Pilot study of nelarabine in combination with intensive chemotherapy in high-risk T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group.

PURPOSE: Children's Oncology Group study AALL00P2 was designed to assess the feasibility and safety of adding nelarabine to a BFM 86-based chemotherapy regimen in children with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL). PATIENTS AND METHODS: In stage one of the study, eight patients with a slow early response (SER) by prednisone poor response (PPR; ≥ 1,000 peripheral blood blasts on day 8 of prednisone prephase) received chemotherapy plus six courses of nelarabine 400 mg/m(2) once per day; four patients with SER by high minimal residual disease (MRD; ≥ 1% at day 36 of induction) received chemotherapy plus five courses of nelarabine; 16 patients with a rapid early response (RER) received chemotherapy without nelarabine. In stage two, all patients received six 5-day courses of nelarabine at 650 mg/m(2) once per day (10 SER patients [one by MRD, nine by PPR]) or 400 mg/m(2) once per day (38 RER patients; 12 SER patients [three by MRD, nine by PPR]). RESULTS: The only significant difference in toxicities was decreased neutropenic infections in patients treated with nelarabine (42% with v 81% without nelarabine). Five-year event-free survival (EFS) rates were 73% for 11 stage one SER patients and 67% for 22 stage two SER patients treated with nelarabine versus 69% for 16 stage one RER patients treated without nelarabine and 74% for 38 stage two RER patients treated with nelarabine. Five-year EFS for all patients receiving nelarabine (n = 70) was 73% versus 69% for those treated without nelarabine (n = 16). CONCLUSION: Addition of nelarabine to a BFM 86-based chemotherapy regimen was well tolerated and produced encouraging results in pediatric patients with T-ALL, particularly those with a SER, who have historically fared poorly.

Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: results of Children's Oncology Group trial P9906.

BACKGROUND: The augmented BFM regimen improves outcome for children with NCI high acute lymphoblastic leukemia (ALL). Patient age, sex, and presenting white blood cell count (WBC) can be used to identify a subset of approximately 12% of children with B-precursor ALL that had a 5-year continuous complete remission (CCR) rate of only about 50% on earlier Pediatric Oncology Group (POG) trials. PROCEDURES: Children's Oncology Group trial P9906 evaluated a modified augmented BFM regimen in 267 patients with particularly high risk B-precursor ALL. Minimal residual disease (MRD) was assessed in blood at day 8 and in marrow at day 29 of induction and correlated with outcome. RESULTS: The 5-year CCR probability for patients in P9906 was significantly better than that observed for similar patients on POG trials 8602/9006 (62.2 ± 3.7% vs. 50.6 ± 2.4%; P = 0.0007) but similar to POG 9406 (63.5 ± 2.4%; P = 0.81). Interim analysis showed poor central nervous system (CNS) control, especially in patients with initial WBC ≥ 100,000/microliter. Day 29 marrow MRD positive (≥ 0.01%) vs. negative patients had 5 year CCR rates of 37.1 ± 7.4% vs. 72.6 ± 4.3%; day 8 blood MRD positive vs. negative patients had 5 year CCR rates of 57.1 ± 4.6% vs.83.6 ± 6.3%. End induction marrow MRD predicted marrow but not CNS relapse. In multivariate analysis, day 29 MRD > 0.01%, initial WBC ≥ 100,000/µl, male gender, and day 8 blood MRD > 0.01% were significant prognostic factors. CONCLUSIONS: Augmented BFM therapy improved outcome for children with higher risk ALL. Day 8 blood and day 29 marrow MRD were strong prognostic factors in these patients.

Reinduction platform for children with first marrow relapse of acute lymphoblastic Leukemia: A Children's Oncology Group Study[corrected].

PURPOSE: Treatment of childhood relapsed acute lymphoblastic leukemia (ALL) remains a significant challenge. The goal of the Children's Oncology Group (COG) AALL01P2 study was to develop a safe and active chemotherapy reinduction platform, which could be used to evaluate novel agents in future trials. PATIENTS AND METHODS: One hundred twenty-four patients with ALL and first marrow relapse received three, 35-day blocks of reinduction chemotherapy: 69 with early relapse (ER; < 36 months from initial diagnosis) and 55 with late relapse (LR). Minimal residual disease (MRD) was measured by flow cytometry after each treatment block. RESULTS: Second complete remission (CR2) rates at the end of block 1 in 117 assessable patients were 68% +/- 6% for ER (n = 63) and 96% +/- 3% for LR (n = 54; P < .0001). Five of seven patients with T-cell ALL (T-ALL) failed to achieve CR2. Among patients in CR2, MRD greater than 0.01% was detected at the end of block 1 in 75% +/- 7% of ER (n = 36) versus 51% +/- 8% of LR (n = 43; P = .0375) and 12-month event-free survival was 80% +/- 7% versus 58% +/- 7% in MRD-negative versus positive patients (P < .0005). Blocks 2 and 3 of therapy resulted in reduction of MRD burden in 40 of 56 patients who were MRD positive after block 1. Toxicity was acceptable during all three blocks with five deaths (4%) from infections. CONCLUSION: The AALL01P2 regimen is a tolerable and active reinduction platform, suitable for testing in combination with novel agents in B-precursor ALL. Alternative strategies are needed for T-ALL. Serial MRD measurements were feasible and prognostic of outcome.

Prospective analysis of TEL gene rearrangements in childhood acute lymphoblastic leukemia: a Children's Oncology Group study.

PURPOSE: To prospectively determine the prognostic significance of the TEL-AML1 fusion in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: TEL gene status was determined for 926 patients with B-precursor ALL enrolled on the Pediatric Oncology Group ALinC 16 trials and patients were observed for a median time of 8 years. RESULTS: Rearrangements of the TEL gene were detected in 244 patients (26%). The estimated 5-year event-free survival rate (+/- SE) for patients with TEL rearrangements was 86% +/- 2%, compared with 72% +/- 2% for those with germline TEL (P < .0001). TEL rearrangements were associated with a superior outcome among patients with standard-risk ALL, high-risk ALL, and rapid early responses to therapy. In a multivariate analysis that included risk group, sex, and day 15 marrow status, TEL status was an independent predictor of outcome (P = .0002). CONCLUSION: We conclude that TEL gene status should be incorporated into risk classification schemes and suggest that patients who have standard-risk features, the TEL-AML1 fusion, and rapid early responses to therapy, should be treated with antimetabolite-based therapy designed to maintain their high cure rates and avoid late effects.

Prognostic significance of cytogenetically detected chromosome 21 anomalies in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study.

Chromosome anomalies have been shown to have prognostic significance in children with acute lymphoblastic leukemia (ALL). Chromosome 21 was evaluated for its ability to predict outcome when found in either a single copy (the Mono21 group) or when involved in a structural aberration (the Misc21 group). Both anomalies were associated with an increased risk of failure for patients with standard-risk ALL, rather than higher-risk ALL. Event-free survival was 50.0% at 5 years and 48.4% at 8 years for standard-risk patients with Mono21+Misc21, compared with 77.8 and 75.5%, respectively, for standard-risk patients without these anomalies of chromosome 21. There was no significant difference in outcome between the Mono21 and the Misc21 group (P = 0.10). Mono21 and Misc21 were determined to be independently prognostic whether or not the primary leukemic clone had fewer than 45 chromosomes. The frequency of an adverse outcome was comparable to other poor prognosis subgroups such as hypodiploidy (<45 chromosomes), t(9;22), or t(4;11), all of which have been targeted for aggressive therapy even if the case is otherwise standard risk.

Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children's Oncology Group Study P9201.

Pediatric Oncology Group (POG) protocol 9201 enrolled children with lesser-risk B-lineage acute lymphoblastic leukemia (ALL) defined by age (1-9), white blood cell count (WBC) less than 50 x 10(9)/L (50,000/microL), DNA findings of trisomies 4 and 10 (or DNA index > 1.16), and lack of overt central nervous system (CNS) leukemia. After vincristine, prednisone, and asparaginase induction, 650 of 653 eligible patients attained remission (3 induction deaths) and received 6 courses of intravenous methotrexate (1 g/m(2)) with daily mercaptopurine. Weekly intramuscular methotrexate was added during maintenance; pulses of vincristine and prednisone were administered with periodic intrathecal chemotherapy. Treatment duration was 2.5 years. No alkylators, epipodophylotoxins, anthracyclines, or radiation were given. The 6-year event-free survival (EFS) was 86.6% with overall survival (OS) of 97.2%. Patients with less than 5% marrow blasts on induction day 15 had superior EFS. A difference not reaching conventional statistical significance (P = .068) was noted for superior outcomes in patients with trisomies of chromosomes 4 and 10 versus those lacking double trisomies. Sex, ethnicity, CNS status, and WBC were not predictive. This indicates the great majority of children with lesser-risk B-lineage ALL are curable without agents with substantial late effects.

Prognostic role of the reduced folate carrier, the major membrane transporter for methotrexate, in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.

PURPOSE: The value of measuring expression of individual genes relevant to particular chemotherapy drugs and encoding metabolizing enzymes, transporters, or drug targets, as predictors of treatment response and outcome in pediatric acute lymphoblastic leukemia (ALL), remains controversial. EXPERIMENTAL DESIGN: In a case-control population of 91 pediatric B-precursor ALL patients [42 relapsed within 4 years (cases) and 49 did not relapse (controls)], we used real-time reverse transcription-PCR to measure transcript levels for 20 genes relevant to chemotherapy with the five major drugs used to treat this disease, including asparaginase, 6-mercaptopurine, methotrexate, prednisone, and vincristine. Results were confirmed in a separate case-control population of 26 patients. RESULTS: Only the human reduced folate carrier (hRFC) gene, encoding the major membrane transporter for methotrexate, showed a significant difference in median transcript levels between the 42 cases and the 49 controls (P = 0.0278, Wilcoxon test). Using cutoffs for hRFC expression levels (based on Akaike information criterion), there were statistically significant associations between hRFC transcripts and treatment relapse (P = 0.0052). hRFC-B, corresponding to the major hRFC transcript form in ALL, was also measured by real-time reverse transcription-PCR and was prognostic. The association between treatment relapse and hRFC levels was validated in a separate study population of 14 cases and 12 controls from an earlier case-control study (P = 0.0221). CONCLUSIONS: Our results strongly suggest the prognostic importance of hRFC gene expression to treatment outcomes in pediatric ALL. They validate our previous studies of hRFC transcriptional regulation in pediatric ALL and provide further compelling evidence for the critical role for methotrexate in the successful treatment of this disease.

Ewing sarcoma/primitive neuroectodermal tumor of the chest wall: impact of initial versus delayed resection on tumor margins, survival, and use of radiation therapy.

OBJECTIVE: To establish outcome and optimal timing of local control for patients with nonmetastatic Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) of the chest wall. METHODS: Patients < or =30 years of age with ES/PNET of the chest wall were entered in 2 consecutive protocols. Therapy included multiagent chemotherapy; local control was achieved by resection, radiotherapy, or both. We compared completeness of resection and disease-free survival in patients undergoing initial surgical resection versus those treated with neoadjuvant chemotherapy followed by resection, radiotherapy, or both. Patients with a positive surgical margin received radiotherapy. RESULTS: Ninety-eight (11.3%) of 869 patients had primary tumors of the chest wall. Median follow-up was 3.47 years and 5-year event-free survival was 56% for the chest wall lesions. Ten of 20 (50%) initial resections resulted in negative margins compared with 41 of 53 (77%) negative margins with delayed resections after chemotherapy (P = 0.043). Event-free survival did not differ by timing of surgery (P = 0.69) or type of local control (P = 0.17). Initial chemotherapy decreased the percentage of patients needing radiation therapy. Seventeen of 24 patients (70.8%) with initial surgery received radiotherapy compared with 34 of 71 patients (47.9%) who started with chemotherapy (P = 0.061). If a delayed operation was performed, excluding those patients who received only radiotherapy for local control, only 25 of 62 patients needed radiotherapy (40.3%; P = 0.016). CONCLUSION: The likelihood of complete tumor resection with a negative microscopic margin and consequent avoidance of external beam radiation and its potential complications is increased with neoadjuvant chemotherapy and delayed resection of chest wall ES/PNET.