No abstract

The online version of this article has a Supplementary Appendix. BackgroundPatients with acute myeloid leukemia who are treated with conventional chemotherapy still have a substantial risk of relapse; the prognostic factors and optimal treatments after relapse have not been fully established. We, therefore, retrospectively analyzed data from patients with acute myeloid leukemia who had achieved first complete remission to assess their prognosis after first relapse. Design and MethodsClinical data were collected from 70 institutions across the country on adult patients who were diagnosed with acute myeloid leukemia and who had achieved a first complete remission after one or two courses of induction chemotherapy. ResultsAmong the 1,535 patients who were treated with chemotherapy alone, 1,015 relapsed. Half of them subsequently achieved a second complete remission. The overall survival was 30% at 3 years after relapse. Multivariate analysis showed that achievement of second complete remission, salvage allogeneic hematopoietic cell transplantation, and a relapse-free interval of 1 year or longer were independent prognostic factors. The outcome after allogeneic transplantation in second complete remission was comparable to that after transplantation in first complete remission. Patients with acute myeloid leukemia and cytogenetic risk factors other than inv(16) or t(8;21) had a significantly worse outcome when they did not undergo salvage transplantation even when they achieved second complete remission. ConclusionsWe found that both the achievement of second complete remission and the application of salvage transplantation were crucial for improving the prognosis of patients with acute myeloid leukemia in first relapse. Our results indicate that the optimal treatment strategy after first relapse may differ according to the cytogenetic risk.Key words: acute myeloid leukemia, allogeneic hematopoietic cell transplantation, first relapse, second remission, cytogenetic risk. 2010;95(11):1857-1864. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Kurosawa S, Yamaguchi T, Miyawaki S, Uchida N, Sakura T, Kanamori H, Usuki K, Yamashita T, Okoshi Y, Shibayama H, Nakamae H, Mawatari M, Hatanaka K, Sunami K, Shimoyama M, Fujishima N, Maeda Y, Miura I, Takaue Y, and Fukuda T. Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse. Haematologica Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse

To evaluate whether rescue with cord blood transplantation (CBT) could improve the poor survival after graft failure (GF), we surveyed the data of 80 adult patients (median age, 51 years) who received CBT within 3 months of GF (primary 64, secondary 16), with fludarabine-based reduced-intensity regimens with or without melphalan, busulfan, cyclophosphamide, and/or 2-4 Gy total-body irradiation (TBI). A median number of 2.4 × 10(7)/kg total nucleated cells (TNC) were infused, and among the 61 evaluable patients who survived for more than 28 days, 45 (74%) engrafted. The median follow-up of surviving patients was 325 days, and the 1-year overall survival rate was 33% despite poor performance status (2-4, 60%), carryover organ toxicities (grade 3/4, 14%), and infections (82%) prior to CBT. Day 100 transplantation-related mortality was 45%, with 60% related to infectious complications. Multivariate analysis showed that the infusion of TNC ≥2.5 × 10(7)/kg and an alkylating agent-containing regimen were associated with a higher probability of engraftment, and that high risk-status at the preceding transplantation and grade 3/4 organ toxicities before CBT were associated with an increased risk of mortality. In conclusion, in an older population of patients, our data support the feasibility of CBT with a reduced-intensity conditioning regimen for GF.

To compare the different stem cell sources used in salvage transplantation for graft failure (GF) after cord blood transplantation (CBT), we retrospectively analyzed data of 220 patients who developed GF after undergoing CBT between January 2001 and December 2007 and underwent a second hematopoietic stem cell transplantation (HSCT) within 3 months. The donor sources for salvage HSCT were cord blood (n = 180), peripheral blood stem cells (PBSCs; n = 24), and bone marrow (BM; n = 16). The cumulative incidence of neutrophil engraftment on day 30 after the second HSCT was 39% with CB, 71% with PBSCs, and 75% with BM. Multivariate analysis revealed that PBSC and BM grafts were associated with a significantly higher engraftment rate than CB (hazard ratio [HR], 7.77; P < .001 and HR, 2.81; P = .016, respectively). Although the incidence of grade II-IV acute graft-versus-host disease was significantly higher in the PBSC group than in the CB group (HR, 2.83; P = .011), the incidence of 1-year nonrelapse mortality was lower in the PBSC group than in the CB group (HR, 0.43; P = .019), and 1-year overall survival was superior in the PBSC group compared with the CB group (HR, 0.45; P = .036). Our results suggest that PBSC is the preferable source of stem cells in salvage HSCT for GF after CBT.

SummaryThe impact of human leucocyte antigen (HLA) incompatibility between donor and recipient on graft-versus-host disease (GVHD) and graft failure after reduced-intensity conditioning stem cell transplantation (RICT) remains to be elucidated. We retrospectively analysed outcome in 341 patients who underwent RICT from related donors for haematological malignancies. The overall cumulative incidence of grade II-IV acute GVHD (aGVHD) was 40% for all subjects; 39% in recipients with HLA-matched donors, 44% in those with one-locus-mismatched donors, and 50% in those with two-to three-loci-mismatched donors. In a Cox regression model adjusted for potential confounders, the tendency for grade II-IV aGVHD (P ¼ 0AE01), chronic GVHD (cGVHD) (P ¼ 0AE05) and graft failure (P ¼ 0AE033) increased with HLA disparity. Use of peripheral blood grafts instead of marrow was a risk factor for cGVHD. Use of antithymocyte globulin was associated with reduced aGVHD and cGVHD. Overall survival (OS) in recipients of two-to three-loci-mismatched RICT at 2 years (18%) was significantly worse than that in patients who received one-locusmismatched RICT (51%) and HLA-matched RICT (48%) (P < 0AE0001). A two-to three-loci mismatch was identified as an independent risk factor for OS (P < 0AE001), but there was no significant difference in OS between HLAmatched and one-locus-mismatched RICT. HLA incompatibility between the donor and recipient is an important risk factor for graft failure, aGVHD, cGVHD and OS after RICT. RICT from a one-locus-mismatched donor may represent an effective alternative approach in patients with high-risk malignancies who lack HLA-matched related donors.

ABSTRACTfirst relapse after being treated with chemotherapy alone during CR1. Methods PatientsAdults with AML who had achieved CR1 were retrospectively registered in a nationwide AML database, which formed the basis of this study. 6,9 This database included patients who were between 16 and 70 years of age, were diagnosed with AML between 1999 and 2006 according to the World Health Organization classification, and had achieved CR with one or two courses of chemotherapy. Seventy institutions contributed patients to the database. In the original database, information was collected on patient-related factors (e.g., age, sex), diseaserelated factors [e.g., cytogenetics, white blood cell (WBC) count at diagnosis], and clinical outcome including the date of relapse and achievement of CR2. For patients who underwent allogeneic HCT after relapse, complementary information on HCT (e.g., interval from relapse to HCT, disease status at the time of HCT, conditioning regimen, and donor source) was also collected. To perform this current study, supplementary information was collected for CBF-AML patients who had their first hematologic relapse. Additional data collected concerned cytogenetics and WBC count at first relapse, chemotherapy regimen adopted after the first relapse, and response to the initial treatment after the first relapse. Chromosome analysis was performed on metaphases from samples of bone marrow using standard banding techniques. Karyotypes were determined according to the International System for Human Cytogenetic Nomenclature. The cytogenetic data at relapse were centrally reviewed by a doctor who specialized in chromosome analysis, and classified into 'same cytogenetics' or 'different cytogenetics' from those at diagnosis. We categorized the "different cytogenetics" into three groups: decrease in cytogenetic abnormalities, increase in cytogenetic abnormalities, and unrelated change. A decrease or increase in cytogenetic abnormalities was defined as different chromosomal karyotypes harboring the original CBF-associated abnormality. Unrelated change was defined as a chromosomal karyotype that lost the original CBF-associated abnormality. The increase in cytogenetic abnormalities was further subdivided into two groups: numerical changes [e.g., 46,XY,inv(16)(p13;q22) → 47,XY,inv(16)(p13q22),+22] and structural changes [e.g., 46,XX,t(8;21)(q22;q22) → 46,XX,t(8;21)(q22;q22), t(9;10)(q34;q11)]. This study was approved by the Institutional Review Board at the National Cancer Centre Hospital. Statistical analysisData were retrospectively reviewed and analyzed as of March 2012. Distributions of patients' characteristics between groups were compared using the chi-square test for categorical variables and the Wilcoxon rank-sum test for continuous variables. A Kaplan-Meier survival analysis was performed to estimate the probabilities of overall survival, which was defined as the time from the first relapse to death or the last visit. Differences in overall survival between groups were compared by means of the log-r...

Dasatinib treatment markedly increases the number of large granular lymphocytes (LGLs) in a proportion of Ph leukemia patients, which associates with a better prognosis. The lymphocytosis is predominantly observed in cytomegalovirus (CMV)-seropositive patients, yet detectable CMV reactivation exists only in a small fraction of patients. Thus, etiology of the lymphocytosis still remains unclear. Here, we identified NK cells as the dominant LGLs expanding in dasatinib-treated patients, and applied principal component analysis (PCA) to an extensive panel of NK cell markers to explore underlying factors in NK cell activation. PCA displayed phenotypic divergence of NK cells that reflects CMV-associated differentiation and genetic differences, and the divergence was markedly augmented in CMV-seropositive dasatinib-treated patients. Notably, the CMV-associated highly differentiated status of NK cells was already observed at leukemia diagnosis, and was further enhanced after starting dasatinib in virtually all CMV-seropositive patients. Thus, the extensive characterization of NK cells by PCA strongly suggests that CMV is an essential factor in the NK cell activation, which progresses stepwise during leukemia and subsequent dasatinib treatment most likely by subclinical CMV reactivation. This study provides a rationale for the exploitation of CMV-associated NK cell activation for treatment of leukemias.

BackgroundPrognosis for adult patients with acute lymphoblastic leukemia (ALL) has been reported to be approximately 35% to 50%, even after allogeneic stem cell transplantation (allo-SCT). We previously reported retrospective analyses of a conditioning regimen of medium-dose etoposide, cyclophosphamide (CY), and total body irradiation (TBI) before allo-SCT for ALL. To prospectively analyze the efficacy of this conditioning regimen, we conducted a trial prospectively.MethodsThe eligibility criteria of this study were as follows: diagnosis of ALL, aged between 15 and 50 years, in complete remission, and first SCT from HLA serologically matched donor. The primary endpoint of this study was event-free survival at 1 year after SCT, and the events were defined as death and relapse.ResultsFifty eligible patients were treated, and the median age of the patients was 33.5 years. Nineteen patients were Philadelphia chromosome-positive, and 47 were in first complete remission at SCT. All patients achieved neutrophil engraftment. Grade 3 to 4 acute graft-versus-host disease and extensive chronic graft-versus-host disease developed in 4 patients and 18 patients, respectively. No patient died within 100 days after SCT. One-year event-free survival was 76.0%, and 1-year overall survival was 80.0%. The cumulative incidences of relapse and non-relapse mortality at 1-year after SCT were 10.0% and 14.0%, respectively.ConclusionsMedium-dose etoposide + CY + TBI is an effective conditioning before allo-SCT for adult patients with ALL, enabling good disease control without an increase in nonrelapse mortality. A phase 3 trial comparing this regimen with the standard CY + TBI regimen for adult patients with ALL is warranted.