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Key Points On AML

Lecture on AML

Age-Specific Myeloid Leukemia Incidence Rates in the US,
Seer Program, 1975-1985

  • AML comprises obout 40% of leukemias in the Western world. Approximately 6500 cases are diagnosed in adults in the US annually.
  • The incidence of AML increases steadily with increasing age. The median age is 55 to 60.
  • AML is more common in males than in females, and more common in whites than in blacks.

References

Cancer Facts and Figures- 1991. Atlanta, American Cancer Society Inc, 1991, pp 1-31.

Linet MS, Devesa SS: Descriptive epidemiology of the leukemias, in Henderson ES, Lister TA ledS): Leukemia, ed 5.


Etiology and Diagnosis

  • An increased incidence of AMl is associated with certain congenital chromosomal abnormalities leg, Down's syndrome, Bloom's syndrome, Fanconi's anemia)
  • Patients with acquired diseases such as myelodysplastic syndromes, myeloproliferative disorders, and other preleukemic states have an increased incidence of AML.
  • A variety of environmental factors, both work- and treatment- related, are known to cause AML. These include:
    1. exposure to ionizing radiation;
    2. chemical exposure to benzene, and possibly hydrocarbons, and solvents;
    3. treatment with alkylating agents (e.g., melphalan, methyl CCNU, nitrogen mustard) or procarbazine;
    4. treatment with other drugs (e.g., chloramphenicol, phenylbutozone)
  • While there is no conclusive evidence that viruses/oncogenes cause AMl, viral oncogenesis is an area of intense epidemiologic research.

References

Wiernik PH: Acute leukemias, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, ed 3. Philadelphia, JB Lippincott, 1989, pp 1809-1835.


Development of the Myeloid Cell Line From the Pluripotent Stem Cell

  • AML represents a block in myeloid differentiation and maturation and an increased proliferation of the blasts.
  • The following growth factors play a role in the differentiation of normal hematopoietic cells:
    • erythropoietin (EPO)
    • thrombopoietin interleukin-1 (IL-1)
    • interleukin-3 (IL-3)
    • interleukin-5 (IL-5)
    • interleukin-6 (IL-6)
    • granulocyte-macrophage colony-stimulating factor (GM-CSF)
    • granulocyte colony-stimulating factor (G-CSF)
    • macrophage colony-stimulating factor (M-CSF)
    • others
  • As a result of chromosomal translocations, alterations in growth factor or growth factor receptorlsl functions may be key to the pathogenesis of AML.

References

Schrier SL: Hematopoiesis and red blood cell function, in Rubenstein E, Federman DD (edsl: Scientific American Medicine, New York, Scientific American, 1988, vol 5, pp 2-8.

Wiernik PH: The acute leukemias, in Kelley WN (ed): Textbook of Internal Medicine. Philadelphia, JB Lippincott, 1989, pp 1173-1177.


Classification of AML

Classification of AML

Type

FAB

Acute myeloid leukemia
(Acute nonlymphocytic leukemia, ANLL)

AML

Acute myelocytic leukemia

AML-M1
AML-M2

Acute promyelocytic leukemia

AML-M3

Acute myelomonocytic leukemia

AML-M4,M4E

Acute monoblastic leukemia

AML-M5

Acute erythroleukemia

AML-M6

Megakaryoblastic leukemia

AML-M7


  • Several terms are used interchangeably to describe AML. Acute myeloid leukemia is generally preferred.
  • Subtypes of leukemia are generally identified by the FAB classification, M1-M7.
  • FAB types M1, M2, and M4 each account for approximately 20% of adult AML patients.
  • Subgroups of AML not defined in the FAB classification are:
    • undifferentiated acute leukemia
    • MO (AML lacking< definitive myeloid differentiation by morphology or conventional cytochemistry but with ultrastructural or immunophenotypic evidence of AML)
    • mixed lineage leukemia
    • hypocellular AML

References

Cheson BD, Cassileth PA, Head DR, et al: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990;8:813-819.

Henderson ES: Definition and classification, in Henderson ES, Lister TA (eds): Leukemia, ed 5 Philodelphia, WB Saunders Co, 1990, pp 13-15.

Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Group. Ann Internal Med 1985; 103:460-462.


Morphological Features of AML

Morphological Features of AML
TYPE(FAB) CHARACTERISTIC MORPHOLOGY
Acute myelocytic leukemia (M1) Cells very undifferentiated, occasionally cytoplasmic granules, some promyelocytes seen.
Acute myelocytic leukemia (M2) Granulated blasts predominate, small number of monocytoid cells may be present, differentiation beyond promyelocytic stage evident, +/- Aeur bodies
Acute promyelocytic leukemia (M3) Typically, hypergranular promyelocytes predominate, cells have large basophilic and esoinophilic granules, +/- Auder bodies
Acute myelomonocytic leukemia (M4) Monocytic and granulocytic precursors seen, serum lysozyme elevated, +/- Auer bodies
Acute monoblastic leukemia (M5) Large monoblasts with abundant, agranular cytoplasm that may be vacuolated and basophilic
Erythroleukemia (M6) Megaloblastoid red cell precursors predominate, myeloid blasts also seen, multinucleated red cell precursors common
Megakaryocytic leukemia (M7) Variable morphology, megakaryocytic features may not be seen with light microscopy
  • Identification of AML subtypes is important because several new drugs have more activity against some varieties than against others.
  • Prognosis and some clinical features may differ considerably among the various AML subtypes.

References

Wiernik PH: Acute leukemias, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, ed 3. Philadelphia, JB Lippincott Co, 1989, pp 1809-1835.

Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Group. Ann Intem Med 1985; 103:460-462.


Histochemical Features of AML

Histochemical Features of AML
FAB HISTOCHEMISTRY
M1 Occasional peroxidate+ granules, PAS-
M2 Strongly peroxidase+, PAS-
M3 Strongly peroxidase+, PAS-
M4 Strongly peroxidase+, some cells may be PAS+
M5 Many be peroxidase+ and PAS+, nonspecific esterase stains are strongly + and inhibited by NAF
M6 Red cell precursors are PAS+, ringed sideroblasts are seen with iron stains
M7 Variable, platelet peroxidase can be demonstrated by electron microscopy

  • Distinction among the various subgroups of AML is now possible with greater precision because of new histochemical studies and immunologic techniques.
  • Immunophenotyping and terminal deoxytransferase (TDT) determination may help distinguish between AML and ALL, and between the various subtypes of AML.

Reference

Wiernik PH: Acute leukemias, in DeVita VTJr, Hellman S, Rosenberg SA ledsl: Cancer: Principles and Practice of Oncology, ed 3. Philadelphia, JB Lippincott Co, 1989, pp 1809-1835.


Peripheral Blood Features of AML

  • The peripheral white blood cell count may be increased, decreased, or normal with approximately equal frequency.
  • Granulocytopenia is very common. Approximately 1/2 of all patients will have granulocyte counts < 1,000/uL.
  • Thrombocytopenia is frequently observed and platelet counts <20,000/uL are common.
  • The hematocrit is generally low but severe anemia is uncommon.
  • Circulating blast cells are absent from the peripheral blood in approximately 15% of AML patients initially, and in 1/2 of patients presenting with leukopenia.

Reference

Wiernik PH: The acute leukemias, in Kelley WN (ed): Textbook of Internal Medicine. Philadelphia, JB Lippincott, 1989, pp 1 173-1 177.


Clinical Diagnostic Features of AML

  • Adults with AML generally present with a vague history of chronic progressive lethargy; granulocytopenia and thrombocytopenia are common.
  • The definitive diagnosis is made by examination of a bone marrow aspirate.
  • As many as 1/3 of patients with AML will be acutely ill at presentation because of a significant skin, soft tissue, or respiratory infection.
  • Petechiae with or without bleeding may be present. Patients with acute promyelocytic (M3) leukemia may have severe hemorrhaging secondary to a clotting factor deficiency, which results in an intravascular coagulopathy.
  • Hyperuricemia is frequent; splenomegaly is present in about 1/3 of patients.
  • Leukemias with a monocytic component (M4 & M5) may be associated with gingival hypertrophy from leukemia infiltration. Patients with these types of AML are most likely to present with or develop meningeal leukemia, retinal infiltration, leukemia cutis, or other localized leukemia infiltrations.
  • Chloromas (granulocytic sarcomas, myeloblastomas) are present in about 5% of patients. They may take on a dull green color due to the high peroxidase content in the leukemia cell, may precede other diagnostic evidence, may occur aher diagnosis, or may indicate relapse. They commonly occur in the skin but can be present in other body organs. They are most ohen associated with M4 and M5 leukemias.
  • Lymphadenopathy and hepatomegaly are uncommon. Increased intracranial pressure secondary to meningeal leukemia may rarely be present at presentation. Such patients usually have FAB M4 morphology and are usually young. In the absence of meningeal signs, a lumbar puncture is not indicated.

Reference

Wiernik PH: The acute leukemias, in Kelley WN (ed): Textbook of Internal Medicine. Philadelphia, JB Lippincott, 1989, pp 1173-1177.


Diagnostically Important AML Markers

  • Morphologic
    • Auer bodies
    • "malignant" primary granules
  • Cytoplasmic organelles
    • chloracetate esterase
    • Sudan B
    • myeloperoxidase
  • Cytogenetic
    • t(8;21)
    • t(15;17)
    • -5,-7
  • Immunologic/biochemical
    • lysozyme
    • cell surface markers
  • A variety of morphologic, cytoplasmic, cytochemical, and biochemical features are associated with AML that can aid in diagnosis.
  • No available marker is either totally specific or sensitive enough to be used in all cases.
  • Cytogenetic analyses should be performed at diagnosis in all patients with AML. Approximately 65% of patients will have abnormal karyotypes.
  • Cytogenetic abnormalities may help determine prognosis.

References

Henderson ES, Afshani E: Clinical manifestation and diagnosis, in Henderson ES, Lister TA (eds): Leukemia, ed 5. Philadelphia, WB Saunders, 1990, pp 291-359.

Cheson BD, Cassileth PA, Head DR, et al: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990;8:813-819.


Work-Up for Patient with AML

  • Complete history:
    • family, work, and medical history
    • radiation and chemical exposure history
  • Complete physical examination, with special attention to:
    • temperature Iymph node-bearing areas and splenic
    • area optic fundi and cranial nerves
    • potential sites of infection:
      • skin, including axillae
      • oropharynx, including gingivae
      • lungs
      • perianal area
    • Peripheral blood studies:
      • hematocrit, leukocyte count, platelet count
      • leukocyte differential count
    • Bone marrow examination:
      • perform biopsy to determine cellularity
      • aspirate smears stained with Wright's, Sudan black, and esterase stains; periodic acid-Schiff reagent; iron stain; and immunofluorescent stain for terminal transferase
      • aspirate for karyotyping and immunophenotyping
      • Blood chemistries and other studies:
        • serum electrolytes, uric acid, blood urea nitrogen, and muramidase (lysozyme)
        • coagulation profile, including fibrinogen level, prothrombin time, and partial thromboplastin time
        • liver function analysis
      • Chest radiographs:
        • chest posteroanterior and lateral radiographic films
      • Transfusion work-up:
        • determine blood type and human leulocyte antigen type if patient has circulating lymphocytes
        • do same for family members who are willing to serve as platelet, granulocyte, or potential marrow donors

References

Wiernik PH: Acute leukemias, in DeVita VT Jr, Hellman S, Rosenberg SA {eds): Cancer: Principles and Practice of Oncology, ed 3 Philadelphia, JB Lippincott, 1989, pp 1809-1835.


Prognostic Factors in AML

Favorable
young age reactivity with CD2(T1)
FAB types M2, M3, M4 t(8;21) and t(15;17) abormality
inversion of chromosome 16
Unfavorable
older age low labeling index/aneuoploidy
FAB type M7 trisomy 8
hyperleukocytosis deletion of all or part of chromosomes 5 and/or 7
prior treatment abormalities of chromosome 11 at band q23
prior heamtologic disorder
infection

  • Although other cutoffs have been used, age greater than 60 is usually considered a poor prognostic factor because older patients generally don't tolerate therapy as well as younger patients. They also have a higher likelihood of having unfavorable prognostic factors such as special cytogenetic abnormalities.
  • Types M2, M3, and M4 have the best prognoses, types M5 and M6 have variable prognoses, and type M7 has the worst prognosis.
  • The presence of certain cell surface markers such as CD2 appears to be associated with a favorable prognosis.
  • Inversion (16) is usually associated with type M4 and marrow eosinophilia. This syndrome has an excellent prognosis for remission induction and duration.

References

Wiernik PH: Acute leukemias, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncotogy, ed 3. Philadelphia, JB Lippincott, 1989, pp 1809-1835.

Cheson BD, Cassileth PA, Head DR, et al: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990;8:813-819.


Definition of Complete Remission of AML

  • The primory focus of AML treatment is to obtain a complete responseóanything less does not improve survival.
  • Complete response is defined as the following for at least 4 weeks:
    • restoration of normal peripheral blood counts
    • maturation of all hemotopoietic cell lines
    • less than 5% blast forms in a normocellular bone marrow
  • The achievement of a complete response has been associated with a reduction in the leukemic burden from 1012 (ie, one trillion) cells to 109 (ie, one billion) cells. Despite this enormous destruction of tumor cells, the remaining, clinically unidentifiable 109 cells represent minimal residual disease and must be eliminated if relapse is to be avoided.

References

Cheson BD, Cassileth PA, Head DR, et al: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 1990;8:813-819.


Preparing the Patient with AML for Definitive Therapy

  • Transfusions
  • Heparin for DIC*
  • Antibiotics
  • Prevent intracerebral leukostasis*
  • Allopurinol
  • Prophylactic bowel decontamination*
  • Central catheter placement if necessary
  • If the clinical situation warrants, blood and platelets should be transfused.
  • Administer heparin prophylactically in patients with laboratory evidence of disseminated intravascular coagulation.*
  • Fever in a granulocytopenic patient should be treated with empiric broad-spectrum IV antibiotics.
  • Prevent intracerebral hemorrhage in patients with greatly elevated blood blast counts (>100,000). Methods include hydration, starting definitive therapy within 24 hours, oral hydroxyurea*, cranial RT*, and leukopheresis.*
  • Assess cenal and liver functions; prophylactic allopurinol should be started and discontinued within 5 to 10 days.
  • Begin prophylactic bowel decontamination if it is to be used.*
  • Insert an indwelling right atrial catheter in preparation for treatment and support.
*Controversy exists about these points.

References

Wiernik PH: Acute leukemias, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, ed 3. Philadelphia, JB Lippincott, 1989, pp 1809-1835.

Rohatiner AZS, Lister TA: The treatment of acute myelogenous leukemia, in Henderson ES, Lister TA (eds): Leukemia, ed 5. Philadelphia, WB Saunders, 1990, pp 485-513.


AML Definitive Treatment Strategies

  • Remission induction therapy: 1 to 2 courses of intensive therapy to achieve a complete response.
  • Post-remission therapy:
    • consolidation therapy: 1 to 2 courses of intensive short- course therapy to further reduce the subclinical body burden of tumor
  • Followed by (in some patients):
    • maintenance therapy: months to years of less intensive therapy to further prevent recurrence
      or
    • autologous bone marrow transplantation

    • or
    • allogeneic bone marrow transplantation

Standard Agents Used to Treat AML

  • Ara-C is generally administered during induction therapy as a continuous infusion at 100 mg/m²/day for 7 days.
  • An anthracycline is combined with the ara-C during induction and consolidation therapies and is administered for 2 to 3 days.
  • 6-Thioguanine has been incorporated into the induction and/or post-remission therapies of some regimens.
  • Mitoxantrone has also been used in combination with ara~ for induction therapy.

Questions About Optimal Therapy for AML

  • What drug should be used in combination with ara-C for induction therapy?
  • Which post-remission therapy is best?
    • consolidation
    • maintenance
    • bone marrow transplantation
  • Is there a role for colony-stimulating factors?
  • The emphasis of clinical trials in AML is to evaluate:
    • other anthracyclines or alternative agents as replacements for daunorubicin in combination with ara-C as standard therapy for induction
    • the relative merits of consolidation, maintenance therapy, and bone marrow transplantation
    • the potential role of colony-stimulating factors in AML treatment

Proposed Development of Post-Remission Therapy in AML

  • The combination of low close ara-C with 6-TG was demonstrated to be superior to no post-remission treatment.
  • Allogeneic bone marrow transplantation was identified as a means to increase the cure rate.
  • Long-term intensive maintenance with the combination of ara-C plus 6-TG increased the cure rate.
  • Early intensification with high-dose ara-C increased the cure rate.
  • High-dose consolidation therapy followed by maintenance therapy was shown to be superior to consolidation therapy alone.
  • High-dose ara-C combined with daunorubicin was shown to be superior to high-dose ara-C alone.
  • Low dose ara-C was shown to be superior to no treatment for AML in second complete remission.

Baltimore Cancer Research Center Trial in AML Intensive Maintenance Therapy

  • In this study, 86 patients (median age = 47) with AML in remission received intensive maintenance chemotherapy with ara C plus 6-TO, at the following doses:
    • Ara-C 100 mg/m² SC q 12h
      until marrow aplastic*
    • 6-TG 100 mg/m² po q 12h *Doses repeated q 3 mo x 3 y
  • The median duration of remission was 21 months, and the median duration of survival for remiHers was 25 months.
  • Compared with historical controls who received less intensive maintenance therapy at the same institution, intensive maintenance therapy significantly improved remission duration and survival.

References

Dutcher JP, Wiernik PH, Markus S, et al: Intensive maintenance therapy improves survival in adult acute nonlymphocytic leukemia: An eight-year follow-up. Leukemia 1988;2:413-419.


Factors Correlating With Response to AML Therapy

  • The following factors have been found to correlate with achievement of a complete response:
    • younger age and good performance status
    • prior bone marrow disorder
    • Auer rods marrow eosinophilia
    • in vitro sensitivity to ara-C and daunorubicin
    • rapid clearance of blast cells from the peripheral blood and a low percentage in the bone marrow aspirate ~ days post-treatment
  • The following factors have had a negative influence on the achievement of a complete response:
    • older age
    • co-morbid diseases
    • specific karyotypic abnormalities
    • specific cell surface antigens
    • abnormalities of the erythroid series

Reference

Rohatiner AZS, Lister TA: The treatment of acute myelogenous leukemia, in Henderson ES, Lister TA {eds): Leukemia, ed 5 Philadelphia, WB Saunders, 1990, pp 485-513.


Prognostic Significance of MDRI Expression in AML

  • Drug resistance may be due to several mechanisms. These include increased expression of multidrug-resistant (MDR1 or MDR3~ gene, alterations in topoisomerase 11 activity, or enhanced glutathione activity.
  • In patients with AML, MDR1 messenger RNA is increased in the minority of de novo cases, but is increased in those with refractory, relapsed, and secondary leukemia.
  • The MDR1 messenger RNA levels correlate with response to therapy.
  • Older patients have a higher incidence of MDR1 messenger RNA than younger patients.

References

Pirker R, Wallner J, Geissler K, et al: MDR1 gene expression and treatment outcome in acute nonlymphocytic leukemia. Ann Hematol 1991;62:A11.

Gerber A, Norgen S, Vitols S: Expression of MDR1 gene in acute leukemias correlates with treatment outcome. Ann Hematol 1991;62:A1O.


All-Trans-Retinoic Acid in Relapsed Acute Promyelocytic (M3) Leukemia

  • The retinoic acid nuclear receptor alpha (RAR-alpha) maps to chromosome 17 in the region of the characteristic cytogenetic abnormolity of the M3 (acute promyelocytic leukemia) translocation, t(l5;17).
  • The differentiating agent, all-trans-retinoic acid at a dose of 45 mg/m²/day produces complete responses in approximately 70% of patients treated.
  • Complete remissions are obtained without marrow hypoplasia.
  • Remission is associated with the disappearance of t(15;17).

Reference

Castaigne S, Chomienne C, Daniel MT, et al: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia: Part 1. Clinical results. Blood 1990;76:704-1709.

Miller WH, Warrell RPJr, Frankel SR, et al: Novel retinoic acid receptor-alpha transcripts in acute promyelocytic leukemia responsive to all-trans-retinoic acid. J Natl Cancer Inst 1990;82:1932-1933

Menger H, Yuchen Y, Shu-rong C, et al: Use of all-trans-retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988;72:567-572.


Allogeneic Bone Marrow Transplantation in AML

  • Allogeneic transplantation can act as a salvage for chemotherapy failures
  • Allogeneic transplantation is feasible only in patients under 45 who have an HLA-compatible donor:
    • 40% of patients with AML are <45 years old.
  • The probability of benefit following allogeneic transplantation in AML is as follows:
    • The complete remission rate is patients < 45 is 75% to 80%; 30% of all AML patients are eligible becuase they are < 45 and are in CR
    • 33% of patients will have an HLA match; 10% of all AML patients are eligible because they are < 45, are in CR, and have an HLA match.
    • 50% of patients treated will be cured with allogeneic transplantation.
  • Therefore, approximately 5% of all AML patients are cured by allogeneic transplantation.
  • The mortality rate following allogeneic transplantation is 25% to 50%.
  • Because of the mortality rate associated with allogeneic bone marrow transplantation, it is recommended by some for patients who achieve a second complete remission or have an early relapse.
  • Subgroups of patients may be identified who may benefit from bone marrow transplantation in first remission versus continued chemotherapy using pretreatment variables.

References

Tallman MS, Kopecky KJ, Amos D, et al: Analysis of prognostic factors for the outcome of marrow transplantation or further chemotherapy for patients with acute nonlymphocytic leukemia in first remission. J Clin Oncol 1989;7:326-337.

Wiernik PH: Approach to the management of leukemia, in Kelley WN (ed): Textbook of Internal Medicine. Philadelphia, JB Lippincott, 1989, pp 1298-1306.


AML Treatment Statistics

  • Between 65% and 70% of patients will achieve a complete remission with first-line therapy; approximately 80% of these will completely respond aher the first course.
  • The median duration of complete remission is 12 to 18 months with some form of intensive post-remission therapy.
  • There is a 25% to 50% 3- to 5-year disease-free survival rate in complete responders in selected series; relapses are rare after 4 to 5 years.
  • As many as 65% of patients will have secondary complete responses aher treatment with high-dose ara-C with or without AMSA or mitoxantrone. However, the cure rate aher such therapies is <5%.
  • Long-term survival rates after bone marrow transplant are:
    • 45% to 50% (first remission)
    • 25% to 30% (second remission)
    • 15% to 20% (in relapse)
  • The mortality rate aher bone marrow transplant is approximately 25% to 50%.
  • The major causes of morbidity and mortality ore infection and bleeding related to pancytopenia.

Reference

Wiernik PH: The acute leukemias, in Kelley WN (ed): Textbook of Internal Medicine. Philadelphia, JB Lippincott, 1989, pp 1173-1177.


Infectious Disease Statistics in Granulocytopenic Patients with AML

  • Infection is the major cause of morbidity and mortality in potients with AML.
  • 75% of gronulocytopenic patients will require broad-spectrum antibiotic therapy for fever.
  • There is an inverse correlation between the granulocyte count and both the incidence and severity of infection, which becomes most prominent at granulocyte counts <0.5 x 109/L.
  • Patients who receive induction therapy are generally granulocytopenic for 3 to 4 weeks; half of the time the gronulocyte count is near 0
  • The organisms that cause infection are those that colonize areas where there is mucosal damage or venipuncture/bone morrow sites. These include gram-negative bacilli (eg, E coli, P aeruginosa, K. pneumoniae), the groin-positive coccus S aureus, Candida sp., and Aspergillus sp.

Reference

Schimpff SC: Infection in the leukemia patient: Diagnosis, therapy, and prevention, in Henderson ES, Lister TA (eds): Leukemia, ed 5. Philadelphia WB Saunders Co. 1990. pp 687-709.


Methods to Prevent Infection in AML

  • Treat the leukemia

  • Reduce invasive and traumatic procedures:
    • scalp vein needles (changed every 48 hoursl or central venous catheters

      • Reduce the acquisition of new organisms:
        • proper handwashing techniques
        • proper housekeeping
        • low microbial diet
        • (?) reverse isolation
        • (?)laminar air flow room

      • Suppress potential pathogens already colonized:
        • oral nonabsorbable antibiotics
        • daily shower and shampoo with antimicrobial soap
        • selective microbial suppression leg, trimethoprim, sulfamethoxazole or norfloxacin and nystatin, with or without ketoconazole)

Reference

Schimpff SC: Infection in the leukemia patient: Diagnosis, therapy, and prevention, in Henderson ES, Lister TA (eds): Leukemia, ed 5 Philadelphia, WB Saunders Co, 1990, pp 687-709.


Infectious Diseases Society of America Febrile Neutropenic Patient Treatment Recommendations

  • Evaluate all febrile patients with neutrophil counts < 500/uL and those with counts of 500 to lOOO/uL in whom a decrease is expected.
  • Patient and infectious disease considerations should include:
    • renal impairment/on nephrotoxic drugs
    • suspect: S. aureus, Staphylococcus coag(-), Pseudomonas aeruginosa
    • hospital acquired infection
    • vascular catheter infection
    • neutrophil count 500 to 1000 uL
  • Treat with broad-spectrum intravenous antibiotics in maximal therapeutic doses.
  • If a causative agent is identified, modify to optimal susceptibility but maintain broad-spectrum coverage.
  • In the afebrile patient, continue antibiotics until cultures are negative, there are no sites of infection, the patient is free of significant symptoms and signs, and for a minimum of 7 days.

Reference

Hughes WE, Bodey GP, Myers JD, et al: Guidelines for use of antimicrobial agents in neuiropenic patients with unexplained fever. J Infect Dis 1990;161:381-396.


Infectious Diseases Society of America Persistent Fever Recommendations

  • Reevaluate patients with persistent fever >3 days.
  • Consider nonbacterial cause, resistant bacterial infection, emergence of a second bacterial infection, inadequate drug levels, drug fever, infection at avascular sites.
  • If patient's condition has not changed, continue initial antibiotic regimen.
  • If there is evidence of progressive disease, change to different antibiotics:
    • add vancomycin if there is evidence of S. epidermidis, Corynebacterium sp, or alpha-hemolytic streptococcus infection
    • if patient was on a triple-drug combination including vancomycin, consider a third-generation cephalosporin
  • Consider the addition of antifungal therapy in patients who remain febrile and profoundly neutropenic for > 1 week.

Reference

Hughes WT, Bodey GP, MyersJD, et al: Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 1990;161:381-396.


Infectious Diseases Society of America Recommendations for Antibiotic Discontinuation in Afebrile Patients

  • Generally, all febrile neutropenic patients should be treated for at least 1 week with antibiotic therapy.
  • If the patient becomes afebrile in 48 to 72 hours and has a neutrophil count >= 500/uL by day 7, consider discontinuing antibiotics.
  • If the patient becomes afebrile in 48 to 72 hours and has a neutrophil count < 500/uL and is clinically well, consider discontinuing antibiotics after 5 to 7 afebrile days; monitor the patient closely.
  • If the patient becomes afebrile in 48 to 72 hours and has a neutrophil count < 500/uL, and is not clinically well, continue antibiotics until neutrophils > 500/uL or clinically well.

Reference

Hughes WL, Bodey GP, MyersJD, et al: Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 1990; 161:381-396.


Infectious Diseases Society of America Recommendations for Antibiotic Discontinuation in Febrile Patients

  • If fever lasts for more thon 3 days and the neutrophil count is < 500/uL, consider discontinuing antibiotics aher 3 weeks (including 2 weeks of amphotericin B), if there is no evidence of infection and the patient is clinically well.
  • If fever lasts for more than 3 days and the neutrophil count is <500/uL despite antibiotic therapy, consider discontinuing antibiotics aher 4 to 5 days of neutrophils > 500/uL, if there is no evidence of infection. Consider a fungal or viral infection.

Reference

Hughes WT, Bodey GP, MyersJD, et al: Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 1990; 161:381-396.


Thrombocytopenia in AML Patients

  • Since the introduction of platelet transfusions, thrombocytopenia is second to infection as a cause of morbidity and mortality.
  • Virtually all patients with AML will require prophylactic platelet transfusions.
  • Patients should be HLA-typed early since many will ultimately require HLA-matched platelets.

Factors Predisposing to Thrombocytopenic Bleeding in AML

The factors that may predispose to bleeding from thrombocytopenia include:

  • concurrent infection which leads to increased platelet destruction
  • vitamin K deficiency leg, associated with antibiotics and poor nutrition) causing coagulopathy
  • DIC associated with infection, tumor Iysis, and the diagnosis of acute promyelocytic leukemia
  • potential bleeding sites such as Gl tract ulcerations and splenomegaly with infarction

Reference

Dutcher JP: Platelet transfusion therapy in patients with malignancy, in Dutcher JP ledl: Modern Transfusion Therapy. Boca Raton, FL, CRC Press, 1990, vol 2, pp 25-50.


Platelet Transfusion Therapy in AML

  • Prophylactic platelet transfusions are generally administered for platelet counts < 20,000/uL.
  • Surgery can be performed if the platelet count is maintained above 50,000/uL.
  • Therapeutic platelet transfusion given in the face of bleeding.
  • Types of platelet transfusion products available include:
    • pooled random donor
    • single donor (apheresis)
    • HLA-matched single donor
    • ymphocyte-depleted
    • autologous frozen
  • Selection of a specific platelet transfusion product depends on patient characteristics and prior response to therapy.

References

Dutcher JP: Platelet transfusion therapy in patients with malignancy, in DutcherJP (ed): Modern Transfusion Theropy. Boca Raton, Fl, CRC Press, 1990, vol 2, pp 25-50

Slichter SJ: Prevention of platelet alloimmunization, in Transfusion Medicine: Recent Technological Advances. New York, Alan R. Liss, 1986, pp 83-97.


Assessing Response to Platelet Transfusions in AML

  • To assess response to platelet transfusions, 30 to 60-minute and 24-hour post-transfusion platelet counts should be obtained.
  • The corrected count increment ICCI) can be calculated by:
  • CCI = (absolute increment)/(# platelets given) x m² (BSA)

  • The following calculated CCI indicates a good response:
  • CCI (at 1 hour) >= 10
    CCI (at 24 hoursl >= 7

  • The factors that may affect response to platelet transfusions and may therefore require daily platelet transfusions include:
    • DlC/bleeding
    • infection
    • fever
    • amphotericin therapy
    • alloimmunization

Reference

Dutcher JP: Platelet transfusion therapy in patients with malignancy, in Dutcher JP (ed): Modern Transfusion Therapy. Boca Raton, FL, CRC Press, 1990, vol 2, pp 25-50.


Treatment of Newly Diagnosed AML Summary

Treatment of Newly Diagnosed AML Summary

CR rates Probability of CRs remaining in remission Estimated cure rates*
Overall 60% to 65% 20% to 30% 20%
Age < 40 75% to 80% 40% 30% to 35%
Age 40-60 70% to 75% 30% 20% to 25%
Age > 60 45% to 50% 20% 10%

  • Twenty years ago the treatment of AML was associated with on occasional complete response and no cures.
  • Today complete remissions in AMl are expected, and the overall cure rate using true estimates by age is approximately 20%.

Future Directions in AML

Areas of treatment and supportive care that will be studied in the future include:

  • optimal post-remission therapy
  • monoclonal antibodies linked to cellular poisons limmunotoxins) to optimize the graft vs leukemia effect
  • growth factors to synchronize leukemia cells
  • differentiating agents (eg, all-trans-retinoic acid)
  • agents to overcome multidrug resistance
  • other antineoplastic agents to improve remission duration (eg, etoposide)
  • improved supportive care for induction therapy
  • development of HLA antigen-free platelets

Consolidation in AML High-Dose Ara-C*/Daunorubicin

  • In this uncontrolled trial, 87 patients in first remission received post-remission consolidation therapy with high-dose ara-C* l3 g/m² IV q 12h x 6d) followed by daunorubicin 30 mg/m²/d IV x 3d), for 1 to 3 courses (median age = 38).
  • There was a lack of uniformity in the number of courses received and whether daunorubicin was administered.
  • At a median follow-up of >3.5 years from diagnosis, 49% of patients were in a continuous remission (CCR).
  • The probability of remaining in a CCR was 83%, 50%, and 23% for age groups < 25, 26 to 45, and > 45 years, respectively.
  • The incidence of serious but nonfatal infections or extramedullary organ toxicity was 59%. The mortality rate due to infection and/or hemorrhage was 5%.
*Investigational

Reference

Wolff SN, Herzig RH, Fay JW, et al: High-dose cytarabine and daunorubicin as consolidation therapy for acute myeloid leukemia in first remission: Long-term follow-up and results. J Clin Oncol 1989;7;1260-1267.


AML in Relapse Treatment Strategies

  • Treatment of refractory or relapsed AML generally includes the use of high-dose ara-C* (3 g/m² q 12h x 6d), with or without one of the following:
    • AMSA
    • mitoxantrone
    • etoposide
  • There is no evidence that one chemotherapy regimen is better than another.
  • Complete responses are obtained in a minority of patients with refractory or relapsed AML, are more frequent in patients who had a lengthy remission, and are generally of brief duration.
*Investigational

Italian Cooperative Group GIMEMA Trial in AML
Idarubicin/Ara-C vs Daunorubicin/Ara-C

  • The results of this study emphasize the importance of supportive care during induction. There was a higher incidence of induction deaths on the idarubicin arm, which may have adversely affected the outcome of this trial. It can be speculated that these results were due to the lack of appropriate supportive care at some of these institutions.

References

Data on file, Adria Laboratories, Division of Erbamont Inc., Columbus, Ohio, 43215.

Petti MC, Mandelli F: Idarubicin in acute leukemias: Experiences of the Italian Cooperative Group GIMEMA. Semin Oncol 1989;16:10-15.




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