In acute myeloid leukemia (AML), malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results in high circulating numbers of immature blood cells and replacement of normal marrow by malignant cells. Symptoms include fatigue, pallor, easy bruising and bleeding, fever, and infection; symptoms of extramedullary leukemic infiltration are present in only about 5% of patients (often as skin manifestations). Examination of peripheral blood smear and bone marrow is diagnostic. Treatment includes induction chemotherapy to achieve remission and postremission chemotherapy (with or without stem cell transplantation) to avoid relapse.
(See also Overview of Leukemia.)
The American Cancer Society estimates that in the United States in 2023 there will be about 20,000 new cases of acute myeloid leukemia (AML) and about 11,300 deaths , almost all in adults. AML is slightly more common among men than women, but the average lifetime risk in both sexes is about 0.5% (1 in 200 Americans).
AML comprises about 25% of childhood leukemias, often developing in infancy. However, the incidence of AML increases with age; it is the most common acute leukemia in adults, with a median age of onset of 68 years. AML also may occur as a secondary cancer after chemotherapy or radiation therapy for a different type of cancer. Secondary AML is difficult to treat with chemotherapy alone.
Pathophysiology of AML
Similar to acute lymphoblastic leukemia, acute myeloid leukemia is caused by a series of acquired genetic aberrations. Malignant transformation usually occurs at the pluripotent stem cell level, although it sometimes involves a committed stem cell with more limited capacity for self-renewal. Abnormal proliferation, clonal expansion, aberrant differentiation, and diminished apoptosis (programmed cell death) lead to replacement of normal blood elements with malignant cells.
Classification of AML
Acute myeloid leukemia has a number of subtypes and precursor neoplasms that are distinguished from each other by morphology, immunophenotype, cytochemistry, and genetic abnormalities (see also The 2016 World Health Organization [WHO] Classification of myeloid neoplasms) all of which have important implications for prognosis and treatment. Seven classes are described in the WHO classification, including
AML with recurrent genetic abnormalities
AML with myelodysplasia-related changes (AML-MRC)
Therapy-related AML (t-AML)
AML, not otherwise specified (NOS)
Myeloid sarcoma
Myeloid proliferations related to Down syndrome
Blastic plasmacytoid dendritic cell neoplasm
Morphologic criteria from the previous French-American-British (FAB) classification system are used for subtypes that are not otherwise specified (NOS).
Acute promyelocytic leukemia (APL) is a subtype of AML with recurrent genetic abnormalities. APL is a particularly important subtype, representing 10 to 15% of all cases of AML, striking a younger age group (median age 31 years) and particular ethnicity (Hispanics). Patients commonly present with a coagulation disorder (eg, disseminated intravascular coagulation [DIC]).
Therapy-related AML (t-AML) is a subtype of AML caused by prior treatment with certain antineoplastic drugs (eg, alkylating agents, hydroxyurea, and topoisomerase II inhibitors). Most t-AMLs occur 3 to 10 years after initial therapy, with a longer latency for alkylating agents and hydroxyurea (mean latency 5 to 7 years) than for topoisomerase II inhibitors (mean latency 6 months to 3 years). Alkylating agents cause chromosomal deletions and unbalanced translocations. Hydroxyurea causes del(17)p and also inhibits TP53 activation. Topoisomerase II inhibitors lead to balanced chromosomal translocations.
Myeloid sarcoma is characterized by extramedullary myeloblastic infiltration of skin (leukemia cutis), gingiva, and other mucosal surfaces.
Symptoms and Signs of AML
Symptoms of acute myeloid leukemia may be present for only days to weeks before diagnosis. The most common presenting symptoms are due to disrupted hematopoiesis with ensuing
Anemia
Thrombocytopenia
Granulocytopenia
Anemia can manifest with fatigue, weakness, pallor, malaise, dyspnea on exertion, tachycardia, and exertional chest pain.
Thrombocytopenia can cause mucosal bleeding, easy bruising, petechiae/purpura, epistaxis, bleeding gums, and heavy menstrual bleeding. Hematuria and gastrointestinal bleeding are uncommon. Patients can present with spontaneous hemorrhage, including intracranial or intra-abdominal hematomas.
Granulocytopenia (neutropenia) can lead to a high risk of infections, including those of bacterial, fungal, and viral etiologies. Patients may present with fevers and a severe and/or recurrent infection. The cause of fever often is not found, although granulocytopenia may lead to a rapidly progressing and potentially life-threatening bacterial infection.
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Leukemia cutis can have various appearances, including papules or nodules, and plaques, and may be erythematous, brown, hemorrhagic, or violaceous/gray-blue.
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Leukemic cell infiltration of other organ systems tends to be less common in AML than in ALL; however:
Infiltration can enlarge the liver, spleen, and lymph nodes.
Bone marrow and periosteal infiltration may cause bone and joint pain.
Meningeal infiltration can result in cranial nerve palsies, headache, visual or auditory symptoms, altered mental status, and transient ischemic attack/stroke.
Diagnosis of AML
Complete blood count (CBC) and peripheral blood smear
Bone marrow examination
Histochemical studies, cytogenetics, immunophenotyping, and molecular biology studies
A diagnosis of acute myeloid leukemia is made when myeloid blast cells are ≥ 20% of marrow nucleated cells or ≥ 20% of nonerythroid cells when the erythroid component is > 50%, or at any blast percentage in the presence of recurrent cytogenetic abnormalities [t(8;21), t(15;17), inv(16) or t(16;16)]. Diagnosis can be made by the same criteria using peripheral blood.
By permission of the publisher. From Chang K, Forman S. In Atlas of Clinical Hematology. Edited by JO Armitage. Philadelphia, Current Medicine, 2004.
CBC and peripheral smear are the first tests done; pancytopenia and peripheral blasts suggest acute leukemia. Blast cells in the peripheral smear may approach 90% of white blood cell (WBC) count.
Aplastic anemia, viral infections such as infectious mononucleosis, vitamin B12 deficiency, and folate deficiency should be considered in the differential diagnosis of severe pancytopenia. Leukemoid reactions (marked granulocytic leukocytosis [ie, WBC > 50,000/mcL, > 50 × 109/L] produced by normal bone marrow) to infectious disease never manifest with high blast counts.
Bone marrow examination (aspiration and needle biopsy) is routinely done. Blast cells in the bone marrow are typically between 25 and 95% in patients with AML.
Histochemical studies, cytogenetics, immunophenotyping, and molecular biology studies help distinguish the blasts of ALL from those of AML or other diseases. Histochemical studies include staining for myeloperoxidase, which is positive in cells of myeloid origin. Crystallization of myeloperoxidase-rich granules leads to formation of Auer rods (linear azurophilic inclusions in the cytoplasm of blast cells), which are pathognomic for AML. Detection of specific immunophenotypic markers (eg, CD13, CD33, CD34, CD117) is essential in classifying the acute leukemias.
Commonly observed cytogenetic abnormalities in AML include t(15;17), trisomy 8, t(8;21), inv(16) or t(16;16) and 11q23.3 rearrangements (see table Common Cytogenetic Abnormalities in Acute Myeloid Leukemia).
Поширені цитогенетичні аномалії при гострому мієлоїдному лейкемії
Cytogenetic Abnormality | Incidence* | Prognosis |
|---|---|---|
t(15;17)(q24.1;q24.1)/PML-RARA | 13% | Favorable |
t(16;16) or inv(16)(p13.1;q22)/CBFB-MYH11 | 5% | Favorable |
t(8;21)/(q22;q22)/RUNX1-RUNX1T1 | 7% | Favorable |
Trisomy 8 | 10% | Poor |
* Data from Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022;140(12):1345-1377. doi:10.1182/blood.2022016867 | ||
Less common cytogenetic abnormalities include
t(9;11)(p22.3;q23.3)/MLLT3-KMT2A
t(1;22)(p13.3;q13.1)/RBM15-MKL1
t(6;9)(p23;q34.1)/DEK-NUP214
inv(3)(q21.3q26.2)
Other laboratory findings may include hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, and elevated lactic dehydrogenase. These findings indicate a tumor lysis syndrome. Elevated serum levels of hepatic transaminases and/or creatinine and pseudohypoglycemia may also be present.
CT of the head is done in patients with central nervous system symptoms. Echocardiography or multi-gated acquisition (MUGA) scan is typically done to assess baseline cardiac function prior to giving anthracyclines, which are cardiotoxic.
Treatment of AML
For medically fit patients: Chemotherapy (induction and consolidation) with or without allogeneic hematopoietic stem cell transplantation
For medically frail patients: Less intensive therapies
For all: Supportive care
Treatment of acute myeloid leukemia depends on the patient's overall medical condition. Medically fit patients tend to be younger and have lower-risk cytogenetic abnormalities, better functional status, and fewer comorbidities than medically frail patients.
Because treatment of AML is complex and evolving, it is best done at the most specialized center available, particularly during critical phases (eg, remission induction); clinical trials are the first choice when available.
Пацієнти з ГМЛ, яким підходить лікування за станом здоров’я
In medically fit patients, initial treatment is induction chemotherapy to try to induce complete remission. Patients in remission then undergo consolidation therapy that may include allogeneic hematopoietic stem cell transplantation.
Complete remission is defined as < 5% blast cells in the bone marrow, absolute neutrophil count > 1000/mcL (> 1 × 109/L), platelet count > 100,000/mcL (> 100 × 109/L), and independence from blood transfusion.
The basic induction regimen (known as 7+3) includes cytarabine by continuous IV infusion for 7 days and daunorubicin or idarubicin given IV for 3 days during this time. Treatment usually results in significant myelosuppression, with infection or bleeding. There is significant latency before marrow recovery. During this time, meticulous preventive and supportive care are vital.
Complete remission rates with 7+3 are about 70 to 85% (favorable genetics—see Prognosis of Acute Myeloid Leukemia Based on Some Common Cytogenetic Abnormalities), 60 to 75% (intermediate genetics), and 25 to 40% (adverse genetics); complete remission rates also depend on patient-specific and other disease risk factors (eg, secondary versus de novo AML). However, most patients who achieve a complete remission with 7+3 (or another conventional induction regimen) ultimately relapse.
Re-induction is usually recommended for patients with residual leukemia on day 14, although there is no high-quality evidence that it improves outcome. Residual leukemia is defined variably as bone marrow blasts > 10% with bone marrow cellularity > 20%. The various recommended re-induction regimens include different dosages of cytarabine. Some include anthracyclines with or without a third agent.
Several drugs can be used with or instead of traditional 7+3 chemotherapy. Addition of midostaurin, a kinase inhibitor, to chemotherapy appears to prolong survival in certain patients (eg, adults < 60 years with newly diagnosed FLT3 mutated AML) (1). Gemtuzumab ozogamicin (a CD33-directed antibody-drug conjugate) can be combined with chemotherapy in patients with newly diagnosed CD33-positive AML. Gemtuzumab ozogamicin is also sometimes used as monotherapy for induction and consolidation.
A consolidation phase follows remission in many regimens. This can be done with the same drugs used for induction or other drugs. High-dose cytarabine regimens may lengthen remission duration, particularly when given for consolidation in patients < 60 years old. For patients with favorable cytogenetic non-APL AML in first complete remission, consolidation with high-dose cytarabine is considered standard post-induction therapy.
Maintenance therapy with an oral formulation of azacitidine has been associated with significantly longer overall survival and relapse-free survival than placebo among patients > 55 years who were in first remission after intensive chemotherapy and were not candidates for hematopoietic stem cell transplantation (2).
A liposomal combination of daunorubicin and cytarabine is available for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). This combination showed superiority in overall survival compared with the standard-of-care cytarabine plus daunorubicin (7+3 regimen) in patients 60 to 75 years of age with newly diagnosed t-AML or AML-MRC (3).
Allogeneic stem cell transplantation done during the first complete remission can generally improve outcome in patients with intermediate or adverse-risk cytogenetics. Generally, it takes 6 to 12 weeks to prepare for stem cell transplant. Recommendations are to proceed with standard high-dose cytarabine consolidation chemotherapy while awaiting definitive stem cell transplantation. Conditions that may render patients ineligible for allogenic stem cell transplantation include poor overall performance status and moderate to severe impairment of pulmonary, liver, kidney, or cardiac function.
In APL and some other cases of AML, disseminated intravascular coagulation (DIC) may be present when leukemia is diagnosed and may worsen as leukemic cell lysis releases procoagulant chemicals. In APL with the translocation t(15;17), all-trans retinoic acid (tretinoin) corrects the DIC in 2 to 5 days; combined with daunorubicin or idarubicin, this regimen can induce remission in 80% to 90% of patients and bring about long-term survival in 65% to 70%. Arsenic trioxide is also very active in APL. Targeted therapy with tretinoin and arsenic trioxide without conventional cytotoxic chemotherapy is very well tolerated and has been extremely successful in APL with a 100% complete remission rate and > 90% cure rate (4).
Слабкі з медичної точки зору пацієнти з ГМЛ
In older and medically frail patients, initial therapy is typically less intensive.
Because the median age for diagnosis of AML is 68 years, most newly diagnosed patients are considered older. Older patients are more likely to have comorbidities that limit their therapeutic options. Older patients also are much more likely to have high-risk cytogenetic abnormalities (eg, complex karyotype, monosomy 7), secondary AML arising from the myelodysplastic syndrome or a myeloproliferative neoplasm, or AML with multidrug resistance.
Although intensive chemotherapy is typically not used in older patients, it nevertheless improves the rate of complete remission and overall survival in patients < 80 years, particularly those with favorable-risk karyotypes. Achieving complete remission also improves quality of life by reducing hospitalizations, infections, and transfusion requirements.
The DNA methyltransferase inhibitors decitabine and azacitidine are pyrimidine nucleoside analogs that modulate DNA by reducing methylation of the promoter region of tumor suppressor genes. They improve clinical outcomes in older patients with de novo AML as well as those with s-AML (AML preceded by a myelodysplastic syndrome), t-AML (therapy-related AML), and AML harboring TP53 mutations. One of these drugs can be given alone as first-line treatment for many older patients, particularly those with compromised functional/performance status, organ dysfunction, or tumor biology (eg, karyotype, molecular aberrations) that predicts poor response to intensive chemotherapy.
Venetoclax, an inhibitor of the anti-apoptotic protein BCL-2, is used in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed AML in adults who are ≥ 75 years or who have comorbidities that preclude use of intensive induction chemotherapy. In a phase 3 study, previously untreated patients with confirmed AML who were ineligible for standard induction therapy were randomized to receive azacitidine plus either venetoclax or a placebo. The incidence of remission was higher and overall survival was longer among patients who received azacitidine plus venetoclax than among those who received azacitidine alone (5).
Glasdegib, a hedgehog pathway inhibitor, may also be used, in combination with low-dose cytarabine for treatment of newly diagnosed AML in patients ≥ 75 years or in patients who have comorbidities that preclude use of intensive induction chemotherapy.
Ivosidenib, an isocitrate dehydrogenase-1 (IDH1) inhibitor, is also used for patients with newly diagnosed IDH1-mutant AML who are ≥ 75 years or who have comorbidities that preclude use of intensive induction chemotherapy.
Following induction therapy and provided their performance status is appropriate, older patients may undergo allogeneic hematopoietic stem cell transplantation. Allogeneic hematopoietic stem cell transplantation prolongs survival in older patients. If patients are not candidates for full-intensity regimens, reduced-intensity (non-myeloablative) regimens can be used. Older and frail patients who do not undergo transplantation usually proceed to consolidation chemotherapy (eg, cytarabine or combined cytarabine and anthracycline at lower doses than used for induction).
Рецидивуючий або резистентний ГМЛ
Patients who have not responded (are resistant) to treatment and patients who have relapsed generally have a poor prognosis. A second remission can be achieved in 30% to 70% of patients who relapsed following a first remission. These second remissions are achieved more readily in patients with initial remissions > 1 year and/or with favorable cytogenetics and are generally shorter in duration than first remissions.
Patients with relapsed or resistant AML may be candidates for allogeneic stem cell transplantation preceded by re-induction salvage chemotherapy. Many salvage chemotherapeutic regimens include various dosages of cytarabine combined with drugs such as idarubicin, daunorubicin, mitoxantrone, etoposide, antimetabolites (eg, cladribine, clofarabine, fludarabine), and asparaginase. Regimens containing decitabine and azacitidine are sometimes used.
Donor lymphocyte infusion is another option in relapsed or resistant AML if initial allogeneic stem cell transplant is unsuccessful. Other novel treatment strategies include enasidenib, an isocitrate dehydrogenase-2 (IDH2) inhibitor, or ivosidenib, an isocitrate dehydrogenase-1 (IDH1) inhibitor, which may be useful for adult patients with relapsed or refractory AML who have an IDH2 or an IDH1 mutation, and gemtuzumab ozogamicin, which may be used as monotherapy for relapsed or refractory AML.
Gilteritinib is a kinase inhibitor used for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation. In the phase 3 study, patients randomized to receive gilteritinib had significantly longer survival than patients treated with chemotherapy (6).
Chimeric antigen receptor T (CAR-T) cells targeting CD123 or CD33 and antibody-drug conjugates targeting CD33 have also been used in clinical trials (7).
Симптоматичне лікування
Supportive care is similar in the acute leukemias and may include
Transfusions
Antimicrobials
Hydration and urine alkalinization
Psychologic support
Transfusions of red blood cells and platelets are administered as needed to patients with anemia or bleeding. Prophylactic platelet transfusion is done when platelets fall to < 10,000/mcL (< 10 × 109/L). Anemia (hemoglobin < 7 or 8 g/dL [< 70 or 80 g/L]) is treated with transfusions of packed red blood cells. Granulocyte transfusions are not routinely used.
Antimicrobials are often needed for prophylaxis and treatment because patients are immunosuppressed; in such patients, infections can progress quickly with little clinical prodrome. After appropriate studies and cultures have been done, febrile patients with neutrophil counts < 500/mcL (< 0.5 × 109/L) should begin treatment with a broad-spectrum bactericidal antibiotic that is effective against gram-positive and gram-negative organisms (eg, ceftazidime, piperacillin/tazobactam, meropenem). Fungal infections, especially pneumonias, are difficult to diagnose, so chest CT to detect fungal pneumonia should be done early (ie, within 72 hours of presentation with neutropenic fever depending on the degree of suspicion). Empiric antifungal therapy should be given if antibacterial therapy is not effective within 72 hours. In patients with refractory pneumonitis, Pneumocystis jirovecii infection or a viral infection should be suspected and confirmed by bronchoscopy and bronchoalveolar lavage and treated appropriately. Posaconazole, a 2nd-generation triazole antifungal agent, is indicated for primary prophylaxis in patients age > 13 years who are at high risk of developing invasive Aspergillus or Candida infections because of immunosuppression. Acyclovir or valacyclovir prophylaxis is generally recommended for all patients.
Hydration and allopurinol or rasburicase are used for treatment of hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia (ie, a tumor lysis syndrome) caused by the rapid lysis of leukemic cells during initial therapy in AML.
Psychologic support may help patients and their families with the shock of illness and the rigors of treatment for a potentially life-threatening condition.
Довідкові матеріали щодо лікування
1. Stone RM, Mandrekar SJ, Sanford BL, et al: Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 377:454–464, 2017.
2. Wei AH, Dohner H, Pocock C, et al: Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med 383:2526–2537, 2020. doi: 10.1056/NEJMoa2004444
3. Lancet JE, Uy GL, Cortes JE, et al: CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol 36:2684–2692, 2018.
4. Lo-Coco F, Avvisati G, Vignetti M, et al: Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369:111–121, 2013.
5. DiNardo CD, Jonas BA, Pullarkat V, et al: Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:617–629, 2020. doi: 10.1056/NEJMoa2012971
6. Perl AE, Martinelli G, Cortes JE, et al: Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med 381:1728–1740. 2019.
7. Pelosi E, Castelli G, Testa U: CD123 a Therapeutic Target for Acute Myeloid Leukemia and Blastic Plasmocytoid Dendritic Neoplasm. Int J Mol Sci 24(3):2718, 2023. doi:10.3390/ijms24032718
Prognosis for AML
Remission induction rate ranges from 50 to 85% (1). Long-term disease-free survival is about 20 to 40% overall but is 40 to 50% in younger patients treated with intensive chemotherapy or stem cell transplantation.
Prognostic factors help determine treatment protocol and intensity; patients with strongly negative prognostic features are usually given intense forms of therapy followed by allogeneic stem cell transplantation. In these patients, the potential benefits of intense therapy are thought to justify the increased treatment toxicity.
The leukemia cell karyotype is the strongest predictor of clinical outcome. Based on the specific chromosomal rearrangements, three clinical groups have been identified: favorable, intermediate, and poor (see table Prognosis of Acute Myeloid Leukemia Based on Some Common Cytogenetic Abnormalities).
Прогноз гострого мієлоїдного лейкозу на основі деяких поширених цитогенетичних аномалій
Prognosis | Cytogenetic Abnormality |
|---|---|
Favorable | t(15;17)(q24.1;q24.1)/PML-RARA t(16;16) or inv(16)(p13.1q22)/CBFB-MYH11 t(8;21)/(q22;q22.1)/RUNX1-RUNX1T1 |
Intermediate | Normal karyotype |
Poor | del(5) del(7) Trisomy 8 Karyotype with > 3 abnormalities |
Molecular genetic abnormalities are also important in refining prognosis and therapy in AML. Many different mutations exist; these are categorized into groups based on their effect on prognosis and treatment. Patients with AML average 5 recurrent gene mutations. Patients with mutations in NPM1, or in CEBPA have a more favorable prognosis. Mutations in FLT3, on the other hand, have a poorer prognosis (including in patients who also have an otherwise favorable NPM1 mutation).
Other factors that suggest a poorer prognosis include a
Preceding myelodysplastic phase
Therapy-related AML
High WBC count (> about 50,000/microL [> 50 × 109/L])
Patient-specific adverse prognostic factors include age ≥ 65, poor performance status, and comorbidities. Older patients are more likely to have high-risk cytogenetic abnormalities (see table Prognosis of AML Based on Some Common Cytogenic Abnormalities), secondary AML, and AML that is resistant to multiple drugs.
Minimal residual disease is defined as having < 0.1 to 0.01% (based on the assay used) leukemic cells in bone marrow. In AML, minimal residual disease can be assessed by multiparameter flow cytometry detection of leukemia-associated immunophenotype or by mutation-specific polymerase chain reaction (PCR). These tools are prognostically accurate but are not quite ready for routine use in clinical practice.
Довідковий матеріал щодо прогнозу
1. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022;140(12):1345-1377. doi:10.1182/blood.2022016867
Ключові моменти
Acute myeloid leukemia (AML) is the most common acute leukemia in adults.
There are a number of subtypes, typically involving very immature myeloid cells.
Chromosomal and molecular genetic abnormalities are common and have implications for prognosis and treatment.
In medically fit patients, treat with induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplantation (in patients with intermediate and unfavorable genetic features).
In medically frail patients, treat with less intensive regimens such as DNA methyltransferase inhibitors and consider allogeneic hematopoietic stem cell transplantation.
In patients with relapsed and/or resistant disease, treat with salvage chemotherapy followed by allogeneic hematopoietic stem cell transplantation when feasible, or use targeted therapies.
Додаткова інформація
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
Leukemia and Lymphoma Society: Resources for Healthcare Professionals: Provides information on education programs and conferences and resources for referrals to specialty care
