Aplastic Anemia: Understanding Your Disease and Treatment Options

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1 APPROXIMATE BLOOD CELL REQUIREMENTS Aplastic Anemia: Understanding Your Disease and Treatment Options Danielle Townsley, MD, MSc Associate Director, Oncology AztraZeneca Medimmune cell type total number life span daily production (days) neutrophils 2 x 2 x platelets x x erythrocytes 3 x x AN HEMATOPOIETIC STEM CELL NEUTROPHIL DIFFERENTIATION Myeloblast Promyelocyte Myelocyte Metamyelocyte Band Segmented neutrophil Pathophysiology of Aplastic Anemia Immune attack (T lymphocytes) Hematopoietic Stem Cells Hematopoietic Progenitors Circulating blood cells

2 % Surviving Cause of Aplastic Anemia/Immune attack on stem cells BONE MARROW FAILURE SYNDROMES AA/PNH PNH LGL Most of the cases of Aplastic Anemia have no identifiable cause SDS Pregnancy, eosinophilic fasciitis, and seronegative hepatitis are associated with AA AA Drugs and chemicals have been reported (Benzene, Chloramphenicol) DKC AML All identifiable triggers explain very few cases of AA AID: MS, IBD, uveitis, DM type, etc. hypocellular MDS MDS MAJOR PROSPECTIVE EPIDEMIOLOGIC STUDIES Europe/Israel (IAAAS): 2/million (Kaufman DW et al: The Drug Etiology of Agranulocytosis and Aplastic Anemia; 99, Oxford) Thailand (NHLBI): 4.4/million (Issarigrisil S et al: Am J Hematol 999; 6:64; Blood 26 7:299) China: 7.4/million (C Yang, X Zhang: Chin Med Sci J 99; 6:23) BLEEDING MANIFESTATIONS OF THROMBOCYTOPENIA AGE AT DIAGNOSIS Aplastic Anemia Admissions to NIH Clinical Center NATURAL HISTORY OF APLASTIC ANEMIA Utah, total (n = 99) Severity Criteria (two of three): platelets <2K/uL reticulocytes <% (6K/uL) ANC <5/uL Super-severe: ANC <2/uL AA 2 Study Utah, extrapolated severe Group, non-transplanted (n = 63) Years Camitta et al, Blood 53:54, 979 Williams et al, Sem Hematol :95, 973 2

3 96 s % survival in year Immunosuppressive therapy Bone marrow transplantation 2 9% survival in year Supportive care Iron Chelation Blood Banking Antifungals Immunosuppressive therapy Therapy terminology Treatment Naïve Anti-thymocyte globulin (ATG) Horse Rabbit Cyclosporine (CsA) Refractory Salvage Therapy Relapsed Term remission not used Anti-thymocyte Globulin (ATG) Production Immunization with human thymocytes Xenogeneic polyclonal antibodies RESPONSE OF SEVERE APLASTIC ANEMIA TO INTENSIVE IMMUNOSUPPRESSION 7, 6, 5, 4, 3, CSA ATG ANC 2,, 24-Sep 4-Oct 4-Oct 24-Oct 3-Nov 3-Nov 23-Nov 3-Dec 3-Dec 23-Dec 2-Jan 2-Jan 22-Jan Thymus T Tx Tx Hct 55, 5, 45, 4, 35, 3, 25, Retic 2, 26 5, Sep 4-Oct 3-Nov 23-Nov 3-Dec 2-Jan, 22-Jan 3 ATG IgG Cytotoxicity assay Purification of sera Tx Tx Tx Tx Platelets 24-Sep 4-Oct 4-Oct 24-Oct 3-Nov 3-Nov 23-Nov 3-Dec 3-Dec 23-Dec 2-Jan 2-Jan 22-Jan 3

4 patients plateletsl x /ml Survival PROGRESS IN IMMUNOSUPPRESSIVE THERAPIES FOR SEVERE APLASTIC ANEMIA Era Drug Response 96s corticosteroids ~% (occasional) 97s ATGs 4-5% 98s ATG plus CSA 6-7% Study Years N Median Age (years) Response Relaps e Clonal Evolution Survival German % 9% 8% 58% at yrs NIH % 35% % 55% at 7 yrs EGMBT % 2% % 87% at 5 yrs Japan % 22% 6% 88% at 3 yrs German/A ustrian INTENSIVE IMMUNOSUPPRESSION FOR SAA COMPARISON OF RESULTS % 2% 6% 87% at 4yrs Japan % 42% 8% 88% at 4 yrs NIH % 37% 9% 8% at 4 yrs EGBMT % 33% 4% 76% at 6 yrs NIH % 26% % 93% at 3yrs NIH % 28% 2% 96% at 3 yrs Young NS, Calado RT, Scheinberg P. Blood 26 ATG AND CSA FOR SEVERE APLASTIC ANEMIA OVERALL SURVIVAL Cytogenetics % response rate Days 4 47, 45, 46, XY, XY+8-7 [] ATG Evolution ATG 6 Evolution ATG CsA CsA TRISOMY CsA response no response 35 3 Evolution Years After Diagnosis 5 5 normal trisomy 8 5q- monosomy 7 Probability Probability of response of response according to age according to age Scheinberg P et al. J Pediatrics 28. 4

5 Survival probability Survival probability Survival probability Survival Survival Probability in Children Survival in refractory SAA 99s. Overall Responders to IST no response Log rank P< Days 4 Improved Survival Over Time Improved Survival Over Time yr survival = 8% yr survival = 74% yr survival = 94% yr survival = 92% yr survival = 9% All patients N = 42 p<. Time (years) yr survival = 64% Responders to IST N = 246 p= Time (years) Improved Survival Over Time ATTEMPTS TO IMPROVE OUTCOMES OF IST FOR SAA yr survival = 66% Add to or replace ATG with megadose corticosteroids No increase in response; high toxicity (Marmontl, Prog Clin Biol Res 984) Replace ATG with high dose cyclophosphamide Toxicity (Tisdale, Lancet 2; Blood 22) Replace ATG with moderate dose cyclophosphamide Excessive toxicity secondary to neutropenia (Scheinberg, Blood 24) yr survival = 37% Add mycophenolate mofetil to ATG/CsA No improvement in response/survival (Scheinberg, Br J Haematol 26) Add sirolimus to ATG/CsA No improvement in response/survival (Scheinberg, Haematologica 29).2 Non-responders to IST N = 74 p<. Time (years) yr survival = 23% Add G-CSF to ATG/CsA No improvement in response/survival (Locasciulli, Haematologica 24) Prolonged CsA (2 years) to prevent relapse Delayed but ultimately equivalent rate (Scheinberg, Am J Hematol 24) Replace horse with rabbit ATG, or alemtuzumab, frontline No improvement in response/survival (Scheinberg, NEJM 22) Clin Infect Dis 5: 726, 2 5

6 Proportion evolving ELTROMBOPAG (EPAG) A NON-PEPTIDE TPO RECEPTOR AGONIST ELTROMBOPAG AND APLASTIC ANEMIA CLINICAL APPLICATIONS Orally administered, t /2 3 hrs. FDA accelerated approval for chronic ITP (28). 4% (7/43) hematologic response rate Durable tri- and bilineage responses Transfusion independence Well-tolerated ELTROMBOPAG FOR REFRACTORY SAA Lineage characteristics of responses Initial Trial-EPAG for Refractory Severe Aplastic Anemia 6 Weeks-Primary Endpoint Best Response at Follow-up P H P H 43 patients refractory to immunosuppressive therapy (median 2.5 cycles) mg daily Dose escalation every 2 weeks to 5 mg daily Primary endpoint Hematologic response 2-6 weeks Responders continue EPAG until robust response or plateau 4 N Platelets Neutrophils Hemoglobin 4 N Subset of non-responders had improvement in counts at 3 months and/or continued improvement in counts and decreased transfusion frequency after EPAG stopped Would extended treatment with EPAG improve response rate in refractory SAA? Olnes et al. NEJM 22 Desmond et al. Blood, 24 Extended Dosing with EPAG for Refractory SAA CLONAL CYTOGENETIC EVOLUTION HISTORIC COHORT 5 mg daily No dose escalation 4 patients refractory to IST (median.5 cycles) Platelet count 3,/µL, ANC <5/µL, Hb<9. g/dl 3 month evaluation Hematologic response 6 month evaluation Primary Endpoint Hematologic response Responders continue EPAG until robust response or plateau All evolution Evolution to monosomy 7 2 responders at 6 months (5%) 3 multi-lineage 5/2 responders were non-responders at 3 months N at risk all evolution mono Days Thomas Winkler, ASH 27 clinicaltrials.gov NCT89994 Scheinberg & Young. Blood 22 6

7 CYTOGENETIC EVOLUTION REFRACTORY SAA ELTROMBOPAG FOR REFRACTORY SAA Can EPAG be discontinued? Pooled analysis of all 83 patients enrolled in both EPAG studies for rsaa 6 patients (8%) had clonal evolution Detected early (3 mo), rarely with dysplasia 6 patients-loss of chromosome 7 or 7q (5 nonresponders) 9 patients-other cytogenetic abnormalities (normalized in 5) patient with AML (no metaphase growth at baseline) Stopping criteria: Robust response: Platelets >5,/ul Hb > g/dl Neutrophils >,/ul or stable counts x 6m 5 robust responders had EPAG stopped - 3 relapses, responded to EPAG - 2 (8%) with durable response, median f/u 3 years Thomas Winkler, ASH 27 clinicaltrials.gov NCT89994 Desmond R et al. Blood 22;23:2 Thomas Winkler, ASH 27 TPO AND HEMATOPOIETIC STEM CELLS ELTROMBOPAG FOR TREATMENT NAÏVE SAA TPO receptor (c-mpl) expressed on HSCs and early progenitor cells TPO expands HSCs in vitro stimulation to expand HSC pool: increase response rate? accelerate count recovery? prevent HSC depletion? avoid clonal progression? Immune attack IST (-) HSC growth factors (+) C-Mpl and Tpo knockout mice have reduced HSCs probability of failure probability of recovery Multi-lineage marrow failure occurs in some congenital amegakaryocytic thrombocytopenia Stem cell number Yoshihara Cell Stem Cell 27; Alexander Blood 996; Qian Cell Stem Cell 27; Ballmaier Ann N Y Acad Sci 23 ELTROMBOPAG ADDED TO STANDARD IST Treatment Naïve SAA HEMATOLOGIC RESPONSE RATES 92 patients 3 months Cohort N=3 Cohort 2 N=3 Cohort 3 N=3 All Cohorts N=92 N (%) N (%) N (%) N (%) Historic rates N=388* OR 23 (77) 24 (77) 27 (87) 74 (8) 6% 5 year follow-up CR 5 (7) 8 (26) 5 (48) 28 (3) 6 months 8% OR 24 (8) 27 (87) 29 (94) 8 (87) 63% CR (33) 8 (26) 8 (58) 36 (39) 2% Townsley DM, et al. NEJM 27; 376:54-5. Townsley DM, et al. NEJM 27; 376:

8 ROBUST COUNT RECOVERY IN RESPONDERS EPAG V. HISTORIC MEDIAN TIME TO BLOOD COUNT RECOVERY 2 Platelets Neutrophils Neutrophils in very SAA ANC>5/uL: 48 days 5 per μl 5 ** per μl 3 2 ** Red cells Transfusion independence: 39 days Baseline IST + EPAG Historic IST 3 months 6 months Baseline 3 months 6 months Platelets Transfusion independence: 32 days Townsley DM, et al. NEJM 27; 376:54-5. Townsley DM, et al. NEJM 27; 376:54-5. BONE MARROW ANALYSIS ADVERSE EVENTS Townsley DM, et al. NEJM 27; 376:54-5. Townsley DM, et al. NEJM 27; 376:54-5. OVERALL SURVIVAL MEDIAN FOLLOW-UP 23 MONTHS RELAPSE MEDIAN FOLLOW-UP X MONTHS 97% at 2 years (95% CI, 94-%) Townsley DM, et al. NEJM 27; 376 One () death on study: Thymoma with paraneoplastic encephalopathy Two (2) deaths after HSCT MDS/AML: HSCT relapsed AML Relapsed aplastic anemia: HSCT GVHD Townsley DM, et al. NEJM 27; 376:54-5. Townsley DM, et al. 57 th ASH 25 Townsley DM, et al. manuscript under review 8

9 2.% % of Patients with Gene Type 8.% 4.%.% A SUBSET OF MUTATIONS CORRELATE WITH SURVIVAL - FREE FROM CLONAL EVOLUTION PIGA DNMT3A Splicing JAKs TP53 Mutation Status in AA (n=256) 23% 5% 7% negative mutation 2 mutations 3 mutations PIGA BCOR/BCORL DNMT3A ASXL SETBP PRC2 LAMB4 TERF/TERT PHF6 RIT 65% IDH2 RBBP4 PRPF8 One-third with at least mutation Yoshizato T et al. N Engl J Med 25;373:35-47 multiple missense nonsense frameshift splicing MPL POT STAT3 DIS3 Yoshizato T et al. N Engl J Med 25;373:35-47 SIMILAR PROPORTION OF PATIENTS WITH MUTATIONS AFTER IST+ELTROMBOPAG IST + EPAG 3 (3%) (%) 6 (8%) 7 (78%) Yoshizato, et al. NEJM 25 5% 7% negative mutation 2 mutations 3 mutations 23% 65% 35% with mutations Townsley DM, ASH 26 Yoshizato T et al. N Engl J Med 25;373: /9 (22%) patients 6 with one gene mutation Chromosome Instability CONSEQUENCES OF TELOMERE EROSION TELOMERES AND CLONAL EVOLUTION EVOLUTION RATE aneuploidy p53 Senescence/ Apoptosis (Hayflick phenomenon)) Telomere length of leucocytes at diagnosis of SAA predicts clonal evolution end-to-end fusion non-reciprocal translocation Scheinberg P et al, J Am Med Assoc 2; 34:358 9

10 TPO level (pg/ml) TPO level (pg/ml) Normalized telomere length TELOMERES AND CLONAL EVOLUTION TELOMERES AND A SEX HORMONE EPAG Stable SAA controls Clonal evolution Months since SAA treatment Predictors for response to EPAG + IST Longer Telomeres (> th percentile) Younger Age Accelerated telomere loss precedes clonal evolution to 7-27 patients with telomere diseases, short telomeres ± mutations were enrolled, study closed early for efficacy (telomere elongation) Dumitriu B, et al. Blood 25; 25:76 Townsley DM, Dumitriu B, et al. N Engl J Med 26;374: THE HIGH TPO PARADOX HOW DOES EPAG IMPROVE HEMATOPOIESIS DESPITE HIGH TPO LEVELS? Endogenous TPO levels are already markedly elevated in patients with severe aplastic anemia (AA) Severe AA ITP Emmons R et al., Blood 87:468 (996) Severe AA Healthy controls Feng X et al., Haematologica 96:62 (2) Dr. Andre Larochelle Heterodimerization of TPO and IFNγ Impairs Human Hematopoietic Stem/Progenitor Cell Signaling and Survival in Chronic Inflammation TPO AND EPAG BIND TO c-mpl AT DISTINCT SITES Thrombopoietin Cytokine Small molecule 59 th ASH Annual Meeting, Plenary Session Luigi J. Alvarado, Hai Cheng, Heather D. Huntsman, Alessio Andreoni, Danielle Townsley, Thomas Winkler, Xingmin Feng, Jay R. Knutson, Cynthia E. Dunbar, Neal S. Young, Andre Larochelle National Heart, Lung, and Blood Institute (NHLBI) National Institutes of Health (NIH) December th, 27 Thrombopoietin (TPO) Signaling pathways c-mpl extracellular domain Hematopoietic stem/progenitor cell (HSPC) Survival Proliferation c-mpl transmembrane domain Signaling pathways Hematopoietic stem/progenitor cell (HSPC)

11 Number of CFC per 3 cells % human CD45+ cells SSC-A % CD34+ cells in BM CD34+ cell count INFLAMMATORY CYTOKINES ARE ELEVATED IN APLASTIC ANEMIA EPAG MAINTAINS MORE CD34+ HSPCs THAN TPO IN THE PRESENCE OF IFNɣ IN VITRO TCR Ag IFNɣ promoter APC T cell IFNɣ SAP Fyn SLAM SLAM.. Ap la s tic p a tie n ts N o r m a l in d iv id u a ls Normal HSPC (CD34+) Alvarado LJ, ASH 27 TPO day ex vivo culture +/- Interferon-γ TPO or eltrombopag Maintenance of CD34+ HSPCs Without IFNɣ With IFNɣ CD34+ cell count HSPC survival and function Without W o u t IFNγ N With IFNγ N Adapted from Young NS et al, Blood 8 (8): 259 (26) CD34 n=26 TPOP O E m b o p a g EPAG MAINTAINS STEM AND PROGENITOR CELLS IN THE PRESENCE OF IFNɣ IN VITRO Model of IFNγ-Mediated Bone Marrow Failure Signaling Inhibition by TPO:IFNγ Heteromers in Human HSPCs Colony forming cell (CFC) assay Transplantation into NSG mice TPO Thrombopoietin (TPO) c-mpl IFNγ occludes TPO:c-MPL low-affinity site C F U s p e r 3 c e lls Without W o u t IF NIFNγ With IFIFNγ N n.s. % h u m a C D c e lls Without IFNγ With IFNγ n.s. Heteromers Signaling + Signaling IFNɣ HSPC survival/proliferation c-mpl n=3 T P O TPO E p a g TPO E E + I T T+ I Signaling + IFNɣ Signaling TPO c-mpl IFNγ CD45+ = human cell engraftment (HSCs) HSPC survival/proliferation Alvarado LJ, ASH 27 SUMMARY EPAG is an effective single agent for refractory severe AA, and in combination with IST associates with markedly higher response rates European (RACE) Trial ongoing ages 5 Global (SOAR) Trial CSA/EPAG for severe AA NIH Extension Trial - ongoing In tx naive SAA, clonal evolution rates similar to IST without EPAG, but longer follow up required to establish late events Somatic myeloid cancer mutations are common in adults with AA, but unclear clinical utility beyond standard cytogenetics Insights into mechanism suggest EPAG may ameliorate cytopenias in other inflammatory states (GVHD, chronic infections) National Institutes of Health Neal S. Young Cynthia E. Dunbar Phillip Scheinberg Thomas Winkler Rodrigo Calado Ronan Desmond Bogdan Dumitriu Katherine Calvo Fernanda Rodrigues Janet Valdez Feng Xingmin Andre Larochelle Keyvan Keyvanfar Stephanie Sellers Sachiko Kajigaya Marie Desierto Harshraj Leuva Charles Bolan Olga Rios Barbara Weinstein Margaret Bevans ACKNOWLEDGEMENTS GSK, Novartis Connie Erickson-Miller Nicole Stone Krista McKerracher Brian Elliott JoAnn Horowitz Socorro Portella Katie McNamara Kelly Haines Neogenomics Maher Albitar Wanlong Ma Univ of Chicago Soma Das Zejuan Li