Split-Dose R-CHOP for Older Patients with Treatment Naïve DLBCL

Introduction:

Split-dose (SD) R-CHOP is a chemotherapy approach utilizing a 50% dose reduction of CHOP on days 1 and 15 with full dose Rituximab on day 1 given up to 6 months (12 cycles). This allows patients to receive the same cumulative dose intensity as R-CHOP-21 spaced over a longer time period with fractionated dosing to reduce treatment related toxicities. Growth factor is given as clinically indicated with each half-dose cycle to minimize neutropenia. Interim results of a Phase II, multi-center study of split-dose R-CHOP in older patients with diffuse large B-cell lymphoma (DLBCL) demonstrated a complete response (CR) rate of 71% (Shah NN, ASCO 2023) with high rates of MRD negativity. We now review real world outcomes of patients treated outside of a clinical trial with split-dose R-CHOP at the Medical College of Wisconsin.

Methods:

We performed a single center retrospective cohort study of DLBCL and associated subtypes of patients treated with SD R-CHOP since April of 2016 at our institution. Descriptive and survival analyses using the Kaplan-Meier methodology were performed. The primary endpoint was end of treatment complete remission (CR) rate and key secondary endpoints were median overall survival (OS) and progression free survival (PFS) which were estimated from the date of diagnosis to death, progression, or last follow-up. Patients who initially received a higher intensity regimen and were de-escalated to split-dose R-CHOP due to intolerance were included in the analysis.

Results:

We identified 35 patients who received split-dose R-CHOP as induction therapy for DLBCL and associated subtypes between 2016 and 2024 at our institution. The median age was 77.3 years (range 47-89 years) at the time of diagnosis. 39% (n=13) of patients had ECOG ≥2. 66% (n=23) had a high international prognostic index (IPI) score ranging 3-5. 68% of patients (n=24) had stage 3-4 disease. At the time of diagnosis LDH was elevated above the normal range in 51% (n=18) of patients and albumin was below the normal range in 51% (n=18) of patients. Cell of origin, determined by the Hans algorithm, was germinal center in 43% of patients (n=15), non-germinal center in 37% of patients (n=13), and not available in 20% of patients (n=7).

83% of patients (n=29) started with split-dose R-CHOP with the remaining 17% (n=6) of patients initially receiving a higher intensity regimen for 1-3 cycles before de-escalation to SD R-CHOP. One patient died of toxicity during therapy. 5% of patients (n=2) required change to split-dose R-CEOP, with substitution of etoposide for doxorubicin due to cardiotoxicity. 20% of patients (n=7) had neutropenia with SD R-CHOP with 83% of patients (n=29) receiving growth factor support during treatment. 34% (n=12) of treated patients were hospitalized for any reason during therapy. The end of treatment CR rate was favorable at 94% (n=33). There was only 1 patient who progressed during treatment. 9% of patients (n=3) have relapsed to date with a median follow-up of 39 months in surviving patients. The median PFS was 86 months, and the median OS was not yet reached.

Conclusions:

SD R-CHOP allows administration of full dose intensity R-CHOP chemotherapy in a de-escalated, fractioned dosing schema to minimize toxicity in older patients or those with other comorbid conditions. This real-world, single institution, dataset further supports the importance of maintaining dose intensity in older patients as seen with the excellent outcomes achieved among this high risk DLBCL patient population. Treatment related mortality was low and with G-CSF administration neutropenia was infrequent showing the increased tolerability of this regimen in a vulnerable, elderly population.

Devata:Pfizer: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Eli Lilly: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Johnson & Johnson: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Bristol Myers Squibb: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; AbbVie: Current equity holder in publicly-traded company; Novo Nordisk: Current equity holder in publicly-traded company; Bayer: Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Research Funding; GSK: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Hamadani:CRISPR: Consultancy; Allovir: Consultancy; Omeros: Consultancy; BMS: Consultancy; Genmab: Consultancy; AstraZeneca: Speakers Bureau; Spectrum Pharmaceuticals: Research Funding; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; Astellas Pharma: Research Funding; Caribou: Consultancy; AbbVie: Consultancy; Sanofi Genzyme: Speakers Bureau; Forte Biosciences: Consultancy; Autolus: Consultancy; Kite Pharma: Consultancy, Speakers Bureau; BeiGene: Speakers Bureau; Byondis: Consultancy; CRISPR: Speakers Bureau; DMC, Inc: Speakers Bureau; Genentech: Speakers Bureau; Myeloid Therapeutics: Speakers Bureau; Takeda: Research Funding. Fenske:AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, Beigene, Janssen, Kite, Lilly, Ono Pharmaceuticals: Consultancy, Honoraria; AstraZeneca, Beigene, Kite, SeaGen: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria. Shah:Miltenyi Biomedicine, Lilly Oncology: Research Funding; Gilead-Kite, BMS-Juno, Miltenyi, Lilly Onclogy, Novartis, Seattle Genetics, Janssen, Abbvie, Cargo, Beigene, Galapagos, AstraZeneca: Honoraria; Tundra Therapeutics: Current holder of stock options in a privately-held company.