Pediatric Acute Myelocytic Leukemia Treatment & Management

Treatment for patients with acute myeloid leukemia involves intensive chemotherapy to destroy the leukemic cell population as rapidly as possible and to prevent the emergence of a resistant clone. Patients are simultaneously given supportive care until their bone marrow achieves hematologic remission and is again producing normal hematopoietic cells.

The role of surgery is limited.

Be vigilant to recognize associated complications, such as infections, hemorrhage, metabolic complications, or early organ dysfunction.

Hospitalization is necessary in patients with acute myeloid leukemia for managing chemotherapy and for treating complications related to the disease and its treatment, usually infections or febrile neutropenic episodes. Some hospitalizations can be lengthy. Numerous changes in antibiotics may be necessary until infections and neutropenia resolve.

After transplantation, most febrile episodes require in-patient treatment and observation until profound neutropenia and clinically significant infection resolves.

Transfer considerations

Transfer to a pediatric cancer center is usually necessary for initial diagnostic studies and is mandatory for management of chemotherapy and treatment-related complications.

For patients with suitable donors, transfer to a center capable of performing stem cell transplantations is usually necessary.

Placement of a central venous catheter

Because of the patient's need for intense chemotherapy and supportive care, guaranteed venous access is critical. An indwelling central venous catheter or port with at least 2 lumens is usually placed before the start of therapy. This catheter provides access for infusing chemotherapeutic drugs and for providing intravenous nutritional support, transfusions, antibiotics, and other supportive medications. In addition, they allowing for blood withdrawal for required testing.

Peripheral indwelling central catheters in the cubital area are sometimes used. These are sometimes added when patients require additional therapy, such as stem cell transplantation, or when a temporary access situation develops (as when an indwelling central line is removed because of infection).

Virtually all chemotherapeutic drug regimens include some combination of an anthracycline (most often daunorubicin [daunomycin]) with cytosine arabinoside (cytarabine). Other drugs that have been administered include fludarabine, etoposide, amsacrine, dexamethasone, 6-thioguanine, cyclophosphamide, and mitoxantrone.

For many years, most children in the United States were treated with chemotherapy protocols developed by the Children’s Cancer Group and the Pediatric Oncology Group. These protocols, which used different multiagent chemotherapies, were associated with improved results as therapy was intensified. Although these treatments prolonged pancytopenia, they decreased induction failures and substantially improved disease-free survival.

After all of the pediatric national groups merged to form the Children's Oncology Group (COG), the recommended regimen, ^[11] based on the Medical Research Council acute myeloid leukemia trials, was adapted; this consisted of 2 cycles of induction therapy with infusions of daunomycin, cytosine arabinoside, etoposide (ADE therapy). 

In September 2017, the FDA approved gemtuzumab ozogamicin (Mylotarg) for the treatment of relapsed or refractory CD33-positive AML in patients aged 2 years and older.

Gemtuzumab ozogamicin originally received accelerated approval in May 2000 as a stand-alone treatment for relapsed CD33-positive AML in older patients, but was voluntarily withdrawn from the market after subsequent confirmatory trials failed to verify clinical benefit and demonstrated safety concerns, including a high number of early deaths. The September 2017 approval includes a lower recommended dose, a different treatment schedule and a new patient population. ^[12]

The International Berlin-Frankfurt-Münster (BFM) Study Group reported that children with relapsed AML who received liposomal daunorubicin (DNX) in conjunction with the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor [G-CSF]) had improved early treatment response. ^{[13, 14]} Although overall long-term survival was similar in the 2 treatment groups, children with core-binding factor (CBF) AML who received FLAG/DNX had a 24% higher 4-year probability of survival than those who received the FLAG regimen alone. ^{[13, 14]}

Patients who are FLT3 positive can benefit from targeted agents, such as sorafenib.

After remission is induced, postinduction treatment is necessary, because more than 90% of patients otherwise relapse without additional treatment. In patients without HLA-matched donors from their family, sequential cycles of chemotherapy are administered by using combinations of cytosine arabinoside and etoposide, mitoxantrone and cytosine arabinoside, and, finally, high-dose cytosine arabinoside with L-asparaginase.

Allogeneic bone marrow transplantation has been shown to reduce relapse rates but does not always improve overall survival because of treatment-related mortality. Autologous bone marrow transplantation has also been shown to reduce relapse rates but does not improve overall survival compared with chemotherapy alone because of treatment-related mortality.

In the COG trials, transplants are not recommended for "low-risk acute myeloid leukemia," which is characterized by chromosome inv(16) and t(8;21) abnormalities; these patients receive additional "consolidation" chemotherapy and are only transplanted in second remission. Allogeneic stem cell transplantation from an HLA-matched sibling or parent is recommended during the first complete remission (ie, after 3 cycles of chemotherapy) for other patients (ie, those with standard-risk acute myeloid [normal cytogenetics] who enter remission with 2 induction courses and those with high-risk acute myeloid leukemia [abnormal karyotypes, including monosomy 7, trisomy 3, 5q- or complex karyotypes]). Transplantation is reserved for the second remission after a relapse for patients with Down syndrome and acute myeloid leukemia. Patients with APL should not receive a transplant during the first remission.

Upon relapse and the achievement of a molecular remission in a child treated with chemotherapy only, stem cell transplantation offers the best chance of cure. If an HLA-matched family donor is not available, the use of unrelated matched donors and autologous bone marrow transplant are options that have shown promise.

Other approaches have met with success in other parts of the world. Nordic and Japanese researches have reported promising results using multiple cycles of high-dose cytosine arabinoside. ^{[6, 15]}

The discovery of effective maturation agents has altered the approach to treating APL.

All-trans retinoic acid (ATRA) can effectively induce remission in most newly diagnosed APLs with the myelosuppressive effects of chemotherapy. The current treatment approach is to begin therapy with ATRA, followed with several days with an anthracycline to induce remission. For patients with a WBC count of more than 10 X 10⁹ (>10 X 10³/microliter), concomitant ATRA and anthracycline are used.

Additional cycles of this combination are used as consolidation chemotherapy. Randomized trials have shown an advantage of maintenance therapy for all patients with ATRA and, particularly, high-risk patients with ATRA in combination with 6-mercaptopurine and methotrexate.

Another approach that is being investigated in clinical trials is the use of arsenic trioxide, which is highly active in newly diagnosed and relapsing APL. It effectively induces remissions in 85% of patients who have a relapse. In a North American Intergroup Study, the introduction of arsenic in consolidation was shown to significantly improve overall outcomes in adults with APL.

Gemtuzumab ozogamicin (withdrawn from US market), or anti-CD33 calicheamicin, is also being tested in patients with APL. The hope is that arsenic and gemtuzumab ozogamicin may reduce exposure to anthracyclines without sacrificing efficacy.

The COG is planning on piloting a trial that will replace an anthracycline course of chemotherapy with arsenic trioxide plus ATRA in order to reduce the anthracycline exposure from an estimated 650 mg/m² to 350 mg/m² in standard-risk patients and to 450 mg/m² in high-risk patients.

Patients with APL and high WBC counts at presentation should not undergo leukophoresis because of an increased risk of bleeding due to activation and degranulation of promyelocytes. Instead, hydration and hydroxyurea can be used, followed by rapid initiation of induction chemotherapy. ^[16]

Unlike most children with acute myeloid leukemia who should receive intense therapy, young children (< 4 y) with Down syndrome fare best with reduced-intensity therapy, which results in an improved likelihood of long-term, disease-free remission. Many children with trisomy 21 have had transient myeloproliferative disease as infants. This picture resembles acute myeloid leukemia in many ways, but it usually disappears with only supportive care. About 20-30% of the children who had this syndrome as neonates develop true acute myeloid leukemia requiring chemotherapy.

Children with Down syndrome also seem to have marked complications of intense therapy. As a result, treatment for children with trisomy 21 involves lowered doses of induction chemotherapy (daunomycin, cytosine arabinoside, and 6-thioguanine) with prolonged periods between treatments. These children receive intensified chemotherapy high-dose cytosine arabinoside rather than bone marrow transplantation. Consolidation and intensification courses of therapy with high-dose cytosine arabinoside do not cause increased toxicity or mortality in patients with Down syndrome.

Age has been shown to be an important prognostic factor for children with Down syndrome; children younger than 2 years have the best outlook. A COG study (A2971) has shown that the 2-year-old to 4-year-old age group does as well as those younger than 2 years. Older children with Down syndrome continue to have a worse outlook than children younger than 4 years.

Radiation treatment is primarily used to treat chloromas and other masses that are pressing on a vital structure and that may imminently cause irreversible damage. Examples include spinal cord compression and superior vena cava syndrome or airway compromise due to mediastinal masses. Corticosteroids and early administration of chemotherapy can effectively relieve most of these complications.

Persistent CNS leukemia usually requires craniospinal irradiation.

Most pretransplantation myeloablative regimens given to children in their first complete remission have replaced total body irradiation with busulfan to decrease the incidence of some long-term adverse effects (ie, growth retardation, brain tumors). Although busulfan is associated with significant, potential, short-term and long-term adverse effects (including seizures and infertility), the incidence of second malignancies is lower than that associated with total body irradiation.

A myeloablative combination of chemotherapy and irradiation followed by rescue with an infusion of HLA-matched stem cells to reconstitute the patient's bone marrow is an effective approach to cure acute myeloid leukemia. ^[17]

In several randomized studies, allogeneic transplantation raised overall and disease-free survival rates. ^[18]

However, this option is often not available, because HLA-matched donors are found for only approximately 25% of patients. In addition, for good-risk patients, transplantation is reserved for a second remission, because the salvage rate is quite high for such patients.

Options have nonetheless substantially increased with the availability of international HLA registries that can help in locating HLA-matched unrelated donors (MUD). Results with MUD are virtually equivalent to HLA-matched family donors.

Umbilical cord blood, which is rich in stem cells, has further expanded the availability of donor stem cells, because increased HLA mismatch appears to be better tolerated with such donor cells in terms of the development of high-grade graft versus host disease (GVHD).

In addition, the use of purged or unpurged autologous stem cells, which offer the advantages of availability and avoidance of graft versus host disease, are under investigation in clinical trials. However, to date, randomized studies in pediatric patients have not shown an overall survival advantage for autologous stem cell transplantation compared with chemotherapy.

Success rates for stem cell transplants have also increased because of improved GVHD prophylaxis and treatment, using different combinations of methotrexate, cyclosporine, tacrolimus, mycophenolate, and corticosteroids to lower mortality rates.

Hepatic veno-occlusive disease (also termed sinusoidal obstructive syndrome), a complication that can be fatal, has shown excellent responses to defibrotide. Defibrotide is a single-stranded polydeoxyribonucleotide derived from porcine tissue that possesses antithrombotic, thrombolytic, anti-inflammatory, and anti-ischemic properties.

In March 2016, the FDA approved defibrotide (Defitelio) for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT). Approval was based on findings of a phase 3 trial (n = 102) which observed significant improvement in survival and complete response with defibrotide 6.25 mg IV q6h compared to 32 historical controls. Survival at Day+100 post-HSCT was 38.2% in the defibrotide group and 25% in the control group (estimated difference of 230%; 95.1% confidence interval [CI] 5.2%-40.8%; P=.0109, using a propensity-adjusted analysis based on 4 prognostic factors of survival). Observed Day+100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% in the controls (19% difference using similar methodology; 95.1% CI 3.5-34.6; P=.0160). ^[19]

Because treatment regimens are intensive, expeditious blood product transfusion support is critical.

Throughout long periods of pancytopenia, platelet and red blood cell (RBC) transfusions are necessary to correct anemia and thrombocytopenia until remission is achieved.

Fresh frozen plasma is occasionally required to correct coagulopathies, particularly in patients with disseminated intravascular coagulation. All transfused products must be irradiated to prevent GVHD in heavily immunosuppressed patients.

Support from the blood bank is mandatory when patients present with extreme hyperleukocytosis and are at high risk for stroke and heart failure due to hyperviscosity. These patients are best treated with leukophoresis or double-volume exchange transfusion to rapidly and safely decrease the leukemic cell burden without contributing to metabolic abnormalities. This procedure also facilitates rapid correction of anemia, which viscosity constraints would otherwise have prohibited.

In rare cases, granulocyte transfusions are administered to treat serious infections that do not respond to appropriate antibiotic therapy. This approach may be most appropriate for gram-negative sepsis, serious intra-abdominal infections, and, sometimes, fungal infections, although the efficacy of this approach as not been definitively proven.

Patients who present with a large leukemic cell burden, either a high circulating WBC count or massive organomegaly, are at risk for severe, often life-threatening metabolic derangements.

Before beginning cytoreduction, correct any existing abnormalities and take measures to prevent new ones.

Hyperkalemia and hyperphosphatemia with associated hypocalcemia result from rapid cell turnover and destruction. Promptly treat elevated potassium levels by using measures such as sodium polystyrene sulfonate (Kayexalate), an insulin and glucose combination, and, sometimes, hemodialysis.

Calcium replacement is often necessary to correct severe hypocalcemia.

Prevention is key to avoiding most serious metabolic complications. The combination of vigorous hydration, administration of allopurinol (a xanthine oxidase inhibitor to prevent the formation of uric acid), and alkalinization of the urine with sodium bicarbonate is usually successful in preventing serious tumor lysis syndromes. For patients at high risk for tumor lysis syndrome, those with renal dysfunction, or those whose uric acid levels are already elevated, rasburicase directly lyses uric acid and can rapidly reduce its levels.

Infection is a major cause of morbidity and mortality in acute myeloid leukemia.

Patients with fever, particularly if they have severe neutropenia, are presumed to have serious infection until proven otherwise.

Empiric, broad-spectrum antibacterial antibiotics are administered when a patient is febrile and has an absolute neutrophil count of less than 7.5-10 X 10⁹/L (< 750-1000/μL) (see the Absolute Neutrophil Count calculator). The choice of antibiotics depends on the typical pathogens found in the community and hospital. It is usually some combination of an aminoglycoside and a cephalosporin or semisynthetic penicillin with beta-lactamase inhibitor, until culture results are available.

When tunnel infections around a central venous catheter are suspected, vancomycin should be administered. At certain institutions, removal of the intravenous line is also recommended.

If a patient presents with abdominal or GI symptoms, the antibiotic chosen should cover anaerobes.

When neutropenia is prolonged, particularly after treatment with broad-spectrum antibacterial agents, fungal disease becomes a great concern.

Empiric use of antifungal therapy is indicated in patients with persistent fever 3-5 days after initiation of broad-spectrum antibiotics and negative bacterial cultures. Although amphotericin has been the standard treatment for many years, other agents, such as voriconazole, caspofungin, and micafungin are increasingly used.

(To facilitate proper diagnosis of infection, bronchoscopy, lung biopsy, and imaging studies are often necessary. CT scanning is often required to detect subtle abscesses in the lungs, liver, spleen, kidneys, or brain.)

Vigilance is most important in the patient with acute myeloid leukemia and persistent fever. Frequent cultures of possible sites of infection should be performed.

Prophylaxis

Prophylactic antibiotics have helped to decrease the incidence of a number of infections. Trimethoprim-sulfamethoxazole dramatically reduced the incidence of Pneumocystis (carinii) jiroveci pneumonia. In some centers, prophylactic penicillin has decreased the incidence serious systemic streptococcal sepsis in patients with severe mucositis. Acyclovir has been useful in preventing herpes simplex infections, particularly in patients who have undergone bone marrow transplantation.

Reports have suggested that prophylactic levofloxacin decreases the incidence of sepsis and other life-threatening infections. ^[20]

Many centers routinely administer fluconazole or nystatin prophylaxis to reduce the risk of fungal infections. Because of the significant incidence of life-threatening Enterococcal infections in this patient population, prophylaxis with penicillin or cephalosporins have also been advised.

Patients who develop GVHD that requires significant immunosuppressive therapy require more intense and more broadened infection prophylaxis.

Granulocyte colony-stimulating factor (G-CSF) and granulocyte monocyte colony-stimulating factor (GM-CSF) shorten the period of chemotherapy-induced neutropenia. However, their role in the treatment of leukemia has not been definitively established, because no improvement in survival has been demonstrated. Their use is not routinely recommended in patients with acute myeloid leukemia.

The role of synthetic erythropoietin has yet to be elucidated, and its use is not recommended.

The role of surgery is limited in acute myeloid leukemia.

Insertion of a central venous catheter is necessary to begin treatment and to manage all aspects of chemotherapy and transfusion support.

Biopsy or aspiration of tissue for culture is often necessary for febrile patients with a possible abscess.

Acute abdomen often results in serious complications (eg, typhlitis) that often requires expeditious surgical intervention.

Careful attention must be directed toward adequate nutrition. Because of prolonged neutropenia with infections that blunt a patient's appetite and recurrent episodes of chemotherapy-induced mucositis, high-calorie oral supplements are often helpful for maintaining weight. They help the patient to tolerate therapy. Most transplantation patients require intravenous total parenteral nutrition or, preferably, nasogastric alimental nutrition.

Low-bacteria diets are often prescribed to patients receiving a blood or marrow transplant to decrease the incidence of infections because of the profound immunosuppression after transplantation. This would include avoiding uncooked fresh vegetables and fruits. These recommendations are probably not necessary for patients with acute myeloid leukemia who are not undergoing transplantation.

Minimal limits on activity are necessary. Patients should avoid crowds and exposure to potentially contagious disorders when they have neutropenia or immunosuppression after transplantation.

During episodes of thrombocytopenia, patients should curtail their participation in potentially traumatic physical sports activities to avoid serious hemorrhage. Medications that can potentiate bleeding, such as antiplatelet agents (eg, aspirin, nonsteroidal anti-inflammatory drugs) should be avoided.

The association of acute myelocytic leukemia with radiation, toxins, and drugs has been well documented. Reduced exposure to ionizing radiation should be an important maxim for every physician who orders diagnostic testing for patients, particularly pregnant women.

Until more evidence is available, general avoidance of chemicals and toxins should be a priority.

No dietary changes are known to affect a person's risk of developing acute myelocytic leukemia.

Blood counts must carefully be monitored during and between phases of treatment.

After all planned therapy, careful physical examinations and blood work are important to ensure continued hematologic remission.

Most supportive medications can be discontinued when chemotherapy is completed. Such medications include prophylactic antibiotics, agents for nutritional support (eg, appetite stimulants), and antiemetics.

Patients usually require prolonged immunosuppressive therapy with prednisone and cyclosporine after transplantation. Penicillin, antifungal medications, acyclovir, and trimethoprim-sulfamethoxazole are continued until all immunosuppressive medications are discontinued.

Consider consulting a urologist when male teenagers are undergoing intense chemotherapy that may cause oligospermia and fertility problems in the future. These conditions are usually temporary. However, they are particularly problematic for patients who undergo high-dose chemotherapy in preparation for blood or marrow transplantation, and they are major problems for patients who may be receiving total-body irradiation. Encourage sperm banking, preferably before these patients begin any treatment that may affect the quality of their sperm.

Patients and their families may experience major stresses as a result of intense treatment and frequent, prolonged hospitalizations for chemotherapy and its resulting complications (especially in patients undergoing stem cell transplant). Another stressor is the real possibility of life-threatening complications. Psychological support, with educational information and numerous meetings and updates, are important for the family's psychological well-being.