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Leukemia is a cancer of the blood or bone marrow characterized by an abnormal proliferation of blood cells, usually white blood cells (leukocytes).
Cancer of the white blood cells Acute or Chronic Affects ability to produce normal blood cells Bone marrow makes abnormally large number of immature white blood cells called blasts
AML 31%
Craigie and Bennett described a case of suppuration of the blood in 1845. Subsequently referred to the disease as
leukocythemia
Rudolph Virchow, also in 1845, described a similar case, but did not think this simply pus in the blood and related it to simultaneous splenic enlargement. Subsequently referred to the disease as Weisses Blut then suggested the term
leukemia
IN
CTR
2004
thick as gruel
leukemia Greek words "leukos" meaning "white" and "haima" meaning "blood,
N Engl J Med 2003; 349:767, Aug 21, 2003. Images in Clinical Medicine
It is more commonly known as AML It is a cancer of the blood that affects the cells producing myeloid blood cells First recognized in 1830 in Germany Physician referred to it as weisses blut The term leukemia stems from the Greek words leukos and haima
~15,000 new cases of acute leukemia per year in the US 11,920 AML 3,700 ALL ~70% of new cases of acute leukemia are AML Most cases occur in adults
Children
The term Myelogenous denotes what type of cell is being affected: Monocytes and Neutrophils Acute refers to rapid progression forming immature cells
Results from acquired genetic damage to the DNA of the bone marrow Immature cells produced are known as blast cells
Myeloi d origin
Acute
Acute Myeloid Leukemia (AML)
Chronic
Chronic Myeloid Leukemia (CML)
Lymphoid origin
Leukemia
Myeloid
Lymphoid
Chronic (CML)
Chronic (CLL)
This microscope image shows AML cells (acute myeloblastic leukemia; also referred to as ANLL, acute nonlymphocytic leukemia). Certain internal cell structures are typical of AML. These include prominent nucleoli (red arrows) and cytoplasmic granules (grainy structures inside the cell which indicate some degree of cell maturation--black arrow).
Platelet Blasts
Arginine.umdnj.edu
Stage 1- Normal
Stage 2- Symptoms
Stage 3- Diagnosis
Features
Cytoplasm Cyt. Granules Nucleus (chromatin)
Myeloblasts
Mod/abundant Common fine
Lymphoblasts
Scant/Mod Uncommon Coarse
Prominent Present
Variable Absent
ALL
nave B-lymphocytes Lymphoid progenitor Plasma cells T-lymphocytes
AML
Hematopoietic stem cell Myeloid progenitor Neutrophils Eosinophils Basophils Monocytes Platelets
Red cells
AML
French-American-British (FAB) Classification M0: Minimally differentiated leukemia M1: Myeloblastic leukemia without maturation M2: Myeloblastic leukemia with maturation M3: Hypergranular promyelocytic leukemia M4Eo: Variant: Increase in abnormal marrow eosinophils M4: Myelomonocytic leukemia M5: Monocytic leukemia M6: Erythroleukemia (DiGuglielmo's disease) M7: Megakaryoblastic leukemia
Ref-Harrisons Principle of Internal Medicine
AML with multilineage dysplasia (more than one abnormal myeloid cell type is involved) AML related to previous chemotherapy or radiation AML not otherwise specified
undifferentiated AML (M0) AML with minimal maturation (M1) AML with maturation (M2) acute myelomonocytic leukemia (M4) acute monocytic leukemia (M5) acute erythroid leukemia (M6) acute megakaryoblastic leukemia (M7) acute basophilic leukemia acute panmyelosis with fibrosis myeloid sarcoma (also known as granulocytic sarcoma or chloroma)
t(8;21), t(16), inv(16), chromosome 11 changes t(15;17) as usually seen with AML M3
Undifferentiated or biphenotypic acute leukemias (leukemias that have both lymphocytic and myeloid features. Sometimes called ALL with myeloid markers, AML with lymphoid markers, or mixed lineage leukemias.)
Cytogenetic changes can determine prognosis (chance of recovery), influence the choice of treatment, and help predict the results of treatment Favorable: presence of changes associated with a good outcome after treatment Intermediate: presence of changes associated with a less favorable prognosis
idiopathic (most) underlying hematologic disorders chemicals, drugs ionizing radiation viruses (HTLV I) hereditary/genetic conditions
Down syndrome
Ataxia telangiectasia
Li-Fraumeni syndrome
Klinefelters syndrome
Fanconis anemia Wiskott-Aldrich syndrome Blooms syndrome
enlargement of liver, spleen, lymph nodes gum hypertrophy bone pain other organs: CNS, skin, testis, any organ
Seen in over 60% of newly diagnosed AML patients Commonly choroid and retina (hemorrhage, cotton wool spots) Can also involve conjunctiva and lacrimal glands Treatment with common induction chemotherapeutic agents and with platelet transfusions as needed
Fatigue Weakness Easy bruising or bleeding Weight loss Fever Bone or abdominal pain Difficulty breathing; dyspnea (shortness of breath) Frequent infections Swollen lymph nodes Swollen or bleeding gums
A B
C
NEJM 1998
Mani, A, Lee, DA. Leukemic Gingival Infiltration. N Engl J Med 2008; 358(3): 274. Copyright 2008 Massachusetts Medical Society
accumulation of blasts in microcirculation with impaired perfusion lungs: hypoxemia, pulmonary infiltrates CNS: stroke only seen with WBC >> 50 x 109/L
Leukostasis predominantly in those with WBC counts > 100,000 (10% of patients); can also be seen in patients with WBC > 50,000
Most common in those with M4 or M5 leukemia Function of the blast cells being less deformable than mature myeloid cells. As a result, intravascular plugs develop. High metabolic activity of blast cells and local production of various cytokines contribute to underlying hypoxia
Thornton, KA, Levis, M. FLT3 Mutation and Acute Myelogenous Leukemia with Leukostasis. N Engl J Med 2007; 357:1639. Copyright 2007 Massachusetts Medical Society
Common symptoms
Pulmonary: dyspnea, chest pain CNS: headaches, altered mentation, CN palsies, ocular symptoms Priapism Myocardial Infarction
Treatment
Chemotherapy with induction agents (e.g cytarabine, anthracycline) or with high dose hydroxyurea Consider low dose cranial irradiation to prevent cell proliferation in the CNS (can see intracranial hemorrhage in patients with leukostasis) Avoid PRBC transfusion if possible as additional blood elements contribute to the hyperviscosity In patients that are unable to undergo immediate chemotx (e.g renal insufficiency, metabolic derangements, etc), leukapheresis is a 2nd option
Leukapheresis
Limited affect on established vascular plugs Limited benefit in those with underlying pulmonary symptoms following chemotx. Symptoms in this case related to leukocyte lysis and subsequent inflammatory response Should not be used as a single modality agent in patients with leukostasis (unless chemotx is delayed) May consider as adjunct to chemotx in patients with WBC >100,000 and symptoms suggestive of leukostasis
WBC usually elevated, but can be normal or low blasts in peripheral blood normocytic anemia thrombocytopenia neutropenia DIC
necessary for diagnosis useful for determining type useful for prognosis Acute leukemias are defined by the presence of > 20% blasts in bone marrow (% of nucleated marrow cells)
AML
M3 hypergranular promyelocytic
Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.
Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.
Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.
From Brunning, RD, McKenna, RW. Tumors of the bone marrow. Atlas of tumor pathology (electronic fascicle), Third series, fascicle 9, 1994, Washington, DC. Armed Forces Institute of Pathology.
M6 erythroleukemia
Note monoblasts:
MPO (right) & Sudan black (left) showing intense localised positivity in blasts
Choice of Rx is influenced by: type (AML vs ALL) age curative vs palliative intent
Favorable
Unfavorable
younger age (<50) WBC <30,000 t(8;21) seen in >50% with AML M2 inv(16) seen in AML M4 eos t(15;17) seen in >80% AML M3 older age (>60) Poor performance status WBC >100,000 Elevated LDH prior MDS or hematogic malignancy CD34 positive phenotype, MRD1 postive phenotype del (5), del (7) trisomy 8 t(6;9), t(9;22) t(9;11) seen in AML M5 FLT3 gene mutation (seen in 30% of patients)
Treatment depends on subtype, morphology, cytogenetics, and the patients overall health Chemotherapy (options include a combination of drugs) Radiation therapy Bone marrow transplantation/stem cell transplantation More than one treatment may be used
Drugs used to kill cancer cells Primary treatment for AML Systemic chemotherapy is given directly into the bloodstream, or by mouth, targeting cancer cells throughout the body Chemotherapy may also be injected into the cerebrospinal fluid
Divided into three phases: remission induction, postremission consolidation, and maintenance (not commonly used in AML) Side effects may include hair loss, mouth sores, fatigue, infection, bleeding, nausea, vomiting, and infertility
Initial period of treatment after diagnosis Intensive therapy kills both leukemia cells and healthy cells
Combination therapy of cytarabine (Cytosar-U) and daunorubicin (Daunomycin, Cerubidine) or idarubicin (Idamycin) is common
Goal is complete remission (normal blood counts, no evidence of leukemia in bone marrow, and no AML symptoms)
Used to kill remaining AML cells after successful induction Two to four courses of high-dose cytarabine is used for younger adults in remission Many different regimens are used for older patients
High-dose chemotherapy used to kill cancer cells New stem cells are introduced from the patient (autologous) or a donor (allogeneic) to form new blood cells May be used for patients at high risk for recurrence Graft-versus-host disease: a serious complication in which the donors immune cells attack the patients healthy cells
The use of high-energy x-rays or other particles to destroy cancer cells External beam: outside the body Used most often for AML that has spread to the brain or to shrink localized masses called chloromas
Side effects may include fatigue, mild skin reactions, nausea and vomiting, and diarrhea
Inhibition of the products of genetic mutations found in AML cells Inhibition of proteins that cause chemotherapy resistance
Techniques to make stem cell transplantation safer, easier, and more effective
Evaluation of drugs called hypomethylating therapy
combination chemotherapy
first goal is complete remission further Rx to prevent relapse
psychosocial support
patient and family
post-remission therapy
permits rescue from otherwise excessively toxic treatment additional advantage of graft-vs-leukemia effect in allogeneic transplants trade-off for allogeneic transplantation: greater anti-leukemic effect but more toxic
Acute Lymphoblastic Leukemia is the most common malignancy of childhood, accounting for 1/3 of all childhood cancers. Approximately 2400 cases diagnosed in the United States each year. Incidence 4 per 100,000 children under age 15.
The annual incidence in India would be approximately 10.000 children per year.
The peak incidence is approximately 4 years of age. More common in boys and in white children. The exact cause is known and it could be combination of genetic and environmental factors.
Most common childhood acute leukemia, ~80% Incidence in adults ~20% Bimodal distribution of occurrence:
Peak at age 2-5 Second increased incidence after age 50
? Infections
Immunologic Subtype
% of cases
FAB Subtype
Cytogenetic Abnormalities
Pre-B ALL
75
L1, L2
T cell ALL
20
L1, L2
14q11 or 7q34
B cell ALL
L3
From: Harrisons Principles of Internal Medicine, 16th ed. 2005. Chapter 97, Malignancies of
Nonspecific Symptoms
Physical Exam
Pallor Ecchymoses Petechiae LAD Hepatosplenomegaly
Lab Abnormalities
anemia wbc vary
0.1 (20-40%) - >100 k (10-16%) Platelets usually LD, uric acid CXR: eval for thymic mass CSF to eval for involvement
ITP Aplastic Anemia Infectious mononucleosis Rheumatoid Arthritis Rheumatic Fever Collagen Vascular Disease
Morphologic
French American British Classification
L1: small uniform blasts (pediatric ALL) L2: larger, more variable sized blasts (adult ALL) L3: uniform cells with basophilic and sometimes vacuolated cytoplasm (mature B cell ALL)
They may be classified on the basis of the cytological features of the lymphoblasts into;
L1 - This is the most common form found in children and it has the best prognosis. The cell size is small with fine or clumped homogenous nuclear chromatin and absent or indistinct nucleoli. The nuclear shape is regular, occasionally clefting or indented. The cytoplasm is scant, with slight to moderate basophilia and variable vacuoles. L2 This is the most frequent ALL found in adults. The cell size is large and heterogenous with variable nuclear chromatin and prominent nucleoli. The nucleus is irregular, clefting and indented. The cytoplasm is variable and often moderate to abundant, the basophilia is variable and may be deep, and vacuoles are variable.
L3 This is the rarest form of ALL. The cell size is large, with fine, homogenous nuclear chromatin containing prominent nucleoli. The The nucleus is regular oval to round. The cytoplasm is moderately abundant and is deeply basophilic and vacuolated.
Incidence ALL is primarily a disease of young children (2-5 years), but it can also occur in adults Clinical findings pancytopenia with resulting fatigue, pallor, fever, weight loss, irritability, anorexia, infection, bleeding, and bone pain. L1 occurs in children, L2 in adults, and L3 is called Burkitts leukemia
Prognosis age, WBC count, and cell type are the most important prognostic indicators
Patients younger then 1 and greater than 13 have a poor prognosis If the WBC count is < 10 x 109/L at presentation, the prognosis is good; If the WBC count is > 20 x 109/L at presentation the prognosis is poor T cell ALL (more common in males) has a poorer prognosis than any of the B cell ALLs which have a cure rate of 70%
Acute Lymphoblastic Leukemia - L1 Morphology: L1 blasts are small and homogeneous. The nuclei are round and regular with little clefting and inconspicuous nucleoli. Cytoplasm is scanty and usually without vacuoles. Staining: MPO is always negative. When is a biopsy necessary ? possible severe aplastic anemia to investigate bone marrow involvement of lymphoma, solid tumor dry tap -> touch prep from biopsy core possible myelofibrosis (e.g. leukemia in Down)
ALL(Lymphoblast)
Blast size :small Cytoplasm: Scant Chromatin: Dense Nucleoli :Indistinct Auer-rods: Never present
AML (Myeloblast)
Large Moderate Fine, Lacy Prominent Present in 50%
trephine biopsy confirm acute leukaemia (blast > 30%) usually hypercellular
1 2 3 4 5
Remission Induction Intensification (Consolidation) Therapy Maintenance Therapy CNS Prophylaxis Allogeneic Stem Cell Transplant
Treatment of tumor lysis (hydration, bicarbonate, allopurinol/recombinant urate oxidase) Appropriate Treatment of febrile neutropenia
ALL
T-lineage
T cell: 4-drug
stand.
high
T cell protocol
dexamethasone vincristine L-asparaginase (PEG) intrathecal chemotherapy (Ara-C day 1, MTX day 8 and, 29)
BM aspirate: day 1, 8 (if not M1 also d15) and 29 (MRD) Lumbar puncture: day 1, 8, 29 Portacath
dexamethasone (14 days, 10mg/m2) or prednisone (60mg/m2/d) vincristine L-asparaginase (PEG) daunorubicin intrathecal chemotherapy (Ara-C day 1, MTX day 8 and, 29)
BM aspirate: day 1, 8 (if not M1 also d15) and 29 (MRD) Lumbar puncture: day 1, 8, 29 Portacath
One of the key drugs in childhood ALL and acts by depletion of asparagine which is essential for survival of malignant lymphoblasts. 3 preparations E Coli asparaginase Erwinia asparaginase 15d PEG asparaginase half life Asparagine 1.280.35d 14-23d 0.650.13d 75.733.24d 26-34d
CNS Status CSF cell count and cytospin < 5 WBC, no blasts < 5 WBC, blasts > 5 WBC, blasts CNS 1 CNS-2 CNS-3
Definitions
M1 M2 M3
Bone marrow on day 7 rapid early response (RER) slow early response (SER) Peripheral blast count after 1 week of prednisone(1x10 9/lt)
prednisone good response prednisone poor response
82%
34%
6-year EFS
MRD
<0.1%
COG
RER M1 on day 8 AND negative MRD on d29 M2, M3 on day 8 but M1 on day 15 AND negative MRD on d29 SER M2 or M3 on d15 OR positive MRD on d29
Low risk
The testis and CNS are the sanctuary sites. The incidence of CNS Relapse was 10-20% in 1980s. Cranial RT with 18-24c Gy reduced the risk to 1%. Concern about the long term side effect of cranial RT with secondary brain tumours always remains.
High dose methotrexate with IT Methotrexate was found to be equally effective in preventing CNS Relapse.
Main drugs (oral methotrexate and 6 mercaptopurine) Duration of therapy( from Interim Maintenance) boys 3 years girls 2 years Target ANC (between 750-1500) Administration of 6 Mercaptopurine in empty stomach in evening. Addition of Vincristine and dexamethasone pulses every month Intrathecal methotrexate every 3 month Compliance is the key to success
These are the group of patients who would require intensification of therapy and would require stem cell transplantation.
equal distribution of lymphoid and myeloid leukemia 4% of pediatric ALL (45% diagnosed during first 6 m)
identical clone specific mutations are present in monozygotic twins Typical infant ALL-high white cell count, usually CD10 negative pre B ALL and MLL gene rearrangement involving 11q chromosome in 2/3 rd patients
Outcome -35-45% Presentation earlier than 6 month of age ,CD10 negativity, presence of MLL gene are associated with bad prognosis.
Constitute 10-20% of childhood ALL Associated with adverse prognostic features High white cell count T cell immunophenotype Low leukemic cell DNA index Lower frequency of favourable cytogenetic features like TEL:AML and hyperdiploidy Higher frequency of unfavourable cytogenetic feature like philadelphia chromosome Treatment with pediatric protocols have been proved to have better outcome compared to adult protocols (65-75% vs 35-45%) (Di Angelio ASH Education 2005)
Constitute 25% of childhood cancers Prognostic factors of ALL relapse time point after diagnosis of primary ALL site immunophenotype treatment intensity (interval between early treatment elements)
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