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low grade NHL- final.pdf
- 1. TREATMENT OF LOWGRADE NON-HODGKIN LYMPHOMA Presenter- Dr Hardik Sharma Moderator- Dr Shikha Goyal
- 2. INTRODUCTION • Heterogenous groupof malignancies of the lymphoid system characterized by an abnormal clonal proliferation of B cells, T cells or NK cells • Increase in incidence has been related to environmental factors, including occupational exposures, longevity • Accounts for up to 3% of all malignancies • In INDIA, ● B-cell lymphomas (80%–85%) ● T-cell (15%–20%) ● NK cell are rare
- 3. B & TCell development & cell of origin of lymphomas
- 5. ETIOLOGY- Risk factorsand diseases associated with NHL
- 6. NHL: CLASSIFICATION • Historically •Gail and Mallory 1940s • Rappaport 1950s • Lukos-collins 1970s • Keil 1970s • Working 1982 • Real 1994 • WHO 2001,2008, 2016 & 2022 6 Indolent Aggressive Very Aggressive CLL/SLL PLL Precursor B- lymphoblastic lymphoma Lymphoplasmacytic Plasmacytoma/multipl e myeloma Burkitt’s lymphoma Primary cutaneous anaplastic cell lymphoma MCL Plasma cell leukemia Splenic marginal zone lymphoma Follicle centre, grade III MZL- • Extranodal (MALT) • Nodal DLBCL Follicle centre lymphoma, follicular grade I-II Primary mediastinal lymphoma
- 7. Indolent Aggressive NHL Proportion40-50% 50-60% Growth Slow Fast Description Often, no symptoms at diagnosis Symptoms are likely before diagnosis & progress is relatively quick Treatment Because growth is slow, treatment is sometimes not needed immediately Because growth is fast, treatment is often needed straight away Outcome Responds very well to treatment, however eventual relapse is likely. Patients can live normally for many years Responds very well to treatment, more likely to be cured
- 8. Low Grade Non-HodgkinLymphoma CLL/SLL Follicular lymphoma Grade I-II Marginal cell lymphoma Hairy cell lymphoma splenic marginal zone lymphoma Lymphoplamscytic lymphoma WHO CLASSFICATION- 5th edition haemotolymphoid neoplasms Subtypes distinguish based on a) Morphology b) Phenotype c) Genetic d) Clinical behaviour
- 9. NON-HODGKIN LYMPHOMA- INCIDENCE Al-Hamadaniet al, American journal of oncology
- 10. FOLLICULAR LYMPHOMA- INTRODUCTION •Is a heterogenous group derived from germinal center B cells, both centrocytes and Centroblasts • Second most common subtype of NHL • Most common type of indolent NHL’s • Incidence increases with age • Most frequently presents in middle-aged & elderly • Median age diagnosis – 65 yrs • Richter’s transformation in 30% cases • Extranodal prentation is uncommon
- 11. PATHOGENESIS ● Variable clinicalcourse • Incurable with standard therapy; multiple remission and relapses • Histological transformation ● t(14;18) (q32;21)- oncogene bcl-2-(85%) FL ● 80-90%- KMT2D gene mutation
- 12. CLINICAL FEATURES • Mostpatients presents with painless peripheral adenopathy • Commonly - waxing and waning course • Some present with relatively large abdominal masses, with or without evidence of GIT/GU obstruction • 20% of the patients presents with B symptoms • Pediatric-type FL- rare with characteristics a) Low stage disease (stage I/II) b) Frequent involvement of the head & neck region c) Predominance of grade 3 histology d) Absence of BCL2 gene rearrangements & infrequent BCL2 protein expression e) Presence of activating mutations involving MAP2K1 & mutation affecting TNFRSF14 f) High rate of apparent cure
- 13. PATHOLOGY • On histology, •Growth pattern • Cell morphology a) Centrocytes- cleaved follicle center cells b) Centroblasts- non-cleaved follicle center cells Grade Characteristic Grade 1 0-5 centroblasts/hpf Grade 2 6-15 centroblasts/hpf Grade 3 > 15 centroblasts/hpf 3a Centrocytes present 3b Solid sheets of centroblasts
- 14. STAGING 14 Lymphnodal regions in lymphoma
- 15. DIAGNOSIS- WORK-UP Classical FL LargeBCL with IRF4 BCL2-R negative,CD 23 +ve FL Pediatric type-FL ESSENTIAL SELECTED CASES ADDITIONAL TESTING (FL) Physical exam: node bearing areas, size of liver & spleen 2D-ECHO Immunophenotyping CD20,CD3,CD5,CD10,BCL2,BCL 6,CD21 or CD23 Performance status Beta-2 microglobulin (FLIPI-2) Molecular analysis – Ig gene rearrangements; BCL2 rearrangements CBC/RFT/LFT/LDH Uric acid Karyotype/FISH: t(14;18), BCL6,IRF4/MUM1 rearrangements- F.L. grade-3 Excisional/ incisional biopsy Hepatitis C IHC panel: ki-67,cyclin D-1 Comprehensive metabolic panel (ca2+,po4,uric acid, k+,mg2+) NGS panel-: EZH2, TNFRSF14 & STAT6 mutation Hepatitis B PET-CT or CECT(T+A+P Bone marrow biopsy
- 16. VARIANTS OF FOLLICLUARLYMPHOMA • 2016 WHO classification of tumors recognizes four additional clinical variants of FL a) Pediatric follicular lymphoma b) Intrafollicular neoplasia/”in situ” follicular neoplasm c) Duodenal-type follicular lymphoma d) Predominantly diffuse follicular lymphoma with IRF4 rearrangement
- 17. EXCISIONAL BIOPSY • Thebiopsy should be obtained before administration of steroids • Analysis – diagnosis and classification of lymphoma requires a) Histology- microscopic appearance of malignant cells b) Immunophenotype- by flow cytometry or by immunohistochemistry c) Cytogenetics- conventional karyotype or FISH d) Molecular analysis- for mutations, gene arrangements and gain or loss of certain genes by PCR, DNA sequencing
- 18. ROLE OF PET-CT •PET-CT has greater sensitivity for extra nodal involvement • May lead to change in stage (8-20% patients) • The lesions typically have low metabolic activity • Low FDG uptake or no uptake & can miss the bone marrow uptake in low grade NHL • PET/CT also has the potential to detect transformation of a low-grade lymphoma to a more aggressive subtype (Richter transformation) based on the degree of FDG avidity • SUV value more than 10 is predictor of aggressive B- cell lineage or presence of aggressive histology 20XX 18
- 19. PROGNOSTIC INDEX PARAMETER FLIPI-1FLIPI-2 PRIMA-PI (advanced FL) Nodal sites >4 LN regions Diameter>6cm lymph node Age > 60yrs >60yrs Serum marker Elevated LDH (> UNL) Elevated B2M Elevated B2M (< or > 3mg/l) Stage III-IV advance d stage Bone marrow involvement Bone marrow involvement haemoglobin <12g/dl <12g/dl Score – FLIPI-1 10yr OS % 2yr OS% • 0-1- low risk 71 98 • 2- intermediate risk 51 94 • 3 or more- high risk 36 87 Score – FLIPI-2 3yr PFS % 3yr OS% • 0- low risk 91 99 • 1-2- intermediate risk 69 96 • 3 or more- high risk 51 84 Score – PRIMA-PI 5yr OS % • 0- low risk 95 • 1-2- intermediate risk 91 • 3 or more- high risk 78 • M7-FLIPI –EZH2, ARID1A, MEF2, EP300, FOXO1, CREBBP & CARD11 • Able to identify patients at risk of for early progression • Low-risk - FFS (5yr) – 78% • High-risk – FFS (5yr) - 22%
- 20.
- 21. STAGE I-II FOLLICULARLYMPHOMA Stage I or contiguous II Non- contiguous II ISRT (preferred) • ISRT + anti CD- 20 antibody +/- chemo • Anti CD-20 antibody +/- chemo • CR/PR • NR • Follow- up • Progress ive disease • Anti-CD antibody +/- chemo +/- ISRT OR • Observation • CR • PR/NR • ISRT if not given before • NR NCCN Stage 1 grade 1,2 3a
- 22. STAGE III-IV FOLLICULARLYMPHOMA Evaluate for indications for treatment- Candidate for trial Symptoms Threatened end-organ function Progressive cytopenia Clinically significant bulky disease Steady or rapid progression No indication Observe Follow-up • Progressive disease • Histologic transformation Indication PET-CT • Suggested regime of chemoimmunoth erapy • Clinical trial and/or palliative ISRT NCCN
- 23. GELF CRITERIA • Involvementof >3 nodal sites, each with diameter of >3cm • Any nodal or extranodal tumor mass with a diameter of >7cm • B symptoms • Splenomegaly • Pleural effusion or peritoneal ascites • Cytopenias • Leukemia • Elevated LDH or b-2-microglobuliny NCCN guidelines Advanced stage low burden FL- consider observation Any one present signifies a high tumor burden
- 24. ADVANCED STAGE III/IVFL Asymptomatic pt with low burden Asymptomatic pt with high burden Symptomatic pt with low burden Symptomatic pt with high burden Observation Or rituximab Observation Or Rituximab + chemotherapy Rituximab + chemotherapy Or Rituximab Rituximab + chemotherapy with maintenance rituximab
- 25. RADIOTHERAPY IN FOLLICULARLYMPHOMA • Radiation therapy results 10yr OS rates of 60-80%; median OS 19 yrs • SEER data, RT was used as the initial treatment, OS and DFS was improved with RT and local relapse at an irradiated area is rare • Relapse usually occur in distant sites & rare after 10 yrs • Risk factor for relapse are age (>60yrs), abnormal LDH and bulky disease Data supports ES –FL – may be cured with RT alone Retrospective analysis • Stage I/II FL (1998-2012) • OS improved with RT VS no RT • 10yr OS (68%) VS (54%) • RT gives better benefit over chemo • Adding chemo to RT provides little benefit ( Kaplan-meier )
- 26. RT DOSE- FOLLICULARLYMPHOMA Interpretation- No diff in OS, PFS,LF • 30Gy dose is appropriate for aggressive NHL • 24Gy dose for indolent NHL Methods (67% stage I-II) • Aggressive NHL- 30Gy/15# • Indolent NHL 24Gy/12# • For all – 40-45Gy/20-23#
- 27. • Stage I-IIFL- 30 Gy vs 30Gy + R-CVP • Adding R-CVP to IFRT improves PFS but OS is unchanged • Systemic therapy after IFRT reduced relapse outside radiation field. • Without definitive data showing survival advantage with CMT, ISRT remains the preferred treatment for most of the patients with FL
- 28. ILROG GUIDELINES FORINDOLENT LYMPHOMA • Historically IFRT was used as a sole treatment for localized FL, NMZL • Nowdays, ISRT volume includes radiologically evident disease sites plus an expansion to encompass potential adjacent microscopic disease sites • Volume includes a) GTV- PET positive nodes and should include enlarged or equivocal nodes b) CTV- GTV plus extend bouandaries of the involved nodal compartment in axial and craniocaudal plane c) PTV- CTV to 0.5 cm margin • 24Gy to 30Gy in 12-15# remains the standard dose for curative therapy of localized FL • 2 to 4Gy in 1-2# palliation of advanced disease ( which may be repeated as needed)
- 29. BOOM-BOOM REGIMEN • Follicular/MZL- indolent type • 24gy vs 4Gy for FL or MZL • 2yr local PFS – 94% VS 80% • 24 Gy leads to better LC than 4Gy but there is no difference in OS • 2*2 allows for repeat treatment , may still opt for the regimen • But improvement in LC, still short course of 12# , strongly supports for many 2Gy*2 still used for palliation, as 50% pts achieved a CR and 81% of patients showed partial response
- 30. CHEMOTHERAPY • Multiple chemotherapy( CHOP, CVP, Fludarabine) in combination with rituximab- no drug has demonstrated superiority over another • Recently, bendamustine ( alkylating agent) with rituximab has been introduced in FL Bendamustine + rituximab vs R-CHOP showed increasy efficacay , PFS & fewer toxic effects
- 31. • Follicular lymphomagrade 1, 2 & 3a • Rituximab maintenance therapy after induction immunochemotherapy provides a significant long term PFS but not OS , benefit over observation
- 32. • Follicular lymphomagrade 1, 2 & 3a & advanced disease • Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones • Increased risk of mortality from oppurunistic infections receiving bendamustine • Prophylaxis with PJP & VZV vaccine should be administered • Prophylaxis
- 33. • Stage III/1VFL with CD20+ • Consolidation of first remission with 90Y-ibritumomab tiuxetan in advanced- stage follicular lymphoma is highly effective with no unexpected toxicities, prolonging PFS by 2 years and resulting in high PR-to-CR conversion rates regardless of type of first-line induction treatment
- 34. CHEMOTHERAPY COMBINATION WITHRITUXIMAB SAMPLE FOOTER TEXT 20XX 34 Showed improved median PFS with rituximab
- 35. PEDIATRIC-TYPE FOLLICULAR LYMPHOMAIN ADULTS • PET-CT • Bone marrow biopsy Stage I,II Excision Or ISRT Or RCHOP for pts with extensive ds who are not candidates for excision or ISRT Observe Restage with PET-CT CR Observe • NR • Progressive disease
- 37. RELAPSE OR REFRACTORYFOLLICULAR LYMPHOMA • A biopsy should be taken • The previous lines of treatment • What is the current situation? a) Patient age/comorbidities b) Disease-related symptoms c) Tumor burden Evaluate patients for treatment
- 38.
- 39. • Relapsed orrefractory indolent lymphoma • Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.
- 40. FDA APPROVED LINESOF CHEMOTHERAPY- FOLLICULAR LYMPHOMA Bendamustine causes grade 3-4 lymphocytopenia, bimonthly CD4 T-helper cells and initiation of P. jiroveci pneumonia prophylaxis for counts <200/ microlitre (T. septran)
- 41. MARGINAL ZONE LYMPHOMA ●10% of all cases of NHL ● Approximately half of the people diagnosed with marginal zone lymphoma are over the age of 60 at the time of diagnosis. ● 3 types ● Nodal marginal zone lymphoma- widespread nodal involvement, if localized- RT ● Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)- m/c ● Splenic marginal zone lymphoma- mostly stage IV but indolent. • Asymptomatic - observation • Symptomatic - splenectomy, Rituximab or chemoimmunotherapy • Patients have a history of autoimmune disorder ( Sjogren syndrome, SLE)
- 42. • Sjogren syndromeincrease in risk of MZL (30 fold) & 1000 times increase risk of parotid INCIDENCE- SITES OF MALTOMA SAMPLE FOOTER TEXT 20XX 42
- 43. ETIOLOGY-PATHOLOGY • Characterized bycentrocyte like B cells, small lymphocytes, and plasma cells • In epithelial tissue, marginal zone B cells typically infiltrate the epithelium defined by invasion and partial obstruction of mucosal glands by tumor cells • Achromobacter xylooxidans- lung EMZL
- 44. CHRONIC AG STIMULATIONCHRONIC INFLAMMATION
- 45. IMMUNOPHENOTYPE CYTOGENETIC NGS MZL(CD20,CD19,CD79A) +ve (CD5,CD23,CD10,CD43) –VE BCL2+ve, Cyclin D-1 7q del - 45% MALTOMA t(11;18), t(14;18) t(1;14), t(3;14) SPLENIC MZL +3,+18,+12, del 6q NOTCH2 (10-20%) NODAL MZL +3,+19,+12, del 6q,-7
- 46. EXTRANODAL MALTOMA • Two-thirdsof the patients have stage I-II disease • MALT is a collection of lymphocytes in the mucosa, which is rich in B cells, can form in the mucosa in response to inflammation to help protect the body from disease and infection • MALT lymphoma can develop almost anywhere in the body where there is lymphoid tissue • Gastric (stomach) type • Non-gastric type • Most common sites- stomach, orbit , bone & less common were parotid, breast, thyroid and lung
- 47. GASTRIC MALT LYMPHOMA •Median age at diagnosis – 60 yrs • Equal in men and women • 2/3rd of the patients with stage I/II disease with B symptoms & bone marrow involvement rare • MALT lymphomas can transform into more aggressive lymphoma but occurs rarely • Most common transformation into ABC- like DLBCL • Nearly half of the lymphomas involves gastric mucosa • 60% associated with an H. pylori infection • Normal T-cells in gastric mucosa attract B-cell population, rise to lymphoid follicles which further lead to prolonged stimulation lead to lymphomas
- 48. SIGNS & SYMPTOMS-GASTRIC MALTOMA • Heart burn & indigestion • Nausea • Vomiting • Loss of appetite • Unexplained weight loss • Gastric bleeding • A mass or irregularity present during an endoscopy
- 49. DIAGNOSTIC CRITERIA –DAWSON’S CRITERIA Used for labelling primary gastrointestinal lymphomas • Absence of peripheral lymphadenopathy at the time of diagnosis • Lack of enlarged mediastinal lymph nodes • Normal total and differential WBC count • Predominance of bowel lesion at the time of laparotomy with only lymph node obviously affected in the immediate vicinity • No lymphomatous involvement of liver and spleen
- 51. PROGNOSTIC FACTORS &DIAGNOSIS • Disease site • Paired organs ( orbit , salivary gland) have a high risk of relapse • Medical history and physical examination • Upper endoscopy for biopsy a) Testing for H.pylori b) Flow cytometry c) Molecular testing ● Hepatitis B & C test • Stains- giemsa • Urea breath test • Rapid urease test • Culture • Serological based studies
- 52. HISTOPATHOLOGY • Closely resemblethe normal malt • Expansion of marginal zone around reactive follicles • Dutcher bodies may be seen • Variable plasma cell infiltrate in 1/3rd of the MALT lymphomas • Infiltration of neoplastic cells into gland/crypt epithelium with destruction of architecture
- 53. DIFFERENTIAL DIAGNOSIS • Reactivelesions ( H. pylori gastritis, lymphoepithelial sialadenitis)- early phases of MALToma resemble reactive process and immunophenotypic & IGH rearrangements by molecular techniques • Follicular lymphoma- CD10+, aberrant expression of bcl-2 protein • Mantle cell lymphoma- CD5+,cyclin-D1 staining • CLL/SLL- CD5+/CD23+ • Burkitt lymphoma- CD19,CD20,CD22,surface IgM +ve, 60-80% of cases CD10+ve
- 54. • Complete response– 80% , of those who received CR, EFS 98% of the pts • Interpretation- Antibiotics in H. pylori +ve gastric MALT lead to excellent control
- 55. MANAGEMENT- STAGE I& II 1/ STAGE IE/T1-3N0M0 H. Pylori +ve, t(11;18) negative or t(11;18) unknown H.Pylori +ve, t(11;18) +ve H.Pylori negative Antibiotic therapy Then evaluate with endoscopy • Antibiotic therapy with ISRT ( preferred) Or • Rituximab ( ISRT is contraindicated) • ISRT (preferred) Or • Rituximab ( ISRT is contraindicated) Evaluate with endoscopy
- 56. MANAGEMENT- STAGE II2/ STAGE IIE- IV/T1-3N2M0/T1-4N1-3M0-1 Evaluate for indication for Rx- a) Candidate for trial b) Symptoms c) GI bleeding d) End organ function e) Clinically bulky disease f) Steady or rapid progression observe Indication present First line chemotherapy Palliative ISRT • Evaluate with endoscopy, if evidence of recurrence (MZL) • If histologic transformation
- 57. RADIOTHERAPY IN MALTOMA •t(11;18) (q21;q21) translocation and lack of response to antibiotic therapy are the two main indications to treat with definitive radiotherapy • Prospective trial British National Lymphoma Investigation – phase III RCT lead to adoption of 24-30Gy as the appropriate dose of curative treatment of FL • For MZL, published data reflect the results of whole organ irradiation ( eg, stomach, salivary glans , thyroid) • For conjunctival MZL, irradiation confined to conjunctival sac is highly effective • For lacrimal gland, treatment may be confined to the lacrimal gland only ILROG
- 58. ILROG GUIDELINES- ISRTEXTRANODAL MZL • GTV- PET positive lesion & PET positive adjacent nodes ( additional information from CT, MRI & endoscopy) • CTV- entire involved organ or compartment – gastric MZL whole organ is irradiated • Equivocally adjacent lymph nodes should be included in CTV • For conjunctival MZL , the entire conjunctival sac is irradiated with no need to irradiate the whole orbit • Partial organ irradiation may be considered in some cases where whole organ irradiation is not feasible (i.e lung, skin, breast) • Adequate ITV/PTV expansion must be used to account for organ motion • Dose- 24-30 Gy is standard for MZL, with 24 Gy used for sensitive sites such as the orbit • Lower doses 2-4 Gy found to be very effective in palliative or advanced FL with response rates of 80-90% with median duration of response 22-4 months.
- 60. FOLLOW-UP 3MONTH RESTAGING& ENDOSCOPY Restage at 3mo with endoscopy/biopsy for H. pylori after antibiotics (restage earlier than 3mo if symptomatic) H. Pylori –ve, Lymphoma -ve H. Pylori –ve, Lymphoma +ve H. Pylori +ve, Lymphoma -ve H. Pylori +ve, Lymphoma +ve Asymptomatic Symptomatic Observe for another 3mo or ISRT ISRT Second-line antibiotic treatment Stable disease Progressive or symptomatic ds ISRT & Second-line antibiotic treatment Follow-up Endoscopy
- 61. FOLLOW-UP 3-6 MONTHRESTAGING & ENDOSCOPY Restage at 3mo with endoscopy & biopsy after ISRT or rituximab H. Pylori –ve, Lymphoma -ve H. Pylori +ve, Lymphoma -ve H. Pylori -ve, Lymphoma +ve H. Pylori +ve, Lymphoma +ve Consider antibiotic treatment First line therapy for MZL Evaluate for indications for Rx Relapse Indications +nt No indication observe Second line therapy for MZL Follow-up Endoscopy
- 62. FOLLOW-UP - MZL Repeat endoscopy after3mo CR NR Follow-up every 3-6 mo for 5yrs and then yearly Recurrence post ISRT Indication for treatment No indication observation Indication present Second line chemo Recurrence post antibiotic Systemic recurrence Local recurrence Locoregional ISRT Relapse Previous ISRT Previous antibiotic Rx First line chemo Relapse Locoregional ISRT Indication for treatment Indication present No indication First line chemo observation
- 63. • RCT-III trial-Low tumor burden indolent lymphoma • In low tumor burden SLL and MZL patients responding to R induction, MR significantly improved TTTF as compared with RR
- 64.
- 65. SITE-SPECIFIC WORKUP INNON-GASTRIC MALT LYMPHOMA
- 66. MANAGEMENT- NON-GASTRIC MALTLYMPHOMA Stage IE or Contiguous Stage IIE ISRT (preferred) Surgery may be considered for some sites +ve margins -ve margins Consolidative ISRT Observe Follow-up Rituximab in selected cases Observation in selected cases Stage IV ISRT Observation Manage per advanced NMZL
- 67. FOLLOW-UP NON-GASTRIC MALTLYMPHOMA Clinical follow-up every 3-6mo for 5yr & then yearly or as clinically indicated Local recurrence Systemic recurrence If histologic transformation ISRT if not previously treated or manage as advanced stage NMZL Evaluate for indication for Rx- a) Candidate for trial b) Symptoms c) GI bleeding d) End organ function e) Clinically bulky disease f) Steady or rapid progression No indication Indication present observation First line or second line chemotherapy
- 68. SPLENIC MARGINAL ZONELYMPHOMA ● The spleen is a soft, spongy organ above the stomach and under the ribs on the left side, about the size of a fist. It is part of the lymphatic system, and it performs several critical functions including: • Filtering out and destroying old, damaged blood cells • Storing red blood cells and platelets • Producing lymphocytes (a type of white blood cell) that fight infection and disease ● The cause of splenic marginal zone lymphoma in unknown in most cases. It is more common in people who have been infected with hepatitis C virus or who have an autoimmune condition. ● The median age at diagnosis is 65 to 70 years
- 69. PATHOGENESIS- SMZL • Arisefrom the post germinal center, memory B cell of splenic type • Molecular studies showed alterations to pathways , result in proliferation and commitment of mature B cells to marginal zone differentiation GENES Percentage in population Notch pathway 40% NF-KB pathway 35-40% KLF2 20-40% MYD88 3-15% CARD11 5-10% KMT2D 7%
- 70. CLINICAL FEATURES- SMZL •Symptoms of an enlarged spleen include: • Pain in the left upper abdomen that may spread to the left shoulder • Feeling full after eating only a small amount (from the enlarged spleen pressing on the stomach) • Decreased appetite • Unexplained weight loss ● Splenic marginal zone lymphoma often spreads to the bone marrow, the soft tissue inside of certain bones, causing low red blood cells and platelet counts
- 71. PATHOLOGY Peripheral smear showsmall lymphoid cells with dark round nuclei Section of spleen- follicles with expanded mantle & marginal zones • Bone marrow- if present, mild and can be subtle • Lymph node- splenic hilar lymph nodes often involved • Immunophenotype- IgM, IgD, CD 19,CD20,CD22 & BCL2 with LFA- 1,CD29 &ICAM-1
- 72. WORK-UP - SMZL •Excisional/ incisional biopsy • Hepatitis B/ hepatitis C • Bone marrow biopsy +/- aspirate • SPEP for qualitative Ig levels • IHC & Molecular testing • Prognostic model Adverse factors Value Risk group 5yr cause specific survival Hemoglobin <9.5g/dl A(0) 88% Albumin <3.5g/dl B (1) 73% LDH More than ULN C(2-3) 50%
- 73. MANAGEMENT- SPMZL Criteria toindicate treatment of Splenic MZL • Progressive or symptomatic splenomegaly • Cytopenia a) HB- <10g/dl b) Neutrophils<1*10 9/L c) Progressive thrombocytopenia • Constitutional symptoms • Progressive nodal disease • Autoimmune haemolytic anaemia
- 74. FOLLOW-UP – SPLENICMARGINAL ZONE LYMPHOMA Clinically follow-up every 3-6mo for 5yr & then yearly or as clinically indicated Recurrence If histologic transformation Evaluate for indications for Rx: • Candidate for clinical trial • Symptoms • Cytopenias • Clinically significant bulky disease • Steady or rapid progression No induction Indication present No induction First line / second line chemotherapy
- 75. FOLLOW-UP – SPLENICMARGINAL ZONE LYMPHOMA • Pneumococcal and meningococcal vaccinations at least two weeks before the splenectomy Vaccination against • Haemophilus influenzae type b (HiB), should also be considered
- 76. NODAL MARGINAL ZONELYMPHOMA • Rare , slow-growing type of MZL • Lymphomas are primarily nodal diseases without evidence of extranodal involvement • Approximately 1% of NHL • Median age at diagnosis 70yrs • Male > female • Pediatric NMZL is a distinct entity with excellent prognosis
- 77. CLINICAL FEATURES • Bsymptoms • Anemia- 25% • Thrombocytopenia- 10% • Elevated LDH- 12-48% • Increased beta-2 microglubin- 29-45% • Monoclonal immunoglobin- 6-33%
- 78. DIAGNOSTIC WORK UP-NMZL • Excisional biopsy • Cell assessment via flow cytometry with CD20+ve, CD5-ve, CD10-ve • Molecular analyses – MYD88 mutation , CXCR4 mutation • Hepatitis B & C • If patient with localized nodal involvement, with high suspicious of marginal zone lymphoma of extranodal primary site a) Axillary node- evaluate for lung, breast,, etc b) Mediastinal node- lung, breast c) Abdominal node- splenic & gastrointestinal d) Neck node- evaluate for parotid, ocular, thyroid,,etc
- 79. TREATMENT- STAGE I,II NMZL Stage I- II Stage I Or contiguous stage II ISRT ( Preferred) ISRT + anti CD- 20 mab +/- chemo anti CD-20 mab +/- chemo CR/PR NR STAGE III, IV CR/PR NR Progressive disease ● Clinical • H&P & labs every 3-6mo for 5 yr and then annually ● Surveillance imaging • Upto to 2yr post completion of Rx- C/A/P CT evety 6 months • >2yr- no more than annually Non- contiguous stage II anti CD-20 mab +/- chemo +/- ISRT for local palliation observation CR PR or NR Consider ISRT if not previously given CR/PR NR
- 80. STAGE – III-IVNMZL Evaluate for indication • Candidate for clinical trial • Symptoms • Threatened end- organ function • Clinically significant cytopenia • Clinically significant bulky • Steady or rapid progression No indication Indication +nt PET-CT scan Suggested regimen (MZL- A) Clinical trial Palliative ISRT Response assessment & additional Rx Indication +nt Clinical • H&P and labs – 3-6 mo for 5yr & then annually or as clinically indicated Surveillance imaging • Upto 2yr- C/A/P CT no more than every 6 mo • >2yr- CT scan no more than annually • Progres sive disease • Histolo gic transfor mation
- 81. FOLLOW-UP NODAL MZL CT(C+A+P) CR PR NR Maintenance therapy for patients related with rituximab Or observe ● Clinical • H&P & labs every 3-6mo for 5 yr and then annually ● Surveillance imaging • Upto to 2yr post completion of Rx- C/A/P CT evety 6 months • >2yr- no more than annually • Relapse or progression • If histologic transformation Evaluate for indications for Rx: • Candidate for clinical trial • Symptoms • Cytopenias • Clinically significant bulky disease • Steady or rapid progression No indication observe Rebiopsy • Third line chemo/ CART- T cell therapy • If histologic transformation PET-CT Chemotherapy/ palliative ISRT
- 82. HISTOLOGICAL TRANSFORMATION OFINDOLENT LYMPHOMA FL/MZL to DLBCL after minimal or no prior therapy With double hit Without double hit MZL to DLBCL Treat as a DLBCL schedule Carry a poor prognosis • Occurs in approximately 2-3% of patients per year & associated with a poor clinical outcome • Canadian trial, treated with after transformation by induction chemotherapy f/b HDC & ASCT, a 5yr survival 65% reported
- 83. FL/MZL TRANSFORMATION TODLBCL • Histologic transformation of FL & MZL to DKBCL ( after multiple lines of prior therapy)
- 84. SMALL LYMPHOCYTIC LYMPHOMA/CLL •Mature peripheral B-cell malignancy • Difference between SLL vs CLL, clinical presentation, with non-leukemic presentation in SLL • SLL represents <5% of all NHLs • Median age at diagnosis 65ys • At least 80% have stage IV disease due to bone marrow involvement at diagnosis
- 85. PATHOLOGY • Small lymphocyteswith condensed chromatin, round nuclei, sometimes with large lymphoid cells with prominent nucleoli can be seen • Larger lymphoid cells are clustered to form proliferative centers, which are pathognomic • 60% have Ig genes , that showed evidence of significant somatic mutation • Express low level of IgM or IgD, HLA-DR, CD19,CD20 and CD23 with tyrosine kinase ZAP70 also • Recurrent mutation which involve the NOTCH 1, SF3B1, TP53, ATM, & MYD88 genes • Cytogenetic abnormalities include trisomy 12, 13q deletions ( most favorable prognosis), 17p deletions( unfavorable prognosis), 11q deletions
- 86. CLINICAL FEATURES • Painlessgeneralized lymphadenopathy, present for several years • B symptoms are rare • Hepatosplenomegaly present in <50% patients • Peripheral blood smear- showed normal or mild lymphocytosis • ANC <5000/microlitre • Hypogammaglobinemia- present at 40% • Both SLL/CLL may develop autoimmune hemolytic anemia, pure red cell aplasia • Elevated LDH is uncommon • Raised level of serum b-2 macroglobulin, marker for disease burden • ( Richter syndrome- present with rapidly growing masses, elevated LDH and B symptoms)
- 87. TREATMENT • Stage 1treated with IFRT only • Stage II-III treated with chemotherapy regimens used for SLL • For advanced stage who do not need systemic therapy, but causing symptoms, low dose palliative RT ( 2Gy *2#) but local control rates are not high as seen with FL
- 88. LYMPHOPLASMACYTIC LYMPHOMA-PATHOLOGY • 1%of all NHLs, with mixed cryoglubulinemia, related with concurrent Hep C infection • Mixture of small lymphocytes, lymphoplasmacytic cells and plasma cells with Russell bodies/ Dutcher bodies are seen • Occasionally cases may also contain frequent larger immunoblastic- like cells • IHC- CD19, CD20, & surface IgM , do not express CD10 or CD23 • Waldenstrom macroglobulinemia (high level of IgM) associated with LPL • MYD88 & CXCR4 are associated mutations but are not specific to it
- 89. CLINICAL PRESENTATION • Similarto SLL • Median age – 60yrs • Nearly all patients have stage IV disease by virtue of bone marrow involvement • Lymph nodes & spleen involvement are common • Patients with waldenstrom macroglubinemia may transform to a more aggressive NHL • B symptoms & serum LDH are uncommon
- 90. • Lymphoplasmacytic lymphoma I.Neoplasm of small B cell, plasmacytoid lymphocytes& plasma cells II. Involving bone marrow & sometimes LN and spleen III. Does not fulfill criteria of any other small B-cell lymphoid neoplasm WHO CRITERIA- LPL AND WALDENSTROM MACROGLOBULINEMIA • Waldenstorm macroglubinemia I. IgM monoclonal antibody II. Bone marrow infiltration of small B lymphocytes, plasma cells III. Diffuse, interstitial or nodular bone marrow infiltration IV. (CD19,CD20, CD5, IgM, CD10, CD23) positivity Revised IPSS criteria WM
- 91. TREATMENT- LPL • Atleast 25% of patients have no indication for therapy at initial presentation Asymptomatic or minimally symptomatic Risk score • Bone marrow inv(%) • S. IgM • S. beta 2- microglobulin • S.albumin • Low risk MTP- 9.2yrs • Intermediate risk MTP- 4.8yrs • High risk MTP-1.8yrs • Low risk Every 12 mo with CBC, metabolic panel, SPEP, S.Ig • Intermediate risk Every 6 mo with CBC, metabolic panel, SPEP, S.Ig • High risk Every 3 mo with CBC, metabolic panel, SPEP, S.Ig Indication for treatment Follow-up Symptoms related to: • Hyperviscosity • Neuropathy • Organomegaly • Amyloidosis • Cold agglutinin • Cryoglobulinemia • Anemia • Cytopenias • Bulky adenopathy • B symptoms
- 92. PRIMARY MANAGEMENT -LPL Plasmapheresis for symptomatic hyperviscosity & Primary therapy Or Clinical trial Treat with chemoimmunotherapy regimen Observe until progressive disease Observe until progressive disease Consider previous regimen, if well tolerated Treated with BTK inhibtors Continue Rx until disease progression or toxicity If persistent symptoms • No response • Progressive disease • Choose alternative therapy • If transformation occur (B cell lymphoma)
- 93. SUMMARY- LOW GRADENHL Localised (S-I/II) indolent/low grade lymphoma Standard therapy: ISRT-24-30Gy Investigational: Combined modality Rx Advanced (S-III/IV) indolent/low grade lymphoma Asymptomatic: Observation with delayed therapy Symptomatic: Chemotherapy or palliative RT
- 94. CONCLUSION- LOW GRADENHL • Low grade NHL – heterogeneous group, indolent course • Histology – cornerstone of diagnosis • PET – lesser role than in aggressive NHL or HL • Follicular NHL – B-cell origin – comprises >30% of all NHL • Primarily a disease of older age • Treatment depends on stage and other prognostic factors • No single therapeutic standard exists • Early stage: RT preferred; Advanced stage: Observation or systemic therapy • MZL – Nodal, Extranodal, Splenic • Stomach MALToma – even H pylori eradication may suffice as therapy in early stage; for advanced stage, therapy depends on indication • RT doses for low grade NHL – 24 Gy in curative setting, 4 Gy in palliative setting 94
- 95.