Childhood Acute Lymphoblastic Leukemia Treatment (Professional) (cont.)
Treatment of Recurrent Childhood ALL
Prognostic Factors in Recurrent Childhood ALL
The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on the following factors: [1,2,3,4,5,6,7,8,9,10,11,12,13]; [Level of evidence: 3iiDi]
- Patient characteristics (e.g., age and peripheral blast count at time of relapse).
- Time from diagnosis to relapse.
- Site of relapse.
Age 10 years and older at diagnosis has been reported as an independent predictor of poor outcome.
The Berlin-Frankfurt-Münster group has also reported that high peripheral blast counts (>10,000/ÁL) at the time of relapse were associated with inferior outcomes in patients with late marrow relapses.
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 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 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.
Site of relapse
Patients who have combined marrow/extramedullary relapses fare better than those who have isolated marrow relapses.[5,13]
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]
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 inferior reinduction failure rate (38.5% TP53 alteration vs. 12.5% TP53 wild-type) and event-free survival (EFS) (9% TP53 alteration vs. 49% TP53 wild-type), of which approximately one-half are newly observed at time of relapse.
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 have a very poor prognosis.
Other prognostic factors for recurrent ALL include the following:
- 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.
- Several studies have demonstrated that minimal residual disease (MRD) levels after the achievement of CR2 are of prognostic significance in relapsed ALL.[17,20,21,22]; [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.
Standard Treatment Options for Recurrent Childhood ALL
Treatment of bone marrow relapse
Standard treatment options for reinduction therapy when cancer has recurred in the bone marrow include the following:
Standard treatment options for postreinduction therapy when cancer has recurred in the bone marrow include the following:
- Chemotherapy (for B-precursor ALL).
- Stem cell transplantation.
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.; [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%).[17,24]
- A United Kingdom-based randomized trial of patients with relapsed ALL compared reinduction with a four-drug combination using idarubicin versus mitoxantrone. [Level of evidence: 1iiA]
- A significant improvement in OS in the mitoxantrone arm (69% vs. 45%, P = .007) due to decreased relapse was reported.
The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation.
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 44% to 56% of patients with refractory or relapsed disease.; [Level of evidence: 2A]
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 (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).[30,31]
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 than a chemotherapy approach.[7,23,32,33,34,35,36,37,38] 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.[9,39,40,41]; [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 SCT) in CR2.
Evidence (chemotherapy for 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. Whether transplantation benefits patients with late marrow relapse but a high level of MRD after reinduction treatment requires further study.
For patients with either an early or late relapse who are treated with chemotherapy and have a second relapse, there is evidence that an unrelated SCT may result in long-term disease-free survival.[Level of evidence: 3iiA] Patients with long first and second remission have the lowest relapse risk, but there is a high rate of nonrelapse mortality.
For patients with T-cell ALL who have marrow relapses, outcomes with chemotherapy alone have generally been poor, and these patients are usually treated with allogeneic SCT in CR2, regardless of time to relapse.
Stem cell transplantation
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.[32,44,45] TBI is often combined with either cyclophosphamide or etoposide. Results with either drug are generally equivalent, although one study suggested that if cyclophosphamide is used, higher-dose TBI may be necessary. The potential neurotoxic effects of TBI should be considered, particularly for very young patients. The use of post-HSCT intrathecal chemotherapy chemoprophylaxis does not appear to offer benefit; however, this is controversial.[49,50,51]
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.[22,52,53,54]
There is no apparent difference in outcome between children and adolescents transplanted in second remission.[Level of evidence: 3iiA]
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.[36,56,57,58,59]; [Level of evidence: 2A]; [Level of evidence: 3iiiA] Rates of clinically extensive graft-versus-host disease (GVHD) and treatment-related mortality remain higher with unrelated than with matched sibling transplants.[37,56,62] 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, treatment-related mortality, and OS have improved over time.; [64,65][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]
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.
Relapse after allogeneic HSCT for relapsed ALL
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 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.[70,71,72] 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.[71,72]
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 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%.[77,78,79] Age older than 6 years at diagnosis is an adverse prognostic factor for patients with an isolated extramedullary relapse. 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 than patients with either no MRD or MRD less than 0.01%.
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.[15,82,83,84]
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 SCT in the treatment of isolated CNS relapse have been published.[85,86]
- 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).[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 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 suggest no benefit.[48,88]
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 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 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.
Evidence (chemotherapy and radiation therapy):
- 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.
- 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.
- 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.[Level of evidence: 3iA]
Treatment Options Under Clinical Evaluation for Recurrent Childhood ALL
Treatment options under clinical evaluation include the following:
COG trials for ALL in first relapse
The COG has divided patients with first relapse into three risk categories as outlined in Table 4. Clinical trials in some risk categories are available.
Table 4. Children's Oncology Group ALL Relapse Risk Stratification for B-Precursor ALLa
|Isolated CNS or Testicular Relapse||Bone Marrow or Combined Relapse|
|ALL = acute lymphoblastic leukemia; CNS = central nervous system.|
|a All relapsed T-cell ALL is considered high risk.|
|<18 months from diagnosis||Intermediate risk||High risk|
|18–36 months from diagnosis||Low risk||High risk|
|>36 months from diagnosis||Low risk||Intermediate risk|
- COG-AALL0433 (Low-Dose or High-Dose Vincristine and Combination Chemotherapy in Treating Young Patients With Relapsed B-Cell ALL [high-dose vincristine arm closed to accrual as of September 2010]): Patients with intermediate-risk relapse are eligible for this study. Patients 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 marrow relapse of T-cell ALL and early marrow relapse (<36 months) of B-precursor 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.
Other trials for ALL in first relapse
- 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).
- COG-ADVL1114 (Temsirolimus, Dexamethasone, Mitoxantrone Hydrochloride, Vincristine Sulfate, and Pegaspargase in Treating Young Patients With Relapsed ALL or Non-Hodgkin Lymphoma [NHL]): This is a phase I trial to determine the feasibility and safety of adding three doses of temsirolimus (intravenously) to the United Kingdom ALL R3 induction regimen for patients with relapsed ALL and NHL.
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.
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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Eckert C, Biondi A, Seeger K, et al.: Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet 358 (9289): 1239-41, 2001.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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- 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.
- 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.
- 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.
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- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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