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HEMATOLOGY-ONCOLOGY Saulius Girnius 07/19/2013 Hem/Onc Emergencies HEMATOLOGY-ONCOLOGY Saulius Girnius 07/19/2013 Hem/Onc Emergencies

Summary • • • 2 Neutropenic Fever Spinal Cord Compression Tumor Lysis Syndrome Hypercalcemia Summary • • • 2 Neutropenic Fever Spinal Cord Compression Tumor Lysis Syndrome Hypercalcemia Superior Vena Cava Syndrome Section of Hematology-Oncology

Neutropenia Fever: Definitions 3 • What is a fever? – Single temperature >101 F Neutropenia Fever: Definitions 3 • What is a fever? – Single temperature >101 F – Sustained temperature >100. 4 for one hour • What is neutropenia? – ANC <500 cells/μL – ANC <1000 cells/μL, with a predicted nadir of <500 cells/μL over the subsequent 48 h Section of Hematology-Oncology

4 Subtleties of Neutropenia 21 yo woman with Hodgkin Lymphoma with fever on day 4 Subtleties of Neutropenia 21 yo woman with Hodgkin Lymphoma with fever on day 14 after ABVD with following CBC WBC [L] 2. 9 K/UL 4. 5 -11. 0 HCT [L] 28. 8 % 38 -47 PLATELET 387 K/UL 150 -400 POLY [L] 17 % 45 -85 LYMPH 50 16 -50 MONO [HH] 24 % 0 -10 EOS 4% 0 -6 BASO [H] 5 % 0 -1 ABSOLUTE POLY [LL] 0. 5 K/UL 1. 8 -7. 7 71 yo man with Non Hodgkin lymphoma with Fever on day 6 after R-CHOP with following CBC WBC [LL] 1. 0 K/UL 4. 0 -11. 0 HCT [L] 36. 6 % 40 -54 PLATELET [LL] 25 K/UL 150 -400 POLY 64 % 45 -85 LYMPH 32 % 16 -50 MONO 1% 0 -10 EOS 3% 0 -6 BASO 0% 0 -1 ABSOLUTE POLY [L] 0. 6 K/UL 1. 8 -7. 8 • G-CSF does not prevent neutropenia • Time of Nadir: Commonly 10 days Section of Hematology-Oncology

Management of Suspected Neutropenia Fever 5 • Be a decider! • Mortality Rate: 5 Management of Suspected Neutropenia Fever 5 • Be a decider! • Mortality Rate: 5 -20% • >60 minute delay of antibiotics: • OR: 1. 81 • Shoot first, ask questions later… sorta Section of Hematology-Oncology

Ask questions… sorta: Work Up while waiting for antibiotics 6 • Talk to patient Ask questions… sorta: Work Up while waiting for antibiotics 6 • Talk to patient • Physical Exam: – Line, cellulitis, localizing symptoms – Nothing in rectum • • • Blood Cultures: 1 from port, 1 from periphery CBC + Differential UA and urine culture Culture Omaya No Lumbar Puncture if circulating blasts p. CXR (I would prefer 2 -V CXR) Section of Hematology-Oncology

Shoot: Empiric Treatment 7 • GNR Coverage: Within 1 hour – Cefepime 2 gm Shoot: Empiric Treatment 7 • GNR Coverage: Within 1 hour – Cefepime 2 gm q 8 hours • (now at BMC Cefepime 500 mg q 6 h) – Ceftazadime 2 gm q 8 h – If PCN/Cephalosporin Allergy DO NOT WAIT FOR CBC TO RETURN • Imipenem 0. 5 gm q 6 h (do not use if Type I hypersensitivity) • Aztreonam 2 gm q 8 h + vancomycin 1 gm + gentamicinx 1 • Ciprofloxacin plus clindamycin – Gentamicin if severe sepsis • GPC Coverage – Skin breakdown, inflammed line/port, h/o MRSA, s/sx of pulmonary source Section of – Vancomycin 15 mg/kg (usually give 1 gm) Hematology-Oncology

Management As Outpatient? MASCC Scoring System • Score >21 consider outpatient monitoring, with fluoroquinolone Management As Outpatient? MASCC Scoring System • Score >21 consider outpatient monitoring, with fluoroquinolone + amox/clavulanate (or clindamycin if penicillin allergy) 8 29 Section of JCOHematology-Oncology 2000: 3038 -3051; Flowers et al JCO 2013

9 Febrile Neutropenia Summary • Must assess patient • Pan-culture • Antibiotics within 1 9 Febrile Neutropenia Summary • Must assess patient • Pan-culture • Antibiotics within 1 hour (esp GNR coverage) Section of Hematology-Oncology

Arghh…. what next? • • • 10 Neutropenic Fever Spinal Cord Compression Tumor Lysis Arghh…. what next? • • • 10 Neutropenic Fever Spinal Cord Compression Tumor Lysis Syndrome Hypercalcemia Superior Vena Cava Syndrome Section of Hematology-Oncology

11 Spinal Cord Compression • Differential Diagnosis for Back Pain – – Musculoskeletal disease 11 Spinal Cord Compression • Differential Diagnosis for Back Pain – – Musculoskeletal disease Spinal epidural abscess (instrumentation, IVDU) Vertebral mets without epidural extension Radiation myelopathy Section of Hematology-Oncology

Spinal Cord Compression: Type of Cancers 90% of cases are due to metastatic tumor Spinal Cord Compression: Type of Cancers 90% of cases are due to metastatic tumor in vertebrae and are therefore anterior 12 Section of Hematology-Oncology

Spinal Cord Compression: Clinical Features 13 • Pain is present in 90% of patients Spinal Cord Compression: Clinical Features 13 • Pain is present in 90% of patients • Delay in Diagnosis – 7 weeks from onset of pain – 10 days from onset of neurologic symptoms to rx • 3 due to patient • 4 to PMD • 4 by hospital • Weakness – 75% of patients – Symmetric lower extremity weakness – >50% are non-ambulatory Section of • Loss of bladder and bowel function in 50% Hematology-Oncology

Spinal Cord Compression: Imaging 14 • MRI vs Myelography • 33% will have multiple Spinal Cord Compression: Imaging 14 • MRI vs Myelography • 33% will have multiple epidural tumor deposits on scanning • At a minimum, thoracic and lumbar spine should be imaged in addition to clinically suspicious region – will miss only 1% of cervical lesions Section of Hematology-Oncology

Initial Treatment: Steroids • High dose dexamethasone 15 – RCT: IV Dex 100 mg Initial Treatment: Steroids • High dose dexamethasone 15 – RCT: IV Dex 100 mg vs 10 mg 16 mg PO daily – Results: • Pain Scale: 5. 2 3. 8 at 3 hrs 2. 8 at 24 hrs 1. 4 at 1 week • No difference in pain, ambulation, and bladder function » Vecht et al. Neurology 1989; 39(9): 1255 • (Really) High Dose Dexamethasone – RCT: XRT +/- dex 96 mg IV/PO x 4 day 10 day taper – Results: • Ambulation at conclusion of therapy: 81% vs 63% • Ambulation at 6 mos: 59% vs 33% • No dif in OS; increased toxicity » Sorenson et al. Eur J Cancer 1994; 30 A(1): 22 Section of Hematology-Oncology

Recommendations 16 • Most authorities reserve high dose treatment (100 mg IV and half Recommendations 16 • Most authorities reserve high dose treatment (100 mg IV and half dose Q 3 days) for paraplegic or paraparetic patients. • Low dose (10 mg IV followed by 16 mg daily) for patients with minimal neurologic dysfunction Section of Hematology-Oncology • Lower dose reduces AE (psychosis, infection, ulcers)

Cord Compression: What to expect from XRT 17 • Radiation rays/particles only work M-F, Cord Compression: What to expect from XRT 17 • Radiation rays/particles only work M-F, 7 AM – 4 PM • Pain: – 70% with improvement – 50% without spinal instability have resolution of pain • Neurologic Function – – If ambulatory 67 -82% remain ambulatory If non-ambulatory 1/3 become ambulatory If paraplegic 2 -6% become ambulatory Duration of motor neuropathy matters • Type of Malignancy – Radiosensitive: less likely to relapse – Radioresistant: consider SRS Section of Hematology-Oncology

Cord Compression: Surgery • Laminectomy: • • 18 Closed at interim analysis. Surgery Arm Cord Compression: Surgery • Laminectomy: • • 18 Closed at interim analysis. Surgery Arm Better Median retained ambulation: 122 vs 12 days OR for ambulation: 6. 2 If paraplegia on Dx, increased ability to walk • 10/16 vs. 3/16 – No effective for anterior tumors – No spine stabilization – No treatment of tumor • Tumor Debulking and Spine Stabilization Section of Hematology-Oncology

Cord Compression: Summary 19 • Image entire spine immediately • Start dexamethasone – If Cord Compression: Summary 19 • Image entire spine immediately • Start dexamethasone – If paraplegia: 100 mg IV and halve dose q 3 days – If just pain: 10 mg IV, then 4 mg q 6 h PO/IV • Call Radiation Oncology and Neurosurgery Section of Hematology-Oncology

Is he really not even halfway through? • • • 20 Neutropenic Fever Spinal Is he really not even halfway through? • • • 20 Neutropenic Fever Spinal Cord Compression Tumor Lysis Syndrome Hypercalcemia Superior Vena Cava Syndrome Section of Hematology-Oncology

Tumor Lysis Syndrome: Pathophysiology 21 • Hyperuricemia: – due to catabolism of purines • Tumor Lysis Syndrome: Pathophysiology 21 • Hyperuricemia: – due to catabolism of purines • Hyperphosphatemia: – Phos concentration 4 x higher in malignancy cells • Uric acid precipitates in calcium phosphate readily – Uric acid is poorly soluble in kidneys • Crystals deposit in renal tubules ARF Howard et al. NEJM 2011 Section of Hematology-Oncology

Tumor Lysis: Clinical Presentation 22 • Electrolyte Derangement – – Hyperuricemia Hyperphosphatemia Hyperkalemia Secondary Tumor Lysis: Clinical Presentation 22 • Electrolyte Derangement – – Hyperuricemia Hyperphosphatemia Hyperkalemia Secondary hypocalcemia • Acute Renal Failure • Symptoms – – Nausea, vomiting, diarrhea, anorexia, lethargy Cardiac dysrhythmia, syncope Tetany Death Section of Hematology-Oncology

Tumor Lysis Syndrome: Risk Factors • Tumor Factors 23 – High proliferative rate – Tumor Lysis Syndrome: Risk Factors • Tumor Factors 23 – High proliferative rate – Chemosensitive disease – Tumor burden • WBC>50 K • >10 cm diameter • Bone Marrow Involvement – Most commonly hematologic malignancies, not solid tumor • Clinical Features – – Serum uric acid >7. 5 mg/d. L or hyperphosphatemia Nephropathy Oliguria Section of Hematology-Oncology Inadequate hydration

Who is at risk Howard et al. NEJM 2011 24 Section of Hematology-Oncology Who is at risk Howard et al. NEJM 2011 24 Section of Hematology-Oncology

Tumor Lysis Syndrome: Prevention/Treatment 25 Section of Hematology-Oncology Tumor Lysis Syndrome: Prevention/Treatment 25 Section of Hematology-Oncology

Tumor Lysis Syndrome: Summary • • • 26 Check Tumor Lysis Labs/G 6 PD Tumor Lysis Syndrome: Summary • • • 26 Check Tumor Lysis Labs/G 6 PD Aggressive hydration Start Allopurinol Consider rasburicase IF TLS Consult renal early Section of Hematology-Oncology

60% Done!!! • • • 27 Neutropenic Fever Spinal Cord Compression Tumor Lysis Syndrome 60% Done!!! • • • 27 Neutropenic Fever Spinal Cord Compression Tumor Lysis Syndrome Hypercalcemia Superior Vena Cava Syndrome Section of Hematology-Oncology

Hypercalcemia: Causes of hypercalcemia 28 • Osteolytic metastases: 20% – Breast Cancer: mets have Hypercalcemia: Causes of hypercalcemia 28 • Osteolytic metastases: 20% – Breast Cancer: mets have PTHr. P local osteolysis – Multiple Myeloma activate osteoclasts • PTH related protein: 80% – Squamous Cell Carcinoma (lung, head&neck), renal, bladder, breast, ovarian – Affects both bone ( resorption) and kidney ( excretion) Section of Hematology-Oncology

Hypercalcemia: Treatment 29 • Hydration – Normal Saline Isotonic Saline: 200 -300 ml/hr UOP: Hypercalcemia: Treatment 29 • Hydration – Normal Saline Isotonic Saline: 200 -300 ml/hr UOP: 100 -150 ml/hr Section of Hematology-Oncology

Hypercalcemia: Furosemide 30 Use only if volume overloaded Section of Hematology-Oncology Hypercalcemia: Furosemide 30 Use only if volume overloaded Section of Hematology-Oncology

Hypercalcemia: “Advanced Management” • Calcitonin 4 IU/kg q 12 h SC/IM 31 – Efficacy: Hypercalcemia: “Advanced Management” • Calcitonin 4 IU/kg q 12 h SC/IM 31 – Efficacy: 48 hours – Rapid reduction – Use if corrected Ca>14 mg/L • Bisphonate: pamidronate or zoledronate – MOA: analog of inorganic pyrophosphate interfere bone absorption – Onset of Effect: 1 -2 days – Max Effect: 2 -4 days – Side Effects: fever, renal failure Drug Pamidronate Zoledronate Dose Response Rate 60 mg for Ca<13. 5 90 mg for Ca>13. 5 70% 4 mg, reduce for CRI 88% Section of Hematology-Oncology

Almost done! May page myself out anyway. • • • 32 Neutropenic Fever Spinal Almost done! May page myself out anyway. • • • 32 Neutropenic Fever Spinal Cord Compression Tumor Lysis Syndrome Hypercalcemia Superior Vena Cava Syndrome Section of Hematology-Oncology

Superior Vena Cava Syndrome UTDOL 33 Section of Hematology-Oncology Superior Vena Cava Syndrome UTDOL 33 Section of Hematology-Oncology

SVC Syndrome: Clinical Presentation • Compression of structures in mediastinum 34 – SVC: • SVC Syndrome: Clinical Presentation • Compression of structures in mediastinum 34 – SVC: • collateralization of over several weeks to months – – Facial/arm swelling Cyanosis Flacial plethora Coma • Airway: Extrinsic Compression • Caution with Anesthesia – Airway obstruction – Cardiovascular Collapse – Facial/Neck/Cord Swelling Section of Hematology-Oncology

SVC Syndrome: Etiology 35 • Non-malignancy: – Thrombosis – Fibrosing Mediastinitis – Postradiation fibrosis SVC Syndrome: Etiology 35 • Non-malignancy: – Thrombosis – Fibrosing Mediastinitis – Postradiation fibrosis • Malignancy: 60 -85% of cases (60% of which are new presentations) – Lung Cancer: NSCLC (50%), SCLC (25%) – Lymphoma (25%): • DLBCL • Lymphoblastic lymphoma • Primary mediastinal large B-cell lymphoma Section of Hematology-Oncology

SVC Syndrome: Treatment vs Diagnosis 36 • Immediate Treatment: – Indications • Central Airway SVC Syndrome: Treatment vs Diagnosis 36 • Immediate Treatment: – Indications • Central Airway Obstruction • Severe laryngeal edema • Cerebral edema coma – Approach: • Endovascular stenting and XRT • If severe airway obstuction high dose corticosteroids • Need tissue diagnosis, if possible – FNA vs Core-Needle Biopsy – Bone Marrow Biopsy – Mediastinoscopy Section of Hematology-Oncology

SVC Syndrome: Treatment 37 • Chemosensitive Tumor – chemotherapy • Chemoresistant Tumor – XRT SVC Syndrome: Treatment 37 • Chemosensitive Tumor – chemotherapy • Chemoresistant Tumor – XRT Section of Hematology-Oncology

He did what? What an xxxx! • • • 38 Neutropenic Fever Spinal Cord He did what? What an xxxx! • • • 38 Neutropenic Fever Spinal Cord Compression Tumor Lysis Syndrome Hypercalcemia Superior Vena Cava Syndrome Acute Promyelocytic Leukemia Section of Hematology-Oncology

Acute Promyelocytic Leukemia: Even a heme onc fellow will come in 39 • Epidemiology Acute Promyelocytic Leukemia: Even a heme onc fellow will come in 39 • Epidemiology – Hispanics>White>African Descent/Pacific Islanders – Women>Men – Age: 20 s to 50 s • Clinical Presentation: variable – Hemorrhagic findings – Weakness/fatigability • Laboratory – Leukopenia (usually) – Can have anemia/thrombocytopenia – DIC Section of Hematology-Oncology

APML: Why should I worry? 40 • Untreated DIC – pulmonary/cerebrovascular hemorrhage: 40% – APML: Why should I worry? 40 • Untreated DIC – pulmonary/cerebrovascular hemorrhage: 40% – Mortality rate: 10 -20% • Treated APML – CR Rate: 95 -100% – 2 year PFS: 97% » Lo. Coco et al. N Engl J Med 2013; 369: 111 -21 Section of Hematology-Oncology

41 APML on peripheral blood smear Section of Hematology-Oncology 41 APML on peripheral blood smear Section of Hematology-Oncology

APML: If Concerned 1) 2) 3) 4) 42 Check DIC panel Look at PBS, APML: If Concerned 1) 2) 3) 4) 42 Check DIC panel Look at PBS, especially feathered edge Ask lab tech to look at smear Call hematology fellow on call Section of Hematology-Oncology

43 Questions? Section of Hematology-Oncology 43 Questions? Section of Hematology-Oncology