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Risk-adapted R-EPOCH in DLBCL
lation-based data demonstrating similar outcomes after six or eight cycles of therapy.3 Poeschel et al. reported the non-inferiority of four cycles of R-CHOP (followed by 2 additional doses of rituximab) compared with six cycles of R-CHOP in a randomized, phase III trial that included 588 immunocompetent patients with stage I-II DLBCL aged 18-60 years and an age-adjusted International Prognostic Index score of 0, indicating that de-escalation of treatment duration may be safely achieved without compromising curability in an appropriately selected patient population.4 This provides a foundation for evaluation of therapeutic de-escalation in other settings using other strategies.
Infusional administration of cytotoxic therapy has been explored as a potential strategy in patients with poor-risk lymphoma,5-8 including human immunodeficiency virus (HIV)-associated lymphoma.9-13 Based upon these consid- erations, the AIDS Malignancy Consortium conducted a randomized, phase II trial of rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH chemotherapy cycle, or sequentially (weekly for 6 weeks) following completion of all chemotherapy in patients with HIV-associated DLBCL and high-grade lymphoma.14 EPOCH consisted of a 96-hour intravenous infusion of etoposide, doxorubicin, and vincristine together with oral prednisone followed by an intravenous bolus of cyclophosphamide given every 21 days for four to six cycles, with cyclophosphamide dose adjusted based on pretreatment CD4 lymphocyte count, and subsequently escalated or reduced based on the absence or presence of treatment-associated cytopenias. The prespecified pri- mary efficacy complete response endpoint of 75% was met in the concurrently treated arm (73%, 95% confi- dence interval [95% CI]: 58%-85%), but not in the arm treated sequentially (55%, 95% CI: 41%-68%).14 Patients were assessed by computed tomography (CT) of the chest, abdomen, and pelvis after every two cycles of EPOCH chemotherapy, and were treated for two cycles beyond achieving a complete response for a minimum of four and a maximum of six cycles of EPOCH. Two-year time to progression rates were similar in the concurrently treated arm (75%, 95% CI: 63%-88%) and the sequen- tially treated arm (71%, 95% CI: 59%-84%). Inspired by the successful de-escalation of R-CHOP therapy to four cycles documented in a low-risk population with DLBCL,4 here we report a post-hoc analysis of the out- comes of patients with HIV-associated DLBCL and high- grade lymphoma with higher risk features who achieved a complete response when treated with four or fewer cycles of therapy, based on having achieved a complete response after two cycles of EPOCH.
Methods
Eligibility criteria and study conduct
Details regarding eligibility criteria, treatment, and clinical out- comes up to 2 years were previously reported.14 Briefly, eligibility criteria included: (i) CD20+ B-cell non-Hodgkin lymphoma, includ- ing DLBCL, Burkitt/Burkitt-like lymphoma, or other aggressive lymphomas; (ii) HIV infection; (iii) stage II-IV disease (or stage I disease with an elevated serum lactate dehydrogenase concentra- tion); (iv) Eastern Cooperative Oncology Group performance sta- tus of 0-2; (v) age 18 years or older;5 and (vi) adequate organ func- tion, similarly to prior trials by the AIDS Malignancy Consortium.15 The study was reviewed and approved by the
Cancer Evaluation Therapy Program of the National Cancer Institute, and by the institutional review board at each participat- ing institution. All patients provided written informed consent to their inclusion in the analysis.
Response assessment and duration of therapy
Response was defined by the 1999 International Response Criteria for Non-Hodgkin Lymphoma (which utilizes anatomical but not functional imaging).16 Response was evaluated after every two cycles of EPOCH therapy with CT of the chest, abdomen, and pelvis, and continued for two cycles beyond the achievement of a complete response for a minimum of four and a maximum of six cycles, including after completion of R-EPOCH in the concur- rently treated arm, and after completion of EPOCH alone and fol- lowing rituximab alone in the sequentially treated arm. All patients had a bone marrow evaluation and lumbar puncture for cerebrospinal fluid cytological examination at baseline. A repeat bone marrow evaluation for confirmation of complete response was required after completion of therapy if the baseline study demonstrated lymphomatous marrow involvement. 2-Deoxy-2- [fluorine-18]fluoro-D-glucose (FDG) positron emission tomogra- phy (PET) scans were not required or consistently performed, and when done were usually performed at the completion of therapy. Event-free survival, time to progression, and overall survival were estimated using the method of Kaplan and Meier. Event-free sur- vival was defined as the time between registration and either relapse or progression of lymphoma or death from any cause (thus corresponding to progression-free survival in other reports17). Time to progression was defined as time to progression or relapse of lymphoma, with deaths from other causes censored. Patients were followed for survival and recurrence up to 5 years after reg- istration. We performed a post-hoc analysis to evaluate the out- comes for patients who received only four cycles of therapy due to achieving a complete response, as determined by CT scan, after two cycles of therapy, compared with those who required five or six cycles of therapy who achieved a complete response after four cycles of therapy.
Results
Patients and response to therapy
A total of 106 evaluable patients were enrolled and ini- tiated treatment at 20 sites of the AIDS Malignancy Consortium between December 2002 and April 2006 and are included in this analysis, as in the original, previously described analysis.14 The disposition and outcomes of all patients enrolled are shown in Figure 1. A complete response was achieved by 64 of the 106 patients (60%, 95% CI: 50%-70%) who received any protocol therapy. The null hypothesis of a complete response rate of 50% was rejected in favor of the alternative of 75% for the con- currently treated arm (P=0.005), but not for the sequential- ly treated arm (P=0.394). Of the 64 patients who had a complete response, 24 received four or fewer cycles of R- EPOCH: 14/35 (40%) in the concurrently treated arm and 10/29 (34%) in the sequentially treated arm.
Characteristics of patients treated with four or fewer versus five or six cycles of EPOCH therapy
Of 64 patients who achieved a complete response, 24 (38%, 95% CI: 26%-51%) received four or fewer cycles of EPOCH based on their having achieved early complete response after two cycles of therapy, whereas the remain- ing 40 (63%, 95% CI: 50%-74%) received five or six
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