Acta Haematol 2014;132:292–297 DOI: 10.1159/000360200

Published online: September 10, 2014

Acute Myeloid Leukemia in Adolescents and Young Adults: Challenging Aspects Yishai Ofran a, b Jacob M. Rowe a–c a

Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, and c Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel b

Abstract Treating adolescents and young adults (AYAs) diagnosed with cancer is a challenge. Acute myeloid leukemia (AML) which is usually diagnosed in a previously healthy kid, requiring immediate aggressive chemotherapy, brings difficulties and conflicts associated with severe illness to extremes. The incidence of AML in adolescents aged 15–19 years approaches 8.5 per million. Only in recent years has it become evident that the prognosis of AYAs diagnosed with AML is poorer compared to younger children diagnosed with AML with similar characteristics. No specific genetic aberration or other known poor risk factor was found to explain the inferior prognosis of AYAs. In acute lymphoblastic leukemia the contribution of differences between adult and pediatric protocols to AYA outcome is established. It has been suggested that pediatric protocols should also apply to AYAs with AML; however, data supporting this are vague. Herein, existing evidence regarding special considerations in treating AYAs with AML is discussed. Mental and psychological age-specific aspects important to consider when treating AYAs with AML are overviewed. Awareness for adolescent

© 2014 S. Karger AG, Basel 0001–5792/14/1324–0292$39.50/0 E-Mail [email protected]

special needs, adherence to protocols and intensive supportive care are important. Multidisciplinary adolescent-oriented staff should be involved in the therapy of any AYA with AML escorting this special patient population on the road to cure. © 2014 S. Karger AG, Basel


Acute myeloid leukemia (AML) is the most common leukemia in adults. The prevalence of AML strongly correlates with age. AML is a relatively rare disease during childhood, and its incidence rises exponentially over the age of 60 [1]. AML characteristics and prognosis change with age and most significantly between pediatric and adult patients. Adolescents and young adults (AYAs) with AML face a significantly worse prognosis compared to younger pediatric AML patients [2, 3]. Differences in the frequency of leukemia subtypes and common molecular aberrations between adult and pediatric patients are well known (table 1). Age is an established independent poor risk factor in adult patients and is associated with higher rates of poor risk cytogenetics and secondary leukemia [1]. Yet, the disease characteristics of AYA and peYishai Ofran, MD Department of Hematology and Bone Marrow Transplantation Rambam Health Care Campus Haifa 31096 (Israel) E-Mail y_ofran @

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Key Words Acute myeloid leukemia · Adolescents · Young adults

Special Considerations during Diagnosis and Primary Evaluation in AYAs

In acute lymphoblastic leukemia, it has been shown not only that AYAs have a poorer prognosis than younger children, but also that this can be overcome if pediatric protocols are applied and strictly executed [4, 5]. Whether a similar attitude should be applied to AYAs with AML is not known. In children and AYAs, AML is almost exclusively de novo [6], abruptly diagnosed in a previously healthy individual. Clinical and laboratory evaluation at diagnosis is similar to the regular adult workup with some specifically pediatric considerations [7]. Leukemia diagnosis and characteristics in AYAs should include morphology evaluation of bone marrow smears, immunophenotyping, cytogenetics, fluorescence in situ hybridization and specific molecular genetic markers. A complete blood count, biochemistry, coagulation tests and chest X-ray are indicated to rule out life-threatening emergencies or infection. In addition and unlike adults, all AYAs should undergo a cerebrospinal diagnostic tap even in the absence of neurological symptoms, due to a high reported risk for asymptomatic central nervous system (CNS) infiltration by leukemic cells in children [8, 9]. CNS involvement approaches 30% in some pediatric AML series, but most cases are of infants and children younger than 4 years [10]. In such a young pediatric population, CNS involvement was reported not to be associated with poorer outcome, but it should be emphasized that most protocols that are in use for this age group contain a routine CNS-directed therapy and prophylaxis. Whether or not a newly diagnosed AYA with a clear CNS spinal fluid requires CNS prophylaxis is debatable. Fertility preservation is challenging in AYA patients newly diagnosed with AML. Time constraints and the high frequency of emergencies are a barrier since therapy should often not be delayed even for few days [11]. Optimal collection for sperm banking requires the collection of multiple samples to maximize the amount of sperm available for cryopreservation prior to chemotherapy initiation [12]. However, male AYAs require quiet and relaxing conditions for sperm collection and often fail when AML in AYAs

being asked to masturbate few hours after being diagnosed with leukemia. If therapy is indicated before a sufficient amount of semen has been collected, it should be noted that following a single induction cycle, most healthy males will maintain adequate sperm quality, and a second collection is indicated prior to the consolidation cycle. Female AYAs diagnosed with AML face other challenges for fertility preservation. Since most female AYAs have no spouse or partner with whom they were planning to become parents, and due to the need for immediate antileukemic therapy, in vitro fertilization and embryo preservation are usually not an option. Time also limits the possibility for preservation of stimulated oocytes because a full hormonal stimulation cycle cannot be conducted prior to chemotherapy [13]. Of special consideration is the fact that, at diagnosis, ovaries may be infiltrated with leukemic cells. It was recently reported that using molecular diagnostic markers, leukemic infiltration was identified in 6/8 cryopreserved ovary cortexes, collected at leukemia diagnosis [14]. Thus, freezing ovary wedge biopsies for future reimplantation carries the risk for iatrogenic reintroduction of leukemic cells into a leukemia survivor. A progress in ex vivo stimulation of frozen ovary sections gives hope to young female AML patients. It might be that in the future a simple and rapid laparoscopic ovary biopsy will be sufficient, and with further ex vivo oocyte stimulation, in vitro fertilization and embryo implantation the parenthood dream can become real for leukemia survivors. Usage of gonadotropin-releasing hormone agonist therapy may protect female patients exposed to chemotherapy in lymphoma protocols [15, 16]. However, AML protocols are much more intensive, and gonadotropin-releasing hormone agonists may not be sufficient in preserving fertility in leukemia survivors. Treating AYAs with chemotherapy is associated with specific psychological, social and body image challenging aspects [17, 18]. In case of AML, these challenges are amplified by the abrupt onset of disease and the immediate need of very intensive therapies. Prolonged hospitalization, especially if isolation is required, may aggravate psychosocial difficulties and even the risk for depression, since for AYAs individuality, independence and social connections are of particular importance at this age. It is essential to create a patient-oriented support network, balancing and collaborating between family and friends synergizing all support sources. Enlistment of immediate family members to help and be involved in the care of AML patients is always encouraged. In addition, the possibility that allogeneic stem cell Acta Haematol 2014;132:292–297 DOI: 10.1159/000360200


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diatric AML patients are very similar; thus, the reason for the poorer outcome of AYAs is not obvious. Herein, evidence for a distinct biological behavior and practical questions regarding treatment protocol selection in AYAs will be discussed. Special challenges in the management of AYA patients will also be reviewed.

Risk Stratification in AYAs – Adults or Children?

Stratification and prognostication of AML differ between adult and pediatric patients (table 1). For example, AML preceded by myelodysplasia is common among patients with advanced age and is very rare among pediatric patients. The frequency of some cytogenetic and molecular abnormalities significantly differs between adults and pediatric patients. For example, core binding leukemia with either t(8: 21) or inv16 cytogenetic aberrations is identified in 20–22% of pediatric and only in 13% of adult AML patients [4]. The NPM1 mutation is more frequent among adults identified in 27.5% [19] compared to 8% of pediatric AML patients [20, 21]. Few studies analyzed the clinical value of genetic aberration frequencies specifically in AYAs. One important source of evidence is an analysis of cytogenetic results from the Medical Research Council (MRC) 10 trial [22]. The MRC 10 was a large prospective study for both children and adults up to the age of 55 years that recruited 1,612 patients. Looking at cytogenetic risk group frequencies, it is clear that standard risk cytogenetics is less frequent over the age of 35 years (table 2). Cytogenetic group distributions among AYAs aged 14–35 equal the distribution among younger children. Interestingly, the prognosis for all cytogenetic groups declines over age and for most in the adverse risk group where the 3-year survival rate dropped from 42% in children to 19% in AYAs (table 2). Some genetic aberrations were reported to have a different prognostic power in adult and pediatric patients. For example, in adults the c-KIT mutation is considered to override the good prognosis associated with t(8: 21) [23]. In contrast, among pediatric and adolescent patients, the 5-year event-free survival was equal for c-KIT mutated and wild-type patients presenting with corebinding leukemia [24]. FLT3-ITD and NUP98/NSD1 translocations are genetic aberrations that are associated with poor prognosis in AML patients. FLT3-ITD is present in 30% of adults 294

Acta Haematol 2014;132:292–297 DOI: 10.1159/000360200

Table 1. AML characterization in adult and pediatric patients

Second AML CBF: t(8:21) or inv16 MLLT3-MLL t(9:11) NPM1 mutation FLT3-ITD

Adult patients

Pediatric patients

frequency, prognosis %

frequency, prognosis %

17 13 2 27 – 35 30

1 20 – 22 7 8 15

adverse favorable intermediate favorable adverse

adverse favorable favorable favorable adverse

CBF = Core-binding factor.

Table 2. Age-related AML risk group distribution (%) and overall

survival (OS) Risk Standard Intermediate Poor

prevalence 3-year OS prevalence 3-year OS prevalence 3-year OS

0 – 14 years

14 – 35 years

>35 years

25.8 78 64.4 55 9.7 42

30.5 66 59.2 51 10.1 19

18.2 65 71.5 37 10.2 5

[25] but only in 15–18% of pediatric AML patients [26], and NUP98/NSD1 translocation is almost exclusively present under the age of 30 years [27]. It has been reported that the combination of FLT3-ITD and NUP98/NSD1 translocation carries a special deleterious effect and is common among AYAs [28]. Whether AYA AML patients have more in common with adult or pediatric patients is not clear. In a large survey evaluating the age effect on AML biology and response to therapy among pediatric patients [29], a clearly defined pattern was reported in the infancy age, but a distinct biology of AYAs could not be clearly identified. Large prospective studies that included both pediatric and adult patients did not report any special consideration or outcome for AYAs [30, 31]. Evidence from adult and pediatric studies established the significance of older age as a poor prognostic factor in each group independently. The age effect is probably a continuum making prognosis in AYAs better than that in adults but worse than in younger children. How aging per se and through which biological mechanisms age affects leukemia prognosis is still a mystery. Ofran /Rowe  


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transplantation will be indicated requires commencing tissue typing tests for patients’ siblings and parents as soon as possible. AYA siblings may be very young; thus, parents should be provided a specific psychological counseling helping them, informing and dealing with siblings’ needs, especially in cases when young kids are required to become hematopoietic cell donors for their sick brother or sister.

Table 3. Major differences between AML adult and pediatric protocols Induction I

Induction II



CNS prophylaxis

Typical adult protocol

D1 – 7: AraC 100 mg/m2 D1 – 3: Dauno 60 – 90 mg/m2

On D14, only if residual disease




Typical pediatric protocol

D1 – 6: AraC 100 mg/m2 D1, 3, 5: Dauno 50 – 60 mg/m2 D1 – 5: VP16 100 mg/m2

As early as D8 to all patients

MiDAC VP16 150 mg/m2 for 5 days or mitoxantrone 12 mg/m2 for 3 days

MiDAC L-asparaginase


D = Day; AraC = cytarabine; Dauno = daunorubicin; HIDAC = high-dose cytarabine; VP16 = etoposide; MiDAC = modified intermediate-dose cytarabine.

Confounding Factors Specific to AYAs

AYAs are cared for by both adult and pediatric hemato-oncologists. Since no AYA-specific protocols have been established, AYAs may be receiving either adult or pediatric regimens according to local preferences. In the nontransplant setting, adult AML protocols contain 1 or 2 cycles for induction of remission followed by risk-adapted postremission therapy. Most commonly, consolidation therapy is based on recurring cycles of high-dose cytarabine. Pediatric protocols are intensified by sequential multiagent chemotherapies (table  3). There are no prospective randomized comparisons of AYAs treated with adult or pediatric protocols. Recently, the outcome of 517 AYA AML patients was compared between those treated with adult and those with pediatric protocols. The 10-year eventfree and overall survivals of patients treated in pediatric Children’s Oncology Group studies were superior to those treated in adult Cancer and Leukemia Group B and Southwest Oncology Group trials (45 vs. 34%, 38 vs. 23%, respectively; p = 0.006) [32]. However, the better prognosis may be attributed to the fact that patients on Children’s Oncology Group protocols were significantly younger (median, 17.2 vs. 20.1 and 19.8 years, p < 0.001). When consecutive St. Jude- and MD Andersonjoined pediatric protocols were compared, the most recent AML02 protocol which is more intensive than previous protocols yielded a better outcome for AYAs [33]. This is worth mentioning because timed sequential therapy was shown to be superior for pediatric [34] but not for adult AML patients [35].

Potential explanations for the worse outcome of AYAs compared to younger pediatric AML patients may be other than the biology of leukemia. Leukemic patients treated within clinical trials usually do better than the average real-world patients. This may reflect the effect clinical trials have on the quality of participating centers [36], or the benefit patients gain from the rigidity of timelines within clinical trials. In the USA, the percentage of AYAs included in clinical trials is much lower than the participating rate among younger children [37]. In Europe, across almost all malignancies survival rates of AYAs are poor, but in the UK, AML is an exception which may be related to the high participation rate in the national MRC trials [38]. AYAs often fail to adhere to intensive prolonged therapies such as AML protocols [39]. It may be suggested that confounding factors between AYAs treated in pediatric wards and those treated in regular adult programs are the involvement of their parents and adherence to the protocol schedule, supportive care and infection prevention rules.


Acta Haematol 2014;132:292–297 DOI: 10.1159/000360200


Treating AYA patients with AML is challenging. The abrupt onset and the immediately required aggressive therapies aggravate the difficulties and challenges that are generally evident in all AYA patients diagnosed with cancer. The prognosis of AYAs diagnosed with AML is inferior to that of younger pediatric patients. However, no genetic or phenotypic aberrations were found to be specific to myeloid leukemia in AYAs. It is controversial 295

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Therapy of AML in AYAs

whether this poor prognosis is derived from an as yet unknown difference in disease biology which may be in accordance with the general deleterious effect of age in AML patients. In addition, some psychosocial difficulties which are specific to adolescence may contribute to the lower adherence to protocols, and a reduced compliance with supportive care instructions may also hamper the outcome in AYAs. The question whether the next AYA AML patient should be referred to pediatric or adult leukemia programs has not yet been answered. Regardless of referral destination, the treating staff should be aware

of age-specific needs and concerns for supportive care. It is recommended that the referral decision considers the patient’s individual fitness to local available pediatric or adult leukemia programs. Participation in clinical trials or in national protocols should be encouraged. Special efforts are required to ensure adherence to a selected protocol. AML is curable for 50% of AYAs, and by enlistment of multidisciplinary adolescent-oriented staff the road to cure can be made with the lowest short- and longterm consequences.

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Acute myeloid leukemia in adolescents and young adults: challenging aspects.

Treating adolescents and young adults (AYAs) diagnosed with cancer is a challenge. Acute myeloid leukemia (AML) which is usually diagnosed in a previo...
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