miércoles, 1 de mayo de 2019

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) 7/8 —Health Professional Version - National Cancer Institute

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version

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. 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.[1] However, 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.[2] Another example is the COG trial for T-cell ALL (AALL0434 [NCT00408005]) that resulted in a 5-year event-free survival (EFS) rate of 83.8% and an OS rate of 89.5%.[3]

Treatment options for T-cell ALL

  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.[4]
    • 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).[5] 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.[2,5]
  2. In the POG-9404 study, patients were randomly assigned to doxorubicin with or without dexrazoxane to determine the efficacy of dexrazoxane in preventing late cardiac mortality.[6][Level of evidence: 1iiDi]
    • There was no difference in EFS between patients with T-cell ALL who were treated with dexrazoxane and patients who were not treated with dexrazoxane (cumulative doxorubicin dose, 360 mg/m2).[6]
    • The frequency of grade 3 and grade 4 toxicities that occurred during therapy was similar between the randomized groups, and there was no difference in cumulative incidence of second malignant neoplasms. Three years after initial diagnosis, left ventricular shortening fraction and left ventricular wall thickness were both significantly worse in patients who received doxorubicin alone than in patients who received dexrazoxane, indicating that dexrazoxane was cardioprotective.[6]
    • With combined data from three COG trials that randomized dexrazoxane with doxorubicin therapy (P9404, P9425, and P9426) and had a median follow-up of 12.6 years, dexrazoxane did not appear to compromise long-term survival.[7][Level of evidence: 1iiA]
  3. 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%).[8,9] With this approach, patients with a presenting WBC count greater than 200,000 had similar outcomes to those with a WBC count of less than 200,000.[10][Level of evidence: 1iiDi]
    • Overall results from POG-9404 and CCG-1961 were similar, although POG-9404 used higher cumulative dose of anthracyclines and cranial radiation for every patient, while CCG-1961 used cranial radiation only for patients with slow morphologic response.[9,5]
    • Among children with NCI standard-risk T-cell ALL, the 7-year EFS for those treated on CCG-1952COG-1991 and POG-9404 is comparable with the CCG regimens utilizing significantly less anthracycline in a less intensive chemotherapy backbone without the prophylactic cranial irradiation included in POG-9404.[11]
  4. 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) [12-14] 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.[15]
    • The COG AALL0434 (NCT00408005) trial treated patients with T-cell ALL on an augmented BFM regimen and randomly assigned patients to receive either high-dose methotrexate with leucovorin rescue or escalating methotrexate without leucovorin (Capizzi).[16] Nearly all patients received either prophylactic (12 Gy) or therapeutic (18 Gy) cranial irradiation; only 10% of patients considered to be low risk were not irradiated. Patients assigned to the Capizzi methotrexate arm received cranial radiation earlier than did patients assigned to the high-dose methotrexate arm (week 8 vs. week 26). Patients on the Capizzi methotrexate arm also received two additional doses of pegaspargase. Results indicate a better DFS for patients who were randomly assigned to the Capizzi arm (5-year DFS, 91.5%) than for patients randomly assigned to the high-dose methotrexate arm (5-year DFS, 85.3%; P = .005).[3] Correspondingly, the cumulative incidence of CNS relapse and isolated bone marrow relapse were reduced for patients receiving Capizzi methotrexate (0.4% and 2.2%, respectively) compared with patients receiving high-dose methotrexate (3.0% and 5.9%, respectively).
  5. The use of prophylactic cranial radiation in the treatment of T-cell ALL is declining. 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, and other groups, such as DFCI, COG, and BFM, are now limiting radiation to patients with very high-risk features or CNS3 disease.

Treatment options under clinical evaluation for T-cell ALL

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  1. 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 pegaspargase 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.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Infants With ALL

Infant ALL is uncommon, representing approximately 2% to 4% of cases of childhood ALL.[17] 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.[18-20]
Infants diagnosed within the first few months of life have a particularly poor outcome. In one study, patients diagnosed within 1 month of birth had a 2-year OS rate of 20%.[21][Level of evidence: 2A] In another study, the 5-year EFS for infants diagnosed at younger than 90 days was 16%.[20][Level of evidence: 2A]
For infants with MLL (KMT2A) gene rearrangement, the EFS rates continue to be in the 35% range.[18-20,22][Level of evidence: 2A] Factors predicting poor outcome for infants with MLL rearrangements include the following:[19,20]; [23][Level of evidence: 3iDii]
  • A very young age (≤90 days).
  • Extremely high presenting leukocyte count (≥200,000–300,000/μL).
  • Poor early response, as reflected by a poor response to a prednisone prophase or high levels of MRD at the end of induction and consolidation phases of treatment.
Infants have significantly higher relapse rates than older children with ALL and are at higher risk of developing treatment-related toxicity, especially infection. With current treatment approaches for this population, treatment-related mortality has been reported to occur in about 10% of infants, a rate that is much higher than the rate in older children with ALL.[19,20] On the COG AALL0631 (NCT00557193) trial, an intensified induction regimen resulted in an induction death rate of 15.4% (4 of 26 patients); the trial was subsequently amended to include a less-intensive induction and enhanced supportive care guidelines, resulting in a significantly lower induction death rate (1.6%; 2 of 123 patients) and significantly higher complete remission (CR) rate (94% vs. 68% with the previous, more intensified induction regimen).[24]

Treatment options for infants with MLL (KMT2A) rearrangements

Infants with MLL (KMT2A) gene rearrangements 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 [KMT2A] rearrangements):
  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 (KMT2A) rearrangements.[19]
  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% for infants with MLL rearrangements.[18]
  3. On the COG P9407 (NCT00002756) trial, infants were treated with a shortened (46-week) intensive chemotherapy regimen. The 5-year EFS for infants with MLLrearrangements was 36%.[20][Level of evidence: 2A]
The role of allogeneic hematopoietic stem cell transplant (HSCT) during first remission in infants with MLL (KMT2A) gene rearrangements remains controversial.
Evidence (allogeneic HSCT in first remission for infants with MLL [KMT2A] rearrangements):
  1. On a Japanese clinical trial conducted between 1998 and 2002, all infants with MLL(KMT2A)-rearrangement were intended to proceed to allogeneic HSCT from the best available donor (related, unrelated, or umbilical cord) 3 to 5 months after diagnosis.[25]
    • 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 CR, 11 infants (27%) relapsed before proceeding to transplant.
  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 HSCT in first CR and those who received chemotherapy alone.[26]
  3. The Interfant clinical trials group, after adjusting for waiting time to transplantation, also did not observe any difference in DFS in high-risk infants (defined by prednisone response) with MLL (KMT2A) rearrangements treated on the Interfant-99 trial with either allogeneic HSCT in first CR or chemotherapy alone.[19]
    • In a subset analysis from the same trial, allogeneic HSCT in first remission was associated with a significantly better DFS for infants with MLL rearrangements who were younger than 6 months at diagnosis and had either a poor prednisone response at day 8 or leukocyte counts of at least 300,000/µL.[27] 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.
  4. For infants with ALL who undergo transplantation in first CR, outcomes appear to be similar with non–total-body irradiation (TBI) regimens and TBI-based regimens.[26,28]

Treatment options for infants without MLL (KMT2A) rearrangements

The optimal treatment for infants without MLL (KMT2A) rearrangements also remains unclear.
  1. On the Interfant-99 trial, patients without MLL (KMT2A) rearrangement achieved a relatively favorable outcome with the cytarabine-intensive treatment regimen (4-year EFS was 74%).[19]
  2. The COG P9407 (NCT00002756) trial of intensified chemotherapy reported a 70% 5-year EFS in infants without the MLL rearrangement.[20][Level of evidence: 2A]
  3. 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;[22] however, that study was limited by small numbers (n = 22) and a highly unusual sex distribution (91% males).

Treatment options under clinical evaluation for infants with ALL

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of national and/or institutional clinical trial that is currently being conducted:
  1. AALL15P1 (NCT02828358) (Azacitidine and Combination Chemotherapy in Treating Infants with ALL and KMT2A Gene Rearrangement): This COG protocol is a nonrandomized pilot study that is testing the feasibility of adding azacitidine (a DNA demethylating agent) to the Interfant chemotherapy backbone. Patients younger than 12 months with newly diagnosed B-cell ALL or acute leukemia of ambiguous lineage are eligible for enrollment. Patients begin treatment with a 4-week multiagent induction phase. Following induction, infants without KMT2A (MLL) rearrangements discontinue therapy at the end of the induction phase, while infants with KMT2Arearrangements continue on the study, receiving four 5-day courses of azacitidine therapy, as epigenetic priming, just before each major block of postinduction chemotherapy on the Interfant chemotherapy backbone. The primary objective of this trial is to determine whether azacitidine can be safely incorporated into the Interfant chemotherapy backbone.

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.[29-31] 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+) and BCR-ABL1-like (Ph-like) disease.
  • Lower incidence of favorable cytogenetic abnormalities.
In addition to more frequent adverse prognostic factors, patients in this age group have higher rates of treatment-related mortality [30-33] and nonadherence to therapy.[32,34]

Treatment options

Studies from the United States and France were among the first to identify the difference in outcome based on treatment regimens.[35] Other studies have confirmed that older adolescent and young adult patients fare better on pediatric rather than adult regimens.[35-42]; [43][Level of evidence: 2A] These study results are summarized in Table 5.
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.[31]
Evidence (use of a pediatric treatment regimen for adolescents and young adults with ALL):
  1. The CALGB-10403 (NCT00558519) trial prospectively studied the feasibility and efficacy of using a pediatric treatment regimen (administered by medical oncologists) for adolescent and young adult patients with newly diagnosed ALL. Of the 318 patients enrolled, 295 were eligible and evaluable for response. The median age was 24 years (range, 17–39 years).[44]
    • Use of the pediatric regimen (from the COG AALL0232 study, which included escalating doses of methotrexate without leucovorin followed by asparaginase) was deemed safe, and the overall treatment-related mortality was 3%.
    • The median EFS was 78.1 months, which is more than double the historical control of 30 months. The 3-year EFS rate was 59%, and the median OS was not reached. The estimated 3-year OS rate was 73%.
    • Pretreatment risk factors associated with a worse outcome were obesity and the presence of the Philadelphia-like expression signature. Of the evaluable patients, 31% had a Philadelphia-like fusion; these patients had a significantly worse outcome, with a 3-year EFS rate of 42%, compared with an EFS rate of 69% for patients without the fusion (hazard ratio, 2.06; log-rank P = .008).
  2. 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%.[35]
Other studies have confirmed that older adolescent patients and young adults fare better on pediatric rather than adult regimens (refer to Table 5).[36,38,41,42]; [43][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:[36]
  • Treatment setting (i.e., site experience in treating ALL).
  • Adherence to protocol therapy.
  • The components of protocol therapy.
Table 5. 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.
AIEOP = Associazione Italiana di Ematologia e Oncologia Pediatrica; CALGB = Cancer and Leukemia Group B; CCG = Children's Cancer Group; DCOG = Dutch Childhood Oncology Group; FRALLE = French Acute Lymphoblastic Leukaemia Study Group; GIMEMA = Gruppo Italiano Malattie EMatologiche 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 [35]   
CCG (Pediatric)1971667, OS 7 y
CALGB (Adult)1241946
 
France [40]   
FRALLE 93 (Pediatric)771667 EFS
LALA 941001841
 
Italy [45]   
AIEOP (Pediatric)1501580, OS 2 y
GIMEMA (Adult)951671
 
Netherlands [46]   
DCOG (Pediatric)471271 EFS
HOVON442038
 
Sweden [47]   
NOPHO 92 (Pediatric)361674, OS 5 y
Adult ALL991839
 
United Kingdom[38]   
MRC ALL (Pediatric)6115–1771, OS 5 y
UKALL XII (Adult)6715–1756
UKALL 2003 [48]22916–2472 EFS
Osteonecrosis
Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.[37,49,50] 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.
Evidence (osteonecrosis):
  1. 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.[49]
    • 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%).
  2. In the COG AALL0232 (NCT00075725) high-risk ALL trial, patients were randomly assigned during induction to receive either 14 days of dexamethasone or 28 days of prednisone.[51]
    • The incidence of osteonecrosis in patients older than 10 years who received dexamethasone was 24.3%, compared with an incidence of 15.9% in those receiving prednisone (P = .001)
    • Efficacy and other toxicities were comparable in the two arms.

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

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
  1. A041501 (NCT03150693) (Inotuzumab Ozogamicin and Frontline Chemotherapy in Treating Young Adults With Newly Diagnosed B-cell ALL): This is a National Clinical Trials Network trial to further expand on the experience of using a pediatric-inspired chemotherapy backbone in young adults with ALL. Patients who are in remission after induction will be randomly assigned to receive the pediatric backbone either with or without two courses of inotuzumab ozogamicin (a toxin-conjugated anti-CD22 monoclonal antibody) before starting consolidation therapy.
  2. COG-AALL1131 (NCT01406756) (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk ALL):
    This protocol is open to patients with B-cell ALL who are aged 30 years or younger. Patients on this trial are classified as high risk if they are NCI high risk (by age or WBC) but lack very high-risk features (see below). Patients are classified as very high risk if they meet any of the following criteria:
    1. Age 13 years and older.
    2. CNS3 at diagnosis.
    3. M3 marrow at day 29.
    4. Unfavorable genetics (e.g., iAMP21, low hypodiploidy, MLL [KMT2A] gene rearrangement).
    5. High marrow MRD (>0.01% by flow cytometry) at day 29 (with the exception of NCI standard-risk patients with favorable genetics).
    Non-Down syndrome patients:
    Patients on this trial receive a four-drug induction (vincristine, corticosteroid, daunorubicin, and IV pegaspargase) with intrathecal chemotherapy. Patients younger than 10 years receive 2 weeks of dexamethasone during induction, and those aged 10 years and older receive 4 weeks of prednisone.
    All patients are screened for BCR-ABL1–like ALL; patients who have a gene fusion involving a kinase that is sensitive to dasatinib (e.g., ABL1ABL2CSF1F, and PDGFRB) are assigned to treatment with dasatinib added to standard chemotherapy (modified augmented BFM backbone, including an interim maintenance phase with high-dose methotrexate and one delayed intensification phase). Dasatinib treatment is initiated after induction therapy is complete, and it continues through maintenance therapy.
    For high-risk patients, the study compared triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone) with intrathecal methotrexate in a randomized fashion to determine whether triple intrathecal chemotherapy reduces CNS relapse rates and improves EFS. Interim monitoring revealed that a futility boundary was crossed, indicating that the study would be unable to demonstrate superiority of the triple intrathecal chemotherapy, and the randomization was closed in 2018. Therefore, high-risk patients without dasatinib-sensitive fusions are removed from the study protocol at the end of induction.
    For very high-risk patients, the study had evaluated whether intensification of the consolidation phase and second-half of delayed intensification phases improved DFS. However, that portion of the trial was closed when a futility boundary was crossed, indicating that the study would not be able to demonstrate the superiority of the experimental arm. Therefore, very high-risk patients without dasatinib-sensitive fusions are also removed from protocol treatment; patients with low end-induction MRD are removed at the end of that phase and patients with M3 marrow at day 29 are also removed. Patients with high end-induction MRD (day 29) receive treatment in the consolidation phase, after which MRD is re-assessed and the patient is removed from study treatment.
    Patients who receive induction therapy on AALL1131 and are identified as having a Philadelphia chromosome–like gene expression with a CRLF2 rearrangement or JAK/STAT pathway kinase mutation may have the option of enrolling in the AALL1521 (NCT02723994) study of ruxolitinib therapy. Patients identified as having Philadelphia chromosome–like ALL with a predicted tyrosine kinase inhibitor–sensitive mutation will be eligible to continue on nonrandomized postinduction treatment with dasatinib on the modified BFM interim maintenance high-dose methotrexate backbone.
    Down syndrome patients:
    Down syndrome patients with NCI high-risk ALL are treated with reduced-intensity induction and postinduction therapy regimens to test, in a nonrandomized fashion, whether the modified therapy reduces the risk of treatment-related morbidity and mortality.

Philadelphia Chromosome–positive (BCR-ABL1–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%.[52] 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.[53] Treatment of this subgroup has evolved from emphasis on aggressive chemotherapy, to bone marrow transplantation, and currently to combination therapy using chemotherapy plus a tyrosine kinase inhibitor.

Treatment options

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.[54] 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.[52] 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.[53]
Factors significantly associated with favorable prognosis in the pre-tyrosine kinase inhibitor era included the following:
  • Younger age at diagnosis.[53]
  • Lower leukocyte count at diagnosis.[53]
  • Early response measures.[53,55,56]
  • Ph+ ALL with a rapid morphologic response or rapid peripheral blood response to induction therapy.[53,55]
Following MRD by reverse transcription polymerase chain reaction (PCR) for the BCR-ABL1fusion transcript may also be useful to help predict outcome for Ph+ patients.[57-59]
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.[60,61]
Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[62-64] Outcome of results for Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[65-69] Clinical trials have also demonstrated that many pediatric Ph+ ALL patients can be successfully treated without transplant using a combination of intensive chemotherapy and a tyrosine kinase inhibitor.[69,70]
Dasatinib, a second-generation inhibitor of tyrosine kinases, has also been studied in the 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.[71] 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.[72]
Evidence (tyrosine kinase inhibitor):
  1. 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.[73]
  2. 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.[64,69]
    • The 5-year DFS for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib mesylate was 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. Five-year DFS was 66% for patients undergoing sibling-donor transplant (n = 21) and 59% for those undergoing unrelated donor transplant (n = 13).
    • Patients with additional cytogenetic abnormalities had worse outcomes (P = .05).
  3. The COG-AALL0622 (NCT00720109) study tested the use of dasatinib (instead of imatinib) combined with a chemotherapy backbone similar to that used in COG-AALL0031.[74][Level of evidence: 2A] On this trial, dasatinib was started on day 15 of induction, resulting in higher rates of CR and a higher proportion of patients with low end-induction MRD compared with AALL0031, on which imatinib was not started until after the induction phase was completed.
    • Outcomes in the two trials were similar: 5-year OS was 81% and 86% and 5-year DFS was 68% and 60% for AALL0031 and AALL0622, respectively.
    • Excessive toxicity with dasatinib was not observed.
    • In a subset analysis that included patients who had diagnostic banked samples available, IKZF1 deletion was identified in 57% of patients and was associated with inferior EFS and OS.
  4. The EsPhALL2004 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.[70]
    • 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.
  5. The subsequent EsPhALL2010 (NCT00287105) trial was a result of amendments to the 2004 trial, which included earlier initiation of imatinib therapy at day 15 of induction and continuous dosing of imatinib until the end of therapy or 1 year after transplant. A subsequent amendment in the trial also changed the indication for HSCT in first CR to only the poor-risk patients. This resulted in an increased rate of CR to 97% at the end of induction (from 78% in the previous trial) and fewer patients being allocated to HSCT (38% on amended trial vs. 81% on initial trial).[75]
    • The EFS and OS rates were similar between the amended trial and the initial trial, even though significantly fewer patients received HSCT in first CR on the amended trial.
    • The EsPhALL chemotherapy backbone combined with continuous dosing of imatinib was associated with a high rate of toxicity (primarily infectious) and treatment-related mortality.

Treatment options under clinical evaluation for Ph+ ALL

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
  1. AALL1631 (NCT03007147) (Imatinib Mesylate and Combination Chemotherapy in Treating Patients with Newly Diagnosed Ph+ ALL): AALL1631 is an international collaborative protocol conducted by the COG and the European EsPhALL group. Ph+ ALL patients enter the trial at day 15 of induction IA and begin daily imatinib at that time. After the induction IB phase (weeks 10–12), MRD is assessed by immunoglobulin H/T-cell receptor (IgH-TCR) PCR, and patients are classified as standard risk (MRD <5 × 10-4) or high risk (MRD >5 × 10-4 ). Standard-risk patients are randomly assigned to receive one of the following two cytotoxic chemotherapy backbones:
    • The EsPhALL backbone used in previous EsPhALL protocols and COG AALL1122; or
    • A less-intensive regimen similar to those typically administered to non-Ph+ high-risk B-cell ALL patients on COG trials.
    Standard-risk patients on both arms will continue to receive imatinib until the completion of all planned chemotherapy (2 years of treatment). The objective of the standard-risk randomization is to determine whether the less-intensive chemotherapy backbone is associated with a similar DFS but lower rates of treatment-related toxicity compared with the standard therapy (EsPhALL chemotherapy backbone).
    High-risk patients (approximately 15%–20% of patients) will proceed to HSCT after completion of three consolidation blocks of chemotherapy. Imatinib will be restarted after HSCT and administered from day +56 until day +365 to test the feasibility of post-HSCT administration of this agent and describe the outcome of patients treated in this manner.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
References
  1. Hunger SP, Lu X, Devidas M, et al.: Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol 30 (14): 1663-9, 2012. [PUBMED Abstract]
  2. Silverman LB, Stevenson KE, O'Brien JE, et al.: Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000). Leukemia 24 (2): 320-34, 2010. [PUBMED Abstract]
  3. Winter SS, Dunsmore KP, Devidas M, et al.: Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia: Results From the Children's Oncology Group AALL0434 Methotrexate Randomization. J Clin Oncol 36 (29): 2926-2934, 2018. [PUBMED Abstract]
  4. LeClerc JM, Billett AL, Gelber RD, et al.: Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber ALL Consortium Protocol 87-01. J Clin Oncol 20 (1): 237-46, 2002. [PUBMED Abstract]
  5. 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]
  6. Asselin BL, Devidas M, Chen L, et al.: Cardioprotection and Safety of Dexrazoxane in Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children's Oncology Group Randomized Trial Pediatric Oncology Group 9404. J Clin Oncol 34 (8): 854-62, 2016. [PUBMED Abstract]
  7. Chow EJ, Asselin BL, Schwartz CL, et al.: Late Mortality After Dexrazoxane Treatment: A Report From the Children's Oncology Group. J Clin Oncol 33 (24): 2639-45, 2015. [PUBMED Abstract]
  8. Seibel NL, Asselin BL, Nachman JB, et al.: Treatment of high risk T-cell acute lymphoblastic leukemia (T-ALL): comparison of recent experience of the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG). [Abstract] Blood 104 (11): A-681, 2004.
  9. Seibel NL, Steinherz PG, Sather HN, et al.: Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 111 (5): 2548-55, 2008. [PUBMED Abstract]
  10. Hastings C, Gaynon PS, Nachman JB, et al.: Increased post-induction intensification improves outcome in children and adolescents with a markedly elevated white blood cell count (≥200 × 10(9) /l) with T cell acute lymphoblastic leukaemia but not B cell disease: a report from the Children's Oncology Group. Br J Haematol 168 (4): 533-46, 2015. [PUBMED Abstract]
  11. Matloub Y, Stork L, Asselin B, et al.: Outcome of Children with Standard-Risk T-Lineage Acute Lymphoblastic Leukemia--Comparison among Different Treatment Strategies. Pediatr Blood Cancer 63 (2): 255-61, 2016. [PUBMED Abstract]
  12. Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol 23 (15): 3376-82, 2005. [PUBMED Abstract]
  13. Kurtzberg J, Ernst TJ, Keating MJ, et al.: Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol 23 (15): 3396-403, 2005. [PUBMED Abstract]
  14. Winter SS, Dunsmore KP, Devidas M, et al.: Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer 62 (7): 1176-83, 2015. [PUBMED Abstract]
  15. Dunsmore KP, Devidas M, Linda SB, et al.: Pilot study of nelarabine in combination with intensive chemotherapy in high-risk T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. J Clin Oncol 30 (22): 2753-9, 2012. [PUBMED Abstract]
  16. Winter SS, Devidas M, Chen S, et al.: Capizzi-Style methotrexate with pegasparagase (C-MTX) is superior to high-dose methotrexate (HDMTX) in t-lineage acute lymphoblastic leukemia (T-ALL): results from Children's Oncology Group (COG) AALL0434. [Abstract] Blood 126 (23): A-794, 2015. Also available online. Last accessed January 31, 2019.
  17. Silverman LB: Acute lymphoblastic leukemia in infancy. Pediatr Blood Cancer 49 (7 Suppl): 1070-3, 2007. [PUBMED Abstract]
  18. Hilden JM, Dinndorf PA, Meerbaum SO, et al.: Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood 108 (2): 441-51, 2006. [PUBMED Abstract]
  19. Pieters R, Schrappe M, De Lorenzo P, et al.: A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 370 (9583): 240-50, 2007. [PUBMED Abstract]
  20. Dreyer ZE, Hilden JM, Jones TL, et al.: Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer 62 (3): 419-26, 2015. [PUBMED Abstract]
  21. 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]
  22. Tomizawa D, Koh K, Sato T, et al.: Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia 21 (11): 2258-63, 2007. [PUBMED Abstract]
  23. Van der Velden VH, Corral L, Valsecchi MG, et al.: Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia 23 (6): 1073-9, 2009. [PUBMED Abstract]
  24. Salzer WL, Jones TL, Devidas M, et al.: Decreased induction morbidity and mortality following modification to induction therapy in infants with acute lymphoblastic leukemia enrolled on AALL0631: a report from the Children's Oncology Group. Pediatr Blood Cancer 62 (3): 414-8, 2015. [PUBMED Abstract]
  25. Kosaka Y, Koh K, Kinukawa N, et al.: Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 104 (12): 3527-34, 2004. [PUBMED Abstract]
  26. Dreyer ZE, Dinndorf PA, Camitta B, et al.: Analysis of the role of hematopoietic stem-cell transplantation in infants with acute lymphoblastic leukemia in first remission and MLL gene rearrangements: a report from the Children's Oncology Group. J Clin Oncol 29 (2): 214-22, 2011. [PUBMED Abstract]
  27. Mann G, Attarbaschi A, Schrappe M, et al.: Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study. Blood 116 (15): 2644-50, 2010. [PUBMED Abstract]
  28. Kato M, Hasegawa D, Koh K, et al.: Allogeneic haematopoietic stem cell transplantation for infant acute lymphoblastic leukaemia with KMT2A (MLL) rearrangements: a retrospective study from the paediatric acute lymphoblastic leukaemia working group of the Japan Society for Haematopoietic Cell Transplantation. Br J Haematol 168 (4): 564-70, 2015. [PUBMED Abstract]
  29. Nachman J: Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia. Br J Haematol 130 (2): 166-73, 2005. [PUBMED Abstract]
  30. Pui CH, Pei D, Campana D, et al.: Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol 29 (4): 386-91, 2011. [PUBMED Abstract]
  31. Nachman JB, La MK, Hunger SP, et al.: Young adults with acute lymphoblastic leukemia have an excellent outcome with chemotherapy alone and benefit from intensive postinduction treatment: a report from the children's oncology group. J Clin Oncol 27 (31): 5189-94, 2009. [PUBMED Abstract]
  32. Pichler H, Reismüller B, Steiner M, et al.: The inferior prognosis of adolescents with acute lymphoblastic leukaemia (ALL) is caused by a higher rate of treatment-related mortality and not an increased relapse rate--a population-based analysis of 25 years of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group. Br J Haematol 161 (4): 556-65, 2013. [PUBMED Abstract]
  33. Burke MJ, Gossai N, Wagner JE, et al.: Survival differences between adolescents/young adults and children with B precursor acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 19 (1): 138-42, 2013. [PUBMED Abstract]
  34. Bhatia S, Landier W, Shangguan M, et al.: Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children's oncology group. J Clin Oncol 30 (17): 2094-101, 2012. [PUBMED Abstract]
  35. Stock W, La M, Sanford B, et al.: What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 112 (5): 1646-54, 2008. [PUBMED Abstract]
  36. Ramanujachar R, Richards S, Hann I, et al.: Adolescents with acute lymphoblastic leukaemia: emerging from the shadow of paediatric and adult treatment protocols. Pediatr Blood Cancer 47 (6): 748-56, 2006. [PUBMED Abstract]
  37. Barry E, DeAngelo DJ, Neuberg D, et al.: Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols. J Clin Oncol 25 (7): 813-9, 2007. [PUBMED Abstract]
  38. Ramanujachar R, Richards S, Hann I, et al.: Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer 48 (3): 254-61, 2007. [PUBMED Abstract]
  39. Ram R, Wolach O, Vidal L, et al.: Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol 87 (5): 472-8, 2012. [PUBMED Abstract]
  40. Boissel N, Auclerc MF, Lhéritier V, et al.: Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 21 (5): 774-80, 2003. [PUBMED Abstract]
  41. Huguet F, Leguay T, Raffoux E, et al.: Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 27 (6): 911-8, 2009. [PUBMED Abstract]
  42. DeAngelo DJ, Stevenson KE, Dahlberg SE, et al.: Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia. Leukemia 29 (3): 526-34, 2015. [PUBMED Abstract]
  43. Ribera JM, Oriol A, Sanz MA, et al.: Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Español de Tratamiento en Hematología pediatric-based protocol ALL-96. J Clin Oncol 26 (11): 1843-9, 2008. [PUBMED Abstract]
  44. Stock W, Luger SM, Advani AS, et al.: A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood : , 2019. [PUBMED Abstract]
  45. Testi AM, Valsecchi MG, Conter V, et al.: Difference in outcome of adolescents with acute lymphoblastic leukemia (ALL) enrolled in pediatric (AIEOP) and adult (GIMEMA) protocols. [Abstract] Blood 104: A-1954, 2004.
  46. de Bont JM, van der Holt B, Dekker AW, et al.: [Adolescents with acute lymphatic leukaemia achieve significantly better results when treated following Dutch paediatric oncology protocols than with adult protocols]. Ned Tijdschr Geneeskd 149 (8): 400-6, 2005. [PUBMED Abstract]
  47. Hallböök H, Gustafsson G, Smedmyr B, et al.: Treatment outcome in young adults and children >10 years of age with acute lymphoblastic leukemia in Sweden: a comparison between a pediatric protocol and an adult protocol. Cancer 107 (7): 1551-61, 2006. [PUBMED Abstract]
  48. Hough R, Rowntree C, Goulden N, et al.: Efficacy and toxicity of a paediatric protocol in teenagers and young adults with Philadelphia chromosome negative acute lymphoblastic leukaemia: results from UKALL 2003. Br J Haematol 172 (3): 439-51, 2016. [PUBMED Abstract]
  49. Mattano LA Jr, Devidas M, Nachman JB, et al.: Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol 13 (9): 906-15, 2012. [PUBMED Abstract]
  50. Mogensen SS, Harila-Saari A, Mäkitie O, et al.: Comparing osteonecrosis clinical phenotype, timing, and risk factors in children and young adults treated for acute lymphoblastic leukemia. Pediatr Blood Cancer : e27300, 2018. [PUBMED Abstract]
  51. Larsen EC, Devidas M, Chen S, et al.: Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group Study AALL0232. J Clin Oncol 34 (20): 2380-8, 2016. [PUBMED Abstract]
  52. Aricò M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 342 (14): 998-1006, 2000. [PUBMED Abstract]
  53. Aricò M, Schrappe M, Hunger SP, et al.: Clinical outcome of children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia treated between 1995 and 2005. J Clin Oncol 28 (31): 4755-61, 2010. [PUBMED Abstract]
  54. Hahn T, Wall D, Camitta B, et al.: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 11 (11): 823-61, 2005. [PUBMED Abstract]
  55. Roy A, Bradburn M, Moorman AV, et al.: Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial. Br J Haematol 129 (1): 35-44, 2005. [PUBMED Abstract]
  56. Schrappe M, Aricò M, Harbott J, et al.: Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood 92 (8): 2730-41, 1998. [PUBMED Abstract]
  57. Cazzaniga G, Lanciotti M, Rossi V, et al.: Prospective molecular monitoring of BCR/ABL transcript in children with Ph+ acute lymphoblastic leukaemia unravels differences in treatment response. Br J Haematol 119 (2): 445-53, 2002. [PUBMED Abstract]
  58. Jones LK, Saha V: Philadelphia positive acute lymphoblastic leukaemia of childhood. Br J Haematol 130 (4): 489-500, 2005. [PUBMED Abstract]
  59. Lee S, Kim YJ, Chung NG, et al.: The extent of minimal residual disease reduction after the first 4-week imatinib therapy determines outcome of allogeneic stem cell transplantation in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer 115 (3): 561-70, 2009. [PUBMED Abstract]
  60. Champagne MA, Capdeville R, Krailo M, et al.: Imatinib mesylate (STI571) for treatment of children with Philadelphia chromosome-positive leukemia: results from a Children's Oncology Group phase 1 study. Blood 104 (9): 2655-60, 2004. [PUBMED Abstract]
  61. Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100 (6): 1965-71, 2002. [PUBMED Abstract]
  62. Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103 (12): 4396-407, 2004. [PUBMED Abstract]
  63. Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 24 (3): 460-6, 2006. [PUBMED Abstract]
  64. Schultz KR, Bowman WP, Aledo A, et al.: Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol 27 (31): 5175-81, 2009. [PUBMED Abstract]
  65. Burke MJ, Trotz B, Luo X, et al.: Allo-hematopoietic cell transplantation for Ph chromosome-positive ALL: impact of imatinib on relapse and survival. Bone Marrow Transplant 43 (2): 107-13, 2009. [PUBMED Abstract]
  66. Lee S, Kim YJ, Min CK, et al.: The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 105 (9): 3449-57, 2005. [PUBMED Abstract]
  67. de Labarthe A, Rousselot P, Huguet-Rigal F, et al.: Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood 109 (4): 1408-13, 2007. [PUBMED Abstract]
  68. Rives S, Estella J, Gómez P, et al.: Intermediate dose of imatinib in combination with chemotherapy followed by allogeneic stem cell transplantation improves early outcome in paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL): results of the Spanish Cooperative Group SHOP studies ALL-94, ALL-99 and ALL-2005. Br J Haematol 154 (5): 600-11, 2011. [PUBMED Abstract]
  69. Schultz KR, Carroll A, Heerema NA, et al.: Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031. Leukemia 28 (7): 1467-71, 2014. [PUBMED Abstract]
  70. Biondi A, Schrappe M, De Lorenzo P, et al.: Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol 13 (9): 936-45, 2012. [PUBMED Abstract]
  71. Porkka K, Koskenvesa P, Lundán T, et al.: Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood 112 (4): 1005-12, 2008. [PUBMED Abstract]
  72. Zwaan CM, Rizzari C, Mechinaud F, et al.: Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium. J Clin Oncol 31 (19): 2460-8, 2013. [PUBMED Abstract]
  73. Jeha S, Coustan-Smith E, Pei D, et al.: Impact of tyrosine kinase inhibitors on minimal residual disease and outcome in childhood Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer 120 (10): 1514-9, 2014. [PUBMED Abstract]
  74. Slayton WB, Schultz KR, Kairalla JA, et al.: Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0622. J Clin Oncol : JCO2017767228, 2018. [PUBMED Abstract]
  75. Biondi A, Gandemer V, De Lorenzo P, et al.: Imatinib treatment of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (EsPhALL2010): a prospective, intergroup, open-label, single-arm clinical trial. Lancet Haematol 5 (12): e641-e652, 2018. [PUBMED Abstract]

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