Standard Treatment Options
Treatment Options Under Clinical Evaluation
Current Clinical Trials

Standard Treatment Options

The prognosis for a child with acute lymphoblastic leukemia (ALL) whose disease recurs depends on the time from diagnosis, site of relapse, and immunophenotype.[1-5][Level of evidence: 3iiDi] Patients with precursor B-cell ALL who experience either an isolated marrow relapse while on treatment or within 6 months of completion of therapy or a combined relapse within 18 months of diagnosis have a very poor prognosis. Patients with an extramedullary relapse while on treatment or within 6 months of completion of therapy, patients with precursor B-cell ALL and a marrow relapse with or without an extramedullary relapse more than 6 months after completing therapy, and patients with precursor B-cell ALL and a combined marrow relapse between 18 and 36 months from diagnosis have an intermediate prognosis. Patients with a late extramedullary relapse (occurring >6 months after completing therapy) have a good prognosis. Despite these findings, no evidence exists that early detection of relapse by frequent surveillance (complete blood counts or bone marrow tests) improves outcome.[6] Patients with T-cell ALL who experience a bone marrow relapse with or without a concurrent extramedullary relapse at any point during treatment or posttreatment have a very poor prognosis.[1-4,7-16] Treatment of children with relapsed T-cell ALL with the T-cell selective agent nelarabine has demonstrated an approximately 50% response rate.[17,18] Data suggest that minimal residual disease (MRD) status after induction of second remission is of prognostic significance in patients with relapsed ALL.[19-21] The German Berlin-Frankfurt-Munster (BFM) group has developed a risk stratification for relapsed ALL. In this risk stratification, duration of first complete remission and immunophenotype are associated with outcome. (See Tables 2 and 3 below.)

The selection of therapy for the child whose disease recurs on or shortly after therapy depends on many factors including prior treatment, whether the recurrence is medullary or extramedullary, and individual patient considerations. Aggressive approaches, including hematopoietic stem cell transplantation (HSCT) should be strongly considered for patients with T-cell ALL and marrow relapse; or patients with precursor B-cell ALL and marrow relapse occurring while on treatment or within 6 months of termination of therapy; or late marrow relapse with high tumor load as indicated by a peripheral blast count of 10,000/µL or more.[12,23,24] For such patients, allogeneic transplant from a human leukocyte antigen (HLA)-identical sibling or matched unrelated donor that is performed in second remission has been reported to result in longer leukemia-free survival when compared with a chemotherapy approach;[9,22,25-30] however, the Children's Cancer Group trial (CCG-1941) comparing chemotherapy versus HSCT (either matched sibling or matched unrelated donor) was not able to show a significant advantage for HSCT over chemotherapy for patients relapsing less than 12 months after stopping therapy.[31] Two retrospective studies and a randomized trial [32] suggest that transplant conditioning regimens that include total-body irradiation (TBI) produce higher cure rates than chemotherapy-only preparative regimens.[25,33,32] TBI is often combined with either cyclophosphamide or etoposide. Results with either drug are generally equivalent,[34] although one study suggested that if cyclophosphamide is used, higher-dose TBI may be necessary.[35] The potential neurotoxic effects of TBI should be considered, particularly for very young patients. For patients with a late marrow relapse, a primary chemotherapy approach should be considered with HSCT reserved for a subsequent marrow relapse.[11,36,37] Whether transplantation benefits patients with late marrow relapse but a high level of residual disease after reinduction treatment requires additional studies.

The value of matched unrelated stem cell or unrelated cord blood transplantation in the therapy of children with recurrent ALL is also under investigation.[38-42] Outcome following matched unrelated donor transplants has improved significantly over the past decade and may offer outcome similar to that obtained with matched sibling donor transplants.[29,41,43] Treatment-related mortality remains high (>20%) and rates of clinically extensive chronic graft-versus-host disease remain high in some reports for matched unrelated donor transplants.[22,43,44] However, there is some evidence that matched unrelated donor transplantation may yield a lower relapse rate.[45] A Center for International Blood and Marrow Transplant Research study suggests that outcome after one or two antigen mismatched cord blood transplant may be equivalent to that for a matched family donor or a matched unrelated donor.[46] In certain cases where no suitable donor is found or an immediate transplant is considered crucial, a haploidentical transplant utilizing large doses of stem cells may be considered.[47] For all types of transplants, pretransplant levels of MRD are an important prognostic factor; patients with high levels of pretransplant MRD have a very poor prognosis.[21,48]

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.[49] 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).[49-51] 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.[50,51] Donor leukocyte infusion has limited benefit for patients with ALL who relapse after allogeneic HSCT.[52]

With the improved success of treatment of children with ALL, the incidence of isolated extramedullary relapse has decreased. The incidence of isolated central nervous system (CNS) relapse is less than 10% and testicular relapse is less than 5%. In the majority of children with isolated extramedullary relapses, submicroscopic marrow disease can be demonstrated using sensitive molecular techniques,[53] and successful treatment strategies must effectively control both local and systemic disease. The level of submicroscopic marrow involvement may also predict response to post-relapse therapy.[53] While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy followed by craniospinal radiation has improved the outlook, particularly for patients who did not receive cranial radiation during their first remission.[54-57] 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.[56] In a follow-up POG study,[57] 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. 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. This group's 4-year EFS was 52%.

A number of case series describing stem cell transplantation in the treatment of isolated CNS relapse have been published. This approach may be of value in patients with high risk of relapse using chemoradiation treatment.[58] In a study comparing outcome of patients treated with either HLA-matched sibling transplants or chemoradiotherapy as in the POG studies above, however, 8-year probablities of leukemia-free survival adjusted for age and duration of first remission were similar (58% and 66%, respectively).[59]

The standard approach for treating isolated testicular relapse is to administer chemotherapy plus radiation therapy. While there is limited clinical data concerning outcome without the use of radiation therapy, the use of chemotherapy (e.g. high-dose methotrexate) that may be able to achieve antileukemia levels in the testes,[60] is being tested in clinical trials. 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.[61] A study that looked at testicular biopsy at the end of therapy failed to demonstrate a survival benefit for patients with early detection of occult disease.[62]

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)

• ADVL04P2: Patients with bone marrow relapse are eligible for this study. In the initial prephase of this protocol, a new experimental antileukemic drug, epratuzumab (an anti-CD22 monoclonal antibody), will be given followed by three blocks of induction chemotherapy. Epratuzumab will also be combined with Block 1 of induction therapy. After the prephase testing is completed in a limited number of institutions, the protocol without the prephase will be available for all COG institutions. MRD will be determined by flow cytometry after each course once a remission is achieved.
  • Block 1: vincristine, prednisone, PEG-L-asparaginase, doxorubicin; cytarabine (by lumbar puncture) and methotrexate (by lumbar puncture).
  
  
  
  • Block 2: etoposide, cyclophosphamide, methotrexate (intravenously and by lumbar puncture).
  
  
  
  • Block 3: high-dose cytarabine, L-asparaginase.
  
  
  



• AALL02P2: Patients with isolated CNS or isolated testicular relapse occurring more than 18 months after initial remission are eligible for this study.

  For patients with isolated testicular relapse, the hypothesis of this protocol is that testicular radiation is not necessary if intensive systemic chemotherapy, including high-dose methotrexate, is administered. Patients will initially receive high-dose methotrexate followed by standard induction therapy. With complete clinical response, treatment with intensive chemotherapy as per a prior successful relapse protocol (POG-9412) [57] will be administered. Testicular radiation therapy is not given.

  For patients with isolated CNS relapse, the hypothesis of this protocol is that reduced-dose cranial radiation (12 Gy) will be adequate to prevent subsequent CNS relapse when combined with a protocol of intensive systemic and coordinated intrathecal therapy. Treatment will be similar to that successfully utilized in POG-9412.

Clinical trials investigating new agents [63,64] and new combinations of agents are available for children with recurrent ALL and should be considered. 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.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References

1. Gaynon PS, Qu RP, Chappell RJ, et al.: Survival after relapse in childhood acute lymphoblastic leukemia: impact of site and time to first relapse--the Children's Cancer Group Experience. Cancer 82 (7): 1387-95, 1998.  [PUBMED Abstract]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. Sadowitz PD, Smith SD, Shuster J, et al.: Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 81 (3): 602-9, 1993.  [PUBMED Abstract]
    
    
14. 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]
    
    
15. 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]
    
    
16. Abshire TC, Buchanan GR, Jackson JF, et al.: Morphologic, immunologic and cytogenetic studies in children with acute lymphoblastic leukemia at diagnosis and relapse: a Pediatric Oncology Group study. Leukemia 6 (5): 357-62, 1992.  [PUBMED Abstract]
    
    
17. 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]
    
    
18. Kurtzberg J, Ernst TJ, Keating MJ, et al.: Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies. J Clin Oncol 23 (15): 3396-403, 2005.  [PUBMED Abstract]
    
    
19. 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.  [PUBMED Abstract]
    
    
20. 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]
    
    
21. 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]
    
    
22. 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]
    
    
23. 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]
    
    
24. 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]
    
    
25. 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]
    
    
26. 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]
    
    
27. 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]
    
    
28. 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]
    
    
29. 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]
    
    
30. 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]
    
    
31. Gaynon PS, Harris RE, Altman AJ, et al.: Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children's Oncology Group study CCG-1941. J Clin Oncol 24 (19): 3150-6, 2006.  [PUBMED Abstract]
    
    
32. 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]
    
    
33. 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]
    
    
34. 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]
    
    
35. 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]
    
    
36. 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]
    
    
37. 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]
    
    
38. Hongeng S, Krance RA, Bowman LC, et al.: Outcomes of transplantation with matched-sibling and unrelated-donor bone marrow in children with leukaemia. Lancet 350 (9080): 767-71, 1997.  [PUBMED Abstract]
    
    
39. Casper J, Camitta B, Truitt R, et al.: Unrelated bone marrow donor transplants for children with leukemia or myelodysplasia. Blood 85 (9): 2354-63, 1995.  [PUBMED Abstract]
    
    
40. Weisdorf DJ, Billett AL, Hannan P, et al.: Autologous versus unrelated donor allogeneic marrow transplantation for acute lymphoblastic leukemia. Blood 90 (8): 2962-8, 1997.  [PUBMED Abstract]
    
    
41. 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]
    
    
42. 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]
    
    
43. 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]
    
    
44. 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]
    
    
45. 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]
    
    
46. 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]
    
    
47. 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]
    
    
48. 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]
    
    
49. 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]
    
    
50. 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]
    
    
51. 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]
    
    
52. 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]
    
    
53. 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]
    
    
54. 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]
    
    
55. 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]
    
    
56. 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]
    
    
57. 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]
    
    
58. 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]
    
    
59. Eapen M, Zhang MJ, Raetz E, et al.: Outcomes after HLA-matched sibling transplants or chemotherapy in children with acute lymphoblastic leukemia in a second remission after an isolated central nervous system relapse. [Abstract] Blood 108 (11): A-49, 2006. 
    
    
60. 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]
    
    
61. 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]
    
    
62. 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]
    
    
63. Jeha S, Gaynon PS, Razzouk BI, et al.: Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol 24 (12): 1917-23, 2006.  [PUBMED Abstract]
    
    
64. Pui CH, Jeha S: New therapeutic strategies for the treatment of acute lymphoblastic leukaemia. Nat Rev Drug Discov 6 (2): 149-65, 2007.  [PUBMED Abstract]
    
    

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