R-CHOP in diffuse large B-cell lymphoma in the elderly

A 68-year-old woman arrives at the emergency department with weight loss, night sweats and a palpable abdominal mass. The CT scan shows clusters of lymph nodes in the retroperitoneum and mesentery. The core needle biopsy confirms diffuse large B-cell lymphoma (DLBCL). She lives alone, looks after her grandchildren two afternoons a week and asks, afraid, whether treatment is worth it at her age. A colleague suggests a lighter regimen, to avoid risk. The scene is fictional and was written for teaching.

This text uses the case as a scenario for clinical reasoning for students and health professionals. The topic is first-line treatment of DLBCL, from the French LNH-98.5 study, which compared R-CHOP with CHOP in patients aged 60 to 80, to the POLARIX study, which tested polatuzumab vedotin in place of vincristine. The question Dr. Alexei proposed for the series is direct: why should age alone not take away the patient's chance of cure? The text does not replace your country's guideline or your service's protocol. If you play the case of the day on NEXO, you know that the first impression of a patient can be the most misleading clue.

Key points

• DLBCL is an aggressive and curable lymphoma, and the goal of first-line treatment is cure.
• In LNH-98.5, adding rituximab to CHOP in patients aged 60 to 80 improved 10-year survival.
• The authors of LNH-98.5 concluded that older adults should be treated like younger ones, with curative chemotherapy.
• In POLARIX, Pola-R-CHP improved progression-free survival compared with R-CHOP in patients with an IPI of 2 to 5.
• At 5 years, the overall survival difference in POLARIX was not statistically significant.
• Frail patients exist, but frailty should be measured, not presumed from age.

Why this is a reasoning scenario

DLBCL is the most common lymphoma and accounts for the largest burden of lymphoma deaths worldwide, according to the review by Barraclough and colleagues (Barraclough and colleagues, 2024). For almost 4 decades, the goal of treatment has been cure, first with CHOP and later with rituximab added to CHOP. Stegemann and colleagues recall that R-CHOP cures about two thirds of patients (Stegemann and colleagues, 2022).

The disease affects all ages, and advanced age is associated with worse outcomes. This creates a temptation: to treat older people less, for fear of toxicity. The problem is that treating a curable lymphoma less often means losing the cure. The clinical reasoning here is to separate two questions that are often mixed together. The first is whether the patient tolerates curative treatment. The second is how old the patient is. Only the first should decide.

The organization of the path between biopsy, pathology and treatment is the topic of the post on lymphomas, from hematopathology to cell therapy. Here the focus is choosing the first-line regimen.

What makes this error easy to make

The patient in the scene seems frail because she is ill. Weight loss, fever and fatigue are symptoms of the lymphoma, and they often improve after the first cycle. Assessing functional capacity at the worst moment of the disease, without separating what is disease from what is baseline frailty, leads to reducing treatment for someone who could be cured. The studies themselves allow a prior phase with prednisone, up to 7 days before the first cycle, precisely to improve the patient's condition before chemotherapy (Hu and colleagues, 2025).

The disease and the prognosis

DLBCL is heterogeneous. Wang and Li describe the two major subtypes by cell of origin, defined by gene expression profile: activated B-cell (ABC), in about 50 of every 100 patients, and germinal center (GCB), in about 30 of every 100 (Wang and Li, 2020). The same authors recall that about 40 of every 100 patients have refractory disease or relapse after R-CHOP, with poor survival.

The international prognostic index

Individual risk is estimated by the international prognostic index (IPI), which adds points for five factors (Stegemann and colleagues, 2022):

• age over 60 years;
• poor functional status on the ECOG scale;
• advanced Ann Arbor stage;
• involvement of more than one extranodal site;
• lactate dehydrogenase (LDH) above normal.

There is also the age-adjusted IPI, which allows comparison of patients in different age groups. The IPI does not say who should or should not receive curative treatment. It estimates risk with standard treatment.

Other markers

Other factors may matter. Sato and colleagues showed that, in a Japanese series, Epstein-Barr virus-positive DLBCL of the elderly had a worse course than the negative form, even in the rituximab era (Sato and colleagues, 2014). Chu and colleagues used the staging CT scan itself to measure skeletal muscle density: among 224 patients, low density predicted 5-year progression-free survival of 60 versus 81 per 100, and overall survival of 58 versus 86 (Chu and colleagues, 2017). Curiously, in that study, sarcopenia measured by muscle mass did not predict worse overall survival.

What LNH-98.5 showed

Before rituximab, CHOP was the standard. Mohammed and colleagues recall that CHOP and its variations resulted in 5-year survival as low as 26 per 100 patients with aggressive non-Hodgkin lymphoma, and that rituximab was the first chimeric monoclonal antibody approved for non-Hodgkin lymphoma, in 1997 in the United States (Mohammed and colleagues, 2019).

LNH-98.5, from the French GELA group, was the first randomized study to compare R-CHOP with CHOP. It included 399 patients aged 60 to 80 with DLBCL. With a median follow-up of 10 years, 10-year progression-free survival was 36.5 per 100 with R-CHOP versus 20 with CHOP, and 10-year overall survival was 43.5 versus 27.6 per 100 (Coiffier and colleagues, 2010).

Two details matter for the reasoning. The risk of death from other diseases, from second cancers and from late relapses was the same in both arms, that is, rituximab brought no visible late toxicity. And relapses after 5 years accounted for only 7 per 100 progressions. The authors close with a sentence that sums up this post: the findings reinforce the need to treat older patients like younger ones, with curative chemotherapy.

Why a study in older patients changed practice for everyone

It is common to think that major advances come from studies in younger patients and are then adapted to older ones. In DLBCL, the path was the reverse. The study that established R-CHOP was conducted precisely in the age group where the doubt about treating with curative intent was greatest, and it showed that cure was possible. This story is a good argument for the conversation with the patient in the scene.

It is also worth noting what the study did not show. There was no excess of deaths from other causes or of second cancers with rituximab over 10 years (Coiffier and colleagues, 2010). The fear that the more complete treatment would carry a greater late cost in older patients was not confirmed in this long follow-up, which weighs in the conversation with patients and families.

The R-CHOP regimen, dose by dose

The R-CHOP arm of POLARIX describes the doses used today in 21-day cycles, for a total of 6 cycles, followed by 2 additional doses of rituximab alone (Hu and colleagues, 2025):

• rituximab 375 mg/m² intravenously on day 1;
• cyclophosphamide 750 mg/m² intravenously on day 1;
• doxorubicin 50 mg/m² intravenously on day 1;
• vincristine 1.4 mg/m² on day 1, with a maximum dose of 2 mg;
• prednisone 100 mg orally once a day, from day 1 to day 5.

In the Pola-R-CHP arm, vincristine was replaced by polatuzumab vedotin 1.8 mg/kg on day 1, and the other doses were maintained. Granulocyte colony-stimulating factor was required as primary prophylaxis for neutropenia (Song and colleagues, 2023). Always check the package insert and your service protocol.

Subcutaneous rituximab

Rituximab also exists in a subcutaneous formulation. In the MabEase study, the first dose was intravenous, 375 mg/m², and the following ones were 1,400 mg subcutaneously (Lugtenburg et al., 2017). The complete response rate at the end of induction was 50.6 per 100 with the subcutaneous route and 42.4 with the intravenous one. Grade 3 or higher adverse effects were similar, and injection site reactions were more common with the subcutaneous route, at 5.7 per 100. The switch shortens time in the infusion chair, which matters for older patients who depend on someone to bring them.

What POLARIX added

Barraclough et al. recall that for about 2 decades, several phase 3 studies tried to improve R-CHOP by adding a new drug, and failed (Barraclough et al., 2024). Stegemann et al. attribute these failures to increased toxicity, to the large share of patients who do not need more than R-CHOP and to the molecular heterogeneity of the disease (Stegemann et al., 2022).

POLARIX was the first phase 3 study to show a progression-free survival gain against R-CHOP. It included 879 patients from 22 countries with untreated DLBCL and an IPI of 2 to 5. In the 5-year update, with a median follow-up of 64.1 months, 5-year progression-free survival was 64.9 per 100 with Pola-R-CHP against 59.1 with R-CHOP, with a hazard ratio of 0.77 (Morschhauser et al., 2025). Overall survival had a hazard ratio of 0.85, without statistical significance. In the expanded population, there were 46 lymphoma-related deaths with Pola-R-CHP and 62 with R-CHOP. Long-term tolerability was similar.

Study	Patients	Comparison	Main result
NHL-98.5	399, aged 60 to 80	R-CHOP against CHOP	10-year overall survival of 43.5 against 27.6 per 100
POLARIX, 5 years	879, IPI of 2 to 5	Pola-R-CHP against R-CHOP	5-year progression-free survival of 64.9 against 59.1 per 100
POLARIX, 60 years or older	629	Pola-R-CHP against R-CHOP	Progression-free survival gain; similar overall survival
POLARIX, Asia	281	Pola-R-CHP against R-CHOP	2-year progression-free survival of 74.2 against 66.5 per 100
MabEase	576	Subcutaneous rituximab against intravenous	Complete response of 50.6 against 42.4 per 100

POLARIX in older patients

A subgroup analysis included 629 patients aged 60 or older. The progression-free survival gain appeared in all age ranges, and was greater in patients aged 70 or older, with a 37 per 100 reduction in the risk of progression, relapse or death (Hu et al., 2025). Overall survival was similar. Grade 3 or 4 adverse effects occurred in similar proportions, but grade 3 or 4 febrile neutropenia was more common with Pola-R-CHP, 16.3 against 7.6 per 100, which reinforces prophylaxis with colony-stimulating factor.

Other populations

In the Asian subpopulation, with 281 patients, 2-year progression-free survival was 74.2 per 100 with Pola-R-CHP against 66.5 with R-CHOP, and safety was comparable (Song et al., 2023). A Chinese retrospective series of 117 patients treated outside a study, almost half without criteria for POLARIX, found a complete response after 6 cycles in 80.6 per 100 of those who reached the outcome, with follow-up still short (Ren et al., 2025).

How to read these numbers

POLARIX showed fewer relapses, but not a significant difference in overall survival. Part of the explanation is that many patients who relapse after R-CHOP are still rescued with second-line therapies, such as transplant or CAR-T cells. For the patient, fewer relapses mean fewer rescue treatments, which are more toxic and expensive. The choice between the two regimens takes into account the IPI, access to the drug, prior neuropathy and patient preference. The post about lymphoma relapse covers what comes next.

Frail older patients and geriatric assessment

There are patients who do not tolerate full R-CHOP. The difference lies in how they are identified. Storti and colleagues included patients over 70 years old prospectively classified as frail by thorough geriatric assessment, and treated them with rituximab and bendamustine (Storti and colleagues, 2018). Complete response occurred in 53 out of every 100 patients, and median progression-free survival was 10 months. The authors note that in this group there is no standard treatment, and that median overall survival usually stays around 20 months even with rituximab.

These numbers show the size of the difference. A fit patient who receives R-CHOP has a good chance of cure. A frail patient who receives an adapted regimen gains disease control for a time, but rarely a cure. Classifying someone as frail without assessing them takes away their best chance.

What the geriatric assessment looks at

• Basic and instrumental activities of daily living.
• Associated diseases and their severity.
• Nutritional status and weight loss.
• Cognition and mood.
• Social support and access to the treatment center.
• Use of many medications at the same time.

In the patient in the scene, the person who cares for her grandchildren and lives alone suggests good function before the disease. Recent weight loss and fatigue point toward lymphoma, not frailty.

Care during treatment

Treating an older patient with curative intent requires attention to the details that maintain dose and interval. Neutropenia is the most predictable effect. In POLARIX, primary prophylaxis with granulocyte colony-stimulating factor was mandatory in both arms (Song and colleagues, 2023). Even so, among patients aged 60 or older, severe febrile neutropenia was more frequent with Pola-R-CHP, which shows that prophylaxis reduces the risk but does not eliminate it (Hu and colleagues, 2025).

Peripheral neuropathy is another point. Vincristine and polatuzumab can cause tingling and loss of sensation in the hands and feet. In the analysis of the older patients in POLARIX, dose reduction of polatuzumab or vincristine occurred in 5.9 out of every 100 patients with Pola-R-CHP and in 10.4 out of every 100 with R-CHOP, and discontinuation occurred in about 18 out of every 100 in both arms (Hu and colleagues, 2025). Asking about falls, difficulty buttoning clothes and constipation at every visit helps adjust before the damage sets in.

• Review the blood count before each cycle and advise the patient about fever.
• Ask about tingling, falls and constipation.
• Record anthracyclines received in the past.
• Test for hepatitis B before rituximab.

Hepatitis B and anthracyclines

The Asian subpopulation of POLARIX illustrates a practical care point. Patients with prior hepatitis B virus infection, defined by a positive total antibody, could enter the study as long as viral DNA was undetectable by PCR at screening, and this group represented about 32 to 42 out of every 100 patients in each arm (Song and colleagues, 2023). The authors highlight that neither peripheral neuropathy nor hepatitis B reactivation increased with Pola-R-CHP. The same study excluded those who had already received anthracyclines, which is a reminder that the history of previous treatments must be taken before prescribing doxorubicin.

In countries where hepatitis B is common, serology before the first cycle is part of the routine for any regimen with rituximab. The approach to a positive result should follow the service protocol, preferably with support from hepatology.

How to talk with the patient in the scene

Her question, whether treatment is worth it at her age, deserves an answer with numbers. Data from LNH-98.5 show that, in patients aged 60 to 80, treatment with R-CHOP left far more people alive at 10 years than treatment without rituximab (Coiffier and colleagues, 2010). It is worth explaining that the current symptoms come from the lymphoma, that they usually improve with the first cycle, and that the team will monitor the effects closely. It is also worth asking what matters to her: continuing to care for her grandchildren is a concrete goal, and the plan can be built around it.

The conversation needs to include logistics. Who will take her to sessions, who stays with her on the days of greatest fatigue, how she will recognize fever and whom she will call. Patients who live alone need a clear plan for the week of the lowest neutrophil count. The post about diagnostic uncertainty brings strategies for talking about risk without promising certainties.

When R-CHOP is not enough

Barraclough and colleagues recall that there are aggressive B-cell lymphomas that are not the usual DLBCL, such as high-grade lymphomas with MYC and BCL2 rearrangements and primary mediastinal lymphoma, and that these groups require their own approach (Barraclough and colleagues, 2024). That is why the biopsy must be adequate and the pathology complete before the first cycle.

Wang and Li review the mechanisms of resistance to R-CHOP, which involve the cell of origin, epigenetic alterations and signaling pathways such as the B-cell receptor, PI3K/Akt, NF-kB and JAK/STAT3 (Wang and Li, 2020). These mechanisms explain why the same regimen cures some and fails in others, and they are the basis of studies with new drugs.

Response assessment

Response at the end of treatment is assessed by PET-CT. A complete metabolic response is the best sign of cure. A partial response or progression during treatment changes the plan and calls for a quick discussion about second line. The use of PET mid-treatment is the topic of the post about interim PET in Hodgkin lymphoma, where it has a more defined role.

Risk of relapse in the central nervous system and lymphomas with MYC

A question that must be asked before the first cycle is whether the lymphoma has a risk of returning in the central nervous system. Relapse in the central nervous system is rare but serious, and it tends to be early, with a median of about 5 months. Soares and Ribeiro describe the most used index to estimate this risk, the CNS-IPI, developed by the German DSHNHL group in more than 2,000 patients treated with R-CHOP (Soares and Ribeiro, 2026). Each item is worth 1 point:

• age over 60 years;
• LDH above normal;
• ECOG of 2 or more;
• Ann Arbor stage III or IV;
• more than one extranodal site;
• kidney or adrenal involvement.

With 4 points or more, the estimated risk of relapse in the central nervous system is around 9 to 10 in every 100, against about 5 in the intermediate risk and 1 in the low risk. The authors recall other sites associated with higher risk that are not part of the index, such as testis, breast, bone marrow, pericardium and paranasal sinuses. The older woman with advanced disease, high LDH and several extranodal sites can add up points quickly, and that is why the count must be done at staging.

Prophylaxis is a field of doubt. Intrathecal methotrexate and high-dose systemic methotrexate were the most studied, but the review shows conflicting results: in a retrospective study with 2,267 high-risk patients, relapse was 8.4 in every 100 without prophylaxis and 9.1 in every 100 with high-dose methotrexate. Part of the relapses may come from occult disease already present at diagnosis, which goes unnoticed because MRI and cerebrospinal fluid examination are not done routinely at staging. The decision is individual and must weigh kidney function and frailty, which weighs heavily in the older patient.

The other clue is MYC. The so-called double-hit lymphomas have a MYC rearrangement together with a BCL2 or BCL6 rearrangement detected by FISH, and are associated with more relapse in the central nervous system. In the fifth edition of the WHO classification, cases with MYC and BCL2 rearrangement form the entity DLBCL/HGBL with MYC and BCL2 rearrangements, and cases with MYC and BCL6 without BCL2 left it and came to be classified as a subtype of DLBCL, not otherwise specified, or as HGBL, not otherwise specified (Alaggio and colleagues, 2022). The International Consensus Classification kept the category of HGBL with MYC and BCL2 and left the group with MYC and BCL6 as a provisional category (Ferry and colleagues, 2024). Double-expressor lymphoma, in turn, has overexpression of the MYC and BCL2 proteins on immunohistochemistry, without the rearrangement, and is not the same thing.

In clinical practice, this means ordering FISH for MYC and, if positive, for BCL2 and BCL6, and taking the result to the multidisciplinary meeting before assuming that R-CHOP is enough.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking for the ICD-10 code. DLBCL in the older adult is a good exercise because age speaks louder than the other clues. The post on differential diagnosis shows how to organize the clues, and the post on clinical decision-making helps you think about the weight of each one.

Three exercises with cases

Change the function. Say what changes if the patient needed help bathing before falling ill.

Change the IPI. Say whether Pola-R-CHP would make sense if the IPI were 1.

Change the pathology. Say what you would do if the biopsy showed MYC and BCL2 rearrangements.

The post on the diagnostic pause helps you avoid settling the approach on the first impression. The limits on using the game are described on the NEXO Economy page. If you research the teaching of clinical reasoning, the page for Researchers explains how to get in touch. Professionals who write or review cases find information under Curator and Creators, and institutions can learn about the proposal on the for partnerships page.

Frequently asked questions

Does age above 80 rule out R-CHOP?

Age alone does not decide. LNH-98.5 included patients up to 80 years old and showed a gain with curative treatment (Coiffier et al., 2010). Above that, the decision depends on functional and geriatric assessment.

How many cycles are given?

In POLARIX, 6 cycles of 21 days, followed by 2 doses of rituximab alone (Hu et al., 2025).

Does Pola-R-CHP replace R-CHOP for everyone?

POLARIX included patients with an IPI of 2 to 5 and showed fewer relapses, with no significant difference in overall survival at 5 years (Morschhauser et al., 2025).

Is subcutaneous rituximab equivalent?

In MabEase, response and safety were similar, with more local reactions on the subcutaneous route (Lugtenburg et al., 2017).

And the truly frail patient?

Adapted regimens, such as rituximab with bendamustine, were tested in frail patients defined by geriatric assessment (Storti et al., 2018).

Final checklist

• I confirmed the diagnosis with an adequate biopsy and complete pathology.
• I calculated the IPI.
• I separated lymphoma symptoms from baseline frailty.
• I performed or requested a geriatric assessment when there was doubt.
• I considered the prior phase with prednisone.
• I planned colony-stimulating factor prophylaxis.
• I discussed R-CHOP and Pola-R-CHP with the patient.
• I scheduled a PET-CT at the end of treatment.

Want to practice reasoning with progressive clues? Play the case of the day.

References

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