Bone Marrow Transplantation (2009) 43, 323–325 & 2009 Macmillan Publishers Limited All rights reserved 0268-3369/09 $32.00
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ORIGINAL ARTICLE
Prognostic impact of diffuse large B-cell lymphoma subgroups in patients undergoing autologous SCT AE Hallack Neto1,2, FL Dulley1, SA Coelho Siqueira3, LF Pracchia1, M Belesso1, R Saboya1, D Sturaro1, JU Amigo-Filho1, A Mendrone Junior1, DAF Chamone1 and J Pereira1 1 Department of Hematology, School of Medicine, Sao Paulo University, Sao Paulo, Brazil; 2Department of Hematology, School of Medicine, Juiz de Fora Federal University, Sao Paulo, Brazil and 3Department of Pathological Anatomy, School of Medicine, Sao Paulo University, Sao Paulo, Brazil
A total of 53 patients aged 18–60 years with highintermediate or high-risk diffuse large B-cell lymphoma (DLBCL) were evaluated to analyze the impact of the cell of origin. Of 53 patients, 16 underwent autologous SCT (ASCT) in first remission and the rest received conventional chemotherapy. Immunohistochemistry was evaluated in 47 cases 17 were of germinal center (GC) origin and 30 were of non-GC origin. There was no survival difference between the two groups. Overall survival (OS) and disease-free survival (DFS) at 3 years were 93 and 83%, respectively, for the 14 patients who underwent ASCT. Their DFS was significantly better than that of patients who achieved CR but did not undergo ASCT. We conclude that ASCT is safe and improves the DFS of high-intermediate and high-risk DLBCL, regardless of the cell of origin. This observation should be confirmed in a larger study. Bone Marrow Transplantation (2009) 43, 323–325; doi:10.1038/bmt.2008.330; published online 13 October 2008 Keywords: lymphoma; autologous BMT; germinal center
Introduction The overall survival (OS) of diffuse large B-cell lymphoma (DLBCL) with high age-adjusted International Prognostic Index (AA-IPI) risk is 30–50% with CHOP (CY, vincristine, doxorubicin and prednisone) or R-CHOP-type chemotherapy.1,2 However, patients with the same AAIPI can have different survival rates and other factors may influence the prognosis. Recently, it was shown that the DLBCL subgroups correlated with prognosis in the prerituximab era, regardless of the IPI. Germinal center (GC) B-cell-like DLBCL has better prognosis than those with
Correspondence: Dr AE Hallack Neto, Department of Haematology, Dr Eneas de Carvalho Aguiar Avenue 155, 1st floor, Room 61—Cerqueira Cesar, Sa˜o Paulo 05403-000, Brazil. E-mail:
[email protected] Received 3 December 2007; revised 26 August 2008; accepted 28 August 2008; published online 13 October 2008
activated B-cell-like (non-GC) DLBCL. Bcl-2 protein expression is also correlated with poor prognosis in DLBCL.3–5 As less than 50% of high-risk patients are cured with conventional chemotherapy, intensive approaches such as ASCT consolidation in first CR have been used.6–8 Recently, the HOVON-40 study showed better disease-free survival (DFS) in high-risk DLBCL with high-dose sequential chemotherapy. Bcl-2 expression and non-GC DLBCL were associated with worse prognosis.9,10 We performed a retrospective analysis to study the prognostic impact of the cell origin and Bcl-2 protein expression in patients with DLBCL who received standard induction therapy followed by ASCT or no ASCT.
Patients and methods Patient population From 1992 to December 2005, 82 high AA-IPI DLBCL patients between 16–60 years (median 38) were treated with eight cycles of CHOP-like regimens with no rituximab at the Clinical Hospital of the Sao Paulo University. Of these, 53 (64%) patients achieved CR. From January 2000 onwards, all the high-intermediate and high AA-IPI patients who achieved CR underwent consolidation with ASCT (n ¼ 16). The 37 patients achieving CR before January 2000 were used as a control group (Table 1). Only one patient had a poor performance status at the time of ASCT. We did not use rituximab because the drug is still unavailable in our public health-care units. Patients with HIV, congestive heart failure, kidney failure or liver failure were not included in the study. Radiotherapy (30 Gy) was given to patients with bulky disease (410 cm) 28 days after the last chemotherapy or ASCT. To harvest stem cells, patients who underwent ASCT were given 60 mg/kg CY daily for 2 days. Of the 16 patients, 14 underwent conditioning with BEAM (carmustine 300 mg/m2 i.v. on day 6, etoposide 200 mg/m2 once daily i.v. on days 5 to 2 (total dose 800 mg/m2), Ara-C 400 mg/m2 once daily i.v. on days 5 to 2 (total dose 1600 mg/m2) and melphalan 140/m2 p.o. on day 1).
ASCT in DLBCL AE Hallack Neto et al
324 Table 1
Patient characteristics Conventional treatment
ASCT
P-value (conventional treatment vs ASCT)
Total
n
%
n
%
n
%
Male Mean age (years) B symptoms Extranodal Marrow involvement Bulky disease High LDH Stage I/II III/IV
23 37.2 30 17 7 15 34
62
44
30 38.3 44 23 13 22 49
57
81 46 19 41 92
7 40.1 14 6 6 7 15
83 43 25 42 93
10 27
27 73
0 16
0 100
10 43
19 81
0.018
CD10 Bcl-6 MUM-1 Bcl-2
4 15 15 9
12 46 46 27
4 11 10 5
29 79 71 36
8 26 25 14
18 55 53 30
0.17 0.037 0.094 0.40
88 38 38 44 94
0.17 ND 0.45 0.40 0.14 0.53 0.65
Abbreviations: ASCT ¼ autologous SCT; LDH ¼ lactate dehydrogenase.
Results
1.0
ASCT
Distribution of clinical and immunohistochemical features Of the 53 patients evaluated, 37 (70%) were treated with CHOP-like regimens and were kept under monitoring and 16 (30%) were treated with CHOP followed by ASCT (Table 1). The number of CD34 þ cells harvested was 2.1–8.7 106/kg (median 3). The median time to 0.5 109/l neutrophils was 11 days. Immunohistochemistry was performed in 33 patients (89%) of the control group and in 14 patients (88%) from the ASCT group (Table 1). Eleven (33%) patients of the control group were classified as GC DLBCL and 22 patients (67%) as non-GC DLBCL.
Survival probability
0.8
Conventional treatment
0.6
0.4
0.2
P = 0.04
0.0 0
50 100 150 Disease-free survival in months
200
Figure 1
Kaplan–Meier curves for disease-free survival of patients in the ASCT and conventional-treatment groups. Tick marks represent censored data.
Histology and immunohistochemistry A survey of the GC Ag (Bcl-6 and CD10), non-GC Ag (MUM1) and Bcl-2 Ag was performed by immunohistochemistry to define the cell of origin.11 We used mouse MoAb against bcl-6 (PIF6, 1:40; Novocastra, Newcastle, UK), MUM-1 (MUMIP, 1:500; Dako, Glostrup, Denmark), CD10 (56C6, 1:250; Novocastra) and bcl-2 (124, 1:200; Dako).12 Immunoreactivity of 410% neoplastic cells was defined as positive for all markers. Response and survival evaluation CR, OS and DFS were defined in a standard manner.13 Time-to-event End points were estimated according to the Kaplan–Meier method. Cox’s proportional hazards regression was used for multivariate analyses of OS and DFS, and SPSS 13.0 program was used for statistical calculation. Bone Marrow Transplantation
Survival The median follow-up time was 34 months for all the patients and 28 months for the ASCT group. OS and DFS were calculated only for 47 patients available to IHC. OS at 3 years was 67% for the GC group and 67% for the nonGC group (P ¼ 0.57). OS at 3 years was 93% for patients undergoing ASCT in first CR and 60% for the control group (P ¼ 0.24). DFS at 3 years was 49% for the control group and 83% for the ASCT group (P ¼ 0.04; Figure 1). In multivariate analysis, ASCT was significantly associated with better DFS (P ¼ 0.01; RR: 7.7). Discussion We did not find any survival difference between the GC and non-GC DLBCL subgroups in the high-intermediate and high AA-IPI groups, in contrast with those studies that looked at all IPI risk groups.3–5 This is similar to what has been observed in the post-rituximab era in the high risk group.2 The addition of the MoAb rituximab to CHOP has been shown to improve the outcome in both the elderly14 and younger patients,15 but 30–50% of the DLBCL remain incurable, especially those with high AA-IPI and poorly revised IPI.2 Other interventions, such as more aggressive
ASCT in DLBCL AE Hallack Neto et al
325
regimens, may increase the survival rates for these patients. The majority of the randomized studies in which high-dose therapy and transplantation were employed in sequential high-dose chemotherapy or third-generation regimens showed no benefit.16–18 Recently, the GOELAMS study demonstrated a longer time to progression and better OS with transplantation compared with CHOP-like regimens, particularly in patients with AA-IPI scores of 1–2.19 There are not many studies on consolidative ASCT in CR patients after full treatment with CHOP-like chemotherapy. Indeed, in a meta-analysis of 15 randomized studies on the impact of ASCT on aggressive lymphomas, none used ASCT after full treatment with CHOP-like regimens. We found that high-risk patients undergoing ASCT as consolidation therapy in first CR after eight CHOP cycles fared better than those treated similarly but not undergoing ASCT. Even though there was a prevalence of advanced Ann Arbor stage in the group that underwent ASCT, this variable did not influence survival rates and all patients were ranked with the same IPI risk group.1 Our results are similar to other studies that have shown improved OS with ASCT.8,19 These studied, similar to ours, included only patients in CR. The better DFS seen by us in the ASCT group was due to lower relapse rates in the ASCT group (Po0.0001). Additional studies are essential to provide more definitive conclusions. However, because of its low toxicity, ASCT may be a reasonable options for high AA-IPI DLBCL in first CR.20–22
9
10
11
12
13
14
15
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