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Hematologic Malignancies

Hematologic Malignancies. WFUBMC Pediatric Residency Noon Conference Pamela Bensimhon, MD 4/28/08. Pediatric Cancer Distribution. The preceeding stats reflect all of childhood, but the incidence actually varies with age. Leukemogenesis. First hit can occur in utero

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Hematologic Malignancies

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  1. Hematologic Malignancies WFUBMC Pediatric Residency Noon Conference Pamela Bensimhon, MD 4/28/08

  2. Pediatric Cancer Distribution

  3. The preceeding stats reflect all of childhood, but the incidence actually varies with age

  4. Leukemogenesis • First hit can occur in utero • Translocations can be found on guthrie cards • Time to development variable • Requires second hit • Predisposing factors • Down syndrome • Chromosome fragility syndromes • Bloom Syndrome/ Fanconi Anemia/ AT • Twins/ siblings • Monozygotic twin of <5yo with Leuk has 20% risk • Sibings have 4-fold increased risk from general pop • Ionizing radiation/ Drugs • Syndromes: • Li-Fraumeni, Klinefelter, Schwachman-Diamond, Kostman, Diamond-Blackfan, Ataxia-Telangiectasia, NF, etc

  5. 3 yo lethargic, pale, refusing to walk, with fevers and some bruising. WBC 4.5, Hb 9.5, plts 50K 16yo boy with cough, decreasing stamina on the soccer field, has large medistinal mass and high WBC 13yo with fatigue, fever and menorrhagia, has gingival hyperplasia, an orbital mass and a WBC of 110K, plt ct 40K Acute Leukemia: Classic Presentations

  6. 3 yo lethargic, pale, refusing to walk, with fevers and some bruising. WBC 4.5, Hb 9.5, plts 50K Pre B-cell ALL 16yo boy with cough, decreasing stamina on the soccer field, has large medistinal mass and high WBC T-cell ALL 13yo with fatigue, fever and menorrhagia, has gingival hyperplasia, a WBC of 110K, plt ct 40K, and an orbital mass. AML Acute Leukemia: Classic Presentations

  7. Most common Lethargy Fever “Classic” Limp or refusal to walk From periosteal or joint infiltration Medistinal mass Thymus in T-cell disease Other common signs and sx Bruising/ bleeding Pallor HSM, LAD Less common considerations: CNS Chloromas Testicular disease SVA syndrome from LAD Skin, renal, GI, etc Acute Leukemia: Clinical Presentation

  8. Leukemic Lines Lucent metaphyseal band. When seen in children over two years of age, if bilateral, are usually indicative of leukemia.

  9. Leukemia: Work-Up • CBC can look like almost anything • WBC can be normal, low, or high (>50K in ~ 20%) • May be neutropenic regardless of WBC • Hb usually <11 (80%) • Platelets are the most reliable • 92% have low platelet counts • 75% <100K • +/- Blasts • Sometimes misread as atypical lymphocytes

  10. Leukemia: Work-Up • LDH/ Uric acid • Usually increased with higher WBC or more extrameduallry dz • Coag profile • Factors V, IX, X and fibrinogen can be decreased in AML

  11. What were this patient’s presenting symptoms?

  12. What were this patient’s presenting symptoms?Nonproductive cough x 2 weeks not responsive to OTC cough medicine. No limitation of normal activity or noted shortness of breath.

  13. Leukemia: Workup • CXR • Mediastinal mass must be r/o before patient is sedated for bone marrow • Can be surprisingly asymptomatic • Compression of airway by >50% or orthopnea portend poor tolerance of anesthesia • Bone Marrow/ Flow cytometry • >5% blasts suggests malignant process • >25% blasts defines leukemia • This is the differentiating factor between ALL and lymphoblastic lymphoma • CSF

  14. BM/ Flow Results: A Fork in the Road

  15. Initial risk grouping: Standard vs High High risk features WBC  50K Age <1 or  10 yrs T cell disease Determines 3 vs 4 drug induction therapy Infants go on separate protocol Subsequent risk assessment: Based on Response to induction Cytogenetics CNS disease Determines further therapy ALL Risk Stratification

  16. Positive Triple trisomy 4, 10, 17 TEL-AML translocation Hyperdiploid (>50 chrom) Rapid Early Responder No Minimal Residual Disease No CNS disease Poor MLL rearrangement Slow Early Responder Minimal Residual Disease CNS disease Subsequent Risk Assessment: Prognostic Factors Bad Philadelphia chrom (9;22) Hypodiploidy (<44 chrom) Induction failure Portends VERY high risk stratification

  17. What happened in the 1960s?

  18. What happened to Improve Outcome? • 1950s • Multidrug therapy to avoid drug resistance • First remission achieved, but not durable • 1960s • CNS therapy regardless of CNS disease status • Increased long term survival by ~ 50% • 1970-1990s • Improvements in supportive care • Chemotherapy adjustments

  19. ALL Therapy • Induction to achieve remission • 3 vs 4 drugs • CNS prophylaxis or therapy • IT chemotherapy • +/- XRT • Consolidation • Intermittent intensification of therapy • Long maintenance phase • Total therapy • 2.5 yrs for girls • 3.5 yrs for boys

  20. ALL Outcomes • Low risk: 90-95% • Standard risk 80% • High risk 70% • Very high risk 35% • Relapsed disease: • Outcome dependent on time to and site of relapse • Extramedullary relapse >2.5 yrs from initial dx: 77% EFS @ 5 yrs • Bone marrow relapse <2 years from initial dx: 7% EFS @5 yrs

  21. ALL Late Effects • Neuropsychologic issues • Intrathecal therapy, cranial XRT • AVN (esp in adolescent males) • Steroids • Cardiomyopathy • Anthracylcines (esp preteen girls) • Infertility • Cyclophosphamide, testicular XRT • Secondary AML, brain tumors • Etoposide, cranial XRT • Endocrine abnormalities (obesity, precocious puberty, short stature) • Cranial XRT

  22. Back to the Fork in the Road

  23. AML • Subtypes less important than they used to be • Treated the same • except M3 (APL) • Can give limited prognostic information • M0, M6, M7 worse • M3 better • Some have associated translocations

  24. Good Down Syndrome <4 yo Rapid remission t(8;21) t(15;17) (APL) Inv 16 (M4e) FLT 3 ITD Poor WBC >100K Infant AML AA race Induction failure/ MRD present after induction Relapsed or Secondary AML Monosomy 5 or 7 Del 5q Abn 3q Complex karyotype MLL rearrangement AML: Prognostic Factors

  25. AML: Therapy • Highly intensive therapy required for cure • CNS prophylaxis included • Matched sibling BMT after induction if available • Treatment related mortality rate: 20-30% • Reaching the ceiling of intensification • BMT considered without matched sibling if: • Infant AML • Monosomy 5 or 7 • Induction failure • Relapse

  26. AML: Outcomes • Overall survival ~60-70% • As low as 30% survival with the poorest prognostic factors • Relapse: • Overall survival of relapsed/ refractory disease • 5-10% if relapse <1 year after therapy • ~35% if relapse > 1 year after therapy • quality of remission at transplant is an important factor

  27. AML Late Effects • Neuropsychologic issues • Intrathecal therapy, cranial XRT, BMT • Cardiomyopathy • Anthracylcines (esp preteen girls) • Infertility • Cyclophosphamide, testicular XRT, BMT • Secondary cancers • Etoposide, cranial XRT • Endocrine abnormalities (obesity, precocious puberty, short stature) • Cranial XRT, BMT • Restrictive lung disease • BMT • CGVHD • BMT

  28. APL • Acute Promyelocytic Leukemia (M3) • Increased frequency of associated coagulopathy/ hemorrhage • t(15;17) PML-RAR • ATRA sensitive • Induces maturation and apoptosis • Often better prognosis

  29. Down Syndrome and Leukemia • First 3 yrs AML>ALL • AML is frequently preceeded by myelodysplastic syndrome • For AML, better outcome with less intensive therapy (incl. no BMT) • Can be difficult to distinguish from Transient Meyloproliferative Disease • Rare types more common • Erythroblastic (M6) • Megakaryocytic (M7) • Prognosis for M6/7 not as poor as usual in DS

  30. Leukemia Supportive Care • Tumor Lysis Syndrome • In rapidly growing or extensive disease • Aggressive alkalinized hydration • Allopurinol/ Rasburicase • Close monitoring of labs for • Uric acid , phos , K , BUN/ Cr  • Ca • Can lead to renal failure, pulmonary edema, arrythmias • Fever and neutropenia • Highest risk with very intensive chemo or prolonged neutropenia • Treat all fevers with broad spectrums antibiotics

  31. Leukemia Therapy Supportive Care • Bactrim • PCP prophylaxis x 6 months after therapy • Immunizations • No live vaccines • No OPV to close contacts (per CDC Varicella is recommended) • Response to killed or inactivated vaccines may be suboptimal • Exposure to varicella w/o previous immunity • Continuous household contact, >1 hr indoor play, or hospital contact • VZIG in 72-96 hours of exposure • IV Acyclovir if sx develop • Live vaccination can restart when off therapy for at least 3 months per the CDC.

  32. Hematopathology

  33. Hodgkin’s Disease: Clinical Presentation • Lymphadenopathy • Enlarged, usually nontender, often discreet, rubbery, elastic • Always be leary of the supraclavicular node • Common locations • Neck (75%) • Mediastinum (>60%) • Spleen, Axilla, Inguinal, Lung, bone marrow, pericardium, liver, etc. • Involved nodal groups usually contiguous • Clinical presentation reflects location of LAD • +/- Systemic symptoms

  34. Hodgkin’s Disease: Clinical Presentation • Systemic symptoms: • Portends poorer prognosis • B symptoms (30%) • Fever >101 • Drenching night sweats • Weight loss  10% • Not prognostic • Puritis (15-25%) • Alcohol-induced pain in areas of nodal involvement (5%)

  35. HD: Work-Up • Labs: • CBC • May have mild anemia • Eosinophilia in 15%, neutrophilia in 50% • ESR/ CRP • May have prognostic value, certainly useful for surveillance • CMP

  36. Radiology CXR CT/MRI PET scan +/- Bone scan Procedures: LN biopsy Preferably not FNA Bilateral BMBx CSF not required HD: Work-Up

  37. HD: Staging and Risk Assessement • Stage I-IV based on: • Number of nodal groups involved • Whether one vs both sides of diaphragm are involved • Number of extranodal regions involved • Risk group based on: • Stage • Presence of B symptoms (A/B) • Presence of bulky mediastinal disease (X) • Splenic or other extralymphatic involvement (S or E)

  38. HD: Therapy • 2-8 short, pulsed cycles of chemotherapy • Number of cycles depends on risk group and response • Involved field radiation • Except in some low risk cases with very good response • Mimized when possible in females • Relapsed or refractory disease • Chemotherapy • Radiation if not already given • Auto-transplant

  39. Good Female gender Low stage Poor Bulky or extranodal disease B symptoms Higher stage Anemia at diagnosis Hypoalbuminemia at diagnosis Leukocytosis or lymphopenia at diagnosis Persistently high ESR HD: Prognostic Factors

  40. HD: Outcomes • Low/ intermediate risk: 90-95% overall survival • Given high survival rate, studies are currently aimed at minimizing treatment toxicity/ long term effects • High risk patients: 85% overall survival • Relapsed disease: • Systemic, extranodal recurrence <1 year from therapy end: • 40-50% OS • Asymptomatic nodal recurrence >1 year from therapy end: • 60-70% OS

  41. Cardiomyopathy, arrythmias Anthracylcines (esp preteen girls), XRT Infertility Cyclophosphamide Secondary cancers, especially breast cancer in girls XRT, etoposide Pneumonitis, abn PFTs Bleomycin, XRT Peripheral neuropathy vincristine Avascular Necrosis prednisone Hypothyroidism XRT HD: Late Effects

  42. NHL: Mature • T-Cell • Anaplastic NHL • 10% of childhood NHL • Presents similarly to advanced HD, with extranodal dz and B symptoms • May have waxing and waning (or persistent) cutaneous disease

  43. NHL: Mature • B-Cell • Burkitt’s Lymphoma (= small noncleaved) • 40-50% of childhood NHL • Most common sites/ presentations (in USA): • Abdominal • classic presentation: intussusception • Abdominal obstruction, “appendicitis” • Head and neck, CNS, BM often involved • Very rapidly growing • High risk of tumor lysis syndrome, even before diagnosis • If >25% marrow involvement, mature B cell leukemia • “Starry Sky” histology due to histiocytes • Diffuse Large B -cell Lymphoma

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