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ORIGINAL ARTICLE

Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen SD Smith, BJ Bolwell, LA Rybicki, S Brown, R Dean, M Kalaycio, R Sobecks, S Andresen, ED Hsi, B Pohlman and JW Sweetenham Department of Hematology and Medical Oncology, Cleveland Clinic Foundation, Taussig Cancer Center, Cleveland, OH, USA

The role of high-dose therapy and autologous stem cell transplantation (ASCT) for patients with peripheral T-cell lymphoma (PTCL) is poorly defined. Comparisons of outcomes between PTCL and B-cell non-Hodgkin’s lymphoma (NHL) have yielded conflicting results, in part due to the rarity and heterogeneity of PTCL. Some retrospective studies have found comparable survival rates for patients with T- and B-cell NHL. In this study, we report our single-center experience of ASCT over one decade using a uniform chemotherapy-only high-dose regimen. Thirty-two patients with PTCL-unspecified (PTCL-u; 11 patients) and anaplastic large-cell lymphoma (21 patients) underwent autologous stem cell transplant, mostly for relapsed or refractory disease. The preparative regimen consisted of busulfan, etoposide and cyclophosphamide. Kaplan–Meier 5-year overall survival (OS) and relapse-free survival (RFS) are 34 and 18%, respectively. These results suggest a poor outcome for patients with PTCL after ASCT, and new therapies for T-cell lymphoma are needed. Bone Marrow Transplantation (2007) 40, 239–243; doi:10.1038/sj.bmt.1705712; published online 28 May 2007 Keywords: autologous bone marrow transplant; anaplastic large-cell lymphoma; peripheral T-cell lymphoma

Introduction Peripheral T-cell lymphoma (PTCL) is a rare disease, comprising 10% of non-Hodgkin’s lymphomas in Western countries, for which the optimal treatment remains undefined.1 In the last decade, the updated World Health Organization (WHO) classification system has permitted more accurate diagnosis and systematic study of PTCL and its heterogeneous subtypes.2 Retrospective analyses using WHO criteria have generally found a worse outcome for PTCL (long-term overall survival (OS) 26–41%) than

Correspondence: Dr SD Smith, Department of Hematology and Medical Oncology, Cleveland Clinic Foundation, Taussig Cancer Center R35, 9500 Euclid Ave, Cleveland, OH 44195, USA. E-mail: [email protected] Received 31 January 2007; revised 10 April 2007; accepted 16 April 2007; published online 28 May 2007

that seen for B-cell lymphoma following conventional chemotherapy, especially if anaplastic large-cell lymphoma (ALCL), a good prognosis subtype of PTCL, is excluded.1,3–6 The favorable outcome of ALCL (60% OS at 5 years after standard therapy) is associated with the expression of anaplastic lymphoma kinase (ALK), seen in half of the cases.4,5,7,8 In general, the initial chemosensitivity but poor ultimate outcome of PTCL has fueled interest in high-dose therapy and autologous stem cell transplantation (ASCT) as a means to improve cure rates. Some retrospective studies have demonstrated that ASCT may achieve long-term survival for patients with relapsed PTCL, comparable to that observed in relapsed Bcell lymphoma.9–11 However, studies tend to involve small numbers of patients with diverse subtypes of PTCL, treated with a variety of conditioning regimens including total body irradiation. Here we report our single-center experience with ASCT for the treatment of PTCL, using a uniform chemotherapy-only conditioning regimen.

Patients and methods Patient population The Unified Transplant Database of the Cleveland Clinic was reviewed, and 32 patients undergoing ASCT for PTCL between May 1996 and May 2005 were identified. Pretransplant characteristics for these patients are summarized in Table 1. Patients either had ALCL (21 patients) or PTCL-unspecified (PTCL-u, 11 patients), confirmed by hematopathology review. Primary refractory disease was defined as no response to treatment or progression during or within 1 month after completing treatment. Chemosensitive disease, by definition, required complete response (CR) or partial response (PR) to salvage chemotherapy. Six patients underwent ASCT as consolidation after initial chemotherapy (that is, in CR1 or PR1), eight patients for primary refractory disease, and 17 for relapsed disease; disease status at the time of transplant was not identifiable for one patient. All six patients undergoing ASCT in CR1/PR1 received anthracycline-based chemotherapy as initial treatment; four received this regimen alone, whereas two patients were treated with an additional regimen at the clinician’s discretion before ASCT. For patients with relapsed disease, salvage chemotherapy was

ASCT in PTCL using a uniform high-dose regimen SD Smith et al

240 Table 1

Pretransplant characteristics

Characteristic

All patients (N, %) 32

N

ALCL (N, %)

PTCL-u (N, %)

21 (66)

11 (34)

15 6 41 4

6 5 53 5

Gender Male Female Age: median (range) BM involvement at diagnosis

21 11 44 9

(66) (34) (16–69) (28)

IPI at transplant Low Low-intermediate High-intermediate High

7 16 6 3

(22) (50) (19) (9)

6 8 4 3

(29) (38) (19) (14)

1 (9) 8 (73) 2 (18) 0

Courses of prior chemotherapy 1 4 (13) 2 21 (66) 3 4 (13) 4 3 (9)

1 17 2 1

(5) (81) (10) (5)

3 4 2 2

(27) (36) (18) (18)

Status at transplant CR1/PR1 Primary refractory First relapse Second or greater relapse Unknown

(19) (26) (45) (10) 1

2 (10) 6 (30) 12 (60) 0 1

4 2 2 3

(36) (18) (18) (27) 0

Among patients in first relapse Response to salvage 13 (93) chemotherapy (CR/PR2)

11 (92)

2 (100)

10 (48) 11 (52)

5 (46) 6 (54)

LDH at transplant Normal Elevated (41  normal)

6 8 14 3

15 (47) 17 (53)

(71) (29) (16–60) (19)

(55) (45) (36–69) (45)

Abbreviations: ALCL ¼ autologous stem cell transplantation; CR ¼ complete response; IPI ¼ international prognostic index; PR ¼ partial response; PTCL-u ¼ peripheral T-cell lymphoma-unspecified.

used to assess chemosensitivity and to reduce disease burden, and commonly consisted of a cisplatin-based regimen. Thirteen of fourteen patients in first relapse demonstrated chemosensitivity to such a regimen. All patients demonstrated adequate cardiac, pulmonary, hepatic and renal function.

Preparative regimen, stem cell processing and supportive care All patients received the same preparative regimen, consisting of busulfan (either 1 mg/kg orally or 0.8 mg/kg i.v. every 6 h for 14 doses), etoposide (60 mg/kg i.v. continuous infusion) and cyclophosphamide (60 mg/kg i.v. daily, for 2 consecutive days). Peripheral blood progenitor cell collection using etoposide and G-CSF priming afforded a median CD34 þ cell dose of 5.01  106/kg (range, 2.05–29.69). Patients were hospitalized for high-dose chemotherapy conditioning and for the subsequent period of pancytopenia. G-CSF was routinely administered starting 5 days after stem cell infusion until neutrophil recovery. Transfusions were administered when platelets declined below 15  103/ml, or for hemoglobin less than 8.5 g/dl. Broadspectrum antibiotics were administered for febrile neutroBone Marrow Transplantation

penic episodes. Patients were managed in single rooms equipped with HEPA filtration systems, and were discharged following hematologic recovery.

Statistical analysis Descriptive statistics are summarized as frequency counts and percentages for categorical variables, and as the median and range for continuous variables. The Kaplan– Meier method was used to estimate OS and relapse-free survival (RFS), measured from the date of autologous transplantation. For the analysis of OS, patients who died due to any cause were counted as events while those who were alive were censored at the date of their most recent follow-up. For the analysis of RFS, patients who relapsed or died were counted as events, while others were censored at the date of most recent follow-up. Kaplan–Meier curves were generated for the group as a whole and for ALCL and PTCL-u groups independently. The log-rank test was used to assess univariate prognostic factors for OS and RFS among ALCL patients, and for the entire group (ALCL and PTCL-u together). Among ALCL patients, nine variables were considered; these included age (o45 vs 445 years), serum lactate dehydrogenase (LDH) (normal vs elevated), International Prognostic Index score at transplant (low and low-intermediate vs high-intermediate and high), Karnofsky Performance Status (o90 vs 490), Ann Arbor Stage (I and II vs III and IV), disease status at transplant (CR1/PR1 vs other), presence of bulky tumor (o10 vs 410 cm), primary refractory disease (vs not), and BM involvement (present vs absent) at diagnosis. For the entire group, univariate analyses comparing patients in first remission vs all others, and those with chemosensitive disease vs non-chemosensitive (resistant) disease, were undertaken. Statistical analyses were done using SAS software (SAS Institute Inc., Cary, NC, USA). All statistical tests were two-sided, and Po0.05 was used to indicate statistical significance.

Results Engraftment and toxicities Recovery to 500 neutrophils/ml occurred at a median 10 days (range, 9–12 days), and platelet recovery to 20  103/ml at 14 days (range, 7–60 days). One patient died within 40 days of transplant of relapse, and six within 100 days of transplant: five from relapsed disease and one of engraftment syndrome. No patient developed a secondary malignancy during the follow-up period. Survival Estimated OS and RFS at 5 years are 34 and 18%, respectively (Figure 1). Median follow-up for 10 survivors is 30 months (range, 7.8–95.2 months). No significant difference in OS or RFS depending on histology (ALCL or PTCL-u) was found (Figures 2 and 3). Patients undergoing ASCT in first remission (CR1/PR1) did not fare significantly better than those with relapsed or refractory disease (P ¼ 0.42 OS, P ¼ 0.24 RFS, Figures 4 and 5). In addition, no significant difference between those with chemosensitive

ASCT in PTCL using a uniform high-dose regimen SD Smith et al

241 100

90

90

80

80

Relapse-free survival (%)

100

70 60 % 50 OS

40 30

RFS

20

P =0.39

70 60 50 40 ALCL (n =21)

30 20 PTCL-u (n =11)

10

10

0

0 0

1

2

3

4

5

6

7

0

8

1

3

2

4

5

6

7

8

Years post transplant

Years post transplant Figure 1 Overall survival (OS) and relapse-free survival (RFS) for all

Figure 3 Relapse-free survival (RFS) by subtype of peripheral T-cell

patients.

lymphoma (PTCL).

100 90

80

ALCL (n =21)

70

80

60

70 Survival (%)

Survival (%)

100

P =0.75

90

50 40 30 20 10

P =0.42

1st remission (n =6)

60 50

Other (n =25)

40 30 20

PTCL-u (n =11)

10

0 0

1

2

3

4

5

6

7

0

8

0

Years post transplant

1

2

Figure 2 Overall survival (OS) by subtype peripheral T-cell lymphoma

disease and all other patients was found (P ¼ 0.98 OS, P ¼ 0.91 RFS). Median RFS is 15.8 months for ALCL patients and 15.6 months for those with PTCL-u. Overall, twenty-two patients relapsed during follow-up: 13 with ALCL (62% of those patients) and nine with PTCL-u (82%). Univariate analysis of the nine potential predictive factors listed above showed none to significantly impact OS or RFS among ALCL patients. Immunohistochemical staining for the ALK protein was available for 11 patients in the ALCL group, and four of five positive for ALK are alive at last follow-up compared to two of six ALK-negative patients.

Discussion PTCLs are rare and heterogeneous diseases, for which few therapies have been prospectively evaluated. Some retrospective analyses have shown comparable outcomes for relapsed T- and B-cell lymphoma following ASCT.

5

4

6

7

8

Figure 4 Overall survival (OS) by disease status at transplant.

100 P =0.24

90 Relapse-free survival (%)

(PTCL).

3

Years post transplant

80 70

1st remission (n =6)

60 50 40 30 20

Other (n =25)

10 0 0

1

2

3

4

5

6

7

8

Years post transplant Figure 5 Relapse-free survival (RFS) by disease status at transplant. Bone Marrow Transplantation

ASCT in PTCL using a uniform high-dose regimen SD Smith et al

242

Previous studies of ASCT have included heterogeneous populations with various international prognostic index (IPI) scores, subtypes of PTCL and disease statuses, making comparison and clinical application of results difficult. The IPI score has been implicated as a prognostic factor following conventional therapy for PTCL3,5,12 and may be relevant after high-dose therapy, as may serum LDH alone.13 Similarly, disease status at the time of transplant may predict long-term outcome. In a recent series, 74 patients with PTCL who underwent ASCT in first complete remission achieved a 5-year OS of 68% and progressionfree survival (PFS) of 63%.14 Our failure to demonstrate a statistically significant difference in outcomes between patients transplanted in first remission vs all others (Figures 4 and 5) is likely due to small patient numbers, and reflects a limitation of this study. The impact of histologic subtype on outcome after ASCT is less clear. Studies demonstrating a relatively good prognosis for ALCL after ASCT (a 3-year OS of 78–85%)11,15,16 include favorable groups of patients who undergo transplant in first remission or whose tumors overexpress ALK. Patients with relapsed ALCL who lack ALK expression may have distinctly poorer outcomes; the median OS of 16 such patients in a series of Zamkoff et al.17 was only 6 months, with a PFS of 3 months following transplant. Of ten deaths reported in that series, nine were secondary to relapse. Fanin et al.18 performed ASCT in 64 ALCL patients whose ALK status was not determined. In that series, 16 patients with relapsed/refractory ALCL had significantly inferior survival compared to those transplanted in first remission. Although these trials suggest poor outcomes for relapsed/refractory patients with ALCL, the relative importance of disease status and other predictive factors is difficult to ascertain due to the small size and retrospective nature of available trials. In this single-center experience using a uniform chemotherapy-only preparative regimen, we found an 18% RFS and a 34% OS at 5 years following autologous transplantation for PTCL, lower than most published trials. The chemotherapy-only preparative regimen used in this series has been found comparable to other common regimens in terms of efficacy and safety, as reported in a review of its use in 382 patients with non-Hodgkin’s lymphoma (NHL).19 These outcomes are therefore unlikely to be a result of an inadequate conditioning regimen. On the other hand, it is noteworthy that most patients (25 of 32) had relapsed/refractory disease. These single-center results and other retrospective data suggest that this strategy is less promising for relapsed PTCL than for Bcell lymphoma, offering long-term disease-free survival in only a minority of patients. Prospective trials are needed to test the role of ASCT as consolidation therapy for high-risk patients, including those with high IPI and ALK-negative ALCL/PTCL-u histologies. In addition, it is clear that new nontransplant therapeutic approaches are needed. A number of agents including purine analogues, monoclonal antibodies, immunotoxins, immunomodulatory agents such as interferon and isotretinoin and histone deacetylase inhibitors have shown activity against PTCL.20–24 The development of these agents and the prospective identificaBone Marrow Transplantation

tion of patients who will benefit most from a high-dose approach offer the chance to improve cure rates.

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