Treatment of Relapsed Childhood ALL
Prognostic Factors After First Relapse of Childhood ALL
The two most important prognostic risk factors after first relapse of childhood ALL are the following:
Other prognostic factors include the following:
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 have a better prognosis than those with a marrow relapse.[5,13]
Time from diagnosis to relapse
For patients with relapsed B-precursor 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 40% to 50% for those whose relapses occur more than 36 months from diagnosis.[5,13]
For patients with isolated central nervous system (CNS) relapses, the overall survival (OS) rates for early relapse (<18 months from diagnosis) are 40% to 50% and 75% to 80% for those with late relapses (>18 months from diagnosis).[13,16] No evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) in off-therapy patients improves outcome.
Age 10 years and older at diagnosis has been reported as an independent predictor of poor outcome. 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, 15%; P = .001).
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.
Children with Down syndrome with relapse of ALL had inferior outcomes as reported in a BFM report before 2000, primarily due to increased induction deaths and treatment-related mortality. However, since 2000, with improvements in supportive care, there have been no differences in outcome between patients with and without Down syndrome. 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 indicated that hematopoietic recovery, graft-versus-host disease (GVHD), and transplant-related mortality were within the expected range for non–Down syndrome ALL patients. In that series, relapse rather than transplant toxicity was the primary cause of treatment failure.[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.
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 (CR2).[Level of evidence: 2Di]; [Level of evidence: 3iiiA] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of CR2 are of prognostic significance in relapsed ALL.[21,23-25]; [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.
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) (9% TP53 alteration vs. 49% TP53 wild-type). Approximately one-half of the TP53 alterations were present at initial diagnosis and half were newly observed at time of relapse. A second genomic alteration found to predict for poor prognosis in patients with B-precursor ALL in first bone marrow relapse is IKZF1 deletion. The frequency of IKZF1 deletion in B-precursor ALL patients at first relapse patients was 33% in patients 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.
RAS pathway mutations (KRAS, NRAS, FLT3, and PTPN11) are common at relapse in B-precursor ALL patients, and they were found in approximately 40% of patients at first relapse in one study of 206 children. 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.[28,30] In the ALL-REZ BFM 2002 (NCT00114348 ) study, an EFS of 84% (± 7%, SE) was observed for patients with ETV6-RUNX1 ALL with bone marrow relapse. 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 for ETV6-RUNX1 patients enrolled on the French Acute Lymphoblastic Leukaemia (FRALLE) 93 study 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. However, the 3-year OS of ETV6-RUNX1 patients who experienced an early relapse (<36 months) was only 31%.
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-cell ALL.[5,21]
Standard Treatment Options for First Bone Marrow Relapse of Childhood ALL
Standard treatment options for first bone marrow relapse include the following:
Initial treatment of relapse consists of reinduction therapy to achieve a CR2. 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 CR2 at the end of the first month of treatment.; [Level of evidence: 2A]; [Level of evidence: 2Di] Patients with early marrow relapses have a lower rate of achieving a morphologic CR2 (approximately 70%) than do those with late marrow relapses (approximately 95%).[21,31]
Evidence (reinduction chemotherapy):
- 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.
- 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.
- A United Kingdom–based randomized trial of ALL patients in first relapse compared reinduction with a four-drug combination using idarubicin versus mitoxantrone.[Level of evidence: 1iiA]
- There was no difference in CR2 rates or end-reinduction MRD levels between the two study arms.
- A significant improvement in OS in the mitoxantrone arm (69% vs. 45%, P = .007) due to decreased relapse after transplantation was reported.
The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.
- 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 versus 5 g/m2 of methotrexate with reinduction showed no advantage at the higher dose.
- The combination of clofarabine, cyclophosphamide, and etoposide was reported to induce remission in 42% to 56% of patients with refractory or multiply relapsed disease.[34,35]; [Level of evidence: 2A]
- The combination of bortezomib plus vincristine, dexamethasone, PEG-L-asparaginase, and doxorubicin was reported to induce complete response (with or without platelet recovery) in 80% of multiply relapsed patients with B-precursor ALL.[Level of evidence: 3iiiDiv] Notably, this trial did not include patients who were refractory to reinduction.
- In a study of induction therapy comprising intensive asparaginase (weekly PEG-L-asparaginase or 12 doses of E.coli asparaginase) with prednisone, vincristine, and doxorubicin for patients with first relapse, the CR2 rate was 86% for those receiving PEG-L-asparaginase and 81% for those receiving E.coli asparaginase.[Level of evidence: 2Di]
Patients with relapsed T-cell ALL have much lower rates of achieving CR2 with standard reinduction regimens than do patients with B-precursor phenotype. 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%. The combination of nelarabine, cyclophosphamide, and etoposide has produced remissions in patients with relapsed/refractory T-cell ALL.
Postreinduction therapy for patients achieving a second complete remission (CR2)
Early-relapsing B-precursor ALL
For B-precursor patients with an early marrow relapse, allogeneic transplant from a human leukocyte antigen (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.[7,26,41-49] 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-precursor ALL
For patients with a late marrow relapse of B-precursor ALL, a primary chemotherapy approach after achievement of CR2 has resulted in survival rates of approximately 50%, and it is not clear whether allogeneic transplantation is associated with superior cure rate.[5,9,32,50-52]; [Level of evidence: 3iiA] End-reinduction MRD levels may help to identify patients with a high risk of subsequent relapse if treated with chemotherapy alone (no HSCT) in CR2. Results from one study suggest that patients with a late marrow relapse who have high end-reinduction MRD may have a better outcome if they receive an allogeneic HSCT in CR2.
Evidence (MRD-based risk stratification for late-relapse of B-precursor ALL):
- In a St. Jude Children's Research Hospital study, which included 23 patients with late relapses treated with chemotherapy in CR2, 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.
- 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-cell ALL treated with chemotherapy alone in CR2 (no HSCT).
- Patients with low MRD (<10-3) had a 10-year EFS of 73%, while those with high MRD (>10-3) had a 10-year EFS of 10%. On multivariate analysis, end-reinduction MRD was the strongest independent prognostic factor.
- 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).
- The EFS of patients with high end-reinduction MRD treated with allogeneic HSCT in CR2 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 receiving HSCT in CR2 (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 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 for these patients was only 37%. Thus, patients with early-combined relapses are no longer considered intermediate risk on BFM trials, and their treatment is not risk-stratified on the basis of end-reinduction MRD.
For patients with T-cell ALL who achieved remission after bone marrow relapse, outcomes with postreinduction chemotherapy alone have generally been poor, and these patients are usually treated with allogeneic HSCT in CR2, regardless of time to relapse.
Standard 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 is generally 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%. One of the main reasons for this is failure to obtain a third remission. In spite of numerous attempts at novel combination approaches, only about 40% of children with second relapse are able to achieve remission. If these patients achieve CR, HSCT has been shown to cure 20% to 35%, with failures occurring due to high rates of relapse and transplant-related mortality.[56-60][Level of evidence: 3iiA]
Hematopoietic Stem Cell Transplantation for First and Subsequent Bone Marrow Relapse
Components of the transplantation process
An updated expert panel review of indications for HSCT has been published. 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:
TBI-containing transplant preparative regimens
For patients proceeding to allogeneic HSCT, TBI appears to be an important component of the conditioning regimen. Two retrospective studies and a randomized trial suggest that transplant conditioning regimens that include TBI produce higher cure rates than do chemotherapy-only preparative regimens.[41,62,63] 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,[64-66] although one study suggested that if cyclophosphamide is used without other chemotherapy drugs, a dose of TBI in the higher range may be necessary. Many standard regimens include cyclophosphamide with TBI dosing between 1.32 and 1.4 Gy. On the other hand, when cyclophosphamide and etoposide were used with TBI, doses above 1.2 Gy resulted in worse survival due to excessive toxicity.
MRD detection just before transplant
Disease 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. 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.[24,69-74][Level of evidence: 3iiA]; [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.
Donor type and HLA match
Survival rates after matched unrelated donor and umbilical cord blood transplantations have improved significantly over the past decade and offer an outcome similar to that obtained with matched sibling donor transplants.[45,76-79]; [Level of evidence: 2A]; [Level of evidence: 3iiiA]; [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.[46,56,76] 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.; [84,85][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. 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. For T cell-depleted CD34-selected haploidentical transplants in which a parent is the donor, patients receiving maternal stem cells may have a better outcome than those who receive paternal stem cells.[Level of evidence: 3iiA]
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.[76,89-91] 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).
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.[92,93] Trials in Europe and the United States have shown that patients defined as having a high risk of relapse based upon increasing recipient chimerism (i.e., increased percentage of recipient DNA markers) can successfully undergo withdrawal of immune suppression without excessive toxicity. 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 of 37% versus 0% in the nonintervention group (P < .001). 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.
Intrathecal medication after HSCT to prevent relapse
Relapse after allogeneic HSCT for relapsed ALL
For patients relapsing after an allogeneic HSCT for ALL, 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. Among the highly selected group of patients able to undergo a second ablative allogeneic HSCT, approximately 10% to 30% may achieve long-term EFS.[101-103]; [60,104][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.[102,103,105] 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.
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.[Level of evidence: 2A] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT.; [Level of evidence: 3iiiA]
Whether a second allogeneic transplant is necessary to treat isolated CNS and testicular relapse is unknown, and a small series has shown survival in selected patients using chemotherapy alone or chemotherapy followed by a second transplant.[Level of evidence: 3iA]
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%.[111-113] As with bone marrow and mixed relapses, time from initial diagnosis to relapse is a key prognostic factor in isolated extramedullary relapses. In addition, age older than 6 years at diagnosis was noted to be an adverse prognostic factor for patients with an isolated extramedullary relapse in one study. Of note, in the majority of children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques, 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, 30%) than do patients with either no MRD or MRD less than 0.01% (5-year EFS, 60%).
Standard treatment options for childhood ALL that has recurred in the CNS include the following:
- Systemic and intrathecal chemotherapy.
- Cranial or craniospinal radiation.
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.[16,114,117,118]
Evidence (chemotherapy and radiation therapy):
- 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.
- 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. The 4-year EFS 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 of 52%.
A number of case series describing HSCT in the treatment of isolated CNS relapse have been published.[119,120] The use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study.
- In a study comparing outcome of patients treated with either HLA-matched sibling transplants or chemoradiation therapy as in the POG studies above, 8-year probabilities of leukemia-free survival adjusted for age and duration of first remission were similar (58% and 66%, respectively).[Level of evidence: 3iiiDii] This retrospective, registry-based study included transplantation of both early (<18 months from diagnosis) and late relapses.
- Because of the relatively good outcome of patients with isolated CNS relapse more than 18 months from diagnosis treated with chemoradiation therapy alone (>75%), transplantation is generally not recommended for this group.
The results of treatment of isolated testicular relapse depend on the timing of the relapse. The 3-year EFS of boys with overt testicular relapse during therapy is approximately 40%; it is approximately 85% for boys with late testicular relapse.
Standard treatment options in North America for childhood ALL that has recurred in the testes include the following:
- Radiation therapy.
The standard approach for treating isolated testicular relapse in North America is to administer intensive chemotherapy that includes high-dose methotrexate. Patients who do not respond with a CR after induction also receive local radiation therapy.
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. While there are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy, the use of chemotherapy (e.g., high-dose methotrexate) that may be able to achieve antileukemic levels in the testes is being tested in clinical trials.
Evidence (treatment of testicular relapse [case reports]):
- 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.
- 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.[Level of evidence: 3iA]
Treatment Options Under Clinical Evaluation for Relapsed Childhood ALL
Trials for ALL in first relapse
Treatment options under clinical evaluation for ALL in first relapse include the following:
- COG-AALL1331; NCI-2014-00631 (NCT02101853) (Risk-Stratified Randomized Phase III Testing of Blinatumomab in First Relapse of Childhood B-Lymphoblastic Leukemia [B-ALL]): This trial is evaluating whether incorporation of blinatumomab improves disease-free survival 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 based on 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. 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 including three cycles of blinatumomab.
- TACL 2008-002 (NCT00981799) (Trial of Nelarabine, Etoposide, and Cyclophosphamide in Relapsed T-cell ALL and T-cell Lymphoblastic Lymphoma): This trial, conducted by the Therapeutic Advances in Childhood Leukemia & Lymphoma clinical trials group, is testing the feasibility of administering nelarabine in combination with cyclophosphamide and etoposide as reinduction for patients with T-cell ALL in first relapse (as well as those who failed primary induction therapy). Doses of nelarabine and cyclophosphamide will be escalated in successive cohorts of patients to determine the maximum tolerated doses of these drugs when given in combination.
- DFCI-11-237 (NCT01523977) (Everolimus With Multiagent Reinduction Chemotherapy in Pediatric Patients With ALL): Patients in first relapse are eligible to enroll on a Dana-Farber Cancer Institute ALL Consortium trial testing the feasibility of administering everolimus, an oral mTOR inhibitor, in combination with multiagent reinduction (vincristine, prednisone, doxorubicin, intravenous PEG-L-asparaginase, and intrathecal chemotherapy).
Trials for ALL in second or subsequent relapse
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.
Chimeric Antigen Receptor (CAR) T-cell Therapy
CAR T-cell therapy is a new strategy under clinical investigation for the treatment of relapsed and refractory ALL in second or subsequent relapse. This strategy includes engineering T cells with a chimeric antigen receptor (CAR) that redirects T-cell specificity and function. 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. Several clinical trials of CAR T cells targeting CD19 in relapsed/refractory ALL are being conducted, with encouraging initial results:
- In pilot clinical trials conducted at the Children’s Hospital of Philadelphia 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.[Level of evidence: 3iiiDi] CR was obtained in 90% of patients, including 15 of 18 patients (83%) who had previously received allogeneic stem cell transplantation. 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 symptomatology (need for vasopressors and/or respiratory support), which was effectively treated by the anti-interleukin-6 receptor antibody tocilizumab.
- A second report from the Pediatric Oncology Branch at the National Cancer Institute described the use of a different CD-19 targeted CAR T-cell product that was prepared using a retroviral vector. This CD19-CAR T-cell product induced complete responses in 70% (14 of 20) of patients (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.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- Reismüller B, Attarbaschi A, Peters C, et al.: Long-term outcome of initially homogenously treated and relapsed childhood acute lymphoblastic leukaemia in Austria--a population-based report of the Austrian Berlin-Frankfurt-Münster (BFM) Study Group. Br J Haematol 144 (4): 559-70, 2009. [PUBMED Abstract]
- Uderzo C, Conter V, Dini G, et al.: Treatment of childhood acute lymphoblastic leukemia after the first relapse: curative strategies. Haematologica 86 (1): 1-7, 2001. [PUBMED Abstract]
- Chessells JM, Veys P, Kempski H, et al.: Long-term follow-up of relapsed childhood acute lymphoblastic leukaemia. Br J Haematol 123 (3): 396-405, 2003. [PUBMED Abstract]
- Rivera GK, Zhou Y, Hancock ML, et al.: Bone marrow recurrence after initial intensive treatment for childhood acute lymphoblastic leukemia. Cancer 103 (2): 368-76, 2005. [PUBMED Abstract]
- Einsiedel HG, von Stackelberg A, Hartmann R, et al.: Long-term outcome in children with relapsed ALL by risk-stratified salvage therapy: results of trial acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Münster Group 87. J Clin Oncol 23 (31): 7942-50, 2005. [PUBMED Abstract]
- Schroeder H, Garwicz S, Kristinsson J, et al.: Outcome after first relapse in children with acute lymphoblastic leukemia: a population-based study of 315 patients from the Nordic Society of Pediatric Hematology and Oncology (NOPHO). Med Pediatr Oncol 25 (5): 372-8, 1995. [PUBMED Abstract]
- Wheeler K, Richards S, Bailey C, et al.: Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical Research Council Working Party on Childhood Leukaemia. Br J Haematol 101 (1): 94-103, 1998. [PUBMED Abstract]
- Buchanan GR, Rivera GK, Pollock BH, et al.: Alternating drug pairs with or without periodic reinduction in children with acute lymphoblastic leukemia in second bone marrow remission: a Pediatric Oncology Group Study. Cancer 88 (5): 1166-74, 2000. [PUBMED Abstract]
- Rivera GK, Hudson MM, Liu Q, et al.: Effectiveness of intensified rotational combination chemotherapy for late hematologic relapse of childhood acute lymphoblastic leukemia. Blood 88 (3): 831-7, 1996. [PUBMED Abstract]
- Bührer C, Hartmann R, Fengler R, et al.: Peripheral blast counts at diagnosis of late isolated bone marrow relapse of childhood acute lymphoblastic leukemia predict response to salvage chemotherapy and outcome. Berlin-Frankfurt-Münster Relapse Study Group. J Clin Oncol 14 (10): 2812-7, 1996. [PUBMED Abstract]
- Roy A, Cargill A, Love S, et al.: Outcome after first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom R2 trial. Br J Haematol 130 (1): 67-75, 2005. [PUBMED Abstract]
- Rizzari C, Valsecchi MG, Aricò M, et al.: Outcome of very late relapse in children with acute lymphoblastic leukemia. Haematologica 89 (4): 427-34, 2004. [PUBMED Abstract]
- Nguyen K, Devidas M, Cheng SC, et al.: Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia 22 (12): 2142-50, 2008. [PUBMED Abstract]
- Locatelli F, Schrappe M, Bernardo ME, et al.: How I treat relapsed childhood acute lymphoblastic leukemia. Blood 120 (14): 2807-16, 2012. [PUBMED Abstract]
- Malempati S, Gaynon PS, Sather H, et al.: Outcome after relapse among children with standard-risk acute lymphoblastic leukemia: Children's Oncology Group study CCG-1952. J Clin Oncol 25 (36): 5800-7, 2007. [PUBMED Abstract]
- Barredo JC, Devidas M, Lauer SJ, et al.: Isolated CNS relapse of acute lymphoblastic leukemia treated with intensive systemic chemotherapy and delayed CNS radiation: a pediatric oncology group study. J Clin Oncol 24 (19): 3142-9, 2006. [PUBMED Abstract]
- Rubnitz JE, Hijiya N, Zhou Y, et al.: Lack of benefit of early detection of relapse after completion of therapy for acute lymphoblastic leukemia. Pediatr Blood Cancer 44 (2): 138-41, 2005. [PUBMED Abstract]
- Freyer DR, Devidas M, La M, et al.: Postrelapse survival in childhood acute lymphoblastic leukemia is independent of initial treatment intensity: a report from the Children's Oncology Group. Blood 117 (11): 3010-5, 2011. [PUBMED Abstract]
- Meyr F, Escherich G, Mann G, et al.: Outcomes of treatment for relapsed acute lymphoblastic leukaemia in children with Down syndrome. Br J Haematol 162 (1): 98-106, 2013. [PUBMED Abstract]
- Hitzler JK, He W, Doyle J, et al.: Outcome of transplantation for acute lymphoblastic leukemia in children with Down syndrome. Pediatr Blood Cancer 61 (6): 1126-8, 2014. [PUBMED Abstract]
- Raetz EA, Borowitz MJ, Devidas M, et al.: Reinduction platform for children with first marrow relapse in acute lymphoblastic lymphoma. J Clin Oncol 26 (24): 3971-8, 2008. [PUBMED Abstract]
- von Stackelberg A, Völzke E, Kühl JS, et al.: Outcome of children and adolescents with relapsed acute lymphoblastic leukaemia and non-response to salvage protocol therapy: a retrospective analysis of the ALL-REZ BFM Study Group. Eur J Cancer 47 (1): 90-7, 2011. [PUBMED Abstract]
- Coustan-Smith E, Gajjar A, Hijiya N, et al.: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse. Leukemia 18 (3): 499-504, 2004. [PUBMED Abstract]
- Sramkova L, Muzikova K, Fronkova E, et al.: Detectable minimal residual disease before allogeneic hematopoietic stem cell transplantation predicts extremely poor prognosis in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 48 (1): 93-100, 2007. [PUBMED Abstract]
- Eckert C, von Stackelberg A, Seeger K, et al.: Minimal residual disease after induction is the strongest predictor of prognosis in intermediate risk relapsed acute lymphoblastic leukaemia - long-term results of trial ALL-REZ BFM P95/96. Eur J Cancer 49 (6): 1346-55, 2013. [PUBMED Abstract]
- Paganin M, Zecca M, Fabbri G, et al.: Minimal residual disease is an important predictive factor of outcome in children with relapsed 'high-risk' acute lymphoblastic leukemia. Leukemia 22 (12): 2193-200, 2008. [PUBMED Abstract]
- Hof J, Krentz S, van Schewick C, et al.: Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia. J Clin Oncol 29 (23): 3185-93, 2011. [PUBMED Abstract]
- Krentz S, Hof J, Mendioroz A, et al.: Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia 27 (2): 295-304, 2013. [PUBMED Abstract]
- Irving J, Matheson E, Minto L, et al.: Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition. Blood 124 (23): 3420-30, 2014. [PUBMED Abstract]
- Gandemer V, Chevret S, Petit A, et al.: Excellent prognosis of late relapses of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia: lessons from the FRALLE 93 protocol. Haematologica 97 (11): 1743-50, 2012. [PUBMED Abstract]
- Tallen G, Ratei R, Mann G, et al.: Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol 28 (14): 2339-47, 2010. [PUBMED Abstract]
- Parker C, Waters R, Leighton C, et al.: Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet 376 (9757): 2009-17, 2010. [PUBMED Abstract]
- von Stackelberg A, Hartmann R, Bührer C, et al.: High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia. Blood 111 (5): 2573-80, 2008. [PUBMED Abstract]
- Locatelli F, Testi AM, Bernardo ME, et al.: Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol 147 (3): 371-8, 2009. [PUBMED Abstract]
- Miano M, Pistorio A, Putti MC, et al.: Clofarabine, cyclophosphamide and etoposide for the treatment of relapsed or resistant acute leukemia in pediatric patients. Leuk Lymphoma 53 (9): 1693-8, 2012. [PUBMED Abstract]
- Hijiya N, Thomson B, Isakoff MS, et al.: Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. Blood 118 (23): 6043-9, 2011. [PUBMED Abstract]
- Messinger YH, Gaynon PS, Sposto R, et al.: Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Blood 120 (2): 285-90, 2012. [PUBMED Abstract]
- Kelly ME, Lu X, Devidas M, et al.: Treatment of relapsed precursor-B acute lymphoblastic leukemia with intensive chemotherapy: POG (Pediatric Oncology Group) study 9411 (SIMAL 9). J Pediatr Hematol Oncol 35 (7): 509-13, 2013. [PUBMED Abstract]
- Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol 23 (15): 3376-82, 2005. [PUBMED Abstract]
- Commander LA, Seif AE, Insogna IG, et al.: Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma. Br J Haematol 150 (3): 345-51, 2010. [PUBMED Abstract]
- Eapen M, Raetz E, Zhang MJ, et al.: Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood 107 (12): 4961-7, 2006. [PUBMED Abstract]
- Barrett AJ, Horowitz MM, Pollock BH, et al.: Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission. N Engl J Med 331 (19): 1253-8, 1994. [PUBMED Abstract]
- Uderzo C, Valsecchi MG, Bacigalupo A, et al.: Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association. J Clin Oncol 13 (2): 352-8, 1995. [PUBMED Abstract]
- Harrison G, Richards S, Lawson S, et al.: Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood Leukaemia Working Party. Ann Oncol 11 (8): 999-1006, 2000. [PUBMED Abstract]
- Bunin N, Carston M, Wall D, et al.: Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission. Blood 99 (9): 3151-7, 2002. [PUBMED Abstract]
- Borgmann A, von Stackelberg A, Hartmann R, et al.: Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis. Blood 101 (10): 3835-9, 2003. [PUBMED Abstract]
- Saarinen-Pihkala UM, Heilmann C, Winiarski J, et al.: Pathways through relapses and deaths of children with acute lymphoblastic leukemia: role of allogeneic stem-cell transplantation in Nordic data. J Clin Oncol 24 (36): 5750-62, 2006. [PUBMED Abstract]
- Thomson B, Park JR, Felgenhauer J, et al.: Toxicity and efficacy of intensive chemotherapy for children with acute lymphoblastic leukemia (ALL) after first bone marrow or extramedullary relapse. Pediatr Blood Cancer 43 (5): 571-9, 2004. [PUBMED Abstract]
- Hahn T, Wall D, Camitta B, et al.: The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 11 (11): 823-61, 2005. [PUBMED Abstract]
- Borgmann A, Baumgarten E, Schmid H, et al.: Allogeneic bone marrow transplantation for a subset of children with acute lymphoblastic leukemia in third remission: a conceivable alternative? Bone Marrow Transplant 20 (11): 939-44, 1997. [PUBMED Abstract]
- Schroeder H, Gustafsson G, Saarinen-Pihkala UM, et al.: Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: a population-based case control study from the Nordic countries. Bone Marrow Transplant 23 (6): 555-60, 1999. [PUBMED Abstract]
- van den Berg H, de Groot-Kruseman HA, Damen-Korbijn CM, et al.: Outcome after first relapse in children with acute lymphoblastic leukemia: a report based on the Dutch Childhood Oncology Group (DCOG) relapse all 98 protocol. Pediatr Blood Cancer 57 (2): 210-6, 2011. [PUBMED Abstract]
- Beck JC, Cao Q, Trotz B, et al.: Allogeneic hematopoietic cell transplantation outcomes for children with B-precursor acute lymphoblastic leukemia and early or late BM relapse. Bone Marrow Transplant 46 (7): 950-5, 2011. [PUBMED Abstract]
- Eckert C, Henze G, Seeger K, et al.: Use of allogeneic hematopoietic stem-cell transplantation based on minimal residual disease response improves outcomes for children with relapsed acute lymphoblastic leukemia in the intermediate-risk group. J Clin Oncol 31 (21): 2736-42, 2013. [PUBMED Abstract]
- Gaynon PS: Childhood acute lymphoblastic leukaemia and relapse. Br J Haematol 131 (5): 579-87, 2005. [PUBMED Abstract]
- Woolfrey AE, Anasetti C, Storer B, et al.: Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children. Blood 99 (6): 2002-8, 2002. [PUBMED Abstract]
- Afify Z, Hunt L, Green A, et al.: Factors affecting the outcome of stem cell transplantation from unrelated donors for childhood acute lymphoblastic leukemia in third remission. Bone Marrow Transplant 35 (11): 1041-7, 2005. [PUBMED Abstract]
- Gassas A, Ishaqi MK, Afzal S, et al.: Outcome of haematopoietic stem cell transplantation for paediatric acute lymphoblastic leukaemia in third complete remission: a vital role for graft-versus-host-disease/ graft-versus-leukaemia effect in survival. Br J Haematol 140 (1): 86-9, 2008. [PUBMED Abstract]
- Nemecek ER, Ellis K, He W, et al.: Outcome of myeloablative conditioning and unrelated donor hematopoietic cell transplantation for childhood acute lymphoblastic leukemia in third remission. Biol Blood Marrow Transplant 17 (12): 1833-40, 2011. [PUBMED Abstract]
- Kato M, Horikoshi Y, Okamoto Y, et al.: Second allogeneic hematopoietic SCT for relapsed ALL in children. Bone Marrow Transplant 47 (10): 1307-11, 2012. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Stern M, Ruggeri L, Mancusi A, et al.: Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor. Blood 112 (7): 2990-5, 2008. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Collins RH Jr, Goldstein S, Giralt S, et al.: Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant 26 (5): 511-6, 2000. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]