Management of Lymphomas: Consensus Document 2018 by an Indian Expert Group

The clinical course of lymphoma depends on the indolent or aggressive nature of the disease. Hence, the optimal management of lymphoma needs a correct diagnosis and classification as B cell, T-cell or natural killer (NK)/T-cell as well as indolent or high-grade type lymphoma. The current consensus statement, developed by experts in the field across India, is intended to help healthcare professionals manage lymphomas in adults over 18 years of age. However, it should be noted that the information provided may not be appropriate to all patients and individual patient circumstances may dictate alternative approaches. The consensus statement discusses the diagnosis, staging and prognosis applicable to all subtypes of lymphoma, and detailed treatment regimens for specific entities of lymphoma including diffuse large B-cell lymphoma, Hodgkin’s lymphoma, follicular lymphoma, T-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, Burkitt’s lymphoma, and anaplastic large cell lymphoma.


Introduction
Lymphomas are a heterogenous group of lymphoproliferative disorders, which are broadly classified as Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). The lymphomas arise from B-cell, T-cell and natural killer (NK)/T-cell lymphocytes. B-cell lymphomas account for 80-85% of all NHLs and T-cell and NK/T-cell lymphomas account for the remaining 15-20% [1][2][3].
The clinical course depends on the indolent or aggressive nature of the lymphoma. While aggressive high-grade lymphomas are generally curable with cytotoxic therapies, indolent lymphomas are controllable for long periods with minimal cytotoxic therapy. Hence, it is not only imperative to make a correct diagnosis of lymphoma, but it is equally important to correctly classify them as B-cell, T-cell or NK/T-cell as well as indolent or high-grade, for optimal management.
Indian Council of Medical Research (ICMR) published a consensus statement in 2017 [1] on the management of aggressive lymphomas. Since then, there have been major changes in the classification of lymphomas, as well as the availability of new therapies to treat lymphomas that relapse. This consensus statement has included the changes in the management of all major subtypes of lymphomas.

Objectives
The objective of this consensus statement is to provide healthcare professionals with current information on the management of lymphomas in patients above 18 years of age. However, it should be noted that the information provided may not be appropriate to all patients and individual patient circumstances may dictate alternative approaches.
The collaborative nature of this consensus statement hopes to emphasize and nurture the need for more such efforts at the national platform in India. An ongoing lymphoma registry program is attempting to capture information on the demographics and outcomes of patients with lymphoma, and many of the participants in this consensus document are members of this volunteer registry. Much more, however, needs to be done on collaborative projects in lymphoma and other cancers at the national and regional platforms.
Following some general comments regarding diagnosis, staging and prognosis applicable to all subtypes of lymphoma, the consensus document discusses in more detail the therapies in relation to specific entities of lymphoma as defined in the World Health Organization (WHO) [4] classification, which include mature B-cell neoplasms, mature T-cell and NK-cell neoplasms, HL, histiocytic and dendritic cell neoplasms and post-transplant lymphoproliferative disorders. In adults, HL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), lymphoblastic lymphoma (LBL), small lymphocytic lymphoma (SLL), Burkitt's lymphoma (BL), Peripheral T cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), etc. are the most common types [1].
Diagnostic Biopsy: Points to Remember [5,6] Excision biopsy of the most prominent and accessible largest palpable lymph node should be considered first.

When the aforementioned is not possible, a Needle
Core Biopsy (NCB) should be advocated with at least 4-5 cores. The NCB can be considered for sites that are difficult to access such as lung, mediastinum, abdomen, retroperitoneum etc. In exceptional circumstances, NCB may also be done in palpable lumps such as in the elderly or severely ill patients. The NCB procedure demands expert radiologists. In patients where NCB or fine-needle aspiration cytology (FNAC) can't be performed, thoracotomy or laparotomy can be considered to obtain adequate tissue to facilitate the diagnosis. Management based on a FNAC diagnosis alone should be avoided as it has limitations. Steroid use has to be restricted, if possible, until diagnostic material is collected, as it may cause remissions in patients with very sensitive disease and delay the diagnosis. 2. The FNAC and body fluids may be sent for flow cytometric immuno-phenotyping (FCI). The laboratory should have standard operating procedures (SOPs) to perform FCI. The prepared slides should also be sent for morphological evaluation. 3. Blunt needles need to be avoided as they cause crushing artifacts, limiting morphological interpretations. 4. The laboratory should have extensive immunohistochemistry (IHC) markers panel. The minimum panel for each type of lymphoma has to be defined in the SOPs. A comprehensive IHC work up is advisable. In resource challenged situations, a practical and validated working algorithm is encouraged. In difficult cases, a second opinion may be taken from an expert lymphoma pathologist. For a specialist hemato-pathologist opinion, referral laboratories should be well defined and documented. Similarly, referral laboratories need to be defined and documented for FCI, fluorescence in situ hybridisation (FISH) and molecular tests.

Essential Evaluation and Staging Work-Up
Staging Work-Up: All Patients [7] Mandatory Clinical History and Examination 1. Clinical history with reference to B symptoms 2. Physical examination with particular attention to nodebearing areas, waldeyer's ring, liver span, splenic enlargement, and testicular enlargement (in males).

Performance status (Eastern Cooperative Oncology
Group; ECOG) including co-morbidity 4. Need to watch for features of an ''oncological emergency'' such as: tumor lysis syndrome, spinal cord compression, luminal obstruction, raised intra-cranial pressures due to mass effect, pericardial tamponade, etc.
Mandatory Staging Procedure

Staging of Lymphoma
The optimal management and prognosis of lymphoma depends, in part, on the stage of the lymphoma. The staging system used for adult high grade lymphomas is based on the Ann Abor system (Table 2) [11]. An international working group incorporated the PET scan and revised the staging criteria [12], which were widely adopted. The 2011 International Conference on Malignant Lymphoma (ICML) in Lugano proposed a revised staging system for primary nodal lymphomas (Table 3) [13,14]. For clinical staging of chronic lymphocytic leukemia (CLL), Rai et al. [15], and Binet et al. [16], proposed criteria, which are based on the concept that CLL is a disease of progressive accumulation of non-functioning lymphocytes (Table 4) [15,16].  [17], also called the WHO or Zubrod score (after C. Gordon Zubrod), is a numbering scale used to determine whether the patients can receive chemotherapy, if dose adjustment is necessary, as a measure for the required intensity of palliative care, and as a measure of quality of life in randomized controlled trials (RCTs) ( Table 5) [17]. The CLL-International Prognostic Index (CLL-IPI) is a revised staging system that combines genetic, biochemical, and clinical parameters for a more targeted treatment of CLL. The IPI is a prognostic model based on 5 parameters (Table 6) [18].

International Prognostic Index
The Ann Arbor classification does not consistently distinguish between patients with different long-term prognoses; hence, the International Non-Hogdkin's Lymphoma Prognostic Factor Project provided the international index and age-adjusted international index for the selection of appropriate therapeutic approaches for individual patients [20]. The IPI is a prognostic model based on 5 parameters (Table 8). Based on these factors, patients with DLBCL can be divided into 4 prognostic categories as summarised in Table 9 [20].  High risk 3 32 aa-IPI age-adjusted international prognostic index

Revised International Prognostic Index (R-IPI)
In the rituximab era, the IPI has been revised and the patients are grouped as shown in Table 11. The revised IPI (R-IPI) is a better predictor of outcome than the standard IPI for patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) [21].
The IPI is less useful in ALCL, mediastinal B cell lymphoma and mature T-cell lymphomas. It should not be used for BL and LBL. The IPI has been adjusted for use in FL. The Follicular Lymphoma International Prognostic Index (FLIPI) predicts survival for FL and is used for other indolent lymphomas as well (Table 12) [22]. The Mantle Cell Lymphoma International Prognostic Index (MIPI) shown in Table 13 is superior to the IPI in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation.

CNS: International Prognostic Index (CNS-IPI)
The CNS-international prognostic index (CNS-IPI; Table 14) is a robust, highly reproducible tool that can be used to estimate the risk of CNS disease in patients with DLBCL [23].

Management of Diffuse Large B Cell Lymphoma
The treatment options vary between patients with localized (stage I-II) and advanced (stage III-IV) disease (Table 19). Prognosis is extremely good for patients with no adverse risk factors (normal LDH, stage I or II nonbulky disease, age \ 60 years or ECOG performance status \ 2). Five-year survival for advanced stage varies from 30 to 50%. In selected cases, RT to bulky sites may be beneficial (Category 2B). Patients at increased risk of CNS relapse (those with high CNS-IPI, involvement of the paranasal sinuses, testes, breast, bone-marrow involvement with large cells or having C 2 extra-nodal sites with elevated LDH, mediastinal large B cell lymphoma and DHL) must undergo CSF cytology and should receive CNS prophylaxis with 4-8 doses of intrathecal methotrexate. An alternative is to consider 3-3.5 g/m 2 of high dose methotrexate during treatment. Patients with CNS involvement or CSF involvement should be considered for CNS directed therapy with 3-3.5 g/m 2 of systemic methotrexate on day 15 of CHOP-R cycles 1, 3 and 5. Elderly patients may be given 1.0 g/m 2 after completing their systemic treatment (data to support and contrary available).

Management of Mantle Cell Lymphoma
The treatment options for mantle cell lymphoma are given in Table 20.

Management of Burkitt's Lymphoma (BL)
There is a high incidence of tumor-lysis syndrome and measures should be taken to prevent and treat this complication. Patients with bulky disease and organ dysfunction may be treated with modified dose therapy (e.g. prephase-CVP), in an attempt to modify the effects of tumor lysis. Then, a more intensive therapy needs to be administered as outlined below [60,61].

Management of Lymphoblastic Lymphoma (LL)
Patients with LL are typically managed (including diagnostics) and treated with regimens appropriate for acute lymphoblastic leukemia (ALL). Patients with systemic LL can be treated with any one of the chemotherapy regimens: • MCP-841 protocol • German multicenter ALL (GMALL) protocol • Hyper-CVAD alternating with high dose methotrexate and cytarabine Young adults may be considered for pediatric based ALL protocols, based on center experience. Patients with complete response (CR) to induction therapy should be continued with other components of the treatment protocols. It is important that patients be treated with a given treatment protocol in its entirety and not be treated with different components taken from different protocols. Patients with high risk features (such as marrow involvement) and with a matched sibling donor should be offered an allogeneic transplantation in first remission.
Non-Hodgkin's Lymphoma: T Cell Lymphoma [62][63][64][65][66][67][68][69][70][71][72][73][74] The T-cell malignancies are rare and often complex diseases. Diagnosis and management should be discussed in a multi-disciplinary team meeting and those patients requiring treatment should generally be referred to a cancer centre or tertiary centre with specialist expertise. The rarity of these diseases and the lack of randomized trials mean that there is no consensus about optimal therapy for T-and NK-cell neoplasms and recommendations are therefore based on small case series, phase II trials and expert opinion.

Nodal Peripheral T-Cell Lymphoma
Peripheral T Cell Lymphoma Not Otherwise Specified (PTCLnos) Treatment with an anthracycline-based chemotherapy regimen-6 cycles of CHOP (or CHOEP) is recommended. The option of autologous HSCT as a consolidative measure may be considered in patients eligible for transplant, having achieved or having an ongoing response, and in those with high risk disease.

Anaplastic Large Cell Lymphoma (ALCL)
Limited stage: ALK-positive ALCL and no adverse prognostic features by IPI should be treated with 3-4 cycles of CHOP chemotherapy and IFRT. A younger fit patient (adolescent young adults) may be considered for the more intensive short course BFM protocol for NHL which includes high dose methotrexate.
Advanced stage: Patients should receive 6-8 cycles of CHOP chemotherapy.
ALK-negative ALCL should be treated as for PTCL-NOS (peripheral T-cell lymphoma not otherwise specified). A younger fit patient (adolescent young adults) may be considered for the more intensive short course BFM protocol for NHL which includes high dose methotrexate. CHOEP is an alternative regimen, for ALK-negative advanced stage lymphoma (however, there is insufficient data to recommend). Consideration should be given to consolidation with auto-HSCT.
Angioimmunoblastic T Cell Lymphoma (AITL) Treatment with CHOP (or CHOEP) is recommended followed by consolidation with HD chemotherapy and auto HSCT. The use of GDP protocol as an alternate to CHOP may be considered from the toxicity perspective with equivalent results. In patients with a relative indolent disease the option of using cyclosporine for inducing response may be considered in relapses following primary therapy.
Alternative regimens include fludarabine, cyclophosphamide, mitoxantrone (FCM) combination, and the use should be considered with individual center experience and access to the drugs. Alemtuzumab, a drug commonly used in this condition is not currently available in India, and can potentially be imported.

T-large granular lymphocytic leukemia (T-LGL):
The management of T-LGL is provided in Table 21.

Chronic lymphoproliferative disease of NK cells (CLPD-NK): Management as for T-LGL.
Aggressive NK cell leukemia: Younger patients must be treated with ALL based protocols.

Adult T cell leukemia lymphoma (ATLL):
The management of ATLL is provided in Table 22.

Extranodal Peripheral T-Cell Lymphomas
Cutaneous T-Cell Lymphomas (CTCL) The CTCL may present with a chronic, patchy infiltrative skin disorder (mycosis fungoides-50% of cutaneous lymphomas) or with a diffuse erythema and malignant T-cells in the peripheral blood (Sezary syndrome) (Table 23). Extranodal NK/T Cell Type Lymphoma, Nasal Type • Stages 1 and II: modified SMILE 9 4 cycles followed by local RT is recommended. RT (55 Gy) as a single modality is recommended for smaller lesions • Advanced stage disease (III and IV): modified SMILE 9 6 cycles followed by local RT is recommended.
Enteropathy associated T cell lymphoma (EATL): CHOP like therapy ± autograft in first remission. Hepatosplenic T cell lymphoma: No satisfactory recommendations. Treatment as applied for PTCL-NoS with CHOEP 9 3 to 4 cycles followed by consideration for HDT and autologous transplant.
Subcutaneous panniculitis T-cell lymphoma: No recommendations per se; however, cyclosporine-A can be considered, especially in the presence of a/b type with CD8 positive and CD 56 negative entities. CHOP like chemotherapy may be considered in case of failure of cyclosporine A. Single agent methotrexate has been found useful in some patients.

HIV-Associated Lymphoma
Treatment options for HIV-associated Burkitt's lymphoma include daEPOCH, CODOX-M/IVAC, or hyper-CVAD ± R. DLBCL should be treated with short course (sc) EPOCH ± R or CHOP ± R. Most cases of primary effusion lymphoma (PEL) are CD20-negative; the addition of rituximab to CHOP is not indicated. Plasmablastic lymphoma (PBL) can be treated with regimens recommended for Burkitt's lymphoma. High-dose methotrexate or RT can be considered for patients with primary CNS lymphoma (PCNSL) as suggested below. Early introduction of highly active antiretroviral therapy (HAART) is associated with superior outcomes. Patient should receive HAART and growth factor support along with full-dose chemotherapy. In patients with persistently low CD4 counts (\ 100/lL), rituximab should be omitted to reduce the risk of serious infections.

Primary CNS Lymphoma and Primary Intra-ocular Lymphoma
Chemotherapy should consist of a regimen that includes high-dose methotrexate (if the histology is DLBCL/BL) (Fig. 1).
• MVP-R 9 5-7 cycles • Consolidation WBRT, 45 Gy in 25 fractions (or 23.4 Gy), should be considered in patients who achieve CR with MTX-based chemotherapy; followed by 2 doses of HD cytosine arabinoside 9 2 cycles • Alternative regimens include whole brain radiation therapy (WBRT) along with temozolomide ± methotrexate • Institutions with adequate expertise can consider the options of intensive therapies like MATRix protocol or a high dose chemotherapy and autologous stem cell rescue consolidation approach [76].
There is no role for CHOP-like chemotherapy in the treatment of primary CNS lymphoma (PCNSL).
In patients under 60 years of age, WBRT should be offered to patients unless there is a significant neurocognitive deficit following chemotherapy. In patients aged 60 years or over, neurocognitive side-effects are more likely to outweigh potential benefits.
Stage IIE: Fig. 2 represents the treatment for stage II E disease.
Management of Advanced Stage Disease (Stage III-IV) Should be treated according to the guidelines for the treatment of advanced stage DLBCL with CHOP-R 9 6 to 8 cycles along with prophylactic scrotal radiotherapy and intrathecal chemotherapy.
The addition of intermediate-high dose methotrexate might improve CNS prophylaxis, especially in the younger patients but this has never been formally demonstrated. High-dose chemotherapy followed by stem cell transplantation is an investigational option.

Primary Gastrointestinal Lymphoma
Treatment is according to histological subtype. Resection of gastrointestinal lymphoma is no longer recommended, unless necessary to establish a definite diagnosis or to control the complications of hemorrhage or perforation.

Primary Cutaneous B-Cell Lymphoma (CBCL)
In the WHO-European Organization for Research and Treatment of Cancer (EORTC) classification, three main types of CBCL are distinguished, which are primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous diffuse large B cell lymphoma, leg type (PCLBCL-LT). The PCMZL and PCFCL are indolent types and PCLBCL-LT has an unfavorable outcome (Table 24) [2]. 1. Histopathological examination with a basic immunehistochemistry diagnostic algorithm is mandatory in the evaluation of relapsed disease. Additional molecular investigations are desirable and will be based on the institutional practice. 2. In the relapsed indolent lymphomas, always rule out Richter's Transformation 3. Subtype specific prognostication of the disease status is highly recommended 4. Re-staging as appropriate to disease subtype is mandatory, and would include whole body PET-CT (or institutional practice) and bone marrow biopsy. 5. Infectious disease screening is required to rule out blood borne viral diseases (e.g., HBsAg, HCV, HIV) 6. Co-morbidity assessment for co-existing medical conditions and fitness for intensive therapy (like HCT) is mandatory (liver and renal function tests, echocardiography/multigated acquisition scan [MUGA] scan, etc.). Assigning a co-morbidity score is desirable.

Management Approach for Relapsed Lymphoma
A suggested management algorithm for relapsed lymphoma is shown in Fig. 3.

Chemotherapy Regimens for Transplant Eligible
Patients [77][78][79][80][81][82][83][84][85] Selection of second-line chemotherapy regimens depends on the pattern of relapse and the agents previously used. Platinum compound based regimens have been associated with good responses and lower levels of myelotoxicity and are widely used for salvage chemotherapy in potential transplant candidates. These include: 2. Disease status should be evaluated with imaging studies and clinical assessment after two to three cycles, following which autologous HSCT should be carried out.

Role of Allogeneic HSCT
Allogeneic HCT may be considered in young patients who are considered fit to undergo intensive conditioning therapies, and have any one of the following, • Stem cell mobilization failure, or • Relapse after autologous HCT, or • High risk/aggressive disease: upfront use in select patients (\ 40 years). These decisions must be made after a multidisciplinary consensus (e.g. primary refractory disease in the young responding to salvage chemotherapy, bone marrow involvement post induction chemotherapy, etc.) Alternative donor sources, reduced intensity conditioning, etc. are still experimental and no guidelines exist for the same.

Follicular Lymphoma
Consider clinical trial recruitment.
1. Alternative chemo-immunotherapy not used upfront (e.g. B-R v/s R-CVP v/s R-CHOP) 2. Obinutuzumab (in riuximab refractory) 3. Idelalisib (rituximab and chemotherapy refractory) 4. Post-induction maintenance therapy must be considered in patients who have partial or complete response.

Hodgkin's Lymphoma
First-line Salvage Therapy 1. In very selected patients with favorable risk localized late relapse: local RT alone may suffice 2. High dose Chemotherapy regimens, as recommended • Other regimens to be considered: mini-BEAM 3. In refractory disease setting, patients who are salvage chemotherapy responsive: consider post-transplant maintenance therapy with brentuximab vedotin (BV) for 1 year. 4. Role of consolidation radiation therapy must be made in the light of the site(s) of relapse, rapidity of relapse, response to salvage therapy and prior radiotherapy. There is limited evidence regarding the timing of radiotherapy and transplant.
Subsequent Salvage Therapy 1. Consider recruitment in clinical trials 2. Brentuximab vedotin (or combination therapies with BV) 3. In BV exposed patients: consider PDL1 checkpoint blockade therapy with nivolumab or pembrolizumab. 4. In fit patients, consolidate with an allogeneic HCT.

Alternative options
• Non-cross resistant combination chemotherapy • Single agent therapy: bendamustine v/s. everolimus v/s. lenalidomide 6. Role of directed or consolidation radiation therapy must be made in the light of the site(s) of relapse, rapidity of relapse, response to salvage therapy and prior radiotherapy. 7. There is limited evidence regarding the timing of radiotherapy and transplant.

Aggressive or High-Grade B-Cell Lymphoma
Burkitt's Lymphoma Limited studies and regimens available. These are not Level-I or Level-II recommendations, and consider clinical trial recruitment.
1. Alternative non-cross resistant therapy to the primary regimen used: • e.g. R-daEPOCH v/s R-ICE v/s R-GDP 2. CNS Prophylaxis always indicated 3. In the young and selected patients: always consider allogeneic HCT consolidation instead of autologous HCT 4. Additional local radiation therapy, as appropriate Mantle Cell Lymphoma (Non-indolent Subtype) Consider Clinical trial recruitment.

Follow-Up of a Patient and Immunization
Patients should be followed-up every 3-4 months for the first 1 year, followed by 6 monthly for the next 2 years, and then annually. The following format is advised (

Immunization
The normal vaccination schedule to prevent flare of viral infections is given in Table 26.