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Initial treatment of advanced stage diffuse large B cell lymphoma

Initial treatment of advanced stage diffuse large B cell lymphoma
Authors:
Arnold S Freedman, MD
Jonathan W Friedberg, MD
Section Editors:
Andrew Lister, MD, FRCP, FRCPath, FRCR
Ann S LaCasce, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Sep 2023.
This topic last updated: Jun 16, 2022.

INTRODUCTION — Diffuse large B cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma (NHL) and it is the most common histologic category of NHL. For treatment purposes, patients with DLBCL are classified as having either limited stage disease (stages I or II) or advanced stage (stages III or IV) (table 1). Approximately two-thirds of patients with DLBCL present with stage III or IV disease. Treatment of advanced stage DLBCL with curative intent using rituximab-based chemotherapy is associated with long-term survival in more than two-thirds of patients.

Initial treatment of adults with advanced stage DLBCL is discussed here.

Diagnosis and prognostic features of DLBCL and treatment of limited stage DLBCL are presented separately.

●(See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

●(See "Prognosis of diffuse large B cell lymphoma".)

●(See "Initial treatment of limited stage diffuse large B cell lymphoma".)

PRETREATMENT EVALUATION — Pretreatment evaluation of a patient with newly-diagnosed DLBCL includes assessment of:

●Disease stage (table 1)

●Comorbid conditions and performance status (table 2)

●Cytogenetic/molecular features

●Risk for central nervous system (CNS) involvement

●International Prognostic Index (IPI) score (table 3)

The general approach to evaluation and diagnosis of non-Hodgkin lymphoma is presented separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

Clinical and laboratory

●Clinical evaluation – The history should assess constitutional ("B") symptoms (ie, fever, sweats, unintentional weight loss) and examination should note enlarged lymph nodes, liver, or spleen; neurologic examination; or other findings likely related to the lymphoma.

●Performance status (PS) – PS should be assessed (table 2).

●Laboratory studies – Laboratory studies include:

•Complete blood count (CBC) with differential.

•Chemistries – Serum electrolytes, glucose, kidney function (blood urea nitrogen [BUN], creatinine), and liver function tests, including lactate dehydrogenase (LDH), uric acid.

•Pregnancy test in women of childbearing age.

●Pathology – We evaluate the diagnostic biopsy specimen for "double-hit" and cell-of-origin status, as discussed separately. (See "Prognosis of diffuse large B cell lymphoma", section on 'Molecular genetics'.)

•"Double-hit" – Double-hit lymphoma is a colloquial term for high-grade B cell lymphoma MYC and BCL2 and/or BCL6 rearrangements, which is a distinct category of aggressive lymphoma, according to the current World Health Organization (WHO) classification [1]. This is not a type of DLBCL, per se, and although it can resemble DLBCL histologically, it is associated with inferior prognosis and requires distinctive treatment, as described below. (See 'High-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6 ("double-hit")' below.)

Double-hit status is determined by fluorescence in situ hybridization (FISH). Immunohistochemistry (IHC) is not an acceptable alternative to FISH, as IHC can detect double expressor status (ie, expression of MYC, BCL2, and/or BCL6) but not double-hit status (ie, rearrangements of those genes). (See "Prognosis of diffuse large B cell lymphoma", section on 'MYC, BCL2, BCL6 abnormalities'.)

•Cell of origin (COO) – COO status is determined using an IHC algorithm (figure 1). COO status can also be assessed with the LymphCx platform, but this is less-widely available. (See "Prognosis of diffuse large B cell lymphoma", section on 'Cell of origin studies'.)

We assign COO as:

-Germinal center B cell (GCB) DLBCL – GCB status is generally associated with more favorable prognosis.

-Non-GCB DLBCL – Cases with non-GCB status generally have higher rates of relapse and a less favorable prognosis.

COO status does not influence the choice of initial treatment for advanced stage DLBCL.

●Imaging – Positron emission tomography (PET)/computed tomography (CT) should assess neck/chest/abdomen/pelvis.

If PET is not available, CT of chest, abdomen, and pelvis with intravenous contrast should be performed. A dedicated contrast-enhanced CT may also be needed to define the extent of disease in special situations, such compression or thrombosis of blood vessels or lymphadenopathy close to bowel.

Other imaging is guided by the clinical evaluation. As an example, magnetic resonance imaging (MRI) with gadolinium or CT of head with intravenous contrast should be performed for abnormal findings from a neurologic examination. (See 'Central nervous system (CNS) evaluation' below.)

●Clinical testing:

•Cardiac testing – Echocardiogram or multigated acquisition (MUGA) scan.

•Infectious diseases – Human immunodeficiency virus (HIV) and hepatitis B testing. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

•Bone marrow examination – Bone marrow examination is not required if PET indicates marrow involvement.

Bone marrow biopsy is optional for patients without PET evidence of marrow involvement. PET has high sensitivity and specificity for detecting marrow involvement with DLBCL, but it may miss low volume, diffuse marrow involvement [2]. Identifying marrow involvement has prognostic value, but it does not affect the choice of initial treatment.

Detection of DLBCL in the bone marrow may also reveal histologic discordance between the diagnostic biopsy and bone marrow involvement, which has prognostic significance [3].

•Lumbar puncture (LP) – We perform a diagnostic LP for patients with neurologic symptoms, abnormal findings on neurologic examination, or evidence of leptomeningeal disease with imaging.

An LP is not required for patients without these findings, but some experts suggest an LP for patients with higher risk of central nervous system (CNS) involvement (eg, testicular involvement), as described below. (See 'Central nervous system (CNS) evaluation' below.)

●Fertility – Men and women with childbearing potential should receive counseling about the potential effect of treatment on fertility and options for fertility-preserving measures.

•Males – Men can often participate in sperm banking.

•Females – We encourage expert consultation for preservation of fertility and reproductive hormone status for women of child-bearing age. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

Central nervous system (CNS) evaluation — All patients should be assessed using the Central Nervous System International Prognostic Index (CNS IPI). Further evaluation should be performed for patients with neurologic abnormalities on clinical examination and for selected patients with higher risk for involvement of the neuraxis (table 4).

We do not routinely perform a LP and CNS imaging for all patients with advanced stage DLBCL.

●CNS IPI – All patients with advanced stage DLBCL should be evaluated using the CNS IPI score (calculator 1), which has been validated in this setting [4]. However, it should be recognized that the CNS IPI does not capture all patients with high risk for CNS relapse (eg, testicular involvement). Factors that have been associated with increased risk for involvement of the neuraxis are listed in the accompanying table (table 4).

•CNS IPI scoring – One point is assigned for each of the following:

-Kidney and/or adrenal glands involved

-Age >60 years

-LDH above normal

-Eastern Cooperative Oncology Group (ECOG) PS >1

-Stage III/IV disease

-Extranodal involvement of ≥2 sites

•Risk of CNS relapse is classified according to the sum of points. The two-year risk of CNS relapse is [4]:

-Low (0 to 1 points) – 0.6 percent

-Intermediate (2 to 3 points) – 3.4 percent

-High (4 to 6 points) – 10.2 percent

Multivariate analysis of 2164 patients with DLBCL reported that the risk of CNS relapse was most strongly associated with age >60, elevated LDH, ECOG PS >1, and stage III/IV disease; in this analysis, kidney or adrenal involvement was associated with increased risk, but extranodal involvement at ≥2 sites was not [4]. However, the risk of CNS relapse was strongly associated with the number of extranodal sites in an independent study of 1532 patients with DLBCL; three-year incidence of CNS relapse was 15 percent for patients with ≥2 extranodal sites, compared with 3 percent for patients with 0 to 1 extranodal sites [5].

●Evaluation of abnormal neurologic findings – Patients with abnormal findings on neurologic examination should be evaluated with:

•Diagnostic LP including cell count, chemistries, cytology, and flow cytometry or molecular analysis for lymphoma cells

•MRI of brain and spine

•Ophthalmologic examination (for symptomatic patients or those with known CNS involvement)

International Prognostic Index — Prognosis in DLBCL is influenced by age, PS, comorbidities, stage, response to therapy, and disease biology.

Patients should be assessed with the International Prognostic Index (IPI) (table 3).

TREATMENT — Advanced stage DLBCL corresponds to stage III or IV disease and accounts for approximately two-thirds of patients who present with DLBCL.

All patients should be evaluated for risk of central nervous system (CNS) involvement (see 'Central nervous system (CNS) evaluation' above) and consideration of CNS prophylaxis. (See 'CNS management' below.)

Special considerations may apply for selected patients (see 'Special scenarios' below):

●Older patients – (See 'Older adults' below.)

●Heart disease – (See 'Heart disease' below.)

●Other high-grade B-cell lymphomas – Some lymphomas that were previously described as subtypes of DLBCL are currently classified as separate lymphoma categories in the current World Health Organization (WHO) classification system [1] and require distinctive management.

Examples are described below. (See 'Other high-grade B cell lymphomas' below.)

Initial therapy — Prior to initiating treatment, consideration should be given to:

●Tumor lysis syndrome (TLS) – Prophylaxis for TLS should be considered for patients who have a high tumor burden (eg, large tumor masses or markedly elevated lactate dehydrogenase [LDH]). TLS most often occurs in the first 12 to 72 hours of treatment [6]. Evaluation and management of TLS are discussed separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Tumor lysis syndrome: Prevention and treatment".)

●Viral reactivation – Treatment with rituximab can increase the risk of reactivation of hepatitis B. Evaluation and management of patients who are positive for hepatitis B are discussed separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Incorporation of rituximab — We recommend including rituximab with remission induction chemotherapy, based on improved survival with minimal additional toxicity in randomized trials.

Trials that support the inclusion of rituximab in initial treatment include:

●Three large randomized trials, which included approximately 2000 patients >65 years with advanced stage DLBCL, reported that, compared with no rituximab, inclusion of rituximab in induction therapy increased overall survival (OS) at 3 (70 versus 57 percent for CHOP alone), 5 (58 versus 45 percent), and 10 (44 versus 28 percent) years [7-11]. Rituximab treatment was not associated with an increase of severe adverse events (AEs).

●A clinical trial that included 824 patients (<60 years) with DLBCL (28 percent stage III/IV and 48 percent with bulky disease) reported that adding rituximab to induction therapy achieved superior OS at three years (93 versus 84 percent) and five years (90 versus 80 percent) and improved event-free survival (EFS) at three years (79 versus 59 percent, respectively) and five years (74 versus 56 percent) [12,13].

Administration and toxicity of rituximab follow:

●Administration – Rituximab is given intravenously (375 mg/m2) on day 1 of each chemotherapy cycle. A phase 3 trial reported no benefit from dose intensification of rituximab during the first four cycles of therapy [14].

A subcutaneous formulation (rituximab-hyaluronidase) that uses a fixed dose and a shorter administration time is an acceptable alternative for patients who have tolerated at least one full dose of intravenous rituximab [15]. Randomized trials have demonstrated comparable efficacy and safety of the two formulations in patients with DLBCL and other CD20-expressing B cell neoplasms [7-12,16-19].

●Adverse effects – Major AEs include infusion reactions, immunosuppression-related infections, and reactivation of hepatitis B in patients who are positive for hepatitis B surface antigen (HBsAg) or antibodies against hepatitis B core antigen (anti-HBc). (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy" and "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab' and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Rituximab is very rarely associated with progressive multifocal leukoencephalopathy caused by reactivation of JC virus infection. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

Choice of regimen — We suggest initial treatment with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or six cycles of R-pola-CHP (rituximab, polatuzumab vedotin, cyclophosphamide, doxorubicin, prednisone). R-CHOP cures approximately 60 percent of patients with DLBCL, is associated with acceptable AEs, and has long been standard initial treatment for DLBCL [7,13]. However, compared with R-CHOP, R-pola-CHP achieved better outcomes with similar toxicity in a phase 3 trial; long-term outcomes from this trial are not yet available [20].

The preferred initial regimen for advanced stage DLBCL may differ for certain patients (eg, >80 years, significant heart disease), as described below. (See 'Special scenarios' below.)

Evidence that supports the treatment suggestions include:

●R-pola-CHP versus R-CHOP – An international, double-blind, placebo-controlled phase 3 trial (POLARIX) reported that R-pola-CHP achieved superior outcomes compared with R-CHOP for adults with newly-diagnosed, intermediate- or high-risk DLBCL; one-third of the 879 patients had activated B cell (ABC)-like DLBCL and nearly two-thirds had a baseline International Prognosis Index (IPI) score of 3 to 5 [20]. OS was 89 percent for both groups, but compared with R-CHOP, R-pola-CHP achieved superior progression-free survival (PFS; ie, no progression, relapse, or death) and EFS (ie, PFS plus biopsy-confirmed post-treatment residual disease and/or subsequent lymphoma therapy). R-pola-CHP was associated with 77 percent two-year PFS, compared with 70 percent with R-CHOP (hazard ratio [HR] 0.73 [95% CI 0.57-0.95]); the HR for EFS was 0.75 (95% CI 0.58-0.96). Serious AEs were reported in 30 to 34 percent of patients (mostly neutropenia and anemia) and grade ≥2 peripheral neuropathy occurred in 14 to 17 percent.

Treatment with full doses of planned therapy is associated with improved clinical outcomes in DLBCL, while dose reductions of CHOP were associated with lower survival rates [21]. In a retrospective analysis of 115 patients who were treated with anthracycline-based regimens, administration of ≥75 percent of recommended dose of doxorubicin in the first 12 weeks of therapy was the single most important predictor of OS [22]. In a retrospective review of 210 patients treated with CHOP, median survival was related to the dose delivered: >90 percent dose (7 years), 85 to 90 percent (3 years), and <85 percent (1.7 years) [23].

Polatuzumab vedotin is approved for use in adults as R-pola-CHP for initial treatment of DLBCL by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

●Number of cycles – We suggest six cycles of initial therapy, rather than eight cycles, based on comparable outcomes with less toxicity.

The preference for six cycles is based on the desire to avoid unnecessary toxicity and the favorable outcomes with six cycles of R-CHOP in the MInT trial [12]. No randomized trial has directly addressed the optimal number of chemotherapy cycles using R-CHOP-21 (21-day treatment cycles) or R-pola-CHP. However, the RICOVER-60 trial reported no difference in three-year OS for patients treated with six versus eight cycles of R-CHOP-14 (14 day cycles; 78 and 73 percent, respectively) in 1222 patients (61 to 80 years) with aggressive non-Hodgkin lymphoma (80 percent DLBCL) [10].

●No role for response-guided intensification of therapy – Interim positron emission tomography (PET) scans have limited prognostic value in advanced stage DLBCL and there is no evidence to support response-guided intensification of therapy.

While advanced stage DLBCL is generally treated with six cycles of therapy, some clinicians perform an interval PET and/or CT after three to four treatment cycles, to ensure that the disease is responding before completing all six cycles. If an interval PET is performed and is positive, a biopsy should be performed to confirm the diagnosis of refractory DLBCL before changing treatment, as discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

In the PETAL trial, patients with PET-positive disease after two cycles of R-CHOP had inferior outcomes compared with those who had a negative PET (ie, complete response [CR]); however, treatment intensification for PET-positive patients did not improve outcomes for PET-positive patients [24]. Furthermore, interval PET can lead to false-positives (eg, inflammatory response to therapy) and many patients have a favorable outcome, despite a positive interval PET [25,26].

●Alternative regimens – Compared with R-pola-CHP and R-CHOP, no alternative regimen or variation in R-CHOP administration has achieved superior outcomes, but some alternative regimens were more toxic. Informative studies include:

•R-CHOP-21 versus R-CHOP-14 – Two randomized trials reported that R-CHOP-21 (21-day cycles) and R-CHOP-14 (14-day cycles) achieved similar outcomes, but R-CHOP-14 was associated with more toxicity. One trial randomly assigned 1080 patients with newly diagnosed DLBCL to eight cycles of R-CHOP-21 versus six cycles of R-CHOP-14 plus two additional doses of rituximab [27]. With median follow-up of 46 months, there was no significant difference in OS or PFS between the two treatment groups. Another trial randomly assigned 600 older adults with DLBCL to eight cycles of R-CHOP-14 versus eight cycles of R-CHOP-21 and reported similar rates of OS, EFS, and overall response rate (ORR) for the two treatment regimens [28]. CHOP-14 has been associated with increased toxicity, including an increased risk of Pneumocystis jirovecii pneumonia [29].

•Dose-adjusted (da)-R-EPOCH versus R-CHOP – A multicenter trial reported no differences in two-year OS, two-year PFS, or ORR among 491 patients who were randomly assigned to (da)-R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) versus R-CHOP [30]. Grade ≥3 AEs were more common with (da)-R-EPOCH, including infections (17 versus 11 percent), febrile neutropenia (35 versus 18 percent), mucositis (8 versus 2 percent), and neuropathy (19 versus 3 percent).

A phase 3 trial (CALGB 50303), presented in abstract form, that compared (da)-R-EPOCH versus R-CHOP reported no significant differences in OS (76 versus 80 percent, respectively), EFS (66 versus 69 percent), or ORR (89 percent for both arms); however, (da)-R-EPOCH was associated with more cytopenias and neuropathy [31].

Other regimens that have been examined for DLBCL include R-CHOP plus lenalidomide [32], R-CHOP plus ibrutinib [33], and R-CHOP plus bortezomib [34,35], but none has been associated with a more favorable balance of outcomes and toxicity.

Administration of R-CHOP and R-pola-CHP is presented below. (See 'Chemoimmunotherapy regimens' below.)

CNS management — There is controversy about CNS management for advanced stage DLBCL, as prophylaxis has not been proven to prevent CNS relapses in the R-CHOP era.

Risk should be assessed with the CNS International Prognostic Index (CNS IPI) (calculator 1), but it does not capture all patients at high risk for CNS relapse (eg, testicular involvement). (See 'Central nervous system (CNS) evaluation' above.)

●Decision to incorporate CNS prophylaxis – We generally do not incorporate CNS prophylaxis into remission induction therapy, but we may consider its use for patients at higher risk for CNS relapse (eg, CNS-IPI score ≥4 points or testicular involvement) on a case-by-case basis.

The preferred approach varies among experts and the decision should be informed by the individual patient's interpretation of the relative risks of prophylaxis versus CNS relapse.

●Choices for CNS prophylaxis include either or both of the following:

•High-dose methotrexate (MTX) – Treatment with MTX (3 to 3.5 g/m2) with leucovorin (LCV) rescue is administered on day 15 of each 21-day cycle of R-CHOP [36].

•Intrathecal (IT) therapy – IT MTX and/or IT cytarabine is administered at least once per systemic therapy cycle.

The preferred method of CNS prophylaxis is controversial. For many years, IT MTX was administered as prophylaxis for higher-risk patients, but IT chemotherapy does not adequately penetrate the brain parenchyma; thus, IT chemotherapy is not sufficient to prevent parenchymal CNS recurrence. High-dose MTX/LCV penetrates the leptomeningeal and parenchymal CNS compartments and retrospective studies suggest that high-dose MTX/LCV is associated with a lower incidence of CNS relapse [36-39], but it has not been proven to have superior efficacy with prospective or randomized studies.

Details of administration, toxicity, and outcomes with prophylaxis regimens are presented separately. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Intrathecal therapy' and "Therapeutic use and toxicity of high-dose methotrexate".)

Initial management of patients who present with concurrent systemic and CNS is discussed separately. (See "Secondary central nervous system lymphoma: Treatment and prognosis".)

●Outcomes – No phase 3 trials have compared CNS prophylaxis versus observation for patients with DLBCL and retrospective studies have not proven a beneficial effect of prophylaxis for reducing relapses:

•A systematic review and meta-analysis of 10 studies (3770 patients with DLBCL and intermediate- or high-risk for CNS relapse) reported no difference in CNS relapse for patients who received or did not receive CNS prophylaxis [40]. Comparing patients who received prophylaxis versus those did not receive prophylaxis, the relative risk (RR) was 1.22 (95% CI 0.81-1.83). Subgroup analysis reported no difference in relapse among those who received IT MTX versus high-dose MTX/LCV.

•Large retrospective studies reported that prophylaxis using high-dose MTX or IT MTX did not affect rates of CNS relapse in patients with DLBCL [41-43].

End-of-treatment PET — PET/CT and clinical evaluation should be performed four to eight weeks after completing chemotherapy.

●Complete response – Patients with PET score 1 to 3 on the five-point scale (also called Deauville score) (table 5) are considered to have a CR and should proceed to post-remission monitoring. (See 'Monitoring' below.)

●Less than CR:

•PET 4 – Patients with PET score 4 should undergo biopsy (to determine if PET activity represents primary refractory disease versus a robust inflammatory response to treatment) or PET can be repeated two weeks later to determine if the response was delayed.

•PET 5 – If PET score 5 is at a new site of activity, biopsy should be performed to exclude an infectious or inflammatory cause. If it is at a site of previous disease, biopsy is generally not needed and the patient should be treated as primary refractory DLBCL. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Relapse <12 months or primary refractory DLBCL'.)

MONITORING — Patients should be monitored for relapse and treatment-related complications. Routine imaging should be avoided in asymptomatic patients to limit radiation exposure.

●Preferred schedule – We schedule patient visits every three months during the first year, every three to six months during the second year, and once or twice annually in years three to five. At these visits, we perform a history and physical examination, complete blood count, chemistries, and lactate dehydrogenase (LDH).

●No routine imaging – We do not perform routine imaging in asymptomatic individuals, given concerns about radiation exposure and the risk for second malignancies, especially in younger individuals [44-46]. Most relapses of DLBCL are symptomatic and they are only rarely identified solely by routine imaging [47,48]. Most relapses occur during the first two years after completion of treatment [49,50] and detecting a relapse a few weeks earlier because of more intense monitoring is unlikely to improve outcomes.

In a retrospective study of more than 500 patients with DLBCL, 20 percent relapsed after achieving a CR [51]. Two-thirds of relapses were identified prior to a scheduled follow-up visit, while <2 percent were identified by surveillance imaging before the development of clinical manifestations. There was no difference in survival after relapse among those detected by imaging versus clinical manifestations. Another population-based study found similar survival rates among patients whose follow-up either included (Danish registry) or did not include (Swedish registry) routine CT [52].

Assessment of a possible relapse is discussed separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit".)

POST-REMISSION MANAGEMENT — There is no evidence to support routine post-remission treatment in patients with advanced stage DLBCL, such as consolidation with autologous hematopoietic cell transplantation (HCT), maintenance therapy, or consolidative radiation therapy (RT).

Consolidation — For patients who achieved a complete response (CR) after induction therapy, we suggest observation rather than consolidation with autologous HCT. Autologous HCT is associated with substantial toxicity and, according to a meta-analysis and multiple phase 3 trials, did not improve survival compared with patients who did not undergo transplantation.

●A Cochrane systematic review and meta-analysis of 15 randomized controlled trials (3079 patients) of aggressive non-Hodgkin lymphoma reported that outcomes were similar for patients who underwent autologous HCT compared with patients observed without transplantation [53]. There was no significant difference in overall survival (OS; hazard ratio [HR] 1.04 [95% CI 0.91-1.18]), event-free survival (EFS; HR 0.93 [95% CI 0.81-1.07]), or treatment‐related mortality (TRM; 6.0 percent with HCT; odds ratio [OR] 1.33 [95% CI 0.91-1.93]). There was no survival difference when stratified according to International Prognostic Index (IPI) categories (ie, low and low‐intermediate IPI or high‐intermediate and high risk IPI).

●Phase 3 trials of autologous HCT in patients with higher-risk DLBCL have not shown a survival advantage with transplantation. Examples include:

•An Italian trial (DLCL04) randomly assigned 399 patients (≤65 years) to autologous HCT versus observation after receiving either eight cycles of R-CHOP-14 or six cycles of R-Mega-CHOP-14 [54]. There was no difference in five-year OS (78 percent with HCT versus 77 percent without transplantation), but transplantation was associated with higher two-year failure-free survival (FFS; 71 versus 62 percent), but more grade ≥3 hematologic adverse events (92 versus 68 percent).

•In an earlier Italian trial, 246 patients with high-intermediate or high IPI scores were randomly assigned to eight cycles of R-CHOP-14 versus three cycles of higher-intensity induction therapy (higher-dose doxorubicin, vincristine, prednisone) followed by autologous HCT [55]. There was no difference between trial arms in three-year OS (74 versus 77 percent, respectively), three-year EFS (62 versus 65 percent), or CR (78 versus 76 percent). Three-year disease-free survival (DFS) favored R-CHOP-14, but it did not translate into superior OS because it was offset by more transplantation-associated hematologic toxicity and infectious complications.

•An intergroup trial (S9704) reported no improvement in outcomes with autologous HCT among 397 patients with high-intermediate-risk and high-risk age-adjusted IPI scores; importantly, one-third of the patients in this trial received CHOP without rituximab [56]. Patients with at least a partial response to five cycles of CHOP-based therapy were randomly assigned to three more cycles (eight cycles total) versus one more cycle of chemotherapy followed by autologous HCT. Although two-year progression-free survival (PFS) was higher with transplantation (69 versus 55 percent), there was no difference in two-year OS (74 versus 71 percent).

•In another phase 3 trial, 162 patients with aggressive B cell lymphoma and high-intermediate or high risk age-adjusted IPI score were randomly assigned to R-CHOEP-14 (R-CHOP-14 plus etoposide) versus dose-escalated high-dose therapy (R-MegaCHOEP) followed by autologous HCT [57]. With median follow-up of 42 months, compared with the R-MegaCHOEP/HCT arm, R-CHOEP-14 resulted in similar estimated three-year EFS (70 versus 61 percent) and OS (74 versus 70 percent). Grade ≥3 hematologic and non-hematologic toxicities were more common with R-MegaCHOEP/HCT. A similar trial conducted by the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) reported no benefit for autologous HCT compared with rituximab-based aggressive conventional chemotherapy (R-CHOP plus etoposide 300 mg/m2 every two weeks) [58].

•A French trial (GOELAMS 075), presented as in abstract form, reported no difference in three-year PFS for patients randomly assigned to eight cycles of R-CHOP-14 versus intensive therapy followed by autologous HCT (two courses of high-dose R-CHOP-like treatment, one cycle of high-dose methotrexate with cytarabine, followed by transplantation) [59]. Three-year PFS did not differ between trial arms (76 versus 83 percent).

Maintenance therapy — There is no proven benefit for maintenance therapy following initial treatment of advanced stage DLBCL.

Maintenance therapy with either rituximab or lenalidomide can improve FFS in patients who achieve CR, but neither agent improves OS. We do not routinely offer maintenance therapy following R-CHOP for advanced DLBCL, because we judge that improved FFS, but not OS, does not outweigh the costs, inconvenience, and toxicity of maintenance therapy.

Studies of maintenance therapy for DLBCL include:

●Rituximab – A multicenter trial randomly assigned maintenance rituximab versus observation to 415 adults ≥60 years old who achieved CR after either R-CHOP or CHOP [9]. After three years, compared with observation, patients who received maintenance rituximab had improved FFS (53 versus 46 percent) but no difference in OS; the FFS benefit was limited to patients who previously received CHOP, but not R-CHOP. Longer-term follow-up, reported in abstract form, also did not demonstrate an OS benefit of maintenance rituximab in this setting [60].

●Lenalidomide – A trial randomly assigned 650 older patients (60 to 80 years old) who achieved CR or partial response to R-CHOP therapy to receive maintenance lenalidomide versus placebo [61]. Lenalidomide resulted in superior PFS (HR, 0.7; 95% CI 0.54-0.93) after three years follow-up but did not improve OS after 52 months. Lenalidomide was associated with more grade ≥3 neutropenia (56 versus 22 percent, respectively) and cutaneous reactions (5 versus 1 percent) than placebo. Longer-term follow-up (>6 years) of this trial reported that lenalidomide maintenance did not lower the incidence of CNS relapses [62].

Adjunctive radiation therapy (RT) — There is no demonstrated role for routine consolidation with RT after achievement of a CR in a patient with advanced stage DLBCL. In selected patients, RT may be considered to isolated skeletal metastases, paraspinal disease, or for an older patient with residual PET activity in initially bulky disease.

No randomized trials of adjuvant/consolidative RT for bulky advanced stage DLBCL have been conducted in the rituximab era. While RT might decrease local relapses, it is unlikely to decrease systemic relapse [63-65].

Retrospective and observational studies of RT for advanced stage DLBCL have reported mixed results [63,64,66,67]:

●The impact of RT was compared across studies in older adults (61 to 80 years) with initial bulky disease (≥7.5 cm) who were treated with six cycles of R-CHOP-14 [68]. Patients enrolled in the RICOVER-60 trial were given 36 Gy RT for bulky disease or extralymphatic disease (regardless of the response to chemotherapy) and were compared with patients in an expansion cohort of the trial who received the same chemotherapy without RT; the groups were not matched for clinical risk factors and use of RT was not randomized. For patients with stage III/IV DLBCL, there was no difference in OS, PFS, and EFS for treatment with RT versus no RT.

●A single-institution study reported that among 279 patients with advanced stage disease (most treated with R-CHOP), 39 had bulky disease (>5 cm) and 23 were given RT [64]. Compared with those who did not receive RT, patients treated with RT had superior five-year OS (89 versus 66 percent) and PFS (76 versus 55 percent), but RT did not affect the outcomes in a matched-pair analysis.

●Analysis of 24 patients with stage III/IV DLBCL and bulky disease who received CHOP without RT, only 10 percent of relapses were at the site of bulk disease, while 90 percent of relapses occurred at distant sites [63].

CHEMOIMMUNOTHERAPY REGIMENS

R-CHOP — R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) given every 21 days has been standard care for DLBCL for decades. Comparisons of R-CHOP-21 versus other chemoimmunotherapy regimens for advanced stage DLBCL are presented above. (See 'Choice of regimen' above.)

●Administration – Six cycles of R-CHOP are given for advanced stage DLBCL, as described above. (See 'Choice of regimen' above.)

Details of drug doses, schedule, and supportive care are presented in the accompanying table (table 6). We cap the total vincristine dose at 2 mg to limit neurotoxicity; some experts instead cap the vincristine dose at 3 mg [69]. Grade ≥3 adverse events (AEs) are predominantly neutropenia, anemia, and peripheral neuropathy.

●Outcomes – The efficacy of R-CHOP in advanced stage DLBCL has been demonstrated in multiple phase 3 trials.

Treatment with six cycles of R-CHOP was associated with 90 percent six-year overall survival (OS) and 80 percent progression-free survival (PFS) in patients 18 to 60 years in the MInT trial [13]. R-CHOP-21 was associated with 81 percent two-year OS and 75 percent two-year PFS in patients ≥21 years [27]. Similar outcomes were reported for patients ≥60 years; three-year OS was 67 percent and three-year failure-free survival (FFS) was 53 percent [9]. Eight cycles of R-CHOP in adults 60 to 80 years was associated with 44 percent 10-year OS and 37 percent 10-year PFS [7].

R-pola-CHP — R-pola-CHP (rituximab, polatuzumab vedotin, doxorubicin, prednisone) is an effective treatment for advanced stage DLBCL.

●Administration – R-pola-CHP resembles R-CHOP-21 but replaces vincristine with polatuzumab vedotin [20]. Grade ≥3 AEs are predominantly neutropenia, anemia, and a low incidence of peripheral neuropathy.

●Outcomes – R-pola-CHP was associated with 89 percent two-year OS, which was similar to R-CHOP, but 77 percent two-year PFS and 76 percent two-year event-free survival (EFS) were superior to R-CHOP in the phase 3 POLARIX trial [20]. Toxicity of the two regimens was similar; grade ≥3 AEs with R-pola-CHP were primarily cytopenias, febrile neutropenia, and 1.6 percent grade ≥3 peripheral neuropathy. (See 'Choice of regimen' above.)

The US Food and Drug Administration (FDA) approved polatuzumab vedotin together with R-CHP for initial treatment of adults with DLBCL.

SPECIAL SCENARIOS — The principles for treating advanced stage DLBCL that are described above (see 'Initial therapy' above), apply to most disease presentations and patient populations, but certain scenarios have distinctive therapeutic implications.

Older adults — Older patients with DLBCL generally have a worse prognosis compared to younger patients due, in part, to more comorbid conditions and lower treatment tolerance.

For patients >80 years with adequate heart, kidney, and liver function and for patients 60 to 80 years with modest impairments, we generally treat with R-mini-CHOP to reduce adverse effects (AE) associated with more intensive regimens.

●Pretreatment evaluation – For older patients, a comprehensive geriatric assessment can aid assessment of comorbid conditions and functional status and facilitate formulation of an appropriate, individualized treatment plan [70-73]. Special considerations for the use of chemotherapy in older patients are discussed separately. (See "Comprehensive geriatric assessment for patients with cancer" and "Systemic chemotherapy for cancer in older adults".)

●Treatment – Our preferred approach for older adults who are unable to tolerate standard doses of R-CHOP-21 is treatment with R-mini-CHOP (rituximab 375 mg/m2, cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, vincristine 1 mg on day 1 of each cycle, 40 mg/m2 prednisone on days 1 to 5) [74].

A pre-treatment phase of a systemic steroid, with or without rituximab, may improve the patient's performance status (PS) and facilitate treatment with R-mini-CHOP.

Frail patients who require symptom palliation but cannot tolerate R-mini-CHOP may benefit from a systemic steroid (with or without rituximab) or single chemotherapeutic agents.

●Outcomes – There are limited data regarding treatment of older patients with DLBCL, but R-mini-CHOP appears to cure some patients [74-78]:

•A multicenter study reported outcomes after six cycles of R-mini-CHOP in 150 patients >80 years with DLBCL (75 percent stage III or IV) [74]. With median follow-up of 20 months, two-year overall survival (OS) and progression-free survival (PFS) were 59 and 47 percent, respectively; overall response rate (ORR) was 74 percent (including 63 percent complete response [CR]). Treatment-related mortality (TRM) occurred in 8 percent, grade ≥3 neutropenia and thrombocytopenia 39 and 7 percent, respectively; and 7 percent experienced febrile neutropenia.

•Analysis of the Surveillance, Epidemiology, and End Results (SEER) database identified 1156 patients >80 years old who had DLBCL [79]. Compared with younger patients with DLBCL, older adults were less likely to receive R-CHOP; instead, they were more likely to receive R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) or to be observed. R-CHOP was the only treatment regimen associated with improved OS (hazard ratio [HR] 0.45; 95% CI 0.33-0.63) and lymphoma-related survival (HR 0.58; 95% CI 0.38-0.88), according to multivariate analysis.

•Retrospective analysis of more than 600 patients ≥60 years with DLBCL who were treated with full-dose R-CHOP every 14 days or every 21 days reported five-year OS of 69 percent (95% CI 65-73 percent) [80]. For both schedules, ≥98 percent of planned doses of all agents were administered; treatment-related deaths were <2 percent. Grade ≥3 AEs occurred in two-thirds of patients in both arms, but R-CHOP-21 was associated with less thrombocytopenia (7 versus 12 percent), but a more neutropenia (61 versus 36 percent), presumably due to less use of granulocyte colony-stimulating factor [G-CSF] with R-CHOP-21).

•The SMARTE-R-CHOP-14 study evaluated the addition of eight additional rituximab doses after six cycles of R-CHOP-14 in 189 older adults (age 61 to 80 years) with DLBCL [81]. Three-year OS was 84 percent, three-year event-free survival (EFS) was 71 percent, and 85 percent had a CR or unconfirmed CR. Compared with historical controls in the RICOVER-60 trial who were treated with six cycles of R-CHOP-14 (without the extra rituximab doses), the additional doses of rituximab were associated with improved three-year OS (80 versus 67 percent) and EFS (67 versus 54 percent), but only in those patients with a high International Prognostic Index (IPI) score (IPI 3 to 5) (table 3).

Older adults have greater pharmacokinetic variability and this may differ by sex. Compared with older men and younger patients of both sexes, older women have reduced rituximab clearance, resulting in higher serum levels and prolonged exposure times. A post hoc analysis of patients enrolled in six prospective clinical trials of rituximab reported that the incremental benefit attributed to rituximab was greatest among older females [82], which may relate to prolonged exposure times.

Heart disease — Treatment of the patient with heart disease must be individualized, as there is no preferred regimen. Although standard therapy for DLBCL includes an anthracycline, good outcomes can be achieved in patients with significant heart disease. Risk factors, prevention, and management of anthracycline cardiotoxicity is discussed separately. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Referral for cardiology consultation can aid treatment planning and management.

Treatment options include:

●Anthracycline-containing regimens – Doxorubicin (or other anthracyclines) should not be administered to patients with a baseline ejection fraction (EF) <30 percent.

For EF ≥30 percent, pegylated liposomal doxorubicin may permit substantially higher cumulative doses with an efficacy that is equivalent to other anthracyclines but a lower incidence of heart failure [83]. Administration of dexrazoxane may lessen anthracycline cardiac toxicity. Use of anthracyclines in patients with heart disease is discussed in detail separately. (See "Risk and prevention of anthracycline cardiotoxicity".)

Mitoxantrone is not a safe alternative in patients with cardiac disease and produces inferior results [84].

●Non-anthracycline regimens – Non-anthracycline-based combination chemotherapy may be acceptable when treatment with an anthracycline is not an option [85]. Intravenous fluid requirements must also be considered; as an example, cisplatin-containing regimens are active in DLBCL, but may require too much fluid administration for a patient with heart failure.

The choice of a chemotherapy regimen should be individualized, but either of the following may be acceptable:

•R-GCVP – A phase 2 study investigated treatment with R-GCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone) in 62 patients with advanced stage DLBCL (median age 77 years) who were unfit for anthracycline-containing chemotherapy because of heart disease; 60 percent had ischemic heart disease and 44 percent had a left ventricular ejection fraction ≤50 percent [86]. Two-thirds of patients received >3 cycles and half were able to complete six cycles. Two-year OS was 56 percent, two-year PFS was 50 percent, and ORR was 61 percent (29 percent CR). Grade ≥3 cardiac AEs were reported in 8 percent and three patients had fatal cardiac events; 55 percent had grade ≥3 hematologic toxicity.

•R-CEOP – Outcomes for 70 patients treated with R-CEOP (rituximab, cyclophosphamide, etoposide, prednisone, procarbazine) were similar to those for 140 patients (matched for age, clinical stage, and IPI score) who were treated with R-CHOP [87]. OS after 10 years was lower in the R-CEOP group (30 versus 49 percent), reflecting the impact of underlying comorbidities and frailty of this population, but 10-year time to progression and disease-specific survival were not significantly different.

Other high-grade B cell lymphomas

AIDS-related lymphomas — The diagnosis of a non-Hodgkin lymphoma in a patient living with HIV is an acquired immunodeficiency syndrome (AIDS)-defining malignancy.

Treatment with curative intent for AIDS-related DLBCL can offer a reasonable expectation of success but is complicated by the immunocompromised state and requires treatment for the HIV infection. Joint management with an infection/immunity team is essential.

Management of AIDS-related lymphomas is discussed separately. (See "HIV-related lymphomas: Treatment of systemic lymphoma".)

High-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6 ("double-hit") — Double-hit lymphoma is a colloquial term for high-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6; this is an aggressive type of B cell lymphoma that is distinct from DLBCL, according to the 2017 World Health Organization (WHO) classification [1,88]. Note that this category does not refer to so-called "double-expressor" DLBCL, which can have rearrangement of MYC, but does not include rearrangement of BCL2 or BCL6. High-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6 is associated with inferior prognosis, compared with DLBCL, as discussed separately. (See "Prognosis of diffuse large B cell lymphoma", section on 'MYC, BCL2, BCL6 abnormalities'.)

●Choice of treatment – For patients with high-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6, we encourage participation in a clinical trial.

Outside of a clinical trial, we generally treat with dose-adjusted (da)-R-EPOCH or another an intensive regimen, based on improved outcomes in a meta-analysis of 11 studies [89]. Intensive regimens are generally associated with excessive toxicity in older or less-fit patients.

●Dose-adjusted R-EPOCH – Administration of (da)-R-EPOCH requires hospitalization because etoposide, doxorubicin, and vincristine are infused over 96 hours. We generally treat with six cycles of (da)-R-EPOCH; doses of etoposide, doxorubicin, and cyclophosphamide are adjusted based upon the nadir absolute neutrophil count and platelet counts [90]. AEs include infections and cytopenias; we generally administer G-CSF and prophylaxis for Pneumocystis jiroveci pneumonia and other opportunistic infections. Details of (da) R-EPOCH drug doses, schedule, and supportive care are presented in the accompanying table (table 7).

●Other intensive regimens – For younger, fit patients, some experts favor treatment with intensive regimens, such as R-CODOX-M/IVAC ("Magrath regimen"; rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine) (table 8) or R-hyperCVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine).

●Outcomes – Compared with R-CHOP, more intensive treatments for high-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6 are associated with longer PFS, but not superior OS:

•A systematic review and meta-analysis of 11 retrospective studies (394 patients) reported that, compared with R-CHOP, treatment with (da)-R-EPOCH was associated with delayed progression (median 22 versus 12 months, hazard ratio [HR] 0.66; 95% CI 0.44-0.96), but this did not translate into improved OS (median 31 versus 21 months; HR 0.77, 95% CI 0.51-1.13) [89].

•A multicenter study of 311 patients reported that, compared with R-CHOP, (da)-R-EPOCH achieved superior PFS, but similar OS [91]. This study also reported that autologous hematopoietic cell transplantation (HCT) was not associated with improved outcomes.

•Another multicenter study reported that, compared with R-CHOP, treatment with an intensive regimen (eg, [da]-R-EPOCH, R-HyperCVAD/MA, R-CODOX-M/IVAC) was associated with superior three-year relapse-free survival (RFS; 88 versus 56 percent, respectively) among 159 patients with double-hit lymphoma [92]. Three-year RFS and OS for the entire cohort were 80 and 87 percent, respectively.

●Post-remission management – A benefit for autologous HCT in first CR (CR1) of high-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6 has not been demonstrated.

For younger, fit patients who achieved CR after R-CHOP (rather than a more intensive regimen), the risks and benefits of autologous HCT should be discussed with a transplant physician. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

A retrospective multicenter study reported that OS and RFS did not differ for 62 patients who underwent autologous HCT in CR1, compared with 97 who were not transplanted [92]. For the entire cohort of patients, three-year OS was 87 percent and three-year RFS was 80 percent. In another retrospective multicenter study, transplantation was not associated with improved survival among patients who attained CR [91]. Median OS did not differ for the 39 patients who underwent HCT in CR1 (28 autologous HCT; 11 allogeneic HCT) compared with those who were observed without HCT.

Other categories — Some other high-grade B cell lymphomas that were previously considered DLBCL variants are now classified as distinctive categories, according to the WHO classification (table 9) [1].

We encourage participation in a clinical trial, as there is no consensus for treatment of these high-grade lymphomas.

●High grade B cell lymphoma, not otherwise specified (NOS) – Most patients are older (median 70 years) and outcomes with standard treatment are generally poor; median OS of 2.5 to 18 months has been reported with R-CHOP [93-96]. Because of age or comorbidities, most patients are not candidates for aggressive regimens that are commonly used for high-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6. (See 'High-grade lymphoma with rearrangements of MYC plus BCL2 and/or BCL6 ("double-hit")' above.)

●B cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma – Outside of a clinical trial, we generally treat with R-CHOP or a related approach, with or without radiation therapy, as with primary mediastinal large B cell lymphoma. (See "Primary mediastinal large B cell lymphoma", section on 'Treatment'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of diffuse large B cell lymphoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Diffuse large B cell lymphoma (The Basics)" and "Patient education: What are clinical trials? (The Basics)" and "Patient education: Neutropenia and fever in people being treated for cancer (The Basics)" and "Patient education: Nausea and vomiting with cancer treatment (The Basics)" and "Patient education: Hair loss from cancer treatment (The Basics)" and "Patient education: When your cancer treatment makes you tired (The Basics)")

●Beyond the Basics topics (see "Patient education: Diffuse large B cell lymphoma in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Diffuse large B cell lymphoma (DLBCL) – DLBCL is the most common category of non-Hodgkin lymphoma (NHL). Advanced stage refers to stage III or IV disease, which accounts for two-thirds of patients with DLBCL.

●Pretreatment evaluation – Pretreatment evaluation includes disease staging (table 1) with positron emission tomography (PET)/computed tomography (CT) and application of the International Prognostic Index (IPI) (table 3) and central nervous system (CNS) IPI. (See 'Pretreatment evaluation' above.)

●Treatment

•Incorporation of rituximab – We recommend including rituximab with remission induction chemotherapy, rather than chemotherapy alone (Grade 1A). (See 'Incorporation of rituximab' above.)

•Choice of induction therapy – We suggest initial treatment with either six cycles of R-CHOP (rituximab, doxorubicin, cyclophosphamide, vincristine, prednisone) or six cycles of R-pola-CHP (rituximab, polatuzumab vedotin, cyclophosphamide, doxorubicin, prednisone) (Grade 2B). (See 'Choice of regimen' above.)

•CNS management – For patients with high risk for CNS relapse (eg, CNS IPI score 4 to 6 or testicular involvement), we consider incorporating CNS prophylaxis into induction therapy, according to patient and clinician preference. CNS prophylaxis has not been proven to prevent CNS relapses in the R-CHOP era. (See 'CNS management' above.)

●Monitoring – Patients are followed clinically for evidence of relapse; we do not perform routine PET/CT for monitoring asymptomatic patients. (See 'Monitoring' above.)

●Post-remission management – (See 'Post-remission management' above.)

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