Hospital Medicine

Acute myelocytic leukemia (acute myeloblastic leukemia, acute myeloid leukemia)

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I. What every physician needs to know.

Acute myelocytic leukemia (AML) is a disorder of uncontrolled proliferation of undifferentiated myeloid precursor cells. This leads to accumulation of immature myeloid cells, myeloblasts, in the bone marrow and usually their presence in the peripheral blood. Acute leukemias are differentiated from chronic leukemias by the predominance of the neoplastic, clonal blast as well as by the pace with which untreated disease leads to hematopoietic failure and death within weeks to months.

In AML, the cancer is the mass of proliferating blasts, which are immature precursors of normal blood cells. The degree of immaturity varies with some cases of AML dominated by extremely immature “stem cell like” myeloblasts and some featuring more differentiated precursors of specific myeloid lineages (i.e. monoblasts, erythroblasts). Pathology is primarily due to accumulation of blasts, replacing healthy marrow and leading to failure of normal hematopoiesis and the humoral and mechanical complications of large numbers of these immature cells in the peripheral circulation and/or tissues.

AML is typically caused by mutations to the deoxyribonucleic acid (DNA) of hematopoetic precursor cells causing arrest of terminal differentiation and then likely a second mutation causing uncontrolled division and proliferation. The best understood causative mutations occur in the World Health Organization (WHO) subtypes of AML with "characteristic cytogenetic abnormalities". Two of three of these abnormalities, t(8:21) and inv(16:16), affect genes known as core binding factors. These mutations form fusion proteins, inactivating native core binding factors that are required for myeloblasts differentiation into mature forms. This leads to differentiation arrest at the myeloblasts stage. It is presumed that a second mutation leads to proliferation of the immature clone and magnification of the neoplastic cell. Further research has shown different cases of AML feature a wide variety of mutations in nuclear transcription factors, DNA methylation genes, and DNA repair genes in certain predictable combinations.

II. Diagnostic Confirmation: Are you sure your patient has acute myelocytic leukemia?

AML is defined by myeloblasts, which are usually present in small numbers in the marrow and not in the peripheral blood, making up greater than or equal to 20% of the leukocytes in the peripheral blood or bone marrow. These cells are morphologically distinct from mature myelocytes by a high nucleus to cytoplasm ratio and characteristic chromatin and cytoplasmic characteristics as well as being distinguishable by cell surface markers detected by immunohistochemistry or flow cytometry. Myeloblasts are differentiated from lymphoblasts (and AML from acute lymphoblastic leukemia [ALL]) by anatomic features (Auer rods), certain staining characteristics (based on the presence of myeloperoxidase), or myeloid related cell surface markers (CD33, CD117, CD13).

In the cases of monoblastic, megakaryoblastic and promyelocytic leukemia (subtypes of AML) the malignant cell has arrested further along its developmental pathway and thus the monoblasts/promonocytes, megakaryoblasts, and abnormal promyelocytes, respectively are malignant cells and count toward the blast percentage. These cells, like myeloblasts, have very specific morphologic and marker characteristics.

Even in the absence of the requisite blast counts, certain characteristic cytogenetic abnormalities define AML if they are present. These are typically discovered on cytogenetics studies (karyotype or fluorescence in situ hybridization (FISH)) and are t(8:21) and inv(16:16), t(16:16), and t(15:17).

Myeloid sarcoma is a rare form of acute leukemia in which myeloblasts form a solid tumor that can develop anywhere in the body. This may occur without any evidence of circulating myeloblasts or with excessive myeloblasts in the marrow. Diagnosis without circulating myeloblasts or excess numbers of myeloblasts in the marrow is by pathology evaluation of a biopsy specimen.

A. History Part I: Pattern Recognition:

The symptoms of AML are protean and thus it is difficult to describe the "typical patient". Fever from disease or infection and/or symptoms from the failure of one or multiple cell lines in the context of marrow replacement by malignant cells are the most common symptoms. Along with fever, mucosal inflammation in the mouth and throat or of the perirectal area is another common consequence of neutropenia.

Patients presenting with symptoms due to the failure of other cell lines often appear with symptomatic anemia (fatigue, dyspnea on exertion, and/or weakness) or petechiae and mucosal bleeding from thrombocytopenia. Bone pain from areas of expanding normal hematopoiesis trying to compensate for areas of neoplastic expansion or from bone marrow necrosis may also be present.

Aside from symptoms of cytopenia and hematopoetic failure there are multiple potential symptoms due to the circulating myeloblasts. Given they are immature forms not meant for peripheral circulation some degree of spontaneous lysis is common, which usually releases uric acid, lactic acid, and potentially potassium and phosphorous.

When the degree of cell lysis becomes great enough to cause markedly elevated uric acid and renal dysfunction, tumor lysis syndrome (TLS) develops. Depending on the degree of maturation of the cancer cell, these tumor cells may have more or less mature granules, which can impact the coagulation cascade and cause disseminated intravascular coagulation (DIC) with bleeding or clotting as is classically seen in acute promyelocytic leukemia (APML).

Another group of potential symptoms of AML at presentation involve infiltration of myeloblasts into various tissues. Skin manifestations of disease caused by infiltration of myeloblasts (termed leukemia cutis) have a broad possible range of appearances but are most often manifested as purplish or violaceous nodules or papules. These are rarely tender or pruritic and may help with diagnosis as biopsy will often reveal myeloblasts.

Liver failure or jaundice with hepatomegaly and/or splenomegaly is also possible from leukemic invasion of the organs, though hepatomegaly and splenomegaly are much less common with AML than with other hematologic malignancies. Central nervous system (CNS) involvement is relatively uncommon in AML but may present with headache and neck stiffness or, more likely, as cranial nerve abnormalities due to small tumor implants. 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.

Finally, very high leukocyte counts (typically greater than 100,000/uL though down to 50,000/uL) can cause leukostasis, which is sludging of hyperviscous blood in small capillaries or small vascular beds. 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.

B. History Part 2: Prevalence:

AML is the most common acute leukemia in adults, representing approximately 80% of acute leukemia in adults. This ratio is essentially reversed in children. Nevertheless, AML remains a rare disease with an incidence of 2-3 cases per 100,000 adults per year.

The primary risk factor for developing acute leukemia is age as demonstrated by the fact that the risk incidence rises to 12-15 cases per 100,000 individuals in the seventh and eighth decades of life. Median age of diagnosis is 67. 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. 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 4-7 years after exposure with preceding MDS) and topoisomerase II inhibitors (with leukemia typically developing 2-3 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.

C. History Part 3: Competing diagnoses that can mimic acute myelocytic leukemia.

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

D. Physical Examination Findings.

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.

Head, ears, eyes, nose and throat (HEENT) exam should focus on exam of the oropharynx particularly looking for pallor, suggesting anemia, or petechiae/bleeding, suggesting thrombocytopenia. 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. 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.

E. What diagnostic tests should be performed?

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

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The most important laboratory study to be ordered is a CBC with differential and visual review of the peripheral smear. The presence of greater than 20% myeloblasts in the circulating blood is diagnostic of AML, but individuals with acute leukemia may have no circulating myeloblasts (so called aleukemic leukemia). 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. The presence of more than 20% myeloblasts in bone marrow is similarly diagnostic of AML (note this is decreased from the previous historical threshold of 30%). Of note, some blasts may be mischaracterized by automatic counters leading to a need for manual visual review of the peripheral smear by a hematologist and/or qualified pathologists in cases where the diagnosis remains a concern.

As well as morphological exam of bone marrow and blood, flow cytometry and cytogenetics/karyotyping should be sent on a bone marrow specimen (optimally) or on peripheral blood. Exact test characteristics and turn-around times for the two specimen types may vary with institution so ideal choice should involve hematology/oncology input. 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. Therefore, a careful conversation with a hematologist/oncologist at the time a marrow sample is obtained to make sure these are appropriately sent is critical.

Translocation 15:17, 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).

Multiple other mutations (nucleophosmin (NPM) 1, Fms-like tyrosine kinase 3 internal tandem duplication (FLT3 ITD) repeats and CCAAT enhancer binding protein alpha (CEBPA) have been used to determine prognosis and may guide therapy. These should ideally be sent on initial diagnostic samples but should be discussed with hematology/oncology consultants to clarify what is expected in your institution.

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.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

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.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

NA

III. Default Management.

Ultimately, suspicion of AML should lead to urgent hematology/oncology consultation in order to obtain bone marrow biopsy and facilitate diagnosis. For patients who are eligible, longterm survival and the possibility of cure will depend on chemotherapeutic treatment under the supervision of an oncology specialist and AML should be considered a hematologic/oncologic emergency with early subspecialty consultation and ideally transfer to a specialized service in a timely fashion. Prior to any chemotherapy or disease specific therapy, however, patients must undergo stabilization.

Patients should have their hematologic and coagulopathic abnormalities corrected and renal/electrolyte balance optimized with transfusions, hydration and treatment for TLS, if present. 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.

The standard management of young patients (typically classified as patients less than 65 years old) with acute myelogenous leukemia is with the 7+3 regimen, which consists of 7 days of continuous infusion cytarabine with anthracycline (typically either idarubicin or daunorubicin) given on days 1, 2 and 3. The goal of initial management is to obtain a complete response (CR) with consolidation with further chemotherapy and/or stem cell transplant depending on various features of the patient and their disease.

Patients with APML associated with the 15:17 translocation require additional, specific management with ATRA in addition to anthracycline. ATRA facilitates differentiation of the malignant promyelocyte and, more importantly for immediate management, is critical to helping prevent and/or manage DIC. With ATRA and anthracycline, patients with APML have among the best prognosis of acute leukemia patients with long-term survival rates well over 80%.

For "elderly" patients with acute myeloid leukemia, who are typically defined as those over age 65, there is no well-defined standard of care. This is due to both more treatment resistant disease and poorer tolerance of aggressive therapy. Previous studies placed mortality rates in the 25% range with standard induction therapy, which was considered unacceptable. 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. For patients not eligible for even these therapies the options of purely supportive care with transfusion and antibiotics (and often cytoreduction with hydroxyurea) and/or hospice care should be considered as the average survival for untreated AML is limited to weeks to months.

A. Immediate management.

Immediate management consists of stabilization of metabolic and hematologic abnormalities.

Febrile patients

Patients with AML can be febrile for a wide variety of reasons but given functional and/or actual neutropenia, febrile patients should be considered as infected until proven otherwise and managed for neutropenic fever. 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 24-48 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. 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. Otherwise antibiotics should be continued until neutropenia resolves.

Acute kidney injury/tumor lysis syndrome

TLS is a metabolic syndrome associated with rapid tumor cell breakdown and release of intracellular electrolytes causing metabolic, renal, neurological, and cardiac toxicity. In AML the high white blood cell (WBC) counts and high lactate dehydrogenase (LDH) values are generally felt to correlate with the risk of TLS.

TLS consists of a combination of high potassium and phosphate with low calcium as well as high uric acid and increased creatinine. Hyperkalemia should be managed as with primary hyperkalemia. Patients should have an electrocardiogram (EKG) to assess for signs associated with hyperkalemia and then be given kayexalate and/or insulin/glucose/calcium/albuterol depending on the presence or absence of signs of cardiologic toxicity. Patients should be monitored on telemetry until the potassium has normalized.

Hydration is the mainstay of TLS prophylaxis with the use of loop diuretics to maintain urine output should it be inadequate in a well hydrated patient. Aside from this and managing other elecrolyte abnormalities the primary concern is for urate nephropathy, which can cause acute renal failure and ultimately lead to end stage renal disease.

Allopurinol was long the mainstay of uric acid lowering therapy and should be used unless there is a clear contraindication. The addition of rasburicase, a highly effective but expensive recombinant urate oxidase, to the therapeutic armamentarium has made the aggressiveness with which to pursue prophylaxis a major issue. This has led to dedicated efforts to come up with a risk stratification system to help determine how aggressively patients should be pretreated and how often they need to be monitored.

High-risk patients require rasburicase prophylactically and monitoring every 4-6 hours. Moderate risk patients should receive alopurinol and 2-3 times daily checks of electrolytes and low risk patients can likely be treated with hydration alone. Given the expense of treatment, risk of end stage renal disease and seriousness of severe TLS, this management should always be done with hematology/oncology and possible nephrology guidance.

Hematologic complications

Patients are typically transfused in order to maintain safe platelet and red blood cell (RBC) counts. This typically means platelet transfusions to keep counts of greater than 10,000/uL to prevent spontaneous bleeding and packed RBC transfusions to hemoglobin greater than 7 g/dL (though 8 may be used as a threshold given expected continued losses). The bleeding patient or patient with symptomatic anemia should be transfused to correct their current symptomatology regardless of transfusion thresholds. All patients should be transfused leukoreduced, irradiated products if available to reduce the risk of RBC sensitization and prevent transfusion associated GVHD respectively.

Coagulopathy

DIC is most commonly associated with acute promeylocytic leukemia (M3) subtype but can occur in all subtypes of AML. This is thought to be due to the release of proteolytic enzymes as cells and granule lysis causing microvascular damage and activation of the clotting cascade.

Patients with elevated PT and PTT as well as thrombocytopenia should have fibrin degradation product (FDP) and fibrinogen checked (D-dimer should also be checked for the diagnosis of DIC but will almost universally be elevated in the case of AML). Given fibrinogen’s role as an acute phase reactant, a normal or low fibrinogen is highly suggestive of DIC. Fibrinogen of less than 100 should trigger treatment with cryoprecipitate in order to reach a level of more than 100. Platelets and fresh frozen plasma (FFP) should be transfused for bleeding patients with platelet counts less than 50 and INR greater than 2 respectively. Some sources also recommend a higher platelet transfusion threshold for non-bleeding patients with DIC of 30-50,000/uL.

For patients with APML, bleeding diathesis continues to be a major cause of early death and previously led to high rates of mortality in induction or prior to induction. This danger is dramatically reduced with prompt treatment with differentiation therapy (ATRA or more recently arsenic trioxide), which helps maturation of the neoplastic promyelocyte and reverses the coagulopathy. The diffuse application of treatment with ATRA to all individuals with AML pending APML being ruled out has been considered but is not yet the standard of care.

Hyperleukocytosis

Patients with white blood cell counts of greater than 50,000/uL with blast predominance, but particularly those with counts over 100,000/uL, are at high risk of leukostatic complications causing respiratory or neurological complications. Hyperleukocytosis also increases the odds of spontaneous TLS and the number of blasts contributing to the uric acid load.

Cytoreduction with hydroxyurea (2-4 grams once or twice a day) is typically used for decreasing the white count (though this will also contribute to anemia and thrombocytopenia) and often will decrease the count by 50% in 24-48 hours and should be continued until the WBC count is below 10,000.

In patients with signs of leukostatic pulmonary or neurological disease or blast counts of greater than 100,000 one session of leukapheresis may instantly drop the WBC count by 20-50%. This does, however, require the placement of a large central catheter for pheresis (posing risks of bleeding and infection) and data regarding actual mortality benefit has not been shown. All patients with hyperleukocytosis should also receive hydration, allopurinol, and almost always rasburicase for tumor lysis prophylaxis.

B. Physical Examination Tips to Guide Management.

Exam during initial management should be focused on assessing complications of therapy and disease. Daily evaluation for signs of bleeding used with the platelet count will help target platelet goals to stop further bleeding. Careful monitoring for localized signs of infection and or sources of infection which may precipitate broadening of coverage (i.e., signs of pulmonary infiltrate, redness around a catheter site, severe mucositis, etc.) should be conducted and help guide antibiotic therapy and/or further diagnostic work-up. Daily weights and exam to assess volume status, particularly in the acute setting, can be crucial.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management.

Patients with hyperleukocytosis receiving hydroxyurea for cytoreductions should receive at least twice daily CBCs to assess response to therapy and assure the WBC count is declining as well as to monitor results of transfusions.

Adults with DIC or with APML receiving transfusion therapy should have at least three times daily assessment of coagulation markers in order to replete missing factors and assure the patient isn't worsening.

TLS and renal failure similarly require at least 2-3 times daily assessment of electrolytes to assure hyperkalemia and hyperuricemia are not worsening, contributing to possible further cardiotoxicity or nephrotoxicity respectively. All patients on chemotherapy should receive daily CBC with differential as well as LFTs and coagulation labs.

D. Long-term management.

To have a chance of long term survival with AML patients must undergo induction chemotherapy to achieve complete remission, as well as further consolidation with chemotherapy and/or stem cell transplant. This will be managed by a hematologist/oncologist in a subspecialty environment.

E. Common Pitfalls and Side-Effects of Management

Differentiation syndrome

Patients with APML treated with ATRA or arsenic trioxide may develop a differentiation syndrome associated with rapid transition from promyeloblasts to mature promeylocytes. This syndrome is associated with respiratory distress, increasing WBC count, pulmonary infiltrates, fever, weight gain, and less commonly effusions, hypotension and renal failure. Management is with discontinuation of ATRA and glucocorticoids. Mortality without these management steps is high. Generally, ATRA will only be given under subspecialty guidance and this is unlikely to be an issue for the lone hospitalist.

IV. Management with Co-Morbidities

In general, significant comorbidities significantly limit an individual's ability to sustain the rigors of aggressive induction and consolidation chemotherapy. Significant renal or hepatic dysfunction in particular will usually exclude an individual from consideration of stem cell transplant, which may be the only curative option for a particular leukemia.

A. Renal Insufficiency.

Renal insufficiency predisposes patients to more severe and less reversible kidney dysfunction than TLS. This may lead to a more aggressive approach to alkalinization and earlier use of rasburicase. Monitoring fluid status throughout chemotherapeutic treatment is crucial, and chemotherapeutic agents will need to be renally dosed.

B. Liver Insufficiency.

Most chemotherapeutic agents (including cytarabine and most anthracyclines) are metabolized in the liver and thus will need dose adjustments and/or may be unable to be given in the context of significant hepatic impairment.

Liver disease and resulting coagulopathy may affect assessment of coagulopathy associated with malignancy.

C. Systolic and Diastolic Heart Failure

The most feared toxicity of anthracyclines is cardiotoxicity and reduction of the ejection fraction (EF). This is related to lifetime dose and thus a diminished EF is not an absolute contraindication to treatment with anthracyclines but may raise concern due to decreased reserve. All patients treated with anthracyclines undergo sequential echocardiograms to monitor EF.

Many chemotherapeutic agents are given with large fluid volumes to minimize side effects and toxicity and this must be monitored closely in the context of systolic or diastolic dysfunction.

D. Coronary Artery Disease or Peripheral Vascular Disease

Patients with active coronary artery disease (CAD) are often transfused to a higher threshold of hematocrit (typically 25) given the concern for hypoperfusing at risk areas. Continued clopidogrel and aspirin in those with fresh coronary artery stents in the context of thrombocytopenia and bleeding risk is without clear guidelines. Often higher platelet counts will be aimed for in order to prevent bleeding in patients whose antiplatelet agents cannot be stopped.

E. Diabetes or other Endocrine issues

Most chemotherapeutic regimens are given with glucocorticoids to minimize nausea. This will often cause increased blood glucose values. Neutropenia associated with disease and therapy will further increase infectious risk.

F. Malignancy

AML may occur as a consequence of prior chemotherapy, particularly alkylating agents and topoisomerase II inhibitors. Aggressive therapies such as stem cell transplant are not typically pursued in the context of underlying uncontrolled malignancy.

G. Immunosuppression (HIV, chronic steroids, etc.).

Patients with chronic immune suppression will be managed similarly to other patients on development of AML.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

Aggressive chemotherapies given for AML or neutropenia from AML itself may cause severe mucositis leading to difficulties eating due to odynophagia and can lead to nutritional compromise requiring total parenteral nutrition (TPN). Neutropenia associated with therapy or disease is also associated with nausea and diarrhea and coagulopathy may lead to bleeding at previous sites of intermittent bleedings (hemorrhoids, arteriovenous malformations (AVMs), etc.).

J. Hematologic or Coagulation Issues

Patients with underlying MDS are at higher risk of developing AML and have poorer prognosis disease.

K. Dementia or Psychiatric Illness/Treatment

Patients with underlying psychiatric illness will be very vulnerable to decompensation in the context of treatment with steroids. Additionally, long-term care such as frequent clinic visits, medication adherence after transplant and similar can be very difficult in the context of uncontrolled or decompensated mental illness.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

AML is a hematologic/oncologic emergency. Early involvement of hematology/oncology consultants with rapid transfer to a dedicated service or careful oncologic supervision is crucial. Sign out of what parts of work-up and evaluation for chemotherapy and long-term management have been performed will be important to facilitate this possible transition.

More crucially to the immediate management, patients with newly diagnosed AML will typically have multiple lab draws per day in order to follow coagulation parameters and electrolytes. Careful sign out of when these are due and the transfusion parameters agreed upon by the primary attending with hematology/oncology input is crucial to safe management of these patients.

B. Anticipated Length of Stay.

Patients who undergo induction chemotherapy will typically stay in the hospital throughout their period of therapy related neutropenia and until their cell lines recover after treatment. This typically is a period of 14-28 days though it may be longer, particularly in elderly individuals who may have prolonged bone marrow aplasia.

C. When is the Patient Ready for Discharge.

Patients are typically discharged after they have undergone induction chemotherapy and are no longer neutropenic for at least 24 hours and no longer febrile.

D. Arranging for Clinic Follow-up

Patients should have follow-up in hematology/oncology clinic at discharge. Ultimately, young patients, except for those with the best risk disease, should be evaluated by a physician for consideration of stem cell transplant. The path of this referral is very center dependent, however, and thus should be arranged through the oncology infrastructure.

Patients who leave the hospital prior to day 14 after initiating therapy should have a bone marrow biopsy arranged around day 14 for assessment of residual disease and to help guide further therapy.

1. When should clinic follow up be arranged and with whom?

All patients should have follow-up with their hematologist/oncologist within the week following discharge in order to check counts and arrange for further cycles of consolidation therapy. Typically, this will be arranged by the specialist as management of acute leukemia is often subspecialized even within malignant hematology.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

Young patients should have human leukocyte antigen (HLA) typing underway at the time of discharge if not otherwise performed in order to prepare for possible transplantation and donor search.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

CBC with differential, LFTs, electrolytes with calcium/magnesium/phosphorus, PT/PTT/and INR should all be ordered prior to follow-up visit.

E. Placement Considerations.

Many skilled nursing facilities are uncomfortable managing patients who are actively on chemotherapy or may anticipate neutropenia. Patients undergoing consolidation chemotherapy may be discharged after chemotherapy and prior to their cell counts hitting their nadir. In these cases, nadir should be anticipated between 10-21 after initiation of chemotherapy.

F. Prognosis and Patient Counseling.

Patients with AML have a highly variable prognosis depending on patient and disease factors. For patients under age 65 without comorbidities who can undergo aggressive therapy, 5-year survival is approximately 40%. This is highly variable, however, as patients with good prognosis disease have 5-year survival of more than 60% with chemotherapy consolidation alone. Unfortunately, those with poor prognostic factors such as older age, multiple (greater than or equal to three) cytogenetic abnormalities or disease arising from previous MDS and/or chemotherapy have 5 year survival values of under 30% even after allogeneic stem cell transplant.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

None.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

The use of growth factors (g-CSF) after chemotherapy is sometimes used to shorten neutropenia and is continued until the ANC is greater than 1000/mm3 (as there is usually a 50% drop of WBC count once growth factors are stopped). Due to aforementioned concerns about promoting disease this is studiously avoided at other centers and therefore discussion with a hematology or oncology consultant is critical. Prophylactic antibiotics for neutropenic patients are highly controversial and not widely recommended at this time.

All patients should be strongly warned about risks of infection and cautioned to appear for any complaints.

VII. What's the evidence?

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Howard, SC, Jones, DP, Pui, CH. "The Tumor Lysis Syndrome". NEJM. vol. 364. 2011. pp. 1844-1854.

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