Original Paper Received: August 12, 2013 Accepted after revision: June 29, 2014 Published online: December 4, 2014
Acta Haematol 2015;133:327–335 DOI: 10.1159/000365563
Outcomes of Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients with Monosomal Karyotypes Joon Ho Moon a Yoo Jin Lee a Sang Kyung Seo a Seo Ae Han a Joon Seok Yoon a Ji Yeon Ham b Jang Soo Suh b Sang Kyun Sohn a Departments of a Hematology/Oncology and b Laboratory Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
For editorial comment see p. 324
Key Words Acute myeloid leukemia · Allogeneic stem cell transplantation · Cytogenetics · Graft-versus-host disease · Monosomal karyotype
Abstract This study investigated the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) patients with monosomal karyotypes (MK). A total of 114 AML patients who received allo-HCT were retrospectively analyzed. At the time of diagnosis, 13 patients were categorized with a favorable cytogenetic risk, 78 with an intermediate risk, and 23 with an adverse risk. MK was found in 12 patients among 23 with adverse cytogenetic risk. Pretransplant disease status was active disease in 5 cases (45.5%) in the adverse-risk without MK group, and 8 cases (66.7%) in the corresponding group with MK, 15 (19.2%) in the intermediate group and 4 (30.8%) in the favorable group. In multivariate analysis, active disease before transplant (hazard ratio, HR 3.913, p < 0.001), acute graft-versushost disease (GVHD) ≥grade 2 (HR 1.908, p = 0.048) and chronic GVHD (HR 0.364, p = 0.001) affected overall survival (OS). The initial cytogenetic risk groups were not a signifi-
© 2014 S. Karger AG, Basel 0001–5792/14/1334–0327$39.50/0 E-Mail [email protected] www.karger.com/aha
cant risk factor for OS in allogeneic settings. The 2-year OS rate was 44.0 ± 15.9% without MK and 20.7 ± 17.9% with MK (p = 0.246). However, the OS rate was better for patients with chronic GVHD (p = 0.025). In conclusion, a survival benefit was observed for MK-positive patients with chronic GVHD in an allogeneic setting. However, the prognosis still remained poor for patients with MK. © 2014 S. Karger AG, Basel
Introduction
Acute myeloid leukemia (AML) is a heterogeneous disease and its prognosis is classified according to the pretreatment karyotype [1–4]. Recently, several studies have identified a monosomal karyotype (MK), defined as the presence of at least two autosomal monosomies or one monosomy plus one or more structural abnormalities, as a poor prognostic factor in AML [5–7]. According to previous reports, patients with MK-positive AML showed disappointing complete remission (CR) rates and overall survival (OS) rates of less than 10%. The Southwest Oncology Group (SWOG) also reported significantly lower CR rates for patients with MK (18%) Sang Kyun Sohn, MD, PhD Department of Hematology/Oncology, Kyungpook National University Hospital Kyungpook National University, School of Medicine Daegu 700-721 (Republic of Korea) E-Mail sksohn @ knu.ac.kr
AML with cytogenetic data (n = 364)
)DYRUDEOH Q ,QWHUPHGLDWH Q $GYHUVH Q 0. Q
Intensive induction chemotherapy (n = 228)
)DYRUDEOH Q ,QWHUPHGLDWH Q $GYHUVH Q 0. Q
W DFXWH promyelocytic leukemia Q /RZGRVHFKHPRWKHUDS\ or supportive care (n = 99)
Chemotherapy (n = 93)
Autologous transplant (n = 21)
&\WRJHQHWLFULVNJURXS )DYRUDEOH Q ,QWHUPHGLDWH Q $GYHUVH Q 0. Q
Fig. 1. Distribution of patients with cytogenetic risk.
Allogeneic transplant (n = 114)
&\WRJHQHWLFULVNJURXS )DYRUDEOH Q ,QWHUPHGLDWH Q $GYHUVH Q
Induction response &5 Q 5HIUDFWRU\ Q
Induction response Induction response &5 Q &5 Q 5HIUDFWRU\ Q 5HIUDFWRU\ Q 1RWHYDOXDEOH Q
than for patients without MK (34%). Furthermore, the 4-year OS was only 3% with MK in contrast to 13% without MK when treated with chemotherapy-based treatment [6]. However, several recent studies have reported that such poor outcomes can be improved by allogeneic hematopoietic cell transplantation (allo-HCT) [8, 9]. Since the role of allo-HCT has not been fully determined for AML patients with MK, the present study was conducted to investigate the outcomes of AML patients with MK who received allo-HCT.
&\WRJHQHWLFULVNJURXS )DYRUDEOH Q ,QWHUPHGLDWH Q $GYHUVH Q 0. Q
these 228 patients, 114 received allo-HCT (fig. 1), and in the current study, the data of these 114 patients were retrospectively analyzed. The median age was 40 years (range 15–67). Thirteen patients (11.4%) showed favorable, 78 (68.4%) intermediate and 23 (20.1%) adverse cytogenetics according to Medical Research Council (MRC) criteria [1]. MK was observed in 12 patients (10.5%) in the adverse group. The pretransplant disease status was CR1 in 76 patients (66.7%), CR2 in 7 (6.1%) and active disease in 31 (22.2%). Eighty-three patients (72.8%) received myeloablative conditioning and 31 (27.2%) received reduced intensity conditioning. The patient characteristics are summarized in table 1. The current study was approved by the ethics committee of the local institutional review board and conducted in accordance with the Declaration of Helsinki.
Methods Patients Between September 1998 and May 2011 at Kyungpook National University Hospital, Daegu, South Korea, a total of 364 patients were diagnosed with AML with available initial cytogenetic data. Through the initial selection process, 37 acute promyelocytic leukemia patients and 99 who received low-dose chemotherapy or supportive care were excluded. The remaining 228 patients were treated with intensive induction chemotherapy. Among
328
Acta Haematol 2015;133:327–335 DOI: 10.1159/000365563
Treatment All patients received standard induction chemotherapy with anthracycline and cytarabine. Those patients who achieved CR were then treated with 1 or 2 courses of consolidation therapy using high-dose cytarabine, while those who failed to achieve CR were treated with salvage chemotherapy. Allo-HCT was performed for patients with intermediate- or adverse-risk cytogenetics at diagnosis. For patients with primary refractory disease or relapsed cases, allo-HCT was generally conducted if there were
Moon /Lee /Seo /Han /Yoon/Ham /Suh / Sohn
Table 1. Patient characteristics
Patients, n Median age, years Sex Male Female Cytogenetic risk group Favorable Intermediate Adverse Without MK/with MK Pretransplant disease status CR1 CR2 Active disease Donor Sibling Unrelated Stem cell source Bone marrow Peripheral blood stem cell Conditioning Myeloablative Reduced intensity GVHD prophylaxis Cyclosporine Tacrolimus HLA disparity Full match Mismatch
114 40 (15 – 67) 61 (53.5) 53 (46.5) 13 (11.4) 78 (68.4) 23 (20.1) 11/12 76 (66.7) 7 (6.1) 31 (27.2) 77 (67.5) 37 (32.5) 15 (13.2) 99 (86.8) 83 (72.8) 31 (27.2) 74 (64.9) 40 (35.1)
Statistical Analysis The continuous variables were compared using a two-sample t test, while the categorical data were analyzed using a χ2 test. OS was defined as the time from transplantation until death from any cause. Event-free survival (EFS) was defined as the time interval from transplantation until relapse or death, which was analyzed using the Kaplan-Meyer method, and both groups were compared using a log-rank test. Time-dependent Cox’s regression model was used to determine the risk factors for OS and EFS considering chronic graft-versus-host disease (GVHD) as a time-dependent variable. For the statistical analyses, SPSS software version 18 (SPSS Inc., Chicago, Ill., USA) was used. A p value
Acta Haematol 2015;133:327–335 DOI: 10.1159/000365563
Outcomes of Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients with Monosomal Karyotypes Joon Ho Moon a Yoo Jin Lee a Sang Kyung Seo a Seo Ae Han a Joon Seok Yoon a Ji Yeon Ham b Jang Soo Suh b Sang Kyun Sohn a Departments of a Hematology/Oncology and b Laboratory Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
For editorial comment see p. 324
Key Words Acute myeloid leukemia · Allogeneic stem cell transplantation · Cytogenetics · Graft-versus-host disease · Monosomal karyotype
Abstract This study investigated the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) patients with monosomal karyotypes (MK). A total of 114 AML patients who received allo-HCT were retrospectively analyzed. At the time of diagnosis, 13 patients were categorized with a favorable cytogenetic risk, 78 with an intermediate risk, and 23 with an adverse risk. MK was found in 12 patients among 23 with adverse cytogenetic risk. Pretransplant disease status was active disease in 5 cases (45.5%) in the adverse-risk without MK group, and 8 cases (66.7%) in the corresponding group with MK, 15 (19.2%) in the intermediate group and 4 (30.8%) in the favorable group. In multivariate analysis, active disease before transplant (hazard ratio, HR 3.913, p < 0.001), acute graft-versushost disease (GVHD) ≥grade 2 (HR 1.908, p = 0.048) and chronic GVHD (HR 0.364, p = 0.001) affected overall survival (OS). The initial cytogenetic risk groups were not a signifi-
© 2014 S. Karger AG, Basel 0001–5792/14/1334–0327$39.50/0 E-Mail [email protected] www.karger.com/aha
cant risk factor for OS in allogeneic settings. The 2-year OS rate was 44.0 ± 15.9% without MK and 20.7 ± 17.9% with MK (p = 0.246). However, the OS rate was better for patients with chronic GVHD (p = 0.025). In conclusion, a survival benefit was observed for MK-positive patients with chronic GVHD in an allogeneic setting. However, the prognosis still remained poor for patients with MK. © 2014 S. Karger AG, Basel
Introduction
Acute myeloid leukemia (AML) is a heterogeneous disease and its prognosis is classified according to the pretreatment karyotype [1–4]. Recently, several studies have identified a monosomal karyotype (MK), defined as the presence of at least two autosomal monosomies or one monosomy plus one or more structural abnormalities, as a poor prognostic factor in AML [5–7]. According to previous reports, patients with MK-positive AML showed disappointing complete remission (CR) rates and overall survival (OS) rates of less than 10%. The Southwest Oncology Group (SWOG) also reported significantly lower CR rates for patients with MK (18%) Sang Kyun Sohn, MD, PhD Department of Hematology/Oncology, Kyungpook National University Hospital Kyungpook National University, School of Medicine Daegu 700-721 (Republic of Korea) E-Mail sksohn @ knu.ac.kr
AML with cytogenetic data (n = 364)
)DYRUDEOH Q ,QWHUPHGLDWH Q $GYHUVH Q 0. Q
Intensive induction chemotherapy (n = 228)
)DYRUDEOH Q ,QWHUPHGLDWH Q $GYHUVH Q 0. Q
W DFXWH promyelocytic leukemia Q /RZGRVHFKHPRWKHUDS\ or supportive care (n = 99)
Chemotherapy (n = 93)
Autologous transplant (n = 21)
&\WRJHQHWLFULVNJURXS )DYRUDEOH Q ,QWHUPHGLDWH Q $GYHUVH Q 0. Q
Fig. 1. Distribution of patients with cytogenetic risk.
Allogeneic transplant (n = 114)
&\WRJHQHWLFULVNJURXS )DYRUDEOH Q ,QWHUPHGLDWH Q $GYHUVH Q
Induction response &5 Q 5HIUDFWRU\ Q
Induction response Induction response &5 Q &5 Q 5HIUDFWRU\ Q 5HIUDFWRU\ Q 1RWHYDOXDEOH Q
than for patients without MK (34%). Furthermore, the 4-year OS was only 3% with MK in contrast to 13% without MK when treated with chemotherapy-based treatment [6]. However, several recent studies have reported that such poor outcomes can be improved by allogeneic hematopoietic cell transplantation (allo-HCT) [8, 9]. Since the role of allo-HCT has not been fully determined for AML patients with MK, the present study was conducted to investigate the outcomes of AML patients with MK who received allo-HCT.
&\WRJHQHWLFULVNJURXS )DYRUDEOH Q ,QWHUPHGLDWH Q $GYHUVH Q 0. Q
these 228 patients, 114 received allo-HCT (fig. 1), and in the current study, the data of these 114 patients were retrospectively analyzed. The median age was 40 years (range 15–67). Thirteen patients (11.4%) showed favorable, 78 (68.4%) intermediate and 23 (20.1%) adverse cytogenetics according to Medical Research Council (MRC) criteria [1]. MK was observed in 12 patients (10.5%) in the adverse group. The pretransplant disease status was CR1 in 76 patients (66.7%), CR2 in 7 (6.1%) and active disease in 31 (22.2%). Eighty-three patients (72.8%) received myeloablative conditioning and 31 (27.2%) received reduced intensity conditioning. The patient characteristics are summarized in table 1. The current study was approved by the ethics committee of the local institutional review board and conducted in accordance with the Declaration of Helsinki.
Methods Patients Between September 1998 and May 2011 at Kyungpook National University Hospital, Daegu, South Korea, a total of 364 patients were diagnosed with AML with available initial cytogenetic data. Through the initial selection process, 37 acute promyelocytic leukemia patients and 99 who received low-dose chemotherapy or supportive care were excluded. The remaining 228 patients were treated with intensive induction chemotherapy. Among
328
Acta Haematol 2015;133:327–335 DOI: 10.1159/000365563
Treatment All patients received standard induction chemotherapy with anthracycline and cytarabine. Those patients who achieved CR were then treated with 1 or 2 courses of consolidation therapy using high-dose cytarabine, while those who failed to achieve CR were treated with salvage chemotherapy. Allo-HCT was performed for patients with intermediate- or adverse-risk cytogenetics at diagnosis. For patients with primary refractory disease or relapsed cases, allo-HCT was generally conducted if there were
Moon /Lee /Seo /Han /Yoon/Ham /Suh / Sohn
Table 1. Patient characteristics
Patients, n Median age, years Sex Male Female Cytogenetic risk group Favorable Intermediate Adverse Without MK/with MK Pretransplant disease status CR1 CR2 Active disease Donor Sibling Unrelated Stem cell source Bone marrow Peripheral blood stem cell Conditioning Myeloablative Reduced intensity GVHD prophylaxis Cyclosporine Tacrolimus HLA disparity Full match Mismatch
114 40 (15 – 67) 61 (53.5) 53 (46.5) 13 (11.4) 78 (68.4) 23 (20.1) 11/12 76 (66.7) 7 (6.1) 31 (27.2) 77 (67.5) 37 (32.5) 15 (13.2) 99 (86.8) 83 (72.8) 31 (27.2) 74 (64.9) 40 (35.1)
Statistical Analysis The continuous variables were compared using a two-sample t test, while the categorical data were analyzed using a χ2 test. OS was defined as the time from transplantation until death from any cause. Event-free survival (EFS) was defined as the time interval from transplantation until relapse or death, which was analyzed using the Kaplan-Meyer method, and both groups were compared using a log-rank test. Time-dependent Cox’s regression model was used to determine the risk factors for OS and EFS considering chronic graft-versus-host disease (GVHD) as a time-dependent variable. For the statistical analyses, SPSS software version 18 (SPSS Inc., Chicago, Ill., USA) was used. A p value
