Diffuse Large B-cell Lymphoma (DLBCL) is the most frequently diagnosed type of aggressive non-Hodgkin lymphoma. The standard initial treatment is a combination chemoimmunotherapy known as R-CHOP. This regimen is highly effective, leading to a durable remission and cure for the majority of patients who receive it. While the outlook is generally positive, the possibility of the cancer returning, or recurring, remains a significant concern for a substantial minority of individuals.
Understanding the Overall Relapse Rate
The success of R-CHOP means that more than 60% to 70% of DLBCL patients are considered cured after their initial treatment. Therefore, the overall rate of relapse or primary refractory disease—cancer that never fully responds to R-CHOP—falls between 30% and 40% of all DLBCL cases.
It is important to distinguish between these two outcomes. Relapse refers to the cancer returning after a patient has achieved a complete response. Conversely, primary refractory disease describes cancer that either progresses while the patient is still on the initial R-CHOP treatment or returns very shortly after the regimen is completed. For those who achieve a complete response, most recurrences happen within the first two years following treatment.
Key Factors That Influence Relapse Risk
The general relapse rate is heavily influenced by a patient’s specific clinical and biological characteristics at the time of diagnosis. Clinicians use the International Prognostic Index (IPI) to estimate an individual patient’s risk of recurrence. The IPI assigns a score based on five factors, with higher scores correlating to a greater likelihood of the lymphoma returning.
The five factors scored are:
- Age greater than 60 years
- Ann Arbor stage III or IV disease
- Elevated serum lactate dehydrogenase (LDH) levels
- An Eastern Cooperative Oncology Group (ECOG) performance status score of two or greater
- Involvement of more than one extranodal site
Each factor present adds one point to the score, stratifying patients into distinct risk groups.
Beyond these clinical factors, the molecular subtype of the lymphoma is a major predictor of relapse risk. DLBCL is broadly categorized into two main subtypes based on the cell of origin: Germinal Center B-cell like (GCB) and Activated B-cell like (ABC). Patients with the ABC subtype generally have a substantially worse prognosis and higher risk of recurrence when treated with standard R-CHOP compared to those with the GCB subtype.
A particularly aggressive subset is known as Double-Hit Lymphoma (DHL), which accounts for about 5% to 7% of all DLBCL cases. DHL is defined by chromosomal rearrangements in the MYC gene and either the BCL2 or BCL6 gene. The concurrent disruption of these genes makes the lymphoma highly resistant to standard chemotherapy and results in a significantly elevated relapse rate and poor prognosis.
Distinguishing Early vs. Late Recurrence
The timing of recurrence is a crucial factor that impacts prognosis and subsequent treatment strategy. Recurrence is generally categorized as either early or late, with the division point typically set at 12 months following the completion of initial therapy. Early relapse, defined as the cancer returning within this first year after treatment, is associated with a significantly poorer outcome.
Patients who experience a recurrence within 12 months often have a very challenging prognosis and a low chance of long-term survival with conventional salvage treatments. Conversely, a late relapse, occurring more than one year after the end of treatment, carries a more favorable prognosis.
Late relapses are sometimes viewed as a new, chemotherapy-naive lymphoma arising from a common precursor cell, which may explain their better response to subsequent therapy. Surveillance for recurrence involves routine physical exams, blood work, and imaging scans like PET or CT scans, usually scheduled every few months for the first two to three years. If a patient remains in complete remission beyond the two-year mark, the chance of future recurrence drops considerably.
Treatment Approaches and Prognosis After Relapse
When DLBCL recurs, the treatment approach shifts to “salvage” therapy. The standard goal for patients who are medically fit and young enough is a high-dose chemotherapy regimen followed by an autologous stem cell transplant (ASCT). The high-dose chemotherapy aims to destroy the remaining cancer cells, and the ASCT restores the patient’s blood-forming cells.
For patients who respond well to the salvage chemotherapy, ASCT offers the best chance for a potential cure after relapse, with long-term survival rates estimated to be between 25% and 35%. However, many patients, particularly those who are older or have other medical conditions, may not be eligible for the intensity of high-dose therapy and ASCT. For those with primary refractory disease or an early relapse, the prognosis remains challenging.
Significant advancements have introduced new options for patients who do not respond to salvage chemotherapy or are ineligible for ASCT. CAR T-cell therapy, a form of immunotherapy where a patient’s own T-cells are genetically modified to attack the lymphoma, has become a major therapeutic option. This therapy can achieve durable remissions and cure a subset of patients who previously had few curative options. Additionally, newer targeted agents like bispecific antibodies and antibody-drug conjugates are providing effective, less intensive alternatives for those with relapsed or refractory disease.