Clinical aspects in pediatric acute myeloid leukemia
Klein, K.
2020
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Klein, K. (2020). Clinical aspects in pediatric acute myeloid leukemia.
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General introduction and outline of this thesis
Parts of the introduction are adapted from:
Klein K, de Haas V, Kaspers GJL. Clinical Challenges in de Novo Pediatric Acute Myeloid Leukemia. Expert Rev Anticancer Ther. 2018 Mar;18(3):277-293.
Although the overall incidence in children is low, cancer is the most frequent non-accidental cause of death during childhood in most developed countries. The global age-standardized incidence rate is 140.6 per million person-year in children aged 0-14 years. Incidences vary between and within cancer type, age, sex, specific regions, and racial and ethnic group. The most common forms of childhood cancer are leukemias, followed by tumors of the central nervous system (CNS), and lymphomas.1 In the
Netherlands, 500-600 children are diagnosed with cancer every year.2 Figure 1.1 shows
an overview of the distribution of childhood cancers in the Netherlands.
Figure 1.1 | Distribution of childhood cancers in The Netherlands
Approximately 150 of these patients (25%) are diagnosed with de novo leukemia. The far majority (80%) concerns acute lymphoblastic leukemia (ALL). Acute myeloid leukemia (AML) accounts for approximately 15% of the pediatric leukemias. Both types of leukemia arise from the hematopoietic stem cell, however at different levels (see Figure 1.2). Chronic forms of leukemia are rare in children.
Chapter 1
Over the past decades the overall survival (OS) of children with leukemia has improved substantially.3 This is partly contributable to the increasing interest in scientific research
and availability of international achievements. Basic and biological studies are needed in order to understand disease etiology and to identify potential targetable pathways in leukemic cells. Translational research bridges bench to bed, which contributes to deliberate decision making on how to proceed to novel clinical trials. Lastly, clinical research is of invaluable importance to proof concepts and to enable the development of evidence-based guidelines in clinical practice.
Figure 1.2 | Cell lines involved in acute myeloid leukemia and acute lymphoblastic leukemia
Epidemiology and outcome of AML
Nowadays, survival rates of ALL exceed 90%4, whereas long-term OS in pediatric AML
is 75%3,5 at best. However, specific subgroups of AML are associated with very good or
very poor survival.6 Inferior outcomes mainly derives from a high relapse rate.3,6 With an
incidence of approximately 0.8 : 100 000, AML is a rare disease in childhood.7
In the Netherlands, all cases of pediatric AML are registered by the Dutch Childhood Oncology Group (DCOG). The DCOG functions as a central reference laboratory for diagnostics of all childhood leukemias, and in a centralized way, they register all childhood leukemia patients (as well as patients with other childhood malignancies) of whom they receive diagnostic and follow-up material for review. Furthermore, as
the trial office for pediatric oncology studies in the Netherlands, they are involved in the development and monitoring of almost all childhood cancer treatment protocols. In the Netherlands approximately 20 to 25 children with AML are diagnosed annually. Population-based incidence rates, survival rates, and epidemiological data over time are, however, not publically available for Dutch patients (this thesis).
Etiology
A series of changes in the DNA of the hematopoietic precursor stem cell alter normal hematopoietic cell growth and differentiation. Class I mutations confer proliferative and/or survival advantages, whereas class II mutations primarily impair differentiation.8
However, pathogenesis is much more complicated, as recent studies identified many novel (epi)genetic alterations and driver-mutations aside from the previously well-known large chromosomal events.3,9-12 A combination of these events usually results in
the accumulation of abnormal, immature myeloid cells in the bone marrow, followed by accumulation in the peripheral blood. Malignant blasts can also accumulate in the cerebral spinal fluid or extramedullary as gingiva hyperplasia or chloromas of the skin. Contrary to in adults, pediatric AML mainly involves de novo disease. AML secondary to myelodysplastic syndrome is rare. Some germline affecting diseases, e.g., Fanconi anemia or Li-Fraumeni syndrome, are associated with an increased risk of AML, as is Down syndrome. However, in the majority of the children the exact underlying etiology or cause of AML remains unknown.
Clinical aspects and diagnostics
Suspicion of AML could yet arise from a thorough history and physical exam. Clinical patterns derive from accumulation of malignant blasts in the bone marrow and subsequent repression of healthy cell lines. Common clinical signs include fatigue, paleness, fever, bleeding tendency, and joint/bone pains. Swollen lymph nodes, an enlarged liver and/or spleen, and cutaneous manifestations may underline the diagnosis. In high-income countries, diagnosis is based on morphological assessment, immunophenotype, tumor cytogenetics, and molecular biology of bone marrow and/ or peripheral blasts. Final diagnosis is made by confirmation of at least 20% malignant myeloid blasts in the peripheral blood and/or bone marrow, and/or (in case of lower percentages) the presence of well-defined AML-specific chromosomal and/or molecular abnormalities.6,13 Cerebrospinal fluid is studied for the presence of CNS involvement of
Chapter 1
Cytomorphology
Initially, AML was classified according to the French-American-British (FAB) classification, based on cytomorphology and –to some extent– immunophenotype profiles of proliferating blasts.14-16 This classification system has been replaced by the World Health
Organization (WHO) classification, based on recurrent cytogenetic and molecular abnormalities.13,17 However, in case of absent recurrent abnormalities (“AML not further
specified") descriptive definitions based on morphological features are still used.13 The
suspicion of acute promyelocytic leukemia (APL) is usually based on morphology as well. Furthermore, there are other associations between morphology and cytogenetics.
Immunophenotyping
Multiparameter flow cytometry is used to distinguish between AML and ALL, to determine the leukemic cell differentiation and maturation, and to assess the leukemia associated immunophenotype (LAIP), useful for both diagnosis and follow-up. According to the WHO classification, lineage assignment criteria include MPO-positivity or monocytic differentiation with at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysosome. Aside from diagnostic purposes, the LAIP can be used for response measurements of minimal residual disease (MRD) after the onset of treatment and for detection of an emerging relapse.
Cytogenetics and molecular aberrations
Numerous studies have shown the importance of cytogenetic characterization as an independent prognostic factor in both adults and children with AML.18-25 The WHO
classification13,17 and pediatric-specific recommendations6 include several predefined,
recurrent cytogenetic subgroups at diagnosis, useful for risk-group stratification. Core-binding factor (CBF) leukemias t(8;21)(q22;q22)/RUNX1-RUNX1T1 [t(8;21)] and inv(16) (p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11 [inv(16)/t(16;16)] are associated with favorable prognosis.6,13,21,22 However, more specific risk-group stratification within these
subgroups might be in place (this thesis). On a molecular level, AML with mutations in the nucleophosmin 1 gene (NPM1)26 or CEBPα gene27 were more recently acknowledged
as favorable aberrations. Approximately 30-40% of the pediatric AML patients harbor favorable aberrations.6 Acute promyelocytic leukemia (APL), typically characterized by
FAB-type M3 and t(15;17)(q22;q21)/PML-RARA, is also considered favorable-risk, but is considered a distinct disease entity within the group of myeloid malignancies.6,28 APL
requires different treatment strategies and was beyond the scope of this thesis.
Aberrations t(6;9)(p23;q34), monosomy 5/del(5q), monosomy 7, t(9;11)(p22;q23), and t(10;11)(p12;q23) KMT2A (previously known as MLL) rearrangements are typically associated with poor outcome.6,13,21,22 However, not all of these adverse aberrations
are included as risk-stratificating aberration for treatment by different international study groups (this thesis). On a molecular level, internal duplications of the FLT3-gene (FLT3-ITD)29,30 and WT1 mutations31,32 are associated with a high relapse risk and poor
outcome. The prognostic impact of FLT3-ITD is influenced by the allelic ratio, with higher ratios being associated with poorer outcomes.29,30 Contrary, low allelic burden and
concomitant NPM1 mutations are associated with intermediate outcome.33,34
Altogether, AML is a molecularly heterogeneous disease, which becomes more and more evident with next-generation sequencing technologies. These novel techniques provide numerous of new insights into the biology of AML, with the potential to find targets for therapeutic intervention.
Risk-based treatment in de novo AML
Risk-group stratification followed by risk-based treatment is applied by all international pediatric AML groups. Defining parameters include cytogenetics, a few molecular aberrations, and treatment response. Most international study groups use
FLT3-ITD as a high-risk marker for treatment adjustments. However, some groups include
concomitant NPM1 and/or allelic ratio, whereas others do not. With regard to other well-known adverse aberrations, consequences for treatment are less uniform.
Apart from cytogenetic and molecular aberrations, response and MRD detection early during therapy are the most important predictors for outcome. Traditionally, morphological response after one or two courses of chemotherapy, i.e., achieving complete remission (CR), was and still is considered the most important outcome predictor. CR is defined as less than 5% malignant blasts in the bone marrow, absence of blasts with Auer rods, absence of extramedullary disease, combined with an absolute neutrophil count of at least 1.0×109/L (1000/μL), platelets above 80×109 (80,000/μL),
and independence of red blood cell transfusions.6 More recently, the LAIP defined by
multiparameter flow cytometry was added to routine response assessment in several protocols. The development in current flow technologies allows for the detection of MRD at a sensitivity of at least 1×10-3 in over 90% of the patients. Multiple study groups
have proven the predictive value of flow-MRD in respect to relapse risk and subsequent outcome.35-40 Furthermore, the leukemic stem cell burden at diagnosis has recently
been reported as a potential marker to identify young AML patients at risk of treatment failure.41
Due to the heterogeneity of the disease and the intensity of the treatment with subsequent side-effects and persistent unsatisfactory relapse rates, working in the field of pediatric AML is full of clinical challenges (this thesis). In general, pediatric AML treatment consists of four or five courses of chemotherapy with high doses of cytarabine
Chapter 1
and anthracyclines as backbone, complemented by other agents.6 Potential additional
agents include etoposide, 6-thioguanine, amsacrine, and gemtuzumab ozogamicin (GO). However, the additive value of most of these agents continues to be an important point of discussion. Classic agents like anthracyclines are now available in liposomal forms, such as liposomal daunorubicin. These liposomal forms may be administered in higher doses with good effect and similar, or even reduced, toxicity (this thesis).5 Although
major efforts are being undertaken to unravel targetable pathways for individualized therapy, the few novel agents that have been studied in phase I/II trials have not shown the results we would hope for.3 Subsequently, the far majority of pediatric AML
patients is still being treated with cytarabine and anthracyclines, sometimes followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first CR (CR1).3
However, the role of allo-HSCT in CR1 has been a point of debate for decades now. 42-44 Although the anti-leukemic effect of HSCT has been established in multiple studies,
efficacy needs to be balanced against HSCT-related mortality and morbidity, especially when considering the relatively good results obtained with chemotherapy alone.45-48
Relapsed AML
Despite intensified treatment, still 25-35% of the pediatric patients with AML relapses.3,49
Although most relapsed patients respond to reinduction therapy, many patients have a second relapse or die due to treatment or HSCT-related toxicity. This results in OS rates after relapse of at best 40%.50 Most important risk factors for relapsed patients include
time to relapse, early treatment response after reinduction therapy, and the cytogenetic profile at time of relapse.51 Whereas complicated risk stratification is applied at initial
diagnosis, most relapse protocols lack risk-based treatment approaches. However, molecular and cytogenetic changes between diagnosis and relapse, explained by either clonal evolution or clonal selection of preexisting minor clones, are frequent events and potentially of prognostic interest (this thesis).52,53
Toxicity and Supportive Care
Aside from leukemia-related death, approximately 3-5% of the patients dies while being in CR54,55 and this number is even higher when including treatment with
allo-SCT in CR148. Main causes of death in CR include infection or bleeding.54,55 Furthermore,
treatment-related morbidity has an important effect on the quality of life of all patients. The most frequently reported forms of severe toxicity include transfusion dependency, febrile neutropenia and infections, gastrointestinal toxicity (including mucositis), and cardiotoxicity. However, up-to-date information on toxicity and treatment-related mortality (TRM) is lacking for Dutch pediatric AML patients (this thesis). Internationally, TRM has improved over time due to the increased interest in supportive care, but
overall, published studies on supportive care are often limited by retrospective designs and/or small patients numbers. Subsequently, available guidelines mainly involve a more general population of children with cancer, without detailed specifications per disease.56,57 Chemo-induced profound neutropenia, disruption of skin and mucosal
barriers, multiple invasive procedures, the use of a central venous line, and hospitalization in general all make pediatric AML patients at high risk for severe infections. Whereas pharmacological prophylaxis with fluoroquinolones and antifungal agents is generally recommended for adult patients with AML58, the role of prophylactic antibiotics in
pediatric AML remains uncertain.59 Despite appeals by experts and working groups in
the field to harmonize guidelines, many divergent regimens among hospitals and study groups seem to exist (this thesis).60-62 Prospective randomized trials in this field are very
much needed (this thesis).
Late effects in survivors
Like many anticancer regimens, AML treatment is associated with late effects that can impair both physical and psychological health at an older age. Up to half of the childhood AML survivors report a chronic medical condition in adulthood.63 Important
late effects among AML survivors include neurocognitive and endocrine abnormalities. Especially high doses of anthracyclines are associated with (late) cardio-toxicity. With the increasing survival, the interest in childhood cancer survivor research has increased substantially. However, long-term follow-up is yet often lacking.
Outline of this thesis
International collaborations are needed for high-quality research on all aspects of pediatric AML, acknowledging the importance of biological, translational, clinical and quality of life studies in this vulnerable population. Several of the studies described in this thesis have been carried out within the international Berlin-Frankfurt-Munster (I-BFM) study group (SG).
This thesis includes several translational and clinical projects related to cytogenetics and clinical aspects of pediatric AML. The aim of all projects outlined in this thesis was to provide more insight in either risk stratification and/or clinical aspects of AML treatment. The first part of this thesis focusses on epidemiology, outcomes, and mortality of children with AML in the Netherlands. Chapter 2 describes the incidence and outcome of pediatric AML in the Netherlands over the past 26 years. Findings described in Chapter
3 are the results of the first project as part of a large national study on toxicity among
children recently treated for AML in the Netherlands, and includes incidence and causes of treatment-related mortality.
Chapter 1
The second part of this thesis focusses on clinical outcome among different cytogenetic subgroups of pediatric AML. Chapters 4-7 focus on the prognostic impact of different cytogenetic aberrations. Initially, risk-group stratification was based on the cytomorphology-based FAB classification.14-16
FAB type AML-M4 with eosinophilia (M4eo) has been associated with better outcome compared to other subgroups in children.64 M4eo morphology has been associated
with the presence of inv(16)/t(16;16) in adults.65 In Chapter 4 the prognostic and clinical
consequences of the presence of eosinophilia morphology in relation to inv(16)/t(16;16) is explored in children with AML-M4.
Aberrations inv(16) and t(16;16) result in the same fusion of the CBFβ subunit and the Myosin-11 heavy chain gene (MYH11).66 This fusion results in a subtype of myeloid
leukemias associated with a favorable prognosis.6,67,68 However, CBFβ-MYH11 fusion
transcripts are heterogeneous and may vary in biological activity.69,70 A few risk factors
have been identified in inv(16)/t(16;16) adult cohorts, but little is known about pediatric t(16;16)-AML patients specifically. The international cohort study described in Chapter
5 evaluated potential prognostic features and outcome in this specific subgroup of
CBF-leukemia patients.
Chapter 6 describes the largest international cohort of pediatric AML patients
with a t(8;21)-aberration, generally classified as favorable-risk. The importance of additional cytogenetic aberrations and the role of different doses of the mainly used chemotherapeutic agents are addressed.
The biological aspects and prognostic impact of cytogenetics and molecular aberrations at diagnosis have been well studied, but little is known about the prognostic significance of cytogenetics, chromosomal instability, and clonal evolution at the time of relapse in pediatric AML. Chapter 7 describes an international effort that aims to provide more insight in the prognostic impact of cytogenetic aberrations at time of relapse.
The third part of this thesis focusses on toxicity and supportive care. With increasing survival rates, toxicity, impact on quality of life, and late effects of initial treatment become of increasing importance.
One of the most important types of myelosuppressive agents concerns anthracyclines. Similar to many drugs used in the treatment of oncologic disease, anthracyclines also inflict damage to many other healthy cells. One of the most important side effects includes cardiotoxicity.71,72 In order to reduce especially this dose-limiting toxicity,
liposomal forms of anthracyclines have been developed. Chapter 8 reviews several aspects of one of the most frequently used liposomal forms of anthracyclines in pediatric AML: liposomal daunorubicin.
Glucocorticoids (GCs) are mainly being used as anti-leukemic drugs in the treatment of ALL, since these cells are much more sensitive to glucocorticoid (GC)-induced cell kill than AML cells.73,74 However, some study groups still use GCs as an anti-leukemic agent75,
whereas other physicians prescribe the GC dexamethasone as supportive anti-emetic drug. Furthermore, GCs are sometimes used as anti-inflammatory drugs during AML treatment, or as part of post-SCT regimens. The aim of the study described in Chapter 9 was to confirm in vitro resistance patterns in pediatric AML, but also to identify potential risks of increased blast proliferation associated with GC exposure.
Intensification of treatment protocols and high doses of chemo have led to an increase of treatment-related complications, with severe infections being one of the most important risks. Despite appeals by experts and working groups in the field to harmonize infection prophylactic guidelines, many divergent regimens among hospitals and study groups seem to exist.60-62 We evaluated the currently available infection prophylaxis
guidelines among international pediatric AML study groups affiliated with the I-BFM-SG, as well as hospital-based guidelines among hospitals affiliated to the NOPHO-DBH AML Study Group. An overview of the results of this survey are presented in Chapter 10. During our repeated discussions on the use of antibiotic prophylaxis and the emerging need for prospective randomized trials, a novel study was set up. The aim of this study is to evaluate whether the use of the glycopeptic antibiotic teicoplanin reduces the number of specific bacterial infections, i.e., Viridans Group Streptococci, in children treated for AML. The concept synopsis of this trial design is presented in Chapter 11. Finally, Chapter 12 provides an overview of the clinical challenges when treating patients with AML, including cytogenetic and molecular diagnostics, the current risk-group stratification, and the fragile balance between efficacy and toxicity.
In the general discussion (Chapter 13) the results of the studies described in this thesis are summarized and discussed in relation to current literature, concluded by future perspectives.
Chapter 1
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Chapter 1
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