UPDATE IN HEMATOLOGY

Lisa B. Weissmann, MD

UPDATE IN HEMATOLOGY

Update on common problems that drive primary care providers crazy Iron deficiency anemia Neutropenia/ Neutrophilia Thrombocytosis Monoclonal Gammopathy

Iron deficiency Iron deficiency

Most common form of anemia Microcytic

R/o Thalessemia, lead toxicity Daily requirement of 5-10mg/day

15mg/day menstruating women 30 mg/day in pregnancy/nursing

IRON DEFICIENCY ETIOLOGY

DIET Need 5-10 mg/day Heme iron (meat) has greater bioavailibility than non-

heme iron Achlorhydria, intestinal disease can diminish absorption

Celiac, gastric bypass, Chrohn’s, H. pylori

BLOOD LOSS Each cc of blood has 0.5mg iron therefore just 10-15cc of

blood loss/day can lead to deficiency Normal menstrual loss is 100-250cc/month(!) Iron deficiency in men/post-menopausal women

MANDATES gi evaluation, including celiac

IRON DEFICIENCY ANEMIA DISTINGUISHING IRON DEFICIENCY FROM ANEMIA OF CHRONIC

DISEASE IRON DEF. ACD SERUM IRON* +/- +/- TIBC HIGH LOW %SAT LOW/VAR NORMAL/VAR FERRITIN** LOW/VAR HIGH FEP*** HIGH (>100) NORMAL sTfR**** HIGH NORMAL BONE MARROW ABSENT STORES ABUNDANT

• *SERUM IRON REFLECTS IRON IN BLOOD AT THAT MOMENT IN TIME • ** FERRITIN CAN BE ELEVATED IN INFLAMMATORY STATES • *** FREE ERYTHROCYTE PROTOPORHYRIN • **** SERUM TRANSFERRIN RECEPTOR

TREATMENT Iron supplementation

Dietary repletion quite difficult once deficient 3oz liver= 7.5mg iron; spinach=2.5mg etc Ascorbic acid enhances absorption Cereals, tanins(tea), antacids inhibit absorption

Supplements: Aim for 60-120mg elemental iron/day Treat for 6 weeks after MCV normalizes or Ferritin over

50 (do not stop for normal Hct/Hgb)

IRON SUPPLEMENTS Oral supplements

Ferrous Fumarate - 33mg elemental iron (Feostat, Fumerin, Homocyte)

Ferrous Gluconate - 36mg elemental iron (Fergon, Fermalat)

Ferrous Sulfate - 60mg elemental iron (Feosol, Slow-Fe, Ferratab)

Ferrous Polysaccharide - 150mg (Niferex, Nu-iron)

Parenteral supplements: LMW Dextan, iron sucrose, iron gluconate, ferumoxytol

Fatigue and low Ferritin Blood, 2011. Krayenbuehl, et al. 118:3222-3227

Neutrophilia

Definition Leukocytosis >11,000

Neutrophils, not lymphocytes, monocytes, etc

Chronic or Acute Primary or Reactive

Neutrophilia

Reactive Cigarettes – can persist for years Infections Inflammation

Autoimmune, stress Paraneoplastic

Lung, kidney, others Medications

Steroids, Lithium Other

Thyroid storm, asplenia

Neutrophilia

Primary/Myeloproliferative CML – bcr-abl mutation P.Vera, Essential Thrombocythemia,

Myloid Metaplasia JAK2 – 99% concordance in PVera MPL 505 Calreticulin (NEJM 12/2013)

Neutrophilia - evaluation History/Physical

Systemic symptoms of infection or Inflammation Fevers, arthralgias, rash, abdominal pain, diarrhea

Splenomegaly, adenopathy, bleeding

Labs CBC – shift to left; toxic granulations – reactive

- immature cells (especially pro-myelocytes/blasts) primary and requires urgent investigation

basophilia/splenomegaly – CML/MPD CRP/ESR; elevated LDH, coagulopathy Bone Marrow aspirate and biopsy

Neutropenia in the Outpatient Adult

ANC<1500 cells/microL 1,000-1500 MILD 500-1,000 MODERATE <500 SEVERE

Isolated Check Hgb and platelets

Acquired or Chronic Chronic –

Benign Ethnic Neutropenia Hereditary Neutropenias

Chronic Neutropenia Extrinsic

Nutritional - B12, Folate, Copper, Protein/Calorie Malnutrition (Anorexia) Immune

Intrinsic Myelodysplasia Acquired bone marrow failure – Aplastic Anemia Congenital bone marrow failure

Isolated neutropenia - Severe congenital neutropenia; cyclic neutropenia Neutropenic Syndromes – other findings Chédiak-Higashi syndrome, Cohen syndrome, Griscelli syndrome type 2, Hermansky-

Pudlak syndrome typ2, and p14 deficiency Disorders of metabolism: glycogen storage disease type 1b, Barth syndrome, Pearson

syndrome Disorders of immune function: hyper-IgM syndrome; warts,hypogammaglobulinemia,

infections, and myelokathexis (WHIM)syndrome; cartilage-hair hypoplasia; Schimke immuno-osseous dysplasi

Disorders of molecular homeostasis: dyskeratosis congenita, Fanconi anemia, Shwachman-Diamond syndrome

Benign Ethnic Neutropenia (BEN)

Higher prevalence in people of African descent also seen in Yemenites, Sephardic Jews, etc

Related to Duffy Antigen Receptor polymorphism SNP (rs2814778) – DARC Homozygosity linked to lower white cell counts (shift of

curve) 80% of African Blacks have homozygositiy and 15% have

absolute neutropenia Not associated with increased infections May offer some protection from malaria

Acquired/Acute Neutropenia

Most common causes: Drug/Toxin Infections

Viral, Bacterial, Rickettsial Autoimmune Nutritional – B12, Folate, Copper

Less common/associated findings Leukemia, PNH, MDS

Severe Agranulocytosis (0 white cells) Almost always drug induced May have genetic susceptibility (HLA subtypes)

Causes of Transient Neutropenia

Infection

Viral – CMV, EBV, HIV, Flu, Parvovirus B19 Bacterial – Brucella, Typhoid, TB, Tularemia, Rickettsia, Anaplasma Protozoan - Malaria

Drugs Anticonvulsant – Carbamazepine, Valproate Antimicrobial – Sulfonamides, Penicillins, Bactrim Antipsychotic- Clozapine, Olanzapine,Phenothiazines Antirheumatic – Gold, Levamisole, Penicillamine Antithyroid - Methimazole, Propylthiouracil Other – Chemotherapy/Rituximab, Cocaine/Levamisole, Ticlopidine, Dipyrone

Autoimmune Disorders SLE, Sjogren’s, RA/Feltys, Crohn’s

Neonatal isoimmune Other

Trali

Evaluation in Outpatient Setting

Asses severity and concomitant illness/infection Severe neutropenia, infection – rapid/urgent evaluation

“Well” patient, mild/moderate neutropenia: Prior CBC, family history, prior infections Repeat CBC with manual differential

Asses other cell lines Asses new drugs/alcohol/ toxins/occupational hazards Infectious exposures – HIV, CMV, tick borne Asses autoimmune disorders Exams for splenomegaly, lymphadenopathy, oral ulcers

Most common reasons for incidentally discovered neutropenia are drugs, nutritional and autoimmune

Monitor every 2-4 weeks until normalization or prove chronic

Thrombocytosis

Reactive – Infectious, Inflammatory, Malignancy – most common in

inpatient setting Iron deficiency – probably most common in outpatient setting Splenectomy

Primary – Essential Thrombocythemia

50% JAK2; 30% Calreticulin P.Vera

99% JAK2 Myelofibrosis

MPL, TET2 mutations

Essential Thrombocythemia Can be associated with classic gene alterations

(JAK2,Calreticulin, etc) but also without Diagnosis of exclusion (reactive and primary)

Can be associated with acquired VWD Large VW multimers “stick” to platelets Usually only seen with very high levels (>1 million)

Do NOT need to treat unless high risk for thrombosis Prior clot, Age >60

If low risk – aspirin daily If high risk – Hydroxyurea to bring platelets<600,000

Monoclonal Gammopathy of Unknown Significance (MGUS)

Monoclonal protein found on

immunoelectrophoresis Very common as we age

incidence of 1-2% in general population 6% from age 62-79 14% over age 90 Higher incidence in African Americans (as for

multiple myeloma)

MGUS - Definition

Immunoglobulin < 3gm Less than 10% plasma cell in the

marrow Absence of related findings

no anemia, hypercalcemia, renal insufficiency

MGUS

Determining “benign” from malignant always problematic Long term follow-up of MGUS

long term studies (since 1956!) show 27% develop lymphoproliferative disorder, 57% die of other disorders, 16% without disease

Kyle, Mayo Clin Proceed July, 2004

IgG, IgA can progress to Myeloma IgM can progress to lymphoma, CLL or

Waldenstrom’s Macroglobulinemia

EVALUATION OF MGUS

Initial Evaluation quantitative IG

supression of other immunoglobulins Bence Jones Protein Hct, Calcium, BUN/Cr Skeletal survey if M spike >2 grams

not bone scan (myeloma associated with lytic lesions which can be missed on bone scans)

Abdominal CT scan if IgM Bone Marrow - ?always needed - should be done if M

spike >3 grams or abnormal Hct, ESR, calcium

Evaluation of MGUS

High Risk for transformation M spike greater than 3grams IgA/IgM subtype (?) Supression of other immunoglobulins Bence Jones Proteinuria

None of these absolutely predict behaviour

MGUS evaluation

New methods to determine behavior: Kappa/lambda light chain ratios

Serum Bence Jones Abnormal ratios can be independent predictor

of progression (Rajkumar et al, Blood 2005) When combined with other risk factors can be

highly predictive of behavior Type of immunoglobulin,amount, FLC ratio

Kyle et al, Oncology, 25:7, 2011

RISK STRATIFICATION FOR MGUS

RISK PROGRESSION AT 20 YEARS

LOW NORMAL FLC, IGG SUBTYPE, M-SPIKE<1.5GM

3%

LOW-INT ANY 1 RISK 10%

HIGH-INT ANY 2 RISK 18%

HIGH ALL 3 RISK 27%

Follow Up for MGUS If low risk

No need for bone marrow IPEP annually for life

If intermediate risk Bone marrow recommended check every 6 months for 2-5 years then annually for life

If high risk Bone marrow Check every 3 months for 2-3 years then every 6 months for

life Repeat skeletal survey, bone marrow only if significant

progression of M spike or other laboratory abnormalities

Selected Bibliography Provan D. Mechanisms and management of iron deficiency anaemia. Br J Haematol 1999;105 Suppl

1:19-26. Ajioka RS, Kusher JP. Clinical consequences of iron overload in hemochromatosis homozygotes. Blood

2003 May 1; 101(9); 3351-3. Bacon BR, et al. Diagnosis and Management of Hemachromatosis: 2011 Practice Guidelines of the

American Association for the Study of Liver Disease. Hepatology 2011; 54:1. Whitloch EP Garlitz, BA, Harris EL, et al. Screening for hereditary Hemochromatosis: A systematic

review for the US Preventive Services Task Force. Ann Int Med 2006 Aug 145(3): 209-223 Boxer, LA. How To Approach Neutropenia. ASH Education Book December 8, 2012 Vol 2012 #1: 174-182. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group

guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87:4990-7.

Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. New England J of Med 2002 Feb 21; 346(8):564-569

Rajkumar SV et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of unknown significance. Blood 2005; 106(3); 812-817

Kyle RA, Buadi F, Rajkumar SV. Management of Monoclonal Gammopathy of Undetermined Significance and Smoldering myeloma. Oncology 2011; 25:7

Conclusion “Before I came here I was confused

about this subject, but now having heard your lecture I am still confused, but at a higher level”

Enrico Fermi, Nobel Laureate, 1938