Split-dose R-CHOP regimen effective for older adults with newly diagnosed lymphoma
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Key takeaways:
- The regimen conferred a 71% complete response rate among older adults with newly diagnosed DLBCL.
- Median PFS and median OS had not yet been reached at median follow-up of 13 months.
CHICAGO — A split-dose approach to the standard R-CHOP chemotherapy regimen resulted in a 71% complete response rate among older adults with newly diagnosed diffuse large B-cell lymphoma, results from a phase 2 study showed.
Data from the trial presented at ASCO Annual Meeting suggested that a more tolerable fractionated approach to a treatment regimen comprising rituximab (Rituxan, Genentech) plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is feasible to deliver without compromising efficacy, investigators noted.
“Split-dose R-CHOP offers a new approach to addressing the unmet need to optimize treatment algorithms for older patients with DLBCL, who are often excluded from clinical trials due to their age,” Nirav N. Shah, MD, MSHP, associate professor of hematology and medical oncology at Medical College of Wisconsin and member of the Healio | Cell Therapy Next Peer Perspective Board, told Healio.
Background
DLBCL is the most common form of non-Hodgkin lymphoma, with an incidence that increases with advanced age.
Because they often present with comorbidities, the toxicities of therapeutic regimens for treatment of DLBCL among older adults have become an emerging issue as the number of people living into their 80s increases, according to Shah.
A treatment cycle lasting 21 days (R-CHOP-21) is the current standard for adults with newly diagnosed DLBCL. However, individuals with DLBCL who are aged 80 years or older, or those 75 years or older with comorbid conditions, are typically given lower-intensity dosing schemes — such as R-miniCHOP — or treatments that lack curative intent, Shah added.
“Despite adequate treatment algorithms in younger, healthier patients, treatment of elderly patients with DLBCL can be challenging,” he said. “Split-dose R-CHOP allows delivery of an equivalent dose intensity as R-CHOP-21 in a deescalated, protracted fashion.”
Methodology
Shah and colleagues conducted a prospective phase 2 open-label study to determine the efficacy and safety of a split-dose R-CHOP regimen for the treatment of older adults with newly diagnosed DLBCL or transformed DLBCL.
The study enrolled adults with newly diagnosed DLBCL aged 75 years or older, or adults aged 70-74 who met specific inclusion criteria.
The multicenter trial treated 14 patients (median age, 81 years; range, 73-88; 57% men) seen within the Wisconsin Oncology Network, which included two academic medical centers.
More than half of study participants (n = 8; 57%) had stage 4 disease.
“The approach is an intermediate option between R-miniCHOP and R-CHOP-21 that gives a 50% dose reduction on day 1 and day 15 of cytotoxic agents, with a full dose of rituximab on day 1 to achieve identical cumulative dose intensity as R-CHOP-21 over a 28-day cycle,” Shah explained during a presentation.
Study participants received split-dose R-CHOP plus growth factor supplementation for 2 months (four doses), followed by an interim response assessment using PET or CT scans and a blood-based assay to evaluate for minimal residual disease (MRD).
“Because older patients could potentially benefit from a shorter course of chemotherapy, we used an interim stratification strategy to de-escalate patients to an abbreviated treatment,” Shah said.
This meant stopping treatment after four cycles of split-dose R-CHOP for certain patients who achieved MRD negativity and had a Deauville score of 1-3, while all other study participants completed six cycles of split-dose R-CHOP.
End-of-treatment complete response (CR) rate served as the study’s primary endpoint.
Key findings
The researchers reported that — with a median follow-up of 13 months for surviving participants — neither median PFS nor median OS had been reached as of the data cutoff date.
Eight of 14 study participants (57%) showed no evidence of disease on interim analysis PET/CT scans, whereas eight of 12 evaluable patients achieved interim MRD-negative status.
Ten of 14 patients (71%) achieved a complete response to therapy by the end of treatment period. This met the interim feasibility endpoint established by investigators of eight or more complete responders within the first 16 patients to continue onto stage 2 of the trial.
Four patients (29%) had progressive disease. Nine patients (65%) achieved MRD-negative status by the end of treatment.
Five patients treated with a de-escalation treatment strategy after the interim response assessment maintained a complete response to therapy as of the study’s data cut-off date.
No treatment-related mortality occurred during the study.
Researchers reported four deaths attributed to progressive disease during the study, with one occurring in a patient with progressive disease and COVID-19.
Seven patients (50%) had grade 3 or greater nonhematologic treatment-related toxicities. Four participants (29%) experienced grade 3 or grade 4 neutropenia during the study period.
Clinical implications
The study met its prespecified efficacy endpoint early and continues to enroll patients.
Notably, none of the five patients in the abbreviated arm of the trial have experienced disease relapse as of the study cutoff date, according to Shah.
This result suggested that a de-escalation approach after achieving disease negativity during an interim analysis can be considered without negatively affecting treatment outcomes, he added.
“Split-dose R-CHOP is a regimen that offers older patients with diffuse large B-cell lymphoma an equivalent dose intensity as R-CHOP-21 through a fractionated dosing schedule to improve tolerability,” he told Healio. “The end-of-treatment complete response rate is comparable to outcomes for R-CHOP observed among younger patients with diffuse large B-cell lymphoma.”
Perspective
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Alexey Danilov, MD, PhD
Older patients with newly diagnosed DLBCL or those with comorbidities present a challenge, as they often are unable to tolerate full-dose R-CHOP. Dose reductions — such as mini-CHOP — may compromise efficacy in this potentially curable disease.
Shah and colleagues presented early results of a phase 2 trial that investigated a novel dosing approach in this group of patients, where standard R-CHOP was administered on a 28-day cycle with split dosing on days 1 and 14. This way, all patients ultimately received full intended doses of chemotherapy. Furthermore, investigators adjusted therapy based on interim PET-CT and MRD assessment.
The investigators demonstrated that this regimen is comparable in efficacy, as judged by complete response rates, to standard R-CHOP-21. Moreover, some patients received “abbreviated therapy” based on interim disease assessment.
A larger cohort of patients needs to be treated with this regimen — with a longer follow-up — before it is adopted in routine clinical practice. Median follow-up in this analysis stands at only 13 months, in a disease that is known to relapse with highest frequency in the first 2 years after completion of therapy. Further analysis with more patients and longer follow-up will ensure full characterization of toxicities, as well as confirm the curative potential of this regimen. This is especially true for patients who received abbreviated therapy based on interim disease assessment, because these patients may be particularly vulnerable to relapse. Furthermore, because polatuzumab vedotin [Polivy, Genentech] is now being incorporated into front-line therapy of DLBCL, it would be of interest to understand how to include this effective novel option within this split-dosing regimen.
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Shah NN, et al. Abstract 7554. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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