jueves, 31 de octubre de 2019

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) 6/9 –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 Childhood ALL

Standard Postinduction Treatment Options for Childhood ALL

Standard treatment options for consolidation/intensification and maintenance therapy include the following:
  1. Chemotherapy.
Central nervous system (CNS)-directed therapy is provided during premaintenance chemotherapy by all groups. Some protocols (Children’s Oncology Group [COG], St. Jude Children's Research Hospital [SJCRH], and Dana-Farber Cancer Institute [DFCI]) provide ongoing intrathecal chemotherapy during maintenance, while others (Berlin-Frankfurt-Münster [BFM]) do not. (Refer to the CNS-Directed Therapy for Childhood ALL section of this summary for specific information about CNS therapy to prevent CNS relapse in children with acute lymphoblastic leukemia [ALL] who are receiving postinduction therapy.)

Consolidation/intensification therapy

Once complete remission (CR) has been achieved, systemic treatment in conjunction with CNS-directed therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some form of intensification after the achievement of CR and before beginning maintenance therapy.
The most commonly used intensification schema is the BFM backbone. This therapeutic backbone, first introduced by the BFM clinical trials group, includes the following:[1]
  1. An initial consolidation (referred to as induction IB) immediately after the initial induction phase. This phase includes cyclophosphamide, low-dose cytarabine, and mercaptopurine.
    An interim maintenance phase, which includes four doses of high-dose methotrexate (typically 5 g/m2) with leucovorin rescue.
  2. Reinduction (or delayed intensification), which typically includes agents and schedules similar to those used during the induction and initial consolidation phases.
  3. Maintenance, typically consisting of daily mercaptopurine (6-MP), weekly low-dose methotrexate, and sometimes, administration of vincristine and a corticosteroid, as well as continued intrathecal therapy.
This backbone has been adopted by many groups, including the COG. Variation of this backbone includes the following:
  • Intensification for higher-risk patients by including additional doses of vincristine and pegaspargase, as well as repeated interim maintenance and delayed intensification phases.[2,3]
  • The use of escalating doses of methotrexate (starting at a dose of 100 mg/m2) without leucovorin rescue instead of high-dose methotrexate during interim maintenance phases.
  • Elimination or truncation of some of the phases for lower-risk patients to minimize acute and long-term toxicity.
Other clinical trial groups utilize a different therapeutic backbone during postinduction treatment phases:
  • DFCI: The DFCI ALL Consortium protocols include 30 weeks of pegaspargase therapy beginning at week 7 of therapy, given in conjunction with maintenance regimen (vincristine/dexamethasone pulses, weekly low-dose methotrexate, daily mercaptopurine).[4] These protocols also do not include a delayed intensification phase, but high-risk patients receive additional doses of doxorubicin (instead of low-dose methotrexate) during the first six months of postinduction therapy.
  • SJCRH: SJCRH follows a BFM backbone but augments the reinduction and maintenance phases for some patients by including intensified dosing of pegaspargase, frequent vincristine/corticosteroid pulses, and rotating drug pairs during maintenance.[5]
Standard-risk ALL
In children with standard-risk B-ALL, there has been an attempt to limit exposure to drugs such as anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects.[6-8] For regimens utilizing a BFM backbone (such as COG), a single reinduction/delayed intensification phase, given with interim maintenance phases consisting of escalating doses of methotrexate (without leucovorin rescue) and vincristine, have been associated with favorable outcomes.[9] Favorable outcomes for standard-risk patients have also been reported by the Pediatric Oncology Group (POG), utilizing a limited number of courses of intermediate-dose or high-dose methotrexate as consolidation followed by maintenance therapy (without a reinduction phase),[7,10,11] and by the DFCI ALL Consortium utilizing multiple doses of pegaspargase (30 weeks) as consolidation, without postinduction exposure to alkylating agents or anthracyclines.[12,13]
However, the prognostic impact of end-induction and/or consolidation minimal residual disease (MRD) has influenced the treatment of patients originally diagnosed as National Cancer Institute (NCI) standard risk. Multiple studies have demonstrated that higher levels of end-induction MRD are associated with poorer prognosis.[14-18] Augmenting therapy has been shown to improve the outcome in standard-risk patients with elevated MRD levels at the end of induction.[19] Therefore, standard-risk patients with higher levels of end-induction MRD are not treated with the approaches described for standard-risk patients who have low end-induction MRD, but are usually treated with high-risk regimens.
Evidence (intensification for standard-risk ALL):
  1. Clinical trials conducted in the 1980s and early 1990s demonstrated that the use of a delayed intensification phase improved outcome for children with standard-risk ALL treated with regimens using a BFM backbone.[20-22] The delayed intensification phase on such regimens, including those of the COG, consists of an 8-week phase of reinduction (including an anthracycline) and reconsolidation containing cyclophosphamide, cytarabine, and 6-thioguanine given approximately 4 to 6 months after remission is achieved.[20,23,24]
  2. A Children's Cancer Group study (CCG-1991/COG-1991) for standard-risk ALL utilized dexamethasone in a three-drug induction phase and tested the utility of a second delayed intensification phase. This study also compared escalating intravenous (IV) methotrexate (without leucovorin rescue) in conjunction with vincristine versus a standard maintenance combination with oral methotrexate given during two interim maintenance phases.[9][Level of evidence: 1iiDi]
    • A second delayed intensification phase provided no benefit in patients who were rapid early responders (M1 or M2 marrow by day 14 of induction).
    • Escalating IV methotrexate during the interim maintenance phases, compared with oral methotrexate during these phases, produced a significant improvement in event-free survival (EFS), which was because of a decreased incidence of isolated extramedullary relapses, particularly those involving the CNS.
  3. In a randomized study conducted in the United Kingdom, children and young adults with ALL who lacked high-risk features (including adverse cytogenetics, and/or M3 marrow morphology at day 8 or day 15 of induction) were risk-stratified on the basis of MRD level at the end of induction (week 4) and at week 11 of therapy. Patients with undetectable MRD at week 4 (or with low MRD at week 4 and undetectable by week 11) were considered low risk, and were eligible to be randomly assigned to therapy with either one or two delayed intensification phases.[25][Level of evidence: 1iiDi]
    • There was no significant difference in EFS between patients who received one and those who received two delayed intensification phases.
    • There was no significant difference in treatment-related deaths between the two arms; however, the second delayed intensification phase was associated with grade 3 or 4 toxic events in 17% of the 261 patients randomly assigned to that arm, and one patient experienced a treatment-related death during that phase.
  4. In the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) ALL-BFM-2000 (NCT00430118) trial, standard-risk patients (defined as those with undetectable MRD at days 33 and 78 and absence of high-risk cytogenetics) were randomly assigned to receive treatment with a single delayed-intensification phase of either standard intensity or reduced intensity (shorter duration, with reduced total dosages of dexamethasone, vincristine, doxorubicin, and cyclophosphamide).[26]
    • Reduced-intensity delayed intensification was associated with an inferior 8-year disease-free survival (DFS) rate (89% vs. 92%, P = .04), resulting from an increased risk of relapse.
    • In a subset analysis, for patients with the ETV6-RUNX1 fusion, no difference in outcome between the two treatment arms was observed (8-year DFS rate, approximately 94% for both arms).
  5. Patients who are standard or intermediate risk at diagnosis, but have high levels of end-induction MRD, have been shown to have a poorer prognosis and should be treated as high-risk patients. The UKALL2003 (NCT00222612) trial used augmented postinduction therapy (extra doses of pegaspargase and vincristine and an escalated-dose of IV methotrexate without leucovorin rescue) to treat standard- or intermediate-risk patients with high levels of end-induction MRD.[19][Level of evidence: 1iiDi]
    • Augmented postinduction therapy resulted in an increased EFS that was comparable to that of patients with low levels of end-induction MRD.
High-risk ALL
In high-risk patients, a number of different approaches have been used with comparable efficacy.[12,27]; [24][Level of evidence: 2Di] Treatment for high-risk patients is generally more intensive than that for standard-risk patients and typically includes higher cumulative doses of multiple agents, including anthracyclines and/or alkylating agents. Higher doses of these agents increase the risk of both short-term and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens.
Evidence (intensification for high-risk ALL):
  1. The former CCG developed an augmented BFM treatment regimen that included a second interim maintenance and delayed intensification phase. This regimen featured repeated courses of escalating-dose IV methotrexate (without leucovorin rescue) given with vincristine and pegaspargase during interim maintenance and additional vincristine and pegaspargase pulses during initial consolidation and delayed intensification. In the CCG-1882 trial, NCI high-risk patients with slow early response (M3 marrow on day 7 of induction) were randomly assigned to receive either standard- or augmented-BFM therapy.[2]
    • The augmented-therapy regimen in the CCG-1882 trial produced a significantly better EFS than did the standard CCG modified-BFM therapy.
    • There was a significantly higher incidence of osteonecrosis in patients older than 10 years who received the augmented therapy (which included two 21-day postinduction dexamethasone courses), compared with those who were treated on the standard arm (one 21-day postinduction dexamethasone course).[28]
  2. In an Italian study, investigators showed that two applications of delayed intensification therapy (protocol II) significantly improved outcome for patients with a poor response to a prednisone prophase.[29]
  3. The CCG-1961 study used a 2 × 2 factorial design to compare both standard- versus augmented-intensity therapies and therapies of standard duration (one interim maintenance and delayed intensification phase) versus increased duration (two interim maintenance and delayed intensification phases) among NCI high-risk patients with a rapid early response. This trial also tested whether continuous versus alternate-week dexamethasone during delayed intensification phases affected rates of osteonecrosis.
    • Augmented therapy was associated with an improvement in EFS; there was no EFS benefit associated with the administration of the second interim maintenance and delayed intensification phases.[3,30][Level of evidence: 1iiA]
    • The cumulative incidence of osteonecrosis at 5 years was 9.9% for patients aged 10 to 15 years and 20.0% for patients aged 16 to 21 years, compared with 1.0% for patients aged 1 to 9 years (P = .0001). For patients aged 10 to 21 years, alternate-week dosing of dexamethasone during delayed intensification phases was associated with a significantly lower cumulative incidence of osteonecrosis, compared with continuous dosing (8.7% vs. 17.0%, P = .0005).[31][Level of evidence: 1iiC]
  4. In the COG AALL0232 (NCT00075725) study (2004–2011), patients with high-risk B-ALL received an augmented BFM backbone with one interim maintenance and delayed intensification phase; only patients with end-induction MRD greater than 0.1% or M2/M3 marrow at day 15 received two interim maintenance/delayed intensification phases. Patients were randomly assigned to receive either high-dose methotrexate or escalating dose IV methotrexate (Capizzi methotrexate) during the interim maintenance phase (the first phase only for those receiving two of these phases).[32,33]
    • The methotrexate randomization was terminated early when planned interim monitoring indicated that high-dose methotrexate was associated with superior outcome. The 5-year EFS rate of patients randomly assigned to high-dose methotrexate was 79.6%, compared with 75% for those randomly assigned to the Capizzi methotrexate arm. High-dose methotrexate was also associated with a superior 5-year overall survival (OS) (P = .025).[33]
    • Patients with MRD less than 0.01% at end of induction had a 5-year EFS rate of 87%, compared with 74% for those with MRD 0.01% to 0.1%. Those with MRD levels greater than 0.1% fared worse.[32]
    • High-dose methotrexate was associated with a superior EFS rate in patients with end-induction MRD greater than 0.01% (high-dose methotrexate, 68%; Capizzi methotrexate, 58%; P = .008).[32]
Because treatment for high-risk ALL involves more intensive therapy, leading to a higher risk of acute and long-term toxicities, a number of clinical trials have tested interventions to prevent side effects without adversely impacting EFS. Interventions that have been investigated include the use of the cardioprotectant dexrazoxane (to prevent anthracycline-related cardiac toxic effects) and alternative scheduling of corticosteroids (to reduce the risk of osteonecrosis).
Evidence (cardioprotective effect of dexrazoxane):
  1. In a DFCI ALL Consortium trial, children with high-risk ALL were randomly assigned to receive doxorubicin alone (30 mg/m2/dose to a cumulative dose of 300 mg/m2) or the same dose of doxorubicin with dexrazoxane during the induction and intensification phases of multiagent chemotherapy.[34,35]
    • The use of the cardioprotectant dexrazoxane before doxorubicin resulted in better left ventricular fractional shortening and improved end-systolic dimension Z-scores without any adverse effect on EFS or increase in second malignancy risk, compared with the use of doxorubicin alone 5 years posttreatment.
    • A greater long-term protective effect was noted in girls than in boys.
  2. On the POG-9404 trial, patients with T-cell ALL were randomly assigned to receive dexrazoxane or not before each dose of doxorubicin (cumulative dose 360 mg/m2).[36]
    • 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).
    • The frequency of grade 3 and 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.
Evidence (reducing risk of osteonecrosis):
  1. In the CCG-1961 study, alternate-week dosing of dexamethasone during delayed intensification was studied with the goal of reducing the frequency of osteonecrosis.[31] On that protocol, patients with high-risk B-ALL and a rapid early morphologic response to induction therapy were randomly assigned to receive either one or two delayed intensification phases. Patients randomly assigned to one delayed intensification phase received daily dosing of dexamethasone (21 consecutive days), while those randomly assigned to two delayed intensification phases received alternate-week dosing of dexamethasone (days 0–6 and 14–21) during each delayed intensification phase.
    • For patients aged 10 years or older at diagnosis, those who received two delayed intensification phases (alternate-week dosing of dexamethasone) had a significantly lower risk of symptomatic osteonecrosis (5-year cumulative incidence of 8.7%, compared with 17% for patients receiving one delayed intensification phase with continuous dexamethasone dosing; P = .001).
    • 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; the incidence of osteonecrosis with alternative-week dexamethasone was 5.6%, compared with 57.6% for those receiving continuous dosing.
(Refer to the Osteonecrosis section of this summary for more information.)
Very high-risk ALL
Approximately 10% to 20% of patients with ALL are classified as very high risk, including the following:[24,37]
  • Infants younger than 1 year, especially if there is a KMT2A(MLL) gene rearrangement present. (Refer to the Infants With ALL subsection in the Postinduction Treatment for Specific ALL Subgroups section of this summary for more information about infants with ALL.)
  • Patients with adverse cytogenetic abnormalities, including BCR-ABL1 (t(9;22)(q34;q11.2)), TCF3-HLF (t(17;19)), KMT2A gene rearrangements, and low hypodiploidy (<44 chromosomes).
  • Patients who achieve CR but have a slow early response to initial therapy, including those with a high absolute blast count after a 7-day steroid prophase, and patients with high MRD levels at the end of induction (week 4) or later time points (e.g., week 12).
  • Patients who have morphologically persistent disease after the first 4 weeks of therapy (induction failure), even if they later achieve CR.
Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase (usually in addition to the typical BFM backbone intensification phases). These additional cycles often include agents not typically used in frontline ALL regimens for standard-risk and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide.[24] However, even with this intensified approach, reported long-term EFS rates range from 30% to 50% for this patient subset.[24,38]
On some clinical trials, very high-risk patients have also been considered candidates for allogeneic hematopoietic stem cell transplantation (HSCT) in first CR.[38-41] However, there are limited data regarding the outcome of very high-risk patients treated with allogeneic HSCT in first CR. Controversy exists regarding which subpopulations could potentially benefit from HSCT.
Evidence (allogeneic HSCT in first remission for very high-risk patients):
  1. In a European cooperative group study conducted between 1995 and 2000, very high-risk patients (defined as one of the following: morphologically persistent disease after a four-drug induction, t(9;22)(q34;q11.2) or t(4;11)(q21;q23), or poor response to prednisone prophase in patients with either T-cell phenotype or presenting white blood cells [WBC] >100,000/μL) were assigned to receive either an allogeneic HSCT in first CR (based on the availability of a human lymphocyte antigen–matched related donor) or intensive chemotherapy.[38]
    • Using an intent-to-treat analysis, patients assigned to allogeneic HSCT (on the basis of donor availability) had a superior 5-year DFS rate compared with patients assigned to intensive chemotherapy (57% ± 7% for transplant vs. 41% ± 3% for chemotherapy, P = .02)
    • There was no significant difference in OS rates (56% ± 6% for transplant vs. 50% ± 3% for chemotherapy, P = .12).
    • For patients with T-cell ALL and a poor response to prednisone prophase, both DFS and OS rates were significantly better with allogeneic HSCT.[39]
  2. In a large retrospective series of patients with initial induction failure, the 10-year OS rate for patients with persistent leukemia was 32%.[42]
    • A trend for superior outcome with allogeneic HSCT, compared with chemotherapy alone, was observed in patients with T-cell phenotype (any age) and with B-ALL who were older than 6 years.
    • Patients with B-ALL who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (KMT2A rearrangement, BCR-ABL1) had a relatively favorable prognosis, without any advantage in outcome with the utilization of HSCT compared with chemotherapy alone.
  3. The AIEOP ALL-BFM-2000 (NCT00430118) study (2000–2006) classified patients as high risk if they met any of the following criteria: poor response to prednisone prophase, failure to achieve CR at the end of the first month of treatment, high MRD levels after induction IB (day 78 of therapy), and t(4;11)(q21;q23). These patients were allocated to allogeneic HSCT in first CR per protocol on the basis of donor availability and investigator preference.[43][Level of evidence: 2Dii]
    • The overall 5-year EFS rate of patients meeting high-risk criteria was 58.9%.
    • The 5-year EFS rate was 74% for patients whose only high-risk feature was prednisone-poor response; there was no significant difference in DFS (P = .31) or OS (P = .91) when comparing HSCT and chemotherapy for patients with poor prednisone response in whom HSCT was allowed per protocol (those with T-cell ALL and/or WBC ≥100,000/mm3).
    • All other high-risk patients (i.e., those with initial induction failure, high day 78 MRD and/or t(4;11)(q21;q23)) had EFS rates less than 50%. For these patients, there was no statistically significant difference in DFS between those who received HSCT (n = 66) and those who received chemotherapy only (n = 88), after adjusting for waiting time to HSCT (5.7 months).
  4. Two retrospective analyses investigated the role of HSCT in first CR for patients with hypodiploid ALL. The studies showed no clear evidence that HSCT improved outcomes when 1) transplanting all patients with hypodiploid ALL, or 2) transplanting hypodiploid patients deemed at high risk on the basis of high MRD after induction. The studies did not examine the strategy of HSCT for persistent MRD after consolidation, nor did they analyze the status of MRD at the time of HSCT.
    1. In a study of 306 hypodiploid patients from 16 ALL cooperative groups treated between 1997 and 2013, a subgroup of 228 patients (42 who underwent HSCT) with 44 or fewer chromosomes who achieved remission were analyzed.[44][Level of evidence: 3iDiii]
      • Favorable prognostic factors included a chromosome number of 44 (compared with 43 or fewer), MRD less than 0.01% after induction, and treatment on an MRD-stratified protocol that intensified therapy for patients with higher MRD after induction.
      • After correction for median time to transplant, patients with low MRD who underwent HSCT had a DFS rate of 73.6%, compared with a DFS rate of 70% for those treated with chemotherapy alone (P = .81); patients with higher MRD after induction who underwent HSCT had a DFS rate of 55.9%, compared with a DFS rate of 40.3% for those treated with chemotherapy (P = .29).
    2. The COG published an analysis of 113 evaluable patients with hypodiploid ALL who were treated between 2003 and 2011; 61 of those patients underwent HSCT in first CR.[45][Level of evidence: 3iA]
      • The 5-year EFS rate was 57.4% for patients who underwent HSCT and 47.8% for patients in the chemotherapy cohorts (P = .49). The OS rate was 66.2% for patients who underwent HSCT and 53.8% for patients in the chemotherapy cohorts (P = .34).
      • Patients with high MRD after induction (≥0.01%) had a very poor EFS rate of 26.7% at 5 years, with no difference between the patients who received HSCT and the patients who received chemotherapy.

Maintenance therapy

Backbone of maintenance therapy
The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy.[46] Studies conducted by the COG have demonstrated significant differences in compliance with mercaptopurine among various racial and socioeconomic groups. Importantly, nonadherence to treatment with mercaptopurine in the maintenance phase has been associated with a significant increase in the risk of relapse.[46,47]
In the past, clinical practice generally called for the administration of oral mercaptopurine in the evening, on the basis of evidence from older studies that this practice may improve EFS.[48] However, in a study conducted by the Nordic Society for Pediatric Hematology and Oncology (NOPHO) group, in which details of oral intake were prospectively captured, timing of mercaptopurine administration (nighttime vs. other times of day) was not of prognostic significance.[49] In a COG study, taking mercaptopurine at varying times of day rather than consistently at nighttime was associated with higher rates of nonadherence; however, among adherent patients (i.e., those who took >95% of prescribed doses), there was no association between timing of mercaptopurine ingestion and relapse risk.[50]
Some patients may develop severe hematologic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency (homozygous mutant) of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.[51,52] These patients are able to tolerate mercaptopurine only if much lower dosages than those conventionally used are administered.[51,52] Patients who are heterozygous for this mutant enzyme gene generally tolerate mercaptopurine without serious toxicity, but they do require more frequent dose reductions for hematologic toxicity than do patients who are homozygous for the normal allele.[51] Polymorphisms of the NUDT15 gene, observed most frequently in East Asian and Hispanic patients, have also been linked to extreme sensitivity to the myelosuppressive effects of mercaptopurine.[53-55]
Evidence (maintenance therapy):
  1. In a meta-analysis of randomized trials that compared thiopurines, thioguanine did not improve the overall EFS, although particular subgroups may benefit from its use.[56] The use of continuous thioguanine instead of mercaptopurine during the maintenance phase is associated with an increased risk of hepatic complications, including veno-occlusive disease and portal hypertension.[57-61] Because of the increased toxicity of thioguanine, mercaptopurine remains the standard drug of choice.
  2. An intensified maintenance regimen, consisting of rotating pairs of agents, including cyclophosphamide and epipodophyllotoxins along with more standard maintenance agents, has been evaluated in several clinical trials conducted by SJCRH and other groups.[62]
    • The intensified maintenance with rotating pairs of agents has been associated with more episodes of febrile neutropenia [63] and a higher risk of secondary acute myelogenous leukemia,[64,65] especially when epipodophyllotoxins are included.[63]
      On the basis of these findings, SJCRH modified the agents used in the rotating pair schedule during the maintenance phase. On the Total XV study, standard-risk and high-risk patients received three rotating pairs (mercaptopurine plus methotrexate, cyclophosphamide plus cytarabine, and dexamethasone plus vincristine) throughout this treatment phase; low-risk patients received more standard maintenance (without cyclophosphamide and cytarabine).[5]
    • A randomized study from Argentina demonstrated no benefit from this intensified approach compared with a more standard maintenance regimen for patients who receive induction and consolidation phases based on a BFM backbone.[63]
Vincristine/corticosteroid pulses
Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although the benefit of these pulses within the context of contemporary multiagent chemotherapy regimens remains controversial.
Evidence (vincristine/corticosteroid pulses):
  1. A CCG randomized trial conducted in the 1980s demonstrated improved outcome in patients who received monthly vincristine/prednisone pulses.[66]
  2. A meta-analysis combining data from six clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone pulses.[67,68] However, overall EFS from these trials was lower than is observed with more contemporary regimens.
  3. A systematic review of the impact of vincristine plus steroid pulses from more recent clinical trials raised the question of whether such pulses are of value in current ALL treatment, which includes more intensive early therapy and risk stratification incorporating early response (MRD) and biologic factors.[68]
  4. In a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM regimen, there was no benefit associated with the addition of six pulses of vincristine/dexamethasone during the continuation phase, although the pulses were administered less frequently than in other trials in which a benefit had been demonstrated.[69]
  5. A small multicenter trial of average-risk patients demonstrated superior EFS in patients receiving vincristine plus corticosteroid pulses. In this study, there was no difference in outcome based on type of steroid (prednisone vs. dexamethasone).[70][Level of evidence: 1iiA]
For regimens that include vincristine/steroid pulses, a number of studies have addressed which steroid (dexamethasone or prednisone) should be used. From these studies, it appears that dexamethasone is associated with superior EFS, but also may lead to a greater frequency of steroid-associated complications, including bone toxicity and infections, especially in older children and adolescents.[20,71-74] Compared with prednisone, dexamethasone has also been associated with a higher frequency of behavioral problems.[72] In a randomized study of 50 patients aged 3 to 16 years who received maintenance chemotherapy, concurrent administration of hydrocortisone (at physiologic dosing) during dexamethasone pulses reduced the frequency of behavioral difficulties, emotional lability, and sleep disturbances.[75]
Evidence (dexamethasone vs. prednisone):
  1. In a CCG study, dexamethasone was compared with prednisone during the induction and maintenance phases for children aged 1 to younger than 10 years with lower-risk ALL.[20,71]
    • Patients randomly assigned to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate.
  2. In a Medical Research Council (MRC) United Kingdom Acute Lymphoblastic Leukaemia (UKALL) trial, dexamethasone was compared with prednisolone during the induction and maintenance phases in both standard-risk and high-risk patients.[72]
    • The EFS and incidence of both CNS and non-CNS relapses improved with the use of dexamethasone.
    • Dexamethasone was associated with an increased risk of steroid-associated toxicities, including behavioral problems, myopathy, and osteopenia.
  3. In a DFCI ALL Consortium trial, patients were randomly assigned to receive either dexamethasone or prednisone during all postinduction treatment phases.[74]
    • Dexamethasone was associated with a superior EFS, but also with a higher frequency of infections (primarily episodes of bacteremia) and, in patients aged 10 years or older, an increased incidence of osteonecrosis and fracture.
The benefit of using dexamethasone in children aged 10 to 18 years requires further investigation because of the increased risk of steroid-induced osteonecrosis in this age group.[28,73]
Duration of maintenance therapy
Maintenance chemotherapy generally continues for 2 to 3 years of continuous CR. On some studies, boys are treated longer than girls;[20] on others, there is no difference in the duration of treatment based on sex.[12,24] It is not clear whether longer duration of maintenance therapy reduces relapse in boys, especially in the context of current therapies.[24][Level of evidence: 2Di] Extending the duration of maintenance therapy beyond 3 years does not improve outcome.[67]
Adherence to oral medications during maintenance therapy
Nonadherence to treatment with mercaptopurine during maintenance therapy is associated with a significant risk of relapse.[46]
Evidence (adherence to treatment):
  1. The COG studied the impact of nonadherence to mercaptopurine during maintenance therapy in 327 children and adolescents (169 Hispanics and 158 non-Hispanic whites).[46]
    • A progressive increase in relapse was observed with decreasing adherence to mercaptopurine, with hazard ratios (HRs) ranging between 4.0% to 5.7% for adherence rates ranging from 94.9% to 90%, 89.9% to 85%, and less than 85%. After adjusting for other prognostic factors (including NCI risk group and chromosomal abnormalities), a progressive increase in relapse was observed with decreasing adherence to mercaptopurine. MRD data were unavailable in this study population, so they were not included in the analysis of prognostic factors.
    • Adherence was significantly lower among Hispanics, patients older than 12 years, and patients from single-mother households. Among adherent patients, Hispanic ethnicity remained an independent predictor of adverse outcome.
  2. A second study of adherence was conducted in 298 children with ALL (71 Asian Americans, 68 African Americans, and 159 non-Hispanic whites).[47]
    • Using an adherence rate of less than 90% to define nonadherence, 20.5% of the participants were nonadherers.
    • An adherence rate of less than 90% was associated with increased relapse risk (HR, 3.9).
    • Adherence rates were significantly lower in Asian Americans and African Americans than in non-Hispanic whites.
  3. In a third study of 742 children, the following key observations were made:[76]
    • Patients with mercaptopurine nonadherence (defined as mean adherence rate of <95%) were at a 2.7-fold increased risk of relapse compared with adherers.
    • Amongst adherers, high intra-individual variability in thioguanine levels (due to varying dose-intensity and drug treatment interruptions) was associated with increased risk of relapse.
  4. The authors of the above studies also found that self-reporting was not a reliable measure of adherence, with 84% of patients over reporting compliance with taking mercaptopurine at least some of the time.[77] The data suggest that additional measures of adherence besides self-reporting are needed.
  5. In a follow-up study, the above authors explored mercaptopurine ingestion habits, red cell thioguanine nucleotide (TGN) levels, adherence, and relapse risk.[50][Level of evidence: 2Diii]
    • The findings showed that certain ingestion habits (e.g., taking with dairy and taking at varying times throughout the day) were associated with nonadherence. However, after adjusting for adherence and other prognostic factors, ingestion habits were not associated with relapse risk.
    • For adherent patients, there was no association between TGN levels and ingestion habits.
    • The authors conclude that commonly practiced restrictions surrounding mercaptopurine ingestion do not appear to impact outcome but may hinder adherence.

Treatment options under clinical evaluation

Risk-based treatment assignment is a key therapeutic strategy utilized for children with ALL, and protocols are designed for specific patient populations that have varying degrees of risk of treatment failure. The Risk-Based Treatment Assignment section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.
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:
COG studies for B-ALL
Standard-risk ALL
  1. 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 protocol is open for NCI standard-risk B-ALL non-Down syndrome patients and all B-ALL patients with Down syndrome (age <31 years) regardless of presenting WBC. The protocol is testing whether the addition of the bispecific T-cell engaging antibody blinatumomab can improve outcome and whether reducing duration of treatment in boys (from 3 years from the start of interim maintenance 1 phase to 2 years from the start of that phase) does not adversely impact DFS.
    All patients receive a three-drug induction (no anthracycline). After completion of induction, patients are classified into one of three groups on the basis of biology and early response measures:
    • Standard-risk favorable: Presence of either ETV6-RUNX1 or double trisomy (chromosomes 4 and 10), day 8 peripheral blood MRD of <1% and day 29 marrow MRD of <0.01%.
    • Standard-risk average: Favorable biology but day 8 peripheral blood MRD of >1% (but day 29 marrow MRD of <0.01%); or presence of double trisomy and day 29 marrow MRD of ≥0.01% but <0.1%; or neutral cytogenetics with day 29 marrow MRD of <0.01%.
    • Standard-risk high: Presence of ETV6-RUNX1 or neutral cytogenetics and day 29 marrow MRD of ≥0.01%; or presence of double trisomy and day 29 MRD of ≥0.1%; or presence of neutral cytogenetics and CNS2 at diagnosis, regardless of early response measures; or presence of unfavorable cytogenetics (iAMP21, KMT2A rearrangement, hypodiploidy (<44 chromosomes), or TCF3-HLF (t(17;19)).
    Standard-risk favorable patients will be treated with standard therapy.
    All standard-risk average patients will have MRD evaluated at day 29 of induction using high-throughput sequencing (HTS)-MRD assay. HTS-MRD undetectable patients will be treated with standard therapy, while patients with HTS-MRD detectable disease (or if HTS MRD is indeterminate or unavailable), as well as those with double trisomies and day 29 marrow flow MRD of ≥0.01% to <0.1% will be eligible to participate in a randomization of standard therapy or standard therapy plus the addition of two cycles of blinatumomab.
    Standard-risk high patients will be treated with the augmented BFM (NCI high risk) backbone. Any patients with end-consolidation MRD of >1% are removed from protocol therapy. Those with end-consolidation MRD of <0.1% will be eligible to participate in a randomization of either the NCI high-risk backbone alone or this therapy plus two cycles of blinatumomab. Those with end-consolidation MRD of ≥0.1% and <1% will be directly assigned to receive NCI high-risk backbone therapy plus two cycles of blinatumomab.
    NCI standard-risk Down syndrome patients who meet definition of standard-risk average will be treated in the same way as non-Down syndrome standard-risk average patients, as detailed above. All other Down syndrome patients, including NCI high-risk Down syndrome patients, those with unfavorable biology, and those with high day 29 MRD will be considered Down syndrome-high, and will be nonrandomly assigned to receive two cycles of blinatumomab added to a deintensified chemotherapy regimen that omits intensive elements of the augmented BFM treatment backbone. Omitted elements include anthracyclines during induction and cyclophosphamide/cytarabine-based chemotherapy during the second half of delayed intensification.
    All patients, regardless of risk group, will receive the same duration of therapy (2 years from the start of interim maintenance 1 phase). This represents a reduction in treatment duration by 1 year for boys compared with standard treatment.
High-risk and very high-risk ALL
  1. COG-AALL1721 (NCT03876769) (Study of Efficacy and Safety of Tisagenlecleucel in High-Risk B-ALL End-of-Consolidation MRD-Positive Patients): This protocol is open to patients with NCI high-risk B-ALL who are aged 1 to 25 years, were in morphologic CR at end of induction and have end-consolidation MRD of ≥0.01%. The primary objective of the trial is to evaluate the efficacy of tisagenlecleucel (a CD19-directed chimeric antigen receptor [CAR] T cell) as definitive therapy in this patient population, specifically to determine whether the 5-year DFS rate with tisagenlecleucel therapy exceeds 55%.
    Patients enrolled on this trial will undergo leukapheresis to collect autologous T cells, which will then be sent for manufacturing of tisagenlecleucel. While awaiting completion of manufacturing, patients will proceed with interim maintenance phase 1 (high-dose methotrexate); this phase may be interrupted as soon as product is available. Once available, patients will then receive lymphodepleting chemotherapy and infusion of tisagenlecleucel. No further anti-leukemic treatment is to be administered after tisagenlecleucel. Marrow samples will be obtained at regular intervals postinfusion, beginning at day 29 after tisagenlecleucel administration to assess disease status; tests of peripheral blood will also be sent to screen for evidence of B-cell aplasia.
    Patients must have evidence of CD19-positivity at diagnosis to enroll on trial. Patients with M3 marrow at end of induction, M2/M3 marrow at end of consolidation, hypodiploidy (<44 chromosomes), Ph+ ALL, or previous treatment with tyrosine kinase inhibitors are excluded from enrollment.
  2. COG-AALL1521 (NCT02723994) (A Phase 2 Study of Ruxolitinib With Chemotherapy in Children With ALL): This nonrandomized study is testing the addition of ruxolitinib (JAK inhibitor) in combination with the modified augmented BFM regimen (similar to AALL1131) for the treatment of NCI high-risk B-ALL (ages 1–21 years) with any of the following genetic abnormalities: 1) rearranged CRLF2; 2) mutations in JAK1 or JAK2; or 3) other alterations involving the JAK pathway (e.g., JAK2 fusions, EPO-R fusions, SH2B3 deletions, IL7RA mutations). Patients enter the study after completing the induction phase. Ruxolitinib will be administered in conjunction with all postinduction treatment phases. The primary objective is to evaluate the safety, tolerability, and efficacy of the combination.
Other studies
  1. St. Jude Total 17 study (TOT17, NCT03117751) (Combination Chemotherapy in Treating Patients With ALL or Lymphoma):
    This trial has the following four main objectives:
    1. To improve the EFS of provisional standard-risk or high-risk patients with genetically or immunologically targetable lesions or MRD of ≥5% at day 15 or ≥1% at the end of remission induction, by the addition of molecular and immunotherapeutic approaches including tyrosine kinase inhibitors or CAR T cells/blinatumomab for refractory B-ALL patients, and the proteasome inhibitor bortezomib for those lacking targetable lesions.
    2. To improve overall treatment outcome of patients with T-cell ALL by optimizing pegaspargase and cyclophosphamide treatment, by the addition of new agents in patients with targetable genomic abnormalities (e.g., activated tyrosine kinases or JAK/STAT mutations) or by the addition of bortezomib for those who have a poor early response to treatment but no targetable lesions, and by administering nelarabine to T-cell ALL patients with leukemia cells in cerebrospinal fluid at diagnosis or MRD of ≥0.01% at the end of induction.
    3. To examine in a randomized study design whether the administration of two doses of rituximab to children with B-ALL during early remission induction therapy decreases allergic reactions to pegaspargase.
    4. To determine in a randomized study design whether the incidence and/or severity of acute vincristine-induced peripheral neuropathy can be reduced by decreasing the dosage of vincristine in patients with the high-risk CEP72 TT genotype or by shortening the duration of vincristine therapy in patients with the CEP72 CC or CT genotype.
  2. DFCI ALL Consortium 16-001 (NCT03020030) (Risk Classification Schemes in Identifying Better Treatment Options for Children and Adolescents with ALL):
    This trial has the following two main objectives:
    1. To test a novel risk classification scheme for children and adolescents with ALL.
    2. To test the feasibility of administering pegaspargase at a reduced dose during postinduction treatment phases (adjusting doses based on serum asparaginase activity levels), with the goal of maintaining therapeutic serum asparaginase activity levels while potentially reducing nonallergic asparaginase-related toxicities.
    Patients are assigned an initial risk group by day 10 of therapy. Patients are considered initial very high risk if any of the following are present: IKZF1 deletion, KMT2A gene rearrangement, TCF3-HLF fusion (t(17;19)), or low hypodiploidy (<40 chromosomes). Patients are considered initial low risk if they meet all of the following criteria: B-cell ALL, aged 1 year to younger than 15 years, WBC count less than 50 × 109, CNS1 or CNS2, absence of iAMP21, and absence of very high-risk features. Initial high-risk patients include all other patients lacking very high-risk features, including all patients with T-cell ALL.
    Intensity of induction depends on initial risk group. Initial low-risk patients receive a three-drug induction (no anthracycline). All other patients receive a four-drug induction (with an anthracycline).
    Final risk group, which determines the intensity of postinduction therapy, is assigned on the basis of MRD (assessed by next-generation sequencing) at the end of induction (day 32; first time point) and week 10 (second time point).
    • Initial low-risk patients with low MRD (<10-4) at the first time point are considered final low risk. They continue treatment per DFCI standard-risk backbone, including 30 weeks of pegaspargase, without any anthracycline.
    • Initial low-risk patients with high MRD (≥10-4) at the first time point but low MRD (<10-3) at the second time point and all initial high-risk patients with low MRD (<10-3) at the second time point continue treatment per DFCI high-risk backbone, including doxorubicin, but with a reduced dose of dexamethasone compared with previous trials.
    • All patients with very high-risk biology and any initial low-risk/high-risk patient with high MRD (≥10-3) at the second time point are considered very high risk and receive an intensified consolidation phase followed by the DFCI high-risk backbone. Any very high-risk patients identified as having Ph-like ALL (BCR-ABL1–like ALL) with a gene fusion involving a kinase that is sensitive to dasatinib (e.g., ABL1, ABL2, CSF1F, and PDGFRB) will receive dasatinib during all postinduction treatment phases.
    Treatment for all risk groups includes 30 weeks of pegaspargase (15 doses given every 2 weeks) during postinduction therapy. All final low-risk/high-risk patients are eligible to participate in a randomized comparison of postinduction pegaspargase dosing: standard dose (2,500 IU/m2/dose) or pharmacokinetic-adjusted reduced dose (starting dose: 2,000 IU/m2). In all patients, nadir serum asparaginase activity (NSAA) is checked before each pegaspargase dose; any patient found to have a nondetectable NSAA is switched to Erwinia asparaginase. On the pharmacokinetic-adjusted reduced-dose arm, the dose may be decreased further to 1,750 IU/m2 if NSAA is found to be extremely high (>1.0 IU/mL) after the fourth pegaspargase dose; the dose will be increased up to standard dose (2,500 IU/m2) if NSAA is low but detectable (<0.4 IU/mL) at any time point. The trial is also piloting a strategy to rechallenge patients with grade 2 hypersensitivity reactions to pegaspargase with pharmacokinetic-monitoring to determine whether such patients will switch to Erwinia or may continue to receive pegaspargase with premedication.

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.
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