Treatment of Recurrent ALL
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. 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. 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
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 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 diagnosis||Intermediate risk [COG-AALL0433]b||High risk [COG-ADVL04P2]b|
|18-36 months from diagnosis ||�||High risk [COG-ADVL04P2]b|
|>36 months from diagnosis||�||Intermediate risk [COG-AALL0433]b|
- COG-ADVL04P2: Patients with high-risk relapse are eligible for this study. Epratuzumab (an anti-CD22 monoclonal antibody) is given in conjunction with a four-drug reinduction (Block 1). Two additional blocks of therapy are given after Block 1. MRD is 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) with epratuzumab.
- Block 2: etoposide, cyclophosphamide, methotrexate (intravenously and by lumbar puncture).
- Block 3: high-dose cytarabine, L-asparaginase.
- COG-AALL0433: 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: 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: 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 graft-versus-host disease 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.