A phase I trial of high-dose clofarabine, etoposide, and cyclophosphamide and autologous peripheral blood stem cell transplantation in patients with primary refractory and relapsed and refractory Non-Hodgkin lymphoma

Shivani Srivastava, David Jones, Lisa L. Wood, Jennifer E. Schwartz, Robert Nelson, Rafat Abonour, Angie Secrest, Elizabeth Cox, Jay Baute, Cheryl Sullivan, Kathleen Kane, Michael Robertson, Sherif Farag

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6 Citations (Scopus)

Abstract

Clofarabine has significant single-agent activity in patients with indolent and aggressive non-Hodgkin lymphoma and synergizes with DNA-damaging drugs. Treatment, however, may be associated with severe and prolonged myelosuppression. We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine in combination with high-dose etoposide and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with refractory non-Hodgkin lymphoma (NHL). Patients received clofarabine at 30-70 mg/m2/day on days -6 to -2 in successive cohorts, in combination with etoposide 60 mg/kg (day -8), and cyclophosphamide 100 mg/kg (day -6), followed by filgrastim-mobilized PBSC on day 0. Sixteen patients of median age 57 (range: 32-67) years with diffuse large B cell (n = 8), follicular (n = 5), or mantle cell (n = 3) lymphoma that was either primary refractory (n = 2) or relapsed and refractory (n = 14) were treated at 5 clofarabine dose levels: 30 (n = 3), 40 (n = 3), 50 (n = 3), 60 (n = 3), and 70 mg/m2/day (n = 4) in combination with etoposide and cyclophosphamide. All patients had grade 4 neutropenia and thrombocytopenia. Grade 3-4 nonhematologic toxicity was evenly distributed across all 5 dose levels, and included diarrhea (n = 3), mucositis (n = 1), nausea (n = 1), reversible elevation of alanine aminotranferease/aspartate aminotransferase (AST/ALT) (n = 1) or bilirubin (n = 1), and hemorrhagic cystitis (n = 1); all resolved by day +30 following transplantation. The MTD was not reached. No treatment-related deaths occurred. At day +30, 13 patients achieved a complete remission (CR) or unconfirmed CR (CRU), and 2 patients achieved a partial response, for an overall response rate of 94%. After a median follow-up of 691 days, the 1-year progression-free survival (PFS) and overall survival (OS) were 63% (95% confidence interval [CI]: 43%-91%) and 68% (95% CI: 49%-96%), respectively. We recommend clofarabine 70 mg/m2/day × 5 days as a phase II dose in combination with high-dose etoposide and cyclophosphamide for further testing as a preparative regimen in NHL patients undergoing autologous PBSC transplantation.

Original languageEnglish
Pages (from-to)987-994
Number of pages8
JournalBiology of Blood and Marrow Transplantation
Volume17
Issue number7
DOIs
StatePublished - Jul 2011

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Peripheral Blood Stem Cell Transplantation
Etoposide
Non-Hodgkin's Lymphoma
Cyclophosphamide
Maximum Tolerated Dose
Confidence Intervals
Mucositis
Cystitis
clofarabine
Autologous Transplantation
Aspartate Aminotransferases
Neutropenia
Bilirubin
Alanine
Nausea
Disease-Free Survival
Diarrhea
Lymphoma
B-Lymphocytes
Transplantation

Keywords

  • Autologous stem cell transplantation
  • Clofarabine
  • Non-Hodgkins lymphoma

ASJC Scopus subject areas

  • Transplantation
  • Hematology

Cite this

A phase I trial of high-dose clofarabine, etoposide, and cyclophosphamide and autologous peripheral blood stem cell transplantation in patients with primary refractory and relapsed and refractory Non-Hodgkin lymphoma. / Srivastava, Shivani; Jones, David; Wood, Lisa L.; Schwartz, Jennifer E.; Nelson, Robert; Abonour, Rafat; Secrest, Angie; Cox, Elizabeth; Baute, Jay; Sullivan, Cheryl; Kane, Kathleen; Robertson, Michael; Farag, Sherif.

In: Biology of Blood and Marrow Transplantation, Vol. 17, No. 7, 07.2011, p. 987-994.

Research output: Contribution to journalArticle

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abstract = "Clofarabine has significant single-agent activity in patients with indolent and aggressive non-Hodgkin lymphoma and synergizes with DNA-damaging drugs. Treatment, however, may be associated with severe and prolonged myelosuppression. We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine in combination with high-dose etoposide and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with refractory non-Hodgkin lymphoma (NHL). Patients received clofarabine at 30-70 mg/m2/day on days -6 to -2 in successive cohorts, in combination with etoposide 60 mg/kg (day -8), and cyclophosphamide 100 mg/kg (day -6), followed by filgrastim-mobilized PBSC on day 0. Sixteen patients of median age 57 (range: 32-67) years with diffuse large B cell (n = 8), follicular (n = 5), or mantle cell (n = 3) lymphoma that was either primary refractory (n = 2) or relapsed and refractory (n = 14) were treated at 5 clofarabine dose levels: 30 (n = 3), 40 (n = 3), 50 (n = 3), 60 (n = 3), and 70 mg/m2/day (n = 4) in combination with etoposide and cyclophosphamide. All patients had grade 4 neutropenia and thrombocytopenia. Grade 3-4 nonhematologic toxicity was evenly distributed across all 5 dose levels, and included diarrhea (n = 3), mucositis (n = 1), nausea (n = 1), reversible elevation of alanine aminotranferease/aspartate aminotransferase (AST/ALT) (n = 1) or bilirubin (n = 1), and hemorrhagic cystitis (n = 1); all resolved by day +30 following transplantation. The MTD was not reached. No treatment-related deaths occurred. At day +30, 13 patients achieved a complete remission (CR) or unconfirmed CR (CRU), and 2 patients achieved a partial response, for an overall response rate of 94{\%}. After a median follow-up of 691 days, the 1-year progression-free survival (PFS) and overall survival (OS) were 63{\%} (95{\%} confidence interval [CI]: 43{\%}-91{\%}) and 68{\%} (95{\%} CI: 49{\%}-96{\%}), respectively. We recommend clofarabine 70 mg/m2/day × 5 days as a phase II dose in combination with high-dose etoposide and cyclophosphamide for further testing as a preparative regimen in NHL patients undergoing autologous PBSC transplantation.",
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AU - Jones, David

AU - Wood, Lisa L.

AU - Schwartz, Jennifer E.

AU - Nelson, Robert

AU - Abonour, Rafat

AU - Secrest, Angie

AU - Cox, Elizabeth

AU - Baute, Jay

AU - Sullivan, Cheryl

AU - Kane, Kathleen

AU - Robertson, Michael

AU - Farag, Sherif

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