Novel agents for the treatment of childhood leukemia: an update
OncoTargets and Therapy
Novel agents for the treatment of childhood leukemia: an update
Ertugrul Er yılmaz 1
Cengiz Canpolat 0
0 Department of Pediatric Hematology and Oncology, Acibadem Kozyatagi Hospital, Acıbadem University School of Medicine , istanbul , Turkey
1 Department of Pediatrics, Division of Pediatric Hematology and Oncology, Acibadem Maslak Hospital
8 1 0 2 - l u J - 2 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s re .
acute lymphoblastic leukemia; acute myeloid leukemia; pediatric leukemia
open access to scientific and medical research
The high success rate of pediatric acute lymphoblastic leukemia (ALL) regimens has
been achieved by risk stratification of patients, based on disease features at presentation
and responses to induction chemotherapy regimens. Traditional multiagent
chemotherapy plays a significant role in the treatment of pediatric ALL and will likely continue
to do so for some time. Innovations in cytogenetics and molecular diagnostics are
identifying new targets and corresponding therapeutic agents. As novel agents reached
developmental milestones and are adopted into practice, higher survival rates and
reduced morbidities have been achieved when compared to traditional cytotoxic
chemotherapy regimens. Risk feature stratification and intensified chemotherapies for
high-risk patients give rise to different treatment patterns from the standard regimens
used in both ALL and acute myeloid leukemia (AML).
Relevant milestones in ALL treatment
In the 1950s, leukemia patients did not survive for .2 years. Improvements in leukemia
treatment were guided by lengths of time, with treatment failures. Relevant milestones
were met, novel agents flourished in the standard regimens since 1950s and
improvements raised survivals every new decade.
In 1948, Farber et al introduced 4-amino-pterylglutamic acid, a folic acid antagonist,
that ushered in the chemotherapeutic treatment era for ALL. This agent caused
intermittent remission in the leukemic bone marrows; the reads of immature cells in
peripheral blood post-mortem studies showed deceleration of the leukemic process,
which was not encountered in 200 post-mortem examinations of patients who were
not treated with folic acid conjugates. From these data, it is concluded that “transient
OncoTargets and Therapy 2017:10 3299–3306 3299
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remission” was induced by aminopterin in the treatment
The introduction of combination therapies in 1971
overcame resistance to folic acid conjugate therapies. These novel
treatment paradigms induced rapid and effective malignant
cell lyses. In one study, both sequential use and combination
therapies containing antimetabolites with 6-mercaptopurine
(6-MP) and methotrexate were analyzed. The use of
com2081 bination therapies revealed that multimodality treatment
l--Ju maximized remission rates and durations while improving
21 toxicity profiles.2
o7n Based on these findings, Pinkel et al proposed a major
.602 breakthrough treatment model that still constitutes the
..94537 bmauclktibpolne-estoefp ApLroLcetshseraaspyfo.lTlohwest:re1a)t mreemnitsfslioown ionudtulicnteiosna;
/yb 2) intensification/consolidation; 3) continuation and 4)
cen.com tral nervous system (CNS) prophylaxis comprising cranial
re . irradiation and intrathecal methotrexate.3
.vdoep lsyeon phylaxis, ultimately caused serious sequelae. However,
Cranial irradiation, which was essential for CNS
/ww lan a pediatric oncology group study showed that intrathecal
tsp rse CNS chemotherapeutic prophylaxis added to a systemic
rom oF chemotherapy backbone was equivalent to cranial irradiation
fd in terms of the length of complete remission (CR).4
Subsedea quently, combined modality treatments using methotrexate,
lonw hydrocortisone and cytarabine for CNS prophylaxis increased
ydo success rates in both low-risk and high-risk B-cell ALL
repa patients.5 Furthermore, addition of dexamethasone further
hT controlled CNS relapse in leukemic patients when compared
dna to prednisolone.6
trsge Stratifications based on genetic polymorphisms have
oaT identified diverse responses to treatment strategies,
leadcnO ing to patient group-specific treatment modifications. For
example, patients with thiopurine S-methyl transferase
(TPMT) deficiency develop severe hematopoietic toxicity
when treated with standard doses of 6-MP or azathioprine.
TPMT has become a standard variant that is tested prior to
Recently, significant improvements have been made in the
treatment of ALL that have achieved .90% 5-year event-free
survival for children younger than 14 years.8 This success
rate has been attributed to: 1) elimination of cranial
irradiation; 2) restriction of doxorubicin as an anti-leukemic agent
in standard-risk patients, and 3) addition of asparaginase to
standard regimens to improve disease-free survival.9
Additionally, molecular agents, such as tyrosine kinase inhibitors
(TKIs), serine/threonine kinase inhibitors, proteasome
inhibitors, epigenetic targets, and antibody-based immunotherapies
emerged in the last 2 decades to treat specific target.10
New advances in childhood AML therapy
In pediatric AML, a large number of subtypes have been
identified, but most lack targeted therapies to address the
mutations; the treatment outcome has improved markedly
for children from 20% in 1980s to 60% recently.11 Advances
have been accomplished through better risk classification,
implementation of excellent supportive care measures,
and therapeutic adaptations based on patient responses.
Additionally, the adaptation of allogeneic hematopoietic
stem cell transplantation has raised the cure rates that are
regularly measured by the International Acute Myeloid
Zavedos® (idarubicin; Pfizer) has activity in AML.
This was first discovered in adults. However, by the end
of the 20th century, idarubicin was seeing substantial
offlabel use in children to avoid daunorubicin (DNR)-induced
Fludara® (fludarabine; Bayer) is a purine analog that
interferes with DNA synthesis. Fludarabine produces high response
rates in comparison to alkylating agents alone in the treatment
of chronic lymphocytic leukemia. Fludarabine was combined
with the Idarubicine-Fludarabine, Cytarabine,
GranulocyteColony Stimulating Factor (IDA-FLAG) regimen in pediatric
patients. In .50% of patients, this agent produced CRs
lasting for .12 months. Thus, fludarabine was recommended as
a therapeutic option prior to allogeneic or autologous bone
marrow transplantations, particularly as an alternative to
standard chemotherapies in certain risk groups.14
Remission induction and consolidation regimens have
remained unchanged in AML since the 1980s. Overall,
pediatric AML cases have been treated as a homogeneous disease,
not differentiated by subtypes. One notable exception is the
AML M3 subtype, which is also named acute promyelocytic
leukemia (APML). The management of APML has changed
dramatically following the introduction of the agent Vesanoid®
(tretinoin, all-trans retinoic acid [ATRA]; Roche). Leukemic
promyelocytes have the unique ability to undergo
differentiation with exposure to retinoic acid; both differentiation and
apoptosis are stimulated by exposure to arsenic trioxide.15
Development of this agent eliminated the need for allogeneic
hematopoietic stem cell transplantation in APML patients and
led to higher survival rates comparable to low-risk ALL.16
Novel agents, in development, that introduce new treatment strategies
Rates of difficult-to-treat leukemia have declined due to
advances in treatment methods and systemic therapy agents.
Additionally, strides made in the biology of leukemic cell
lines have led to earlier recognition of residual diseases.
Together, these factors have successfully guided new arms
of research and improved the treatment paradigms.
Specifically, genetic players in the leukemic DNA landscape have
emerged as actionable targets for interventions. The large
body of literature that has accumulated recognizing biological
underpinnings of childhood leukemia has made tailored
therapies both possible and effective.17 Relapsed patients,
who are rarely cured, will continue to represent the highest
unmet need in this space. Although novel therapies are
usually developed as single agents, some will also be evaluated
in combination with chemotherapeutic backbones. Each class
of agent is discussed in detail later.
Targeted therapies and/or agents
In Philadelphia chromosome-positive (ph+) ALL, BCR/
ABL1 gene rearrangements lead to actionable protein
products. TKIs, eg, Gleevec® (imatinib; Novartis), can specifically
inhibit the rearrangement and have improved the outcomes for
ALL patients.17 It should be noted that two novel agents,
Sprycel® (dasatinib; Bristol-Myers Squibb [BMS]) and Tasigna®
(nilotinib; Novartis), were developed to overcome the
potential over imatinib resistance, after exposure to imatinib.18 Both
were formerly used successfully to the extent that allogeneic
stem cell transplant was deferred in the setting of optimal
response to TKI-based regimens in the first CR.19
ALL patients with mixed lineage leukemia (MLL)
rearrangements have poor treatment outcomes with conventional
chemotherapy. MLL rearrangements occur in 80% of infants
and 5% of older children. FLT3 is one unique gene
expression profile that is altered in MLL-rearranged ALL. In all,
18% of MLL-rearranged ALL cases harbor FLT3-activating
mutations that lead to high expression levels.20 In vitro
studies have demonstrated that a novel enzyme inhibitor
of FLT3, Hydrate® (CEP-701, lestaurtinib; Cephalon Inc.),
suppresses FLT3-driven leukemic cell survival.21
Lestaurtinib is an orally available inhibitor that selectively inhibits
FLT3 autophosphorylation, thereby killing leukemic cells.
However, lestaurtinib is unlikely to be curative if used as
monotherapy in MLL-rearranged ALL patients who
Another actionable mutation in childhood leukemia is
purine nucleoside phosphorylase, a catalytic enzyme in the
purine salvage pathway. Loss of this enzyme is specifically
associated with T-cell lymphopenia and with humoral
deficiency. Mundesine® (forodesine; Mundipharma AG) is the
most potent agent used to target this pathway. Forodesine
is a purine nucleoside phosphorylase inhibitor. In vitro and
in vivo studies demonstrate that it targets lymphoid cells and
disrupts DNA synthesis. Forodesine has shown promise in
early phase clinical trials as a monotherapy for the treatment
of relapsed/refractory hematologic malignancies. Trials
testing combination therapies are warranted to further improve
Other enzyme inhibitors such as the DNA
methyltransferase inhibitor Dacogen® (decitabine; Janssen-Cilag
International NV/Eisai) and the histone deacetylase inhibitor
Zolinza® (vorinostat; Merck/MSD/Taiho) have shown
promise as targeted therapies treating relapsed ALL.24
Zebularine (CAS 3690-10-6; Sigma-Aldrich) is another
potent DNA methyltransferase inhibitor associated with
gene demethylation and enhancement of tumor
chemosensitivity. Zebularine is a nucleoside analog of cytidine and
is considered a prototypical epigenetic therapy for cancer
Cluster of designation (CD) antibodies
CD antibodies are cell surface molecules present on all
cells are useful in hematopoietic malignancies because they
harbor critical information about lymphoblasts. Evaluation
of CD makeup indicates the type of progenitor cells that
are accumulating in bone marrow. Flow cytometry studies
are used extensively for both diagnostic and therapeutic
purposes in childhood ALL treatment. Minimal residual
disease (MRD) sampling at the end of treatment or during
follow-up also evaluates CD status to guide practitioners
regarding responses and need for additional treatment
modalities. Monoclonal antibodies (mAbs) against CD
receptors theoretically serve as targeted therapies to selectively
induce blast deformations.
In contrast to current frontline regimens used in adults,
mAb therapies are not extensively used in de novo childhood
ALL. One exception is Rituxan® (rituximab; Roche), which
is used as the first-line treatment for Burkitt leukemia/
lymphoma.26 Rituximab targets CD20, a cell surface receptor
that is present in approximately half of patients with mature
pre-B-cell lymphoma and ALL. As a single agent, rituximab
has minimal activity in ALL. In the early 21st century,
rituximab added to standard chemotherapy was shown to
improve outcomes. Rituximab-based combination therapies
have also been promising second-line treatment choices and
have been used concomitant within hematopoietic stem-cell
transplantation for high-risk patients.27
The mAb Campath® (alemtuzumab; Sanofi) targets
CD52, which is found on T- and B-lymphocytes, natural
killer cells and monocytes. Alemtuzumab was first approved
by the US Food and Drug Administration (FDA) in 2001
for the treatment of B-cell chronic lymphocytic leukemia.28
Rituximab and alemtuzumab are examples of naked mAb
therapies without an element added to the compound.
Another example is LymphoCide® (epratuzumab;
Immunomedics), but this agent has shown very limited single-agent
activity in pediatric clinical studies.29
Other examples of conjugated mAbs includes the
antiCD33 antibody Mylotarg® (gemtuzumab ozogamicin; Pfizer/
Wyeth-Ayerst Laboratories), which is a recombinant,
humanized anti-CD33 mAb covalently attached to the cytotoxic
antitumor antibiotic calicheamicin via a bifunctional linker.
Since 2000, when gemtuzumab ozogamicin was approved for
clinical use, treatment trials and pilot studies have revealed
potential expanded applications along with additional
limitations. Therapy can induce blast reduction in childhood AML,
which has no further conventional treatment options.30
CMC-544 (inotuzumab ozogamicin; Wyeth and
UCBCelltech) is a CD22-targeted immunoconjugate of
cali.vdoepw lsyeonu icnhepaamtieicnitns,wwithhicnhonw-Hasoedvgakliuna’tseldy minpPhhoamsae,IaInIdcltihneicraelsetrairaclhs
/ww lan INO-VATE evaluated inotuzumab ozogamicin as part of a
tsp rse chemotherapy regimen in ALL in the frontline setting.31
th rp Finally, another antibody–drug conjugate, SGN-CD19A
(Seattle Genetics), is composed of a CD19-targeting mAb
combined with the cytotoxic agent monomethyl auristatin F.
Phase I clinical trials of SGN-CD19A are ongoing in patients
with refractory B-lineage ALL.32
Recent developments have led to the introduction of several
immunotherapy models. Both cell-based therapies and
antibodies are being used as targeted therapies. Cell-based
therapies can use normal/autologous T-cells collected from the
patient that are amplified, activated and targeted against
cancer cells. Autologous T-cells are not able to fight a patient’s
own cancer cells unless modified to gain this activity.
Currently, two cell therapy approaches are under
investigation, both of which use autologous T-cell manipulation
The first is chimeric antigen receptor (CAR) T-cell
technology. This is a brand new approach to immunotherapy.
This technology involves genetic engineering of autologous
T-cells to activate potent cytotoxic cellular effector
mechanisms upon recognition of human leukocyte antigen
(HLA)independent CD19 antigen-positive ALL cells. The efficacy
of this approach was recently demonstrated in clinical trials.
CAR expressing T-cells were infused into adult and
pediatric patients with B-cell malignancies, where they killed the
leukemic cells.33 Adult patients in an early phase clinical trial
experienced sustained complete responses after treatment
with CAR T-cells. This population was refractory to other
treatments. Nonetheless, relapsed/refractory ALL patients
showed remarkable complete response rates of ~90%.34
The second technology utilizes a “smart antibody”.
Blincyto® (blinatumomab; Amgen) is a novel mAb that
combines single-chain antibody fragments of CD19 and CD3.
Together these fragments bring a T-cell in close proximity
to a malignant lymphoblastic cell, producing redirected
lysis. Blinatumomab is infused into the patient where it then
engages with normal T-cells and redirects them to tumor
cells. As with the CAR T-cell approach, autologous T-cells
fight the leukemic cells. This bispecific T-cell-engaging
antibody (BiTE) has shown encouraging results in relapsed/
refractory ALL patients and in patients in morphologic
remission, but with evidence of minimal residual disease.35 In a
recent multi-center Phase II trial, blinatumomab was tested
in relapsed or refractory B-precursor ALL adult patients.
Results showed that blinatumomab was safe and had
Given that autologous T-cells are genetically manipulated
outside of the body, CAR T-cell technology is an ex vivo
process. Conversely, blinatumomab-based BiTE technology
works in vivo. CAR T-cells persist in the recipient for months
and remain continuously active. In contrast, blinatumomab
and other BiTE agents are only active during the course of
administration. Overall, both approaches provide proof of
principle that patients’ autologous T-cells can be
manipulated, either in vivo or ex vivo, to act against host leukemic
cells. CARs are generated by fusing antigen-binding regions
of mAbs or other ligands to membrane-spanning and
intracellular-signaling domains. They have recently shown
clinical benefit in patients treated with CD19-directed
autologous T-cells. These recent successes suggest that
modification of T-cells with CARs will be a powerful approach for
developing safe and effective cancer therapeutics.37
In children, other efforts are being undertaken that test
hard-to-treat childhood leukemic cases with
immunotherapeutic agents. Autologous tumor cell vaccines are applied de
novo shortly after hematopoietic transplant. These
personalized tumor vaccines are meant to bolster selective immune
responses. The vaccines are composed of the patients’
own inactivated leukemic cells combined with an immune
stimulant granulocyte-macrophage colony-stimulating factor
Finally, dendritic cell (DC) vaccinations stimulate immune
responses and have demonstrated anti-leukemic effects
when presenting the Wilms tumor gene (WT1) antigen.
Additionally, mRNA-transfected DC vaccines are emerging as
nontoxic strategies to prevent or delay relapses in AML.40
Radio immunotherapy (also called radiolabeled mAb therapy)
is another type of conjugated mAb therapy. The radio
immunotherapy mechanism of action links an mAb to another
radioactive isotope, thus delivering radiation directly to cancer
cells. Zevalin® (ibritumomab; Spectrum Pharmaceuticals) and
iodine I-131-based Bexxar® (tositumomab; GlaxoSmithKline)
were both FDA approved in 2002–2003.41
Ibritumomab is indicated for adults with previously
untreated follicular non-Hodgkin lymphoma (NHL) who
achieve partial or complete responses to the first-line
chemotherapy. It is also labeled for adults with relapsed or refractory
low-grade or follicular B-cell NHL, including those who are
refractory to rituximab.42
Tositumomab is indicated for relapsed or refractory,
low-grade, follicular or transformed NHL, which expresses
the CD20 antigen, and for rituximab-refractory NHL.36,43
The safety and efficacy of these two agents have not been
established in children.42,43
The prototypical examples of effective small molecules for
this disease are TKIs such as imatinib, dasatinib and nilotinib.
These TKIs target the disease-specific BCR/ABL1 rearranged
Similar research principles are being applied to other
mutations and have led to novel agents. The NOTCH1 gene
is mutated in approximately half of ALL patients stimulating
blastic cells to proliferate. Several drugs are in development
to block activating NOTCH1 mutation, thereby preventing
the leukemia cells from dividing.45
Researchers have identified several other targetable
mutated gene products. These can target the gene, which is
involved in methylation, as well as multiple targets,
inhibiting Janus kinase (JAK), signal transducer and activator
of transcription (STAT), mammalian target of rapamycin
(mTOR) plus the phosphatidylinositol-3-kinase (PI3K)
Non-targeted therapies and/or agents
New chemotherapy drugs with considerable efficacy are
approved by the FDA for treatment of ALL. For example,
Evoltra® and Clolar® (clofarabine; Genzyme [US]/Bioenvision
[EU]) was the first agent approved for relapsed ALL in children
and young adults that raised complete cure rates from 20%
to 30%. Additionally, Arranon® (nelarabine; Novartis) was
approved for T-cell ALL in both adults and children, which
boasts a single-agent CR rate of ~30%.50
Both clofarabine and nelarabine are being tested as
frontline treatment in combination with other chemotherapy
regimens. Clofarabine is being studied in pediatric patients,
while nelarabine has been also focused on adults with
A third drug that was recently approved for ALL is
Erwinaze® (asparaginase Erwinia chrysanthemi; Jazz
Pharmaceuticals/Ohara Pharmaceutical). Asparaginase
Erwinia chrysanthemi is indicated for patients who develop
hypersensitivity to Escherichia coli-derived asparaginase and
achieve efficacious therapeutic serum drug concentrations.52
De novo liposomal agents
Liposomes are organic structures of lipid molecules that
form hollow spheres that encapsulate a wide range of cargo
molecules. During the last several decades, liposomes have
developed as extremely flexible vehicles for delivering
chemotherapies to cancer cells, while minimizing unwanted
systemic side effects. Marqibo® (liposomal vincristine
sulfate; Talon Therapeutics), DepoCyte® (sustained-release
DepoFoam cytarabine; Mundipharma International),
DaunoXome® (liposomal formulation DNR; Galen/Sayre
Therapeutics), Myocet® (liposomal formation doxorubicin;
Cephalon/Teva Pharmaceuticals) and Oncaspar®
(pegaspargase, PEG-l -asparaginase; Shire/Medac/Rhone-Poulenc)
are novel liposomal agents that are essential to standard
childhood leukemia treatment regimens.
Liposomal vincristine sulfate is a recently approved
liposomal form of vincristine. The molecular structure
of liposomal vincristine sulfate is a sphingomyelin- and
cholesterol-based liposome that encapsulates vincristine.
The agent is delivered in 1 hour weekly infusions. In adult
Ph-negative ALL patients, vincristine is slowly released from
the liposome and delivered into the tissues more efficiently
than with the standard preparation.53 Trials are ongoing,
testing liposomal vincristine sulfate in pediatric patients.
For example, the pivotal trial, “Vincristine Sulfate Liposome
Injection Marqibo® In Combination with UK ALL R3
Induction Chemotherapy for Children, Adolescents, and Young
Adults with Relapsed ALL” is currently recruiting patients
in the UK and is sponsored by the Therapeutic Advances in
Childhood Leukemia Consortium (NCT 02879643).
Sustained-release DepoFoam cytarabine is a slow-release
formulation of cytarabine that is considered a safe and
efficient component of triplet intrathecal CNS prophylaxis
regimens. The use of sustained-release DepoFoam cytarabine,
once every 2 weeks, maintains cytotoxic concentrations of
cytarabine in the cerebrospinal fluid for .14 days. Standard
cytarabine injections must be performed twice weekly.54
Liposomal formulation DNR is a liposome
encapsu2810 lated form of DNR. It has better pharmacokinetics and
l--Ju pharmacodynamics and improved cardiotoxicity compared
12 to free-form DNR. The use of liposomal formulation DNR
o7n improved early treatment responses in relapsed AML
.620 in children.55,56
.945 Liposomal formation doxorubicin is a non-pegylated
73 liposomal doxorubicin with an impressive safety profile,
/yb particularly regarding acute cardiac toxicity, in childhood
.com leukemia. However, special attention must be given to
re . trol infectious complications, as both liposomal formation
.vdoep lsyeon cdaouxsoerusebviceirne manydelloipsuopsopmreassliofonr.m57 ulation DNR may easily
//:ww loan Pegaspargase is a pegylated formula of L-asparaginase
tsp rse that is used to replace the native form of the molecule.
trhom rpoF Replacement with a pegylated version decreases
immunogefd nicity and increases circulating half-life. PEG-L-asparaginase
ade is well-tolerated and can be utilized in patients who are
lnow hypersensitive to un-pegylated products.58
yod Annamycin® (l -annamycin; Moleculin Biotech) is a
liporaep somal formulation that has promising activities in both the
hT pediatric and adult leukemic settings. This agent is intended
dan for the treatment of relapsed or refractory AML. Currently,
trsge l -annamycin has been tested in six early phase clinical
aoT trials spanning 114 patients. There have been no reports of
cnO cardiotoxicity. Two of the clinical trials focused on leukemia.
Data from these trials indicated that l -annamycin had less
dose-limiting toxicity when compared to patients receiving
doxorubicin. Additionally, cardiotoxicity was eliminated
while avoiding multi-drug resistance effects.59
interferons and interleukins
Interferons and interleukins are naturally secreted by various
types of cells in the body. They act on other cells to stimulate
or inhibit certain actions of the cells. For example, some
interferons serve as cytokines that increase production of
immune cells as part of a natural response to infection and
cancer. Interferons and interleukins are sometimes referred to
as nonspecific immunotherapies. For example, interferon-α
molecules are produced by lymphocytes to resist
infections and cancers. High-dose interferon-α behaves like a
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chemotherapeutic agent by blocking cancer cell growth.
Interferons also stimulate innate immune-based defenses.
Using interferon-α with other immune modifiers
augments the effects of chemotherapy. Interferon-α molecules
are administered either daily or multiple times per week.
They are commonly used to treat patients with hairy cell
leukemia, chronic myeloid leukemia, NHL and cutaneous
T-cell lymphoma.60 Novel formulations of interferon such
as Pegasys® (pegylated-IFN-α; Roche/Chugai) are available
on once weekly dosing schedules.61
Donor lymphocyte infusion (DLi)
DLI is another type of immunotherapy. First, patients receive
an allogeneic stem cell transplant from a donor. Next,
lymphocytes are collected from the same donor and then infused
into the patient. The donor and the recipient may have very
similar, but not necessarily identical, blood types. As a result,
the donor lymphocytes may identify recipient cells as targets.
Infusing allografts of Granulocyte-Colony Stimulating Factor
(GCSF)-mobilized peripheral blood progenitor cells,
allodepleted donor T-cells and infusions of donor-derived, ex
vivo-expanded CD8(+) cytotoxic T lymphocytes as DLI have
decreased relapse rates and improved transplant outcomes.62
New modalities used as best treatment practice for both
ALL and AML are remarkable in their diversity. Over the
last decade, important biological and clinical differences
have been identified between leukemic cells at diagnosis
and relapse. For example, cancers may acquire new
chromosomal abnormalities and gene mutations and have reduced
responsiveness to chemotherapeutic agents. Nonetheless,
the clinical relevance of new agents and the best settings in
which to apply these agents might take some time to
elucidate, given that many trials share common methods and
designs. However, high-risk patients who benefited from
recent trials experienced higher survival rates and the same
or less morbidity, suggesting that these agents will be added
to the pediatric leukemia arsenal.
Overall, outcomes for patients with pediatric
hematopoietic malignancies are excellent. Thus, new trials to evaluate
novel therapies in children and young adults with refractory,
resistant or relapsed disease have a high bar to pass and will
be a challenge. For these rare malignancies, small sample
sizes take a long time to analyze, because they are reached
slowly in this setting. Given the fragility of risk populations
and the success of current agents, combination therapies may
be difficult to test. Nonetheless, they are probably necessary
to further improve outcomes in the relapsed or resistant
population. Phase II window studies could partly overcome
this problem, as could Phase II multiarm studies.63
Owing to very high cure rates in childhood ALL, current
clinical research goals may be non-inferiority or reduced
toxicity. However, in the relapsed or resistant setting, evidence
of better survival with acceptable toxicity may be the aim.
Describing the safety and efficacies of new therapies or agents,
which are then translated into improved patient outcomes, will
face many challenges. Collaborative relationships between
scientists, academics, clinical investigators and regulatory
bodies should shorten the developmental time frame needed for
approval of pediatric hematologic malignancy treatments.
The arsenal of agents in the fight against childhood
leukemia is expanding. Novel agents hold the promise of being
used as single agents or being combined with chemotherapy
In the near future, personalized treatment strategies
will be developed based on detailed genetic and epigenetic
characteristics or responses to early treatments and MRD
monitoring. Such strategies will require precise supportive
care. There are many questions that need to be addressed to
determine whether treatment should be limited to patients
with overt disease or whether it should include those with
MRD. Future studies will resolve whether novel agents that
have limited activities are improved when combined with
chemotherapy. The most effective types of chemotherapy
used in combination therapies remain to be determined and
will be selected based on better outcomes and less toxicity.
The authors report no conflicts of interest in this work.
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