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Childhood Acute Lymphoblastic Leukemia Treatment (Professional) (cont.)

Treatment of Recurrent ALL

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Pediatric Treatment Editorial Board uses a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Prognostic Factors in Recurrent ALL

The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on the time from diagnosis to relapse and site of relapse, as well as cytogenetics and immunophenotype.[1,2,3,4,5,6,7,8,9,10,11,12,13]; [14][Level of evidence: 3iiDi] For patients with relapsed B-precursor ALL, early relapses fare worse than later relapses, and marrow relapses fare worse than isolated extramedullary relapses. For instance, survival rates after marrow relapse 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 are 75% to 80% for those with late relapses (>18 months from diagnosis).[13,15] No evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) in off-therapy patients improves outcome.[16]

Patients who have combined marrow/extramedullary relapses fare better than those with isolated marrow relapses.[5,13] The Berlin-Frankfurt-Muenster (BFM) group has also reported that high peripheral blast counts at the time of relapse (>10,000/ÁL) were associated with inferior outcomes in patients with late marrow relapses.[10] The Children's Oncology Group (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] Age older than 10 years has also been reported as an independent predictor of poor outcome.[13]

Immunophenotype is an important prognostic factor at relapse. Patients with T-cell ALL who experience a marrow relapse (isolated or combined) at any point during treatment or posttreatment have a very poor prognosis.[5]

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 remission (CR2).[17][Level of evidence: 2Di] Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of CR2 are of prognostic significance in relapsed ALL.[17,18,19,20]; [21][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.

Treatment of Bone Marrow Relapse

Reinduction chemotherapy

Initial treatment of relapse consists of induction 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.[5];[22][Level of evidence: 2A]; [17][Level of evidence: 2Di] A United Kingdom-based randomized trial of patients with relapsed ALL compared reinduction with a four-drug combination using idarubicin versus mitoxantrone. A significant improvement in OS in the mitoxantrone arm (69% vs. 45%, P = .007) due to decreased relapse was reported.[23][Level of evidence: 1iiA] The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation. Patients with early marrow relapses have a lower rate of achieving a morphologic CR2 (approximately 70%) compared with those with late marrow relapses (approximately 95%).[17,22] Compared with patients with B-precursor phenotype, patients with relapsed T-cell ALL have much lower rates of achieving CR2 with standard reinduction regimens.[17] 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%.[24] The combination of nelarabine, cyclophosphamide, and etoposide has produced remissions in patients with relapsed/refractory T-cell ALL.[25]

Other combinations of agents have been reported to induce remissions in patients with multiple-relapsed or refractory ALL. The combination of clofarabine, cyclophosphamide, and etoposide was reported to induce remission in 56% of patients with refractory or relapsed disease.[26]

Postreinduction therapy (second complete remission)

Post-CR2 therapy for patients who experience a bone marrow relapse (either isolated or combined) while on therapy or within 6 months of discontinuing therapy generally includes hematopoietic stem cell transplantation (HSCT).[27,28] 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 longer leukemia-free survival when compared with a chemotherapy approach.[7,21,29,30,31,32,33,34,35] However, even with transplantation, the survival rate for patients with early marrow relapse is less than 50%.

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.[9,36,37] End-reinduction MRD levels may help to identify patients with a high risk of subsequent relapse if treated with chemotherapy alone (no SCT) in CR2. 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.[19] Whether transplantation benefits patients with late marrow relapse but a high level of MRD after reinduction treatment requires further study.

For patients with T-cell ALL and marrow relapse, outcomes with chemotherapy alone have generally been poor,[5] and these patients are usually treated with allogeneic SCT in CR2, regardless of time to relapse.

For patients proceeding to allogeneic SCT, total-body irradiation (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 chemotherapy-only preparative regimens.[29,38,39] TBI is often combined with either cyclophosphamide or etoposide. Results with either drug are generally equivalent,[40] although one study suggested that if cyclophosphamide is used, higher-dose TBI may be necessary.[41] The potential neurotoxic effects of TBI should be considered, particularly for very young patients.

In addition to the conditioning regimen, disease status at the time of transplantation also appears to be an important predictor of outcome. Several studies have demonstrated that the level of MRD at the time of transplant is an important predictor of survival in patients in CR2.[20,42,43]

Outcomes following matched unrelated donor and umbilical cord blood transplants have improved significantly over the past decade and may offer outcome similar to that obtained with matched sibling donor transplants.[33,44,45,46,47]; [48][Level of evidence: 2A]; [49][Level of evidence: 3iiiA] Rates of clinically extensive graft-versus-host disease (GVHD) and treatment-related mortality (TRM) remain higher with unrelated than with matched sibling transplants.[34,44,50] However, there is some evidence that matched unrelated donor transplantation may yield a lower relapse rate, and National Marrow Donor Program and Center for International Blood and Marrow Transplant Research (CIBMTR) analyses have demonstrated that rates of GVHD, TRM, and OS have improved over time.[51]; [52,53][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.[54] 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.[55] 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.[56][Level of evidence: 3iiA] There are a number of new options under study for preventing subsequent relapse after transplantation, including withdrawal of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal antibodies and natural killer cell therapy.[57]

For patients relapsing after an allogeneic HSCT for relapsed ALL, a second ablative allogeneic HSCT may be feasible. However, many patients will be unable to undergo a second HSCT procedure due to failure to achieve remission, early toxic death, or severe organ toxicity related to salvage chemotherapy.[58] Among the highly selected group of patients able to undergo a second ablative allogeneic HSCT, approximately 10% to 30% may achieve long-term event-free survival (EFS).[58,59,60] Prognosis is more favorable in patients with longer duration of remission after the first HSCT and in patients with complete remission at the time of the second HSCT.[59,60] Reduced intensity approaches can also cure a percentage of patients when used as a second allogeneic transplant approach, but only if patients achieve a complete remission confirmed by flow cytometry.[61][Level of evidence: 2A] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT.[62]; [63][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.[64][Level of evidence: 3iA]

Treatment of Extramedullary Relapse

With the improved success of treatment of 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%.[65,66,67] Age older than 6 years at diagnosis is an adverse prognostic factor for patients with an isolated extramedullary relapse.[68] In the majority of children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques,[69] 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 compared with patients with either no MRD or MRD less than 0.01%.[69]

CNS relapse

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.[15,70,71,72] 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 greater 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.[72] In a follow-up POG study, children who had not previously received radiation therapy and with 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.[15] 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 SCT in the treatment of isolated CNS relapse have been published.[73,74] In a study comparing outcome of patients treated with either HLA-matched sibling transplants or chemoradiotherapy 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).[75][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. However, use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study. The use of post-HSCT intrathecal chemotherapy has been controversial, although the most current data would suggest no benefit.[76]

Testicular relapse

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.[77] The standard approach for treating isolated testicular relapse in North America is to administer chemotherapy plus 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. 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. 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.[78] 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.[79] In a small series of boys who had an isolated testicular relapse after a SCT for a prior systemic relapse of ALL, five of seven boys had extended EFS without a second SCT.[64][Level of evidence: 3iA]

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

Children's Oncology Group (COG)

The COG has divided patients with relapse into three risk categories as outlined in Table 1. Clinical trials in some risk categories are available.

Table 1. COG B-Cell ALL Relapse Risk Stratificationa and Clinical Trials

ALL = acute lymphoblastic leukemia; CNS = central nervous system; COG = Children's Oncology Group.
a All relapsed T-cell ALL is considered high risk—COG-AALL07P1.
b All intermediate-risk patients with matched siblings choosing allogeneic transplant, and all high-risk patients undergoing related or unrelated transplantation are encouraged to enroll in COG-ASCT0431 (see below) after completion of the three induction blocks associated with these protocols.
Isolated CNS or Testicular Relapse [Clinical Trial]Bone Marrow or Combined Relapse [Clinical Trial]
<18 months from diagnosisIntermediate risk [COG-AALL0433]b
18–36 months from diagnosis
>36 months from diagnosisIntermediate risk [COG-AALL0433]b
  • COG-AALL0433 (Low-Dose or High-Dose Vincristine and Combination Chemotherapy in Treating Young Patients With Relapsed B-Cell ALL [high-dose vincristine closed to accrual as of September 2010]): Patients with intermediate-risk relapse are eligible for this study. Patients in this study will receive a chemotherapy regimen similar to POG studies, POG-9061 and POG-9412, which have been shown to be efficacious in the isolated relapse setting and well tolerated. Intensification of vincristine is being studied in a randomized fashion. For patients with a matched sibling, the choice of bone marrow transplant or chemotherapy is left to the discretion of the treating physician and/or family. The vincristine randomization has been closed for patients younger than 10 years at diagnosis due to increased toxicity in the higher-dose vincristine arm.
  • COG-AALL07P1 (Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed ALL or Lymphoblastic Lymphoma): Patients with relapse of T-cell ALL are eligible for this study. This is a phase II pilot study to determine the feasibility and safety of adding bortezomib to intensive reinduction chemotherapy. Bortezomib is a proteasome inhibitor that has been shown to sensitize leukemic cells to apoptosis induced by chemotherapy.
  • COG-ASCT0431 (Tacrolimus and Methotrexate With or Without Sirolimus in Preventing GVHD in Young Patients Undergoing Donor Stem Cell Transplant for ALL in Complete Remission): Patients with very high-risk CR1 (primary induction failure, hypodiploid [<44 chromosomes], Ph+ with high MRD) ALL or CR2 (B cell relapse <36 months, T-cell or Ph+ bone marrow relapse and any donor or bone marrow relapse =36 months, isolated extramedullary relapse <18 months and matched sibling donors only) ALL are eligible. This phase III transplant trial randomizes a standard tacrolimus/methotrexate GVHD prophylaxis approach with tacrolimus/methotrexate/sirolimus. The hypothesis is that the anti-leukemic effects of the mTOR inhibitor, sirolimus, will decrease relapse and improve survival.

Other clinical trials investigating new agents and new combinations of agents are available for children with recurrent ALL and should be considered.[80,81,82] Targeted therapies specific for ALL are being developed, including monoclonal antibody-based therapies and using drugs that inhibit signal transduction pathways required for leukemia cell growth and survival.

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.

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