Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version - National Cancer Institute 4/8

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®)–Health Professional Version

Treatment of Childhood AML

In This Section

• Induction Therapy
  • Chemotherapy
  • Gemtuzumab ozogamicin
  • Supportive care
  • Induction failure (refractory AML)
  • Granulocytic sarcoma/chloroma
• Central Nervous System (CNS) Prophylaxis for AML
• Postremission Therapy for AML
  • Chemotherapy
  • HSCT
  • Current Clinical Trials
• Recurrent or Refractory Childhood AML and Other Myeloid Malignancies
  • Recurrent childhood AML
  • Refractory childhood AML (induction failure)
  • Current Clinical Trials
• Current Clinical Trials

The general principles of therapy for children and adolescents with acute myeloid leukemia (AML) are discussed below, followed by a more specific discussion of the treatment of children with Down syndrome and acute promyelocytic leukemia (APL).

Overall survival (OS) rates have improved over the past three decades for children with AML, with 5-year survival rates now in the 55% to 65% range.[1-5] Overall remission-induction rates are approximately 85% to 90%, and event-free survival (EFS) rates from the time of diagnosis are in the 45% to 55% range.[2-5] There is, however, a wide range in outcome for different biological subtypes of AML (refer to the Molecular Evaluation and Risk Classification Systems sections of this summary for more information); after taking specific biological factors of their leukemia into account, the predicted outcome for any individual patient may be much better or much worse than the overall outcome for the general population of children with AML.

Induction Therapy

Contemporary pediatric AML protocols result in 85% to 90% complete remission (CR) rates.[6-8] Approximately 2% to 3% of patients die during the induction phase, most often caused by treatment-related complications.[6-9] To achieve a CR, inducing profound bone marrow aplasia (with the exception of the M3 APL subtype) is usually necessary with currently used combination-chemotherapy regimens. Because induction chemotherapy produces severe myelosuppression, morbidity and mortality from infection or hemorrhage during the induction period may be significant.

Treatment options for children with AML during the induction phase may include the following:

1. Chemotherapy.
2. Gemtuzumab ozogamicin.
3. Supportive care.

Chemotherapy

The two most effective and essential drugs used to induce remission in children with AML are cytarabine and an anthracycline. Commonly used pediatric induction therapy regimens use cytarabine and an anthracycline in combination with other agents such as etoposide and/or thioguanine.[3,10,11]

Evidence (induction chemotherapy regimen):

1. The United Kingdom Medical Research Council (MRC) AML10 trial compared induction with cytarabine, daunorubicin, and etoposide (ADE) versus cytarabine and daunorubicin administered with thioguanine (DAT).[12]
   • The results showed no difference between the thioguanine and etoposide arms in remission rate or disease-free survival (DFS), although the thioguanine-containing regimen was associated with increased toxicity.
2. The MRC AML15 trial demonstrated that induction with daunorubicin and cytarabine (DA) resulted in equivalent survival rates when compared with ADE induction.[13]

The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[3,10,11] although idarubicin and the anthracenedione mitoxantrone have also been used.[6,14,15] Randomized trials have attempted to determine whether any other anthracycline or anthracenedione is superior to daunorubicin as a component of induction therapy for children with AML. In the absence of convincing data that another anthracycline or mitoxantrone produces superior outcome over daunorubicin when given at an equitoxic dose, daunorubicin remains the anthracycline most commonly used during induction therapy for children with AML in the United States.

Evidence (anthracycline):

1. The German Berlin-Frankfurt-Münster (BFM) Group AML-BFM 93 study evaluated cytarabine plus etoposide with either daunorubicin or idarubicin (ADE or AIE).[11,14]
   • Similar EFS and OS were observed for both induction treatments.
2. The MRC-LEUK-AML12 (NCT00002658) clinical trial studied induction with cytarabine, mitoxantrone, and etoposide (MAE) in children and adults with AML compared with a similar regimen using daunorubicin (ADE).[6,16]
   • For all patients, MAE showed a reduction in relapse risk, but the increased rate of treatment-related mortality observed for patients receiving MAE led to no significant difference in DFS or OS when compared with ADE.[16]
   • Similar results were noted when analyses were restricted to pediatric patients.[6]
3. The AML-BFM 2004 (NCT00111345) clinical trial compared liposomal daunorubicin (L-DNR) to idarubicin at a higher-than-equivalent dose (80 mg/m2 vs. 12 mg/m2 per day for 3 days) during induction.[17]
   • Five-year OS and EFS rates were similar in both treatment arms.
   • Treatment-related mortality was significantly lower with L-DNR than with idarubicin (2 of 257 patients vs. 10 of 264 patients).

Evidence (reduced-anthracycline induction regimen):

1. Although the combination of an anthracycline and cytarabine is the basis of initial standard induction therapy for adults and children, there is evidence that alternative drugs can be used to reduce the use of anthracyclines when necessary. In the St. Jude Children's Research Hospital (SJCRH) AML08 (NCT00703820) protocol, patients were randomly assigned to receive either clofarabine/cytarabine (CA) or high-dose cytarabine combined with daunorubicin and etoposide (HD-ADE) for induction I; all patients then received the anthracycline-containing, standard-dose ADE regimen for induction II.[18]
   • Despite a higher rate of minimal residual disease (MRD) in the CA group at day 22 of induction I (47% vs. 35%; P = .04), 3-year EFS and OS were similar between the two groups.

The intensity of induction therapy influences the overall outcome of therapy. The CCG-2891 study demonstrated that intensively timed induction therapy (4-day treatment courses separated by only 6 days) produced better EFS than standard-timing induction therapy (4-day treatment courses separated by 2 weeks or longer).[19] The MRC has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days.[10]

In adults, another method of intensifying induction therapy is to use high-dose cytarabine. While studies in nonelderly adults suggest an advantage for intensifying induction therapy with high-dose cytarabine (2–3 g/m2/dose) compared with standard-dose cytarabine,[20,21] a benefit for the use of high-dose cytarabine compared with standard-dose cytarabine in children was not observed using a cytarabine dose of 1 g/m2 given twice daily for 7 days with daunorubicin and thioguanine.[22] A second pediatric study also failed to detect a benefit for high-dose cytarabine over standard-dose cytarabine when used during induction therapy.[23]

Gemtuzumab ozogamicin

Because further intensification of induction regimens has increased toxicity with little improvement in EFS or OS, alternative approaches, such as the use of gemtuzumab ozogamicin, have been examined.

Evidence (gemtuzumab ozogamicin):

1. The Children's Oncology Group (COG) has completed a series of trials—AAML03P1 (NCT00070174), a pilot study, and AAML0531 (NCT00372593), a randomized trial—that examined the incorporation of the anti-CD33 conjugated antibody gemtuzumab ozogamicin into induction therapy.[8,9]
   • With the use of gemtuzumab ozogamicin during induction cycle one, dosed at 3 mg/m2 on day 6, the randomized trial identified an improved EFS but not OS; this was because of a reduction in postremission relapse overall and specifically in distinct subsets of patients. These subsets included patients with low-risk cytogenetics, patients with intermediate-risk AML who went on to receive stem cell transplantation (SCT) from a matched-related donor, and patients with high-risk AML (FLT3-ITD high-allelic ratio, >0.4) who then received a SCT from any donor.[24]
   • The expression intensity of CD33 on leukemic cells appeared to predict which patients benefited from gemtuzumab ozogamicin on the COG AAML0531 clinical trial.[25][Level of evidence: 1iiD] Patients whose CD33 intensity fell into the highest three population quartiles benefited from gemtuzumab ozogamicin (improved relapse risk, DFS, and EFS), whereas those in the lowest quartile had no reduction in relapse risk, EFS, or OS. This impact was seen for low-, intermediate-, and high-risk patients.
2. In a retrospective analysis of the ALFA-0701 (NCT00927498) trial of older adults, higher CD33 expression corresponded with greater benefit from treatment with gemtuzumab ozogamicin.[26]
3. The CD33 receptor on AML cells exhibited architectural variability (polymorphism) that resulted in 51% of patients expressing the single nucleotide polymorphism (SNP) rs12459419 (designated CC), for whom there was a significant reduction in relapse with the use of gemtuzumab ozogamicin compared with patients who did not use gemtuzumab ozogamicin (26% vs. 49%; P < .001). The alteration of this SNP resulted in a CD33 isoform lacking the CD33 IgV domain to which gemtuzumab ozogamicin binds and that is used in diagnostic immunophenotyping.[27]
   • For patients with either a one or two allele C>T mutation (CT and TT phenotypes, respectively) at this SNP, there was no reduction in relapse when adding gemtuzumab ozogamicin therapy (5-year cumulative incidence of relapse [CIR], 39% vs. 40%; P = .85).
4. A meta-analysis of five randomized clinical trials that evaluated gemtuzumab ozogamicin for adults with AML observed the following:[28]
   • The greatest OS benefit was for patients with low-risk cytogenetics (t(8;21)(q22;q22) and inv(16)(p13;q22)/t(16;16)(p13;q22)).
   • Adult AML patients with intermediate-risk cytogenetics who received gemtuzumab ozogamicin had a significant but more modest improvement in OS.
   • There was no evidence of benefit for patients with adverse cytogenetics.
   • The evidence for a benefit in patients with FLT3-ITD mutations was mixed; the French ALFA-0701 (NCT00927498) trial showed a trend towards a benefit, whereas the five-trial meta-analysis study did not find a benefit.[28,29] These trials did not examine the outcomes specifically for the combination of gemtuzumab ozogamicin followed by stem cell transplant, as was reported by the COG.[24]

Supportive care

In children with AML receiving modern intensive therapy, the estimated incidence of severe bacterial infections is 50% to 60%, and the estimated incidence of invasive fungal infections is 7.0% to 12.5%.[30-32] Several approaches have been examined in terms of reducing the morbidity and mortality from infection in children with AML.

Hematopoietic growth factors

Hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF) during AML induction therapy have been evaluated in multiple placebo-controlled studies in adults with AML in attempts to reduce the toxicity associated with prolonged myelosuppression.[7,33] These studies have generally shown a reduction in the duration of neutropenia of several days with the use of either G-CSF or GM-CSF [33] but have not shown significant effects on treatment-related mortality or OS.[33] (Refer to the Treatment Option Overview for AML section in the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.)

Routine prophylactic use of hematopoietic growth factors is not recommended for children with AML.

Evidence (hematopoietic growth factors):

1. A randomized study in children with AML that evaluated G-CSF administered after induction chemotherapy showed a reduction in duration of neutropenia but no difference in infectious complications or mortality.[34]
2. A higher relapse rate has been reported for children with AML expressing the differentiation defective G-CSF receptor isoform IV.[35]

Antimicrobial prophylaxis

The use of antibacterial prophylaxis in children undergoing treatment for AML has been supported by several studies. Studies, including one prospective randomized trial, suggest a benefit to the use of antibiotic prophylaxis.

Evidence (antimicrobial prophylaxis):

1. A retrospective study from SJCRH in patients with AML reported that the use of intravenous (IV) cefepime or vancomycin in conjunction with oral ciprofloxacin or a cephalosporin significantly reduced the incidence of bacterial infection and sepsis compared with patients receiving only oral or no antibiotic prophylaxis.[36]
2. The SJCRH results were confirmed in a subsequent study.[37]
3. A retrospective report from the COG AAML0531 (NCT00372593) trial demonstrated significant reductions in sterile-site bacterial infection and particularly gram-positive, sterile-site infections with the use of antibacterial prophylaxis.[38] This study also reported that prophylactic use of G-CSF reduced bacterial and Clostridium difficile infections.[38]
4. In a study that compared the percentage of bloodstream infections or invasive fungal infections in children with acute lymphoblastic leukemia (ALL) or AML who underwent chemotherapy and received antibacterial and antifungal prophylaxis, a significant reduction in both variables was observed when compared with a historical control group that did not receive any prophylaxis.[39]
5. In the prospective COG ACCL0934 trial for children receiving intensive chemotherapy, patients were enrolled in two separate groups—patients with acute leukemia (consisting of AML or relapsed ALL) and patients undergoing stem cell transplant. Patients with acute leukemia were randomly assigned to receive levofloxacin (n = 96) or no prophylactic antibiotic (n = 99) during the period of neutropenia in one to two cycles of chemotherapy.[40]
   • Analysis of the 195 children with acute leukemia revealed a significant reduction in bacteremia (43.4% to 21.9%, P = .001) and neutropenic fever (82.1% to 71.2%, P = .002) in the levofloxacin prophylaxis group compared with the control group, without increases in fungal infections, C. difficile–associated diarrhea, or musculoskeletal toxicities.
   • There was no significant decrease in severe infections (3.6% vs. 5.9%, P = .20), and no bacterial infection–related deaths occurred in either group.
   • Levofloxacin prophylaxis is consistent with the guidelines published by the American Society of Clinical Oncology and Infectious Diseases Society of America in 2018 for adult cancer patients considered at high risk of infection by virtue of neutropenia (<100 neutrophils/µl) in excess of 7 days.[41]

Antifungal prophylaxis

The role of antifungal prophylaxis has not been studied in children with AML using randomized, prospective studies.

Evidence (antifungal prophylaxis):

1. Two meta-analysis reports have suggested that antifungal prophylaxis in pediatric patients with AML during treatment-induced neutropenia or during bone marrow transplantation does reduce the frequency of invasive fungal infections and, in some instances, nonrelapse mortality.[42,43]
2. Another study that analyzed 1,024 patients with AML treated on the COG AAML0531 (NCT00372593) clinical trial reported no benefit of antifungal prophylaxis on fungal infections or nonrelapse mortality.[38]
3. Several randomized trials in adults with AML, however, have reported significant benefit in reducing invasive fungal infection with the use of antifungal prophylaxis. Such studies have also balanced cost with adverse side effects; when effectiveness at reducing invasive fungal infection is balanced with these other factors, posaconazole, voriconazole, caspofungin, and micafungin are considered reasonable choices.[39,44-48]

Cardiac monitoring

Bacteremia or sepsis and anthracycline use have been identified as significant risk factors in the development of cardiotoxicity, manifested as reduced left ventricular function.[49,50] Monitoring of cardiac function through the use of serial exams during therapy is an effective method for detecting cardiotoxicity and adjusting therapy as indicated. The use of dexrazoxane in conjunction with bolus dosing of anthracyclines can be an effective method of reducing the risk of cardiac dysfunction during therapy.[51]

Evidence (cardiac monitoring):

1. In the COG AAML0531 (NCT00372593) trial, 8.6% of enrolled patients experienced a reduction in left ventricular function during protocol therapy, with a cumulative incidence of left ventricular dysfunction of 12% within 5 years of completing therapy.[49]
   • Risk factors for left ventricular dysfunction during therapy included black race, older age, underweight body mass, and bacteremia.
   • The occurrence of left ventricular dysfunction adversely impacted 5-year EFS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.16–2.14; P = .004) and OS (HR, 1.59; 95% CI, 1.15–2.19; P = .005), which was primarily a result of nonrelapse mortality.
   • In patients who experienced left ventricular dysfunction during therapy, there was a 12-fold greater risk of left ventricular dysfunction in the 5 years after the completion of therapy.
2. The use of dexrazoxane was assessed in patients enrolled on the COG AAML1031 (NCT01371981) trial.[51]
   • Among the approximately 10% of children (96 of 1,014) who received dexrazoxane with each dose of anthracycline, there was significantly less decline in ejection fraction (range of course-specific median absolute change in ejection fraction from baseline: 0 to -4.0 versus 0 to -6.4; all P < .05) and an overall lower risk of early left ventricular systolic dysfunction (6.3% vs. 19.2%; relative risk [RR], 0.33; 95% CI, 0.15–0.72; P = .005).
   • Patients who received dexrazoxane had a nonsignificantly improved 3-year EFS (54.4% vs. 44.2%, P = .070) and OS (71.9% vs. 63.0%, P = .093) compared with patients who did not receive dexrazoxane.

Hospitalization

Hospitalization until adequate granulocyte (absolute neutrophil or phagocyte count) recovery has been used to reduce treatment-related mortality. The COG-2961 (NCT00002798) trial was the first to note a significant reduction in treatment-related mortality (19% before mandatory hospitalization was instituted in the trial along with other supportive care changes vs. 12% afterward); OS was also improved in this trial (P <.001).[3] Another analysis of the impact of hospitalization using a survey of institutional routine practice found that those who mandated hospitalization had nonsignificant reduction in patients' treatment-related mortality (adjusted HR, 0.60 [0.26–1.36, P = .22]) compared with institutions who had no set policy.[38] Although there was no significant benefit seen in this study, the authors noted the limitations, including its methodology (survey), an inability to validate cases, and limited power to detect differences in treatment-related mortality. To avoid prolonged hospitalizations until count recovery, some institutions have used outpatient IV antibiotic prophylaxis effectively.[37]

Induction failure (refractory AML)

Induction failure (the morphologic presence of 5% or greater marrow blasts at the end of all induction courses) is seen in 10% to 15% of children with AML. Subsequent outcomes for patients with induction failure are similar to those for patients with AML who relapse early (<12 months after remission).[52,53]

Granulocytic sarcoma/chloroma

Granulocytic sarcoma (chloroma) describes extramedullary collections of leukemia cells. These collections can occur, albeit rarely, as the sole evidence of leukemia. In a review of three AML studies conducted by the former Children's Cancer Group, fewer than 1% of patients had isolated granulocytic sarcoma, and 11% had granulocytic sarcoma along with marrow disease at the time of diagnosis.[54] This incidence was also seen in the NOPHO-AML 2004 (NCT00476541) trial.[55]

Importantly, the patient who presents with an isolated tumor, without evidence of marrow involvement, must be treated as if there is systemic disease. Patients with isolated granulocytic sarcoma have a good prognosis if treated with current AML therapy.[54]

In a study of 1,459 children with newly diagnosed AML, patients with orbital granulocytic sarcoma and central nervous system (CNS) granulocytic sarcoma had better survival than did patients with marrow disease and granulocytic sarcoma at other sites and AML patients without any extramedullary disease.[55,56] Most patients with orbital granulocytic sarcoma have a t(8;21) abnormality, which has been associated with a favorable prognosis. The use of radiation therapy does not improve survival in patients with granulocytic sarcoma who have a complete response to chemotherapy, but may be necessary if the site(s) of granulocytic sarcoma do not show complete response to chemotherapy or for disease that recurs locally.[54]

Central Nervous System (CNS) Prophylaxis for AML

CNS involvement by AML and its impact on prognosis has been discussed above in the Prognostic Factors in Childhood AML section of this summary. Therapy with either radiation or intrathecal chemotherapy has been used to treat CNS leukemia present at diagnosis and to prevent later development of CNS leukemia. The use of radiation has essentially been abandoned as a means of prophylaxis because of the lack of documented benefit and long-term sequelae.[57] The COG has used single-agent cytarabine for both CNS prophylaxis and therapy. Other groups have attempted to prevent CNS relapse by using additional intrathecal agents.

Evidence (CNS prophylaxis):

1. The COG AAML0531 (NCT00372593) trial used single-agent cytarabine for prophylaxis.[58]
   • The results of this approach found a total CNS relapse incidence of 3.9% in the 71% of enrolled patients who had no evidence of CNS leukemia at diagnosis (CNS1).
   • Patients who had minimal evidence of CNS leukemia at diagnosis (CNS2 or blasts present when CSF WBC was <5 cells/HPF; 16% of newly diagnosed patients) were given twice-weekly intrathecal cytarabine until the CSF cleared. For the CNS2 patients who initially cleared their CSF (95.8%) of leukemic blasts, 11.7% had later evidence of CNS relapse.
   • Among those with CNS3 involvement at diagnosis (13%), using the same approach of additional twice-weekly intrathecal cytarabine until clear (which had a 90.7% success rate), 17.7% later experienced a CNS relapse. For these CNS3 patients, even with multivariate analysis, their risk of isolated CNS relapse was significantly worse (HR, 7.82; P = .0003).
2. Another methodology uses additional intrathecal agents, including triples, a combination of intrathecal cytarabine, hydrocortisone, and methotrexate.[59]
   • SJCRH reported that after switching from triples (their previous standard treatment) to single-agent cytarabine, the incidence of isolated CNS relapse increased from 0% (0 of 131 patients) to 9% (3 of 33 patients), prompting them to return to triples, which then reproduced a 0% (0 of 79 patients) CNS relapse rate.

Postremission Therapy for AML

A major challenge in the treatment of children with AML is to prolong the duration of the initial remission with additional chemotherapy or hematopoietic stem cell transplantation (HSCT).

Treatment options for children with AML in postremission may include the following:

1. Chemotherapy.
2. HSCT.

Chemotherapy

Postremission chemotherapy includes some of the drugs used in induction while also introducing non–cross-resistant drugs and, commonly, high-dose cytarabine. Studies in adults with AML have demonstrated that consolidation with a high-dose cytarabine regimen improves outcome compared with consolidation with a standard-dose cytarabine regimen, particularly in patients with inv(16) and t(8;21) AML subtypes.[60,61] (Refer to the Adult AML in Remission section in the PDQ summary on Adult Acute Myeloid Leukemia Treatment for more information.) Randomized studies evaluating the contribution of high-dose cytarabine to postremission therapy have not been conducted in children, but studies employing historical controls suggest that consolidation with a high-dose cytarabine regimen improves outcome compared with less intensive consolidation therapies.[11,62,63]

The optimal number of postremission courses of therapy remains unclear, but appears to require at least three courses of intensive therapy inclusive of the induction course.[3]

Evidence (number of postremission courses of chemotherapy):

1. A United Kingdom Medical Research Council (MRC) study randomly assigned adult and pediatric patients to either four or five courses of intensive therapy. Five courses did not show an advantage in relapse-free survival and OS.[6,16][Level of evidence: 1iiA]
2. Based on this MRC data, in the COG AAML1031 (NCT01371981) trial, non–high-risk patients treated without HSCT in first CR (73% of all patients) received four cycles of chemotherapy (two induction cycles and two consolidation cycles) rather than five cycles (two induction cycles and three consolidation cycles); nontransplanted patients had received five cycles of chemotherapy on the previous COG AAML0531 (NCT00372593) and AAML03P1 (NCT00070174) trials.[64]
   • In a retrospective analysis, patients treated without HSCT on the COG AAML1031 trial (four chemotherapy cycles) had significantly worse outcomes than did those who had received five cycles of chemotherapy on the AAML0531 or AAML03P1 trials; outcomes included inferior OS (HR, 1.83; 95% CI, 1.22–2.74; P = .003), inferior DFS (HR, 1.49; 95% CI, 1.13–1.97; P = .005), and higher cumulative risk of relapse (HR, 1.42; 95% CI, 1.08–1.88; P = .013).
   • An exception was found in the low-risk subgroup defined by favorable cytogenetics or molecular genetics who were minimal residual disease (MRD) negative at the end of induction cycle 1. This subset of patients had similar outcomes regardless of whether they received four chemotherapy cycles (AAML1031) or five chemotherapy cycles (AAML0531 or AAML03P1).
   Additional study of the number of intensification courses and specific agents used will better address this issue, but these data suggest that four chemotherapy courses should only be administered to the favorable group described above, and that all other nontransplanted patients should receive five chemotherapy courses.

HSCT

The use of HSCT in first remission has been under evaluation since the late 1970s, and evidence-based appraisals concerning indications for autologous and allogeneic HSCT have been published.[65] Prospective trials of transplantation in children with AML suggest that overall, 60% to 70% of children with HLA-matched donors available who undergo allogeneic HSCT during their first remission experience long-term remissions,[10,66] with the caveat that outcome after allogeneic HSCT is dependent on risk-classification status.[67]

In prospective trials of allogeneic HSCT compared with chemotherapy and/or autologous HSCT, a superior DFS has been observed for patients who were assigned to allogeneic transplantation based on availability of a family 6/6 or 5/6 HLA-matched donor in adults and children.[10,66,68-72] However, the superiority of allogeneic HSCT over chemotherapy has not always been observed.[73] Several large cooperative group clinical trials for children with AML have found no benefit for autologous HSCT over intensive chemotherapy.[10,66,68,70]

Current application of allogeneic HSCT involves incorporation of risk classification to determine whether transplantation should be pursued in first remission. Because of the improved outcome in patients with favorable prognostic features (low-risk cytogenetic or molecular mutations) receiving contemporary chemotherapy regimens and the lack of demonstrable superiority for HSCT in this patient population, this group of patients typically receives matched-family donor (MFD) HSCT only after first relapse and the achievement of a second CR.[65,67,74,75]

There is conflicting evidence regarding the role of allogeneic HSCT in first remission for patients with intermediate-risk characteristics (neither low-risk or high-risk cytogenetics or molecular mutations):

Evidence (allogeneic HSCT in first remission for patients with intermediate-risk AML):

1. A study combining the results of the POG-8821, CCG-2891, COG-2961 (NCT00002798), and MRC AML10 studies identified a DFS and OS advantage for allogeneic HSCT in patients with intermediate-risk AML but not favorable-risk (inv(16) and t(8;21)) or poor-risk AML (del(5q), monosomy 5 or 7, or more than 15% blasts after first induction for POG/CCG studies); the MRC study included patients with 3q abnormalities and complex cytogenetics in the high-risk category.[67] Weaknesses of this study include the large percentage of patients not assigned to a risk group and the relatively low EFS and OS rates for patients with intermediate-risk AML assigned to chemotherapy, as compared with results observed in more recent clinical trials.[6,17]
2. The AML99 clinical trial from the Japanese Childhood AML Cooperative Study Group observed a significant difference in DFS for intermediate-risk patients assigned to MFD HSCT, but there was not a significant difference in OS.[76]
3. The AML-BFM 99 clinical trial demonstrated no significant difference in either DFS or OS for intermediate-risk patients assigned to MFD HSCT versus those assigned to chemotherapy.[73]

Given the improved outcome for patients with intermediate-risk AML in recent clinical trials and the burden of acute and chronic toxicities associated with allogeneic transplantation, many childhood AML treatment groups (including the COG) employ chemotherapy for intermediate-risk patients in first remission and reserve allogeneic HSCT for use after potential relapse.[6,76,77]

There are conflicting data regarding the role of allogeneic HSCT in first remission for patients with high-risk disease, complicated by the differing definitions of high risk used by different study groups.

Evidence (allogeneic HSCT in first remission for patients with high-risk AML):

1. A retrospective analysis from the COG and Center for International Blood and Marrow Transplant Research (CIBMTR) compared chemotherapy only with matched-related donor and matched-unrelated donor HSCT for patients with AML and high-risk cytogenetics, defined as monosomy 7/del(7q), monosomy 5/del(5q), abnormalities of 3q, t(6;9), or complex karyotypes.[78]
   • The analysis demonstrated no difference in the 5-year OS among the three treatment groups.
2. A Nordic Society for Pediatric Hematology and Oncology study reported that time-intensive reinduction therapy followed by transplant with best available donor for patients whose AML did not respond to induction therapy resulted in 70% survival at a median follow-up of 2.6 years.[79][Level of evidence: 2A]
3. A single-institution retrospective study of 36 consecutive patients (aged 0–30 years) with high-risk AML (FLT3-ITD, 11q23 KMT2A [MLL] rearrangements, presence of chromosome 5 or 7 abnormalities, induction failure, persistent disease), who were in a morphologic first remission before allogeneic transplant.[80]
   • The investigators reported a 5-year 72% OS and a 69% leukemia-free survival (from the time of transplant) with the use of a myeloablative conditioning regimen.
   • They also reported a 17% treatment-related mortality.
   • These outcomes were similar to 14 standard-risk AML patients transplanted during the same time period.
4. A subgroup analysis from the AML-BFM 98 clinical trial demonstrated improved survival rates for patients with 11q23 aberrations allocated to allogeneic HSCT, but not for patients without 11q23 aberrations.[73]
5. For children with FLT3-ITD (high-allelic ratio), patients who received MFD HSCT (n = 6) had higher OS than did patients who received standard chemotherapy (n = 28); however, the number of cases studied limited the ability to draw conclusions.[81]
6. A subsequent retrospective report from three consecutive trials in young adults with AML found that patients with FLT3-ITD high-allelic ratio did benefit from allogeneic HSCT (P =.03), whereas patients with low-allelic ratio did not (P = .64).[82]
7. A subset analysis of the COG phase 3 trial evaluated gemtuzumab ozogamicin during induction therapy in children with newly diagnosed AML.[24]
   • For patients with FLT3-ITD high-allelic ratio who received HSCT, a lower relapse rate was observed for those who also received gemtuzumab ozogamicin (15% vs. 53%, P = .007).
   • Conversely, patients receiving gemtuzumab ozogamicin showed higher treatment-related mortality (19% vs. 7%, P = .08), resulting in overall improved DFS (65% vs. 40%, P = .08).

Many, but not all, pediatric clinical trial groups prescribe allogeneic HSCT for high-risk patients in first remission.[75] For example, the COG frontline AML clinical trial (COG-AAML1031) prescribes allogeneic HSCT in first remission only for patients with predicted high risk of treatment failure based on unfavorable cytogenetic and molecular characteristics and elevated end-of-induction MRD levels. On the other hand, the AML-BFM trials restrict allogeneic HSCT to patients in second CR and to refractory AML. This was based on results from their AML-BFM 98 study, which found no improvement in DFS or OS for high-risk patients receiving allogeneic HSCT in first CR, as well as the successful treatment using HSCT for a substantial proportion of patients who achieved a second CR.[73,83] Additionally, late sequelae (e.g., cardiomyopathy, skeletal anomalies, and liver dysfunction or cirrhosis) were increased for children undergoing allogeneic HSCT in first remission on the AML-BFM 98 study.[73]

Because definitions of high-, intermediate-, and low-risk AML are evolving because of the ongoing association of molecular characteristics of the tumor with outcome (e.g., FLT3 internal tandem duplications, WT1 mutations, and NPM1 mutations) and response to therapy (e.g., MRD assessments postinduction therapy), further analysis of subpopulations of patients treated with allogeneic HSCT will be an ongoing need in current and future clinical trials.

If transplant is chosen in first CR, the optimal preparative regimen and source of donor cells has not been determined, although alternative donor sources, including haploidentical donors, are being studied.[72,84,85] There are no data that suggest total-body irradiation (TBI) is superior to busulfan-based myeloablative regimens.[73,74] Additionally, outstanding outcomes have been noted for patients who were treated with treosulfan-based regimens; however, trials comparing treosulfan with busulfan or TBI are lacking.[86]

Evidence (myeloablative regimen):

1. A randomized trial that compared busulfan plus fludarabine with busulfan plus cyclophosphamide as a preparative regimen for AML in first CR demonstrated that the former regimen was associated with less toxicity and comparable DFS and OS.[87]
2. In addition, a large prospective CIBMTR cohort study of children and adults with AML, myelodysplastic syndromes (MDS), and chronic myelogenous leukemia (CML) showed superior survival of patients with early-stage disease (chronic-phase CML, first CR AML, and MDS-refractory anemia) with busulfan-based regimens compared with TBI.[88]

Other than the APL subtype, there are no data that demonstrate that maintenance therapy given after intensive postremission therapy significantly prolongs remission duration. Maintenance chemotherapy failed to show benefit in two randomized studies that used modern intensive consolidation therapy,[62,89] and maintenance therapy with interleukin-2 also proved ineffective.[3]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Recurrent or Refractory Childhood AML and Other Myeloid Malignancies

The diagnosis of recurrent or relapsed AML according to COG criteria is essentially the same as the criteria for making the diagnosis of AML. Usually this is defined as patients having more than 5% bone marrow blasts who were in previous remission after therapy for a diagnosis of AML according to World Health Organization (WHO) classification criteria.[90,91]

Despite second remission induction in over one-half of children with AML treated with drugs similar to drugs used in initial induction therapy, the prognosis for a child with recurrent or progressive AML is generally poor.[52,92]

Recurrent childhood AML

Approximately 50% to 60% of relapses occur within the first year after diagnosis, with most relapses occurring by 4 years from diagnosis.[92] The vast majority of relapses occur in the bone marrow, and CNS relapse is very uncommon.[92]

Prognosis and prognostic factors

Factors affecting the ability to attain a second remission include the following:

• Length of first remission. Length of first remission is an important factor affecting the ability to attain a second remission; children with a first remission of less than 1 year have substantially lower rates of second remission (50%–60%) than children whose first remission is greater than 1 year (70%–90%).[52,93,94] Survival for children with shorter first remissions is also substantially lower (approximately 10%) than that for children with first remissions exceeding 1 year (approximately 40%).[52,93-95] The Therapeutic Advances in Childhood Leukemia and Lymphoma Consortium also identified duration of previous remission as a powerful prognostic factor, with 5-year OS rates of 54% ± 10% for patients with greater than 12 months first remission duration and 19% ± 6% for patients with shorter periods of first remission.[96] In this same analysis, outcomes, primarily in early relapsing patients, declined with each attempt to reinduce remission (56% ± 5%, 25% ± 8%, and 17% ± 7% for each consecutive attempt).
• Molecular alterations. In addition, specific molecular alterations at the time of relapse have been reported to impact subsequent survival. For instance, the presence of either WT1 or FLT3-ITD mutations at first relapse were associated, as independent risk factors, with worse OS in patients achieving a second remission.[97]

Additional prognostic factors were identified in the following studies:

• In a report of 379 children with AML who relapsed after initial treatment on the German BFM group protocols, a second complete remission rate was 63% and OS was 23%.[98][Level of evidence: 3iiiA] The most significant prognostic factors associated with a favorable outcome after relapse included achieving second complete remission, a relapse greater than 12 months from initial diagnosis, no allogeneic bone marrow transplant in first remission, and favorable cytogenetics (t(8;21), t(15;17), and inv(16)).
• The international Relapsed AML 2001/01 (NCT00186966) trial also found that early response to salvage therapy was highly prognostic.[99][Level of evidence: 3iiD]
• A retrospective study of 71 patients with relapsed AML from Japan reported a 5-year OS rate of 37%. Patients who had an early relapse had a 27% second remission rate compared with 88% for patients who had a late relapse. The 5-year OS rate was higher in patients who underwent HSCT after achieving a second complete remission (66%) than in patients not in remission (17%).[95]
• Patients who relapsed on two consecutive Nordic Society of Pediatric Hematology and Oncology (NOPHO) AML trials between 1993 to 2012 were analyzed for survival (208 patients relapsed of 543 children initially treated). Second remissions were achieved in 146 children (70%) with a variety of reinduction regimens. Five-year OS was 39%. Favorable prognostic factors included late relapse (≥1 year from diagnosis), no HSCT in first remission, and a core-binding factor AML subtype. For the children in second remission who underwent HSCT, the 5-year OS was 61%, as opposed to a 5-year OS of 18% for those who did not include HSCT in their therapy (P < .001).[100]

Treatment of recurrent AML

Treatment options for children with recurrent AML may include the following:

1. Chemotherapy.
2. HSCT.
3. Second transplant after relapse following a first transplant.

Chemotherapy

Regimens that have been successfully used to induce remission in children with recurrent AML have commonly included high-dose cytarabine given in combination with the following agents:

• Mitoxantrone.[52]
• Fludarabine and idarubicin.[101-103]
• L-asparaginase.[104]
• Etoposide.
• Liposomal daunorubicin. A study by the international BFM group compared fludarabine, cytarabine, and G-CSF (FLAG) with FLAG plus liposomal daunorubicin. Four-year OS was 38%, with no difference in survival for the total group; however, the addition of liposomal daunorubicin increased the likelihood of obtaining a remission and led to significant improvement in OS in patients with core-binding factor mutations (82%, FLAG plus liposomal daunorubicin vs. 58%, FLAG; P = .04).[105][Level of evidence: 1iiA]

Regimens built upon clofarabine have also been used;[106-108][Level of evidence: 2Div] as have regimens of 2-chloroadenosine.[109] The COG AAML0523 (NCT00372619) trial evaluated the combination of clofarabine plus high-dose cytarabine in patients with relapsed AML; the response rate was 48% and the OS rate, with 21 of 23 responders undergoing HSCT, was 46%. MRD before HSCT was a strong predictor of survival.[110][Level of evidence: 2Di]

The standard-dose cytarabine regimens used in the United Kingdom MRC AML10 study for newly diagnosed children with AML (cytarabine and daunorubicin plus either etoposide or thioguanine) have, when used in the setting of relapse, produced remission rates similar to those achieved with high-dose cytarabine regimens.[94] In a COG phase II study, the addition of bortezomib to idarubicin plus low-dose cytarabine resulted in an overall CR rate of 57%, and the addition of bortezomib to etoposide and high-dose cytarabine resulted in an overall CR rate of 48%.[111]

HSCT

The selection of additional treatment after the achievement of a second complete remission depends on previous treatment and individual considerations. Consolidation chemotherapy followed by HSCT is conventionally recommended, although there are no controlled prospective data regarding the contribution of additional courses of therapy once a second complete remission is obtained.[92]

Evidence (HSCT after second complete remission):

1. The BFM group examined outcomes of children with AML over a 35-year period and found that the greatest improvement in overall outcome was the improvement in survival after relapse. This improved EFS after relapse or refractory disease was only seen in patients who received a stem cell transplant as part of their salvage therapy.[112]
2. Unrelated donor HSCT has been reported to result in 5-year probabilities of leukemia-free survival of 45%, 20%, and 12% for patients with AML transplanted in second complete remission, overt relapse, and primary induction failure, respectively.[113][Level of evidence: 3iiA]
3. A number of studies, including a large, prospective CIBMTR cohort study of children and adults with myeloid diseases, have shown similar or superior survival with busulfan-based regimens compared with TBI.[88,114,115]
4. Matched-sibling donor transplantation has generally led to the best outcomes, but use of single-antigen mismatched related or matched unrelated donors results in very similar survival at the cost of increased rates of GVHD and nonrelapse mortality.[116] Umbilical cord outcomes are similar to other unrelated donor outcomes, but matching patients at a minimum of 7/8 alleles (HLA A, B, C, DRB1) leads to less nonrelapse mortality.[117] Haploidentical approaches are being used with increasing frequency and have shown comparable outcomes to other stem cell sources in pediatrics.[118] Direct comparison of haploidentical and other unrelated donor sources has not been performed in pediatrics, but studies in adults have shown similar outcomes.[119]
5. Reduced-intensity approaches have been used successfully in pediatrics, but mainly in children unable to undergo myeloablative approaches.[120] A randomized trial in adults showed superior outcomes with myeloablative approaches compared with reduced-intensity regimens.[121]

Second transplant after relapse following a first transplant

There is evidence that long-term survival can be achieved in a portion of pediatric patients who undergo a second transplant subsequent to relapse after a first myeloablative transplant. Survival was associated with late relapse (>6–12 months from first transplant), achievement of complete response before the second procedure, and use of a second myeloablative regimen if possible.[122-124]

CNS relapse

Isolated CNS relapse occurs in 3% to 6% of pediatric AML patients.[58,125,126] Factors associated with an increased risk of isolated CNS relapse include the following:[125]

• Age younger than 2 years at initial diagnosis.
• M5 leukemia.
• 11q23 abnormalities.
• CNS2 or CNS3 involvement at initial diagnosis.[58]

The risk of CNS relapse increases with increasing CNS leukemic involvement at initial AML diagnosis (CNS1: 0.6%, CNS2: 2.6%, CNS3: 5.8% incidence of isolated CNS relapse, P < .001; multivariate HR for CNS3: 7.82, P = .0003).[58] The outcome of isolated CNS relapse when treated as a systemic relapse is similar to that of bone marrow relapse. In one study, the 8-year OS for a cohort of children with an isolated CNS relapse was 26% ± 16%.[125] CNS relapse may also occur in the setting of bone marrow relapse and its likelihood increases with CNS involvement at diagnosis (CNS1: 2.7%, CNS2: 8.5%, CNS3: 9.2% incidence of concurrent CNS relapse, P < .001).[58]

Refractory childhood AML (induction failure)

Treatment options for children with refractory AML may include the following:

1. Chemotherapy.
2. Gemtuzumab ozogamicin.

Like patients with relapsed AML, induction failure patients are typically directed towards HSCT once they attain a remission, because studies suggest a better EFS than in patients treated with chemotherapy only (31.2% vs. 5%, P < .0001). Attainment of morphologic CR for these patients is a significant prognostic factor for DFS after HSCT (46% vs. 0%; P = .02), with failure primarily resulting from relapse (relapse risk, 53.9% vs. 88.9%; P = .02).[127]

Evidence (treatment of refractory childhood AML with gemtuzumab ozogamicin):

1. In the SJCRH trial AML02 (NCT00136084), gemtuzumab ozogamicin was given alone (n = 17), typically where MRD was low but still detectable (0.1%–5.6%), or in combination with chemotherapy (n = 29) to those patients with high residual MRD (1%–97%) after the first induction cycle.[128]
   • When given alone, 13 of 17 patients became MRD negative.
   • When given in combination with chemotherapy, 13 of 29 patients became MRD negative and 28 of 29 patients had reductions in MRD.
   • Compared with a nonrandomized cohort of patients with 1%–25% MRD after induction 1, addition of gemtuzumab ozogamicin to chemotherapy versus chemotherapy alone resulted in significant differences in MRD (P = .03); MRD was eliminated or reduced in all patients who received gemtuzumab ozogamicin versus in only 82% of patients who did not receive gemtuzumab ozogamicin. This was seen despite higher postinduction 1 MRD levels in the cohort receiving gemtuzumab ozogamicin (median, 9.5% vs. 2.9% in the no gemtuzumab ozogamicin group, P < .01). There was a nonstatistically significant improvement in 5-year OS (55% ± 13.9% vs. 36.4% ± 9.7%, P = .28) and EFS (50% ± 9.3% vs. 31.8% ± 13.4%, P = .28).
   • No impact upon HSCT treatment-related mortality was seen.
2. In a phase II trial of gemtuzumab ozogamicin alone for children with relapsed/refractory AML failing previous reinduction attempts, 11 of 30 patients achieved a CR or partial CR, with a 27% versus 0% (P = .001) 3-year OS for responders versus nonresponders.[129]

Treatment options under clinical evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

1. NCT03071276 (Selinexor, Fludarabine Phosphate, and Cytarabine in Treating Younger Patients with Refractory or Relapsed AML, ALL, or MDS): SJCRH-sponsored, single-arm, open label, phase II trial examining whether the addition of the selective inhibitor of nuclear export, selinexor, when added to a common AML reinduction backbone improves the study endpoint, complete response.
2. NCT02538965 (A Study of Lenalidomide in Pediatric Subjects With Relapsed or Refractory AML): This joint industry/COG study, AAML1522, is a single-arm, open label, phase II trial to evaluate the activity, safety, and pharmacokinetics of lenalidomide as a single agent for children with relapsed or refractory AML with complete response within a maximum of four cycles as the primary outcome.
3. NCT02642965 (Liposomal Cytarabine-Daunorubicin CPX-351, Fludarabine Phosphate, Cytarabine, and Filgrastim in Treating Younger Patients with Relapsed or Refractory AML): This phase I/II COG trial, AAML1421, for children in first relapse of their AML, uses a novel liposomal preparation of the two agents, cytarabine and daunomycin in a fixed 5:1 molar concentration in cycle 1, that exams whether this method of formulation of these two traditional AML agents is less toxic and more effective determined by the primary outcomes of toxicity and overall response.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Ries LAG, Melbert D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2005. Bethesda, Md: National Cancer Institute, 2007. Also available online. Last accessed April 11, 2019.
2. Gibson BE, Wheatley K, Hann IM, et al.: Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia 19 (12): 2130-8, 2005. [PUBMED Abstract]
3. Lange BJ, Smith FO, Feusner J, et al.: Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group. Blood 111 (3): 1044-53, 2008. [PUBMED Abstract]
4. Creutzig U, Büchner T, Sauerland MC, et al.: Significance of age in acute myeloid leukemia patients younger than 30 years: a common analysis of the pediatric trials AML-BFM 93/98 and the adult trials AMLCG 92/99 and AMLSG HD93/98A. Cancer 112 (3): 562-71, 2008. [PUBMED Abstract]
5. Kaspers GJ, Creutzig U: Pediatric acute myeloid leukemia: international progress and future directions. Leukemia 19 (12): 2025-9, 2005. [PUBMED Abstract]
6. Gibson BE, Webb DK, Howman AJ, et al.: Results of a randomized trial in children with Acute Myeloid Leukaemia: medical research council AML12 trial. Br J Haematol 155 (3): 366-76, 2011. [PUBMED Abstract]
7. Creutzig U, Zimmermann M, Lehrnbecher T, et al.: Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98. J Clin Oncol 24 (27): 4499-506, 2006. [PUBMED Abstract]
8. Cooper TM, Franklin J, Gerbing RB, et al.: AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: a report from the Children's Oncology Group. Cancer 118 (3): 761-9, 2012. [PUBMED Abstract]
9. Gamis AS, Alonzo TA, Meshinchi S, et al.: Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol 32 (27): 3021-32, 2014. [PUBMED Abstract]
10. Stevens RF, Hann IM, Wheatley K, et al.: Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council's 10th AML trial. MRC Childhood Leukaemia Working Party. Br J Haematol 101 (1): 130-40, 1998. [PUBMED Abstract]
11. Creutzig U, Ritter J, Zimmermann M, et al.: Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone: results of Study Acute Myeloid Leukemia-Berlin-Frankfurt-Münster 93. J Clin Oncol 19 (10): 2705-13, 2001. [PUBMED Abstract]
12. Hann IM, Stevens RF, Goldstone AH, et al.: Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Blood 89 (7): 2311-8, 1997. [PUBMED Abstract]
13. Burnett AK, Russell NH, Hills RK, et al.: Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol 31 (27): 3360-8, 2013. [PUBMED Abstract]
14. Creutzig U, Ritter J, Zimmermann M, et al.: Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group. Leukemia 15 (3): 348-54, 2001. [PUBMED Abstract]
15. Pession A, Masetti R, Rizzari C, et al.: Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia. Blood 122 (2): 170-8, 2013. [PUBMED Abstract]
16. Burnett AK, Hills RK, Milligan DW, et al.: Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol 28 (4): 586-95, 2010. [PUBMED Abstract]
17. Creutzig U, Zimmermann M, Bourquin JP, et al.: Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004. Blood 122 (1): 37-43, 2013. [PUBMED Abstract]
18. Rubnitz JE, Lacayo NJ, Inaba H, et al.: Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial. J Clin Oncol 37 (23): 2072-2081, 2019. [PUBMED Abstract]
19. Woods WG, Kobrinsky N, Buckley JD, et al.: Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group. Blood 87 (12): 4979-89, 1996. [PUBMED Abstract]
20. Weick JK, Kopecky KJ, Appelbaum FR, et al.: A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88 (8): 2841-51, 1996. [PUBMED Abstract]
21. Bishop JF, Matthews JP, Young GA, et al.: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87 (5): 1710-7, 1996. [PUBMED Abstract]
22. Becton D, Dahl GV, Ravindranath Y, et al.: Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421. Blood 107 (4): 1315-24, 2006. [PUBMED Abstract]
23. Rubnitz JE, Inaba H, Dahl G, et al.: Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol 11 (6): 543-52, 2010. [PUBMED Abstract]
24. Tarlock K, Alonzo TA, Gerbing RB, et al.: Gemtuzumab Ozogamicin Reduces Relapse Risk in FLT3/ITD Acute Myeloid Leukemia: A Report from the Children's Oncology Group. Clin Cancer Res 22 (8): 1951-7, 2016. [PUBMED Abstract]
25. Pollard JA, Loken M, Gerbing RB, et al.: CD33 Expression and Its Association With Gemtuzumab Ozogamicin Response: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531. J Clin Oncol 34 (7): 747-55, 2016. [PUBMED Abstract]
26. Olombel G, Guerin E, Guy J, et al.: The level of blast CD33 expression positively impacts the effect of gemtuzumab ozogamicin in patients with acute myeloid leukemia. Blood 127 (17): 2157-60, 2016. [PUBMED Abstract]
27. Lamba JK, Chauhan L, Shin M, et al.: CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children's Oncology Group Trial AAML0531. J Clin Oncol 35 (23): 2674-2682, 2017. [PUBMED Abstract]
28. Hills RK, Castaigne S, Appelbaum FR, et al.: Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 15 (9): 986-96, 2014. [PUBMED Abstract]
29. Castaigne S, Pautas C, Terré C, et al.: Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet 379 (9825): 1508-16, 2012. [PUBMED Abstract]
30. Sung L, Gamis A, Alonzo TA, et al.: Infections and association with different intensity of chemotherapy in children with acute myeloid leukemia. Cancer 115 (5): 1100-8, 2009. [PUBMED Abstract]
31. Kaya Z, Gursel T, Kocak U, et al.: Invasive fungal infections in pediatric leukemia patients receiving fluconazole prophylaxis. Pediatr Blood Cancer 52 (4): 470-5, 2009. [PUBMED Abstract]
32. Kobayashi R, Kaneda M, Sato T, et al.: The clinical feature of invasive fungal infection in pediatric patients with hematologic and malignant diseases: a 10-year analysis at a single institution at Japan. J Pediatr Hematol Oncol 30 (12): 886-90, 2008. [PUBMED Abstract]
33. Ozer H, Armitage JO, Bennett CL, et al.: 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol 18 (20): 3558-85, 2000. [PUBMED Abstract]
34. Lehrnbecher T, Zimmermann M, Reinhardt D, et al.: Prophylactic human granulocyte colony-stimulating factor after induction therapy in pediatric acute myeloid leukemia. Blood 109 (3): 936-43, 2007. [PUBMED Abstract]
35. Ehlers S, Herbst C, Zimmermann M, et al.: Granulocyte colony-stimulating factor (G-CSF) treatment of childhood acute myeloid leukemias that overexpress the differentiation-defective G-CSF receptor isoform IV is associated with a higher incidence of relapse. J Clin Oncol 28 (15): 2591-7, 2010. [PUBMED Abstract]
36. Kurt B, Flynn P, Shenep JL, et al.: Prophylactic antibiotics reduce morbidity due to septicemia during intensive treatment for pediatric acute myeloid leukemia. Cancer 113 (2): 376-82, 2008. [PUBMED Abstract]
37. Inaba H, Gaur AH, Cao X, et al.: Feasibility, efficacy, and adverse effects of outpatient antibacterial prophylaxis in children with acute myeloid leukemia. Cancer 120 (13): 1985-92, 2014. [PUBMED Abstract]
38. Sung L, Aplenc R, Alonzo TA, et al.: Effectiveness of supportive care measures to reduce infections in pediatric AML: a report from the Children's Oncology Group. Blood 121 (18): 3573-7, 2013. [PUBMED Abstract]
39. Yeh TC, Liu HC, Hou JY, et al.: Severe infections in children with acute leukemia undergoing intensive chemotherapy can successfully be prevented by ciprofloxacin, voriconazole, or micafungin prophylaxis. Cancer 120 (8): 1255-62, 2014. [PUBMED Abstract]
40. Alexander S, Fisher BT, Gaur AH, et al.: Effect of Levofloxacin Prophylaxis on Bacteremia in Children With Acute Leukemia or Undergoing Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial. JAMA 320 (10): 995-1004, 2018. [PUBMED Abstract]
41. Taplitz RA, Kennedy EB, Bow EJ, et al.: Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol 36 (30): 3043-3054, 2018. [PUBMED Abstract]
42. Ethier MC, Science M, Beyene J, et al.: Mould-active compared with fluconazole prophylaxis to prevent invasive fungal diseases in cancer patients receiving chemotherapy or haematopoietic stem-cell transplantation: a systematic review and meta-analysis of randomised controlled trials. Br J Cancer 106 (10): 1626-37, 2012. [PUBMED Abstract]
43. Robenshtok E, Gafter-Gvili A, Goldberg E, et al.: Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis. J Clin Oncol 25 (34): 5471-89, 2007. [PUBMED Abstract]
44. Mandhaniya S, Swaroop C, Thulkar S, et al.: Oral voriconazole versus intravenous low dose amphotericin B for primary antifungal prophylaxis in pediatric acute leukemia induction: a prospective, randomized, clinical study. J Pediatr Hematol Oncol 33 (8): e333-41, 2011. [PUBMED Abstract]
45. Mattiuzzi GN, Kantarjian H, Faderl S, et al.: Amphotericin B lipid complex as prophylaxis of invasive fungal infections in patients with acute myelogenous leukemia and myelodysplastic syndrome undergoing induction chemotherapy. Cancer 100 (3): 581-9, 2004. [PUBMED Abstract]
46. Mattiuzzi GN, Kantarjian H, O'Brien S, et al.: Intravenous itraconazole for prophylaxis of systemic fungal infections in patients with acute myelogenous leukemia and high-risk myelodysplastic syndrome undergoing induction chemotherapy. Cancer 100 (3): 568-73, 2004. [PUBMED Abstract]
47. Tacke D, Buchheidt D, Karthaus M, et al.: Primary prophylaxis of invasive fungal infections in patients with haematologic malignancies. 2014 update of the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Ann Hematol 93 (9): 1449-56, 2014. [PUBMED Abstract]
48. Grau S, de la Cámara R, Sabater FJ, et al.: Cost-effectiveness of posaconazole versus fluconazole or itraconazole in the prevention of invasive fungal infections among high-risk neutropenic patients in Spain. BMC Infect Dis 12: 83, 2012. [PUBMED Abstract]
49. Getz KD, Sung L, Ky B, et al.: Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report From the Children's Oncology Group. J Clin Oncol 37 (1): 12-21, 2019. [PUBMED Abstract]
50. Feijen EAM, Leisenring WM, Stratton KL, et al.: Derivation of Anthracycline and Anthraquinone Equivalence Ratios to Doxorubicin for Late-Onset Cardiotoxicity. JAMA Oncol 5 (6): 864-871, 2019. [PUBMED Abstract]
51. Getz KD, Sung L, Leger K, et al.: Effect of dexrazoxane on left ventricular function and treatment outcomes in patients with acute myeloid leukemia: a Children’s Oncology Group report. [Abstract] J Clin Oncol 36 (Suppl 18): A-10501, 2018. Also available onlineExit Disclaimer. Last accessed April 08, 2019.
52. Wells RJ, Adams MT, Alonzo TA, et al.: Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951. J Clin Oncol 21 (15): 2940-7, 2003. [PUBMED Abstract]
53. Aplenc R, Alonzo TA, Gerbing RB, et al.: Safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy for pediatric acute myeloid leukemia: a report from the Children's Oncology Group. J Clin Oncol 26 (14): 2390-3295, 2008. [PUBMED Abstract]
54. Dusenbery KE, Howells WB, Arthur DC, et al.: Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: a report from the Children's Cancer Group. J Pediatr Hematol Oncol 25 (10): 760-8, 2003. [PUBMED Abstract]
55. Støve HK, Sandahl JD, Abrahamsson J, et al.: Extramedullary leukemia in children with acute myeloid leukemia: A population-based cohort study from the Nordic Society of Pediatric Hematology and Oncology (NOPHO). Pediatr Blood Cancer 64 (12): , 2017. [PUBMED Abstract]
56. Johnston DL, Alonzo TA, Gerbing RB, et al.: Superior outcome of pediatric acute myeloid leukemia patients with orbital and CNS myeloid sarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 58 (4): 519-24, 2012. [PUBMED Abstract]
57. Creutzig U, Zimmermann M, Bourquin JP, et al.: CNS irradiation in pediatric acute myleoid leukemia: equal results by 12 or 18 Gy in studies AML-BFM98 and 2004. Pediatr Blood Cancer 57 (6): 986-92, 2011. [PUBMED Abstract]
58. Johnston DL, Alonzo TA, Gerbing RB, et al.: Central nervous system disease in pediatric acute myeloid leukemia: A report from the Children's Oncology Group. Pediatr Blood Cancer 64 (12): , 2017. [PUBMED Abstract]
59. Pui CH, Howard SC: Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol 9 (3): 257-68, 2008. [PUBMED Abstract]
60. Mayer RJ, Davis RB, Schiffer CA, et al.: Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 331 (14): 896-903, 1994. [PUBMED Abstract]
61. Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992. [PUBMED Abstract]
62. Wells RJ, Woods WG, Buckley JD, et al.: Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: a Childrens Cancer Group study. J Clin Oncol 12 (11): 2367-77, 1994. [PUBMED Abstract]
63. Wells RJ, Woods WG, Lampkin BC, et al.: Impact of high-dose cytarabine and asparaginase intensification on childhood acute myeloid leukemia: a report from the Childrens Cancer Group. J Clin Oncol 11 (3): 538-45, 1993. [PUBMED Abstract]
64. Getz KD, Alonzo TA, Sung L, et al.: Four versus five chemotherapy courses in patients with low risk acute myeloid leukemia: a Children’s Oncology Group report. [Abstract] J Clin Oncol 35 (Suppl 15): A-10515, 2017. Also available onlineExit Disclaimer. Last accessed April 11, 2019.
65. Oliansky DM, Rizzo JD, Aplan PD, et al.: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 13 (1): 1-25, 2007. [PUBMED Abstract]
66. Woods WG, Neudorf S, Gold S, et al.: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 97 (1): 56-62, 2001. [PUBMED Abstract]
67. Horan JT, Alonzo TA, Lyman GH, et al.: Impact of disease risk on efficacy of matched related bone marrow transplantation for pediatric acute myeloid leukemia: the Children's Oncology Group. J Clin Oncol 26 (35): 5797-801, 2008. [PUBMED Abstract]
68. Ravindranath Y, Yeager AM, Chang MN, et al.: Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group. N Engl J Med 334 (22): 1428-34, 1996. [PUBMED Abstract]
69. Feig SA, Lampkin B, Nesbit ME, et al.: Outcome of BMT during first complete remission of AML: a comparison of two sequential studies by the Children's Cancer Group. Bone Marrow Transplant 12 (1): 65-71, 1993. [PUBMED Abstract]
70. Amadori S, Testi AM, Aricò M, et al.: Prospective comparative study of bone marrow transplantation and postremission chemotherapy for childhood acute myelogenous leukemia. The Associazione Italiana Ematologia ed Oncologia Pediatrica Cooperative Group. J Clin Oncol 11 (6): 1046-54, 1993. [PUBMED Abstract]
71. Bleakley M, Lau L, Shaw PJ, et al.: Bone marrow transplantation for paediatric AML in first remission: a systematic review and meta-analysis. Bone Marrow Transplant 29 (10): 843-52, 2002. [PUBMED Abstract]
72. Koreth J, Schlenk R, Kopecky KJ, et al.: Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301 (22): 2349-61, 2009. [PUBMED Abstract]
73. Klusmann JH, Reinhardt D, Zimmermann M, et al.: The role of matched sibling donor allogeneic stem cell transplantation in pediatric high-risk acute myeloid leukemia: results from the AML-BFM 98 study. Haematologica 97 (1): 21-9, 2012. [PUBMED Abstract]
74. Creutzig U, Reinhardt D: Current controversies: which patients with acute myeloid leukaemia should receive a bone marrow transplantation?--a European view. Br J Haematol 118 (2): 365-77, 2002. [PUBMED Abstract]
75. Niewerth D, Creutzig U, Bierings MB, et al.: A review on allogeneic stem cell transplantation for newly diagnosed pediatric acute myeloid leukemia. Blood 116 (13): 2205-14, 2010. [PUBMED Abstract]
76. Tsukimoto I, Tawa A, Horibe K, et al.: Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: the AML99 trial from the Japanese Childhood AML Cooperative Study Group. J Clin Oncol 27 (24): 4007-13, 2009. [PUBMED Abstract]
77. Abrahamsson J, Forestier E, Heldrup J, et al.: Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate. J Clin Oncol 29 (3): 310-5, 2011. [PUBMED Abstract]
78. Kelly MJ, Horan JT, Alonzo TA, et al.: Comparable survival for pediatric acute myeloid leukemia with poor-risk cytogenetics following chemotherapy, matched related donor, or unrelated donor transplantation. Pediatr Blood Cancer 61 (2): 269-75, 2014. [PUBMED Abstract]
79. Wareham NE, Heilmann C, Abrahamsson J, et al.: Outcome of poor response paediatric AML using early SCT. Eur J Haematol 90 (3): 187-94, 2013. [PUBMED Abstract]
80. Burke MJ, Wagner JE, Cao Q, et al.: Allogeneic hematopoietic cell transplantation in first remission abrogates poor outcomes associated with high-risk pediatric acute myeloid leukemia. Biol Blood Marrow Transplant 19 (7): 1021-5, 2013. [PUBMED Abstract]
81. Meshinchi S, Alonzo TA, Stirewalt DL, et al.: Clinical implications of FLT3 mutations in pediatric AML. Blood 108 (12): 3654-61, 2006. [PUBMED Abstract]
82. Schlenk RF, Kayser S, Bullinger L, et al.: Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood 124 (23): 3441-9, 2014. [PUBMED Abstract]
83. Beier R, Albert MH, Bader P, et al.: Allo-SCT using BU, CY and melphalan for children with AML in second CR. Bone Marrow Transplant 48 (5): 651-6, 2013. [PUBMED Abstract]
84. Liu DH, Xu LP, Liu KY, et al.: Long-term outcomes of unmanipulated haploidentical HSCT for paediatric patients with acute leukaemia. Bone Marrow Transplant 48 (12): 1519-24, 2013. [PUBMED Abstract]
85. Locatelli F, Masetti R, Rondelli R, et al.: Outcome of children with high-risk acute myeloid leukemia given autologous or allogeneic hematopoietic cell transplantation in the aieop AML-2002/01 study. Bone Marrow Transplant 50 (2): 181-8, 2015. [PUBMED Abstract]
86. Nemecek ER, Hilger RA, Adams A, et al.: Treosulfan, Fludarabine, and Low-Dose Total Body Irradiation for Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation: Prospective Phase II Trial of the Pediatric Blood and Marrow Transplant Consortium. Biol Blood Marrow Transplant 24 (8): 1651-1656, 2018. [PUBMED Abstract]
87. Liu H, Zhai X, Song Z, et al.: Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study. J Hematol Oncol 6: 15, 2013. [PUBMED Abstract]
88. Bredeson C, LeRademacher J, Kato K, et al.: Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation. Blood 122 (24): 3871-8, 2013. [PUBMED Abstract]
89. Perel Y, Auvrignon A, Leblanc T, et al.: Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit--multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group. Leukemia 19 (12): 2082-9, 2005. [PUBMED Abstract]
90. Arber DA, Vardiman JW, Brunning RD: Acute myeloid leukaemia with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 110-23.
91. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
92. Webb DK: Management of relapsed acute myeloid leukaemia. Br J Haematol 106 (4): 851-9, 1999. [PUBMED Abstract]
93. Stahnke K, Boos J, Bender-Götze C, et al.: Duration of first remission predicts remission rates and long-term survival in children with relapsed acute myelogenous leukemia. Leukemia 12 (10): 1534-8, 1998. [PUBMED Abstract]
94. Webb DK, Wheatley K, Harrison G, et al.: Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party. Leukemia 13 (1): 25-31, 1999. [PUBMED Abstract]
95. Nakayama H, Tabuchi K, Tawa A, et al.: Outcome of children with relapsed acute myeloid leukemia following initial therapy under the AML99 protocol. Int J Hematol 100 (2): 171-9, 2014. [PUBMED Abstract]
96. Gorman MF, Ji L, Ko RH, et al.: Outcome for children treated for relapsed or refractory acute myelogenous leukemia (rAML): a Therapeutic Advances in Childhood Leukemia (TACL) Consortium study. Pediatr Blood Cancer 55 (3): 421-9, 2010. [PUBMED Abstract]
97. Bachas C, Schuurhuis GJ, Reinhardt D, et al.: Clinical relevance of molecular aberrations in paediatric acute myeloid leukaemia at first relapse. Br J Haematol 166 (6): 902-10, 2014. [PUBMED Abstract]
98. Sander A, Zimmermann M, Dworzak M, et al.: Consequent and intensified relapse therapy improved survival in pediatric AML: results of relapse treatment in 379 patients of three consecutive AML-BFM trials. Leukemia 24 (8): 1422-8, 2010. [PUBMED Abstract]
99. Creutzig U, Zimmermann M, Dworzak MN, et al.: The prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: results of the international study Relapsed AML 2001/01. Haematologica 99 (9): 1472-8, 2014. [PUBMED Abstract]
100. Karlsson L, Forestier E, Hasle H, et al.: Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia. Br J Haematol 178 (4): 592-602, 2017. [PUBMED Abstract]
101. Dinndorf PA, Avramis VI, Wiersma S, et al.: Phase I/II study of idarubicin given with continuous infusion fludarabine followed by continuous infusion cytarabine in children with acute leukemia: a report from the Children's Cancer Group. J Clin Oncol 15 (8): 2780-5, 1997. [PUBMED Abstract]
102. Fleischhack G, Hasan C, Graf N, et al.: IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II trial. Br J Haematol 102 (3): 647-55, 1998. [PUBMED Abstract]
103. Tavil B, Aytac S, Balci YI, et al.: Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) for the treatment of children with poor-prognosis acute leukemia: the Hacettepe experience. Pediatr Hematol Oncol 27 (7): 517-28, 2010. [PUBMED Abstract]
104. Capizzi RL, Davis R, Powell B, et al.: Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia--a Cancer and Leukemia Group B Study. J Clin Oncol 6 (3): 499-508, 1988. [PUBMED Abstract]
105. Kaspers GJ, Zimmermann M, Reinhardt D, et al.: Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol 31 (5): 599-607, 2013. [PUBMED Abstract]
106. Hijiya N, Gaynon P, Barry E, et al.: A multi-center phase I study of clofarabine, etoposide and cyclophosphamide in combination in pediatric patients with refractory or relapsed acute leukemia. Leukemia 23 (12): 2259-64, 2009. [PUBMED Abstract]
107. Jeha S, Razzouk B, Rytting M, et al.: Phase II study of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia. J Clin Oncol 27 (26): 4392-7, 2009. [PUBMED Abstract]
108. Shukla N, Kobos R, Renaud T, et al.: Phase II trial of clofarabine with topotecan, vinorelbine, and thiotepa in pediatric patients with relapsed or refractory acute leukemia. Pediatr Blood Cancer 61 (3): 431-5, 2014. [PUBMED Abstract]
109. Chaleff S, Hurwitz CA, Chang M, et al.: Phase II study of 2-chlorodeoxyadenosine plus idarubicin for children with acute myeloid leukaemia in first relapse: a paediatric oncology group study. Br J Haematol 156 (5): 649-55, 2012. [PUBMED Abstract]
110. Cooper TM, Alonzo TA, Gerbing RB, et al.: AAML0523: a report from the Children's Oncology Group on the efficacy of clofarabine in combination with cytarabine in pediatric patients with recurrent acute myeloid leukemia. Cancer 120 (16): 2482-9, 2014. [PUBMED Abstract]
111. Horton TM, Perentesis JP, Gamis AS, et al.: A Phase 2 study of bortezomib combined with either idarubicin/cytarabine or cytarabine/etoposide in children with relapsed, refractory or secondary acute myeloid leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 61 (10): 1754-60, 2014. [PUBMED Abstract]
112. Rasche M, Zimmermann M, Borschel L, et al.: Successes and challenges in the treatment of pediatric acute myeloid leukemia: a retrospective analysis of the AML-BFM trials from 1987 to 2012. Leukemia 32 (10): 2167-2177, 2018. [PUBMED Abstract]
113. Bunin NJ, Davies SM, Aplenc R, et al.: Unrelated donor bone marrow transplantation for children with acute myeloid leukemia beyond first remission or refractory to chemotherapy. J Clin Oncol 26 (26): 4326-32, 2008. [PUBMED Abstract]
114. Woodard P, Carpenter PA, Davies SM, et al.: Unrelated donor bone marrow transplantation for myelodysplastic syndrome in children. Biol Blood Marrow Transplant 17 (5): 723-8, 2011. [PUBMED Abstract]
115. Uberti JP, Agovi MA, Tarima S, et al.: Comparative analysis of BU and CY versus CY and TBI in full intensity unrelated marrow donor transplantation for AML, CML and myelodysplasia. Bone Marrow Transplant 46 (1): 34-43, 2011. [PUBMED Abstract]
116. Shaw PJ, Kan F, Woo Ahn K, et al.: Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors. Blood 116 (19): 4007-15, 2010. [PUBMED Abstract]
117. Eapen M, Klein JP, Ruggeri A, et al.: Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood 123 (1): 133-40, 2014. [PUBMED Abstract]
118. Locatelli F, Merli P, Pagliara D, et al.: Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion. Blood 130 (5): 677-685, 2017. [PUBMED Abstract]
119. Rashidi A, DiPersio JF, Westervelt P, et al.: Comparison of Outcomes after Peripheral Blood Haploidentical versus Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia: A Retrospective Single-Center Review. Biol Blood Marrow Transplant 22 (9): 1696-1701, 2016. [PUBMED Abstract]
120. Pulsipher MA, Boucher KM, Wall D, et al.: Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood 114 (7): 1429-36, 2009. [PUBMED Abstract]
121. Scott BL, Pasquini MC, Logan BR, et al.: Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol 35 (11): 1154-1161, 2017. [PUBMED Abstract]
122. Meshinchi S, Leisenring WM, Carpenter PA, et al.: Survival after second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia. Biol Blood Marrow Transplant 9 (11): 706-13, 2003. [PUBMED Abstract]
123. Nishikawa T, Inagaki J, Nagatoshi Y, et al.: The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: long-term outcomes. Pediatr Transplant 16 (7): 722-8, 2012. [PUBMED Abstract]
124. Yaniv I, Krauss AC, Beohou E, et al.: Second Hematopoietic Stem Cell Transplantation for Post-Transplantation Relapsed Acute Leukemia in Children: A Retrospective EBMT-PDWP Study. Biol Blood Marrow Transplant 24 (8): 1629-1642, 2018. [PUBMED Abstract]
125. Johnston DL, Alonzo TA, Gerbing RB, et al.: Risk factors and therapy for isolated central nervous system relapse of pediatric acute myeloid leukemia. J Clin Oncol 23 (36): 9172-8, 2005. [PUBMED Abstract]
126. Abbott BL, Rubnitz JE, Tong X, et al.: Clinical significance of central nervous system involvement at diagnosis of pediatric acute myeloid leukemia: a single institution's experience. Leukemia 17 (11): 2090-6, 2003. [PUBMED Abstract]
127. Quarello P, Fagioli F, Basso G, et al.: Outcome of children with acute myeloid leukaemia (AML) experiencing primary induction failure in the AIEOP AML 2002/01 clinical trial. Br J Haematol 171 (4): 566-73, 2015. [PUBMED Abstract]
128. O'Hear C, Inaba H, Pounds S, et al.: Gemtuzumab ozogamicin can reduce minimal residual disease in patients with childhood acute myeloid leukemia. Cancer 119 (22): 4036-43, 2013. [PUBMED Abstract]
129. Zwaan CM, Reinhardt D, Zimmerman M, et al.: Salvage treatment for children with refractory first or second relapse of acute myeloid leukaemia with gemtuzumab ozogamicin: results of a phase II study. Br J Haematol 148 (5): 768-76, 2010. [PUBMED Abstract]