Version May 2024
INTRODUCTION — Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) is the most common cancer in children, accounting for nearly one-third of all childhood malignancies. The World Health Organization (WHO) classification considers ALL and LBL to be the same entity, distinguished only by the primary location of the disease [1,2].
Treatment of pediatric ALL/LBL is intensive, complex, and prolonged. Using contemporary approaches, approximately 90 percent of children achieve long-term survival and only small percentages have disease that is refractory to initial treatment or that relapses (recurs) [3,4]. For children who relapse, only half achieve long-term survival [5], but advances in treatment options, including immunotherapy, are likely to improve these outcomes.
This topic discusses management of relapsed and refractory ALL/LBL in children and adolescents.
Clinical presentation, diagnosis, classification, risk group stratification, treatment, and outcomes of childhood ALL/LBL are discussed separately.
●(See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)
DESCRIPTIONS — Most children with ALL/LBL are cured with contemporary treatment. However, a minority of patients do not achieve an adequate response to initial therapy or experience a disease recurrence. Initial treatment of ALL/LBL is discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents".)
Definitions of relapsed and refractory ALL/LBL differ among research groups, but consensus definitions have been proposed [6]:
●Primary refractory ALL/LBL – Primary refractory ALL/LBL (also called treatment failure) refers to persistence of leukemic blasts in the blood, bone marrow, or any extramedullary site after four to six weeks of induction therapy [6]. This is frequently defined as either >1 percent blasts (M1 morphology) or measurable residual disease (MRD) ≥1 percent at the end of induction or the end of consolidation.
Treatment failure was reported in 2.4 percent of 44,017 children ≤18 years with previously untreated ALL/LBL, according to a retrospective analysis from 14 cooperative study groups [7]. In that study, primary refractory ALL/LBL was associated with age >6 years, leukocyte count >100,000 cells/microL (>100 x 109/L), T cell leukemia, central nervous system (CNS) involvement, and 11q23 chromosomal rearrangement.
In a French study of 1395 children with newly diagnosed ALL/LBL, the overall risk of treatment failure was 3.8 percent [8]. Multivariate analysis identified clinical and laboratory features associated with induction failure, using immunophenotype (B cell versus T cell), Philadelphia chromosome, and mediastinal mass to classify patients into three risk groups. Compared with the low-risk group, children in the intermediate- and high-risk groups had 7- and 28-fold increased risk for induction failure, respectively.
●Relapsed ALL/LBL – Relapsed ALL/LBL refers to a recurrence of ALL/LBL at any point after achieving complete remission (CR). Relapse risk is associated with age, white blood cell (WBC) count at diagnosis, immunophenotype, leukemic blast cytogenetic/molecular findings, and the response to early treatment, as discussed separately. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents", section on 'Prognostic factors'.)
Response to initial treatment is the most powerful prognostic factor in childhood ALL/LBL [9,10]; the level of MRD at the end of induction and/or at the end of consolidation has largely replaced morphological assessment for this purpose [11]. Nevertheless, half of all relapses occur in children with an excellent MRD response. For B cell ALL/LBL, end-of-induction MRD is the best predictor of outcome, but for T cell ALL/LBL, end-of-consolidation MRD is a better predictor of adverse outcomes [12]. MRD can also predict outcomes in infants with ALL/LBL [13].
The interval between diagnosis and relapse is prognostically important. Although the terminology and details of timing differ between cooperative groups, the following can be used for describing the timing of relapse [14,15]:
•Very early – <18 months
•Early – 18 months to 36 months (or the end of chemotherapy)
•Late – ≥3 years or after completion of therapy
In some children, an apparent late relapse of ALL/LBL reveals a distinctly different molecular profile compared with the initial presentation; such presentations may actually reflect a second leukemia, rather than relapse, and they are associated with a more favorable prognosis [16].
PATHOGENESIS — The molecular causes of relapse differ between B cell and T cell ALL/LBL. Identifying molecular events associated with relapse may offer future therapeutic opportunities.
●Primary refractory ALL/LBL – Pathologic features associated with induction failure, such as T cell phenotype and cytogenetic/molecular features are described separately. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents", section on 'Prognostic factors'.)
●Relapsed ALL/LBL – Relapse involves complex genetic evolution of leukemic blasts, including abnormalities that were present at initial diagnosis and effects of secondary genetic alterations. Cytogenetic and molecular features associated with adverse outcomes at initial presentation of pediatric ALL/LBL are discussed separately. (See "Prognostic factors and risk group stratification for acute lymphoblastic leukemia/lymphoblastic lymphoma in children and adolescents".)
The dominant clone at relapse can often be identified retrospectively as a minor clone that was present at initial presentation; genetic features of that clone may have contributed to chemotherapy resistance.
Different pathophysiologic mechanisms contribute to relapse of B lineage and T lineage disease; insight into the biology of relapse may offer novel therapeutic opportunities [17-20].
•B cell ALL/LBL – Relapse of B cell ALL/LBL is often associated with secondary genetic alterations in epigenetic regulators and chromatin modifiers that confer resistance to therapeutic agents.
As examples, mutations in CREBBP are found in 20 percent of relapsed B cell ALL/LBL; this gene encodes CREB binding protein, which is a transcriptional coactivator and acetyl transferase that influences expression of many genes and is associated with an impaired response to glucocorticoids [21]. Gain-of-function mutations in NT5C2, which encodes the cytosolic 5'-nucleotidase cytosolic II, were found in one-sixth of relapsed B cell ALL/LBL and confer resistance to 6-MP [22,23]. Other somatic mutations that are enriched in relapsed B cell disease include WHSC1, TP53, USH2A, NRAS, IKZF1, and the DNA mismatch repair genes, PMS2 and MSH6 [24].
•T cell ALL/LBL – Relapsed T cell ALL/LBL is associated with heterogeneous secondary genetic changes with chromosomal abnormalities in almost all patients [25], but few of these mutations are actionable at present. The most common secondary abnormalities include:
-NOTCH – Activation of NOTCH signaling is found in approximately 80 percent of cases of relapsed T cell ALL/LBL; it is a common finding at diagnosis, as well. Constitutive NOTCH activation is generally caused by an activating mutation in NOTCH1 or a loss-of-function mutation in FBXW7 [25,26]. More than 70 percent of individuals with NOTCH activation also have loss of p16 (INK4A) and p14 (ARF) suppressors that are encoded in the CDKN2A locus; this suggests that activation of NOTCH signaling cooperates with CDKN2A deletions to promote oncogenesis [27].
-Transcription factors – Chromosomal translocations that place key lymphocyte transcription factor genes under the control of T cell receptor enhancers are present in half of patients with T cell ALL/LBL. Overexpressed oncogenic transcription factors include TAL1, TAL2, LYL1, OLIG2, LMO1, LMO2, TLX1 (HOX11), TLX3 (HOX11L2), NKX2-1, NKX2-2, NKX2-5, HOXA genes, MYC, MYB, and TAN1 [28]. Less often, rearrangements cause loss of expression of tumor suppressor genes, such as WT1, LEF1, ETV6, BCL11B, RUNX1, or GATA3 [28].
-Chromatin modification – Mutations involving components of the PRC2 complex, which is involved in chromatin modification, are found in one-quarter of cases of relapsed/refractory (r/r) T cell ALL/LBL; most common are loss-of-function mutations and deletions of AZH2 and SUZ12 [29,30]. PHF6, a homeodomain factor with a role in the epigenetic regulation of gene expression, is mutated or deleted in one-sixth of children with T cell ALL/LBL [31].
-Signal transduction – Genetic alterations in signal transduction pathways include mutational loss of PTEN, an essential regulator of the PI3K-AKT signaling pathway, in 5 to 10 percent of patients [32] and rearrangements of ABL1 to form gene fusions with NUP214, EML1, and ETV6 in 8 percent [33-35]. MAPK alterations are more common at relapse than at diagnosis; such mutations are often associated with resistance to glucocorticoids and MAPK inhibitors restored corticosteroid sensitivity in preclinical models [36].
Identification of underlying molecular events may provide future treatment opportunities for relapsed ALL/LBL. Examples might include effective (and less toxic) functional gamma secretase inhibitors for patients with NOTCH mutations or agents that target NF-kB (via proteasome inhibition), P13K/AKT/mTOR, JAK/STAT, D-type cyclins, or epigenetic changes in selected cases [37,38].
PRETREATMENT EVALUATION — Relapsed or refractory (r/r) disease should be suspected in a child with a history of ALL/LBL who has systemic signs or symptoms that are concerning for either medullary or extramedullary relapse; detection of blasts in blood, marrow, or other sites; or unexplained abnormalities on complete blood count (CBC)/differential count that may lead to testing for measurable residual disease (MRD) or other evaluations. Most relapses occur within one to three years from initial diagnosis, with symptoms similar to their initial presentation.
Clinical and laboratory evaluation
●Clinical – The clinical evaluation is similar to that for initial presentation. All children with relapsed ALL/LBL should be evaluated for involvement of both medullary (bone marrow) and central nervous system (CNS) involvement. All males should be evaluated for testicular involvement. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Pretreatment evaluation'.)
●Pathology – Defining the immunophenotype and cytogenetic/molecular features of the leukemic blasts is important for management.
Microscopy, flow cytometry, cytogenetics, and molecular studies should be performed on bone marrow, blood, and/or extramedullary disease specimen. While the percentage of blasts in marrow should be determined, there is not a specific threshold required for the diagnosis of r/r ALL/LBL [1,6,39].
•Immunophenotype – Flow cytometry and/or immunohistochemistry distinguish B cell from T cell disease, which guides management of r/r ALL/LBL. (See 'B cell ALL/LBL' below and 'T cell ALL/LBL' below.)
•Cytogenetic and molecular studies – In addition to conventional cytogenetic analyses to characterize the biology of the relapse, next-generation sequencing (NGS), DNA/RNA-based fusion gene testing, and evaluation for Philadelphia chromosome (Ph)-like molecular features can be applied to identify potentially targetable molecular lesions [40,41].
Cytogenetic and molecular findings are prognostically important and may guide therapy, as described below. (See 'Reinduction therapy' below.)
Initial diagnosis and classification of ALL/LBL are presented separately. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children", section on 'Diagnosis of ALL/LBL' and "Classification, cytogenetics, and molecular genetics of acute lymphoblastic leukemia/lymphoma".)
Prognostic stratification
Prognostic factors — Identification of adverse prognostic features is important for management of r/r ALL/LBL.
Important prognostic features include time to relapse (early versus late), immunophenotype (B cell versus T cell), cytogenetic/molecular features, and site of relapse (bone marrow versus isolated extramedullary relapse). In general, better outcomes are associated with longer duration between diagnosis and relapse, isolated extramedullary relapse (compared with bone marrow relapse), and robust response to reinduction.
●Clinical features
•Timing of relapse – Time from initial diagnosis to relapse was the strongest predictor of survival in an analysis of 1961 patients with relapsed ALL/LBL in Children's Oncology Group (COG) clinical trials; five-year overall survival (OS) was 21 percent for early relapses (<18 months after diagnosis) compared with 50 percent for late relapses (>36 months after diagnosis) [42].
•Site of relapse – Isolated CNS relapse was more favorable than combined CNS and bone marrow relapse or isolated marrow relapse, with 59, 24, and 39 percent five-year OS, respectively [43].
•Clinical features – After adjusting for site and time of relapse, multivariate analysis of 1391 patients demonstrated that older age (>10 years), presence of CNS disease at diagnosis, and T cell disease were associated with lower survival rates. Prospective studies reported similar risk factors [44-46].
•Treatment intensity – Prognosis at the time of relapse does not appear to be related to the intensity of the treatment at initial diagnosis; three-year OS was similar (36 versus 39 percent) for children who were randomly assigned to standard intensity versus augmented intensity post-induction therapy [47].
●Cytogenetic/molecular features – As with newly diagnosed ALL/LBL, cytogenetic and molecular findings are associated with outcomes for r/r disease. Outcomes of children with high-risk cytogenetic findings in relapsed B cell disease was similar to that of children with high-risk clinical features [48]. Similarly, mutant TP53 and other adverse features (eg, TCF3::HLF fusion) detected at relapse are associated with poor outcome [48-50].
Stratification schemes — Prognostic stratification varies among research groups. The prognostic stratification scheme that is used for an individual patient should be the same as that used in the chosen treatment protocol. We generally use the COG schema [42,51], but the Berlin-Frankfurt-Münster (BFM) [15] or UK [14] stratification approaches are appropriate, if those protocols are selected.
To illustrate, COG stratifies risk as follows:
●Low
•Late marrow relapse (≥36 months) of B cell disease, with end-of-induction MRD <0.1 percent
•Late isolated extramedullary relapse (≥18 months) with end-of-induction MRD <0.1 percent
●Intermediate
•Late marrow relapse (≥36 months) of B cell disease, with end-of-induction MRD ≥0.1 percent
•Late isolated extramedullary relapse (≥18 months), with end-of-induction MRD ≥0.1 percent
●High
•Early marrow relapse (<36 months) of B cell disease
•Early isolated extramedullary relapse (<18 months)
•T cell disease at any site and any timing
FIRST RELAPSE OR PRIMARY REFRACTORY ALL/LBL — Optimal outcomes are associated with adherence to a contemporary research protocol and treatment at a site with substantial experience in managing pediatric ALL/LBL (or in close consultation with an experienced pediatric hematologist/oncologist). We encourage participation in a clinical trial, whenever possible.
Patients with primary refractory ALL/LBL or first relapse usually require remission reinduction therapy coupled with central nervous system (CNS) management. This is followed by consolidation therapy using immunotherapy, chemotherapy, and/or allogeneic hematopoietic cell transplantation (HCT). Some current clinical trials instead begin treatment with immunotherapy (eg, blinatumomab plus nivolumab); at present, such an approach should only be used in the context of a research study because the long-term outcomes are not well-defined.
CNS management — All children with relapsed or refractory (r/r) ALL/LBL should receive CNS therapy.
CNS management involves either prophylaxis or treatment of CNS leukemic involvement, according to results from lumbar puncture (LP) and/or imaging, and it is guided by the chosen treatment protocol. Examples include:
●No CNS involvement – Prophylaxis using intrathecal (IT) methotrexate (MTX).
●CNS involvement – Treatment for CNS involvement may include cranial irradiation, IT MTX, and/or "triple therapy" (ie, IT MTX, cytarabine, and hydrocortisone); treatment may also include systemic chemotherapy that has CNS penetration, such as high-dose MTX with leucovorin rescue or high-dose cytarabine.
Management of isolated CNS relapse (ie, no other sites of relapse) is discussed below. (See 'Isolated CNS or extramedullary relapse' below.)
Reinduction therapy — For children with primary refractory disease or first relapse of ALL/LBL, we suggest reinduction therapy using a four-drug platform (ie, glucocorticoid, vincristine, anthracycline, pegaspargase), as guided by the chosen research group protocol.
Drugs, doses, and schedules vary among cooperative groups. No randomized trials have directly compared protocols for relapsed disease, and there is no preferred regimen. Various contemporary protocols are associated with similar outcomes [14,15,49,51,52] and it is difficult to compare retrospective studies because of heterogeneous patient populations, lack of a randomized control group, and different stratification schemes and outcomes measures.
Composition of the reinduction regimen, including selection of an anthracycline and glucocorticoid are discussed below. (See 'Reinduction platform' below.)
●Additional agents – Other agents may be added to the four-drug platform for children with certain features, as guided by the chosen research protocol:
•T cell ALL/LBL – T cell disease is associated with less favorable responses to reinduction (eg, 30 to 40 percent complete remission [CR]) [38,53]. Some ongoing clinical trials use nelarabine as a component of reinduction therapy [54-56] or add agents such as bortezomib to the four-drug reinduction platform [57]. Nelarabine has been shown to improve CR rates for intermediate-risk and high-risk T cell ALL patients. (See 'Other agents' below.)
•Philadelphia chromosome (Ph)-positive disease – For children with t(9;22)/BCR::ABL1, we add imatinib or dasatinib to the four-drug reinduction platform. (See 'Philadelphia chromosome (Ph)-positive' below.)
•Ph-like ALL – For children with a JAK2 or ABL-class kinase mutation, some studies add a targeted agent (eg, ruxolitinib for JAK2 mutation, tyrosine kinases inhibitors for ABL-class abnormalities) [58,59], especially for children with high-risk features (eg, marked leukocytosis or age >10 years), although clinical benefits are not proven [5]. Allogeneic HCT frequently follows reinduction or induction and consolidation chemotherapy with a tyrosine kinase inhibitor (TKI).
We suggest not using immunotherapy for reinduction, as we await results of ongoing clinical trials that are evaluating blinatumomab (AALL1731, AALL1821), inotuzumab ozogamicin, and chimeric antigen receptor (CAR)-T cell therapy in patients with high-risk first relapse (NCT04276870, NCT02443831).
●Hospitalization – We generally hospitalize patients until recovery of blood counts to best manage infections, transfusion support, and other complications. Prophylaxis for Pneumocystis jirovecii (eg, sulfamethoxazole-trimethoprim, dapsone, or pentamidine) is routinely given, while prophylaxis for fungal, bacterial and viral agents varies among institutions [60,61].
●Outcomes – Response to the core reinduction regimen varies with the leukemic immunophenotype (ie, B versus T lineage), timing of relapse (ie, early versus late), and site of relapse (ie, bone marrow versus CNS or other extramedullary sites).
Children with first relapse of ALL/LBL have approximately 50 percent five-year overall survival (OS) [62]. In a cooperative group study of 124 children with first relapse of ALL/LBL, CR ranged from approximately 25 percent (T cell disease) to nearly 100 percent (late relapses); MRD <0.01 percent at end of induction was present in 25 percent for children with early relapses and 50 percent with late relapses [52]. Infection-related deaths during reinduction therapy occurred in 2 percent of patients.
Outcomes are likely to change as results emerge from ongoing studies that incorporate immunotherapy.
Post-remission management
B cell ALL/LBL — For children with r/r B cell ALL/LBL, post-remission management is guided by the risk category, which is determined by patient-specific clinical features, biology of the leukemic blasts, and response to reinduction therapy. Similar to de novo disease, response is assessed in the bone marrow and extramedullary sites at end-of-induction. (See 'Prognostic stratification' above.)
Low-risk B cell — Most studies use chemotherapy for a total of two years for children with low-risk disease.
There is no consensus approach for managing low-risk r/r B cell ALL/LBL. Some experts favor UKALL R3 because of its lower cumulative doses of chemotherapy compared with other regimens [49,51,63,64]. Other acceptable regimens include ALL-REZ-BFM 2002 [51], COG AALL0433 [63], or COG AALL07P1 [64]. (See 'Outcomes' below.)
Low-risk relapsed B cell ALL/LBL is associated with favorable prognosis and approximately 70 percent long-term OS. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents".)
Intermediate- or high-risk B cell — For children with intermediate-risk or high-risk relapsed B cell ALL/LBL, consolidation therapy is guided by response to reinduction therapy.
Our approach follows:
●≤25 percent blasts – For children who achieve CR (ie, <5 percent marrow blasts) or M2 marrow (5 to 25 percent blasts) at end-of-induction, we suggest post-remission treatment with blinatumomab, rather than standard chemotherapy, particularly if the patient has not previously been treated with blinatumomab or remains CD19+ after initial blinatumomab treatment. This suggestion is based on superior survival and less toxicity compared with conventional chemotherapy in a randomized clinical trial [65].
A phase 3 COG trial (AALL1331) of 214 patients (age 1 to 30 years) with first relapse of B cell ALL/LBL reported that, compared with chemotherapy, blinatumomab achieved superior OS, more patients were able to proceed to HCT, and there were fewer adverse events (AEs) [65]. After receiving a four-drug reinduction regimen, patients were randomly assigned to two four-week cycles of blinatumomab versus two cycles of multiagent chemotherapy, each followed by allogeneic HCT. For the blinatumomab and chemotherapy arms, two-year OS rates were 71 and 58 percent, respectively (hazard ratio [HR] for mortality 0.62 [95% CI 0.39-0.98]), but disease-free survival (DFS; the primary end-point) was not significantly different (54 versus 39 percent; HR 0.70 [95% CI 0.47-1.03]). Compared with chemotherapy, patients treated with blinatumomab were more likely to proceed to transplantation (70 versus 43 percent) and achieve MRD negativity (75 versus 32 percent). There were fewer grade ≥3 AEs with blinatumomab, including infections (15 versus 65 percent), febrile neutropenia (5 versus 58 percent), sepsis (2 versus 27 percent), and mucositis (1 versus 28 percent).
For children treated with blinatumomab, further management is guided by subsequent MRD status.
•MRD-negative – If the child is MRD-negative after blinatumomab treatment, we generally proceed to allogeneic HCT as soon as a suitable donor is identified, because the durability of remission with blinatumomab is uncertain at present. Longer follow-up of AALL1331 and other studies may find that blinatumomab can achieve long-term disease control without transplantation. (See 'Blinatumomab (anti-CD19)' below.)
For some children with late relapse (ie, >36 months) who are MRD-negative, consolidation chemotherapy alone (eg, per UKALL R3, ALL-REZ-BFM 2002, COG AALL0433) is associated with approximately 70 percent long-term OS [49,51,63].
•MRD-positive – We generally seek to convert children who are MRD-positive (eg, ≥0.01 percent) after receiving blinatumomab to MRD-negative status, followed by allogeneic HCT. Leukemic blasts should be re-evaluated for expression of CD19 to avoid the possibility of not responding to further CD19-directed therapy [66].
Options for achieving MRD-negative status with B cell ALL/LBL include:
-Additional blinatumomab.
-Inotuzumab ozogamicin (anti-CD22 monoclonal antibody); importantly, inotuzumab has been associated with sinusoidal obstruction syndrome (SOS) both pre- and post-HCT. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in children".)
-Chimeric antigen receptor (CAR)-T cell therapy (if available).
We generally proceed to allogeneic HCT after achieving MRD-negative status because the long-term durability of response with these approaches is uncertain at present. Importantly, outcomes are better when transplantation is performed when the patient is MRD-negative [67].
Treatment and outcomes with blinatumomab, inotuzumab ozogamicin, and allogeneic HCT are discussed below. (See 'Treatment regimens' below.)
●>25 percent blasts – For children with an M3 marrow (>25 percent marrow blasts) at end-of-induction, treatment is similar to that for MRD-positive patients (above). Achieving MRD-negative status may require several additional cycles of blinatumomab or treatment with either inotuzumab ozogamicin or CAR-T cell therapy.
T cell ALL/LBL — Consolidation therapy for children with first relapse or primary refractory T cell ALL/LBL is guided by bone marrow examination at the end of induction. Outcomes are generally less favorable for patients with relapsed T cell ALL/LBL disease, compared with relapsed B cell disease.
●MRD-negative – In general, we proceed to allogeneic HCT using the best available donor as soon as an MRD-negative CR is achieved. (See 'Allogeneic transplantation' below.)
●MRD-positive or less than CR – For patients with T cell ALL/LBL who are MRD-positive at end-of-induction, therapeutic options include nelarabine, bortezomib, daratumumab, or venetoclax/navitoclax.
We generally favor nelarabine if it was not given during initial therapy. A COG phase 2 study (AALL07P1) suggested that bortezomib was associated with improved CR rates in T cell ALL/LBL [68]. Bortezomib had an encouraging signal in COG AALL1231, particularly with lymphoblastic lymphoma, but the trial closed before the effectiveness of bortezomib for T cell lymphoblastic leukemia could be determined [69].
OUTCOMES — Outcomes for pediatric patients with relapsed or refractory (r/r) ALL/LBL have generally been poor, with long-term survival in only one-half of patients. Outcomes are related to time to relapse and site of relapse.
Outcomes for relapsed ALL/LBL are associated with the duration of first complete remission (CR1) and the number of previous salvage attempts [63,70,71]. Early relapse (ie, <36 months after initial diagnosis for bone marrow relapse or <18 months after initial diagnosis for isolated extramedullary relapse) are associated with inferior outcomes.
Allogeneic hematopoietic cell transplantation (HCT) is the only proven curative therapy for early relapse of B cell ALL/LBL. At present, it is uncertain if patients treated with chimeric antigen receptor (CAR)-T cells or other immunotherapy can maintain long-term remission without subsequent HCT [72]. Chemotherapy alone may be sufficient for selected patients with late relapses of B cell ALL/LBL or late isolated central nervous system (CNS) relapses of T cell ALL/LBL [14,63].
Examples of studies of r/r ALL/LBL include:
●UKALL R3 – In this trial, patients (1 to 18 years) were stratified into standard-, intermediate-, or high-risk groups (based on the duration of CR1, site of relapse, and immunophenotype) and randomly assigned to mitoxantrone versus idarubicin on days 1 and 2 of reinduction therapy [63]. The high-risk group and patients in the intermediate-risk group who were measurable residual disease (MRD)-positive at end-of-induction (ie, ≥10-4 cells) underwent allogeneic HCT. With median follow-up of seven years, progression-free survival (PFS) was 60 percent. Mitoxantrone achieved superior three-year overall survival (OS; 69 versus 45 percent) and three-year PFS (65 versus 36 percent). Among the 92 children who underwent transplantation, 63 percent remained in second CR (CR2), 14 percent died of complications, and 23 percent relapse after transplantation; among the 70 patients who continued on chemotherapy alone, 70 percent remained in CR2, 3 percent died of complications, and 27 percent relapsed [70]. After five years, PFS was 56 percent for MRD-positive patients and 72 percent for MRD-negative patients [70].
Superior survival with mitoxantrone in UKALL R3 must be balanced against increased cardiotoxicity; mitoxantrone is associated with a 10-fold increased risk of permanent cardiotoxicity compared with doxorubicin [73].
●COG AALL01P2 – This study reported that undetectable MRD (by flow cytometry) after one cycle of reinduction therapy was associated with better outcomes [52]. Children with first bone marrow (BM) relapse (69 with early relapse and 55 with late relapse) were treated with three 35-day blocks of reinduction chemotherapy. For early versus late relapse, rates of CR2 after cycle 1 were 68 and 96 percent, respectively, and rates of MRD-positive (>0.01 percent) were 75 and 51 percent. For children who were MRD-positive after block 1, MRD burden was reduced in 40 of 56 patients following blocks 2 and 3. Toxicity was acceptable during all three blocks, with 4 percent deaths from infections.
Similar results were obtained in a study (COG AALL07P1) of 146 patients who were treated with the same induction regimen plus bortezomib [68].
●ALL-REZ BFM 90 – This study stratified 525 patients (<19 years) into risk groups: A (early BM relapse), B (late BM relapse), and C (isolated extramedullary relapse) and were treated with alternating short-course intensive chemotherapy and cranial/craniospinal irradiation followed by maintenance therapy [46]. Patients in the poor-prognosis groups (ie, groups A or B) were eligible for either treatment based on in vitro resistance profiles or for pilot protocols using treatments planned for a subsequent study of relapsed disease. A total of 117 patients received HCT. CR2 was achieved by 84 percent (83, 94, and 100 percent in groups A, B, and C, respectively), 5 percent died during induction, and 11 percent did not show response; 117 patients received HCT. Duration of CR1, site of relapse, immunophenotype, and transplantation were associated with event-free survival in multivariate analysis.
Outcomes of treatment for isolated CNS or other extramedullary relapse are discussed below.
SPECIAL SCENARIOS
Philadelphia chromosome (Ph)-positive — The t(9;22)/BCR::ABL1 rearrangement (Philadelphia chromosome) generates the constitutively active tyrosine kinase, BCR::ABL1. Ph+ ALL/LBL accounts for <5 percent of children at initial diagnosis and is considered an adverse prognostic feature [74,75]. Either B cell or T cell ALL/LBL can be Ph+. Development of BCR::ABL1 tyrosine kinase inhibitors (TKI) has greatly improved outcomes in children with Ph-positive disease.
BCR::ABL1 kinase domain (KD) mutation analysis (eg, T315I) should be performed. An appropriate TKI should be added to the reinduction regimen, but management is otherwise similar to that for relapsed or refractory (r/r) Ph-negative disease. Allogeneic hematopoietic cell transplantation (HCT) is generally used as first-line consolidation for relapsed Ph+ ALL/LBL, if not previously performed.
Examples of mutation-guided selection of a TKI are presented separately. (See "Overview of the treatment of chronic myeloid leukemia", section on 'Disease resistance'.)
Ph-like ALL/LBL — Ph-like ALL/LBL is a subgroup of B cell ALL/LBL that occurs in approximately 15 percent of pediatric patients and is associated with unfavorable prognosis [76].
Management is similar to that of other Ph-negative ALL/LBL. Most cases of r/r Ph-like ALL/LBL have cytokine receptor or kinase-activating alterations (eg, CRLF2 or JAK) and ongoing studies are examining the role of JAK inhibitors (eg, ruxolitinib) or TKIs in treatment [77-79]. IKZF1 mutations are frequent and associated with a poor prognosis; overall survival (OS) is 30 to 60 percent, with outcomes that are generally better in younger patients.
Isolated CNS or extramedullary relapse — Children with a relapse limited to the central nervous system (CNS) or another extramedullary site (eg, testis) generally have better prognosis than those with a bone marrow relapse.
These children require distinctive treatment, which may include radiation therapy (RT) [51,80,81]. Nevertheless, the greatest cause of treatment failure in these patients is a systemic (ie, bone marrow) relapse, so they also require therapy for systemic relapse, as discussed above. (See 'First relapse or primary refractory ALL/LBL' above.)
●Isolated CNS relapse – Children with an isolated CNS relapse (ie, no apparent systemic relapse) have better prognosis than those with a bone marrow relapse, but both require systemic and CNS-directed treatments [80]. An Ommaya reservoir placement can be considered for frequent delivery of intraventricular CNS therapy.
•Management – Treatment varies according to the interval since diagnosis and institutional approach:
-Late isolated CNS relapse – For late isolated CNS relapse (≥18 months after diagnosis), we favor two years of intensive chemotherapy with delayed cranial radiation (18 gray [Gy]) at around 12 months [82,83].
For late isolated CNS relapses, event-free survival (EFS) is 75 to 80 percent; treatment using intermediate- or high-dose methotrexate and cytarabine with delayed RT (to maximize early delivery of intensive chemotherapy) is associated with approximately 50 percent longer term EFS, but substantial systemic and CNS adverse effects (AEs) [82].
POG 9412 reported that 12 months of intensive chemotherapy with reduced-dose cranial radiation (18 Gy) was highly effective for children with isolated CNS relapse and first complete remission (CR1) ≥18 months [82]. Treatment included intensified systemic therapy and delay of cranial radiation for 12 months. Nearly all (97 percent) achieved CR2, and four-year EFS for patients with B cell disease was 70 percent. Compared with children who had CR1 <18 months, patients with late relapse had superior four-year EFS (78 versus 52 percent). Most relapses involved the bone marrow, and three second malignancies were reported.
In COG AALL02P2, 118 patients with late isolated CNS relapse of B cell ALL/LBL were treated with intensified systemic therapy, triple intrathecal (IT) chemotherapy, 12 Gy cranial irradiation at 12 months, with maintenance chemotherapy continuing until 104 weeks post-diagnosis [84]. Three-year OS and EFS were 80 percent and 64 percent, respectively.
-Early isolated CNS relapse – For early isolated CNS relapse (<18 months after diagnosis), after achieving CR we generally proceed to allogeneic HCT with a total body irradiation (TBI) preparative regimen with a CNS boost.
Patients with early isolated CNS relapse do less well, compared with late isolated CNS relapse with 40 to 50 percent three-year OS [83].
Preference for allogeneic HCT for early isolated CNS relapse is based on trends toward improved outcomes using HCT rather than chemotherapy/cranial RT alone in COG AALL0433, UKALL R3, and single-institution studies [51,83,85].
Ongoing studies are exploring how to reduce acute and long-term toxicities from intensive chemotherapy and cranial RT; importantly, there was an increase in treatment failures when cranial RT was reduced to 12 cGy, compared with 18 Gy in COG AALL02P2 [86]. Chimeric antigen receptor (CAR)-T cells circulate in the cerebrospinal fluid [87] and a clinical trial is testing this modality for isolated CNS relapse (NCT04276870). CAR-T cell therapy may be useful if the response to reinduction was suboptimal, transplantation is contraindicated, or the patient is very young (because of increased risk of long-term neurologic toxicity following cranial RT) [88].
●Isolated extramedullary relapse – Isolated extramedullary relapse is associated with inferior outcomes compared with isolated CNS relapse.
Many patients with isolated extramedullary relapses have detectable measurable residual disease (MRD) in bone marrow at the time of relapse [89,90]. We generally treat patients with isolated extramedullary relapse according to either POG 9412 [82] or COG AALL02P2 [84]. We pursue allogeneic HCT only in patients who remain MRD-positive at end-of-induction, because of the association of MRD with adverse outcomes [91,92].
Retrospective analysis of children with isolated extramedullary relapse reported that, for very early isolated extramedullary relapses (<18 months), HCT was associated with improved long-term survival, compared with chemotherapy/RT (52 versus 20 to 30 percent) [93].
SECOND OR LATER RELAPSE — Outcomes are inferior for second or later relapse, compared with first relapse. We encourage enrollment in a clinical trial when possible.
Multiply relapsed B cell ALL/LBL — Management of multiply relapsed ALL/LBL is guided by prior therapy. ALL/LBL that relapses after both allogeneic hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR)-T cell therapy is especially challenging. We offer palliative therapy to lessen symptoms for all children [94]. ALL/LBL that relapses after allogeneic HCT historically has had a dismal prognosis, with increased complications and long-term survival of only 25 to 30 percent in those who achieved complete remission (CR) [95-98]. Time between transplantation and subsequent relapse is prognostic, with low survival for relapse within 6 to 12 months, but outcomes are better for those who relapse >12 months after HCT and undergo a second transplant in remission [98].
When ALL/LBL relapses after CAR-T cell therapy, it can be CD19+ or CD19-negative (so-called antigen escape). Mechanisms of antigen escape include point mutations, frameshift mutations, and alternative splicing of CD19 transcripts that remove the domain recognized by the CAR-T cell anti-CD19 antibody [99,100]. Following CAR-T cell therapy, there may be an increased risk for a CD19-negative relapse or failure to achieve MRD-negativity [101].
Our general approach follows:
●CD19-negative – If the relapse is CD19-negative, we generally treat with chemotherapy, second transplant, or CD22-directed CAR-T cell therapy (NCT02315612, NCT04088864, NCT02650414), because blinatumomab and anti-CD19 CAR-T cells are not options. Inotuzumab ozogamicin can be given if the blasts are CD22-positive, but it may increase the risk of hepatic sinusoidal obstruction syndrome (veno-occlusive disease) with transplantation, particularly if multiple cycles are administered [102,103].
●CD19+ – If the relapse is CD19+, in addition to the options mentioned above, blinatumomab or treatment with CD19-directed CAR-T cell therapy may be considered.
Comprehensive genomic profiling may identify a potentially targetable gene alteration. Examples include treatment with an mTOR inhibitor (NCT01523977; NCT01614197, NCT03328104, NCT01614197), proteasome inhibitor (NCT02303821, NCT03888534, NCT03817320), CDK4/6 inhibitor (NCT03792256, NCT03515200), or BCL-2 inhibitor (NCT03236857) in combination with chemotherapy. Treatment for these patients is best performed in the context of a clinical trial for patients with multiply relapsed disease.
Multiply relapsed T cell ALL/LBL — Options include:
●Combination chemotherapy – Regimens that include nelarabine or bortezomib may be considered. (See 'Other agents' below.)
Nelarabine, cyclophosphamide, and etoposide (NECTAR) showed high CR rates with acceptable neurotoxicity, but concomitant administration of nelarabine and intrathecal (IT) chemotherapy should be avoided to reduce the risk of neurotoxicity; NECTAR may be more practical to administer after reinduction, especially if CNS involvement is present [104].
In COG AALL07P1, bortezomib is added to a prednisone-based four-drug reinduction platform [68]. Addition of bortezomib was effective for relapsed lymphoblastic lymphoma, but efficacy for T cell ALL is uncertain because a phase 2 study (AALL07P1) was not powered to determine efficacy and the phase 3 clinical trial was closed early [68].
●Immunotherapy – Immunotherapy has promise for relapsed or refractory (r/r) T cell ALL/LBL [105]. The CD38-directed monoclonal antibody, daratumumab, has shown preclinical activity in T cell and early T cell precursor ALL/LBL; daratumumab combined with chemotherapy is being tested in r/r T cell ALL/LBL (NCT03384654) [106].
●Cyclin inhibition – The cyclin D-CDK4/6 axis is implicated in T cell leukemogenesis and clinical trials are investigating the CDK4/6 inhibitor, palbociclib, combined with chemotherapy (NCT03792256, NCT03515200) and ribociclib with everolimus (NCT03740334) [107,108].
●BCL2 inhibition – Venetoclax (selective BCL2 inhibitor) and/or navitoclax (inhibitor of BCL-2, BCL-XL, and BCL-W) have shown single-agent activity in preclinical models, synergistic activity in ALL xenografts, and promising activity in early phase clinical studies [109-112].
Other targeted approaches are being investigated for r/r T cell ALL/LBL [113]. NOTCH1 signaling is an attractive target because of the high frequency of mutations in this pathway. Development of gamma-secretase inhibitors that target the NOTCH1 pathway has been hampered by severe gastrointestinal toxicity, but more selective inhibitors may overcome this problem [25,26,114].
TREATMENT REGIMENS
Chemotherapy
Reinduction platform — All research groups use a four-drug reinduction chemotherapy regimen (ie, glucocorticoid, vincristine, anthracycline, calaspargase pegol), but choices of agents, doses, and schedules vary. The selected regimen should adhere to the prognostic and stratification schemes described in the trial chosen for overall therapy.
Choice of anthracycline and glucocorticoid may be influenced by the following:
●Anthracycline – There is no preferred anthracycline. Daunorubicin, which is associated with less cardiac toxicity ratio compared with doxorubicin, is frequently used, particularly prior to allogeneic hematopoietic cell transplantation (HCT). Some institutions favor mitoxantrone, based on a phase 3 trial that reported superior overall survival (OS) and progression-free survival (PFS) using mitoxantrone compared with daunorubicin [14]; however, mitoxantrone is more cardiotoxic than doxorubicin and daunorubicin, making it less attractive for treatment in children with prior cumulative anthracycline exposure >200 mg/m2.
●Glucocorticoid – The choice of glucocorticoid should be guided by the chosen protocol. Dexamethasone generally has greater anti-leukemic effect and better central nervous system (CNS) penetration than prednisone, but it is associated with increased toxicity (eg, avascular necrosis), especially in adolescents [115,116]. The current COG trial (AALL1821) uses dexamethasone.
Administration and toxicity of components of the core reinduction regimen are discussed separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Remission induction'.)
Other agents
●Nelarabine – Nelarabine is a purine nucleoside prodrug that is converted in vivo to ara-GTP. It has shown efficacy as a single agent for the treatment of relapsed or refractory (r/r) T cell ALL/LBL in children and adults.
Overall response rate (ORR) with nelarabine monotherapy was 55 percent for the first relapse and 27 percent for the second relapse in children and adolescents [54].
Administration and toxicity of nelarabine are discussed separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Nelarabine'.)
Nelarabine is approved by the US Food and Drug Administration (FDA) for treatment of r/r T cell ALL/LBL in children and adults.
●Bortezomib – Bortezomib is a proteasome inhibitor that prevents degradation of misfolded proteins. Bortezomib was shown to synergize with steroids in preclinical studies [117,118].
Response rates of 68 to 73 percent were reported in very early relapse of B cell and T cell ALL/LBL, when combined with chemotherapy [64,119]. Bortezomib has been tested in clinical trials for newly diagnosed T cell ALL/LBL [68,69,119]
●Clofarabine – Clofarabine is a deoxyadenosine analog that is approved by the US FDA for treatment of children (1 to 21 years) with r/r ALL/LBL who have experienced treatment failure with two prior regimens.
Informative studies of clofarabine in children with r/r ALL/LBL include:
•In a multicenter study, 61 heavily pretreated children (1 to 20 years) received a median of three cycles of clofarabine and achieved an ORR of 30 percent (seven complete response [CR], five CR without platelet recovery, six partial remissions) [120]. The most common grade ≥3 adverse events (AEs) were febrile neutropenia, anorexia, hypotension, and nausea.
•A retrospective multicenter study reported 61 percent ORR (52 percent CR) among children treated with clofarabine alone or combined with other agents; half of the children were able to proceed to allogeneic HCT [121].
Clofarabine has been combined with other cytotoxic chemotherapy, including etoposide, cyclophosphamide, and cytarabine, but such regimens were associated with high rates of infections and other AEs [122,123].
Use of clofarabine in adults with r/r ALL/LBL is discussed separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Clofarabine'.)
Blinatumomab (anti-CD19) — Blinatumomab is a bispecific T cell engager (BiTE) anti-CD3/CD19 monoclonal antibody that directs CD3+ effector memory T cells to CD19+ ALL/LBL tumor cells.
The phase 3 trial (COG AALL1331) reported superior survival with blinatumomab, compared with chemotherapy consolidation [65], as described above. (See 'Intermediate- or high-risk B cell' above.)
Blinatumomab is approved by the US FDA for children with relapsed B-ALL/LBL.
Inotuzumab ozogamicin (anti-CD22) — Inotuzumab ozogamicin was associated with 67 percent CR with r/r ALL/LBL, as part of a compassionate-use program in pediatric patients (age range of 2 to 21 years) [102].
In a phase 3 trial in adults with r/r ALL/LBL, compared with standard intensive chemotherapy, treatment with inotuzumab ozogamicin achieved superior OS, PFS, CR, duration of remission, and measurable residual disease (MRD)-negative status [103], as discussed separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Inotuzumab ozogamicin'.)
Inotuzomab ozogamicin was granted fast-track approval by the US FDA and the European Medicines Agency (EMA) for adult patients with r/r ALL/LBL. However, inotuzumab has been associated with hepatic sinusoidal obstruction syndrome (SOS; also called veno-occlusive disease) both pre- and post-HCT, resulting in the closure and dose reduction of two contemporary clinical trials.
Use of inotuzomab ozogamicin in adults is described separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Inotuzumab ozogamicin'.)
CAR-T cell therapy — Chimeric antigen receptor (CAR)-T cells are a form of genetically modified autologous immunotherapy that can be directed at B cell ALL/LBL. This is a customized treatment in which the individual's own T lymphocytes are genetically modified (transduced) with a gene that encodes a CAR to direct the patient's T cells against the leukemic cells, a process that takes four to eight weeks. The T cells are genetically modified ex vivo, expanded in a production facility, and then infused back into the patient.
As with other immunotherapies, CAR-T cells depend on expression of their target antigen; loss of the target is a major mechanism by which tumor cells can escape immunotherapy, as discussed above. (See 'Multiply relapsed B cell ALL/LBL' above.)
CAR-T cell therapy is associated with neurologic events and cytokine release syndrome (CRS; a systemic response with high fever, flu-like symptoms, hypotension, mental status changes). Facilities that dispense these products require special certification, staff must be trained to recognize and manage its adverse events, and tocilizumab (a humanized monoclonal antibody against the interleukin 6 receptor) must be available for immediate administration. In the United States, tisagenlecleucel is only available through a risk evaluation and mitigation strategy (REMS), and its label carries a boxed warning for neurologic events and for CRS. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'CAR-T'.)
Tisagenlecleucel is a CD19-directed CAR-T cell immunotherapy that may achieve long-term survival after r/r ALL/LBL, including those with low-level CNS disease. Early efficacy of CD19-redirected CAR T-cells in r/r ALL is well-established [72,124-126]. Tisagenlecleucel was associated with 65 to 90 percent ORR for r/r pediatric ALL/LBL [127]. Most studies show that 25 to 50 percent of patients who achieve CR with CAR-T cell therapy subsequently relapse; longer follow-up is needed to better define the relapse risk [128].
●In a single-center study, a single infusion of tisagenlecleucel achieved 81 percent CR, and all patients who had a response were negative for MRD by flow cytometry [72]. At six months, rates of OS and EFS were 90 and 73 percent, respectively; corresponding rates at 12 months were 76 and 50 percent. However, grade ≥3 AEs occurred in 73 percent.
●A multicenter trial of 63 pediatric and young adult patients reported an 83 percent overall remission rate (including 63 percent CR and 19 percent CR with incomplete hematologic recovery); all responding patients were negative for MRD by flow cytometry [129].
Tisagenlecleucel is approved by the US FDA for treatment of patients ≤25 years of age with primary refractory or second or later relapse of B cell ALL/LBL [130].
Allogeneic transplantation — Allogeneic HCT is considered the only modality that can reliably cure r/r ALL/LBL.
We proceed to allogeneic HCT for most children with r/r ALL/LBL, including early and very early relapse, T cell ALL/LBL, and poor MRD response (note that threshold levels of MRD vary among research groups). Exceptions include [5]:
●Late (>18 months) isolated CNS or other extramedullary site (eg, testis) relapse
●Late medullary (bone marrow) relapse (>3 years) with MRD-negativity at end-of-induction
●Children who are medically-unfit for transplantation
We pursue transplant using the best available donor, since survival rates are similar with HCT using human leukocyte antigen (HLA)-matched siblings, fully matched unrelated donors, and haploidentical donors [131,132].
Reports of allogeneic HCT for r/r ALL/LBL include retrospective studies that suggest patients with primary refractory disease or T cell ALL/LBL have superior outcomes with transplantation [7,133-135]. In a study that compared transplantation versus chemotherapy alone, OS was similar for the 198 patients who underwent HCT (43 percent) and the 427 patients who received chemotherapy alone (41 percent). However, the effect of HCT on survival differed according to cytogenetic risk subgroup. As an example, children <6 years with B cell ALL/LBL without KMT2A rearrangement (ie, low-risk) had higher OS when treated with chemotherapy, compared with HCT (73 versus 59 percent). By contrast, older children, those with elevated white blood cell counts, T cell ALL/LBL, and additional cytogenetic risk factors had higher OS with a matched related donor HCT rather than chemotherapy alone (59 versus 35 percent). A similar study in Europe showed that adolescents and young adults with T cell ALL/LBL also did better with allogeneic HCT compared with chemotherapy alone (67 versus 42 percent) [133].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute lymphoblastic leukemia".)
SUMMARY AND RECOMMENDATIONS
●Descriptions – Relapsed and refractory (r/r) acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) are defined as follows (see 'Descriptions' above):
•Primary refractory ALL/LBL – Primary refractory leukemia refers to persistence of leukemic blasts in blood, marrow, or extramedullary site after four to six weeks of induction therapy; this is frequently defined as either >1 percent blasts (M1 marrow morphology) or measurable residual disease (MRD) >1 percent at the end of induction or the end of consolidation.
•Relapsed ALL/LBL – Recurrence of ALL/LBL at any point after achieving complete remission (CR).
●Pathogenesis – Genetic causes of r/r ALL/LBL differ for B cell and T cell ALL/LBL. (See 'Pathogenesis' above.)
●Pretreatment evaluation – The pretreatment evaluation includes immunophenotype and cytogenetic/molecular features of leukemic blasts and prognostic stratification, based on clinical and pathologic features. (See 'Clinical and laboratory evaluation' above and 'Prognostic stratification' above.)
●Treatment – Treatment of r/r ALL/LBL involves remission reinduction therapy, central nervous system (CNS) management, and consolidation therapy (eg, immunotherapy, chemotherapy, and/or allogeneic hematopoietic cell transplantation [HCT]).
Treatment should adhere to a contemporary research protocol at a site with substantial experience in managing pediatric ALL/LBL. Participation in a clinical trial is encouraged.
•CNS management – All children with r/r ALL/LBL should receive either prophylaxis or treatment of CNS involvement, according to clinical symptoms, findings from lumbar puncture, and/or imaging. (See 'CNS management' above.)
•Reinduction therapy – We treat with a four-drug reinduction regimen (eg, dexamethasone or prednisone, vincristine, mitoxantrone, calaspargase pegol). Other agents may be added to the four-drug platform for children with certain pathologic features. (See 'Reinduction therapy' above.)
•Post-remission – Management varies with immunophenotype, risk group, and response to reinduction therapy:
-Low-risk disease B cell – We favor consolidation chemotherapy, as guided by the chosen research protocol. Blinatumomab may be added if there are additional high-risk features. (See 'Low-risk B cell' above.)
-Intermediate/high-risk B cell – For children with ≤25 percent blasts at end-of-induction, we suggest blinatumomab, rather than consolidation chemotherapy (Grade 2C). (See 'Intermediate- or high-risk B cell' above.)
For children with >25 percent marrow blasts at end-of-induction, we treat with blinatumomab, inotuzumab ozogamicin, or chimeric antigen receptor (CAR)-T cell therapy.
-T cell – Management is guided by MRD status at end-of-induction; prompt allogeneic HCT for MRD-negative or other options to achieve MRD negativity for others. (See 'T cell ALL/LBL' above.)
●Special scenarios – Philadelphia chromosome (Ph)-positive or Ph-like ALL/LBL and isolated CNS or extramedullary relapse are described above. (See 'Special scenarios' above.)
●Treatments – Chemotherapy, immunotherapy, and allogeneic HCT are described above. (See 'Treatment regimens' above.)
●Second or later relapse – Management of multiply relapsed ALL/LBL is guided by prior therapy, as described above. (See 'Second or later relapse' above.)
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