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Page 1: Winter 2015 FOR DONORS - Leukemia & Lymphoma Society · PDF fileFOR DONORS Winter 2015 The Leukemia & Lymphoma Society ... If blood cells fail to die when ... PBS documentary series,

HIGHLIGHTS

Harnessing A Natural Process to Kill Cancer

FOR DONORSWinter 2015

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.

www.LLS.org

To make room for new cells, the body tells billions of unwanted cells each day to die in a natural biological

process known as apoptosis. If blood cells fail to die when they should, they can develop into leukemia, lymphoma or myeloma. A team of researchers led by Jerry Adams, PhD, at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia has received extensive funding from LLS over a dozen years to investigate how impaired apoptosis contributes to blood cancers and becomes a 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 inactivating the pro-survival function of other proteins. Tumors often use pro-survival proteins to resist death. To overwhelm those proteins and switch on the apoptosis machinery, the Adams team developed BH3 mimetics, small molecules that are capable of mimicking the BH3-only proteins. With earlier LLS funding, the Adams team collaborated with Genentech and Abbott (now known as AbbVie) to test a first-generation compound that targeted three pro-survival proteins in the BCL-2 family. It showed promising clinical results but caused a severe decrease of platelets in the blood, which limited dosing. The team continued the collaboration to help develop a more specific and potent mimetic known as ABT-199 that spares the platelets.

Adams’ team member, Andrew Roberts, MB, MS, PhD, conducted a Phase 1 trial of ABT-199 as a single agent for treatment-resistant chronic lymphocytic leukemia (CLL) patients. It showed marked falls in tumors in the blood and lymph nodes and reduced infiltration to the bone marrow in 90 percent of the patients. This substantial activity against CLL is highly encouraging and ABT-199 is being tested in Phase 1, 2 and 3 trials as a monotherapy and in combinations with rituximab and bendamustine. Data from a Phase 2 trial in relapsed CLL patients are due in coming months and could be submitted to the FDA for review. To explore the full potential of the apoptotic machinery to kill tumor cells, LLS is also funding other researchers, including Anthony Letai, MD, PhD, at Dana Farber Cancer Institute, studying non-Hodgkin lymphomas.

signal cell damage

keep Bax and Bak in check

switch on apoptosis machinery

BH3-only proteins

Bax and Bak

Pro-survival Bcl-2 proteins

Page 2: Winter 2015 FOR DONORS - Leukemia & Lymphoma Society · PDF fileFOR DONORS Winter 2015 The Leukemia & Lymphoma Society ... If blood cells fail to die when ... PBS documentary series,

Right Patient, Right Therapy in HCL

IDH 1 and 2 (isocitrate dehydrogenase) are enzymes that are mutated in many blood cancers. IDH proteins normally break down nutrients and generate energy; but when mutated, they prevent cells from maturing to become specialized blood cell types. In acute myeloid leukemia (AML), 15-20 percent of patients have IDH mutations. Recent clinical trials for two oral IDH inhibitors, AG-221 and AG-120, produced a 50-60 percent response rate in refractory AML patients. LLS funded Daniel Pollyea, MD, at University of Colorado in this trial and has other active grants at University of Toronto and Memorial Sloan-Kettering Cancer Center that are also studying this target. Unlike most therapies that seek to destroy cancer cells, this approach actually transforms them into normal cells.

New AML Therapy to Watch For

Immature cell

Normal cellAML

Tumor cell

Normal IDH 1 or 2

X

AG-120 AG-221

Hairy cell leukemia (HCL), a slow-growing blood cancer that mostly affects middle-aged adults,

gets its name from the short, thin projections that look like hair on its cells. HCL starts with a mutation in the DNA of a single stem cell and multiplies uncontrollably in the bone marrow, liver and spleen. More than 90 percent of patients treated with cladribine (Leustatin®) achieve complete remission and many remain disease free for years or decades. But in about 40 percent of patients, the leukemia returns and becomes less responsive to chemotherapy. Further, the chemotherapy also kills normal cells in the bone marrow and immune system and severe infections can follow. More specific and less toxic treatments are needed. Using next-generation sequencing technologies on more than 20,000 human genes, LLS-funded researcher Enrico Tiacci, MD, in Perugia, Italy looked for the activating mutation in HCL. In his study of 500 HCL patients, Dr. Tiacci found one mutation in a gene known as B-RAF in nearly all of them. This 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 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 trial for HCL patients who do not respond or have severe side effects from standard chemotherapy. Of 26 patients, 25 showed an overall response—nine with complete remissions and 16 with partial remissions. Six of those with complete remissions and five of those with partial remissions had normal blood counts a year after treatment. Independently, LLS-funded researcher Jae Park, MD, at Memorial Sloan-Kettering in New York was doing complementary research in a Phase 2 trial of relapsed or refractory HCL patients treated with vemurafenib. Of 17 patients evaluated, six achieved complete remission and the remainder achieved partial remission. While longer-term follow up is needed, vemurafenib shows promise for relapsed or refractory HCL patients. Subsequent studies will be needed to prove if inhibiting B-RAF might be the best initial therapy.

Stephan Grupp, MD, PhD, at Children’s Hospital of Philadelphia is part of the Carl June Specialized Center of Research team to which LLS has committed nearly $21 million. He recently reported long-term follow up data from an immunotherapy trial with 39 children and young adults with relapsed, acute lymphoblastic leukemia (ALL). Relapsed ALL patients currently have no good treatment options. After the experimental therapy in which patients’ own immune T cells were genetically engineered and reintroduced to the body to kill cancer cells, 36 of 39 children achieved a complete response. After six months, 70 percent of those in the study remained cancer free and 75 percent survived. Only five children received subsequent treatment. A Phase 2, multi-site trial will continue to study the long-term efficacy of the treatment and evaluate its potential as a replacement for stem cell transplant for children with relapsed, treatment-resistant ALL.

Long-term Investment Pays Off

Page 3: Winter 2015 FOR DONORS - Leukemia & Lymphoma Society · PDF fileFOR DONORS Winter 2015 The Leukemia & Lymphoma Society ... If blood cells fail to die when ... PBS documentary series,

Cancer complexity and diversity is a recognized reality and precisely targeted medicines are the best

promise for patients. As more therapies are developed to target specific abnormalities and selectively kill cancer cells, accurate diagnoses, including the exact classification of lymphoma subtypes, can dramatically affect treatment selection and patient outcomes. Patients need to have biopsies and medical information collected, analyzed and interpreted by an expert in hematological malignances with the detailed diagnosis communicated to the treating physician in a timely manner and actionable format. Yet even with today’s advanced technology, patients are misdiagnosed with surprising frequency. In common B-cell lymphomas, inaccurate diagnoses occur about 5 percent of the time and escalating to 40 percent for less common lymphomas. As a result, too many patients will receive inappropriate treatments. Why do misdiagnoses occur?

• Pathologists receive incomplete medical records.• Sample collection is insufficient or inappropriate.• Pathologists without specific hematopathology

experience misinterpret the data. To address the obstacles to receiving accurate diagnoses, LLS will begin a new partnership with public and private

sector experts to improve diagnostics, including the exact classification of lymphoma subtypes. Initially, the two-year project will define the magnitude and scope of lymphoma misdiagnoses, especially those that impact treatment selection in community treatment centers versus academic medical centers. Subsequent steps include the following:

• Develop and validate diagnostic tools that utilize widely used core biopsies and/or fine needle aspirates to diagnose recognized lymphoma subtypes and select optimal treatments;

• Develop and validate a protocol(s) for automatic and timely second diagnostic opinions;

• Evaluate new diagnostic techniques and sequential testing to achieve accurate diagnoses that are both clinically and cost effective.

The goal of this partnership is to reduce costs, achieve better outcomes, and save lives.

Good Outcomes Require Good Diagnoses

Testing a New Approach for High Risk Myeloma PatientsOver the past several years researchers have been achieving good results treating cancers with genetically engineered cells. Known as adoptive T cell therapy, this method takes T cells from patients, grows them in the lab and returns them to the patients to destroy the cancer. Sources for the T cells often include blood or cells within a solid tumor (an approach used in treating patients with skin cancer). Ivan Borrello, MD, at Johns Hopkins University is looking to augment the effectiveness of adoptive T cell therapy using T cells taken from within the bone marrow to treat myeloma patients. These marrow-infiltrating lymphocytes are known as MILs. The rationale for this approach stems from findings in Dr. Borrello’s lab that MILs located in proximity to the myeloma cells are highly tumor specific. When manipulated in the lab, the cells can be grown in patients to further increase their tumor specificity and killing potential. Further, they can be given to the patients with minimal toxicity and can have measureable anti-tumor activity when they make their way back to the bone marrow.

This MIL therapy could be especially useful to the 20 percent of myeloma patients who are considered high risk and don’t achieve long-term remissions with current therapies. Dr. Borrello began a randomized Phase 2 clinical trial in late 2013 to examine this therapy. It is currently enrolling high risk myeloma participants who are either newly diagnosed or in a first relapse. The first trial site opened in Baltimore and a second is expected shortly in Tampa at the Moffitt Cancer Center. Patients have MILs collected through a bedside bone marrow aspiration and are randomized to undergo an autologous stem cell transplant either with or without the addition of MILs. Of 18 patients in the LLS-supported study who have been transplanted so far, ten received MILs and eight did not. To date, none of the patients who received MILs have relapsed. Of the eight who did not receive MILs, two have relapsed. This study, which originated in an earlier LLS grant to Dr. Borrello, was selected for further development in our Therapy Acceleration Program to hasten the advancement of a promising new treatment for patients.

“...even with today’s advanced technology, patients are misdiagnosed with surprising frequency.”

Page 4: Winter 2015 FOR DONORS - Leukemia & Lymphoma Society · PDF fileFOR DONORS Winter 2015 The Leukemia & Lymphoma Society ... If blood cells fail to die when ... PBS documentary series,

The Leukemia & Lymphoma Society | 1311 Mamaroneck Ave, Suite 310 | White Plains, NY 10605

CANCER:  THE  EMPEROR  OF  ALL  MALADIES  

how someday

becomes todayWhen Dr. Siddhartha Mukherjee’s

book, 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, because Dr. Mukherjee has devoted his life to caring for people with cancer and he wrote the book to better understand the disease. In a very human history of cancer, he chronicles how modern treatments came into existence and provides a rich background on illness and medical ethics. Now, LLS is a proud production supporter of the PBS documentary series, Ken Burns Presents CANCER: THE EMPEROR OF ALL MALADIES, a film by Barak Goodman. The series traces the progression of

cancer treatment and the researchers at the forefront of change. The series will air on local PBS stations on three consecutive nights beginning March 30th. LLS will host special screenings in Washington, D.C., New York, Charlotte, Seattle and select other markets. The series has been described as “an extraordinary moment of great promise in cancer research and treatment.” We feel it dramatizes our message that Someday is Today.

The Emperor of All Maladies

Please remember The Leukemia & Lymphoma Society in your will or as a beneficiary in your retirement plan.For additional information please contact: Kay Koehler, National Director of Estate Planning

561-312-3573 or [email protected]

Research + Investment = Cures

Advocating for Patients

The LLS Government Affairs team is poised to engage on legislation expected from the House Energy & Commerce committee this winter. The legislation, known as “21st Century Cures,” is the result of a bipartisan effort led by Chairman Fred Upton from Michigan and Representative Diana DeGette from Colorado to improve the process that gets cures to patients. LLS expects draft legislation soon and the House of Representatives seeks to pass a 21st Century Cures bill by late May. The LLS focus on this legislation has been in two key areas: first, to ensure that the patient perspective is considered in a more transparent and standardized way during the drug development process at the FDA;

second, to bring greater clarity to the process known as “expanded access,” which is how patients potentially gain access to experimental drugs outside of a clinical trial before the drug has been approved. LLS regularly mobilizes advocates nationwide to speak out on key issues like the 21st Century Cures Act that impact blood cancer patients’ access to treatment and cures. The advocacy team works with patients, family members, and healthcare providers to give the blood cancer community a voice in state and federal policy and legislative arenas. To connect with your local manager for updates and action alerts and to become an advocate for LLS, contact Jon Hoffman at [email protected].