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J Clin Oncol. 2010 April 10; 28(11): 1896–1903.
Published online 2010 March 8. doi:  10.1200/JCO.2009.26.5942
PMCID: PMC3651601

Risk-Adapted Dose-Dense Immunochemotherapy Determined by Interim FDG-PET in Advanced-Stage Diffuse Large B-Cell Lymphoma

Abstract

Purpose

In studies of diffuse large B-cell lymphoma, positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET) performed after two to four cycles of chemotherapy has demonstrated prognostic significance. However, some patients treated with immunochemotherapy experience a favorable long-term outcome despite a positive interim FDG-PET scan. To clarify the significance of interim FDG-PET scans, we prospectively studied interim FDG-positive disease within a risk-adapted sequential immunochemotherapy program.

Patients and Methods

From March 2002 to November 2006, 98 patients at Memorial Sloan-Kettering Cancer Center received induction therapy with four cycles of accelerated R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by an interim FDG-PET scan. If the FDG-PET scan was negative, patients received three cycles of ICE (ifosfamide, carboplatin, and etoposide) consolidation therapy. If residual FDG-positive disease was seen, patients underwent biopsy; if the biopsy was negative, they also received three cycles of ICE. Patients with a positive biopsy received ICE followed by autologous stem-cell transplantation.

Results

At a median follow-up of 44 months, overall and progression-free survival were 90% and 79%, respectively. Ninety-seven patients underwent interim FDG-PET scans; 59 had a negative scan, 51 of whom are progression free. Thirty-eight patients with FDG-PET–positive disease underwent repeat biopsy; 33 were negative, and 26 remain progression free after ICE consolidation therapy. Progression-free survival of interim FDG-PET–positive/biopsy-negative patients was identical to that in patients with a negative interim FDG-PET scan (P = .27).

Conclusion

Interim or post-treatment FDG-PET evaluation did not predict outcome with this dose-dense, sequential immunochemotherapy program. Outside of a clinical trial, we recommend biopsy confirmation of an abnormal interim FDG-PET scan before changing therapy.

INTRODUCTION

In the diagnosis of diffuse large B-cell lymphoma (DLBCL), positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET) has proved to be highly sensitive for determining sites of disease.1,2 In addition, residual FDG positivity at the end of therapy was predictive for survival.3 Furthermore, initial reports have suggested that an interim FDG-PET scan performed after two to four cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy could identify patients who are likely to relapse.4,5 Subsequent data, using different chemotherapy regimens such as R-CHOP (rituximab + CHOP) or ACVBP (cyclophosphamide, doxorubicin, vindesine, bleomycin, and prednisone with or without rituximab) partially confirmed the value of interim FDG-PET scans in prognostication; however, a significant portion of patients do well long-term despite FDG-positive disease on the interim scan.6,7

This study was a risk-adapted sequential immunochemotherapy program that incorporated both pretreatment clinical prognostic factors (International Prognostic Index [IPI]) and interim evaluation with FDG-PET scans to direct therapy. We sought to determine whether interim FDG-PET scans could identify patients who might benefit from high-dose therapy/autologous stem-cell rescue (HDT/ASCR) as part of initial treatment and to determine whether HDT/ASCR could be avoided in patients with multiple IPI risk factors but normal interim restaging (defined as a negative interim FDG-PET scan and/or a negative biopsy of FDG-positive disease), using our strategy of dose-dense sequential therapy. We also prospectively evaluated the prognostic significance of individual biomarkers and cell of origin. The chemotherapy regimen for this study was based on sequential trials at Memorial Sloan-Kettering Cancer Center that attempted to improve outcome with CHOP, which was established by the National Intergroup study as the standard of care.8

PATIENTS AND METHODS

Eligibility Criteria

Eligible patients were age 18 to 65 years with a histologic diagnosis of CD20+ DLBCL or primary mediastinal DLBCL (PMBL). Patients with DLBCL with concurrent small cleaved cells in bone marrow were also eligible. Patients were required to have one to three of the following adverse risk factors: Karnofsky performance status ≤ 70%; lactate dehydrogenase above normal; or stage III or stage IV disease according to age-adjusted IPI (aaIPI),9 corresponding to low-intermediate risk (LIR), high-intermediate risk (HIR), or high-risk (HR) disease, respectively. Patients with LIR, non-bulky, localized disease were excluded.

All patients were eligible for transplantation and had FDG-PET–positive evaluable disease, normal left ventricular function, serum creatinine ≤ 1.5 mg/dL (or creatinine clearance > 60 mL/min), absolute neutrophil count of > 1,000/μL, and platelet count of > 50,000/μL. Patients had to be HIV-negative, hepatitis B surface antigen–negative, and hepatitis C antibody–negative. Patients with CNS involvement were excluded. All patient data were presented at the weekly lymphoma staging conference. Those patients with a positive interim FDG-PET scan were presented again before a second biopsy.

Treatment

Induction chemotherapy consisted of four doses of accelerated R-CHOP (R-CHOPac) administered within a 14-day cycle. One additional dose of rituximab preceded cycle 1 on day −2. R-CHOPac was given as follows: rituximab at 375 mg/m2 intravenous (IV) infusion, cyclophosphamide at 1,000 mg/m2 IV piggyback, doxorubicin at 50 mg/m2 IV push (IVP), vincristine at 1.4 mg/m2 (uncapped) IVP, and prednisone at 100 mg/d orally for 5 days. Either filgrastim or pegfilgrastim was administered after each cycle. If grade 3/4 neurotoxicity developed, vincristine was reduced or discontinued. If necessary, treatment was delayed until absolute neutrophil count was > 1,000/μL and platelet count was > 50,000/μL (Fig 1).

Fig 1.
Treatment schema: R-CHOP dosing: rituximab at 375 mg/m2, cyclophosphamide at 1,000 mg/m2, doxorubicin at 50 mg/m2, vincristine at 1.4 mg/m2 (uncapped), and prednisone at 100 mg/d for 5 days. ICE dosing: ifosfamide at 5,000 mg/m2 admixed with mesna at ...

Concomitant medications included oral acyclovir at 200 mg twice daily, sulfamethoxazole/trimethoprim 160 mg/800 mg orally every other day, and fluconazole at 100 mg orally every day. Allopurinol at 300 mg was administered orally during the first 14 days of the first cycle starting on day −2.

Interim Restaging

Computed tomography (CT) and FDG-PET scans were repeated 10 to 14 days after the start of the fourth cycle of R-CHOPac. Patients who had resolution of all FDG-positive sites of disease (without development of new sites) proceeded to consolidation A (three cycles of ICE [ifosfamide, carboplatin, etoposide] chemotherapy).10 Patients with residual FDG-positive disease that correlated with CT findings underwent repeat biopsy. If the biopsy was negative, the patient received consolidation A therapy; if the biopsy was positive, the patient received consolidation B (two cycles of ICE and then one cycle of RICE [rituximab + ICE] followed by HDT and autologous stem-cell transplantation). Those patients whose bone marrow was initially positive and remained positive after induction received consolidation B (Fig 1). Consolidation B therapy was divided into three parts: (1) two cycles of ICE, (2) one cycle of RICE with peripheral blood progenitor stem-cell collection,11 and (3) HDT/ASCR.12 (See Appendix, online only, for more detail.)

Radiation Therapy and Intrathecal Prophylaxis

Consolidative radiation therapy was permitted only in testicular lymphoma. Intrathecal prophylaxis with four to six doses of either methotrexate (12 mg) or cytarabine (60 mg) was administered to all patients with IPI HR disease, as well as those with nasopharyngeal, sinus, or testicular disease.

FDG-PET Analysis

All interim scans were reviewed alongside baseline scans to verify residual abnormal uptake at sites of previously identified disease; decision to biopsy a residual abnormality was based on this review. FDG-PET scans were interpreted visually with correlation to a concurrent or simultaneous CT scan of the chest, abdomen, and pelvis (when done as integrated PET/CT). No standard uptake value (SUV) exists to distinguish between malignant and nonmalignant FDG-avid disease. We instead relied on visual comparison with the baseline FDG uptake and uptake in surrounding normal tissue at interim. Prior studies applied similar criteria for visual interpretation.13,14 A negative interim scan was defined as absence of FDG uptake at any site of FDG-positive disease identified in the baseline study, and lack of new FDG-positive disease. A positive scan was defined as any FDG uptake greater than local background activity, with a corresponding abnormality on CT scan. Exploratory analyses, compared SUV changes from baseline with interim (Δ SUV) between patients with and without residual disease in the biopsy specimen obtained after a positive interim FDG-PET scan (see Results).

Biostatistics

The primary end point was to determine complete response rate. The study was designed to have a 90% power of detecting an increase in complete response rate from 75% to 90% in the LIR group and from 53% to 75% in the HIR/HR groups. Progression-free survival (PFS) and overall survival (OS) were evaluated as clinical end points. OS was defined as the interval from the start of treatment with R-CHOPac until death or last follow-up for patients who were still alive. PFS was defined as the interval from the start of treatment with R-CHOPac until progression of DLBCL, death from any cause, or last follow-up. The probabilities of being alive and progression free 3 years after therapy initiation were calculated based on Kaplan-Meier estimates.

The secondary objective was to determine whether interim FDG-PET could accurately identify those patients who had a poor prognosis after induction immunochemotherapy and who might benefit from HDT/ASCR consolidation. A landmark analysis was performed at 10 weeks when the interim FDG-PET scan was evaluated, and the PFS of FDG-positive and FDG-negative patients were compared. In addition, we were interested in whether biopsy results could be predicted by SUV values; we used the Wilcoxon signed rank test to compare biopsy-positive/biopsy-negative patients with respect to SUV measurements at the interim PET scan, as well as the changes in SUV from pretreatment to the interim evaluation. Furthermore, we used two established receiver operating characteristic–based methods (Youden's Index and the closest to [0,1] criterion) in an attempt to identify a threshold on the SUV range that best predicted biopsy results.1517

Kaplan-Meier estimates of PFS and OS stratified by various prognostic factor categories were calculated and compared by means of log-rank test statistics. The best cut point for the biomarker Ki-67 in predicting PFS was found by using the method of Mazumdar and Glassman.18 Associations were considered significant if P was < .05. All P values were two-sided. All analyses were conducted using SAS version 9.1 (SAS Institute, Carey, NC).

RESULTS

From March 26, 2002, through November 3, 2006, a total of 98 newly diagnosed, DLBCL patients who were eligible for transplantation were prospectively enrolled onto Memorial Sloan-Kettering Cancer Center Protocol 01-142, which was approved by the institutional review board. The median age was 47 years; 16 patients (16%) were between age 60 and 65 years. Written informed consent was obtained from all patients. Patient demographics and pretreatment clinical and pathologic characteristics are described in Table 1.

Table 1.
Patient Characteristics (N = 98)

One patient progressed on therapy, and 97 patients received all of the planned therapy. The dose of vincristine was uncapped; however, 18 patients had dose reductions, and all patients received R-CHOP-14 on schedule. No dose reduction with ICE chemotherapy was permitted, but platelet count had to be at least 50,000/μL for cycle 2 and cycle 3 to begin. The planned time interval for the three cycles of ICE was 31 to 37 days; the median time interval in this study was 37 days (range, 29 to 53 days), and delays were nearly always secondary to thrombocytopenia.

Treatment Outcome

At a median follow-up of 44 months, the Kaplan-Meier estimates of patients alive and progression free were 90% (95% CI, 83% to 98%) and 79% (95% CI, 69% to 89%), respectively (Fig 2A). Sixteen of 23 patients had an event related to DLBCL, and nine of these patients died. Four of the 16 patients had primary refractory disease (one during induction, three during consolidation); all died of progressive DLBCL. Twelve patients relapsed, four with parenchymal disease in the brain despite intrathecal prophylaxis. Seven of these 12 patients are currently in second remission, six after HDT/ASCR. The remaining events included three cases of low-grade non-Hodgkin's lymphoma after antecedent DLBCL, two cases of non–small-cell lung cancer (both patients had a history of heavy tobacco use, and one of these patients died), one case of acute myelogenous leukemia, and one case of myelodysplasia (this patient died).

Fig 2.
Outcome estimates based on Kaplan-Meier analysis. (A) Progression-free survival (PFS) and overall survival (OS) analyzed by intent to treat. (B) PFS based on interim positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET): positive versus ...

Interim FDG-PET

At 10 weeks after start of therapy, the results of the interim FDG-PET scan did not correlate with PFS (P = .146; Fig 2B). When the PFS of interim FDG-PET–positive biopsy-negative patients was compared with that of patients with a negative interim FDG-PET scan, the outcomes were identical (P = .27; Fig 2C). Pretherapeutic FDG-PET scans were positive in all patients with a median maximum SUV (SUVmax) value of 17 (range, 6 to 73). Ninety-seven patients had interim restaging FDG-PET scans (Fig 3). Fifty-nine patients had a negative interim FDG-PET scan and received consolidation A; 51 are progression free. The remaining 38 patients had FDG-PET–positive disease at a site that was also abnormal on CT scan. These patients underwent repeat biopsy (Table 2). Five of the 38 patients had a positive biopsy and received consolidative transplantation (consolidation B); three of those five patients are alive and progression free. The 33 patients with a negative biopsy received ICE without ASCR (consolidation A); 26 of those patients remain alive without evidence of DLBCL.

Fig 3.
Outcome based on interim evaluation. R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; PET, positron emission tomography; POD, progression of disease; Bx, biopsy; pts, patients; Pos, positive; Neg, negative; PF, progression-free. ...
Table 2.
Outcome of Patients With Interim Restaging of FDG-Positive Disease Using FDG-PET Scan (n = 38)

Interim Restaging Biopsy

Thirty-three biopsies showing no residual tumor were analyzed to determine why the FDG-PET scan was false-positive. All specimens showed inflammation. There was no correlation between the degree of inflammation and SUV.

Exploratory Analysis of Interim FDG-PET–Positive Scans

In searching for a cutoff value in patients with a positive interim FDG-PET scan, we found no significant difference in SUV measurements (Table 3). We investigated highest SUVmax values at the biopsy site as well as change in SUVmax between pretreatment values and interim evaluation values but failed to identify a meaningful threshold. Additionally, there was an overlap between biopsy-negative and biopsy-positive patients with respect to interim SUV and ratio SUV at the biopsy site.

Table 3.
Correlation Between SUV and Biopsy Result

Final FDG-PET Scan Results

Because of biopsy-proven disease at interim evaluation, five patients received a consolidative transplantation after three cycles of ICE. We evaluated outcome on the basis of final FDG-PET scan results at 4 to 6 weeks after ICE, or 90 to 100 days after transplantation for these five patients. There was no difference in outcome for patients with FDG-PET–negative versus residual FDG-PET–positive disease (P =. 70).

Prognostic Factors

Associations between reported clinical and biologic prognostic factors and PFS were calculated by univariate analysis. There was no outcome difference with any of the single IPI risk factors: age (P = .97), performance status (P = .38), stage (P = .16), lactate dehydrogenase (P = .56), or two or more extranodal sites (P = .74). The same was true of the full IPI model (five factors), the revised IPI model,19 and the aaIPI score used for study enrollment.

The cell of origin (germinal center v non-germinal center) as determined by immunohistochemistry did not affect PFS. We specifically included patients with PMBL, a cohort that typically presents with bulky nodal disease and an unusual relapse pattern. This had no impact on PFS or OS data (Fig 2D). Neither bone marrow involvement nor tumor bulk of ≥ 10 cm correlated with outcome.

The only statistically significant pretreatment factor was the proliferation marker Ki-67, of which 87 samples were available. Forty-nine (89%) of the 55 patients whose tumors had less than 80% proliferation rate were progression free at the end of the follow-up period versus 22 (69%) of 32 patients whose Ki-67 expression was ≥ 80% (P = .002).

DISCUSSION

The ability to predict an unfavorable outcome early in the course of DLBCL therapy has important clinical and research implications. FDG-PET is well established for staging and restaging of DLBCL and Hodgkin's lymphoma and has recently been incorporated into the International Workshop Criteria for determining response.20 A negative interim restaging FDG-PET scan has also been associated with an excellent outcome. However, because of inconsistent results in patients with interim FDG-PET–positive scans as well as the need to improve therapy for patients who are eligible for transplantation and who have multiple IPI factors, we conducted this risk-adapted clinical trial for patients with LIR, HIR, and HR DLBCL.

As in other reports, a negative interim restaging FDG-PET scan in our study was associated with an excellent outcome: 87% of these patients are progression free. Only eight (13%) of 59 patients with a negative test relapsed after R-CHOPac followed by ICE consolidation. Unexpectedly, of the 38 patients with positive interim restaging FDG-PET scans, only five (13%) had biopsy-confirming active DLBCL. The remaining patients had negative biopsies. Two patients who had a negative interim biopsy underwent a repeat biopsy at the conclusion of therapy for persistent FDG-positive disease at the same site that demonstrated active DLBCL; thus, in these patients, interim biopsies likely missed the viable tumor. Sampling error in other patients cannot be entirely excluded; however, if biopsies consistently failed to identify tumor, outcomes would differ between patients with FDG-positive residual disease and those with complete resolution of FDG positivity at interim restaging. This was not the case.

There are numerous potential explanations for the number of false-positive scans. FDG as a marker is not highly specific and shows uptake in infectious and inflammatory processes.2126 In addition, variation in the induction regimens may have had some effect. Using interim FDG-PET scans may be effective if standard CHOP is administered at 21-day intervals but may have only limited utility when other regimens, including R-CHOP, are given.27

All interim biopsies in this study demonstrated some degree of inflammation and/or necrosis. It may be that the timing of the scan affected FDG positivity. When we initiated this study, a position paper by the European Organisation for Research and Treatment of Cancer (EORTC) recommended a time interval of 1 to 2 weeks between completion of a chemotherapy cycle and FDG-PET scan to avoid transient flare at the diseased sites.28 Seven chemotherapy cycles were administered in our study. The plan was for cycle 1 to begin on day 1, and cycle 2 to begin on day 15. After cycle 4 of R-CHOPac, an FDG-PET scan was ordered so that before administering cycle 1 of ICE, we could decide either to biopsy or to continue chemotherapy. The scan occurred at a median of day 12 in the 2-week period; no patient had the scan before day 10. The final FDG-PET scan was performed at least 4 weeks after ICE therapy.

It is also possible that the use of immunotherapy increased lesion inflammation. Antibody-mediated cellular cytotoxicity and complement activation are important rituximab mechanisms.2931 Both processes recruit mediators of inflammation to the tumor site. The greater use of rituximab in the current study compared with use in the prior studies of Spaepen et al (none)3,5 and Haioun (41%)6 could have contributed to the high rate of FDG positivity unrelated to tumor activity.

We specifically included patients with PMBL in this study. Although the outcome of PMBL is favorable, long-term disease-free remission rates have been achieved with combined-modality therapy, including radiation to the mediastinum, which was specifically excluded in our study.32 However, other reports also suggest that with novel treatment programs, radiotherapy can be avoided without compromising outcome.33 Even excluding patients with PMBL, the fundamental conclusion of this study remains unchanged, ie, that interim FDG-PET scans, as conducted in this protocol, do not predict outcome.

Consolidative therapy may have overcome the adverse outcome expected for patients with FDG-PET–positive disease after R-CHOPac induction therapy. That is, even if there were false-negative biopsies, the results were excellent because ICE effectively eradicated residual DLBCL. However, in our 15-year experience with ICE-based salvage therapy, we have reported that it is unlikely for ICE to overcome disease refractory to R-CHOP to the extent that outcomes are identical to those of patients with a negative interim FDG-PET scan, who presumably have highly chemosensitive disease. Nevertheless, these results compare favorably with standard R-CHOP, R-CHOPE (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide), and R-EPOCH (r ituximab + etoposide, d oxorubicin, v inristine, c yclophosphamide, and p rednisolone)34 and have similar PFS rates to R-ACVBP (rituximab + ACVBP) and consolidative transplantation for all patients, as recently reported at the 2009 American Society of Hematology meetings by the Groupe d'Etude des Lymphomes (GELA; Appendix Table A1, onlineonly).

It is likely that some combination of these described factors contributed to rendering the interim FDG-PET–positive scans invalid for predicting treatment outcome. We selected FDG-PET as a tool for interim response evaluation on the basis of prior studies that used this imaging test for patients receiving chemotherapy for DLBCL. However, interim FDG-PET lost its validity as a predictive and prognostic marker because of alterations in trial design, which included introduction of immunochemotherapy, altered timing between treatment and interim scan, and possibly the use of more effective consolidation. Our experience in this study illustrates that a marker of response assessment will be valid only if it is used in a manner nearly identical to the one in which it was established.

This study demonstrates a highly effective strategy for the treatment of advanced-stage DLBCL, one that cured approximately 80% of patients. However, an interim FDG-PET scan did not identify those patients at high risk for a poor outcome. At present, suspected residual active DLBCL on interim restaging FDG-PET scans should be confirmed by biopsy before initiating a change in therapy.

Appendix

Treatment

Induction chemotherapy consisted of four doses of accelerated R-CHOP (R-CHOPac; rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone), administered with a cycle duration of 14 days. One additional dose of rituximab preceded cycle 1 (day −2). R-CHOPac was given as follows: rituximab at 375 mg/m2, cyclophosphamide at 1,000 mg/m2 intravenous bolus (IVB), doxorubicin at 50 mg/m2 intravenous push (IVP), vincristine at 1.4 mg/m2 (uncapped) IVP, and prednisone at 100 mg/d orally for 5 days. Filgrastim was administered subcutaneously (SC) on days 7 through 11 at either 300 μg (< 70 kg) or 480 μg (≥ 70 kg) per day or pegfilgrastim was administered SC at 6 mg once every 24 to 48 hours after completion of the IV chemotherapy. If patients developed grade 3/4 neurotoxicity from vincristine, the dose could be reduced at the discretion of the primary attending physician. Treatment was delayed until the absolute neutrophil count (ANC) was > 1,000/μL and the platelet count was > 50,000/μL.

Required concomitant medications included acyclovir at 200 mg orally twice daily, sulfamethoxazole/trimethoprim at 160/800 mg orally every other day, and fluconazole at 100 mg orally once daily. Allopurinol at 300 mg was administered orally for the first 14 days starting on day −2.

Interim Restaging

Computed tomography (CT) and positron emission tomography with [18F]fluorodeoxyglucose (FDG-PET) scans were repeated 10 to 14 days after the start of the fourth cycle of R-CHOPac. Patients who had resolution of all FDG-avid sites of disease (without the development of new sites) proceeded to consolidation A. Patients with residual FDG-avid disease that correlated to a finding on the CT scan underwent a repeat biopsy. If the biopsy was negative, the patient received consolidation A; if the biopsy was positive, the patient received consolidation B. A patient whose bone marrow was initially positive and remained positive after induction therapy received consolidation B.

Consolidation A: Three Cycles of ICE Chemotherapy

ICE chemotherapy was administered every 14 days as follows: ifosfamide with mesna, both at 5 mg/m2, given as a continuous 24-hour infusion beginning on day 2; carboplatin was dosed to achieve an area under the serum concentration-time curve (AUC) equal to 5 mg/mL and administered on day 2 (AUC dosing is calculated by the Calvert formula: 5 × [CrCl + 25]); and etoposide at 100 mg/m2 IV on days 1, 2, and 3. Carboplatin dose was capped at 800 mg).11 Filgrastim or pegfilgrastim were dosed as above and administered on days 5 through 12 or once at least 24 to 48 hours after completion of the IV chemotherapy, respectively. Re-treatment was planned for day 15, though delays were permitted for bone marrow recovery; required levels of a platelet count ≥ 50,000/μL and an ANC ≥ 1,000/μL was necessary for re-treatment. No rituximab was administered in consolidation A. In addition, no consolidative radiotherapy was permitted except for testicular disease.

Consolidation B: Two Cycles of ICE Followed by One Cycle of RICE and HDT/ASCR

Part 1: Patients whose biopsy was positive after interim restaging received two cycles of ICE chemotherapy as described above.

Part 2: A third cycle of consolidative ICE chemotherapy was administered as above, with rituximab (RICE) at 375 mg/m2 on days −3 and −1 to provide in vivo purging before peripheral blood progenitor stem-cell collection. Patients received filgrastim at 960 μg SC daily starting on day 5, and continuing until the completion of peripheral blood hematopoietic progenitor stem-cell collection. Pegfilgrastim was not permitted for stem-cell mobilization. Leukapheresis was initiated when the WBC was > 5,000/μL and continued until the target yield (5 × 106 CD34+ cells/kg) or a maximum of 5 days was reached. In addition, no consolidative radiotherapy was permitted except for testicular disease.

Part 3: The methods and details of high-dose therapy/autologous stem-cell rescue (HDT/ASCR) have been previously described.12 Patients received one of two HDT regimens: total-body irradiation with ifosfamide and etoposide or BEAM (carmustine, etoposide, cytarabine, melphalan).

Intrathecal prophylaxis with four to six doses of either methotrexate (12 mg) or cytarabine (60 mg) was administered to all patients with IPI (International Prognostic Index) high-risk disease, as well as those with either nasopharyngeal, sinus, or testicular disease.

Table A1.

Outcome of Patients With DLBCL Based on First-Line Therapy

RegimenNHIR/HR (%)5-Year EFS (%)5-Year OS (%)Overcome IPIOvercome Ki-67Age (years)Trial TypeReference
R-CHOP-21*202605253NoN/R60-80RandomizedCoiffier et al35
DA-R-EPOCH72407980NoYesAll agesWilson et al36
CHOPE-14177336279NoN/R18-59RandomizedPfreundschuh37
CHOP-14178434453NoN/R60-80RandomizedPfreundschuh38
R-CHOP-14610426070NoN/R60-80RandomizedPfreundschuh39
R-CHOP followed by ICE9879%79%90%YesNo18-65This study

Abbreviations: DLBCL, diffuse large B-cell lymphoma; HIR, high-intermediate risk; HR, high risk; EFS, event-free survival; OS, overall survival; IPI, International Prognostic Index; R-CHOP, rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone; N/R, not recorded; DA-R-EPOCH, dose-adjusted rituximab + etoposide, doxorubicin, vinristine, cyclophosphamide, prednisolone; CHOPE, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide; ICE, ifosfamide, carboplatin, and etoposide.

*Groupe d'Etude des Lymphomes (GELA) trial data and several other studies support these data.
Pretreatment with prednisone and vincristine eliminated some poor-risk patients.
Progression-free survival for Ki-67 > 80% is ≈60%.

Footnotes

Supported by the Singer Family Lymphoma Research Fund and the Lymphoma Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00039195.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Andrew D. Zelenetz, Genentech (C), Roche (C) Stock Ownership: None Honoraria: Paul A. Hamlin, Genentech Research Funding: Craig H. Moskowitz, Genentech, Bristol-Myers Squibb; Carol S. Portlock, Genentech; Andrew D. Zelenetz, Roche Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Craig H. Moskowitz, Heiko Schöder, Julie Teruya-Feldstein, Carol S. Portlock, David Straus, Ariela Noy, Maria L. Palomba, Owen A. O'Connor, Steven Horwitz, Daniel A. Filippa, Paul A. Hamlin, Andrew D. Zelenetz

Financial support: Craig H. Moskowitz

Administrative support: Craig H. Moskowitz, Andrew D. Zelenetz

Provision of study materials or patients: Craig H. Moskowitz, Carol S. Portlock, David Straus, Ariela Noy, Maria L. Palomba, Owen A. O'Connor, Steven Horwitz, Daniel A. Filippa, James F. Caravelli, Paul A. Hamlin, Andrew D. Zelenetz

Collection and assembly of data: Craig H. Moskowitz, Jessica L. Meikle, Daniel A. Filippa, James F. Caravelli, Paul A. Hamlin, Andrew D. Zelenetz

Data analysis and interpretation: Craig H. Moskowitz, Heiko Schöder, Julie Teruya-Feldstein, Camelia Sima, Alexia Iasonos, Sarah A. Weaver, Paul A. Hamlin, Andrew D. Zelenetz

Manuscript writing: Craig H. Moskowitz, Heiko Schöder, Julie Teruya-Feldstein, Camelia Sima, Alexia Iasonos, Carol S. Portlock, David Straus, Ariela Noy, Maria L. Palomba, Owen A. O'Connor, Steven Horwitz, Sarah A. Weaver, Jessica L. Meikle, Daniel A. Filippa, James F. Caravelli, Paul A. Hamlin, Andrew D. Zelenetz

Final approval of manuscript: Craig H. Moskowitz, Heiko Schöder, Julie Teruya-Feldstein, Camelia Sima, Alexia Iasonos, Carol S. Portlock, David Straus, Ariela Noy, Maria L. Palomba, Owen A. O'Connor, Steven Horwitz, Sarah A. Weaver, Jessica L. Meikle, Daniel A. Filippa, James F. Caravelli, Paul A. Hamlin, Andrew D. Zelenetz

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