Dr-Usama F Shaalan-Leukemias

Lecture Notes On Leukemia
Edited and quoted By

Dr Usama F Shaalan (M.D.,Ph.D)

The leukemias are the most common malignant neoplasms in childhood, accounting for about 41% of all malignancies that occur in children younger than 15 yr of age. In 2000, approximately 3,600 children were diagnosed with leukemia in the United States, for an annual incidence of 4.1 new cases per 100,000 children younger than 15 yr of age. Acute lymphoblastic leukemia (ALL) accounts for about 77% of cases of childhood leukemia, acute myelogenous leukemia (AML) for about 11%, chronic myelogenous leukemia (CML) for 2–3%, and juvenile chronic myelogenous leukemia (JCML) for 1–2%. The remaining 7–9% of cases include a variety of acute and chronic leukemias that do not fit classic definitions for ALL, AML, CML, or JCML.
The leukemias may be defined as a group of malignant diseases in which genetic abnormalities in a hematopoietic cell give rise to a clonal proliferation of cells. The progeny of these cells have a growth advantage over normal cellular elements owing to an increased rate of proliferation, a decreased rate of spontaneous apoptosis, or both. The result is a disruption of normal marrow function and, ultimately, marrow failure. The clinical features, laboratory findings, and responses to therapy vary depending on the type of leukemia.
Acute Lymphoblastic Leukemia
Childhood ALL was the first disseminated cancer shown to be curable and as such has represented the model malignancy for the principles of cancer diagnosis, prognosis, and treatment. It is actually a heterogeneous group of malignancies with a number of distinctive genetic abnormalities that result in varying clinical behaviors and responses to therapy.
Approximately 2,800 children are diagnosed with ALL in the United States annually. It has a striking peak incidence between 2–6 yr of age and occurs slightly more frequently in boys than in girls. This peak age incidence was apparent decades ago in white populations in advanced socioeconomic countries, but more recently has also been confirmed in the black population of the United States. The disease is more common in children with certain chromosomal abnormalities such as Down syndrome, Bloom syndrome, ataxia-telangiectasia, and Fanconi syndrome. Among identical twins, the risk to the second twin if one develops leukemia is greater than that in the general population. The risk may be as high as 100% if the first twin is diagnosed during the first year of life and the twins shared the same (monochorionic) placenta. If the first twin develops ALL by 5–7 yr of age, the risk to the second twin is at least twice that in the general population, regardless of zygosity.
In virtually all cases, the etiology of ALL is unknown, although several genetic and environmental factors are associated with childhood leukemia ( Box Lk–1 ). Exposure to medical diagnostic radiation both in utero and in childhood has been associated with an increased incidence of ALL. In addition, published descriptions and investigations of geographic clusters of cases have raised concern that environmental factors may increase the incidence of ALL. Thus far, no such factors other than radiation have been identified, except for an association between B-cell ALL and Epstein-Barr viral infections in certain developing countries.
The classification of ALL depends on characterizing the malignant cells in the bone marrow to determine the morphology, phenotypic characteristics as measured by cell membrane markers, and cytogenetic and molecular genetic features. Morphology alone is usually adequate to establish a diagnosis, but the other studies are essential for disease classification, which may have a major influence on both the prognosis and the choice of appropriate therapy. In terms of clinical significance, the most important distinguishing morphologic feature is the French-American-British (FAB) L3 subtype, which is evidence of a mature B-cell leukemia. The L3 type, also known as Burkitt leukemia, is one of the most rapidly growing cancers in humans and requires a different therapeutic approach. Phenotypically, surface markers show that about 85% of cases of ALL are derived from progenitors of B cells, about 15% are derived from T cells, and about 1% are derived from B cells. A small percentage of children diagnosed with leukemia have a disease characterized by surface markers of both lymphoid and myeloid derivation.
Chromosomal abnormalities are found in most patients with ALL ( Table Lk–1 ). The abnormalities, which may be related to chromosomal number, translocations, or deletions, provide important prognostic information. Specific chromosomal findings, such as the t(9;22) translocation, suggest a need for additional, molecular genetic studies. The polymerase chain reaction and fluorescence in situ hybridization techniques, for example, offer the ability to pinpoint molecular genetic abnormalities and to detect small numbers of malignant cells during follow-up; however, the clinical utility of these findings has yet to be firmly established.

Clinical Manifestations
The initial presentation of ALL is usually nonspecific and relatively brief. Anorexia, fatigue, and irritability are often present, as is an intermittent, low-grade fever. Bone or joint pain, particularly in the lower extremities, may be present. Patients often have a history of an upper respiratory tract infection in the proceeding 1–2 mo. Less commonly, symptoms

( Box Lk–1 ) Chromosomal abnormalities found in most patients with ALL (see attached pictures)

( Table Lk–1 )Chromosomal abnormalities are found in most patients with ALL -ALL = acute lymphoblastic leukemia; AML = acute myelogenous leukemia. *Per the French-American-British classification of acute myelogenousleukemia (see TableLk–2 ).
may be of several months’ duration, may be predominantly localized to the bones or joints, and may include joint swelling. As the disease progresses, signs and symptoms of bone marrow failure become more obvious with the occurrence of pallor, fatigue, bruising, or epistaxis, as well as fever, which may be caused by infection.
On physical examination, findings of pallor, listlessness, purpuric and petechial skin lesions, or mucous membrane hemorrhage may reflect bone marrow failure. The proliferative nature of the disease may be manifested as lymphadenopathy, splenomegaly, or, less commonly, hepatomegaly. In patients with bone or joint pain, there may be exquisite tenderness on bone palpation or objective evidence of joint swelling and effusion. Rarely, patients show signs of increased intracranial pressure that indicate leukemic involvement of the central nervous system (CNS). These include papilledema , retinal hemorrhages, and cranial nerve palsies. Respiratory distress is usually related to anemia but may occur in patients with an obstructive airway problem, owing to a large mediastinal mass of lymphoblasts. This problem is most typically seen in adolescent boys with T-cell ALL.
The diagnosis of ALL is strongly suggested by peripheral blood findings indicative of bone marrow failure. Anemia and thrombocytopenia are seen in most patients. Leukemic cells are often not observed in the peripheral blood in routine laboratory examinations. Most patients with ALL present with total leukocyte counts of less than 10,000/µL. In such cases, the leukemic cells are often initially reported to be atypical lymphocytes, and it is only with further evaluation that the cells are found to be part of a malignant clone. When the results of an analysis of peripheral blood suggest the possibility of leukemia, a bone marrow examination should be done promptly to establish the diagnosis. Bone marrow aspiration alone is usually sufficient, but sometimes a bone marrow biopsy is needed to provide adequate tissue for study or to exclude other possible causes of bone marrow failure.
ALL is diagnosed by a bone marrow evaluation that demonstrates more than 25% of the bone marrow cells as a homogeneous population of lymphoblasts. Staging of ALL is partly based on a cerebrospinal fluid (CSF) examination. If lymphoblasts are found and the CSF leukocyte count is elevated, overt CNS (or meningeal) leukemia is present; a worse stage is implied and additional CNS and systemic therapies are indicated. The staging lumbar puncture may be performed in conjunction with the first dose of intrathecal chemotherapy if the diagnosis of leukemia has been previously established from bone marrow evaluation.
Acute lymphoblastic leukemia must be differentiated from acute myelogenous leukemia (AML); other malignant diseases that may invade the bone marrow and cause marrow failure such as neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma, and retinoblastoma; and causes of primary bone marrow failure, such as aplastic anemia (either congenital or acquired) and myelofibrosis. Failure of a single cell line, as in transient erythroblastic anemia, immune thrombocytopenia, and congenital or acquired neutropenia, sometimes produces a clinical picture that is difficult to distinguish from ALL and that may require bone marrow examination. A high index of suspicion is required to differentiate ALL from infectious mononucleosis in patients with acute onset of fever and lymphadenopathy and from rheumatoid arthritis in patients with fever and joint swelling. These presentations also may require bone marrow examination.
The single most important prognostic factor in ALL is the treatment: without effective therapy the disease is fatal. The survival rates of children with ALL over the past 40 yr have improved as the results of clinical trials have improved the therapies and outcomes ( Fig. Lk–1 ).
The choice of treatment of ALL is based on the estimated clinical risk of relapse in the patient, which varies widely among the subtypes of ALL. Three of the most important predictive factors are the age of the patient at the time of diagnosis, the initial leukocyte count, and the speed of response to treatment (i.e., how rapidly the blast cells can be cleared from the marrow or peripheral blood). Different study groups use various factors to define risk, but a patient between 1–10 yr of age and with a leukocyte count of less than 50,000/µL is widely used to define average

Figure Lk.1-1 (see attached pictures)
Survival rates of children with acute lymphoblastic leukemia treated on sequential Children’s Cancer Group (COG) clinical trials over 30 yr. (Data provided by H. N. Sather.)
risk. Patients considered to be at higher risk are children who are older than 10 yr of age or who have an initial leukocyte count of more than 50,000/µL. Recent trials have shown that the outcome for patients at higher risk can be improved by administration of more intensive therapy despite the greater toxicity of such therapy. Infants with ALL, along with patients who present with specific chromosomal abnormalities such as t(9;22) or t(4;11), have an even higher risk of relapse despite intensive therapy. Clinical trials have also demonstrated that the prognosis for patients with a slower response to initial therapy may be improved by therapy that is more intensive than the therapy considered necessary for patients who respond more rapidly.
Most children with ALL are treated on clinical trials conducted by national or international cooperative groups. In general, the initial therapy is designed to eradicate the leukemic cells from the bone marrow and is known as remission induction. During this phase, therapy is usually given for 4 wk and consists of vincristine weekly, a corticosteroid such as dexamethasone or prednisone, and either repeated doses of native l-asparaginase or a single dose of a long-acting asparaginase preparation. Intrathecal cytarabine or methotrexate, or both, may also be given. Patients at higher risk also receive daunomycin at weekly intervals. With this approach, 98% of patients are in remission, as defined by less than 5% blasts in the marrow and a return of neutrophil and platelet counts to near-normal levels after 4–5 wk of treatment. Intrathecal chemotherapy is usually given at the time of diagnosis and once more during induction.
The second phase of treatment focuses on CNS therapy in an effort to prevent later CNS relapses. Intrathecal chemotherapy is given repeatedly by lumbar puncture in conjunction with intensive systemic chemotherapy. The likelihood of later CNS relapse is thereby reduced to less than 5%. A small proportion of patients with features that predict a high risk of CNS relapse receive irradiation to the brain and spinal cord. This includes those patients who have lymphoblasts in the CSF and an elevated CSF leukocyte count at the time of diagnosis.
After remission induction, many regimens provide 14–28 wk of multiagent therapy, with the drugs and schedules used varying depending on the risk group of the patient. Finally, patients are given daily mercaptopurine and weekly methotrexate, usually with intermittent doses of vincristine and a corticosteroid. This period, known as the maintenance phase of therapy, lasts for 2–3 yr, depending on the protocol used. A small number of patients with particularly poor prognostic features, principally those with the t(9;22) translocation known as the Philadelphia chromosome, may undergo bone marrow transplantation during the first remission. In ALL, this chromosome is similar but not identical to the Philadelphia chromosome of chronic myelogenous leukemia (CML).
The major impediment to a successful outcome is relapse of the disease. Relapse occurs in the bone marrow in 15–20% of patients with ALL and carries the most serious implications, especially if it occurs during or shortly after completion of therapy. Intensive chemotherapy with agents not previously used in the patient followed by allogeneic stem cell transplantation can result in long-term survival for a few patients with bone marrow relapse.
Patients with relapse in the CNS usually present with signs and symptoms of increased intracranial pressure and may present with isolated cranial nerve palsies. The diagnosis is confirmed most readily by demonstrating the presence of leukemic cells in the CSF and, rarely, by imaging studies. The treatment includes intrathecal medication and craniospinal irradiation. Systemic chemotherapy must also be used because these patients are at high risk for subsequent bone marrow relapse. Most patients with leukemic relapse confined to the CNS do well, especially those in whom the CNS relapse occurs after chemotherapy has been completed or during the latter phase of chemotherapy.
Testicular relapse occurs in 1–2% of boys with ALL, usually after completion of therapy. Such relapse presents as painless swelling of one or both testes. The diagnosis is confirmed by biopsy of the affected testis. Treatment includes systemic chemotherapy and local irradiation. A high proportion of boys with a testicular relapse can be successfully re-treated, and the survival rate of these patients is good.
Close attention to the medical supportive care needs of the patients is essential in successfully administering aggressive chemotherapeutic programs. Patients with a large tumor burden are prone to tumor lysis syndrome as therapy is initiated. Chemotherapy often produces severe myelosuppression, which may require erythrocyte and platelet transfusion and which always requires a high index of suspicion and aggressive empirical antimicrobial therapy for sepsis in febrile children with neutropenia. Patients need to receive prophylactic treatment of Pneumocystis carinii pneumonia during chemotherapy and for several months after completing treatment.
The success of therapy has changed ALL from an acute disease with a high mortality rate to a chronic disease. However, such chronic treatment can incur substantial academic, developmental, and psychosocial costs for children with ALL and considerable financial costs and stress for their families. Because of the intensity of therapy, long-term and acute toxicity effects may occur. An array of cancer care professionals with training and experience in addressing the myriad of problems that may arise is essential to minimize the complications and achieve an optimal outcome.
Most children with ALL can now be expected to have long-term survival, with the rate greater than 80% after 5 yr (see Fig Lk–1 (see attached pictures) ). The most important prognostic factor is the choice of appropriate risk-directed therapy, with the type of treatment chosen according to the type of ALL, the stage of disease, the age of the patient, and the rate of response to initial therapy. Characteristics generally believed to adversely affect outcome include an age younger than 1 yr or older than 10 yr at diagnosis, a leukocyte count of more than 100,000/µL at diagnosis, or a slow response to initial therapy. Chromosomal abnormalities, including hypodiploidy, the Philadelphia chromosome, and t(4;l1), portend a poorer outcome. More favorable characteristics include a rapid response to therapy, hyperdiploidy, and rearrangements of the TEL/AML1 genes.

Acute Myelogenous Leukemia
AML comprises 11% of the cases of leukemia in childhood in the United States, with approximately 380 children diagnosed with AML annually. One subtype, acute promyelocytic leukemia (APL), is more common in certain other regions of the world, but incidence of the other types is generally uniform. Several chromosomal abnormalities associated with AML are identified, but no predisposing genetic or environmental factors can be identified in most patients (see Table Lk–1 ).
The characteristic feature of AML is more than 30% of bone marrow cells on bone marrow aspiration or biopsy touch preparations that constitute a rather homogeneous population of blasts cells with features similar to those that characterize early differentiation states of the myeloid-monocyte-megakaryocyte series of blood cells. The most common classification of the subtypes of AML is the FAB system ( Table Lk–2 ). Although this system is based on morphologic criteria alone, current practice also requires the use of flow cytometry for identification of cell surface antigens and of chromosomal and molecular genetic techniques for additional diagnostic precision and also to aid the choice of therapy.

TABLE -Lk.2 French-American-British (FAB) Classification of Acute Myelogenous Leukemia Subtype (see attached pictures)
Clinical Manifestations
The production of symptoms and signs of AML, as in ALL, is due to replacement of bone marrow by malignant cells and to secondary bone marrow failure. Thus, patients with AML may present with any or all of the findings associated with marrow failure in ALL. In addition, patients with AML present with signs and symptoms that infrequently occur with ALL, including subcutaneous nodules or “blueberry muffin” lesions, infiltration of the gingiva, signs and laboratory findings of disseminated intravascular coagulation (especially indicative of acute promyelocytic leukemia), and discrete masses, known as chloromas or granulocytic sarcomas. These masses may occur in the absence of apparent bone marrow involvement and are typically associated with the M2 subcategory of AML with a t(8;21) translocation.

Analysis of bone marrow aspiration and biopsy specimens of patients with AML typically reveals the features of a hypercellular marrow consisting of a rather monotonous pattern of cells with features that permit FAB subclassification of disease. Special stains assist in identification of myeloperoxidase-containing cells, thus confirming both the myelogenous origin of the leukemia and the diagnosis. Some chromosomal abnormalities and molecular genetic markers are characteristic of specific subtypes of disease (see Box Lk–1 ) (see attached pictures)
Aggressive multiagent chemotherapy is successful in inducing remission in about 80% of patients. Up to 10% of patients die of either infection or bleeding before a remission can be achieved. Matched-sibling bone marrow or stem cell transplantation after remission has been shown to achieve long-term disease-free survival in 60–70% of patients. Continued chemotherapy for patients who do not have a matched donor is less effective than marrow transplantation but nevertheless is curative in some patients.
Acute promyelocytic leukemia, characterized by a gene rearrangement involving the retinoic acid receptor, is very responsive to retinoic acid combined with anthracyclines. The success of this therapy makes marrow transplantation in first remission unnecessary for patients with this disease.
The supportive care needs of patients with AML are basically the same as those given for ALL. The very intensive therapy required in AML produces prolonged bone marrow suppression with a very high incidence of serious infections.
Down Syndrome and Acute Leukemia and Myeloproliferation
Acute leukemia occurs about 14 times more frequently in children with Down syndrome than in the general population. The ratio of ALL to AML in patients with Down syndrome is the same as that in the general population. In Down children with ALL, the expected outcome of treatment is the same as that for other children. However, patients with Down syndrome demonstrate a remarkable sensitivity to methotrexate and other antimetabolites, which can result in substantial toxicity if standard doses are administered. In AML, however, patients with Down syndrome have much better outcomes, with a greater than 80% long-term survival rate, than does the non-Down syndrome population. After induction therapy, these patients require less intensive therapy to achieve the better results.
Neonates with Down syndrome are prone to develop a transient leukemia or myeloproliferative syndrome characterized by high leukocyte counts, blast cells in the peripheral blood, and associated anemia, thrombocytopenia, and hepatosplenomegaly. These features usually resolve within days to a few weeks after onset. Although these neonates may require temporary transfusion support, they do not require chemotherapy. However, patients who have Down syndrome and who develop this transient leukemia or myeloproliferative syndrome require close follow-up because 20–30% will develop typical leukemia within the first few years of life.
Chronic Myelogenous Leukemia
CML is a clonal disorder of the hematopoietic tissue that accounts for 2–3% of all cases of childhood leukemia. About 99% of the cases are characterized by a specific translocation, t(9;22)(q34;q11), known as the Philadelphia chromosome. The disease has been associated with exposure to ionizing radiation but very few children with CML have a history of such exposure. The disease is characterized clinically by an initial chronic phase in which the malignant clone produces an elevated leukocyte count with a predominance of mature forms but with increased numbers of immature granulocytes. The spleen is often greatly enlarged, often resulting in pain in the left upper quadrant of the abdomen. In addition to leukocytosis, the blood counts may reveal mild anemia and thrombocytosis.
Typically, the chronic phase terminates 3–4 yr after onset when the CML moves into the accelerated or “blast crisis” phase. At this point, the blood counts rise dramatically and cannot be controlled with drugs such as hydroxyurea. Additional manifestations may occur, including hyperuricemia and neurologic symptoms, which are related to increased blood viscosity with decreased CNS perfusion.
The presenting symptoms of CML are entirely nonspecific and may include fever, fatigue, weight loss, and anorexia. Splenomegaly may also be present. The diagnosis is suggested by increased numbers of myeloid cells with differentiation to mature forms in the peripheral blood and bone marrow and is confirmed by cytogenetic studies that demonstrate the presence of the characteristic Philadelphia chromosome. Molecular techniques usually demonstrate the BCR-ABL gene rearrangement. The translocation, although characteristic of CML, is also found in a small percentage of patients with ALL or AML.
The signs and symptoms of CML in the chronic phase can be controlled with hydroxyurea, which will gradually return the leukocyte count to normal. However, this treatment is not definitive and does not eliminate the abnormal clone or prevent progression of the disease. Therapy with interferon-a produces hematologic remission in up to 70% of patients and cytogenetic remission in about 20% of patients. Combination chemotherapy has been successful in achieving remission in a small proportion of patients with CML; however, the optimum therapy is allogeneic bone marrow or stem cell transplantation from an HLA-matched sibling, which is curative in up to 80% of children.
Exciting results have recently been reported with imatinib mesylate, an agent designed specifically to inhibit the BCR-ABL tyrosine kinase. Although this drug is very effective in adult patients, trials in children are just beginning. It is hoped that this agent will usher in a new era of therapy for CML by specifically targeting the genetic abnormality of the malignant clone of cells.
Juvenile Chronic Myelogenous Leukemia
Juvenile chronic myelogenous leukemia (JCML), also known as juvenile myelomonocytic leukemia, is a clonal proliferation of hematopoietic stem cells that typically affects children younger than 2 yr of age. Patients with this disease do not have the Philadelphia chromosome that is characteristic of CML. Patients with JCML present with rashes, lymphadenopathy, and splenomegaly. Analysis of the peripheral blood often shows an elevated leukocyte count and may also show thrombocytopenia and the presence of erythroblasts. The bone marrow shows a myelodysplastic pattern, with blasts accounting for less than 30% of cells. No distinctive cytogenetic abnormalities are seen. JCML is rare constituting less than 2% of all cases of childhood leukemia. Therapeutic reports are largely anecdotal. Patients with neurofibromatosis have a predilection for this type of leukemia. Stem cell transplantation offers the best opportunity for cure, but much less so than for classic CML.
Infant Leukemia
Only about 2% of cases of leukemia during childhood occur before the age of 1 yr. Several unique biologic features and a particularly poor prognosis are characteristic of ALL during infancy. More than two thirds of the cases demonstrate rearrangements of the MLL gene, classically a translocation involving the q23 band of chromosome 11, and it is this subset of patients that largely accounts for the very high relapse rate. These patients often present with hyperleukocytosis and extensive tissue invasion, including CNS disease. Subcutaneous nodules (leukemia cutis) and tachypnea due to diffuse pulmonary infiltration by leukemic cells are more frequently observed in infants than in older children. The leukemic cell morphology is usually that of large irregular lymphoblasts (FAB L2) with a phenotype negative for the CD10 (cALLa) marker.
Very intensive chemotherapy programs including stem cell transplantation are being explored in infants with rearrangement of MLL in band 11q23, but none has yet proved satisfactory. Infants with leukemia who lack the 11q23 rearrangements have a prognosis similar to that of older children with ALL. Infants with AML often present with CNS or skin involvement and have the FAB M4 subtype, which is commonly known as acute myelomonocytic leukemia. The treatment may be the same as that for older children with AML. Meticulous supportive care is necessary because of the young age and aggressive therapy needed in these patients.

Usama F Shaalan (M.D.MSc.Pediatrics, Molecular Diagnosis,Ph.D.),Lecturer of Pediatrics Molecular Diagnosis(GEBRI),Menofia University (Shaalan pediatrics)
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Dr Usama F Shaalan