- Acute and chronic myeloid leukemia
- The myeloid leukemias are a heterogeneous group of diseases characterized by infiltration of the blood, bone marrow, and other tissues by neoplastic cells of the hematopoietic system.
Acute myeloid leukemia
- The age-adjusted incidence is higher in men than in women (2.9 versus 1.9).
- AML incidence increases with age; it is 1.3 in individuals younger than 65 years and 12.2 in those older than 65.
- Heredity, radiation, chemical and other occupational exposures, and drugs have been implicated in the development of AML.
- Certain syndromes with somatic cell chromosome aneuploidy, such as trisomy 21 noted in Down syndrome, are associated with an increased incidence of AML.
- Inherited diseases with defective DNA repair, e.g., Fanconi anemia, Bloom syndrome, and ataxia telangiectasia, are also associated with AML.
- Survivors of the atomic bomb explosions in Japan had an increased incidence of myeloid leukemias that peaked 5–7 years after exposure
- Exposure to benzene is associated with an increased incidence of AML.
- Smoking and exposure to petroleum products, paint, embalming fluids, ethylene oxide, herbicides, and pesticides, have also been associated with an increased risk of AML.
- Anticancer drugs are the leading cause of treatment-associated AML.
The World Health Organization (WHO) classification
- AML with recurrent genetic abnormalities
- AML with multilineage dysplasia
- AML and myelodysplastic syndromes, therapy-related
- AML not otherwise categorized
French-American-British (FAB) Classification
- M0: Minimally differentiated leukemia
- M1: Myeloblastic leukemia without maturation
- M2: Myeloblastic leukemia with maturation
- M3: Promyelocytic leukemia
- M4: Myelomonocytic leukemia
- M5: Monocytic leukemia
- M6: Erythroleukemia (DiGuglielmo’s disease)
- M7: Megakaryoblastic leukemia
- Patients with AML most often present with nonspecific symptoms that begin gradually or abruptly and are the consequence of anemia, leukocytosis, leukopenia or leukocyte dysfunction, or thrombocytopenia.
- Nearly half have had symptoms for 3 months or more before the leukemia is diagnosed.
- Half mention fatigue as the first symptom, but most complain of fatigue or weakness at the time of diagnosis.
- Anorexia and weight loss are common.
- Fever with or without an identifiable infection is the initial symptom in ~10% of patients.
- Signs of abnormal hemostasis (bleeding, easy bruising) are noted first in 5% of patients.
- On occasion, bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis is the presenting symptom.
- Rarely patients may present with symptoms from a mass lesion located in the soft tissues, breast, uterus, ovary, cranial or spinal dura, gastrointestinal tract, lung, mediastinum, prostate, bone, or other organs.
- The mass lesion represents a tumor of leukemic cells and is called a granulocytic sarcoma, or chloroma.
- Fever, splenomegaly, hepatomegaly, lymphadenopathy, sternal tenderness, and evidence of infection and hemorrhage are often found at diagnosis.
- Significant gastrointestinal bleeding, intrapulmonary hemorrhage, or intracranial hemorrhages occur most often in M3 AML.
- Bleeding associated with coagulopathies may also occur in M5 AML and with extreme degrees of leukocytosis or thrombocytopenia in other FAB subtypes.
- Retinal hemorrhages are detected in 15% of patients.
- Infiltration of the gingivae, skin, soft tissues, or the meninges with leukemic blasts at diagnosis is characteristic of the monocytic subtypes (M4 and M5).
- Anemia is usually present at diagnosis and can be severe.
- The anemia is usually normochromic normocytic.
- Decreased erythropoiesis often results in a reduced reticulocyte count, and erythrocyte survival is decreased by accelerated destruction.
- Active blood loss also contributes to the anemia.
- The median presenting leukocyte count is about 15,000/uL.
- Twenty-five to 40% of patients have counts <5000/uL, and 20% have counts >100,000/uL.
- Platelet counts <100,000/uL are found at diagnosis in ~75% of patients, and about 25% have counts <25,000/uL.
- Treatment of the newly diagnosed patient with AML is usually divided into two phases, induction and postremission management
- The initial goal is to quickly induce CR.
- Once CR is obtained, further therapy must be used to prolong survival.
- The most commonly used complete remission induction regimens (for patients with all FAB subtypes except M3) consist of combination chemotherapy with cytarabine (cytosine arabinoside) and an anthracycline.
- After induction chemotherapy, the bone marrow is examined to determine if the leukemia has been eliminated.
- If >5% blasts exist with >20% cellularity, the patient has traditionally been retreated with cytarabine and an anthracycline in doses similar to those given initially, but for 5 and 2 days, respectively.
- Patients who fail to attain CR after two induction courses should immediately proceed to an allogeneic stem cell transplant (SCT) if an appropriate donor exists.
- With the 7 and 3 cytarabine/daunorubicin regimen outlined above, 65 to 75% of adults with de novo AML achieve CR.
- Two-thirds achieve CR after a single course of therapy, and one-third require two courses.
- High-dose cytarabine-based regimens have very high CR rates after a single cycle of therapy.
- The hematologic toxicity of high-dose cytarabine-based induction regimens has typically been greater than that associated with 7 and 3 regimens.
- Toxicity with high-dose cytarabine includes myelosuppression, pulmonary toxicity, and significant and occasionally irreversible cerebellar toxicity.
- Measures geared to supporting patients through several weeks of granulocytopenia and thrombocytopenia is critical to the success of AML therapy
- Recombinant hematopoietic growth factors have been incorporated into clinical trials in AML.
- Adequate and prompt blood bank support is critical to therapy of AML.
- Platelet transfusions should be given as needed to maintain a platelet count >10,000 to 20,000/uL.
- Red blood cell transfusions should be administered to keep the hemoglobin level >80 g/L (8 g/dL) in the absence of active bleeding or DIC.
- Infectious complications remain the major cause of morbidity and death during induction and postremission chemotherapy for AML.
- Oral nystatin or clotrimazole are recommended to prevent localized candidiasis.
- For patients who are herpes simplex virus antibody titer-positive, acyclovir prophylaxis is effective in preventing reactivation of latent oral herpes infections.
- Early initiation of empiric broad-spectrum antibacterial and antifungal antibiotics has significantly reduced the number of patients dying of infectious complications
Treatment of Promyelocytic Leukemia
- ATRA is an oral drug that induces the differentiation of leukemic cells bearing the t (15; 17); it is not effective in other forms of AML.
- Acute promyelocytic leukemia is responsive to cytarabine and daunarubicin, but about 10% of patients treated with these drugs die from DIC induced by the release of granule components by dying tumor cells.
- ATRA does not produce DIC but produces another complication called the retinoic acid syndrome.
- Occurring within the first 3 weeks of treatment, it is characterized by fever, dyspnea, chest pain, pulmonary infiltrates, pleural and pericardial effusions, and hypoxia.
- The syndrome is related to the adhesion of differentiated neoplastic cells in the pulmonary vasculature.
- Glucocorticoids, chemotherapy, and/or supportive measures can be effective. About 10% of patients die from this syndrome.
- Induction of a durable first CR is critical to long-term disease-free survival in AML.
- Without further therapy virtually all patients experience relapse.
- Once relapse has occurred, AML is generally curable only by SCT.
- Postremission therapy is designed to eradicate any residual leukemic cells.
- Therefore, it should prevent relapse and prolong survival.
- Approaches to postremission therapy in AML include intensive chemotherapy and allogeneic or autologous SCT.
Chronic myeloid leukemia
- Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate.
- Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells
- The incidence of chronic myelogenous leukemia (CML) is 1.5 per 100,000 people per year
- The age-adjusted incidence is higher in men than in women (1.7 versus 1.0).
- The incidence of CML increases slowly with age until the middle forties, when it starts to rise rapidly.
- Chronic myelogenous leukemia (CML) accounts for 20% of all leukemias affecting adults.
- No clear correlation with exposure to cytotoxic drugs has been found, and no evidence suggests a viral etiology.
- Atomic bomb survivors had an increased incidence; the development of a CML cell mass of 10,000/L took 6.3 years
- Cigarette smoking has been shown to accelerate the progression to blast crisis and therefore has an adverse effect on survival in CML.
- The effect of radiation but only large doses of radiation can induce CML.
- Chronic myelogenous leukemia (CML) is an acquired abnormality that involves the hematopoietic stem cell.
- It is characterized by a cytogenetic aberration consisting of a reciprocal translocation between the long arms of chromosomes 22 and 9; t(9;22).
- The translocation results in a shortened chromosome 22, an observation first described by Nowell and Hungerford and subsequently termed the Philadelphia (Ph) chromosome after the city of discovery
- The product of the fusion gene resulting from the t (9; 22) plays a central role in the development of CML.
- This chimeric gene is transcribed into a hybrid BCR/ABL mRNA in which exon 1 of ABL is replaced by variable numbers of 5’ BCR exons.
- Bcr/Abl fusion proteins, p210BCR-ABL, are produced that contain NH2-terminal domains of Bcr and the COOH-terminal domains of Abl.
- Bcr/Abl fusion proteins can transform hematopoietic progenitor cells in vitro.
- Messenger RNA for BCR/ABL can occasionally be detected in normal individuals.
- However, attachment of the BCR sequences to ABL results in three critical functional changes: (1) the Abl protein becomes constitutively active as a tyrosine kinase enzyme, (2) the DNA protein-binding activity of Abl is attenuated, and (3 ) the binding of Abl to cytoskeletal actin microfilaments is enhanced.
- The clinical onset of the chronic phase is generally insidious.
- Accordingly, some patients are diagnosed while still asymptomatic, during health screening tests; other patients present with fatigue, malaise, and weight loss or have symptoms resulting from splenic enlargement, such as early satiety and left upper quadrant pain or mass.
- Less common are features related to granulocyte or platelet dysfunction, such as infections, thrombosis, or bleeding.
- Occasionally, patients present with leukostatic manifestations due to severe leukocytosis or thrombosis such as vasoocclusive disease, cerebrovascular accidents, myocardial infarction, venous thrombosis, priapism, visual disturbances, and pulmonary insufficiency.
- Progression of CML is associated with worsening symptoms.
- Unexplained fever, significant weight loss, increasing dose requirement of the drugs controlling the disease, bone and joint pain, bleeding, thrombosis, and infections suggest transformation into accelerated or blastic phases.
- Fewer than 10 to 15% of newly diagnosed patients present with accelerated disease or with de novo blastic phase CML.
- In most patients the abnormal finding on physical examination at diagnosis is minimal to moderate splenomegaly; mild hepatomegaly is found occasionally.
- Persistent splenomegaly despite continued therapy is a sign of disease acceleration.
- Lymphadenopathy and extramedullary myeloid tumors (granulocytic sarcomas) are unusual except late in the course of the disease; when they are present, the prognosis is poor.
- Elevated white blood cell counts, with various degrees of immaturity of the granulocytic series, are present at diagnosis.
- Usually <5% circulating blasts and <10% blasts and promyelocytes are noted.
- Platelet counts are almost always elevated at diagnosis, and a mild degree of normochromic normocytic anemia is present.
- Leukocyte alkaline phosphatase is characteristically low in CML
- Serum levels of vitamin B12and vitamin B12-binding proteins are generally elevated.
- At diagnosis, bone marrow cellularity, primarily of the myeloid and megakaryocytic lineages, with a greatly altered myeloid to erythroid ratio, is increased in almost all patients with CML.
- Disease acceleration is defined by the development of increasing degrees of anemia unaccounted for by bleeding or chemotherapy, cytogenetic clonal evolution, or blood or marrow blasts between 10 and 20%, blood or marrow basophils >20%, or platelet count <100,000/uL.
- Blast crisis is defined as acute leukemia, with blood or marrow blasts >20%.
- Blast cells can be classified as myeloid, lymphoid, erythroid, or undifferentiated, based on morphologic, cytochemical, and immunologic features.
- About half the cases are myeloid, one-third lymphoid, 10% erythroid, and the rest are undifferentiated.
- The diagnosis of CML is established by identifying a clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22.
- This translocation results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22q11 with the ABL (named after the abelson murine leukemia virus) gene located on chromosome 9q34.
- Untreated, the disease is characterized by the inevitable transition from a chronic phase to an accelerated phase and on to blast crisis in a median time of 4 years.
- The goal of therapy in CML is to achieve prolonged, durable, nonneoplastic, nonclonal hematopoiesis, which entails the eradication of any residual cells containing the BCR/ABL transcript.
- A new approach to treatment of chronic myelogenous leukemia (CML) is to directly inhibit the molecular cause of the disease, that is, using a protein-tyrosine kinase inhibitor that inhibits the bcr-abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Ph chromosome translocation abnormality
- STI571, or imatinib mesylate (Gleevec), inhibits proliferation and induces apoptosis by inhibiting tyrosine kinase activity in cells positive for BCR/ABL and fresh leukemic cells in chronic myelogenous leukemia (CML) that is positive for the Ph chromosome
- With imatinib at 400 mg/d orally in patients with newly diagnosed Ph-positive CML in the chronic phase, the complete cytogenetic response rate is 70% and the estimated 3-year survival rate is 94%.
- With higher doses of 800 mg/d, the complete cytogenetic response rate increases to 98%, the major molecular response rate is 70%, and the complete molecular response rate is 40-50%.
- For patients with chronic-phase chronic myelogenous leukemia (CML), imatinib at 400 mg/d is the best candidate for primary therapy, because it induces a complete hematologic response in almost all patients and causes a high cytogenetic response rate.
- Myelosuppressive therapy, which was formerly the mainstay of treatment to convert a patient with chronic myelogenous leukemia (CML) from an uncontrolled initial presentation to one with hematologic remission and normalization of the physical examination and laboratory findings, may soon fall out of favor as the new agents prove to be more effective with fewer adverse events and longer survival
- Hydroxyurea (Hydrea), an inhibitor of deoxynucleotide synthesis, is the most common myelosuppressive agent used to achieve hematologic remission
- Busulfan (Myleran) is an alkylating agent that has traditionally been used to keep the WBC counts less than 15,000 cells/µL.
- However, the myelosuppressive effects may occur much later and persist longer, making maintaining the numbers within normal limits more difficult.
- Long-term use can cause pulmonary fibrosis, hyperpigmentation, and prolonged marrow suppression lasting for months
- Interferon alfa was the treatment of choice for most patients with chronic myelogenous leukemia (CML) who are too old for bone marrow transplantation (BMT) or who do not have a matched bone marrow donor.
- BMT should be considered early in young patients (<55 y) who have a matched sibling donor
- Transplantation has been relegated to patients who do not achieve molecular remissions or show resistance to imatinib and failure to second-generation bcr-abl kinase inhibitors such as dasatinib
CHRONIC LYMPHOCYTIC LEUKEMIA
Essentials of Diagnosis
- Most patients asymptomatic at presentation.
- Splenomegaly typical.
- Lymphocytosis > 5000/uL.
- Mature appearance of lymphocytes.
- Co-expression of CD19, CD5.
- Chronic lymphocytic leukemia (CLL) is a clonal malignancy of B lymphocytes.
- The cells of origin in the majority of patients with chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) are clonal B cells arrested in the B-cell differentiation pathway, intermediate between pre-B cells and mature B cells.
- B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20, CD21, and CD23 monoclonal antibodies.
- In addition, they express CD5, which is more typically found on T cells.
- Because normal CD5+ B cells are present in the mantle zone (MZ) of lymphoid follicles, B-cell chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is most likely a malignancy of an MZ-based subpopulation of anergic self-reactive cells devoted to the production of polyreactive natural autoantibodies
- Morphologically in the peripheral blood, these cells resemble mature lymphocytes
- The disease is usually indolent, with slowly progressive accumulation of long-lived small lymphocytes.
- These cells are immunoincompetent and respond poorly to antigenic stimulation.
- Chronic lymphocytic leukemia is manifested clinically by immunosuppression, bone marrow failure, and organ infiltration with lymphocytes.
- Immunodeficiency is also related to inadequate antibody production by the abnormal B cells.
- With advanced disease, chronic lymphocytic leukemia may cause damage by direct tissue infiltration.
Symptoms and Signs
- Chronic lymphocytic leukemia is a disease of older patients, with 90% of cases occurring after age 50 and a median age at presentation of 65.
- Many patients will be incidentally discovered to have lymphocytosis.
- Others present with fatigue or lymphadenopathy.
- On examination, 80% of patients will have lymphadenopathy and half will have enlargement of the liver or spleen.
- A prognostically useful staging system (Rai system) has been developed as follows: stage 0, lymphocytosis only; stage I, lymphocytosis plus lymphadenopathy; stage II, organomegaly; stage III, anemia; and stage IV,
- Chronic lymphocytic leukemia usually pursues an indolent course; a variant, prolymphocytic leukemia, is more aggressive.
- The morphology of the latter cases is different, characterized by larger and more immature cells.
- In 5-10% of cases, chronic lymphocytic leukemia may be complicated by autoimmune hemolytic anemia or autoimmune thrombocytopenia.
- In approximately 5% of cases, while the systemic disease remains stable, an isolated lymph node transforms into an aggressive large cell lymphoma (Richter’s syndrome).
- The hallmark of chronic lymphocytic leukemia is isolated lymphocytosis.
- The white blood count is usually greater than 20,000/uL and may be markedly elevated to several hundred thousand.
- Usually 75-98% of the circulating cells are lymphocytes.
- The bone marrow is variably infiltrated with small lymphocytes
- The immunophenotype of CLL is unique in that it co-expresses the B lymphocyte lineage marker CD19 with the T lymphocyte marker CD5.
- Hypogammaglobulinemia is present in half and becomes more common with advanced disease.
- In some, a small amount of IgM paraprotein is present in the serum.
- The original 5-stage Rai-Sawitsky staging system was revised in 1987 to a simpler 3-stage system.
- The revised Rai staging system divides patients into low-, intermediate-, and high-risk groups.
- Low risk (formerly stage 0) – Lymphocytosis in the blood and marrow only
- Intermediate risk (formerly stages I and II) – Lymphocytosis with enlarged nodes in any site or splenomegaly or hepatomegaly
- High risk (formerly stages III and IV) – Lymphocytosis with disease-related anemia (hemoglobin <11 g/dL) or thrombocytopenia (platelets <100 x 109/L)
- The Binet staging system uses 3 stages — A, B, and C — based on the areas of involvement and anemia/thrombocytopenia.
- Areas of involvement are: head and neck lymph nodes (multiple sites counts as 1 area), axillary lymph nodes (bilateral counts as 1 area), inguinal lymph nodes (bilateral counts as 1 area), splenomegaly, and hepatomegaly.
- Stage A – Hemoglobin greater than or equal to 10 g/dL, platelets greater than or equal to 100 X 109/L, and fewer than 3 lymph node areas involved.
- Stage B – Hemoglobin and platelet levels as in stage A and 3 or more lymph node areas involved.
- Stage C – Hemoglobin less than 10 g/dL or platelets less than 100 X 109/L, or both.
- Most cases of early indolent chronic lymphocytic leukemia require no specific therapy.
- Indications for treatment include progressive fatigue, symptomatic lymphadenopathy, or anemia or thrombocytopenia
- These patients have either symptomatic and progressive stage II disease or stage III/IV disease.
- Fludarabine has now replaced chlorambucil as front-line therapy.
- Fludarabine requires intravenous infusion 5 days a week once a month for 4-6 months and causes immunosuppression that is often long-lasting.
- Combination therapy with fludarabine plus either rituximab or cyclophosphamide (or both) produces better rates of response and complete response.
- Associated autoimmune hemolytic anemia or immune thrombocytopenia may require treatment with prednisone or splenectomy
- Allogeneic transplantation offers potentially curative treatment for patients with CLL, but it should be used only in patients whose disease cannot be controlled by standard therapies.