GEMCITABINE INSTEAD OF DOXORUBICIN FOR DLBCL

For patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who have cardiac comorbidities, the substitution of doxorubicin with gemcitabine in chemotherapy regimens shows promise, a single-group phase 2 trial has found.

The results were published online November 12 in the Journal of Clinical Oncology.

The treatment of choice for DLCBCL is a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). However, doxorubicin is known to be associated with an increased risk for cardiac toxicity, particularly heart failure, with increasing doses, note Paul A. Fields, MBChB, PhD, from Guys and St. Thomas' Hospital in London, United Kingdom, and colleagues.

So they used gemcitabine instead of doxorubicin. The regimen of rituximab, gemcitabine, cyclophosphamide, vincristine, and prednisolone (R-GCVP) was "active and reasonably well tolerated" in patients with newly diagnosed DLBCL who are unfit for anthracycline-containing chemoimmunotherapy because of cardiac comorbidity, the researchers report.

"Given the group of patients presented in this study were at high risk, as defined by poor ejection fraction or borderline ejection fraction plus presence of multiple cardiac risk factors, the results emphasize that it is still possible to offer such groups of patients treatment with curative intent," they write.

In the single-group phase 2 study, 61 of 62 elderly patients with DLBCL and cardiac comorbidity received R-GCVP — administered on day 1, with gemcitabine repeated on day 8 of a 21-day cycle — for a median of 6 cycles. One patient died before receiving treatment as a result of sepsis/lung abscess.

Of the 62 patients with advanced disease, 27 (43.5%) had left ventricular ejection fraction of 50% or less and 35 (56.5%) had borderline ejection fraction (between 50% and 55%) and comorbid cardiac risk factors, such as ischemic heart disease, diabetes, or hypertension.

Thirty-eight patients responded to treatment, for an overall response rate (the primary outcome) of 61.3% (95% confidence interval [CI], 49.2 - 73.4). Eighteen patients achieved a complete response, 6 achieved an undocumented/unconfirmed complete response, and 14 achieved a partial response.

The overall response rate was 81.8% for those who received at least 3 cycles of treatment (44 patients), the researchers note.

The 2-year progression-free survival rate was 49.8% (95% CI, 37.3 - 62.3), and the 2-year overall survival rate was 55.8% (95% CI, 43.3 - 68.4).

The researchers note that it is tough to find direct comparative studies, but a previous study from a team in Vancouver, British Columbia, reported a 5-year overall survival rate of 49% with cyclophosphamide, etoposide, procarbazine, and prednisolone (R-CEOP).

In their study, Dr. Field and colleagues found that hematologic toxicity of grade 3 or higher occurred in 34 patients (55.7%). Cardiac events of any grade occurred in 15 patients, 3 of which were fatal, "reflecting the poor cardiac status of the study population," they note.

Further testing of the R-GCVP regimen "is warranted to confirm its efficacy in a larger randomized clinical trial against novel R-CVP (rituximab, cyclophosphamide, vincristine, and prednisolone) regimens, with enhancement of either the chemotherapeutic or immunotherapeutic component," they write.

Cardiac Comorbidity a Significant Problem

The issue of treatment-limiting comorbidities will become more critical in future studies because the number of elderly patients with DLBCL is increasing because of changing demographics, the researchers note.

James Armitage, MD, from the University of Nebraska Medical Center in Omaha, who wasn't involved in the study, agrees. "How to deal with people with DLBCL who are often older and have pre-existing heart disease and heart failure is a significant problem," he told Medscape Medical News.

This study helps "sort that out," he said, but added that "it's not a solved problem."

Dr. Armitage noted that the Vancouver team substituted etoposide for doxorubicin, whereas Dr. Field's team substituted gemcitabine for doxorubicin. However, "both groups showed a significant response rate, with patients doing reasonably well."

The study was supported in part by Roche, Amgen, Eli Lilly, the UK National Research Institute, the National Institute for Health Research Cancer Research Network, and Cancer Research UK. Some of the authors report relationships with Roche and Amgen, as detailed in the paper. Dr. Armitage has disclosed no relevant financial relationships.

J Clin Oncol. Published November 12, 2013. Abstract