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

In This Section

• Prognostic Factors After First Relapse of Childhood ALL
  • Site of relapse
  • Time from diagnosis to relapse
  • Patient characteristics
  • Risk group classification at initial diagnosis
  • Response to reinduction therapy
  • Cytogenetics/genomic alterations
  • Immunophenotype
• Standard Treatment Options for First Bone Marrow Relapse of Childhood ALL
  • Reinduction chemotherapy
  • Postreinduction therapy for patients achieving a second complete remission
• Treatment Options for Second and Subsequent Bone Marrow Relapse
• Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse
  • Components of the transplantation process
  • Intrathecal medication after HSCT to prevent relapse
  • Relapse after allogeneic HSCT for relapsed ALL
• Immunotherapeutic Approaches for Refractory ALL
  • Monoclonal antibody therapy
  • CAR T-cell therapy
• Treatment of Isolated Extramedullary Relapse
  • Isolated CNS relapse
  • Isolated testicular relapse
• Treatment Options Under Clinical Evaluation for Relapsed Childhood ALL
  • Trials for ALL in first relapse
  • Trials for ALL in second or subsequent relapse or refractory ALL
  • Current Clinical Trials

Prognostic Factors After First Relapse of Childhood ALL

The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on multiple factors.[1-14]; [15][Level of evidence: 3iiDi]

The following two important risk factors after first relapse of childhood ALL are key to determining prognosis and treatment approach:

• Site of relapse.
• Time from diagnosis to relapse.

Other prognostic factors include the following:

• Patient characteristics (e.g., age and peripheral blast count at time of relapse).
• Risk group classification at initial diagnosis.
• Response to reinduction therapy.
• Cytogenetics/genomic alterations.
• Immunophenotype.

Site of relapse

Patients who have isolated extramedullary relapse fare better than those who have relapse involving the marrow. In some studies, patients with combined marrow/extramedullary relapse had a better prognosis than did those with a marrow relapse; however, other studies have not confirmed this finding.[5,13,16]

Time from diagnosis to relapse

For patients with relapsed B-ALL, early relapses fare worse than later relapses, and marrow relapses fare worse than isolated extramedullary relapses. For example, survival rates range from less than 20% for patients with marrow relapses occurring within 18 months from diagnosis to higher than 60% for those whose relapses occur more than 36 months from diagnosis.[5,13,17]

For patients with isolated central nervous system (CNS) relapses, the overall survival (OS) rates are 40% to 50% for early relapse (<18 months from diagnosis) and 75% to 80% for those with late relapses (>18 months from diagnosis).[13,18] No evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) in off-therapy patients improves outcome.[19]

Patient characteristics

Age 10 years and older at diagnosis and at relapse have been reported as independent predictors of poor outcome.[13,16] A Children’s Oncology Group (COG) study further showed that although patients aged 10 to 15 years at initial diagnosis do worse than patients aged 1 to 9 years (35% vs. 48%, 3-year postrelapse survival), those older than age 15 years did much worse (3-year OS rate, 15%; P = .001).[20]

The Berlin-Frankfurt-Münster (BFM) group has also reported that high peripheral blast counts (>10,000/μL) at the time of relapse were associated with inferior outcomes in patients with late marrow relapses.[10]

Children with Down syndrome ALL who relapse have generally had inferior outcomes resulting from increased induction deaths, treatment-related mortality, and relapse.

• The BFM group showed that since 2000, improvements in supportive care have led to decreases in treatment-related mortality in children with Down syndrome, but the risk of relapse remains high.[21]
• An analysis of data from the Center for International Blood and Marrow Transplant Research (CIBMTR) on 27 Down syndrome patients with ALL who underwent hematopoietic stem cell transplantation (HSCT) between 2000 and 2009 substantiated this finding. They noted that with current transplant practices, hematopoietic recovery, graft-versus-host disease (GVHD), and transplant-related mortality were within the expected range compared with non–Down syndrome ALL patients. However, relapse was higher than expected (>50%) and was the primary cause of treatment failure, leading to poor survival (24% disease-free survival [DFS] rate at 3 years).[22][Level of evidence: 3iiiA]

Risk group classification at initial diagnosis

The COG reported that risk group classification at the time of initial diagnosis was prognostically significant after relapse; patients who met National Cancer Institute (NCI) standard-risk criteria at initial diagnosis fared better after relapse than did NCI high-risk patients.[13]

Response to reinduction therapy

Patients with marrow relapses who have persistent morphologic disease at the end of the first month of reinduction therapy have an extremely poor prognosis, even if they subsequently achieve a second complete remission (CR).[23][Level of evidence: 2Di]; [24][Level of evidence: 3iiiA] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of second CR are of prognostic significance in relapsed ALL.[23,25-27]; [28][Level of evidence: 3iiiDi] High levels of MRD at the end of reinduction and at later time points have been correlated with an extremely high risk of subsequent relapse.

Cytogenetics/genomic alterations

Changes in mutation profiles from diagnosis to relapse have been identified by gene sequencing.[29,30] While oncogenic gene fusions (e.g., TCF3-PBX1, ETV6-RUNX1) are almost always observed between the time of initial diagnosis and relapse, single nucleotide variants and copy number variants may be present at diagnosis, but not at relapse, and vice versa.[29] For example, while RAS family mutations are common at both diagnosis and relapse, the specific RAS family mutations may change from diagnosis to relapse as specific leukemic subclones rise and fall during the course of treatment.[29] By contrast, relapse-specific mutations in NT5C2 (a gene involved in nucleotide metabolism) have been noted in as many as 45% of ALL cases with early relapse.[29,31,32]

TP53 alterations (mutations and/or copy number alterations) are observed in approximately 11% of patients with ALL at first relapse and have been associated with an increased likelihood of persistent leukemia after initial reinduction (38.5% TP53 alteration vs. 12.5% TP53 wild-type) and poor event-free survival (EFS) rates (9% TP53 alteration vs. 49% TP53 wild-type).[33] Approximately one-half of the TP53 alterations were present at initial diagnosis and half were newly observed at time of relapse.[33] A second genomic alteration found to predict for poor prognosis in patients with B-ALL in first bone marrow relapse is IKZF1 deletion.[34] The frequency of IKZF1 deletion in B-ALL patients at first relapse was 33% in the Acute Lymphoblastic Leukemia Relapse (ALL-REZ) BFM 2002 (NCT00114348 ) study, which was approximately twice as high as the frequency described in children at initial diagnosis of ALL.[34]

RAS pathway mutations (KRAS, NRAS, FLT3, and PTPN11) are common at relapse in B-ALL patients, and they were found in approximately 40% of patients at first relapse in one study of 206 children.[29,35] As observed at diagnosis, the frequency of RAS pathway mutations at relapse differs by cytogenetic subtype (e.g., high frequency in hyperdiploid cases and low frequency in ETV6-RUNX1 cases). The presence of RAS pathway mutations at relapse was associated with early relapse. However, presence of RAS pathway mutations at relapse was not an independent predictor of outcome.

Patients with ETV6-RUNX1-positive ALL appear to have a relatively favorable prognosis at first relapse, consistent with the high percentage of such patients who relapse more than 36 months after diagnosis.[34,36]

• In the ALL-REZ BFM 2002 (NCT00114348) study, an EFS rate of 84% (± 7%) was observed for patients with ETV6-RUNX1 ALL with bone marrow relapse.[34] In this study, 94% of patients with ETV6-RUNX1 had a duration of first remission that extended at least 6 months beyond completion of their primary treatment, and on multivariate analysis, time to relapse (and not the presence of ETV6-RUNX1) was an independent predictor of outcome.
• Similarly, the 5-year OS rate for ETV6-RUNX1 patients enrolled on the French Acute Lymphoblastic Leukaemia Study Group (FRALLE) 93 trial who relapsed at any site more than 36 months after diagnosis was 81%, and the presence of ETV6-RUNX1 was associated with a favorable survival outcome compared with other late relapsing patients.[36] However, the 3-year OS rate of ETV6-RUNX1 patients who experienced an early relapse (<36 months) was only 31%.

Immunophenotype

Immunophenotype is an important prognostic factor at relapse. Patients with T-cell ALL who experience a marrow relapse (isolated or combined) at any time during treatment or posttreatment are less likely to achieve a second remission and long-term EFS than are patients with B-ALL.[5,23]

Standard Treatment Options for First Bone Marrow Relapse of Childhood ALL

Standard treatment options for first bone marrow relapse include the following:

1. Reinduction chemotherapy.
2. Postreinduction therapy for patients achieving a second CR.

Reinduction chemotherapy

Initial treatment of relapse consists of reinduction therapy to achieve a second CR. Using either a four-drug reinduction regimen (similar to that administered to newly diagnosed high-risk patients) or an alternative regimen including high-dose methotrexate and high-dose cytarabine, approximately 85% of patients with a marrow relapse achieve a second CR at the end of the first month of treatment.[5]; [37][Level of evidence: 2A]; [23][Level of evidence: 2Di] Patients with early marrow relapses have a lower rate of achieving a morphologic second CR (approximately 70%) than do those with late marrow relapses (approximately 95%).[23,37]

Evidence (reinduction chemotherapy):

1. A COG study used three blocks of intensive reinduction therapy with an initial four-drug combination including doxorubicin followed by two intensive consolidation blocks before either HSCT or chemotherapy continuation.[23]
   • Second remission was achieved after block 1 in 68% of patients with early relapse (<36 months from initial diagnosis) and in 96% of those with later relapse.
   • Blocks 2 and 3 reduced MRD in 40 of 56 patients who were MRD positive after block 1.
2. A United Kingdom–based randomized trial of ALL patients in first relapse compared reinduction with a four-drug combination using idarubicin versus mitoxantrone.[38][Level of evidence: 1iiA]
   • There was no difference in second CR rates or end-reinduction MRD levels between the two study arms.
   • A significant improvement in the OS rate in the mitoxantrone arm (69% vs. 45%; P = .007) resulting from decreased relapse after transplantation was reported.
   The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.
3. Investigators from the ALL-REZ BFM group used a six-drug reinduction approach, including high-dose methotrexate. A randomized comparison of 1 g/m2 of methotrexate delivered over 36 hours versus 5 g/m2 of methotrexate delivered over 24 hours with reinduction showed no difference in outcome, but the 36-hour infusion was associated with a higher incidence of mucositis.[39]
4. The combination of clofarabine, cyclophosphamide, and etoposide was reported to induce remission in 42% to 56% of patients with refractory or multiply relapsed disease.[40,41]; [42][Level of evidence: 2A]
5. The combination of bortezomib plus vincristine, dexamethasone, pegaspargase, and doxorubicin has been reported to induce complete response (with or without platelet recovery) in 70% to 80% of multiply relapsed patients with B-ALL.[43][Level of evidence: 3iiiA]; [44][Level of evidence: 3iiiDiv]

Patients with relapsed T-cell ALL have much lower rates of achieving second CR with standard reinduction regimens than do patients with B-cell phenotype.[23] Treatment of children with first relapse of T-cell ALL in the bone marrow with single-agent therapy using the T-cell selective agent, nelarabine, has resulted in response rates of approximately 50%.[45] The combination of nelarabine, cyclophosphamide, and etoposide has also been used in patients with relapsed/refractory T-cell ALL.[46]

Reinduction failure is a poor prognostic factor, but subsequent attempts to obtain remission can be successful and lead to survival after HSCT, especially if MRD becomes low or nondetectable (refer to the Late-relapsing B-ALL section of this summary for more information on MRD risk stratification). Approaches have traditionally included the use of drug combinations distinct from the first attempt at treatment; these regimens often contain newer agents under investigation in clinical trials. Although survival is progressively less likely after each attempt, two to four additional attempts are often pursued, with diminishing levels of success measured after each attempt.[47] Because studies of chimeric antigen receptor (CAR) T cells, blinatumomab, and inotuzumab have been shown to lead to high rates of remission in multiply relapsed and chemotherapy-refractory B-ALL patients (refer to the Immunotherapeutic Approaches for Refractory ALL section of this summary for more information), trials testing these agents after initial relapse are underway.

Postreinduction therapy for patients achieving a second complete remission

Early-relapsing B-ALL

For B-ALL patients with an early marrow relapse, allogeneic transplant from an HLA-identical sibling or matched unrelated donor that is performed in second remission has been reported in most studies to result in higher leukemia-free survival than a chemotherapy approach.[7,28,48-56] However, even with transplantation, the survival rate for patients with early marrow relapse is less than 50%. (Refer to the Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse section of this summary for more information.)

Late-relapsing B-ALL

Previous studies of late marrow relapse in patients with B-ALL showed that a primary chemotherapy approach after achievement of second CR resulted in survival rates of approximately 50%, and it was not clear whether allogeneic transplantation was associated with a superior cure rate.[5,9,38,57-59]; [60][Level of evidence: 3iiA] Subsequent data have shown that the presence of end-reinduction MRD identifies patients with a high risk of ensuing relapse if treated with chemotherapy alone (no HSCT) in second CR. A number of studies have shown that patients with a late marrow relapse who have high end-reinduction MRD have better outcomes if they receive an allogeneic HSCT in second CR after achieving low or nondetectable MRD status.[17,61]

Evidence (MRD-based risk stratification for late-relapse of B-ALL):

1. In a St. Jude Children's Research Hospital study, which included 23 patients with late relapses treated with chemotherapy in second CR, the 2-year cumulative incidence of relapse was 49% for the 12 patients who were MRD positive at the end of reinduction and 0% for the 11 patients who were MRD negative.[25]
2. In BFM studies, patients are considered to be intermediate risk if they have a late isolated marrow relapse or an early or late combined marrow/extramedullary relapse. In the ALL-REZ BFM P95/96 study from this group, end-reinduction MRD (assessed by a polymerase chain reaction–based assay) significantly predicted outcomes of children with intermediate-risk relapsed B-ALL treated with chemotherapy alone in second CR (no HSCT).[27]
   • Patients with low MRD (<10-3) had a 10-year EFS rate of 73%, while those with high MRD (≥10-3) had a 10-year EFS rate of 10%. On multivariate analysis, end-reinduction MRD was the strongest independent prognostic factor.
3. In a subsequent BFM study (ALL-REZ BFM 2002 [NCT00114348]), patients with intermediate-risk relapse were allocated to allogeneic HSCT if they had high MRD at the end of the first month of treatment. Those who had low end-reinduction MRD were treated with chemotherapy only (no HSCT).[61]
   • The EFS rate of patients with high end-reinduction MRD treated with allogeneic HSCT in second CR was 64%, which was significantly better than what had been observed on the previous P95/96 trial, during which such patients received chemotherapy without HSCT. The improvement in EFS was primarily because of a significantly lower risk of relapse in the cohort who underwent HSCT in second CR (cumulative incidence of relapse, 27% on the 2002 trial compared with 59% on the P95/96 trial).
   • Patients with late marrow-involved relapses and low end-reinduction MRD, treated with chemotherapy only, had a 5-year EFS rate of 76%, confirming the results seen in the previous P95/96 trial. However, the chemotherapy-only strategy resulted in a significantly worse outcome for patients with early-combined relapses (marrow plus extramedullary site) and low end-reinduction MRD; the 5-year EFS rate for these patients was only 37%. Because of this data, patients with early-combined relapses are now considered high risk on BFM trials.
4. The United Kingdom ALLR3 trial assigned patients who relapsed more than 6 months after completion of front-line therapy to HSCT if their end-reinduction MRD was ≥10-4 or to chemotherapy for those with MRD of <10-4.[17]
   • Of the 228 patients treated, 220 patients achieved CR; 127 patients were allocated to HSCT (high MRD) and 93 were allocated to chemotherapy (low or not evaluable MRD). Five-year EFS rates were 72% for patients with low MRD versus 56% for patients with high MRD; 5-year OS rates were 87% for low MRD and 64% for high end-reinduction MRD.
   • On the basis of this data, investigators from the United Kingdom recommend HSCT for late-relapsing patients with B-ALL who have MRD of ≥10-4 after reinduction therapy and chemotherapy alone for those with end-reinduction MRD of <10-4.

T-cell ALL

For patients with T-cell ALL who achieve remission after bone marrow relapse, outcomes with postreinduction chemotherapy alone have generally been poor,[5] and these patients are usually treated with allogeneic HSCT in second CR, regardless of time to relapse. At 3 years, the OS rate after allogeneic transplant for T-cell ALL in second remission was reported to be 48%, and the DFS rate was 46%.[62][Level of evidence: 3iiiA]

Treatment Options for Second and Subsequent Bone Marrow Relapse

Although there are no studies directly comparing chemotherapy with HSCT for patients in third or subsequent CR, because cure with chemotherapy alone is rare, transplant has generally been considered a reasonable approach for those achieving remission. Long-term survival for ALL patients after a second relapse is particularly poor, in the range of less than 10% to 20%.[54] One of the main reasons for this is failure to obtain a third remission. Numerous attempts at novel combination approaches have resulted in only about 40% of children in second relapse achieving remission.[63] However, two studies that added bortezomib to standard reinduction agents in multiply relapsed refractory patients have resulted in 70% to 80% CR rates.[43][Level of evidence: 3iiiA]; [44][Level of evidence: 3iiiDiv] If these patients achieve CR, HSCT has been shown to cure 20% to 35%, with failures occurring because of high rates of relapse and transplant-related mortality.[64-68][Level of evidence: 3iiA]

Given the poor outcomes for multiply relapsed B-ALL patients who are treated with chemotherapy followed by HSCT, CAR T-cell therapy has been tested in this population and has resulted in high rates of remission and improved short-term survival (long-term follow-up pending; refer to the CAR T-cell therapy section of this summary for more information). Immune therapies such as blinatumomab and inotuzumab have also greatly facilitated the achievement of remission, which has generally been followed by HSCT.[69,70] Comparative studies of immune and cell therapy approaches have yet to be performed in this population, so data to inform optimal approaches to first therapy or sequence of therapies are lacking.

Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse

Components of the transplantation process

An expert panel review of indications for HSCT was published in 2012.[71] Components of the transplant process that have been shown to be important in improving or predicting outcome of HSCT for children with ALL include the following:

1. Total-body irradiation (TBI)-containing transplant preparative regimens.
2. MRD detection just before transplant.
3. MRD detection posttransplant.
4. Donor type and HLA match.
5. Role of GVHD/graft-versus-leukemia (GVL) in ALL and immune modulation after transplant to prevent relapse.

TBI-containing transplant preparative regimens

For patients proceeding to allogeneic HSCT, TBI appears to be an important component of the conditioning regimen. Two registry studies and a small randomized trial showed that transplant conditioning regimens that include TBI resulted in higher cure rates than chemotherapy-only preparative regimens.[48,72,73] An international study (United States, Europe, and Australia) that combined data sets from prospective trials and single-center data showed that the use of non-TBI regimens was an independent risk factor for poor outcome. TBI for all but the youngest children (age <3 or 4 years) remains standard of care in most centers in North America and Europe.[62,67] Fractionated TBI (total dose, 12–14 Gy) is often combined with cyclophosphamide, etoposide, thiotepa, or a combination of these agents. Study findings with these combinations have generally resulted in similar rates of survival,[74-76] although one study suggested that if cyclophosphamide is used without other chemotherapy drugs, a dose of TBI in the higher range may be necessary.[77] Many standard regimens include cyclophosphamide with TBI dosing between 13.2 and 14 Gy. On the other hand, when cyclophosphamide and etoposide were used with TBI, doses above 12 Gy resulted in worse survival resulting from excessive toxicity.[75]

MRD detection just before transplant

Remission status at the time of transplantation has long been known to be an important predictor of outcome, with patients not in CR at HSCT having very poor survival rates.[78] Several studies have also demonstrated that the level of MRD at the time of transplant is a key risk factor in children with ALL in CR undergoing allogeneic HSCT.[26,79-86][Level of evidence: 3iiA]; [87][Level of evidence: 3iiB] Survival rates of patients who are MRD positive pretransplant have been reported between 20% and 47%, compared with 60% to 88% in patients who are MRD negative.

When patients have received two to three cycles of chemotherapy in an attempt to achieve an MRD-negative remission, the benefit of further intensive therapy for achieving MRD negativity must be weighed against the potential for significant toxicity. In addition, there is not clear evidence showing that MRD positivity in a patient who has received multiple cycles of therapy is a biological disease marker for poor outcome that cannot be modified, or whether further intervention bringing such patients into an MRD negative remission will overcome this risk factor and improve survival.

• In one report, 13 patients with ALL and high MRD at the time of planned transplant received an additional cycle of chemotherapy in an attempt to lower MRD before proceeding to HSCT. Ten of the 13 patients (77%) remained in CR post-HSCT, with no relapses observed in the eight patients who achieved low MRD after the additional chemotherapy cycle. In comparison, only 6 of 21 high-MRD patients (29%) who proceeded directly to HSCT without receiving additional pre-HSCT chemotherapy remained in CR.[80]

MRD detection posttransplant

The presence of detectable MRD post-HSCT has been associated with an increased risk of subsequent relapse.[86,88-91] The accuracy of MRD for predicting relapse increases as time from HSCT elapses and relapse risk is higher for patients who have higher levels of MRD detected at any given time. One study showed higher sensitivity for predicting relapse using next-generation sequencing assays than with flow cytometry, especially early after HSCT.[90]

Donor type and HLA match

Survival rates after matched unrelated donor and umbilical cord blood transplantation have improved significantly over the past decade and offer an outcome similar to that obtained with matched sibling donor transplants.[52,92-95]; [96,97][Level of evidence: 2A]; [98][Level of evidence: 3iiiA]; [99][Level of evidence: 3iiiDii] Rates of clinically extensive GVHD and treatment-related mortality remain higher after unrelated donor transplantation compared with matched sibling donor transplants.[53,64,92] However, there is some evidence that matched unrelated donor transplantation may yield a lower relapse rate, and National Marrow Donor Program and CIBMTR analyses have demonstrated that rates of GVHD, treatment-related mortality, and OS have improved over time.[100-102]; [103,104][Level of evidence: 3iiA]

Another CIBMTR study suggests that outcome after one or two antigen mismatched cord blood transplants may be equivalent to that for a matched family donor or a matched unrelated donor.[105] In certain cases in which no suitable donor is found or an immediate transplant is considered crucial, a haploidentical transplant utilizing large doses of stem cells may be considered.[106] Improved approaches to haploidentical HSCT using alpha-beta T-cell receptor (TCR)/CD19 depletion or posttransplant cyclophosphamide have shown survival rates that are similar to those in studies using other stem cell sources.[107] A large multicenter trial from Italy showed similar outcomes using alpha-beta TCR/CD19–depleted haploidentical donors compared with matched unrelated donors, with lower rates of GVHD.[108]

Role of GVHD/GVL in ALL and immune modulation after transplant to prevent relapse

Most studies of pediatric and young adult patients that address this issue suggest an effect of both acute and chronic GVHD in decreasing relapse.[92,109-111]

• In a COG trial of transplantation for children with ALL, grades I to III acute GVHD were associated with lower relapse risk (hazard ratio [HR], 0.4; P = .04) and better EFS (multivariate analysis, HR, 0.5; P = .02). Any effect of grade IV acute GVHD in decreasing relapse risk was obscured by a marked increase in transplant-related mortality (HR, 6.4; P = .003), while grades I to III acute GVHD had no statistically detectable effect on transplant-related mortality (HR, 0.6; P = .42).[111]
• In a multivariate model, both pretransplant MRD and acute GVHD were independent predictors of relapse, with the lowest risk of relapse observed in patients with both low pretransplant MRD and grades I to III acute GVHD.[89] For patients who did not develop acute GVHD by day 55 post-HSCT, nearly all relapses occurred between days 100 and 400 post-HSCT.

Harnessing this GVL effect, a number of approaches to prevent relapse after transplantation have been studied, including withdrawal of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal antibodies and natural killer cell therapy.[112,113] Trials in Europe and the United States have shown that patients defined as having a high risk of relapse based on increasing recipient chimerism (i.e., increased percentage of recipient DNA markers) can successfully undergo withdrawal of immune suppression without excessive toxicity.[114,115]

• One study showed that in 46 patients with increasing recipient chimerism, the 31 patients who underwent immune suppression withdrawal, donor lymphocyte infusion, or both therapies had a 3-year EFS rate of 37% versus 0% in the nonintervention group (P < .001).[116]
• Other studies have shown better-than-expected rates of survival of pre-HSCT, MRD-positive patients when tapering has occurred for MRD detected after HSCT.[117]

Intrathecal medication after HSCT to prevent relapse

The use of post-HSCT intrathecal chemotherapy chemoprophylaxis is controversial.[118-121]

Relapse after allogeneic HSCT for relapsed ALL

For patients with B-ALL who relapse after allogeneic HSCT and can be successfully weaned from immune suppression and have no GVHD, tisagenlecleucel and other 4-1BB CAR T-cell approaches have resulted in EFS rates exceeding 50% at 12 months.[122] For patients with T-cell ALL who relapse or for patients with B-ALL who are unable to undergo CAR T-cell therapy, a second ablative allogeneic HSCT may be feasible. However, many patients will be unable to undergo a second HSCT procedure because of failure to achieve remission, early toxic death, or severe organ toxicity related to salvage chemotherapy.[123] Among the highly selected group of patients able to undergo a second ablative allogeneic HSCT, approximately 10% to 30% will achieve long-term EFS.[123-128]; [68,129][Level of evidence: 3iiA] Prognosis is more favorable in patients with longer duration of remission after the first HSCT and in patients with CR at the time of the second HSCT.[125,126,130] In addition, one study showed an improvement in survival after second HSCT if acute GVHD occurred, especially if it had not occurred after the first transplant.[131]

Reduced-intensity approaches can also cure a percentage of patients when used as a second allogeneic transplant approach, but only if patients achieve a CR confirmed by flow cytometry.[132][Level of evidence: 2A] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT.[133]; [134][Level of evidence: 3iiiA]

Whether a second allogeneic transplant is necessary to treat isolated CNS and testicular relapse after HSCT is unknown. A small series has shown survival in selected patients using chemotherapy alone or chemotherapy followed by a second transplant.[135][Level of evidence: 3iA]

Immunotherapeutic Approaches for Refractory ALL

Immunotherapeutic approaches to the treatment of refractory ALL include monoclonal antibody therapy and CAR T-cell therapy.

Monoclonal antibody therapy

The following two immunotherapeutic agents have been studied for the treatment of patients with refractory B-ALL:

• Blinatumomab. Blinatumomab is a bispecific monoclonal antibody with one site for CD3 (T cells) and the other site for CD19 (present on most B-ALL cells). Thus, blinatumomab promotes the binding of the patient’s own cytotoxic T cells to B lymphoblasts, resulting in tumor being killed. In a phase I/II trial of children younger than 18 years with relapsed/refractory B-ALL, 27 of 70 patients (39%) treated at the recommended phase II dose achieved a CR with single-agent blinatumomab; 52% of those achieving CR were MRD negative.[136]
• Inotuzumab. Inotuzumab is an anti-CD22 monoclonal antibody that is conjugated to calicheamicin. In trials of adult patients with relapsed/refractory B-ALL, CR was achieved in approximately 80% of patients.[137,138] In a retrospective study of 51 heavily pretreated children with relapsed/refractory B-ALL who received inotuzumab, CR occurred in 67% of patients, with MRD-negative CR occurring in 71% of those patients. Of patients proceeding to HSCT after therapy, 11 of 21 developed veno-occlusive disease (VOD), with an increased risk in patients undergoing a second HSCT.[69] Expert panel recommendations for the prevention of VOD associated with HSCT after inotuzumab include limiting inotuzumab to two doses, avoiding dual-alkylator HSCT regimens, avoiding hepatotoxic agents, and considering VOD prophylactic agents.[139]

CAR T-cell therapy

Chimeric antigen receptor (CAR) T-cell therapy is a therapeutic strategy for pediatric B-ALL patients with refractory disease or those in second or subsequent relapse. This treatment involves engineering T cells with a CAR that redirects T-cell specificity and function.[140] One widely utilized target of CAR-modified T cells is the CD19 antigen expressed on almost all normal B cells and most B-cell malignancies.

Treatment with CAR T cells has been associated with cytokine release syndrome, which can be life-threatening.[141,142] Cytokine release syndrome presents as fever, headache, myalgias, hypotension, capillary leak, hypoxia, and renal dysfunction. Neurotoxicity, including aphasia, altered mental status, and seizures, has also been observed with CAR T-cell therapy and the symptoms usually resolve spontaneously. CNS symptoms have not responded to interleukin-6 receptor (IL-6R)–targeting agents or other approaches. Other CAR T-cell therapy side effects include coagulopathy, hemophagocytic lymphohistiocytosis–like laboratory changes, and cardiac dysfunction. Between 20% and 40% of patients require treatment in the intensive care unit, mostly pressor support, with 10% to 20% of patients requiring intubation and/or dialysis.[140,141,143] Severe cytokine release syndrome has been effectively treated with tocilizumab, an anti–IL-6R antibody.[141] Long-term persistence of CAR T cells can lead to B-cell aplasia, necessitating immunoglobulin replacement.[141]

Several clinical trials of CAR T cells targeting CD19 in relapsed/refractory ALL have been conducted, with encouraging results.

Evidence (CAR T-cell therapy):

1. In pilot clinical trials conducted at the Children’s Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania, 30 children and adults (25 of whom were aged 22 years or younger) with multiply relapsed or refractory CD19-positive ALL were given T cells transduced with CD19-directed CAR lentiviral vector.[141][Level of evidence: 3iiiDi]
   • CR was obtained in 90% of patients, including 15 of 18 patients (83%) who had previously received allogeneic HSCT.
   • The 6-month EFS rate was 67%, with most patients showing persistence of the CAR T cells and B-cell aplasia through 6 months.
   • All 30 patients experienced some degree of cytokine release syndrome. Eight patients (27%) had severe symptoms requiring vasopressors and/or respiratory support. Cytokine release syndrome was effectively treated with tocilizumab.
2. A second report from the Pediatric Oncology Branch at the NCI described the use of a different CD-19 targeted CAR T-cell product that was prepared using a retroviral vector.[144]
   • This CD19-CAR T-cell product induced complete responses in 70% of patients (14 of 20) (aged 1–30 years) with relapsed/refractory B-ALL.
   • Persistence of CAR T cells in this study was 1 to 2 months, with recovery of normal B-cell lymphopoiesis in patients who achieved CR.
3. A third report of a phase I trial of 45 children and young adults with relapsed/refractory CD19-positive B-ALL who received 4-1BB–based lentiviral vector expanded CAR T cells showed the following:[143]
   • An overall remission rate of 89% for all patients enrolled using an intent-to-treat analysis.
   • Improved long-term persistence of CAR T cells and B-cell aplasia in patients who: (1) received lymphodepleting strategies that contain fludarabine and cyclophosphamide, and (2) started the treatment with a higher percentage of cells expressing CD19, either on blasts or normal B cells.
4. A global phase II trial of the anti-CD19 4-1BB vector developed at the CHOP and the University of Pennsylvania led to U.S. Food and Drug Administration approval of tisagenlecleucel for children with multiply relapsed or refractory B-ALL.[122]
   • Of 92 patients enrolled, 75 were infused with successfully manufactured CAR T cells. Eighty-one percent of infused patients had two measures noting CR within the first 3 months of infusion and 100% of the remissions were MRD negative.
   • The EFS rate of infused patients was 73% at 6 months and 50% at 12 months. The OS rate of infused patients was 90% at 6 months and 70% at 12 months.

At least 50% of relapses after CD19-targeted CAR T-cell therapy have occurred because of antigen escape, which has been shown to be related to mutations in the CD19 protein that delete the binding sites used by CAR T-cell constructs.[145] Salvage after antigen escape has been documented with cell and immune therapy approaches targeting a second lymphoid antigen, CD22. Studies looking specifically at inotuzumab rescue of CD19-negative relapse have not been published, but two groups have reported high rates of subsequent achievement of remission and survival, generally when CD22 CAR T-cell therapy is followed by HSCT therapy.[146,147] Because the CD22 antigen can be downregulated, there is concern about targeting CD22 alone for long-term CAR T-cell response; consequently, this approach is often paired with HSCT.

Evidence (CD22-targeted CAR T-cell therapy):

1. Investigators at the NCI reported a phase I/II trial of 21 children and young adults treated with a CD22-targeted CAR T-cell approach. Response was dose dependent, with 11 of 15 patients (73%) who were treated at a dose of greater than or equal to 1 x 106 CD22 CAR T cells/kg attaining CR. Of patients treated at the phase II dose, nine of ten patients had received previous CD19-directed immunotherapy, including five of five patients who enrolled with diminished or negative CD19 B-ALL and one patient who was refractory to both CD19-targeted CAR T cells and blinatumomab.[146]
2. A Chinese group treated 34 patients who had failed previous CD19-targeted CAR T-cell therapy with CD22 CAR T cells. CR occurred in 80% of the patients evaluable at day 30 (71% of all patients). Seven patients received no further therapy, and three patients remained in remission at 5 to 13 months after therapy. Eleven patients went on to HSCT, with a 1-year leukemia-free survival rate of 72%. This study demonstrated that long-term salvage of patients failing CD19-targeted CAR T cells can occur with CD22-targeted CAR T cells plus HSCT.[147]

Treatment of Isolated Extramedullary Relapse

With improved success in treating children with ALL, the incidence of isolated extramedullary relapse has decreased. The incidence of isolated CNS relapse is less than 5%, and testicular relapse is less than 1% to 2%.[148-150] As with bone marrow and mixed relapses, time from initial diagnosis to relapse is a key prognostic factor in isolated extramedullary relapses.[151] In addition, age older than 6 years at relapse was noted in one study as an adverse prognostic factor for patients with an isolated extramedullary relapse, while a second study suggested age 10 years as a better cutoff.[16,152] Of note, in most children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques,[153] and successful treatment strategies must effectively control both local and systemic disease. Patients with an isolated CNS relapse who show greater than 0.01% MRD in a morphologically normal marrow have a worse prognosis (5-year EFS rate, 30%) than do patients with either no MRD or MRD less than 0.01% (5-year EFS rate, 60%).[153]

Isolated CNS relapse

Standard treatment options for childhood ALL that has recurred in the CNS include the following:

1. Systemic and intrathecal chemotherapy.
2. Cranial or craniospinal radiation.
3. HSCT.

While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy followed by cranial or craniospinal radiation has improved the outlook, particularly for patients who did not receive cranial radiation during their first remission.[18,151,154,155]

Evidence (chemotherapy and radiation therapy):

1. In a Pediatric Oncology Group (POG) study using this strategy, children who had not previously received radiation therapy and whose initial remission was 18 months or longer had a 4-year EFS rate of approximately 80%, compared with EFS rates of approximately 45% for children with CNS relapse within 18 months of diagnosis.[151]
2. In a follow-up POG study, children who had not previously received radiation therapy and who had initial remission of 18 months or more were treated with intensive systemic and intrathecal chemotherapy for 1 year followed by 18 Gy of cranial radiation only.[18] The 4-year EFS rate was 78%. Children with an initial remission of less than 18 months also received the same chemotherapy but had craniospinal radiation (24 Gy cranial/15 Gy spinal) as in the first POG study and achieved a 4-year EFS rate of 52%.

A number of case series describing HSCT in the treatment of isolated CNS relapse have been published.[156,157] Although some reports have suggested a possible role for HSCT for patients with isolated CNS disease with very early relapse and T-cell disease, there is less evidence for the need for HSCT in early relapse and no evidence in late relapse. The use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study.

Evidence (HSCT):

1. Another study compared the outcome of patients treated with either HLA-matched sibling transplants or chemoradiation therapy as in the POG studies above.[158][Level of evidence: 3iiiDii] This retrospective, registry-based study included transplantation of both early (<18 months from diagnosis) and late relapses.
   • The 8-year probabilities of leukemia-free survival adjusted for age (58%) and duration of first remission (66%) were similar.
   • Because of the relatively good outcome of patients with isolated CNS relapse more than 18 months from diagnosis who were treated with chemoradiation therapy alone (>75%), transplantation is generally not recommended by the COG for this group.
2. The MRC ALLR3 trial tested intensive induction with mitoxantrone versus idarubicin in relapsed ALL patients, defining a superior outcome when mitoxantrone was used. A subanalysis of 80 patients entering the trial with isolated CNS relapse included 13 patients with very early relapse (defined as <18 months from first diagnosis), 55 patients with early relapse (defined as >18 months from initial diagnosis but within 6 months of being off therapy), and 12 patients with late relapse.[16][Level of evidence: 2A]
   • Patients with late relapse did very well with chemotherapy/cranial radiation therapy, with 11 of 12 patients surviving.
   • Allogeneic HSCT was recommended for very early and early relapse. Sixty-six patients were alive and relapse free after the planned three induction courses. Fifty-four patients with early and very early isolated CNS relapse were eligible for protocol-recommended HSCT, and 39 patients (72%) received HSCT. Twenty-one percent of these patients relapsed, compared with a relapse rate of 71% in the group that did not receive HSCT.
   • Of those eligible for transplant, treatment with mitoxantrone rather than idarubicin during reinduction was associated with a survival advantage (3-year progression-free survival rates, 61% vs. 21%; P = .027). As in the larger trial, the major advantage from the mitoxantrone arm occurred in those who received HSCT.[16] Small patient numbers in the very early group prohibited detailed analysis of this cohort, and rates of failure within the early group treated with chemotherapy/cranial radiation therapy are inferior to other published experiences, calling into question this chemotherapy approach to early isolated CNS relapse patients.

Isolated testicular relapse

The results of treatment of isolated testicular relapse depend on the timing of the relapse. The 3-year EFS rate of boys with overt testicular relapse during therapy is approximately 40%; it is approximately 85% for boys with late testicular relapse.[159]

Standard treatment options in North America for childhood ALL that has recurred in the testes include the following:

1. Chemotherapy.
2. Radiation therapy.

Standard approaches for treating isolated testicular relapse in North America include local radiation therapy along with intensive chemotherapy. In some European clinical trial groups, orchiectomy of the involved testicle is performed instead of radiation. Biopsy of the other testicle is performed at the time of relapse to determine if additional local control (surgical removal or radiation) is to be performed. A study that looked at testicular biopsy at the end of frontline therapy failed to demonstrate a survival benefit for patients with early detection of occult disease.[160]

There are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy. Treatment protocols that have tested this approach have incorporated intensified dosing of chemotherapy agents (e.g., high-dose methotrexate) that may be able to achieve antileukemic levels in the testes.

Evidence (treatment of testicular relapse):

1. The COG AALL02P2 (NCT00096135) trial tested whether radiation therapy could be eliminated for patients with late isolated testicular relapse (occurring more than 18 months from diagnosis).[161] On this trial, testicular size was reassessed after the initial month of reinduction chemotherapy, which included high-dose methotrexate. If the testicle remained enlarged, biopsy was performed, and if positive, patients were to be treated with local radiation therapy. Those with testes that normalized in size or who had negative biopsies were to be treated without radiation therapy. Postinduction chemotherapy for all patients (whether or not they were irradiated) included multiple courses of high-dose methotrexate.[162]
   • Of 40 patients enrolled, 26 had persistent testicular enlargement after reinduction. Testicular biopsy was positive in 12 of these 26 patients, 11 of whom received testicular radiation therapy; all other patients on the trial were treated without radiation.
   • Participants who received testicular radiation therapy achieved a 5-year EFS rate of 73% versus 61% for those who did not receive radiation (P = .6); the 5-year OS rate was 73% for those who received testicular radiation versus 71% (P = .9) for those who did not receive testicular radiation.
   • Thus, for patients with isolated testicular relapse achieving a favorable response after initial induction (documented by size reduction and/or biopsy), omission of testicular radiation therapy may be a feasible option.
2. Dutch investigators treated five boys with a late testicular relapse with high-dose methotrexate during induction (12 g/m2) and at regular intervals during the remainder of therapy (6 g/m2) without testicular radiation. All five boys were long-term survivors.[161]
3. In a small series of boys who had an isolated testicular relapse after a HSCT for a prior systemic relapse of ALL, five of seven boys had extended EFS without a second HSCT.[135][Level of evidence: 3iA]

Treatment Options Under Clinical Evaluation for Relapsed Childhood ALL

Trials for ALL in first relapse

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

1. COG-AALL1331; NCI-2014-00631 (NCT02101853) (Risk-Stratified Randomized Phase III Testing of Blinatumomab in First Relapse of Childhood B-ALL): This trial is evaluating whether incorporation of blinatumomab improves DFS in patients with B-ALL in first relapse. Blinatumomab is a bi-specific antibody that binds to the CD19 antigen, expressed on nearly all B-ALL cells and the CD3 antigen expressed on T cells; in this way, blinatumomab juxtaposes B-lymphoblasts with a patient’s own T cells, promoting leukemia cell lysis. Patients are risk-stratified on the basis of site of relapse (marrow-involved vs. isolated extramedullary relapse), time to relapse, and MRD status after the first month of treatment. The chemotherapy backbone for the trial is based on the United Kingdom ALLR3 regimen.[38] After the first month of treatment, high-risk and intermediate-risk patients are randomly assigned to receive either two blocks of consolidation chemotherapy or two cycles of blinatumomab. These patients will then proceed to HSCT. Low-risk patients are treated without transplant; they are randomly assigned to either a control arm based on the ALLR3 protocol or an investigational arm based on the same chemotherapy backbone and also include three cycles of blinatumomab.
2. TACL 2012-002 (NCT02879643) (Vincristine Sulfate Liposome Injection in Combination with UKALL R3 Induction Chemotherapy for Children, Adolescents, and Young Adults with Relapsed ALL): This trial is assessing the safety and feasibility of vincristine sulfate liposome injection as replacement for standard vincristine in the UKALL R3 induction regimen in ALL patients (B-ALL or T-cell ALL) with first, second, or third relapse. Patients with either M2 (5%–24% blasts) or M3 (>25% blasts) marrow involvement are eligible.

Trials for ALL in second or subsequent relapse or refractory ALL

Multiple clinical trials investigating new agents and new combinations of agents are available for children with second or subsequent relapsed or refractory ALL and should be considered. These trials are testing targeted treatments specific for ALL, including monoclonal antibody–based therapies and drugs that inhibit signal transduction pathways required for leukemia cell growth and survival. Multiple clinical trials investigating new agents, new combinations of agents, and immunotherapeutic approaches are available. (Refer to the ClinicalTrials.gov website for more information.)

Current Clinical Trials

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

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69. Bhojwani D, Sposto R, Shah NN, et al.: Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia 33 (4): 884-892, 2019. [PUBMED Abstract]
70. Pulsipher MA: Are CAR T cells better than antibody or HCT therapy in B-ALL? Hematology Am Soc Hematol Educ Program 2018 (1): 16-24, 2018. [PUBMED Abstract]
71. Oliansky DM, Camitta B, Gaynon P, et al.: Role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005 evidence-based review. Biol Blood Marrow Transplant 18 (4): 505-22, 2012. [PUBMED Abstract]
72. Davies SM, Ramsay NK, Klein JP, et al.: Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia. J Clin Oncol 18 (2): 340-7, 2000. [PUBMED Abstract]
73. Bunin N, Aplenc R, Kamani N, et al.: Randomized trial of busulfan vs total body irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric Blood and Marrow Transplant Consortium study. Bone Marrow Transplant 32 (6): 543-8, 2003. [PUBMED Abstract]
74. Gassas A, Sung L, Saunders EF, et al.: Comparative outcome of hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia following cyclophosphamide and total body irradiation or VP16 and total body irradiation conditioning regimens. Bone Marrow Transplant 38 (11): 739-43, 2006. [PUBMED Abstract]
75. Tracey J, Zhang MJ, Thiel E, et al.: Transplantation conditioning regimens and outcomes after allogeneic hematopoietic cell transplantation in children and adolescents with acute lymphoblastic leukemia. Biol Blood Marrow Transplant 19 (2): 255-9, 2013. [PUBMED Abstract]
76. Bakr M, Rasheed W, Mohamed SY, et al.: Allogeneic hematopoietic stem cell transplantation in adolescent and adult patients with high-risk T cell acute lymphoblastic leukemia. Biol Blood Marrow Transplant 18 (12): 1897-904, 2012. [PUBMED Abstract]
77. Marks DI, Forman SJ, Blume KG, et al.: A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission. Biol Blood Marrow Transplant 12 (4): 438-53, 2006. [PUBMED Abstract]
78. Duval M, Klein JP, He W, et al.: Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol 28 (23): 3730-8, 2010. [PUBMED Abstract]
79. Shen Z, Gu X, Mao W, et al.: Influence of pre-transplant minimal residual disease on prognosis after Allo-SCT for patients with acute lymphoblastic leukemia: systematic review and meta-analysis. BMC Cancer 18 (1): 755, 2018. [PUBMED Abstract]
80. Balduzzi A, Di Maio L, Silvestri D, et al.: Minimal residual disease before and after transplantation for childhood acute lymphoblastic leukaemia: is there any room for intervention? Br J Haematol 164 (3): 396-408, 2014. [PUBMED Abstract]
81. Goulden N, Bader P, Van Der Velden V, et al.: Minimal residual disease prior to stem cell transplant for childhood acute lymphoblastic leukaemia. Br J Haematol 122 (1): 24-9, 2003. [PUBMED Abstract]
82. Bader P, Kreyenberg H, Henze GH, et al.: Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group. J Clin Oncol 27 (3): 377-84, 2009. [PUBMED Abstract]
83. Leung W, Pui CH, Coustan-Smith E, et al.: Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia. Blood 120 (2): 468-72, 2012. [PUBMED Abstract]
84. Ruggeri A, Michel G, Dalle JH, et al.: Impact of pretransplant minimal residual disease after cord blood transplantation for childhood acute lymphoblastic leukemia in remission: an Eurocord, PDWP-EBMT analysis. Leukemia 26 (12): 2455-61, 2012. [PUBMED Abstract]
85. Bachanova V, Burke MJ, Yohe S, et al.: Unrelated cord blood transplantation in adult and pediatric acute lymphoblastic leukemia: effect of minimal residual disease on relapse and survival. Biol Blood Marrow Transplant 18 (6): 963-8, 2012. [PUBMED Abstract]
86. Sutton R, Shaw PJ, Venn NC, et al.: Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia. Br J Haematol 168 (3): 395-404, 2015. [PUBMED Abstract]
87. Sanchez-Garcia J, Serrano J, Serrano-Lopez J, et al.: Quantification of minimal residual disease levels by flow cytometry at time of transplant predicts outcome after myeloablative allogeneic transplantation in ALL. Bone Marrow Transplant 48 (3): 396-402, 2013. [PUBMED Abstract]
88. Bader P, Kreyenberg H, von Stackelberg A, et al.: Monitoring of minimal residual disease after allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia allows for the identification of impending relapse: results of the ALL-BFM-SCT 2003 trial. J Clin Oncol 33 (11): 1275-84, 2015. [PUBMED Abstract]
89. Pulsipher MA, Langholz B, Wall DA, et al.: Risk factors and timing of relapse after allogeneic transplantation in pediatric ALL: for whom and when should interventions be tested? Bone Marrow Transplant 50 (9): 1173-9, 2015. [PUBMED Abstract]
90. Pulsipher MA, Carlson C, Langholz B, et al.: IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients. Blood 125 (22): 3501-8, 2015. [PUBMED Abstract]
91. Liu J, Wang Y, Xu LP, et al.: Monitoring mixed lineage leukemia expression may help identify patients with mixed lineage leukemia--rearranged acute leukemia who are at high risk of relapse after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 20 (7): 929-36, 2014. [PUBMED Abstract]
92. Locatelli F, Zecca M, Messina C, et al.: Improvement over time in outcome for children with acute lymphoblastic leukemia in second remission given hematopoietic stem cell transplantation from unrelated donors. Leukemia 16 (11): 2228-37, 2002. [PUBMED Abstract]
93. Saarinen-Pihkala UM, Gustafsson G, Ringdén O, et al.: No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission. J Clin Oncol 19 (14): 3406-14, 2001. [PUBMED Abstract]
94. Muñoz A, Diaz-Heredia C, Diaz MA, et al.: Allogeneic hemopoietic stem cell transplantation for childhood acute lymphoblastic leukemia in second complete remission-similar outcomes after matched related and unrelated donor transplant: a study of the Spanish Working Party for Blood and Marrow Transplantation in Children (Getmon). Pediatr Hematol Oncol 25 (4): 245-59, 2008. [PUBMED Abstract]
95. Jacobsohn DA, Hewlett B, Ranalli M, et al.: Outcomes of unrelated cord blood transplants and allogeneic-related hematopoietic stem cell transplants in children with high-risk acute lymphocytic leukemia. Bone Marrow Transplant 34 (10): 901-7, 2004. [PUBMED Abstract]
96. Kurtzberg J, Prasad VK, Carter SL, et al.: Results of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies. Blood 112 (10): 4318-27, 2008. [PUBMED Abstract]
97. Peters C, Schrappe M, von Stackelberg A, et al.: Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial. J Clin Oncol 33 (11): 1265-74, 2015. [PUBMED Abstract]
98. Smith AR, Baker KS, Defor TE, et al.: Hematopoietic cell transplantation for children with acute lymphoblastic leukemia in second complete remission: similar outcomes in recipients of unrelated marrow and umbilical cord blood versus marrow from HLA matched sibling donors. Biol Blood Marrow Transplant 15 (9): 1086-93, 2009. [PUBMED Abstract]
99. Zhang MJ, Davies SM, Camitta BM, et al.: Comparison of outcomes after HLA-matched sibling and unrelated donor transplantation for children with high-risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant 18 (8): 1204-10, 2012. [PUBMED Abstract]
100. Gassas A, Sung L, Saunders EF, et al.: Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in unrelated transplantations. Bone Marrow Transplant 40 (10): 951-5, 2007. [PUBMED Abstract]
101. Harvey J, Green A, Cornish J, et al.: Improved survival in matched unrelated donor transplant for childhood ALL since the introduction of high-resolution matching at HLA class I and II. Bone Marrow Transplant 47 (10): 1294-300, 2012. [PUBMED Abstract]
102. Majhail NS, Chitphakdithai P, Logan B, et al.: Significant improvement in survival after unrelated donor hematopoietic cell transplantation in the recent era. Biol Blood Marrow Transplant 21 (1): 142-50, 2015. [PUBMED Abstract]
103. MacMillan ML, Davies SM, Nelson GO, et al.: Twenty years of unrelated donor bone marrow transplantation for pediatric acute leukemia facilitated by the National Marrow Donor Program. Biol Blood Marrow Transplant 14 (9 Suppl): 16-22, 2008. [PUBMED Abstract]
104. Davies SM, Wang D, Wang T, et al.: Recent decrease in acute graft-versus-host disease in children with leukemia receiving unrelated donor bone marrow transplants. Biol Blood Marrow Transplant 15 (3): 360-6, 2009. [PUBMED Abstract]
105. Eapen M, Rubinstein P, Zhang MJ, et al.: Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet 369 (9577): 1947-54, 2007. [PUBMED Abstract]
106. Klingebiel T, Handgretinger R, Lang P, et al.: Haploidentical transplantation for acute lymphoblastic leukemia in childhood. Blood Rev 18 (3): 181-92, 2004. [PUBMED Abstract]
107. Locatelli F, Merli P, Pagliara D, et al.: Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion. Blood 130 (5): 677-685, 2017. [PUBMED Abstract]
108. Bertaina A, Zecca M, Buldini B, et al.: Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia. Blood 132 (24): 2594-2607, 2018. [PUBMED Abstract]
109. Gustafsson Jernberg A, Remberger M, Ringdén O, et al.: Graft-versus-leukaemia effect in children: chronic GVHD has a significant impact on relapse and survival. Bone Marrow Transplant 31 (3): 175-81, 2003. [PUBMED Abstract]
110. Dini G, Zecca M, Balduzzi A, et al.: No difference in outcome between children and adolescents transplanted for acute lymphoblastic leukemia in second remission. Blood 118 (25): 6683-90, 2011. [PUBMED Abstract]
111. Pulsipher MA, Langholz B, Wall DA, et al.: The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood 123 (13): 2017-25, 2014. [PUBMED Abstract]
112. Pulsipher MA, Bader P, Klingebiel T, et al.: Allogeneic transplantation for pediatric acute lymphoblastic leukemia: the emerging role of peritransplantation minimal residual disease/chimerism monitoring and novel chemotherapeutic, molecular, and immune approaches aimed at preventing relapse. Biol Blood Marrow Transplant 15 (1 Suppl): 62-71, 2008. [PUBMED Abstract]
113. Lankester AC, Bierings MB, van Wering ER, et al.: Preemptive alloimmune intervention in high-risk pediatric acute lymphoblastic leukemia patients guided by minimal residual disease level before stem cell transplantation. Leukemia 24 (8): 1462-9, 2010. [PUBMED Abstract]
114. Horn B, Soni S, Khan S, et al.: Feasibility study of preemptive withdrawal of immunosuppression based on chimerism testing in children undergoing myeloablative allogeneic transplantation for hematologic malignancies. Bone Marrow Transplant 43 (6): 469-76, 2009. [PUBMED Abstract]
115. Pochon C, Oger E, Michel G, et al.: Follow-up of post-transplant minimal residual disease and chimerism in childhood lymphoblastic leukaemia: 90 d to react. Br J Haematol 169 (2): 249-61, 2015. [PUBMED Abstract]
116. Bader P, Kreyenberg H, Hoelle W, et al.: Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 22 (9): 1696-705, 2004. [PUBMED Abstract]
117. Gandemer V, Pochon C, Oger E, et al.: Clinical value of pre-transplant minimal residual disease in childhood lymphoblastic leukaemia: the results of the French minimal residual disease-guided protocol. Br J Haematol 165 (3): 392-401, 2014. [PUBMED Abstract]
118. Rubin J, Vettenranta K, Vettenranta J, et al.: Use of intrathecal chemoprophylaxis in children after SCT and the risk of central nervous system relapse. Bone Marrow Transplant 46 (3): 372-8, 2011. [PUBMED Abstract]
119. Thompson CB, Sanders JE, Flournoy N, et al.: The risks of central nervous system relapse and leukoencephalopathy in patients receiving marrow transplants for acute leukemia. Blood 67 (1): 195-9, 1986. [PUBMED Abstract]
120. Oshima K, Kanda Y, Yamashita T, et al.: Central nervous system relapse of leukemia after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 14 (10): 1100-7, 2008. [PUBMED Abstract]
121. Ruutu T, Corradini P, Gratwohl A, et al.: Use of intrathecal prophylaxis in allogeneic haematopoietic stem cell transplantation for malignant blood diseases: a survey of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 35 (2): 121-4, 2005. [PUBMED Abstract]
122. Maude SL, Laetsch TW, Buechner J, et al.: Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med 378 (5): 439-448, 2018. [PUBMED Abstract]
123. Mehta J, Powles R, Treleaven J, et al.: Outcome of acute leukemia relapsing after bone marrow transplantation: utility of second transplants and adoptive immunotherapy. Bone Marrow Transplant 19 (7): 709-19, 1997. [PUBMED Abstract]
124. Kuhlen M, Willasch AM, Dalle JH, et al.: Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial. Br J Haematol 180 (1): 82-89, 2018. [PUBMED Abstract]
125. Eapen M, Giralt SA, Horowitz MM, et al.: Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant 34 (8): 721-7, 2004. [PUBMED Abstract]
126. Bosi A, Laszlo D, Labopin M, et al.: Second allogeneic bone marrow transplantation in acute leukemia: results of a survey by the European Cooperative Group for Blood and Marrow Transplantation. J Clin Oncol 19 (16): 3675-84, 2001. [PUBMED Abstract]
127. Willasch AM, Salzmann-Manrique E, Krenn T, et al.: Treatment of relapse after allogeneic stem cell transplantation in children and adolescents with ALL: the Frankfurt experience. Bone Marrow Transplant 52 (2): 201-208, 2017. [PUBMED Abstract]
128. Yaniv I, Krauss AC, Beohou E, et al.: Second Hematopoietic Stem Cell Transplantation for Post-Transplantation Relapsed Acute Leukemia in Children: A Retrospective EBMT-PDWP Study. Biol Blood Marrow Transplant 24 (8): 1629-1642, 2018. [PUBMED Abstract]
129. Nishikawa T, Inagaki J, Nagatoshi Y, et al.: The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: long-term outcomes. Pediatr Transplant 16 (7): 722-8, 2012. [PUBMED Abstract]
130. Bajwa R, Schechter T, Soni S, et al.: Outcome of children who experience disease relapse following allogeneic hematopoietic SCT for hematologic malignancies. Bone Marrow Transplant 48 (5): 661-5, 2013. [PUBMED Abstract]
131. Schechter T, Avila L, Frangoul H, et al.: Effect of acute graft-versus-host disease on the outcome of second allogeneic hematopoietic stem cell transplant in children. Leuk Lymphoma 54 (1): 105-9, 2013. [PUBMED Abstract]
132. Pulsipher MA, Boucher KM, Wall D, et al.: Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood 114 (7): 1429-36, 2009. [PUBMED Abstract]
133. Collins RH, Goldstein S, Giralt S, et al.: Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant 26 (5): 511-6, 2000. [PUBMED Abstract]
134. Levine JE, Barrett AJ, Zhang MJ, et al.: Donor leukocyte infusions to treat hematologic malignancy relapse following allo-SCT in a pediatric population. Bone Marrow Transplant 42 (3): 201-5, 2008. [PUBMED Abstract]
135. Bhadri VA, McGregor MR, Venn NC, et al.: Isolated testicular relapse after allo-SCT in boys with ALL: outcome without second transplant. Bone Marrow Transplant 45 (2): 397-9, 2010. [PUBMED Abstract]
136. von Stackelberg A, Locatelli F, Zugmaier G, et al.: Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol 34 (36): 4381-4389, 2016. [PUBMED Abstract]
137. Kantarjian H, Thomas D, Jorgensen J, et al.: Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer 119 (15): 2728-36, 2013. [PUBMED Abstract]
138. Kantarjian HM, DeAngelo DJ, Stelljes M, et al.: Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N Engl J Med 375 (8): 740-53, 2016. [PUBMED Abstract]
139. Kebriaei P, Cutler C, de Lima M, et al.: Management of important adverse events associated with inotuzumab ozogamicin: expert panel review. Bone Marrow Transplant 53 (4): 449-456, 2018. [PUBMED Abstract]
140. Grupp SA, Kalos M, Barrett D, et al.: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368 (16): 1509-18, 2013. [PUBMED Abstract]
141. Maude SL, Frey N, Shaw PA, et al.: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371 (16): 1507-17, 2014. [PUBMED Abstract]
142. Fitzgerald JC, Weiss SL, Maude SL, et al.: Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia. Crit Care Med 45 (2): e124-e131, 2017. [PUBMED Abstract]
143. Gardner RA, Finney O, Annesley C, et al.: Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 129 (25): 3322-3331, 2017. [PUBMED Abstract]
144. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al.: T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385 (9967): 517-28, 2015. [PUBMED Abstract]
145. Sotillo E, Barrett DM, Black KL, et al.: Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discov 5 (12): 1282-95, 2015. [PUBMED Abstract]
146. Fry TJ, Shah NN, Orentas RJ, et al.: CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 24 (1): 20-28, 2018. [PUBMED Abstract]
147. Pan J, Niu Q, Deng B, et al.: CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia. Leukemia : , 2019. [PUBMED Abstract]
148. 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]
149. 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]
150. 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]
151. Ritchey AK, Pollock BH, Lauer SJ, et al.: Improved survival of children with isolated CNS relapse of acute lymphoblastic leukemia: a pediatric oncology group study . J Clin Oncol 17 (12): 3745-52, 1999. [PUBMED Abstract]
152. Domenech C, Mercier M, Plouvier E, et al.: First isolated extramedullary relapse in children with B-cell precursor acute lymphoblastic leukaemia: results of the Cooprall-97 study. Eur J Cancer 44 (16): 2461-9, 2008. [PUBMED Abstract]
153. Hagedorn N, Acquaviva C, Fronkova E, et al.: Submicroscopic bone marrow involvement in isolated extramedullary relapses in childhood acute lymphoblastic leukemia: a more precise definition of "isolated" and its possible clinical implications, a collaborative study of the Resistant Disease Committee of the International BFM study group. Blood 110 (12): 4022-9, 2007. [PUBMED Abstract]
154. Ribeiro RC, Rivera GK, Hudson M, et al.: An intensive re-treatment protocol for children with an isolated CNS relapse of acute lymphoblastic leukemia. J Clin Oncol 13 (2): 333-8, 1995. [PUBMED Abstract]
155. Kumar P, Kun LE, Hustu HO, et al.: Survival outcome following isolated central nervous system relapse treated with additional chemotherapy and craniospinal irradiation in childhood acute lymphoblastic leukemia. Int J Radiat Oncol Biol Phys 31 (3): 477-83, 1995. [PUBMED Abstract]
156. Yoshihara T, Morimoto A, Kuroda H, et al.: Allogeneic stem cell transplantation in children with acute lymphoblastic leukemia after isolated central nervous system relapse: our experiences and review of the literature. Bone Marrow Transplant 37 (1): 25-31, 2006. [PUBMED Abstract]
157. Harker-Murray PD, Thomas AJ, Wagner JE, et al.: Allogeneic hematopoietic cell transplantation in children with relapsed acute lymphoblastic leukemia isolated to the central nervous system. Biol Blood Marrow Transplant 14 (6): 685-92, 2008. [PUBMED Abstract]
158. Eapen M, Zhang MJ, Devidas M, et al.: Outcomes after HLA-matched sibling transplantation or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research. Leukemia 22 (2): 281-6, 2008. [PUBMED Abstract]
159. Wofford MM, Smith SD, Shuster JJ, et al.: Treatment of occult or late overt testicular relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. J Clin Oncol 10 (4): 624-30, 1992. [PUBMED Abstract]
160. Trigg ME, Steinherz PG, Chappell R, et al.: Early testicular biopsy in males with acute lymphoblastic leukemia: lack of impact on subsequent event-free survival. J Pediatr Hematol Oncol 22 (1): 27-33, 2000 Jan-Feb. [PUBMED Abstract]
161. van den Berg H, Langeveld NE, Veenhof CH, et al.: Treatment of isolated testicular recurrence of acute lymphoblastic leukemia without radiotherapy. Report from the Dutch Late Effects Study Group. Cancer 79 (11): 2257-62, 1997. [PUBMED Abstract]
162. Barredo JC, Hastings C, Lu X, et al.: Isolated late testicular relapse of B-cell acute lymphoblastic leukemia treated with intensive systemic chemotherapy and response-based testicular radiation: A Children's Oncology Group study. Pediatr Blood Cancer 65 (5): e26928, 2018. [PUBMED Abstract]

Changes to This Summary (10/22/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed and extensively revised.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Acute Lymphoblastic Leukemia Treatment are:

• Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
• Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Michael A. Pulsipher, MD (Children's Hospital Los Angeles)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Acute Lymphoblastic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/child-all-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389206]

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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• Updated: October 22, 2019