Four Cycles of CHOP Instead of Six for Favorable DLBCL

Alexander M. Castellino, PhD

December 02, 2018

SAN DIEGO — Standard therapy for young patients with favorable-prognosis diffuse large B-cell lymphoma (DLBCL) is six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin [hydroxydaunomycin], vincristine [Oncovin], and prednisolone) given every 21 days.

New data suggest that these patients can be spared two cycles of CHOP, with rituximab still given over six cycles, and have excellent clinical outcomes, similar to those seen after the standard six cycles of R-CHOP.

These new data come from the German FLYER trial, reported here at the American Society of Hematology (ASH) 2018 meeting  (abstract 781).

The FLYER results show that 3-year progression-free survival (PFS) with four cycles of CHOP was 96%, which was noninferior to the 94% seen with six cycles of CHOP. The 3-year event-free survival rates were identical in both groups and corresponding 3-year overall survival rates were 99% and 98%.  

"We showed that efficacy was maintained with four cycles of R-CHOP followed by two cycles of rituximab and toxicity was considerably reduced," said lead author Viola Poeschel, MD, from the Saarland University Medical School, Homburg/Saar, Germany.

With the new regimen of four cycles of CHOP, chemotherapy lasts a total of 84 days compared with 126 days with the six-cycle regimen. This will come as welcome news for patients, who often must put their lives on hold as they cope with the side effects of chemotherapy, the researchers noted in an ASH statement.

"Our study shows you can spare two cycles of chemotherapy and it is equally effective. We think this will be the new standard treatment for this patient population," Poeschel said. "With a shorter duration of chemotherapy, patients are back to daily life with their families and back to work more quickly," she noted."

Lessons From FLYER for Clinical Practice

Moderating the press conference, David Steensma, MD, associate professor of medicine and attending physician at the Dana-Farber Cancer Institute, Boston, Massachusetts, said, "We are always looking to make treatment easier for our patients by reducing adverse events. For this group of patients, we can make the treatment shorter."

"The results will have implications for clinical practice both in the United States and globally," he said.

Medscape Medical News reached out to experts not associated with the study for their insights into the study.

 "These are provocative results," said Catherine Diefenbach, MD, from the Perlmutter Cancer Center at NYC Langone Health, New York City.

She explained that the study was interesting because no one looked into therapy minimization in DLBCL. In Hodgkin's lymphoma, a condition encountered mainly in younger patients and about which clinicians are concerned with late toxicity effects, therapy minimization has been considered.

"DLBCL mainly presents in older patients with a median age of 65 years, and the main focus is on increasing cure rates in patients," Diefenbach said.  

She pointed out that this FLYER trial was conducted in a subgroup of patients with DLBCL: those with the lowest risk (ie, International Prognostic Index [IPI] of 0; age ≤ 60 years; no bulky disease).

This represents about 10% of the total DLBCL patient population, Diefenbach pointed out, adding: "That is why it took 10 years to accrue patients into the study."

She said the results with four cycles of chemotherapy do not apply to the majority of  patients with DLBCL.

"I am not sure this study is practice changing," Diefenbach told Medscape Medical News.

"There are pros and cons of treating with six cycles of R-CHOP vs four cycles of R-CHOP followed by two additional cycles of CHOP," she said. She explained that R-CHOP is not highly toxic and after chemotherapy many patients continue to work, with minimal long-term toxicity.

She favored discussing both approaches with patients before settling on how to proceed. "Minimizing therapy by giving four cycles of CHOP is a reasonable strategy," she said.

"These findings should not be extrapolated to patients who do not fit these criteria [favorable-prognosis DLBCL]," Diefenbach emphasized. Most patients with DLBCL are not in the lowest-risk category. With a median age at diagnosis of 65 years, most patients are older than 60 years of age, she pointed out. Additionally, most patients have an IPI of 1 and/or bulky disease, she noted.

Another expert approached for comment, Michael Jain, MD, PhD, from the Moffitt Cancer Center, Tampa, Florida, said the results are practice changing for the subgroup of patients with DLCBL who studied in the FLYER trial.

 "The concept being addressed is: What is the right amount of chemotherapy in aggressive lymphoma?" he said. "Do all patients need R-CHOP, or are there a group of patients who can get adequate disease control with fewer cycles of chemotherapy?"

By using IPI, which is a powerful clinical risk predictor, he commented, this study showed that it is possible to give fewer cycles of CHOP to patients in the lowest-risk category.

"For DLBCL patients in the lowest0risk category, this study establishes a new standard," he said.

Jain noted that the results were practice changing in this group of patients. "This is a large randomized study for hematology, it is phase 3 study, it was well powered, and it provides the best evidence," he said.

However, Jain indicated that the study did not integrate other risk predictors, such as positron emission tomography (PET) and minimal residual disease, into the approach.

 Chemotherapy Should Not Be Reduced in the Elderly

Lead author Poeschel told Medscape Medical News that reducing chemotherapy from six to four cycles of CHOP should be considered only for patients who are 18 to 60 years of age — the age range for patients enrolled in the FLYER study. "This should not be extended to elderly patients," she said.

A corresponding study — OPTIMAL — is enrolling elderly patients with favorable-prognosis DLBCL, she pointed out. This is a PET-guided study. After four cycles of R-CHOP, patients with PET-negative disease will receive an additional four cycles of rituximab. Patients with PET-positive disease will get an additional two cycles of R-CHOP followed by two cycles of rituximab and radiotherapy to the initially involved sites.

FLYER Study Details

Between December 2005 and October 2016, FLYER enrolled 592 patients aged 18 to 60 years. All patients were required to have stage I/II DLBCL, which was considered to be low risk (age-adjusted IPI of 0; maximum disease diameter < 7.5 cm). Patients were randomly assigned to receive six (n = 295) or four (n = 293) cycles of CHOP every 21 days. All patients received the standard six cycles of rituximab.

The primary endpoint was PFS, with events defined as progressive disease, relapse, or death. The study assumed a 3-year PFS of 93% for patients in the six-cycle arm and was planned to show a noninferiority margin of 5.5%.

Patients had a median age of 48 years (range, 18 to 60 years) and were followed from 5 to 11 years.

For the primary endpoint of PFS, four cycles of CHOP was considered noninferior to six cycles of CHOP: Three-year PFS was 94% (95% confidence interval [CI], 91% - 97%) and 96% (95% CI, 94% - 99%).   

Fewer hematologic events were reported with four cycles of CHOP compared with six cycles for any-grade leukocytopenia (171 vs 237 events) and anemia (107 vs 172 events). Grade 3/4 events were also lower with four cycles of chemotherapy (for leukocytopenia, 80 vs 110; for anemia, 2 vs 8).

Similarly, there were fewer nonhematologic toxicities with four than with six cycles of CHOP (835 vs 1295 for any-grade event and 46 vs 70 for grade 3/4 events). Common adverse events were paresthesia, nausea, infection, vomiting, and mucositis.

"Overall nonhematologic adverse events were reduced by a third. This is an important and meaningful benefit to patients" Poeschel said

The researchers will continue to follow patients for an additional 5 years to determine whether reducing the cycles of chemotherapy will help reduce long-term side effects.

This study was supported by Deutsche Krebshilfe, a German nonprofit foundation. Poeschel reports travel grants from Roche and Amgen and consultancy and/or research funding from Bristol-Myers Squibb , Amgen, Roche, Merck Sharp & Dohme, and Spectrum. Steensma reports consultancy with Imedex, Janssen, Novartis, Otsuka; has equity ownership in Incyte; and is on the advisory committee for Janssen and Takeda

American Society of Hematology (ASH) 2018. Presented December 2, 2018. Abstract 781.  

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