June 29, 2022

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BLOOD reviews: Primary mediastinal large B-cell lymphoma

BLOOD reviews: Primary mediastinal large B-cell lymphoma



BLOOD reviews: Primary mediastinal large B-cell lymphoma.  PMBCL can also invade the CNS when it recurs.

Recently, a review of “BLOOD” just published, titled “Primary mediastinal Large B-cell Lymphoma”. In this article, the author analyzes the unique pathogenesis of primary mediastinal large B-cell lymphoma and shows detailed treatment strategies.


Epidemiological and clinical characteristics

Primary mediastinal (thymus) large B-cell lymphoma (PMBCL) accounts for about 2-4% of non-Hodgkin’s lymphoma and 10% of large B-cell lymphoma. It mostly occurs in young adults and women, with a median age of 35 years. , The ratio of male to female is 1:2. The clinical manifestations are usually local compression symptoms caused by a huge anterior mediastinum mass, including dyspnea, coughing, dysphagia, and superior vena cava syndrome (incidence up to 50%).

PMBCL is usually diagnosed as stage I or II, but it may invade the lungs and/or chest wall, or be accompanied by pleural/pericardial effusion (often associated with poor prognosis of the patient). In addition, about 10% of patients may be accompanied by extrathoracic lesions, including rare invasion of the kidney or adrenal glands, but the main lesion is still the anterior mediastinum.

In addition, PMBCL can also invade the CNS when it relapses.


Pathology and immunophenotype

The typical pathological manifestation of PMBCL is diffuse hyperplasia of large B cells, which can be classified according to bands of sclerosis, as shown in the figure.

BLOOD reviews: Primary mediastinal large B-cell lymphoma.  PMBCL can also invade the CNS when it recurs.

In addition, PMBCL can have a wide range of morphological/cytological characteristics, the size and shape of tumor cells are variable, and multi-splitting cells similar to Hodgkin R-S cells (Reed-Sternberg cells, HRS) can also be seen.

It should be noted that due to the location of PMBCL tumor cells and the small biopsy sample accompanied by crush artefact, the diagnosis may be difficult.

When dividing fibrosis examination, PMBCL may be misdiagnosed as cancer or thymoma, so sufficient samples must be obtained for immunohistochemical examination. In addition, PMBCL needs to be distinguished from nodular sclerosis classical Hodgkin lymphoma (NScHL). and DLBCL with secondary mediastinal infiltration. In some cases, hollow needle biopsy is not sufficient to distinguish PMBCL from mediastinal gray zone lymphoma (MGZL), so a larger biopsy is required.

In addition to expressing the common leukocyte antigen CD45, PMBCL can also express B-cell antigens CD19, CD20, CD22, etc. (see the figure above and the table below), but unlike other B-cell lymphomas, PMBCL tumor cells often lack surface or cytoplasmic immune spheres Protein (Ig), but can express the Ig co-receptor CD79a. Generally, the expression of CD10 and CD21 is negative, but most patients have the MUM1/IRF4+ phenotype and the expression of BCL6 is inconsistent. About 30% of patients are positive for CD30, but the expression is generally weak and heterogeneous (see the figure above, the table below), and CD15 is not expressed.

The expression of CD200, CD23 and MAL (lipid raft assembly), as well as TRAF1 and nuclear cREL are the characteristics of PMBCL, and the latter two are also the focus of distinguishing DLBCL. The assumed origin of PMBCL is thymic bone marrow B cells, and its phenotype and MAL expression characteristics are similar to DLBCL. The current commercial MAL antibody has a specificity of 100%, and its expression in PMBCL and DLBCL is 72% and 0%, respectively. And better than CD200 (specificity 87%).

BLOOD reviews: Primary mediastinal large B-cell lymphoma.  PMBCL can also invade the CNS when it recurs.

The abnormalities associated with 9p24.1 in PMBCL cells are the expression of PDL1 (B7-H1) and PDL2, the latter of which is more specific because PDL1 is also expressed in tumor-associated macrophages.

It should be noted that the WHO classification of GZL as B-cell lymphoma cannot be classified, and its characteristics are between DLBCL and cHL. 60-70% of GZL has mediastinal infiltration (MGZL). If the tumor’s gene and/or phenotype exists The overlap of cHL and PMBCL is diagnosed as MGZL (see table above).

The unique molecular characteristics and pathogenesis of PMBCL, etc., slightly


Treatment of PMBCL

BLOOD reviews: Primary mediastinal large B-cell lymphoma.  PMBCL can also invade the CNS when it recurs.

First-line treatment of PMBCL

There is no randomized controlled study on the best first-line treatment of PMBCL, so there are differences in the existing international treatment guidelines.

BLOOD reviews: Primary mediastinal large B-cell lymphoma.  PMBCL can also invade the CNS when it recurs.

The current data mostly come from non-random prospective studies and retrospective studies, and there are selection biases. In addition, the diagnosis of PMBCL is a clinicopathological diagnosis, so the diagnosis will inevitably affect the results of research comparisons. The problem is that there are few studies that use the gold standard of molecular diagnosis.

In addition, patients with PMBCL are generally younger, so it is necessary to balance the relationship between cure and potential long-term toxicity (such as secondary tumors, cardiovascular complications), which is also an important part of the treatment of PMBCL that needs to be considered.

Most current studies support the addition of rituximab to CHOP/CHOP-like chemotherapy as the first-line treatment of PMBCL, and it is believed that its clinical benefit is the same as that of DLBCL. However, a study does not clearly support the above conclusions. The R-MACOPB or VACOP regimen was used in the study (69% of patients received radiotherapy at the same time), and the results were similar to the V/MACOPB+RT historical control (see Table 2).

In contrast, another study showed that R-VACOPB had PFS improvement compared with VACOPB (P=0.06) but no OS benefit (P=0.2). In addition, some studies believe that the PFS of R-VACOPB is similar to R-CHOP (P=0.3), indicating that rituximab may reduce the benefits of dose enhancement to a certain extent.

The problem is that the number of cases in the above studies is small, so none of them are authoritative conclusions.

In general, the 2-year PFS rate of R-CHOP or R-CHOP-like regimens in most analyses is about 80%, and the 2-year OS rate is about 90%. However, most studies have routinely performed mediastinal radiotherapy, especially when using the CHOP regimen (see Table 2), which may bring long-term secondary complications.

The DA-EPOCHR regimen can be used to treat aggressive lymphomas to overcome drug resistance. Compared with the CHOP regimen, it has 3 major modifications: 1. Etoposide is added to increase activity and synergy. 2. Etoposide, vincristine and poly In vitro studies of continuous infusion of rubicin believe that it can reduce drug resistance. 3. Individual dose adjustments can be made according to the lowest value of neutrophils in the previous cycle (under growth factor support therapy).

In the phase 2 NCI study, 51 patients with PMBCL were enrolled. The DA-EPOCHR regimen had a significant effect. The 5-year EFS and OS were 93% and 97%, respectively, and only 2 patients received radiotherapy (see Table 2). In addition, the same report also retrospectively analyzed 16 patients treated with DA-EPOCHR, and they were still disease-free and alive at the time of analysis.

The largest retrospective study on DA-EPOCHR for PMBCL (see Table 2) analyzed a total of 156 patients, most of which (118 cases) were adults, and the 3-year EFS and OS rates for all patients were 86% and 95%, respectively. Among them, the 5-year EFS and OS rates for adults ≥21 years old were 87.4% and 97%, and 16% received mediastinal radiotherapy; the 3-year EFS rates for children and adults were 81% and 97% (P=0.34) There is no statistical difference, but children are more likely to upgrade to dose level 4 and above than adults (54% vs 33%, P=0.03). The author believes that DA-EPOCHR can be used as an option for patients with PMBCL of all ages.

However, contrary to the above study, a phase 2 study published on ASH in 2017 concluded that when almost half of patients received a dose ≥ 4 treatment, the two-year EFS and OS were only 69% and 82%. 40% of the patients in this study received COP (cyclophosphamide, vincristine, prednisone) treatment 1 week before the study, and multivariate analysis found that extrathoracic lesions were associated with poor prognosis.

The phase 3 CALGB 50303 study (see Table 2) compared DA-EPOCHR and R-CHOP in newly diagnosed DLBCL patients (including morphological subtypes and PMBCL), but did not show the benefit of the enhanced regimen in 35 patients with PMBCL : The PFS of the two regimens are similar, DA-EPOCHR2/15 (13%) vs R-CHOP 3/20 (15%). None of the patients were treated with radiotherapy, but the important thing is that there is no subgroup analysis in the design of this study, so the overall The result cannot be applied to PMBCL.

At present, there are many studies comparing DA-EPOCHR and R-CHOP (general combined radiotherapy), but only some studies in PMBCL have confirmed its advantages, while others show no difference. In addition, the inclusion criteria of each scheme are different and the statistical power is insufficient .

In addition, safety is also a factor that needs to be considered. For example, the DA-EPOCHR regimen in the CALGB 50303 study increased the dose, and at the same time increased acute hematological toxicity compared with R-CHOP, including neutropenic fever (35% vs 18% , P<.001), and non-hematological toxicity is also higher, including grade 3/4 neurotoxicity (10.8% vs 3.3%). In another study, 40% of lymphoma patients treated with DA-EPOCHR had central venous catheter complications, including overflow. It is for this reason that the author supports the use of PICC catheters.

Overall, the 2-year PFS and OS rates of the DA-EPOCHR regimen in the treatment of adult PMBCL were 81-93% and 92-97%, respectively (see Table 2). Although there is a lack of cross-controlled studies, the DA-EPOCHR program is still reliable for a considerable number of patients (especially patients with aggressive manifestations, including patients with advanced extrathoracic infiltration).

Application of radiotherapy consolidation and PET scanning in PMBCL

Consolidation of mediastinal radiotherapy is still a commonly used strategy after R-CHOP treatment, but its impact on the recurrence rate or OS is still unclear, especially for patients who have already obtained CR. In addition, the current retrospective study results are contradictory. For example, in the SEER study, 250 patients with stage 1/2 PMBCL diagnosed from 2001 to 2012, the 5-year OS result was that radiotherapy was better than non-radiotherapy (90% vs 79%, P= 0.029), but there is a lack of treatment and remission data in this study, and the FDA only approved rituximab in 2006, and early patients may not receive rituximab treatment.

In contrast, another SEER study included 258 patients with PMBCL in all stages diagnosed from 2006 to 2011. There was no difference between radiotherapy and no radiotherapy (5-year OS rate 82.5% vs 78.6%, P=0.47). However, the proportion of patients in the non-radiotherapy group was higher (31 vs 19%).

One of the main advantages of the DA-EPOCHR program is that it is less dependent on mediastinal radiotherapy. Although the long-term effects of modern radiotherapy dose/radiotherapy field are not clear (especially when guided by PET), its potential long-term cardiovascular complications and subsequent Tumors, so it still makes sense for young patients to avoid radiotherapy.

Currently, there are few studies evaluating R-CHOP alone or R-CHOP-like regimens in the treatment of PMBCL, and there are few studies on whether PET can guide radiotherapy. The MACOPB study evaluated the role of PET in guiding radiotherapy for the first time. Only PET-positive (IHP standard) patients received radiotherapy. As a result, the 10-year PFS rate has nothing to do with the end of treatment (EOT) PET scan status, which is about 90% ( P=0.85).

In another study (see Table 3), the International Extranodal Lymphoma Study Group (IELSG) assessed the remission status at the end of the treatment through PET scan after R-VACOPB/RMACOPB chemotherapy + radiotherapy consolidation, but used more refined Deauville’s 5 points method. The study confirmed that D3 (uptake> mediastinum but less than or equal to liver) should be included in the criteria for complete metabolic remission at the end of treatment.

The author of this article also recently reported on the outcome of patients with PMBCL in British Columbia. It is believed that the PET scan at the end of R-CHOP treatment can guide consolidation radiotherapy. In the study, PET-positive patients at the end of the treatment are recommended to receive radiotherapy, while negative patients regardless of the initial tumor size. Always observe. Results Among the 113 PET-evaluable patients, the 5-year TTP and OS rates of PET-negative patients at the end of treatment were 82% and 94%, respectively; for the patients whose PET scans were evaluated by Deauville, PET-negative (D1-3, DX) ) And positive (D4, D5) rates were 71% and 29%, respectively (see Table 3). The 5-year TTP and OS of PET-negative patients were 91% and 97%, respectively, and only 11% of patients received radiotherapy. , The reason is that the early scan results were re-evaluated using the Deauville criterion.

In addition to the above studies, other studies (see Table 3) can also confirm that the predictive value of PET negative after R-CHOP without radiotherapy or DA-EPOCHR treatment is higher, (PFS rates) are 92%-97% and 95%, respectively- 100%, and can continue to increase if recurrence outside the mediastinum (including CNS recurrence) is excluded.

However, a larger study is needed to compare the negative predictive value of DA-EPOCHR and R-CHOP. More importantly, the phase 3 IELSG37 study (NCT01599559) is assessing in PMBCL, the value of radiotherapy for chemotherapy with rituximab-containing chemotherapy when EOT PET is negative, but there is no result yet.

Unlike PET negative, the positive predictive value (PFS rate) of patients with PET positive (about 30% of patients) at the end of treatment is very low (see Table 3).

Taking into account comprehensive considerations, most patients treated with the R-CHOP (like) regimen can be effectively treated without radiotherapy, but radiotherapy is still used more frequently in these patients than DA-EPOCHR. Part of the reason is that it is impossible to determine whether PET Deauville D4 represents a disease. False positive. In addition, DA-EPOCHR can still be used as the first choice for hematological oncology institutions, because it can avoid most mediastinal radiotherapy.

PET imaging of PMBCL

Through baseline 18FDGPET/CT quantification, PET imaging has gradually become an important predictor of clinical outcome. The IELSG study found that volume-based metabolic assessments are related to patient prognosis, including SUVmax, metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Among them, TLG combined with the tumor volume and metabolism of the baseline PET-/CT scan has gradually become the most powerful predictor of outcome. The 5-year PFS rates of low TLG and high TLG are 99% and 64%, respectively. Under DA-EPOCHR treatment The same is true (the 2-year PFS rate, low TLG and high TLG are 95% and 60%, respectively).

Based on the above data, the IELSG study also assessed metabolic heterogeneity (MH), and found that only MH and TLG were associated with shorter PFS in a multivariate analysis, and the combination of the two could identify 10% of all patients Of the patients, the 5-year PFS rate of these patients is only 11%.

However, there are still challenges in applying risk prediction models in PMBCL, and other methods may be needed to identify subgroups of patients that require additional treatment.

Relapsed/Refractory PMBCL

Almost all treatment failures of PMBCL occurred within the first 2 years, except for the relatively rare long-term CNS recurrence (incidence rate 2.5-4.5%).

The treatment of relapsed/refractory (R/R) PMBCL corresponds to DLBCL, that is, if remission after salvage treatment, high-dose chemotherapy and ASCT are given. However, there are few studies on the clinical outcome of R/R PMBCL, especially rituximab Research in the anti-epoch, in addition, there are very few studies on the ITT population.

As can be seen from the above table, most studies believe that ASCT can significantly improve the survival of patients with R/R PMBCL.

In addition, refractory patients have a poor prognosis and require other treatments.

New treatment for relapsed/refractory PMBCL

PD1 inhibitor

The first validation of the efficacy of PD1 inhibitors for PMBCL was the Phase 1 KEYNOTE-013 study. The patients were relapsed/refractory lymphomas including PMBCL. The updated results of the study showed that the ORR of R/R PMBCL reached 48% (CR 33%). It is consistent with the results of the subsequent phase 2 study (KEYNOTE-170 study, ORR 45%, CR13%). The median follow-up of the two studies was 29.1 and 12.5 months, the median PFS was 10.4 and 5.5 months, respectively, and the median DOR was not reached. In addition, 9 patients used K-medicine bridge transplantation. In terms of safety, the incidence of grade 3/4 treatment-related adverse events was 23%, of which neutropenia was the most common high-grade adverse event, with an incidence of 13.5%.

Another PD1 inhibitor-O drug was combined with verbutuximab in the CheckMate 436 study. Some of the patients had R/R PMBCL, although verbutuximab was treated as a single agent in a previous study The ORR of R/R PMBCL is only 13%, but it can reach 73% after the combination of O drugs, of which CR 37%, which reflects the synergistic effect of PD1 and other systemic treatments. In addition, half of the remission patients (11 cases) subsequently received After transplantation, there was no recurrence. In terms of adverse reactions, the grade 3/4 adverse reactions (53%) of the combined regimen were higher than those of PD1 single agent, of which 30% were neutropenia and 10% were PN (overall 27%). In addition, 10 patients reported Immune-related adverse events, of which 3 patients were grade 3.

Research on the use of PD1 in the first-line treatment of PMCL is ongoing, mostly O drugs.

Molecular therapy

CAR-T cell therapy is a kind of molecular therapy. It has changed the treatment mode of R/R CD19+ aggressive large B-cell lymphoma, including PMBCL, of course, and this therapy is generally effective for advanced patients with OS less than 6 months. It seems to have healing potential.

The ZUMA-1 and TRANSCEND NHL001 studies tested axicabtagene ciloleucel (axi-cel) and tisagenlecleucel in patients with R/R aggressive large B-cell lymphoma (including PMBCL) who had failed ≥2 lines of previous treatment, respectively. The analysis of two studies on R/R PMBCL subgroups showed that the ZUMA-1 study was followed up for a median of 27 months, and 5 of the 8 cases of PMBCL remained in remission, while 14 cases of the TRANSCEND study could assess the ORR of R/R PMBCL Up to 79%.

CAR-T therapy is the first choice for patients with R/R PMBCL who have failed previous second-line treatment, including patients after ASCT.

Other new therapies

Because most patients with PMBCL are CD30+, a phase 1/2 study evaluated verbutuximab+CHP in the treatment of CD30+ B-cell lymphoma. Among them, the 2-year PFS and OS of 22 cases of PMBCL were 86% and 100%, respectively, and There was no difference in radiotherapy consolidation or not (P=0.95). This study also confirmed that the clinicopathological diagnosis of PMBCL is not accurate enough.

The ADC drug locastuximab (ADCT-402) was also evaluated in R/R B-cell NHL, although only 2 of them were PMBCL. The ORR of the overall patient was 42%, of which CR was 23%, and the overall hematological toxicity was moderate (71% for thrombocytopenia, 59% for neutropenia).

Bispecific antibodies are being explored in a series of B-cell lymphomas, but PMBCL is not explicitly included in patients.

In addition, although PMBCL has abnormal JAK/STAT pathway activation, the effect of JAK2 inhibitors is not ideal. In a study of Rucotinib in the treatment of R/R cHL and R/R PMBCL, none of the patients with R/R PMBCL remission. In addition, it is still unknown whether the combination of rocotinib and PD1 can be converted into clinical benefit.


Summary

In the past 20 years, the biodynamic research of PMBCL has made great progress. Among them, the immune-privileged phenotype is an integral part of the pathogenesis, which led to the key research of PD1 in R/R PMBCL and was approved.

Although most patients have a good prognosis under R-immunochemotherapy, 10% of patients are still refractory. This is the basic principle of the integration of PD1 inhibitors into the first-line treatment of PMBCL.

In addition, further studies of imaging and markers at the time of diagnosis can identify which patients can benefit from alternative therapies.

(source:internet, reference only)


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