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Autografting

A phase I/II study of CY and topotecan in patients with high-risk malignancies undergoing autologous hematopoietic cell transplantation: the St Jude long-term follow-up

Bone Marrow Transplantation volume 47, pages 1448–1454 (2012)Cite this article

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Abstract

Fifty-eight consecutive children with high-risk malignancies were treated with CY, and targeted topotecan followed by autologous hematopoietic cell transplantation (AHCT) in a phase I/II Institutional Review Board-approved study. Twelve participants enrolled in phase I; 5 received dose level 1 of topotecan 3 mg/m2 per day, with subsequent doses targeted to total systemic exposure of 100±20 ng h/mL and CY 750 mg/m2 per day. Seven participants received dose level 2. CY dose escalation to 1 g/m2 per day was considered excessively toxic; one died from irreversible veno-occlusive disease and two experienced reversible hepatotoxicity. These adverse events halted further dose escalation. A total of 46 participants were enrolled in phase II; results are on the 51 participants who received therapy at dose level 1, the maximum tolerated dose. Diagnoses included neuroblastoma (26), sarcoma (9), lymphoma (8), brain tumors (5), Wilms (2) and retinoblastoma (1). Twenty participants (39.3%) were in ⩾CR1 at enrollment; median age was 5.1 years. Most common non-hematological grade III–IV toxicity was gastrointestinal (n=37). Neutrophil and platelet engraftment occurred at a median of 15 and 24 days, respectively. Twenty-six (51%) participants remain alive at a median of 6.4 years after AHCT. CY 3.75 g/m2, and targeted topotecan followed by AHCT are feasible and produce acceptable toxicity in children with high-risk malignancies.

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References

  1. Shih CS, Hale GA, Gronewold L, Tong X, Laningham FH, Gilger EA et al. High-dose chemotherapy with autologous stem cell rescue for children with recurrent malignant brain tumors. Cancer 2008; 112: 1345–1353.

    Article  CAS  PubMed  Google Scholar 

  2. Hale GA . Autologous hematopoietic stem cell transplantation for pediatric solid tumors. Expert Rev Anticancer Ther 2005; 5: 835–846.

    Article  PubMed  Google Scholar 

  3. London WB, Frantz CN, Campbell LA, Seeger RC, Brumback BA, Cohn SL et al. Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol 2010; 28: 3808–3815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zage PE, Kletzel M, Marcus R, Castleberry R, Zhang Y, London WB et al. Outcomes of the POG 9340/9341/9342 trials for children with high-risk neuroblastoma: a report from the Children's Oncology Group. Pediatr Blood Cancer 2008; 51: 747–753.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Carol H, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Reynolds CP et al. Initial testing of topotecan by the pediatric preclinical testing program. Pediatr Blood Cancer 2010; 54: 707–715.

    PubMed  PubMed Central  Google Scholar 

  6. Metzger ML, Stewart CF, Freeman III BB, Billups CA, Hoffer FA, Wu J et al. Topotecan is active against Wilms’ tumor cells: results of a multi-institutional II phase study. J Clin Oncol 2007; 25: 3130–3136.

    Article  CAS  PubMed  Google Scholar 

  7. Daw NC, Santana VM, Iacono LC, Furman WL, Hawkins DR, Houghton PJ et al. Phase I and pharmacokinetic study of topotecan administered orally once daily for 5 days for 2 consecutive weeks to pediatric patients with refractory solid tumors. J Clin Oncol 2004; 22: 829–837.

    Article  CAS  PubMed  Google Scholar 

  8. Saylors RL, Stewart CF, Zamboni WC, Wall DA, Bell B, Stine KC et al. Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric Oncology Group study. J Clin Oncol 1998; 16: 945–952.

    Article  CAS  PubMed  Google Scholar 

  9. Santana VM, Furman WL, Billups CA, Hoffer F, Davidoff AM, Houghton PJ et al. Improved response in high-risk neuroblastoma with protracted topotecan administration. J Clin Oncol 2005; 23: 4039–4037.

    Article  CAS  PubMed  Google Scholar 

  10. National Cancer Institute Cancer Therapy Evaluation Program. Common Toxicity Criteria, Version 2.0, DCTD, NCI, NIH, DHHS. March 1998.

  11. Simon R . Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1–10.

    Article  CAS  PubMed  Google Scholar 

  12. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assn 1958; 53: 457–481.

    Article  Google Scholar 

  13. Mantel N . Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–170.

    CAS  PubMed  Google Scholar 

  14. Kalbfleisch JD, Prentice RL . Relative risk (Cox) regression models. In: Kalbfleisch JD, Prentice RL (eds). The Statistical Analysis of Failure Time Data. John Wiley & Sons: New York, 1980, pp 163–188.

    Google Scholar 

  15. Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  16. Hubbard KE, Schaiquevich P, Bai F, Fraga CH, Miller L, Panetta JC et al. Application of a highly specific and sensitive fluorescent HPLC method for topotecan lactone in whole blood. Biomed Chromatogr 2009; 23: 707–713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 1999; 341: 1165–1173.

    Article  CAS  PubMed  Google Scholar 

  18. Ladenstein R, Potschger U, Le Deley MC, Whelan J, Paulussen M, Oberlin O et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING-99 trial. J Clin Oncol 2010; 28: 3284–3291.

    Article  CAS  PubMed  Google Scholar 

  19. Presson A, Moore TB, Kempert P . Efficacy of high-dose chemotherapy and autologous stem cell transplant for recurrent Wilms’ tumor: a metanalysis. J Pediatr Hematol Oncol 2010; 32: 454–461.

    Article  CAS  PubMed  Google Scholar 

  20. Stiff PJ, Agovi MA, Antman KH, Blaise D, Camitta BM, Cairo MS et al. High-dose chemotherapy with blood or bone marrow transplants for rhabdomyosarcoma. Biol Blood Marrow Transplant 2010; 16: 525–532.

    Article  PubMed  Google Scholar 

  21. Bradley MB, Cairo MS . Stem cell transplantation for pediatric lymphoma: past, present, and future. Bone Marrow Transplant 2008; 41: 149–158.

    Article  CAS  PubMed  Google Scholar 

  22. Dunkel IJ, Khakoo Y, Kernan NA, Gershon T, Gilheeney S, Lyden DC et al. Intensive multimodality therapy for patients with stage 4a metastatic retinoblastoma. Pediatr Blood Cancer 2010; 55: 55–59.

    PubMed  Google Scholar 

  23. Hunold A, Weddeling N, Paulussen M, Ranft A, Liebscher C, Jürgens H . Topotecan and cyclophosphamide in patients with refractory or relapsed Ewing tumors. Pediatr Blood Cancer 2006; 47: 795–800.

    Article  PubMed  Google Scholar 

  24. Panetta JC, Schaiquevich P, Santana VM, Stewart CF . Using pharmacokinetic and pharmacodynamic modeling and simulation to evaluate importance of schedule in topotecan therapy for pediatric neuroblastoma. Clin Cancer Res 2008; 14: 318–325.

    Article  CAS  PubMed  Google Scholar 

  25. Penson RT, Seiden MV, Goodman A, Fuller Jr AF, Berkowitz RS, Matulonis UA et al. Phase 1 trial of escalating doses of topotecan in combination with a fixed dose of pegylated liposomal doxorubicin in women with müllerian malignancies. Gynecol Oncol 2004; 93: 702–707.

    Article  CAS  PubMed  Google Scholar 

  26. Chen AY, Choy H, Rothenberg ML . DNA topoisomerase 1-targeting drugs as radiation sensitizers. Oncology (Williston Park) 1999; 13: 39–46.

    CAS  Google Scholar 

  27. Cho LC, Choy H . Topoisomerase 1 inhibitors in the combined-modality therapy of lung cancer. Oncology (Williston Park) 2004; 18: 29–39.

    Google Scholar 

  28. Horn B, Reiss U, Matthay K, McMillan A, Cowan M . Veno-occlusive disease of the liver in children with solid tumors undergoing autologous hematopoietic progenitor cell transplantation: a high incidence in patients with neuroblastoma. Bone Marrow Transplant 2002; 29: 409–415.

    Article  CAS  PubMed  Google Scholar 

  29. Fraser CJ, Weigel BJ, Perentesis JP, Dusenbery KE, DeFor TE, Baker KS et al. Autologous stem cell transplantation for high-risk Ewing's sarcoma and other pediatric solid tumors. Bone Marrow Transplant 2006; 37: 175–181.

    Article  CAS  PubMed  Google Scholar 

  30. Cheuk DK, Wang P, Lee TL, Chiang AK, Ha SY, Lau YL et al. Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant 2007; 40: 935–944.

    Article  CAS  PubMed  Google Scholar 

  31. Kushner BH, Cheung NK, Kramer K, Dunkel IJ, Calleja E, Boulad F . Topotecan combined with myeloablative doses of thiotepa and carboplatin for neuroblastoma, brain tumors and other poor-risk solid tumors in children and young adults. Bone Marrow Transplant 2001; 28: 551–556.

    Article  CAS  PubMed  Google Scholar 

  32. de Jonge ME, Huitema AD, Beijnen JH, Rodenhuis S . High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy. Br J Cancer 2006; 94: 1226–1230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McDonald GB, Slattery JT, Bouvier ME, Ren S, Batchelder AL, Kalhorn TF et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 2003; 101: 2043–2048.

    Article  CAS  PubMed  Google Scholar 

  34. Donato ML, Aleman A, Champlin RE, Weber D, Alexanian R, Ippoliti CM et al. High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of multiple myeloma. Leuk Lymphoma 2004; 45: 755–759.

    Article  CAS  PubMed  Google Scholar 

  35. Kazmi SM, Saliba RM, Donato M, Wang M, Hosing C, Qureshi S et al. Phase II trial of high-dose topotecan, melphalan, and CY with autologous stem cell support for multiple myeloma. Bone Marrow Transplant 2011; 46: 510–515.

    Article  CAS  PubMed  Google Scholar 

  36. Litzow MR, Peethambaram PP, Safgren SL, Keeney GL, Ansell SM, Dispenzieri A et al. Phase I trial of autologous hematopoietic SCT with escalating doses of topotecan combined with CY and carboplatin in patients with relapsed or persistent ovarian or primary peritoneal carcinoma. Bone Marrow Transplant 2010; 45: 490–497.

    Article  CAS  PubMed  Google Scholar 

  37. Donato ML, Aleman A, Champlin RE, Saliba RM, Wharton JT, Burke TW et al. Analysis of 96 patients with advanced ovarian carcinoma treated with high-dose chemotherapy and autologous stem cell transplantation. Bone Marrow Transplant 2004; 33: 1219–1224.

    Article  CAS  PubMed  Google Scholar 

  38. Gilheeney SW, Khakoo Y, Souweidane M, Wolden S, Boulad F, Dunkel IJ . Thiotepa/topotecan/carboplatin with autologous stem cell rescue in recurrent/refractory/poor prognosis pediatric malignancies of the central nervous system. Pediatr Blood Cancer 2010; 54: 591–595.

    PubMed  Google Scholar 

  39. Bernbeck B, Bahci S, Meisel R, Troeger A, Schönberger S, Laws HJ et al. Serial intense chemotherapy combining topotecan, etoposide, carboplatin and cyclophosphamide (RTECC) followed by autologous hematopoietic stem cell support in patients with high risk soft tissue sarcoma (STS). Klin Padiatr 2007; 219: 318–322.

    Article  CAS  PubMed  Google Scholar 

  40. Pérez-Martinez A, Lassaletta A, González-Vicent M, Sevilla J, Díaz MA, Madero L . High-dose chemotherapy with autologous stem cell rescue for children with high risk and recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors. J Neurooncol 2005; 71: 33–38.

    Article  PubMed  Google Scholar 

  41. Pérez-Martinez A, Quintero V, Vicent MG, Sevilla J, Díaz MA, Madero L . High-dose chemotherapy with autologous stem cell rescue as first line of treatment in young children with medulloblastoma and supratentorial primitive neuroectodermal tumors. J Neurooncol 2004; 67: 101–106.

    Article  PubMed  Google Scholar 

  42. Crump M, Couban S, Meyer R, Rudinskas L, Zanke B, Gluck S et al. Phase II study of sequential topotecan and etoposide in patients with intermediate grade non-Hodgkin's lymphoma: a National Cancer Institute of Canada Clinical Trials Group study. Leuk Lymphoma 2002; 43: 1581–1587.

    Article  CAS  PubMed  Google Scholar 

  43. Steinherz PG, Shukla N, Kobos R, Steinherz L . Remission re-induction chemotherapy with clofarabine, topotecan, thiotepa, and vinorelbine for patients with relapsed or refractory leukemia. Pediatr Blood Cancer 2010; 54: 687–693.

    Article  PubMed  Google Scholar 

  44. Tiersten A, Selleck M, Smith DH, Wertheim I, Kaufman E, Hershman D et al. Phase I/II study of tandem cycles of high-dose chemotherapy followed by autologous hematopoietic stem cell support in women with advanced ovarian cancer. Int J Gynecol Cancer 2006; 16: 57–64.

    Article  CAS  PubMed  Google Scholar 

  45. McLeod HL, Krynetski EY, Relling MV, Evans WE . Genetic polymorphisms of thiopurinemethyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 2000; 14: 567–572.

    Article  CAS  PubMed  Google Scholar 

  46. Evans WE, Relling MV . Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286: 487–491.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank research nurses Margaret Armond, Cynthia Walker and Patricia Johnson for data collection, Frances Curran for data entry and Sara Williams for manuscript preparation. We also thank Paula Condy, Margaret Edwards, Lisa Walters, Teri Kuehner and Sheri Ring for assistance in obtaining the topotecan pharmacokinetic samples. Thank you to the pharmacokinetic and clinical pharmacists who assisted in the care of these patients. This work was supported in part by the NIH Cancer Center Support Grant P 30CA 21765 and American Lebanese Syrian Associated Charities (ALSAC).

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Authors and Affiliations

  1. Division of Pediatric Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    K A Kasow

  2. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA

    C F Stewart

  3. Department of Hematology/Oncology, Duke University, Durham, NC, USA

    R C Barfield

  4. Transplant and Gene Therapy Program, Cancer Center, St Jude Children's Research Hospital, Memphis, TN, USA

    N L Wright & L C Bowman

  5. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA

    C Li & D K Srivastava

  6. Division of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, TN, USA

    W Leung

  7. Department of Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA

    E M Horwitz

  8. Department of Hematology/Oncology and General Pediatrics, University Hospital of Tuebingen, Tuebingen, Germany

    R Handgretinger

  9. Division of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, All Children's Hospital, St Petersburg, FL, USA

    G A Hale

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Correspondence to K A Kasow.

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Kasow, K., Stewart, C., Barfield, R. et al. A phase I/II study of CY and topotecan in patients with high-risk malignancies undergoing autologous hematopoietic cell transplantation: the St Jude long-term follow-up. Bone Marrow Transplant 47, 1448–1454 (2012). https://doi.org/10.1038/bmt.2012.51

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