THE REGIMEN of four cycles of rituximab (Rituxan)/cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) plus two cycles of rituximab was noninferior to that of six cycles of R-CHOP in younger patients with favorable-risk diffuse large B-cell lymphoma (DLBCL), according to the results of the randomized phase III FLYER trial presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition.¹ The de-escalated protocol reduced chemotherapy by two cycles.

Viola Poeschel, MD

“With a shorter duration of chemotherapy, patients are back to daily life with their families and back to work more quickly,” said lead study author Viola Poeschel, MD, of Saarland University Medical School, Homburg (Saar), Germany. “Our study shows you can spare two cycles of chemotherapy, and it is equally effective without compromising outcome in this population. We think this will be the new standard treatment for younger patients with a favorable prognosis.” Dr. Poeschel added that she expects these results will impact future therapy guidelines for this patient population.

Dr. Poeschel explained that six cycles of CHOP-like chemotherapy plus rituximab is standard treatment for young patients with DLBCL. With 6 cycles, chemotherapy is given for up to 126 days, whereas with the de-escalated regimen, treatment is continued for a total of up to 84 days.

A previous study identified a subgroup of favorable-risk patients with DLBCL defined as 0 on the International Prognostic Index (IPI) and no bulky disease.² On standard therapy, the patients in this group had a 3-year event-free survival of 89%, progression-free survival of 95%, and overall survival of 98%.

Dr. Poeschel and co-investigators hypothesized that four cycles of CHOP plus two cycles of rituximab would be noninferior to the standard treatment of six cycles of R-CHOP in this population.

“Our study shows you can spare two cycles of chemotherapy, and it is equally effective without compromising prognosis in this population [favorable-risk DLBCL].”

— Viola Poeschel, MD

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Study Description

THE INTERNATIONAL, multicenter FLYER trial randomly assigned 592 patients with favorable-risk, stage I or II DLBCL to receive either 6 cycles of R-CHOP or 4 cycles of R-CHOP plus 2 cycles of rituximab. Each treatment cycle was 21 days. Radiotherapy was not part of the planned protocol, but it could be given prophylactically to the testes in patients with testicular lymphoma. The primary endpoint of the study was progression-free survival, with events defined as progressive disease, relapse, or death. Dr. Poeschel presented the final analysis of FLYER, based on 588 evaluable patients: 295 assigned to 6 cycles of R-CHOP and 293 to 4 cycles of R-CHOP plus 2 cycles of rituximab.

Demographics were comparable in both arms. The mean age was 48 years (range, 18–60 years); 99% were classified as IPI = 0 and 1%, IPI = 1; bulky disease was present in 0.3%; 59% had stage I, 40% had stage II, and 1% had stage III disease; 32% had extranodal involvement; 6% had B symptoms.

Key Findings

PATIENTS WERE followed for a median of 5 years and up to 11 years. Efficacy results were similar for both treatment arms, and de-escalation of CHOP did not seem to compromise outcomes. The 3-year rate of progression-free survival was 94% in the standard arm and 96% in the experimental arm. These results met the prespecified criteria for noninferiority,

Dr. Poeschel said. Three-year event-free survival was identical in both treatment arms: 89%. Three-year overall survival was 98% in the standard arm and 99% in the experimental arm.

A multivariate analysis adjusted for stage and extranodal involvement showed no difference in progression-free survival between the treatment arms. Relapse rates were similar between the two arms: 5% for the standard arm and 4% for the experimental arm.

Reduced Toxicity

ADHERENCE TO the protocol was similar between the two arms, whereas there was a difference with respect to toxicity, both hematologic and nonhematologic, with reduced hematologic and nonhematologic adverse events in the experimental arm. The number of leukocytopenia events of any grade was 171 in the experimental arm and 237 in the standard therapy arm; grade 3 or 4 leukocytopenia events numbered 80 and 110, respectively. The number of anemia events of any grade was 107 and 172, respectively; the number of cases of grade 3 or 4 anemia was 2 and 8, respectively. The number of thrombocytopenia events was similar between the two arms.

The number of nonhematologic adverse events was reduced by about one-third in the experimental arm, with a total of 835 adverse events compared with 1,295 adverse events in the patients treated with 6 cycles of R-CHOP. The most common nonhematologic events were paresthesia, nausea, infection, vomiting, and mucositis. “The reduction in toxicity is important and meaningful to patients,” Dr. Poeschel said.

“The big advantages of de-escalating chemotherapy are reducing side effects, improving convenience, and reducing cost somewhat.”

— Robert A. Brodsky, MD

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“Although one-third of relapses occurred during the first 2 years of the study, relapses continue to be seen with longer follow-up in both arms,” she stated. Patients will be followed for an additional 5 years to observe any differences between treatment arms in terms of long-term toxicity.

Additional Commentary

“CHEMOTHERAPY WITH CHOP can have late effects, including cardiotoxicity and second malignancies. The big advantages of de-escalating chemotherapy are reducing side effects, improving convenience, and reducing cost somewhat. I believe this study will be practice-changing,” stated ASH Secretary Robert A. Brodsky, MD, who discussed this abstract at a premeeting webinar.

Dan Landsburg, MD

Dan Landsburg, MD, Assistant Professor of Hematology-Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, said in an e-mail, “FLYER is a very interesting and well-conducted study. It is possible that this result could change practice and R-CHOP × 4 + 2 additional cycles of rituximab may become standard of care for these patients.” 

“However, data on long-term toxicities, such as second malignancy, infertility, and heart failure, are needed to determine whether the rates were lower in the de-escalated arm. Additionally, it seems that a high percentage of late relapses have occurred. It is suggested that the relapse rates are equivalent,” he continued.

Dr. Landsburg looks forward to hearing more details with longer-term follow-up. ■

DISCLOSURE: The study was supported by Deutsche Krebshilfe. Dr. Poeschel disclosed financial support for travel from Roche and Amgen. Dr. Brodsky is an advisor/board member with Apellis and Alexion; is a consultant for Achillion; and has received research funding from Achillion and Alexion. Dr. Landsburg is an advisor/board member with Celgene, is a consultant for Curis, Inc., and has received research funding from Takeda and Curis, Inc.

REFERENCES

1. Poeschel V, Held G, Ziepert M, et al: Excellent outcome of young patients (18–60 years) with favourable-prognosis diffuse large B-cell lymphoma treated with 4 cycles CHOP plus 6 applications of rituximab: Results of the 592 patients of the FLYER trial of the Dshnhl/GLA. 2018 ASH Annual Meeting & Exposition. Abstract 781. Presented December 3, 2018.

2. Pfreundschuh M, Trümper L, Osterborg A, et al: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379-391, 2006.