Phase II Trial of Clofarabine in Combination with Topotecan, Vinorelbine, and Thiotepa (TVTC) in Pediatric Patients with Refractory or Relapsed Acute Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1514-1514
Author(s):  
Neerav Shukla ◽  
Rachel Kobos ◽  
Thomas M. Renaud ◽  
Laurel Steinherz ◽  
Peter G Steinherz
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Phase I ◽  
Cell Transplantation ◽  
Phase Ii ◽  
Phase I Study ◽  
Phase Ii Trial ◽  
Myelogenous Leukemia ◽  
Significant Activity

Abstract Abstract 1514 Background: Outcomes for children with relapsed/refractory acute leukemia remain dismal. Clofarabine has been approved for the treatment of relapsed acute lymphoblastic leukemia (ALL). However activity in pediatric acute myelogenous leukemia (AML), and optimal combination chemotherapy regimens have yet to be established. We previously reported a 36% complete remission (CR) rate with gemcitabine in combination with topotecan, vinorelbine, and thiotepa (TVTG) in relapsed/refractory pediatric acute leukemias. In an effort to improve on the outcomes of TVTG, we substituted clofarabine for the gemcitabine to create the TVTC protocol. Methods: Following completion of a phase I study, a phase II trial of TVTC was conducted. Patients with relapsed/refractory ALL or AML were eligible. Patients were treated at the maximum tolerated dose (MTD) as determined from the preceding phase I study: clofarabine 40mg/m2/day IV × 5 days, topotecan 1mg/m2/day IV continuous infusion × 5 days, vinorelbine 20mg/m2/week IV × 3, and thiotepa 15mg/m2/day IV × 1 day. The primary endpoint was overall response rate (ORR), defined as CR or CR without platelet recovery (CRp). 17 patients were enrolled. The median age was 10 years (8 months – 24 years). 12 patients had AML, 4 had pre-B ALL, and 1 had biphenotypic leukemia. 13 patients had relapsed disease, and 4 had refractory disease. 2 of the 17 patients were inevaluable for response; one patient was enrolled with minimal residual disease positivity of leukemia, and one patient is currently undergoing therapy. Results: Of the 15 patients evaluable for response, the ORR was 73% (10 CR, 1 CRp). Among the 11 responders, 10 (91%) proceeded to stem cell transplantation. Of the 4 non-responders, 2 patients had no detectable leukemia in their follow-up marrow samples, but failed to have count recovery. The other 2 patients were refractory to therapy. 16 of the 17 patients were evaluable for overall survival (OS), as one patient is currently undergoing therapy. The OS of the 16 evaluable patients is 53%, with a median OS time of 16.2 months (1.5 – 57.7 months). The most common grade 3 or higher toxicities included febrile neutropenia (69%), transient transaminase elevation (50%), and catheter-related infection (44%). One of the patients died from cardiac arrest 45 days after beginning TVTC. There were no cases of VOD. Conclusion: TVTC demonstrates significant activity in patients with relapsed/refractory acute leukemia. Infectious complications occurred at similar rates to previously reported clofarabine combination studies. The activity seen in relapsed/refractory AML patients was very encouraging, with 8 of 11 (73%) evaluable patients achieving a CR/CRp. Given the high response and stem cell transplantation rates in relapsed AML patients on this study, patients with high risk de novo AML may benefit from incorporation of TVTC therapy into their treatment regimens. This regimen warrants further exploration in a larger cohort of relapsed leukemia patients. Disclosures: Off Label Use: Use of Clofarabine for patients with AML. Steinherz:Genzyme: Research Funding.

scholarly journals A First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury

2018 ◽  
Vol 22 (6) ◽  
pp. 941-950.e6 ◽  
Author(s):  
Erik Curtis ◽  
Joel R. Martin ◽  
Brandon Gabel ◽  
Nikki Sidhu ◽  
Teresa K. Rzesiewicz ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Cell Transplantation ◽  
Neural Stem Cell ◽  
Phase I Study ◽  
Chronic Spinal Cord Injury ◽  
Cord Injury

Phase I Trial of High-Dose Clofarabine and Busulfan as a Myeloablative Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory Acute Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 198-198 ◽  
Author(s):  
Sherif Farag ◽  
Lisa L Wood ◽  
Jennifer E. Schwartz ◽  
Shivani Srivastava ◽  
Robert P. Nelson ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Phase I ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Phase I Trial ◽  
High Dose ◽  
Dose Levels

Abstract Abstract 198 Fludarabine in combination high-dose busulfan (Bu) is an effective myeloablative preparative regimen for allogeneic stem cell transplantation. At doses used, however, fludarabine has only modest anti-leukemic activity. Clofarabine (Clo) is a second-generation purine nucleoside antimetabolite with significant single agent activity in patients with AML and ALL. The novel combination of Clo with Bu may provide improved disease activity safely. Therefore, we conducted a phase I trial to determine the maximum tolerated dose (MTD) of Clo in combination with Bu in patients with high-risk acute leukemia. Patients received i.v. Bu (Busulfex) 0.8 mg/kg q 6 hrs on days −6 to −3 and Clo at 30–60 mg/m2/day on days −6 to −2 in successive cohorts. Stem cells were infused day 0. GvHD prophylaxis included sirolimus plus tacrolimus starting day −2 to day 100, tapering to day 180. Patients were eligible if they were 18–60 years, had primary refractory or relapsed and refractory AML or ALL, or were in CR2 or higher, had Karnofsky performance status ≥70%, and adequate organ function. Donors were HLA-matched related (5/6 or 6/6 antigen-matched) or unrelated (10/10 allele-matched). Toxicity was scored using the Common Terminology Criteria for Adverse events, version 3.0. Dose limiting toxicity (DLT) was defined as any grade 3–4 non-hematologic toxicity that did not resolve to grade 2 or less by day 30. A total of 15 patients were treated at 4 Clo dose levels, 30 (n=3), 40 (n=3), 50 (n=3), and 60 mg/m2 (n=6). Seven males and 8 females of median age 48 (30–58) years, with AML (n=13) or ALL (n=2) were treated. At transplant, leukemia was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1). Median number of lines of treatment failed before transplant was 2 (1–3). Median marrow blasts at transplant was 12% (3%–83%). Hematopoietic cell transplants were from related (n=9) and unrelated (n=6) donors. All patients engrafted. Median time to neutrophils >0.5×109/l was 16 (12–20) days, and to platelets >20×109/l was 15 (10–42) days. One patient treated at the 30 mg/m2 dose level failed to achieve platelets > 20×109/l. No DLT was observed. Transient Grades 3–4 non-hematological toxicities were evenly distributed across all 4 dose levels, and included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), and elevation of AST/ALT (n=10). Grades 3–4 elevation of AST/ALT occurred in 2 of 3 patients treated at 30 mg/m2, 3 of 3 at 40 mg/m2, 2 of 3 at 50 mg/m2, and 3 of 6 patients at 60 mg/m2 dose levels. AST/ALT peaked at day −1 or 0 and returned to baseline in all patients by day 10, with no long-term sequelae. There was no correlation between Clo dose and peak AST/ALT. One patient developed acute renal failure at the 60 mg/m2 dose on day +12 in association with elevated tacrolimus levels, although the creatinine subsequently normalized. Two patients, both at the 30 mg/m2 dose, developed mild veno-occlusive disease of the liver which was self-limiting. One treatment-related death due to sepsis was observed at day +104 in a patient treated at the 30 mg/m2 dose. Thirteen of 15 patients were in CR by day 30; 2 patients, treated at 40 mg/m2 and 50 mg/m2, respectively, failed to achieve CR. Day 100 mortality was 0. With a median follow-up of 313 days, the 1-year relapse-free survival was 51% ± 15%, and the 1-year overall survival was 61% ± 14%. Clo at doses as high as 60 mg/m2/day × 5 days in combination with Bu 3.2 mg/kg/day × 4 days is well tolerated and demonstrates promising efficacy in a very-high risk acute leukemia population. The MTD has not been reached. We recommend Phase II testing of Clo 60 mg/m2/day × 5 days in combination with high-dose Bu as a myeloablative regimen for allogeneic stem cell transplantation in patients with acute leukemia. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document