Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) 4/5 —Health Professional Version - National Cancer Institute

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

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

Treatment Option Overview for Childhood ALL

In This Section

• Special Considerations for the Treatment of Children With Cancer
• Phases of Therapy
• Sanctuary Sites
  • Central nervous system (CNS)
  • Testes

Special Considerations for the Treatment of Children With Cancer

Because treatment of children with ALL entails complicated risk assignment and therapies and the need for intensive supportive care (e.g., transfusions; management of infectious complications; and emotional, financial, and developmental support), evaluation and treatment are best coordinated by a multidisciplinary team in cancer centers or hospitals with all of the necessary pediatric supportive care facilities. [1] A multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgical subspecialists.
• Radiation oncologists.
• Pediatric medical oncologists/hematologists.
• Rehabilitation specialists.
• Pediatric nurse specialists.
• Social workers.
• Child life professionals.
• Psychologists.

Guidelines for cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1] Treatment of childhood ALL typically involves chemotherapy given for 2 to 3 years. Because myelosuppression and generalized immunosuppression are anticipated consequences of leukemia and chemotherapy treatment, adequate facilities must be immediately available both for hematologic support and for the treatment of infections and other complications throughout all phases of therapy. Approximately 1% to 3% of patients die during induction therapy and another 1% to 3% die during the initial remission from treatment-related complications.[2-5] It is important that the clinical centers and the specialists directing the patient’s care maintain contact with the referring physician in the community. Strong lines of communication optimize any urgent or interim care required when the child is at home.

Clinical trials are generally available for children with ALL, with specific protocols designed for children at standard (low) risk of treatment failure and for children at higher risk of treatment failure. Clinical trials for children with ALL are generally designed to compare therapy that is currently accepted as standard for a particular risk group with a potentially better treatment approach that may improve survival outcome and/or diminish toxicities associated with the standard treatment regimen. Many of the therapeutic innovations that produced increased survival rates in children with ALL were established through clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial.

Risk-based treatment assignment is an important therapeutic strategy utilized for children with ALL. This approach allows children who historically have a very good outcome to be treated with less intensive therapy and to be spared more toxic treatments, while allowing children with a historically lower probability of long-term survival to receive more intensive therapy that may increase their chance of cure. (Refer to the Risk-Based Treatment Assignment section of this summary for more information about a number of clinical and laboratory features that have demonstrated prognostic value.)

Phases of Therapy

Treatment for children with ALL is typically divided as follows:

1. Remission induction (at the time of diagnosis).
2. Postinduction therapy (after achieving complete remission).
   • Consolidation/intensification therapy.
   • Maintenance or continuation therapy.

Sanctuary Sites

Historically, certain extramedullary sites have been considered sanctuary sites (i.e., anatomic spaces that are poorly penetrated by many of the orally and intravenously administered chemotherapy agents typically used to treat ALL). The two most important sanctuary sites in childhood ALL are the central nervous system (CNS) and the testes. Successful treatment of ALL requires therapy that effectively addresses clinical or subclinical involvement of leukemia in these extramedullary sanctuary sites.

Central nervous system (CNS)

At diagnosis, approximately 3% of patients have CNS3 disease (defined as cerebrospinal fluid specimen with ≥5 white blood cells/μL with lymphoblasts and/or the presence of cranial nerve palsies). However, unless specific therapy is directed toward the CNS, most children will eventually develop overt CNS leukemia whether or not lymphoblasts were detected in the spinal fluid at initial diagnosis. CNS-directed treatments include intrathecal chemotherapy, CNS-directed systemic chemotherapy, and cranial radiation; some or all of these are included in current regimens for ALL. (Refer to the CNS-Directed Therapy for Childhood ALL section of this summary for more information.)

Testes

Overt testicular involvement at the time of diagnosis occurs in approximately 2% of males. In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear.[6,7] The role of radiation therapy for testicular involvement is also unclear. A study from St. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.[6] The Children's Oncology Group has also adopted this strategy for boys with testicular involvement that resolves completely during induction chemotherapy.

References

1. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]
2. Rubnitz JE, Lensing S, Zhou Y, et al.: Death during induction therapy and first remission of acute leukemia in childhood: the St. Jude experience. Cancer 101 (7): 1677-84, 2004. [PUBMED Abstract]
3. Christensen MS, Heyman M, Möttönen M, et al.: Treatment-related death in childhood acute lymphoblastic leukaemia in the Nordic countries: 1992-2001. Br J Haematol 131 (1): 50-8, 2005. [PUBMED Abstract]
4. Vrooman LM, Stevenson KE, Supko JG, et al.: Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31 (9): 1202-10, 2013. [PUBMED Abstract]
5. Lund B, Åsberg A, Heyman M, et al.: Risk factors for treatment related mortality in childhood acute lymphoblastic leukaemia. Pediatr Blood Cancer 56 (4): 551-9, 2011. [PUBMED Abstract]
6. Hijiya N, Liu W, Sandlund JT, et al.: Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation. Leukemia 19 (8): 1399-403, 2005. [PUBMED Abstract]
7. Sirvent N, Suciu S, Bertrand Y, et al.: Overt testicular disease (OTD) at diagnosis is not associated with a poor prognosis in childhood acute lymphoblastic leukemia: results of the EORTC CLG Study 58881. Pediatr Blood Cancer 49 (3): 344-8, 2007. [PUBMED Abstract]

Treatment of Newly Diagnosed Childhood ALL

In This Section

• Standard Treatment Options for Newly Diagnosed ALL
  • Remission induction chemotherapy
  • Response to remission induction chemotherapy
• Current Clinical Trials

Standard Treatment Options for Newly Diagnosed ALL

Standard treatment options for newly diagnosed childhood acute lymphoblastic leukemia (ALL) include the following:

1. Chemotherapy.

Remission induction chemotherapy

The goal of the first phase of therapy (remission induction) is to induce a complete remission (CR). This phase typically lasts 4 weeks. Overall, approximately 98% of patients with newly diagnosed precursor B-cell ALL achieve CR by the end of this phase, with somewhat lower rates in infants and in noninfant patients with T-cell ALL or high presenting leukocyte counts.[1-5]

Induction chemotherapy typically consists of the following drugs, with or without an anthracycline (either doxorubicin or daunorubicin):

• Vincristine.
• Corticosteroid (either prednisone or dexamethasone).
• L-asparaginase.

The Children's Oncology Group (COG) protocols administer a three-drug induction (vincristine, corticosteroid, and pegaspargase) to National Cancer Institute (NCI) standard-risk B-cell ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus anthracycline) to NCI high-risk B-cell ALL and all T-cell ALL patients. Other groups use a four-drug induction for all patients.[1-3]

Corticosteroid therapy

Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy, although controversy exists as to whether dexamethasone benefits all subsets of patients. Some trials also suggest that dexamethasone during induction may be associated with more toxicity than prednisone, including higher rates of infection, myopathy, and behavioral changes.[1,6-8] The COG reported that dexamethasone during induction was associated with a higher risk of osteonecrosis in older children (aged >10 years),[8] although this finding has not been confirmed in other randomized studies.[1,7]

Evidence (dexamethasone vs. prednisone during induction):

1. The Children's Cancer Group conducted a randomized trial that compared dexamethasone and prednisone in standard-risk B-cell ALL patients receiving a three-drug induction without anthracycline.[6]
   • Dexamethasone was associated with a superior event-free survival (EFS).
   • Dexamethasone was associated with a higher frequency of reversible steroid myopathy and hyperglycemia. No significant differences in rates of infection during induction were observed between the two randomized arms.
2. Another randomized trial that included both standard-risk and high-risk patients was conducted by the United Kingdom Medical Research Council.[7]
   • The trial demonstrated that dexamethasone was associated with a more favorable outcome than prednisolone in all patient subgroups.
   • Patients who received dexamethasone had a significantly lower incidence of both central nervous system (CNS) and non-CNS relapses than did patients who received prednisolone.
   • Dexamethasone was associated with a higher incidence of steroid-associated behavioral problems and myopathy, but an excess risk of osteonecrosis was not observed. There was no difference in induction death rates between the randomized groups.
3. The Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) ALL-BFM-2000 (NCT00430118) trial randomly assigned 3,720 patients to receive either dexamethasone (10 mg/m2/d) or prednisone (60 mg/m2/d) during multiagent remission induction (including anthracycline for all patients) after a 7-day prednisone prophase.[9]
   • Dexamethasone was associated with higher incidence of life-threatening events (primarily infections), resulting in a significantly higher induction death rate (2.5% for dexamethasone vs. 0.9% for prednisone; P = .00013).
   • There was no difference in rates of osteonecrosis between the randomized groups.
   • The 5-year cumulative incidence of relapse was significantly lower with dexamethasone (11% vs. 16%; P < .0001), resulting in superior 5-year EFS (84% for dexamethasone vs. 81% for prednisone, P = .024) despite the increased induction death rate.
   • No difference in overall survival (OS) was observed based on steroid randomization, although the study was not sufficiently powered to detect small differences in OS.
4. The COG conducted a randomized trial of dexamethasone and prednisone in NCI high-risk B-cell ALL patients.[8] Patients were randomly assigned to receive 14 days of dexamethasone or 28 days of prednisone during a four-drug induction (with anthracycline). This trial also included a randomized comparison of high-dose and escalating-dose methotrexate during the interim maintenance phase.
   • Dexamethasone was associated with a higher rate of infection, but there was no difference in the induction death rate when comparing dexamethasone and prednisone.
   • For patients who were younger than 10 years at diagnosis, there was a significant interaction between the corticosteroid and methotrexate randomizations; however, the best outcome for this group of patients was observed in those who received both dexamethasone during induction and high-dose methotrexate during interim maintenance.
   • The corticosteroid randomization was closed early for patients aged 10 years or older at diagnosis because of excessive rates of osteonecrosis in patients randomly assigned to dexamethasone; however, it did not appear that there was any EFS benefit associated with dexamethasone in these older patients (5-year EFS of 73.1% with dexamethasone and 73.9% with prednisone; P = .78)

The ratio of dexamethasone to prednisone dose used may influence outcome. Studies in which the dexamethasone to prednisone ratio was 1:5 to 1:7 have shown a better result for dexamethasone, while studies that used a 1:10 ratio have shown similar outcomes.[10]

L-asparaginase

Several forms of L-asparaginase have been used in the treatment of children with ALL, including the following:

• Pegaspargase (PEG-asparaginase).
• Asparaginase Erwinia chrysanthemi (Erwinia L-asparaginase).
• Native Escherichia coli (E. coli) L-asparaginase.

Only pegaspargase and Erwinia L-asparaginase are available in the United States. Native E. coli L-asparaginase remains available in other countries.

Pegaspargase (PEG-asparaginase)

Pegaspargase, a form of L-asparaginase in which the E. coli–derived enzyme is modified by the covalent attachment of polyethylene glycol, is the most common preparation used during both induction and postinduction phases of treatment in newly diagnosed patients treated in the United States and Western Europe.

Pegaspargase may be given either intramuscularly (IM) or intravenously (IV).[11] Pharmacokinetics and toxicity profiles are similar for IM and IV pegaspargase administration.[11] There is no evidence that IV administration of pegaspargase is more toxic than IM administration.[11-13]

Pegaspargase has a much longer serum half-life than native E. coli L-asparaginase, producing prolonged asparagine depletion after a single injection.[14]

Serum asparaginase enzyme activity levels of more than 0.1 IU/mL have been associated with serum asparagine depletion. Studies have shown that a single dose of pegaspargase given either IM or IV as part of multiagent induction results in serum enzyme activity of more than 0.1 IU/mL in nearly all patients for at least 2 to 3 weeks.[11,12,15,16]

Evidence (use of pegaspargase instead of native E. coli L-asparaginase):

1. A randomized comparison of IV pegaspargase versus IM native E. coli asparaginase was conducted. Each agent was administered for a 30-week period after the achievement of CR.[13][Level of evidence: 1iiC]
   • Serum asparaginase activity (SAA) levels were significantly higher with IV pegaspargase and exceeded goal therapeutic levels (>0.1 IU/mL) in nearly all patients throughout the 30-week period.
   • There was no significant difference in EFS and OS between the randomized arms.
   • There was no difference in rates of asparaginase-related toxicities, including hypersensitivity, pancreatitis, and thromboembolic complications.
   • Similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients.
   • IV pegaspargase was associated with less treatment-related anxiety, as assessed by patient and parent surveys.
2. Another randomized trial of patients with standard-risk ALL assigned patients to receive either pegaspargase or native E. coli asparaginase in induction and each of two delayed intensification courses.[15]
   • A single dose of pegaspargase given in conjunction with vincristine and prednisone during induction therapy appeared to have similar activity and toxicity as nine doses of IM E. coli L-asparaginase (3 times a week for 3 weeks).[15]
   • The use of pegaspargase was associated with more rapid blast clearance and a lower incidence of neutralizing antibodies.

Patients with an allergic reaction to pegaspargase are typically switched to Erwinia L-asparaginase. Measurement of SAA levels after a mild or questionable reaction to pegaspargase may help to differentiate patients for whom the switch to Erwinia is indicated (because of inadequate SAA) versus those for whom a change in preparation may not be necessary.[17,18]

Several studies have identified a subset of patients who experience silent inactivation of asparaginase, defined as absence of therapeutic SAA levels without overt allergy.[19,20] In a trial conducted by the Dana-Farber Cancer Institute (DFCI) Consortium, 12% of patients treated initially with native E.coli L-asparaginase demonstrated silent inactivation; these patients had a superior EFS if their asparaginase preparation was changed.[20] The frequency of silent inactivation in patients initially treated with pegaspargase appears to be low (<10%).[13,19] Determination of the optimal frequency of pharmacokinetic monitoring for pegaspargase-treated patients, and whether such screening impacts outcome, awaits further investigation.

Asparaginase Erwinia chrysanthemi (Erwinia L-asparaginase)

Erwinia L-asparaginase is typically used in patients who have experienced allergy to native E. coli or pegaspargase.

The half-life of Erwinia L-asparaginase (0.65 days) is much shorter than that of native E. coli(1.2 days) or pegaspargase (5.7 days).[14] If Erwinia L-asparaginase is utilized, the shorter half-life of the Erwinia preparation requires more frequent administration to achieve adequate asparagine depletion.

Evidence (increased dose frequency of Erwinia L-asparaginase needed to achieve goal therapeutic effect):

1. A COG trial demonstrated that IM Erwinia L-asparaginase given three times a week to patients with an allergy to pegaspargase leads to therapeutic serum asparaginase enzyme activity levels (defined as a level ≥0.1 IU/mL). On that trial, 96% of children achieved a level of 0.1 IU/mL or more at 2 days after a dose of Erwinia L-asparaginase and 85% did so at 3 days after a dose.[21]
2. A trial of IV Erwinia L-asparaginase given on a Monday-Wednesday-Friday schedule to patients with an allergy to pegaspargase demonstrated therapeutic serum asparaginase enzyme activity (defined as ≥0.1 IU/mL) in 83% of patients 48 hours after a dose but in only 43% of patients 72 hours after a dose. If IV Erwinia is given on a Monday-Wednesday-Friday schedule, the authors suggest that 72-hour nadir enzyme activity levels be monitored to ensure therapeutic levels.[22]

Anthracycline during induction

The COG protocols administer a three-drug induction (vincristine, corticosteroid, and pegaspargase) to NCI standard-risk B-cell ALL patients and a four-drug induction (vincristine, corticosteroid, and pegaspargase plus anthracycline) to NCI high-risk B-cell ALL and all T-cell ALL patients. Other groups use a four-drug induction for all patients.[1-3]

In induction regimens that include an anthracycline, either daunorubicin or doxorubicin are typically utilized. In a randomized trial comparing the two agents during induction, there were no differences in early response measures, including reduction in peripheral blood blast counts during the first week of therapy, day 15 marrow morphology, and end-induction minimal residual disease (MRD) levels.[23][Level of evidence: 1iiDiv]

Response to remission induction chemotherapy

More than 95% of children with newly diagnosed ALL will achieve a CR within the first 4 weeks of treatment. Of those who fail to achieve CR within the first 4 weeks, approximately one-half will experience a toxic death during the induction phase (usually caused by infection) and the other half will have resistant disease (persistent morphologic leukemia).[24-26]; [27][Level of evidence: 3iA]

Most patients with persistent leukemia at the end of the 4-week induction phase have a poor prognosis and may benefit from an allogeneic hematopoietic stem cell transplant (HSCT) once CR is achieved.[28,29,4] In a large retrospective series, the 10-year OS for patients with persistent leukemia was 32%.[30] A trend for superior outcome with allogeneic HSCT compared with chemotherapy alone was observed in patients with T-cell phenotype (any age) and precursor B-cell patients younger than 6 years. Precursor B-cell ALL patients who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (MLL (KMT2A) rearrangement, BCR-ABL1) had a relatively favorable prognosis, without any advantage in outcome with the utilization of HSCT compared with chemotherapy alone.[30]

For patients who achieve CR, measures of the rapidity of blast clearance and MRD determinations have important prognostic significance, particularly the following:

• The percentage of morphologically detectable marrow blasts at 7 and 14 days after starting multiagent remission induction therapy has been correlated with relapse risk,[31] and has been used in the past by the COG to risk-stratify patients. However, in multivariate analyses, when end-induction MRD is included, these early marrow findings lose their prognostic significance.[32,33]
• End-induction levels of submicroscopic MRD, assessed either by multiparameter flow cytometry or polymerase chain reaction, strongly correlates with long-term outcome.[32,34-36] Intensification of postinduction therapy for patients with high levels of end-induction MRD is a common component of most ALL treatment regimens. In a randomized trial conducted by the UK-ALL group, augmented postinduction therapy was shown to improve outcome for standard-risk and intermediate-risk patients with high end-induction MRD.[37]
• MRD levels earlier in induction (e.g., days 8 and 15) and at later postinduction time points (e.g., week 12 after starting therapy) have also been shown to have prognostic significance in both B-cell and T-cell ALL.[32,33,36,38-41]

(Refer to the Response to initial treatment section of this summary for more information.)

(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 newly diagnosed ALL.)

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. Möricke A, Zimmermann M, Reiter A, et al.: Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 24 (2): 265-84, 2010. [PUBMED Abstract]
2. Pui CH, Pei D, Sandlund JT, et al.: Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia 24 (2): 371-82, 2010. [PUBMED Abstract]
3. 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]
4. Oudot C, Auclerc MF, Levy V, et al.: Prognostic factors for leukemic induction failure in children with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study. J Clin Oncol 26 (9): 1496-503, 2008. [PUBMED Abstract]
5. Salzer WL, Devidas M, Carroll WL, et al.: Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children's oncology group. Leukemia 24 (2): 355-70, 2010. [PUBMED Abstract]
6. Bostrom BC, Sensel MR, Sather HN, et al.: Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 101 (10): 3809-17, 2003. [PUBMED Abstract]
7. Mitchell CD, Richards SM, Kinsey SE, et al.: Benefit of dexamethasone compared with prednisolone for childhood acute lymphoblastic leukaemia: results of the UK Medical Research Council ALL97 randomized trial. Br J Haematol 129 (6): 734-45, 2005. [PUBMED Abstract]
8. 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]
9. Möricke A, Zimmermann M, Valsecchi MG, et al.: Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood 127 (17): 2101-12, 2016. [PUBMED Abstract]
10. McNeer JL, Nachman JB: The optimal use of steroids in paediatric acute lymphoblastic leukaemia: no easy answers. Br J Haematol 149 (5): 638-52, 2010. [PUBMED Abstract]
11. Silverman LB, Supko JG, Stevenson KE, et al.: Intravenous PEG-asparaginase during remission induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia. Blood 115 (7): 1351-3, 2010. [PUBMED Abstract]
12. Rizzari C, Citterio M, Zucchetti M, et al.: A pharmacological study on pegylated asparaginase used in front-line treatment of children with acute lymphoblastic leukemia. Haematologica 91 (1): 24-31, 2006. [PUBMED Abstract]
13. Place AE, Stevenson KE, Vrooman LM, et al.: Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol 16 (16): 1677-90, 2015. [PUBMED Abstract]
14. Asselin BL, Whitin JC, Coppola DJ, et al.: Comparative pharmacokinetic studies of three asparaginase preparations. J Clin Oncol 11 (9): 1780-6, 1993. [PUBMED Abstract]
15. Avramis VI, Sencer S, Periclou AP, et al.: A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 99 (6): 1986-94, 2002. [PUBMED Abstract]
16. Tram Henriksen L, Gottschalk Højfeldt S, Schmiegelow K, et al.: Prolonged first-line PEG-asparaginase treatment in pediatric acute lymphoblastic leukemia in the NOPHO ALL2008 protocol-Pharmacokinetics and antibody formation. Pediatr Blood Cancer 64 (12): , 2017. [PUBMED Abstract]
17. van der Sluis IM, Vrooman LM, Pieters R, et al.: Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica 101 (3): 279-85, 2016. [PUBMED Abstract]
18. Bleyer A, Asselin BL, Koontz SE, et al.: Clinical application of asparaginase activity levels following treatment with pegaspargase. Pediatr Blood Cancer 62 (6): 1102-5, 2015. [PUBMED Abstract]
19. Tong WH, Pieters R, Kaspers GJ, et al.: A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia. Blood 123 (13): 2026-33, 2014. [PUBMED Abstract]
20. Vrooman LM, Stevenson KE, Supko JG, et al.: Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31 (9): 1202-10, 2013. [PUBMED Abstract]
21. Salzer WL, Asselin B, Supko JG, et al.: Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: a report from the Children's Oncology Group. Blood 122 (4): 507-14, 2013. [PUBMED Abstract]
22. Vrooman LM, Kirov II, Dreyer ZE, et al.: Activity and Toxicity of Intravenous Erwinia Asparaginase Following Allergy to E. coli-Derived Asparaginase in Children and Adolescents With Acute Lymphoblastic Leukemia. Pediatr Blood Cancer 63 (2): 228-33, 2016. [PUBMED Abstract]
23. Escherich G, Zimmermann M, Janka-Schaub G, et al.: Doxorubicin or daunorubicin given upfront in a therapeutic window are equally effective in children with newly diagnosed acute lymphoblastic leukemia. A randomized comparison in trial CoALL 07-03. Pediatr Blood Cancer 60 (2): 254-7, 2013. [PUBMED Abstract]
24. Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104 (9): 2690-6, 2004. [PUBMED Abstract]
25. Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95 (11): 3310-22, 2000. [PUBMED Abstract]
26. Moghrabi A, Levy DE, Asselin B, et al.: Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109 (3): 896-904, 2007. [PUBMED Abstract]
27. Prucker C, Attarbaschi A, Peters C, et al.: Induction death and treatment-related mortality in first remission of children with acute lymphoblastic leukemia: a population-based analysis of the Austrian Berlin-Frankfurt-Münster study group. Leukemia 23 (7): 1264-9, 2009. [PUBMED Abstract]
28. Balduzzi A, Valsecchi MG, Uderzo C, et al.: Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet 366 (9486): 635-42, 2005 Aug 20-26. [PUBMED Abstract]
29. Silverman LB, Gelber RD, Young ML, et al.: Induction failure in acute lymphoblastic leukemia of childhood. Cancer 85 (6): 1395-404, 1999. [PUBMED Abstract]
30. Schrappe M, Hunger SP, Pui CH, et al.: Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med 366 (15): 1371-81, 2012. [PUBMED Abstract]
31. Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer 80 (9): 1717-26, 1997. [PUBMED Abstract]
32. Borowitz MJ, Devidas M, Hunger SP, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood 111 (12): 5477-85, 2008. [PUBMED Abstract]
33. Borowitz MJ, Wood BL, Devidas M, et al.: Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232. Blood 126 (8): 964-71, 2015. [PUBMED Abstract]
34. van Dongen JJ, Seriu T, Panzer-Grümayer ER, et al.: Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352 (9142): 1731-8, 1998. [PUBMED Abstract]
35. Zhou J, Goldwasser MA, Li A, et al.: Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood 110 (5): 1607-11, 2007. [PUBMED Abstract]
36. Conter V, Bartram CR, Valsecchi MG, et al.: Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 115 (16): 3206-14, 2010. [PUBMED Abstract]
37. Vora A, Goulden N, Mitchell C, et al.: Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol 15 (8): 809-18, 2014. [PUBMED Abstract]
38. Coustan-Smith E, Sancho J, Behm FG, et al.: Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 100 (1): 52-8, 2002. [PUBMED Abstract]
39. Basso G, Veltroni M, Valsecchi MG, et al.: Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 27 (31): 5168-74, 2009. [PUBMED Abstract]
40. Schrappe M, Valsecchi MG, Bartram CR, et al.: Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood 118 (8): 2077-84, 2011. [PUBMED Abstract]
41. Karsa M, Dalla Pozza L, Venn NC, et al.: Improving the identification of high risk precursor B acute lymphoblastic leukemia patients with earlier quantification of minimal residual disease. PLoS One 8 (10): e76455, 2013. [PUBMED Abstract]

Postinduction Treatment for Childhood ALL

In This Section

• Standard Postinduction Treatment Options for Childhood ALL
  • Consolidation/intensification therapy
  • Maintenance therapy
  • Treatment options under clinical evaluation
• Current Clinical Trials

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.
2. An interim maintenance phase, which includes multiple doses of high-dose methotrexate (typically 5 g/m2) with leucovorin rescue or escalating doses of methotrexate (starting dose 100 mg/m2) without leucovorin rescue.
3. Reinduction (or delayed intensification), which typically includes agents and schedules similar to those used during the induction and initial consolidation phases.
4. Maintenance, typically consisting of daily mercaptopurine, 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]
• 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 20 to 30 weeks of pegaspargase therapy beginning at week 7 of therapy, given in conjunction with maintenance regimen (vincristine/dexamethasone pulses, low-dose methotrexate, nightly mercaptopurine).[4] These protocols also do not include a delayed intensification phase, but high-risk patients receive additional doses of doxorubicin (instead of methotrexate) during intensification.
• 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-cell 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 (20–30 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 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 based on 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 inferior 8-year disease-free survival (DFS) (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, 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 increased EFS to be 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 generally is 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 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][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).[30][Level of evidence: 1iiC]
4. In the COG AALL0232 (NCT00075725) study (2004–2011), patients with high-risk B-cell 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).[31,32]
   • The methotrexate randomization was terminated early when planned interim monitoring indicated that high-dose methotrexate was associated with superior outcome. The 5-year EFS 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).[32]
   • Patients with MRD less than 0.01% at end of induction had a 5-year EFS of 87%, compared with 74% for those with MRD 0.01% to 0.1%. Those with MRD levels greater than 0.1% fared worse.[31]
   • High-dose methotrexate was associated with a superior EFS in patients with end-induction MRD greater than 0.01% (high-dose methotrexate, 68%; Capizzi methotrexate, 58%; P = .008).[31]

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.[33,34]
   • 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).[35]
   • 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.[30] On that protocol, patients with high-risk B-cell ALL and a rapid early morphologic response to induction therapy were randomly assigned to receive either one or two delayed intensification phases. Those 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:[24,36]

• Infants younger than 1 year, especially if there is an MLL (KMT2A) 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 t(9;22)(q34;q11.2), t(17;19), MLL 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.

COG also considers patients who are aged 13 years or older to be very high risk, although this age criterion is not utilized by other groups.

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.[24,37]

On some clinical trials, very high-risk patients have also been considered candidates for allogeneic hematopoietic stem cell transplantation (HSCT) in first CR.[37-40] 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.[37]
   • Using an intent-to-treat analysis, patients assigned to allogeneic HSCT (on the basis of donor availability) had a superior 5-year DFS 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 (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.[38]
2. In a large retrospective series of patients with initial induction failure, the 10-year OS for patients with persistent leukemia was 32%.[41]
   • A trend for superior outcome with allogeneic HSCT, compared with chemotherapy alone, was observed in patients with T-cell phenotype (any age) and with precursor B-cell ALL who were older than 6 years.
   • Patients with precursor B-cell ALL who were aged 1 to 5 years at diagnosis and did not have any adverse cytogenetic abnormalities (MLL [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.[42][Level of evidence: 2Dii]
   • The overall 5-year EFS of patients meeting high-risk criteria was 58.9%.
   • The 5-year EFS 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).

Maintenance therapy

Backbone of maintenance therapy

The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate. Clinical practice generally calls for the administration of oral mercaptopurine in the evening, based on evidence from older studies that this practice may improve EFS.[43] 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.[44] Studies conducted by the COG have demonstrated significant differences in compliance with mercaptopurine (6-MP) amongst various racial and socioeconomic groups. Importantly, nonadherence to treatment with mercaptopurine in the maintenance phase was associated with a significant increase in the risk of relapse.[44,45]

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.[46,47] These patients are able to tolerate mercaptopurine only if dosages much lower than those conventionally used are administered.[46,47] 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.[46] 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.[48,49]

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.[50] 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.[51-55] 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.[56]
   • The intensified maintenance with rotating pairs of agents has been associated with more episodes of febrile neutropenia [57] and a higher risk of secondary acute myelogenous leukemia,[58,59] especially when epipodophyllotoxins are included.[57]
     Based on these findings, SJCRH has 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.[57]

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 receiving monthly vincristine/prednisone pulses.[60]
2. A meta-analysis combining data from six clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone pulses.[61,62]
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.[62]
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.[63]
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).[64][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.[20,65-68] Compared with prednisone, dexamethasone has also been associated with a higher frequency of behavioral problems.[66] 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.[69]

Evidence (dexamethasone vs. prednisone):

1. In a CCG study, dexamethasone was compared with prednisone for children aged 1 to younger than 10 years with lower-risk ALL.[20,65]
   • Patients randomly assigned to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate.
2. In an MRC UK-ALL trial, dexamethasone was compared with prednisolone during induction and maintenance therapies in both standard-risk and high-risk patients.[66]
   • 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.[68]
   • 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.[28,67]

Duration of maintenance therapy

Maintenance chemotherapy generally continues until 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.[61]

Adherence to oral medications during maintenance therapy

Nonadherence to treatment with mercaptopurine during maintenance therapy is associated with a significant risk of relapse.[44]

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).[44]
   • 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.
   • Adherence was significantly lower among Hispanics, patients older than 12 years, and patients from single-mother households.
2. A second study of adherence was conducted in 298 children with ALL (71 Asian Americans, 68 African Americans, and 159 non-Hispanic whites).[45]
   • An adherence rate of less than 90% was associated with increased relapse risk (HR, 3.9).
   • Using an adherence rate of less than 90% to define nonadherence, 20.5% of the participants were nonadherers.
   • 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:[70]
   • Patients with mercaptopurine nonadherence (defined as mean adherence rate < 95%) were at 2.7-fold increased risk of relapse compared to 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.[71] 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.[72][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 National Cancer Institute (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 precursor B-cell ALL

Standard-risk ALL

1. COG-AALL0932 (NCT01190930) (Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk ALL):
   All patients will receive a three-drug induction (dexamethasone, vincristine, and IV pegaspargase) with intrathecal chemotherapy. Postinduction therapeutic questions have been answered for low-risk and average-risk patients, and trials have met accrual goals and are closed; protocol therapy ends after the first month of therapy for all patients, except for those with Down syndrome who have low bone marrow MRD on day 29. The study objective is to describe the outcome of standard-risk Down syndrome patients treated with a standardized treatment and enhanced supportive care. Non–Down syndrome patients on this study who are found to have high-risk features are eligible to enroll on COG-AALL1131 after induction.

High-risk and very high-risk ALL

1. 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 patients 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., ABL1, ABL2, CSF1F, 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 so randomization was closed in 2018. Therefore, high-risk patients without dasatinib-sensitive fusions are removed from 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.
   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.
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-cell ALL (ages 1–21 years) with any of the following genetic abnormalities: 1) rearranged CRLF2 (CRLF-R); 2) mutations in JAK1or JAK2; or 3) other alterations involving the JAK pathway (e.g., JAK2 fusions, EPO-Rfusions, 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. Total XVI study (TOTXVI) (Total Therapy Study XVI for Newly Diagnosed Patients With ALL): A study at SJCRH is randomly assigning patients to receive either standard-dose (2,500 u/m2) or high-dose (3,500 u/m2) pegaspargase during postremission therapy.
2. DFCI ALL 16-001 (NCT03020030) (Risk Classification Schemes in Identifying Better Treatment Options for Children and Adolescents with ALL): This trial has two main objectives: 1) To test a novel risk classification scheme for children and adolescents with ALL, and 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, MLLgene rearrangement, 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 anthracycline).
   Final risk group, which determines the intensity of postinduction therapy, is assigned based on 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 (<104) at the first time point are considered final low risk. They continue treatment per DFCI standard-risk backbone, including 30 weeks of pegaspargase, but without any anthracycline.
   • Initial low-risk patients with high MRD (>104) at the first time point but low MRD (<103) at the second time point and all initial high-risk patients with low MRD (<103) 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 initial very high-risk patients and any initial low-risk/high-risk patient with high MRD (>103) 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 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 Erwiniaor 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.

References

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