Progress in the treatment of newly diagnosed diffuse large B-cell lymphoma

Author: This article is the author's permission Chunlan Qiugui NMT Medical publish, please do not reprint without authorization.

Diffuse large B-cell lymphoma (DLBCL) is a very heterogeneous disease.

Most patients are in the advanced stage of the disease at onset, and the standard first-line immunochemotherapy regimen R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone) can only cure about 60% of DLBCL patient.

In recent years, researchers have continuously explored and optimized first-line treatment strategies for DLBCL, hoping to further improve the cure rate of patients.

This article aims to summarize the treatment progress of newly diagnosed DLBCL patients in recent years for your reference.

The treatment of newly diagnosed DLBCL patients in the advanced stage is newly explored.
Most (about 70%) DLBCL patients are in the advanced stage at onset.

Previous studies have shown that in the era of traditional chemotherapy, the 8-cycle CHOP regimen is the first-line standard treatment regimen for DLBCL; the addition of anti-CD20 monoclonal antibody significantly prolongs the survival period of newly diagnosed DLBCL patients, thereby laying the first-line R-CHOP regimen The status of the gold standard for treatment [1].

Intensive treatment options such as R-ACVBP (rituximab combined with doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) versus R-COHP, the international prognostic index after age adjustment ( aaIPI) has a survival advantage in newly diagnosed DLBCL patients with a score of 1.

However, the accompanying increase in toxicity limits the widespread use of this regimen in clinical practice.

Strengthening the dose of chemotherapy (with or without hematopoietic stem cell transplantation) or shortening the interval between R-CHOP cycles to 14 days did not benefit newly diagnosed DLBCL patients.

In a randomized clinical study involving newly diagnosed DLBCL patients [2], DA-EPOCH-R has greater toxicity than R-CHOP, and did not improve the progression-free survival (PFS) and total of the entire cohort.
Lifetime (OS).

It is worth noting that this clinical study is under-represented for high-risk patients; post-mortem analysis showed that DA-EPOCH-R in newly diagnosed DLBCL patients with an IPI score of 3-5 points can improve PFS, but does not improve the patient’s OS .

Existing studies have shown that the DA-EPOCH-R regimen has shown encouraging effects in patients with double- or triple-hit high-grade B-cell lymphoma and patients with primary mediastinal large B-cell lymphoma.

The relevant research results of the new anti-CD20 monoclonal antibody Obinutuzumab (Otuzumab) in newly diagnosed DLBCL showed that there is no additional benefit compared with rituximab.

In addition, studies have shown that [3], compared with 6 cycles of R-CHOP treatment, 8 cycles of treatment did not bring additional clinical benefits to patients.

Therefore, the current standard treatment for newly diagnosed DLBCL in the advanced stage is 6 cycles of R-CHOP (1 cycle every 3 weeks) regimen.

In addition, the value of consolidating radiotherapy after immunochemotherapy has not been proven.

After immunochemotherapy, PET/CT is used to evaluate patients who have achieved complete metabolic remission (CMR) without radiotherapy.

In some patients with no signs of disease progression, PET/CT assessment shows residual positive lesions, and the lesion site is suitable for radiotherapy, you can consider combining radiotherapy after the end of immunochemotherapy.

New exploration of targeted therapy based on R-CHOP In recent years, people have conducted in-depth studies on the biological heterogeneity of DLBCL, suggesting that targeted drugs may only benefit some subgroups of DLBCL patients.
Therefore, patients should be treated before adding targeted drugs.
Perform biomarker evaluation.

At present, several large randomized clinical trials have evaluated the efficacy and safety of adding new drugs on the basis of R-CHOP.

The results of a study showed that the addition of the proteasome inhibitor bortezomib on the basis of R-CHOP could not benefit newly diagnosed DLBCL patients [4].

Based on the R-CHOP protocol, the Phase III study of Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib showed that [5], in the non-germinal center (non-GCB) subtype (by the immune group (Chemical determination) In DLBCL patients, the clinical outcome of the intention-to-treat population cannot be improved; however, a subgroup analysis shows that R-CHOP combined with ibrutinib has a survival benefit in patients under 60 years of age.

A randomized phase II clinical trial [6] evaluated the efficacy of adding lenalidomide (R2-CHOP) on the basis of R-CHOP in newly diagnosed DLBCL patients, and the results showed that it can improve patients' PFS and OS.

However, the results of phase III clinical trials in DLBCL patients with activated B-cell-like (ABC) subtypes (determined by gene expression profiles) showed that R2-CHOP does not benefit patients compared with R-CHOP [7].

In addition, several phase III clinical trials are designed to evaluate whether the new drug maintenance treatment after R-CHOP treatment can benefit newly diagnosed DLBCL; the drugs studied include rituximab, Enzastaurin, everolimus or lenalidomide Etc.
, the results showed that none of the patients' survival conditions were improved [1].

However, in the context of many limitations of clinical research, the negative results in recent clinical trials should be interpreted with caution.

In order to maximize the possibility of successful clinical trials of new drugs, future trials need to be more targeted.

Therefore, outside of clinical trials, regardless of the immunohistochemical classification and molecular subtype of newly diagnosed DLBCL patients, R-CHOP is still the standard treatment for newly diagnosed DLBCL.

Treatment progress of patients with limited-stage DLBCL patients with limited-stage DLBCL accounts for about 30% of newly diagnosed DLBCL patients, and are usually defined as stage I or II patients with non-large masses and no systemic symptoms.

Limited-stage patients usually have good clinical outcomes.

Prior to the application of rituximab, the standard treatment for patients with limited-stage newly diagnosed DLBCL included 3 cycles of CHOP and involved field radiotherapy (ISRT); compared with 8 cycles of CHOP, the former increased the patient’s OS rate [8 ].

However, with longer follow-up, due to late recurrence and the occurrence of second malignant tumors related to radiotherapy, the survival advantage of the 3-cycle CHOP combined with ISRT treatment mode is gradually lost.

In general, the 5-year OS rate for patients with limited initial DLBCL diagnosis is 85%-95%; recent clinical research focuses on limiting the number of cycles of chemotherapy or omitting radiotherapy to reduce the long-term side effects of patients.

The results of a randomized clinical trial have confirmed [9] that for newly diagnosed limited-stage non-large-mass DLBCL patients ≤60 years old with Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and normal lactate dehydrogenase levels , 4 cycles of R-CHOP treatment can be used alone, without additional radiotherapy and more cycles of treatment.

In a phase III clinical trial [10], among newly diagnosed patients with limited-stage DLBCL, patients who achieved complete metabolic remission (CMR) assessed by PET/CT after 4 cycles of R-CHOP did not benefit from radiotherapy.

The results of a phase II clinical trial showed that [11], newly diagnosed patients with limited-stage DLBCL can achieve CMR after only 3 cycles of R-CHOP treatment, using PET/CT assessment.

For limited-stage patients with positive mid-term PET/CT assessments or high IPI scores or high-risk biological characteristics with high-risk biological characteristics, recent clinical trials have hardly covered them, so there is currently no suitable treatment.

The treatment progress of newly diagnosed DLBCL patients who cannot tolerate standard therapies Approximately 20%-25% of newly diagnosed DLBCL patients cannot tolerate standard first-line treatment (such as R-CHOP), mainly due to advanced age and comorbidities.

For patients with good physical status at baseline, if their poor functional status is caused by lymphoma, standard treatment can still be considered.

A comprehensive evaluation or functional test of elderly patients in advance may help determine the best induction treatment plan for such patients.

For newly diagnosed DLBCL patients who cannot tolerate standard therapies, a reduced dose of R-CHOP, such as R-mini-CHOP, is recommended.

In addition, short-term glucocorticoids with or without vincristine before treatment may improve treatment-related side effects.

For newly diagnosed DLBCL patients with contraindications to anthracyclines, the use of gemcitabine or etoposide as a replacement may achieve satisfactory results [12-13].

Central nervous system (CNS) prevention in DLBCL patients The incidence of central nervous system (CNS) recurrence in DLBCL patients is 3% to 5%; and the prognosis of patients with CNS recurrence is extremely poor, with a median OS of less than 6 months.

In addition, CNS recurrence in DLBCL patients usually occurs early after the end of first-line treatment, suggesting that there may be occult CNS involvement at the time of diagnosis.

The CNS-IPI risk model [14] includes five IPI risk factors and whether there is renal or adrenal involvement.
Patients are divided into different risk categories.
The high-risk group of CNS recurrence accounts for 12% of patients.
This group of patients has CNS.
The risk of recurrence is 10%-12%.

In addition, other factors may also increase the risk of CNS recurrence in DLBCL patients, including ABC subtypes, dual expression of MYC and BCL2, and testicular involvement at the time of diagnosis.

In newly diagnosed DLBCL patients, the use of drugs that can penetrate the blood-brain barrier for systemic CNS prevention is still controversial; in addition, the role of intrathecal chemotherapy in preventing CNS is also controversial.

References 1.
Laurie H.
Sehn, and Gilles Salles.
Diffuse Large B-Cell Lymphoma.
N Engl J Med 2021;384:842-58.
2.
Bartlett NL, Wilson WH, Jung SH,et al.
Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: clinical outcomes of the phase III Intergroup Trial Alliance/CALGB 50303.
J Clin Oncol 2019;37:1790-9.
3.
Pfreundschuh M, Schubert J, Ziepert M,et al.
Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60).
Lancet Oncol2008;9:105-16.
4.
Davies A, Cummin TE, Barrans S, et al.
Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial.
Lancet Oncol 2019;20:649 -62.
5.
Younes A, Sehn LH,Johnson P, et al.
Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma.
J Clin Oncol 2019;37:1285-95.
6.
Nowakowski GS, Hong F, Scott DW,et al.
Addition of lenalidomide to R-CHOP improves outcomes in newly diagnosed diffuse large B-cell lymphoma in a randomized phase II US Intergroup study ECOG-ACRIN E1412.
J Clin Oncol 2021 February 8 (Epub ahead of print).
7.
Nowakowski GS, Chiappella A, Gascoyne R, et al.
ROBUST: a phase III study of lenalidomide plus R-CHOP versus placebo plus R-CHOP in previously untreated patients with ABC-type diffuse large B-cell lymphoma.
J Clin Oncol (in press).
8.
Miller TP, Dahlberg S, Cassady JR, et al.
Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade nonHodgkin's lymphoma.
N Engl J Med 1998;339:21-6.
9.
Poeschel V, Held G, Ziepert M, et al.
Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3,non-inferiority trial.
Lancet 2019;394:2271-81.
10.
Lamy T, Damaj G, Soubeyran P, et al.
R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma.
Blood 2018;131:174-81.
11.
Persky DO, Li H, Stephens DM, et al.
Positron emission tomography-directed therapy for patients with limited-stage diffuse large B-cell lymphoma: results of Intergroup National Clinical Trials Network Study S1001.
J Clin Oncol 2020;38:3003-11.
12.
Fields PA,Townsend W, Webb A, et al.
De novo treatment of diffuse large B-cell lymphoma with rituximab, cyclophosphamide, vincristine, gemcitabine, and prednisolone in patients with cardiac comorbidity: a United Kingdom National Cancer Research Institute trial.
J Clin Oncol 2014; 32:282-7.
13.
Moccia AA, Schaff K, Freeman C, et al.
Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines.
Blood Adv (in press).
14.
Schmitz N , Zeynalova S, Nickelsen M,et al.
CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP.
J Clin Oncol 2016;34:3150-6.
Poke" read Original ", we make progress togetherand prednisolone in patients with cardiac comorbidity: a United Kingdom National Cancer Research Institute trial.
J Clin Oncol 2014;32:282-7.
13.
Moccia AA, Schaff K, Freeman C, et al.
Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines.
Blood Adv (in press).
14.
Schmitz N, Zeynalova S, Nickelsen M,et al.
CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B- cell lymphoma treated with R-CHOP.
J Clin Oncol 2016;34:3150-6.
Poke "read the original text", we make progress togetherand prednisolone in patients with cardiac comorbidity: a United Kingdom National Cancer Research Institute trial.
J Clin Oncol 2014;32:282-7.
13.
Moccia AA, Schaff K, Freeman C, et al.
Long-term outcomes of R-CEOP show curative potential in patients with DLBCL and a contraindication to anthracyclines.
Blood Adv (in press).
14.
Schmitz N, Zeynalova S, Nickelsen M,et al.
CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B- cell lymphoma treated with R-CHOP.
J Clin Oncol 2016;34:3150-6.
Poke "read the original text", we make progress together14.
Schmitz N, Zeynalova S, Nickelsen M,et al.
CNS International Prognostic Index:a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP.
J Clin Oncol 2016;34:3150-6 .
Poke "read the original text", we make progress together14.
Schmitz N, Zeynalova S, Nickelsen M,et al.
CNS International Prognostic Index:a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP.
J Clin Oncol 2016;34:3150-6 .
Poke "read the original text", we make progress together