hematologic and oncologic emergencies wes miller fellow pediatric

hematologic and oncologic emergencies wes miller fellow, pediatric hematology and oncology october 31 2007

objectives: AMBITIOUS! • review common presentation, pathophysiogy and (emergent) management of the following – the bleeding hemophiliac – “the bleeding patient with immune thrombocytopenia purpura (ITP)” – tumor lysis syndrome in the patient with a new malignancy – hyperleukocytosis in acute leukemias or myeloproliferative disease (MPD) – typhlitis – superior vena cava syndrome in the patient with a mediastinal mass

the sickler. . . • presents a whole new set of emergencies – potential for great morbidity and mortality • more familiar to most ED docs in Atlanta • not addressed here

but, first. . . • THANKS for the job you do for out patients • we realize our patients are HIGH MAINTENANCE • our attitude on the phone is often one of caution – at risk population – subtleties matter

the bleeding hemophiliac • 8 month old male • presented to PMD with 1 week hx of progressive bilateral LE weakness – diagnosed with GBS, sent to SR ED • at SR ED, noted to have multiple bruises over body (not just over shins), many nodular and hard • history of sublingual frenular bleed x 10 days following mild trauma in past • history of 2 weeks of oozing at surgical site following neonatal circumcision • history of LP at 6 weeks of life for fever (RSV) – waxing and waning “bulging bruise” at site EVER SINCE

the bleeding hemophiliac • family history negative for bleeding disorders • child with history of vit K ppx at birth, no warfarin or rat poison exposures, no recent antibiotics or diarrhea. • Formula fed; typical baby foods • PE: alert, smiling, clapping. VS wnl. no spontaneous movement of BLE, no withdrawal from painful stimuli, patellar areflexia • CBC normal, platelets robust • PT: 12. 6 seconds (normal) • PTT: 125. 6 seconds (not normal) • ultrasound: massive thoracolumbosacral paraspinal hematoma

the bleeding hemophiliac

the bleeding hemophiliac • normally, the known hemophiliac will present to your ED • hemophilia – – – – A (“classic”): factor 8 deficiency B (“christmas disease”): factor 9 deficiency both coded on X chromosome disease due to absent or dysfunctional protein clinically INDISTINGUISHABLE prevalence: 1 in 7500 males hemophilia A seven times more common than hemophilia B

the bleeding hemophiliac • hemophilia graded according to degree of factor dysfunctionality: – severe: <1% native activity – moderate: 1% - 5% native activity – mild: >5% native activity • where do hemophiliacs bleed? – everywhere!!! – mucocutaneous bleeds (epistaxes, oral, GI) – SOFT TISSUE BLEEDS • • HEMARTHROSES!!!!! muscle bleeds (ileopsoas!) eyes, renal/GU, throat CNS !!!!!!!

the bleeding hemophiliac • treatment options – – – • respective recombinant factor replacement (both F 8 and F 9 deficiency) DDAVP (mild factor 8 deficiency) FFP **** (factor 9 deficiency) cryoprecipitate **** (factor 8 deficiency) antifibrinolytics (amicar) treatment strategies – – – “on demand” primary prophylaxis secondary prophylaxis

the bleeding hemophiliac • DOSING SPECIFICS – recombinant factor 8 dosing: • 1 unit/kg of factor 8 raises the activity level 2% – recombinant factor 9 dosing: • 1. 5 unit/kg of r-factor 9 raises the acvity level 1% • beware anaphylaxis in F 9 replacement • FUNDAMENTAL PRINCIPLE: – when in doubt, treat!!!! • standard rule of thumb: – correct the bleeding hemophiliac child to 80% - 100% activity

the bleeding hemophiliac • barriers to therapy: the dreaded factor inhibitor – 25% - 30% in F 8 deficiency – 3% in F 9 deficiency • options for patients with inhibitors – FEIBA • do not use antifibrinolytics with FEIBA – recombinant VIIa (novoseven) – antifibrinolytics (amicar)

ITP • 3 y/o male presents with sudden onset, 1 day history full body petechiae and purpura • no epistaxis, melena, hematochezia, hematuria, no h/a, no emesis • no recent fever, no bony pains; excellent energy and appetite • no chronic medications, but mom gave robitussin 2 weeks ago for “cold” • mom frantic: just saw Fox. News special and wants to know if child dying of “meningitis”

ITP • PE: vs wnl • child jumping up and down on exam bed • 8 year old brother then tackles patient who is giggling and about to fall off the bed • head to toe petechia and purpura • OC with multiple purpura, none oozing • CN exam normal, neuro exam normal • no HSM • CBC with differential: – WBC 6 k/micro. L, relative lymphocytosis, 10% atypical lymphocytes, ANC 2000 – hgb 11. 8 g/d. L – platelets <10 k/micro. L

ITP • the most common AI disorder affecting a hematologic element (1: 10, 000 kids/year) • peak age: 2 - 6 years • males = females (children) • 2 flavors: – acute (spontaneous resolution < 6 months) – chronic (persistance > 6 months)

ITP • cause: macrophagic destruction of antibodysensitized platelets – occurs in RES – primary site: spleen • clinical course – usually, antecedent viral illness/vaccination in weeks prior to onset – abrupt onset bleeding/bruising – otherwise HEALTHY kid

ITP • how low do they go? ? – plts < 20 K: over 80% – usually isolated: expect normal WBC, hgb • anemia in 15% of cases: extracorporeal losses • splenomegaly? – palpable spleen present in 10% • peripheral smear “mandatory” – confirm true t’penia (rule out spurious!) – may see large plts – important negatives: • no WBC abnormalities • no evidence of MAHA • no evidence of AIHA • other work-up: – direct antibody test (DAT/direct Coomb’s) – ABO/Rh blood type

ITP treatment intracranial hemorrhage risk

ITP • where, exactly, do ITP kiddos bleed? ? – “most” with petechiae/ecchymoses/purpura – epistaxis/oral wet purpura in < 30% – GI (melena/hematochezia), hematuria in < 10% – menorrhagia in appropriate age group – ICH: 0. 1% - 0. 9% • how prone to serious bleeding are ITP patients? ? – not very!!! – concept of total body platelet mass – bone marrow: LOTS of megakaryocytes! – compare to other thrombocytopenic contexts • iatrogenic post chemo! – risk stratification with absolute platelet count • < 20 K/micro. L: greatest • 20 K - 50 K/micro. L: moderate • >50 K : insignificant

ITP • reasons to treat: – suspected ICH – known ITP with significant trauma – recurrent or unabating mucosal bleeding – anemia secondary to loss – rarely: extenuating social situation • NOT reasons to treat: – parental anxiety – petechiae or purpura, no matter how florid

ITP • management armamentarium 1. 2. 3. 4. 5. 6. educate, educate anticipatory guidance counsel to avoid antiplatelet meds (ASA, NSAIDs) Platelets are NOT TYPICALLY HELPFUL**** observation is commonest strategy Win. Rho: monoclonal anti-Rho D antigen antibody 1. only for non-anemic, DAT negative, Rh+ patients 7. 8. 9. 10. IVIG steroids***** other immunomodulatory agents splenectomy

ITP • to marrow or not to marrow? ? ? – good concensus: do not marrow if • clinical gestalt consistent with ITP • plan observation alone • plan IVIG and/or anti-D therapy – debatable • plan corticosteroid treatment (even in kids with clinical constellation classic for ITP) – good concensus: marrow if atypical clinical picture • natural history: – resolution in 50% by 4 - 8 weeks – resolution in 65% by 3 months – resolution in 75% by 6 months – 1/3 of “chronic” patients will spontaneously resolve – factors associated with chronicity: • females • age older than 10 (also very young? ) • insidious onset

tumor lysis syndrome (TLS) • 8 year old male presents with rapidly distending abdomen, first noticed 4 days ago • febrile, anorexic, pale; stooled yesterday; decreasing UOP • PE: mild distress, large palpable discreet mass in right lower abdomen • CT: large mass near ileocecum • CBC: – WBC 10 K/micro. L – 3% blasts – mild anemia. • chemistries: – – – LDH 22, 000 U/L (quite high) uric acid: 12 mg/d. L (quite high) K: 6. 1 mmol/L (elevated) creatinine: 1. 3 mg/d. L (elevated) phos: 9 mg/d. L (elevated)

TLS high [K+] purines high [phos]

TLS • sudden burden of intravascaular potassium, phosphate and uric acid spilled by dying tumor cells – rhabdomyolysis – crush injuries – thermal injuries (burns/hypothermic exposure) • secondary to massive synchronous release of intracellular contents into extracellular space • typically seen at initiation of therapy for new malignancy, but MAY BE SEEN AT PRESENTATION • consequences: – acute renal failure (urate and Ca. Phos crystal tubulopathy) – cardiac dysrhythmias – acute hypocalcemia

TLS • identifying patients at risk: – lymphomas: • classically, Burkitt’s lymphoma (practically, any NHL with short doubling time and bulky disease) – leukemias: • especially with high peripheral WBC (>100 k/micro. L) • especially with large extramedullary disease burden: massive HSM, bulky T cell leukemia/lymphoblastic lymphoma • especially with nephromegaly: suggests leukemic renal parenchymal involvement – lymphoproliferative disorders • CML, JMML

TLS • interventions: – hyper-hydration: • beware of oliguria • 2 -3 x maintenance of NON POTASSIUM CONTAINING IVF • ? alkalanization – NOT AT CHOA – kayexelate (ideally, oral only), concomitant insulin and glucose, albuterol, Ca. Gluconate**** – renagel – be CAUTIOUS: give supplemental calcium only with EKG changes with hyperkalemia or symptomatic hypocalcemia • goal: keep calcium-phosphate product LOW (<60)

TLS • interventions: – allopurinol • inhibits hypoxanthine oxidase • enzyme critical in metabolic pathway from →uric acid purine → → – rasburicase • • urate oxidase converts uric acid to soluble metabolite (allantoin) $$$$$ consult with heme/onc before giving – begin treating malignancy!!!!

hyperleukocytosis • 7 year old male presents to SR ED with CC of decreased energy x 7 days, unresponsive today • exam: – – – combative, confused, averbal pupils anisocoric, but responsive hemiparesis pallor tachycardic with gallop massive HSM • CBC: – WBC: 327 K/micro. L, 94% blasts – hgb: 4. 6 g/d. L – plts: 16 K/micro. L • DIC panel: – – PT: 24 seconds (prolonged) PTT: 28 seconds (normal) firbrinogen: 60 (low) DDimers: 4100 (elevated)

hyperleukocytosis

hyperleukocytosis • • patient intubated surgery emergently consulted to place vas-cath patient leukapheresed x multiple cycles in PICU flow cytometry: acute T-cell lymphoblastic leukemia • progressed to renal failure, CVVH • worsening neurologic picture, unilateral fixed pupil • neurosurgery: cranial flap

hyperleukocytosis

hyperleukocytosis • presence of excessive blastemia in the leukemic • defined by peripheral WBC of at least 100 K/micro. L • risk of symptomatology greatly increased for counts of 300 K/micro. L or more • risk of symptomatology greatly increased in AML and CML with increased circulating myeloblasts • seen in – AML: 5%- 20% at presentation – ALL: 9% - 13% at presentation – CML: nearly all patients at presentation

hyperleukocytosis • pathophysiology: – supraphysiologic whole blood viscosity: LEUKOSTASIS – aggregation of blasts in microvasculature • rheologic properties of MYELOBLASTS contribute to worse outcomes in AML or CML – larger than lymphoblasts – less distensible than lymphoblasts – “stickier” than lymphoblasts

hyperleukocytosis • Pathophysiology – inappropriate activation of soluble phase clotting cascade – microvascular occlusion • • distal ischemic injury/metabolic acidosis MAHA (on top of myelophthistic cytopenias) DIC reperfusion hemorrhage – MSOF (CNS, pulmonary, renal, hepatic, cardiac, dactylitis, priapism, etc. )

hyperleukocytosis • Interventions DECREASE WHOLE BLOOD VISCOSITY: – primary intervention: CYTOREDUCTION • leukapheresis • cytoreductive chemotherapy – immediately notify heme/onc • we will urgently activate ARC cytapheresis folks – in the meantime, tip balance to LESS viscosity • immediately begin hyper-hydration (2 -3 x maintenance) with non-K+ containing IVF • AVOID PRBC transfusions! – markedly increase whole blood viscosity – if necessary, transfuse with ceiling hgb of 8 -9 g/d. L • may transfuse platelets liberally if necessary

hyperleukocytosis • interventions: – correct coagulopathy? ? ? • depends! – make plans for urgent placement of vas-cath – manage TLS • who gets leukapheresed? – ANY PATIENT WHO IS SYMPTOMATIC FROM SUSPECTED LEUKOSTASIS SYNDROME – asymptomatic patients: • suspected AML: WBC > 100 K/micro. L • suspected ALL: WBC > 200 K/micro. L • suspected CML: WBC > 200 K/micro. L

typhlitis • 4 year old female • fever to 103, abdominal pain, emesis, bloody diarrhea x one day • undergoing induction chemotherapy for standard risk, Bprecursor ALL – finished 2 week steroid course 3 days go • exam: – – – toxic appearing tachycardic and hypotensive mild abdominal distension, hypoactive bowel sounds guarding on abdominal exam with marked TTP in RLQ Central capillary refill > 5 seconds • KUB and cross-table lateral: no free air, possible pneumatosis intestinalis noted • CT abdomen: marked cecal bowel wall thickening, peumoatosis intestinalis present

typhlitis • inflammation of the bowel wall, especially at the level of the cecum • seen in children with PROLONGED and PROFOUND neutropenia • Increased risk following chemotherapeutic drugs which cause mucositis • pathogenesis is essentially parallel to neonatal NEC (nectrotizing enterocolitis) – transmural bacterial translocation: PI – risk of bowel perforation – risk of translocated bacteremia: SIRS • pseudomonas aeruginosa • clostridium septicum

typhlitis • at risk patients: – leukemics or NHL patients in induction • may be seen in consolidation for higher intensity regimens – following systemic cytarabine (ARA-C) therapy • especially post high dose cytarabine – any patient with prolonged, profound neutropenia – beware the child “in leukemic induction, coming off steroids, with sudden fever and acute abdomen/signficant RLQ pain”

typhlitis • interventions: – fluid resuscitation – blood culture; stool culture if available – avoid rectal exam – empiric broad spectrum antibiotics (GP, GN, anaerobic coverage) • vancomycin, meropenem +/- aminoglycoside – evaluate for perforation (KUB/CT) • surgery consult if present – inotropic support for hypotension unresponsive to fluid resuscitation

superior vena cava syndrome • 12 year old male, previously healthy • 6 week history of worsening cough – treated 1 week into symptoms with 2 weeks of systemic steroids for “bronchitis” – initially cough improved and felt much better – now worsening – 20 pound weight loss • past week: – worsening orthopnea (sleeping upright in chair) – fevers • past 2 days: – expanding mass in supraclavicular area

SVCS • exam: – alert and non-toxic; completely oriented – facial edema – no stridor, not dyspneic – tachypneic, absent breath sounds R lung – palpable, firm nodes in right supraclavicular chain – splenomegaly

SVCS

SVCS

SVCS • CBC: – WBC: 12 K/micro. L, 13% blasts – hgb: 11. 9 g/d. L – plts: 144 K/micro. L • quantitative βh. CG (tumor marker): normal • quantitative AFP (tumor marker): normal • stat peripheral flow: T cell acute lymphoblastic lymphoma (leukemia? )

SVCS • Interventions: – ICU observation – begun on empiric high dose solumedrol • based upon presence of blasts in smear – next day, begun on induction chemotherapy per flow cytometric diagnosis

SVCS • signs and symptoms from impedence to flow in the SVC – – – – plethora facial edema JVD dyspnea orthopnea cough stridor • for advanced SVC obstruction, may see – – confusion lethargy headache vision changes • usually, abnormal SVC flow results from extravascular compression, not a primary intraluminal thrombus

SVCS • causes: mediastinal badness – malignancy • • • NHL (70% of malignant causes of SVCS) HL neuroblastoma leukemias*** germ cell tumors – granulomatous disease – aortic aneurysms – primary SVC thrombus

SVCS • accurate diagnosis is critical. . . • . . . however, tissue acquisition can be problematic – do NOT sedate – do NOT give anxiolytics – avoid anything which will compromise • muscular tone • venous return • an already taxed cardiopulmonary state

SVCS • workup: – CXR, CT to evaluate mass location, size, airway patency, encasement of vessels, presence of pleural effusion, etc. – evidence of hematolymphoid malignancy? • BLASTS on peripheral smear • empirically send peripheral blood flow cytometry • bone marrow aspirate and biopsy under local anesthesia – meticulous lymphatic exam • may reveal tissue source obtainable via local anesthetic only – urine catecholamines (VMA/HVA) if clinical picture consistent with neuroblastoma – serum QUANTITATIVE (tumor marker) βh. CG and AFP for GCT – transthoracic echocardiogram: presence of pericardial effusion – PPD/ID titers

SVCS • consult anaesthesia for symptomatic or unstable patient • unstable for general anesthesia: – >50% reduction in cross-sectional diameter of trachea at any level – <50% predicted PEFR on PFT’s

SVCS • interventions: – • however, may BE FACED WITH UNSTABLE PATIENT and no diagnosis: – – • ultimately, begin treatment for underlying cause awaiting pathologic analysis of obtained sample, or danger of obtaining any sample for tissue diagnosis initiate empiric therapy: – – – solumedrol: 2 mg/kg/day divided tid external beam radiation if high clinical suspicion of GCT or NBL, initiate appropriate chemotherapy