Acute Leukemias

Allogeneic hematopoietic stem cell transplantation for adult AML patients with granulocytic sarcoma

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Abstract

We recently reported that adult acute myeloid leukemia (AML) patients with granulocytic sarcoma (GS) possessed unique clinical features and poor prognosis. However, the optimal therapeutic strategy for this entity has not been established. Therefore, the aim of this study was to assess the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the management of AML with GS. We retrospectively analyzed 503 consecutive adult AML patients (median age, 44 years; range, 15–73 years) who received allo-HSCT. A total of 44 patients (8.7%) had GS before transplantation. Patients with GS achieved comparable survival to those without GS (5-year overall survival (OS), 47% vs 44%, respectively, P=0.621). In patients with GS, excellent outcomes were seen in those that underwent allo-HSCT while in complete remission, whereas nine out of ten patients with GS at the time of transplant experienced a relapse within 6 months after allo-HSCT. Local irradiation for GS prior to allo-HSCT and acute and chronic graft-versus-host disease did not affect survival significantly. Multivariate analysis identified age, disease status and the use of myeloablative conditioning as independent prognostic factors for OS. These data suggest that better control of GS prior to allo-HSCT is crucial to improve the outcome of transplantation for those with GS.

Introduction

Granulocytic sarcoma (GS) is a tumor consisting of malignant granulocytic precursor cells occurring at anatomical sites other than the bone marrow. GS commonly develops concurrently or after the diagnosis of acute myeloid leukemia (AML), but can rarely occur without bone marrow infiltration.1, 2, 3 The rarity of this presentation has been an obstacle to characterize its clinical features and prognosis. However, we recently reported that adult AML patients with GS had unique characteristics at the time of diagnosis, including younger age, higher white blood cell counts and higher frequency of French-British-American M4 and M5 morphology when compared with those without GS. Furthermore, GS was associated with higher relapse rate and lower disease-free survival.4 As several investigators have previously reported, these findings indicate that GS is one of the features of high-risk disease in adult AML.5, 6

However, the optimal therapeutic strategy for GS remains unclear, especially in regards to the indications for need of allogeneic hematopoietic stem cell transplantation (allo-HSCT). To date, only one study of allo-HSCT for AML patients with GS has been reported.7 That study reported favorable outcomes for 51 patients with GS undergoing allo-HSCT, but their study included 14 children and was a single-arm study. Therefore, we perform a large-scale retrospective analysis of 503 adult AML patients undergoing allo-HSCT in order to characterize the posttransplant clinical course and treatment outcome among the patients with and without GS.

Patients and methods

Study population

This study included all consecutive adult AML aged over 15 years, excluding patients with acute promyelocytic leukemia, who underwent allo-HSCT for the first time between January 2000 and December 2008 at the nine institutions participating in the Kanto Study Group for Cell Therapy. All patients gave informed consent in accordance with the Declaration of Helsinki before initiation of treatment and this study was approved by the Institutional Review Board of the each institute.

Definition

Diagnosis of AML was made according to the French-British-American8 or the World Health Organization classification.9 GS was defined as extramedullary tumors that were identified at any time from the diagnosis to transplantation by physical examination and/or imaging studies (computed tomography scan and/or magnetic resonance imaging) and that responded to chemotherapy or irradiation. Pathological confirmation of GS was not necessarily required. We excluded patients with hepatomegaly, splenomegaly or disseminated infiltration of leukemia cells in the skin and the infiltration in the cerebrospinal fluid that did not associated with tumors of the central nervous system. Cytogenetic subgroups were classified as favorable, intermediate and adverse risk according to a largely accepted classification system as follows:10 (1) favorable risk included t(8;21), t(15;17) and inv(16); (2) intermediate risk included normal karyotypes, 11q23 aberrations and others; and (3) adverse risk included −5, −7, del(5), 3q abnormalities and complex karyotype (five or more abnormalities). The cumulative incidences of acute and chronic graft-versus-host disease (GVHD) were graded according to published criteria11, 12 in patients who were alive without relapse until day 30 and 100 after transplantation, respectively. Non-relapse mortality was defined as any death in continuous complete remission (CR).

Statistical analysis

Overall survival (OS) was defined as the interval from the date of transplantation to the date of death. Leukemia-free survival (LFS) was defined as the interval from the date of transplantation to the date of the relapse or the date of death in CR, whichever came first. The χ2-test was used for comparison of binary variables. The Mann–Whitney U-test was used for comparison of continuous variables. OS and LFS were estimated by the Kaplan–Meier method and were compared using the log-rank test. The Cox proportional hazards regression model was used for multivariate analysis of prognostic factors. P<0.05 was considered to represent statistical significance. All calculations were performed using the SAS software package (SAS Institute Inc., Cary, NC, USA).

Results

Clinical characteristics of the GS and non-GS groups

Of the 503 AML patients who underwent allo-HSCT, 301 patients were male and 202 were female. The median age was 44 years (range, 15–73 years). A total 44 patients (8.7%) had GS before transplantation. Patients are stratified according to the presence of GS, and their clinical characteristics are shown in Table 1. GS group was significantly younger and had higher white blood cell counts compared with non-GS group as our previous report.4

Table 1 Clinical characteristics at diagnosis of 503 consecutive AML patients who underwent allo-HSCT

Clinical characteristics of the GS group

In 44 patients with GS, the most frequently site of GS was the lymph nodes. GS occurred at two distinct sites concomitantly in six patients. Before transplantation, all patients received AML-type chemotherapy, and eight patients also received local irradiation for GS (Table 2). At the time of allo-HSCT, 10 patients had GS.

Table 2 Clinical characteristics of 44 patients with GS

Transplantation procedures of the GS and non-GS groups

There was no difference in the stem cell source, conditioning regimen and GVHD prophylaxis when comparing the GS and non-GS groups (Table 3).

Table 3 Transplant procedures of 503 consecutive AML patients who underwent allo-HSCT

Treatment outcomes of the GS and non-GS groups

The cumulative incidence of grade II–IV acute GVHD was 48% in the GS group and 38% in the non-GS group (P=0.241), and that of chronic GVHD was 33% in the GS group and 44% in the non-GS group (P=0.234). Likewise, no significant difference was found in non-relapse mortality at 1 year between two groups (16% in the GS group vs 24% in the non-GS group, P=0.227). The 5-year OS and LFS rates were also similar when comparing the GS and non-GS groups (OS: 47% vs 44%, P=0.621; LFS: 41% vs 38%, respectively, P=0.646) (Figure 1). Because patients in the GS group were significantly younger than those in the non-GS group, subgroup analysis was performed on 336 patients aged 50 years or younger (37 patients in the GS group and 298 patients in the non-GS group). Median ages were similar between two subgroups, and there was no significant difference in the 5-year OS rate (59% vs 54%, respectively, P=0.837) and the 5-year LFS rate (45% vs 46%, respectively, P=0.517) (Figures 2a and b). Additionally, a subset analysis according to disease status at transplant showed that there was no significant difference in the survival rate between the GS and non-GS group; among patients in CR at transplant, the 5-year OS rate (75% vs 62%, respectively, P=0.579) and the 5-year LFS rate (57% vs 53%, respectively, P=0.851), and among those in non-CR, the 5-year OS rate (24% vs 20%, respectively, P=0.608) and the 5-year LFS rate (20% vs 17%, respectively, P=0.670).

Figure 1
figure1

Probability of survival in all consecutive patients. (a) OS after transplantation with or without GS (GS). (b) LFS after transplantation with or without GS.

Figure 2
figure2

Probability of survival in patients aged 50 years or younger. (a) OS after transplantation with or without GS (GS). (b) LFS after transplantation with or without GS.

Treatment outcomes of the GS group

A total of 24 patients (55%) experienced relapse after allo-HSCT; only GS, only bone marrow and both bone marrow and GS were involved in 1 patient (4%), 13 patients (54%) and 10 patients (42%), respectively. Furthermore, in 7 (64%) out of 11 patients with GS at relapse, GS recurred in the same organ as that before allo-HSCT.

We then evaluated whether OS and LFS in GS group were adversely affected by disease status, prior local irradiation, stem cell sources, conditioning regimen and the presence of acute or chronic GVHD. Patients in CR at the time of allo-HSCT achieved significantly superior 5-year OS and LFS rates when compared with those in non-CR (OS: 75% vs 24%, respectively, P=0.002; LFS: 60% vs 24%, respectively, P=0.046) (Figures 3a and b). In 10 out of 22 patients who were not in CR and still had GS at the time of allo-HSCT, 9 experienced a relapse within 6 months after allo-HSCT. Eight patients received prior local irradiation for GS, and their 5-year OS and LFS rates did not significantly differ compared with those who did not receive (OS: 64% vs 50%, respectively, P=0.284; LFS: 38% vs 40%, respectively, P=0.966). There was no significant difference in survival rate between transplantation using related donors and others (OS: 42% vs 49%, respectively, P=0.562; LFS: 29% vs 46%, respectively, P=0.248). In all four patients conditioned with reduced intensity regimen, death occurred within 6 months after allo-HSCT. Finally, acute GVHD did not significantly affect the 5-year OS and LFS rates (OS: 51% vs 60%, respectively, P=0.638; LFS: 51% vs 37%, respectively, P=0.616), nor did chronic GVHD (OS: 58% vs 58%, respectively, P=0.955; LFS: 58% vs 54%, respectively, P=0.877).

Figure 3
figure3

Probability of survival in patients with GS. (a) OS after transplantation by disease status at transplantation. (b) LFS after transplantation by disease status at transplantation.

Multivariate analysis identified age, disease status and use of a myeloablative conditioning regimen as independent prognostic factors for OS (Table 4).

Table 4 Multivariate analysis of OS and LFS for patients with GS

Discussion

This retrospective study aims at clarifying how the presence of GS during the course of AML before allo-HSCT affect the transplant outcome. Although patients with GS may have worse prognosis in response to chemotherapy when compared with those without GS, the 5-year OS and LFS after allo-HSCT in the present study were similar when comparing patients with or without GS. Thus in overall, the presence of GS during the course of AML itself was not considered as a negative prognostic factor after allo-HSCT in the present study. Notably, excellent outcomes were seen in patients who received allo-HSCT while in CR. Therefore, human leukocyte antigen-matched related or unrelated donor allo-HSCT in early CR conditioned with a myeloablative regimen is an appropriate therapeutic option for adult AML patients with GS. The rarity of GS makes it difficult to perform a prospective trial, which is typically required to establish an indication for allo-HSCT. Thus, our retrospective assessment may provide useful information to guide whether allo-HSCT should be performed in these patients.

In contrast, patients of the GS group who were not in CR at the time of allo-HSCT, especially those who had GS at the time of transplant, possessed poor outcomes, suggesting that existing transplantation procedures for those patients are not satisfactory, even though myeloablative conditioning were used. Therefore, just like the general AML population, the investigation for tailored therapeutic strategy was essential such as posttransplant maintenance therapies or selective enhancement of anti-AML property of conditioning regimens essential for that population.

Chevallier et al.7 reported that the 5-year OS and disease-free survival rate for patients with GS received allo-HSCT were 47% and 36%, respectively, which were similar to those seen in this study. Those investigators also reported significantly better OS in patients who underwent transplant from a related donor and any form of GVHD tended to be associated with better prognosis. In contrast, multivariate analysis identified age (>15 years) and remission status as independent prognostic factors, which is consistent with findings from the present study. The role of graft-versus-leukemia effect associated with GVHD also remains to be elucidated. But, the results of studies described above including the present study do not strongly support the anti-GS effect.

Several investigators have reported a high incidence of an extramedullary relapse after allo-HSCT.13, 14, 15 Simpson et al.13 reported that 10 (45%) out of 22 relapses after allo-HSCT conditioned with busulfan and cyclophosphamide against AML occurred at extramedullary sites.10 Although we could not fully analyze the incidence of GS at relapse in all of our cohort, among patients with GS, almost half of relapses accompanied with GS. Furthermore, 64% of relapses with GS occurred in an organ that was previously affected. Thus, vigilance is required regarding the potential recurrence of GS, particularly in the same organ, after allo-HSCT for patients with GS.

The role of local irradiation for the treatment for GS remains unknown. In a study of 21 patients with non-leukemic GS, the addition of local irradiation was associated with a prolonged failure-free survival, and therefore, those investigators advocated use of this therapeutic modality.16 Several cases of successful allo-HSCT after prior local irradiation have also been described.17, 18, 19 In our cohort, eight patients had received prior local irradiation, three of whom experienced relapse in the bone marrow, despite no relapse with GS within the irradiation field. Thus, prior local irradiation for GS could not improve the survival rates. However, in consideration of the high incidence of relapse within the same organ and the poor prognosis in patients with GS at transplantation, we think it fair to recommend administering local irradiation whenever possible.

In conclusion, this large-scale study demonstrated that comparable treatment outcomes were achieved with allo-HSCT in adult AML patients with and without GS except for those with GS at the time of transplant. Appropriately timed allo-HSCT together with innovative approaches to treat GS could result in the further improvement of transplant outcomes for the patients with this serious disease.

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Acknowledgements

We wish to thank all of the staff in the participating institutions of the Kanto Study Group for Cell Therapy.

HS and TS designed and performed research, analyzed data and wrote the manuscript. MT, TM, TS, NK, YK, CN, SY, HF, SF, SM, and HK provided the patient data; SO provided the patient data and contributed to the final version of the manuscript.

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Correspondence to H Shimizu.

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The authors declare no conflict of interest.

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Shimizu, H., Saitoh, T., Tanaka, M. et al. Allogeneic hematopoietic stem cell transplantation for adult AML patients with granulocytic sarcoma. Leukemia 26, 2469–2473 (2012) doi:10.1038/leu.2012.156

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Keywords

  • granulocytic sarcoma
  • acute myeloid leukemia
  • allogeneic stem cell transplantation

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