Diagnosis and Management of Diffuse Large B-Cell Lymphoma: Society of Medical Oncology, Pakistan Society of Hematology, and Pakistan Society of Clinical Oncology Joint Clinical Practice Guideline

Diffuse large B-cell lymphoma (DLBCL) is the commonest non-Hodgkin lymphoma encountered by hematopathologists and oncologists. Management guidelines for DLBCL are developed and published by countries with high income and do not cater for practical challenges faced in resource-constrained settings. This report by a multidisciplinary panel of experts from Pakistan is on behalf of three major national cancer societies: Society of Medical Oncology Pakistan, Pakistan Society of Hematology, and Pakistan Society of Clinical Oncology. The aim is to develop a practical and standardized guideline for managing DLBCL in Pakistan, keeping in view local challenges, which are similar across most of the low- and middle-income countries across the globe. Modified Delphi methodology was used to develop consensus guidelines. Guidelines questions were drafted, and meetings were convened by a steering committee to develop initial recommendations on the basis of local challenges and review of the literature. A consensus panel reviewed the initial draft recommendations and rated the guidelines on a five-point Likert scale; recommendations achieving more than 75% consensus were accepted. Resource grouping initially suggested by Breast Health Global Initiative was applied for resource stratification into basic, limited, and enhanced resource settings. The panel generated consensus ratings for 35 questions of interest and concluded that diagnosis and treatment recommendations in resource-constrained settings need to be based on available resources and management expertise.


INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) is the commonest non-Hodgkin lymphoma encountered by hematopathologists and oncologists. 1,2 A study from Southern Pakistan reported higher DLBCL frequency (76.4%) and a younger median age (47.2 years) among newly diagnosed non-Hodgkin lymphoma patients compared with the Western data. 3 Management guidelines for DLBCL are developed and published by countries with high income and do not cater for practical challenges faced in the low-resource countries. This report by a multidisciplinary panel of experts from Pakistan is on behalf of three major national cancer societies: Society of Medical Oncology Pakistan, Pakistan Society of Hematology, and Pakistan Society of Clinical Oncology. The aim is to develop a practical and standardized guideline for managing DLBCL in Pakistan, keeping in view local challenges which are similar across most of the low-and middle-income countries across the globe.

Methodology
The modified Delphi method was used to generate consensus statement as recommended by the ASCO. [4][5][6] Literature search was done using PubMed, Embase, and Web of Science. A steering committee comprising seven members reviewed the evidence and drafted initial recommendations after appropriate rationale. A guideline panel comprising 23 experts was formed, which rated the guidelines forwarded by the steering committee on a five-point Likert scale (strongly agree = 1 point to strongly disagree = 5 points). The ratings were accepted if consensus ≥ 75% was achieved.
We used the resource grouping suggested by Breast Health Global Initiative 7 and applied this to DLBCL.
Author affiliations and support information (if applicable) appear at the end of this article.
1. Basic: Basic-level services are typically provided in a single clinical interaction and include patient review by general practitioners and nononcology fellows. 2. Limited: In addition to basic resources, these are second-tier services that may involve multiple clinical interactions. The aim is timely and accurate diagnosis and to proceed with evidence-based treatments with an aim to produce major improvements in outcome.
3. Enhanced: In addition to basic and limited resource level services, enhanced services will provide third-tier diagnostic and management services required for patients requiring high-intensity chemotherapy and hematopoietic stem-cell transplant (HSCT) for relapsed-refractory or high-risk patients.
Detailed distribution of resource environments as per resource availability is summarized in Table 1. Level of evidence and grading recommendations 8 are listed in Table 2. Summary of resource-guided interventions is mentioned in Table 3.

CONTEXT Key Objective
To develop management guidelines for patients with diffuse large B-cell lymphoma (DLBCL), keeping in view the challenges faced in resource-limited countries. Knowledge Generated This report by a multidisciplinary panel of experts from Pakistan is on behalf of three major national cancer societies, namely Society of Medical Oncology Pakistan, Pakistan Society of Hematology, and Pakistan Society of Clinical Oncology. Consensus guidelines are generated for diagnosis and management of patients with newly diagnosed and relapsed refractory DLBCL patients. Relevance Management guidelines for DLBCL are developed by countries with high income and do not cater for practical challenges faced in resource-constrained settings. These guidelines are developed keeping in view local challenges, which are similar across most of the low-and middle-income countries across the globe. In cases with leukemic presentation and tissue biopsy inconclusive, for detection of lymphoma cells in pleural fluid, ascitic fluid, or CSF. f A certified hematopathologist or a histopathologist with adequate experience in lymphoma reporting should be available. Complete IHC panel will include CD45, CD20, CD79a, CD10, BCL2, BCL6, MYC, Ki67, MUM1/IRF4, Cyclin D1, CD5, CD23, and EBER-ISH.

GUIDELINE QUESTIONS
1. Diagnosis 1.1. Which essential investigations are required for the diagnosis of DLBCL-not otherwise specified (NOS)? A surgical excisional biopsy is widely accepted as the gold standard for diagnosis of lymphoma (1A). 9,10 Core needle biopsies offer an alternative to excisional or incisional biopsy but frequently yield small and insufficient sample. Fineneedle aspiration is discouraged (IIA). 10,11 For rare cases, bone marrow (BM) examination or microscopic evaluation of pleural fluid, ascitic fluid, and cerebrospinal fluid by cell block histology and confirmation by immunohistochemistry (IHC; limited/extended) or flow cytometry may be required to establish the diagnosis. For cases of suspected primary CNS lymphoma, it is preferable to refer patient to enhanced resource setting for evaluation. Typical morphologic features of DLBCL include complete effacement of normal architecture by sheets of atypical large cells. Tumor cells are large and often resemble centroblasts or immunoblasts. Diagnosis of primary mediastinal B-cell lymphoma (PMBCL) can be made with characteristic clinical presentation and morphology, presence of pan-B markers, and additional staining of CD30, CD200, and TRAF-1.
Once a diagnosis is given, the patient enters treatment pathway. It is therefore imperative that a correct diagnosis is made within the available resources. 12 Basic resources Timely referral to the subject experts for diagnosis and management without advising biopsy or radiologic investigations requiring long waiting times (100% agreement).
Limited resources Excisional/incisional biopsy is preferred. Morphologic diagnosis of DLBCL needs to be confirmed by using limited IHC, CD3, and CD20 (IIIB) 13 ; 91% agreement (one suggestion to include Hans algorithm for all cases, one panelist suggested use of only CD3 and CD20 for IHC).
Enhanced resources It is recommended to include CD 3, CD 20, CD 10, BCL6, BCL2, C-MYC, CD 30, Ki-67, MUM1, and cyclin D1 9 to confirm diagnosis, document cell of origin (COO), and differentiate DLBCL from doubleexpressor lymphomas (DEL). For characteristic morphology with CD20-negative biopsy, CD138 and leukocyte common antigen are indicated to rule out plasmablastic lymphoma. For cases with immunoblastic morphology, Epstein-Barr virus-encoded RNA in situ hybridization is recommended; 95% agreement (one panelist suggested use of CD3 and CD20 IHC only). Limited resources Not recommended routinely. Selected cases at high risk of MYC positivity (ki67% . 90%, early relapse or refractory disease, blastoid morphology, transformation from pre-existing follicular lymphoma) can be referred to enhanced settings; 90% agreement (two suggestions not to do testing for HGBCL and BL).
Enhanced resources If feasible, all DLBCL cases need to be tested for MYC expression and further testing for MYC and BCL2/BCL6 rearrangements in case of MYC expression. 40% and BCL2 . 50% (strong and cytoplasmic). Fluorescent in situ hybridization (FISH) break-apart probes are used, and FISH testing is recommended for all DEL with germinal center-b phenotype and high Ki67 baseline CNS involvement and extensive extra nodal disease (IB) 10 : 90% agreement (two suggestions not to do testing for HGBCL and BL). Limited resources Contrast-enhanced computed tomography (CT) scan of the neck, chest, abdomen, and pelvis is recommended. Positron emission tomography (PET) scan can divert resources away from treatment, and careful consideration is required when advising PET-CT scan: 95% agreement (one panelist suggested use of CT scan for all cases).  Enhanced resources PET-CT scan if clinical condition of patient permits (1B) 9,10 : 95% agreement (1 panelist suggested use of CT for all cases).

1.3.2.
What is the role of staging BM examination? Basic resources Not applicable.
Limited resources If CT scan is used for staging, BM examination is needed 10,14 : 95% agreement.

Treatment of Newly Diagnosed DLBCL
It is recommended to have hematology oncology multidisciplinary team (MDT) meetings and counseling for fertility preservation in all institutions offering enhanced-level care to patients with lymphoma. [20][21][22] If radiotherapy (RT) is part of consensus recommendation of MDT, consultation may be sought from the radiation oncologist before initiation of therapy. 23 Limited resources Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) 6 rituximab (R)* × three cycles + 30 Gy RT OR CHOP 6 R* × six cycles.
*R-CHOP is preferable (1A); however, it is not recommended to withhold treatment because of nonaffordability of rituximab, and CHOP chemotherapy can be given 25 : 95% agreement.
Enhanced resources Options include the following: i. Disease at sites with low RT morbidity (groin, neck, and axilla): three cycles of R-CHOP + RT 30 Gy (1B). 9,10 ii. For IPI = 0, provide four cycles of R-CHOP followed by two cycles of rituximab if interim PET (iPET) scan document complete metabolic response (Deauville score 1-3). 26 If IPI . 0 and disease at sites where RT needs to be avoided, provide six cycles of R-CHOP(1A). 10 iii. PET-directed therapy using three cycles of R-CHOP followed by iPET assessment. If iPET-negative (Deauville score 0-3), one additional R-CHOP without RT and if iPET-positive (Deauville score 4), an additional cycle of R-CHOP followed by RT 30 Gy and end-of-treatment (EOT) PET scan. For the Deauville score of 5, repeat biopsy is advised 27 (95% agreement, and one panelist suggested PET-directed therapy for all patients).

Limited-stage bulky ( ‡ 7.5 cm). Basic resource Not applicable.
Limited resources CHOP 6 R* for six cycles *R-CHOP is preferable (1A); however, it is not recommended to withhold treatment because of nonaffordability of rituximab, and CHOP chemotherapy can be given (100% agreement).
Enhanced resources R-CHOP for six cycles 9,10,28 : 95% agreement, and one panelist suggested PET-directed therapy for all patients. RT may be considered as per physician and patient discretion keeping in mind the risks and benefits (IIB).

What initial treatment is recommended for advancedstage DLBCL?
Over the past decade, the attempts to improve on R-CHOP with dose intensification and incorporation of novel agents have been largely futile. [29][30][31][32][33] Basic resources Not applicable.
Limited resources CHOP 6 R* for six cycles (95% agreement, and one suggestion to treat as per COO) *R-CHOP is preferable (1A); however, it is not recommended to withhold treatment because of nonaffordability of rituximab, and CHOP chemotherapy can be given.
Enhanced resources R-CHOP for six cycles (1A) 9,10,34 (95% agreement, and one suggestion to treat as per COO). RT may be considered for initial bulky disease as per physician and patient discretion (IIB).

2.3.
What is the optimal CNS prophylaxis for newly diagnosed DLBCL? Basic resources Not applicable.
Limited resources IT chemotherapy: 100% agreement. 35,36 Enhanced resources IT chemotherapy or high-dose methotrexate (HD-MTX) as per physician and patient discretion (95% agreement, and one panelist suggested use of IT chemotherapy only). 37 Basic resources Not applicable.
Limited resources CT scan for response assessment as per Lugano response assessment criteria 16 : 95% agreement, and one panelist suggested use of PET-CT.
Enhanced resources PET-CT scan: 95% agreement, and one panelist suggested the use of CT.

2.4.2.
What is the optimal time between EOT and response assessment? For patients receiving chemotherapy, CT scan needs to be done after 4 weeks and PET scan 4-8 weeks after treatment: 100% agreement. PET scan is recommended 12 weeks after RT (III B) 39  Enhanced resources No radiologic imaging for limitedstage DLBCL. CT scan every 6 months for 2 years for advanced stage may be considered, at physician discretion (95% agreement, and one panelist suggested no imaging for advanced stage disease).

2.5.
What is the role of EOT consolidative RT in patients with bulky disease? The role of RT following CR (on the basis of CT scan) was documented by German RICOVER-noRTh trial, 28 where addition of RT improved event-free survival (HR 2.1, P = .005) and a trend toward improved OS (HR 1.6, P = .127). However, a recent study by Freeman et al 40 documented that for patients with EOT-negative PET scan, RT can be avoided without increasing relapse risk and compromising OS in patients with bulky diseases at diagnosis.

Basic resources Not applicable.
Limited resources If EOT remission is documented by CT scan, RT to bulky or isolated skeletal sites as per data from RICOVER-noRTh and MInT trial. Observe without RT if PET scan is used to document CR 40 : 100% agreement.
Enhanced resources If EOT remission is documented by CT scan, RT to bulky or isolated skeletal sites as per data from RICOVER-noRTh and MInT trial. Observe without RT if PET scan is used to document CR 40 : 100% agreement.

What is the role of iPET-CT assessment in limited-stage and advanced-stage DLBCL? Basic resources Not applicable.
Limited resources Not recommended; 100% agreement.
Enhanced resources Not recommended: 95% agreement, and one suggestion to use iPET scan.

2.7.
What is the role of maintenance therapy in DLBCL? When will you offer it? Elderly patients with DLBCL relapsing after first-line chemoimmunotherapy have limited therapeutic options and poor OS. A phase III randomized REMARC trial documented that lenalidomide maintenance improved PFS versus placebo in elderly patients with DLBCL responding to first-line R-CHOP. 41,42 Basic resources Not applicable.
Limited resources Not recommended: 100% agreement.
Enhanced resources Lenalidomide maintenance (2B) for patients age 60-80 years 41 as per physician and patient discretion (86% agreement, and one suggestion to avoid, one suggestion to use in partial response [PR], and one suggestion to use in clinical trial).

How to Manage Relapsed-Refractory Patients
3.1. What investigations are to be advised for relapsedrefractory patients? The postpredictive value of a PETpositive lesion is low (50%-82%), and a rebiopsy is strongly recommended before second-line treatment. For patients with presumed CNS relapse on the basis of presentation and supportive MRI findings, repeat brain biopsy is not recommended as it provides little clinical benefit and adds to morbidity and mortality. 43 Basic resources Not applicable.
Enhanced resources Repeat biopsy (excisional, core biopsy; 1A), PET-CT (95% agreement, and one suggestion to use PET-CT only if transplant eligible). Extended IHC, cyclin D1, and Epstein-Barr virus-encoded RNA in situ hybridization need to be done.

3.2.
What salvage treatment is to be offered for relapsedrefractory patients? Basic resources Not applicable.
Limited resources If transplant eligible, gemcitabine, dexamethasone, and cisplatin (GDP) 6 R preferable because of lesser neutropenia and ease of outpatient administration. Other options include ifosfamide, carboplatin, and etoposide (ICE) 6 R, dexamethasone, cytarabine, and cisplatin (DHAP) 6 R, and referral to a transplant facility if in CR or PR (95% agreement, and one suggestion to use ICE 6 R preferably and use salvage only if transplant eligible).
Enhanced resources ICE 6 R, DHAP 6 R, and GDP 6 R salvage followed by autologous HSCT (AHSCT) consolidation if in CR or PR. Rituximab to be included if disease relapsed after 6 months and rebiopsy shows CD20 expression. For primary refractory DLBCL, rituximab can be omitted in salvage (NCCN ver 4.2021) (95% agreement, and one suggestion to use ICE 6 R preferably and use salvage only if transplant eligible).

3.3.
What further treatment will you offer to patients not responding to first-line salvage? Basic resources Not applicable.
Limited resources Option of palliative versus novel agents needs to be discussed depending on transplant eligibility and patient resources/wishes. Referral to centers with enhanced resources if patient wants to pursue further treatment with curative intent: 95% agreement, and one panelist suggested palliation for all cases.
Enhanced resources For patients with available resources and good functional status, options include polatuzumab + bendamustine + rituximab. Patients with MYD-88 mutation have shown impressive responses to ibrutinib. Alternatively , brentuximab vedotin (CD30-positive lymphoma), blinatumomab and tafasiamab can be considered 34 : 91% agreement, and two panelists suggested palliation for all cases. Limited resources Not recommended in CR1: 100% agreement.
Enhanced resources Not recommended in CR1: 100% agreement.

Transplant indications in relapsed-refractory DLBCL. Basic resources Not applicable.
Limited resources Second complete remission (CR2) and beyond: 95% agreement, and one suggestion to offer palliation.
Enhanced resources CR2 and beyond. Some cases can be offered transplant in PR if chemosensitive: 95% agreement, and one suggestion to offer palliation.

4.4.
Till what age will you offer AHSCT to patients with DLBCL with otherwise good functional status and low hematopoietic stem-cell transplant comorbidity index score? For patients age , 65 years with good performance status, Eastern Cooperative Oncology Group (ECOG) 0-1, and no major organ dysfunction, AHSCT can be considered: 100% agreement.

What are the indications for allogenic HSCT in DLBCL?
Recommended in the following subsets of patients 45 (100% agreement): i. Relapsing after autologous HSCT (IIB) ii. Those failing to harvest stem cells for autologous transplant (IIB) iii. Richter transformation (IIB)

Management of Special Circumstances
5.1. How will you manage limited-stage and advanced-stage DLBCL in pregnancy? Management of lymphoma in pregnancy requires management by MDT. Diagnosis and staging of lymphoma require investigations with an aim to minimize radiation exposure to mother. Whole-body MRI, xray chest, and ultrasonography are preferable in this context as per resource availability.
First trimester Pregnancy termination is recommended. For selected cases with limited-stage disease and unwilling for termination, watchful waiting till second trimester 46 (100% agreement).
Second and third trimesters CHOP/R-CHOP can be administered after first trimester. Risk of fetal malformations is not increased; however, risk of preterm birth is higher. 47 Methotrexate needs to be avoided throughout pregnancy: 95% agreement, and one suggestion to delay chemotherapy till delivery.
Delivery and lactation Delivery to be scheduled 2-3 weeks after cycle completion and breastfeeding is discouraged for patients receiving chemotherapy in the last trimester (100% agreement).

What treatment will you offer to patients with Richter's transformation? Basic resources Not applicable.
Limited resources R-CHOP 21 and if in CR and transplant eligible, referral for reduced-intensity conditioning allogeneic HSCT consolidation: 95% agreement, and one panelist suggested observation after chemotherapy.
Enhanced resources R-CHOP 21 and if CR after chemoimmunotherapy, consolidation with reducedintensity conditioning allogeneic HSCT. 48 For patients not responding to first-line R-CHOP, other options include R-GDP, R-DHAP, and R-ICE. Off-label use of rituximab + lenalidomide + ibrutinib (RLI), checkpoint inhibitors, and venetoclax: 95% agreement, and one panelist suggested observation after chemotherapy.

5.3
. What treatment will you offer as upfront therapy for PMBCL. Because of lack of randomized trials, optimal firstline treatment in patients with PMBCL is unknown. Aviles et al reported the use of RT as adjuvant treatment in patients with CR after six cycles of R-CHOP and documented improvement in the PFS and OS with minimal toxicities. 49 PET-directed approach to omit RT for EOT PET-negative patients is supported by recent studies 50,51 and currently being evaluated in the IELSG37 trial. A phase II trial conducted by the National Cancer Institute using DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) without radiation documented a 5-year event-free survival of 93% among 51 patients.
Limited resources R-CHOP + RT if CT scan is used for remission assessment. For PET-based EOT assessment, RT can be omitted (optional as per physician and patient preference) if EOT PET is negative (41): 95% agreement, and one panelist suggested CT imaging.
Enhanced resources DA-EPOCH-R preferred. The other option is R-CHOP 6 RT as per EOT PET response: 95% agreement, and one panelist suggested R-CHOP and CT imaging.

5.4
. What treatment will you offer to patients with testicular lymphoma? Testicular involvement in DLBCL is associated with increased CNS involvement at diagnosis, increased risk of CNS relapse, and adverse prognosis.

5.5.
What is the optimal first-line treatment for patients with DEL and DHL? Basic resources Not applicable.
Limited resources DEL: six × R-CHOP + ITchemotherapy DHL: Referral to enhanced resource setup for intensive regimens. If referral not possible, it is suggested to give six × R-CHOP with IT chemotherapy (95% agreement).
Enhanced resources DEL: six × R-CHOP + IT chemotherapy/HD-MTX DHL: six × DA-EPOCH-R + IT chemotherapy/HD-MTX (95% agreement, and one panelist suggested R-CHOP and IT chemotherapy for DHL) 5.6. How to manage elderly patients with DLBCL? 5.6.1. What age limit will you consider for classifying patients as elderly in Pakistani population? Generally, geriatric assessment needs to be done routinely for patients age . 60 years; 100% agreement. 5.6.2. What factors will you consider in deciding upfront treatment (curative v palliative)? Use of ECOG alone is not recommended to decide upfront treatment. Elderly patients with low Charlson Comorbidity Index (CCI) score and low Cumulative Illness Rating Scale-Geriatric (CIRS-G) score are candidates for curative therapy 36 : 95% agreement, and one panelist suggested low-intensity treatment for all patients age . 60 years. 5.6.3. How will you approach management of newly diagnosed elderly patients with DLBCL?
i. Consider steroid prephase if ECOG . 2 (2B) ii. Primary granulocyte colony-stimulating factor prophylaxis for patients age . 65 years or those who are frail and with significant comorbidities (1A) iii. Dose reduction if high CCI or CIRS-G score iv. Standard R-CHOP for low CCI and CIRS-G patients age , 70 years v. R-mini-CHOP for patients age . 70 years vi. Alternatives include RLI; 53 bendamustine-rituximab; 54 R-cyclophosphamide, vincristine, and prednisolone (CVP); R-gemcitabine, cyclophosphamide, vincristine, and prednisolone (GCVP) (95% agreement, and one suggestion to avoid doxorubicin for patients age . 60 years and use CVP 6 R) 5.7. What treatment will you offer to patients with reduced ejection fraction (EF)? What cutoff of EF will you consider for treatment modification? The definition of chemotherapyrelated heart dysfunction is decline in EF of at least 5% to below 55% with accompanying signs or symptoms of congestive heart failure, or a decline in EF of at least 10% to below 55% without accompanying signs or symptoms. 55 For patients with cardiac dysfunction, substitution of doxorubicin with etoposide, gemcitabine, or liposomal doxorubicin may be considered (IIIC). 56 Basic resources. Not applicable.
5.8. How will you manage patients with concurrent CNS disease at presentation? Basic resources Not applicable.
Limited resources Referral to center with enhanced resources. Alternatively, CHOP-21 6 R with IT chemotherapy and whole-brain radiotherapy (WBRT): 95% agreement, and one suggestion to consider CHOP 6 R and HD-MTX.

5.9
. What treatment plan would you offer for primary CNS large B-cell lymphoma in first line and relapse setting in young/fit and older/less fit individuals? Newly diagnosed Limited resources WBRT, HD-MTX + temozolomide 6 rituximab, and HD-MTX + procarbazine + vincristine 6 rituximab (100% agreement).
Relapsed refractory Treatment options for relapsed refractory PCNS DLBCL are limited, and outcomes are dismal.
Basic resources Not applicable.