Role of Chemotherapy and Radiotherapy in Non Hodgkin Lymphoma

Dr. Ayush Garg

Introduction

• Non-Hodgkin’s lymphomas (NHLs) are a heterogeneous group of lymphoid malignancies that differ greatly in clinical presentation, prognosis, and response to therapy.

Epidemiology

• Non-Hodgkin lymphoma (NHL), accounts for about 4% of all cancers. This the sixth most common malignancy in men and fifth most common in women.

• In India incidence is 5.1 per 100000.• In USA incidence is 19.1 per 100000.• More than 95% of cases occur in adults. • NHL can occur at any age, but about half of

patients are older than 66

Risk Factors

• For the majority of patients not clear.• A minority of patients of FL or chronic

lymphocytic leukemia (CLL) have the risk of histologic transformation of about 5–7% per year.

• In CLL, histologic progression to DLBCL is called Richter’s transformation.

• Studies of survivors of atomic bombs and nuclear reactor accidents, (thyroid cancer, and non-Hodgkin lymphoma.)

• Other documented risk factors for DLBCL include HIV disease.

• Some autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE or lupus), Sjogren disease, celiac sprue (gluten-sensitive enteropathy).

• Translocations, most cases of follicular lymphoma have a translocation between chromosomes 14 and 18, which turns on the bcl-2 oncogene.

.

Certain infections • The human T-cell leukemia/lymphoma virus (HTLV-1) and

the Epstein- Barr virus (EBV)• Human herpes virus 8 (HHV8) can also infect lymphocytes.

Another name for this virus is Kaposi sarcoma- associated herpes virus (KSHV).

• Helicobacter pylori (MALT). • Chlamydophila psittaci (ocular adnexal marginal zone

lymphoma• Campylobacter jejuni (MALT)• HCV (splenic marginal zone lymphoma)• Breast implants (some women develop anaplastic large cell

lymphoma in the scar tissue around their breast implant)

Signs and Symptoms• Enlarged lymph nodes • Swollen abdomen • Feeling full after only a

small amount of food • Chest pain or pressure • Shortness of breath or

cough • Fever • Weight loss

• Night sweats • Fatigue (extreme tiredness) • Low red blood cell counts (anemia)

B symptoms , such as: • Unexplained weight loss • Fever • Drenching night sweats (enough to soak

clothing and sheets)

Commonly Involved Lymph Nodes

• Extranodal : 1.Intestinal lymphoma ( abdominal pain, anemia, dysphagia); 2.CNS ( headache, cranial nerve palsies, spinal cord compression) ;

3.Skin, Testis; Thyroid; Lung 4.Bone marrow (low grade): Pancytopenia

WHO Classification of Lymphoid NeoplasmsB-Cell Neoplasms

Precursor B-cell neoplasmPrecursor B-lymphoblastic

leukemia/lymphoma (precursor B-acute

lymphoblastic leukemia)Mature (peripheral) B-neoplasmsB-cell chronic lymphocytic leukemia / small

lymphocytic lymphoma

B-cell prolymphocytic leukemiaLymphoplasmacytic lymphoma‡

Splenic marginal zone B-cell lymphoma (+ villous

lymphocytes)*Hairy cell leukemia

Plasma cell myeloma/plasmacytomaExtranodal marginal zone B-cell lymphoma of MALT

typeNodal marginal zone B-cell lymphoma

(+ monocytoid B cells)*

Follicular lymphomaMantle cell lymphomaDiffuse large B-cell lymphoma

Mediastinal large B-cell lymphomaPrimary effusion lymphoma†

Burkitt’s lymphoma/Burkitt cell leukemia§

T and NK-Cell NeoplasmsPrecursor T-cell neoplasm

Precursor T-lymphoblastic leukemia/lymphoma

(precursor T-acute lymphoblastic leukemia

‡ Formerly known as lymphoplasmacytoid lymphoma or immunocytoma II Entities formally grouped under the heading large granular lymphocyte leukemia of T- and NK-cell types* Provisional entities in the REAL classification

Mature (peripheral) T neoplasmsT-cell chronic lymphocytic leukemia / small

lymphocytic lymphomaT-cell prolymphocytic leukemiaT-cell granular lymphocytic leukemiaII Aggressive NK leukemiaAdult T-cell lymphoma/leukemia (HTLV-1+)Extranodal NK/T-cell lymphoma, nasal type#

Enteropathy-like T-cell lymphoma**Hepatosplenic γδ T-cell lymphoma*Subcutaneous panniculitis-like T-cell lymphoma*Mycosis fungoides/Sézary syndromeAnaplastic large cell lymphoma, T/null cell,

primary cutaneous typePeripheral T-cell lymphoma, not otherwise

characterized Angioimmunoblastic T-cell lymphomaAnaplastic large cell lymphoma, T/null cell,

primary systemic typeHodgkin’s Lymphoma (Hodgkin’s Disease)

Nodular lymphocyte predominance Hodgkin’s lymphomaClassic Hodgkin’s lymphoma

Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)

Lymphocyte-rich classic Hodgkin’s lymphomaMixed cellularity Hodgkin’s lymphomaLymphocyte depletion Hodgkin’s lymphoma

† Not described in REAL classification § Includes the so-called Burkitt-like lymphomas

** Formerly known as intestinal T-cell lymphoma # Formerly know as angiocentric lymphoma

Indolent (35%)

Diffuse largeB-cell (31%)Armitage et al. J Clin Oncol. 1998;16:2780–

2795

Mantle cell (6%)

Peripheral T-cell (6%)

Other subtypes with a frequency 2% (9%)

Frequency of NHL Subtypes in Adults

Composite lymphomas (13%)

Involvement of a single lymph node or of a single extranodal organor site (IE)

Ann Arbor Staging System

• Involvement of 2 or more lymph node regions on the same side of the diaphragm, or localized involvement of an extranodal site or organ (IIE) and 1 or more lymph node regions on the same side of the diaphragm

• Involvement of lymph node regions on both sides of the diaphragm, which may also be accompanied by localized involvement of an extranodal organ or site (IIIE) or spleen (IIIS) or both (IIISE)

• Diffuse or disseminated involvement of 1 or more distant extranodal organs with or without associated lymph node involvement

Cases are subclassified to indicate the absence (A) or presence (B) of B symptoms

Initial evaluation

• A thorough physical exam with attention to nodal areas and assessment of performance status.

• Laboratory studies including a CBC with differential, LDH, uric acid, calcium, liver function tests as well as an HIV test and other viral markers.

• Imaging studies including USG,CT scans of the neck, chest, abdomen, and pelvis. (PET scans are routinely performed)

• Assessment of ejection fraction with echocardiography

• A bone marrow aspirate and biopsy.

• A lumbar puncture (CSF involvement).

• Immunohistochemistry

• Flow cytometry

• Cytogenetics

• Molecular genetic tests

• Fluorescent in situ hybridization (FISH)

• Polymerase chain reaction (PCR)

EXCISIONAL LN BIOPSY• Histologic evaluation includes:

– Assessment of the morphology;– Pattern of lymph node involvement.

• Morphology: Morphological changes have prognostic impact.

• Pattern(s) of lymph node involvement:– Nodular/follicular pattern – Diffuse pattern – Change from a nodular to a diffuse pattern in adjacent nodes – Change from a lower to a higher grade of involvement within a single

node

Favorable Prognosis Unfavorable Prognosis

Nodular/follicular architecture Diffuse architecture

Small cell size Large cell size

Cleaved nucleus Un-cleaved nucleus

DIFFUSE LARGE B-CELL LYMPHOMA

• The two most common types of NHL, diffuse large B-cell lymphoma and follicular lymphoma (FL), account for nearly 2/3 of the cases.

• Pathological analysis in case of DLBCL will usually show large lymphocytes with nuclei greater than twice the size of normal small lymphocyte nuclei, prominent nucleoli, and basophilic cytoplasm.

• Malignant cells express the B-cell antigens CD19, CD20, CD22, and CD79a.

• About 1 in 3 of these lymphomas is only in one part of the body (localized) when it is found. Lymphomas are easier to treat when they are localized than when they have spread to other parts of the body.

• Genetic tests have shown that there are different subtypes of DLBCL. These subtypes seem to have different outcomes (prognoses) and responses to treatment.

• DLBCL is a fast-growing lymphoma, but it often responds well to treatment.

• Overall, about 3 out of 4 people will have no signs of disease after the initial treatment, and many are cured with therapy.

Follicular lymphoma

• About 1 out of 5 lymphomas is follicular lymphoma. The term follicular means that the cells tend to grow in a circular pattern in lymph nodes.

• The average age for people with this lymphoma is about 60. It’s rare in very young people

• Follicular lymphomas are often slow-growing and respond well to treatment, but they are hard to cure.

• These lymphomas may not require treatment when they are first diagnosed. Instead, treatment may be delayed until the lymphoma is causing problems.

• Over time, about 1 in 3 follicular lymphomas turns into a fast-growing diffuse B-cell lymphoma.

Chronic lymphocytic leukemia /small lymphocytic lymphoma

• These are closely related diseases. In fact, many consider them different versions of the same disease. The same type of cancer cell (known as a small lymphocyte ) is seen in both chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

• The only difference is where the cancer cells are found. In CLL most of the cancer cells are in the blood and bone marrow. In SLL, the cancer cells are mainly in the lymph nodes and spleen. About 5% to 10% of all lymphomas are SLLs.

• Treatment is the same for CLL and SLL.• They are usually not curable with standard treatments, but

depending on the stage and growth rate of the disease, most patients live longer than 10 years..

Mantle cell lymphoma

• Only about 5% of lymphomas are this type. The cell size is small to medium.

• Men are affected most often. The average age of patients is the early 60s. When this lymphoma is diagnosed, it is usually widespread in the lymph nodes, bone marrow, and often the spleen.

• This usually isn’t a very fast-growing lymphoma, but it can be challenging to treat. Newer treatments might be more effective than those used in the past, and may offer a better chance for long-term survival for patients now being diagnosed.

Marginal zone B-cell lymphomas

• Marginal zone lymphomas account for about 5% to 10% of lymphomas. The cells in these lymphomas look small under the microscope. There are 3 main types of marginal zone lymphomas.

• Extranodal marginal zone B-cell lymphomas, also known as mucosa-associated lymphoid tissue (MALT) lymphomas

• Nodal marginal zone B-cell lymphoma• Splenic marginal zone B-cell lymphoma

Burkitt lymphoma

• This type makes up about 1% to 2% of all lymphomas. It is named after the doctor who first described this. The cells are medium- sized. Another kind of lymphoma, Burkitt-like lymphoma, has slightly larger cells.

• This is a very fast-growing lymphoma. It is linked to infection with the Epstein-Barr virus

• The lymphoma usually starts in the abdomen, where it forms a large tumor mass. It can also start in the ovaries, testicles, or other organs, and can spread to the brain and spinal fluid.

• Close to 90% of patients are male. Although this is a fast-growing lymphoma, more than half of patients can be cured by intensive chemotherapy.

T-cell lymphomas

• T-cell lymphomas make up less than 15% of non-Hodgkin lymphomas. There are many types of T-cell lymphoma, but they are all fairly rare. eg

• Precursor T-lymphoblastic lymphoma• Peripheral T-cell lymphomas • Cutaneous T-cell lymphomas (mycosis fungoides,

Sezary syndrome, and others)

• Adult T-cell leukemia/ lymphoma Angioimmunoblastic• Extranodal natural killer/T-cell lymphoma, nasal type• Enteropathy-associated intestinal T-cell lymphoma

(EATL)• Anaplastic large cell lymphoma (ALCL)• Peripheral T-cell lymphoma, unspecified

Factors of the International Prognostic Index

Treatment

The main types of treatment for Non-Hodgkin Lymphoma are:

• Chemotherapy • Immunotherapy • Targeted Therapy • Radiation Therapy• Bone Marrow Transplant In rare cases, surgery is also used.

Some of the drugs commonly used to treat lymphoma include

• Alkylating agents • Cyclophosphamide • Chlorambucil • Bendamustine • Ifosfamide

• Corticosteroids • Prednisone • Dexamethasone• Platinum drugs • Cisplatin • Carboplatin • Oxaliplatin • Purine analogs • Fludarabine • Pentostatin •

Cladribine• Anti-metabolites • Cytarabine • Gemcitabine •

Methotrexate • Pralatrexate• Others • Vincristine • Doxorubicin • Mitoxantrone •

Etoposide • Bleomycin

• Often drugs from different groups are used in combination. One of the most common combination of drugs is CHOP.

• Chemo is often combined with immunotherapy, especially the monoclonal antibody rituximab RCHOP

CHOP

• Cyclophosphamide: 750 mg/m2 IV on day 1• Doxorubicin: 50 mg/m2 IV on day 1• Vincristine: 1.4 mg/m2 IV on day 1 (maximum,

2 mg)• Prednisone: 40 mg/m2 PO on days 1–5Repeat cycle every 21 days upto 6 cycles

CHOP + Rituximab

• Cyclophosphamide: 750 mg/m2 IV on day 1• Doxorubicin: 50 mg/m2 IV on day 1• Vincristine: 1.4 mg/m2 IV on day 1 (maximum, 2

mg)• Prednisone: 40 mg/m2 PO on days 1–5• Rituximab: 375 mg/m2 IV on day 1Repeat cycle every 21 days. Rituximab is to be administered first, followed by cyclophosphamide, doxorubicin, and vincristine.

Non-Hodgkin’s LymphomaAggressive chemotherapy regimens

• Dose-dense CHOP• CHOP-Bleomycin• CEOP-Bleomycin• DexaBEAM• HyperCVAD

It uses high doses of X-rays, gamma rays, or other types of ionizing (damaging) radiation to kill cancer cells. It may be applied to the whole body or to a specific zone.

Radiotherapy

• Although current treatment regimens vary widely among institutions, they commonly include three to eight cycles of R-CHOP, succeeded by IFRT. Radiation dose of 30–36 Gy for 10 fractions is recommended.

• For patients with partial response (PR) to chemotherapy with residual, doses of at least 40 Gy should be considered.

INDICATIONS FOR PALLIATIVE RADIATION IN ADVANCED-STAGE INDOLENT NHL

Palliative low-dose RT for follicular and marginal zone lymphomas (4 Gy in two fractions) often provides local control and relief of symptoms.

Monoclonal antibodies

A number of monoclonal antibody drugs used to treat NHL target the CD20 antigen, a protein found on the surface of B lymphocytes. These include:

• Rituximab • Ibritumomab tiuxetan • Obinutuzumab • Ofatumumab

Primary mechanism of action of Rituximab

• Binds to a protein called CD-20 (located on the surface of B-cells)

• Causes destruction of the B-cells

Radioimmunotherapy with Y-90

• Ibritumomab– Murine monoclonal

antibody parent of Rituximab

• Tiuxetan– Conjugated to

antibody, forming strong urea-type bond

– Stable retention of Y-90

Y-90 radionuclideBeta radiation

Chelator

Monoclonal antibody

Hematopoietic stem cell transplant (HCT)

• Autologous HCT may be beneficial for some patients in complete or near-complete remission after their first chemotherapy regimen

• Autologous HCT may be of benefit for patients who have a CR or PR to second-line chemotherapy for relapsed disease,

• Although treatment-related mortality is approximately 30%, myeloablative allogeneic HCT may be curative in some patients.

• Non-myeloablative (reduced intensity) allogeneic HCT decreases treatment-related mortality and can provide long-term progression-free survival (PFS)

Indications1. Refractory disease

2. Relapse

3. High risk in CR

4. Lymphoblastic, Burkitt’s, and gamma delta-t-cell lymphomas

Sources of Hematopoietic Stem Cells

Lugano Response Criteria

Relapsed / Refractory

Some Salvage Chemotherapy Regimens are• ICE – Ifosfamide, Carboplatin, Etoposide• DHAP – Dexamethasone, high-dose Cytarabine,

Procarbazine • ESHAP – Etoposide, Methylprednisolone,

Cytarabine, Cisplatin • R-EPOCH – Infusional Etoposide, Doxorubicin, and

Vincristine, with Prednisone and Cyclophosphamide boluses and Rituximab

Treatment algorithm for NHL

Take Home Message• NHLThe most common types are diffuse large B-cell (~30%) and follicular lymphoma (~25%).

• Biologic CharacteristicsLymphomas are a diverse group of diseases clinically, pathologically, and genetically.

• Staging EvaluationStaging requires a thorough history and physical examination, CBC, LDH level, bone marrow biopsy, CT of the neck, thorax, abdomen & pelvis, and FDG-PET.

• Primary Therapy• Stage I and II follicular lymphomas are treated with IFRT, expecting a

greater than 95% local control rate and 50% long-term disease-free survival.

• Stage III and IV follicular lymphomas are treated with chemotherapy and RT, which are effective in controlling the disease.

• Stage I and II diffuse large B-cell lymphoma are treated with combined modality therapy, with a cure expected in 70% to 90% of patients.

• Stage III and IV diffuse large B-cell lymphoma are treated primarily with doxorubicin based chemotherapy.

• Salvage Therapy• Patients with bulky disease or incomplete

response to salvage chemotherapy receive local RT to sites of disease as planned combined salvage treatment. RT may be delivered before or after autologous stem cell transplantation.

• Patients so treated have a cure rate of 30% to 50%.

• Palliation• Palliative low-dose RT for follicular and

marginal zone lymphomas (4 Gy in two fractions) often provides local control and relief of symptoms