NEJM review: diffuse large B-cell lymphoma (pictured: new drugs, treatment processes, prognosis, molecular division)

It is estimated that there are approximately 150,000 new cases of large B-cell lymphoma each year in the world.

Patients usually present with progressive lymphadenopathy, extra-lymph node lesions, or both, and most of them are in advanced stages at the time of treatment.

In the past 20 years, we have gained in-depth understanding of the epidemiology, prognostic factors, and biological heterogeneity of large B-cell lymphoma, improved the classification of diseases, and developed new therapies.

"New England Journal of Medicine" (NEJM) yesterday published a review "Diffuse large B-cell lymphoma" (Sehn LH, Salles G.
Diffuse large B-cell lymphoma.
N Engl J Med 2021;384:842-858.
), we In this introduction review the prognostic factors and treatment methods of diffuse large B-cell lymphoma (DLBCL).

For other content, such as pathological features and molecular classification, please visit NEJM Medical Frontiers official website, APP or WeChat applet to read the full text translation.

Figure 1.
Outcome, risk factors and biological characteristics of diffuse large B-cell lymphoma (DLBCL).
The diagnosis of large B-cell lymphoma depends on a detailed examination of the tumor tissue.
It is best to have a hematological pathologist on the excised biopsy specimen to evaluate.

In addition to morphological features, the accurate classification of lymphoma requires special tests, including immunohistochemistry, flow cytometry, fluorescence in situ hybridization (FISH), and molecular testing.

Fine needle aspiration biopsy specimens are not sufficient for pathological evaluation.

Although coarse needle biopsy specimens are commonly used, they are often insufficient for a complete evaluation, and coarse needle biopsy should only be performed if resection biopsy is not feasible.

Table 1.
According to the World Health Organization (WHO) classification, the pathological and clinical characteristics of large B-cell lymphoma.
The data in this table is based on the latest WHO classification. For most other large B-lymphomas marked as "rare", it is strongly recommended that a hematology pathologist with expertise in lymphoma be diagnosed and treated.

Table 2.
Biological factors related to the outcome of DLBCL patients.
Detailed analysis of molecular aberrations (including gene mutations and increase or decrease in copy number) prompted us to propose a new classification of DLBCL, which resulted in cells beyond the origin, according to the genetic definition Unique subtypes (Figure 1C).

The median age of patients with DLBCL at diagnosis is about 65 years old; 30% of patients are >75 years old.

Although we do not believe that DLBCL is a genetic disease, and there is currently no screening method, genome-wide association studies have discovered multiple genetic susceptibility sites, involving pathways related to immune function.

Staging and response assessment The grading and response assessment should be carried out in accordance with the Ann Arbor staging and Lugano classification criteria.

In recent years, PET-CT has replaced CT due to its high sensitivity.

The total metabolic tumor volume at diagnosis may have prognostic significance.

The staged bone marrow biopsy results of 15%-20% of cases are positive, and when there are consistent large B cells, the above-mentioned positive results are related to poor prognosis.

For patients who have received PET-CT staging, bone marrow biopsy is no longer a necessary examination item, but small-volume lesions or mixed indolent lymphoma (not changing the outcome) are occasionally missed.

The assessment of response at the end of treatment is best performed by PET-CT, interpreted according to the Deauville five-point scale, and the mediastinal and liver uptake as a reference score.

A score of 1 or 2, and possibly a score of 3 can be considered as a complete metabolic response.

Evaluation of response during treatment can use CT to detect non-response or disease progression.

Studies evaluating the significance of mid-term PET-CT have yielded conflicting results, but PET-CT after 2 to 4 cycles of treatment seems to have prognostic significance, especially when quantitative methods are used to assess response.

However, only adjusting the treatment plan based on the mid-term PET-CT results did not change the outcome, so it is not recommended to do this outside of clinical trials.

Recently, circulating tumor DNA has been shown to be a tool for mid-term response assessment.

Prognostic factors The International Prognostic Index (IPI) is still the main clinical tool for predicting outcomes and stratifying patients in clinical trials.

IPI has been validated and improved in modern times, and the National Comprehensive Cancer Network IPI (NCCN-IPI) can better distinguish high-risk patients (Table 3).

However, these clinical indicators cannot identify extremely high-risk patients, nor can they identify biological heterogeneity.

Many biological factors are related to the outcome (Table 2).

But they have not yet been included in the validated prognostic index.

Table 3.
Clinical indicators that can predict the outcome of DLBCL patients.
Main treatment options.
Advanced disease DLBCL depends on systemic treatment.

Most patients (approximately 70%) are in the advanced stage when they see a doctor, and 8 cycles of CHOP have been identified as the preferred chemotherapy regimen.

The addition of the anti-CD20 monoclonal antibody rituximab significantly prolonged overall survival.

In patients with an age-adjusted IPI score of 1 (the score ranges from 0 to 3 points, higher scores indicate greater risk), rituximab combined with doxorubicin, cyclophosphamide, vindesine, and bolite The dose-enhanced regimen of R-ACVBP and prednisone is the only regimen that has a survival advantage compared to R-CHOP.

However, clinically significant toxicity limits the application of the R-ACVBP regimen.

Although patients with double-strike or triple-strike high-grade B-cell lymphoma and patients with primary mediastinal B-cell lymphoma have received encouraging results after DA-EPOCH-R treatment, DA-EPOCH-R is used in patients with high-risk DLBCL It is still experimental.

Research conducted on the anti-CD20 monoclonal antibody obinutuzumab (obinutuzumab) shows that it has no additional benefits compared to rituximab.

This study shows that compared with 6 cycles, 8 cycles of CHOP treatment has no additional significance, thus confirming that once every 3 weeks, a total of 6 cycles of R-CHOP treatment is the standard treatment.

The significance of consolidation radiotherapy after immunochemotherapy has not been confirmed.

Patients who showed a complete metabolic response on PET-CT after treatment had good outcomes without radiotherapy.

Patients with a positive PET-CT test result may receive biopsy and further systemic treatment.
For some patients with no evidence of disease progression and residual positive lesions on PET-CT, consolidation radiotherapy may be considered when radiotherapy is suitable.
.

In view of the biological heterogeneity of DLBCL, targeted drugs may only be beneficial to specific patient subgroups, so biomarker evaluation is required.

Several large-scale randomized trials have evaluated the effects of adding new drugs to R-CHOP.

However, the addition of the proteasome inhibitor bortezomib did not show any benefit, and the results of the addition of the Bruton tyrosine kinase inhibitor ibrutinib were mixed.

A phase 3 trial compared the effects of Ibritinib combined with R-CHOP therapy and R-CHOP therapy alone in non-GCB DLBCL patients (selected based on immunohistochemical test results).
The results showed that in the intention-to-treat population, two There was no significant difference in group outcomes, but the secondary analysis suggested that for patients under 60 years of age, the addition of ibrutinib had a survival benefit; the toxic effects on elderly patients hindered the application of R-CHOP.

A randomized phase 2 trial evaluated the effect of R-CHOP plus Nalidomide (R2-CHOP) in unselected patients.
The results suggested that progression-free survival and overall survival were prolonged, but included ABC subtype DLBCL The definitive phase 3 trial in patients showed that lenalidomide had no additional significance.

Several phase 3 trials have shown that maintenance therapy with rituximab, enzastaurin, everolimus or lenalidomide after R-CHOP treatment has no survival benefit.

Outside of clinical trials, R-CHOP has been commonly used as the standard treatment for diffuse large B-cell lymphoma (regardless of its immunohistochemical characteristics or molecular subtypes).

However, many limitations of the negative results of recent tests should be considered when interpreting them.

Delays in treatment due to the detection of biomarkers may lead to selection bias, so the number of high-risk patients who need immediate treatment is small, which limits the statistical power of the detection of benefits.

Most importantly, despite the enrichment of cells of origin, the molecular complexity of DLBCL leads to biological heterogeneity, which may limit the ability to detect benefits in various patient subgroups.

Future trials need to adopt adaptive design to increase the probability of success.

Approximately 30% of patients with limited-stage disease are in limited-stage disease at the time of presentation.
The definition is usually stage I or stage II disease with no large masses (largest mass, <7.
5-10 cm), anatomically limited lesions and no systemic symptoms.

These patients often have low-risk clinical features and good outcomes, but long-term recurrence patterns have been found.

Prior to the successful development of rituximab, standard treatment included 3 cycles of CHOP and radiotherapy to the affected area, because the above-mentioned regimen can prolong overall survival compared with 8 cycles of CHOP.

However, the above advantages are lost after longer follow-up due to long-term recurrence and a second cancer that is likely to be related to radiotherapy.
Therefore, it suggests that chemotherapy alone may be an appropriate option.

The 5-year overall survival rate of patients with limited-stage disease is in the range of 85% to 95%.
Recent research focuses on limiting the number of chemotherapy cycles or omitting radiotherapy.

About 20% to 25% of patients whose standard treatment is not feasible are not suitable for standard first-line treatment (such as R-CHOP) because of age-related poor health, comorbidities, or cardiac dysfunction.

The baseline performance status score is good, but patients whose functional status is impaired by lymphoma may be considered for standard treatment.

A comprehensive evaluation or simple functional examination of elderly patients may help identify patients who need an improved regimen.

For these patients, reduced-dose R-CHOP (such as R-mini-CHOP) can be used for treatment for the purpose of curing the disease.

Short-term early glucocorticoid therapy (with or without vincristine) may improve treatment-related side effects.

In patients with contraindications to anthracyclines, the use of gemcitabine or etoposide to replace anthracyclines may achieve satisfactory results, while clinical trials of other anthracyclines or cardioprotective drugs have not been satisfactory.
Convincing evidence of safety or efficacy.

Central nervous system disease prevention occurs in 3% to 5% of patients.
The recurrence of central nervous system (CNS) disease is extremely devastating.
The median overall survival of such patients is less than 6 months.

CNS recurrence often appears early after the treatment ends, suggesting that there has been occult central nervous system disease at the time of diagnosis.

The CNS-IPI risk model includes 5 IPI risk factors and renal or adrenal involvement.
12% of patients have a high risk of CNS recurrence.

There are other factors that may increase the above risk, including ABC subtypes, dual expression of MYC and BCL2, and testicular involvement at the time of consultation.

The use of systemic drugs that can enter the CNS for CNS prevention has not yet been proven and is controversial.

For DLBCL patients, preventive chemotherapy through intrathecal administration is no longer recommended.

Treatment of relapsed or refractory disease.
Among patients receiving R-CHOP treatment, about 10% to 15% of patients have primary refractory disease (that is, incomplete remission or relapse within 6 months after receiving treatment).
Another 20% to 25% of patients relapse after initial remission, usually within 2 years.

For patients who have failed first-line treatment, especially those with refractory diseases (their median overall survival is about 6 months), the outcome is still poor.

Patients with long-term recurrence (>2 years after treatment) have a slightly better outcome, but indolent lymphoma may recur, which highlights the need for repeated biopsy.

Patients eligible for transplantation For patients with chemotherapy-sensitive, relapsed or refractory diseases, high-dose chemotherapy and autologous stem cell transplantation (ASCT) are the best opportunities to cure the disease, but due to advanced age and comorbidities, only half of the patients are suitable for transplantation treatment.

In randomized trials, platinum rescue programs are commonly used (rituximab combined with dexamethasone, high-dose cytarabine and cisplatin [R-DHAP], rituximab combined with ifosfamide, carboplatin And etoposide [R-ICE], rituximab combined with gemcitabine, dexamethasone and cisplatin [R-GDP]) have similar effects.

About 50% of patients achieved remission after receiving the initial rescue plan, and then received ASCT treatment, the total cure rate was 25% to 35%.

Allogeneic transplantation may also cure the disease, but the benefits of the graft's anti-tumor effect are offset by higher treatment-related mortality.

Patients who are not eligible for transplantation are not suitable for ASCT treatment (patients with poor health or comorbidities due to age), patients without remission after salvage treatment, and patients who relapse after ASCT treatment are classified as not eligible for transplantation condition.

Most patients with relapsed or refractory DLBCL are eventually classified into this category, sequential single-agent chemotherapy or multi-drug treatment with acceptable side effects (such as rituximab, gemcitabine, and oxaliplatin [R-GemOx] ) Is often used in palliative care.

However, compared with traditional therapies, the continuous listing of new drugs (including CAR T cell therapies) provides alternative therapies that have the potential to control the disease for a long time and have obvious survival advantages.

CAR T cell therapy CAR T cell therapy is a genetically modified cell therapy that represents a major shift in the paradigm of treatment for relapsed or refractory DLBCL.

The first approved product uses autologous T cells that target CD19.

In key trials, for patients with relapsed or refractory aggressive B-cell lymphoma, the related total remission rate and complete remission rate of axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel ranged from 52% to 82% and 40% to 54%, respectively Inside (Table 4).

The latest follow-up results of the key study of axicabtagene ciloleucel showed that 37% of patients remained in complete remission at a median follow-up of 27 months.

However, due to the selection of patients, the outcome report may be optimistic.

These CAR T-cell products have been approved by regulatory agencies and can be used in patients with relapsed or refractory aggressive B-cell lymphoma who have received at least second-line systemic therapy.
In addition, randomized studies are evaluating the possibility of using CAR T-cell therapy to replace ASCT.
.

CAR T cell therapy has obvious toxicity, and its application is still limited by the following factors: potential toxic effects, insufficient overtreatment of patients with rapid disease progression, patients requiring special treatment, and economic considerations.
Cost-benefit analysis shows that CAR T therapy has some advantages Clinical facilities may not be feasible.

Ongoing research and development (including evaluating the structure of other targets or multi-targets and allogeneic "off-the-shelf" products) may increase patient options in the future.

Table 4.
Some DLBCL treatment drugs under development** The table lists the results of early clinical trials conducted in patients with relapsed or refractory DLBCL.

New therapies Although CAR T cell therapy has made progress, relapsed or refractory DLBCL still needs new therapies.

A variety of drugs are being evaluated.
Table 4 lists some of the drugs of concern.

Antibody-drug conjugates can selectively deliver cytotoxic drugs to tumor cells through targeting antibodies.

Polatuzumab vedotin is an antibody-drug conjugate that targets CD79b (part of the B cell receptor complex).

The combination of polatuzumab vedotin and bendamustine-rituximab has been approved by regulatory agencies, based on the randomized phase 2 trial of patients who are not eligible for transplantation, compared with the use of bendamustine alone- Compared with rituximab, the complete metabolic response rate, progression-free survival rate and overall survival rate of the combination treatment group were significantly improved.

A phase 3 trial evaluated whether polatuzumab vedotin can be used to replace vincristine in R-CHOP in previously untreated patients.
The trial has been completed and the results have not yet been announced.

Other antibody-drug conjugates are undergoing clinical evaluation.

selinexor is a selective inhibitor of nuclear export protein XPO1, which can accumulate tumor suppressor protein in the nucleus.
The drug has also been approved by regulatory agencies and can be used in patients with relapsed or refractory DLBCL who have received at least two-line treatment.
It is the result of a phase 2 trial (monotherapy has certain activity).

Tafasitamab is a humanized anti-CD19 monoclonal antibody, and the benefit of monotherapy is small, but the results of the phase 2 study of tafasitamab + lenalidomide combination therapy have shown efficacy.
Therefore, the drug has been approved by the regulatory agency and can be used for non-compliant transplants.
Conditional DLBCL patients.

Since this drug has the same target as the CD19-directed CAR T cell therapy, it is necessary to evaluate the appropriate sequence of the above treatment options.

Various other immunotherapies are under investigation.

Although PD-1 inhibitors are effective for primary mediastinal B-cell lymphoma, they are not beneficial for DLBCL patients85.

magrolimab is a macrophage immune checkpoint inhibitor that can block the "don't eat me" molecule CD47.
This drug seems to work synergistically with rituximab to enhance the phagocytic function of macrophages, and has been shown in early clinical trials An encouraging activity.

Bispecific antibodies target tumor cells and antigens on T cells, thereby inducing T cell activation and producing cell-mediated cytotoxicity.

Bispecific antibodies have shown potential in relapsed or refractory DLBCL, and we have observed durable remissions.

Blinatumomab is a bispecific T cell engager for CD3 and CD19, and it is active on DLBCL, but the development of this drug is hindered by continuous infusion protocols and related neurotoxicity.

Several full-length bispecific antibodies against CD3 and CD20 are under development.
They have a longer half-life and can be administered once every 3 to 4 weeks, and may be administered subcutaneously.

The results of an ongoing phase 1-1b study of mosunetuzumab indicate that patients with relapsed or refractory DLBCL (including patients who have failed CAR T therapy) have achieved promising remission rates and observed durable remissions.

Other drugs targeting CD3 and CD20 that are under development and have shown initial efficacy include glofitamab, odronextamab and epcoritamab.

Targeting apoptosis (BCL2 inhibitor venetoclax), B cell receptor pathway (Bruton tyrosine kinase inhibitors ibrutinib and lenalidomide) and epigenetic regulators (EZH2 inhibitors) Other drugs of tazemetostat have shown limited single-agent therapeutic activity and are currently being studied in a variety of combination treatment options.

Figure 2.
The treatment process of large B-cell lymphoma.
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