Conditioning Regimens Decitabine with Allogeneic Peripheral Blood
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Bone Marrow Transplantation (2001) 27, 1221–1225 2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt Conditioning regimens Decitabine with allogeneic peripheral blood stem cell transplantation in the therapy of leukemia relapse following a prior transplant: results of a phase I study F Ravandi1, H Kantarjian1, A Cohen1, M Davis1, S O’Brien1, P Anderlini1, B Andersson1, D Claxton1, M Donato1, J Gajewski1, I Khouri1, M Korbling1, N Ueno1, D deVos2, R Champlin1 and S Giralt1 1Department of Hematology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and 2Pharmachemie BV, Haarlem, The Netherlands Summary: Despite significant advances in the understanding and treat- ment of leukemias over the past decade, the majority of Relapse after allogeneic progenitor cell transplant is patients with transformed CML and advanced acute leuke- associated with a poor prognosis for patients with mia cannot be cured. Allogeneic stem cell transplantation advanced leukemia, with few curative options available. used as consolidation therapy, or for the treatment of Use of novel chemotherapeutic agents with limited tox- relapsed disease, has the potential to cure some patients, icity is warranted. We investigated the role of decitab- but is associated with a high relapse rate.1 Available options ine, a pyrimidine analogue with significant anti-leu- for treatment of relapse following allogeneic transplant are kemic effect and limited toxicity, in this setting. limited and include donor lymphocyte infusion (DLI), Fourteen patients with advanced acute leukemia or investigational and conventional salvage regimens, and a transformed chronic myelogenous leukemia (CML) who second transplant.2 Conventional chemotherapy regimens had failed previous allogeneic transplant were treated. achieve complete remissions in a minority of patients and Decitabine at doses of 100 mg/m2 to 150 mg/m2 given are rarely durable.1–3 Intensifying novel therapeutic agents every 12 h for 5 days was followed by infusion of stem for treatment of relapse after an allogeneic transplant may cells from the original donor 2 to 5 days after the com- improve results. pletion of chemotherapy. Dose of decitabine was esca- Methylation of CpG dinucleotide islands in human DNA, lated in cohorts of three patients based on the modified as maintained by the enzyme cytosine DNA methyltransfer- Fibonacci scheme. The primary study end-point was ase, has been the subject of intensive research.4 Hyperme- assessment of the toxicity of the regimen with secondary thylation of promoter regions has emerged as an important endpoints of response and survival. Eight patients mechanism of suppression of several genes including the responded with either a complete remission or partial calcitonin gene, p16, p15, Igf-2, c-abl and others, putatively hematological remission (absence of blasts in peripheral involved in the control of growth of leukemic cells.4 The blood and bone marrow but with platelet count inhibition of the enzyme DNA methyltransferase is associa- Ͻ100 × 109/l). Toxicity was limited with no grade 3 or ted with hypomethylation, and reactivation of such tumor 4 toxicity directly attributable to the treatment. The suppressor genes.4 median survival for all patients was 190 days (range Decitabine (5-aza-2′-deoxycitidine; DAC) is a pyrim- 11 to 1215+ days). Decitabine at doses of 100 mg/m2 to idine analogue, initially synthesized in 1964.5 Its anti-leu- 150 mg/m2 given every 12 h for 5 days, followed by stem kemic potential was first realized by Sorm and Vesely in cell infusion from the original donor was well tolerated, 1968.6 Recent studies have demonstrated that the anti-leu- and was associated with acceptable myelosuppression. kemic activity of decitabine, and its analogue 5-azacytidine, Current response data should encourage further study may be related to their ability to inhibit DNA methyl- of this drug, either alone or in combination with other transferase by forming covalent adducts with the enzyme.7,8 agents, for treatment of relapsed acute leukemia after The activation of silent genes is believed to be responsible an allogeneic transplant. Bone Marrow Transplantation for the induction of terminal differentiation of the leukemic (2001) 27, 1221–1225. cells leading to senescence and apoptosis.7,9,10 Laboratory Keywords: decitabine; allogeneic SCT; advanced studies, carried out on the peripheral blood and bone mar- leukemia row cells of patients treated with decitabine has revealed phenotypic modification of the leukemic cells, with the reduction of expression of CD13 and CD33 and an increase Correspondence: Dr S Giralt, Department of Hematology, Box 65, Univer- sity of Texas – MD Anderson Cancer Center, 1515 Holcombe Boulevard, in antigenic density of surface determinants of mature 11,12 Houston, Texas 77027, USA myeloid cells such as CD16 and CD11c. Of interest, Received 11 July 2000; accepted 7 February 2001 the expression of MHC class I molecules, HLA-DR and Decitabine in allogeneic stem cell transplantation F Ravandi et al 1222 beta-2-microglobulin on the surface of leukemic cells is received GVHD prophylaxis with intravenous cyclosporine markedly increased during decitabine therapy.12 Therefore, or FK506 (Tacrolimus) beginning on day −2, and converted decitabine treatment may increase the efficacy of an to oral dosing as soon as tolerated. Cyclosporine and immune-mediated therapy such as IL-2 or the graft-versus- FK506 doses were adjusted according to the measured leukemia effect associated with transplantation or donor blood levels, to achieve target levels of 150 to 250 ng/ml, lymphocyte infusions.7,13 and 5 to 15 ng/ml, respectively. Solumedrol was adminis- Several phase I and II studies have demonstrated the tered at a dose of 0.5 mg/kg starting on day 5 followed by efficacy of decitabine in achieving responses in patients a rapid taper of the drug. Cyclosporine dose was tapered with relapsed or refractory leukemia.14–16 Of particular by 20% weekly starting on day 50 and the dose of FK506 interest is the limited extramedullary toxicity associated was gradually tapered based on clinical assessment. with decitabine, with myelosuppression being the major Collection of the stem cells was performed using the drug-related toxicity.15 However, in patients starting ther- standard techniques with G-CSF priming starting 2–4 days apy with an absolute neutrophil count of у0.5 × 109/l an prior to the first collection followed by leukopheresis per- aplastic phase is unusual.14–16 formed daily until Ͼ4 × 106 CD34+ cells/kg were collected. Here, we report the results of a phase I study of single Patients received prophylactic antibiotic therapy against agent decitabine with stem cell re-infusion for relapse after Pneumocystis carinii, cytomegalovirus, bacterial and fungal allogeneic progenitor cell transplant. infections according to current standard regimens. Filtered and irradiated blood products were used to maintain the hemoglobin above 8.5 g/dl and platelet count above Patients and methods 20 × 109/l. Eligibility criteria Study endpoints and statistical considerations Patients with acute leukemia, myelodysplastic syndrome or Engraftment was defined as the first of 3 consecutive days chronic myelogenous leukemia (CML) in accelerated or with a neutrophil count of greater than 0.5 × 109/l. Criteria blast phases who had relapsed after allogeneic bone marrow for response to therapy were defined as follows: Complete or stem cell transplantation were eligible to enter the study. remission was defined as having a normocellular bone mar- Ͻ Eligibility criteria were: age 60, adequate renal, liver and row with р5% blast cells, normal peripheral counts with р cardiac function with a serum bilirubin 3 mg/dl, serum a granulocyte count of Ͼ1.0 × 109/l and platelet count of р creatinine 2 mg/dl, and a left ventricular ejection fraction Ͼ100 × 109/l, and with reconstitution of donor hemopoiesis у 40%, respectively, absence of an active uncontrolled documented by cytogenetics or by restriction fragment р infection, performance status of 3, absence of active length polymorphism (RFLP). Remission with partial hem- у graft-versus-host disease (GVHD) grade 2 or extensive atologic recovery was defined as the presence of the above chronic GVHD, absence of pregnancy, active neurologic criteria with the exception of a platelet count of disease or serious inter-current illness. The protocol was Ͻ100 × 109/l. Hematologic remission with mixed chimer- approved by the Institutional Review Board; patients signed ism was defined as the above with persistence of residual a written informed consent prior to the initiation of treat- host hematopoiesis as identified by cytogenetics or RFLP. ment. Toxicity was scored using Bearman’s criteria.17 Acute and chronic GVHD were scored as previously reported.18,19 Treatment plan The dose of decitabine was escalated in the absence of extramedullary toxicity of grade 3 or worse and absence of All patients had relapsed following an allogeneic transplant engraftment failure. Cohorts of three patients were entered from an HLA-matched sibling. In the initial transplant all at each dose level: if grade 3 extramedullary toxicity or patient had received un-manipulated stem cells except for failure of engraftment was encountered three more patients one patient who had received a CD8-depleted graft. Decita- were entered at the same dose level. Incidence of extramed- bine at a dose of 100 mg/m2 was administered intra- ullary toxicity of grade 3 or greater in у two patients at venously as a 6 h infusion every 12 h for 5 days (total dose any dose level was indicative of that level being the level 1000 mg/m2) followed by infusion of unmanipulated stem above the maximum tolerated dose (MTD). cells from the original donor 2 days after the last dose of decitabine. The dose was escalated to 125 mg/m2 and then 2 2 2 150 mg/m (total dose 1250 mg/m and 1500 mg/m , Results respectively) in subsequent cohorts of patients.