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   Haematology Updates 2010 41 Acute Lymphoblastic Leukemia Dr. Nadir Ali Consultant Haematologist, Armed Forces Institute of Pathology, Rawalpindi Acute lymphoblastic leukemia (ALL) dominates as an acute hematological malignancy in children; however the disease can appear at any age. The onset may be insidious or acute, fatigue, lethargy, persistent fever, bleeding manifestations, bone and joint pain are the most common  presenting features. Young children may present with gait disturbances and inability to walk. In a small percentage of cases patient may present with compression fracture of vertebral column due to wide spread osteoporosis. Bone and  joint pains may be the presenting features. Skeletal symptoms are most frequently encountered with disease  presenting without organomegaly, lymphadenopathy or leukocytosis. 2-3% children may present with preceding aplastic anaemia followed by appearance of leukaemia. Central nervous system involvement and symptoms may be  present in approximately 2% children. In adults generally clinical manifestations are similar to children and are as a consequence of bone marrow involvement or extramedullary infiltrates. Almost 50%  patients may have fever at presentation. Other common features are bleeding manifestations, fatigue, lethargy, and  joint pains. Approximately one half of adult patients have hepatomegaly, splenomegaly, or lymphadenopathy at diagnosis. Mediastinal masses are frequent finding in case of T-ALL which is a common type of ALL in adults. In almost 10% of adult patients central nervous system symptoms may  be present. The common symptoms include headache, vomiting, neck stiffness, alteration in mental status, and focal neurologic abnormalities. Other sites of extramedullary involvement include testis, retina, and skin, although virtually any organ can be infiltrated by leukemic blast cells. In a minority of cases the patients are detected during blood counts and blood film examination performed for investigation of fever, unexplained pallor or bleeding manifestations. Finding abnormal mononuclear cells or  blasts raises the suspicion of acute leukemia and bone marrow examination is suggested. In The diagnostic workup includes two most important tiers, the clinical history & examination and lab studies. 1. Clinical History & examination. Clinical history: It is the back bone in diagnosis of ALL, it must record symptoms related to the disease, and exclusion of other possible causes of such symptoms. Pattern of fever, duration and associated symptoms may help in excluding the possibility of commonly encountered tropical, viral, and bacterial diseases thus saving unnecessary invasive procedures. Clinical examination: Common clinical findings are raised body temperature, rapid pulse, pallor, purpuric spots, ecchymoses, palpable superficial lymph nodes, liver, and spleen. Occasionally, patients have rashes resulting from infiltration of the skin with leukemic cells. Imaging studies: Chest x-ray films may reveal signs of pneumonia and/or a prominent mediastinal mass in some cases of ALL. In case of presentation with bone and joint  pains radiological changes may show bone destruction or  periosteitis, juxtametaphyseal demineralisation and effusions. Osteopenia occurs secondarily to diffuse infiltration and lytic lesions can radiographically mimic osteomyelitis. Ultrasound examination of abdomen for assessment of visceromegaly and lymphadenopathy may be required. In few cases computerized tomography scan or magnetic resonance imaging scan of chest or abdomen may  be required to assess lymphadenopathy, space occupying lesions or nature of visceromegaly. 2. Lab Studies a. Blood counts with differential are usually the first and most important investigations. White cell count is highly variable, falls between 0.1-1500 X 10 9 /L, mostly around 15 X 10 9 /L. T-ALL in adults usually presents with high blood counts. The most important finding is the presence of blasts in peripheral film. Blasts may be sparse or absent in blood counts <2 x 10 9 /L, however a careful peripheral smear examination in well stained slide is extremely important. Profound neutropenia, and thrombocytopenia with platelet count around 50 X 10 9 /L is usual. More than 75% patients  present with mild to moderate anemia, hemoglobin around 8 g/dl in most of the cases. In case if leukemia develops rapidly anemia may be mild or even absent initially. A deranged coagulation profile including prothrombin time, activated partial thromboplastin time, fibrinogen degradation  products may suggest concomitant disseminated intravascular coagulation (DIC)  b. Bone marrow (BM) aspiration usually confirms the diagnosis of ALL. Aspirate slides should be stained for morphology and cytochemical stains, sample should also be  preserved for cytogenetics and immunophenotyping. For morphology of blast cells, one of the Romanowsky stains  preferably Leishman's stain or combined May-Grünwald-Giemsa may be used. For cytochemical stains Myeloperoxidase (MPO)/Sudan black B(SBB), terminal deoxynucleotidyl transferase (TdT), acid phospatase (ACP), and Periodic acid-schiff (PAS) reaction are used. The diagnosis of ALL is almost confirmed if blast cells are   Haematology Updates 2010 42 MPO/SBB negative and show TdT positivity. With SBB very fine positive cytoplasmic granules may be present; these fine granules probably represent mitochondria. Rare cases of apparent ALL may show coarse granular positivity with SBB. In ALL the great majority of neutrophils are MPO positive and show strong positivity with SBB whereas in AML there may be a variable population of SBB/MPO-negative neutrophils. More than 95% of cases of ALL are  positive for TdT, but it is not specific for ALL. TdT is  present in some subtypes of AML such as M0. Additionally, TdT is absent in cases of ALL-L3. TdT may also helps to distinguish ALL from malignancies of more mature lymphocytes. The pattern of PAS positivity if present is also helpful, about 95% of cases of ALL show positive blocks or granules of bright red PAS positive material. This may be  present in very few blasts (< 1%) or in the majority. ACP reaction is strongly positive in T cell acute leukemias, the activity is localized commonly called as polar positivity. c. In order to avoid confusion with some types of acute myeloid leukaemia like M0, M5a, and M7, which are also SBB/MPO negative, and to confirm T or B lineage immunophenotyping should be performed. Patients with AML show myeloid markers like MPO, CD 13, and CD33, whereas patients with ALL show lymphoid markers. Confusion may arise when some patients with ALL express aberrant myeloid markers, such as CD13. If the cells are TdT-positive, myeloperoxidase-negative, CD33-negative and show lymphoid markers, the leukemia is considered ALL. Eighty-five percent of cases of ALL are derived from B cells. The primary distinction is between (1) early (pro-B) ALL which is TdT positive, CD10 & surface immunoglobin G negative (2) precursor B ALL, which is TdT positive, CD10 positive, but surface immunoglobin G negative, and (3) mature B cell (Burkitt) ALL, which is TdT negative, and surface immunoglobin G positive. Fifteen percent of cases are derived from T cells. These cases are sub-classified into different stages corresponding to the phases of normal thymocyte development. The early subtype is surface CD3 negative, cytoplasmic CD3 positive and either double negative (CD4 - , CD8 - ) or double positive (CD4 + , CD8 + ). The latter subtype is surface CD3 positive and positive for either CD4 or CD8. d. Studies for bcr-abl  analysis by polymerase chain reaction or cytogenetics may help distinguish patients with Philadelphia chromosome positive ALL from those with the lymphoid blastic phase of chronic myeloid leukemia. Most  patients with Ph+ ALL have the p190 type of bcr-abl, whereas patients with chronic myeloid leukaemia in lymphoid blast transformation have the p210 type of bcr-abl. Cytogenetic abnormalities occur in approximately 70% of cases of ALL in adults. These abnormalities include t(10;14)(q24;q11), 6q, 14q11, 9p, t(1;19)(q23;p13), t(8;14)(q24;q23), t(2;8)(p12;q24), t(8;22)(q24;q11), t(9;22)(q34;q11), t(4;11)(q21;q23). However, abnormalities of chromosome number (hypodiploidy, hyperdiploidy) are much more common. Classification Presently most of the centres follow both French-American-British (FAB) and World Health Organization (WHO) classifications, however in times to come WHO classification may prove gold standard. FAB Classifies ALL in three subtypes depending upon appearance of blasts (1) L1 - Small cells with homogeneous chromatin, regular nuclear shape, small or absent nucleolus, and scanty cytoplasm; subtype represents 25-30% of adult cases (2) L2 - Large and heterogeneous cells, heterogeneous chromatin, irregular nuclear shape, and nucleolus often large; subtype represents 70% of cases (3) L3 - Large and homogeneous cells with multiple nucleoli, moderate deep blue cytoplasm, and cytoplasmic vacuolization that often overlies the nucleus (most  prominent feature); subtype represents 1-2% of adult cases The WHO classifies the L1 and L2 subtypes of ALL as Precursor Lymphoid Neoplams including (a) B lymphoblastic leukemia/lymphoma not otherwise specified, (b) B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities, and (c) T lymphoblastic leukemia/lymphoma. The L3 subtype of ALL is included in the group of mature B-cell neoplasms, as the subtype Burkitt lymphoma/leukemia. The characteristic features of each are as follow: 1. B-Lymphoblastic leukemia/lymphoma, not otherwise specified It comprises of 75% cases of children less than 6 years of age. Bone marrow is involved in almost all cases while extramedullary involvement is frequent; CNS, lymph nodes, spleen, liver, and testes are commonly involved. Most of the patients present with features of BM failure,  bone pains, arthralgia, and visceromegaly is usual. TLC may  be normal, increased or decreased. B-lymphoblastic lymphoma (B-LBL) is often asymptomatic, most patients may have limited disease, head & neck presentations are common. Bone marrow often shows blasts < 25% with variable morphology. Typically blasts are small with scant cytoplasm and indistinct nucleoli, chromatin is condensed. Less commonly larger blasts with light blue to blue-gray cytoplasm, occasionally vacuolated, dispersed chromatin, multiple nucleoli, with round, irregular, or convoluted nuclei are also seen. In a minority of cases coarse azurophilic granules, cytoplasmic pseudopods like hand mirror are also seen. Cytochemistry shows MPO/SBB negative, PAS may be  positive. Immunophenotyping shows CD 19, cyt CD79a, cyt CD 22, CD 10, CD 22, CD 24, and TdT positivity. 2. B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities a. B-lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2) BCR-ABL 1:   Haematology Updates 2010 43 This subtype is more common in adults, approximately 25% of adult ALL and, 2-4% of childhood ALL belong to this subtype. It carries worst prognosis  b. B-lymphoblastic leukemia/lymphoma with t(v;11q23): Characterized by MLL gene translocation which can be identified by FISH technology in neonates, it is CD 19+ve, CD 10 –ve, and CD24 –ve c. B-lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) TEL-AML 1: It is common in children, comprises of 25% cases of B-ALL, and is rare in adults. It is CD 19 +, CD 10+, most often CD 34 + and carries favorable prognosis, cures in > 90% of children. d. B-lymphoblastic leukemia/lymphoma with hyperdiploidy: Karyotype often shows > 50 chromosomes, typically without translocations or structural alterations. Subtype is common in children, comprises 25% of cases of B-ALL. It is CD 19+, and CD 10+. Trisomies carry best prognosis. e. B-lymphoblastic leukemia/lymphoma with hypodiploidy: Usually < 46 chromosomes, accounts 5% of ALL cases, children and adults, both are equally affected. It is CD 19+, and CD10+. f. B-lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) IL3-IGH: It is rare subtype, accounts 1% of ALL cases. Both children and adults are affected. This subtype may have increased circulating reactive eosinophils,  blasts are usually sparse. g. B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3) E2A-PBX1(TCF3-PBX1): It is relatively common in children, accounting 6% of cases of B-ALL. It is CD 10+, and CD 19+. This subtype carries poor  prognosis 3. T lymphoblastic leukemia / lymphoma Comprises 15% of childhood, and 25% of cases of adult ALL, it is more common in adolescents, and in males. T-LBL comprises of 85-90% of all lymphoblastic lymphomas, and is frequent in adolescent males; BM is involved in almost all cases. Aleukemic presentation in the face of BM involvement is uncommon. Extramedullary sites include thymus, lymph nodes, skin, tonsils, liver, spleen, CNS, and testes. Commonly it presents with high TLC, and large mediastinal mass. BM haematopoiesis may be relatively spared. Morphologically blasts may be Indistinguishable from B-ALL blasts. Blasts are heterogeneous, of medium size and with high N: C ratio, but considerable range of small blasts with very condensed nuclear chromatin, and inconspicuous nucleoli may also be seen. In majority of cases large blasts with fine chromatin,  prominent nucleoli, and round to irregular to convoluted nuclei are seen. In few of the blasts cytoplasmic vacuoles may be present. Occasionally blasts resemble more mature lymphocytes. The cytochemistry may show focal or polar ACP positivity. Immunophenotyping shows TdT positive  blasts that express CD1a, CD2, CD3, CD4, CD5, CD7, and cytoCD3. Abnormal Karyotype is seen in 50-70% cases. Patients with this subtype are at more risk of induction failure, early relapse, and isolated CNS relapse. Management Supportive Care a. Infections are the most frequent threat to a neutropenic patient. Patient should be placed in reverse isolation. Meticulous hand washing by health care personnal must be ensured. Blood culture, throat swab, intravenous canula, and urine should be sent for culture in case of fever. Patient should be placed on empiric antibiotic therapy while waiting for microbial/fungal culture reports. If the patient remains febrile 24 to 72 hours after institution of broad-spectrum antibiotics, coverage with an antifungal agent, should be initiated.  b. Transfusion therapy: Anaemia must be corrected by red cell concentrate and thrombocytopenia with platelet counts below 10x10 9 /L by platelet concentrates. With multiple platelet transfusions, patients develop alloimmunization and become progressively more refractory to subsequent platelet transfusion. Alloimmunization may be reduced by using leukocyte antigen matched donors. Because many patients subsequently undergo BMT, it is critically important to administer blood products that are negative for cytomegalovirus (CMV) to those patients who are CMV negative at presentation. All blood products (except fresh frozen plasma and cryoprecipitable) should be irradiated to avoid GVHD. c. Hematopoietic growth factors: The use of hematopoietic growth factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF), can reduce the period of neutropenia and the mortality and morbidity related to infections. d. DIC may develop in patients with any acute leukemia at presentation or may develop during therapy, when cells are lysed, and release thrombogenic material. Frequent monitoring of coagulation parameters is necessary. If there is no evidence of clinical bleeding and only mild coagulation abnormality is present, close observation is sufficient. If evidence of clinical bleeding or severe DIC is apparent, platelet concentrate and fresh frozen plasma should be instituted according to the laboratory coagulation results. In life-threatening bleeding if unresponsive to treatment, low doses of heparin, 300 to 500 U per hour by continuous infusion, may be considered. e. Tumor lysis syndrome may occur in ALL patients with high cell counts when treatment with corticosteroids is instituted. Thus, it is important to begin hydration and to administer allopurinol and bicarbonate before initiating the therapy. The most common laboratory abnormalities are hypocalcemia, hyperkalemia, hyperphosphatemia, hyperuricemia, elevated creatinine, blood urea nitrogen, and   Haematology Updates 2010 44 LDH. Leukapheresis is often used to reduce high cell counts  before beginning chemotherapy. Patients should be started on allopurinol, 300 to 600 mg daily, administered orally. For those at significant risk for development of tumor lysis syndrome, vigorous hydration with urinary alkalinization is used. Induction Therapy Irrespective of the phenotype or cytogenetic abnormality, all patients with ALL receive identical induction regimens. Various regimens are adopted by centres treating these cases according to experience, facilities and convenience. A typical regimen for induction of ALL involves two phases: Phase I called remission induction consists of daunorubicin, 45 to 60 µg/m2 given on days 1, 8, 15, and 22; vincristine, 1.4 mg/m given days 1, 8, 15 to 22; and prednisone given twice daily at a dose of approximately 60 mg/m2 for a total of 28 days. l-asparaginase, 5,000 to 10,000/m2 units is usually added for 7 to 12 days beginning on day 15 to 17 of phase I. Phase II called consolidation , which is administered very soon after completion of phase I, usually includes cyclophosphamide, cytarabine, and 6-mercaptopurine as well as prophylaxis with intrathecal methotrexate or cytosine arabinoside. Induction therapy in ALL yields an 80% to 85% complete remission rate and must be followed by additional therapy. If CNS leukemia is present, methotrexate usually is given intrathecally weekly at a dose of 12 to 15 mg until  blasts have cleared in the cerebrospinal fluid. Craniospinal irradiation is usually administered concurrently with phase II of the induction therapy. Post-remission Therapy Following induction therapy, patients require  prolonged maintenance therapy for 9 to 24 months. This therapy includes alternating regimens of several effective drugs, including anthracyclines, cytosine arabinoside, cyclophosphamide, methotrexate, L-asparaginase, vincristine, and prednisone. a. Central Nervous System (CNS) Prophylaxis: It is given during intensification and maintenance therapy. Cranial irradiation, intrathecal prophylaxis, or systemic therapy appears to provide satisfactory CNS prophylaxis, thus preventing late CNS relapses.  b. Bone Marrow Transplantation (BMT): Once  patients have had a relapse, irrespective of the duration of the first remission, the outcome is always fatal without BMT. Patients who have suffered relapses should be referred for allogeneic transplantation after a second subsequent remission has been attained. If no donors are available autologous BMT or matched unrelated or mismatched related donors may be considered. References 1.   Riley RS, Hogan TF, Pavot DR, et al. A pathologist's perspective on bone marrow aspiration and biopsy: Performing a bone marrow examination. J Clin Lab Anal. 2004;18(2):70-90. 2.   Bain BJ. Morbidity associated with bone marrow aspiration and trephine biopsy - a review of UK data for 2004. Haematologica. Sep 2006;91(9):1293-4. 3.   Fend F, Tzankov A, Bink K, et al. Modern techniques for the diagnostic evaluation of the trephine bone marrow biopsy: methodological aspects and applications. Prog Histochem Cytochem. 2008;42(4):203-52. 4.   Reda.elli A. A systematic literature review of the clinical and epidemiological burden of acute lymphoblastic leukaemia (ALL). Eur J Cancer Care. 2005;14(1): 53-62. 5.    Jones LK, Saha V. Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J Haematol. Aug 2005;130(4):489-500 6.   Bain B J, Lewis S M. Preparation and staining methods for blood and bone marrow films. In Dacie and Lewis (eds) Practical Hematology 10 th  ed. London: Churchill Livingstone 2006:61-64 7.   Bates I. Bone marrow biopsy. In Dacie and Lewis (eds) Practical Hematology 10 th  ed. London: Churchill Livingstone 2006:116-126 8.   Bain B J. Diagnosis and classification of acute leukemia. In Hoffbrand AV, Catovsky D, Edward GD (eds) Postgraduate Hematology 5 th  ed. Australia: Blackwell Publishing 2005:476-91 9.   Hoelzer D, Gokboget N. Adult acute Lymphoblastic leukemia. In Hoffbrand AV, Catovsky D, Edward GD (eds) Postgraduate Hematology 5 th  ed. Australia: Blackwell Publishing 2005:525-39 10.   Liang DC, Pui CH. Childhood acute Lymphoblastic leukemia. In Hoffbrand AV, Catovsky D, Edward GD (eds) Postgraduate Hematology 5 th  ed. Australia: Blackwell Publishing 2005:542-559. 11.   Browtiz MJ, Chan JKC. Precursor Lymphoid Neoplasms. In. Swerdlow SH, Campo E, Harris NL, Pileri SA, Stein H, Thiele  J, Vaediman JW (eds) WHO Classification of tumours of haematopoietic and lymphoid tissue 4 th  ed. Lyon France: International Agency for research on cancer 2007:157-177 12.   Mazza JJ. Acute Lymphoblastic Leukemia. In Manual of Clinical Hematology, 3rd Edition Lippincott Williams & Wilkins 2002:124 13.   Wintrobe's Clinical Hematology, Greer JP, Foerster J, Rodgers GM, Paraskevas F, Glader B, ArberDA, Means RT Jr(eds) 12th edition. 2007
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