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Zhaohui Gu, PhD Postdoctoral Research Associate  St. Jude Children's Research Hospital, TN MedicalResearch.com:  What is the background for this study?  What are the main findings? Response:B-progenitor acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy and the leading cause of childhood cancer death. B-ALL includes multiple subtypes that are defined by distinct genetic alterations and that play an important role in diagnosis, prognosis and therapy of patients.  Advances in transcriptome sequencing (RNA-seq)have helped researchers discover additional subtypes and driver mutations inB-ALL and identify possible new therapeutic targets.  Still, up to 30% of B-ALL cases do not fit into established subtypes. These patients lack targeted therapeutic approaches and commonly relapse. Fort his study, we used integrated genomic analysis of 1,988 childhood and adult cases to revise the classification system of B-ALL. The system includes eight new subtypes and a total of 23 B-ALL subtypes. The subtypes are defined by chromosomal rearrangements, sequence mutations, or heterogeneous genomic alterations. Many show a marked variation in prevalence according to age. The newly identified subtypes included one (n=18) defined by rearrangements of gene BCL2, MYC and/or BCL6 anda distinctive gene expression profile (GEP). Patients in this subtype were mostly adults (n=16) with very poor outcomes. Another novel subtype was defined by IKZF1 N159Y missense mutation. N159Y is in the DNA-binding domain of IKZF1, and is known to disrupt IKZF1 function, with distinct nuclear mis-localization and induction of aberrant intercellular adhesion. There were eight cases in this subtype that shared highly similar GEPs. We also identified two subtypes with distinct GEP and characterized by PAX5 alterations. One, PAX5 altered (PAX5alt), included 148 cases. PAX5alt was characterized by diverse PAX5 alterations including rearrangements (n=57), sequence mutations (n=46) and/or focal intragenic amplifications (n=8). These PAX5 alterations were found in 73.6% of PAX5alt cases. The second distinct subtype comprised 44 cases, all with PAX5 P80R missense mutations. Bi-allelic PAX5 alterations were commonly seen in this subtype in the form of PAX5 P80R coupled with a second sequence mutation or deletion of the wild-type PAX5 allele. Adult PAX5 P80R cases showed better 5-year OS (61.9±13.4%) than those in PAX5alt subtype (42.1±10.2%). In addition, Pax5 P80R heterozygous and homozygous mice developed B lineage leukemia with a median latency of 166 and 87 days, respectively.  The heterozygous mice acquired alterations on the second allele, which faithfully recapitulated the condition of the patient leukemia. MedicalResearch.com: What should readers take away from your report? Response: Identification of subtypes accurately is very important for diagnosis, intensity-tailored therapy, and to identify targetable lesions. In this large scale genomic study, we demonstrated the power of using RNA-seq to classifying B-ALL and established a revised B-ALL taxonomy with 23 distinct subtypes. We identified 8 novel subtypes, including two defined by PAX5 alterations. Through in vitro and in vivo experiments, we demonstrated that PAX5 P80R could impair B cell differentiation and initiate leukemia. Together with the subtype defined by IKZF1 N159Y mutation, we showed for the first time that transcription factor missense mutations could be a subtype defining genetic lesions. MedicalResearch.com: What recommendations do you have for future research as a result of this work? Response:B-ALL classification has been conventionally used in scientific research and clinicaltreatment. However, due to the complexity of genetic alterations and geneexpression profile analysis, a comprehensive and robust classification is stillchallenging for many researchers and clinicians. This study establishes anRNA-seq data based B-ALL classification pipeline, which could assign over 90%of the B-ALL cases into distinct subtypes. The raw sequence data and well-curatedgenetic information of 1,988 B-ALL case have been deposited to public database(https://www.ebi.ac.uk/ega/). The dataare also accessible through an interactive St. Jude data portal (https://pecan.stjude.cloud/proteinpaint/study/PanALL),which serve as invaluable resource for future research and clinical diagnosis. We have identified eight new subtypes in previously uncategorized B-other cases. We described each subtypes’ gene expression signatures, driver genetic lesions and clinical outcomes, but in-depth functional studies and development of customized treatments for the novel subtypes are still needed. The genetic background of patients in each subtype is similar, making it easier to evaluate and compare patients’ response to specific treatments. That should potentially speed-up the development of more effective treatment for these previously uncategorized cases. Despite the progress, about 6% of the B-ALL cases still cannot be classified into any subtypes. We propose to perform more comprehensive genomic analysis, including whole genome sequence, to identify the hidden driver lesions. Ultimately, the goal is to classify all B-ALL patients into distinct subtypes and assign customized regimens for them. MedicalResearch.com: Is there anything else you would like to add? Response: This was an international effort and multiple institutional collaborative project. The participants were St. Jude Children’s Research Hospital, The Children's Oncology Group, ECOG-ACRIN Cancer Research Group, Cancer and Leukemia Group B, M.D. Anderson Cancer Center, University of Toronto, Northern Italian Leukemia Group, Southwestern Oncology Group, Medical Research Council UK and City of Hope. Citation: Abstract presented at the 2018 ASH abstract Publication Number: 565                                                             Submission ID: 111219 Title: Characterization of Novel Subtypes in B Progenitor Acute Lymphoblastic Leukemia Zhaohui Gu, PhD1, Michelle L. Churchman, PhD1, Kathryn G. Roberts, PhD1, Ian Moore, MS1, Xin Zhou, PhD2, Joy Nakitandwe, PhD1, Kohei Hagiwara, MD2, Stephane Pelletier, PhD3, Sebastien Gingras, PhD4, Hartmut Berns, PhD5, Debbie Payne-Turner, BS1, Ashley Hill, BS1, Ilaria Iacobucci, PhD1, Lei Shi, PhD6, Stanley Pounds, PhD6, Cheng Cheng, PhD6, Deqing Pei, MS6, Chunxu Qu, PhD1, Meenakshi Devidas, PhD7, Yunfeng Dai, MS7, Shalini C. Reshmi, PhD8, Julie Gastier-Foster, PhD8, Elizabeth A. Raetz, MD9, Michael J. Borowitz, MD, PhD10, Brent L. Wood, MD, PhD11, William L. Carroll, MD12, Patrick A. Zweidler-McKay, MD, PhD13, Karen R. Rabin, MD, PhD14, Leonard A. Mattano, MD15,Kelly W. Maloney, MD16, Alessandro Rambaldi, MD17, Orietta Spinelli, PhD17, Jerald P. Radich, MD18, Mark D. Minden, MD, PhD19, Jacob M. Rowe, MD20, Selina Luger, MD21, Mark R. Litzow, MD22, Martin S. Tallman, MD23, Janis Racevskis, PhD24, Yanming Zhang, MD25, Ravi Bhatia, MD26, Jessica Kohlschmidt, PhD27, Krzysztof Mrózek, MD, PhD27, Clara D. Bloomfield, MD27, Wendy Stock, MD28, Steven Kornblau, MD29, Hagop M. Kantarjian, MD29, Marina Konopleva, MD29, Williams Evans, PharMD30, Sima Jeha, MD31, Ching-Hon Pui, MD31, Jun Yang, PhD30, Elisabeth Paietta, PhD24, James Downing, MD1, Mary V. Relling, PharMD30, Jinghui Zhang, PhD2, Mignon L. Loh, MD32, Stephen P. Hunger, MD33, Charles Mullighan, MBBS, MD1 1Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 2Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 3Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 4Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261 5Department of Transgenic Core Facility, St. Jude Children’s Research Hospital, Memphis, TN 6Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 7Department of Biostatistics, University of Florida, Gainesville, FL 8Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH 9Division of Pediatric Hematology-Oncology, New York University, New York, NY 10016, 10Division of Hematologic Pathology, Johns Hopkins University, Baltimore, MD 11Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 12Perlmutter Cancer Center, NYU-Langone Health, New York, NY 13ImmunoGen, Inc, Waltham, Massachusetts 14Baylor College of Medicine, Houston, TX 15HARP Pharma Consulting, Mystic, CT 16University of Colorado School of Medicine and Children’s Hospital, Aurora CO 17Hematology and Bone Marrow Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy 18Fred Hutchinson Cancer Research Center, Seattle, WA  19Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 20Hematology, Shaare Zedek Medical Center, Jerlem, Israel  21Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 22Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 23Memorial Sloan Kettering Cancer Center, New York, NY 24Cancer Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 25Cytogenetics Laboratory, Memorial Sloan Kettering Cancer Center 26Division of Hematology-Oncology, University of Birmingham, Alabama 27Comprehensive Cancer Center, The Ohio State University, Columbus, OH  28University of Chicago Medical Center, Chicago, IL  29Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX  30Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN 31Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN 32Department of Pediatrics, UCSF Benioff Children’s Hospital and the Helen Diller Family 33Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website. Read the full article

Dr. List Dr. Alan List MD President and Chief Executive Officer Moffitt Cancer Center Tampa, FL MedicalResearch.com: What is the background for this study?   Response: In patients with lower risk Myelodysplastic Syndromes (MDS), which accounts for the vast majority of patients with MDS overall, the most common symptomatic cytopenia is anemia. These patients, overtime, become dependent upon red blood cell transfusions and with that, they face a risk of iron loading as well as complications that occur with it. The standard first line therapy that we consider for these patients is erythropoietin-stimulating agents (ESAs). Patients who are transfusion dependent have a low response rate to ESAs, and responses are of short duration. There limited effective limited treatment options for those patients unresponsive or lose response to ESAs. For years, we’ve known that the transforming growth factor (TGF)-β pathway play an important pathogenetic role in suppressing red cell maturation and cell survival. Luspatercept is an agent that acts as an erythroid maturation agent by inhibiting the TGF-β signaling pathway by neutralizing a select group of TGF-β superfamily ligands.  MedicalResearch.com: What are the main findings? Response: This was a randomized phase III, placebo-controlled study in patients with lower risk . Myelodysplastic Syndromes  and ring sideroblasts that were transfusion dependent. The primary endpoint for the study was transfusion independence for 8 weeks or longer and overall, 37.9% of patients achieved that endpoint with luspatercept treatment compared to 13.2% in the placebo arm. These results were durable, with about 40% of those patients remaining transfusion free at one year. Additionally, there was a robust rise in hemoglobin - a median of 2.55 grams per deciliter reaching as high as 4.1 grams per deciliter in luspatercept patients achieving RBC transfusion independence. A key secondary endpoint was erythroid hematologic improvement, which was defined by a 4 unit or greater reduction in red blood cell transfusion needs over 8 weeks, or a 1.5 gram per deciliter rise in hemoglobin for those patients with a lower transfusion burden. Overall, erythroid improvement was achieved in 52.9% in patients on the luspatercept arm, compared 11.8% receiving placebo. The safety profile of luspatercept was also quite favorable with no significant differences in treatment-emergent AEs. MedicalResearch.com: What should readers take away from your report? Response: This study tells us that we have a new, potentially effective strategy for people with lower-risk Myelodysplastic Syndromes  with ring sideroblasts who are transfusion dependent. We’ve observed that luspatercept has potentially long-lasting responses in these patients with a favorable safety profile. We also found that serum ferritin levels declined in luspatercept-treated patients over time, whereas they continued to rise on the placebo arm. This has the potential to not only impact the quality of life for these patients but also decrease the risk of iron loading over time. MedicalResearch.com: What recommendations do you have for future research as a result of this work? Response: One of the encouraging parts of this study was that among the two most important determinants of response to ESAs – i.e., transfusion load and serum erythropoietin level – patients who responded to luspatercept responded across all levels of serum erythropoietin, suggesting that this agent may whave greater activity in the upfront setting compared to ESA treatment. That is the subject of the next phase three COMMANDS trial.  Disclosures: - I chaired the steering committee for the study.  Citation: The Medalist Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions Pierre Fenaux, MD, PhD1, Uwe Platzbecker, MD2, Ghulam J. Mufti3*, Guillermo Garcia-Manero, MD4, Rena Buckstein, MD, FRCPC5, Valeria Santini6, María Díez-Campelo7*, Carlo Finelli, MD8*, Mario Cazzola9, Osman Ilhan, MD10*, Mikkael A. Sekeres, MD, MS11, José F. Falantes12*, Beatriz Arrizabalaga, MD. PhD13*, Flavia Salvi14*, Valentina Giai14*, Paresh Vyas, MRCP FRCP FRCPath15, David Bowen, MD16, Dominik Selleslag, MD17*, Amy E. DeZern, MD18, Joseph G. Jurcic, MD19, Ulrich Germing, MD20*, Katharina S. Götze, MD21, Bruno Quesnel22, Odile Beyne-Rauzy23*, Thomas Cluzeau, MD, PhD24*, Maria Teresa Voso25, Dominiek Mazure26*, Edo Vellenga27, Peter L Greenberg, M.D.28, Eva Hellstrom Lindberg, MD, PhD29, Amer M. Zeidan, MBBS, MHS30*, Abderrahmane Laadem, MD31, Aziz Benzohra32*, Jennie Zhang31*, Anita Rampersad31*, Peter G. Linde33, Matthew L. Sherman33, Rami S. Komrokji, MD34 and Alan F. List, MD34   The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.   Read the full article

Dr. Sundaram Murali Sundaram, MBA, Ph.D. Director of Real World Value and Evidence Oncology, Janssen MedicalResearch.com: What is the background for this study? Response: Ibrutinib is a novel Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with newly diagnosed chronic lymphocytic leukemia (CLL). Ibrutinib is administered orally while standard of care (CD20 monoclonal antibody-based chemoimmunotherapy ) is administered intravenously. This difference in route of administration impacts what type of benefit covers these treatments (i.e., pharmacy benefit for oral ibrutinib and medical benefit for intravenous CIT). Previous studies evaluating the costs burden of patients treated with ibrutinib versus CIT did not include the full spectrum of real-world healthcare costs. MedicalResearch.com: What are the main findings?  Response: Using a commercial insurance claims database, this study found that patients receiving ibrutinib as a first treatment for CLL had a longer period of time before initiating the next line of treatment than patients taking different medications for the same type of cancer. After 24 months following first treatment initiation, 89% of patients initiated on ibrutinib did not initiate a new treatment, compared to 76% of the patients initiated on CIT. In addition, first line treatment with ibrutinib resulted in net monthly cost savings of greater than $3,700 for the specific health care payers that were included in this research. This monthly savings were driven by lower medical costs of more than $10,500 per patient per month which fully offset the approximately $6,800 higher pharmacy costs per patient per month associated with the use of ibrutinib compared to CIT.  MedicalResearch.com: What should readers take away from your report? Response: This real-world study adds to the efficacy results of the clinical trials, by finding that patients treated with ibrutinib had a longer period of time before initiating the next line of treatment, which can serve as a proxy for progression-free survival (PFS). From a payer’s perspective, the use of ibrutinib is associated with net monthly cost savings as compared to CIT.  MedicalResearch.com: What recommendations do you have for future research as a result of this work?  Response: The current study was conducted among a commercially-insured population. Further research is warranted to evaluate whether these findings are applicable in different populations (e.g., Medicare population). It would also be interesting to see if these results hold in particular subgroups of the population with different disease characteristics (e.g., IGVH-mutated vs. IGVH-unmutated patients). MedicalResearch.com: Is there anything else you would like to add?  Response: From a payer’s perspective, a thorough assessment of the economic implications of treating CLL with ibrutinib requires that total healthcare costs, including both medical and pharmacy costs, needs to be considered. Citation: ASH18 abstract Front-line Ibrutinib Treatment Is Associated with Longer Time to Next Treatment, Net Total Cost Reduction, and Lower Healthcare Resource Utilization Compared to Chemoimmunotherapy in Patients with Chronic Lymphocytic Leukemia Song Wang, PhD1*, Bruno Emond, MSc2*, Hela Romdhani, PhD2*, Patrick Lefebvre, MA2*, Murali Sundaram, MBA, PhD1* and Anthony R Mato, MD3 Janssen Scientific Affairs, Horsham, PA Analysis Group, Inc, Montreal, QC, Canada Memorial Sloan Kettering Cancer Center, New York, NY  The information on MedicalResearch.com is provided for educational purposes only, and is in no way intended to diagnose, cure, or treat any medical or other condition. Always seek the advice of your physician or other qualified health and ask your doctor any questions you may have regarding a medical condition. In addition to all other limitations and disclaimers in this agreement, service provider and its third party providers disclaim any liability or loss in connection with the content provided on this website.   Read the full article

Dr. Vorhees Peter Voorhees, MD Plasma Cell Disorders Program Department of Hematologic Oncology and Blood Disorders Levine Cancer Institute Atrium Health MedicalResearch.com: What is the background for this study? Response: All multiple myeloma arises from its precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Although the rate of progression to multiple myeloma for patients with MGUS is low (~5% over 5 years), patients with SMM have a ~50% likelihood of requiring therapy for their multiple myeloma within the first 5 years of diagnosis. For those at intermediate to high risk of disease progression, early intervention to delay progression of disease, thereby averting disease-related morbidities related and potentially changing the natural course of the disease, is highly desirable. On the other hand, given the fact that these patients are by definition asymptomatic and would otherwise be monitored off treatment, it is critical that any intervention applied in this group of patients is well tolerated. Daratumumab is a highly attractive candidate in this particular space, because it has single agent activity in heavily-pretreated relapsed/refractory multiple myeloma and a favorable side effect profile relative to many other myeloma therapeutics. Additionally, given the importance of impaired immune surveillance in multiple myeloma, the immuno-stimulatory effects of daratumumab in the bone marrow microenvironment could potentially reawaken robust T cell responses to the disease. MedicalResearch.com: What are the main findings? Response: The CENTAURUS study was a randomized phase II trial evaluating 3 different dosing schedules of daratumumab for the treatment of smoldering multiple myeloma at intermediate to high risk of progression to active disease. Patients either received 8 weekly doses (short arm), 8 weekly doses followed by once every 8-week dosing for 19 additional 8-week cycles (intermediate arm) or 8 weekly doses followed by every 2-week dosing for 16 weeks, every 4-week dosing for 32 weeks and then once every 8-week dosing for an additional 13 8-week cycles (intense arm). Importantly, the overall response rate was 56% (27% PRs, 24% VGPRs, 5% CRs/sCRs) and the 24-month progression free survival (progression from SLiM - CRAB criteria of multiple myeloma) was 90% in the intense arm compared with 75% in the short arm. When considering biochemical progression and SLiM - CRAB criteria, the 24-month progression-free survival  was 78% for the intense arm, 27% for the short arm. Serious adverse events related to daratumumab occurred in only 2 of 142 patients and only 2 patients discontinued treatment due to daratumumab-related adverse events. Hematologic treatment-emergent adverse events occurred in Read the full article