John Gregory

Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710

Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: A report from the Children's Oncology Group†‡

FLT3 mutations (FLT3/Mut) are prevalent in de novo AML and are associated with early relapse. The prevalence and prognostic significance of FLT3/Mut have not been well defined in childhood acute promyelocytic leukemia (APL).

Treatment of children with acute promyelocytic leukemia: Results of the first North American intergroup trial INT0129

This report focuses on the children enrolled on the first North American Intergroup study of APL (INT0129). This study was designed to compare the rates of CR, disease‐free survival (DFS), overall survival (OS) and toxicity of therapy with all‐trans‐retinoic acid (ATRA) for remission induction and/or maintenance compared to conventional chemotherapy in patients with previously untreated APL.

Hematopoietic Stem Cell Transplant for Pediatric Acute Promyelocytic Leukemia

The optimal form of treatment for children with relapsed or refractory acute promyelocytic leukemia (APL) is unclear. We retrospectively analyzed the results of 32 (11 autologous, 21 allogeneic) hematopoietic stem cell transplants (HSCT) performed for children originally treated on either the Eastern Cooperative Group E2491 Trial or the Cancer and Leukemia Group B C9710 Trial and subsequently diagnosed with relapsed or refractory APL. For autologous HSCT, the incidence of treatment-related mortality (TRM) and relapse was 0% (95% confidence interval [CI], 0%-30%) and 27% (95% CI, 9%-57%), respectively. The 5-year event-free survival (EFS) and overall survival (OS) following autologous HSCT was 73% (95% CI, 43%-91%) and 82% (95% CI, 51%-96%), respectively. For allogeneic HSCT, the incidence of TRM and relapse was 19% (95% CI, 7%-41%) and 10% (95% CI, 2%-30%), respectively. The 5-year EFS and OS following allogeneic HSCT was 71% (95% CI, 50%-86%) and 76% (95% CI, 55%-90%), respectively. There was no significant difference in EFS or OS between autologous and allogeneic HSCT. This data demonstrates that autologous and allogeneic HSCT are both effective therapies for treatment of children with relapsed or refractory APL. Autologous HSCT is associated with a low incidence of TRM, whereas allogeneic HSCT is associated with a low incidence of relapse, suggesting a strong GVL effect against residual APL.

Induction mortality, ATRA administration, and resource utilization in a nationally representative cohort of children with acute promyelocytic leukemia in the United States from 1999 to 2009

Limited data exist on induction mortality of pediatric patients with acute promyelocytic leukemia in the United States, usage of all‐trans retinoic acid (ATRA) during acute promyelocytic leukemia induction, and the resources needed to deliver induction therapy.

Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children's Oncology Group Phase III Historically Controlled Trial AAML0631

Purpose The Childrens Oncology Group AAML0631 trial for newly diagnosed pediatric acute promyelocytic leukemia (APL) was a phase III historically controlled trial to determine the survival of patients receiving arsenic trioxide (ATO) consolidation and reduced doses of anthracyclines. Patients and Methods Patients age 2 to 21 years with de novo APL confirmed by PML-RARα polymerase chain reaction were stratified as standard risk (SR) or high risk (HR) on the basis of diagnostic WBC count. All patients received all-trans retinoic acid (ATRA) during induction, each consolidation course, and maintenance. All patients received two cycles of ATO therapy during consolidation 1, an additional two (SR) or three (HR) consolidation courses that included high-dose cytarabine and anthracycline, and maintenance therapy comprising ATRA, oral methotrexate, and mercaptopurine. Results One hundred one patients (66 SR and 35 HR) were evaluable for outcome. The 3-year overall survival was 94%, and event-free survival (EFS) was 91%. For SR and HR patients with APL, the overall survival was 98% versus 86% ( P = .003), and EFS was 95% versus 83% ( P = .03), respectively. The EFS for SR patients in AAML0631 was noninferior to that of patients in the AIDA 0493 historical control, which used a significantly higher anthracycline dose and did not include ATO consolidation. Relapse risk for patients in AAML0631 from end consolidation 1 (after ATO treatment) was only 4% at 3 years and did not differ significantly between SR and HR patients. Conclusion ATO consolidation cycles were well tolerated in pediatric patients with APL and allowed significant reduction in cumulative anthracycline doses while maintaining excellent survival and a low relapse risk for both SR and HR patients with APL.

Management of relapsed and refractory childhood acute promyelocytic leukaemia: recommendations from an international expert panel.

Oussama Abla, Matthew A. Kutny, Anna Maria Testi, James H. Feusner, Ursula Creutzig, John Gregory Jr, Brenda Gibson, Guy Leverger, Raul C. Ribeiro, Owen Smith, Franco Locatelli and Gertjan Kaspers Division of Hematology/Oncology, Department of Pediatrics, the Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada, Department of Pediatrics, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, USA, Department of Cellular Biotechnologies and Haematology, Sapienza University of Rome, Rome, Italy, Division of Hematology/ Oncology, Children’s Hospital and Research Center Oakland, Oakland, CA, USA, Paediatric Haematology/Oncology, Hannover Medical School, Hannover, Germany, Atlantic Health System, Goryeb Children’s Hospital, Morristown, NJ, USA, Department of Haematology and Oncology, Royal Hospital for Children, Glasgow, UK, Haematology/Oncology, Hôpital Armand Trousseau, Paris, France, Department of Oncology, Division of Leukemia/Lymphoma, St. Jude Children’s Research Hospital, Memphis, TN, USA, Department of Haematology/Oncology, Our Lady’s Children’s Hospital, Dublin, Ireland, Department of Paediatric Haematology and Oncology, IRCCS Ospedale Pediatrico Bambino Ges u, Rome, University of Pavia, Pavia, Italy, Paediatric Oncology, VU University Medical Centre, Amsterdam and Academy of Princess Máxima Centre for Paediatric Oncology, Utrecht, The Netherlands