Pediatric Board Review Course Pediatric Hematology/Oncology

1. Pediatric Board Review CoursePediatric Hematology/Oncology Kusum Viswanathan, MD Vice Chair, Dept of Pediatrics Director, Divn of Pediatric Hematology/Oncology Brookdale Univ Hospital and Medical Center

2. Case 1 • 6 week old term infant referred for anemia. No Sx • Hb 7.5, Retic 2 %, Bili 3.5, Direct 0.5. • Mother O+, Baby A -, Direct Coombs + • Cord blood Hb 14.2 g/dL. Bilirubin 15mg/dL at 48 hours of life, recd photo Rx and d/c at 5 days.

3. Most likely explanation for the anemia is • G 6 PD deficiency • Hereditary spherocytosis • Physiologic anemia • ABO incompatibilty • Rh hemolytic disease

4. Newborn -anemia • Hemoglobin at birth is 17 g/dl, MCV over 100. • Falls to 11-12 by 6 weeks of age- nadir. • Erythropoietin production shifts from liver to kidneys and reduces because of increase in PaO2. • Anemia at birth could be : • hemoglobin not have equilibrated- repeat • Hemorrhage, may not have had time to mount a retic response • Acute hemorrhage- pallor and tachypnea • Look at MCV- low MCV-suggestive of • chronic feto-maternal hemorrhage • Alpha Thalassemia trait. • Kleihauer-Betke- Hb F resistance to acid elution

5. Newborn-Thrombocytopenia • A newborn has a completely normal physical exam except for a few petechiae. Platelet 50,000. • Differential diagnosis: • Production defects: • TAR, Megakaryocytic hypoplasia, Trisomy 13, 18. • Wiskott-Aldrich (small plt, X-linked, eczema , SCT cure) • Infections- viral, bacterial, Infiltration (Gauchers, Niemann Pick, Leukemia) • Destruction: • Allo-immune (iso-immune)- Platelet group incompatibilty • Auto-immune: Mat ITP, Drugs (thiazide, tolbutamide), SLE • Infections: CMV, Rubella, herpes, DIC • Loss: Kasabach- Merritt syndrome (hemangiomas, DIC- Rx DIC and hemangioma with Steroids, interferon, VCR)

6. The treatment of choice for alloimune neonatalthrombocytopenia is: • random platelet transfusion • IVIG • Steroids • Exchange transfusion • Washed maternal platelets

7. Immune thrombocytopenia • Auto-immune: Pregnant women with ITP/Hx of ITP • Passive transfer of antibodies (IgG) from mother. • Even when mother has a normal platelet count (Splenectomy) • Nadir-few days; Platelets < 50,00 have 1% risk of ICH. • IVIG to mother, Fetal platelet counts, C sec, US, IVGG to baby • Allo or Iso-Immune: Normal platelet count in mother • Similar to Rh disease; PL A1 antigen/ Zw a negative mother. • 97% of population is PL A 1 positive • Sensitization early in pregnancy • Plt function defect because Anti-PL A1 interferes w/aggregation. • Severe bleeding more likely; first born affected; • Recovery in 2-3 weeks • Mother’s washed (PLA1 neg) platelets; IVIG; Ultrasound; Steroids

8. Kasabach- Merritt, TAR

9. 15 months old girl presented in ER with h/o URI, and scattered petechiae and ecchymoses over the body and lower extremities. Physical exam normal, no hepatosplenomegaly. WBC-6,000, Hb 12.8, Plts-5,000, Diff: Normal Smear- The next step is to • perform a bone marrow aspirate to confirm the diagnosis • Do a skeletal survey to rule out bony fractures • Start treatment with either IVIG or anti-D • Administer platelet transfusion

10. ITP • Usually acute onset; immune mediated; post viral • Peak 2-5 years of age, males=females • Spontaneous bruises, petechiae • PE –no lymphadenopathy (LN), hepatosplenomegaly. • CBC- other cell lines normal, large plts on smear • Treat if plt< 10,000 or wet ITP, avoid NSAIDS, Aspirin • Treat- IVIG best response, 48-72 hours; Side effects. • Anti-D (WInRho) Rh+ ,hemolysis, quick response • Steroids good response, SE, inexpensive, need BM • BM- Increased megakaryocytes, otherwise normal

11. Petechiae, HSP

12. Petechiae • ITP- Thrombocytopenia • Hemolytic Uremic Syndrome • Low pltct, Hemolysis, high LDH, sick patient, Uremia, microangiopathic hemolysis on smear. • Henoch-SchonleinPurpura • Purpuric lesions on lower extremities and buttocks • Abdominal pain, arthritis. IgA deposition, normal plt ct. • ALL • Low pltct, lymphadenopathy (LN), hepatosplenomegaly, other cell lines affected • Drug induced- • Likely • By reducing production or increasing destruction • DIC

13. Normal platelet 7-10 days Large platelets: ITP May Hegglin(Dohle bodies in neutrophils, Plt function normal). Bernard Soulier syndrome (AR, Plat function disorder). Small platelets: Wiskott Aldrich syndrome( X-linked, recurrent infections, eczematoid rash, platelet dysfunction) Platelet Size

14. A 2 year old boy presents for evaluation of a chronic pruritic eruption. His medical history is remarkable for recurrent epistaxis, otitis media, and pneumonia. Physical examination reveals erythematous, slightly scaling patches on the trunk and in the antecubital and popliteal fossae. Petechiae are present profusely. This is most suggestive of • Acrodermatitisenteropathica • Ataxia telangiectasia • Atopic dermatitis • Langerhans cell histiocytosis • Wiskott-Aldrich syndrome 6

15. Platelet function defects • Normal platelet number • Glanzmannthrombasthenia • AR, Abnormal aggregation • Bleeding disorder, check h/o consanguinity • HermanskyPudlak Syndrome: • AR, Decreased dense granules • In Puerto Ricans • Oculocutaneous albinism

16. Thrombocytosis • H- Hemorrhage, Hereditary Asplenia, Down myeloprol. • I- Infections, Kawasaki, Immune:GVH, Nephrotic syndrome • P- Polycythemia vera, Myeloproliferative, Essential • L- Leukemia (CML) • A- Anemia,- Iron, Vit E, Sideroblastic • T- Tumors • E- Epinephrine, Steroids • L- Lymphoma, Hodgkins • E- Exercise, T- Trauma, Fractures • S- Splenectomy

17. Anemia • An 18 month old girl brought in for pallor. Normal diet and PMH. She is alert, interactive, only pallor, normal vital signs, No hepatosplenomegaly, lymph nodes or bruises. • CBC- Normal WBC, Plt, Hb 4.5g/dl, MCV 74, • Anemia • Reduced production • Increased destruction • Loss • What else do you want??

18. Reticulocyte count • Normal/Low- reduced production • Iron deficiency anemia- MCV will be low • ALL (leukemia)- other findings, LN, HSM • Diamond Blackfan anemia-Us < 1 year of age; facial/thumb abn, Cong heart dis, MCV Incr, rbc ADA increased, responds to steroids, BMT curative. • TEC: Over 1 year of age, Pallor, transient rbc production failure, recovers, MCV and Hb F high during recovery, rbc transfusion, rbc ADA normal .

19. Aplastic Anemia • Congenital- Fanconi anemia, Dyskeratosiscongenita, Shwachman-Diamond syndrome, Amegakaryocytic thrombocytopenia • Fanconi’s anemia-AR, short stature, microcephaly, microphthalmia, epicanthal folds, Café au lait, dangling thumbs, congenital dislocated hips. Chromosomal breakage increased by diepoxybutane (DEB) or mitomycin C. Hemorrhages, infections, leukemia, myelodysplastic syndrome, liver tumors, • Acquired • Infection- hepatitis, EBV,CMV, parvovirus B19, HIV • Drug induced- Chloramphenicol • Exposure to Toxins, Radiation • Autoimmune disease such as lupus • Idiopathic Treatment- BM/Stem cell transplant

20. Normal smear

21. Microcytic anemia is a characteristic laboratory abnormality of all listed diseases except • Iron deficiency • Lead poisoning • Sickle cell disease • Thalassemia trait

22. Microcytic anemia

23. Iron deficiency • Low MCV, low MCHC, low retic, RDW normal initially, will increase after treatment, Low Iron, Incr TIBC, Transferrin low, Ferritin low • Causes: Inadequate dietary intake • Toddlers, too much milk, less solids, Breast fed need iron supplements • poor absorption • Blood loss: Menstrual, GI tract, Meckels, Epistaxis • D/D: Thalassemia trait- MCV much lower in prop to anemia, Anemia of chronic disease- low Fe, low TIBC, normal /high Ferritin.

24. Quantitative defect in globin chains Reduced production of Beta chains Hb electrophoresis Hb A- 2 Alpha, 2 Beta Hb F- 2 Alpha, 2 Gamma Hb A2- 2 Alpha, 2 Delta Excess Alpha combines with Gamma or Delta- Increased Hb F and A2. Smear abnormalities significant even with MILD anemia. Anemia Low MCV, normal RDW, normal retic Smear shows aniso and poikulocytosis, target cells, microcytes, misshapen cells, basophilic stippling Hb Electrophoresis: Increased Hb A2 and/or F. Normal iron studies, no response to iron Beta Thalassemia Minor

25. Beta Thalassemia Major • No production of Beta chains • Autosomal recessive • 25 % chance with each pregnancy • Pre-natal testing for carriers • Chorionic villous sampling for diagnosis • Transfusion dependent-allows for normal development • Pen Prophylaxis, Anti oxidants • Splenectomy after age 5 • Iron overload- inherent and transfusion • Need chelators

26. Thalassemia- Alpha • Reduced Alpha chains • 4 types- carried on 4 allelles. (xx/xx) • One absent- Silent carrier (x-/xx) • 2 absent- Alpha Thal trait (xx/- - or x-/x-) • 3 absent- Hb H disease (x-/- -) Has 4 excess Beta chains) • 4 absent- Hydrops fetalis (- -/- -) • NB period: Excess Gamma chains form Hb Barts- FAST moving Hb on Newborn screening

27. Megaloblastic anemias • Vitamin B 12 or Folate deficiency (defective DNA synthesis) • Defective maturation of other cell lines- leukopenia and/or Thrombocytopenia • Hypersegmented neutrophils, large metamyelocytes and bands • Causes hyperhomocysteinemia. • Dietary deficiency of vitamin B12 due to vegetarianism. • Can occur in breast-fed infants of vitamin B12–deficient mothers • Severe vitamin B12 deficiency - a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia, and developmental regression • Underlying mechanisms • delayed myelination or demyelination of nerves • alteration in the S-adenosylmethionine:S-adenosylhomocysteine ratio • imbalance of neurotrophic and neurotoxic cytokines • accumulation of lactate in brain cells • Elevated methylmalonic acid and/or total homocysteine are sensitive indicators of vitamin B12–deficient diets

28. Case • 3 year old patient is brought to the ER with complaints of feeling very tired over the past 3 days. • Patient is pale, jaundiced with the spleen tip palpable. • CBC Hb 5, Retic 5 %, LDH Increased, • What does this sound like??

29. Reticulocyte count- Increased • Hemolysis • Intrinsic- • Membrane defects-Hereditary spherocytosis (HS) • Enzyme-G 6 PD deficiency • Hemoglobinopathies • Extrinsic- AIHA (Auto-immune hemolytic anemia), DIC, IV hemolysis • Loss • Blood loss

30. Question • A previously well African-American child visited Africa and was given malarial prophylaxis. He experienced pallor, fatigue, and dark urine. His hemoglobin level decreased from 14.8 to 9 g/dL. • SMEAR

31. An African-American child visited Africa and was given malarial prophylaxis. He experienced pallor, fatigue, and dark urine. His hemoglobin level decreased from 14.8 to 9 g/dL. The most likely diagnosis is • Hereditary spherocytosis • Sickle cell disease • Hepatitis • G6PD deficiency 6

32. Hemolytic anemia • History; Recent infection, drug exposure, illness, dark urine, anorexia, fatigue, pallor • Family h/o gallstones, splenectomy • Physical Examination: Pallor, tachycardia, tachypnea, splenomegaly. • Peripheral smear: Blisters, spherocytes

33. Children with congenital spherocytosis have all of the listed conditions except: • positive Direct Coombs • splenomegaly, gallbladder stones • abnormalities in spectrin and /or ankyrin • increased MCHC • abnormal osmotic fragility test. 6

34. Spherocytes Nucleated rbc Coombs-AIHA Osmotic fragility-HS Spherocytes

35. HS- with severe anemia • A 6 year old girl who has hereditary spherocytosis presents with a 1 week history of fever. Physical examination and history reveal abdominal pain, vomiting, fatigue and pallor. Her hemoglobin is typically about 10 g/dL with a reticulocyte count of 9%, but now, her hemoglobin is 4 g/dL and the reticulocyte count is 1%. Her bilirubin is 1 mg/dL. Of the following, the MOST likely cause for this girl’s present illness is infection with • Coxsackie virus • Parvovirus B19 • Epstein-Barr virus • Hepatitis A virus • Influenza A virus

36. HS- with severe anemia • Coxsackie virus • Parvovirus B19 • Epstein-Barr virus • Hepatitis A virus • Influenza A virus 6

37. Newborn Screening • You get a call from a frantic parent because she received a letter from the State regarding her baby’s test results on NBS. • FS- SS disease, S-B0 Thal, Sickle cell w/ HPFH. • FSA- Sickle B+ thal, Sickle cell trait • FSC- SC disease • FAS- Sickle cell trait • FAC- Hb C trait • FAE- Hb E trait • FE - Hb EE disease, E-Thal

38. Hemolysis- life span 20-50 days. Abnormal cell shape, abnormal adherence to endothelium, decreased oxygenation, Increased polymerization. Symptoms start by 2-4 months of age. Hb electrophoresis, S >75 %. Start Penicillin daily and give until age 5. Prevention of pneumococcal infections. PPV (Pnu-23) age 2, 5 Meningococcal vaccine Folic acid daily Sickle cell

39. The mother of a 10 month old baby with SS disease asks you about prognostic indicators. All of the following indicate likelihood of more severe disease except: • High WBC • Associated alpha thalassemia trait • Low hemoglobin • Repeated episodes of dactylitis

40. Sickle cell crises • Vaso-occlusive crisis-dactylitis, long bones, back, chest. Trt. Pain meds, hydration. • Aplastic crisis: low Hb, low retic, Secondary to Parvovirus infection. • Splenic sequestration crisis: spleen palpation • Hyperhemolytic crisis

41. Sickle cell Acute Chest Syndrome • New infiltrate on X-ray, fever, chest pain, back pain, hypoxia. • Due to infarction, infection, BM fat embolism • Treat: Antibiotics to cover pneumococcus, Mycoplasma, Chlamydia, Bronchodilator, Oxygen, Incentive spirometry, transfusion, Steroids (controversial). • Avoid overhydration

42. Pulmonary Hypertension • Prevalence of pulmonary HT in SCD from 20-40 %. • The presence of hemolysis, chronic anemia, and the need for frequent transfusions were directly associated with development of PHT. • On follow-up, PHT was significantly associated with an increased risk of death. -Am J Hematol July 2004 -N Engl J Med Feb 2004.

43. A routine TCD on a 4 year old patient with SS disease shows a Cerebral blood flow (CBF) of 210 cm/second. What is the next step? STOP studies- STOP I and II TCD- Transcranial Doppler

44. According to the STOP protocols, all children with abnormal TCD require enrollment in hypertransfusion protocol till (choose one) • Repeat TCD is normal • Continue indefinitely • the child reaches 18 years • MRA/MRI are reported normal 6

45. Sickle cell and Stroke • Affects 10 % of patients • Infarctive stroke (younger patients) and Hemorrhagic stroke (older) • STOP I study established the role of yearly TCD (transcranial doppler) to measure cerebral blood flow velocity as a tool for determining stroke risk. • Transfusion therapy as current therapy for high risk patients (CBF> 200cm/sec) • Reversal of CBF velocity is not sufficient to stop transfusion therapy. (STOP II)

46. Sickle cell and Transfusions • Transfusion indications: • Acute anemia (Aplastic, Hyperhemolytic, Sequestration) • Hypoxia (ACS, chronic lung disease, Pulmonary hypertension) • Stroke and stroke prevention • Intractable pain, pre-operative preparation • Types of transfusions • Intermittent • Chronic simple • Exchange (Partial, Total, Erythrocytapheresis) • Hypertransfusion (transfusions in an effort to prevent patient from producing their own red cells)

47. Which of the complications of sickle cell disease is more common in SC patients compared to SS disease • Sickle retinopathy • Ischemic stroke • Acute Chest syndrome • Pulmonary Hypertension • Leg ulcers 6

48. One unit -200mg Iron No physiologic way of removal 10-20 transfusions Desferioxamine available. Can be given IV or subq infusion or subq shots. Compliance an issue. December 2005- Oral chelator available (Deferasirox)- FDA approved. Iron overload

49. Sickle cell and Hydoxyurea • FDA approved for adults • Studies in children demonstrated efficacy and safety. • Increases hemoglobin F level • Increases hemoglobin • Decreases WBC – ancillary effect • Hydroxyurea is recommended by the hematologist for patients who have recurrent vaso-occlusive crises, acute chest syndrome.

50. Other important points • Median life expectancy: • Males 42 years, females 48 years • Improvement related to Penicillin, immunizations, education. • Bone marrow transplant (BMT) is a cure • Cord blood storage