Greenbury logan childhood leukemia

Published in final edited form as: Semin Hematol. Jul;50(3)– doi: /ematol

Abstract

The 50^th anniversary of Seminars in Hematology coincides with the 50th of St. Jude Children’s Research Hospital, and both milestones are inexorably linked to studies contributing to the cure of childhood acute lymphoblastic leukemia (ALL).

We thought it fitting, therefore, to mark these events by traveling back in time to point out some of the achievements, institutions, study groups and individuals that have made cure of childhood ALL a reality. In many instances, progress was driven by new ideas, while in others it was driven by new experimental tools that allowed more precise assessment of the biology of leukemic blasts and their utility in selecting therapy.

We also discuss a number of contemporary advances that point the way to exciting future directions. Whatever pathways are taken, a clear challenge will be to use emerging genome-based or immunologic-based treatment options in ways that will enhance, rather than duplicate or compromise, recent gains in outcome with classic cytotoxic chemotherapy.

The theme of this journey serves as a reminder of the chief ingredient of any research directed to a catastrophic disease such as ALL. It is the audacity of a small group of investigators who confronted a childhood cancer with the goal of cure, not palliation, as their mindset.

INTRODUCTION

Since the inauguration of the Seminars of Hematology and the opening of St.

Jude Children’s Research Hospital approximately half a century ago, there has been remarkable progress in the study of childhood acute lymphoblastic leukemia (ALL). This once uniformly fatal cancer has been transformed to one with a cure rate approaching 90% in many developed countries (Figure 1), and its dissection in the laboratory has uncovered many of the principles underlying our current knowledge of tumor cell biology -- advances that are often considered one of the pivotal success stories of modern medicine.

In this review, we summarize the historical perspective for these achievements and point to recent developments in the biology and treatment of ALL that will shape future directions for research and treatment advances.

Historical Perspective

Therapeutic Advances (Table 1)

Table 1.

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In , Farber et al.¹ described “temporary remissions” induced by aminopterin, a folic acid antagonist, in five children with acute leukemia, opening the era of chemotherapy for this disease.

This landmark demonstration was reinforced in , when Frei et al.² achieved a complete remission rate of 59% and a 2-year survival rate of approximately 20% in 39 pediatric patients, using a combination of mercaptopurine and methotrexate. Nonetheless, despite the introduction of several new antileukemic drugs, ALL continued to be fatal in the vast majority of patients.

To meet this challenge, Pinkel and colleagues at the newly opened St. Jude Children’s Research Hospital initiated a novel curative approach (“total therapy”) to ALL treatment in that featured multiple components of therapy -- remission induction, central-nervous-system (CNS)-directed therapy with cranial irradiation and intrathecal methotrexate, intensification (consolidation) therapy, and continuation treatment -- four components that still form the backbone of ALL treatments today.³ Responses to one of these regimens (Total Therapy Study V, –68) were remarkable, leading to cures in approximately half of the 35 patients who were enrolled.⁴ This success stimulated the conduct of similar clinical trials worldwide, with two pivotal studies in the s showing that intensification therapy relatively soon after remission induction could boost cure rates to near 70%.^5,6 In one study, Riehm et al.⁵ of the Berlin-Frankfurt-Münster group introduced so-called “Protocol II”, treatment which specified a reinduction phase (essentially repetition of the initial remission induction therapy), while in the other, Sallan et al.⁶ at the Dana-Farber Cancer Center incorporated weekly high-dose asparaginase into their multiagent protocol.

During the same period, concern over radiation-induced complications prompted the development of triple intrathecal therapy with methotrexate, hydrocortisone and cytarabine,⁷ and intermediate-dose intravenous methotrexate⁸ to replace prophylactic cranial irradiation. These pioneering studies demonstrated the importance of effective systemic chemotherapy when utilizing triple intrathecal therapy as CNS-directed therapy and the effectiveness of higher doses of intravenous methotrexate to reduce systemic and testicular relapse.

A subsequent trial showed that dexamethasone was more effective than prednisone in preventing CNS relapse.⁹ Taken together, these advances opened the way for successful elimination of prophylactic cranial irradiation in all patients with ALL who are treated with effective systemic and intrathecal therapy.¹⁰

Another turning point in the development of ALL therapy came with the finding that the systemic exposure to methotrexate (i.e., steady-state serum concentration) correlated with treatment outcome.¹¹ This discovery gave impetus to a randomized study showing that individualized doses of high-dose methotrexate, teniposide and cytarabine based on the ability of individual patients to clear the drugs, could improve outcome,¹² providing proof-of-principle for the “personalized dosing” in cancer treatment.

These data also established that it is possible that some patients were not being cured because their leukemia cells are exposed to sub-optimal concentrations of antileukemic agents, and not because their leukemia cells are resistant to chemotherapy. Indeed, as reviewed later, this early work laid the groundwork for our use of different doses of methotrexate in individual patients based on the phenotype and genotype of the leukemic cells, and different doses of mercaptopurine based on the patient’s inherited pharmacogenetic traits.¹³ Finally, the marked improvement in treatment outcome among patients with Philadelphia chromosome-positive ALL who receive an ABL tyrosine kinase inhibitor (imatinib), together with intensive chemotherapy,¹⁴ illustrates the potential of oncogenic pathway-directed therapy in ALL and provides a paradigm for the future design of targeted treatments in this disease.

Biologic Advances (Table 2)

Table 2.

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Cytogenetic studies of ALL began in ,¹⁵ and ultimately dramatically altered perceptions of ALL pathobiology.

Discovery of the Philadelphia chromosome in ALL by Propp and Lizzi,¹⁶ the clinical significance of modal chromosomal number (ploidy) by Secker-Walker et al. ¹⁷ and immunophenotype-specific chromosomal translocations by Williams et al.¹⁸ left little doubt that ALL is a disease involving DNA abnormalities.

Moreover, the demonstration of T-cell markers on leukemic lymphoblasts by Borella and Sen¹⁹ taught us that ALL can arise in the T- or the B- lymphoid compartment of the immune system.

The early hypothesis that consistent translocations pinpoint chromosomal segments containing genes critically involved in malignant transformation of ALL resulted in identification of numerous oncogenes by molecular genetic studies.

Not surprisingly, the earliest genes identified as partners of these reciprocal translocations were immunoglobulin genes or T-antigen receptor chain genes, the price paid for immunological diversity.^20,21 With the availability of antibodies for leukocyte differentiation antigens, early studies showed that T-cell ALL expresses terminal deoxynucleotidyl transferase and other T-cell markers, a finding that allowed the first minimal residual disease (MRD) studies in patients with ALL.²² With completion of the first draft of the human genome in the early s and the advent of molecular genetic technology, genome-wide studies of ALL became feasible with global gene expression profiling²³.

This advance, together with the interrogation of changes in DNA copy number using genome-wide SNP analyses and other high-throughput methods²⁴ and more recently the use of whole genome sequencing²⁵ has improved our ability to define the spectrum of genomic alterations that contribute to ALL pathogenesis.

Parallel studies of germline DNA from normal leukocytes has led to the detection of inherited germline single-nucleotide polymorphisms (SNPs) in genes that increase susceptibility to ALL.^26,27

Recent Research Development in Biology and Treatment

The optimal use of antileukemic agents, improved supportive care, and precise risk assessment have improved 5-year event-free survival rates to more than 85% and 5-year overall survival rates to more than 90% in several contemporary clinical trials (Table 3).^10,28–35 Paralleling these advances has been the improved understanding of ALL pathobiology, the mechanisms of drug resistance, and the disposition of antileukemic drugs in the host.

With the advent of high-resolution whole genome and transcriptome sequencing, virtually all cases of ALL can now be classified according to their specific genetic abnormalities,^36,37 opening the way for new drug discovery and targeted treatment of increasing numbers of patients.

Table 3.

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Novel leukemia subtypes

ALL is broadly classified into B-lymphoblastic and T-lymphoblastic leukemias, which can be further subclassified according to specific genetic abnormalities.³⁷ Among T-ALL cases, it is only important to distinguish a high-risk subgroup, now termed early T-cell precursor ALL,³⁸ whose immunologic markers, gene expression profile and mutational spectrum are reminiscent of myeloid leukemia, suggesting that this is a stem cell disease.²⁵ The prevalence of mutations in genes regulating RAS signaling, cytokine receptor expression and chromatin modification suggests that myeloid-directed or epigenetic therapy may improve the clinical outcome for this ALL variant.²⁵ Traditionally, about 70% to 80% of B-ALL cases were classified by modal chromosomal number (ploidy) and specific genetic rearrangements into prognostically relevant subgroups.^39,40 Now, with the advent of genome-wide analyses, virtually all B-ALL cases can be classified genetically.^36,37 One of the newly discovered subtypes is characterized by CRLF2 expression and affects 5% to 7% of children with B-ALL and, remarkably, about 50% of Down syndrome patients with ALL.⁴¹ Many of these cases have cryptic translocations involving a tyrosine kinase gene (e.g., JAK), and probably require intensive chemotherapy.⁴² Another subtype, termed Philadelphia chromosome-like (or BCR-ABL1-like) ALL, accounts for nearly 10% of B-ALL cases and exhibits a gene expression profile similar to that of Philadelphia chromosome (BCR-ABL1)-positive ALL with IZKF1 alteration.^43,44 A recent study with whole genome sequencing identified alterations and mutations activating kinase and cytokine receptor signaling in all 12 cases studied.⁴⁵ Importantly, several cases had genetic abnormalities that responded to ABL1 tyrosine kinase inhibitors (e.g., NUPABL1, EBF1-PDGFRB) or to JAK inhibitors (e.g., BCR-JAK2, mutated IL7R).⁴⁵ Although hypodiploid ALL is known to identify a high-risk subgroup and can be subdivided cytogenetically into near-hypodiploid cases with 24–31 chromosomes, low-hypodiploid cases with 32–39 chromosomes, and rarely high-hypodiploid cases with 40–43 chromosomes, the genetic bases of these novel variants were only recently uncovered by a genome-wide study.⁴⁶ Near-haploid cases have alterations involving receptor tyrosine kinase signaling and Ras signaling, while low-hypodiploid cases are characterized by alterations in TP53 and RB1.

Interestingly, both subgroups are sensitive to P13K and mTOR inhibitors, suggesting that these agents might be useful as a new strategy of targeted treatment.⁴⁶

Host pharmacokinetics, pharmacodynamics and pharmacogenetics

Early studies at St. Jude Children’s Research Hospital showed that pharmacokinetic variability can influence treatment outcome in ALL, with fast clearance of certain medications conferring an inferior treatment response.^11,12 Subsequent studies found many sources of variation, some environmental (e.g., hydration status, drug interactions) and others genetic.¹³ The classic example is the relation between inherited polymorphisms in gene encoding thiopurine methyltransferase (TPMT) and the metabolism and hematopoietic toxicity of mercaptopurine.

Patients who inherit one or two variant alleles that encode unstable and/or non-functional TPMT proteins are at increased risk of hematopoietic toxicity⁴⁷ and the development of therapy-related leukemia,³⁵ but can be safely treated with a reduced dose of mercaptopurine.¹³ Based on these data, we have been pre-emptively genotyping all patients for this enzyme and adjusting mercaptopurine dose accordingly (e.g., a 90% dose reduction in patients with two non-functional TPMT alleles).

This has resulted in markedly lower hematopoietic toxicity, without compromising efficacy of ALL treatment.^48,49

Genome-wide SNP analyses have identified several germline genetic variations that affect treatment outcome. In our early study, we identified germline SNPs associated with MRD, antileukemic drug disposition, and risk of relapse; one of the strongest signals came from 5 SNPs located within the IL15 gene locus, which encodes a proliferation-stimulating cytokine.⁵⁰ Subsequent studies showed that germline SNPs of the organic anion transporter gene SLCO1B1 are associated with methotrexate clearance⁵¹ and those of ARID5B with greater methotrexate polyglutamate accumulation, offering a plausible mechanism by which this genetic variant is linked to treatment outcome.^26,52

Genome-wide SNP analyses have also identified polymorphisms of several genes (ARID5B, IKZF1, CEBPE, BMI1-PIP4K2A) associated with the development of ALL in children.^26,27,52,53 Interestingly, the frequency of ARID5B and BMI1-PIP4K2A risk alleles increased in the order of African Americans, European Americans, and Hispanic Americans, corresponding to the increasing incidence of ALL in these racial/ethnic groups.^52,53 That patients with hyperdiploid>50 ALL have a greater probability of carrying germline ARID5B variants than do those with other genotypes also suggests an interaction between inherited and acquired genetic variations during leukemogenesis.^26,27

Precise risk stratification

As the arsenal of effective antileukemic agents and the understanding of ALL pathobiology grow, so does the need for new systems of risk assessment to avoid over- or under-treatment of individual patients.

Of the many variables that influence prognosis in ALL, age at diagnosis, initial leukocyte count, leukemic cell genetics, and especially the initial response to treatment are perhaps the most useful for risk stratification.³⁷ Variable treatment responses may be evident even among cases of the same genetic subtype, partly because of differences in the target cell that underwent malignant transformation and partly because of differences in cooperating driver mutations.^36,54 Such differences may also be related to host differences in drug metabolism and pharmacokinetics.

Even so, it is well recognized that effective treatment can abolish the adverse prognostic impact of many clinical or biologic features. In one recent example (St. Jude Total Therapy Study XV), early intensive treatment with dexamethasone, vincristine, asparaginase, and triple intrathecal therapy, as well as high-dose methotrexate, not only yielded high cure rates for older adolescents and black patients, once considered high risk subgroups,^55,56 but has also eliminated the prognostic significance of a high initial white blood cell count.¹⁰ Similarly, the poor outcome associated with genetic evidence of >10% Native American ancestry for patients with Hispanic ethnicity or for those self-reported as white with more than 10% genetic Native American ancestry was abrogated by an additional course of delayed intensification therapy in a Children’s Oncology Group (COG) study.⁵⁷ Nonetheless, some features still have prognostic implications in the context of effective treatment and warrant modifications in treatment strategy.

Thus, intensive regimens are used for T-cell ALL in most clinical trials, and for patients with intrachromosomal amplification of chromosome 21 in a United Kingdom ALL trial.⁵⁸

Not surprisingly, response to treatment in vivo as determined by MRD measurement has become a highly reliable prognostic indicator because it not only reflects intrinsic drug sensitivity, but also host pharmacodynamics and pharmacogenomics, treatment adherence, and treatment efficacy.³⁷ Notably, this variable assessed at a later time in the clinical course (e.g., at day 78 of extended remission induction of a Berlin-Frankfurt-Münster protocol) is more predictive of ultimate outcome because it reflects the drug sensitivity or resistance to more drugs that the patients have received.⁵⁹ Thus, in one study, remission induction failure at day 28 to day 42 did not predict a dismal prognosis for children with B-ALL who did not have other adverse prognostic features and especially for those with hyperdiploidy which confers a favorable response to high-dose methotrexate and mercaptopurine, drugs used only after 4 to 6 weeks of remission induction.⁶⁰ However, assessment of treatment response early during remission induction (e.g., at day 15) is still useful in gauging the intensity of subsequent remission induction therapy to avoid overtreatment of patients with a favorable prognosis, especially those treated in developing countries with limited resources and insufficient supportive care.

The usual methods of monitoring MRD include flow cytometric detection of aberrant immunophenotypes and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) amplification of immunoglobulin and T-cell receptor genes.

The flow cytometric method requires a high level of expertise to interpret results, while ASO-PCR amplification is both time consuming and laborious. Moreover, both strategies have a limited capacity to monitor clonal evolution during treatment, with the potential pitfall of false-negative results. New deep-sequencing methods can overcome these limitations, are more precise, and can detect very low levels of leukemia (below %).⁶¹ In this regard, very low levels of MRD at the end of induction therapy may have prognostic significance.⁶²

Optimizing risk-directed therapy

Although an overall complete remission rate of 98% or 99% can be achieved in most study cohorts with improved supportive care and chemotherapy,³⁷ there is no consensus on the optimal regimen or duration of remission induction therapy.

Although dexamethasone is used in virtually all protocols because of its superior CNS control compared to results with prednisone or prednisolone,⁶³ it is not often included during remission induction because of concern over high rates of toxicity and toxic death, especially at high doses (e.g., 10 mg/m²) in patients 10 years of age or older, a finding partly related to slower clearance of dexamethasone in this age group.³⁷ In the COG protocols, dexamethasone is used during remission induction for children less than 10 years old with high-risk B-ALL because it yielded superior event-free survival than prednisone for this age group in a randomized study, and for patients with T-cell ALL based on promising results of two European studies for this subtype.⁶⁴

Infant or adolescent cases and patients with Down syndrome continue to have lower induction rates, partly because they have more high-risk leukemia and partly because they are more susceptible to fatal infection, a risk that extends into the post-remission phase.^65–67 Hence, remission induction should be moderate in intensity for these patients as well as those with a low- or standard-risk of relapse, reserving intensive chemotherapy for the consolidation phase of treatment, when normal hematopoiesis has been restored.

Although immunoglobulin replacement therapy and prophylactic antibiotic and antifungal treatment have been used in some centers when these patients become severely immunosuppressed and myelosuppressed, prospective studies are required to establish the efficacy of this approach. As mentioned earlier, we measure MRD levels after 2 weeks of remission induction therapy, and add more asparaginase for patients with a high level of residual leukemia (i.e., 1% or more leukemic cells in the bone marrow).

A simple and inexpensive flow cytometric assay, based on the property of exquisite sensitivity of normal lymphoid progenitors (CD19+, CD10+, and/or CD34+) to corticosteroids, can be used to measure MRD for B-ALL at this early interval.⁶⁸

Intensification of treatment after remission induction is essential for all patients, but again there is no consensus on the best regimen or duration of treatment.

Consolidation treatment is generally given soon after remission induction and consists of high-dose methotrexate and daily mercaptopurine. To achieve an adequate response in patients with T-cell ALL or perhaps B-ALL with the TCF3-PBX1 fusion, both of which accumulate methotrexate polyglutamates less avidly than other subtypes of ALL, methotrexate should be given at higher dose (~5 g/m²) over 24 hours.^69,70 While it is debatable whether high-dose methotrexate is necessary for low-risk ALL, delayed intensification (also termed reinduction), given within 2 to 3 months post-remission is clearly beneficial to all patients.³⁷ This phase of treatment consists of asparaginase, dexamethasone, and vincristine, which act synergistically,^71,72 with or without an anthracycline, mercaptopurine and methotrexate.³⁷ It should be noted that the intensity of delayed intensification is more important than its duration.⁷³ Indeed, intensification therapy for 6 months was as effective as 10 months of the same treatment,⁷⁴ and in three randomized trials, two reinduction courses or one reinduction course yielded the same event-free survival in standard- or high-risk patients who had a rapid early response to remission induction.^34,73,75 Because the second reinduction course was started rather late in each of the three randomized studies (week 32 to week 48),^34,73,75 it remains to be determined whether a second reinduction introduced earlier in the treatment course will improve outcome.

Intensive use of asparaginase, dexamethasone and vincristine accounts for much of the recent improvement in treatment outcome in patients with ALL.

Despite its higher cost, the pegylated form of Escherichia coli asparaginase (PEG-asparaginase), which is less allergenic than the native E. coli product, has become the first-line asparaginase treatment in the United States, and is used increasingly in the other countries. The preparation derived from Erwinia chrysanthemia does not cross-react with the E.

coli preparation and is used as a second-line therapy for patients with hypersensitivity reaction or “silent inactivation” (due to antibodies) to native E.

coli asparaginase or PEG-asparaginase.⁷⁶ Depending on the preparation used, the treatment schedule and the concomitant immunosuppressive agent, 10% to 60% of patients will develop hypersensitivity reactions⁷⁶ and 10% to 30% of those without clinical hypersensitivity may develop silent inactivation.⁷⁷ Importantly, the presence of anti-asparaginase not only affects the efficacy of asparaginase but may also increase systemic clearance of dexamethasone, leading to increased risk of bone marrow and CNS relapse.^77,78 In a recent study, a very low rate of asparaginase hypersensitivity reaction (% overall and % in high-risk cases)³⁴ may be attributed to the optimal use of PEG-asparaginase, which was either preceded by a dexamethasone pulse or administered without interruption (in high-risk cases).⁷⁹ In another recent study, patients randomized to receive individualized doses of native E.

coli asparaginase based on nadir serum asparaginase activity and, in the presence of silent inactivation, to receive Erwinia or PEG-asparaginase, despite receiving a lower median dose of asparaginase, had a significantly better event-free survival rate than did the controls, who were treated with a fixed dose of asparaginase.³¹ Hence, prospective identification of patients with silent inactivation of asparginase could be an important strategy to justify a switch to alternative forms of asparaginase.

In this regard, commercial tests to measure asparaginase levels are now available, but guidelines for modifying therapy based on such measurements have yet to be developed.

During continuation treatment with weekly low-dose methotrexate and daily mercaptopurine, tailoring the dosages of these drugs to the limits of tolerance has been associated with a better outcome.³⁷ The preponderance of evidence indicates that the time has come to customize the dosage of mercaptopurine based on pre-emptive testing for TPMT status (e.g., genotype) to reduce acute hematopoietic toxicities and the late development of mercaptopurine-induced myeloid malignancy in patients with an inherited deficiency of this enzyme, particularly if they receive high-dose mercaptopurine (e.g., 75 mg/m² per day).³⁵ To this end, the international Clinical Pharmacogenetics Implementation Consortium has developed guidelines for TPMT genotyping and dosing of thiopurines (updates at ).⁸⁰ In most clinical trials, weekly methotrexate is given orally for convenience and cost savings, but we prefer to give it intravenously to partly circumvent the problems of variable bioavailability and to ensure better treatment adherence (hence, avoiding an increased risk of relapse) as shown in a recent COG study.⁸¹ This approach might have been partly responsible for the improved prognosis of older adolescents treated in our Total Therapy XV study.⁵⁵ Additional studies are needed to determine the optimal dosage of methotrexate for continuation therapy, which ranges from 20 mg/m² orally to 40 mg/m² intravenously per week, and the optimal duration of continuation treatment, which ranges from 2 to 3 years in various protocols.

Omission of prophylactic cranial irradiation

Despite the well-recognized devastating complications associated with prophylactic cranial irradiation, including second cancers, neurocognitive impairment and multiple endocrinopathy, this treatment is still used for up to 20% of patients judged to be at high risk of CNS relapse [e.g., T-cell ALL with hyperleukocytosis or the presence of overt CNS leukemia (CNS3 status)].⁸² Historically, the reluctance to omit cranial irradiation in such cases could be attributed to concern not only over the risk of CNS relapse, but also the potential seeding of the bone marrow by residual leukemic cells from the CNS, the so-called “sanctuary site.”.

There is also an ongoing debate over the optimal form of intrathecal therapy, owing to the mixed results of the randomized CCG study for standard-risk ALL, in which triple intrathecal therapy resulted in a significantly lower incidence of isolated CNS relapse but more hematologic and testicular relapses (hence poorer survival), compared to treatment with intrathecal methotrexate.⁸³ Conceivably, hematologic, testicular and CNS relapses are competing events, and improved CNS control with triple intrathecal therapy in the CCG study might have favored leukemic relapse in other sites.

Thus, effective systemic therapy is needed to realize the full benefit of triple intrathecal therapy. To this end, a recent meta-analysis showed that adding intravenous methotrexate to regimens incorporating triple intrathecal therapy improves outcome by reducing both CNS and non-CNS relapses, whereas adding it to those treated with intrathecal methotrexate yields little benefit.⁸⁴

Three studies (St.

Jude Study XV, Dutch Childhood Oncology Group protocol ALL-9, and UKALL ), featuring effective systemic therapy, early intensification of intrathecal therapy, and omission of prophylactic cranial irradiation in all but the few patients with CNS3 status in the UKALL study, resulted in excellent 5-year event-free survival rates (%, 81% and %) and low isolated CNS relapse rates (%, % and %), respectively.^10,30,34 In St.

Jude Study XV, all 11 patients with an isolated CNS relapse remained in subsequent remission for 4 to 11 years after retrieval therapy, and in all likelihood are cured of their leukemia.¹⁰ With the exception of some adverse effects on complex fine-motor function observed among patients treated in the Dutch ALL-9 study⁸⁵ and early attention deficits among those in St.

Jude Study XV,⁸⁶ global cognitive abilities were well preserved in patients treated without cranial irradiation. These results, together with the finding of a substantial risk of a second malignancy in the field of irradiation, even with 12 Gy cranial irradiation,⁸⁷ should encourage others to eliminate CNS irradiation while optimizing chemotherapy for all patients in future studies.

Future Directions

Although protocol-directed therapy remains the best option for patients with cancer, it was estimated that only 56% of children with ALL were enrolled in COG protocols between and in the U.S.²⁹ Indeed, the low proportion of patients in the SEER program who had been treated in COG protocols may partly account for their inferior outcome as compared to that in single-institution studies.⁵⁶ Hence, efforts should be made to improve protocol enrollment rates nationwide.

Given the high cure rates being achieved in patients treated on contemporary protocols, those designing and conducting new leukemia treatment protocols face challenges that come from success: a radical change in treatment for all patients could jeopardize past gains in outcome, whereas modest changes are unlikely to yield significant improvements.

Hence, current effort has focused increasingly on small subsets of patients with high-risk subtypes of leukemia. Recognizing the importance of international collaboration to advance the cure rates for these subtypes, Ponte di Legno Childhood ALL Working Group was formed in ⁸⁸ and has since been joined by virtually all major study groups in North America, Europe and Asia.⁸⁹ The collaborative efforts of this group have been very fruitful, identifying optimal treatment for specific subtypes of ALL and facilitating design of clinical trials by sharing unpublished data, and promise to make further advances in the field.⁸⁹

All existing antileukemic agents have acute toxic side effects, and many are fraught with the hazard of long-term sequelae, underscoring the need to develop more effective and less toxic targeted agents.

In the coming decade, the decreasing cost and increasing availability of genomic analyses will permit the entire cancer and germline genomes of every child with ALL to be sequenced and genetics and epigenetic variations interrogated at diagnosis to guide the selection of agents for the individual patient.⁹⁰ It is also hoped that new targeted therapies will emerge from discoveries of driver mutations that can be reversed or mitigated with small molecules.

In the meantime, new formulations of some existing agents (e.g., pegylated asparaginase and sphingosomal vincristine) may be less toxic for patients, and new nucleoside analogues (e.g., clofarabine), monoclonal antibodies (e.g., rituximab, inotuzumab and blinatumomab), genetically modified T cells or natural killer cells, and molecularly targeted agents (e.g., tyrosine kinase inhibitors and proteasome inhibitors) may improve cure rates for selected groups of high risk patients (Table 4).^91– Various other new agents under investigation in the relapsed setting or preclinical models were summarized in a recent review. Finally, ongoing genome-wide association studies promise to identify additional inherited polymorphisms that are not only associated with the response to treatment, but also with the risk of leukemic transformation, opening the way for the development of potential preventive measures.^26,27,52,53,

Table 4.

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Acknowledgments

Supported in part by National Institutes of Health Grants No.

CA, CA and GM, and by the American Lebanese Syrian Associated Charities (ALSAC)

Footnotes

References

• 1.Farber S, Diamond LK, Mercer RD, et al.
  Greenbury logan childhood leukemia center Just like his contemporary Wyatt Earp, Ben Hodges made a living playing, cheating and hustling cards. When available each biological parent completed questions on their family history. She was freed at the age of nineteen during Thus, prevention of childhood leukemia CL remains an essential goal to reduce this significant health burden and requires a better understanding of CL etiologies.

  Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid N Engl J Med. ;– doi: /NEJM [DOI] [PubMed] [Google Scholar]

• 2.Frei E, Freireich EJ, Gehan E, et al. Studies of Sequential and Combination Antimetabolite Therapy in Acute Leukemia: 6-Mercaptopurine and Methotrexate.

  Blood. ;– [Google Scholar]

• 3.Pinkel D. Five-year follow-up of “total therapy” of childhood lymphocytic leukemia. JAMA. ;– [PubMed] [Google Scholar]
• 4.Aur RJ, Simone J, Hustu HO, et al. Central nervous system therapy and combination chemotherapy of childhood lymphocytic leukemia. Blood. ;– [PubMed] [Google Scholar]
• 5.Henze G, Langermann HJ, Brämswig J, et al.

  The BFM 76/79 acute lymphoblastic leukemia therapy study (author’s transl) Klin Padiatr. ;– doi: /s [DOI] [PubMed] [Google Scholar]

• 6.Sallan SE, Hitchcock-Bryan S, Gelber R, et al. Influence of intensive asparaginase in the treatment of childhood non-T-cell acute lymphoblastic leukemia. Cancer Res.

  ;–7. [PubMed] [Google Scholar]

• 7.Sullivan MP, Chen T, Dyment PG, et al. Equivalence of intrathecal chemotherapy and radiotherapy as central nervous system prophylaxis in children with acute lymphatic leukemia: a pediatric oncology group study. Blood. ;– [PubMed] [Google Scholar]
• 8.Freeman AI, Weinberg V, Brecher ML, et al.

  Childhood leukemia cure: They believed his dark skin was made of charcoal because, at the time, it was customary for victorious tribal warriors to coat themselves in charcoal after winning a battle. She paid for all of their travel costs. Some of the topics we can assist with include: Referrals to patient-related programs or resources Donations, website, or event-related assistance Tobacco-related topics Volunteer opportunities Cancer Information For medical questions, we encourage you to review our information with your doctor. Open in a new tab.

  Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children. N Engl J Med. ;– doi: /NEJM [DOI] [PubMed] [Google Scholar]

• 9.Jones B, Freeman AI, Shuster JJ, et al. Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia.

  Med Pediatr Oncol.

• Backtracking to the future: unraveling the origins of ...
• The Childhood Leukemia International Consortium - PMC
• Item 1 of 1
• Logan’s Battle Brings Awareness to Childhood Cancers and ...

;– doi: /mpo [DOI] [PubMed] [Google Scholar]

• Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. ;– doi: /NEJMoa [DOI] [PMC free article] [PubMed] [Google Scholar]
• Evans WE, Crom WR, Abromowitch M, et al. Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia.

  Identification of a relation between concentration and effect. N Engl J Med. ;–7. doi: /NEJM [DOI] [PubMed] [Google Scholar]

• Evans WE, Relling MV, Rodman JH, et al. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. New Engl J Med. ;– doi: /NEJM [DOI] [PubMed] [Google Scholar]
• Krynetski EY, Schuetz JD, Galpin AK, et al.

  A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc Natl, Acad Sci. ;– doi: /pnas [DOI] [PMC free article] [PubMed] [Google Scholar]

• Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study.

  J Clin Oncol. ;– doi: /JCO [DOI] [PMC free article] [PubMed] [Google Scholar]

• Ford CE, Jacobs PA, Lajtha LG. Human Somatic Chromosomes. Nature. ;– doi: /a0. [DOI] [PubMed] [Google Scholar]
• Propp S, Lizzi FA. Philadelphia chromosome in acute lymphoblastic leukemia. Blood. ;– [PubMed] [Google Scholar]
• Secker-Walker LM, Lawler SD, Hardisty RM.

  Prognostic implications of chromosomal findings in acute lymphoblastic leukaemia at diagnosis. Br Med J. ;– doi: /bmj [DOI] [PMC free article] [PubMed] [Google Scholar]

• Williams DL, Look AT, Melvin SL, et al. New chromosomal translocations correlate with specific immunophenotypes of childhood acute lymphoblastic leukemia.

  Cell. ;– doi: /(84) [DOI] [PubMed] [Google Scholar]

• Borella L, Sen L. T cell surface markers on lymphoblasts from acute lymphoblastic leukemia. J Immunol. ;– [PubMed] [Google Scholar]
• Kirsch IR, Morton CC, Nakahara K, Leder P. Human immunoglobulin heavy chain genes map to a region of translocations in malignant B lymphocytes.

  Science. ;– doi: /science [DOI] [PubMed] [Google Scholar]

• Croce CM, Isobe M, Palumbo A, et al. Gene for 3-chain of human T-Cell receptor: location on chromosome 14 region involved in T-Cell neoplasms. Science. ;– doi: /science [DOI] [PubMed] [Google Scholar]
• Bradstock KF, Janossy G, Tidman N, et al. Immunological monitoring of residual disease in treated thymic acute lymphoblastic leukaemia.

  Leuk Res. ;– doi: /(81) [DOI] [PubMed] [Google Scholar]

• Yeoh EJ, Ross ME, Shurtleff SA, et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. ;– doi: /s(02) [DOI] [PubMed] [Google Scholar]
• Mullighan CG, Goorha S, Radtke I, et al.

  Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. ;– doi: /nature [DOI] [PubMed] [Google Scholar]

• Zhang J, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. ;– doi: /nature [DOI] [PMC free article] [PubMed] [Google Scholar]
• Treviño LR, Yang W, French D, et al.

  Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet. ;– doi: /ng [DOI] [PMC free article] [PubMed] [Google Scholar]

• Papaemmanuil E, Hosking FJ, Vijayakrishnan J, et al. Loci on 7p, 10q and 14q are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet.

  ;– doi: /ng [DOI] [PMC free article] [PubMed] [Google Scholar]

• Möricke A, Zimmermann M, Reiter A, et al.
  Greenbury logan childhood leukemia Several studies of ALL have examined family history of disease, but have not provided consistent conclusions [ 6 — 15 ]. Top: ALL molecular subtype frequencies were modified from Pui et al. Some other childhood cancers, such as neuroblastoma or rhabdomyosarcoma , start in other organs and can spread to bone marrow, but these cancers are not leukemia. Similar articles.

  Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from to Leukemia. ;– doi: /leu [DOI] [PubMed] [Google Scholar]

• Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between and a report from the children’s oncology group.

  J Clin Oncol. ;– doi: /JCO [DOI] [PMC free article] [PubMed] [Google Scholar]

• Veerman AJ, Kamps WA, van den Berg H, et al. Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (–) Lancet Oncol.

  ;– doi: /S(09) [DOI] [PubMed] [Google Scholar]

• Vrooman LM, Stevenson KE, Supko JG, et al. Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00– J Clin Oncol.

  ;– doi: /JCO [DOI] [PMC free article] [PubMed] [Google Scholar]

• Yamaji K, Okamoto T, Yokota S, Watanabe A, et al. Minimal residual disease-based augmented therapy in childhood acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group. Pediatr Blood Cancer. ;– doi: /pbc [DOI] [PubMed] [Google Scholar]
• Yeoh AE, Ariffin H, Chai EL, et al.

  Minimal residual disease-guided treatment deintensification for children with acute lymphoblastic leukemia: results from the Malaysia-Singapore acute lymphoblastic leukemia study. J Clin Oncol. ;– doi: /JCO [DOI] [PubMed] [Google Scholar]

• Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL ): a randomised controlled trial.

  Lancet Oncol. ;– doi: /S(12) [DOI] [PubMed] [Google Scholar]

• Schmiegelow K, Forestier E, Hellebostad M, et al. Long-term results of NOPHO ALL and ALL studies of childhood acute lymphoblastic leukemia. Leukemia. ;– doi: /leu [DOI] [PubMed] [Google Scholar]
• Downing JR, Wilson RK, Zhang J, et al.

  The Pediatric Cancer Genome Project. Nat Genet. ;– doi: /ng [DOI] [PMC free article] [PubMed] [Google Scholar]

• Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]
• Coustan-Smith E, Mullighan CG, Onciu M, et al.

  Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. ;– doi: /S(08) [DOI] [PMC free article] [PubMed] [Google Scholar]

• Chen B, Wang YY, Shen Y, et al. Newly diagnosed acute lymphoblastic leukemia in China (I): abnormal genetic patterns in childhood and adult cases and their comparison with reports from Western countries.

  Leukemia. ;– doi: /leu [DOI] [PubMed] [Google Scholar]

• Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med. ;– doi: /NEJMra [DOI] [PubMed] [Google Scholar]
• Mullighan CG, Collins-Underwood JR, Phillips LA, et al. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia.

  Nat Genet. ;– doi: /ng [DOI] [PMC free article] [PubMed] [Google Scholar]

• Chen IM, Harvey RC, Mullighan CG, et al. Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children’s Oncology Group study. Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]
• Mullighan CG, Su X, Zhang J, et al.

  Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. ;– doi: /NEJMoa [DOI] [PMC free article] [PubMed] [Google Scholar]

• Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.

  Lancet Oncol. ;– doi: /S(08) [DOI] [PMC free article] [PubMed] [Google Scholar]

• Roberts KG, Morin RD, Zhang J, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. ;– doi: / [DOI] [PMC free article] [PubMed] [Google Scholar]
• Holmfeldt L, Wei L, Diaz-Flores E, et al.

  The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. ;– doi: /ng [DOI] [PMC free article] [PubMed] [Google Scholar]

• Relling MV, Hancock ML, Rivera GK, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. ;– doi: /jnci/ [DOI] [PubMed] [Google Scholar]
• Cheok MH, Evans WE.

  Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy. Nat Rev Cancer. ;– doi: /nrc [DOI] [PubMed] [Google Scholar]

• Crews KR, Hicks JK, Pui CH, et al. Pharmacogenomics and individualized medicine: translating science into practice. Clin Pharmacol Ther. ;– doi: /clpt [DOI] [PMC free article] [PubMed] [Google Scholar]
• Yang JJ, Cheng C, Yang W, et al.

  Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA. ;– doi: /jama [DOI] [PMC free article] [PubMed] [Google Scholar]

• Ramsey LB, Panetta JC, Smith C, et al. Genome-wide study of methotrexate clearance replicates SLCO1B1.

  Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]

• Xu H, Cheng C, Devidas M, et al. ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol. ;– doi: /JCO [DOI] [PMC free article] [PubMed] [Google Scholar]
• Xu H, Yang W, Perez-Andreu V, et al.

  Novel susceptibility variants at 10p– for childhood acute lymphoblastic leukemia in ethnically diverse populations. J Natl Cancer Inst. ;– doi: /jnci/djt [DOI] [PMC free article] [PubMed] [Google Scholar]

• Vogelstein B, Papadopoulos N, Velculescu, et al. Cancer genome landscapes. Science. ;– doi: /science [DOI] [PMC free article] [PubMed] [Google Scholar]
• Pui CH, Pei D, Campana D, et al.

  Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol. ;– doi: /JCO [DOI] [PMC free article] [PubMed] [Google Scholar]

• Pui CH, Pei D, Pappo AS, et al. Treatment Outcomes in Black and White Children With Cancer: Results From the SEER Database and St Jude Children’s Research Hospital, Through J Clin Oncol.

  ;– doi: /JCO [DOI] [PMC free article] [PubMed] [Google Scholar]

• Yang JJ, Cheng C, Devidas M, et al. Ancestry and Pharmacogenomics of Relapse in Acute Lymphoblastic Leukemia. Nat Genet. ;– doi: /ng [DOI] [PMC free article] [PubMed] [Google Scholar]
• Moorman AV, Ensor HM, Richards SM, et al.

  Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol. ;– doi: /S(10) [DOI] [PubMed] [Google Scholar]

• Schrappe M, Valsecchi MG, Bartram CR, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL study.

  Blood. ;– doi: /blood [DOI] [PubMed] [Google Scholar]

• Schrappe M, Hunger SP, Pui CH, et al. Outcome after induction failure in childhood acute lymphoblastic leukemia. N Eng J Med. ;– doi: /NEJMoa [DOI] [PMC free article] [PubMed] [Google Scholar]
• Faham M, Zheng J, Moorhead M, et al. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia.

  Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]

• Stow P, Key L, Chen X, et al. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]
• Inaba H, Pui CH.

  Glucocorticoid use in acute lymphoblastic leukemia. Lancet Oncol. ;– doi: /S(10) [DOI] [PMC free article] [PubMed] [Google Scholar]

• Hunger SP, Loh ML, Whitlock JA, et al. Children’s Oncology Group’s blueprint for research: acute lymphoblastic leukemia. Pediatr Blood Cancer. ;– doi: /pbc [DOI] [PMC free article] [PubMed] [Google Scholar]
• Pieters R, Schrappe M, De Lorenzo P, et al.

  A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant): an observational study and a multicentre randomised trial. Lancet. ;– doi: /S(07)X. [DOI] [PubMed] [Google Scholar]

• Pichler H, Reismüller B, Steiner M, et al. The inferior prognosis of adolescents with acute lymphoblastic leukaemia (ALL) is caused by a higher rate of treatment-related mortality and not an increased relapse rate - a population-based analysis of 25 years of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group.

  Br J Haematol. ;– doi: /bjh [DOI] [PubMed] [Google Scholar]

• Buitenkamp TD, Pieters R, Gallimore NE, et al. Outcome in children with Down’s syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia. ;– doi: /leu [DOI] [PubMed] [Google Scholar]
• Coustan-Smith E, Ribeiro RC, Stow P, et al.

  A simplified flow cytometric assay identifies children with acute lymphoblastic leukemia who have a superior clinical outcome. Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]

• Mikkelsen TS, Sparreboom A, Cheng C, et al. Shortening infusion time for high-dose methotrexate alters antileukemic effects: a randomized prospective clinical trial.

  J Clin Oncol. ;– doi: /JCO [DOI] [PMC free article] [PubMed] [Google Scholar]

• Asselin BL, Devidas M, Wang C, et al. Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children’s Oncology Group (POG ) Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]
• Bhojwani D, Pei D, Sandlund JT, et al.

  ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy. Leukemia. ;– doi: /leu [DOI] [PMC free article] [PubMed] [Google Scholar]

• Kawedia JD, Liu C, Pei D, et al. Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia.

  Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]

• Seibel NL, Steinherz PG, Sather HN, et al. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]
• Gaynon PS, Angiolillo AL, Carroll WL, et al.

  Long-term results of the children’s cancer group studies for childhood acute lymphoblastic leukemia – a Children’s Oncology Group Report. Leukemia. ;– doi: /leu [DOI] [PMC free article] [PubMed] [Google Scholar]

• Matloub Y, Bostrom BC, Hunger SP, et al. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group.

  Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]

• Pieters R, Hunger SP, Boos J, et al.
  Childhood leukemia ages He continued to work for ranchers and fine-tuned his cowboy skills. Biddy Mason offered the court two days testimony. Ask us how you can get involved and support the fight against cancer. Juvenile myelomonocytic leukemia.

  L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer. ;– doi: /cncr [DOI] [PMC free article] [PubMed] [Google Scholar]

• Liu C, Kawedia JD, Cheng C, et al. Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia. Leukemia. ;– doi: /leu [DOI] [PMC free article] [PubMed] [Google Scholar]
• Kawedia JD, Liu C, Pei D, et al.

  Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia. Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]

• Pui CH. Reducing delayed intensification therapy in childhood ALL. Lancet Oncol. ;– doi: /S(13) [DOI] [PubMed] [Google Scholar]
• Relling MV, Gardner EE, Sandborn WJ, et al.

  Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther. ;– doi: /clpt [DOI] [PMC free article] [PubMed] [Google Scholar]

• Bhatia S, Landier W, Shangguan M, et al. Non-adherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: A Report from the Children’s Oncology Group.

  J Clin Oncol. ;– doi: /JCO [DOI] [PMC free article] [PubMed] [Google Scholar]

• Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol. ;– doi: /S(08) [DOI] [PubMed] [Google Scholar]
• Matloub Y, Lindemulder S, Gaynon PS, et al.

  Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children’s Cancer Group (CCG) study for standard-risk acute lymphoblastic leukemia, reported by the Children’s Oncology Group. Blood. ;– doi: /blood [DOI] [PMC free article] [PubMed] [Google Scholar]

• Richards S, Pui CH, Gaynon P Childhood Acute Lymphoblastic Leukaemia Collaborative Group (CALLCG) Systematic review and meta-analysis of randomized trials of central nervous system directed therapy for childhood acute lymphoblastic leukaemia.

  Pediatr Blood Cancer. ;– doi: /pbc [DOI] [PMC free article] [PubMed] [Google Scholar]

• Jansen NC, Kingma A, Schuitema A, et al. Neuropsychological outcome in chemotherapy-only-treated children with acute lymphoblastic leukemia. J Clin Oncol. ;– doi: /JCO [DOI] [PubMed] [Google Scholar]
• Conklin HM, Krull KR, Reddick WE, et al.

  Cognitive outcomes following contemporary treatment without cranial irradiation for childhood acute lymphoblastic leukemia. J Natl Cancer Inst. ;– doi: /jnci/djs [DOI] [PMC free article] [PubMed] [Google Scholar]

• Schrappe M, Reiter A, Ludwig WD, et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM German-Austrian-Swiss ALL-BFM Study Group.

  Blood. ;– [PubMed] [Google Scholar]

• Pui CH, Schrappe M, Masera G, et al. Ponte di Legno Working Group: statement on the right of children with leukemia to have full access to essential treatment and report on the Sixth International Childhood Acute Lymphoblastic Leukemia Workshop. Leukemia. ;– doi: / [DOI] [PubMed] [Google Scholar]
• Hunger SP, Baruchel A, Biondi A, et al.

  The thirteenth international childhood acute lymphoblastic leukemia workshop report: La Jolla, CA, USA, December 7–9, Pediatr Blood Cancer. ;– doi: /pbc [DOI] [PubMed] [Google Scholar]

• Evans WE, Crews KR, Pui CH. A Health-Care System Perspective on Implementing Genomic Medicine: Pediatric Acute Lymphoblastic Leukemia as a Paradigm.

  Clin Pharmacol Ther. Jan 17; doi: /clpt [Epub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]

• Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. ;– doi: /JCO [DOI] [PMC free article] [PubMed] [Google Scholar]
• Panetta JC, Gajjar A, Hijiya N, et al.

  Comparison of native E. coli and PEG asparaginase pharmacokinetics and pharmacodynamics in pediatric acute lymphoblastic leukemia. Clin Pharmacol Ther. ;– doi: /clpt