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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 138AChildhood Acute Lymphoblastic Leukemia

, MD, , MD, and , MD, PhD.

Childhood acute lymphoblastic leukemia (ALL) is the most common malignancy in children, with a yearly incidence of 31/1,000,000 children younger than 15 years of age (Table 138A.1).1,2 The peak incidence is between 3 and 6 years of age with a male predominance, except for infants younger than 1 year of age where girls predominate. Contemporary therapies may cure more than 75% of patients overall. Conventionally, children age 1 to 9 years with presenting white blood count (WBC) < 50,000/uL are designated standard risk (SR). Children age 1 to 9 years with presenting WBC ≥ 50,000 and adolescents age 10 years and older with any WBC are designated higher risk (HR).3,4 Some treat patients with T-lineage disease differently from how they treat patients with B-lineage disease. Most exclude patients with mature B-cell immunophenotype and FAB L3 morphology disease, i.e., Burkitt’s lymphoma, from the category of childhood ALL. The presence or absence of extramedullary leukemia, clonal cytogenetic or molecular abnormalities, and/or initial response to therapy may modify this initial designation. In terms of morphology, immunophenotype, cytogenetics, molecular features, initial response to therapy, and clinical outcome, childhood ALL is a heterogeneous group of diseases.

Table 138A.1. Incidence of Childhood Cancer Diagnoses in the United States.

Table 138A.1

Incidence of Childhood Cancer Diagnoses in the United States.

The etiology of childhood ALL remains unclear. Although a number of epidemiologic factors have been correlated with increased risk, inconsistent results plague the literature.5–11 Taken together, the existing data suggest that the interaction of multiple environmental and host factors may be involved in etiology of ALL. Further studies are required.

Deeper understanding of the biology of ALL requires an integration of clinical, cellular and molecular findings with the physiology and evolution of the malignant cell. Host factors affecting the pharmacokinetics, pharmacodynamics of chemotherapeutic agents, and patient/physician compliance with therapy add additional layers of complexity.

Improvements in outcome in childhood ALL derive from well-designed, adequately sized clinical trials and equal or surpass gains in other areas of childhood cancer. In osteosarcoma, Link and co-workers demonstrated the value of adjuvant chemotherapy and improved progression-free survival from 17 to 66%.12 In acute myeloblastic leukemia (AML), intensively timed induction therapy improved disease-free survival after chemotherapy, allogeneic bone marrow transplantation (BMT), and autologous BMT.13 Addition of ifosfamide and etoposide improved progression-free survival in Ewing’s sarcoma.14 In neuroblastoma, purged autologous BMT was shown to be superior to a chemotherapy consolidation,15 and postconsolidation cis-retinoic acid improved progression-free survival.16 In these successful randomized trials, the failure rate was reduced between 20 and 59%.

Since 1978, the Children’s Cancer Group (CCG) has obtained similar advances in childhood ALL, independent of risk classification and lineage (Table 138A.2).17–28 The gains achieved have been similar to the best obtained in other areas of childhood cancer. Others have reported similar results.29–34

Table 138A.2. Improved Outcome for Children with ALL.

Table 138A.2

Improved Outcome for Children with ALL.

Heterogeneity

ALL, generally heralded by the appearance of neoplastically transformed lymphoid blast cells in the peripheral blood, is the most common cancer in children, as well as the most common form of childhood leukemia,1,2 and represents a highly heterogeneous group of diseases with respect to the morphologic, immunophenotypic, cytogenetic, and molecular features of the neoplastic cells.

Technical improvements in immunofluorescence staining and flow cytometry, together with the availability of numerous monoclonal antibodies (mAb) that recognize various lineage-associated membrane molecules, have uncovered the immunophenotypic heterogeneity in ALL.35–37 Leukemic cells may express various combinations of surface antigens that are normally found on lymphocyte precursors at discrete stages of maturation.26,27,38,39 Malignant clones are thought to originate from normal lymphoid progenitor cells arrested at early stages of B- or T-lymphocyte ontogeny. While cells from the majority (~ 85%) of pediatric ALL patients express B lineage–associated antigens, those from approximately 15% express the T lineage–associated antigens. In addition, a subset express both T and B40,41 or myeloid and B cell–associated antigens.42–45

Cytogenetic abnormalities are frequent among patients with ALL and contribute to substantial biologic heterogeneity.46–48 Hyperdiploidy, especially high hyperdiploidy with modal chromosome number 51-63 or trisomy 10, has been associated with an excellent treatment outcome among children with ALL, whereas pseudodiploidy and hypodiploidy have been associated with a poor outcome.49–54 Also, “near tetraploid” chromosome number (> 65) is more often associated with T-lineage ALL and poor outcome.55 Nonrandom translocations are more frequently found in association with the pseudodiploid than the hyperdiploid karyotype. Defective cell cycle surveillance mechanisms are likely to be the major factors that lead to first tolerance of chromosomal abnormalities and later to unrestrained leukemic cell proliferation.

By conventional banded cytogenetics, the most frequently observed translocation among B-lineage ALL patients is t(1;19)(q23;p13), which occurs in approximately 6% of all cases and 25% of cases with the pre-B immunophenotype.56,57 Overall, t(1;19) carries no adverse prognostic significance in the context of contemporary treatment protocols. However, the one-third of patients with a balanced translocation may have a poor outcome. The translocation t(4;11) carries adverse prognostic significance for infants but not for children aged 1 to 10 years.58–60 The translocation t(9;22), the Philadelphia chromosome, is a well-known significant adverse risk factor for children with B-lineage ALL.61–64

By comparison, translocations observed among patients with T-lineage ALL preferentially occur in the T-cell receptor (TCR) loci on chromosomes 7 and 14, and those involving the TCRβ locus at 7q32-36 and the TCRαδ at 14q11 collectively occur in approximately 20% of all T-lineage ALL cases.65 The recent CCG review of T lineage–specific cytogenetic abnormalities revealed that numerous abnormalities, including del(6q), 14q11 rearrangements, del(9p), 11q23 rearrangements, trisomy 8, 7q32-q36 rearrangements, and 14q32 rearrangements, lacked prognostic significance.27,66

Many of the chromosomal translocations observed in childhood ALL result in production of chimeric oncoproteins, which are thought to contribute to leukemogenesis.67 The prototype of such translocations, t(9;22)(q34;q11), results in the production of BCR-ABL fusion transcripts and proteins.

Conventional cytogenetics alone do not reveal the full extent of chromosomal abnormalities. The most common translocation in childhood ALL, t(12;121), is rarely identified without molecular studies.68–70 The reverse transcriptase polymerase chain reaction (RT-PCR) may ascertain additional cases with translocations missed by conventional cytogenetics.71 No more than age, WBC, or immunophenotype, single cytogenetic or molecular findings also fail to define homogeneous patient populations.56,57,60,72,73

Ikaros

Ikaros, a member of the Kruppel family zinc-finger DNA-binding proteins, is a master regulator essential for the early development of lymphoid progenitors as well as for the later events of T-cell maturation.74–77 Ikaros, mapping to chromosome 7p11.2-3 in humans and chromosome 11 in mice, encodes at least eight lymphoid-restricted zinc-finger proteins by differential splicing that are highly conserved between human and mouse. All share a common C-terminal domain containing a bipartite transcription activation motif and two zinc-finger motifs required for dimerization and interactions with other proteins but differ in their N-terminal zinc-finger composition and in their overall DNA binding and transcriptional activation properties. At least three out of four N-terminal zinc fingers are required for the high-affinity, sequence-specific DNA-binding activity. The three DNA-binding isoforms are also larger in size, compared with the others.74–77

Various Ikaros isoforms localize to distinct subcellular compartments. The DNA-binding isoforms localize to the nucleus and isoforms without DNA-binding activities localize to the cytoplasm. DNA-nonbinding isoforms can get into the nucleus through heterodimerization with DNA binding isoforms. However, heterodimers are transcriptionally inactive and lead to a diffuse rather than focal nuclear localization.74–77

Mice with a germline Ikaros-null mutation were generated by deletion of the shared C-terminal exon required for activation, dimerization, and other protein interactions. In mice homozygous for this mutation, B-cell development is completely blocked at a very early stage. The definitive pro-B and pre-B precursors are not detected in the fetal liver as well as adult spleen, peritoneum, and bone marrow. All fetal waves of T-cell progenitors are missing in these mice, and the fetal thymus is devoid of any identifiable lymphoid cells. However, during the first week after birth, increasing numbers of thymocyte precursors are seen in the thymus. These give rise to conventional αβ and some γδ T cells, but not to natural killer (NK) cells or any significant numbers of dendritic antigen-presenting cells.74–77

In contrast, mice heterozygous for this mutation are born with “normal” lymphoid compartments. But thymocytes from these mice display augmented proliferation on activation through the TCR complex. Lymphoproliferative disorders, usually T-cell leukemia, develop from the third month after birth. The key indication of this leukemia is the clonal expansion of leukemic T cells accompanied by invasion of other tissues. Ikaros activity decreases stepwise in the developing thymocytes and localization changes from nucleus to cytoplasm. Ikaros proteins generated by the dominant negative mutant Ikaros, in which the DNA-binding domain is deleted, cannot bind DNA. However, these isoforms have the intact C-terminal zinc-finger dimerization domain and engage readily in protein-protein interactions. These interactions may interfere with the activities of other transcription factors working in concert with Ikaros to regulate lymphocyte differentiation and proliferation and may account for the more severe phenotype observed in these mice.74–78

Sun and co-workers found high levels of expression of aberrantly spliced, DNA-nonbinding ikaros isoforms in 16 of 17 cases of T-lineage ALL and 42 of 42 cases of childhood B-lineage ALL. In place of the focal nuclear localization found in normal lymphoid tissue, cytoplasmic and/or diffuse nuclear localization was present in all cases studied by confocal laser scanning microscopy.79,80 The prognostic significance of Ikaros abnormalities is currently unknown.

Apoptosis

Chemotherapeutic agents frequently act through apoptosis or programmed cell death. Several general steps may be identified, namely, (1) insult generation—drug entry into a cell, activation, interaction with a target; (2) signal transduction; (3) decision and execution.81 Each step provides a possible opportunity for resistance. However, endonuclear DNA cleavage and DNA laddering—often cited hallmarks of apoptosis—may constitute its aftermath.82 Loss of endonuclease in c. elegans mutants prevents laddering but does not preserve viability.83 Caspase inhibitors may prevent the classic morphologic manifestations of apoptosis but do not prevent cell death, while Bcl-2 and Bcl-XL may also prevent or reduce cell death.84

Although p53 function is usually intact at presentation, loss of p53 function is common in ALL with primary resistance85 or at relapse.86,87 p53 protein plays a critical role in apoptosis, linking DNA damage to cell cycle arrest and apoptosis.88 Many chemotherapeutic agents damage DNA and require p53 function, for example, cyclophosphamide, etoposide, anthracyclines, ara-C, and methotrexate.81,89 Their utility against blasts with diminished p53 function may be limited.

In vitro, high levels of Bcl-2 may shift a decision from death to life.90,91 Bcl-2 levels are generally higher and more consistent in B-lineage than in T-lineage cases of childhood ALL. However, constitutive levels of Bcl-2 did not correlate with outcome in any of several studies.92–96

Antitubulin agents, asparaginase, and glucocorticoids may not require p53 function and may provide more benefit.81,97 A past CCG trial showed that addition of vincristine, a p53-independent agent, to Capizzi I sequential methotrexate/asparaginase doubled the duration of CR2.98 Other antitubulin agents are in development. Better understanding of apoptosis may lead to new therapeutic strategies. Cancer itself arises from an inappropriate tolerance of carcinogenic genetic changes.

Given the substantial improvement that obtained with a number of treatment strategies, it is imperative that the heterogeneity of childhood ALL be clarified. A significant proportion of children with ALL, who might benefit from proven interventions now reserved for recognized higher-risk patients, may be “undertreated.” A proportion of patients for whom less morbid therapy may provide similarly excellent results may be “overtreated.” More precise estimation of prognosis through better understanding of presenting cytogenetic and molecular features may allow selection of more appropriate therapy.

Response and Outcome

Early Marrow Response

In addition to the features apparent at presentation, response to therapy has been a consistent prognostic factor. Failure to achieve remission, that is, fewer than 5% blasts by day 28 of induction, remains a consistent adverse prognostic factor in CCG trials. On the 1988 to 1995 series trials, 1.6% of children survived induction with an M2 marrow with between 5% and 24% blasts and 1.0% of children survived induction with an M3 marrow with more than 25% marrow blasts. M2 patients have 5-year event-free survival (EFS) of 50%. Of M3 patients, one-third never achieve remission and have a dismal outcome, and two-thirds ultimately achieve remission and have a 5-year EFS of 40%.99 The vast majority of relapses still occur among patients with an apparently good marrow response at the end of induction.

The percentage of marrow blasts on day 7 and 14 of induction therapy continues to identify groups with disparate treatment outcomes100–104 (Table 138A.3). Among an SR population with an 85% EFS, if 20% of events are found among the 10% of patients with a poor response on day 14, then the EFS for the better and worse response subsets are about 87% and 70%, respectively. The day 7 response data on four recent CCG studies are fairly consistent and somewhat more sensitive but are relatively nonspecific. The day 7 poor response group captures about 60% of events. In an SR population with an 85% EFS, if 60% of events are found among the 50% of patients with a poor response on day 7, then the EFS for the better and worse response subsets are about 88% and 82%, respectively.

Table 138A.3. “Early” Marrow Response.

Table 138A.3

“Early” Marrow Response.

CCG has employed early marrow response to allocate therapy. On a past HR trial, Nachman and co-workers showed that many patients with more than 25% marrow blasts on day 7 might be rescued with the augmented regimen (AR).24 On our 1995 to 1999 SR trial, patients with more than 25% marrow blasts on day 14 were allocated to the augmented intensive regimen (AIR). The Berlin Frankfurt Munster (BFM) Group has similarly employed the peripheral blood response after one dose of methotrexate and 1 week of prednisone for treatment allocation.105

The value of measures of response is limited by the quality of marrow samples and by the ability to identify residual leukemia. A dilute specimen may not be representative of marrow disease. Schultz and co-workers found substantial differences between estimates of marrow blast percentage on the basis of marrow aspirates and biopsies.106 The burden of leukemia in a single marrow aspirate may not be representative because leukemia may be anatomically heterogenous.107

Precise identification of marrow blasts on day 7 or 14 by light microscopy may be difficult. Thomson and co-workers estimated blast percentage by both microscopy and by flow cytometry. They found that 3 of 15 day 7 marrows had fewer than 5% blasts by microscopy and more than 25% marrow blasts by flow cytometry.108

Minimal Residual Disease

Conventional light microscopy has allowed classification of marrow responses in three categories: M1 (< 5% blasts), M2 (5–25% blasts), and M3 (more than 25% blasts). Detection of leukemic blasts below the conventional level for remission or 5% may still have clinical significance. Sandlund and co-workers have identified patients with < 1% and 1 to 4% marrow lymphoblasts on day 15 and 22 to 25 by light microscopy and shown divergent outcomes.109 Yet lower levels may also be important.

Residual leukemia at levels too low for detection by conventional microscopy has been termed minimal residual disease (MRD).110,111 Candidate measures of MRD include multi-dimensional flow cytometry,112,113 fluorescent antibody cell sorting/leukemia progenitor cell (FACS/LPC) assay,114 PCR amplification of immunoglobulin heavy chain (IgH) and/or TCR gene rearrangements,115–118 and RT-PCR amplification of specific fusion transcripts.119 These strategies may provide an opportunity to divide the conventional HR or SR group into subsets with substantially different prognoses, in whom one might conceivably employ different therapies.

Multi-parameter flow cytometry can identify a leukemia-specific or leukemia-associated immunophenotype in a substantial proportion of cases. Two-marker flow cytometry can identify a leukemia-specific pattern in 35% of cases.120 Three-marker flow cytometry can identify a leukemia-specific pattern in 90% of cases121 and four-marker flow cytometry in > 95% of cases.122 Quantitation of the percentage of cells bearing the leukemia-specific immunophenotype allows an assessment of disease burden at the level of 1 cell in 104.

Coustan-Smith and co-workers have demonstrated prognostic significance for MRD assessed by multi-dimensional flow cytometry (Table 138A.4).113 Flow cytometry identified a poor response group, including about 25% of patients with about 50% of events. Specificity and sensitivity appear better than early marrow response.

Table 138A.4. End Induction Disease Burden.

Table 138A.4

End Induction Disease Burden.

PCR can be used to identify clonotypic immunoglobulin heavy chain (IgH) gene or TCR gene rearrangements in a substantial proportion of cases also. IgH gene undergoes rearrangement in > 95% of cases of B-lineage ALL. TCR gene undergoes rearrangement in 95% of cases of T-lineage ALL and greater than 50% of cases of B-lineage ALL. Reaction product may be quantitated by dot blot,123 limit dilution,124,125 competitive,126 or real-time127,128 assays, in order to provide an estimate of leukemic burden on the order 10-3 to 10-5.111

Goulden and co-workers,116 Cave and co-workers,117 and van Dongen and co-workers118 have demonstrated prognostic significance for MRD assessed by PCR (see Table 138A.4). About one-half of patients are found to have a poor response with levels between 10-2 and 10-3 at the end of induction.111 The poor response group includes about 80% of events. Specificity and sensitivity again appear better than early marrow response.

MRD may also be employed to assess the efficacy of treatment. Roberts and co-workers found that more recent patients who had received postinduction intensification had disease burden one log10 less than earlier patients who had not received intensification.129 Zur Stadt and co-workers treated 73 patients with a three-drug (vincristine, prednisone, and daunomycin) induction and found end-induction MD at 10-2 in 33% and at 10-3 in 33%. Van Dongen and co-workers employed a four-drug (vincristine, prednisone, daunomycin, and L-asparaginase) induction and found 16% at 10-2 and 22% at 10-3.118

MRD determinations, like assessment of early marrow response, depend on the quality of marrow samples. The sensitivity is limited by the number of cells or amount of DNA studied. Marrow disease may be present in the absence of peripheral blood disease.111 Sykes and co-workers found levels four-fold higher in marrow trephine material than in aspirate material.130 The variation was higher at lower levels of disease.

As with early marrow response, blasts must be identified. Identified cells may share a clonotypic feature but may not be leukemogenic. Both detailed immunophenotype and TCR/immunoglobulin gene rearrangements are subject to oligoclonality and “drift.”110,131–133 Both may change between diagnosis and relapse. Van Wering and co-workers found changes in immunophenotype between diagnosis and relapse in 29 of 40 cases studied.134 Beishuizen and co-workers found changes in Ig or TCR gene rearrangements at diagnosis and relapse in 25 of 40 studied cases.135 Either could lead to an inaccurate assessment of disease burden.

However, thorough evaluation may lessen the impact. In cases with oligoclonal immunoglobulin gene rearrangements, the variability of the D-N-J junctional sequences is less than that of the VH-D sequences. When novel Ig or TCR gene rearrangements appear at relapse, one rearrangement, present at initial diagnosis, will usually persist.111 Definition of the leukemic clone by multi-parameter flow cytometry can lessen the impact of immunophenotypic drift.134 Variability occurs because neither detailed immunophenotype or immunoglobulin or TCR gene rearrangements are central to the cell proliferation and the malignant process.

The clinical significance of response and MRD—however measured—may be partially confounded by the heterogeneity of childhood leukemia. The significance of residual E2A PBX1 fusion transcript positive cells may differ from the significance of residual BCR-ABL fusion transcript positive cells may differ from the significance of residual BCR-ABL fusion transcript positive cells.136 Relapse may arise from a small, resistant subclone that is completely hidden at diagnosis by a more sensitive majority population.137 However, laboratory assessment of end-induction disease burden may offer an opportunity to distinguish more precisely patients for whom current therapies are adequate from patients who require innovative treatment strategies and to compare treatment strategies.

Advances in Primary Therapy

Postinduction Intensification

In 1976, the Berlin Frankfurt Munster (BFM) Group added a 2-month phase of intensive therapy, that is, protocol II or delayed intensification (DI), to the intensive induction/consolidation (protocol I) that they had introduced in 1970.138 Two subsequent CCG trials for higher-risk patients showed the superiority of the BFM approach—protocol I and protocol II—over the then-current CCG strategies.18–20,103

CCG also showed that DI improved EFS for average-risk patients.21 Administration of protocol I provided no additional benefit for Rome/NCI SR patients who also received DI. However, protocol I appeared to benefit eligible patients older than 10 years, all of whom presented with WBC < 50,000/uL. The value of protocol I has not been tested rigorously for other NCI/Rome HR patients.

CCG built on these results and then showed that DI also improved outcome for subset of patients believed at lowest risk for relapse as defined by age, WBC, and early marrow response.22 However, the impact of DI in the CCG study, 85% versus 79% (see Table 138A.2), was much less than in the BFM-83 trial, where addition of protocol II increased EFS from 61 to 82%. The CCG trial employed maintenance intrathecal methotrexate and vincristine/predisone pulses,17 unlike BFM-83.139 These two interventions may have improved the outcome of the no-DI arm of the CCG trial, while adding less—if anything—for patients who also received DI. Interventions that are useful individually, may be redundant in combination, in whole or in part. A current International BFM Group (I-BFM) trial is examining the role of vincristine/dexamethasone pulses when patients also receive protocol II. CCG also showed that two courses of DI were superior to one course of DI for average-risk patients.23 Double DI provides the backbone for the current CCG (1995–1999) SR trial.

The augmented intensive regimen provides longer and stronger postinduction intensification. Patients receive 10 pulses of Capizzi I,98 namely, sequential vincristine, escalating-dose intravenous methotrexate (with no rescue), and L-asparaginase, two DI phases, and additional vincristine and asparaginase. Nachman and co-workers showed that HR patients with a poor marrow response on day 7 of therapy might be “rescued” with longer and stronger postinduction intensification.24,140 The reduction in failure rate was 40%, compared with the 25% reduction obtained for average-risk patients who received longer but not stronger postinduction intensification, that is, double DI. The BFM Group has had less success to date in salvaging patients with a poor response to the vorphase.31 CCG is now testing longer versus stronger postinduction intensification for patients with a good day 7 marrow response on the current CCG (1996–2001) HR trial.

The day 7 marrow response may define a large subgroup of SR patients for whom a second DI phase provides no additional benefit.23 On the past trial, double DI provided benefit overall but in retrospective analyses that benefit seemed confined to the one-half of patients with ≥5% marrow blasts on day 7 of therapy.

Presymptomatic Central Nervous System Therapy

Effective presymptomatic central nervous system (CNS) therapy, pioneered by Pinkel and co-workers at St. Jude Children’s Research Hospital, is a prerequisite to all subsequent advances in the treatment of childhood ALL.141,142 Nesbit and co-workers showed that 24 Gy craniospinal irradiation might be replaced with 24 Gy cranial radiation and six doses of intrathecal methotrexate,143 and 24 Gy cranial irradiation might be safely replaced with 18 Gy.144 Bleyer and co-workers devised a widely adopted age-based dosage schedule for intrathecal methotrexate.145

Elimination of cranial irradiation has been a priority for more than two decades. Cranial irradiation has been linked to second malignancies146,147 and neurocognitive damage.148–150 Lesser problems are seen in patients who received no cranial irradiation.151 However, other elements of therapy may also be neurotoxic. Intermediate dose methotrexate (IDM) was implicated in a 10 to 16% incidence of CNS toxicity in three recent trials.152–154 The ultimate neurocognitive consequences of these studies have not yet been reported.

Improved systemic therapy has allowed elimination of cranial irradiation for most patients. Freeman and co-workers showed that cranial irradiation might be replaced safely with IDM and no maintenance intrathecal therapy.155–157 CCG showed that cranial irradiation might be replaced with maintenance intrathecal methotrexate in the lowest-risk patients by age and WBC.17 Then CCG showed that cranial irradiation might be replaced with maintenance intrathecal methotrexate in average-risk patients, provided that patients received either intensive induction/consolidation (protocol I) or DI (protocol II).158 Finally, CCG showed that cranial irradiation might be replaced with additional intrathecal methotrexate for HR patients with a rapid initial response to therapy in the context of BFM-based systemic therapy.159 CCG now limits cranial irradiation to HR patients with a poor initial response to therapy and to patients (about 15%) with overt CNS leukemia at diagnosis. Contrary to the experience of some,160 CCG studies find that neither overt nor occult CNS disease at diagnosis adversely impacts on prognosis.161–163

Current intrathecal therapy may be excessive for some subsets of patients in the context of today’s effective systemic therapy. Children on CCG trials receive more than 20 doses of intrathecal therapy over the course of treatment. Children on BFM trials receive only 11 doses of intrathecal therapy over the first 6 months of treatment and no subsequent maintenance intrathecal treatment.31

Dexamethasone

On the basis of observations that dexamethasone impeded egress of granulocytes from the circulation less completely than prednisone, the Cancer and Leukemia Group B (CALGB) compared dexamethasone and prednisone in childhood ALL between 1971 and 1977 with the hope that dexamethasone would be less immunosuppressive. They found that dexamethasone resulted in fewer CNS relapses, but that overall EFS was similar for dexamethasone and prednisone.164

More recently, Balis and co-workers showed that dexamethasone provided higher relative cerebrospinal fluid (CSF) levels than prednisone.165 The Dutch Group found that in vitro sensitivity to glucocorticoid is an important predictor of outcome,166 and that dexamethasone was 16-fold more potent than prednisolone in vitro.167 On the other hand, Ito and co-workers suggested that the cytotoxicity of dexamethone and prednisone were more in keeping with the conventional 1:6 to 7 activity ratio.168 The Dutch Group changed to dexamethasone with the Dutch ALL VI study, with promising results relative to historical controls.169

Between 1992 and 1995, CCG conducted a randomized comparison of prednisone and dexamethasone in SR patients. Patients received either prednisone 40 mg/m2 or dexamthasone 6 mg/m2 in induction and maintenance. All patients received dexamethasone in DI. At 5 years, the EFS for dexamethasone was 87% versus 81% for prednisone, p < .01.28 The difference in CNS relapse was greater than in marrow relapse, but both favored dexamethasone which provided a 36% reduction in hazard. A previous study had found no benefit for higher-dose prednisone 60 mg/m2 with daunomycin, cyclophosphamide, and cytosine arabinoside versus prednisone 40 mg/m2 in SR patients.21

Parenteral Methotrexate and Rescue

Pursuant of earlier studies in CALGB,155–157 both Pediatric Oncology Group (POG) and St. Jude investigators employ a postinduction intensification “backbone” of IDM,152,170–172 BFM family regimens include IDM in the “M” phase between protocol I and protocol II.31

However, clear demonstration of the contribution of IDM to postinduction intensification has been lacking. St. Jude Study Total X showed an advantage for a complex regimen including IDM relative to a second complex regimen excluding IDM.170,171

Two CCG trials examined the role of IDM for SR patients and found no advantage for either methotrexate 0.5 g/m2173 or for 33.6 g/m2174 over conventional oral methotrexate. More recently (UKALL) XI found no advantage for methotrexate 6 to 8 g/m2175 and (FRALLE) 93 found no advantage for methotrexate 8 g/m2176 for average- or intermediate-risk patients.

CCG has achieved good outcomes with no IDM and avoided significant neurotoxicity and additional hospital stays. The dexamethasone/oral 6-MP arm of CCG-1922 provided a 5-year EFS of 87% for NCI/Rome SR patients with no IDM.28 Omission of IDM accounts for a 25-day-per-patient advantage in median hospital stay, compared with a contemporary IDM regimen.177 IDM methotrexate was implicated in a 10 to 16% incidence of CNS toxicity in three recent trials.152–154 The ultimate neurocognitive consequences of these studies have not yet been reported. Neurotoxicity may be prevented with less frequent IDM and earlier or more generous rescue. However, earlier and more generous use of leucovorin may diminish any therapeutic benefit.178 Much remains to be learned about methotrexate.

Bone Marrow Transplantation

Marrow ablative therapy and stem cell rescue or, more simply, bone marrow transplantation (BMT) has been advocated for children with ALL and very-high-risk (VHR) features in first complete remission (CR1). Rigorous evaluation has been confounded by waiting-time bias, selection bias, and variability in the details of prior chemotherapy, marrow ablative therapy, and graft-versus-host disease (GVHD) prophylaxis. Outcome after BMT begins with BMT and does not include the experience of patients who never achieve remission or relapse before a BMT may be performed. Patients with pre-existing severe organ dysfunction or deep-seated infection may be refused BMT and never appear in BMT statistics.

CCG tried to address these challenging issues in a clinical trial.179 Patients with age > 10 years and WBC > 2000,000/uL, t(4;11), t(9;22), modal chromosome number < 45, or greater than 5% marrow blasts on day 28 of induction. Because the number of children with any single VHR feature is small, these subsets were examined in aggregate.

A total of 42 patients with VHR features and compatible matched family donors were identified. Twenty-eight underwent BMT in CR1. The outcome of patients with donors who underwent BMT was better than that of patients with donors who did not undergo BMT—sometimes because of very early relapse. However, in the critical intent-to-treat—donor availability—analysis, the outcome of patients with donors was not superior to the outcome of patients with no donors. These data are similar to the data reported from the much larger U.K. Medical Research Council (MRC) study.180

In the CCG trial, an advantage for matched sibling donor BMT was apparent only for children with (PH) plus ALL.179 This result supports the conclusions of the 10-group collaborative overview by Arico and co-workers on pediatric Philadelphia chromosome–positive ALL.63 Contrary to the poor result with matched unrelated donors in that overview, Marks and co-workers report a more positive experience.181

BMT is not a complete answer to the problem of very-high-risk ALL. Any advantage for BMT over contemporary chemotherapy remains to be demonstrated. Donor availability is not the primary constraint on the clinical utility of BMT. Although the clinical decision between BMT options and chemotherapy options is critical, any one study compares one BMT approach and one chemotherapy approach. Generalization to all BMT approaches and all chemotherapy approaches is perilous.

Treatment After Relapse

Despite signal progress, to date, in the treatment of newly diagnosed ALL, relapsed ALL remains a major problem in pediatric oncology.1,2 Numerically, there are more children with ALL and relapse than there are new diagnoses of a number of relatively common childhood cancers (see Table 138A.1).

Outcome after relapse depends on the duration of first remission and the site of relapse. Table 138A.5 summarizes the experience of patients with relapse who had been diagnosed between 1983 and 1988 and enrolled on the CCG-100 series trials.182 Seventy percent of relapses involve the bone marrow.

Table 138A.5. Survival after Relapse on the CCG-100 Series.

Table 138A.5

Survival after Relapse on the CCG-100 Series.

Outcomes are particularly unfavorable for marrow relapse prior to 3 years from diagnosis and isolated CNS relapse prior to 18 months. Outcomes are somewhat better for testicular and late marrow relapse, especially late combined marrow, as first reported by the BFM Group,183 and extramedullary relapse. British data are similar.184

Matched sibling donor BMT has been proposed as the treatment of choice for children with bone marrow relapse. For patients in second remission (CR2), Barrett and co-workers examined 255 matched pairs from the International Bone Marrow Transplant Registry and found a 5-year disease free survival (DFS) of 40% for BMT versus 17% for a historical chemotherapy control.185 Hoogerbrugge and co-workers compared 25 BMT patients with 97 matched controls and found DFS of 44% and 24%, respectively.186 Uderzo and co-workers reported a DFS of 37% for 57 BMT patients and 22% for 230 matched chemotherapy patients.187 Schroeder and co-workers reported a DFS of 35% for BMT versus 15% for chemotherapy in an analysis of 63 cases and 126 matched controls.188 Boulad reported 62% for 37 BMT patients and 26% for 29 chemotherapy patients.189 P values may vary with sample sizes as well as the exact magnitude of the differences, but a trend is clear. Some found a greater advantage for BMT for patients with earlier marrow relapse186,187,190 and others do not.185,189 Case-control analyses can compensate for waiting-time bias, but selection bias may still confound comparisons. Comparison of BMT experience from the past 20 years with chemotherapy experience from the last several years may be misleading.191

Matched sibling donor BMT requires that patients achieve and maintain a remission and possess a matched sibling donor. If 80% of relapsed patients achieve CR2 and 80% of these maintain remission long enough to undergo BMT, then only 64% of patients with matched related donors may undergo BMT in CR2, and a post-BMT disease-free survival of 40% corresponds to a post-relapse EFS of only 25%. Most patients lack a matched sibling donor.

Alternative stem cell sources, such as matched unrelated donor marrow or umbilical cord blood, haplo-identical related donors, and purged autologous marrow have been proposed.192,193 Neither Borgmann and co-workers nor Wheeler and co-workers found any advantage for purged autologous BMT over chemotherapy.194,195

Results for matched unrelated donor (MUD) BMT are generally similar to those for matched sibling donor BMT.196 However, the time from CR2 to transplantation may be longer, introducing greater waiting time and a shrinking subset of still eligible CR2 patients. Balduzzi and co-workers report a 47% DFS for 15 patients transplanted in CR1 or CR2.197 Oakhill and co-workers report a 2-year DFS of 53% for 50 patients transplanted in CR2 after T-cell depletion.198 Davies and co-workers report a 2-year DFS of 20% for 19 patients.199 Whether the results of single centers can be replicated more widely remains to be demonstrated. Adequately controlled trials are lacking.

BMT is not a complete answer to the problem of early marrow relapse. Too many patients never achieve CR2. Too many patients who achieve CR2 relapse before a BMT can be performed. Too many patients die of BMT complications or relapse after BMT. Wheeler and co-workers report only 2 survivors among 16 BMTs in CR2 following an on-therapy marrow relapse.195 Lausen and co-workers note a higher relapse rate for patients transplanted following relapse from more recent, more effective primary treatment regimens.191 Post-BMT interventions can have no benefit for the majority of patients who can never get as far as a BMT.

Novel Therapeutic Strategies

A recent CCG trial in AML may point to a useful strategic paradigm.13 Intensively timed induction led to a lower disease burden—presumably—and a better outcome after allogeneic BMT, autologous BMT, and chemotherapy consolidation. Uckun and co-workers and Knechtli and co-workers showed that in ALL, outcome after BMT is related to disease burden prior to BMT.114,200 The challenge is the reduction of disease burden. This may be accomplished by more effective use of conventional agents, as in the AML trial, or by introduction of agents active against otherwise resistant blasts. When an agent retains activity at relapse, better use of that agent prior to relapse may prevent the relapse. Better understanding of the biology of leukemia may reveal new therapeutic targets.

Conventional Agents

Better asparagine depletion may lead to better response for patients in relapse after prior exposure to native Escherichia coli asparaginase. Kurtzberg and co-workers showed that the appearance of antiasparaginase antibodies was associated with poor response to vincristine, prednisone, and asparaginase therapy in second relapse.201 Abshire and co-workers found similarly that the appearance of antiasparaginase antibodies was associated with poor response to vincristine, prednisone, asparaginase, and daunomycin therapy in first relapse.202 The recent CCG trial also found that induction response was strongly linked to asparagine depletion in first relapse.203 More effective asparaginase schedules might be employed or non–cross-reactive products might be substituted to guarantee asparagine depletion.

Steroid resistance is a hallmark of relapsed ALL,204 and identification of ligands with activity against prednisolone-resistant blasts may make a major contribution to therapy. The (MTT) response to prednisolone is a reliable predictor of outcome.166 Klumper and co-workers found that the median prednisolone LC50 was 100-fold higher at relapse than at presentation, representing relapse of steroid-resistant patients rather than late emergence of prednisolone resistance. Cortivazol, a pyrazolosteroid, induces apoptosis in severe prednisolone-resistant cell lines.205 Six of 10 multiply relapsed patients achieved complete or partial remission after treatment with single-agent cortivazol.206 Further studies are underway.

Arabinosylguanine (ara-G) or 506U is a purine analogue in clinical trials. In vitro, concentrations are 15- to 250-fold higher in T cells than in B cells.207,208 Considerable clinical activity has been shown against T-lineage leukemia and lymphoma.209,210 Significant neurotoxicity has been encountered. Further studies are underway.

Novel Agents

New agent development for patients with leukemia has remained problematic. The number of potential single-agent and multiple-agent phase I trials surpass the number of available relapsed patients. Phase I studies are conducted in end-stage patients with confounding disease-related morbidity. In phase II, identification of novel, nonredundant activity may be difficult in a relapsed population, where some patients may still respond to vincristine, prednisone, and L-asparaginase. In phase III, integration and evaluation of novel agents in the context of somewhat effective primary therapy requires substantial patient numbers for statistical potency, which places a severe limit on the number of trials that may be conducted.

The SCID mouse model provides an opportunity to investigate the activity and toxicity of novel agents, singly and in combination, at defined levels of disease burden. In vitro assays provide no insight into the potential toxicity. SCID mouse studies may contribute to the design of more productive clinical trials.211

B43-PAP (anti-CD19 pokeweed antiviral protein)212–214 and TXU3-PAP (anti-CD7 pokeweed antiviral protein215,216 show striking antileukemic effect in the SCID mouse model. These immunotoxins join a monoclonal antibody against a surface antigen—CD 19 or CD 7—that persists at relapse and triggers pinocytosis when attached to the antibody and PAP—a depurinating ribosomal poison.217,218 B43-PAP showed single agent activity against relapsed CD19+ childhood ALL. In the SCID mouse model, B43-PAP was shown to be highly synergistic with vincristine, prednisone, and L-asparaginase219 and with cytosine arabinoside but not carmustine, adriamycin, or etoposide.220 Pediatric phase I trials of B43-PAP plus vincristine, prednisone, asparaginase, and daunomycin have been completed.221 Pediatric phase I trials of TXU3-PAP are underway.

Many cytokines induce tyrosine phosphorylation. Signaling pathways involving JAKs and DNA-binding proteins called signal transducers and activators of transcription (STATs) allow the rapid transduction of an extracellular signal into the nucleus. After phosphorylation by JAKs, cytoplasmic STATs dimerize, translocate into the nucleus, bind to DNA, and modulate gene expression. In Abelson murine leukemia virus transformed cells, the v-abl oncogene is physically associated with JAK1 and JAK3.222 Constitutive tyrosine phosphorylation has been observed in many B-lineage leukemias.223,224 JAK and STAT are constitutively activated in most BCR-ABL leukemia cell lines.225

The protein tyrosine kinase (PTK) inhibitor, B43-genistein, induces apoptosis in NALM6 cells in the SCID mouse model.211 AG-490, a JAK2 and JAK3 inhibitor,226 induces apoptosis in leukemia cells freshly derived from three patients with relapsed B-lineage ALL, both in vitro and in the SCID mouse model.227 The ABL-specific PTK inhibitor ST1571 specifically inhibits the growth of BCR-ABL–postive leukemia cells in vitro228,229 and reverses the BCR-ABL– induced phenotype.230 Recent reports of clinical responses in BCR-ABL–positive CML and ALL are encouraging.231,232

Bruton’s tyrosine kinase (BTK) is a member of the Src-related Tec family protein tyrosine kinases. Mutations in the btk gene have been linked to severe developmental blocks in human B-cell ontogeny leading to human X-linked agammaglobulinemia.233 Recent studies revealed unique biochemical and genetic evidence that BTK is an inhibitor of the Fas/APO-1 death–inducing signaling complex in B-lineage ALL and lymphoma cells. BTK associates with Fas and prevents its interaction with FADD, which is essential for the recruitment and activation of FLICE by Fas during the apoptotic signal.234,235 A rationally designed specific inhibitor of BTK is currently under development as a chemosensitizing agent.236,237

Conclusion

Treatment outcome depends on disease, host, and treatment factors. Treatment factors are paramount and may alter the significance of disease and host factors. Disease factors include features apparent at diagnosis, features that may appear in response to therapy, and factors that become apparent only at relapse. Single cytogenetic or molecular findings define outcome no more than blast morphology or immunophenotype. Host factors refer to differences among patients with regard to drug absorption and metabolism. Considerable heterogeneity has been described with respect to host pharmacology of thiopurines238 and vincristine.239,240 Population variability has been described with respect to sensitivity to glucocorticosteroids.241,242

Much has been accomplished, and much remains to be accomplished. Strategies, like postinduction intensification, which were successful at one level, for example, delayed intensification or protocol II, have been successfully employed at a higher level, for example, double delayed intensification or the augmented intensive regimen. Strategies successful in one patient population have been extended to other populations with similar success.

In childhood ALL, disease at relapse may often still retain sensitivity to the original agents. More effective use of conventional agents may prevent relapse. Introduction of novel agents with activity against resistant blasts provides a strategy to treat or prevent more resistant disease. To date, BMT has not provided an adequate answer to the problem of very-high-risk disease or relapse. However, BMT may be more useful if disease burden can be reduced prior to it. Lessons learned in the treatment of childhood ALL may have value in the treatment of other cancers in other populations.

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