Guidelines Overview China Guidelines for the Diagnosis and Treatment of Mantle Cell Lymphoma (2022 Edition)

Mantle cell lymphoma (MCL) is a small, to medium-sized, monomorphically mature B-cell tumor with a specific immune phenotype and reproducible genetic abnormalities, accounting for 6% to 8%
of non-Hodgkin lymphoma (NHL).
Patients with MCL usually have expression traits of CD5 and SOX11, and more than 95% of patients have rearrangement of the CCND1 gene and lead to high expression within the nucleus of the Cyclin D1 protein; Patients are predominantly elderly men, often invading the extranodal loci, and are characterized by
rapid progression of aggressive lymphoma and incurable incurable lymphoma.

Since the release of the "Chinese Expert Consensus on the Diagnosis and Treatment of Mantle Cell Lymphoma (2016 Edition)", it has greatly promoted the understanding of the disease among medical workers in China and standardized clinical diagnosis and treatment
.
In recent years, significant progress has been made in basic translational research and clinical treatment of MCL
.
In order to further improve the understanding of the disease among Chinese medical workers and promote standardized diagnosis and treatment, the Hematology and Oncology Professional Committee of the Chinese Anti-Cancer Association, the Hematology Branch of the Chinese Medical Association and the Lymphoma Expert Committee of the Chinese Society of Clinical Oncology jointly organized relevant domestic experts to jointly formulate the "China Guidelines for the Diagnosis and Treatment of Mantular Cell Lymphoma (2022 Edition)"
.
The main contents of the medical pulse are summarized as follows
.

1.
Diagnostics

Mainly based on typical histomorphological features combined with mature B cell immune features, as well as immunohistochemical CD5 and Cyclin D1 intranuclear positive
.
For leukemia-type non-lymph node MCL, such as tumor cell immunophenotype conforming to typical MCL, routine chromosomal karyotyping analysis, or fluorescence in situ hybridization (FISH) detection of t(11; 14) MCL
can also be diagnosed.

If histomorphological features and immunophenotype conform to typical MCL, but Cyclin D1 and t(11; 14) All negative, then immunohistochemical test SOX11, if SOX11 is positive, can also diagnose MCL, conditional hospitals can add FISH detection CCND2 or CCND3 rearrangement
.

2.
Typing

(1) Classical MCL, accounting for the vast majority of MCL, has a variety of biological behaviors;

(2) Leukemia non-lymphadenopathic MCL, most of the clinical manifestations are inert, a few are highly aggressive, prone to rapid progression, the evaluation can refer to the following criteria: (1) clinically inert onset, leukemia manifestations, spleen enlargement without significant enlargement of lymph nodes; (2) Biological characteristics: not accompanied by complex karyotypes, immunoglobulin heavy chain variable region (IGHV) gene mutant type, no expression or low expression of SOX11, Ki-67% is usually < 10%.

In situ mantle cell tumor (ISMCN): B cells that refer to Cyclin D1-positive (often accompanied by CCND1 gene rearrangement) are localized in the lymphatic follicular sleeve area, but do not destroy the lymph node structure and do not meet the diagnostic criteria for
MCL.
ISMCN is often discovered by chance, rarely progresses, sometimes coexists with other lymphomas, and can present with disseminated manifestations
.

Mainly to distinguish from other B-cell lymphoproliferative diseases, especially chronic lymphocytic leukemia (CLL), please refer to the "Chinese Expert Consensus on Diagnosis and Differential Diagnosis of B-cell Chronic Lymphoproliferative Diseases (2018 Edition)"
.

Classical MCL is divided into stage I.
, stage II.
, stage II with large lumps, and stage III and IV.
according to the Ann Arbor staging system revised by Lugano
.
There is no unified staging standard for leukemia-type non-lymphadenoid MCL, and the relevant standards can be referred to (see "Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma in China", 2018).

At present, the International Prognostic Scoring System (MIPI) (Table 1) of simple mantle cell lymphoma and the combined MIPI Prognostic Score System (MIPI-C) (Table 2) combined with Ki-67 index are commonly used clinically for prognostic stratification
.

Table 1 International Prognostic Score System for Simple Mantle Cell Lymphoma (MIPI)

Table 2 Joint MIPI Prognostic Scoring System (MIPI-C) combined with Ki-67 Index

Other biological prognostic indicators include: cytogenetic abnormalities such as del (17p) or TP53 mutations, MYC amplification/translocation, CDKN2A (9p) deletion, Ki-67 proliferation index, blast cell variant, etc
.

1.
Indications for treatment

2.
Pre-treatment evaluation

A comprehensive evaluation of the patient should be performed prior to treatment (including in patients with relapses) and should include, at a minimum:

(1) medical history and physical examination (especially superficial lymph nodes and hepatospleen size);

(2) Physical fitness status score: ECOG score;

(3) B symptoms: fever, night sweats, weight loss, etc.
;

(4) Laboratory tests: blood count, liver and kidney function, blood LDH, β2-microglobulin;

(5) HBV, HIV and other virus-related tests;

(6) Pathological examination: (1) lymph node pathology + immunohistochemistry; (2) Bone marrow biopsy + immunohistochemistry + flow cytometry to analyze the immune phenotype; (3) Chromosomal karyotyping and FISH technology detection t(11; 14)；

(7) Imaging examination: (1) Whole body PET-CT examination or enhanced CT examination of neck, chest and whole abdomen is recommended; (2) Gastrointestinal endoscopy is carried out when gastrointestinal tract involvement is suspected, and patients with stage I to II are recommended to conduct routine gastrointestinal endoscopy; (3) Lumbar puncture and magnetic resonance imaging (MRI) examination when the blast type or central nervous system involvement is considered; (4) Cardiac color ultrasound (left ventricular ejection fraction) or multigated detection (MUGA) scan: when
considering the use of anthracycline regimen chemotherapy.

In addition, IGHV mutation detection and FISH detection of TP53 deletion, CDNK2A deletion and MYC abnormalities are recommended, and lymphoma-related second-generation gene sequencing is recommended for those with conditions, including TP53, ATM, CCND1, KMT2D, SP140, BIRC3, WHSC1, NOTCH1/2, SMARCA4, CARD11 and UBR5
.

3.
First-line treatment

• Ann Arbor Phase I.
  to II

For a small number of patients with stage I or continuous stage II (one target radiotherapy may be given) without risk factors, a treatment strategy similar to follicular lymphoma can be adopted, with isolated affected field radiotherapy (IRST), immunochemotherapy with or without IRST, and radiation therapy at a dose of 30 to 36 Gy
.
For patients with discontinuous stage II and no risk factors, conventional immunochemotherapy (non-intensive regimen)
is recommended.
The treatment flow is shown in Figure 1
.

Figure 1 Treatment flow of early primary mantle cell lymphoma

Treatment of patients with stage I.
to II with risk factors is recommended as advanced (stage III to IV
).
Risk factors include large mass lesions (≥5 cm), Ki-67>30%, TP53 mutations/deletions
, and aggressive variants of cell morphology.

• Ann Arbor stage III.
  to IV.
  or stage I to II with risk factors

Treatment of patients with advanced MCL or leukemia-induced leukemia non-lymph node MCL requires stratified treatment based on the patient's age, general condition, and genetic abnormalities such as TP53, and the treatment selection process is shown in Figure 2 and Table 3
.

Figure 2 Treatment flow of advanced initial mantle cell lymphoma

Table 3 Treatment options for the initial treatment of mantle cell lymphoma

For patients ≤ age 65 years and generally in good condition who are suitable for autologous hematopoietic stem cell transplantation (ASCT), rituximab plus regimen with medium to high doses of cytarabine should be induction therapy and ASCT consolidation
after remission.
For patients > age 65 years or generally poor condition who are not suitable for ASCT, a combination chemotherapy regimen with less adverse effects and better tolerance should be chosen, and combination rituximab chemotherapy can improve long-term survival
.

The high-risk group included TP53 mutations, TP53 and CDNK2A deletions, invasive variants, and MIPI-c high-risk groups
.
Patients in the high-risk group have poor efficacy in conventional treatment, and there is currently no standard treatment regimen
.

• Maintenance therapy

In younger patients, maintenance therapy with rituximab (375 mg/^m2 every 2 to 3 months for 2 to 3 years) after ASCT significantly prolongs PFS and OS time
.
Lenalidomide 10 to 15 mg/day after ASCT for 28 days per cycle for 24 months on days 1 to 21, significantly prolongs PFS time
in patients with no maintenance therapy.

For patients ≥ 65 years of age, rituximab maintenance therapy (375 mg/^m2 every 2 to 3 months for 2 to 3 months or until disease progression) is recommended for further improvement of OS (class 1)
after remission of R-CHOP regimen.
In patients undergoing induction chemotherapy with a B-R regimen, rituximab maintenance may not be granted if CR is achieved, and rituximab maintenance can significantly prolong OS if
only partial remission is achieved.

Note: Refer to the NCCN's classification of evidence and consensus: Category 1: Based on a high level of evidence, the NCCN unanimously agreed that this treatment was reasonable
.

4.
Salvage treatment

Rescue drugs/regimens are shown in Table 4
.
Patients with relapses after first-line therapy are preferred to participate in well-designed clinical trials, and in the absence of clinical trials, the choice is based on whether the patient has high-risk factors, including TP53 mutation/deletion, CDKN2A deletion, aggressive variant, Ki-67%, > 50%.

Table 4 Salvage treatment options for relapsed/refractory mantle cell lymphoma

The efficacy evaluation criteria of MCL were carried out
according to the Lugano 2014 standard.
Patients with the condition are first considered for efficacy evaluation
with PET-CT.
Efficacy evaluation is carried out every 2 courses during treatment and a comprehensive evaluation is carried out every 4 courses, including PET-CT until CR
.
This test is not performed after a negative PET-CT unless disease progression
is considered.
Because MCL often invades peripheral blood or bone marrow, minimal residual disease monitoring
may be considered.

Follow-up should be performed every 3 months for the first 2 years after completion of treatment, including medical history, physical examination, blood count, and biochemical examination, and CT examination (including neck, chest, and whole abdomen)
every 6 months.
Follow-up is performed semi-annually for the 3rd to 5th year after completion of treatment and CT is
performed every 12 months.
Follow-up visits are performed annually after 5 years or when symptoms are present, and if there are abnormalities or disease progression is considered, an enhanced CT is performed, etc
.

This article is excerpted from the Hematology and Oncology Professional Committee of the Chinese Anti-Cancer Association, the Hematology Branch of the Chinese Medical Association, and the Lymphoma Expert Committee of the Chinese Society of Clinical Oncology.
Guidelines for the diagnosis and treatment of mantle cell lymphoma in China (2022 edition) [J] .
Chinese Journal of Hematology, 2022, 43(7): 529-536.
DOI: 10.
3760/cma.
j.
issn.
0253-2727.
2022.
07.
001.
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