Hematology and Oncology
Melanie E. Fields
David Wilson
FEVER AND NEUTROPENIA
General Principles
Absolute neutrophil count (ANC) <1,500/µL is defined as neutropenia.
Risk of infection increases dramatically with severe neutropenia (ANC <500/µL).
Differential diagnosis:
Congenital neutropenia: severe congential neutropenia, cyclic neutropenia, reticular dysgenesis, autoimmune neutropenia, Shwachman-Diamond syndrome, Fanconi anemia
Acquired neutropenia: malignancy, chemotherapy, radiation, aplastic anemia (autoimmune), infection (viral, bacterial sepsis), and hypersplenism
Laboratory evaluation: complete blood count (CBC), blood cultures (including each lumen of venous access device)
Only 30% of patients have positive blood cultures.
The most common organisms are Streptococcus spp., Staphylococcus epidermidis, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, methicillin-resistant S. aureus, Enterococcus faecalis, Campylobacter jejuni, Candida albicans, and vancomycin-resistant Enterococcus.
Obtain urine culture if the patient has hematuria or symptoms of a urinary tract infection (UTI).
Treatment: Immediately start a broad-spectrum antibiotic, such as cefepime.
Alternate lumens if more than one is present.
For patients allergic to penicillin/cephalosporins, alternatives include meropenem, imipenem, or aztreonam.
Add vancomycin (dosing per age and renal function) after 48 hours of persistent fever.
Start vancomycin immediately for unstable patients, patients with acute myeloid leukemia (AML) on chemotherapy (at risk for α-streptococcal sepsis), signs of sinus infection (also consider fungal coverage), cutaneous breakdown, or history of prior gram-positive infection.
Add antifungal therapy, amphotericin B or voriconazole, if fever lasts for >5 days.
For signs of sepsis (e.g., hypotension), consider adding an aminoglycoside.
Continue trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis.
For oncology patients with fever, neutropenia, and negative blood culture results, continue antibiotic therapy until the patient is afebrile for 24 hours and has a rising ANC.
If an oncology patient has a positive blood culture, he/she should complete a 7-10-day course of antibiotics (choice of antibiotic depends on sensitivity analysis of the isolated organism) after the first negative blood culture, and should not be discharged until afebrile for a minimum of 24 hours with a rising ANC.
Evaluate patients with tachypnea, low O2 saturation, and fever for Pneumocystis jirovecii infection.
Lung signs are often minimal.
Chest radiograph may show diffuse interstitial disease.
Definitive testing includes bronchoalveolar lavage.
Treatment includes glucocorticoid pulses and high-dose TMP-SMX.
ONCOLOGIC EMERGENCIES
Superior Vena Cava Syndrome/Superior Mediastinal Syndrome
Clinical presentation: cough, hoarseness, dyspnea, orthopnea, wheezing, stridor, chest pain, upper body or facial swelling, plethora and cyanosis of the face and neck, and diaphoresis
Differential diagnosis depends on the location of the mass causing the syndrome.
Posterior mediastinum: neuroblastoma, paraganglionic masses, and primitive neuroectodermal tumor (PNET)
Anterior/superior mediastinum: T lymphoma, teratoma, thymoma, and thyroid masses
Because of risks of anesthesia, the diagnosis should be established using the least invasive means possible.
Check serum α-fetoprotein and human chorionic gonadotropin to differentiate germ-cell tumors from lymphomas.
Use spiral computed tomography (CT) to differentiate calcification in neuroblastoma.
Use peripheral smear in the case of lymphoblastic lymphomas.
Treatment
High risk: empiric therapy of prednisone 40 mg/m2/day divided four times a day and/or radiotherapy should be given.
After the patient has been stabilized, the lesion should be biopsied.
Low-risk: biopsy, then treatment
Symptomatic patients should be monitored in the intensive care unit (ICU).
Pleural/Pericardial Effusion
Thoracentesis: send for protein content, specific gravity, cell count, lactate dehydrogenase (LDH), cytology, culture, and other biologic/immunologic assays.
Tamponade: chest radiograph shows water bag cardiac shadow, and electrocardiogram (ECG) shows low-voltage QRS.
Treatment: pericardiocentesis may relieve cardiac symptoms, but the underlying etiology must ultimately be treated.
Massive Hemoptysis
Differential diagnosis: invasive pulmonary aspergillosis (incidence with hemoptysis is 2%-26%), metastatic disease, toxicity from therapy, coagulopathy (disseminated intravascular coagulation [DIC]) and thrombocytopenia
Diagnosis involves chest radiography and chest CT.
Treatment involves lying on same side as hemorrhage to prevent collection in the normal lung, transfusion with platelets, RBCs, fresh frozen plasma (FFP) and cryoprecipitate as needed, and volume resuscitation.
Neutropenic Enterocolitis (Typhlitis)
Inflammation of the bowel wall, most commonly of the terminal ileum and cecum, in a neutropenic patient
Signs and symptoms are abdominal pain in setting of severe neutropenia, fever, and either diarrhea or paralytic ileus.
Monitor closely for an acute, surgical abdomen because these patients are at a high risk for perforation.
Diagnose with abdominal ultrasound or CT scan.
Treatment
Broad-spectrum antibiotics to cover Gram-negative enterics and anaerobes.
Bowel rest/decompression.
Consider treatment with G-CSF and irradiated granulocytes.
Surgical intervention is reserved for patients with bowel perforation or other dire complications.
Hemorrhagic Cystitis
Painless blood in the urine (microscopic more common than macroscopic) secondary to chemotherapy (most commonly cyclophosphamide or ifosfamide)
Prevention: vigorous hydration during and after chemotherapy treatment, and mercaptoethane sulfonate (Mesna)
Diagnosis: urinalysis, ultrasound (boggy, edematous bladder wall), cystoscopy
BK virus or adenovirus infection should be considered in bone marrow transplant (BMT) patients
Treatment
Stop radiation treatment/chemotherapy.
Hydration
Transfusion to correct low platelets and coagulopathy
Consult urology for bladder irrigation with cold saline via catheter or cystoscope to remove blood clots.
Altered Consciousness
Differential diagnosis: metastatic disease, sepsis/DIC, primary central nervous system (CNS) infection (fungal, bacterial, or viral encephalitis), metabolic abnormality, leukoencephalopathy, intracranial hemorrhage, cerebrovascular accident (CVA), oversedation, hypercalcemia, hyperammonemia because of hepatic dysfunction
Chemotherapy-induced
Ifosfamide may cause symptoms of acute somnolence, neurologic deterioration, seizure, and coma.
Patients are at higher risk with poor renal clearance, which leads to a buildup of the toxic metabolite chloroacetaldehyde.
Other chemotherapy agents to consider: carmustine, cisplatin, thiotepa, highdose cytarabine (Ara-C), amphotericin, interleukin-2, trans-retinoic acid
Cerebrovascular Accident (Stroke)
Differential diagnosis: cerebral arterial/venous thrombosis as a result of inherited thrombophilic states, intracranial hemorrhage, chemotherapy-related (L-asparaginase), sepsis/DIC, and radiation therapy-induced vascular occlusions
The most common cause of stroke within the hematology/oncology patient population is sickle cell disease (SCD) (discussed below).
Diagnose with magnetic resonance imaging (MRI) and CT (most helpful if concerned for hemorrhage)
The MRI may need to be repeated in 7-10 days to evaluate full extent of infarct.
Treatment: Consider corticosteroids, mannitol, FFP (± antithrombin III concentrate in patients with L-asparaginase-induced CVA), and platelets depending on etiology and symptoms.
Seizures
Differential diagnosis: metastatic disease, CVA, infection, chemotherapy (intrathecal methotrexate, Ara-C, etc.), syndrome of inappropriate secretion of antidiuretic hormone/hyponatremia (vincristine)
Laboratory evaluation: consider electrolyte evaluation, anticonvulsant drug levels, EEG, CT with and without contrast, MRI, and cerebrospinal fluid (CSF) analysis
Treatment
Seizure safety precautions (roll patient on side in case of vomiting, move patient to safe environment, remove all items from mouth) and monitor vital signs to provide supplemental O2 as needed
Anticonvulsant therapy to acutely stop seizure activity
Lorazepam (Ativan): 0.05-0.1 mg/kg IV push over 2 minutes (max dose 4 mg)
Diazepam (Valium): Administer per rectum. Dosing dependent on age and weight.
Monitor closely for respiratory depression with these medications.
Address underlying problem (e.g., infection).
Spinal Cord Compression
Symptoms: back pain (local or radicular) occurs in 80% of cases.
Any patient with cancer and back pain should be considered to have spinal cord compression until proven otherwise.
Evaluation: spine radiographs (diagnosis confirmed by x-ray in <50% of cases), bone scan, and MRI (with and without gadolinium)
If patients are not ambulatory, they should undergo emergent MRI (or myelography).
Treatment: dexamethasone bolus dose of 1-2 mg/kg IV immediately, followed by MRI
Hyperleukocytosis
White blood cell (WBC) count >100,000/µL
Signs and symptoms: hypoxia, dyspnea, blurred vision, agitation, confusion, stupor, cyanosis
Treatment: hydration, alkalinization, allopurinol or urate oxidase (rasburicase), leukapheresis, and/or hydroxyurea
Transfuse RBCs with caution (keep Hb <10 g/dL to minimize viscosity)
Complications: death, CNS hemorrhage, thrombosis, pulmonary leukostasis, metabolic derangements (hyperkalemia, hypocalcemia/hyperphosphatemia), renal failure, gastrointestinal hemorrhage
Tumor Lysis Syndrome
Cell lysis resulting in the triad of hyperuricemia, hyperkalemia, and hyperphosphatemia, which can then cause secondary renal failure and symptomatic hypocalcemia
May trigger DIC, especially in patients with high tumor burdens
Risk factors: bulky abdominal tumors (e.g., Burkitt lymphoma), hyperleukocytosis, increased uric acid and LDH levels, poor urinary output
Laboratory studies: CBC, serum electrolytes, calcium, phosphorus, uric acid, urinalysis, LDH, prothrombin time/partial thromboplastin time (PT/PTT)
Consider D-dimer, fibrinogen, and fibrin degradation product (FDP) if concerned for DIC
Imaging: ECG for hyperkalemia, ultrasound to rule out kidney infiltrations or ureteral obstruction
Treatment
Hydration: D5W + 40 mEq/L NaHCO3 at 3,000 mL/m2/day
Avoid potassium in IV fluid.
Allopurinol: 10 mg/kg/day or 300 mg/m2/day (divided t.i.d., maximum of 600 mg/day), or urate oxidase (Rasburicase) 0.15 mg/kg IV once (subsequent dosing dependent on uric acid levels)
Test for glucose-6-phosphate dehydrogenase (G6PD) deficiency prior to giving urate oxidase in males of African or Mediterranean descent.
Monitor serum electrolytes, phosphorus, calcium, uric acid, and urinalysis (DIC profile if needed) multiple times per day until laboratory values stabilize.
Consider dialysis if the patient is symptomatic from electrolyte derangements and/or the patient’s electrolytes cannot be normalized
For hyperkalemia, stop all potassium infusions, Kayexalate (1 g/kg PO with 50% sorbitol), calcium gluconate for cardioprotection only, insulin (0.1 unit/kg + 2 mL/kg of 25% glucose), and albuterol nebulizer therapy for temporary palliation.
Hypercalcemia
Symptoms: anorexia, nausea, vomiting, polyuria, diarrhea resulting in dehydration, gastrointestinal/renal impairment, lethargy, depression, hypotonia, stupor, coma, bradycardia, and nocturia
Risk factors: paraneoplastic syndrome, hyperleukocytosis, and tumor lysis syndrome
Treatment: Note that a serum calcium level <14 mg/dL may respond to loop diuretics alone (see later discussion).
Pamidronate
Hydration with normal saline (three times maintenance) and loop diuretics
Glucocorticoids (prednisone 1.5-2 mg/kg/day): requires 2-3 days to work
BMT ISSUES
Sinusoidal Obstructive Syndrome
Capillary endothelial inflammation of the liver leading to third spacing of fluids
Clinical presentation usually occurs in the first 30 days post-BMT, while the greatest risk is within the first 10 days post-BMT.
Hepatomegaly right upper quadrant pain, jaundice (usually hyperbilirubinemia without any other liver function abnormalities until end-stage), ascites/weight gain, and platelet consumption
Risk factors: preexisting hepatitis, antibiotic usage before treatment (vancomycin, acyclovir), age >15 years, CMV seropositive, female sex, pretreatment radiation to abdomen, intensive conditioning (single-dose total body irradiation [TBI], use of busulfan), and second BMT
Treatment is primarily supportive
Defibrotide, a single-stranded polydeoxyribonucleotide with antithrombotic properties, is the only pharmacologic therapy available.
Fluid Management
BMT patients are fluid restricted starting 12-24 hours infusion of stem cells at 1,500/m2/day until engraftment occurs.
Infection
The threshold for suspecting infection in children undergoing transplant is very low. Any change in clinical status should alert a resident to the possibility of infection.
Prophylactic antibiotics may be used when ANC is <500/µL.
Consider the addition of vancomycin and amphotericin, respectively, at 24 hours and 48 hours of continued fevers.
Drug interaction of antifungals, such as voriconazole, with immunosuppressants, such as cyclosporine A, should be considered when adding or adjusting medications.
Vaccination
Vaccinations are resumed in BMT recipients 1 year posttransplant.
Patients should avoid all family members who have received a live virus vaccine for 4 weeks.
Graft-versus-Host Disease
Graft-versus-host disease (GVHD) occurs in recipients of allogeneic transplants when donor lymphocytes recognize and attack the “foreign” host cells.
Acute GVHD occurs 20-100 days after BMT
Symptoms: dermatitis (rash), hepatitis, colitis (diarrhea)
Treatment: glucocorticoids, cyclosporine A (target range of 250-350 ng/mL), and tacrolimus (target range of 8-12 ng/mL)
Chronic GVHD occurs 100 or more days after BMT.
Symptoms: sicca syndrome with thickened skin, lichen planus and/or papules, cholestatic jaundice, colitis (diarrhea) and eye lesions (dry eyes)
Treatment: glucocorticoids, cyclosporine A, azathioprine, mycophenolate, thalidomide, psoralen ultraviolet A (PUVA) (skin), hydroxychloroquine, and pentostatin
ACUTE LYMPHOBLASTIC LEUKEMIA
Epidemiology: Acute lymphoblastic leukemia (ALL) is the most common cancer in pediatrics.
Clinical presentation: ALL presents with increased or decreased WBC with low platelets and/or hemoglobin (2 or more cell lines affected)
Signs and symptoms: low-grade fever, fatigue, pallor, bone pain, night sweats, mucosal bleeds, petechiae, generalized lymphadenopathy, hepatomegaly, and/or splenomegaly
Retinal hemorrhage or leukemic infiltrates may be seen on funduscopy.
Risk assessment: age <1 year and >10 years, male sex, WBC >100,000/µL at diagnosis, CNS disease, unfavorable cytogenetics, and pretreatment with glucocorticoids
Presence of trisomy +4, +10, +17, or t(12;21)(p13;q22) (ETV6/RUNX1) in the leukemia cells confers a favorable prognosis.
Presence of the Philadelphia chromosome [t(9;22)(q34;q11)] (BCR/ABL) or translocations involving the mixed lineage leukemia (MLL) gene on 11q23 confers a poor prognosis.
Classification: Types of ALL are differentiated by surface markers.
Precursor-B ALL is the most common, and is CD19+ and CD20+, often with CD10+.
T cell: CD4+, CD8+, and TdT+
Burkitt or mature B cell: surface immunoglobulin and CD20+
Treatment lasts ˜2 years for females, and 3 years for males.
Therapy starts with a 28-day induction cycle.
Prednisone, vincristine, and asparaginase
Adriamycin or daunorubicin is added for four-drug induction therapy in highrisk patients.
If the child is in remission at end of induction, he/she receives consolidation therapy for ˜24 weeks. Drugs used for consolidation therapy include vincristine, methotrexate, 6-mercaptopurine (6-MP), and others.
Maintenance therapy of ˜130 weeks follows consolidation therapy, and typically involves daily oral 6-MP, weekly oral methotrexate, a monthly oral corticosteroid pulse, monthly vincristine, and intrathecal methotrexate once every 12 weeks.
Children with CNS leukemia receive additional intrathecal therapy and occasionally radiation therapy.
ACUTE MYELOBLASTIC LEUKEMIA
AML has a poor prognosis when compared to ALL.
Classification of AML is determined by surface markers (Table 19-1).
Risk assessment is determined by cytogenetics and response to induction therapy.
Presence of t(8;21)(q22;q22), inversion of chromosome 16, NPM mutation or CEBPα mutation confers a favorable prognosis.
Presence of t(15;17)(q22;q21), which is characteristic of acute promyelocytic leukemia (APL), confers a favorable prognosis.
Presence of FLT3 mutations, monosomy 5, monosomy 7, 5q-, or 11q23 abnormalities confers a worse prognosis.
Residual disease (bone marrow or extramedullary) at the end of induction confers a worse prognosis.
Treatment is of shorter duration (˜6 months) but entails more intense chemotherapy compared with ALL.
Various chemotherapy combinations exist, but the mainstays of treatment are anthracyclines (e.g., daunorubicin, mitoxantrone, or idarubicin) and Ara-C.
Induction recovery and clinical remission is followed by courses of consolidation therapy.
Siblings are tested for human leukocyte antigen (HLA) matching for potential matched sibling allogeneic BMT if a patient has a poor response to induction therapy or has high-risk cytogenetics.
Patients without a matched sibling are usually offered chemotherapy only if they have a complete remission after induction therapy.
Matched, unrelated donor transplant is considered at the time of relapse, or in the case of resistant leukemias, because of the risks associated with unrelated donor transplant.
AML therapy is associated with prolonged and severe neutropenia, and AML patients have a high risk of Gram-positive sepsis, such as α-streptococcal and staphylococcal infections.
TABLE 19-1 Surface Markers for Acute Myeloblastic Leukemia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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NON-HODGKIN LYMPHOMA
Non-Hodgkin lymphoma (NHL) encompasses >12 neoplasms.
It is the most frequent malignancy in children with AIDS; thus HIV screening should be performed in all children with NHL.
Lineage category information is presented in Table 19-2.
Clinical presentation depends on classification and grade.
Low grade: Painless, diffuse peripheral lymphadenopathy (LAD) seen primarily in older adults.
Intermediate grade: Painless peripheral LAD is the most common, but localized extranodal disease is also seen (e.g., GI and bone).
Median age is 55 years, but this type of NHL is also common in children and young adults.
High-grade lymphomas are most commonly seen in children and young adults.
Lymphoblastic lymphoma most commonly presents with mediastinal involvement, which manifests as shortness of breath, dyspnea, wheezing, stridor, dysphagia, and head/neck swelling.
Approximately two-thirds of patients with lymphoblastic lymphoma are male.
Small non-cleaved cell lymphoma (SNCCL)/Burkitt/non-Burkitt is also usually considered a childhood disease, but has a second peak after 50 years of age.
Burkitt lymphoma commonly presents in the abdomen and GI tract (˜80%).
Non-Burkitt lymphoma presents in the bone marrow and with peripheral LAD.
Presentation in the right lower quadrant is common and can be confused with appendicitis.
Diagnosis: physical examination, CBC, serum electrolytes with liver function studies, LDH, uric acid, chest radiograph, chest CT (if chest radiograph is abnormal), abdominal CT, bilateral bone marrow aspiration/biopsy, CSF analysis
Also consider a bone scan, MRI for bone marrow involvement, and/or positron emission tomography (PET) scan.
Treatment of NHL is dependent on pathologic subtype and stage.
Therapy of Burkitt lymphoma is usually short (around 4-6 months), whereas T-cell lymphomas require treatment for a longer duration period, with emphasis on CNS prophylaxis.
Resistant Burkitt may benefit by addition of rituximab (anti-CD20) to the therapeutic protocol.
Patients with Burkitt lymphoma are at high risk for tumor lysis syndrome.
TABLE 19-2 Classification of Non-Hodgkin Lymphoma | ||||||||||||||
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