jueves, 31 de octubre de 2019

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) 8/9 –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 B-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 B-ALL. For example, the 10-year overall survival (OS) rate 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-ALL.[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-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]
    • This POG study was the first clinical trial to provide evidence that high-dose methotrexate can improve outcome for children with T-cell ALL (10-year EFS rates, 78% with high-dose methotrexate vs. 68% without high-dose methotrexate). 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 receive 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. On protocols of the former Children’s Cancer Group (CCG), children with T-cell ALL received the same treatment regimens as did children with B-ALL; protocol and treatment assignment were based 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 the CCG-1961 trial for high-risk ALL, which included patients with 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 rate, 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 a higher cumulative dose of anthracyclines and cranial radiation therapy for every patient, while CCG-1961 used cranial radiation therapy only for patients with slow morphologic response.[9,5]
    • Among children with NCI standard-risk T-cell ALL, the 7-year EFS rates for those treated on CCG-1952, COG-1991, and POG-9404 is comparable with the CCG regimens that used 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 B-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 who received 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).[3] 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 therapy 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. The overall 5-year EFS rate was 83.8%, and the OS rate was 89.5%. Results indicate a better DFS for patients who were randomly assigned to the Capizzi arm (5-year DFS rate, 91.5%) than for patients randomly assigned to the high-dose methotrexate arm (5-year DFS rate, 85.3%; P = .005).[3] Correspondingly, the cumulative incidence of central nervous system (CNS) relapse and isolated bone marrow relapse were reduced for patients who received Capizzi methotrexate (0.4% and 2.2%, respectively) compared with patients who received high-dose methotrexate (3.0% and 5.9%, respectively).
  5. The use of prophylactic cranial radiation therapy in the treatment of patients with 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 therapy in first-line treatment of ALL, and other groups, such as DFCI, COG, and BFM, are now limiting radiation therapy 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.

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.[16] 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.[17-19]
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%.[20][Level of evidence: 2A] In another study, the 5-year EFS rate for infants diagnosed at younger than 90 days was 16%.[19][Level of evidence: 2A]
For infants with KMT2A (MLL) gene rearrangements, the EFS rates at 4 to 5 years continue to be in the 35% range.[17-19,21][Level of evidence: 2A] Factors predicting poor outcome for infants with KMT2A rearrangements include the following:[18,19]; [22][Level of evidence: 3iDii]; [23][Level of evidence: 2A]
  • 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.[18,19] 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 KMT2A rearrangements

Infants with 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 KMT2A rearrangements):
  1. The international Interfant trial 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 rate of 37% for infants with KMT2A rearrangements.[18]
  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 rate of 34% for infants with KMT2A rearrangements.[17]
  3. On the COG P9407 (NCT00002756) trial, infants were treated with a shortened (46-week) intensive chemotherapy regimen. The 5-year EFS rate for infants with KMT2A rearrangements was 36%.[19][Level of evidence: 2A]
  4. The international Interfant-06 study tested whether acute myeloid leukemia (AML)-style consolidation chemotherapy was superior to ALL-style chemotherapy.[23][Level of evidence: 2A]
    • The 6-year EFS rate was 46.1%, and the OS rate was 58.2%; these rates were not statistically different from the rates observed in the predecessor Interfant-99 protocol.
    • For infants with KMT2A rearrangements, the 6-year EFS rate was 36.4%, with no significant difference between the AML and ALL approach.
The role of allogeneic hematopoietic stem cell transplant (HSCT) during first remission in infants with KMT2A gene rearrangements remains controversial.
Evidence (allogeneic HSCT in first remission for infants with KMT2A rearrangements):
  1. On a Japanese clinical trial conducted between 1998 and 2002, all infants with KMT2A rearrangements 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 rate for all enrolled infants was 44%. This outcome resulted, in part, from the high frequency of early relapses, even with intensive chemotherapy; of the 41 infants with KMT2A rearrangements 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 KMT2A rearrangements treated on the Interfant-99 trial with either allogeneic HSCT in first CR or chemotherapy alone.[18]
    • In a subset analysis from the same trial, allogeneic HSCT in first remission was associated with a significantly better DFS for infants with KMT2A 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. On the Interfant-06 study, infants considered to be high risk (all of the following: KMT2A rearrangements, age <6 months, and WBC ≥300,000/μL) were considered eligible for allogeneic HSCT in first CR.[23][Level of evidence: 2A]
    • About one-half of the high-risk patients did not proceed to transplant in the first CR primarily because of early relapse.
    • The 6-year EFS rate of the entire high-risk group was 21%.
    • For the highly-selected population who were transplanted, the 4-year DFS rate was 44%.
  5. 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 KMT2A rearrangements

The optimal treatment for infants without KMT2A rearrangements also remains unclear, in part because of the paucity of data on the use of standard ALL regimens used in older children.
  1. On the Interfant-99 trial, patients without KMT2A rearrangements achieved a relatively favorable outcome with the cytarabine-intensive treatment regimen (4-year EFS rate was 74%).[18]
  2. The COG P9407 (NCT00002756) trial of intensified chemotherapy reported a 70% 5-year EFS rate in infants without the KMT2A rearrangement.[19][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;[21] however, that study was limited by small numbers (n = 22) and a highly unusual sex distribution (91% males).
  4. On the Interfant-06 study, the 6-year EFS rate for infants without KMT2A rearrangements was 73.9%, and the OS rate was 87.2%.[23][Level of evidence: 2A]

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 rearrangements discontinue therapy at the end of the induction phase, while infants with KMT2A rearrangements 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 Ph-like (BCR-ABL1-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 11.
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 Ph-like expression signature. Of the evaluable patients, 31% had a Ph-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 rate 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 rate of 34%.[35]
  3. In a Canadian population-based cohort study, the effect of adapting pediatric protocols for adolescent and young adult patients with ALL was determined over a 20-year period.[45]
    • The 5-year EFS rate of adolescent and young adult patients treated at pediatric centers was 72%, compared with an EFS rate of 56% for adolescent and young adult patients treated at adult centers (P = .03).
    • In the most recent period (2006–2011), the outcome of adolescent and young adult patients treated at adult centers with pediatric protocols was superior to those treated with adult protocols (EFS rate, 72% vs. 60%), but inferior to adolescent and young adult patients treated at pediatric centers (EFS rate, 81%; P = .02).
    • The authors conclude that besides protocol therapy, there may be other differences between adult and pediatric centers that may explain the disparate outcomes.
Other studies have confirmed that older adolescent patients and young adults fare better on pediatric rather than adult regimens (refer to Table 11).[36,38,41,42,46]; [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.[34]
  • The components of protocol therapy.
Table 11. 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 [47]   
AIEOP (Pediatric)1501580, OS 2 y
GIMEMA (Adult)951671
 
Netherlands [48]   
DCOG (Pediatric)471271 EFS
HOVON442038
 
Sweden [49]   
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 [50]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.[37,51,52] 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 were needed for management of symptoms and impaired mobility in more than 40% of cases. Most cases are diagnosed within the first 2 years of therapy and the symptoms are often 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 determine whether the osteonecrosis risk could be reduced.[51]
    • 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.[53]
    • 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 who received 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. Eligibility includes patients aged 18 to 39 years with newly diagnosed CD22-positive 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-AALL1521 (NCT02723994) (A Phase II Study of Ruxolitinib With Chemotherapy in Children With ALL): This is a nonrandomized study of ruxolitinib in combination with a standard multiagent chemotherapy regimen for the treatment of B-ALL. Part 1 of the study will optimize the dose of study drug (ruxolitinib) in combination with the chemotherapy regimen. Part 2 will evaluate the efficacy of combination chemotherapy and ruxolitinib at the recommended dose determined in part 1.
  3. COG-AALL1721 (NCT03876769) (Study of Efficacy and Safety of Tisagenlecleucel in High-Risk B-ALL End-of-Consolidation MRD-Positive Patients): The objective of the study is to evaluate the efficacy of CD19 chimeric antigen receptor (CAR) T-cell therapy (tisagenlecleucel) in patients who are MRD positive at the end of consolidation by measuring 5-year EFS. Other objectives include assessing proportion of subjects who are disease free without allogeneic transplant at 1 year, OS, and proportion of subjects who achieve MRD-negative CR or CRI at 3 months after tisagenlecleucel.
  4. COG-AALL1731 (NCT03914625) (A Study to Determine the Outcomes of Patients With Localized B-Cell Lymphoblastic Lymphoma When Treated With Standard-Risk B-ALL Therapy): This study will test whether the addition of blinatumomab to standard chemotherapy will improve DFS. For the re-eligibility of adolescent and young adult patients, patients must be older than 365 days and younger than 31 years with Down syndrome. Patients with Down syndrome and high-risk features will be nonrandomly assigned to receive blinatumomab added to a chemotherapy backbone that omits intensive elements of therapy. Patients with Down syndrome without high-risk features will be eligible for randomization to chemotherapy with or without blinatumomab. Patients with Murphy stage I and stage II B-cell lymphoblastic lymphoma will receive standard B-ALL therapy without blinatumomab.

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 a poor outcome. In 2000, an international pediatric leukemia group reported a 7-year EFS rate of 25%, with an OS rate of 36%.[54] In 2010, the same group reported a 7-year EFS rate of 31% and an OS rate of 44% in Ph+ ALL patients treated without tyrosine kinase inhibitors.[55] 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

Standard therapy for patients with Ph+ ALL includes the use of a tyrosine kinase inhibitor (e.g., imatinib or dasatinib) in combination with cytotoxic chemotherapy, with or without allogeneic HSCT in first CR.
Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and phase 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.[56,57]
Clinical trials in adults and children with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[58-60] Outcome of results for patients with Ph+ ALL demonstrated a better outcome after HSCT if imatinib was given before or after transplant.[61-65] Clinical trials have also demonstrated that many pediatric patients with Ph+ ALL will have a comparable EFS using chemotherapy and a tyrosine kinase inhibitor than with transplant.[65,66]
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.[67] 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 grade 4 adverse events.[68]
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 midinduction, are associated with lower end-induction MRD.[69]
  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.[60,65]
    • The 5-year DFS rate for the 25 patients who received intensive chemotherapy with continuous dosing of imatinib mesylate was 70% (± 12%). These patients fared better than historic controls who were treated with chemotherapy alone (without imatinib mesylate), and at least as well as the other patients on the trial who underwent allogeneic transplantation. The 5-year DFS rate was 66% for patients who underwent sibling-donor transplant (n = 21) and 59% for those who underwent 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.[70][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: the 5-year OS rates were 81% and 86%, and the 5-year DFS rates were 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 on the basis of early response measures and remission status at the end of induction. Good-risk patients (n = 90) were randomly assigned to receive imatinib or no imatinib; poor-risk patients (n = 70) were directly assigned to treatment with imatinib. Interpretation of this study is limited because of the high noncompliance rate with randomized assignment in good-risk patients and early closure before reaching goal accrual because of the publication of the results of the COG AALL0031 trial on which imatinib had been given continuously with chemotherapy.[66]
    • 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.[71]
  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).[72]
    • 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 infections) 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
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