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Aplastic Anemia / Pure Red Cell Aplasia 9/24/2018 Nikolai Podoltsev, MD, Phd 1 Aplastic Anemia / Pure Red Cell Aplasia 9/24/2018 Aplastic Anemia (AA) and Aplastic Anemia (AA) Pure Red Cell Aplasia (PRCA) Dr. Paul Ehrlich (1888) described AA as a Nikolai Podoltsev, MD, PhD non-malignant hematologic disorder Assistant Professor of Medicine characterized by an injured, markedly Department of Internal Medicine / Hematology Section hypocellular, and thus ineffective bone marrow Yale University School of Medicine September 22, 2018 P E. Uber einen Fall von Anaemie mit Bemerkungen uber regenerative Veranderungen des Knochenmarks. Charité-Annale 1888; 13: 300-5. Aplastic Anemia: Epidemiology Congenital Aplastic Anemia • Rare: 2 cases per 1 mln per year in the US Disorder Etiology Diagnostic testing Fanconi’s anemia Mutations in at least 10 Clastogenic assay using different genes diepoxybutane (DEB) or and Europe (short stature, arm anomalies, café-au-lait mitomycin to assay for • 3 times higher in Asia spots) increased chromosomal breakage • Male / Female ratio: 1:1 Dyskeratosis congenita Mutations in different Telomere length genes including DKC1 measurement, • Affects all age groups (abnormal skin pigmentation, nail (stabilizes telomerase sequence analysis of TERC DKC1 TER, TERT st dystrophy, mucosal complex), , – 1 peak at age 20 leukoplakia) (telomerase RNA component), TERT – 2nd peak at age 60 (telomerase reverse transcriptase) Skeletal Defects in Fanconi’s Anemia Dyskeratosis Congenita Panel A: nail dystrophy Panel B: tongue leukoplakia Panel C: reticulated hypopigmentation of the neck Kelmenson DA, Hanley M. N Engl J Med 2017;376:1460-1460. Nikolai Podoltsev, MD, PhD 1 Aplastic Anemia / Pure Red Cell Aplasia 9/24/2018 Telomere Structure Etiology of Acquired AA • Idiopathic • Viral infections • Cytotoxic drugs and radiation – Epstein-Barr virus – Seronegative hepatitis • Drug reaction – HIV – Anti-seizure agents – Other herpes viruses – Antibiotics: chloramphenicol • Immune disorders – Nonsteroidal anti-inflammatory drugs – Eosinophilic fasciitis – Anti-thyroid medications – SLE – Gold – Graft-versus-host disease – Arsenicals • Toxic chemicals • Miscellaneous – PNH – Benzene – Thymoma – Solvents – Pregnancy – Glue vapors – Anorexia nervosa Calado RT, Young NS. N Engl J Med 2009;361:2353-2365. Etiology of Acquired AA Types of Stem Cell Injury in Aplastic Anemia • Idiopathic • Viral infections • Cytotoxic drugs and radiation – Epstein-Barr virus – Seronegative hepatitis (30%) • Drug reaction – HIV – Anti-seizure agents – Other herpes viruses – Antibiotics: chloramphenicol • Immune disorders – Nonsteroidal anti-inflammatory drugs – Eosinophilic fasciitis – Anti-thyroid medications – SLE – Gold – Graft-versus-host disease – Arsenicals • Toxic chemicals • Miscellaneous – PNH – Benzene – Thymoma – Solvents – Pregnancy – Glue vapors – Anorexia nervosa Phillip Scheinberg et al. ASH 2016;2016:489-520 Hematopoiesis Hematopoietic stem / progenitor cell (HSPC) Shalis et al. EJH 2018; doi: 10.1111/ejh.13153 Nikolai Podoltsev, MD, PhD 2 Aplastic Anemia / Pure Red Cell Aplasia 9/24/2018 51 y.o. teacher's assistant Pancytopenia Referred in 4/17 after she presented with fatigue and Reduction in all of the three major cell lineages present in the peripheral blood pancytopenia, bruising, petechia and “wet purpura” (white blood cells, red blood cells, platelets) Normal range Patient White blood cell 4-10 x1000/µL 2.6 count (WBC) Absolute neutrophil 1-10 x1000/µL 0.1 count (ANC) Hemoglobin (Hgb) 12-18 g/dL 4.1 Platelets (Plts) 140-440 x1000/µL 8 Absolute 0.0230-0.1400 0.0185 (0.69%) reticulocyte count x106 cells/uL NEJM, March 28, 2002 Causes of Pancytopenia Diagnostic Test for Patients with Suspected AA • Non clonal (non malignant) • CBC, Reticulocyte count, blood smear, LFTs • Flow cytometry for PNH – Toxins (alcohol) • Vitamins: B12 (MMA, homocysteine) and folate – Nutritional deficiencies (B12) • Viral studies: Hepatitis A/B/C, EBV, CMV, HIV, – Infections (HIV, tick-born anaplasmosis) Parvo B19 – Immune (aplastic anemia) • Rheumatology work up: ANA and anti-ds DNA • Clonal (malignancy): most common Younger patients (< 40 years old) – Acute myeloid leukemia (AML) • Blood chromosomal breakage analysis to r/out Fanconi’s anemia: Diepoxybutane test (DEB test) – Myelodysplastic syndrome (MDS) • Blood leukocyte telomere length Killick s et al. BJH. Jan 2016 Paroxysmal Nocturnal hemoglobinuria (PNH) 51 y.o. teacher's assistant • Acquired mutations in the PIG-A gene • Referred in 4/17 after she presented with fatigue and • Deficiency of GPI-anchor proteins pancytopenia, bruising, petechia and “wet purpura” • Peripheral blood flow cytometry to detect surface • She received RBC and Plt transfusions and prophylactic proteins (CD59, CD55, FLAER) antibiotics (acyclovir, levofloxacin; voriconazole not started • FLAER is a fluorescently labeled variant of aerolysin that binds directly to the GPI anchor due to insurance issues) • Work up: normal / negative CD59 GPI-anchor CD55 – Normal vitamin B12, serum folate, iron panel – Negative: EBV, CMV, HIV, hepatitis B/C, parvovirus B19 – Blood flow for paroxysmal nocturnal hemoglobinuria (PNH) Nikolai Podoltsev, MD, PhD 3 Aplastic Anemia / Pure Red Cell Aplasia 9/24/2018 Causes of Pancytopenia Bone Marrow Findings • Non clonal (non malignant) – Toxins (alcohol) – Nutritional deficiencies (B12) – Infections (tick-born anaplasmosis) – Immune (aplastic anemia) • Clonal (malignancy): most common – Acute myeloid leukemia (AML) – Myelodysplastic syndrome (MDS) Bone marrow evaluation Normal Patient: Marrow Aplasia 51 y.o. teacher's assistant Aplastic Anemia: Pancytopenia in Association with Bone Marrow Hypoplasia / Aplasia • Bone marrow aspiration / biopsy done on 4/14/17 Classification Criteria – Hypocellular marrow with < 5% cellularity Severe BM cellularity < 30% and (SAA) > 2 of the following: – Karyotype was normal • Peripheral blood neutrophil count < 0.5x109/L • Diagnosis: • Peripheral blood platelet count < 20x109/L – Very severe aplastic anemia • Transfusion dependence with peripheral blood – Alloimmunized to platelet transfusions reticulocyte count < 60x109/L Very severe As above but peripheral blood neutrophil count (vSAA) mast be < 0.2x109/L Non severe Hypocellular marrow with depression of at least or moderate 2/3 hematopoietic lineages in peripheral blood (MAA) not meeting criteria for severe aplastic anemia Progress of Immunosuppressive Aplastic Anemia (AA): Treatment Therapies (IST) for Severe Aplastic Anemia • Non severe (moderate) AA may be Era Treatment Response observed or treated with supportive care 1960s corticosteroids ~10% and mild immunosuppression 1970s ATG 40-50% • SAA or vSAA require treatment as unless 1980s ATG+CSA 60-70% patients successfully treated, over 70% 1960s - 10% survival 2010 - 90% survival may die within one year in 1 year in 1 year IST, bone marrow transplant, supportive care Nikolai Podoltsev, MD, PhD 4 Aplastic Anemia / Pure Red Cell Aplasia 9/24/2018 Algorithm for Initial Management of SAA Supportive Care Stop suspected drug; treat infection • Blood product transfusions – Irradiated products – Single donor psoralen treated platelets • Severe neutropenia – Antibiotics / antifungals • IST: Acyclovir / inhaled pentamidine • Iron chelation Immunosuppressive therapy (IST) HLA typing of the patient and siblings at the time of SAA diagnosis Höchsmann B et al. Bone Marrow Transplant. 2013 Feb;48(2):168-73. Killick s et al. BJH. Volume 172, Issue 2 January 2016 Pages 187–207 Phillip Scheinberg et al. ASH 2016;2016:489-520 Bone marrow rather then peripheral stem cells are used due to lower incidence of Graft-versus-Host Disease Andrea Bacigalupo Blood 2017;129:1428-1436 Andrea Bacigalupo Blood 2017;129:1428-1436 Horse vs Rabbit ATG: Clonal Evolution of SAA to PNH and MDS and AML Overall Survival after IST Testing for PNH by blood AML flow cytometry: • At the time of diagnosis • Every 3-6 months AA during the 1st 2 years • Yearly after PNH MDS • Clinically relevant PNH: 15-25% • “PNH-type” cells: up to 67% Scheinberg P et al. N Engl J Med • MDS/AML: 5-15% (observation period of 5 to 11.3 years) 2011;365:430-438. Seishi Ogawa Blood 2016;128:337-347 Nikolai Podoltsev, MD, PhD 5 Aplastic Anemia / Pure Red Cell Aplasia 9/24/2018 Management of Relapsed/Refractory SAA Andrea Bacigalupo Blood 2017;129:1428-1436 Phillip Scheinberg et al. ASH 2016;2016:489-520 51 y.o. teacher's assistant Eltrombopag (EPAG): Non-peptide TPO Receptor Agonist Thrombopoietin • Bone marrow aspiration / biopsy done on 4/14/17 (TPO) – Hypocellular marrow with < 5% cellularity – Karyotype was normal • Diagnosis: – Very severe aplastic anemia – Alloimmunized to platelet transfusions • Treatment started on 5/12/17 – Clinical trial at the NIH (EPAG) – ATG + Cyclosporine + Eltrombopag Eltrombopag (EPAG) • Orally administered • FDA approved for chronic immune thrombocytopenic purpura (2008) TPO and EPAG Bind C-MPL at Distinct Sites Inflammatory cytokines are elevated in aplastic anemia Alvarado LJ, ASH 2017 Shalis et al. EJH 2018; doi: 10.1111/ejh.13153 Nikolai Podoltsev, MD, PhD 6 Aplastic Anemia / Pure Red Cell Aplasia 9/24/2018 Model of IFNγ-Mediated Bone Marrow Failure: Signaling Inhibition by TPO:IFNγ Heteromers in EPAG for Refractory Severe Aplastic Anemia (rSAA) Human HSPCs • 40% (17/43) hematologic response rate • Durable bi- and trilineage responses – Transfusion independence – Response persistence after discontinuation • Well-tolerated (rash, LFT abnormalities) • Clonal evolution: 18% (16/83) patients enrolled in 2 EPAG studies for rSAA* Eltrombopag was FDA approved for patients with SAA
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