Speaker Disclosure: Anemia & Other Cytopenias Atara … · 2017-06-13 · •aplastic anemia Vitamin B12 Organ failure •renal •liver •endocrine Hemoglobinopathy •Sickle •Thalassemia

Anemia & Other Cytopenias

May 25, 2017 and June 22, 2017

Lloyd E. Damon, MDDivision of Hematology-Oncology

Speaker Disclosure:

Atara Biopharmaceuticals (myself)Gilead Sciences (spouse)

Actelion Pharmaceuticals (spouse)Otsuka Pharmaceuticals (spouse)Janssesn Pharmaceuticals (spouse)

Case Presentation

§80 year old women is brought to ED because of progressive fatigue and pallor

§Eats very little meat, but takes vitamins frequently§Denies any GI bleeding

§On exam: extremely pale, tachycardia, no HSM, but has 2+ lower extremity

§4 years ago:

• Neutrophils 0.67 xe9/L, Hgb 10.8 g/dL, MCV 100 FL, Platelets 165 xe9/L

5/25/17Anemia & Other Cytopenias3

Case (2)

Normal PatientWBC (xe9/L) (3.4 – 10) 1.9

Hgb (g/dL) (12 – 15.5) 4.2

Hct (%) (36 – 46) 16.3

MCV (FL) (80 – 100) 80

Platelets (xe9/L) (140 – 450) 208

Retic (xe9/L) (25.6 – 91.9) 35.3

ANC (xe9/L) (1.8 – 6.8) 0.52

ALC (xe9/L) (1 – 3.4) 0.8

AMC (xe9/L) (0.2 – 0.8) 0.5


Case (2)


Hgb (g/dL) (12 – 15.5) 4.2

Hct (%) (36 – 46) 16.3

MCV (FL) (80 – 100) 80

Platelets (xe9/L) (140 – 450) 208

Retic (xe9/L) (25.6 – 91.9) 35.3

ANC (xe9/L) (1.8 – 6.8) 0.52

ALC (xe9/L) (1 – 3.4) 0.8

AMC (xe9/L) (0.2 – 0.8) 0.5


Case (2)


Hgb (g/dL) (12 – 15.5) 4.2

Hct (%) (36 – 46) 16.3

MCV (FL) (80 – 100) 80

Platelets (xe9/L) (140 – 450) 208

Retic (xe9/L) (25.6 – 91.9) 35.3

ANC (xe9/L) (1.8 – 6.8) 0.52

ALC (xe9/L) (1 – 3.4) 0.8

AMC (xe9/L) (0.2 – 0.8) 0.5


Case (3)

§Over 4 years:• Neutropenia is stable

• Anemia has worsened (normocytic and hypoproliferative)

• MCV has dropped

• Platelets remain normal§ Iron studies return:

• Ferritin 8 (18-340 mcg/L)

• Serum iron 9 (29-189 mcg/L)• Transferrin 301 (182-360 mg/d)

• % saturation 2 (10-47%)

5/25/17Anemia & other cytopenias7

Diagnosing Iron Deficiency

§Normal or low MCV§Normal of low serum iron

§Normal or high transferrin

§Low % saturation

§Ferritin <12 or <30 if anemic §High soluble transferrin receptor

§Low reticulocyte Hgb concentration

§Absent bone marrow iron stores§Low hepcidin levels

§Hgb response to iron administration


Diagnosing Iron Deficiency

§Normal or low MCV (normal, 80)§Normal of low serum iron (low, 9)

§Normal or high transferrin (normal, 301)

§Low % saturation (low, 2)

§Ferritin <12 or <30 if anemic (low , 8)§High soluble transferrin receptor (ND)

§Low reticulocyte Hgb concentration (ND)

§Absent bone marrow iron stores (ND yet)§Low hepcidin levels (not available)

§Hgb response to iron administration (Pending)


Case (4)

§The patient clearly has iron deficiency§But with a Hgb of 4.2, while her MCV is low normal (80) [but has dropped in 4 years (100 -> 80)], and ….

§With this degree of anemia, the MCV should be in the 60s if pure iron deficiency, …

§This must be a mixed (multifactorial) anemia

§And, iron deficiency does not explain neutropenia…


Etiologic Classification of AnemiasNutritional Chronic Disease Hemolytic Bone MarrowIron Inflammation Autoimmune Primary

•MDS•myeloproliferative

neoplasms•lymphoproliferative

neoplasms•aplastic anemia

Vitamin B12 Organ failure•renal•liver•endocrine

Hemoglobinopathy•Sickle•Thalassemia•Others

Secondary•metastatic cancer•metabolic infiltrative

disorders•infectious infiltrative

diseasesFolate Elderly MembrameThyroid Infection


Etiologic Classification of AnemiasNutritional Chronic Disease Hemolytic Bone MarrowIron Inflammation Autoimmune Primary

•MDS•myeloproliferative

neoplasms•lymphoproliferative

neoplasms•aplastic anemia

Vitamin B12 Organ failure•renal•liver•endocrine

Hemoglobinopathy•Sickle•Thalassemia•Others

Secondary•metastatic cancer•metabolic inflitrative

disorders•infectious infiltrative

diseasesFolate Elderly MembrameThyroid Infection


Case (5)

§Nutritional Labs• Vitamin B12 – 1407 (211-911 mcg/L)

• RBC folate – 760 (280 – 791 mcg/L)

• TSH 2.79 (0.45-4.12 mIU/L)

§Organ Function• Cr and LFTs normal

§Highly suggestive of iron deficiency with a bone marrow disorder

• Especially with chronic neutropenia• MDS highest on the differential


Iron Repletion

§PRBC transfusions• Addresses immediate clinically significant anemia

• Iron availability is delayed -> after transfused RBC are destroyed and heme iron is re-circulated

§Oral iron (ferrous sulfate)

• GI side effects significant

• Hgb response less than IV iron*§ IV Iron

• Very safe with fast infusion times

• Far fewer GI side effects vs oral iron

5/25/17Anemia & other cytopenias14 *Plos One 2015;10:e0117383

IV Iron

§HMWID (high-molecular weight iron dextran)• Significant infusion reactions common

• Defined anaphylaxis rate (~0.5%)

• Long infusions times

• Iron not tightly bound to the carbohydrate -> high labile free iron levels

§Newer Formulations• Iron is bound tightly to the carbohydrate shell

• Infusion reactions are uncommon and are mild

• Short infusion times


IV Iron Formulations

§LMWID (low molecular weight iron dextran) – USA• Infusion 1 hour

§Ferumoxytol – USA

• Infusion 15 minutes

§Ferric Carboxymaltose – USA• Infusion 15 minutes

§ Iron Sucrose – USA

• 2-5 minutes§ Iron Isomaltoside – Europe

• Infusion 15 minutes


Current Uses of IV Iron

To Correct Iron-deficient or Iron-restricted Erythropoiesis

§ IBD (inflammatory bowel disease)§Post Roux-en-Y

§Post bariatric surgery

§Obstetric-Gynecologic bleeding

§ In conjunction with ESA (erythropoietic stimulating agents) during cancer chemotherapy

§ESRD – renal replacement therapy in conjunction with ESA§Prevent altitude sickness in iron-replete climbers


Hematology Am Soc Hematol Educ Program 2016;216:57

Odds of GI Side Effects Favor IV Iron

5/25/17Anemia & other cytopenias18 Plos One 2015;10:e0117383

Approved for educational reproduction via the fair use copyright exemption

Severe Adverse ReactionsIV Iron (n=10930) vs Placebo (n=3335), no iron (1329), oral iron (4044), IM iron (n= 155)

SAE RR 95% CIAll iron studies 1.04 0.93 – 1.17

By ComparatorPlaceboNo ironOral ironIM iron

0.831.061.131.36

0.64 – 1.080.90 – 1.250.95 – 1.350.22- 8.49

Infusion Reactions 2.47 1.43 – 4.28*

Mortality 1.06 0.81 – 1.39

Infections 1.17 0.83 – 1.65

Gastrointestinal 0.55 0.51 – 0.61*


*statistically significant

Mayo Clin Proc 2015;90:12

Case (6)

§Receives 6 units of PRBC over 3 days§Receives IV iron sucrose

§FOB is negative

§EGD/colonoscopy is negative except for a tubular adenoma in the sigmoid


Anemia of the Elderly§A house keeping category to account for anemia in older individuals for whom no etiology is determined

§Anemia occurs in 10% > 60 yrs and 20% of individuals over age 85 years – it is unexplained in 34% of cases

§May occur in conjunction with other cytopenias (should be MDS, but…)

§Pathophysiology• Relative resistance of erythropoiesis to erythropoietin signals

• Reduced erythropoietin production relative to nephron mass

• Dampening of erythropoiesis from inflammatory cytokines• ? Role of clonal hematopoiesis


Hematology Am Soc Hematol Educ Program 2010;2010:271Hematology Am Soc Hematol Educ Program 2016;201667

MDS (Myelodysplastic Syndrome)

§Clonal hematopoietic stem cell disorder§Disease of adults and the incidence rises with age

§Diagnosis

• One or more cytopenias

• Dysplasia in one or more of the 3 major cell lines on BM biopsy• <20% blasts

• The marrow is usually hypercellular

• Karyotype might be normal or abnormal


Dysplastic Neutrophil


Dysplastic Megakaryocyte


MDS (2)

§Natural History• 1 or more significant cytopenias (anemia, neutropenia, thrombocytopenia)

• Dysfunctional neutrophils -> bacterial and fungal infections

• Many become RBC- or Platelet-transfusion dependent

• Depending on several factors, a high risk to convert to AML

• Short survival


MDS Classification


Subtype CharacteristicsRefractory Anemia ± Ringed Sideroblasts

<5% blasts, erythroiddysplasia± >15% ringed sideroblasts

5q- Syndrome <5% blasts, 5q-, normal or elevated platelets

Refractory Cytopenia with Multilineage Dysplasia

<5% blasts, dysplasia in 2-3 lineages

Refractory anemia with Excess Blasts

5-19% blasts

MDS Prognosis


MDS Subtype Overall Survival (years)

Refractory anemia 75q- Syndrome 10Refractory Cytopenia with Multilineage Dysplasia

4

Refractory anemia with Excess Blasts

2

MDS – Overall SurvivalRevised International Prognosstic Score

5/25/17Anemia & other cytopenias28 Leukemia 2015;29:1502



MDS – Leukemia Free SurvivalRevised Inernational Prognostic Score

5/25/17Anemia & other cytopenias29 Leukemia 2015;29:1502


Genetics of MDS

§40% have an abnormal karyotype

• -5 or del(5q) – 10-15%• -7 or del(7q) – 10%

• i17q or t(17p) – 2-3%

• del(12p) or t(12p) – 1-2%

• del(11q) – 1-2%• -13 or del(13q) – 1-2%

§More than 85% have myeloid gene mutations

§1 founding mutation and 1 or more evolutionary subclonemutations (allele frequency >20%)

• TET2 – 20-49%

• DNMT3A – 10-19%

• ASXL1 – 10-19%• SF3B1 – 20-49%

• SRSF2 – 10-19%



Treatment of MDS

§Cure• Allogeneic stem cell transplantation

‒ 40% long-term survival if blasts <5%

‒ 20% long term survival is blasts 5-19%

§Palliation• Supportive care

‒ Transfusions, myeloid growth factors, ESAs, antibiotics

• Hypomethylating agents‒ 5-azacitidine or decitabine

• Lenalidomide [del(5q)] – an immunomodulatory agent


Somatic Mutations in Patients Unselected for Hematopoietic Disorders


N=32,290

Hematology Am Soc Hematol Educ Program 2015;2015:299Approved for educational reproduction via the fair use copyright exemption

CHIP (Clonal Hematopoiesis of Indeterminate Potential)

§ Increasing incidence with age in a healthy population§Normal CBC or very mild cytopenia(s)

§No or minimal dysplasia in the bone marrow

§Bone marrow does not meet hematopathologic WHO criteria for MDS or other hematopoietic malignancy

§Evidence for hematopoietic clonality

• Abnormal karyotype (non-malignancy defining), and/or• Somatic mutation in at least one myeloid-related gene

5/25/17Anemia & other cytopenias33 Blood 2015;126:9

CHIP§Somatic mutation variant allele frequency <20%§Most common somatic mutations resemble those in MDS

§13-fold increased chance of evolving to a myeloid malignancy compared to those without somatic mutations• DNMT3A

• TET2

• JAK2• ASXL1

• TP53

• SF3B1

§This translates to a 0.5-1% evolution rate per year


Hematologic Malignancy Precursor States

State Malignancy Rate (% per Year)MGUS(monoclonal gammopathyof uncertain significance)

Multiple myeloma, CLL, Waldenstrom macroglobulinemia, primary amyloid, cryoglobulinemia

1

MBL(monoclonal B-cell lymphocytosis)

CLL 1-2

CHIP(clonal hematopoiesis of indeterminate potential)

MDS, other myeloid neoplasms 0.5-1


ICUS (Idiopathic Cytopenias of Undetermined Significance)§One or more cytopenias§Bone marrow biopsy and adjunctive hematopoietic evaluations do not yield a hematologic diagnosis

§No known clonal mutation is demonstrated

§Should be “MDS”, but can not establish this diagnosis

§579/2899 (20%) bone marrow biopsies done at the Mayo Clinic over 3 years for suspicion of MDS or other hematopoietic disorder were non-diagnostic (ICUS)

• Natural history information is lacking


CCUS (Clonal Cytopenias of Undetermined Signficance)

§One or more cytopenias requiring hematologic evaluation§Bone marrow biopsy does not meet WHO criteria for MDS or other hematopoietic malignancy

§There is a somatic mutation in at least one myeloid-related gene

§Natural history unclear, but suspicious for the middle step from CHIP to MDS or other hematopoietic malignancy


The New Classification of CytopenicConditions

State Features Somatic Gene MutationsICUS •cytopenia(s)

•no or little BM dysplasia•no clonality established•0 or unknown mutations

CHIP •normal CBC or minimal cytopenias•no or little BM dysplasia

•clonality established•usually 1 mutation

CCUS •cytopenia(s)•no or little BM dysplasia

•clonality established•often 2 or more mutations or sometimes CHIP + a 2nd

extrinsic cause of cytopeniaMDS •cytopenia(s)

•BM dysplasia; blasts <20%•clonality established•4-6 mutations



The New Classification of CytopenicConditions



Anemia of the Elderly

§CHIP is likely the precursor clonal hematopoietic state leading to other hematopoietic clonal diseases

§The Anemia of the Elderly can now be reclassified as• ICUS

• CCUS


Case (7)

§Bone marrow biopsy is performed as MDS suspected• Normal morphology

• No infiltrative disorder evident

• 46XX

• Myeloid gene seqeuncing reveals 2 tier 1 mutations‒ DNMT3A (variant allele frequency 22%)

‒ SRSF2 (variant allele frequency 15%)


Case (8)

§ Iron deficiency• Etiology unknown

§CCUS

• Perhaps explains the chronic neutropenia

§Plan• Complete iron replacement IV

• Monitor the CBC

• Complete search for occult solid malignancy


Key Points

§Suspect a mixed anemia when the MCV does match an identified etiology

§ Iron deficiency is evident for a ferritin <12 or <30 if anemic§ IV iron repletion

• Is safe and effective

• Much better tolerated than oral iron

• Infusion reactions are mild and transitory, anaphylaxis is very rare


Key Points (2)

§Clonal hematopoiesis incidence rises with advanced age§CHIP defines people with somatic hematopoietic gene mutations but normal CBC

§CHIP is likely a precursor to MDS or other myeloid malignancies

§ ICUS is significant cytopenia(s) without established hematopoietic clonality – natural history is uncertain

§CCUS is a significant cytopenia(s) with established hematopoietic clonaltiy – natural history is uncertain

§Anemia of the Elderly is now likely ICUS or CCUS


Documents

Speaker Disclosure: Anemia & Other Cytopenias Atara … · 2017-06-13 · •aplastic anemia Vitamin B12 Organ failure •renal •liver •endocrine Hemoglobinopathy •Sickle •Thalassemia