fever, (cervical>axillary>inguinal), lethargy, sweats, anorexia, pharyngitis, 146 tender Causes EBV, CMV, Toxoplasma, Brucella, Coxsackie and adenoviruses, HIV sero- conversion ill ness. Pathophysiology In EBV related illness, EBV infection of B lymphocytes results in immortal- isation and generates a T cell response (the atypical lymphocytes) which controls EBV prol iferation. In severe immunodeficiency following pro- longed use of cyclosporin, oligoclonal EBV-related lymphoma may develop which usually regresses with reduction of immunosuppressi ve therapy but may evolve to a monoclonal and aggressive lymphoma e.g. after MUD stem cell transplant. In malarial Africa, EBV infection is associ- ated with an aggressive lymphoma \200\224Burkitt \200\231s lymphoma see p204. Diagnosis \200\223 hematological features 2 Atypical lymphocytes on blood movie (recognize d by the dark blue cyto- plasmic edge to cells and invagination (scalloping) around red blo od cells). 2 Usually lymphocytosis with mild neutropenia. 2 Occasionally anemia due to cold antibody m ediated haemolysis (anti-i) \200\224identify with cold haemagglutinin titre. 2 Paul Bunnell/monospot test for presence of heterophile antibody +ve when cause is EBV but only in the first few weeks. False +ves can occur in lymphoma. 2 4 bilirubin and abnormal LFTs. 2 Serological testing should include EBV capsid Ag, CMV Ig M, Toxoplasma titre, Brucella titre, HIV 1 and 2 Ag and Ab. 2 Immunophenotype of peripheral blood B lymphocytes shows poly- clonality (distinguishes from lymphoma and other lymphoproliferative disorders). Treatment Rest and symptom relief are mandatory. No other specific treatment has been shown to influence outcome. 03-WBC abnormalities.qxd 10.12.2003 04.12 PM Page 147 White blood cell abnormalities 147 03-WBC abnormalities.qxd 10.12.2003 04.12 PM Page 148 This page intentionally left blank 148 04-leukemia.qxd 10.12.2003 04.12 PM Page 149 Leukemia 4 Acute myeloblastic leukemia (AML) 150 Acute lymphoblastic leukemia (ALL) 158 Chronic myeloid leukemia (CML) 164 Chronic lymphocytic leukemia (B-CLL) 168 Cell markers in chronic lymphoproliferative disorders 174 Prolymphocytic leukemia (PLL) 176 Hairy cell leukemia and variant 178 Sple nic lymphoma with villous lymphocytes (SLVL) 182 Mantle cell lymphoma 184 Large granular lymphocyte leukemia (LGLL) 186 Adult T-cell leukemia-lymphoma (ATLL) 188 S zary syndrome (SS) 190 04-leukemia.qxd 10.12.2003 04.12 PM Page 150 Acute myeloblastic leukemia (AML) Malignant tumor of haemopoietic precursor cells of non-lymphoid lineage, almost certainly a rising in the bone marrow. Incidence Commonest acute leukemia in adults. 3 per 100,000 annually. Increasing frequency with age (median 64 years; incidence 35/100,000 at age 90). Infrequent in children under 15 years. Etiology Unclear \200\224association with pre-existing myelodysplasia, previous cytotoxic c hemotherapy (particularly alkylating agents and epipodophyllotoxins), ionizing radiation, b enzene exposure, constitutional chromosomal abnor- malities (e.g. Down \200\231s (older pat ients) and Fanconi \200\231s syndromes) and smoking. 150 Diagnosis Made by examination of the peripheral blood movie and bone marrow ( \211 20% blas ts). Cytochemical stains, immunological markers, cytogenetic analysis and molecular markers are necessary to differentiate AML from ALL and further classify the disease in preparatio n for therapy. Morphological classification The French \200\223American \200\223British (FAB) system is ba sed on predominant dif- ferentiation pathway and degree of differentiation: Bone marrow showing myeloblasts in AML . AML: myeloblast with large Auer rod (top left). 04-leukemia.qxd 10.12.2003 04.12 PM Page 151 Leukemia M0 AML with minimal differentiation (SB & MPO cytochemistry negative but myeloid immunophenoty ping; may also express CD4 & CD7); 3% of cases. AML without maturation (<10% promyelocytes/ myelocytes or monocytes; may have Auer rods) 20% of cases. AML with maturation ( \211 10% p romyelocytes/myelocytes; < 20% monocytes; may have Auer rods; t(8;21)) commonest subtype: 3 0% of cases. Acute promyelocytic leukemia (>30% promyelocytes; multiple Auer rods (faggot c ells); t(15;17)) 10% of cases. Microgranular variant of APL (high WBC count; minimal granul ation; Auer rods rare; t(15;17)). Acute myelomonocytic leukemia (mixed myeloid (>20% blasts & promyelocytes) & monocytic ( \211 20%) maturation; monocytic cells are non-specific este rase positive; may have Auer rods) 20% of cases. M4 variant with 5 \200\22330% eosinophils; associated with inv(16) chromosome abnormality. 5% of cases Acute monoblastic leukemia (po orly differentiated subtype with \211 80% monocytoid cells of which \211 80% are monoblas ts; Auer rods unusual) 10 \200\22315% cases are M5a or M5b. Acute monocytic leukemia (diffe rentiated subtype with \211 80% monocytoid cells including NSE-positive cells with typical monocytic appearance; Auer rods rare) Acute erythroleukaemia (myeloblasts sometimes with A uer rods plus \211 50% bizarre often multinucleated erythroblasts; erythroblasts often PAS -positive) 3 \200\2235% of cases but 10 \200\22320% of secondary leukaemias. Acute megakary oblastic leukemia (difficult to diagnose morphologically; often dry tap due to fibrosis; re quires immunophenotyping with anti-platelet antibodies or electron microscope analysis of p latelet peroxidase) rare. M1 M2 151 M3 M3v M4 M4Eo M5a M5b M6 M7 Cytochemistry Former mainstay of leukemia diagnosis; Sudan black (SB), myeloperoxi- dase (M PO) and esterase (chloroacetate and non-specific esterase) stains are positive in AML and n egative in ALL (<3% blasts positive). Non-spe- cific esterase (NSE) is positive in monocyti c cells. World Health Organization (WHO) classification of acute myeloid leukemia Although the FAB c lassification has provided a morphological classification of AML for almost 30 years the co rrelation between morphology and both genetic and clinical features is imperfect. The WHO c lassification attempts to correlate morphological, genetic and clinical features to cate- g orise cases of AML into unique clinical and biological subgroups. In the WHO classification the blast threshold for the diagnosis of AML is reduced from 30% to 20% BM blasts (i.e. most patients previously diag- 04-leukemia.qxd 10.12.2003 04.12 PM Page 152 nosed as RAEB-t will be classified as AML with multilineage dysplasia) and patients with t( 8;21)(q22;q22), inv(16)(q13q22), t(16;16)(p13;q22) or t(15;17)(q22;q12) should be con- side red to have AML regardless of the blast percentage. clonal recurring abnormalities WHO classification of acute myeloid leukemia Acute myeloid leukemia with recurrent genetic abnormalities 2 Acute myeloid leukemia with t (8;21)(q22;q22), (AML1/ETO) 2 Acute myeloid leukemia with abnormal BM eosinophils and inv(16)(q13;q22) or t(16;16)(p13;q22), (CBFb/MYH11) (= FAB M4Eo) 2 Acute promyelocytic leuk emia with t(15;17)(q22;q12), (PML/RARa) and 152 variants (= FAB M3) 2 Acute myeloid leukemia with 11q23 (MLL) abnormalities Acute myeloid leukemia with multilineage dysplasia 2 Following MDS or MDS/MPD 2 Without ant ecedent MDS or MDS/MPD, but with dysplasia in at least 50% of cells in 2 or more myeloid lineages Acute myeloid leukemia and myelodysplastic syndromes, therapy-related 2 Alkylating agent/ra diation-related type 2 Topoisomerase II inhibitor-related type (some may be lymphoid) 2 Oth ers Acute myeloid leukemia, not otherwise categorized Categorize as: 2 Acute myeloid leukemia, minimally differentiated (= FAB M0) 2 Acute myeloid leukemia, without maturation (= FAB M1) 2 Acute myeloid leukemia with maturation (= FAB M2) 2 Acute myelomonocytic leukemia (= FAB M4) 2 Acute monoblastic/ acute monocytic leukemia (= FAB M5a/5b) 2 Acute erythroid leukemi a: erythroid/myeloid ( \211 50% erythroid precursors plus \211 20% blasts; = FAB M6) and pure erythroleukaemia ( \211 80% immature erythroid precursors) 2 Acute megakaryoblastic leukemia (= FAB M7) 2 Acute basophilic leukemia 2 Acute panmyelosi s with myelofibrosis (= acute myelofibrosis) 2 Myeloid sarcoma Immunophenotyping Monoclonal antibodies to cell surface antigens reliably differentiate AML from ALL and confirm the diagnosis of M0, M6 and M7 ((cid:9)p153). 04-leukemia.qxd 10.12.2003 04.12 PM Page 153 Leukemia Panel of monoclonal antibodies to differentiate AML & ALL Myeloid Anti-MPO; CD13; CD33; CDw65; CD117 B lymphoid CD19; cytoplasmic CD22; CD79a; CD10 T lymphoid Cytoplasmic CD3; CD2; CD7 Immunophenotypic patterns in AML subtypes 153 Undifferentiated (M0) Anti-MPO; CD13; CD33; CD34; CDw65; CD117; negative cytochemistry; lymphoid markers Myelomonocytic (M1-M5): anti-MPO; CD13; CD33; CDw65; CD117 Monocytic (M4 & M5) Stronger expression of CD11b & CD14 Erythroid (M6) Anti-glycophorin A Megakaryocytic (M7) CD41; CD61 Bain, B.J. et al. (2002) Revised guideline on immunophenotyping in acute leukaemias and chr onic lymphoproliferative disorders. Clin Lab Haematol, 24, 1 \200\22313. (cid:27) http://ww w.bcshguidelines.com/pdf/CLH135.PDF Lineage infidelity It is sometimes impossible to define a single lineage for leukaemic blas ts on the basis of phenotypic marker expression. The expression of markers of more than one cell lineage by a leukaemic cell is termed lineage infi- delity and may reflect abnormal g ene expression in the clone or abnormal maturation of an early uncommitted precursor. Blast s can display cyto- chemical and immunophenotypic markers of both myeloid and lymphoid prec ursors. Up to 50% of myeloid leukaemias may be positive for lym- phoid antigens, most commo nly CD2 (34%) and CD7 (42%) and this does not appear to have prognostic significance. Biphenotypic leukaemias A minority of acute leukaemias ( 7%) have two distinct leukaemic ce ll populations on phenotyping and are characterized as biphenotypic leukaemias. Most common ly these cell populations express B-lymphoid and myeloid markers and are associated with a high frequency of t(9;22)(q34;q11), the Ph chromosome. These patients have variable respons e rates. Some may display \200\230lymphoid \200\231 features such as marked lym- phadenopa thy and high blast counts. Cytogenetic analysis Should be performed in all cases of acute leukemia. It detects translo cations and deletions that provide independent prognostic information in AML. 04-leukemia.qxd 10.12.2003 04.12 PM Page 154 \200\230Favorable risk \200\231 cytogenetics 2 t(8;21)(q22;q22): FAB M2; 5 \200\2238% adul ts <55 years, rare older; fusion gene AML1/ETO. 2 inv(16)(p13;q22) or t(16;16)(p13;q22): FAB M4Eo; 10% adults <45 years, rare older; fusion gene CBFb/MYH11. 2 t(15;17)(q21;q11): FAB M3; 15% adults <45 years, rare older; fusion gene PML-RARa. Varian ts: t(11;17)(q23;q11) fusion gene PLZF-RARa; t(5;17)(q32;q11) fusion gene NPM-RARa; t(11;17 )(q13;q11) fusion gene NuMA-RARa. \200\230Intermediate risk \200\231 cytogenetics 2 Normal karyotype: any FAB type; 15 \200 \22320% adults. 2 + 8: any FAB type; 10% adults. 2 abnormal 11q23*: >50% infant AML cases; 5 \200\2237% adults; fusion gene MLL. 2 Others: del(9q)*; del(7q)*; +6; +21; +22; \200\223 Y and 3 \200\2235 complex abnor- malities* plus other structural or numerical defects not i ncluded in the good risk or poor risk groups. 154 \200\230Poor risk \200\231 cytogenetics 2 \200\2235/del(5q): any FAB type; >10% adults >4 5years. 2 \200\2237/del(7q): any FAB type; >10% adults >45 years. 2 Complex karyotypes (>5 abnormalities*) 2 Others: t(6;9)(p23;q34); t(3;3)(q21;q96); 20q; 21q; t(9;22); abn 17p. No te: This classification is based on the MRC-UK scheme1. Abnormalities marked * are classed as \200\230unfavorable \200\231 i.e. \200\230poor risk \200\231 in the scheme used by US Cooperative Groups2. Molecular analysis Fluorescence in situ hybridisation (FISH) and reverse transcriptase-poly - merase chain reaction (RT-PCR) methods add sensitivity and precision to the detection of translocations, deletions and aneuploidy in cases where conventional cytogenetics fails or gives normal results. RT-PCR detects minimal residual disease overlooked by conventional me thods. Clinical features 2 Acute presentation usual; often critically ill due to effects of bone marrow failure. 2 Symptoms of anemia: weakness, lethargy, breathlessness, lightheaded- ness and palpitations. 2 Infection: particularly chest, mouth, perianal, skin (Staphylococcus, Pseudomonas, HSV, Candida). Fever, malaise, sweats. 2 Hemorrhage (especially M3 due to DIC): purpura, menorrhagia and epistaxis, bleeding gums, rectal, retina. 2 Gum hypertrophy and skin infiltration (M4, M5). 2 Signs of leucostasis e.g. hypoxia, reti nal hemorrhage, confusion or diffuse pulmonary shadowing. 2 Hepatomegaly occurs in 20%, splenomegaly in 24%; the latter should raise the question of transformed CML; lymphadenopathy is infrequent (17%) 2 CNS involvement at presentation is rare in adults with AML. 1 Grimwade, D. et al. (2001) The predictive value of hierarchical cytogenetic classificatio n in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood, 98, 1312 \200\2231320 2 Sm ith, M.A. et al. (1996) The secondary leukemias: challenges and research directions. J Natl Cancer Inst, 88, 407 \200\223418. 04-leukemia.qxd 10.12.2003 04.12 PM Page 155 Leukemia 155 Gum hypertrophy in AML. Investigations and diagnosis 2 FBC and blood movie. 2 Bone marrow aspirate biopsy. 2 Bon e marrow cytogenetics. 2 Immunophenotyping of blood or marrow blasts. 2 Total WBC usually i ncreased with blasts on blood movie \200\224but WBC may be low. 2 Hb, neutrophils and platelets usually 5. 2 Bone marrow heavily infiltrated with blasts ( \211 20%) 2 Further recommended investigations \200\224(cid:9)p544. Emergency treatment 2 Seek expert help immediately. 2 Intensive cardiovascular and respirat ory resuscitation may be needed if septic shock or massive hemorrhage. 2 Immediate empirical broad spectrum antibiotic treatment for neu- tropenic sepsis. 2 Leucapheresis if peripheral blast count high or signs of leucostasis (retinal hemorrhage, reduced conscious level, diffuse pulmonary shad- owing on CXR, or hypo xia). 2 Intensive hydration with alkalinisation of the urine to prevent acute tumor lysis syndrom e in patients with a high peripheral blast cell count (>100 109/L). Supportive treatment 2 Explain diagnosis and offer counseling \200\224the word \200\230leu kemia \200\231 and prospect of prolonged chemotherapy are often distressing. 2 RBC and platelet transfusion support will continue through treatment. 2 Start neutropenic regimen ((cid:9)p550) as prophylaxis. 2 Start hydration aiming for urine output >100mL/h t hroughout induc- tion therapy. 2 Start allopurinol or Rasburicase to prevent hyperuricaemia. 2 Insert tunneled central ven ous catheter ((cid:9)p568). 04-leukemia.qxd 10.12.2003 04.12 PM Page 156 Specific treatment Initial aim of therapy is to eliminate the leukaemic cells and achieve a com- plete hematological remission (CR), defined as normal BM cellularity with blast cells <5% and normal representation of trilineage haematopoiesis, normalization of peripheral bl ood count with no blast cells, neutrophils \211 1.5 109/L, platelets \211 100 109/L and Hb>10g/dL. Leukemia is undetectable by conventional morphological techniques but may b e demonstrated by more sensitive molecular techniques (when available) and CR is not synony mous with cure. CR may result from a three-log kill from 1012 leukaemic cells at diagnosis to 109 at CR. Treatment consists of 3 phases: (1) remission induction to achieve CR (usually 1 \200\2232 courses of combination chemotherapy); (2) consolidation therapy to reduce leukemia burden f urther and reduce risk of relapse (optimum number unknown, usually 2 \200\2234 which may in clude an \200\230intensifica- tion \200\231 phase or an autologous or allogeneic stem cell transplant); (3) main- tenance therapy has been abandoned in AML except in some elderly pa tients where intensive consolidation cannot be tolerated. 156 2 Enter patient into MRC or other high quality trial if possible. MRC ran- domised studies in acute leukemia are based on large patient numbers and compare incremental experimental t herapy with best treatment arm from previous trials. 2 Treatment protocols are age related; patients >60 only tolerate less intensive treatments and very rarely transplantation. 2 Supportive treatment alone is a valid treatment option in the >75 age group or if there a re coexistent serious general medical problems. 2 Outline treatment for patients <60 years is 4 \200\2235 courses of intensive combination chemotherapy initially including daunorubicin or another anthracycline and cyto sine arabinoside each lasting 5 \200\22310 days with a 2 \200\2233 week period of profound myelosuppression. 2 Major complications are infective episodes which may be bacterial (Gram +ve and Gram \200\223ve), fungal (Candida and Aspergillus), and less commonly viral (esp. HSV, HZV). 2 APML (FABM3) is a distinct category of AML requiring different treat- ment. The risk of D IC prior to and during initial therapy due to release of thromboplastins from leukaemic cel ls is an indication for urgent treatment. The use of all-trans-retinoic acid (ATRA) with in itial therapy reduces the risk of DIC. After this the prognosis is good. ATRA induces diffe rentiation of the abnormal clone by overcoming the mole- cular block resulting from the t(1 5;17) translocation. ATRA alone cannot achieve sustained remission but in combination with chemotherapy 70% of patients may be cured. Arsenic trioxide appears to be a useful agent in those patients who relapse. Persistence of the fusion product after therapy detected by RT -PCR predicts relapse. 2 Autologous stem cell transplantation is an option for intensive co nsoli- dation of younger patients (<60) with intermediate or poor-risk disease who achieve CR. It has lower procedure-related mortality or morbidity than an allograft but lacks a graft-vers us-leukemia effect and has a relapse rate of 40 \200\22350%. 2 Allogeneic stem cell transplantation from a compatible sibling donor is an option for you nger patients (<45) with intermediate or poor-risk disease. Significant mortality (7 \200 \22313%) and morbidity may be reduced 04-leukemia.qxd 10.12.2003 04.12 PM Page 157 Leukemia by non-myeloablative conditioning regimens and increase the age range. Unrelated donor graf ts have higher toxicity. Donor lymphocyte infusion (DLI) is used to treat recurrence after an allogeneic transplant. 2 In the longer term, relapse is the main complication. Prognosis 2 70 \200\22380% of patients aged <60 years will achieve a CR with a modern 157 regimen and good supportive care; more intensive induction and con- solidation regimens red uce the risk of relapse. 2 Relapse risk at 5 years in patients <60 with favorable risk cytoge- netics is 29 \200\223 42%; intermediate risk 39 \200\22360%; poor risk 68 \200\22390%. 2 50 \200\22360% of patients aged \211 60 years achieve CR with induction treat- ment (rat e drops with each decade) but relapse occurs in 80 \200\22390%; a higher proportion have po or risk karyotype, previous myelodysplasia and co-morbidity; treatment-related morbidity an d mortality is high. Prognostic factors The most important prognostic factors predicting for achievement of remi ssion and for subsequent relapse are: 1. Advancing patient age; <50 favorable; >60 unfavora ble. 2. Presenting leucocyte count; <25 109/L favorable; >100 109/L unfavorable. 3. History of antecedent MDS or leukaemogenic therapy: unfavorable. 4. Presence of specific cytogenetic abnormalities ((cid:9)p154). 5. FAB subtype: M3, M4Eo favorable; M0, M5a, M5b, M6, M7 unfavorable. 6. Failure to achieve CR with first cycle of induction therapy predicts for relapse. Management of relapse 2 Most relapses occur in the first 2 \200\2233 years. 2 Younger age a nd longer duration of first CR are good prognostic factors for achieving second CR. 2 50% of patients achieve second CR with further therapy; under 10% survive over 3 years without a transplant procedure. 04-leukemia.qxd 10.12.2003 04.12 PM Page 158 Acute lymphoblastic leukemia (ALL) Malignant tumor of haemopoietic precursor cells of the lymphoid lineage probably arising fr om the marrow in most cases. Incidence Commonest malignancy in childhood with the majority of cases in the 2 \200\22310 age group (median 3.5 years). Five times more frequent in childhood than AML. Rare leukemia in adults, 0.7 to 1.8/100,000 annually. In adults, there is a peak at 15 \200\22324 years and a further peak in old age (2.3/100,000 >80 years). 158 Etiology Unknown. Predisposing factors are ionizing radiation (AML is more common) and cong enital predisposition in Down \200\231s (20-fold in childhood), Bloom \200\231s, Klinefelte r \200\231s and Fanconi \200\231s syndromes. Chemicals, pollution, viruses, urban/rural pop ulation movements, father \200\231s radiation exposure, radon levels and proximity to power lines have all been postulated. Morphological Classification (French \200\223American \200\223British, FAB) L1 Small monomorphic type \200\224small homogeneous blasts, single inconspicuous nucleolus, re gular nuclear outline; commonest subtype. Large heterogeneous type \200\224larger blasts, m ore pleomorphic and multinucleolate, irregular frequently clefted nuclei with conspicuous n ucleoli. Burkitt cell type \200\224large homogeneous blasts, abundant strongly basophilic c ytoplasm with vacuoles; associated with B-cell phenotype. L2 L3 Immunophenotyping A panel of monoclonal antibodies is used to differentiate ALL from AML (( cid:9)p153). A further panel of B-and T-lineage markers and lymphocyte maturation markers s ubclassify ALL. Immunological classification of ALL B lineage 2 Pro B-ALL: HLA-DR+,TdT+,CD19+ (5% children; 11% adults). 2 Common ALL: HLA-DR+,TdT+,CD19+,CD10+ (65% children; 51% adults). 2 Pre B-ALL: HLA-DR+,TdT+,CD19+,CD10 ,cytoplasmic IgM+ (15% children; 10% adults). 2 B-cell ALL: HLA-DR+,CD19+,CD10 ,surface IgM+ (3% children; 4% adults) T lineage 2 Pre-T ALL: TdT+,cytoplasmic CD3+,CD7+ (1% children; 7% adults). 2 T-cell ALL: T dT+,cytoplasmic CD3+, CD1a/2/3+,CD5+ (11% children; 17% adults). 04-leukemia.qxd 10.12.2003 04.12 PM Page 159 Leukemia Cytogenetic analysis 2 Provides important prognostic information in both childhood and adul t ALL. Abnormalities are detected in up to 85%. The major abnormali- ties are clonal transl ocations: t(9;22), t(4;11), t(8;14), t(1;19) or t(10;14) and other structural abnormalities (9p, 6q or 12p). If no struc- tural abnormalities are present, the abnormalities can be cl assified by the modal chromosome number: <46 (hypodiploid); 46 with other structural abnorm alities (pseudodiploid); 47 \200\22350 (hyperdiploid); >50 (hyper-hyperdiploid). With the e xception of t(9;22) each has an inci- dence in the order of 5 \200\22310% or less. 159 2 t(9;22)(q34;q11) produces the Philadelphia chromosome found in 5% of children and 25% of adults with ALL and is a very strong adverse prog- nostic factor in both; the resultant BCR -ABL hybrid product is the same 210 kDa protein detected in CML in 33% but is a smaller 180 kDa protein in 66%; it can be used for minimal residual disease detection. 2 t(8;14) is as sociated with B-cell ALL (L3 morphology) and occurs in 5% of cases (dysregulates the myc pr oto-oncogene), t(1;19) is associated with B-cell precursor ALL; t(4;11) occurs in 80% of in fants with ALL and 6% of adults and fuses the MLL gene from 11q23 to the AF4 gene from 4q21 which can be detected by PCR; all these abnormalities are associated with refractory disea se and early relapse 2 Hyper-hyperdiploidy (>50 chromosomes) confers a favorable prog- nosis; combined +4, +10 c onfers a favorable outcome in B-cell pre- cursor ALL; patients with hypoploidy (<46 chromos omes) and pseudodiploidy fare less well. Clinical features 2 Acute presentation usual; often critically ill due to effects of bone marrow failure. 2 Symptoms of anemia: weakness, lethargy, breathlessness, lightheaded- ness and palpitations. 2 Infection: particularly chest, mouth, perianal, skin (Staphylococcus, Pseudomonas, HSV, Candida). Fever, malaise, sweats. 2 Hemorrhage: purpura, menorrhagia and epistaxis, bleeding gums, rectal, retina. 2 Signs of leucostasis e.g. hypoxia, retinal hemorrhage, confusion or diffuse pulmonary shadowing. 2 Mediastinal involvement occurs in 15% and may cause SVC obstruction 2 CNS involvement occ urs in 6% at presentation and may cause cranial nerve palsies especially of facial VII nerv e, sensory disturbances and meningism. 2 Signs include widespread lymphadenopathy in 55%, mild to moderate splenomegaly (49%), hepatomegaly (45%) and orchidomegaly. Investigations and diagnosis 2 FBC and blood movie. 2 Bone marrow aspirate biopsy. 2 Bon e marrow cytogenetics. 04-leukemia.qxd 10.12.2003 04.12 PM Page 160 160 Mediastinal mass in T-ALL. 2 Immunophenotyping of blood or marrow blasts. 2 Total WBC usually high with blast cells on movie but may be low (previ- ously known as aleukaemic leukemia). 2 Hb, neutrophils and platelets often low and clotting may be deranged. 2 Bone marrow heavi ly infiltrated with blasts ( \211 20%). 2 CXR and CT scan needed if ALL has B-cell or T-cel l phenotype for abdominal or mediastinal lymphadenopathy respectively. 2 Lumbar puncture mandatory to detect occult CNS involvement but may be postponed until treatment reduces high peripheral blast count to prevent seeding (No te \200\224fundoscopy, CT head scan and platelet transfusion usually required). Bone marrow: lymphoblasts in ALL L1. Bone marrow: lymphoblasts in ALL L3. 04-leukemia.qxd 10.12.2003 04.12 PM Page 161 Leukemia Emergency treatment 2 iiSeek expert help immediately. 2 Cardiovascular and respiratory resu scitation may be needed if septic shock or massive hemorrhage. 2 Immediate empirical broad spectrum antibiotic treatment for neu- 161 tropenic sepsis. 2 Leucapheresis may be needed if peripheral blast count high or signs of leucostasis (retin al hemorrhage, reduced conscious level, diffuse pul- monary shadowing on CXR or hypoxia). 2 LP if meningism (note precautions above). Supportive treatment 2 Provide explanation and offer counseling \200\224the word \200\230l eukemia \200\231 and prospect of prolonged chemotherapy are often distressing. 2 RBC and platelet transfusion support will continue through treatment. 2 Start neutropenic regimen ((cid:9)p550) as prophylaxis against infections. 2 Start hydration aiming for urin e output >100mL/h throughout induc- tion therapy ((cid:9)p560 Tumor lysis syndrome \200\224 a special problem in B- cell or T-cell ALL). 2 Start allopurinol to prevent hyperuricaemia (Note: interaction with 6- mercaptopurine: di scontinue allopurinol or reduce dose of 6-MP) or Rasburicase (especially with high counts). 2 Insert tunneled central venous catheter ((cid:9)p568). Specific treatment The aims of treatment are outlined under specific treatment in AML. The regimens used in adult ALL have evolved from successful treatments for childhood ALL. Treatment for ALL consists of four contiguous phases: 1. Remission induction using vincrist ine, prednisolone, daunorubicin and asparaginase to achieve complete remission; more intens ive induction using more anthracycline improves leukemia-free survival. 2. CNS prophylaxis generally combines cranial irradiation (18 \200\22324 Gy in 12 fractions over 2 weeks) and intrathecal (IT) chemotherapy (methotrexate cytarabine or prednisolon e) given early in the consol- idation phase; IT therapy is continued in the consolidation a nd mainte- nance phases; CNS prophylaxis reduces the rate of CNS relapse from 30%75%. 3. Consolidation therapy to reduce tumor burden further and reduce risk of relapse and deve lopment of drug-resistant cells; consists of alternating cycles of induction agents and oth er cytotoxics; usually includes one or two \200\230intensification \200\231 phases; combin ations of methotrexate at high dose, cytarabine, etoposide, m-amsacrine, mitox- antrone (mi tozantrone) and idarubicin are used. 4. Maintenance therapy is necessary for all patients who do not proceed to a stem cell tran splant; daily 6-MP and weekly methotrexate for 2 \200\2233 years plus cyclical administrati on of IV vincristine and IT methotrexate. 04-leukemia.qxd 10.12.2003 04.12 PM Page 162 (ii methotrexate MUST be avoided as errors can be fatal) simultanous administration of IV vincristine and IT or Allogeneic stem cell transplantation: an option for adults <50 with a compatible sib; leuke mia-free survival is superior after first remission allograft in patients with high risk di sease (40% vs. <10% for Ph+ ALL); treatment-related mortality up to 30%; in low risk patien ts SCT should be reserved for second CR. Matched unrelated donor transplant: an option in younger patients (<40) with very high risk disease (Ph/BCR-ABL positive ALL) but has up to 48% treatment-related mortality. 162 or Autologous stem cell transplantation: an alternative for adults up to 60: lower treatment r elated mortality (up to 8%); no clear survival advan- tage over maintenance therapy in firs t remission for most patients but may improve survival in very high risk disease without op tion of allo- graft. 2 Enter patient into MRC or other high quality trial if possible. 2 Major complications are infective episodes which may be bacterial (Gram +ve and Gram \200\223ve), viral (esp. HSV, HZV) and fungal (Candida and Aspergillus) . 2 In the longer term, relapse is the main complication. 2 Mature B-cell ALL is treated with shorter more intensive cycles including high dose methotrexate, high dose cytarabine and fraction- ated cyclophosphamide; it has a higher incidence of CNS disease at diagnosis and relapse. 2 CNS leukemia at diagnosis is treated by adding intensified intrathecal triple therapy to cranial irradiation; IT methotrexate, cytarabine and prednisolone 2 \200\2233 times week ly over 3 \200\2234 weeks until 2 consecutive CSF samples are negative; insertion of an Omm aya reservoir facilitates such frequent IT therapy. Minimal residual disease detection Flow cytometry for clonal immunophenotypes or FISH or RT -PCR for fusion proteins or clonal Ig/TCR gene rearrangements identified at diagnosis can d etect minimal residual disease (MRD) at a sensitivity of 10 \200\2233 \200\22310 \200\2236. Morphological and molecular CR can be distinguished and detection of MRD has strong negati ve prognostic implications. Prognosis Overall 75% of adults with ALL achieve a CR with a modern regimen and good suppo rtive care; more intensive induction and consolidation reduces relapse risk but adds toxici ty; results in patients >50 are less good. In contrast to the high cure rate in childhood ALL, leukemia free survival in adult ALL in general is <30% at 5 years (patients > 50 years 10 \200\22320%). Leukemia-free survival (LF S) after chemotherapy in patients without adverse risk factors is >50% whereas that for ver y high risk Ph/BCR-ABL+ ALL is <10%; hence the latter should have an allograft in CR1 if po ssible. 04-leukemia.qxd 10.12.2003 04.12 PM Page 163 Leukemia Prognostic factors The most important prognostic factors are listed below. These are useful for risk stratification to identify patients who require transplantation in first CR. 2 Pa tient age (<50y CR >80%, LFS>30%; \211 50y CR <60%, LFS <20%) 2 High leucocyte count (>30 109/L in B precursor-ALL; >100 109/L in T-ALL) poor risk. 163 2 Immunophenotype: pro-B-ALL and pro-T-ALL have poorer outcomes; common pre-B-ALL still poo r; mature B-cell ALL and T-cell ALL had poorer outcomes before the use of more intensive re gimens, now better. 2 Cytogenetics: Ph+ very poor prognosis: <10% LFS after chemotherapy; for others ((cid:9)p159). 2 Long time to CR (>4 \200\2235 weeks) 2 High MRD level after induction (>10 \200\2233); pe rsistent/increasing MRD during consolidation. Management of relapse 2 Relapse rate is highest within the first 2 years but may occur afte r 7 years. 2 20% occur outside the bone marrow, generally CNS; testis and other sites occur in 5%. 2 Isolated extramedullary relapse is often followed by hematological relapse; these patients require local treatment followed by reinduction therapy. 2 Best predictive factor for response is duration of first CR (better >18 months). 2 With second-line regimens 50 \200\22360% of patients will achieve a short second CR (gene rally <6 months) and prompt BMT offers the only prospect of LFS and cure. 04-leukemia.qxd 10.12.2003 04.12 PM Page 164 Chronic myeloid leukemia (CML) Malignant tumor of an early haemopoietic progenitor cell. The clonal marker is found in all three myeloid lineages and in some B and T lympho- cytes demonstrating a primitive origin. Incidence Rare disease with a frequency of 1.25 per 100,000. Rare in children and median ag e of onset is 50 years with slight 9 excess. Irradiation is the only known epidemiological factor. Classification Classified as a myeloproliferative disorder ((cid:9)p238) with which it shar es a number of clinical features. However, it also has certain unique biological properties : 2 Characterized in >80% patients by the presence of the Philadelphia 164 chromosome (Ph). Reciprocal translocation between chromosomes 9 and 22, (t9;22)(q34;q11), i nvolving two genes, BCR and ABL that form a fusion gene BCR-ABL on chromosome 22. This prod uces an aberrant 210 kDa protein that has greater tyrosine kinase activity than the normal ABL protein. This gene is believed to play a role in the patho- genesis of CML but addition al genetic changes appear necessary. 2 10% of patients have variant translocations involving chromosome 22 9 and other chromo somes. A further 8% with typical clinical features lack the Ph chromosome, i.e. have Ph-neg ative CML; half of these have the hybrid BCR-ABL gene: Ph-negative, BCR-ABL-positive CML. Natural history 2 Biphasic or triphasic disease \200\224chronic phase, accelerated phase an d blast crisis; 50% transform directly from chronic phase to blast crisis. 2 >85% patients present in chronic phase. 2 Duration of chronic phase varies (typically 3 \200\2236 years; median 4.2 years). 2 Transformation is least likely in the 2 years immedia tely after diagnosis but occurs at an annual rate of 20 \200\22325% thereafter. 2 Accelerated phase characterized by blood counts and organomegaly becoming increasingly refractory to therapy; some have constitutional symptoms; generally b rief. 2 Blast crisis resembles acute leukemia with >20% blasts and promyelo- cytes in blood or marrow. Clinical symptoms and signs 2 30% asymptomatic at diagnosis; present after routine FBC. 2 F atigue, lethargy, weight loss, sweats. 2 Splenomegaly in >75%; may cause (L) hypochondrial pain, satiety and sensation of abdominal fullness. 2 Gout, bruising/bleeding, splenic infarction and occasionally priapism. 2 Signs include mo derate to large splenomegaly (40% >10cm), hepatomegaly (2%), lymphadenopathy unusual. 2 Occasional signs of leucostasis at presentati on. 04-leukemia.qxd 10.12.2003 04.12 PM Page 165 Leukemia Diagnosis and investigations 2 FBC and blood movie show 4 WBC (generally >25 109/L, ofte n 100 \200\223300 109/L): predominantly neutrophils and myelocytes; basophilia; sometime s eosinophilia. 2 Anemia common; platelets typically normal or 4. 2 Neutrophil alkaline phosphatase (NAP) s core and ESR 5 in absence of secondary infection. 2 LDH and urate levels 4. 2 Bone marrow shows marked hypercellularity due to myeloid hyper- 165 plasia (blasts <10% in chronic phase; >10% in accelerated phase; >20% blasts + promyelocyte s = blast crisis); trephine useful to assess marrow fibrosis. 2 Cytogenetic examination of blood or marrow for confirmatory t(9;22). Peripheral blood movie in CML: note large numbers of granulocytic cells at all stages of di fferentiation. Differential diagnosis Differentiate chronic phase CML from leukaemoid reaction due to infe c- tion, inflammation or carcinoma (NAP 4 or normal; absent Ph chromo- some) and CMML (abso lute monocytosis; trilineage myelodysplasia; absent Ph chromosome); 5% present with predomi nant thrombocytosis and must be differentiated from ET (NAP 4/normal; absent Ph chromosome) . Prognostic factors 2 Sokal score based on age, spleen size, platelet count and % blasts in blood can be used to identify good, moderate and poor prognosis groups; (see p685) 2 Response to IFN-a therapy is an important prognostic factor. Treatment of chronic phase 2 HLA-type patients aged <50 years and their sibs; 30% have a co mpat- ible sibling donor; if no compatible sibling and aged <40, perform pre- liminary MUD search to determine prospective donor availability. 2 Therapeutic decision making in chroni c phase is difficult: allogeneic transplantation is the only curative treatment; however, it carries sig- nificant morbidity and mortality and many patients find this a difficult 04-leukemia.qxd 10.12.2003 04.12 PM Page 166 option; it is vital that each patient is aware of treatment options and their risks and ben efits. 2 Leukapheresis should be performed with cryopreservation of stem cells which may be used for future autologous rescue if required; it may also be necessary for tr eatment of leucostasis or priapism. 2 Allopurinol should be commenced. 2 Hydroxyurea has been drug of choice for controlling WB C, \200\230normalizing \200\231 the FBC and reducing spleen size in chronic phase. Maintenance 1 \200\2231.5g PO od. No eff ect on cytogenetics or natural history. Side effects: rash, mouth ulcers and diarrhea. 2 Interferon-a (IFN-a) at a target dose of 5 million units/m2/day SC corrects hematological abnormalities in 75% and produces complete cytogenetic response (CCR) in 10 \200\22315% an d major cytogenetic response (MCR; <33% Ph+ cells) in 15 \200\22330%. 166 2 Treatment with IFN-a is associated with prolonged time to progression and longer survival (57% at 5 years), most significantly in those with com- plete and major responses; adding cytarabine increases CCRs to 25 \200\22335% and improves survival. 2 IFN-a side effects (malaise, febrile reactions, anorexia and weight loss, depression) red uce quality of life and not tolerable for many patients. 2 Polyethylene glycol-IFN administered once weekly and has a more favorable side effect profile. 2 Imatinib (Glivec \200\232) gives better cytogenetic responses and progression free surviv al with fewer side effects; has changed the therapeutic algorithm in CML; a small molecule signal transduction inhibitor that specifically targets BCR-ABL and some other tyrosine kin ases: \200\223 400mg PO od in newly diagnosed patients in chronic phase pro-