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Cyclophosphamide/etoposide in pediatric B-ALL
between the two arms. Substitution of this therapy for very high-risk B-cell acute lymphoblastic leukemia patients on the Children’s Oncology Group AALL1131 trial (NCT02883049) randomized to cyclophosphamide/etoposide during part 2 of consolidation and delayed intensification did not improve disease-free survival.
Introduction
With modern chemotherapy regimens, approximately 90% of patients with pediatric B-cell acute lymphoblastic leukemia (B-ALL) are now cured.1,2 However, subsets of patients remain at very high-risk (VHR) of relapse with an expected 4-year disease-free survival (DFS) rate <80%. Current post-induction intensification strategies, which have focused on optimizing the use of drugs commonly administered in ALL therapy, have delivered sub-optimal results for these VHR B-ALL patients. In the absence of a specific targeted intervention (such as Abl-tyrosine kinase inhibitors in Philadelphia chromosome-positive ALL), intensive chemotherapy continues to be the mainstay of treatment. We hypothesized that further optimization or intensification of the dose and schedule of established agents or combination regimens typically used to treat newly diagnosed ALL patients would probably not improve outcomes further for VHR B-ALL patients, and therefore novel or targeted therapies should be investigat- ed. Given that there was not a molecularly targeted agent available for this population of patients at the time the study was conceived, this trial was designed to test the use of different consolidation strategies, based on drugs not commonly used in frontline ALL trials, including fractionat- ed cyclophosphamide and etoposide.
The Children’s Oncology Group (COG) AALL1131 trial thus aimed to determine, in a randomized fashion, whether replacing cyclophosphamide, cytarabine, and 6-mercaptop- urine during consolidation or cyclophosphamide, cytara- bine, and 6-thioguanine during delayed intensification with cyclophosphamide and etoposide (experimental arm 1) dur- ing the consolidation and reconsolidation phases of COG augmented Berlin-Frankfurt-Münster therapy (control arm)3 would improve the 4-year DFS of children, adolescents, and young adults with VHR B-ALL. The cyclophosphamide/ etoposide combination was well tolerated in prior relapse B-ALL studies4,5 and a similar combination of ifosfamide/etoposide yielded 40% complete remission rates in children with refractory ALL,6 making cyclophos- phamide/etoposide an encouraging combination to study.
Methods
COG AALL1131 (NCT02883049), a phase III trial for patients aged 1-30 years with newly diagnosed high-risk B-ALL opened to enrollment on February 27, 2012 and the VHR randomization closed on February 15, 2017. Eligibility criteria included: 1-9 years of age inclusive with a presenting white blood cell count ≥50x109/L; ≥10 to <31 years of age with any white blood cell count; >1 to <31 years of age with testicular leukemia, central nervous system leukemia (CNS3; ≥5/mL white blood cells and cytospin positive for blasts in the cerebral spinal fluid and/or clini- cal signs of CNS leukemia), or steroid pre-treatment in patients <10 years of age for whom no pre-steroid white blood cell count was obtained.7 At the end of induction therapy, patients were fur-
ther classified as VHR if they had any of the following criteria: ≥13 years of age; CNS3 leukemia at diagnosis; day 29 bone marrow minimal residual disease ≥0.01% determined by flow cytometry;7,8 induction failure [>25% bone marrow blasts (M3) on induction day 29], severe hypodiploidy (DNA index <0.81 and/or <44 chro- mosomes); intrachromosomal amplification of chromosome 21, or lysine methyltransferase 2A (KMT2A, formerly mixed lineage leukemia, MLL) rearrangement. In addition, patients with National Cancer Institute standard-risk B-ALL, enrolled on the COG study AALL0932 (NCT01190930) for standard-risk B-ALL (≥1 to <10 years of age with a white blood cell count <50x109/L), were classi- fied as VHR following induction if they met any of the above VHR criteria or if they had day 29 bone marrow minimal residual dis- ease ≥0.01% in the absence of favorable cytogenetics (no trisomies of chromosomes 4 and 10 and no ETV6/RUNX1 fusion). Patients with Down syndrome were not eligible for the VHR stratum given the concern of increased toxicity of the regimen. Toxicities were graded using the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0. The study was approved by the National Cancer Institute, the Pediatric Central Institutional Review Board, and institutional review boards at each participating COG institution.
The AALL1131 study was originally designed to investigate the addition of clofarabine to cyclophosphamide/etoposide as experi- mental arm 2 versus cyclophosphamide/etoposide (experimental arm 1) versus the control arm in a 2:2:1 randomization for patients with VHR B-ALL. The study design was later amended to a 2:1 randomization between experimental arm 1 and the control arm, retaining those patients initially randomized to experimental arm 1 and the control arm, after the clofarabine arm (experimental arm 2) was closed because of unacceptable toxicity (September 2014).7 Patients classified as VHR were subsequently randomized after induction in a 1:2 fashion to cyclophosphamide (1 g/m2 day 29)/cytarabine (75 mg/m2 days 29-33 and 36-40)/6-mercaptopurine (60 mg/m2 days 29-42 consolidation) or thioguanine (60 mg/m2 days 29-42 during part 2 of delayed intensification) (control arm) or cyclophosphamide (440 mg/m2, days 29-33)/etoposide (100 mg/m2, days 29-33) (experimental arm 1) during part 2 of consoli- dation and delayed intensification. Both arms included the same dose and schedule of pegaspargase (2,500 IU/m2) on day 43 and vincristine (1.5 mg/m2) on days 43 and 50 of consolidation and delayed intensification. The delayed intensification also included intrathecal methotrexate on days 29 and 36 on all arms. Patients with CNS3 leukemia received 1800 cGy of cranial irradiation dur- ing the first month of maintenance therapy. Any patient with tes- ticular leukemia at diagnosis that did not resolve by the end of induction received 2400 cGy testicular irradiation during consoli- dation. The remainder of the VHR therapy was identical between the two arms.7 The complete AALL1131 VHR treatment regimen is shown in Table 1. The study did not capture detailed informa- tion on patients who underwent hematopoietic stem cell trans- plantation off protocol therapy. The VHR randomization was powered (80%) to compare a 4-year DFS of 70% versus 79% (HR=0.661) using a two-sided log-rank test (a=5%). DFS was defined as the time from post-induction randomization to first event (death in remission, relapse, or second malignant neoplasm) or date of last contact for those who remained event-free. Survival
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