HIGHLIGHTS Winter 2015 FOR DONORS The Leukemia & Lymphoma Society (LLS) exists to find cures and ensure access to treatments for all blood cancer patients. Because there are no means of preventing or screening for most blood cancers, 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 cell 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. www.LLS.org 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 mutation 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 mutations. 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 infections 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 genes, 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 gene 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 patients currently have no good treatment options. Independently, LLS-funded researcher Jae Park, MD, 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).