Hematologic Malignancies: Acute Leukemias

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Laboratory studies

This complication is diagnosed by CSF sampling by lumbar puncture, which is usually deferred until circulating blasts clear to avoid a traumatic tap leading to false diagnosis of CNS disease. The two most vulnerable vascular beds are the brain neurological manifestations including headache, confusion, somnolence, or eventually coma and the lungs where leukostatic syndrome can manifest as bilateral central infiltrates or be invisible on chest radiograph.

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This ratio is essentially reversed in children. Nevertheless, AML remains a rare disease with an incidence of cases per , adults per year. The primary risk factor for developing acute leukemia is age as demonstrated by the fact that the risk incidence rises to cases per , individuals in the seventh and eighth decades of life. Median age of diagnosis is Other major risk factors involve preceding myelodysplastic syndrome MDS and myeloproliferative disorders, all of which have a risk of conversion to AML.

Many rare genetic disorders leading to chromosomal instability trisomy 21, Blooms syndrome, Kleinfelter syndrome, Fanconi anemia also increase the risk of AML. The strongest associations are with other antineoplastic treatments including chemotherapy and radiation.

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Ten percent of cases of acute myelocytic leukemia are thought to develop from previous chemotherapy or radiation exposure. The most prominent specific agents that increase this risk are alkylating agents with leukemia typically developing years after exposure with preceding MDS and topoisomerase II inhibitors with leukemia typically developing years later without preceding MDS. Much weaker associations with environmental exposures including ionizing radiation and industrial solvents, particularly benzene, have been seen and slightly increase the risk of myeloid malignancies.

Differentiation of AML from ALL acute lymphoblastic leukemia is rarely clinically important for emergent stabilization but does have major implications for treatment.

Assessing Your Risk for Cancer

It can be a difficult task depending on the prematurity of the involved neoplastic cell and the presence of specific myeloid or lymphoid markers. Rare biphenotypic leukemias, which involve immature lymphoblasts and myeloblasts, also occur. Myelodysplastic syndromes may also reveal circulating blasts on a complete blood count CBC and differential as will myeloproliferative syndromes, including chronic myelogenous leukemia CML.

One major distinguishing feature between acute and chronic myeloid leukemia is the presence of the so-called leukemic hiatus in AML, where the neoplastic myeloblast will be present in the blood as well as a population of mature neutrophils with no or few intermediate forms. In CML, conversely, all intermediate forms are present as well as all subsets of mature myelocytes.

In young individuals, acute mononucleosis can raise concern for acute leukemia given the presence of pancytopenia and reactive lymphocytes, which may be difficult to distinguish from lymphoblasts or myeloblasts on initial gross examination.

Risk Factors

Aplastic anemia, which causes pancytopenia, will also remain on the differential for many patients who may not have circulating blasts until bone marrow examination is performed and reveals a neoplastic population of cells in the marrow as opposed to a very hypocellular marrow in the case of aplastic anemia. In general, AML is a systemic disease with few pathognomonic exam findings. However, the exam should focus on signs suggesting cytopenias or the complications of the disorder, particularly bleeding and infection. Gum hypertrophy may be seen, particularly with the monocytic variants of AML, due to myeloblast or monoblast infiltration into the gum tissue.

A full neurological exam should be performed in patients with a new diagnoses of AML to look for isolated cranial nerve neuropathies that may suggest CNS infiltration of disease. Lymph node exam should be performed but unlike in lymphomas or other hematologic malignancies, lymphadenopathy is not usually seen in AML. Altered mental status may suggest developing leukostasis, and ideally a fundoscopic exam should be performed to look for signs of retinal hemorrhages or congestion that could be harbingers of incipient leukostatic complications. Exam of the chest should focus on looking for signs of infection or infiltrate.

Crackles at one base suggest infection or pneumonia in the context of neutropenia whereas a more diffuse pattern of abnormalities may suggest leukostasis and pulmonary compromise. Still, many patients with leukostasis will have normal pulmonary exams. Unlike in other hematologic malignancies, lymphadenopathy and hepatosplenomegaly are uncommon with AML and when these occur they may suggest preceding myeloproliferative disorders. A tender and enlarged liver may suggest hepatic infiltration and is a poor prognostic sign.

Careful skin exam is important to look for lesions.

Hematologic cancers: Risk factors and epidemiology

Petechiae are extremely common in the context of thrombocytopenia, particularly at sites of trauma or on the anterior shins around hair follicles. Skin lesions of leukemia cutis tend to be non-specific and can range from papules, to nodules, to purpura. These are important to assess as biopsy may help with diagnosis.

As previously stated there are no pathognomonic signs of AML on physical exam.

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The signs discussed above can support a diagnosis of AML but are not individually diagnostic. Laboratory and pathologic evaluations as described below are typically key in coming to a final diagnosis. The most important laboratory study to be ordered is a CBC with differential and visual review of the peripheral smear.

This is why diagnostic evaluation for individuals with AML should always involve a bone marrow aspirate and core biopsy specimen, which will typically be obtained with hematologic consultation. Immunophenotyping by staining or flow cytometry will typically allow differentiation of blasts into myeloblasts or lymphoblasts and thus help distinguish AML from ALL. Cytogenetics is particularly important as certain cytogenetic abnormalities are considered diagnostic of AML even in the absence of the requisite number of myeloblasts.

Even in the absence of diagnostic ambiguity these tests are critical, however, in counseling patients on consolidation options for therapy. Aside from standard metaphase cytogenetics, FISH panel and PCR can be used to recognize several of the most common crucial mutations and turn- around times vary by institution. Translocation , which marks acute promyelocytic leukemia is of particular importance given the high rates of DIC associated with this diagnosis and associated mortality, which can be modified by treatment with all-trans retinoic acid ATRA.

Aside from the diagnostic leukocyte population, the full CBC may reveal other cytopenias, which are suggestive of leukemia and marrow replacement. Skin biopsy of lesions suggestive of leukemia cutis may reveal infiltrating blasts and are highly suggestive if not completely diagnostic of this entity.

Aside from cell count studies, full assessment of electrolytes including potassium, calcium and phosphorous as well as uric important acid is in order to assess renal function and for signs of TLS. Hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia in the context of acute kidney injury give concern for spontaneous TLS.

Coagulation parameters including prothrombin time PT , partial thromboplastin time PTT and international normalized ratio INR should similarly be assessed to evaluate for signs of DIC, which may be present at the time of diagnosis. Liver function tests LFTs should be assessed primarily, as liver function may have implications for chemotherapeutic agents available for treatment.

Acute Lymphoblastic Leukemia (ALL) - Down Syndrome - tDt positive

Most patients with AML should have a chest radiograph in order to assess for signs of pneumonia. Given the functional neutropenia even in the absence of low absolute neutrophil count ANC , the diagnostic possibilities for infiltrates are broad and include fungal or other atypical pathogens. Symmetric, bilateral infiltrates, particularly in individuals with very high white counts and hypoxia, should prompt concerns for leukostasis syndrome in the lungs. Echocardiogram should be obtained soon after diagnosis as for patients eligible for aggressive treatment; anthracyclines are a preferred agent and echocardiographic assessment is key to proceeding with these agents.

Prior to any chemotherapy or disease specific therapy, however, patients must undergo stabilization. In the context of hyperleukocytosis, cytoreduction may be pursued with hydroxyurea, but only under the supervision of a hematologist. Patients with severe leukocytosis and immediate neurologic or pulmonary compromise may need urgent cytoreduction with leukapheresis.

Aside from assessment of kidney and liver function, echocardiogram should be performed to assess ejection fraction, as this is necessary to treat with anthracycline crucial to the initiation of therapy in those eligible for aggressive management. Finally, most candidates for initial therapy should have central venous access obtained prior to chemotherapy and likely therapy induced neutropenia and thrombocytopenia. The preferred type of central access is somewhat institution dependent and should ideally be chosen in consultation with the primary hematologist who will manage the patient in the long term.

This is due to both more treatment resistant disease and poorer tolerance of aggressive therapy. Now there is broad if not uniform agreement that patients over age 65 with no comorbidities and generally good organ function may benefit from aggressive induction and that those previous mortality rates likely no longer hold true with better supportive care.

For patients of greater ages or with comorbidities there have been considerable efforts to develop new agents or use alternative agents. This management would fall to hematologist consultation. This typically includes empiric treatment with a broad-spectrum beta lactam with broad gram negative including anti-pseudomonal activity. Cefepime and ceftazidime are the most commonly used agents, though pipercillin-tazobactam or carbapenems are also reasonable with aztreonam typically used for patients with true, severe penicillin allergies.

Gram positive activity with vancomycin should be provided for individuals with signs of redness or inflammation around indwelling lines, severe mucositis, pulmonary infiltrates, or any risk factors for gram positive infection, and for individuals who remain neutropenic and fail to defervesce after hours of broad gram negative coverage. Finally, patients with new diagnoses of AML may present with fungal mold infections in the context of functional neutropenia.

Aspergillus infection is associated with the highest mortality and is of particular concern with individuals with atypical pulmonary infiltrates and may prompt empiric treatment with voriconazole, posaconazole, or echinocandins depending on formulary and protocol issues. Diagnostic work-up should not postpone therapy but should include blood and urine cultures as well as chest radiograph to look for sources of infection.

The use of growth factors to improve counts has been debated but is currently not recommended for individuals who will receive aggressive chemotherapy for their malignancy.

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The Infectious Diseases Society of America IDSA guidelines recommend narrowing therapy if a presumptive source is identified and that in stable patients without a clear source of infection who have no gram-positive organisms in culture at 48 hours, vancomycin can be discontinued. Combined treatment with panobinostat and decitabine may potentiate antileukemia activity against human AML cells by other mechanisms as well.

In K myeloid leukemia cells, co-treatment with panobinostat and decitabine caused greater diminution of DNMT1 and EZH2 levels than either agent alone. Molecular perturbations resulting from exposure to DACi lower the threshold for apoptosis by multiple mechanisms. Additional support for this basic concept stems from studies in solid tumors, demonstrating that co-treatment with DACi, e.

The potential value of combining DACi with topoisomerase II-inhibitors is based on preclinical studies suggesting a DACi-mediated stimulation of the enzyme in human leukemic cells [ 64 , 65 ]. The pan-DACi panobinostat was tested in combination with doxorubicin on AML cell lines and primary leukemia blasts and induced cell death by an increase in the mitochondrial outer membrane permeability and release of cytochrome c from the mitochondria, resulting in caspase-dependent apoptosis accompanied by upregulation of Bax, Bak and Bad.

Hematologic Malignancies: Acute Leukemias Hematologic Malignancies: Acute Leukemias
Hematologic Malignancies: Acute Leukemias Hematologic Malignancies: Acute Leukemias
Hematologic Malignancies: Acute Leukemias Hematologic Malignancies: Acute Leukemias
Hematologic Malignancies: Acute Leukemias Hematologic Malignancies: Acute Leukemias
Hematologic Malignancies: Acute Leukemias Hematologic Malignancies: Acute Leukemias
Hematologic Malignancies: Acute Leukemias Hematologic Malignancies: Acute Leukemias

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