1. Low grade NHLs Dr. Binay Kumar Shah Hematologist/Medical Oncologist
St. Joseph Regional Cancer Center

2. Lymphoma
Malignant neoplasm of lymphoid organs
B cell or T cell

3. Lymphocyte development
B cell maturation
Early stage
Late stage
T cell maturation

4. Biology of lymphoma

5. Lymphoma HD, NHL NHLs are biologically and clinically heterogeneous.
Most NHLs are of B cell origin
WHO classification of lymphoma has approximately 60 entities

6. World Health Organization classification of B-cell and T-cell neoplasms
Savage, K. J. et al. ASH-SAP 2010;2010:
Copyright ©2010 American Society of Hematology. Copyright restrictions may apply.

7. World Health Organization classification of B-cell and T-cell neoplasms
Savage, K. J. et al. ASH-SAP 2010;2010:
Copyright ©2010 American Society of Hematology. Copyright restrictions may apply.

8. Due to biological and clinical heterogeneity of lymphomas, it is crucial to establish accurate diagnosis and staging for optimal treatment.
The natural history, prognosis, and treatment of NHL depends on the specific subtype of lymphoma and the clinical stage
lymphoid tumors into one of two categories, namely, indolent lymphomas versus aggressive lymphomas, based upon on the characteristics of the disease at the time of presentation and the patients' life expectancy if the disease is left untreated

9. Low grade lymphomas Follicular lymphoma Marginal zone lymphoma
Lymphoplasmacytic lymphoma
Hairy cell leukemia

10. Follicular lymphoma
Most common indolent lymphoma – 20% of all lymphomas
Derived from germinal center B cells
Characterized by tumor cells CD20+, CD10+, BCL6+, BCL2+, and CD5–
Almost all the tumors have t(14;18)

11. Clinical presentation
Painless lymphadenopathy
B symptoms
Symptoms from organ involvement
Upto 70% have BM involvement

12. Case 1
65 yo female presented to her surgeon with gradually enlarging right cervical lymph node. She first noticed this lymph node 6 months ago. She denied any fever, oral pain, night sweats. She had mild fatigue.
O/E She was found to have a right sided cervical lymphadenopathy of size 6 cm. Oral exam is normal.
What is your next step?

13. Options
FNA
Core biopsy
Excisional biopsy
Trial of antibiotics

14. Diagnosis Incisional/excisional bx is ideal specimen
Immunophenotyping/flow cytometry and sometimes cytogenetics/FISH is required for the diagnosis
CD20+, CD10+, BCL6+, BCL2+, and CD5–.
Up to 90% of follicular lymphomas have a t(14;18) with a higher frequency observed in grade 1 or 2 follicular lymphomas.

15. Excisional biopsy was performed.
Pathology report

16. Grading of FL Grade 1 – 0 – 5 centroblasts/hpf
3A (Centrocytes present)
3B (Solid sheets of centroblasts)
Tt of Gr 3 FL s the same as that of DLBCL

17. Patient “Stage, treatment?”
Patient asks
What is the stage of my cancer?
What treatment do you think I should receive?

18. Workup/Staging Comprehensive physical exam
CBC, CMP, LDH, Beta2microglobulin
CT scan
Bone marrow aspiration/biopsy
Pregnancy testing in young women
MUGA scan

19. CBC – WBC 3, Hb 9, platelet count 100
CT scan – Right sided cervical lymph node, extensive mediastinal lymphadenopathy and retroperitoneal lymphadenopathy with largest tumor size 6 cm.
Bone marrow – positive for involvement by lymphoma
MUGA scan – EF 52%

20. Stage III/IV Treatment for symptomatic disease Symptoms Cytopenia
Bulky disease
Significant progression
Patient’s anxiety
Clinical trial

21. Treatment options
R-CVP
RCHOP RB
Radioimmunotherapy

22. Prognostic tools

23. PFS of 827 patients with FL stratified by the FLIPI into low risk (0–1 risk factors, 40% of patients, black lines), intermediate risk (2 risk factors, 33% of patients, blue lines), or high risk (3–5 risk factors, 27% of patients, red lines). Of the 827 patients, 267 were treated with chemotherapy regimens without rituximab (dotted lines) and 560 were treated with rituximab-containing regimens (solid lines).

24. Treatment
Stage I/II
Stage III/IV

25. Stage I/II
IFRT is the standard of care for stage I or contiguous stage II
Chemoimmunotherapy is another option

26. Radioimmunotherapy
RI targeted to CD20 - a viable option for patients with indolent B-cell NHL if the bone marrow is minimally involved and disease is not bulky.
FDA approved agents for relapsed follicular lymphomas _ iodine-131 (131I) (tositumomab) or 90Y (ibritumomab tiuxetan).
These agents are the most active single agents in the relapsed disease setting, although their use is limited to patients with adequate leukocyte and platelet counts and <25% marrow involvement by lymphoma.
Response duration is, on average, 11 to 15 months.

28. (A) Progression-free survival and (B) overall survival after a median follow-up of 30.6 months among 59 patients treated.
56% of the patients showed a CR or CRu and 31% achieved a PR
(A) Progression-free survival and (B) overall survival after a median follow-up of 30.6 months among 59 patients treated. (C) Progression-free survival curves of patients achieving a complete response (CR) or unconfirmed CR (CRu) compared with patients achieving a partial response (PR).
Scholz C W et al. JCO 2013;31:
©2013 by American Society of Clinical Oncology

30. Relapsed/refractory follicular lymphoma
Multiple options but depends on duration of prior response, patient age, comorbidities
If a durable remission was achieved with alkylator therapy (>2 years), it may be used again.
For shorter remission durations, fludarabine is an option. However, it must be used with caution in heavily pretreated or elderly patients due to immunosuppression; and those who are being considered for ASCT. RI
High dose chemo + ASCT
Single agent rituximab in frail patients

31. Bendamustine
Bifunctional agent with an alkylator and purine analog characteristics.
Indicated for rituximab-refractory indolent B-cell lymphomas and CLL. A 77% ORR in heavily treated pts

33. Multicenter, RCT
549 patients with indolent and MCL
6 cycles of R-B or R-CHOP
Median follow up – 45 months
Median PFS 69.5 vs 31.2 months
No OS benefit

34. Stem cell transplant
autologous or allogeneic transplantation for follicular lymphoma.
Durable remissions could be induced with either technique.
Allogeneic transplantation remains the only known curative option; however, a lower 5-year recurrence rate with allogeneic transplantations is offset by a higher treatment- related mortality compared with autologous transplantation, leading to similar 5-year survival rates of 51% to 62%.

35. Maintenance rituximab
The ECOG evaluated maintenance R in advanced indolent lymphomas, the majority of which were follicular lymphomas.
All patients received induction therapy with CVP followed by randomization for patients achieving a CR or partial remission (PR) to scheduled R qwk x 4 every 6 months x2 yrs versus obs .
A significant benefit was identified in the maintenance rituximab arm with regard to PFS (3-year PFS, 68% maintenance rituximab vs 33% observation; P = 4.4 x 10–10) and OS (3-year OS, 92% maintenance rituximab vs 86% observation; one-sided P = .05).

36. Marginal zone lymphomas
Marginal zone B-cell lymphomas (MZL)
extranodal MZL of MALT,
nodal MZL, and
splenic MZL.
MZL is characterized by an infiltrate of centrocyte-like small cleaved cells, monocytoid B cells, or small lymphocytes and may exhibit an expanded marginal zone surrounding lymphoid follicles.
The cells are positive for expression of CD20 but lack of CD5 or CD10 expression; this marker profile is useful in distinguishing MZL from SLL, MCL, and follicular lymphoma.

37. MALT Lymphoma 50% to 70% of all MZLs.
Involves mucosal sites, predominantly gastric or intestinal, and some nonmucosal extranodal sites, including the lung, salivary gland, periorbital or soft tissue, skin, and thyroid.
Common association with chronic infection or inflammation, such as Sjögren syndrome involving the parotid gland or Hashimoto thyroiditis.
The typical presentation of MALT lymphoma is an isolated mass extranodal sites or an ulcerative lesion in the stomach.
Characterized by the t(11;18)(q21;q21) in approximately 40% of cases and, less commonly, the t(1;14)(p22;q32) translocation.

38. Most common site of MALT lymphoma - stomach
H Pylori infection is common in gastric MALT lymphoma
Presentation – gastric ulcer, occasionally gastric mass.
Tt – Antibiotics; 70% of gastric MALT lymphomas regress
Responses can be slow, taking up to 6 mo to 1 yr. Assess for H pylori eradication by histologic exam or a urea breath test
Patients to respond may be from large-cell transformation or the t(11;18) translocation. These tumors are ag- independent IFRT is highly effective in localized MALT lymphomas with disease- free survival or PFS rates of >80% at 5 and 10 years
Advanced disease – treat like follicular lymphoma

39. Nongastric MALT lymphomas - indolent course, including most of the 20% to 25% of patients who present with stage IV disease.
Treatment approaches depend on both stage and site of primary involvement and may include surgery, radiation therapy, or chemotherapy.
Patients with resected stage IE lesions, as in the lung, may be followed expectantly without systemic or other therapy until evidence of progression. Other localized MALT lymphomas are often treated with radiotherapy with excellent results.

40. Nodal MZL Nodal MZL – look for extranodal MALT (in 30-35% cases)
Upto 45% patients have advanced disease.
Evaluation should include endoscopy or other procedures as clinically indicated.
IgM monoclonal gammopathy in approximately 10% of cases.
HCV infection in up to 25% of patients.
The 5-year OS is 60% to 70%

41. Splenic MZL rare and occur in elderly
Splenomegaly in the absence of nodal involvement +_ mesenteric/hepatic involvement, and the BM
Hep C infection may be +; may respond to Hep C tt
Diagnosis is usually based on spleen histology following splenectomy, bone marrow involvement, or the presence of circulating villous lymphocytes.
Median survival times exceeding 10 years.
Splenectomy is considered the optimal first-line therapy in symptomatic patients or in the case of cytopenias not felt to be related to bone marrow infiltration.

42. Lymphoplasmacytic lymphoma and Waldenstrom macroglobulinemia
LPL – Positive for CD19 and CD20; neg for CD5 and CD10
Waldenström macroglobulinemia (WM) – LPL w/ BM involvement + IgM gammopathy
Disease of elderly
Symptoms –
due to tumor infiltration (marrow, spleen, liver, and LN),
circulating IgM (hyperviscosity, cryoglobulinemia, or cold agglutinin hemolytic anemia), and
tissue deposition of IgM (neuropathy, glomerular disease, and/or amyloid).

43. Hyperviscosity syndrome –
Coagulopathies result from IgM binding to clotting factors, platelets, and fibrin.
Hyperviscosity syndrome –
visual disturbances, headaches,
dizziness,
decreased level of consciousness,
cardiopulmonary symptoms, or
a bleeding diathesis.

44. Treatment
Alkylator-based chemotherapy or nucleoside analogs are first-line tt. Vincristine is often omitted d/t underlying neuropathy.
RR of 75% with nucleoside analogs fludarabine and cladribine in newly diagnosed pts c/w approx 50% w/ alkylator-based tt
R may be combined w/ cytoxan and dex (ORR, 83%), CHOP (PR, 91%), and fludarabine/cyclophosphamide (PR, 79% in primarily relapsed disease).
R - Abrupt increases in IgM --- symptoms of hyperviscosity.
Other agents - Thalidomide lenalidomide, bortezomib are active agents. Autologous or allogeneic transplantation are considered in patients with aggressive high-risk disease.

45. Treatment of hyperviscosity – plasmapheresis followed by chemo
The treatment approach to lymphoplasmacytic lymphoma is more like that of indolent lymphoma or CLL
Patients without symptoms are managed by close monitoring .
Prognostic factors at the time of initial treatment associated with decreased survival include age >65 and anemia. The use of these 2 factors can identify those patients at high (2 factors), intermediate (1 factor), and low risk (0 factors).
The median survival times in a study of 122 patients for the high-, intermediate-, and low-risk groups were 46, 107, and 172 months, respectively.

46. Hairy cell leukemia Uncommon
Middle aged man with pancytopenia, splenomegaly, dry tap on BM aspiration
PBS - cytoplasmic "hairy" projections on the cell surface
The malignant cells - positive tartrate-resistant acid phosphatase stain, and are positive for surface Ig, CD19, CD20, CD22, CD11c, CD25, and CD103.
BM - a mononuclear cell infiltrate with a "fried egg" appearance of a halo around the nuclei and increased reticulin and collagen fibrosis.

47. Treatment Hairy cell leukemia – sensitive to purine analogs
Cladribine or pentostatin – high RR and durable remissions
Cladribine is preferred because of short duration of therapy and favorable toxicity profile.
HCL – responsive to rituximab
Newer molecules - ….

48. Accurate diagnosis important because of its favorable prognosis; 10 year OS >90%