Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study

Abstract

Summary:Relapse after allogeneic progenitor cell transplant is associated with a poor prognosis for patients with advanced leukemia, with few curative options available. Use of novel chemotherapeutic agents with limited toxicity is warranted. We investigated the role of decitabine, a pyrimidine analogue with significant anti-leukemic effect and limited toxicity, in this setting. Fourteen patients with advanced acute leukemia or transformed chronic myelogenous leukemia (CML) who had failed previous allogeneic transplant were treated. Decitabine at doses of 100 mg/m 2 to 150 mg/m 2 given every 12 h for 5 days was followed by infusion of stem cells from the original donor 2 to 5 days after the completion of chemotherapy. Dose of decitabine was escalated in cohorts of three patients based on the modified Fibonacci scheme. The primary study end-point was assessment of the toxicity of the regimen with secondary endpoints of response and survival. Eight patients responded with either a complete remission or partial hematological remission (absence of blasts in peripheral blood and bone marrow but with platelet count Ͻ100 × 10 9 /l). Toxicity was limited with no grade 3 or 4 toxicity directly attributable to the treatment. The median survival for all patients was 190 days (range 11 to 1215+ days). Decitabine at doses of 100 mg/m 2 to 150 mg/m 2 given every 12 h for 5 days, followed by stem cell infusion from the original donor was well tolerated, and was associated with acceptable myelosuppression. Current response data should encourage further study of this drug, either alone or in combination with other agents, for treatment of relapsed acute leukemia after an allogeneic transplant. Bone Marrow Transplantation (2001) 27, 1221-1225.

Disease burden may identify patients more likely to benefit from second allogeneic hematopoietic stem cell transplantation to treat relapsed acute myelogenous leukemia

“…Other factors that have been reported to impact the outcome after the second transplant are the absence of aGVHD at the time of second HSCT, 5,23 remission status at second transplant, 6,20,21 using a female donor, 13 development of chronic GVHD after the second HSCT, 23 and source of stem cells. 24 Al-Qurashi et al 25 and Eapen et al 22 did not find any advantage to using a different donor for the second transplant procedure.…”

Management of relapse after allo-SCT for AML and the role of second transplantation

“…19,59 Santourlidis et al 60 reported that treatment with DNAdemethylating agents results in rapid and stable induction of transcription and cell surface expression of formerly unexpressed KIRs (killer Ig-like receptors) in natural killer cells that are involved in the specific recognition of leukemic target cells and are able to generate a GVL effect. Furthermore, treatment with low-dose azacytidine is associated with only marginal non-hematopoietic toxicity.…”

“…Other factors reported to be associated with outcome after second allo-SCT are remission status at the time of second transplant; 12,13,17,18 using a female donor; 19 development of GVHD after the second allo-SCT; 20,21 and the source of stem cells. 22 Leukemia burden at the time of first transplantation is considered to be a bad prognostic factor.…”

Efficacy of a 3-day, low-dose treatment with 5-azacytidine followed by donor lymphocyte infusions in older patients with acute myeloid leukemia or chronic myelomonocytic leukemia relapsed after allografting

“…11,12 Measures to enhance the therapeutic index of DLI by the addition of IL-2 13 or low-dose cytarabine (LD-AraC) combined with GM-CSF 14 have not shown a consistent improvement. To use the particular mechanisms of action of DNA demethylating agents within the transplant setting, decitabine had been incorporated into the treatment of patients before allografting 15,16 and 5-azacytidine treatment followed by DLI has recently been described for a patient relapsed after allografting for MDS. 17 However, the optimal dose of a hypomethylating agent in this setting, where hematopoiesis may be much more sensitive to the myelotoxicity mediated sometimes by even low doses of the drugs, has not yet been established.…”