scholarly journals 202: Preliminary Results of a Phase I Study of Immuno-Chemotherapy (CTX) Conditioning with Gemtuzumab Ozogamicin (GO), Busulfan (Bu) and Cyclophosphamide (Cy) Followed by Allogeneic Stem Cell Transplantation (AlloSCT) in Pediatric Recipients with High Risk (HR) CD33+ Acute Myelogenous Leukemia (AML)

2008 ◽  
Vol 14 (2) ◽  
pp. 75
Author(s):  
I. Waxman ◽  
M. Bhatia ◽  
E. Qualter ◽  
Z.Z. Jin ◽  
V. Kohl ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Allogeneic Stem Cell Transplantation ◽  
Phase I Study ◽  
Gemtuzumab Ozogamicin ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
Pediatric Recipients

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.

5-Azacitidine in Combination with Donor Lymphocyte Infusions for the Treatment of Patients with MDS or AML Relapsing after Allogeneic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5341-5341 ◽  
Author(s):  
Akos Czibere ◽  
Thorsten Graef ◽  
Jens Lind ◽  
Norbert Gattermann ◽  
Fabian Zohren ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Progressive Disease ◽  
Myelogenous Leukemia ◽  
Graft Versus Host

Abstract Purpose: Therapeutic options for patients with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) who relapse after allogeneic stem cell transplantation (SCT) are limited and prognosis is dismal. If applicable, transfusion of donor lymphocytes (DLI) with or without chemotherapy is the current standard therapy. But, in contrast to chronic myelogenous leukemia (CML), response rates after sole DLI in patients with relapsing MDS or AML after allogeneic SCT are poor. Addition of chemotherapy, usually low-dose cytarabine 100mg/m2 as continuous infusion for 7 days, can increase response rates only marginally. Also important, duration of response is short and long term survival even rare. The demethylating agent 5-aza-2′-deoxycytidine (5-Aza) has been shown to be effective in the treatment of MDS and AML. In addition to a direct cytotoxic effect, treatment with this demethylating drug also results in a rapid and stable transcription and cell surface expression of formerly unexpressed killer Ig-like receptors (KIRs) in natural killer cells (NK cells), thereby possibly enhancing the GvL effect of DLI. Patients & treatment: In an intent-to-treat approach we treated 6 patients with high risk MDS or AML who relapsed after allogeneic SCT with 5-Aza plus DLI. Patients’ median age was 47.5 years (range 32–71 years). Before allogeneic SCT 4 patients had active disease, and 2 were in complete remission (CR). Two had family donors, 4 had unrelated donors. Median time for relapse after SCT was day +99 (range day +84 to day +300). Once relapse was diagnosed patients received 100mg/m2 5-Aza for five days via subcutaneous injection in two to four weeks intervals. If practical, patients received 1×106 CD3+ cells/kg bodyweight following the first course of 5-Aza, and in the absence of graft-versus host disease, this was followed by additional 5×106 CD3+ cells/kg bodyweight after 3 months. Results: Five out of 6 patients responded to treatment with 5-Aza and DLI. Three patients achieved a complete remission (CR), two a partial remission (PR) and one patient died early due to progressive disease. Two patients developed extensive graft-versus host disease (GvHD), while, so far, four patients did not show any signs of GvHD. Side effects were manageable and limited to the hematopoietic system. Of the three patients achieving CR, two patients relapsed again at extramedullary sites (heart and CNS). Two of these three patients achieving initial CR are alive, one in CR, one in PR, while one patient died due to CNS disease. One of the patients achieving a PR died due to progressive disease, and the other died after a second allogeneic SCT with progressive disease. Median survival of all patients was 125 days (range 39–397 days). Conclusion: Overall, induction of CR after treatment with 5-Aza, and consolidation of CR via DLI followed the 5-Aza treatment is promising.

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