Your Speaker. Outline 10/2/2017. Myelodysplastic Syndromes and Myeloid Neoplasms. Introduction and classifications Epidemiology Presentation Workup

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1 Myelodysplastic Syndromes and Myeloid Neoplasms Abdulraheem Yacoub, MD Associate Professor Of Medicine Clinical Director of Ambulatory Hematology clinics The University of Kansas Cancer Center Your Speaker Abdulraheem Yacoub, MD Associate Professor of Medicine Board certified in Internal Medicine, Medical Oncology, and Hematology. Medical Director of Outpatient Hematology Clinic, The University of Kansas Cancer Center. Associate Program Director, Hematology and Oncology Fellowship Program Memberships: SWOG Leukemia Committee Leukemia and Lymphoma Society Board of Trustees. Outline Introduction and classifications Epidemiology Presentation Workup Diagnosis Prognosis Biology Treatment options 1

2 Classification of Human Cancers Classification of Myeloid Cancers Liquid Tumors; Hematologic Cancers e.g. Lymphoma Leukemias Multiple Myeloma Solid Tumors; e.g. Breast Cancer Lung Cancer Colorectal cancer Lymphoid Myeloid MDS Progression to Acute Myeloid Leukemia Common Myeloid Progenitor Hematopoietic Stem Cell 1 st Hit Cytogenetic, genetic and/or epigenetic MDS Stem Cell Common Myeloid Progenitor 2 nd Hit Aberrant growth signals and reduced apoptosis Leukemic Stem Cell MDS is Cancer A heterogeneous group of malignant stem cell disorders characterized by dysplastic and ineffective hematopoiesis. A Syndrome Megakaryocyte RBC Progenitor Myeloblast Megakaryocyte RBC Progenitor Myeloblast Platelets Red Blood Cells Monocyte Basophil Neutrophil Platelets Red Blood Cells Neutrophil Proliferation of Blasts AML Macrophage Eosinophil 7 1. Lichtman MA, et al. Williams Hematology. New York, NY: McGraw-Hill; Blood. 2013;121(19): Chan SM, Majeti R. Int J Hematol. 2013;98:

3 How myelodysplastic syndrome was first described to patients. Note that patients could select more than one answer th WHO Classification Sekeres M A et al. The Oncologist 2011;16: Myelodysplastic Syndromes (MDS) Recognized for over 50 years, termed Preleukemia, Smoldering Leukemia, Oligoblastic Leukemia, and Refractory Anemia. Denotes a variable risk of progression to: BM failure AML: Severe cytopenia, increased blasts, or cytogenetic abnormalities correlate with poor outcomes not different from acute leukemia. Lack of these features is associated with long survival. Epidemiology The precise incidence of de novo MDS is not known. Believed to be underestimated SEER data Estimated to be 3.3 (2-12.6) per 100,000 >60,000 individuals in USA >10,000 new cases /year Overall relative 3-year survival was 45%. The median age is 65 years, with a male predominance Incidence increases with age Rollison D et al. Blood. 2008;112(1):45. Williamson PJ, et al. Br J Haematol. 1994;87(4):743. 3

4 Epidemiology AGE Incidence per 100,000 < >80 Clinical Presentation and Diagnosis No specific associated symptoms or signs. Clinical Features of MDS Anemia is hallmark - challenging to treat, many will require RBC transfusions Most diagnoses are made subsequent to abnormal routine laboratory testing showing quantitative changes of one or more blood elements. Definitions: ANEMIA : decreased Red Blood Cells /Hemoglobin THROMBOCYTOPENIA: decreased Blood Platelets NEUTROPENIA: decreased White Blood Cells (Neutrophils) PNH Iron Overload Immune Disorders Thrombocytopenia: bleeding Anemia AML Transformation Hyperuricemia Neutropenia- infections 1. Fenaux and Ades, Blood 2013;121:

5 Clinical Presentation and Diagnosis Symptoms are related to the degree of anemia, less commonly due to thrombocytopenia, and neutropenia. Associated constitutional symptoms, or autoimmune deregulation are uncommon. Clinical Presentation and Diagnosis Findings at time of diagnosis: Anemia is almost uniformly present: % Pancytopenia 50 % Isolated neutropenia, thrombocytopenia, or monocytosis in the absence of anemia: Less than 5 % Predisposing Factors Advanced age Mutagen exposure: Chemotherapy Alkylators Topoisomerase II inhibitors Radiation exposure Hematopoietic cell transplantation Environmental Benzene Tobacco use: (HR 1.68, 3.17) Other primary hematologic disorders: Aplastic anemia Paroxysmal nocturnal hemoglobinuria (PNH) Myloproliferative disorders Heridatory predisposition: DNA repair defects Congenetal and genetic disorders Obesity (HR 1.15 and 2.18 ) Ma X, et al. Am J Epidemiol. 2009;169(12):

6 Diagnosis and Classification Careful evaluation of the peripheral smear. Evaluation of the duration of abnormal blood counts and other potential causes Exclusion of confounding factory: nutritional deficiencies, co-morbidities, chronic infections or autoimmune disorders. Diagnosis and Classification Diagnosis is confirmed by a BM biopsy and aspirate. Identify and quantify dysplastic features, and involved lineages. Assess marrow cellularity, fibrosis, and topography Sample for cytogenetic studies Molecular testing, mutation analysis and DNA sequencing Classification Has prognostic relevance. Bennett JM, et al. Br JHaematol. 1982;51:

7 MDS subtype WHO Classification 2016 MDS with single lineage dysplasia MDS with multilineage dysplasia MDS with ring sideroblasts MDS with excess blasts MDS unclassified MDS with isolated del(5q) Abbreviation Notes MDS-SLD MDS-MLD MDS-RS MDS-EB MDS-U - 1 dysplastic lineage and 1 2 cytopenias 2 3 dysplastic lineages and 1 3 cytopenias 15% ring sideroblasts, or 5% ring sideroblasts if mutation of SF3B1 present 5 9% BM blasts (MDS-EB-1) or 10 19% BM blasts (MDS-EB-2) del(5q) cytogenetic abnormality alone or with 1 additional abnormality other than 7 or del(7q) MDS/MP N MDS ICUS / CHIP AML- MDS-r AML AA 7

8 Idiopathic Cytopenia of Undetermined Significance - ICUS Establishing MDS diagnosis may be challenging Earlier diagnosis - insufficient dysplasia, absent cytogenetic changes Must have relevant cytopenia, persists 6 months Hb <11 g/dl, ANC <1.5 x 10 9 /L platelets <100,000 x 10 9 /L Cannot be explained by other diseases Does not meet clear definition of MDS Clonal hematopoiesis of indeterminate potential (CHIP) Presence of a somatic mutation known to be associated with hematologic malignancy in absence of definitive diagnostic criteria of MDS Risk of developing clinical heme malignancy elevated 13X Risk further increased when variant allele fraction 0.10 risk of developing heme malignancy 0.5%-1% per year Obtain gene mutation analysis in ICUS 31 8

9 Prognosis International Prognostic Scoring System (IPSS) was developed by The International MDS Risk Analysis Workshop. Time in Years Median OS AML in 25% low risk Int Int high risk Age Median OS < > > Greenberg P, et al. Blood. 1997;89: IPSS-Revised Survival based on IPSS-R prognostic risk-based categories. n=7012. AML evolution based on IPSS-R prognostic risk-based categories. n=6485 Greenberg PL, et al. Blood June 27, 2012 Greenberg PL, et al. Blood June 27,

10 Other Prognostic Models WHO PROGNOSTIC SCORING SYSTEM (WPSS) MD ANDERSON CANCER CENTER MDS MODEL Individual risk factors: Increased age Poor performance status, presence of comorbidities Total WBC >20,000/microL, Eosinophilia (>350/microL) and basophilia (>250/microL) Absolute lymphocyte count <1200/microL Severity of anemia, Transfusion dependence Refractory or severe (<30,000/microL) thrombocytopenia CD34 positivity of bone marrow nucleated cells Gene expression profiling Increased DNA methylation Following treatment failure with decitabine Increased expression of the Wilms' tumor gene (WT1) Increased serum beta-2 microglobulin concentration Mutations of the FLT3, EZH2, or ETV6 genes, Absence of TET2 mutations Presence of marrow fibrosis Biology Advances in the identification of recurring chromosomal abnormalities, translocations, mutations, and other molecular genetic defects have provided great insight into the pathobiology of MDS. Cytogenetic Defects Chromosomal abnormalities can be detected in 50% of de novo MDS, and 70% in t-mds. Diagnosis Classification Prognosis Predictive of response. 10

11 Cytogenetic Defects Cytogenetic abnormalities in MDS are among the most valuable independent prognostic determinants. Cytogenetic Defects Del 5q The most common chromosomal abnormality (15 %) Cytogenetic risk groups are defined as Good: normal, isolated - Y, del(5q), and del(20q) Poor: complex [ 3 abnormalities], any chromosome 7 anomalies Double with - Complex: 3 Complex: > 3 Intermediate: all other abnormalities 7/del(7q), abnormalities, abnormalities, 2.10% 7% 1.20% Any other single or Double with double, del(5q), 1.60% 12.50% +19, 0.40% i(17q), 0.40% inv(3)/t(3q)/del( 3q), 0.40% del(7q), 0.50% del(12q), 0.60% Normal 50% del(11q), 0.70% 7, 2% del(20q), 1.70% Y, 2.20% +8, 4.70% del(5q), 6.50% Jerez A, et al.j Clin Oncol. 2012;30(12):1343 Bejar R, ET AL. J Clin Oncol. 2011;29(5):504 Ebert. Sem. In Onc. Volume 38, Issue 5, Oct. 2011, Epigenetic Modifications Mutations Epigenetic Modifications The two prominent modes of epigenetic regulation involve DNA methylation and histone modifications Figueroa et al. Blood 114(16):

12 Point Mutations BM samples 439 patients, evaluated by next-generation sequencing for somatic mutations in 18 genes 51% of all patients had at least one point mutation Next Gen Sequencing: 80-90% show genetic abnormalities Mutations detected in nearly all MDS 845/944 (90%) patients with > 1 mutation; median 3 (0-12) Six most frequently (>10%) mutated genes: TET2, SF3B1, ASXL1, SRSF2, DNMT3A, RUNX1 BejarR, et al. N Engl J Med Jun 30;364(26): Haferlach et al. Leukemia Leukemia-Free Survival Relative to the Number of Oncogenic Mutations Clinical Impact of TP53 Mutations in MDS OS: All Patients PFS: All Patients OS: Poor Risk Cytogen etics OS: 5qalone Papaemannuil et al, Blood, 2013 Kulasekararaj et al, Br J Haematol

13 Treatment Risk-based therapy Age, performance status, comorbidities influence the benefit/toxicity ratio of medical interventions. Rate of decline of blood counts Patient s wishes and preferences. HSCT is the only known curative modality, and remains underutilized. Treatment Supportive Measures Supportive care Low intensity therapy Hematopoietic growth factors Immune modulatory agents Hypomethylating agents ATG / Immune supression High intensity therapy Intensive combination chemotherapy HSC transplantation Clinical trials Low risk disease Stable, mild cytopenias Low leukemic transformation risk High risk disease Severe symptomatic cytopenias High leukemic transformation risk Clinical monitoring Psychosocial support Quality of life assessment Blood products transfusion Antibiotics Antifibrinolytic therapy Cytokines and GF support 13

14 Iron chelation Increase in free, non transferrin-bound iron (NTBI) due to transfusions and ineffective erythropoiesis. Labile plasma iron (LPI), mediates tissue damage through superoxide generation. Iron chelation: Feasible, Effective Benefit NCCN task force recommend considering chelation therapy in patients with low/int-1 risk with> 20 units of RBC transfusions, or ferritin levels >2500 ng/ml, aiming to decrease the levels to less than1000 ng/ml. Erythropoiesis stimulating agents (ESA) ESAs ± G-CSF are effective in raising hemoglobin levels / decreasing transfusion requirements in low- or int-1 risk MDS. Doses needed are markedly larger than in CKD. Epoetin 40,000 to 60,000 Units 1-3 times /week. Darbepoetin 150 to 300 mcg weekly. Median time to response: 6-8 weeks G-CSF might have a synergistic erythropoietic activity EPO level >500 mu/ml usually predictive of lack of response Ross SD, et al. Oncologist. 2007;12(10):1264. Mantovani L, Lentini G, et al.br J Haematol. 2000;109(2):367. Casadevall N et al. Blood Jul 15;104(2): Erythropoiesis stimulating agents (ESA) In ECOG 1996, phase 3 trial: long-term safety of ESAs ± G-CSF plus BSC vs. BSC alone Response rates were 47% versus 9.6%. Improvement in multiple quality-of-life domains. No difference in overall survival (3.1 vs 2.6 years) No difference in transformation to AML (7.5% and 10.5% ) Increased survival in erythroid responders (5.5 vs2.3 years). Immunemodulatory drugs: Lenalidomide MDS 003: Phase II trial: List A, Dewald G, Bennett J, et al. N Engl J Med. 2006;355(14):1456. MDS 004: Phase III trial: Fenaux P, Giagounidis A, Selleslag D, et al. Blood. 2011;118(14):3765. Greenberg PL, et al. Blood Sep 17;114(12):

15 Lenalidomide: MDS 003 Lenalidomide: MDS Patients Randomized Del(5q) ± other >2U RBC/8weeks Len 10 mg 21/28 days Len 10 mg 28/28 days 205 Patients Randomized Len 10 mg 21/28 days (69) Len 5 mg 28/28 days (69) Transfusion Independence 67% Minor response (>50% less transfusion) 9% All erythroid responses: 76% Time to response 4.6 weeks Hb increase 5.4 grams Response duration 2.2 years Complete Cytogenetic response 45% Partial Cytogenetic response 28% Cytogenetic response % Placebo (n 67) Placebo (67) Lenalidomide 5 mg (n 69) CR ** PR CR + PR ** RBC-TI for > 26 weeks ** Lenalidomide 10 mg (n 69) Lenalidomide in non-del(5q) MDS Raza A, et al. Blood Jan 1;111(1):

16 Hypomethylating agents Azacitidine Survival Study AZA 001 This phase III, multicenter, randomized, controlled, open-label trial. Subjects with int-2 or high risk MDS MDS-tr, or planned allo-sct were excluded. 75 mg/m2 D1-7/ 28 days Fenaux P, et al. Lancet Oncol Mar;10(3): Azacitidine Survival Study AZA 001 Aza 001 continued use 87% at 6 cycles 50.8% 25.2% 50% at 2 cycles Silverman LR, et al. Cancer Jun 15;117(12):

17 Decitabine Phase III study Hypomethylating Agents Decitabine 15 mg/m2 given IV every 8 hours for 3 vs. best supportive care. IPSS score vs. 7.8 mos [P = 0.16] Hypomethylating agents in combination have not been successful Examples: Azacitidine with vorinostat Azacitidine with Panapenostat Azacitidine with Revlimid Kantarjian H, et al. Cancer Apr 15;106(8): Side Effects of Therapies EPO: hypertension (HTN), renal insufficiency; be careful not to raise hemoglobin too high to prevent cardiovascularevents G-CSF: bone pain; monitor for excessive rise in white blood cell count; no evidence for increased risk of leukemia; not encouraged in patients with high-risk MDS AML Lenalidomide: gastrointestinal upset/diarrhea; (scalp) itching; excessive reduction of white blood cell and platelet counts; possible increased risk of thrombosis; rash; mild neuropathy ATG + Cyclosporine: serum sickness; infection; liver/kidney function monitoring, HTN Azacitidine / decitabine: decreased blood counts; nausea; injection site irritation (azacitidine); monitor kidney and liver function; diarrhea or constipation; neutropenic fever/infection Hypomethylating Agents Hypomethylating agents are standard of care in high risk MDS Azacitidine 75 mg/m2 D1-7 ( or 5+2) every 28 days, Sub-cutaneusly Decitabine 20mg/m2 D1-5 every 28 days, Intravenously. Result in: Disease response Improvement in Blood counts Improvement in quality of life Improvement in life expectancy in responders Dose density and dose intensity are very important Response are delayed, and responses improve with longer treatment. Combinations are being evaluated 17

18 Outcomes of High-Risk MDS Patients after Azacitidine Failure Overall survival better with intensive chemotherapy versus best supportive care Overall survival better with investigational therapy or transplant versus intensive chemotherapy Hematopoietic Stem Cell Transplantation The only curative treatment for higher-risk MDS. Advanced age Multiple co-morbidities Donor availability Prolonged DFS in about 30% to 50% of patients. Prebet et al, J Clin Oncol, 2011 Median survival after azacitidine failure: 5.6 months 2-year survival probability: 15% C. Chang, et al. Blood, 110 (2007), pp Cutler C.S. et al. Blood, 104 (2004), pp (IBMTR) Stem cell transplant- Issues Careful selection of patients is important for success. Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) is a good predictor of Transplant related mortality and survival. Hypomethylating agents and SCT have are being compared in randomized controlled trial. 18

19 Allogeneic Stem cell Transplant Remains underutilized. Early HLA typing is important. With Reduced intensity Conditioning, more people are eligible for transplant. More than the chronological age, it is the physiological age which affects the outcomes. In patients with out matched related or unrelated donors, alternative donor transplant ( cord blood / Haploidentical transplant) could be performed. Future Directions: Clinical Trials available at the University of Kansas: Low risk MS: (Open) Lenalidomide and Eltrombopag in Low and Intermediate Risk MDS High risk MDS: (Open) GO29754, A Safety and Pharmacology Study of MPDL3280A (Anti-PD-L1 Antibody) Administered Alone or in Combination With Azacitidine in MDS (pending) M15-531, A Study Evaluating Venetoclax in Combination With Azacitidine Compared With Azacitidine Alone in Participants With Previously Un-treated MDS Future Directions: Clinical Trials available at the University of Kansas: Relapsed disease: (Open) INSPIRE: Phase III Controlled Study of Rigosertib Versus Physician's Choice of Treatment in MDS Pts After Failure of HMA (Open) STML-401: SL-401 in Patients with Advanced, High Risk Myeloproliferative Neo-plasms (CMML only) (Pending) MDS-006 A Phase 2 study to evaluate the efficacy and safety of CC-486 (Oral Azacitidine) alone and in combination with Durvalumab in subjects with Myelodysplastic syndromes who fail to achieve an objective response to treatment with Azacitidine /Decitabine Current Horizons in Treatment Increased role of genomic annotation in MDS: IDH1, IDH2, RAS, Flt-3 Better understanding cellular effect of HMAs Newer agents: anticd33, anticd123, ABT-119, TGF-b inhibitors Lower dose HMAs for lower risk MDS TGF-B modulators New HMAs and combinations 19

20 Barriers to Clinical Trial Enrollment Lack of information about available clinical trials I don t want to be a guinea pig Time, travel, or financial constraints Concern about receiving low/ineffective dose Randomization design; use of placebo; lack of crossover Trial eligibility criteria Chronologic or biologic age; ageism Conclusion MDS is a common hematologic neoplasm with variable clinical course. Pathobiology is better understood due to the continued improvement in the molecular tools Many available therapeutic options can impact the natural course of the disease, with little toxicity to the patients. Allo-HSCT remains the only curative therapy, and should be explored in candidates for this modality Need to emphasize clinical trials enrolment. Nihilism on behalf of patients and referring doctors Abdulraheem Yacoub, MD Associate Professor. The University of Kansas Cancer Center ayacoub@kumc.edu Office: New patient referral: