Leukemia (2003) 17, 1967–1972 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu A new multidrug reinduction protocol with topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine for relapsed or refractory acute leukemia EA Kolb1 and PG Steinherz1 1Department of Pediatrics at Memorial Sloan-Kettering Cancer Center, New York, NY, USA We report the results of a phase 2 nonrandomized single-arm combination of thiotepa, topotecan, and carboplatin followed trial of a combination therapy for relapsed or refractory by autologous SCT offers a favorable antitumor effect for leukemia. From January 1999 to June 2002, 28 patients with pediatric solid tumors.22 multiple relapsed or refractory acute leukemia received a 23,24 combination of topotecan, vinorelbine, thiotepa, dexametha- Vinorelbine is a semisynthetic Vinca rosea alkaloid. Early sone, and, for patients with an M3 marrow on day 7, in vitro data suggest that vinorelbine may have a role in the gemcitabine. A total of 14 patients had pre-B-ALL (acute treatment the acute leukemias, although it appears to be less lymphoblastic leukemia), three had T-cell leukemia, nine acute active in acute myeloblastic leukemia (AML) when compared to myeloblastic leukemia (AML), and two biphenotypic leukemia. acute lymphoblastic leukemia (ALL).23,25,26 In adult solid In all, 13 patients achieved a significant response (10 complete tumors, vinorelbine has been used successfully in combination responses and three partial responses). Among the respon- 27 ders, five had pre-B-ALL, two had T-cell leukemias, five had with both gemcitabine and topotecan, but there are no clinical AML, and one had biphenotypic leukemia. In total, 10 of these data to define its role in the treatment of leukemias. patients subsequently underwent hematopoietic stem cell Gemcitabine is a novel deoxycytidine analog with activity in transplantation, and four are alive without disease. One patient hematogenous malignancies. The structure and metabolism of died, while in remission, of complications resulting from an gemcitabine resemble that of cytarabine.28,29 However, after episode of sepsis and pneumonia that occurred during phosphorylation, gemcitabine achieves higher relative concen- topotecan, vinorelbine, thiotepa, dexamethasone, and gemcita- 30–31 bine (TVTG) reinduction. Other toxicities included grade 4 trations, and is retained longer than cytarabine. In vitro neutropenia in all patients and transient grade 2 hepatotoxicity cytotoxicity data suggest that gemcitabine has significant activity in 10 patients (36%). In summary, we report that 47% of heavily in acute leukemias.32–34 Furthermore, in clinical studies, either pretreated pediatric patients with multiply relapsed or refrac- alone,35–38 or in combination with other agents,39,40 gemcita- tory leukemia achieved a significant response after therapy on bine has activity against human leukemias. the TVTG protocol. Further studies are warranted to evaluate the role of the TVTG combination in the treatment of leukemia. Glucocorticoids are a mainstay in the treatment of pediatric Leukemia (2003) 17, 1967–1972. doi:10.1038/sj.leu.2403097 lymphoid and myeloid leukemias. Dexamethasone may be Keywords: topotecan; thiotepa; vinorelbine; gemcitabine; leukemia preferable to prednisone due to enhanced penetration into the cerebral spinal fluid.41 Many hypothesize that saturation of the glucocorticoid receptor over extended periods of time with high doses of corticosteroids will optimize the antileukemic effect of Introduction these agents. Results of a recent trial at the Dana-Farber Cancer Institute support this hypothesis. They observed enhanced bone marrow and peripheral blood blast response to 18 and 150 mg/ Topotecan is a semisynthetic water-soluble inhibitor of topoi- 2 1–5 m /day dexamethasone when compared to the standard 6 mg/ somerase I, and acts in the S-phase of the cell cycle. The m2/day.42 unique, cell-cycle-specific effect of topotecan suggests that its We report results of an institutional phase 2 nonrandomized antitumor activity may be schedule dependent. Accordingly, single-arm reinduction protocol, incorporating a combination of results in murine xenograft models of human tumors demon- topotecan, vinorelbine, thiotepa, gemcitabine, and high-dose strate peak activity when the drug is given as a protracted 3 dexamethasone, for patients with multiple relapsed or refractory infusion. Using similar schedules, excellent antitumor activity 6 acute leukemias. While the chemotherapeutic agents employed is observed in L1210 leukemia, an aggressive murine leukemia, all share the dose-limiting toxicity of myelosuppression, they and xenografts of human poor risk acute lymphoblastic 7 8–13 differ in mechanism of action and metabolism. Furthermore, leukemia (ALL). Furthermore, recent clinical trials in adults 14 these are agents not commonly used in current leukemia and children demonstrate that continuous infusion topo- protocols, and they therefore offer potentially novel mechanisms tecan has antileukemia activity. of action, either alone or in combination, against otherwise Preclinical data suggest that the inhibition of topoisomerase I heavily pretreated leukemia cells. The ‘TVTG’ (topotecan, by topotecan will render the cell more susceptible to DNA- 15 vinorelbine, thiotepa, dexamethasone, and gemcitabine) proto- damaging agents. The combination of topotecan, plus either 16 17 18 19 col is designed to induce disease remission that is of sufficient cyclophosphamide, idarubicin, etoposide, cisplatin, or 9,11,16,18 duration to identify a matched unrelated stem cell donor, and to cytarabine exhibits antitumor activity in adult patients 9,11,16–18 19 permit hematopoietic stem cell transplantation in a recipient with leukemia and solid tumors. In hematologic free of infections and vital organ dysfunction. malignancies, thiotepa is an active antileukemic agent that is successfully used in the cytoreduction regimens preceding 20,21 allogeneic stem cell transplantion (SCT). Additionally, the Patients and methods Correspondence: E Anders Kolb, Department of Pediatrics, Memorial Patients with acute leukemias, who had disease recurrence Sloan-Kettering Cancer Center, P.O. Box, 1275 York Avenue, New York, NY 10021, USA; Fax: þ 1 212 717 3239 despite exhausting all conventional therapeutic options, and/or Received 28 March 2003; revised 28 May 2003; accepted 24 June were refractory to conventional therapeutic agents, were eligible 2003 for treatment. Between January 1999 and June 2002, 28 patients Re-induction therapy for refractory leukemia EA Kolb and PG Steinherz 1968 were treated with a combination of topotecan, vinorelbine, graded according to the National Cancer Institute common thiotepa, and dexamethasone, with or without gemcitabine toxicity criteria, version II. according to the Memorial Sloan-Kettering Cancer Center TVTG protocol. All patients had relapsed and/or refractory leukemia, and no patient had therapeutic options of greater curative Results potential. The diagnosis of ALL or AML was made according to the FAB classification. Confirmation of immunophenotype was Among the 28 patients enrolled (Table 2), 19 were male and available prior to treatment. All patients had a normal serum nine female. The mean age at the initial leukemia diagnosis was creatinine, liver transaminases less than five times normal, and a 8.1 years (range 3 months–21 years), and the mean age at total serum bilirubin less than 1.5 times normal. enrollment was 10.8 years (1–24 years). A total of 14 patients According to institutional guidelines, written informed con- (50%) had Pre-B-cell ALL, three (11%) T-cell ALL, two (7%) sent was obtained from all patients or their guardians before the biphenotypic leukemia, and nine (32%) AML. Three of the nine initiation of therapy. Institutional Review Board approval was cases of AML were secondary to treatment for a previous obtained for the analysis of the results. malignancy (t-AML). A total of 12 patients (43%) had disease The specific schedule and dosages of the prescribed refractory to either first remission induction (n ¼ 3) or refractory chemotherapy is shown in Table 1. Gemcitabine was infused to remission reinduction after the first (n ¼ 6) or subsequent on day 7 if the following criteria were met: there were greater relapse (n ¼ 3). The remaining 16 patients (57%) had a median than 25% leukemic blasts in the day 7 bone marrow or a of two relapses (range 1–9) per patient, including five patients persistence of circulating blasts in the peripheral blood; and who relapsed after myeloablative therapy and subsequent liver transaminases were less than five times normal, with a allogeneic SCT (patients 4, 6, 10, 14, and 19). There were six bilirubin less than 1.5 times normal. Starting on day 7, patients (21%) who received TVTG as the primary remission administration of daily subcutaneous granulocyte colony- reinduction therapy following a first relapse: patient 3 relapsed stimulating factor was initiated and continued until leukocyte while on a high-risk ALL protocol, patient 16 had relapsed AML recovery. Additional courses of TVTG were offered to those after only 6 weeks of remission, patients 18 and 19 experienced patients with a significant response to the first cycle, and an early relapse after primary refractory disease (refers to disease only when the absolute neutrophil count (ANC) exceeded that was refractory to standard initial remission induction 1000/ml and the platelet count exceeded 75,000/ml (Table 1). All