Autologous transplantation for relapsed or primary refractory peripheral T-cell lymphoma

Authors


Dr T Kewalramani, Box 427, 1275 York Avenue, New York, NY 10021, USA.
E-mail: kewalrat@mskcc.org

Summary

Autologous transplantation (ASCT) is the standard of care for chemosensitive relapsed or primary refractory aggressive lymphoma, but little is known about its efficacy in the subset of patients with peripheral T-cell lymphoma (PTCL). We undertook a retrospective review of patients with PTCL who underwent ASCT for relapsed or refractory disease after responding to second-line therapy, excluding patients with indolent histologies and those with anaplastic lymphoma kinase (ALK) expressing anaplastic large cell lymphoma. The results of 24 patients with PTCL were compared with those of 86 consecutive patients with chemosensitive relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL). With a median follow-up time of 6 years for surviving patients with PTCL and DLBCL, the 5-year progression-free survival (PFS) rates for PTCL and DLBCL patients were 24% and 34% respectively (P = 0·14); the corresponding overall survival (OS) rates were 33% and 39% respectively. There were no significant differences between the two groups with respect to time to disease progression or survival after progression. The second-line age-adjusted international prognostic index was the only variable prognostic for PFS and OS in a multivariate analysis. The outcome of ASCT for patients with chemosensitive relapsed or primary refractory PTCL is similar to that for patients with DLBCL.

Mature T- and natural killer (NK)-cell lymphomas, herein referred to as peripheral T-cell lymphomas (PTCLs), comprise a heterogeneous set of neoplasms that comprise approximately 5% of all lymphoid neoplasms in the United States (Morton et al, 2006) [approximately 10% worldwide (The Non-Hodgkin's Lymphoma Classification Project, 1997)]. Among the entities recognised by the World Health Organisation classification (Jaffe et al, 2001) peripheral T-cell lymphoma, unspecified, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma (ALCL) and mycosis fungoides/Sézary syndrome comprise the majority of PTCLs. With the exception of mycosis fungoides and primary cutaneous ALCL, PTCLs have an aggressive clinical course. When stratified by the international prognostic index (IPI), treatment with standard anthracycline-based regimens results in outcomes that are significantly inferior to those for diffuse large B-cell lymphoma (DLBCL) (Melnyk et al, 1997; Gisselbrecht et al, 1998; Intragumtornchai et al, 2003) and long-term disease-free survival is achieved in only 20–30% of patients (Ascani et al, 1997; Melnyk et al, 1997; Gisselbrecht et al, 1998; Lopez-Guillermo et al, 1998; Arrowsmith et al, 2003; Intragumtornchai et al, 2003). A notable exception is ALCL that expresses the anaplastic lymphoma kinase (ALK) protein, an entity that is generally considered to have an outcome that is better than that of DLBCL (Shiota et al, 1995; Falini et al, 1999; Gascoyne et al, 1999).

High-dose chemotherapy, supported by autologous haematopoietic stem cell transplantation (ASCT), offers the best chance of long-term remission for patients with relapsed or primary refractory aggressive non-Hodgkin lymphoma (NHL) that is sensitive to second-line chemotherapy (Philip et al, 1995; Kewalramani et al, 2000). Among patients with DLBCL, ASCT confers long-term disease-free survival to approximately 35–40% of patients (Hamlin et al, 2003). Its effectiveness in patients with relapsed or primary refractory PTCL is unclear as patients with PTCL comprised a significant minority in most studies of ASCT for aggressive NHL and because large-scale prospective randomised studies have not been performed in PTCL patients because of its low incidence.

A number of reports have attempted to address this issue, but it is not resolved; some studies suggest an inferior outcome compared to DLCBL (Angelopoulou et al, 2003; Song et al, 2003) and others suggest an equivalent outcome (Blystad et al, 2001; Rodriguez et al, 2001, 2003; Vose et al, 1990). The variability of these results may be because of interstudy heterogeneity with respect to prognostic factors, such as chemosensitivity and the second-line age-adjusted IPI (sAAIPI), the inclusion of patients transplanted in first remission and the inclusion of patients with ALK-positive ALCL, a group recently described to have a significantly better outcome compared with the ALK-negative variant when transplanted for relapsed or refractory disease (Jagasia et al, 2004). To address these concerns, we conducted a retrospective review of patients with relapsed or primary refractory PTCL who underwent ASCT after responding to second-line therapy. We specifically excluded patients with ALCL who expressed ALK or in whom ALK expression could not be documented. A cohort of consecutive patients with chemosensitive relapsed or primary refractory DLBCL who underwent ASCT served as a reference group for comparison.

Patients and methods

Patients

Consecutive patients with PTCL who underwent ASCT for chemosensitive relapsed or primary refractory disease between April 1993 and July 2003, allowing a minimum followup of 2 years, were identified from a transplant database that has been maintained prospectively since 1993. Only those patients who failed a single anthracycline-based first-line regimen and who attained at least a partial remission (PR), i.e. a minimum of 50% reduction of all measurable disease, to a single second-line regimen were selected for this analysis. Patients with ALCL who expressed the ALK protein were excluded, as were patients in whom ALK expression could not be documented. Consecutive patients with DLBCL that relapsed after, or was refractory to, a single anthracycline-based regimen and who underwent ASCT after attaining at least a PR to a single second-line regimen were identified from the same database and were selected as controls. Patients with DLBCL who had been treated with rituximab containing primary or second-line regimens or who received post-ASCT adjuvant treatment with rituximab were excluded from serving as controls. Given these considerations, the control group comprised patients who underwent ASCT between April 1993 and September 1999, which is before we started routinely using rituximab as a component of second-line therapy and/or as post-transplant adjuvant therapy in patients with DLBCL.

Statistical analyses

Categorical variables were compared using the two-sided Fisher exact test (Rosner, 1994). Progression-free survival (PFS) and overall survival (OS) were assessed from the time of ASCT until either disease progression or death from any cause respectively. Survival curves were generated using the method of Kaplan and Meier (1958) and compared using the log-rank test (Mantel, 1966). In analysing PFS, deaths in remission were censored. Factors that were predictive of survival were included in a multivariate analysis using the Cox proportional hazards model (Cox, 1972). All statistical analyses were performed using the statistical package for the social sciences (spss), version 12·0 (SPSS Inc., Chicago, IL, USA). P-values ≤ 0·05 were considered significant.

Results

We identified 24 patients with relapsed or primary refractory PTCL who underwent ASCT after responding to second-line chemotherapy (Table I). While 15 of the 16 patients (94%) with relapsed disease underwent biopsies to prove persistent disease, a repeat biopsy was obtained in only two of the eight patients with primary refractory disease. The patients were not significantly different from the control group of consecutive patients with DLBCL with respect to the sAAIPI (P = 1·0), but more patients with PTCL were in complete remission after second-line therapy (63% vs. 41%, P = 0·07). The proportion of patients who received total body irradiation as a component of the conditioning regimen was similar in both groups. High-dose therapy was supported by peripheral blood progenitor cells (>2 × 106 CD34+ cells/kg) in 20 patients, bone marrow in two patients and both peripheral blood progenitor cells (<2 × 106 CD34+ cells/kg) and bone marrow in two patients. No patient received adjuvant antitumour therapy following ASCT.

Table I.   Patient characteristics.
CharacteristicsPTCL (n = 24)DLBCL (n = 86) P
  1. PTCL, peripheral T-cell lymphoma; ALCL, anaplastic large cell lymphoma; DLBCL, diffuse large B-cell lymphoma; CR, complete response; PR, partial response; IPI, International Prognostic Index; TBI, total body irradiation; ALK, anaplastic lymphoma kinase.

Median age, years (range)48 (24–73)47 (18–68) 
Histology
 PTCL, unspecified14 
 Angioimmunoblastic 4 
 ALCL (ALK-negative) 4 
 Extranodal NK/T 1 
 Hepatosplenic 1 
 DLBCL86 
Response to first-line therapy
 Relapse16600·81
 Primary refractory 826 
Response to second-line therapy
 CR15350·07
 PR 951 
Second-line IPI
 Low/low-intermediate15570·81
 High-intermediate/high 929 
Second-line age-adjusted IPI
 Low/low-intermediate11401·0
 High-intermediate/high1346 
Conditioning regimen
 TBI based12480·65
 Chemotherapy only1238 

Disease progression occurred in 83% (n = 20) of patients with PTCL and 65% of patients (n = 56) with DLBCL (P = 0·13). The median follow-up times for patients alive were 72 and 76 months for patients with PTCL and DLBCL respectively. The 5-year PFS rates for patients with PTCL and DLBCL were 24% and 34% respectively (P = 0·14; Fig 1). The 5-year OS rates for patients with PTCL and DLBCL were 33% and 39% respectively (P = 0·64; Fig 2).

Figure 1.

 Progression-free survival. Deaths in remission were censored.

Figure 2.

 Overall survival.

In univariate analyses of survival for patients with PTCL, response to second-line therapy and the sAAIPI were prognostic for both PFS and OS (Table II). In a multivariate analysis, only the sAAIPI was prognostic for both PFS [hazard ratio (HR) 1·9; 95% confidence interval (CI) 1·2–3·0, P = 0·01) and OS (HR 2·4; 95% CI 1·5–3·9, P < 0·01]. When stratified by the sAAIPI, the PFS for patients with PTCL was similar to that of patients with DLBCL for both the low/low-intermediate (P = 0·54) and high-intermediate/high risk (P = 0·09) groups.

Table II.   Univariate analysis of survival for PTCL.
VariablePFSOS
  1. PFS, progression-free survival; OS, overall survival; CR, complete response; PR, partial response; L, low; LI, low-intermediate; HI, high-intermediate; H, high; TBI, total body irradiation; PTCL, peripheral T-cell lymphoma; IPI, IPI, International Prognostic Index.

Response to first-line therapy (relapse versus primary refractory)0·380·15
Response to second-line therapy (CR versus PR)<0·010·01
Second-line age-adjusted IPI (L/LI versus HI/H)0·01<0·01
Conditioning regimen (TBI versus no TBI)0·240·76

Among patients who progressed, the median time to progression was 5 months for patients with PTCL and DLBCL (P = 0·69). Fifteen of the 20 patients (75%) with PTCL who progressed did so within 12 months of ASCT. Survival following documentation of progressive disease was similar between PTCL and DLBCL patients (Fig 3), with median survival times of 6·2 and 8 months respectively.

Figure 3.

 Postprogression survival.

Discussion

The present retrospective analysis of a consecutive series of patients with chemosensitive relapsed or primary refractory PTCL who underwent ASCT found that T-cell histology per se was not an adverse prognostic factor. In the earliest report of ASCT for T-cell lymphomas Vose et al (1990) observed that T-cell histology was not of prognostic significance, but the major limiting factor of that study was that it was conducted at a time when the importance of chemosensitivity in determining the outcome of ASCT was not fully appreciated (Philip et al, 1987). Thus, having included patients with disease who were resistant to chemotherapy or in whom chemosensitivity was not tested, the applicability of the results of that study to current practice is limited, as chemosensitivity is a widely accepted requirement for ASCT (Shipp et al, 1999). Subsequent studies, while consisting primarily of patients with chemosensitive disease, are difficult to interpret because of the inclusion of patients undergoing ASCT in first remission (Blystad et al, 2001; Angelopoulou et al, 2003) and those with ALK-positive ALCL. Relapsed ALK-positive ALCL appears to have an excellent response to ASCT (Jagasia et al, 2004) and including such patients may overestimate the benefit of ASCT for PTCL of other histologies. Indeed, subset analyses of studies that have included patients with ALCL have shown that patients with ALCL have done better than patients with other histologies, although the proportions of patients with ALK-positive tumours are not consistently reported (Blystad et al, 2001; Rodriguez et al, 2001; Song et al, 2003).

Our analysis included a homogeneous population of patients with respect to chemosensitivity and specifically excluded patients with ALK-expressing ALCL. In this cohort of patients the most significant predictor of outcome was the sAAIPI, a prognostic marker for patients with relapsed or primary refractory DLBCL (Caballero et al, 2003; Hamlin et al, 2003), which has also been shown to be an important determinant of outcome for relapsed or primary refractory PTCL (Blystad et al, 2001; Rodriguez et al, 2001, 2003). However, it was surprising to find that the outcomes of PTCL and DLBCL patients were similar when stratified by the sAAIPI, in stark contrast to patients undergoing first-line chemotherapy, where T-cell histology consistently confers a poorer prognosis across IPI subgroups (Melnyk et al, 1997; Gisselbrecht et al, 1998; Intragumtornchai et al, 2003). Song et al (2003) reported that the outcome of ASCT for 20 patients with chemosensitive relapsed or primary refractory peripheral T-cell lymphoma, unspecified, was inferior to that for DLBCL, with 3-year EFS rates of 23% and 42% respectively (P = 0·028) (Song et al, 2003). All failures among PTCL patients occurred within approximately 1  year of ASCT and this rapid failure pattern may be due to the composition of patients with respect to the sAAIPI, although this information was not reported. Rodriguez et al (2003) reported on the largest series of patients with PTCL who underwent ASCT for relapsed or primary refractory disease (n = 78). Although the results were not directly compared with those of patients with DLBCL, the 5-year time-to-treatment failure rate was 39%. The majority of patients (81%) in this study had low or low-intermediate risk disease by the sAAIPI. This may explain the lower failure rate compared with our study.

It is important to note that the results reported here reflect the effect of high-dose therapy itself and not the aggregate effect of all interventions that may be included as components of autologous transplantation. For example, we specifically excluded as controls those patients with DLBCL who received rituximab as a component of second-line therapy or as post-transplant consolidation therapy. The available evidence suggests that rituximab in either setting may improve the outcome of ASCT (Hoerr et al, 2004; Horwitz et al, 2004; Kewalramani et al, 2004) and although these data are not derived from prospective randomised studies, it is likely that the use of rituximab in second-line therapy and as an adjuvant to ASCT will indeed result in long-term DFS rates that exceed 50–60%. Thus, while the direct effect of high-dose therapy for DLCBL and PTCL may be similar, the net effect of the procedure as practiced today is likely to be significantly better for DLCBL.

While our results may suggest that the clinical behaviour of relapsed or primary refractory PTCL and DLBCL are similar, it is critical to note that this analysis was restricted to patients with chemosensitive disease and did not address the response rate to second-line therapy. As eligibility for ASCT is dependent upon having chemosensitive disease, the response rate to second-line therapy is a critical determinant of outcome. Despite similar outcomes after ASCT, a lower response rate to second-line therapy in PTCL patients would make fewer patients eligible for ASCT, thereby resulting in inferior outcomes compared with DLBCL patients. Unfortunately, robust data describing the response rate to second-line therapy in patients with relapsed or primary refractory PTCL are not available.

Based on the available data, patients with relapsed or primary refractory PTCL should be treated with second-line therapy with the intent of ASCT for patients with chemosensitive disease. Ideally, such patients should be treated in the context of clinical trials, and studies of second-line therapy and ASCT that are dedicated to patients with PTCL are warranted. Given the low incidence of PTCL, however, conducting studies of adequate power to generate clinically meaningful results will require multicentre co-operation.

Acknowledgements

This study was supported in part by the Deborah Bradus Memorial Fund of the Lymphoma Foundation.

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