HIGHLIGHTS Winter 2015 FOR DONORS

The Leukemia & Lymphoma Society (LLS) exists to find cures and ensure access to treatments for all blood patients. Because there are no means of preventing or screening for most blood , we focus on finding cures. LLS values your generosity because progress happens when smart money and smart research meet.

Harnessing A Natural Process to Kill Cancer

o make room for new cells, the body tells billions of Tunwanted cells each day to die in a natural biological BH3-only proteins process known as apoptosis. If blood cells fail to die when signal damage they should, they can develop into leukemia, lymphoma or myeloma. A team of researchers led by Jerry Adams, PhD, Pro-survival Bcl-2 proteins at the Walter and Eliza Hall Institute of Medical Research keep Bax and Bak in check in Melbourne, Australia has received extensive funding from LLS over a dozen years to investigate how impaired Bax and Bak apoptosis contributes to blood cancers and becomes a switch on apoptosis machinery major barrier to therapy. The key regulators of cell death in lymphoma are interacting proteins of the B-cell lymphoma 2 family (BCL-2). Within that family, BH3-only proteins initiate apoptosis by transmitting signals of cellular damage and Adams’ team member, Andrew Roberts, MB, MS, PhD, inactivating the pro-survival function of other proteins. conducted a Phase 1 trial of ABT-199 as a single agent for Tumors often use pro-survival proteins to resist death. To treatment-resistant chronic lymphocytic leukemia (CLL) overwhelm those proteins and switch on the apoptosis patients. It showed marked falls in tumors in the blood and machinery, the Adams team developed BH3 mimetics, lymph nodes and reduced infiltration to the bone marrow small molecules that are capable of mimicking the BH3- in 90 percent of the patients. This substantial activity only proteins. against CLL is highly encouraging and ABT-199 is being With earlier LLS funding, the Adams team collaborated tested in Phase 1, 2 and 3 trials as a monotherapy and in with Genentech and Abbott (now known as AbbVie) to test combinations with rituximab and bendamustine. Data from a first-generation compound that targeted three pro-survival a Phase 2 trial in relapsed CLL patients are due in coming proteins in the BCL-2 family. It showed promising clinical months and could be submitted to the FDA for review. results but caused a severe decrease of platelets in the blood, To explore the full potential of the apoptotic machinery which limited dosing. The team continued the collaboration to kill tumor cells, LLS is also funding other researchers, to help develop a more specific and potent mimetic known including Anthony Letai, MD, PhD, at Dana Farber as ABT-199 that spares the platelets. Cancer Institute, studying non-Hodgkin lymphomas.

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Right Patient, Right New AML Therapy Therapy in HCL to Watch For

airy cell leukemia (HCL), a slow-growing blood IDH 1 and 2 (isocitrate dehydrogenase) are cancer that mostly affects middle-aged adults, enzymes that are mutated in many blood cancers. H IDH proteins normally break down nutrients and gets its name from the short, thin projections that generate energy; but when mutated, they prevent look like hair on its cells. HCL starts with a cells from maturing to become specialized blood in the DNA of a single stem cell and multiplies cell types. In acute myeloid leukemia (AML), 15-20 uncontrollably in the bone marrow, liver and spleen. percent of patients have IDH . Recent More than 90 percent of patients treated with clinical trials for two oral IDH inhibitors, AG-221 cladribine (Leustatin®) achieve complete remission and and AG-120, produced a 50-60 percent response rate in refractory AML patients. LLS funded Daniel many remain disease free for years or decades. But in Pollyea, MD, at University of Colorado in this trial about 40 percent of patients, the leukemia returns and and has other active grants at University of Toronto becomes less responsive to chemotherapy. Further, the and Memorial Sloan-Kettering Cancer Center that chemotherapy also kills normal cells in the bone marrow are also studying this target. Unlike most therapies and immune system and severe can follow. that seek to destroy cancer cells, this approach More specific and less toxic treatments are needed. actually transforms them into normal cells. Using next-generation sequencing technologies on more than 20,000 human , LLS-funded Immature researcher Enrico Tiacci, MD, in Perugia, Italy looked cell AG-120 for the activating mutation in HCL. In his study of AG-221 500 HCL patients, Dr. Tiacci found one mutation Normal X in a known as B-RAF in nearly all of them. This IDH 1 or 2 gene normally plays a pivotal role in the regulation of cell proliferation and survival. The mutated version was not present in other B-cell blood cancers but is AML Normal cell Tumor cell frequently found in melanoma. An oral B-RAF inhibitor, vemurafenib, which has already been found to be safe and effective in melanoma patients, offers potential for long-term control of HCL. With LLS funding, Dr. Tiacci conducted a phase 2 Long-term Investment Pays Off trial for HCL patients who do not respond or have severe side effects from standard chemotherapy. Of 26 Stephan Grupp, MD, PhD, at Children’s Hospital patients, 25 showed an overall response—nine with of Philadelphia is part of the Carl June Specialized Center of Research team to which LLS has complete remissions and 16 with partial remissions. Six committed nearly $21 million. He recently reported of those with complete remissions and five of those with long-term follow up data from an immunotherapy partial remissions had normal blood counts a year after trial with 39 children and young adults with relapsed, treatment. acute lymphoblastic leukemia (ALL). Relapsed ALL Independently, LLS-funded researcher Jae Park, MD, patients currently have no good treatment options. After the experimental therapy in which patients’ at Memorial Sloan-Kettering in New York was doing own immune T cells were genetically engineered complementary research in a Phase 2 trial of relapsed or and reintroduced to the body to kill cancer cells, refractory HCL patients treated with vemurafenib. Of 36 of 39 children achieved a complete response. 17 patients evaluated, six achieved complete remission After six months, 70 percent of those in the study and the remainder achieved partial remission. remained cancer free and 75 percent survived. Only five children received subsequent treatment. While longer-term follow up is needed, vemurafenib A Phase 2, multi-site trial will continue to study the shows promise for relapsed or refractory HCL patients. long-term efficacy of the treatment and evaluate its Subsequent studies will be needed to prove if inhibiting potential as a replacement for stem cell transplant B-RAF might be the best initial therapy. for children with relapsed, treatment-resistant ALL. Good Outcomes Require Good Diagnoses

ancer complexity and diversity is a recognized ...even with today’s Creality and precisely targeted medicines are the best “ promise for patients. As more therapies are developed to advanced technology, target specific abnormalities and selectively kill cancer patients are misdiagnosed cells, accurate diagnoses, including the exact classification of lymphoma subtypes, can dramatically affect treatment with surprising frequency. selection and patient outcomes. Patients need to have ” biopsies and medical information collected, analyzed and sector experts to improve diagnostics, including the exact interpreted by an expert in hematological malignances classification of lymphoma subtypes. Initially, the two-year with the detailed diagnosis communicated to the treating project will define the magnitude and scope of lymphoma physician in a timely manner and actionable format. misdiagnoses, especially those that impact treatment Yet even with today’s advanced technology, patients selection in community treatment centers versus academic are misdiagnosed with surprising frequency. In common medical centers. Subsequent steps include the following: B-cell lymphomas, inaccurate diagnoses occur about 5 • Develop and validate diagnostic tools that utilize percent of the time and escalating to 40 percent for less widely used core biopsies and/or fine needle common lymphomas. As a result, too many patients will aspirates to diagnose recognized lymphoma receive inappropriate treatments. subtypes and select optimal treatments; Why do misdiagnoses occur? • Develop and validate a protocol(s) for automatic • Pathologists receive incomplete medical records. and timely second diagnostic opinions; • Sample collection is insufficient or inappropriate. • Evaluate new diagnostic techniques and sequential • Pathologists without specific hematopathology testing to achieve accurate diagnoses that are both experience misinterpret the data. clinically and cost effective. To address the obstacles to receiving accurate diagnoses, The goal of this partnership is to reduce costs, achieve LLS will begin a new partnership with public and private better outcomes, and save lives.

Testing a New Approach for High Risk Myeloma Patients Over the past several years researchers have been This MIL therapy could be especially useful to the 20 achieving good results treating cancers with genetically percent of myeloma patients who are considered high risk and engineered cells. Known as adoptive T cell therapy, this don’t achieve long-term remissions with current therapies. method takes T cells from patients, grows them in the lab Dr. Borrello began a randomized Phase 2 clinical and returns them to the patients to destroy the cancer. trial in late 2013 to examine this therapy. It is currently Sources for the T cells often include blood or cells within enrolling high risk myeloma participants who are either a solid tumor (an approach used in treating patients newly diagnosed or in a first relapse. The first trial site with skin cancer). Ivan Borrello, MD, at Johns Hopkins opened in Baltimore and a second is expected shortly in University is looking to augment the effectiveness of Tampa at the Moffitt Cancer Center. Patients have MILs adoptive T cell therapy using T cells taken from within the collected through a bedside bone marrow aspiration bone marrow to treat myeloma patients. These marrow- and are randomized to undergo an autologous stem cell infiltrating lymphocytes are known as MILs. transplant either with or without the addition of MILs. Of The rationale for this approach stems from findings 18 patients in the LLS-supported study who have been in Dr. Borrello’s lab that MILs located in proximity to transplanted so far, ten received MILs and eight did not. the myeloma cells are highly tumor specific. When To date, none of the patients who received MILs have manipulated in the lab, the cells can be grown in relapsed. Of the eight who did not receive MILs, two patients to further increase their tumor specificity have relapsed. and killing potential. Further, they can be given to the This study, which originated in an earlier LLS grant patients with minimal toxicity and can have measureable to Dr. Borrello, was selected for further development anti-tumor activity when they make their way back to in our Therapy Acceleration Program to hasten the the bone marrow. advancement of a promising new treatment for patients. The Emperor of All Maladies how someday

hen Dr. Siddhartha Mukherjee’s Wbook, The Emperor of All Maladies: A Biography of Cancer, was selected for the 2011 Pulitzer Prize for non-fiction, the jury described the work as “an elegant inquiry, at once clinical and personal.” It was personal, becomes today because Dr. Mukherjee has devoted his life to caring for people with cancer cancer treatment and the researchers at the forefront of and he wrote the book to better understand the disease. change. The series will air on local PBS stations on three In a very human history of cancer, he chronicles how consecutive nights beginning March 30th. LLS will CANCER: THE EMPEROR OF ALL MALADIES modern treatments came into existence and provides a host special screenings in Washington, D.C., New York, rich background on illness and medical ethics. Charlotte, Seattle and select other markets. Now, LLS is a proud production supporter of the The series has been described as “an extraordinary PBS documentary series, Ken Burns Presents CANCER: moment of great promise in cancer research and THE EMPEROR OF ALL MALADIES, a film by treatment.” We feel it dramatizes our message that Barak Goodman. The series traces the progression of Someday is Today.

Advocating for Patients

The LLS Government Affairs team is poised to engage on second, to bring greater clarity to the process known as legislation expected from the House Energy & Commerce “expanded access,” which is how patients potentially gain committee this winter. The legislation, known as “21st access to experimental drugs outside of a clinical trial Century Cures,” is the result of a bipartisan effort led by before the drug has been approved. Chairman Fred Upton from Michigan and Representative LLS regularly mobilizes advocates nationwide to speak Diana DeGette from Colorado to improve the process out on key issues like the 21st Century Cures Act that that gets cures to patients. LLS expects draft legislation impact blood cancer patients’ access to treatment and soon and the House of Representatives seeks to pass a 21st cures. The advocacy team works with patients, family Century Cures bill by late May. members, and healthcare providers to give the blood The LLS focus on this legislation has been in two cancer community a voice in state and federal policy and key areas: first, to ensure that the patient perspective legislative arenas. To connect with your local manager for is considered in a more transparent and standardized updates and action alerts and to become an advocate for way during the drug development process at the FDA; LLS, contact Jon Hoffman at [email protected].

Research + Investment = Cures

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