I. What every physician needs to know.
Acute lymphoblastic leukemia (ALL) is a hematologic malignancy of undifferentiated lymphoid precursor cells, which leads to excessive production of abnormal lymphoblasts in the bone marrow and subsequent hematopoietic failure. Though ALL most commonly occurs in children, it can be seen in all age groups.
II. Diagnostic Confirmation: Are you sure your patient has acute lymphoblastic leukemia?
If suspected, the work-up for ALL begins with a complete blood cell count (CBC) and a peripheral blood smear. Diagnosis of ALL is indicated by the presence of lymphoblasts on a peripheral blood smear and is confirmed through a bone marrow biopsy with the presence of greater than 20% primitive cells (blasts) under the microscope or by flow cytometry.
Biopsy of masses and lymph nodes may also be necessary in order to analyze cell characteristics and genetic material, which are important for prognostication. In all cases (if possible), a lumbar puncture is also performed to assess for central nervous system (CNS) involvement.
A. History Part I: Pattern Recognition:
Like other leukemias, patients may present with vague complaints of low-grade fever, fatigue, bone and/or joint pain, loss of appetite, weight loss, abdominal pain, and heaviness. Infiltration of the bone marrow by leukemic cells usually suppresses one or more cell lines, leading to recurrent infections (due to granulocytopenia), easy/excessive bruising, petechiae, mucocutaneous bleeding and other bleeding (from thrombocytopenia), and anemia (causing fatigue, dyspnea on exertion and/or weakness).
CNS involvement is common in ALL and may present a diffuse meningitic picture. Symptoms may include headache and neck stiffness, cranial nerve, or other neurologic abnormalities.
The onset of symptoms may be subtle or acute.
B. History Part 2: Prevalence:
ALL most commonly occurs between the ages of 2 and 4 and after the age of 50. It is more prevalent in males versus females and whites versus blacks.
In the United States in 2010, an estimated 24,690 men and 18,360 women were diagnosed with leukemia, 4% (roughly 5,300 of the 43,050 total) of which were diagnosed with ALL.
Approximately 80% of adults diagnosed with ALL will enter complete remission after undergoing initial treatment and 5-year survival rates are roughly 40%.
Although the exact etiology of ALL is not yet known and most cases are considered idiopathic, ALL has been associated with environmental factors such as radiation and chemical exposures, viral infections (e.g., human T-cell lymphoma/leukemia virus-1 and Epstein-Barr virus) and inherited chromosomal abnormalities (e.g., Down syndrome, Klinefelter syndrome) that reveal a genetic predisposition.
C. History Part 3: Competing diagnoses that can mimic acute lymphoblastic leukemia.
Patients with ALL typically present with non-specific symptoms, the causes of which must be differentiated from those listed below:
Leukemias (e.g., acute myeloid leukemia (AML), hairy cell leukemia (HCL), chronic lymphocytic leukemia (CLL), prolymphocytic leukemia, marginal zone lymphoma)
Infectious diseases (e.g., tuberculosis, infectious mononucleosis, Epstein-Barr virus)
Autoimmune diseases (e.g., lupus, polyarteritis nodosa)
Myelodysplastic syndromes (MDS)
The differentiation between ALL and AML based on the microscopic appearance of the involved neoplastic cells may be difficult.
The information from an appropriate medical history, physical examination, peripheral smear, and thorough evaluation of bone marrow biopsy samples, including immunophenotyping by flow cytometry can be used to differentiate ALL from the above causes.
D. Physical Examination Findings.
ALL is associated with a wide variety of physical examination findings, which include signs of easy bleeding (from thrombocytopenia) such as recurrent epistaxis, bruises and petechiae, recurrent infections (e.g., pneumonia), and signs of anemia (e.g., pallor, lethargy). Other findings include abdominal masses due to hepatosplenomegaly, cachexia and lymphadenopathy. Rarely, some patients may also present with neurological symptoms (e.g., headaches, nuchal rigidity, vomiting, or nerve palsies).
A thorough neurological examination should be performed in patients diagnosed with ALL with special attention given to the evaluation of isolated cranial nerve abnormalities.
E. What diagnostic tests should be performed?
Though no characteristic physical findings can independently confirm a diagnosis of ALL, as with any other leukemia, a series of signs and symptoms can provide clues to the diagnosis. Diagnosis of ALL is based on the results of blood tests and bone marrow biopsies.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Most patients with ALL develop leukocytosis with a reduction in other blood cell lines (anemia and/or thrombocytopenia) or a reduction in all cell lines (pancytopenia) due to the infiltration of the bone marrow with lymphoblasts. If ALL is suspected, a CBC with differential, a peripheral smear and a complete metabolic panel should be ordered.
The presence of lymphoblasts in the peripheral blood is diagnostic of ALL. Importantly, however, patients may have no circulating lymphoblasts (so called aleukemic leukemia).
If patients are suspected of having a hematologic malignancy based upon their medical history and the results of their physical examination, a CBC and peripheral smear are obtained before further work-up. The presence of lymphoblasts in the peripheral smear strongly suggests a diagnosis of leukemia. Flow cytometry of the peripheral blood may be ordered for rapid confirmation of leukemia type.
Absolute diagnostic confirmation requires bone marrow aspiration and core biopsy for evaluation by flow cytometry, histopathology, cytogenetics/karyotyping, and molecular analysis. Flow cytometry is the primary method for distinguishing myeloblasts from lymphoblasts and thus distinguishing AML from ALL. Molecular testing, such as polymerase chain reaction (PCR) assay for the Philadelphia chromosome (resulting in the gene BCR-Abl), the product of a translocation between chromosomes 9 and 22, is important for prognostication.
Following diagnosis, lumbar puncture should be obtained to establish if there is CNS involvement. CSF tests include cell count and differential, glucose, protein, cytology, and flow cytometry. Without directed therapy to the CNS, up to 50% of adults will develop CNS disease. Therefore, intrathecal chemotherapy is then given as either prophylaxis or treatment (depending on if the CNS is negative or positive for disease).
Hematology/oncology consultation should be obtained immediately when ALL is suspected so that the appropriate work-up can be conducted and the appropriate treatment initiated expeditiously.
Biopsy of tissue and lymph node masses are also performed in cases in which bone marrow biopsies are inconclusive or there is no involvement in the marrow. The latter is extremely unusual in ALL, but may be seen in a related lymphomatous disease, lymphoblastic lymphoma, which shares histologic features, sensitivity to chemotherapy and prognosis with ALL.
A complete metabolic panel should also be requested. Special attention should be given to ruling out spontaneous tumor lysis syndrome (requiring 2 out of 4 of hyperuricemia, hyperkalemia hyperphosphatemia, and hypocalcemia) which often results in acute renal insufficiency. Liver function tests are required, as liver function has implications for treatment selection and dosing. Baseline coagulation studies are recommended as well, since ALL treatment (particularly L-asparaginase) may induce a therapy-related disorder similar to disseminated intravascular coagulation (DIC).
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
All patients with ALL should undergo chest x-ray upon initial diagnosis. Computed tomography (CT) scans of the chest, abdomen and pelvis are recommended only if involvement of internal organs is suggested by physical examination, laboratory abnormalities or findings on other radiography studies. Except in young patients with no history of cardiac disorders or exposure to cardiotoxic treatments, echocardiography or multigated acquisition (MUGA) scan is needed to verify normal systolic function prior to treatment with potentially cardiotoxic chemotherapy.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
III. Default Management.
After ALL has been definitively diagnosed by review of a bone marrow aspirate and core biopsy, treatment should be started immediately upon performing hematology/oncology consultation. Patients must be adequately stabilized prior to the initiation of chemotherapy. Stabilization includes management of electrolyte abnormalities and severe cytopenias and treatment of infections. Treatments may include hydration, antibiotics, transfusions, and management of tumor lysis syndrome.
Other important points include inserting a central venous line for chemotherapy infusion and obtaining echocardiography to evaluate cardiac function before infusion of chemotherapy drugs.
During and following chemotherapy, which will be discussed next, it is important to provide opportunistic infection prophylaxis with an antiviral (acyclovir or valacyclovir). If the patient has prolonged neutropenia, then often a fluoroquinolone (e.g., ciprofloxacin) and antifungal (e.g., fluconazole) are prescribed. Furthermore, Pneumocystis jirovecii prophylaxis is often necessary and covered by trimethoprim-sulfamethoxazole or dapsone.
Details about treatment of ALL are beyond the scope of this chapter, but, briefly, hospitalists must be aware of the following:
The treatment can be broken down into three parts: induction of remission, consolidation/intensification therapy and maintenance therapy.
Induction of remission
During induction of remission, (simply called “induction” by most treating physicians) the patient remains hospitalized for approximately 4 weeks to receive and recover from chemotherapy. The treatment usually includes a combination of cyclophosphamide, vincristine and an anthracycline (e.g., daunorubicin, doxorubicin) along with steroids. Recent regimens have also included the use of polyethylene glycol (PEG) asparaginase due to its anti-ALL activity.
In consolidation/intensification therapy, the physician may choose from among three treatments, each of which requires a few months to complete:
Bone marrow transplant
In maintenance therapy, patients receive chemotherapy monthly in addition to taking pills on specifically indicated days. This last part of the default management treatment takes approximately 2 to 2.5 years. Though it is unclear how long the patient should continue receiving therapy in this third part of the treatment plan, many patients receive treatment for an additional 2 to 2.5 years.
A. Immediate management.
Because ALL is fast growing, therapy needs to be initiated as soon as possible to prevent complications of incipient bone marrow failure, or complications of associated electrolyte abnormalities or coagulopathies.
In some cases, additional immediate management may be necessary. Patients presenting with profound bone marrow failure (leading to severe anemia, thrombocytopenia and/or neutropenia), may require immediate transfusion when the hemoglobin is below a safe range (generally accepted to be 7gm/dL) or when the platelet count is sufficiently low that spontaneous hemorrhage is a concern (platelet count of 10,000/uL is a reasonable threshold for transfusion).
ALL patients may also present with serious infections, septic shock and life threatening bleeding, all of which require immediate attention as well.
Fever, usually due to infection and occurring in the setting of neutropenia in ALL patients, should be treated with broad-spectrum antibiotics (e.g., an antipseudomonal beta-lactam is considered a first line empiric therapy).
Splenic rupture, although exceedingly rare, can cause severe abdominal pain and symptoms of hypotensive shock. In such presentations, a CBC along with imaging studies of the abdomen is recommended.
B. Physical Examination Tips to Guide Management.
Though there are no specific physical examination findings that a hospitalist can follow to monitor response to therapy or complications from therapy, the potential side effects of the respective medications must be monitored.
Side effects of the many chemotherapy medicines include, but are not limited to the following: nausea and vomiting, diarrhea, mouth sores, anemia, increased risk of infections, and bleeding.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
The goal of the first part of treatment, induction of remission, is to reduce the total body leukemia cell population below the level of detection by microscopic analysis of the bone marrow.
Patients in complete clinical remission should have a bone marrow aspiration and a biopsy every 3 to 6 months for at least 2 years to ensure that there are no detectable lymphoblasts in the blood or bone marrow and that the bone marrow is functioning normally.
Usual side effects of chemotherapeutic agents such as pancytopenia, bleeding, and severe anemia can also occur after the administration of chemotherapy drugs and should be followed by a series of CBCs.
The frequency of monitoring blood and neutrophil counts should be tailored to each patient’s kinetics of blood cell recovery following chemotherapy.
D. Long-term management.
After completing the long-term maintenance therapy phase, patients should return every 3 to 6 months for peripheral blood analysis. If leukemia cells are found in the peripheral blood analysis, chemotherapy, radiation, or bone marrow transplantations might be deemed necessary.
In asymptomatic patients, the spleen, lymph nodes, constitutional symptoms and signs of pancytopenia should be closely monitored in addition to completing serial blood tests and physical examinations. Lastly, attention should also be given to the patient’s social issues and psychiatric outcomes associated with malignancy and its respective treatments.
E. Common Pitfalls and Side-Effects of Management
Side effects of treatments can range from nausea, vomiting, severe thrombocytopenia (causing life threatening bleeding), severe anemia (requiring blood transfusions), granulocytopenia (leading to opportunistic infections and septic shock), DIC and venous thromboembolism (in association with asparaginase therapy), serious neurological toxicities, and prolonged immunosuppression. Further details regarding medications and the respective dosages are beyond the scope of this chapter.
Long-term pitfalls include opportunistic infections, relapse and secondary malignancies ranging widely from skin to gastrointestinal cancers to other non-Hodgkin lymphomas. Whether ALL or its treatment increase the risk of these secondary malignancies, is not yet clear.
The specific common side effects of the chemotherapy drugs used in treating ALL are listed below. These lists are not exhaustive.
Cyclophosphamide: hemorrhagic cystitis, hair loss, nausea, and vomiting.
Vincristine: constipation, hair loss, nausea, and vomiting.
Daunorubicin: nausea, vomiting, increased risk of bleeding, hair loss, cardiac toxicity (e.g., systolic dysfunction), and darkened fingernails and toenails.
Doxorubicin: nausea, vomiting, loss of appetite, diarrhea, difficulty swallowing, thinned hair, skin irritation, cardiac toxicity, darkened fingernails and toenails, swelling, pain, redness, and peeling of the skin on the palms and soles of the feet.
Prednisone: hyperglycemia, fluid retention, insomnia, nervousness, muscle weakness and hypertension.
PEG-asparaginase (or L-asparaginase): DIC, venous thromboembolism, transaminase elevation, hyperbilirubinemia, and hypersensitivity reactions.
IV. Management with Co-Morbidities
Treatment of ALL may need adjustment in patients with the following medical comorbidities.
A. Renal Insufficiency.
The dosages of cyclophosphamide, vincristine and anthracyclines (daunorubicin or doxorubicin) may require alterations for patients with renal impairment.
B. Liver Insufficiency.
The dosages of cyclophosphamide, vincristine, anthracyclines (daunorubicin and doxorubicin), and PEG-asparaginase may require alterations for patients with liver disease, including hepatitis.
C. Systolic and Diastolic Heart Failure
Systolic heart failure may be a contraindication to or require a dose adjustment of anthracycline (daunorubicin and doxorubicin) therapy.
D. Coronary Artery Disease or Peripheral Vascular Disease
No change in standard management.
E. Diabetes or other Endocrine issues
Careful management of serum glucose levels are necessary during treatment with corticosteroids, especially in patients with pre-existing glucose intolerance.
No change in standard management.
G. Immunosuppression (HIV, chronic steroids, etc).
No change in standard management.
H. Primary Lung Disease (COPD, Asthma, ILD)
No change in standard management.
I. Gastrointestinal or Nutrition Issues
Vincristine and anthracycline drugs interfere with the body’s rapidly growing cells by preventing them from dividing or reproducing. In patients, though these drugs do prevent cancer cells from dividing, they also interfere with the production of cells lining the gastrointestinal tract. This often results in mucositis, odynophagia, nausea, vomiting, diarrhea, and abdominal pain.
J. Hematologic or Coagulation Issues
Coagulopathies, which may be present upon initial diagnosis or during PEG-asparaginase therapy, should be monitored and corrected with blood product (i.e., plasma) therapy to maintain an international normalized ratio (INR) less than or equal to 1.5 and fibrinogen greater than 100mg/dL.
K. Dementia or Psychiatric Illness/Treatment
In patients suffering from severe dementia, their families should be informed in appropriate detail about the benefits and downsides of their respective treatment plans and the potential consequences if they do receive the treatments. There is no change in standard management in patients with psychiatric illness; however, the side effects of corticosteroid therapy may exacerbate underlying psychiatric illness, especially anxiety.
V. Transitions of Care
A. Sign-out considerations While Hospitalized.
In asymptomatic patients who present with a new onset of abdominal pain, the overnight team should consider evaluating for complications of splenomegaly (e.g., rupture, infarction) or intestinal infections (e.g., typhlitis).
If the patient is admitted after chemotherapy, the overnight team may need to repeat an erythrocytes count with the plan to transfuse with rapidly dropping counts. A low threshold should be kept to seek for any opportunistic infection. In addition, low platelet counts should also be closely monitored with prophylactic transfusions given as per institutional guidelines (generally when platelet count is less than 10,000 or 20,000/uL or there is active bleeding).
B. Anticipated Length of Stay.
Ultimately, the typical length of stay for patients with ALL varies from patient to patient and also depends on the individual’s age and other health conditions. Generally during induction of remission, patients stay in the hospital for approximately 4 weeks to receive and recover from chemotherapy. The consolidation/intensification phase lasts for approximately a few months and is generally manageable in the outpatient setting. The maintenance therapy phase lasts for approximately 2 to 2.5 years, during which patients undergo outpatient chemotherapy once monthly.
C. When is the Patient Ready for Discharge?
If patients are admitted to the hospital for induction of remission, they can be discharged after approximately 4 weeks of chemotherapy when they demonstrate an adequate treatment response i.e., clearance of blasts from the peripheral blood and a subsequent increase in neutrophil count above the neutropenic range (count recovery). It is important to note, though, that patients may still require red blood cell and/or platelet transfusions for a short period following re-establishment of normal neutrophil counts. Therefore, appropriate outpatient follow-up is imperative.
D. Arranging for Clinic Follow-up
Close follow-up is required upon discharge from hospitalization for induction of remission to ensure that patients have achieved a complete remission and recovery of all blood counts. Routine management includes many subsequent cycles of chemotherapy. Therefore, it is important that patients have a designated hematological care provider that they will see following discharge, preferably within a few days.
1. When should clinic follow up be arranged and with whom.
ALL patients in complete clinical remission need close follow-up with their hematologist during outpatient intensification and maintenance therapy and then every 3 to 6 months for the subsequent 2 years for repeated blood analyses and bone marrow evaluations. These patients also need to be followed-up with their primary care providers for general health maintenance.
Surgical consults could also be included in the plan of care for patients with severe splenomegaly and/or bulky/painful lymphadenopathy. Once treatment is initiated, the specialist(s) can decide on further follow-up.
Patients in complete remission for 5 years or longer are considered to no longer have ALL.
2. What tests should be conducted prior to discharge to enable best clinic first visit.
If a patient with newly diagnosed ALL is admitted to the hospital, they will remain hospitalized for roughly 4 weeks and be discharged only after they have completed induction chemotherapy. A CBC and complete chemistry panel should be performed on the day prior to or day of discharge to serve as an important focus for follow-up care in the outpatient hematology clinic.
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
A CBC should be performed after discharge, but prior to the first clinic visit to check for the number of leukocytes, erythrocytes and platelets.
A CMP should also be performed prior to the first clinic visit if there were any preceding abnormalities upon time of discharge.
E. Placement Considerations.
Hospitalists with plans to initiate outpatient chemotherapy should consider obtaining a central venous access before discharging symptomatic patients.
F. Prognosis and Patient Counseling.
Though approximately 80% of adults with ALL enter complete remission after initial induction of remission, it is usually short-lived. Therefore, once remission is achieved, additional therapy is necessary to avoid relapse.
Twenty-five percent of adults with ALL are resistant to initial induction of remission. Furthermore, roughly 50-65% of adults who do reach complete remission eventually relapse. Though a second remission is achievable, retreatment is usually unsuccessful and many will eventually die.
Patients may be directed toward aggressive therapy with allogeneic hematopoietic cell transplants based on age or high-risk disease features (e.g., specific cytogenetic abnormalities such as t(9;22), also known as Philadelphia chromosome positive ALL, and other high risk molecular features). Five-year survival following allogeneic bone marrow transplant ranges between 20-45%, depending on age, disease features and donor relatedness.
Prognosis of ALL varies from patient to patient and also depends on the patient’s age, initial white blood cell count, ALL subtype (i.e., subtype of T cell or B cell), chromosome translocations, response to chemotherapy, and other underlying comorbidities.
Detailed discussions regarding the treatment strategy, including observation in asymptomatic patients and discussions about the need of initiation of treatment, should be done with the patient’s family. Patients should be educated to monitor possible complications of ALL.
VI. Patient Safety and Quality Measures
A. Core Indicator Standards and Documentation.
Not applicable for ALL patients.
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
To aid in prophylaxis measures, patients should be educated about the physical symptoms that could re-appear (e.g., fevers, signs of infection) and the possible signs, symptoms and complications from ALL (e.g., complications from pancytopenia, splenomegaly and lymphadenopathy near vital organs, though this is rare). The most common indication for re-admission is usually for treatment of infections occurring during continued outpatient leukemia therapy.
Education should also be given to follow-up with a primary care physician if any complications of ALL appear. Lastly, patients should be told about the importance of follow-up appointments with their hematology and oncology specialists for their exams and blood tests, for earlier identification of clinical manifestations that could help prevent frequent admissions and re-admissions.
VII. What's the evidence?
Faderl, S, O’Brien, S, Pui, C, Stock, W, Wetzler, M, Hoelzer, D, Kantarjian, HM. “Adult Acute Lymphoblastic Leukemia: Concepts and Strategies”. Cancer. vol. 116. 2010. pp. 1165-1176.
Swerdlow, SH, Campo, E, Harris, NL, Jaffe, ES, Pileri, SA, Stein, H, Thiele, J, Vardiman, JW. “WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, International Agency for Research on Cancer, Lyon”. 2008.
Fielding, AK. “Current Therapeutic Strategies in Adult Acute Lymphoblastic Leukemia”. Hematol Oncol Clin North Am. vol. 25. 2011. pp. 1255-1279.
Pasquini, MC, Wang, Z. “Current Use and Outcome of Hematopoietic Stem Cell Transplantation: CIBMTR Summary Slides”. 2001.
Mahmoud, HH, Rivera, GK, Hancock, ML. “Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia”. N Engl J Med. vol. 329. 1993. pp. 314-319.
Gafter-Gvili, A, Fraser, A, Paul, M. “Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy”. Cochrane Database Syst Rev. vol. 1. 2012. pp. CD004386
Warkentin, DI, Epstein, JB, Campbell, LM. “Valacyclovir versus acyclovir for HSV prophylaxis in neutropenic patients”. Ann Pharmacother. vol. 36. 2002. pp. 1525
Akan, H, Antia, VP, Kouba, M. “Preventing invasive fungal disease in patients with haematological malignancies and the recipients of haematopoietic stem cell transplantation: Practical aspects”. J Antimicrob Chemother. vol. 68. 2013. pp. iii5
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- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has acute lymphoblastic leukemia?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic acute lymphoblastic leukemia.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management
- IV. Management with Co-Morbidities
- A. Renal Insufficiency.
- B. Liver Insufficiency.
- C. Systolic and Diastolic Heart Failure
- D. Coronary Artery Disease or Peripheral Vascular Disease
- E. Diabetes or other Endocrine issues
- F. Malignancy
- G. Immunosuppression (HIV, chronic steroids, etc).
- H. Primary Lung Disease (COPD, Asthma, ILD)
- I. Gastrointestinal or Nutrition Issues
- J. Hematologic or Coagulation Issues
- K. Dementia or Psychiatric Illness/Treatment
- V. Transitions of Care
- A. Sign-out considerations While Hospitalized.
- B. Anticipated Length of Stay.
- C. When is the Patient Ready for Discharge?
- D. Arranging for Clinic Follow-up
- 1. When should clinic follow up be arranged and with whom.
- 2. What tests should be conducted prior to discharge to enable best clinic first visit.
- 3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
- E. Placement Considerations.
- F. Prognosis and Patient Counseling.
- VI. Patient Safety and Quality Measures
- A. Core Indicator Standards and Documentation.
- B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.