Abstract
Background: Acute Lymphoblastic Leukemia (ALL) is the most common form of malignancy in children. Advances in treatments have made ALL the disease highly curable; however relapse is the most common form of treatment failure. The prognosis for relapsed ALL is poor, and the ability to achieve a durable second remission is influenced by the length of the initial remission and, potentially, the re-induction therapy chosen. We present a series of 60 pediatric ALL patients with first relapse (54 pre B-cell and 6 T-cell) treated with a standardized four-drug induction therapy followed by either intensification therapy or hematopoietic stem cell transplant (HSCT).
Methods: Patients treated at Children’s Hospital and Regional Medical Center, Seattle, WA with a common re-induction regimen for first relapse ALL were reviewed in this IRB-approved retrospective study. Patients included isolated or combined bone marrow (BM) relapse, isolated central nervous system (CNS) relapse alone, or isolated testicular relapse. Re-induction consisted of a four-drug combination of dexamethasone (dex) (day 0-6, 14-20), vincristine (VCR) (weekly for 4 weeks), peg-aspargase (weekly for 4 weeks), and idarubicin (10 mg/m2/day × 2-3 doses) and intrathecal triple (ITT) drug therapy. After achieving second complete remission (CR2), patients proceeded to HSCT or continued chemotherapy at the discretion of the physician. Allogeneic HSCT was total body irradiation based and a variety of stem cell sources. Continuation chemotherapy was alternating blocks every 3 weeks for up to 8 courses: Block A, consisting of dex, VCR, 6-thioguanine (TG), peg-asparagase and methotrexate (MTX) and ITT, and Block B, consisting of etoposide and ifosfamide and ITT. Maintenance chemotherapy with MTX, VCR and TG with cranial, craniospinal or testicular radiation completed the two year regimen.
Results: Among the 54 pre-B-cell patients, there were 32 with BM relapse (either isolated or with CNS), 16 CNS relapses, and 6 testicular relapses. CR2 was achieved in 96% of the patients. Two did not achieve remission, dying of toxicity during re-induction.
BM (± CNS) Isolated CNS Testicular Duration of CR1 n 3 yr. EFS (95% CI) n 3 yr. EFS (95% CI) n 3 yr. EFS (95% CI) <18 months 5 0% (± 52%) 3 67% (± 54%) - - >18 months 27 39% (± 24%) 13 75% (± 26%) 6 67% (± 38%)
Among the patients with BM relapse, the 3 year Event Free Survival (EFS) was 33.2% (95% CI: ± 20.8%). The 3 year EFS for the 18 who proceeded to HSCT was 35.0% (95% CI: ± 27.4%), while 3-year EFS for chemotherapy only patients was 31.7% (95% CI: ± 31.8%). There were 6 patients with T-cell relapsed disease, which were evaluated separately. Their EFS was 0% (95% CI: ±46%) at three years, and 2 failed to achieve CR2.
Discussion: We present a large single institution series of patients treated with a common reinduction regimen followed by chemotherapy or HSCT. Although intensive, the regimen was tolerable (less than 4% toxic death rate) and highly successful in achieving CR2. Among the patients with later BM relapse, there was minimal difference in 3-year EFS between chemotherapy and HSCT, offering a reasonable continuation chemotherapy regimen to these patients. Our data confirmed the excellent outcome of isolated CNS and testicular relapse and the poor outcome of very early relapse and T cell disease.
Bispecific T-cell engaging antibodies in B-cell precursor acute lymphoblastic leukemias: focus on blinatumomab
