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Shorter chemotherapy course 'equally effective' in diffuse large B-cell lymphoma
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SAN DIEGO — Reducing administration of CHOP chemotherapy by two cycles appeared as effective as the standard six cycles for younger patients with low-risk diffuse large B-cell lymphoma, according to results of the phase 3 FLYER trial presented at ASH Annual Meeting and Exposition.
Six cycles of CHOP chemotherapy — which contains cyclophosphamide, doxorubicin, vincristine and prednisone — plus six courses of rituximab (Rituxan; Genentech, Biogen), or R-CHOP, is the standard of care for young patients aged 18 to 60 years with DLBCL.
Results of the MInT trial — published in 2006 in The Lancet Oncology — established a subgroup of patients with DBLCL with an age-adjusted International Prognostic Index of 0 and no bulky disease who had favorable prognosis.
“As we learned from the MInT trial that there is a patient population with an excellent prognosis, we wanted to investigate whether we could de-escalate therapy in these patients without compromising their prognosis and whether this would also lead to less toxicity,” Viola Poeschel, MD, of Saarland University Medical School in Homburg/Saar, Germany, told HemOnc Today. “We believed that this should be possible and that reducing chemotherapy, and therefore toxicity, would represent a major benefit for patients. Data from the MInT trial were presented for the first time during ASH 2004, and our trial started recruiting in December 2005.”
With the reduced regimen — which includes four cycles of R-CHOP with two additional cycles of rituximab — patients receive 84 days of chemotherapy, compared with 126 days with the standard regimen.
“With a shorter duration of chemotherapy, patients are back to daily life with their families and back to work more quickly,” Poeschel said in a press release. “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.”
The analysis included 588 patients aged 18 to 60 years (median age, 48 years) with stage I to stage II DLBCL, 295 of whom received six cycles of R-CHOP and 293 of whom received four cycles of R-CHOP with two additional cycles of rituximab alone.
PFS served as the study’s primary endpoint.
Median follow-up was 66 months.
Researchers found that PFS, EFS and OS appeared as good with the shorter cycle as with the longer treatment cycle.
Ninety-six percent (95% CI, 94-99) of patients assigned the shorter regimen achieved 3-year PFS compared with 94% (95% CI, 91-97) of patients assigned the standard regimen. The difference met noninferiority criteria of the trial.
Three-year EFS was 89% in both groups, and 3-year OS was 99% (95% CI, 98-100) with the shorter regimen and 98% (95% CI, 96-99) with the longer regimen.
Multivariable analyses showed HRs of 1 (95% CI, 0.7-1.6) for EFS, 0.9 (95% CI, 0.5-1.6) for PFS and 0.8 (95% CI, 0.4-1.9) for OS.
Relapse occurred in 4% (95% CI, 2-7) of patients in the shorter treatment group and 5% (95% CI, 3-8) in the longer treatment group. Although 33% of relapses occurred within the first 2 years, researchers noted they continue to observe relapses with longer follow-up.
“A standard of care is established after a scientific discussion, which will start now,” Poeschel told HemOnc Today. “Our results may contribute so that future therapy guidelines for this patient population might be changed in the way that these patients received four cycles of R-CHOP in 21-day cycles plus two courses of rituximab instead of six 21-day cycles of R-CHOP. As the relapse pattern in both arms were similar, I don’t anticipate any reluctance.”
Researchers observed a reduction in toxicity of about a third in the shorter treatment group —1,295 adverse events occurred among those who underwent six cycles of R-CHOP compared with 835 adverse events among those who underwent four cycles.
The number of documented events of leukocytopenia (any grade, 237 vs. 171; grade 3-4, 110 vs. 80), anemia (any grade, 172 vs. 107; grade 3-4, 8 vs. 2) and thrombocytopenia (any grade, 17 vs. 16; grade 3-4, 7 vs. 5) were higher in the longer treatment group. There also were fewer cases of paresthesia (any grade, 370 vs. 227; grade 3-4, 14 vs. 12), nausea (any grade, 319 vs. 195; grade 3-4, 12 vs. 6), infection (any grade, 156 vs. 98; grade 3-4, 23 vs. 20) and mucositis (any grade, 105 vs. 68; grade 3-4, 3 vs. 1).
Researchers plan to follow the patients for an additional 5 years to determine the effect of the shorter treatment cycle on long-term side effects.
“It would also be very interesting to investigate whether therapy could even be more de-escalated by performing an early PET, for example, after two cycles of R-CHOP, or to investigate whether patients being PET positive after four cycles of R-CHOP would profit from an irradiation after six cycles of R-CHOP,” Poeschel told HemOnc Today. – by Alexandra Todak
References :
Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391.
Poeschel V, et al. Abstract 781. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures: Poeschel reports travel grants from Amgen and Roche. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Andre Goy, MD, MS
There is a trend in medicine — especially in Hodgkin lymphoma, chronic lymphocytic leukemia and other diseases — focusing on whether we can move away from chemotherapy using a combination of novel agents. Thus, the FLYER trial is getting a lot of traction and visibility at ASH. Researchers built this trial after results from the MInT trial — which looked at low-risk patients treated with six vs. eight cycles of CHOP-like chemotherapy with or without rituximab — showed that six cycles are sufficient.
Researchers of the current analysis evaluated favorable patients with large-cell lymphoma who are aged younger than 60 years, with a good performance status and early-stage, nonbulky disease. This is a very favorable patient population. When you look historically at localized large-cell lymphoma presenting in the neck or somewhere else, we give three to four cycles of chemotherapy or some combination, and if they are PET negative, we don’t give radiation. Despite that practice, this is the first large-scale analysis of around 600 patients comparing four cycles of R-CHOP followed by two infusions of rituximab with six cycles of R-CHOP. The results showed no difference in EFS and OS, and complete response rate was similar.
Looking at the overall picture, the findings are not really surprising. However, I would be cautious in the way we interpret these data, because this was a very favorable population, almost like a localized large-cell lymphoma, and we already did not use a lot of cycles of chemotherapy for them.
The relapse rate was about 4% to 5% in each arm. However, when you see the relapse rate and the survival curve, usually relapses for these patients occur in the first 2 years — that is why 24-month EFS has become an endpoint of interest. But, most of the relapses in this study occurred after 24 months, when it is really rare to relapse. It is an interesting trend that they saw more relapses later than we would expect for this population. When it comes to “undertreat” these patients, we don’t have data on germinal center vs. non-germinal center subset and there was no functional imaging in the study, but there is no question that if we can give less chemotherapy, it is better.
The benefit of functional imaging for large-cell lymphoma is that, after a week or two cycles of chemotherapy, the patients often who will have a response already are PET negative at that time; they respond very quickly. Those patients do extremely well regardless of other factors.
We still need to realize that most of the failures in general are early. We are starting to use liquid biopsies to look deeper at the molecular signature to determine if a patient will likely need more than R-CHOP. Or, you can look at the kinetics of cell-free DNA to look at patients with localized, early-stage disease to stratify them by the disappearance in their cell-free DNA.
That’s why we have to go deeper into this; we can’t just overnight treat all low-risk large-cell lymphoma with four cycles of R-CHOP. We need to understand better these 5% patients who relapse and how to manage them better.
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David Steensma, MD
The study focused on reducing the number of cycles of chemotherapy that the patients received. This international analysis had 600 patients meeting the primary follow-up. The key finding was that patients could in many cases reduce the number of cycles down from the current six, to four, thereby reducing the number of adverse events and finishing their treatment sooner.
We are certainly always looking for ways to make treatments easier for our patients to reduce adverse events. For this well-defined subgroup of patients, it appears that we can make their treatment shorter with less burden, but equivalent efficacy. We can’t extend that, though, to other subtypes of large cell lymphoma, but that is always a laudable goal. This will immediately influence clinical practice.
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