Non Hodgkins Lymphoma

Dr. Ujjwal Chalise MD-RT IIIrd yr resident

 4-5% of all cancer cases and most common hematological malignancy. 5th leading cause of cancer death Incidence in increasing since last 4 decades especially in the western Geographic differences in histologic subtypes of NHL ( Burkitts-africa EBV, MALT-Italy, T-cell China, intestinal- middle east) CNS lymphoma- AIDS

Etiology of NHL
Immune suppression
congenital (Wiskott-Aldrich) organ transplant (cyclosporine) AIDS increasing age

DNA repair defects

ataxia telangiectasia xeroderma pigmentosum

Etiology of NHL
Chronic inflammation and antigenic stimulation
Helicobacter pylori inflammation, stomach Chlamydia psittaci inflammation, ocular adnexal tissues Sjogrens syndrome

Viral causes
EBV and Burkitts lymphoma HTLV-I and T cell leukemia-lymphoma HTLV-V and cutaneous T cell lymphoma Hepatitis C

Histologic classification of nonHodgkins lymphomas - Working Formulation (WF)

1. Low grade 2. Intermediate grade 3. High grade

Low grade A. - Small lymphocytic cell. B. - Follicular, predominantly small cleaved cell C. - Follicular mixed, small cleaved and large cell

Intermediate grade D. - Follicular, predominantly large cell. E. - Diffuse small cleaved cell. F. - Diffuse mixed, small and large cell. G. - Diffuse large cell

High grade H - Large cell immunoblastic. I. - Lymphoblastic. J. - Small noncleaved cell: Burkitts

WHO classification
B-cell neoplasms Precursor B-cell neoplasm Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) Mature (peripheral) B-cell neoplasms B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma (with or w/o villous lymphocytes) Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma of mucosa- associated lymphoid tissue type Nodal marginal zone B-cell lymphoma (with or w/o monocytoid B cells) Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Mediastinal large B-cell lymphoma Primary effusion lymphoma Burkitt's lymphoma/Burkitt's cell leukemia T- and NK-cell neoplasms Precursor T-cell neoplasm Precursor T-lymphoblastic lymphoma/leukemia (precursor T- cell acute lymphoblastic leukemia) Mature (peripheral) T-cell neoplasms T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-cell leukemia Adult T-cell lymphoma/leukemia (human T-cell lymphotropic virus type I positive) Extranodal NK/T-cell lymphoma, nasal type Enteropathy type T-cell lymphoma Hepatosplenic gammadelta T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sezary syndrome Anaplastic large cell lymphoma, T/null-cell, primary cutaneous type Peripheral T-cell lymphoma, not otherwise characterized Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, T/null-cell, primary systemic type

REAL /Revised European-American Lymphoma/-WHO classification of non-Hodgkins lymphomas

Precursor B- or T-cell lymphomas - acute lymphoblastic leukemia - lymphoblastic lymphoma

Peripheral B- or T-cell lymphomas

 Peripheral B cell lymphomas - Chronic lymphocytic leukemia/lymphocytic lymphoma - Chronic prolymphocytic leukemia - Immunocytoma/lymphoplasmocytic lymphoma - Mantle cell lumphoma - Marginal zone lymphoma /MALT-type/ - Hairy cell leukemia cont.

Cont.
- Follicle center cell lymphoma - Plasma cell myeloma/plasmocytoma - Diffuse large B cell lymphoma - Burkitts lymphoma - Splenic marginal zone B cell lymphoma

REAL /Revised European-American Lymphoma/-WHO classification of non-Hodgkins lymphomas

Precursor T cell lymphomas - Acute lymphoblastic leukemia -Lymphoblastic lymphoma

REAL /Revised European-American Lymphoma/-WHO classification of non-Hodgkins lymphomas Peripheral T cell lymphomas
T cell chronic lymphocytic leukemia T cell chronic prolymphocytic leukemia Large granular lymphocyte leukemia /LGL/ Mycosis fungoides /Szary syndrome Peripheral T cell lymphomas, unspecified

continued
Angioimmunoblastic T cell lymphoma Angiocentric lymphoma Intestinal T cell lymphoma Adult T cell lymphoma/leukemia Anaplastic large cell lymphoma

Indolent NHL
Follicular lymphoma grade I-IIIa (70% of cases Small lymphocytic lymphoma (SLL) Lymphoplasmacytoid lymphoma, and marginal zone lymphomas (MZL, nodal or extranodal).

Very aggressive non-Hodgkins lymphomas

B-, T-cell acute lymphoblastic leukemia B-, T-cell lymphoblastic lymphomas Burkitts lymphoma Adult T cell lymphoma/leukemia

B- B symptom E- extranodal disease X- bulky disease

IPI score:
Age over 60 years Late-stage disease (Stages 3 and 4) More than one extranodal site High LDH Poor general health score: 0-2 low risk 2-3 low/int/high > 4 HIGH

High risk aggressive non-Hodgkins lymphomas

1. Age abowe 60 years. 2. Disease stage III and IV. 3. Extranodal involvement of more than 1 site. 4. Serum LDH concentration >1 x normal. 5. Performance status < 80%.

B -symptoms known to have an adverse prognosis: fever night sweats unexplained weight loss.

Management:

Diagnosis of NHL
Incisional/ Excisional biopsy. Excisional biopsy is preferred to show nodal architecture (follicular vs diffuse). FNA- not recommended Immunohistochemistry
LCA (leukocyte common antigen) Monoclonal staining with Igk or Igl

Flow cytometry:
CD 19, CD20 for B cell lymphomas CD 3, CD 4, CD8 for T cell lymphomas

 Chromosome changes
14;18 translocation in follicular lymphoma
bcl-2 oncogene

t(8;14), t(2;8), t(8;22) in Burkitts lymphoma

c-myc oncogene

t(11;14) in mantle cell lymphoma

cyclin D1 gene

CD markers:
Stem cell : CD 34 + all leukocyte groupsCD45+ B lymphocyte CD45+, CD19+ or CD45+, CD20 +, CD24+ T lymphocyteCD45+, CD3+ T helper cell CD45+, CD3+, CD4 + Granulocytes :CD45+, CD15 +, CD24 +, CD114 +, CD182+ Monocyte CD45+, CD14 +, CD114+, CD11a, CD91+

Staging Workup
Complete physical examination CBC, chemistries, LDH, urinalysis CT scans of chest, abdomen and pelvis Bone marrow biopsy and aspirate (Lumbar puncture)
AIDS lymphoma T cell lymphoblastic lymphoma High grade lymphoma with positive marrow

Treatment
Depends upon various factors: Aggressiveness of disease( indolent or aggressive) Tumor stage Phenotype (B-cell, T-cell or natural killer (NK) cell/nullcell) Histology (ie, low-, intermediate-, or high-grade) Symptoms Performance status Patient age Comorbidities

Treatment modalities:
Radiotherapy( mainly for localised disease) Chemotherapy( for advance and generalised disease) Surgery( historical importance, now only limited to diagnosis of the disease) Immunotherapy High dose chemotherapy with stem cell transplantation

Treatment results of patients under age 60 with aggressive non-Hodgkins lymphomas according to the risk group
Risk group No of risk CR 5-year survival factors________%_______________%_________ 0 92 87 1 2 78 57 69 46

Low
Low intermediate High intermediate

High

46

32

Management of Early stage Indolent Lymphoma (Stage I and II)

Standard management consists of Radiotherapy alone.
40% of patients with limited-stage disease remained disease-free at 10 years after radiation in a study done by Mac Manus and Hoppe. No randomized study has shown combined chemotherapy and radiation to be better than radiation alone Early treatment in asymptomatic patients has not been shown to improve survival.

 RT (2500-4000 cGy) gives a 10-year diseasefree survival rate of 50-60%, with an overall survival (OS) rate of 60-80%. Adj chemo can be given to selected patients with stage I-II NHL with unfavorable prognostic factors (eg, B symptoms, >2 nodal sites), and to those with follicular mixed histology.

Treatment Options in Advanced Indolent Lymphomas

Incurable with current treatment modalities due to poor response rate and resistance. Observation only in asymptomatic pt. Radiotherapy to site of problem. Systemic chemotherapy
oral agents: chlorambucil and prednisone IV agents: CHOP, COP, fludarabine

Antibody against CD20: Rituximab Stem cell or bone marrow transplant.

 Combination chemotherapies are used in younger patients with the goal of achieving a complete remission. Frequently used combination regimens are: - CHOP - CVP - Fludarabine alone or in combination (eg, with cyclophosphamide or mitoxantrone). Combination agents are useful in bulky and rapidly progressive disease and have higher response rates than single agents, but there is no improvement in overall survival

 Single-agent treatment with chlorambucil or cyclophosphamide (with or without prednisone) is useful in elderly patients with significant comorbidities. However, only a few achieve remission; most achieve palliation

 Randomized trials have shown that adding Rituximab to chemotherapy regimens results in higher response rates, longer time to progression, and longer survival than chemotherapy. Czuczman et al reported a 95% overall response rate and increase in time to progression with addition of rituximab to CHOP chemotherapy. Rituximab as a single agent is also useful in patients who are unable to tolerate chemotherapy

New developments in management of indolent NHL

In 2011, the NCCN upgraded the combination of rituximab and bendamustine to a category 1 recommendation for suggested first-line therapy of follicular lymphoma. Promising outcomes have been seen with the combination of lenalidomide plus rituximab for both rituximab-refractory and non rituximab-refractory indolent NHL

 A study by Gaulard et al found that Rituximab plus low-dose CHOP (R-miniCHOP) offered a good compromise between efficacy and safety in patients older than 80 years. A study by Watanabe et al found that a dense dose R-CHOP strategy was not associated with improved progression-free survival in patients with untreated indolent B-cell lymphoma

Management of Indolent Recurrent NHL

Single alkylating agents (chlorambucil or bendamustine) Combination chemotherapy - CVP, CHOP, and others Atumumab, lenalidomide, and temsirolimus[35] Purine analogues - Fludarabine, 2-CDA Rituximab (results in a 40-50% RR in patients with relapsed/refractory indolent B-cell lymphomas) in standard or extended schedules of administration Radioimmunotherapy131 Iodine-rituximab radioimmunotherapy Tositumomab (a murine IgG2a lambda monoclonal antibody directed against CD20 antigen) plus131 I (Bexxar) has been approved by the US Food and Drug Administration for relapsed or refractory, low-grade, follicular, or transformed NHL.[37, 38] Ibritumomab tiuxetan plus90 Yttrium (Zevalin)

Treatment Options for Early Stage Aggressive Lymphomas

Often in Stage I or II
potentially curable disseminates through bloodstream early must use systemic chemotherapy

 Aggressive stage I and contiguous stage II (nonbulky or < 10 cm) NHL (intermediate grade) CHOP x 3 cycles followed by IFRT Based on 2 large randomized trials SWOG,ECOG chemo + IFRT have significantly better progression-free survival rates (ie, 77% versus 66%) and 5-year overall survival (OS) rates (ie, 82% versus 72%) compared with 8 cycles of chemotherapy (ie, CHOP) alone.

Treatment Options for Advanced Stage Aggressive Lymphomas

the treatment of aggressive lymphomas consisted of chemotherapy regimens using multiple drugs +/- Rituximab. CHOP Prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, and etoposide cyclophosphamide, etoposide, Adriamycin, cytarabine, bleomycin, Oncovin, methotrexate, leucovorin, and prednisone (ProMACE-CytaBOM)

 Methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, Oncovin, and dexamethasone (m-BACOD) Methotrexate-leucovorin, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin (MACOP-B) Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with methotrexate and cytarabine) plus rituximab (MCL) Bendamustine and rituximab

Treatment results of aggressive advanced non-Hodgkins lymphomas using different chemotherapy programs
1. First-generation: CHOP - CR: 50-55%. Long-term survival: 35-50 %. 2. Second-generation: mBACOD, ProMACO-MOPP - CR: 70-80%. Long-term survival: 50-60%. 3. Third-generation: MACOP-B - CR: 84%. Long-term survival: 75% - CR: 52-57%. Long-term survival: 47-56%

 Intrathecal chemotherapy 4-6 IT Mtx In PNS, testicular tumor,AIDS patients and CNS involvement Radiotherapy Spinal cord compression, bulky disease

Management of Aggressive Recurrent Adult NHL

High-dose chemotherapy plus stem-cell transplantation is the treatment of choice for patients who have recurrent aggressive lymphomas. the PARMA trial : the event-free survival (EFS) rate was significantly better with transplantation (46% versus 12%), and the OS rate was also better (53% versus 32%).

 Pt who respond to initial therapy and who respond to conventional salvage therapy prior to bone marrow transplantation have better survival outcomes. Patients who relapse late (>12 mo after diagnosis) have better Patients who are not candidates for transplantation can be treated with chemotherapy with or without monoclonal antibodies.

2nd-line chemotherapy regimens ICE (ifosfamide, carboplatin, etoposide) DHAP (dexamethasone, high-dose cytarabine, cisplatin) EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone) +/- Rituximab

Management of T-cell Lymphomas

T-cell lymphomas are divided into 2 subgroups: Cutaneous T-cell lymphomas (CTCL) are managed with topical agents and oral disease modifiers during the early stage of the disease Systemic T-cell disorders:

Systemic T-cell lymphomas

CHOP, CHOP plus etoposide gemcitabine based-regimens Single chemotherapy agents - Pralatrexate Monoclonal antibodies - Alemtuzumab (effective in prolymphocytic T-cell leukemia and hepatosplenic gamma-delta T-cell lymphoma) Immunotoxin - Denileukin diftitox Histone deacetylase inhibitors (vorinostat, panobinostat, romidepsin), lenalidomide, and bortezomib

Radiotherapy dose:( RT alone)

Stanford Univ and Princess Margaret Hospital. Fuks and Kaplan 1973 : doses in the range of 44 Gy achieved local control of FL in more than 95% of instances. Princess Margaret Hospital : 50% local control rate was achieved with a dose of 20 Gy, rising to 70% at 30 Gy and 80% at 40 Gy with a plateau thereafter. patients with small-volume (<2.5 cm) DLBCL, a local control rate >90% was achieved regardless of dose tumor bulk influence the outcome. tumor size >6 cm doses of at least 40 Gy were necessary

 Univ of Florida: For patients with low-grade lymphomas treated with RT alone (mostly FL), doses of 30 Gy achieved local control in >90% of patients. For those with intermediate-/highgrade disease, doses of 30 to 50 Gy also achieved local control in >95% MALT : high local control rates are achieved with doses of approx 30 Gy

RT dose in CMT
Vancouver group : DLBCL CHOP + IFRT ( 30-35 Gy @ 2-3 Gy/# 82% 10 yrs survival MD Anderson ( I-IV DLBCL post 6 CHOP) : primary tumor <3.5cm -96% local cont >3.510cm 40% with 30-40 Gy 98% with 40-50Gy . Conclusion: > 40Gy dose needed for tumor>10 cm. Kroke et al: no difference 26 Gy vs 40 Gy in stage I DLBCL post CR to CHOP Duke uni stage I and II DLBCL post CR to CHOP : 92% local control with dose averaging 30Gy

Field
As most failure occur locally IFRT is most appropriate. For tonsil, base of tongue, or nasopharynx presentations of DLBCL, after a CR to chemotherapy the specific primary site should be radiated with 3-D CRT/IMRT.

Total body irradiation TBI

Used in the past for Palliation for advanced FL still used as a part of various regimens of highdose chemotherapy (HDC) used in conjunction with stem cell transplantation dose 12-15 Gy @ 1.2-2 Gy/ #