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Minimal Identifiable Disease and the Role of Conditioning Intensity in Hematopoietic Cell Transplantation for Myelodysplastic Syndrome and Acute Myelogenous Leukemia Evolving from Myelodysplastic Syndrome.

ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is the only known treatment with curative potential for myelodysplastic syndrome, but relapse is a major cause of failure. We studied results in 289 patients transplanted between June 2004 and December 2013. Minimal identifiable disease (MID) markers pre-HCT were determined by multiparameter flow cytometry (MFC) and cytogenetics on marrow aspirates. The impact of MID on outcome after low- and high-intensity conditioning HCT was determined. Among 287 assessable patients, 68 (23.7%) had more than 5% marrow blasts at HCT; 219 patients were in morphologic remission but 154 (53.7%) were MID positive, whereas 65 (22.6%) were MID negative. The impact of MID on outcome was significantly different between patients who received low-intensity conditioning and patients who received a high-intensity regimen. The impact of conditioning intensity differed across the various MID categories. In particular, the risk of overall mortality was higher with low-intensity than with high-intensity regimens for patients who were positive for MID by cytogenetics regardless of positivity by MFC (HR, 1.67 if MFC positive/cytogenetics positive, HR, 7.23 if MFC negative/cytogenetics positive). On the other hand, patients who were MID negative by both MFC and cytogenetics had similar risks of mortality with low- and high-intensity regimens (HR, .99). The main factor responsible for mortality after low-intensity conditioning in MID-positive patients was relapse. The presence of MID should be considered when deciding on conditioning intensity because it identifies subgroups of patients who may benefit from high- or low-intensity conditioning.

SUBMITTER: Festuccia M

PROVIDER: S-EPMC4999078 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Minimal Identifiable Disease and the Role of Conditioning Intensity in Hematopoietic Cell Transplantation for Myelodysplastic Syndrome and Acute Myelogenous Leukemia Evolving from Myelodysplastic Syndrome.

Festuccia Moreno M Deeg H Joachim HJ Gooley Theodore A TA Baker Kelsey K Wood Brent L BL Fang Min M Sandmaier Brenda M BM Scott Bart L BL

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20160406 7

Allogeneic hematopoietic cell transplantation (HCT) is the only known treatment with curative potential for myelodysplastic syndrome, but relapse is a major cause of failure. We studied results in 289 patients transplanted between June 2004 and December 2013. Minimal identifiable disease (MID) markers pre-HCT were determined by multiparameter flow cytometry (MFC) and cytogenetics on marrow aspirates. The impact of MID on outcome after low- and high-intensity conditioning HCT was determined. Amon ...[more]

PMID: 27064057

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Project description:Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML), have a poor prognosis. An earlier Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 868 allogeneic hematopoietic cell transplantations (allo-HCTs) performed between 1990 and 2004 showed a 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%, respectively. Modern supportive care, graft-versus-host disease prophylaxis, and reduced-intensity conditioning (RIC) regimens have led to improved outcomes. Therefore, the CIBMTR analyzed 1531 allo-HCTs performed in adults with t-MDS (n = 759) or t-AML (n = 772) between and 2000 and 2014. The median age was 59 years (range, 18 to 74 years) for the patients with t-MDS and 52 years (range, 18 to 77 years) for those with t-AML. Twenty-four percent of patients with t-MDS and 11% of those with t-AML had undergone a previous autologous (auto-) HCT. A myeloablative conditioning (MAC) regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Nonrelapse mortality at 5 years was 34% (95% confidence interval [CI], 30% to 37%) for patients with t-MDS and 34% (95% CI, 30% to 37%) for those with t-AML. Relapse rates at 5 years in the 2 groups were 46% (95% CI, 43% to 50%) and 43% (95% CI, 40% to 47%). Five-year OS and DFS were 27% (95% CI, 23% to 31%) and 19% (95% CI, 16% to 23%), respectively, for patients with t-MDS and 25% (95% CI, 22% to 28%) and 23% (95% CI, 20% to 26%), respectively, for those with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low-risk t-MDS and those with t-AML undergoing HCT with MAC while in first complete remission, but worse for those with previous auto-HCT, higher-risk cytogenetics or Revised International Prognostic Scoring System score, and a partially matched unrelated donor. Relapse remains the major cause of treatment failure, with little improvement seen over the past 2 decades. These data mandate caution when recommending allo-HCT in these conditions and indicate the need for more effective antineoplastic approaches before and after allo-HCT.

Project description:Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m(2)/day × 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which ≤ 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the optimal dose rather than 15 mg/m(2), where most hematological toxicities occurred.

Dataset Information

Minimal Identifiable Disease and the Role of Conditioning Intensity in Hematopoietic Cell Transplantation for Myelodysplastic Syndrome and Acute Myelogenous Leukemia Evolving from Myelodysplastic Syndrome.

Publications

Minimal Identifiable Disease and the Role of Conditioning Intensity in Hematopoietic Cell Transplantation for Myelodysplastic Syndrome and Acute Myelogenous Leukemia Evolving from Myelodysplastic Syndrome.

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