, it is important to monitor for any signs of infection and to start antibiotics if they are noted, as therapy of any sort can weaken further the resistance to infection, at least during and immediately after therapy. Furthermore, therapy can weaken an ongoing immune response to some viruses, such as the hepatitis virus. For this reason, patients are screened for evidence of hepatitis virus infection prior to treatment. Finally, there is a rare but reported complication of therapy with anti- CD20 monoclonal antibodies called progressive multifocal leukoencephalopathy (PML), which we have not observed in any of our patients treated at the Moores Cancer Center. This is a debilitating condition that may be related to an occult infection that gets out of control following treatment. Anti-ROR1 Monoclonal Antibodies (UC-961 or Cirmtuzumab) We also reported on our progress in developing antibodies against the ROR1 protein that is found on leukemia cells. Unlike CD20, ROR1 is not found on normal mature B cells or most other cells of healthy adults. This makes targeting ROR1 attractive in that it provides the potential for highly specific monoclonal antibody therapy for patients with CLL. At the ASH meeting in December 2013, we reported on developing UC-961, a humanized monoclonal antibody that could be suitable for use in clinical studies. We also reported on our work to couple the anti-ror1 monoclonal antibody with drugs that could then be delivered specifically to the leukemia cell. Such antibody-drug conjugates (or ADCs), could provide for selective treatment of only the leukemia with drugs that might not be tolerated well if given without the monoclonal antibody. Finally, we reported on work to develop a new mouse model for human CLL in which the mouse leukemia cells also express human ROR1. This model is allowing us to test the activity of these monoclonal antibodies against the leukemia in mice prior to testing them in clinical studies. The results of this work also were reported in a paper recently accepted for publication in the Proceedings of the National Academy of Sciences, USA. Bcl-2 Inhibitors ABT-199 ABT-199 is an orally active drug that can inhibit a protein called bcl-2. CLL cells have high-levels of bcl-2, which serves as a shield that protects CLL cells from dying. Inhibiting bcl-2 removes this shield, allowing CLL cells to die spontaneously or in response to anti-leukemia drugs or monoclonal antibodies. At the ASH meeting the results were presented of a study involving patients treated with ABT-199 at the Moores Cancer Center. Our patients generally tolerated this oral medication with few noted side effects. Taking this drug over the course of several months has resulted in complete remissions for some of our patients. Moreover, some of the treated patients did not have enlarged lymph nodes or detectable leukemia cells in the blood or marrow by sensitive testing, allowing us to consider stopping the medication. ABT-199 appears highly potent. This was dramatically demonstrated in two patients who were treated at other medical centers and who had very large tumor burdens, with lymph nodes that exceeded 11 cm in diameter (over 4 wide or the size of an orange). After initiating therapy with this drug, the leukemia cells in the lymph nodes underwent cell-death, releasing their contents, most notably potassium, into the blood. This unfortunately was too much for the body to take, resulting in a fatal tumor lysis syndrome. Although we have not experienced this at the Moores Cancer center, all studies with ABT-199 were placed on hold to change the protocol and to develop measures intended to safe-guard against such a catastrophe. Because these reactions are noted when patients when they first initiate therapy and are not likely to occur in patients who had been taking the drug, our patients were allowed to continue taking ABT-199 with close monitoring even when the trials here and elsewhere were closed to accepting new patients. Some of these patients eventually achieved a complete response and were found to lack evidence of CLL in their blood or bone marrow. After over a six-month hiatus, studies using ABR-199 have again re-opened with measures intended to mitigate the risk for serious tumor lysis syndrome. First we assess how much tumor burden there is, namely high, medium, or low. If the tumor burden is high, then the patient is assigned into the high-risk category, which requires closer monitoring. Currently, all patients who initiate therapy with ABT-199 are admitted to the hospital the night before to check the lab values and ensure ample hydration. Patients start a very low dose of the medicine in the morning of the next day. Blood samples are taken every couple of hours to monitor for the signs of tumor lysis, which may be asymptomatic. Patients are given treatment for tumor lysis, which if extensive, could involve use of hemodialysis. Fortunately such measures have not been necessary to date, as patients are started on a very low dose, which is increased gradually and under close supervision. Currently, we have several clinical trials open that are actively accruing patients. Some of these trials involve the use of ABT-199 alone or in combination with other drugs, such as the anti-cd20 monoclonal antibodies discussed in the preceding section. Clearly ABT-199 has anti-leukemia activity, which we hope to harness for the benefit of our patients without suffering any of the problems associated with tumor lysis. Kinase Inhibitors We have been investigating the activity of kinase inhibitors. These orally active drugs inhibit enzymes inside the leukemia cell called kinases, which are themselves enzymes that modify other proteins inside the leukemia cell after it has been stimulated to grow or stay alive. Such stimulation appears to occur in the lymph node, spleen, or marrow, where leukemia cells interact with accessory cells in the so-called leukemia microenvironment and receive growth and/or survival signals. By inhibiting the enzymes that modify other proteins in response to such signals, these kinase inhibitors can cut the Continued on next page 5

4 New Weapons In The Fight Against CLL Continued from previous page The Mechanism of Action of Lenalidomide in CLL 6 lines of communication so that the leukemia cell fails to get the signal to grow or survive. This can result in the death of the leukemia cell by neglect. Many of these drugs also interfere with the capacity of the leukemia cell to home to the lymph nodes, spleen, or marrow, causing the leukemia cells to empty out into the blood. Because of this, patients can experience a paradoxical rise in the white blood cell count upon initiating therapy. Fortunately, patients also experience concomitant shrinkage in the lymph nodes and spleen, resulting from the emptying out of leukemia cells from these sites into the blood. Over time the leukemia cell counts can decline over time, resulting in a therapeutic response. Most patients experience an excellent partial response to therapy that is long lasting, provided the patients continue taking the drug, which for many appears to be well tolerated. Ibrutinib (Imbruvica ) Ibrutinib (Imbruvica ) just recently was approved for treatment of patients with relapsed mantle cell lymphoma, a disease that shares many features in common with CLL. Ibrutinib (Imbruvica ) is an inhibitor of the kinase Bruton tyrosine kinase, or btk for short. Btk first was found in studies investigating children with severe combined immune deficiency who could not make any antibodies. Some were found to have a defect in btk, making it impossible for them to produce normal B cells. As such, btk plays an important role in the development of B cells. It is also is found inside leukemia B cells where it can help convey growth and survival signals to the CLL cell. Inhibiting this enzyme with ibrutinib is proving to be a highly effective means for reducing the size of the lymph nodes and in inducing excellent partial responses in patients. Such responses appear long-lived as long as patients continue taking the medication. Because of the results experienced to date on studies also involving patients treated here at the Moores Cancer Center, it is anticipated that ibrutinib soon will be approved by the FDA for use in the treatment of patients with CLL. At the ASH meeting in December 2013, data were presented on the studies involving ibrutinib when used alone or in combination with monoclonal antibodies, such as rituximab. Also, reports on the analysis of the few patients to date that have become resistant to ibrutinib were discussed at the ASH. These studies are helping us to understand how patients can become resistant to the effects of these drugs, allowing us to consider approaches that will mitigate the risk of developing such drug-resistance. Idelalisib (GS-1101 or CAL-101) Ibrutinib Also in the news at the recent ASH meeting was the drug idelalisib. Idelalisib is another small molecule that can inhibit a kinase called Phosphatidylinositide 3-kinase, or PI3K for short. As in the treatment with ibrutinib, patients often experience dramatic reductions in the sizes of the lymph nodes and spleen following initiation of treatment with idelalisib. A late-breaking abstract Idelalisib at the ASH reported on a study also conducted here at the Moores Cancer Center involving patients with relapsed disease who received therapy with either rituximab and idelalisib or rituximab and placebo. The results of the study found that patients taking rituximab and idelalisib had a superior response to treatment than patients treated with rituximab alone (placebo). Unlike the patients treated with rituximab alone, most of the patients treated with rituximab and idelalisib achieved an excellent partial response to therapy that appears long-lasting provided the patients continue treatment with idelalisib. It appears likely that such studies also will provide sufficient information to the FDA to judge whether it also should be approved for the treatment of patients with CLL. Other Kinase Inhibitors A number of other kinase inhibitors are also undergoing evaluation for their use in the treatment of patients with CLL. Reported at the ASH meeting in December 2013 were updated results from studies on several such orally active drugs, such as AV-292 (CC-292, a drug that can inhibit btk), or other inhibitors of PI3Ks, (e.g. IPI-145, AMG-319, etc.). It is uncertain how this will sort itself out. Some of these drugs might be better tolerated by some patients or useful in patients who develop resistance to other kinase inhibitors. A similar situation exists in the treatments available to patients with chronic myelogenous leukemia (or CML), who have the option for taking any one of a variety of drugs able to inhibit a key enzyme response for CML. Special Thanks To The Patients Who Participate In Clinical Trials The most important elements of any clinical study are the patients who participate in clinical trials. Because of clinical trials conducted here and elsewhere we have identified how best to use several new drugs that are sure to help other patients in need of therapy. However, it would not be possible to identify the merits of any drug without the people who volunteer to participate in clinical trials. Although each trial is intended to provide for an improvement in therapy, in each trial we are sailing in waters that have not been fully charted. Like the pilgrims who first settled in New England, clinical trial participants face the risk of the unknown to help find a better future for themselves and others. Without this intrepid spirit, we would not be able to offer the improvement in therapy that we currently enjoy or anticipate in the years ahead. For their courageous spirit, we owe the patients who participate on clinical trials our tremendous gratitude and appreciation. Dr. Jessie-Farah Fecteau, Ph.D., Assistant Project Scientist Lenalidomide is currently evaluated in clinical trials for treatment of patients with CLL and is showing promise. However, its mechanism of action on CLL cells is still unclear. Dr. Fecteau has been working to develop a culture system allowing for CLL cells to proliferate in vitro as a novel way to study this important question. She observed for the first time that lenalidomide inhibits the proliferation of CLL cells, what could account for the frequent partial and complete remissions observed in patients. Her work demonstrates that this inhibition of proliferation is mediated, at least in part, by the induction of a molecule called p21 WAF1/Cip1, which is a Richter s Syndrome Research Fund Donation by Joel Jastromb in memory of his sister Judy Silverman. Richter s syndrome (RS) refers to the development of aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Histologically, the majority of cases are diffuse large B-cell lymphoma (DLBCL), but with prognosis far inferior to typical cases of DLBCL. Though clinical trials conducted at our center have shown that intensive chemoimmunotherapy regimens such as oxaliplatin, fludarabine, ara-c, and ritxumab (OFAR) have improved response rates, the treatment of RS is still an unmet need. The Kipps laboratory has been involved in seminal studies of RS, including the first to establish the clonal relationship between CLL and RS lymphoma through primary structural analysis of immunoglobulin variable region genes (IgVH) (Cherepakhin et al, Blood 1993). Others have expanded on this to find risk factors like TP53 mutation, unmutated IgVH, and the VH4-39 gene in particular that may predispose a patient to RS. Preliminary genomic characterization has determined that alterations of micrornas involved in the MYC pathway occur more frequently with RS rather than de novo DLBCL (Scandurra et al, Hematol Oncol 2010). The MYC pathway has been implicated in many cancers, and results in unregulated expression of genes that promote B-cell proliferation. Multiple other signaling pathways interact with the MYC pathway as well. In non-rs CLL cases, our laboratory has been using c-myc gene expression as a marker of the activity of the Wnt signaling pathway, which has been a focus of investigation in our lab as potential target for new therapies (Lu, PNAS 2011). However, further studies are required to more fully understand the biological basis of RS, and to rationally design targeted therapies for it. cell cycle regulator naturally responsible to prevent cells from replicating. Since p21 WAF1/Cip1 induction was not only observed in vitro but also in samples from CLL patients treated with lenalidomide, it suggests it could be part of the mechanism in vivo. Her work also describes a strong association between the inhibition of proliferation and the levels of p21 WAF1/Cip1 induction by lenalidomide in vitro, what may be further developed into a pre-clinical testing platform to identify patients that would be most susceptible to benefit from treatment with lenalidomide. Her research was selected for presentation at the recent ASH meeting held in December, Through the Richter s Syndrome Research Fund, we propose the following: 1. We will design a RS specific database, building off of the infrastructure of the CLL Research Consortium (CRC) multi-institutional biorepository and database managed by Dr. Laura Rassenti. This will promote efficient collection of samples and corresponding clinical data from all cases of RS and allow evaluation of outcomes specific to various treatments and genetic and biologic characteristics, including IgVH mutation and VH gene expression. In addition, by comparing RS cases with the several thousands of patients in the CRC database, we will seek to understand why some CLL patients transform and others do not. 2. When available, we will perform next generation sequencing of a targeted panel of CLL and DLBCL related genes from pre and post transformation samples to determine the genetic events that may accompany RS. Ideally, paired samples would be analyzed, though analysis of only post-transformation samples may still be informative if there are recurring mutations. 3. We will perform gene expression analysis and subnetwork analysis of pathways implicated in transformation. 4. If we find that certain pathways are recurrently activated, then in vitro testing of targeted therapies can be performed, using viability or gene expression as markers of drug activity. Our group is currently investigating the activity of therapies against novel CLL targets including CD44, ROR1, and Wnt. The latter may be relevant, as MYC (shown by other groups to be implicated in RS) is one gene modulated by Wnt signaling (Lu, PNAS 2011). 7

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