Phase 2 trial of combined cisplatin, etoposide, gemcitabine, and methylprednisolone (PEGS) in peripheral T-cell non-Hodgkin lymphoma

Southwest Oncology Group Study S0350

Authors


Abstract

BACKGROUND:

Patients with peripheral T-cell lymphomas (PTCLs) have inferior progression-free survival (PFS) and overall survival (OS) compared with patients who have aggressive B-cell non-Hodgkin lymphoma. Because PTCLs over express multidrug resistance gene 1/P-glycoprotein (MDR-1/P-gp), we devised platinum, etoposide, gemcitabine, and methylprednisolone (PEGS) with agents that are not substrates of the efflux pump. Gemcitabine was included because of its excellent single-agent activity in PTCL.

METHODS:

Patients who had PTCL with stage II bulky disease, stage III or IV disease with extra-nodal, nodal, and transformed cutaneous presentations were eligible. Patients received intravenous cisplatin 25 mg/m2 on days 1 through 4, etoposide 40 mg/m2 on days 1 through 4, gemcitabine 1000 mg/m2 on day 1, and methylprednisolone 250 mg on days 1 through 4 of a 21-day cycle for 6 cycles.

RESULTS:

In total, 34 patients were enrolled, 33 were eligible, and 79% were newly diagnosed. Histologic types were PTCL not otherwise specified (n = 15), anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (n = 4), angioimmunoblastic T-cell lymphoma (n = 6), or other T-cell non-Hodgkin lymphomas (n = 8). Adverse events included 1 grade 5 infection with grade 3 or 4 neutropenia and 9 grade 4 hematologic toxicities. The overall response rate was 39% (47% in PTCL not otherwise specified, 33% in angioimmunoblastic T-cell lymphoma, 25% in ALK-negative and 38% in other T-cell non-Hodgkin lymphomas). The PFS rate at 2 years was 12% (95% confidence interval, 0.1%-31%), and the median PFS was 7 months. The OS rate at 2 years was 30% (95% confidence interval, 8%-54%), and the median OS was 17 months. Immunohistochemical analysis of P-gp expression revealed strong positivity in a subset of lymphoma cells (n = 6) and tumor endothelium (n = 25).

CONCLUSIONS:

Overall, PEGS was well tolerated, but OS was not considered promising given the design-specified targets. These results may serve as a benchmark for future comparisons for non-CHOP regimens. Cancer 2013. © 2012 American Cancer Society.

INTRODUCTION

Noncutaneous lymph node and extra-lymph node peripheral T-cell lymphomas (PTCLs) are a rare heterogeneous group of clinically aggressive non-Hodgkin lymphomas (NHLs) with a poor prognosis.1 The World Health Organization (WHO) classification includes many subtypes,2 but understanding the pathophysiology and development of clinically effective therapies for each entity is currently very difficult.3 Among the subtypes of PTCL, different outcomes are observed. According to the International Prognostic Index (T-IPI), the 5-year overall survival (OS) rate was 11% for patients with high-risk (IPI 3-5) PTCL, not otherwise specified (NOS); 25% for patients with high-risk anaplastic lymphoma kinase (ALK)-negative angioimmunoblastic T-cell lymphoma (AITL); and 13% to 33% for patients with high-risk ALK-negative anaplastic large cell lymphoma (ALCL).4 Frequently, patients with a diagnosis of PTCL receive anthracycline-based therapy (eg, cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or CHOP-like regimens); however, their event-free survival and OS are inferior to those of patients who have aggressive B-cell NHL.5, 6 Relapsed/refractory disease is common for most patients with PTCL who receive current agents7 with inadequate salvage therapy. Autologous stem cell transplantation may be curative in a small subset of fit, chemosensitive patients.8

The optimal therapy for PTCL is an area of controversy because of the rarity of the disease subtypes, variable clinical course, biologic heterogeneity, and lack of clinical trials. Studies using the Lymphoma Biology Tissue Bank of the Southwest Oncology Group, a federally funded cancer research cooperative group, have indicated that patients with advanced stage PTCLs using the standard IPI have worse survival than patients with B-cell lymphomas (P < .01), with a median progression-free survival (PFS) of 6 months (compared with 17 months for patients with aggressive B-cell NHL [B-NHL]) and a 2 year PFS rate of 21% (compared with 46% for patients with B-NHL).9 The biologic explanation for this difference is unknown.

Several biomarkers of prognostic significance that predict for a poor survival in PTCL have been identified, including factors that drive aberrant proliferation (eg, Ki-67 and p53).7 In fact, p53 is a critical prognostic factor that correlates well with multidrug resistance gene 1/P-glycloprotein (MDR-1/P-gp) expression (adenosine triphosphate [ATP]-binding cassette subfamily B1 [ABCB1]), which confers chemotherapy resistance.10, 11 However, the differential expression of P-gp within the tumor and the microenvironment has not been elucidated. Hence, we hypothesized that combination chemotherapy with agents not effluxed by MDR-1 (ABCB1) may overwhelm P-gp and abrogate drug resistance, leading to an increased response rate that would improve PFS and OS. Therefore, we devised a protocol based on combined cisplatin, etoposide, cytosine arabinoside (ara-C), and methylprednisolone (Solu Medrol) (ESHAP), a typical second-line chemotherapy regimen, by replacing ara-C with gemcitabine: ie, platinum, etoposide, gemcitabine, and methylprednisolone (known as “PEGS”). Gemcitabine was included in PEGS because it has potent single-agent activity in PTCL12 and is not a substrate of ABCB1. In 44 previously treated patients with mycosis fungoides (MF) (n = 30) and peripheral T-cell lymphoma unspecified (PTCLU) (n = 14), gemcitabine administered on days 1, 8, and 15 of a 28-day cycle (1200 mg/m2) produced 5 complete responses (CRs) and 26 partial responses (PRs). The CR and PR rates were similar for MF and PTCLU, with a median duration of CR and PR of 15 months and 10 months, respectively.12

MATERIALS AND METHODS

Patient Population

This study was conducted by Southwest Oncology Group (S0350; National Clinical Trials [NCT] identification number NCT00109928) with appropriate regulatory and institutional review board approval for each site, and all patients provided informed consent. Patients had to have either newly diagnosed NHL of T-cell lineage or relapsed or progressing disease after 1 prior treatment with a nonplatinum based chemotherapy (eg, CHOP or a CHOP-like regimen). Patients with ALK-positive ALCL were excluded, be cause they fare better with CHOP-like therapy. All samples had central pathology review by 1 of the authors (C.M.S.). PTCL included extra-lymph node types (extra-lymph node natural killer [NK]/T-cell lymphoma, nasal type; enteropathy type T-cell lymphoma; hepatosplenic T-cell lymphoma; and subcutaneous panniculitis-like T-cell lymphoma) and lymph node types (peripheral T-cell lymphoma, NOS; ALCL, ALK-negative ALCL; and AITL). Patients who had cutaneous T-cell lymphoma (CTCL) transformed to PTCL with systemic involvement (not local skin transformation) also were eligible. Patients had bulky stage II, stage III, or stage IV disease according to the Ann Arbor classification.13 All patients were required to have bidimensionally measurable disease documented within 28 days before registration. Patients with nonmeasurable disease in addition to measurable disease were required to have the nonmeasurable disease assessed within 42 days before registration. Patients were required to undergo a bilateral or unilateral bone marrow aspirate and biopsy within 42 days before registration.

Patients were aged ≤18 years. Women had to be of nonchildbearing potential (postmenopausal or history of bilateral oophorectomy or hysterectomy), not pregnant, or willing to use contraception. Inclusion criteria included a life expectancy ≥12 weeks; a Zubrod performance status of 0, 1, or 2; an absolute neutrophil count ≥1500/mm3 and platelets ≥75,000/mm3; a creatinine clearance ≥30 mL/minute or an estimated creatinine clearance ≥30 mL/minute; serum bilirubin ≤2 times the institutional upper normal limit (ULN); and alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels >2.5 the reference range ULN range or >5 times the reference range ULN with liver metastases. No prior malignancy was allowed except for adequately treated basal cell (or squamous cell) skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for 5 years. Exclusion criteria included >1 prior chemotherapy or radiotherapy within 4 weeks of study start; a left ventricular ejection fraction less than the institutional lower limit of normal; a history of ischemic heart disease or myocardial infarction within 3 months of the study; severe or uncontrolled systemic conditions or current unstable or uncompensated respiratory or cardiac conditions; central nervous system involvement by lymphoma; or positive human immunodeficiency virus status.

Study Objectives

This was a phase 2 study of patients with PTCL who received the PEGS regimen, and the primary objective was estimating 2 year OS. Secondary clinical objectives were to assess toxicity, the response rate (complete unconfirmed response [CRu], CR, and PR), PFS, and P-gp expression in patients with untreated and treated T-NHL.

Lesions were measured accurately in 2 dimensions by computed tomography, magnetic resonance imaging, medical photograph (skin or oral lesion), plain x-ray, or other conventional technique. We recorded either the greatest transverse tumor dimension ≥1 cm or palpable lesions with 2 diameters ≥2 cm. Computed tomography scans were the standard imaging modality for the evaluation of lymph node disease. Responses (CR, PR, stable disease [SD], and progressive disease [PD]) were evaluated according to modified Cheson criteria.14

Drug Administration

Eligible patients received intravenous cisplatin 25 mg/m2 on days 1 through 4, etoposide 40 mg/m2 on days 1 through 4, gemcitabine 1000 mg/m2 on day 1, and methylprednisolone 250 mg on days 1 through 4 of a 21-day cycle for a maximum of 6 cycles. Dose reductions (up to 50%) and/or delays (up to 4 weeks) were allowed. Bone marrow colony-stimulating factors were not to be used routinely in this protocol. However, such factors could be used in individual patients if the presence of severe neutropenia required either delays in therapy or a dose reduction or in patients with neutropenic fever.

P-Glycoprotein Expression by Immunohistochemistry

Thirty-three patients underwent histologic evaluation. Two were excluded from the P-gp analysis because there was insufficient tissue for study. All others were evaluated for P-gp using both JSB-1 (Covance, Dedham, Mass) and C494 (Covance, Dedham, Mass) murine monoclonal antibodies, which target the 170-kDa, ATP-dependent, multispecific drug transporter ABCB1.15 Immunohistochemical staining was performed using the Ventana Ultra automated stainer (Ventana Medical Systems, Tucson, Ariz). Tissue sections were cut at 3 microns, and an initial antigen retrieval process was performed on the Ultra. After antigen amplification, antibody detection was performed using the Ultra. After a hematoxylin and eosin counterstain was performed, each slide was coverslipped and evaluated. Evaluation included both tumor and residual background components. If the lymphoma was composed of large cells, then determination of their P-gp status was certain. However, when tumor cells and residual small lymphocytes were of similar size, the P-gp status of each group was not always able to be determined with complete certainty.

Statistical Methods

The primary objective of this study was to estimate 2 year OS. We calculated that, if 30 patients accrued over 4 years with an additional 2 years of follow-up, this would be sufficient to estimate 2-year survival to within ±0.18. Assuming an historic 2-year survival probability of 0.48 for patients advanced stage T-cell lymphomas, with 30 patients, this would have 81% power (1-sided 0.03 level; 1-sample exact binomial test) to detect an improvement to a 2-year survival probability of 0.72 assuming complete follow-up on all patients for 2 years. An estimated 2-year survival probability of 0.67 would warrant further investigation of this regimen. Thirty patients also would be sufficient to estimate response, the probability of any particular adverse event, and PFS to within ±18%. Any adverse event that occurs with at least 8% probability is likely to be observed at least once (92% chance).

The following definitions applied to time-related endpoints. OS was defined as the time between study registration and death from any cause. PFS was defined as the time between study registration and documented disease progression or death if no progression was observed. The time to response (TTR) was defined as the time between study registration and the first documentation of a response (either first documentation of PR, or, if no documentation of PR, then first documentation of a confirmed CR or a CRu). Response duration was defined as the time between the first documentation of response and progression, death, or the date of last contact (if the patient remained alive without progression). Median and range values are provided for the TTR. Median and 2-year estimates of PFS, OS, and response duration and their 95% confidence intervals (CIs) were estimated using Kaplan-Meier to account for censoring.16

RESULTS

Patient Characteristics

Thirty-four patients were enrolled. One patient was ineligible because of insufficient prestudy documentation. Among the 33 eligible patients, the T-NHL subtypes were PTCL, NOS (n = 15); AITL (n = 6); ALK-negative ALCL (n = 4); nasal NK/T-NHL (n = 2); and other T-NHLs (n = 6; including 1 subcutaneous, panniculitis-like T-cell lymphoma; 1 enteropathy-associated T-cell lymphoma, type II; and 4 T-cell lymphomas with likely diagnoses of enteropathy-associated T-cell lymphoma [n = 1], AITL [n = 2], and ALK-negative ALCL [n = 1]). Most diagnostic biopsies were from lymph nodes (19 of 33 biopsies; 58%), and the remaining biopsies originated from varied sites. The median patient age was 60 years (range, 20-92 years), and 22 patients (67%) were men. The majority of patients enrolled on S0350 were newly diagnosed and chemotherapy-naive (79%) (Table 1).

Table 1. Patient Characteristics
CharacteristicNo. of Patients (%)
  1. Abbreviations: AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK−, anaplastic lymphoma kinase-negative; IPI, International Prognostic Index; LDH, lactate dehydrogenase; NK/T-NHL, natural killer/T-cell non-Hodgkin lymphoma; PTCL, peripheral T-cell lymphoma; NOS, not otherwise specified; T-NHL; T-cell non-Hodgkin lymphoma; ULN, upper normal limit.

Age: Median [range], years60 [20-92]
Sex 
 Men22 (67)
 Women11 (33)
Race 
 White28 (85)
 Black4 (12)
 Asian1 (3)
Ethnicity 
 Hispanic2 (6)
 Non-Hispanic31 (94)
No. of prior treatments 
 026 (79)
 17 (21)
Histology 
 PTCL, NOS15 (45)
 AITL6 (18)
 ALCL, ALK−4 (12)
 Nasal NK/T-NHL, extra lymph node2 (6)
 Other T-NHL6 (18)
Symptoms 
 A16 (48)
 B17 (52)
Bulky disease 
 No25 (76)
 Yes8 (24)
Stage 
 II5 (15)
 III9 (27)
 IV19 (58)
Performance status 
 07 (21)
 121 (64)
 25 (15)
Bone marrow involvement 
 No23 (70)
 Yes10 (30)
LDH 
 Normal11 (33)
 >ULN22 (67)
Extra lymph node involvement 
 No11 (33)
 Yes22 (67)
IPI risk group 
 Low6 (18)
 Low-intermediate13 (39)
 High-intermediate8 (24)
 High6 (18)

Patient characteristics also were analyzed between those with newly diagnosed disease versus recurrent disease. Although these groups did not differ in the proportion of patients with PTCL, NOS, most tumors with AITL histology were in the patients with recurrent disease (57% vs 8%; P = .003). There was also a trend toward more newly diagnosed patients having B symptoms (58% vs 29%); however, this trend was not statistically significant, perhaps because of lack of power. No other differences were evident.

Treatment Administration

The majority of patients (n = 21; 64%) completed all 6 cycles of treatment. The remaining patients received either 4 cycles (n = 1), 3 cycles (n = 3), 2 cycles (n = 3), or 1 cycle (n = 5). Patients who did not complete treatment were removed because of toxicity (n = 2), progression (n = 6), early death before assessment for response or progression (n = 2), or other reasons (n = 2).

Adverse Events

The number of patients with a given type and grade of adverse event are reported, whereas adverse events that were unlikely to be related or that were not related to treatment are excluded (Table 2). One patient died from an infection with grade 3 or 4 neutropenia, which probably was related to treatment. The worst toxicity observed was grade 3 adverse events in 14 patients and grade 4 adverse events in 13 patients. The most common grade 3 and 4 toxicities were hematologic (n = 21), metabolic (n = 8), and infection (n = 7).

Table 2. Grade 3 and 4 Adverse Events
Treatment-Related Adverse Events (n = 33)TotalGrade 3Grade 4
  1. Abbreviations: CNS, central nervous system.

Constitutional   
 Fatigue1820
 Fever400
Hematologic   
 Neutropenia1987
 Anemia2471
 Thrombocytopenia1525
Gastrointestinal   
 Nausea2300
 Vomiting900
 Diarrhea1220
 Constipation1100
Infectious   
 Febrile neutropenia431
 Blood infection1 (Grade 5)00
 Other infection1150
Renal/metabolic   
 Renal failure220
 Hyperglycemia1140
 Hyponatremia311
 Tumor lysis syndrome110
Neurologic   
 CNS hemorrhage101
 Neuropathy1011
 Tinnitus410
Thrombosis/embolism010
Maximum grade of any adverse event271413

Tumor Response

Restaging was performed 4 to 6 weeks after receipt of the last cycle of PEGS using modified Cheson criteria.14 The overall response rate (ORR) was 39% (13 of 33 patients) and included 24% confirmed and unconfirmed CRs (8 of 33 patients) and 15% PRs (5 of 33 patients). SD was observed in 12% of patients (4 of 33 patients). Among patients who had the different subtypes of T-NHL, the ORR was 47% (7 of 15 patients) for those with PTCL, NOS; 33% (2 of 6 patients) for those with AITL; 25% (1 of 4 patients) for those with ALK-negative ALCL; and 38% (3 of 8 patients) for those with other T-NHLs. The CR rate was 26% (4 of 15 patients) for those with PTCL, NOS; 17% (1 of 6 patients) for those with AITL; 25% (1 of 4 patients) for those with ALK-negative ALCL; and 25% (2 of 8 patients) for those with other T-NHLs. Among the 26 previously untreated patients, the ORR was 38% (10 of 26 patients), the CR rate (confirmed and unconfirmed) was 23%, and the PR rate was 15%. Among the 7 previously treated patients, the ORR rate was 43% (3 of 7), the CR rate was 29%, and the PR rate was 14%.

The median TTR was 2.2 months (range, 1.6-2.9 months). Among the 8 patients who attained a CR (confirmed or unconfirmed), the median TTR was 2.1 months (range, 1.6-2.9 months). Among the 5 patients who had a PR, the median TTR was 2.2 months (range, 1.8-2.4 months). The median response duration was 19.5 months (95% CI, 3.0-21.2 months). Among the 8 patients who attained a CR (confirmed or unconfirmed), the median response duration was 21.2 months (95% CI, 2.4-21.2 months). Among the 5 patients who had a PR, the median response duration was 3.0 months (95% CI, 1.0-19.5 months).

Progression-Free and Overall Survival

Through August 5, 2011, the median follow-up for the patients who remained alive was 1.6 years. Twenty-three of 33 eligible patients relapsed or died. The 2-year PFS rate was 12% (95% CI, 0.1%-31%), and the median PFS was 7 months (95% CI, 5-21 months) (Fig. 1). Eighteen patients died. The 2-year OS rate was 31% (95% CI, 8%-54%), and the median OS was 17 months (95% CI, 10 months to not defined) (Fig. 2). Among the subset of 26 patients with newly diagnosed disease, the 2-year PFS rate was 14% (95% CI, 0.1%-36%), and the 2-year OS rate was 36% (95% CI, 13%-59%). None of the 7 patients who had recurrent disease had a PFS or an OS ≥2 years.

Figure 1.

Progression-free survival at 2 years is illustrated for Southwest Oncology Group trial S0350.

Figure 2.

Overall survival at 2 years is illustrated for Southwest Oncology Group trial S0350.

P-Glycoprotein (MDR-1/ABCB1) Is Expressed on Peripheral T-Cell Lymphoma Tumor Endothelium

Both monoclonal antibodies C494 and JSB-1 were used to detect P-gp expression. Two patients did not have sufficient tissue for further study, which left 31 patient samples for analysis. C494 revealed reactivity in a subset of tumor cells in 6 patients; in these patients, the tumor cells were large cells. However, at least a subset of small lymphocytes was positive in 20 patients. This included patients whose tumor cells were small in size, making distinction between tumor and residual T cells problematic. Endothelium was focally to diffusely positive in 25 patients. Four representative samples of T-NHL that were analyzed for P-gp expression are provided in Figure 3.

Figure 3.

P-glycoprotein levels were evaluated with immunohistochemical staining (using the C494 monoclonal antibody) in a representative group of T-cell lymphomas. (Top Left) In a sample of peripheral T-cell non-Hodgkin lymphoma-not otherwise specified (PTCL [NOS]), staining of the large cells is observed. (Top Right) In a sample of anaplastic lymphoma kinase-negative (ALK-) anaplastic large cell lymphoma staining of both large cells and small cells is observed. (Bottom Left) In a sample of angioimmunnoblastic T-cell lymphoma (AITL), reactivity is observed only in a subset of small lymphocytes. (Bottom Right) A sample of panniculitis-like T-cell lymphoma reveals staining of the tumor cells that rim the fat cells as well as small foci of small lymphocytes between the adipose cells.

DISCUSSION

The rarity of PTCL makes it difficult to conduct biologically guided clinical trials that help clinicians determine the best therapeutic options for each of the subtypes. To our knowledge, the current study is the largest completed US cooperative group study of PTCL to date.

Patients with PTCL have received treatment similar to the CHOP-21 regimen (CHOP every 3 weeks) received by patients with aggressive B-NHL; however, anthracycline-based regimens are associated with a 5-year OS rate of <40%.15 In the interim, investigators have developed 3 strategies to improve outcomes—dose escalation of standard chemotherapy, new chemotherapy combinations, and novel agents.3, 4, 7 However, none of those strategies have improved the OS of patients with PTCL. The mechanistic explanation for unresponsiveness to CHOP-like therapy is unknown, but expression of MDR-1/P-gp (ABCB1) and other ATP-binding cassette (ABC) transporters may be a mechanism of chemoresistance. Hence, we devised a chemotherapy protocol incorporating agents that are known to be active in PTCL (eg, cisplatin, gemcitabine, etoposide, and methylprednisolone)17-19 and are not effluxed by the ATP-dependent P-gp efflux pump to abrogate drug resistance, with the potential to increase the response rate with an associated improvement in PFS and OS. The chemotherapy regimen PEGS was based on a regimen of combined cisplatin, etoposide, ara-C, and methylprednisolone (ESHAP)20 in which ara-C was replaced with gemcitabine. ESHAP has not been evaluated in patients with PTCL except as part of intensive chemotherapy (high-dose CHOP/ESHAP) followed by autologous stem cell transplantation in previously untreated patients with PTCL who achieved a combined CR and PR rate of 48%.21 However, ESHAP treatment for relapsed and refractory B-NHL achieved a combined CR and PR rate of 64%. The median CR duration was 20 months, and 28% of remitters were still in CR at 3 years. The median OS duration was 14 months, and the survival rate at 3 years was 31%. ESHAP was identified as an active, tolerable chemotherapy regimen for patients with relapsing and refractory lymphoma.20

Overall, PEGS was well tolerated, and 21 of 33 patients completed 6 cycles of therapy. The major grade 3/4 adverse event was myelosuppression, and the only grade 5 adverse event was systemic infection (Table 2). The observed outcomes, however, have been disappointing—24% of patients achieved a CR/CRu, 15% achieved a PR, and 12% had SD with a median PFS of 9 months, a median OS of 17 months, a 2-year PFS rate of 12% (95% CI, 0.1%-31%), and a 2-year OS rate of 31% (95% CI, 8%-54%). The results did not reach the design target of a 2-year OS rate of 67%. The ORR did not differ between histologic subgroups; however, power to assess differences between subgroups was limited by the small sample size. Results for PFS, OS, and response were similar when the analysis was restricted to 26 previously untreated patients and were worse than those reported for typical CHOP-based regimens (Table 3).17, 22-26

Table 3. Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP)-Based Response Data for Peripheral T-Cell Lymphoma
Regimen (Reference)No. of PatientsHistologyResponsePFS or EFS or FFSOS
  1. Abbreviations: AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; CHOEP-ASCT, combined cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone plus autologous stem cell transplantation; CHOP-21, CHOP every 3 weeks; CHOP-ASCT, combined CHOP plus autologous stem cell transplantation; CHOP-EG, combined CHOP plus etoposide and gemcitabine; CR, complete response; EFS, event-free survival; FFS, failure-free survival; NKT, natural cell/T-cell non-Hodgkin lymphoma; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PTCL, peripheral T-cell lymphoma; VIP-r-ABVD, etoposide, ifosfamide, and cisplatin alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine.

CHOP-21 vs VIP-r-ABVD (Simon22)88PTCL, 65%; AITL, 17%; ALCL, 16%CR: 29% PTCL, 29%; AITL, 53%EFS, 41% at 2 yMedian, 42 mo
CHOP-like: Meta-analysis (Abouyabis17)2912NRCR, 55%NR37% at 5 y
CHOP-ASCT (Reimer23)83PTCL, 33%; AITL, 39%; ALCL, 16%ORR, 79%; CR, 39%PFS, ∼35% at 3 y48% at 3 y
CHOEP-ASCT (d'Amore24)160PTCL, 39%; AITL, 19%; ALCL; 19%ORR, 88%; CR, 40%aPFS, 44% at 5 y51% at 5 y
CHOP-EG (Kim25)26PTCL, 54%; NKT, 31%CR, 61%50% at 1 y70% at 1 y
CHOP-alemtuzumab Gallamini26)24PTCL, 58%; AITL, 25% ALCL, 12% ORR, 75%CR, 71%54% at 1 y70% at 1 y

Possible reasons for these disappointing results include a relatively unfavorable patient mix, with older patients (median age, 60 years), unfavorable PTCL histologies (no ALK-positive ALCL), and extensive disease (58% of patients had stage IV disease, and 67% had elevated lactate dehydrogenase levels) (Table 1). Because of the expected older cohort and the multicenter setting, the cisplatin dose was fractionated at 25 mg/m2 daily on days 1 thorough 4, and methylprednisolone doses were reduced to 250 mg on days 1 through 4, which also may have contributed to decreased efficacy. Similarly, if the P-gp hypothesis was not correct, then the omission of cytarabine may have contributed to decreased regimen efficacy. Conversely, the cooperative group trial setting, which represents both academic and community-based centers, may have mitigated selection bias and may have produced a more realistic reflection of the chemotherapy outcomes in the general population of patients with PTCL.

However, the response duration of PEGS in previously treated patients was relatively favorable compared with the duration achieved by other second-line regimens (Table 4),27-32 although the number of patients treated in first relapse was too small to draw strong conclusions. This is not surprising, because PEGS is based on a second-line regimen, ESHAP, and this raises the possibility that PEGS may be a viable option for second-line treatment.

Table 4. Novel Agent Response Data in Relapsed Peripheral T-Cell Lymphoma
Regimen (Reference)No. of PatientsResponseDR, moPFS, moOS
  • Abbreviations: auto-SCT, autologous stem cell transplantation; Cis, cisplatin; CR, complete response; DHAP, dexamethosone, cytarabine, cisplatin; DR, duration of response; Gem, gemcitabine; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TTP, time to progression.

  • a

    These included 2 patients with mycosis fungoides.

Bendamustine (Damaj27)38aORR, 47%; CR, 29%5.1NRNR
Pralatrexate (O'Connor28)111ORR, 29%; CR, 11%10.1Median, 3.5Median, 14.5 mo
Romidepsin (Coiffier29)130ORR, 25%; CR, 15%17Median, 4 
DHAP-alemtuzumab plus auto-SCT (Kim30)24ORR, 50%; CR, 21%Median, 2.9NRMedian, 6 mo
Gem-Cis-methylpred (Arkenau31)16ORR, 69%; CR 19%Median, TTP, 4NR69% at 1 y
Alemtuzumab (Enbald32)14ORR, 36%; CR, 22%Median, 6NRNR

Previous investigators demonstrated that P-gp is expressed variously in normal peripheral blood T-cells, which, in general, over express P-gp relative to B cells.33 In fact, some subsets of T cells (CD8 and CD4 cells) and NK cells express as much as 40-fold the amount of P-gp as circulating B cells.33 The level of detection of P-gp is several-fold greater than the level at which drug resistance is observed, and its expression is increased further in patients who have relapsed/refractory T-NHL and B-NHL. In the S0350 study, the analysis of P-gp expression was conducted on diagnostic (pretreatment) biopsies, and post-treatment biopsies were not available. P-gp expression was positive on small T cells (n = 20) and in a subset of large T cells (n = 6) within the tumor. The pattern of P-gp expression varied among the lymphoma subtypes (PTCL, NOS; ALK-negative ALCL, AITL, and panniculitis-like T-NHL) (Fig. 3).

Twenty-five patients had P-gp expression identified on the tumor vascular endothelium (Fig. 3). It is known that ABC transporters decorate the luminal plasma membrane of the brain capillary endothelium facing the vascular space, and they protect the central nervous system from entry of neurotoxins.34, 35 Our data suggest that the tumor microenvironment of small T-lymphocytes and blood vessels that over express P-gp effectively efflux the administered chemotherapy and allow tumor growth in the presence of chemotherapy. This may explain the ineffectiveness of anthracycline-based chemotherapy in patients with PTCL. Furthermore, it is known that doxorubicin enhances constitutive P-gp expression, resulting in the exclusion of doxorubicin from tumor cells and endothelial cells of the tumor vasculature.35 Because vascularization and P-gp expression are prerequisites for tumor growth in a hypoxic environment,36 the inhibition of P-gp in tumor endothelial cells may be a clinical approach to enhance the effectiveness of chemotherapy. It is noteworthy that, of 9 patients with PTCL who had B-cell leukemia/lymphoma 2 (Bcl2) expression evaluated, 8 demonstrated Bcl2 expression within tumor cells. This finding, coupled with an environment in which drug levels are subtherapeutic because of P-gp expression, may explain the poor relapse-free survival and outcome in the majority of our patients.

In conclusion, to our knowledge, S0350 is the largest completed US cooperative group study of PTCL to date to test a novel chemotherapy regimen (PEGS). Further work on P-gp should focus not only on tumor cells but also on the tumor microenvironment, including blood vessels. PEGS may be considered a benchmark for future comparisons with non-CHOP regimens in PTCL and for the design of rational combinations with targeted agents.

FUNDING SOURCES

This investigation was supported in part by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: CA32102, CA38926, CA11083, CA13612, CA45807, CA46282, CA20319, CA46441, CA46136, CA128567, CA142559, CA63848, CA37981, and CA35119. This work also was supported in part by Eli Lilly and Company.

Acknowledgements

We thank the patients who participated in this clinical study, their families, the Southwest Oncology Group Operations Office and Statistical Center, and all of the contributing member sites.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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