1111thth Annual St. Vincent’s Cancer Care Annual St. Vincent’s Cancer CareINDY HEMATOLOGY REVIEW 2014INDY HEMATOLOGY REVIEW 2014

State of Hematology: State of Hematology: Reporting from ASH 2013Reporting from ASH 2013

Ruemu E. Birhiray, MD

Program ChairPartner, Hematology Oncology of Indiana, PC

CEO, Indy Hematology Education, Inc

T-Cell cell SignalingT-Cell cell Signaling

The Cancer Immunoediting Concept.

R D Schreiber et al. Science 2011;331:1565-1570

Published by AAAS

Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B‑cell cancer with T cells expressing anti-CD19 chimeric antigen receptors

Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46

Chimeric Antigen Receptors (CARS)

CAR technology evolution through the generation of more potent CARs. First-generation CARs classically contain only one signaling domain, typically the cytoplasmic signaling

domain of the CD3 TCRζ chain.

Brentjens R J , and Curran K J Hematology 2012;2012:143-151

©2012 by American Society of Hematology

T-Cell vs. CAR-T cell SignalingT-Cell vs. CAR-T cell Signaling

Gene-engineered T cells attacking cancer cells

Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B‑cell cancer with T cells expressing anti-CD19 chimeric antigen receptors

Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46

A 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 receptors

Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46

Eradication of bone marrow lymphoma and normal B cells occurred after anti‑CD19 CAR T cell infusion

The CD19 and CD79a panels of part a are reproduced with permission from American Society of Hematology © Kochenderfer et al. Blood 116, 4099–4102 (2010)

Kochenderfer, J. N. & Rosenberg, S. A. (2013) Treating B‑cell cancer with T cells expressing anti-CD19 chimeric antigen receptors

Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.46

Regression of adenopathy occurred in a patient with CLL after treatment with chemotherapy followed by an infusion of anti‑CD19 CAR T cells and

IL‑2

Parts a, b and c reproduced with permission from American Society of Hematology © Blood 119, 2709–2720 (2012)

Clinical Responses to CTL019 Infusion in Two Children with Relapsed, Chemotherapy-Refractory Acute Lymphoblastic Leukemia (ALL).

Grupp SA et al. N Engl J Med 2013;368:1509-1518

• Chimeric antigen receptor–modified T cells have demonstrated efficacy in CLL

• Efficacy shown in two patients with rapidly progressive, treatment-refractory ALL

• TOXICITIES: Clinical and laboratory evidence of the cytokine-release syndrome and the macrophage activation syndrome

• In 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.

Study Overview

Targeting of BCR Signaling as a Therapeutic Strategy in CLL.

Hallek M Blood 2013;122:3723-3734©2013 by American Society of Hematology

Chronic Lymphocytic LeukemiaChronic Lymphocytic LeukemiaMichael J. Keating, M.B., B.SMichael 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

CLLCLL• CLL10 Trial: Phase III trial interim analysis: FCR has greater

efficacy than Bendamustine/Rituximab in the treatment of advanced CLL

• CLL11 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 CLL

• Idelalisib 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

INDOLENT LYMPHOMA: Myron Czuzcman, MDINDOLENT LYMPHOMA: Myron Czuzcman, MD

Professor of OncologyHead, Lymphoma/Myeloma ServiceHead, Lymphoma Translational Research Laboratory, Department of ImmunologyRoswell Park Cancer Institute, NY

Aggressive LymphomaJohn P. Leonard, M.D.

Richard T. Silver Distinguished Professor of Hematology and Medical OncologyWeill Cornell Medical CollegeProfessor of MedicineWeill Cornell Medical College

LYMPHOMASLYMPHOMAS• REAL07: Lenalidomide plus R CHOP21 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 lesions

• Understanding molecular subsets of lymphoma: BCR pathway mutations and response to Ibrutinib

Blockade of BCR signaling in ABC DLBCL with ibrutinib, an irreversible inhibitor of BTK. Shown is the pilot analysis of ABC DLBCL gene mutations and response to ibrutinib.

Wilson W H Hematology 2013;2013:584-590

©2013 by American Society of Hematology

CARD11 and MYD88 L265P mutant tumors are resistant to ibrutinib suggesting that response requires upstream BCR signaling.

ACUTE LYMPHOCYTIC LEUKEMIA/LYMPHOMAACUTE LYMPHOCYTIC LEUKEMIA/LYMPHOMADr. Jessica AltmanDr. Jessica Altman

Associate Professor,

Medicine, Hematology Oncology Division; Northwestern University

Feinberg School of Medicine, Chicago, IL

MYELODYSPLASTIC SYNDROMEMYELODYSPLASTIC SYNDROME

Richard Stone, MDRichard Stone, MD

Professor, Department of Medicine, Harvard Medical School

Clinical Director, Adult Leukemia Program,

Dana-Farber Cancer Institute,

Boston, MA

Acute Myeloid LeukemiaAcute Myeloid Leukemia

Chief, Leukemia ServiceMemorial Sloan Kettering Cancer Center, New YorkChair of the Leukemia Committee of the Eastern Cooperative Oncology Group (ECOG)

BONE MARROW TRANSPLANTATIONRichard 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

Acute 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 MDS

• Low-dose Quizartinib active and decreases QT Signal in FLT3-ITD+ Adults with relapsed or refractory AML

• Lenalidomide 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)

MYELOMA: Kenneth Anderson, MD

Kraft Family Professor,

Harvard Medical School, Myeloma

Program Director and Chief, Division of Hematologic Neoplasias,

Dana Faber Cancer Institute, Boston, MA

Myeloma• FIRST 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 = .00006)

• Afuresertib, an AKT Inhibitor plus bortezomib/dexamethasone: Active in bortezomib-refractory patients, overcoming resistance to bortezomib.

• SAR650984 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 Myeloma

• Lenalidomide maintenance: Conflicting results ?

Myeloma: Lenalidomide (LM) MaintenanceMyeloma: Lenalidomide (LM) Maintenance

• Meta-analysis: RCTs demonstrates significant improvement in PFS and modest improvement in OS with LM, with increased SPMs.

• IFM 2005-02 Trial Update: Primary analysis LM better PFS, current analysis (2nd PFS); LM appears inferior ? Resistance ?

2nd PFS 2= from 1st to 2nd PFS

IFM 2005-02 Update

CHRONIC MYELOID LEUKEMIA: Dr. Richard Larson

Professor of Medicine,

University of Chicago,

Director, Hematologic Malignancies Program

Chicago, IL

CML• 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 crisis Nilotinib associated with more cardiovascular events compared with imatinib

• DASISION: 4-year follow-up, dasatinib continues to show superior efficacy vs imatinib as frontline treatment of chronic-phase CML

• Observational 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 Months

• PACE: Ponatinib in heavily pretreated CML active with increasing incidence of cardiovascular AEs in 2-year follow-up

• SPIRIT2: Subanalysis, missed or reduced doses of imatinib or dasatinib within first 3 months associated with poorer molecular response

MYELOPROLIFERATIVE DISORDERSDr. Ayalew Tefferi

Professor of MedicineMayo Clinic,

Rochester, MN

T. Howard Lee Keynote LectureT. Howard Lee Keynote Lecture

                              

T. HOWARD LEE, MDFounder and President Emeritus,Hematology Oncology of Indiana, PC

ROSS L. LEVINE, MDLaurence Joseph Dineen Chair in Leukemia ResearchMemorial Sloan Kettering Cancer Center , New York

Disorders Associated with Mutations of JAKs and STATs.

O'Shea JJ et al. N Engl J Med 2013;368:161-170

JAK-Related Disorders and JAK Inhibitors.

O'Shea JJ et al. N Engl J Med 2013;368:161-170

NOT SO BENIGN HEMATOLOGY

Dr. Robert Brodsky

Director, Division of HematologyProfessor of Medicine and OncologyThe Johns Hopkins Family Professor,

Johns Hopkins University,

Baltimore, MD

BENIGN HEMATOLOGYBENIGN HEMATOLOGYCraig M Kessler, MDCraig M Kessler, MD

Professor of Medicine and Pathology Director of Division of Coagulation and Director of Therapeutic and Cellular Apheresis Unit Director of the Comprehensive Hemophilia and Thrombophilia Treatment Center, Georgetown University Medical Center and the Lombardi Comprehensive Cancer Center, Washington, DC, USA

American 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.

And the Champions are …..And the Champions are …..

'I'm just about that action, boss'

SAVE THIS DATESAVE THIS DATE ! !

12th Annual St. Vincent’s Hematology Review 2014

(http://www.indyhematologyreview.com)

March 7th, 2015

The Conrad Hotel,

50 Washington Street,

Indianapolis, IN 46204