AA&MDSIF 2016 MDS Research Summary AMERICAN SOCIETY OF CLINICAL ONCOLOGY (ASCO) EUROPEAN HEMATOLOGY ASSOCIATION (EHA) A Summary of Selected Scientific Abstracts for Patients with Myelodysplastic Syndromes (MDS) and Their Caregivers The Aplastic Anemia and MDS International Foundation (AAMDSIF) is an independent non-profit organization. Our mission is to support patients, families and caregivers coping with: • Aplastic anemia • MDS (myelodysplastic syndromes) • PNH (paroxysmal nocturnal hemoglobinuria) • Related bone marrow failure diseases This booklet offers summaries of selected abstracts presented at the 2016 Annual Meetings of The American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA). It provides some of the most up-to-date information about new research into the biology and treatment of myelodysplastic syndromes (MDS). Although the information in this booklet has undergone a thorough, independent medical review to insure its accuracy, this material is not intended to be a substitute for the advice of your doctor. You should always seek medical advice from a qualified physician. For more information, call us at (800) 747-2820, or visit us online at www.aamds.org. Aplastic Anemia and MDS International Foundation 4330 East West Highway, Suite 230 Bethesda, MD 20814 (301) 279-7202 or (800) 747-2820 [email protected] www.aamds.org Copyright © 2016, Aplastic Anemia and MDS International Foundation This publication is made possible through an unrestricted education grant from Celgene Corporation. 2 AAMDSIF MDS RESEARCH SUMMARY I ASCO/EHA 2016 I N T R O D U C T I O N Dear Patient or Caregiver, The purpose of this abstract summary is to provide you with the most up-to-date information about new research into the biology and treatment of myelodysplastic syndromes (MDS), as presented at the major hematology and oncology scientific meetings this year. • American Society of Clinical Oncology (ASCO) • European Hematology Association (EHA) These are some of the world’s largest meetings of hematologists and hematological oncologists– doctors who care for patients with blood disorders or blood and bone marrow cancers. This is where many major findings in the field of blood and marrow disorders are first announced to the larger medical and scientific community and the media. New information that researchers hope is important enough to be presented at this meeting is submitted a few months ahead of the conference in the form of an “abstract”, a brief summary of the study and its results. Authors of the most interesting and noteworthy abstracts are asked by conference organizers to present their research in more detail, either in the format of a large displayed poster with text and illustrations, or an oral (podium) presentation. We selected the abstracts in this summary because we feel they are the most relevant and important for MDS patients to know about. By reviewing the information presented in the booklet, we hope you will: • Learn how ongoing research on MDS may affect the diagnosis, treatment, and prognosis of patients in the near term as well as the more distant future • Understand how researchers are approaching the most promising areas of MDS therapy • Learn about the importance of clinical trials in identifying novel therapies for MDS • Know the most important issues about MDS which you may want or need to understand and to ask your health care providers about as part of your ongoing treatment Please note that the research results discussed at these meetings often involve experimental drugs that are not yet approved for general use by the U.S. Food and Drug Administration (FDA) or investigations of potential new uses of previously approved treatments. By providing summaries of the research presented, we do not intend to recommend or endorse any particular medication or treatment approach. Our goal is simply to inform you about current news and trends in research related to MDS. If you are interested in participating in research studies such as those discussed in this booklet, we encourage you to speak with your doctor about clinical trials or to visit www.clinicaltrials.gov. As always, please contact AAMDSIF if you have questions about these summaries or any aspect of managing your disease. Mikkael Sekeres, MD, MS Cleveland Clinic Taussig Cancer Institute Co-Chair AAMDSIF Medical Advisory Board 2 3 AAMDSIF MDS RESEARCH SUMMARY I ASCO/EHA 2016 APLASTIC ANEMIA AND MDS INTERNATIONAL FOUNDATION | WWW.AAMDS.ORG P R E D I C T I N G T R E AT M E N T R E S P O N S E S EHA S446 Results: Genetic Mutations that Predict • At the time they were diagnosed with a Therapy-Related Blood Cancers secondary blood cancer, the 14 patients had mutations in 21 genes known to drive Koichi Takahashi, Feng Wang, Hagop Kantarjian, Doss leukemia. Denaha, Kanhav Khanna, Erika Thompson, Keyur Patel, • The most common mutations were in TP53 Sattva Neelapu, Curtis Gumbs, Carlos Bueso-Ramos, (29% of patients), DNMT3A (21%), TET2 (21%), Courtney DiNardo, Simona Colla, Farhad Ravandi, Song and RUNX1 (20%). Xingzhi, Jianhua Zhang, Xifeng Wu, Felipe Samaniego, Guillermo Garcia-Manero, Andrew Futreal • Ten (71%) of the patients had a leukemia driver mutation at the time their primary cancer was diagnosed—on average, 3 years before their secondary cancer diagnosis. Patients sometimes develop blood cancers after treatment with chemotherapy or radiation Conclusions: therapy for another cancer. Recent research suggests that patients might have mutations in • Leukemia driver mutations can be found in the TP53 gene years before they develop one the genes of patients who later develop AML of these therapy-related cancers (known as or MDS at the time their primary cancer is secondary cancers). These secondary cancers diagnosed. can include MDS and acute myelogenous leukemia (AML). The TP53 mutations might • These data could be used to develop a model drive the development of secondary cancers. for assessing risk of treatment-related cancer at the time a primary cancer is diagnosed. A research team decided to find out whether mutations that drive leukemia can be detected in patients who develop a therapy-related blood cancer at the time their first (primary) cancer is diagnosed. They sequenced 280 genes known to be associated with leukemia in specimens from 14 patients. Five of the patients (36%) developed treatment-related acute myelogenous leukemia (AML) and 9 (64%) developed treatment-related MDS. 4 AAMDSIF MDS RESEARCH SUMMARY I ASCO/EHA 2016 P R E D I C T I N G T R E AT M E N T R E S P O N S E S EHA S129 Results: Effect of Low Platelet Count in MDS • The CC-486 response rate was the same— on Azacitidine Treatment Outcomes 42%—in patients with low platelet counts and those with high platelet counts. Guillermo Garcia-Manero, Steven D Gore, Bart L Scott, • Two patients (14%) in the low-platelet group Michael R Savona, Christopher R Cogle, Thomas E Boyd, stopped needing platelet transfusions, and 17 Suman Kambhampati, Joel Hetzer, Qian Dong, Keshava (24%) developed high platelet counts. Kumar, Stacey M Ukrainskyj, Barry S Skikne • Serious bleeding events were rare. The low platelet group had no serious bleeding events, whereas these events occurred in 5 About 40% to 65% of patients with MDS have a patients in the high platelet group. shortage of platelets in the bloodstream. Patients with low platelet counts have poorer outcomes • Rates of serious side effects were similar in than those with normal platelet counts. Some the two groups. experts believe that patients who have severe platelet shortages and lower-risk MDS at Conclusions: diagnosis should be given the same treatments as patients with higher-risk MDS. • Patients with lower-risk MDS, even those with low platelet counts, tolerate CC-486 well. This study assessed the safety and efficacy of • Patients with low or high platelet counts were CC-486, the oral version of azacitidine (Vidaza®), equally likely to respond to CC-486 treatment. in patients with MDS who do or do not have a low platelet count. The investigators analyzed data on 137 patients with MDS (median age 72 years) who had participated in one of three phase I/II clinical trials. Of these patients, 72 had a low platelet count. 4 5 AAMDSIF MDS RESEARCH SUMMARY I ASCO/EHA 2016 APLASTIC ANEMIA AND MDS INTERNATIONAL FOUNDATION | WWW.AAMDS.ORG G E N E M U TAT I O N S A N D M D S P R O G R E S S I O N EHA Education Session: Some somatic mutations are also useful for predicting how a patient will respond Myelodysplastic Syndromes– to a given treatment. For example, patients Effects of Gene Mutations in MDS with a mutation in TET2 are more likely to respond to treatment with azacitidine Rafael Bejar (Vidaza®) or decitabine (Dacogen®). Those with a TP53 mutation aren’t likely to respond well to azacitidine, decitabine, lenalidomide More than 90% of patients with MDS have a (Revlimid®), or stem cell transplantation. mutation in at least one gene known to be associated with MDS. Testing for these genes Doctors don’t consider gene mutations when can sometimes help doctors choose the best they diagnose MDS. But mutations might be treatment for a patient. helpful for diagnosing unexplained blood cell shortages. Doctors use the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R) to classify patients into different risk categories. But some somatic (not inherited) mutations in MDS genes offer predictive information beyond the IPSS and other scoring tools. For example, having a mutation in certain genes (such as TP53, EZH2, ASXL1, CBL, and U2AF1) increases the risk that MDS will progress in patients with lower-risk IPSS-R categories. But mutations in SF3B1 mean that a patient is likely to survive longer than their IPSS-R category says. 6 AAMDSIF MDS RESEARCH SUMMARY I ASCO/EHA 2016 G E N E M U TAT I O N S A N D M D S P R O G R E S S I O N EHA P257 Findings: Gene Mutations and Risk of • 37 patients (62%) had a mutation in at least 1 Progression to MDS of 20 genes assessed in the study. • The most common mutation—found in 26 Jakob Werner Hansen, Maj Karoline Westman, Lene patients (43%)—was in TET2. Dissing Sjö, Leonie Saft, Lasse Sommer Kristensen, Andreas Due Ørskov, Marianne Treppendahl, Mette • Six patients (10%) developed MDS or chronic Klarskov Andersen, Kirsten Grønbæk myelomonocytic leukemia (CMML) over the next 1 to 8 years. o Five of these patients had 1 of the 20 Low blood cell counts are common in elderly mutations when they joined the study. patients. Doctors often use several tests to try to o At the time they developed MDS or find the cause. CMML, 4 patients had a new mutation in NRAS, TP53, GATA2 or ASXL1. The purpose of this study was to measure the frequency of gene mutations known to be Conclusions: associated with MDS in patients with long- lasting low blood cell counts with an unknown • Patients with persistent low blood cell counts cause after routine testing. The study included and no clear diagnosis often have mutations 60 patients (median age 70 years) who had had in genes associated with blood cancers. low blood cell counts for at least 6 months. • Next-generation sequencing (a new technique to study genomes) might be useful for diagnosing low blood cell counts with an unknown cause. 6 7 AAMDSIF MDS RESEARCH SUMMARY I ASCO/EHA 2016 APLASTIC ANEMIA AND MDS INTERNATIONAL FOUNDATION | WWW.AAMDS.ORG G E N E M U TAT I O N S A N D M D S P R O G R E S S I O N EHA S442 Findings: Changes in Genes and Clones in • Patients with higher-risk MDS had more MDS Progression mutations, more mutations in different genes, and larger clones. Hideki Makishima, Tetsuichi Yoshizato, Kenichi Yoshida, • Many more patients with AML had large Thomas LaFramboise, Matthew Ruffalo, Mikkael numbers of mutations in many different Sekeres, Hiromichi Suzuki, Bartlomiej Przychodzen, genes than patients with lower-risk MDS. Yasunobu Nagata, Manja Meggendorfer, Masashi Sanada, Yusuke Okuno, Yusuke Sato, Aiko Sato-Otsubo, • New mutations often developed before the Tomas Radivoyevitch, Naoko Hosono, Yuichi Shiraishi, disease progressed. Kenichi Chiba, Claudia Haferlach, Wolfgang Kern, • Patients with AML were more likely than Hiroko Tanaka, Yusuke Shiozawa, Inés Gómez-Seguí, those with higher-risk MDS to have Holleh Husseinzadeh, Swapna Thota, Kathryn Guinta, mutations in FLT3, PTPN11, IDH1, CBL, or Brittney Dienes, Tsuyoshi Nakamaki, Shuichi Miyawaki, NRAS. Yogen Saunthararajah, Shigeru Chiba, Satoru Miyano, o In patients with these mutations, MDS Lee-Yung Shih, Torsten Haferlach, Seishi Ogawa, progressed more quickly to AML than in Jaroslaw Maciejewski patients without these mutations. o Patients with mutations in TP53, GATA2, RUNX1, IDH2, STAG2, ASXL1, and NPM1 Clones in MDS are immature white blood had a higher risk of dying before their cells. A bone marrow failure disease like MDS MDS progressed to AML than patients starts when a clone becomes abnormal. This with other mutations. abnormal clone makes clones of itself. These cells might not be able to make normal blood Conclusions: cells or they might not make as many blood cells as the body needs. • Changes in clones are closely associated with This research team studied the relationships mutations in different genes. between gene mutations and clones in • These changes are also associated with the 779 patients with MDS or secondary acute likelihood that MDS will progress to AML or myelogenous leukemia (AML). that the patient will die before developing AML. • Screening for these mutations might help doctors predict outcomes in MDS. 8 AAMDSIF MDS RESEARCH SUMMARY I ASCO/EHA 2016 N O V E L T R E AT M E N TS EHA S128 Results: Clinical Trial of Darbepoetin • The darbepoetin alfa reduced the number Alfa for Anemia in Patients with of transfusions that patients needed Lower-Risk MDS significantly compared with placebo. • Eleven patients (14.7%) treated with Uwe Platzbecker, Argiris Symeonidis, Esther Oliva, darbepoetin had an erythroid response, Jeroen S Goede, Michel Delforge, Jiri Mayer, Sejal Badre, meaning that their red blood cell counts Eduard Gasal, Bhakti Mehta, Janet Franklin returned to normal. None of the patients in the placebo group had an erythroid response. • Negative side effects that were more Treatment guidelines for health-care common in the darbepoetin group were practitioners often recommend erythropoiesis- fatigue, fever, headache, and muscle pain. stimulating agents (ESAs) to treat anemia in patients with lower-risk MDS. However, Conclusions: regulatory agencies in some countries haven’t approved ESAs for this use. • Darbepoetin alfa treatment for 24 weeks significantly reduced transfusions in patients This phase III clinical trial evaluated the with low-risk and intermediate-1-risk outcomes of darbepoetin alfa (Aranesp®), MDS and increased rates of red blood cell an ESA, in 147 patients with low-risk or response. intermediate-1-risk MDS in nine European countries. Patients were treated with • Darbepoetin alfa had no safety concerns. darbepoetin alfa injection or placebo for 24 weeks. 8 9 AAMDSIF MDS RESEARCH SUMMARY I ASCO/EHA 2016 APLASTIC ANEMIA AND MDS INTERNATIONAL FOUNDATION | WWW.AAMDS.ORG N O V E L T R E AT M E N TS EHA P248 Results: Clinical Trial of Epoetin Alfa • Red blood cell counts returned to normal in for Anemia in Patients with 32% of the epoetin alfa group and 4% of the Lower-Risk MDS placebo group. • In patients who responded, red blood cell Pierre Fenaux, Valeria Santini, Maria Antonietta counts stayed in the target range for a Aloe Spiriti, Aristoteles Giagounidis, Rudolf Schlag, median of 197 days. Atanas Radinoff, Liana Gercheva-Kyuchukova, Achilles • The proportion of patients needing red blood Anagnostopoulos, Esther Oliva, Argiris Symeonidis, cell transfusions dropped from 52% before the Anna Potamianou, Hari Haralampiev, Robert Wapenaar, study to 25% by week 24 in the epoetin alfa Iordanis Milionis, Uwe Platzbecker group. This proportion didn’t change in the placebo group. • Quality of life improved in the epoetin alfa Treatment guidelines for health-care group compared with the placebo group. practitioners often recommend erythropoiesis- stimulating agents (ESAs) for anemia in patients • Treatment safety was similar in the epoetin with lower-risk MDS. However, regulatory alfa and placebo groups. agencies in some countries haven’t approved ESAs for this use. Conclusions: This international Phase III clinical trial • Epoetin alfa reduced anemia by increasing compared the efficacy and safety of epoetin hemoglobin counts in patients with low-risk alfa, an ESA, to placebo in patients with anemia or intermediate-1-risk MDS. low-risk or intermediate-1-risk MDS. The 130 • Epoetin alfa also reduced the amount of red participants in the study (median age 75 years) blood cell transfusions that patients needed. were randomly assigned to treatment with epoetin alfa or placebo for 24 weeks. 10 AAMDSIF MDS RESEARCH SUMMARY I ASCO/EHA 2016