Presentation on theme: "11th Annual St. Vincent’s Cancer Care INDY HEMATOLOGY REVIEW 2014 State of Hematology: Reporting from ASH 2013 Ruemu E. Birhiray, MD Program Chair Partner,"— Presentation transcript:
111th Annual St. Vincent’s Cancer Care INDY HEMATOLOGY REVIEW State of Hematology: Reporting from ASH 2013Ruemu E. Birhiray, MDProgram ChairPartner, Hematology Oncology of Indiana, PCCEO, Indy Hematology Education, Inc
4The Cancer Immunoediting Concept. The cancer immunoediting concept. Cancer immunoediting is an extrinsic tumor suppressor mechanism that engages only after cellular transformation has occurred and intrinsic tumor suppressor mechanisms have failed. In its most complex form, cancer immunoediting consists of three sequential phases: elimination, equilibrium, and escape. In the elimination phase, innate and adaptive immunity work together to destroy developing tumors long before they become clinically apparent. Many of the immune molecules and cells that participate in the elimination phase have been identified, but more work is needed to determine their exact sequence of action. If this phase goes to completion, then the host remains free of cancer, and elimination thus represents the full extent of the process. If, however, a rare cancer cell variant is not destroyed in the elimination phase, it may then enter the equilibrium phase, in which its outgrowth is prevented by immunologic mechanisms. T cells, IL-12, and IFN-γ are required to maintain tumor cells in a state of functional dormancy, whereas NK cells and molecules that participate in the recognition or effector function of cells of innate immunity are not required; this indicates that equilibrium is a function of adaptive immunity only. Editing of tumor immunogenicity occurs in the equilibrium phase. Equilibrium may also represent an end stage of the cancer immunoediting process and may restrain outgrowth of occult cancers for the lifetime of the host. However, as a consequence of constant immune selection pressure placed on genetically unstable tumor cells held in equilibrium, tumor cell variants may emerge that (i) are no longer recognized by adaptive immunity (antigen loss variants or tumors cells that develop defects in antigen processing or presentation), (ii) become insensitive to immune effector mechanisms, or (iii) induce an immunosuppressive state within the tumor microenvironment. These tumor cells may then enter the escape phase, in which their outgrowth is no longer blocked by immunity. These tumor cells emerge to cause clinically apparent disease. [Figure adapted from (18)]R D Schreiber et al. Science 2011;331:Published by AAAS
5Chimeric Antigen Receptors (CARS) CARs are composed of an Ag-specific binding domain (most commonly a single-chain–variable fragment derived from the fusedvariable heavy- and light-chain domains of a tumor-targeted mAb) fused to a transmembrane domain followed by one or morecytoplasmic signaling domains (Figure 1). In initial designs, CARs were designed to contain a single cytoplasmic signaling domain derived most commonly from the TCR-derived CD3 chain. These “first-generation” CARs, when expressed in T cells, mediate a primary activation signal upon encounter with the targeted Ag termed signal 1), but in the absence of additional costimulation (ie, signal 2) undergo activation-induced apoptosis or senescence, termed anergy. To address this limitation, we and others further modified CAR structure to add additional cytoplasmic signaling domains, including T cell– costimulatory signaling domains (eg, CD28, 4-1BB, or OX-40), resulting in “second-generation” CARs. These second-generation CARs containing costimulatory signaling domains are capable of delivering both signal 1 and signal 2 uponencounter with the targeted tumor Ag. Given the promising preclinical results with T cells modified to express second generation CARs, investigators have favored this CAR design in initial clinical trials. Further modification of CAR design includesadding more than one costimulatory signaling domain in addition to the CD3 chain, resulting in “third-generation” CARs; this has also been translated to the clinical setting.Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B‑cell cancer with T cells expressing anti-CD19 chimeric antigen receptorsNat. Rev. Clin. Oncol. doi: /nrclinonc
7T-Cell vs. CAR-T cell Signaling a | T cell receptor (TCR) genes, made up of α- and β-chains, can be derived from tumour-specific T cells, which can naturally occur in humans, or from the immunization of human leukocyte antigen (HLA)-transgenic mice. Alternatively, they can be derived from screening bacteriophage libraries of antibodies. The α- and β-chains associate with the γ-, δ-, ε- and ζ-chains of the CD3 complex. When the TCR encounters a processed tumour antigen peptide fragment displayed on the major histocompatibility complex (MHC) of the tumour cell, phosphorylation of immunoreceptor tyrosine-base activation motifs (ITAMs) occurs, leading to a cascade of intracellular signalling that results in the release of cytokines and cytotoxic compounds from T cells. b | Chimeric antigen receptors (CARs) are composed of a single-chain antibody variable fragment (scFv) extracellular domain linked through hinge and transmembrane domains to a cytoplasmic signalling region. Genes encoding the scFv are derived from a B cell that produces a tumour-specific antibody. An scFv is shown linked by a CD8 hinge to transmembrane cytoplasmic signalling regions derived from CD3ζ. CARs usually exist as a dimer, and they recognize tumour antigen directly (with no requirement for MHC) on the surface of a tumour cell. MHCI, MHC class I.
8Gene-engineered T cells attacking cancer cells The T cells depicted here (shown in beige) have been genetically modified to express an antigen receptor and additional genes to enable responses against cancer cells (blue). The schematic represents a timeline of progress in the research field, with some of the earliest strategies showing T cells modified with one or two genes to address individual issues such as specificity, proliferation, elimination of self-reactive T cells and the ability to circumvent inhibition mediated by transforming growth factor-β (TGFβ) (part A). In the future, it may be possible, with advances in gene-transfer technology, to modify T cells to express many genes to address several issues necessary for an effective response against tumours (part B). The six functions chosen in the representation of a futuristic T cell (which have all been shown to work individually when engineered into T cells) include genes encoding two chimeric antigen receptors (CARs) (part a), specific for two tumour-associated antigens, which together transmit a primary activation signal (signal 1) and a co-stimulatory signal (signal 2). Signal 1 alone is suboptimal and will not in itself activate the T cells, but both signals together will cause the activation and the secretion of cytokines and perforin-containing lytic granules against cancer cells. A transgene encoding a chemokine receptor (part b) facilitates the migration of T cells towards chemokines that are secreted by cells within tumours. Normal tissue cells (part c) are not damaged by T cells as long as normal cells express one antigen but not both. The T cell is genetically instructed (part d) to secrete a cytokine, such as interleukin-12 (IL-12), on encounter with tumours. IL-12 can serve to modify regulatory cells, such as myeloid cells, to render the tumour microenvironment less suppressive to immunity. IL-12 can also act as a growth factor for T cells. Genes to upregulate expression (part e) of anti-apoptotic molecules — for example, BCL-2 — can lead to the increased survival and proliferation of T cells. Cell surface molecules (part f), such as CD20 in this example, can be genetically conferred on T cells. These molecules can track T cells after transfer to patients, or can be used to deplete T cells (for example, using rituximab) if T cell-mediated toxicity is experienced. TAM, tumour-associated macrophage.
9A schematic of anti‑CD19 CAR T cell therapy Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B‑cell cancer with T cells expressing anti-CD19 chimeric antigen receptorsNat. Rev. Clin. Oncol. doi: /nrclinonc
12Clinical Responses to CTL019 Infusion in Two Children with Relapsed, Chemotherapy-Refractory Acute Lymphoblastic Leukemia (ALL).Study OverviewChimeric antigen receptor–modified T cells have demonstrated efficacy in CLLEfficacy shown in two patients with rapidly progressive, treatment- refractory ALLTOXICITIES: Clinical and laboratory evidence of the cytokine-release syndrome and the macrophage activation syndromeIn vivo expansion of CTL019, persistent B-cell aplasia, and prominent antileukemic activity suggest that CTL019 cells have substantial and sustained effector functions in children with advanced ALL.Figure 1 Clinical Responses to CTL019 Infusion in Two Children with Relapsed, Chemotherapy-Refractory Acute Lymphoblastic Leukemia (ALL). The two children, both of whom had CD19+ B-cell–precursor ALL, received infusions of CTL019 cells on day 0. Panel A shows changes in serum lactate dehydrogenase (LDH) levels and body temperature after CTL019 infusion, with the maximum temperature per 24-hour period indicated by the circles. Patient 1 was given methylprednisolone starting on day 5 at a dose of 2 mg per kilogram of body weight per day, tapered to 0 by day 12. On the morning of day 7, etanercept was given at a dose of 0.8 mg per kilogram. At 6 p.m. on day 7, tocilizumab was given at a dose of 8 mg per kilogram. A transient improvement in pyrexia occurred after the administration of glucocorticoids on day 5, with complete resolution of fevers occurring after the administration of cytokine-directed therapy. Panel B shows serum levels of cytokines and inflammatory markers measured at the indicated time points after CTL019 infusion. Cytokine values are shown with the use of a semilogarithmic plot indicating change from baseline. Baseline values (on day 0 before infusion) in Patient 1 and Patient 2, respectively, were as follows: interleukin-1β, 0.9 and 0.2 pg per milliliter; interleukin-6, 4.3 and 1.9 pg per milliliter; interferon-γ, 0.08 and 0.23 pg per milliliter; tumor necrosis factor α (TNF-α), 1.5 and 0.4 pg per milliliter; interleukin-2 receptor α, and pg per milliliter; interleukin-2, 0.7 and 0.4 pg per milliliter; interleukin-10, 9.9 and 2.3 pg per milliliter; and interleukin-1 receptor α, 43.9 and 27.9 pg per milliliter. Pronounced elevations in a number of cytokines and cytokine receptors developed in both patients, including soluble interleukin-1 receptor α; interleukin-2 receptor; interleukin-2, 6, and 10; TNF-α; and interferon-γ. Panel C shows changes in the circulating absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and white-cell count. The increase in the ALC was primarily from activated CTL019 T lymphocytes.Grupp SA et al. N Engl J Med 2013;368:
14Chronic Lymphocytic Leukemia Michael J. Keating, M.B., B.S. Professor of Medicine and Internist, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
15CLLCLL10 Trial: Phase III trial interim analysis: FCR has greater efficacy than Bendamustine/Rituximab in the treatment of advanced CLLCLL11 Trial: Obinutuzumab (GA101) plus chlorambucil superior to rituximab plus chlorambucil or chlorambucil alone in previously untreated CLL.Ibrutinib plus rituximab shows high emission rates (90%) and good tolerability in patients with high-risk CLLIdelalisib plus rituximab improves outcomes in relapsed CLL: ORR: > 90%, CR: 10%ABT-199: Active in relapsed/refractory CLL or SLL: ORR 84%, including CR 23%. Similar efficacy in high-risk patients with del(17p) and fludarabine-refractory disease
16INDOLENT LYMPHOMA: Myron Czuzcman, MD Professor of Oncology Head, Lymphoma/Myeloma Service Head, Lymphoma Translational Research Laboratory, Department of Immunology Roswell Park Cancer Institute, NY
17Aggressive Lymphoma John P. Leonard, M.D. Richard T. Silver Distinguished Professor of Hematology and Medical Oncology Weill Cornell Medical CollegeProfessor of Medicine Weill Cornell Medical College
18LYMPHOMASREAL07: Lenalidomide plus RCHOP21 effective in poor prognosis elderly untreated patients with DLBCL.2-year PFS in intermediate high/high (IH/H) International Prognostic Index (IPI) risk: 74%2-year PFS in non–germinal center (GC) group: 81%ORR in both GC and non-GC groups: 88%Idelalisib, a novel PI3Kδ inhibitor, improves ORR and PFS in double-refractory indolent NHL.Brentuximab vedotin induces ORR of 89% and CR of 63% in patients with HL 60 years of age or older, 100% of patients experienced reduction in size of target lesionsUnderstanding molecular subsets of lymphoma: BCR pathway mutations and response to Ibrutinib
20ACUTE LYMPHOCYTIC LEUKEMIA/LYMPHOMA Dr. Jessica Altman Associate Professor,Medicine, Hematology Oncology Division; Northwestern UniversityFeinberg School of Medicine, Chicago, IL
21MYELODYSPLASTIC SYNDROME Richard Stone, MD Professor, Department of Medicine, Harvard Medical SchoolClinical Director, Adult Leukemia Program,Dana-Farber Cancer Institute,Boston, MA
22Acute Myeloid Leukemia Chief, Leukemia ServiceMemorial Sloan Kettering Cancer Center, New YorkChair of the Leukemia Committee of the Eastern Cooperative Oncology Group (ECOG)
23BONE MARROW TRANSPLANTATION Richard Childs, MD Clinical Director, National Heart, Lung, and Blood Institute (NHLBI)Senior Clinical Investigator ,Commander, United States Public Health Service,National Institutes of Health, Bethesda, MD
24Acute Leukemias/MDS/MPD T Cells engineered to express a CD19-Targeting CAR induce proliferation of in vivo T Cells, CRs, and durable persistence without GVHD in relapsed, refractory ALL.AML Meta-Analysis: Gemtuzumab Ozogamicin plus induction chemotherapy improves OS in favorable or intermediate-risk cytogenetics.Oral dual inhibitor of p38 MAPK and Tie2: ARRY-614 active in low- to intermediate-1–Risk MDSLow-dose Quizartinib active and decreases QT Signal in FLT3-ITD+ Adults with relapsed or refractory AMLLenalidomide plus 7+3; High CRs and tolerable in elderly with higher-risk MDS and AML.Puzzle solved ?: Somatic mutations in CALR (Calreticulin) found in a majority of patients with MPNs with nonmutated JAK2 and MPL.How old is old ?: Encouraging outcomes in older patients following nonmyeloablative haploidentical blood or marrow transplantation, similar outcomes for 273 patients irrespective of age 50s, 60s, and 70s (39, 36, and 39%, respectively)To more fully demonstrate the utility of haploidentical bone marrow or peripheral blood stem cell transplants (haploBMT) as an alternative to fully matched transplants, this study evaluated nonmyeloablative, related haploBMT (with post-transplantation cyclophosphamide) among patients aged 50 – 75 with poor-risk hematologic malignancies.Results of 273 such transplants performed at Johns Hopkins were compared to determine the impact of older age on outcomes.The two-year probability of progression-free survival was very similar among patients in their 50s, 60s, and 70s (39, 36, and 39%, respectively), as was the two-year probability of overall survival (51, 56, and 44%).Among these age groups, there were also no statistically significant differences in the risks of non-relapse death or severe graft-versus-host disease.“The similarly positive outcomes we observed among patients in their 50s, 60s, and 70s clearly illustrate that advanced age need no longer be a significant barrier to successful outcomes after half-matched BMT,” said study author Yvette Kasamon, MD, of the Johns Hopkins Kimmel Cancer Center in Baltimore.“These results underscore that a reduced-intensity, related haploidentical transplant should be considered a very reasonable treatment option for suitable patients up to at least age 75 who require a transplant.”
25MYELOMA: Kenneth Anderson, MD Kraft Family Professor,Harvard Medical School, MyelomaProgram Director and Chief, Division of Hematologic Neoplasias,Dana Faber Cancer Institute, Boston, MA
26MyelomaFIRST trial: Continuous lenalidomide plus low-dose dexamethasone (Rd) lowered risk of disease progression vs standard MPT as a first-line therapy in patients with newly diagnosed MM who were either elderly or not considered candidates for stem cell transplantation (HR: 0.72; P = )Afuresertib, an AKT Inhibitor plus bortezomib/dexamethasone: Active in bortezomib-refractory patients, overcoming resistance to bortezomib.SAR Anti-CD38 antibody well tolerated and active in Myeloma.Oral ixazomib plus lenalidomide and dexamethasone active first line therapy or as single agent and in combination with dexamethasone in patients with relapsed myeloma and no exposure or limited previous exposure to bortezomib.Panobinostat and carfilzomib combination safe and effective in patients with relapsed or relapsed/refractory Multiple MyelomaLenalidomide maintenance: Conflicting results ?
27Myeloma: Lenalidomide (LM) Maintenance Meta-analysis: RCTs demonstrates significant improvement in PFS and modest improvement in OS with LM, with increased SPMs.IFM Trial Update: Primary analysis LM better PFS, current analysis (2nd PFS); LM appears inferior ? Resistance ?IFM Update2nd PFS 2= from 1st to 2nd PFS
28CHRONIC MYELOID LEUKEMIA: Dr. Richard Larson Professor of Medicine,University of Chicago,Director, Hematologic Malignancies ProgramChicago, IL
29CML 5-year follow-up of ENESTnd: Trend for improved PFS and OS Significantly higher rates of EMR, MMR, and deeper molecular responses including molecular responses ≥ 4.5 logs (MR4.5)Reduced risk of disease progression to AP/blast crisisNilotinib associated with more cardiovascular events compared with imatinibDASISION: 4-year follow-up, dasatinib continues to show superior efficacy vs imatinib as frontline treatment of chronic-phase CMLObservational study: Reduction of BCR-ABL Level < 10% by 6 months of treatment improves long-term clinical outcome for CML patients with suboptimal response at 3 MonthsPACE: Ponatinib in heavily pretreated CML active with increasing incidence of cardiovascular AEs in 2-year follow-upSPIRIT2: Subanalysis, missed or reduced doses of imatinib or dasatinib within first 3 months associated with poorer molecular response
30MYELOPROLIFERATIVE DISORDERS Dr. Ayalew Tefferi Professor of Medicine Mayo Clinic,Rochester, MN
31T. Howard Lee Keynote Lecture ROSS L. LEVINE, MDLaurence Joseph Dineen Chair in Leukemia ResearchMemorial Sloan Kettering Cancer Center , New YorkT. HOWARD LEE, MDFounder andPresident Emeritus,Hematology Oncology of Indiana, PC
32Disorders Associated with Mutations of JAKs and STATs. Figure 1 Disorders Associated with Mutations of JAKs and STATs. A major subset of cytokines includes those that signal through Janus kinases (JAKs) and signal transducers and activators (STATs). These cytokines include (but are not limited to) interferons, such as interferon-γ, interferon-α, and interferon-β; interleukin-6; erythropoietin; growth hormone; interleukin-2; and interleukin-7. There are four JAKs: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Activated JAKs phosphorylate (P) and activate STATs and other pathways. Some JAKs are associated with many different cytokine receptors, but JAK3 associates with only one subunit, the common interleukin-2Rγ chain, or γc. Loss-of-function mutations (denoted by a solid line, with an X) of the genes encoding γc and JAK3 result in severe combined immunodeficiency (SCID). Mutation of TYK2 also results in immunodeficiency. Gain-of-function JAK2 mutations (denoted by an orange line) underlie polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF). Constitutive activation and mutation of JAKs is also associated with a variety of cancers. Activated JAKs, in turn, activate STATs and other pathways. Activated STATs translocate to the nucleus, bind DNA, and regulate gene expression. Mutations of STAT1 result in several distinct disorders. Autosomal dominant loss-of-function mutations result in susceptibility to mycobacteria only. Autosomal recessive mutations cause susceptibility to mycobacteria and viruses. In contrast, autosomal dominant gain-of-function mutations cause chronic mucocutaneous candidiasis, other infections, and aneurysms. Loss-of-function mutations of STAT3 result in the hyper-IgE syndrome. Mutations in STAT3 also cause large granular lymphocytic (LGL) leukemia. Constitutive STAT3 and STAT5 activation (an orange line) is associated with many cancers. Mutations of STAT5B result in a syndrome characterized by dwarfism and autoimmunity. In addition to their effect on STATs, JAKs can have direct nuclear effects by phosphorylating histones.O'Shea JJ et al. N Engl J Med 2013;368:
33JAK-Related Disorders and JAK Inhibitors. Table 1 JAK-Related Disorders and JAK Inhibitors.O'Shea JJ et al. N Engl J Med 2013;368:
34NOT SO BENIGN HEMATOLOGY Dr. Robert Brodsky Director, Division of Hematology Professor of Medicine and Oncology The Johns Hopkins Family Professor,Johns Hopkins University,Baltimore, MD
35BENIGN HEMATOLOGY Craig M Kessler, MD Professor of Medicine and PathologyDirector of Division of Coagulation and Director of Therapeutic and Cellular Apheresis UnitDirector of the Comprehensive Hemophilia and Thrombophilia Treatment Center, Georgetown University Medical Center and the Lombardi Comprehensive Cancer Center, Washington, DC, USA
36American Society of Hematology Choosing Wisely®: Five Things Physicians and Patients Should Question Don’t transfuse more than the minimum number of red blood cell (RBC) units necessary to relieve symptoms of anemia or to return a patient to a safe hemoglobin range (7 to 8 g/dL in stable, non-cardiac in-patients).Don’t test for thrombophilia in adult patients with venous thromboembolism (VTE) occurring in the setting of major transient risk factors (surgery, trauma or prolonged immobility).Don’t use inferior vena cava (IVC) filters routinely in patients with acute VTE.Don’t administer plasma or prothrombin complex concentrates for non-emergent reversal of vitamin K antagonists (i.e. outside of the setting of major bleeding, intracranial hemorrhage or anticipated emergent surgery).Limit surveillance computed tomography (CT) scans in asymptomatic patients following curative-intent treatment for aggressive lymphoma.
37And the Champions are …..'I'm just about that action, boss'
38SAVE THIS DATE ! 12th Annual St. Vincent’s Hematology Review 2014 (http://www.indyhematologyreview.com)March 7th, 2015The Conrad Hotel,50 Washington Street,Indianapolis, IN 46204