 \212 \212 618 Prevention Genetic counseling; prenatal tests. Parental education and prompt medical attent ion for febrile illnesses prevents 90% of childhood deaths from infection, sequestration cr ises. Management of sickle-cell crisis Seek expert help. \212 \212 Give Cross-match blood. CBC, reticulocytes, blood cultures, chest x-ray (CXR). Rehydrate wi th IV fluids and keep warm. Give O Empiric antibiotics for fever after culturing. Measure h ematocrit (HCT), reticulocytes, liver, and spleen size daily. prompt , generous analgesia with opiates. \212 \212 \212 \212 2 by mask if P a O 2 \206\223 . Give blood transfusion if HCT or reticulocytes fall sharply, or if there are CNS or lung co mplications (when the proportion of sickled cells should be reduced to <30%). This may requ ire urgent exchange transfusion. The acute chest syndrome entails pulmonary infiltrates ass ociated with chest pain and fever. It is a serious condition. Incidence: 0.1 episodes/pati ent/ yr. 13% in the landmark Vichinsky study needed ventilation, 11% had CNS symptoms, and 9% of those >20 yrs old died. Prodromal painful crisis oc- cur 2.5 d before any abnormalit ies on CXR in 50% of patients. The chief causes of the infiltrates are fat embolism from bo ne marrow; infection with Chlamydia , Mycoplasma , or virus; and sickled RBCs. Bronchodilat ors have proved to be very effective in 20% having wheezing or obstructive pulmo- nary func tion at presentation. Antibiotics have an important role. Red cell transfusion improves oxy genation; red cell exchange should be emergently arranged if respiratory status deteriorate s. \212 y g o o t a m e H l Thalassemia Hemoglobin (Hb) is a tetramer consisting of 2 - and 2 \222 -globin molecule s. Hb is heterogeneous. Adults have 95% HbA ( 2 \222 2 ) and a little HbA 2 ( 2 2 ). HbF ( 2 2 ) predominates in fetal life and HbA predominates after birth. HbA 2 an d fetal hemoglobins may be relatively elevated in \222 -chain disorders such as \222 -tha lassemia and sickle cell anemia. The thalassemias are a group of disorders resulting from r educed rate of production of one or more globin chains. This leads to an imbalance between - and \222 -chains, precipitation of excess globin chains, and anemia due to ineffectiv e erythropoiesis and hemolysis. They are common in a band stretching from the Mediterranean to the Far East. The most important are - and \222 -thalassemia, in which there is red uced production of - and \222 -chains, respectively. Since there are two genes for \222 -globin and four for -globin in each individual, there are numerous varieties of ge netic defects associated with thalassemias. It is possible to correlate clinical severity w ith the specific genetic defect to some extent, although many other genetic and acquired fa ctors modify the clinical phenotype. \222 -thalassemia major: This is the homozygous form in which very few \222 -chains are formed, and it results in a severe anemia presenting in the first year, often as failure to thrive. Death results in 1 yr without transfusion. If adequate transfusion is given, development is normal but symptoms of iron overload appear a fter 10 yrs as endocrine failure, liver disease, and cardiac toxicity. Death usually occurs at 20 \200\22330 yrs due to cardiac siderosis if long-term iron chelation is not provided. If transfusion is inadequate, there is chronic anemia with reduced growth and skeletal def ormity due to bone marrow hyperplasia (bossing of skull). The smear shows very hypochromic, microcytic cells with target cells and nucleated RBCs. HbF \206\221 , HbA 2 variable, HbA absent. Prevalence of carriers: Cypriot 1:7; southern Italy 1:10; Greek 1:12; Turkish 1:20 ; English 1:100. \222 -Thalassemia minor: This is the heterozygous state, recognized as MC V <75 fL, HbA 2 >3.5%, and mild anemia (9 \200\22311 g/dL) that is usually well toler- ated but may be worsened in pregnancy. -Thalassemia: Four varieties are defined, depending o n the number of de- fective genes. Absence of one or two genes is common in individuals of African descent and is either undetectable or produces a mild microcytic anemia. Hb H di sease: In patients with three gene deletions, HbH ( \222 4 ) is present at 5 \200\22330 % throughout life with moderate hemolytic anemia and splenomegaly. Prognosis: Good. 619 Hb Barts: Infants are stillborn or have neonatal jaundice (hydrops fetalis). They lack all genes. Hb Barts is 4 , and physiologically useless. Obstetric problems are common. Th alassemia intermedia: This is a term used to describe individuals with thalassemia of inter mediate severity who are not transfusion-dependent but have severe anemia. They often have substantial splenic enlargement. Usu- ally the explanation for the mildness of the disease is a residual ability to make \222 -chains. Diagnosis Family history, CBC, MCV, smear, iro n, HbA 2 , HbF, Hb electrophoresis. Treatment \212 \212 Transfusion to keep Hb >9 g/dL Iron-chelating agent, e.g., deferoxamine. *Large doses of as corbic acid also increase iron output but can cause cardiac failure due to sudden, rapid ir on release, Perform splenectomy if hypersplenism exists. Give folate supplements. A histoco mpatible marrow transplant can offer the chance of a cure in childhood . 1 Genetic counseli ng should be offered. It may be particularly useful if abortion is an acceptable option. \212 \212 Bleeding disorders After trauma, three processes control hemorrhage: Vasoconstriction, plat e- let adhesion and aggregation, and fibrin deposition from activation of the coagulation c ascade. Disorders of hemostasis fall into these three groups. The pattern of bleeding is im portant to the diagnostic approach \200\224vascular and platelet disorders lead to prolonge d bleeding from cuts, purpura, and bleeding from mucous membranes, whereas coagulation diso rders produce prolonged bleeding after injury, into joints, muscle, and the GI and GU tract s. Vascular defects Causes may be congenital (Osler \200\223Weber \200\223Rendu) or acquire d (senile purpura, steroids, trauma, pressure, vasculitis, diabetes, connective tissue dise ase, scurvy). Platelet disorders These may be due to quantitative or qualitative platelet d efects. Causes of thrombocytopenia include: \212 Marrow failure states, megaloblastosis, drugs (che- Decreased production: motherapy), liver disease, alcohol Immune thrombocytopenia (ITP), inf ection (EBV), Increased destruction: DIC, drugs, SLE, TTP, hypersplenism, heparin induced t hrombocytopenia, pregnancy, sepsis \212 Qualitative platelet defects are most frequently acquired from drugs (aspi- rin, Plavix ), uremia, myeloproliferative disorders, or, less commonly, can be due to congenital platelet disorders (Glanzmann \200\231s thrombasthenia, Bernard \200\223Soulier). ITP may be acute or chronic. Acute ITP is most commonly observed in children after viral infections, with ra pid onset and spontaneous resolution within a year. Chronic ITP is the rule in adults, with a fluctuating course of bleeding, purpura, or epistaxis. Treatment is indicated when sympt om- atic bleeding occurs or when platelet counts are <20,000/mcL. Treatment options include steroids, splenectomy, high-dose immune globulin, or anti-D (WinRho). Other treatments inc lude rituximab and other immuno- suppressive agents and thrombopoietic mimetics. Platelets transfusions are only transiently successful and should be used if serious bleeding ensues. 620 1 Rund D. Rachmilewitz E. Beta-thalassemia. NE JM 2005; 353 :1135 \200\2231146. Coagulation disorders Coagulation defects include congenital disorders such as hemophilia a nd von Willebrand \200\231s disease or acquired processes including anticoagulants, liver d isease, DIC (p. 626), vitamin K deficiency, or acquired factor inhibitors. Hemophilia A: Co ngenital factor VIII deficiency, sex-linked recessive in 1 of 10,000 male births. New mutat ions are common. The presentation depends on the severity of the deficiency and is frequent ly detected early in life, after surgery or trauma, or due to spontaneous bleeding into joi nts and muscle. Acquired hemophilia is due to factor VIII autoantibodies. These may appear in pregnancy, autoimmune diseases, or malignancy. Diagnosed by family history, bleeding his tory, prolongation of the activated PTT (aPTT), and factor VIII assay. Management: Seek exp ert advice. Avoid antiplatelet agents and IM injections. Major bleeding (hemarthrosis) requ ires factor VIII levels to be raised to 50% of normal. Life-threatening or CNS bleeding req uires levels of 100% of normal. Both recombinant and plasma-derived factors are available. Hemophilia B (Christmas disease): Due to factor IX deficiency and behaves clinically like h emophilia A. Liver disease produces a complicated bleeding disorder, with decreased clottin g factor synthesis, dysfibrinogenemia, and decreased clearance of circulating anticoagulant s. Malabsorption leads to reduced absorption of vitamin K. Treatmen: Vitamin K 10 mg sq or FFP for acute hemorrhage. y g o o t a m e H l The intrinsic and extrinsic pathways of blood coagulation Figure 15.1 The intrinsic and extrinsic pathways of blood coagulation Extrinsic System Extrinsic System Intrinsic System Intrinsic System XII (on contact with vasular endothelium XIIa Tissue factor + VII + Ca2+ XI XIa IX IXa + VIII + Ca2+ +phospholipid X Xa + V + Ca2+ +phospholipid 621 XIII prothrombin Thrombin XIIIa Fibrin Fibrinogen crosslinking (Continued) Figure 15.1 (Continued) The fibrinolytic system The coagulation cascade simultaneously acti- vates factors that res ult in fibrin dissolution by the activation of plasmin from plasminogen. The process starts by the release of tissue plasmi- nogen activator (t-PA) from endothelial cells, a process stimulated by fibrin formation. t-PA converts inactive plasminogen to plasmin, which can th en cleave fibrin, as well as several other factors. Fibrinolytic agents 1 Alteplase (RT-PA; Actilyse ; from recombinant DNA) is a fibrinolytic enzyme imitating t-PA, as above. Plasma t = 5 min. 2 Anistreplase (anisoylated plasminogen streptokinase activator complex; APSAC ) is a comp lex of human plasminogen and streptokinase (so anaphylaxis is possible). Plasma t = 90 m in. 3 Streptokinase is a streptococcal exotoxin and forms a complex in plasma with plasminogen to form an activator complex which forms plasmin from unbound plasminogen. Initially, there is rapid plasmin for- mation that can cause uncontrolled fibrinolysis. However, plasminoge n is rapidly consumed in the complex and then plasmin is only produced as more plasminogen is synthesized. 4 Urokinase is produced by the kidney and is found in urine. It also cleaves plasminogen. Coagulation tests Coagulation tests If using sodium citrate tube, beware of falsely elevate d results if tube is incompletely filled or insufficiently mixed. See Table 15.2. 1 aPTT: A ctivated partial thromboplastin time; measure of the intrinsic pathway. Prolonged by abnorm alities in fibrinogen (I), II, VII, IX, X f XI, XII. Abnormalities can be qualitative (dysf ibrinogenemia), quantitative (von Willebrand \200\231s disease, hemophilia), or acquired (h eparin therapy, DIC, VIII antibodies). Also prolonged by the misnamed lupus \200\234antico agulant \200\235 as an artifact of cross-reaction with the lipid component of the test. 2 Prothrombin time: (PT) Expressed as a ratio compared to control: International Normalized Ratio (INR); normal, 0.9 \200\2231.2. Thromboplastin is added to test the extrinsic system . Prolonged by abnormalities in factors I, II, VII, X; warfarin, liver disease, or vitamin K deficiency. 3 Thrombin time: Thrombin is added to plasma to convert fibrinogen to fibrin. Prolonged in heparin treatment, DIC, or dysfibrinogenemia. Reptilase time is similar to the thrombin tim e but is not affected by hepa- rin, which can help distinguish heparin effect from other ca uses. 622 4 Bleeding time: A measure of platelet and vascular function. Prolonged in von Willebrand \200\231s disease, NSAIDs, uremia, all platelet numeric or func- tional defects, vascular p roblems (diabetes). 5 Platelet aggregation studies: Used to evaluate defects in platelet function. Abnormal in NSAIDs, congenital defects, myeloproliferative or myelodys- plastic disorders. 6 Mixing studies and inhibitor screens: Used for evaluating prolonged PT or aPTTs. If prolo ngation of the PT or aPTT is corrected by the addition of normal plasma, then a factor defi ciency is established. If addition of normal plasma does not correct the clotting test, the n inhibitors are suspected and further testing is required. Seek expert help for evaluation and treatment. y g o o t a m e H Table 15.2 Interpreting investigations into bleeding disorders l Disorder INR aPTT Thrombin Platelet count \206\224 \206\223 Bleeding time \206\224 \206\221 Notes time \206\221 \206\221 \206\221 \206\221 Heparin DIC \206\224 \206\221 \206\221 \206\221 \206\221 \206\221 \206\221 FDP \206\221 (p. 626) \206\221 LFTs Liver disease Platelet defect Vitamin K def Hemophilia v on Willebrand \200\231s \206\221 \206\224 \206\221 \206\221 \206\224 \206\224 \206\221 \206\224 \206\224 \206\221 \206\221 \206\221 \206\221 \206\221 \206\224 \206\224 \206\224 \206\224 \206\224 \206\223 \206\224 \206\224 \206\223 \206\224 \206\224 \206\224 \206\224 \206\221 \206\221 \206\224 \206\224 \206\221 p. 570 Special tests may often be required. Consult a hematologist. FDP, fibrin degradation produc ts. Anticoagulants Consider bleeding as a cause of any symptom in anyone on anticoagulants. The main indications for anticoagulation \212 Deep vein thrombosis/pulmonary emboli To preven t embolism in atrial fibrillation or in those with mechanical \212 heart valves To prevent deep venous thrombosis/pulmonary emboli in high-risk patients (p. 446) \212 Types of anticoagulant Standard unfractionated( 13,000 daltons) heparin (IV or SC) is inexp ensive, acts fast, and is monitored by the aPTT. Heparin inactivates thrombin by binding to antithrombin III, leading to inactivation of coagulation enzyme Xa. Plasma infusion will n ot reverse the effect of heparin. Low - molecular weight-heparin preparations (5,000 dalton s, dalteparin, enoxaparin) T 1/2 are two- to fourfold longer than unfractionated heparin, a nd response is more predictable. They can be given once daily SC, no monitoring is needed, and can be used in the outpatient setting. Low-molecular-weight heparin inactivates factor Xa, and its activity can be monitored by Xa levels. se : Bleeding (at operative site, intra cranial, retroperitoneal). Contraindications (CI) : Uncontrolled bleeding/risk of bleeding (active peptic ulcer); endocarditis. Warfarin: Warfarin inhibits the vitamin K-dependent pr oduction of the co- agulation factors II, VII, IX, and X, and the anticoagulants protein C and S. Warfarin has both a large volume of distribution and a very long t 1/2 . Therapy is monitored with the INR. CI : Peptic ulcer, bleeding disorders, severe hypertension, liver f ailure, infective endocarditis, cerebral aneurysms, history of falls. Use with caution in t he elderly and those with remote GI bleeds. Beginning anticoagulation Heparin bolus (5,000 \200\22310,000 U IV over 5 min) if anticoagulation is urgent (e.g., deep vein thrombosus [D VT], pulmonary embolus (PE), unstable angina, myocardial infarction [MI]). Giving a bolus i s contraindicated (by convention) for stroke. Infusion: Start at 800 \200\223l,400 U/h. Che ck aPTT 4 \200\2236 h after starting; aim for target of 1.5 \200\2232.5 \227 the upper 623 limit of the control (target = 60 \200\22380 sec). Adjust as follows (check with the guidel ines established in your institution): PTT (sec) <50 50 \200\22359 60 \200\22380 81 \200\223110 >II0 Bolus ( U ) 5000 0 0 0 0 Hold (min) 0 0 Rate change ( U / h ) +120 +120 0 \200\22350 \200\223160 Repeat ptt 4 \200\2236 h 4 \200\2236 h Next day 4 \200\2236 h 4 \200\2236 h 30 60 \212 Start warfarin 10 mg PO qd when aPTT is therapeutic on heparin. If the INR at 18 h after th e first dose is <1.8, continue 10 mg of warfarin; if INR >1.8, reduce to 5 mg. Use the slid ing scale below to keep INR in the target range. Do INR daily for 5 d, then alternate days until stable, then weekly or less often. \212 <2 INR Third dose 10 mg Maintenance 6 mg 2 5 mg 5.5 mg 2.5 4 mg 4.5 mg 2.9 3 mg 4 mg 3.3 2 mg 3.5 mg 3.6 0.5 mg 0 mg 3 mg 4.1 Skip a dose; give 1 \200\2232 mg the next day (if INR >4.5, skip two doses) Stop heparin when INR >2. Check platelet count if on heparin >5 d. \212 Antidotes Consult a hematologist. Stop anticoagulation; if further steps are needed, protamine sulfate can co unteract heparin: 1 mg IV neutralizes 100 U heparin given within 15 min. Maximum dose: 50 m g (if exceeded, may itself have anticoagulant effect). For warfarin reversal or overdose, u se phytomenadione (vitamin K): 5 \200\22310 mg PO or SC for serious bleeding, 0.5 \200\2232 mg for simple hematuria or epistaxis; consider 0.5 mg if INR >7 without any bleeding. This takes some hours to act and may last for weeks. If serious bleeding, and INR \206\221 , g ive a concentrate of activated clotting factors, activated VII, or, if unavailable, infuse fresh frozen plasma. Thrombin inhibitors and Factor Xa inhibitors Are anticoagulants availa ble in oral and parenteral formulations and are indicated in patients who cannot be exposed to heparins (due to the development of heparin-induced thrombocytopenia [HIT]). Oral throm bin inhibitors are approved in some instances and can replace warfarin-based anticoagulatio n regimens. Warfarin: INR guidelines The target level represents a balance between too litt le anticoagulation (and risk of thromboembolism) and too much anticoagulation (risk of blee ding). Since the risks of thromboembolism vary with the clinical situation, opti- mum INR v aries. Recommendations are likely to change as further trials are done: Check with a hemato logist. Choose a target INR within the range (not the range itself). This reduces the chanc e that the INR will stray outside the optimum range. The incidence of fatal bleeding due to warfarin is 0.3/100 patient years. Severe bleeding is tenfold more common. \212Prosthetic heart valves . The degree of anticoagulation depends on the loca- tion and type of prosthe tic valve, the presence of atrial fibrillation or CHF, and the left atrial size. Aortic val ves 2.5 (2 \200\2233) INR, mitral 3 (2.5 \200\2233.5). Caged-ball valves generally require higher INR. 624 \212Atrial fibrillation : Important clinical parameters in determining thrombotic risk inc lude congestive heart failure, hypertension, age >75, diabetes, and previous stroke, TIA, o r systemic embolic event. For medium-risk patients (one or two risks), guidelines are an IN R of 2 \200\2233; for higher risk, 2.5 \200\2233.5. An alternative for low-risk patients (0 risks) is aspirin, particularly if the risk of bleeding is high (serious comorbidity or difficulty with monitoring INR). y g o o t a m e H \212Pulmonary embolism and above-knee DVT : Aim for INR of 2 \200\2233, and treat l for 3 \200\2236 months (depends on risk of recurrence). Leukemia and the resident Patients with leukemia fall ill suddenly and can deteriorate rapi dly. The most important acute issues are bleeding, infection, and leukostasis. Unlike the d ifferentiated cells in chronic lymphocytic leukemia (CLL) and myeloprolif- erative disorder s, where elevated cell counts are not usually dangerous in themselves, leukemic blasts are large and sticky and can obstruct the small circulations in the lungs, heart, and brain. Le ukemic blasts can also secrete substances that generate disseminated intravascular coagulat ion. Thus it is important not only to review the blood smear in patients presenting with el evated white cell counts to make the diagnosis of leukemia, it is also crucial to evaluate and treat leukemic patients who present with markedly elevated blast counts. Neutropenic pr ecautions and approach to febrile neutropenia If the absolute neutrophil count is <500/mcL, then neutropenic precautions are as follows: \212 \212 \212 \212 \212 \212 Strict hand washing No rectal temperatures or unnecessary rectal examinations No IM injecti ons Low-bacteria diet (fresh fruit and vegetables carry risk of No fresh flowers Examine mo uth, perineum, axillae, IV sites, and indwelling catheter sites carefully Vital signs q4h C ulture urine, sputum, stool, blood (peripheral and catheter lines), CXR, computed tomograph y (CT) of chest and sinuses, place PPD Oral Pseudomonas ) \212 \212 \212 Antibiotic use in neutropenia: Treat known infections promptly. After cul- tures are drawn, start empiric antibiotics for fever >38.3 C or >38 C on separate occasions 1 \200 \2232 h apart. In the absence of fever, empiric antibiotics should also be given if the pat ient has hypotension, tachycardia, or a new oxygen requirement. The choice of antibiotic co verage should conform to organisms common in your community and hospital. Generally, an ant ip- seudomonal penicillin or fourth-generation cephalosporin with the addition of vancomyci n (if line sepsis is suspected or if there is a high prevalence of community-onset methicil lin-resistant strep [MRSA]) is acceptable. Any suggestion of a fungal infection (sinusitis, thrush) mandates early antifungal therapy. If there are chest symptoms or significant hypo xia, additionally treat presumptively for Pneumocystis . Continue antibiotics until afebril e and neutrophils recover. If fever persists despite antibiotics, start antifungal therapy. If the patient has a defect in cell-mediated immunity (AIDS, chronic immunosuppression for solid tumor, or in the setting of bone marrow transplant) consider treatment for cytomegal ovirus (CMV). Recombinant human colony-stimulating factors (G-CSF, GM-CSF) usually are not useful in the treatment of neutropenic fever, although their use in individual cases may be indicated. Hyperviscosity If the white cell count is >70 \200\223100,000/dL, WBC thrombi m ay form in the brain, lung, and heart. Emergent leukapheresis with concomitant high doses o f cyclophosphamide or hydroxyurea must be considered in patients with leukostasis. Cell lys is syndrome Hyperkalemia and hyperuricemia follows the massive destruction of cells from tu mor necrosis and chemotherapy. Maintain a high Candida prophylaxis 625 urine output, alkalinize the urine, and give allopurinol or rasburicase before cytotoxic th erapy. Disseminated intravascular coagulation Occurs in many leukemias and particularly in acute promyelocytic leukemia. DIC is the result of pathological thrombin formation, leading to inappropriate intravascular fibrin deposition, and platelet and clotting factor consump tion. In addition to leukemia, DIC also occurs in malignancy, infection, trauma, and in obs tetrical disasters. DIC results in both small vessel clotting and bleeding and is associate d with extensive purpura, oozing from venipuncture sites, and bleeding in the brain, GI tra ct, and lungs. The blood smear may identify schistocytes (red cell fragments). Fibrinogen a nd platelets are reduced, whereas PT, aPTT, and fibrin degradation products are elevated. T reatment of DIC includes reversal of the underlying medical condition, platelet and plasma support. Heparin may have a place in the treatment of DIC, but it is case- and center-depen dent in its use. The use of all transretinoic acid (ATRA) has significantly reduced the ris k of DIC in patients with acute promyelocytic anemia. Acute lymphoblastic leukemia Many leukemias are associated with specific gene mutations, de letions, or translocations. Acute lymphoblastic leukemia (ALL) manifests as a neoplas- tic proliferation of lymphoblasts. The latest WHO classification of tumors divides ALL into pre cursor B lymphoblastic leukemia/lymphoblastic lym- phoma and precursor T lymphoblastic leuk emia/lymphoblastic lymphoma. However, the immunologic classification is still widely applie d. Immunologic classification \212 ALL: 75%; defined by the presence of CD10 on the blasts. Any Common age may be affected; common in 2 \200\2234-yr-olds. T-cell mediastinal mass and a hi gh white cell count. B-cell Surface immunoglobulin is present on the blasts. Null cell \212 ALL: Any age but peaks in adolescent males, who present with a \212 ALL: Burkitt or Burkitt-like leukemia. Rare, with a poor prognosis. \212 The French American British (FAB) Morphologic classification classification divides A LL into three types, L1, L2, L3, by microscopic appearance. It provides only limited inform ation compared with other systems. Signs and symptoms: Anemia, infection, bleeding, splenom egaly, lymphadenopathy, thymic enlargement, CNS involvement (cranial nerve palsies). Common infections: Zoster, CMV, measles, candidiasis, pneumocystic pneu- monia (p. 567), bacterem ia. Consider immune globulin for patients in con- tact with measles or zoster when on chemo therapy. Diagnosis Characteristic cells in blood and bone marrow. Treatment \212 ALL: Undifferentiated; lacking the markers listed above. 626 Blood and platelet transfusions, IV antibiotics (p. 625) at Supportive care: first sign of infection (neutropenic regimen). Chemotherapy: trials. A typ ical program is organized to achieve: \212 As with most leukemias, patients are entered into clinical induction : Vincristine, prednisone, L-asparaginase, and 1 Remission daunorubicin 2 cns prophylaxis : Intrathecal methotrexate; cranial irradiation 3 Consolidation : Courses of high-dose chemotherapy for 2 \200\2233 yrs. Relapse is common in blood, CNS, and testes. Hematological remission means no evidence of leukemia in the blood, a normal or recovering blood count, and <5% blasts in a normal regenerating bone marrow, and normal cytogenetics. Bone marrow transplant (p. 627) is considered for patients with high-risk leukemia (especia lly those with 9:22 translocation). Other poor prognostic indicators are adults, males, pre sentation with CNS signs or WBC >100,000, B-cell phenotype. Cure rates in children are 70 \200\22390% while only 35% in adults and even worse in older adults. Future therapy will mo re specifically target leukemic cells according to their specific genetic defect. y g o o t a m e H l Acute myeloid leukemia Acute myeloid leukemia (AML) arises from a normal marrow hematopoiet ic stem cell that has acquired genetic damage leading to aberrant proliferation and variabl e degrees of differentiation. It is a very rapidly progressive malig- nancy in which surviv al is on the order of weeks to months if untreated. Morphological classification is now bas ed on the WHO criteria, which is complex and requires specialist interpretation. The WHO cl assification rec- ognizes important prognostic information from cytogenetics and molecular genetics and includes five main types: 1 AML with recurrent genetic abnormalities 2 AML wit h multilineage dysplasia 3 AML and myelodysplastic syndromes, therapy-related 4 AML not oth erwise categorized 5 Acute leukemias of ambiguous lineage Incidence is 1/10,000/yr and incr eases with age. AML is becoming more common as a consequence of high-dose chemotherapy for both solid tumors and lymphoma. Signs and symptoms: Anemia; infection (often Gram negative) ; bleeding; DIC; hepatosplenomegaly; lymphadenopathy; bone pain (sternal tenderness); leuke mic infiltration of gums, testes, and orbit; CNS involvement (cranial nerve palsies, cord c ompression). Diagnosis : WBC is variable, and blasts are few in the peripheral blood of up to one-third of AML patients. Diagnosis relies therefore on bone marrow biopsy. Differentia tion from ALL may be evident from microscopy, where presence of Auer rods is diagnostic for AML, but overall is secured by flow cytometric immunophenotyping and molecular methods. Mo lecular basis of the leukemia may dictate the specific type of treatment and helps determin e prognosis. Complications Infection, related both to the disease and complications of its therapy. Be alert to septicemia (p. 625). Oral infections are common. Both tumor lysis synd rome and leukostasis (p. 625) are common and must be treated. Treatment Supportive care: Re d cell and platelet support, antibiotics, neutropenic precautions. AML itself can cause fev ers, common organisms can present oddly, and candida and aspergillus are not uncommon. Chem otherapy: Courses are intensive and include cytosine arabinoside and daunorubicin. Prognosi s is better for younger patients and is also linked to specific lesions. Bone marrow transp lant (BMT): Allogeneic transplants from histocompat- ible siblings or from unrelated donors (accessed through national and international databases) may be indicated after remissions are obtained with chemotherapy. The idea is to destroy residual leukemic cells and the pati ent \200\231s own immune system with high-dose cyclophosphamide and total body irradiation, then intravenously infuse the donor \200\231s marrow to replace 627 the host \200\231s. BMT allows the most intensive chemotherapy regimens because marrow supp ression is not an issue. Immunosuppressants are required to restrain the donor immune syste m from attacking the patient \200\231s body (graft vs. host disease). Complications of BMT include graft versus host disease (graft vs. leukemia effect is very important to the overa ll success of BMT in AML); infections; venoocclusive disease; leukemia relapse. Prognosis A l- logeneic transplant survival may approach 60%. Autologous BMT in AML is intermediate bet ween chemotherapy alone and allogeneic BMT; the role of reduced-conditioning BMT is under s tudy. Chronic myeloid leukemia CML is a hematopoietic stem cell disorder in which there is uncont rolled proliferation of well-differentiated myeloid cells. It accounts for 15% of leu- kemi as. As a myeloproliferative neoplasm (MPN) (p. 637), it has features common to other MPNs i ncluding splenomegaly. However, given its unique molecular pathogenesis and natural history , it is considered separately from the other MPNs. It commonly presents with constitutional symptoms, but may be picked up inadvertently on routine blood work. It occurs most often i n the middle-aged, with a slight male predominance. Philadelphia chromosome (Ph 1 ) A hybri d chromosome due to translocation between the long arms of chromosome 9 and 22 (t9:22). The translocation generates an oncogene, BCR/ABL, that constitutively signals within the cell, causing aberrant growth. The Philadelphia chromosome is present in granulocytes, platelet, and red cell precursors in >95% of those with CML. Those without the Philadelphia chromoso me have a worse prognosis. Some patients have a masked translocation in which standard cyto genetics do not reveal Ph 1 , but the BCR/ABL oncogene can be detected by fluorescent in si tu hybridization (FISH). Symptoms and signs Mostly chronic and insidiuous: Malaise, weight loss, gout, fever, night sweats, bleeding or abdominal pain. Splenomegaly, hepatomegaly, an emia, bruising. Diagnosis WBC is often markedly elevated, with an orderly left shift in the differential and an increase in basophils and eosinophils. Hb can be normal or low, platel ets usually are elevated. Leukocyte alkaline phosphatase (LAP) is reduced. Uric acid and al kaline phosphatase are increased. Natural history Untreated median survival of 3 \200\2235 yrs. Three phases: Chronic, lasting months or years with few or any symptoms; accelerated p hase, with increasing symptoms, spleen size, and difficulty in controlling counts; blast cr isis occurs uniformly and has features of acute leukemia. Treatment I Imatinib mesylate a specific tyrosine kinase inhibitor, has revolutionized the management o f CML. It is more effective than the previous gold standard therapy for CML, -interferon , plus or minus cytarabine, in chronic-phase patients. Imatinib therapy produced complete h emato- logic responses, major cytogenetic responses, and complete cytoge- netic responses i n the majority of patients treated in chronic phase and improved survival over interferon w hen compared using historical controls. The drug is also effective in patients who have fai led inter- feron and to some extent in both accelerated phase and blast crisis. Side effect s include nausea, cramps, edema, skin rash, cytopenias, and abnormal LFTs. 628 II The use of interferon in CML has declined dramatically with the intro- duction of tyrosi ne kinase inhibitors (imatinib, desatinib), but it may still have a role in combination the rapy. III The role of allogeneic transplantation from a HLA matched sibling or unrelated donor mu st be reconsidered given the success of tyrosine kinase inhibitors. This approach should be considered as first-line ther- apy in patients in whom trans-plant-related mortality is es timated to be very low. Other patients should be offered a trial of a tyrosine kinase inhib itor first. y g o o t a m e H l IV Treatment of transformed CML is difficult. Although patients may respond to imatinib, th is is temporary. Some patients who develop a lymphoblastic transformation may respond to th erapy as for ALL. Patients who develop a myeloblastic transformation rarely achieve lasting remission, and allogeneic transplant offers the only hope of long-term survival. Chronic lymphocytic leukemia CLL is a monoclonal proliferation of small lymphocytes that ar e most fre- quently of B-cell origin. CLL typically occurs in adults >40 yrs, with men more frequently affected than women. CLL comprises 25% of all leukemias and is the most common hematopoietic malignancy. Staging correlates with survival: 0 I II III IV Absolute lymphocytosis >15,000/mcL Stage 0 + enlarged lymph nodes Stage I + enlarged liver or spleen Stage II + anemia Stage III + thrombocytopenia Symptoms None in 25%; weight loss, bleeding, infection, anorexia. Signs Enlarged nontender nodes, hepatosplenomegaly Blood smear This is a diagnosis made by observing small, normal-a ppearing lymph nodes, many of which fracture on the smear and are termed \200\234smudge ce lls. \200\235 May also be signs of autoimmune hemolytic anemia (spherocytes) or autoimmune thrombocytopenia (large platelets). Complications (1) Autoimmune hemolytic anemia; (2) infe ction, either bacterial of the respiratory tract due to low immunoglobulin levels or viral due to altered cell-mediated immunity; (3) bone marrow failure; (4) immune-mediated thrombo cytopenia. Natural history Some remain in Stage 0 for years without progressing. Usually, n odes slowly enlarge. Death is often via infection (pneumococcus, haemophilus, meningococcus , candida, aspergillosis) or transformation to aggressive lymphoma (Richter \200\231s syndr ome). Treatment Chemotherapy is often not required initially. Chlorambucil, effective in re ducing WBC and node size, was the mainstay of therapy, but is now being supplanted by ritux imab, fludarabine, bendamustine, other monoclonal antibody therapies, and other agents in c linical trials. Steroids are useful in controlling autoimmune processes. Radiotherapy can b e used for relief of lymphadenopathy or splenomegaly. Supportive care: Transfusions, prophy lactic antibiotics, immune globulin. Prognosis is often good, depending on stage, age, and molecular/ immuno-logical factors such as ZAP70 or CD38. 629 Hodgkin \200\231s lymphoma Hodgkin \200\231s lymphoma (HL) is a cancer characterized by the presence of clonal malignant Reed \200\223Sternberg cells within a reactive cellular backg round comprised of variable numbers of granulocytes, plasma cells, and lympho- cytes. Reed \200\223Sternberg cells are transformed B lymphocytes, many of which contain Epstein \200 \223Barr genome, suggesting an association of previous infec- tion in the pathogenesis of H L in many patients. Classification (in order of incidence) Nodular sclerosing Mixed cellularity* Lymphocyte pre dominant Lymphocyte depleted* Prognosis: Good Good Good Poor Higher incidence and worse prognosis if HIV positive. Clinical features The usual presentation is with enlarged, painless lymph nodes, usually in the neck or axillae. Rarely, there may be alcohol-induced pain or features due to the mass effect of the nodes. 25% have constitutional symptoms such as fever, weight loss, night sw eats (often drenching), pruritus, and loss of energy. If the fever alternates with long per iods (15 \200\22328 d) of normal or low temperature, it is termed a Pel \200\223Ebstein fev er (other causes of this rare fever: TB, renal cell cancer). Signs: Lymphadenopathy (note p osition, consistency, mobility, size, tenderness). Look for weight loss, anemia, hepatosple nomegaly. Tests Lymph node biopsy for diagnosis. CBC, smear, ESR, LFTs, CXR, bone marrow bi opsy, abdominal or magnetic resonance imaging (MRI) scan. Lymphangiography is no longer use d routinely. Staging laparotomy is performed if finding abdominal disease will change the t herapy. It involves splenectomy with liver and lymph node biopsy. Staging influences treatm ent and prognosis. I Confined to single lymph node region II Involvement of \211 2 region s on same side of diaphragm III Involvement of nodes on both sides of diaphragm IV Spread b eyond the lymph nodes Each stage is subdivided into A (no systemic symptoms) or B (presence of weight loss >10% in last 6 months, unexplained fever >38 C, or night sweats). These in dicate more extensive disease. Pruritus is not a B symp- tom. Extranodal disease is indicat ed by a subscripted \200\234E \200\235 (e.g., IA e ). Treatment XRT for stages IA and (IA, chemotherapy for IIA \206\222 IVB). HA patients with very large mediastinal masses also r eceive chemotherapy. Chemotherapy is given with an \200\234*ABVD \200\235-type regimen (Ad riamycin, bleomycin, vinblastine, dacarbazine). Regimens containing nitrogen mustard such a s MOPP are less common because of the risk of sterility and secondary AML. Recently, more i ntensive regimens have been used, particularly for advanced disease. Peripheral stem-cell t ransplantation: Autologous or allogeneic transplantation of blood progenitor cells helps re store marrow function after myeloablative therapy, as do agents that stimulate progenitor c ells (e.g., filgrastim). Complications of treatment: Radiation-induced lung fibrosis and hy pothy- roidism. Chemotherapy \200\224nausea, alopecia, infertility in men, infection due to myelosuppression, mucositis, and second malignancies, especially AML, breast cancer, and n on-Hodgkin \200\231s lymphoma (NHL). Autologous marrow transplant may help in relapses afte r chemotherapy or in previously irradi- ated sites. 630 5-yr survival Depends on stage and grade, ranging from >90% in IA lymphocyte-predominant di sease to <40% with IVB lymphocyte depletion. Emergency presentations SVC obstruction presen ts with JVP \206\221 , a sensation of fullness in the head, dyspnea, blackouts, and facial edema. Arrange urgent radiotherapy (XRT). High-dose corticosteroids may also be useful. y g o o t a m e H l