Postinduction Treatment for Specific ALL Subgroups
Historically, patients with T-cell acute lymphoblastic leukemia (ALL) have had a worse prognosis than children with precursor B-cell ALL. With current treatment regimens, outcomes for children with T-cell ALL are now approaching those achieved for children with precursor B-cell ALL. For example, the 10-year overall survival (OS) for children with T-cell ALL treated on the Dana-Farber Cancer Institute (DFCI) DFCI-95001 (NCT00004034) trial was 90.1% compared with 88.7% for patients with B-cell disease. However, in a review of a large number of patients treated on Children's Oncology Group (COG) trials over a 15-year period, T-cell immunophenotype still proved to be a negative prognostic factor on multivariate analysis.
- Protocols of the former Pediatric Oncology Group (POG) treated children with T-cell ALL differently from children with B-lineage ALL. The POG-9404 protocol for patients with T-cell ALL was designed to evaluate the role of high-dose methotrexate. The multiagent chemotherapy regimen for this protocol was based on the DFCI-87001 regimen.
- Results of the POG-9404 study indicated that the addition of high-dose methotrexate to the DFCI-based chemotherapy regimen resulted in significantly improved event-free survival (EFS) in patients with T-cell ALL (10-year EFS, 78% for those randomly assigned to high-dose methotrexate versus 68% for those randomly assigned to therapy without high-dose methotrexate, P = .05).
- High-dose methotrexate was associated with a lower incidence of relapses involving the central nervous system (CNS). This POG study was the first clinical trial to provide evidence that high-dose methotrexate can improve outcome for children with T-cell ALL. High-dose asparaginase, doxorubicin, and prophylactic cranial irradiation were also important components of this regimen.[1,4]
- Protocols of the former Children’s Cancer Group (CCG) treated children with T-cell ALL on the same treatment regimens as children with precursor B-cell ALL, basing protocol and treatment assignment on the patients' clinical characteristics (e.g., age and white blood cell [WBC] count) and the disease response to initial therapy. Most children with T-cell ALL meet National Cancer Institute (NCI) high-risk criteria.
- Results from CCG-1961 for high-risk ALL including T-cell ALL showed that an augmented Berlin-Frankfurt-Münster (BFM) regimen with a single delayed intensification course produced the best results for patients with morphologic rapid response to initial induction therapy (estimated 5-year EFS, 83%).[5,6] Almost 60% of events in this group, however, were isolated CNS relapses.
- Overall results from POG-9404 and CCG-1961 were similar, although POG-9404 used cranial radiation for every patient, while CCG-1961 used cranial radiation only for patients with slow morphologic response.[6,4]
- Among children with NCI standard-risk T-cell ALL, the EFS for those treated on CCG-1952 and COG-1991 studies was inferior to the EFS for those treated on the POG-9404 study.
- In the COG, children with T-cell ALL are not treated on the same protocols as children with precursor B-cell ALL. Pilot studies from the COG have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) [8,9] in the context of a BFM regimen for patients with newly diagnosed T-cell ALL. The pilot study showed a 5-year EFS rate of 73% for all patients receiving nelarabine and 69% for those patients with a slow early response.
- The role of prophylactic cranial radiation in the treatment of T-cell ALL is controversial. Some groups, such as St. Jude Children's Research Hospital (SJCRH) and the Dutch Childhood Oncology Group (DCOG), do not use cranial radiation in first-line treatment of ALL, while other groups, such as DFCI, COG, and BFM, use radiation for the majority of patients with T-cell ALL.
Treatment options under clinical evaluation for T-cell ALL
Treatment options under clinical evaluation for T-cell ALL include the following:
- NCI-2014-00712; AALL1231 (NCT02112916) (Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II–IV T-Cell Lymphoblastic Lymphoma): This phase III trial is utilizing a modified augmented BFM regimen for patients aged 1 to 30 years with T-cell ALL. Patients are classified into one of three risk groups (standard, intermediate, or very high) based on morphologic response at day 29, minimal residual disease (MRD) status at day 29 and end of consolidation, and CNS status at diagnosis. Age and presenting leukocyte count are not used to stratify patients. The objectives of the trial include the following:
- To compare EFS in patients who are randomly assigned to receive or not to receive bortezomib on a modified augmented BFM backbone. For those randomly assigned to receive bortezomib, it is given during the induction phase (four doses) and again during the delayed intensification phase (four doses).
- To determine the safety and feasibility of modifying standard COG therapy for T-cell ALL by using dexamethasone instead of prednisone during the induction and maintenance phases and additional doses of PEG-asparaginase during the induction and delayed intensification phases.
- To determine whether prophylactic cranial radiation can be omitted in 85% to 90% of T-cell ALL patients (non–very high risk, non-CNS3) without an increase in relapse risk, compared with historic controls.
- To determine the proportion of patients with end consolidation MRD >0.1% who become MRD-negative after intensification therapy using three high-risk BFM blocks that include high-dose cytarabine, high-dose methotrexate, ifosfamide, and etoposide.
- DFCI-11-001 (NCT01574274) (SC-PEG Asparaginase versus Oncaspar in Pediatric ALL and Lymphoblastic Lymphoma):
Patients with T-cell ALL are eligible to enroll on a DFCI ALL Consortium protocol that is comparing the pharmacokinetics and toxicity of two forms of intravenous PEG-L-asparaginase (pegaspargase [Oncaspar] and calaspargase pegol [SC-PEG]). Patients will be randomly assigned to receive a single dose of one of these preparations during multiagent induction, and then either pegaspargase every 2 weeks (15 doses total) or calaspargase pegol every 3 weeks (10 doses total) during the 30-week consolidation phase.
This protocol is also testing whether antibiotic prophylaxis (with fluoroquinolones) reduces rates of bacteremia and other serious bacterial infections during the remission induction phase. All T-cell patients are treated on the high-risk arm of this trial, regardless of other presenting characteristics.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with T-cell childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Infants With ALL
Infant ALL is uncommon, representing approximately 2% to 4% of cases of childhood ALL. Because of their distinctive biological characteristics and their high risk of leukemia recurrence, infants with ALL are treated on protocols specifically designed for this patient population. Common therapeutic themes of the intensive chemotherapy regimens used to treat infants with ALL are the inclusion of postinduction intensification courses with high doses of cytarabine and methotrexate.[12-14] Despite intensification of therapy, long-term EFS rates remain below 50%. Infants with congenital leukemia (diagnosed within 1 month of birth) have a particularly poor outcome (17% OS).[Level of evidence: 2A]
For infants with MLL gene rearrangement, the EFS rates continue to be in the 17% to 40% range.[12,13,15-17][Level of evidence: 2A] Factors predicting poor outcome for infants with MLL translocations include the following:; [Level of evidence: 3iDii]
- A very young age (<6 months).
- Extremely high presenting leukocyte count (≥200,000–300,000/μL).
- High levels of MRD at the end of induction and consolidation phases of treatment.
Treatment options for infants with MLL translocations
Infants with MLL gene translocations are generally treated on intensified chemotherapy regimens using agents not typically incorporated into frontline therapy for older children with ALL. However, despite these intensified approaches, EFS rates remain poor for these patients.
Evidence (intensified chemotherapy regimens for infants with MLL translocations):
- The international Interfant clinical trials consortium utilized a cytarabine-intensive chemotherapy regimen, with increased exposure to both low- and high-dose cytarabine during the first few months of therapy, resulting in a 5-year EFS of 37% for infants with MLL translocations.
- The COG tested intensification of therapy with a regimen including multiple doses of high-dose methotrexate, cyclophosphamide, and etoposide, resulting in a 5-year EFS of 34%.
The role of allogeneic hematopoietic stem cell transplant (HSCT) during first remission in infants with MLL gene translocations remains controversial.
Evidence (allogeneic HSCT in first remission for infants with MLL translocations):
- On a Japanese clinical trial conducted between 1998 and 2002, all infants with MLL-rearrangement were intended to proceed to allogeneic HSCT from the best available donor (related, unrelated, or umbilical cord) 3 to 5 months after diagnosis.
- The 3-year EFS for all enrolled infants was 44%. This result was due, in part, to the high frequency of early relapses, even with intensive chemotherapy; of the 41 infants with MLL-rearrangement on that study who achieved complete remission (CR), 11 infants (27%) relapsed before proceeding to transplant.
- In a COG report that included 189 infants treated on CCG or POG infant ALL protocols between 1996 and 2000, there was no difference in EFS between patients who underwent HSCT in first CR and those who received chemotherapy alone.
- The Interfant clinical trials group, after adjusting for waiting time to transplantation, also did not observe any difference in disease-free survival (DFS) in high-risk infants (defined by prednisone response) with MLL translocations treated on the Interfant-99 trial with either allogeneic HSCT in first CR or chemotherapy alone.
- In a subset analysis from the same trial, allogeneic HSCT in first remission was associated with a significantly better DFS for infants with MLL translocations who were younger than 6 months at diagnosis and had either a poor response to steroids at day 8 or leukocyte counts of at least 300,000/µL. In this subset, HSCT in first remission was associated with a 64% reduction in the risk of failure resulting from relapse or death compared with chemotherapy alone.
Treatment options for infants without MLL translocations
The optimal treatment for infants without MLL translocations also remains unclear.
- On the Interfant-99 trial, patients without MLL translocations achieved a relatively favorable outcome with the cytarabine-intensive treatment regimen (4-year EFS was 74%).
- A favorable outcome for this subset of patients was obtained in a Japanese study using therapy comparable to that used to treat older children with ALL; however, that study was limited by small numbers (n = 22) and a highly unusual gender distribution (91% males).
Treatment options under clinical evaluation for infants with ALL
Treatment options under clinical evaluation include the following:
- Interfant-06 Study Group trial (DCOG-INTERFANT-06) (Different Therapies in Treating Infants With Newly Diagnosed Acute Leukemia): The Interfant-06 Study Group is conducting an international collaborative randomized trial (including sites in the United States) to test whether an ALL/acute myeloid leukemia hybrid regimen might improve outcomes for infants with MLL-rearranged ALL. The role of allogeneic transplantation in first remission is also being assessed in high-risk patients (defined as infants with MLL-rearranged ALL, younger than 6 months, and WBC >300,000 /µL) or poor peripheral blood response to steroid prophase. Infants with MLL-rearranged ALL with high MRD at end of consolidation phase are also eligible for allogeneic HSCT in first remission regardless of other presenting features.
Adolescents and Young Adults With ALL
Adolescents and young adults with ALL have been recognized as high risk for decades. Outcomes in almost all studies of treatment are inferior in this age group compared with children younger than 10 years.[22-24] The reasons for this difference include more frequent presentation of adverse prognostic factors at diagnosis, including the following:
- T-cell immunophenotype.
- Philadelphia chromosome–positivity (Ph+).
- Lower incidence of favorable cytogenetic abnormalities.
Studies from the United States and France were among the first to identify the difference in outcome based on treatment regimens. Other studies have confirmed that older adolescent and young adult patients fare better on pediatric rather than adult regimens.[28-32]; [Level of evidence: 2A] These study results are summarized in Table 3.
Given the relatively favorable outcome that can be obtained in these patients with chemotherapy regimens used for high-risk pediatric ALL, there is no role for the routine use of allogeneic HSCT for adolescents and young adults with ALL in first remission.
Evidence (pediatric treatment regimen):
- Investigators reported on 197 patients aged 16 to 21 years treated on the CCG study (a pediatric ALL regimen) who showed a 7-year EFS of 63% compared with 124 adolescents and young adults treated on the Cancer and Leukemia Group B (CALGB) study (an adult ALL regimen) with a 7-year EFS of 34%.
- A study from France of patients aged 15 to 20 years and diagnosed between 1993 and 1999 demonstrated superior outcome for patients treated on a pediatric trial (67%; 5-year EFS) compared with patients treated on an adult trial (41%; 5-year EFS).
- In the COG high-risk study (CCG-1961), the 5-year EFS rate for 262 patients aged 16 to 21 years was 71.5%.[Level of evidence: 1iiDi] For rapid responders randomly assigned to early intensive postinduction therapy on the augmented intensity arms of this study, the 5-year EFS rate was 82% (n = 88).
- The DFCI ALL Consortium reported that a study of 51 adolescents aged 15 to 18 years in a pediatric trial had a 5-year EFS of 78%.
- In an SJCRH study, 44 adolescents aged 15 to 18 years had an EFS of approximately 85% ± 5%.
- In a Spanish study, 35 adolescents (aged 15–18 years) and 46 young adults (aged 19–30 years) with standard-risk ALL were treated with a pediatric-based regimen.[Level of evidence: 2A]
- EFS rate was 61%.
- The OS rate was 69%.
- There were no differences in outcome between adolescents and young adults.
The reason that adolescents and young adults achieve superior outcomes with pediatric regimens is not known, although possible explanations include the following: 
- Treatment setting (i.e., site experience in treating ALL).
- Adherence to protocol therapy.
- The components of protocol therapy.
|Site and Study Group||Adolescent and Young Adult Patients (No.)||Median age (y)||Survival (%)|
|ALL = acute lymphoblastic leukemia; EFS = event-free survival; OS = overall survival.|
|AEIOP = Associazione Italiana Ematologia Oncologia Pediatrica; CALGB = Cancer and Leukemia Group B; CCG = Children's Cancer Group; DCOG = Dutch Childhood Oncology Group; FRALLE = French Acute Lymphoblastic Leukaemia; GIMEMA = Gruppo Italiano Malattie e Matologiche dell'Adulto; HOVON = Dutch-Belgian Hemato-Oncology Cooperative Group; LALA = France-Belgium Group for Lymphoblastic Acute Leukemia in Adults; MRC = Medical Research Council (United Kingdom); NOPHO = Nordic Society for Pediatric Hematology and Oncology; UKALL = United Kingdom Acute Lymphoblastic Leukaemia.|
|United States |
|CCG (Pediatric)||197||16||67, OS 7 y|
|FRALLE 93 (Pediatric)||77||16||67 EFS|
|AEIOP (Pediatric)||150||15||80, OS 2 y|
|DCOG (Pediatric)||47||12||71 EFS|
|NOPHO 92 (Pediatric)||36||16||74, OS 5 y|
|United Kingdom |
|MRC ALL (Pediatric)||61||15–17||71, OS 5 y|
|UKALL XII (Adult)||67||15–17||56|
Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.[30,38] Before the use of postinduction intensification for treatment of ALL, osteonecrosis was infrequent. The improvement in outcome for children and adolescents aged 10 years and older was accompanied by an increased incidence of osteonecrosis.
The weight-bearing joints are affected in 95% of patients who develop osteonecrosis and operative interventions are needed for management of symptoms and impaired mobility in more than 40% of cases. The majority of the cases are diagnosed within the first 2 years of therapy and often the symptoms are recognized during maintenance.
- In the CCG-1961 high-risk ALL study, alternate-week dosing of dexamethasone was compared with standard continuous dexamethasone during delayed intensification to see if the osteonecrosis risk could be reduced.
- The median age at symptom onset was 16 years.
- The cumulative incidence was higher in adolescents and young adults aged 16 to 21 years (20% at 5 years) than in those aged 10 to 15 years (9.9%) or in patients aged 1 to 9 years (1%).
- Operative interventions are needed for management of symptoms and impaired mobility in more than 40% of cases.
- The use of alternate-week dosing of dexamethasone as compared with standard continuous dexamethasone during delayed intensification in CCG-1961 reduced the risk of osteonecrosis. The greatest impact was seen in females aged 16 to 21 years, who showed the highest incidence of osteonecrosis with standard therapy containing continuous dexamethasone; osteonecrosis was reduced with alternate-week dexamethasone postinduction (57.6% to 5.6%).
Treatment options under clinical evaluation for adolescent and young adult patients with ALL
Treatment options under clinical evaluation include the following:
- NCI-2014-00712; AALL1231 (NCT02112916) (Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage II–IV T-Cell Lymphoblastic Lymphoma): This phase III trial for patients aged 1 to 30 years with T-cell ALL is utilizing a modified augmented BFM regimen. Patients are classified into one of three risk groups (standard, intermediate, or very high) based on morphologic response at day 29, MRD status at day 29 and end of consolidation, and CNS status at diagnosis. Age and presenting leukocyte count are not used to stratify patients. The objectives of the trial include the following:
- To compare EFS in patients who are randomly assigned to receive or not to receive bortezomib on a modified augmented BFM backbone.
- To determine the safety and feasibility of modifying standard COG therapy for T-ALL by using dexamethasone instead of prednisone during the induction and maintenance phases and additional doses of PEG-asparaginase during the induction and delayed intensification phases.
- To determine whether prophylactic cranial radiation can be omitted in 85% to 90% of T-ALL patients (non-very high risk, non-CNS3) without an increase in relapse risk, compared with historic controls.
- To determine the proportion of patients with end consolidation MRD >0.1% who become MRD-negative after intensification therapy using three high-risk BFM blocks that include high-dose cytarabine, high-dose methotrexate, ifosfamide, and etoposide.
Philadelphia Chromosome–positive ALL
Philadelphia chromosome–positive (Ph+) ALL is seen in about 3% of pediatric ALL cases, increases in adolescence, and is seen in 15% to 25% of adults. In the past, this subtype of ALL has been recognized as extremely difficult to treat with poor outcome. In 2000, an international pediatric leukemia group reported a 7-year EFS of 25%, with an OS of 36%. In 2010, the same group reported a 7-year EFS of 31% and an overall survival of 44% in Ph+ ALL patients treated without tyrosine kinase inhibitors. Treatment of this subgroup has evolved from emphasis on aggressive chemotherapy, to bone marrow transplantation, and currently to combination therapy using chemotherapy plus tyrosine kinase inhibitor.
Pre-tyrosine kinase inhibitor era
Before the use of imatinib mesylate, HSCT from a matched sibling donor was the treatment of choice for patients with Ph+ ALL.[41-43] Data to support this include a retrospective multigroup analysis of children and young adults with Ph+ ALL, in which HSCT from a matched sibling donor was associated with a better outcome than standard (pre-imatinib mesylate) chemotherapy. In this retrospective analysis, Ph+ ALL patients undergoing HSCT from an unrelated donor had a very poor outcome. However, in a follow-up study by the same group evaluating outcomes in the subsequent decade (pre-imatinib mesylate era), transplantation with matched-related or matched-unrelated donors were equivalent. DFS at the 5-year time point showed an advantage for transplantation in first remission compared with chemotherapy that was borderline significant (P = .049), and OS was also higher for transplantation compared with chemotherapy, although the advantage at 5 years was not significant.
Factors significantly associated with favorable prognosis in the pre-tyrosine kinase inhibitor era included the following:
Tyrosine kinase inhibitor era
Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and II studies of single-agent imatinib in children and adults with relapsed or refractory Ph+ ALL have demonstrated relatively high response rates, although these responses tended to be of short duration.[49,50]
Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[51-53] Preliminary outcome of results for Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[54-57]
Evidence (tyrosine kinase inhibitor):
- A retrospective study of 30 pediatric patients with Ph+ ALL (19 patients treated between 1991–2004 without a tyrosine kinase inhibitor, and 11 patients treated between 2004–2012 with either imatinib or dasatinib) indicated that tyrosine kinase inhibitors, when started mid-induction, are associated with lower end-induction MRD.
- The COG-AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with Ph+ ALL. Patients received imatinib mesylate in conjunction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic HSCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases.[53,59]
- The 5-year EFS for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib mesylate is 70% ± 12%. These patients fared better than historic controls treated with chemotherapy alone (without imatinib mesylate), and at least as well as the other patients on the trial who underwent allogeneic transplantation. Longer follow-up is necessary to determine whether this novel treatment improves cure rate or merely prolongs DFS.
- A nonrandomized study reported the outcome in 16 pediatric patients with Ph+ ALL who were treated with chemotherapy, imatinib, and allogeneic HSCT.
- With a median follow-up of 65 months, the 5-year EFS was 81% for patients who received imatinib compared with 30% (P = .01) for a historic control group treated similarly, but without imatinib. Of note, only one of the 16 patients received prophylactic imatinib posttransplant.
- The EsPhALL trial tested whether imatinib (administered discontinuously) given in the context of intensive chemotherapy improves outcome for pediatric Ph+ ALL patients, most of whom (80%) received an allogeneic HSCT in first CR. Patients were classified as either good risk or poor risk based on early response measures and remission status at the end of induction. Good- risk patients (N = 90) were randomly assigned to receive imatinib or not; poor-risk patients (N = 70) were directly assigned to imatinib. Interpretation of this study is limited due to the high noncompliance rate with randomized assignment in good-risk patients and early closure before reaching goal accrual due to publication of the results of the COG AALL0031 trial on which imatinib had been given continuously with chemotherapy. The overall DFS of patients treated on this trial appeared to be better than historic controls, and when analyzed as-treated (and not by intent-to-treat), good-risk patients who received imatinib had a superior DFS. The EsPhALL trial has since been amended to test continuous dosing of imatinib; results are pending.
Dasatinib, a second-generation inhibitor of tyrosine kinases, is currently being studied in the initial treatment of Ph+ ALL. Dasatinib has shown significant activity in the CNS, both in a mouse model and a series of patients with CNS-positive leukemia. The results of a phase I trial of dasatinib in pediatric patients indicated that once-daily dosing was associated with an acceptable toxicity profile, with few nonhematologic grade 3 or 4 adverse events.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with Philadelphia chromosome positive childhood precursor acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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- 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 9404). Blood 118 (4): 874-83, 2011. [PUBMED Abstract]
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- van der Linden MH, Valsecchi MG, De Lorenzo P, et al.: Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol. Blood 114 (18): 3764-8, 2009. [PUBMED Abstract]
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