1. THE ACUTE LEUKEMIAS
S. Sami Kartı, MD, Prof.

2. Definition
Normal hematopoiesis requires tightly regulated proliferation and differentiation of pluripotent hematopoietic stem cells that become mature peripheral blood cells.
Acute leukemia is the result of a malignant event or events occurring in an early hematopoietic precursors.
Instead of proliferating and differentiating normally, the affected cell gives rise to progeny that fail to differentiate and instead continue to proliferate in an uncontrolled fashion.

3. Pictures Of Blood Blood with leukemia Normal human blood White Cell
Red Cell
Platelet
Blood with leukemia
Blasts
Red Cell
Platelet
White Cell
Sources from beyond2000.com
Sources from Arginine.umdnj.edu

4. Development of Leukemia in the Bloodstream
Stage 1- Normal
Stage 2- Symptoms
Stage 3- Diagnosis
Stage 4- Worsening
Sources from Leukemia, by D. Newton and D. Siegel

5. As a result, immature myeloid cells (in acute myelogenous leukemia-AML) or lymphoid cells (in acute lymphocytic leukemia-ALL), aften called blasts, rapidly accumulate and progressively replace the bone marrow;
diminished production of normal red cells, white cells, and platelets ensues.
This loss of normal marrow function in turn gives rise to the common clinical complications of leukemia
Anemia
Infection
Bleeding.

6. With time, the leukemic blasts pour out into the blood stream and eventually occupy the lymph nodes, spleen, and other vital organs.
If untreated, acute leukemia is rapidly fatal; most patients die within several months of diagnosis.
However, with appropriate therapy, the natural history of acute leukemia can be markedly altered, and many patients can be cured.

7. Etiology
In most cases acute leukemia develops for no known reason, but sometimes a possible cause can be identified.

8. Radiation Ionizing radiation is leukomogenic.
ALL, AML, and chronic myelogenous leukemia (CML) are all increased in incidence in patients given radiation therapy for ankylosing spondylitis and in survivors of the atomic bomb blasts at Hiroshima and Nagasaki.

9. Oncogenic viruses
Human T-cell lymphotropic virus type I (HTLV-I), an enveloped, single-stranded RNA virus, is considered the causative agent of adult T-cell leukemia.
This distinct form of leukemia is found within geographic clusters in southwestern Japan, the Carribbean basin, and Africa.
The virus can be spread vertically from mother to fetus or horizontally by sexual contact or through blood products.
HTLV-I seropositivity is rare in Turkey.

10. Genetic and congenital factors
If leukemia develops before 10 years of age in a patient with an identical twin, the unaffected twin has one in five risk of leukemia subsequently developing.
In occasional families, an identical form of leukemia has developed in multiple members.
Several autosomal recessive disorders associated with chromosomal instability are prone to terminate in acute leukemia
Bloom syndrome
Fanconi’s anemia
Ataxia-telangectasia.
Other congenital disorders associated with an increased incidence of leukemia are Down syndrome and infantile X-linked agmmaglobulinemia.

11. Chemicals and drugs
Heavy occupational exposure to benzene and benzene-containing compounds such as kerosene and carbon tetrachloride may lead to marrow damage, which can take the form of aplastic anemia, myelodysplasia, or AML.
Prior exposure to alkylating agents such as melphalan and the nitrosoureas is associated with an increased risk of AML.

12. Chemicals and drugs
These so called secondary leukemias are often manifested as a myelodysplastic syndrome, frequently have abnormalities of chromosomes 5, 7, and 8, but have no distinct morphologic features;
they typically develop 4-6 years after alkylating agent exposure, and their incidence may be increased with greater intensity and duration of drug exposure.
Prolonged exposure to eppodophyllotoxins (etoposide) has also been identified as a risk factor for the development of AML.

13. Incidence
The annual new case incidence af all leukemias is 8 to10 per 100,000.
The relative incidences for the four categories of leukemia are as follows:
ALL, 11%;
CLL, 29%;
AML, 46%,
CML, 14%.

14. Incidence
The leukemias account for about 3% of all cancers in the USA.
ALL is the most common cancer and the second leading cause of death in childeren younger than 15 years.
ALL has a maximal incidence between 2-10 years of age, with a second, more gradual rise in frequency later in life.
The incidence of AML gradually increases with age, without an early peak.

15. Pathophysiology
The precise molecular events that cause leukemic transformation are unknown; the end result, however, is relentless proliferation of immature hematopoietic cells that have lost their capacity to differentiate normally.
The development of leukemia may be a multistep process, as demonstrated by the fact that in many cases acute leukemia develops in patients with a pre-existing myelodysplastic disorder.
The disease is monoclonal, i.e., the final leukemic event occurs in a single cell.

16. Pathophysiology
The level of differentiation at which malignancy becomes evident is variable.
In some cases of AML it appears that malignancy occurs in a very undifferentiated cell
In other cases of AML, the malignant event may occur in a more differentiated cell
In almost all cases of ALL; the myeloid lineage is not malignant, which suggest that in ALL the malignant event occurs in a cell that is at least partially differentiated.

17. Pathophysiology
As the malignant clone expands, it does so at the expense of normal hematopoesis.
The mechanism of normal marrow suppression in leukemia is complex: in many patients with hyper cellular marrow, the pancytopenia is probaly the result, at least in part, of physical replacement of normal marrow precursors by leukemic cells.
In some patients with acute leukemia, however, a pancytopenia with hypocellular marrow develops, thus suggesting that marrow failure is not simply due to physical replacement of the marrow space but may also be due to substances relased by the malignant cells.

18. Morphology
Leukemic cells in AML are typically with discreate nuclear chromatin, multiple nucleoli, and cytoplasm that usually contain azurophilic granules.
Auer rods, which are slender, fusiform, cytoplasmic inclusions that stain red with Wright-Giemsa stain, are virtually pathognomonic of AML.
The French-American-British (FAB) collaborative group has subdivided AML into eight subtypes based on morphology and histochemistry:M0, M1,M2, amd M3 reflect increasing degrees of differentiation of myeloid leukemic cells; M4 and M5 leukemias have features of monocytic lineage; M6 has features of erythroid cell lineage; and M7 is acute megacaryocytic leukemia.

28. Morphology
The leukemic cells in ALL tend to be smaller than AML blasts and relatively devoid of granules.
ALL can be divided by FAB criteria, into L1, L2, and L3 subgroups.
L1 blasts are uniform in size, with homogenous nuclear chromatin, indistinct nukleoli, and scanty cytoplasm with few, if any granules.
L2 blasts are larger and more variable in size and may have nucleoli.
L3 blasts are quite distinct, with prominent nucleoli and deeply basophilic cytoplasm with vacuoles.

29. Cell surface markers
Monoclonal antibodies reactive with cell surface antigens have been used to classify acute leukemias.
Antibodies that react with antigens found on normal immature myeloid cells, including CD13, CD14, CD33, and CD34, also react with blast cells from most patients with AML.
Exceptions are M6 and M7 subgroups, which have antigens restricted to the red cell and platelet lineage, respectively.
Myeloid leukemia blasts also express HLA-DR antigens but usually lack T-cell, B-cell, and other lymphoid antigens.
In 10 to 20% of patients, however, AML blasts, beside myeloid markers, will also express antigens usually restricted to B- or T-cell lineage.

30. Cell surface markers
ALL can be divided into several forms based on cell surface antigen expression.
Approximately 60% of cases of ALL express the common ALL antigen (CALLA) on the cell surface.
CALLA (CD10) is a glycoprotein also found on occasional normal early lymphocytes and other non-hematopoietic tissues.
Cases of CALLA-positive ALL are thought to represent an early pre-B-cell differentiation state.

31. Cell surface markers
About 20% of cases of CALLA-positive ALL have intracytoplasmic immunoglobulin and are termed pre-B-cell ALL.
B-cell ALL is signified by the presence of immunoglobulin on the cell surface and accounts for fewer than 5% of cases of ALL.
About 20% of ALL are of the T-cell phenotype and express antigens found on normal early T cells such as CD5, CD3, or CD2.
Aproximately 15% of cases of ALL fail to express CALLA, B-, or T-cell markers and are termed null cell ALL.
In about 25% of patients with ALL, the leukemic cells also express myeloid antigens. This group has a worse prognosis.

32. Cytogenetic abnormalities
More than a third of AML show some cytogenetic abnormality.
There is a great deal of diversity, however, in the types of abnormalities observed, and as yet, there are only a few correlations between cytogenetic markers and either prognosis and response to therapy.

33. Cytogenetic abnormalities
A common abnormality in AML, present in about 10% of cases, and associated with a relatively poor prognosis, is trisomy of chromosome 8.
The t(8;21) translocation or inv(16), seen in 40% of AML M2 is associated with a somewhat better prognosis.
Prognostically adverse cytogenetic findings include -5/del(5q), -7, abnormal 3q, and complex karyotype.

34. Cytogenetic abnormalities
An important example is translocation between chromosome 15 and 17 [t(15;17)] that can be detected in most cases of acute promyelocytic leukemia (AML M3).
It involves two genes, one on chromosome 15 known as PML and the other on chromosome 17 that is a receptor for retinoic acid, a cofactor known to induce differentiation in many cell types.
The translocation, known as PML-RAR functions as an oncogene by inhibiting cell differentiation and causing an arrest in development at the promyelocytic stage.
From a therapeutic standpoint, the function of PML-RAR oncogene can be inhibited by all-trans retinoic acid (ATRA).
This has been applied with great effectiveness in the treatment of promyelocytic leukemia.

35. Cytogenetic abnormalities
The most common cytogenetic abnormality seen in the adults with ALL is the Piladelphia (Ph) chromosome [t(9;22)], a translocation that results in fusion of the bcr gene on chromosome 22 to the abl thyrosine kinase gene on chromosome 9.
This translocation appears to result in constitutive activation of abl.
The bcr-abl fusion is associated with both ALL and CML, with a minor difference in the breakpoint of bcr distinguishing the two.
A slightly smaller 190-kd protein is generally found in ALL, whereas a larger 210-kd protein is characteristic of CML.
The t(9;22) abnormality is seen in 20% of adult and 5% of childhood cases and is associated with a poor prognosis.

36. Cytogenetic abnormalities
The t(8;14) translocation is highly correlated with B-cell ALL of the L3 morphology.
These, then, are all good examples of the growing importance of gene-expression profiling in leukemia diagnosis and management.
It is also anticipated that this new technology will open the door to a better understanding of the origin of the leukemic cell, and better therapeutic modalities.

37. Clinical Manifestations
The signs and symptoms of acute leukemia result from decreased normal marrow function and invasion of bone marrow and other organs by leukemic blasts.
Anemia is present at diagnosis in most patients and causes fatigue, pallor, and in predisposed patients angina or heart failure.
Thrombocytopenia is usually present, and aproximately one third of the patients have clinically evident bleeding at diagnosis, usually in the form of petechiae, ecchymoses, bleeding gums, epistaxis, or hypermenorrhea.
Most patients with acute leukemia are significantly granulocytopenic at diagnosis. As a result, one third of patients with AML and ALL have significant or life-threatening infections when initially seen, most of which are bacterial origin.

38. Clinical Manifestations
In addition to suppressing normal marrow function, leukemic cells can infiltrate normal organs.
In general, ALL tends to infiltrate normal organs more often than AML does.
Enlargement of lymph nodes, liver, and spleen is common at diagnosis.

39. Clinical Manifestations
Bone pain, thought to result from leukemic infiltration of the periosteum or expansion of the medullary cavity, is a common complaint, particularly in children with ALL, in many of whom were misdiagnosed as juvenile rheumatoid arthritis.
Leukemic cells sometimes infiltrate skin and result in a raised, non-pruritic rash, a condition termed ‘‘leukemia cutis’’.

40. Clinical Manifestations
Leukemic cell may infiltrate the leptomeninges and cause leukemic meningitis which causes headache and nausea.
As the disease progresses, central nervous system (CNS) palsies and seizures may develop.
Although fewer than 5% of patients have CNS involvement at diagnosis, the CNS is a frequent site of relapse, particularly in ALL; because of the so-called blood-brain barrier, the CNS requires special therapy.

41. Clinical Manifestations
Testicular involvement is also seen in ALL and the testicles are a frequent site of relapse.
In AML, collections of leukemic blast cells, often referred to as granulocytic sarcomas, can occur in virtually any soft tissue and appear as rubbery, fast-growing masses.

42. Clinical Manifestations
Certain clinical manifestations are unique to spesific subtypes of leukemia.
Patients with APL (AML-M3) commonly have subclinical or clinically evident disseminated intravascular coagulation (DIC) caused by tissue thromboplastins that are present in the leukemic cells and released as these cells die.
Acute monocytic or myelomonocytic leukemias are the forms of AML most likely to have extramedullary involvement.
M6 leukemia often has a long prodromal phase.
Patients with T-cell ALL frequently have mediastinal masses.

43. Laboratory
Abnormalities in peripheral blood counts are usually the initial laboratory evidence of acute leukemia.
Anemia and thrombocytopenia is present in most of the patients.
One quarter of the patients are severely thrombocytopenic (platelets, <20,000/µL).

44. Laboratory
Although most patients are granulocytopenic at diagnosis, the total peripheral white cell count is more variable; approximately 25% of patients have very high white cell counts(>50,000/µL), approximately 50% have white cell counts between 5000 and 50,000 and about 25% have a low white cell count (<5000/µL).
In most cases, blasts are present in the peripheral blood, although in some patients the percentage of blasts may be quite low or blasts may be absent.

45. Laboratory
The diagnosis of acute leukemia is generally established by marrow aspiration and biyopsy, usually from posterior iliac crest.
Marrow aspirates and biyopsy specimen are generally hypercellular and contain 20 to 100% blast cells, which largely replace the normal marrow.
Occasionally, in addition to the blast infiltrate, other findings are present, including marrow fibrosis (especially with M7 AML) or bone marrow necrosis.

46. Laboratory
The thrombin and partial thromboplastin times are sometimes elevated.
In APL, reduced fibrinogen and evidence of DIC are also often seen.
Other laboratory abnormalities frequently present are hyperuricemia and increased lactate dehydrogenase (LDH).

47. Differential Diagnosis
The diagnosis of acute leukemia is usually straightforward but can occasionally be more difficult.
Both leukemia and aplastic anemia can be manifested by peripheral pancytopenia, but the finding of hypoplastic marrow without blasts distinguishes aplastic anemia.
A number of processes other than leukemia can lead to appearence of immature cells in the peripheral blood.
Although other small round cell neoplasms can infiltrate the marrow and sometimes mimic leukemia, immunologic markers are effective in differentiating the two.

48. Differential Diagnosis
Leukemoid reactions to infections such as tuberculosis can result in the outpouring of large numbers of young myeloid cells, but virtually never does the proportion of blasts in marrow or perpheral blood reach 20% in a leukemoid reaction.
Infectious nucleosis and other viral illnesses can sometimes resemble ALL, particularly when large numbers of atypical lymphocytes are present in the peripheral blood and when the disease is accompanied by immune thrombocytopenia or hemolytic anemia.

49. Treatment Therapy for AML should begin promptly after the diagnosis.
Because the disease is rapidly progressive, any delay can decrease the chance of therapeutic success.
In elderly patients, the possibility of a sustained remission is less and in the case of extreme age or debility, only symptomatic and supportive therapy may be indicated.

50. Treatment Other adverse prognostic factors, besides age include;
AML resulting from prior chemotherapy or myelodysplasia,
an initial blast count in excess of 20,000/µL,
an elevated LDH, and
a poor initial performance status.

51. Treatment
Patients who fall in a favorable prognostic group, with a better than 85% chance of remission and low relapse rate, are younger and have either a t(15;17), t(8;21), or inv(16) mutation.
Unfavorable cases have mutations involving more than two chromosomes, a deletion or abnormality of the long arm of chromosome 3 or 5, a t11q23 translocation, or monosomies of chromosome 5 or 7.
Regardless of age, these patients have a survival rate of less than 20% at 5 years.

52. Treatment
Predictable complications such as anemia, thrombocytopenia, a coagulopathy, or infection should never delay therapy since they are unlikely to improve until a remission is obtained.
They should be treated with appropriate transfusions and antibiotics at the same time the chemotherapy begun.
The goal of therapy is to ablate the leukemic cell line and allow normal progenitor cells to repopulate the marrow.

53. Treatment
This process will require a period of marrow aplasia and marked granulocytopenia that can extend 2-4 weeks or even longer.
Because of this, leukemia therapy must be carried out in a hospital setting, preferably in a dedicated cancer nursing unit.

54. Treatment
Remission induction and consolidation regimens include anthracycline (daunomycine or idarubicine) and cytarabine.

55. Treatment in APL APL differ in therapy from other subgroups of AML.
Complete remission can be induced in at least 90% of patients with APL by using all-trans-retinoic acid (ATRA).
ATRA works by inducing differentiation of leukemic cells.
A unique toxicity of ATRA in the treatment of APL is development of hyperleukocytosis accompanied by respiratory distress and pulmonary infiltrates (ATRA syndrome).
The syndrome responds to temporary discontinuation of ATRA and the administration of corticosteroids.

56. Treatment
Soon after diagnosis, ALL must be treated with an intensive multidrug regimen that has a high probability of inducing remission.
The drugs commonly used to treat ALL are vincristine, prednisolone, asparaginase, daunorubicine, methotrexate, 6-mercaptopurine, cyclophosphamide, and cytarabine.

57. Treatment
ALL patients should be given CNS prophylaxis with intrathecal chemotherapy (methotrexate) and irradiation.
ALL patients should also must undergo a maintenance chemotherapy usually consists of 6-mercaptopurine, vincristine, methotrexate, and prednisolone.

58. General Guidelines
Reliable vascular access is essential and usually requires placement of an in-dwelling catheter (e.g., Hickman-Broviac catheter, Grosshong catheter).
The patient should be hydrated and receive allopurinol mg/day by mouth to prevent hyperuricemia as tumor cells are lysed.
In those patients who are at increased risk for DIC, a full coagulation profile should be measured daily for the first several days of chemotherapy.
Hypofibrinogenemia (fibrinogen less than 100mg/dL) should be corrected by infusion of cryoprecipitate, whereas marked prolongations of the PT and PTT may be corrected with fresh frozen plasma.

59. General Guidelines
In the absence of cardiovascular disease the hematocrit should remain in the vicinity of 25-30% to decrease the frequency of red blood cell transfusions.
Platelet transfusions should only be given when the platelet count falls below 10,000/µL.
In febrile patient platelets should be administered below 20,000/µL.
The treatment of ongoing infection must be very aggressive, and potential sources of infection should be eliminated.
Good nursing care of the mouth, skin, and rectum is very important.

60. Bone Marrow Transplantation
For patients with acute leukemia in whom an initial remission can not achieved or for patients who have a relapse after chemotherapy, marrow transplantation from HLA-identical sibling offers the best chance for cure.
If there is no available HLA-identical sibling HLA-matched unrelated transplantation is indicated.