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Childhood Acute Lymphoblastic Leukemia Treatment (Professional) (cont.)

Postinduction Treatment for Specific ALL Subgroups

T-Cell ALL

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 5-year event-free survival (EFS) for children with T-cell ALL treated on the Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols was 75% compared with 84% for children with precursor B-cell ALL.[1]

Treatment options

  1. 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.[2]
    • Results of the POG-9404 study indicated that the addition of high-dose methotrexate to the DFCI-based chemotherapy regimen resulted in significantly improved 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).[3] 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]
  2. 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 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] 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.[7]
  3. In the Children's Oncology Group (COG), children with T-cell ALL are no longer 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.[10]
  4. 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:

  1. COG-AALL0434 (NCT00408005) (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma):

    COG-AALL0434 is a phase III trial 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 (low, intermediate, or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and minimal residual disease (MRD) level at day 29. The objectives of the trial include the following:

    • To determine the safety and efficacy of adding nelarabine to the modified augmented BFM regimen in high- and intermediate-risk patients.
    • To determine the relative safety and efficacy of high-dose (5 g/m2) versus Capizzi escalating lower-dose methotrexate without rescue during interim maintenance.
    • To test the efficacy of treating NCI standard-risk T-cell ALL patients who are rapid responders (about 15% of patients) without cranial radiation.
  2. 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 (IV) 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.[11] Because of their distinctive biological characteristics and their high risk for 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.[12,13,14] 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% overall survival [OS]).[15][Level of evidence: 2A].

For infants with MLL gene rearrangement, the EFS rates continue to be in the 17% to 40% range.[12,13,15,16,17][Level of evidence: 2A] Factors predicting poor outcome for infants with MLL translocations include the following:[13]; [18][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 withMLLtranslocations

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):

  1. 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.[13]
  2. 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%.[12]

The role of allogeneic stem cell transplant (SCT) during first remission in infants with MLL gene translocations remains controversial. Case series have suggested that allogeneic transplants in first remission may be effective.[19,20,21]; [22][Level of evidence: 3iA]

Evidence (allogeneic SCT in first remission for infants with MLL translocations):

  1. On a Japanese clinical trial conducted between 1998 and 2002, all infants with MLL-rearrangement were intended to proceed to allogeneic SCT 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 prior to proceeding to transplant.[22]
  2. 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 SCT in first CR and those who received chemotherapy alone.[23]
  3. 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 SCT in first CR or chemotherapy alone.[13]
    • In a subset analysis from the same trial, allogeneic SCT 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 levels of at least 300 g/L.[24] In this subset, SCT 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 withoutMLLtranslocations

The optimal treatment for infants without MLL translocations also remains unclear.

  1. 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%).[13]
  2. 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;[16] however, that study was limited by small numbers.

Treatment options under clinical evaluation for infants with ALL

Treatment options under clinical evaluation include the following:

  1. 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 SCT in first remission regardless of other presenting features.
  2. COG-AALL0631(Combination Chemotherapy With or Without Lestaurtinib in Treating Infants With Newly Diagnosed ALL): In this COG study of infant ALL, an FLT3 inhibitor, lestaurtinib, is being studied in infants with MLL rearrangement. Infants with MLL rearrangement are known to have a high level of FLT3 mRNA expression and lestaurtinib has been shown to selectively kill MLL-rearranged ALL cells in vitro and in vivo.[25] This study combines lestaurtinib with intensive chemotherapy previously utilized in POG-P9407. There is an initial safety/activity phase followed by an efficacy phase in which children will be randomly assigned to chemotherapy with or without lestaurtinib. Infants with germline MLL will be nonrandomly assigned to less-intensive chemotherapy without lestaurtinib.

Adolescent and Young Adult Patients With ALL

Treatment options

Older children and adolescents (aged 10 years and older) with ALL more frequently present with adverse prognostic factors at diagnosis, including T-cell immunophenotype and Philadelphia chromosome–positivity (Ph+), and have a lower incidence of favorable cytogenetic abnormalities.[26,27] These patients have a less favorable outcome than children aged 1 to younger than 10 years at diagnosis, and more aggressive treatments are generally employed.[28]

Studies from the United States and France were among the first to identify the difference in outcome based on treatment regimens.[29] Other studies have confirmed that older adolescent and young adult patients fare better on pediatric rather than adult regimens.[27,29,30,31,32]; [33][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 pediatric ALL, there is no role for the routine use of allogeneic SCT in first remission for adolescents and young adults with ALL.[34]

Evidence (pediatric treatment regimen):

  1. Investigators reported on 197 patients aged 16 to 21 years treated on the CCG study 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 with a 7-year EFS of 34%.[29]
  2. 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).[35]
  3. In the COG high-risk study (CCG-1961), the 5-year EFS rate for 262 patients aged 16 to 21 years was 71.5%.[34][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).
  4. 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%.[27]
  5. In an SJCRH study, 44 adolescents aged 15 to 18 years had an EFS of approximately 85% ± 5%.[36]
  6. 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.[33][Level of evidence: 2A]
    • EFS rate was 61%.
    • The OS rate was 69%.
    • There were no differences in outcome between adolescents and young adults.

Other studies have confirmed that older adolescent patients and young adults fare better on pediatric rather than adult regimens (see Table 3).[27,29,30,31]; [33][Level of evidence: 2A]

The reason that adolescents and young adults achieve superior outcomes with pediatric regimens is not known, although possible explanations include the following: [30]

  • Treatment setting (i.e., site experience in treating ALL).
  • Adherence to protocol therapy.
  • The components of protocol therapy.

Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.[27,37,38,39] High body mass index is also a risk factor for osteonecrosis [40] and may be associated with a higher relapse rate in older patients.[41]

Table 3. Outcome According to Treatment Protocol for Adolescents and Young Adults with ALL

Site and Study GroupAdolescent 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[29]
CCG (Pediatric)1971667, OS 7 y
CALGB (Adult)1241946
France[35]
FRALLE 93 (Pediatric)771667 EFS
LALA 941001841
Italy[42]
AEIOP (Pediatric)1501580, OS 2 y
GIMEMA (Adult)951671
Netherlands[43]
DCOG (Pediatric)471271 EFS
HOVON442038
Sweden[44]
NOPHO 92 (Pediatric)361674, OS 5 y
Adult ALL991839
United Kingdom[31]
MRC ALL (Pediatric)6115–1771, OS 5 y
UKALL XII (Adult)6715–1756

Treatment options under clinical evaluation for adolescent and young adult patients with ALL

Treatment options under clinical evaluation include the following:

  1. COG-AALL0434 (NCT00408005) (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed T-Cell ALL or T-cell Lymphoblastic Lymphoma): This is a phase III trial for patients aged 1 to 30 years with T-cell ALL utilizing a modified augmented BFM regimen. Patients are classified into one of three risk groups (low, intermediate, or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and MRD level at day 29. The objectives of the trial are (1) to determine the safety and efficacy of adding nelarabine to the modified augmented BFM regimen in high- and intermediate-risk patients, (2) to determine the relative safety and efficacy of high-dose versus Capizzi methotrexate during interim maintenance, and (3) to test the efficacy of treating low-risk T-cell ALL patients without cranial radiation.
  2. OSU-08066 (Combination Chemotherapy in Treating Adult Patients With Newly Diagnosed ALL): DFCI protocol 06-254 (OSU-08066) is a phase II trial conducted by the DFCI ALL Consortium for patients aged 18 to 50 years with newly diagnosed ALL. The treatment regimen is similar to the very high-risk arm on the pediatric DFCI protocol, DFCI-05001, and includes 30 weeks of postinduction consolidation with IV PEG-asparaginase (given every 3 weeks). Older adolescents (aged 15–18 years) are treated on pediatric protocol DFCI-11-001 (NCT01574274) as high-risk patients.
  3. COG-AALL1131 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL): The COG-AALL1131 protocol for patients with high-risk B-precursor ALL includes a randomized comparison of intrathecal triple chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate, with the objective of determining whether intrathecal triple chemotherapy reduces CNS-relapse rates and improves overall EFS. Only patients with CNS3 status at diagnosis will receive cranial radiation (18 Gy). Patients with induction failure or low hypodiploidy are eligible for allogeneic SCT in first remission.

Philadelphia Chromosome–Positive ALL

Treatment options

Prior to use of imatinib mesylate (see below), hematopoietic stem cell transplantation (HSCT) from a matched sibling donor was the treatment of choice for patients with Ph+ ALL.[45,46,47] 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.[48] 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.[49]

Factors significantly associated with favorable prognosis in the pre-imatinib mesylate era included the following:

  • Younger age at diagnosis.[49]
  • Lower leukocyte count at diagnosis.[49]
  • Early response measures.[49,50,51]
  • Ph+ ALL with a rapid morphologic response or rapid peripheral blood response to induction therapy.[49,50]

Following MRD by reverse transcription polymerase chain reaction for the BCR-ABL fusion transcript may also be useful to help predict outcome for Ph+ patients.[52,53,54]

Tyrosine kinase inhibitor therapy

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.[55,56]

Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[57,58,59] Preliminary outcome of results for Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[60,61,62,63]

Evidence (imatinib mesylate):

  1. 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 SCT after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases.[59]
    • The 3-year EFS for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib mesylate is 87.7% ± 10.9%. 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.

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.[64]

Treatment options under clinical evaluation for Philadelphia chromosome–positive ALL

Treatment options under clinical evaluation include the following:

  1. COG-AALL1122 (NCT01460160) (Pediatric Ph+ ALL): In this international collaborative study, patients receive dasatinib, which has increased affinity for BCR/ABL1, in conjunction with a chemotherapy backbone based on the European EsPhALL regimen. Allogeneic SCT in first remission is reserved for those patients with suboptimal early response to therapy, as measured by morphology and MRD techniques. The goals of this study include the following:
    • To determine the safety and feasibility of administering dasatinib with this chemotherapy regimen.
    • To determine the 3-year EFS of patients treated in this manner.
    • To compare outcomes with patients treated on prior trials using similar chemotherapy with imatinib mesylate.

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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