B Cell Lymphoma: Aggressive
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1 B Cell Lymphoma: Aggressive UpToDate: Introduction: Risk Factors: Biology: Symptoms: Diagnosis: Ibrutinib approved for mantle cell lymphoma as 2nd line therapy. - Aggressive lymphomas are a group of malignant neoplasm derived from B-cell precusor cells. - Usually present acutely or subacutely with a rapidly growing mass, B symptoms (ie, fever, night sweats, weight loss), and/or elevated LDH and uric acid, including diffuse large B cell lymphoma, Burkitt lymphoma, adult T cell leukemia-lymphoma, and precursor B and T lymphoblastic leukemia/lymphoma. - Oncologic emergency can occur (see oncologic emergency). - EBV: Burkitt lymphoma (endemic and sporadic) - HIV: risk of aggressive B-cell lymphoma - HHV-8: Kaposi sacoma, primary effusion lymphoma (PEL), multicentric Castleman dz. - HepC: Mantle cell lymphoma A. Molecular Subtypes of DLBCL: - GCB (germinal center like B-cell): improved survival - ABC (activated B-cell type): worse survival, resemble HL A. DLBCL: lymphadenopathy B. MCL: advanced stage at diagnosis with splenomegaly, GI (multiple lymphomatous polyposis of the large bowel) and BM involvement. C. Burkit Lymphoma: rapid, aggressive, and fetal. Sx: * Jaw or facial mass (African childern); * Bulky abdominal mass (Western) with frequent BM (70%) and CNS (40%) involvement. A. Diagnosis test: Excisional biopsy (pathology) - Bone marrow biopsy, cytogenetics, lab (CBC, CMP, LDH, uric acid, β2- microglobulin) - CT a/p/c, PET-CT (DLBCL), hepatitis B testing, MUGA scan B. Specific tests - LP for Burkitt or DLBCL (if paranasal sinuses, testicular, epidural space, bone marrow involvement) or MCL (blastic form) or HIV lymphoma, or > 2 extranodal sites and LDH, or ovarian or breast DBLCL. - Colonoscopy/Endoscopy for MCL C. Classification: - Diffuse Large B-Cell Lymphoma (DLBCL) * T cell rich large B cell lymphoma * Primary mediastinal large B-cell lymphoma * Intravascular lymphoma - Double-Hit Lymphoma (DH Lymphoma) - Mantle Cell Lymphoma (MCL) Page 1 of 5
2 Pathology: - Burkit Lymphoma * Burkit Lymphoma (BL) * Burkit-Like Lymphoma (BLL) - Lymphoblastic Lymphoma: lymphoma form of ALL. [A]. Types of Aggressive Lymphomas: 1) DLBCL: diffuse large cell effacement of lymph node structure - IHC: * Pos for CD20, CD19, CD22, CD79a; variably pos for CD10+, BCL6+. Ki-67 40%- 90%; * No typical cytogenetic change. 2) Mentle Cell Lymphoma (MCL): - Morphology: * small cell with notched nuclei similar to SLL/CLL (indolent); * Blastoid with high mitotic rate and pleomorphic (aggressive). - IHC: Pos for cyclin D1, CD20 and CD5. Neg for CD23 and CD10. - Cytogenetics: t(11;14)/cyclin D1 3) Burkit Lymphoma: a/w EBV - Morphology (BL, BLL): medium-sized cells, "starry-sky" pattern, vacuoles. - IHC: Pos for CD19, CD20, CD22, CD79a, CD10, Bcl6 (nuclear staining); Neg for CD5, CD23, and Bcl2. Ki %. Neg TdT (r/o ALL). - Cytogentics: * t(8:14): c-myc/ig heavy chain (chr 14); * t(2:8): c-myc/κ (chr 2); * t (8:22): c-myc/λ (chr 22) 4) Double-Hit Lymphoma (DH-Lymphoma): also known as gray-zone lymphoma - Morphology: diffuse large cell pattern with GC and (+) for Bcl2. - IHC: similar to BL but pos for both Bcl2 and c-myc - Cytogenetics: c-myc (8q24) and t(14;18)(q32;q21) involving BCL2. 5) Follicular, Grades IIIb: [B]. Staging: Stage I: Single LN or single extranodal site Stage II: > 2 LN in the same side of diaphram or localized extranodal extension plus one or more nodal regions Stage III: Nodal involvement on both sides of the diaphram, may be accompnied by localized extralymphatic extension or splenic involvement Stage IV: Dissemination to one or more extranodal sites, with or without nodal involvement A: asymptomatic B: fever >38, night sweats, weight loss of >10% in preceding 6 months E: extranodal dz X: bulky dz (>10 cm) Prognosis: A. IPI score for pts > 60yrs: * Age > 60 yr, * LDH > nl, * stage III/IV, * PS 2-4, * extranodal dz (>2 sites) Risk Factor 5-yr OS (%) Page 2 of 5
3 Low Low-intermediate 2 51 High-intermediate 3 43 High B. Age-adjusted IPI score for pts <60 yrs: * LDH > nl, * PS 2-4, * stage III/IV. Risk Factor 5-yr OS (%) Low 0 83 Low-Intermediate 1 69 High-Intermediate 2 46 High C. MIPI (Mantle Cell International Prognostic Index): * Age, * PS, * LDH, * WBC ** Risk: Low (44%, score <5.7), Int (35%, score ), High (21%, score >6.2) Tx Principle: A. Diffuse Large B Cell Lymphoma (DLBCL): 1) Limited Diseases (stage I/II): BM biopsy to r/o systemic disease prior to tx. - Non-Bulky (<10cm): R-CHOP x 3 cycles plus RT (rather than chemo alone) - Bulky (>10cm): R-CHOP x 6 cycles plus XRT (category 1). - Special DLBCL: * Testicular DLBCL: Orchiectomy, R-CHOP x 6 cycles, then low dose RT to testis bilaterally, CNS prophylasix with IT chemo or high dose MTX. * Primary mediastinal large B cell lymphoma (PMLBCL): R-CHOP x 6 cycles plus RT * Ovarian DLBCL (poor prognosis): BSO-TAH adj R-CHOP x 6 cycles CNS prophylasix * Breast Lymphoma: DLBCL (common), indolent NHL (less common) IE DLBCL: R-CHOP x 3 cycles plus RT CNS prophylasix IIE DLBCL: R-CHOP (systemic) CNS propylasix * CNS Involvement: concurrent with peripheral dz Parenchymal: R-CHOP HD-MTX at count recovery Leptomeningeal: R-CHOP IT MTX/AraC or systemic HD MTX - Role of PET in pre-rt eval for stage I/II: PET after R-CHOP (6-8 wks after chemo) * if neg PET (CR) complete RT, then observe. * if pos PET (PR) complete RT at higher dose, then repeat PET (8 wks after RT) if PET negative, then clinical follow-up if PET still positive, re-biopsy start salvage chemo as indicated. 2) Advanced Disease: - Tx (NCCN): R- CHOP-14 x 6 cycles (GELA trial in 2002), category 1. (c/o CHOP-21, CHOP-14 outcome in elderly patients (>60yrs) w/o increasing toxicity.) * Note: for advanced DLBCL with Bulky Disease: current guideline DOES NOT advocate RT to bulky sites in the advanced setting. - Interim PET: PET after 2-4 cycles of R-CHOP Page 3 of 5
4 * If PET neg, continue RCHOP for a total of 6 cycles * If PET pos, continue RCHOP for a total of 8 cycles or clinicl trial - Post-chemo PET: * If PET neg, observe (prefered) or RT to initial bulky sites (category 2B) or Auto- SCT for high-risk DLBCL (high IPI score). * If PET pos, re-biopsy treat as relapse or refractory dz as indicated. 3) Special Consideration: - If pt has cardiac disease, use R-CEPP (cyclophosphamide, etoposide, prednisone, procarbazine) rather than R-CHOP - DLBCL in AIDS patient: cont HARRT during chemo * If CD4 >50, R-CHOP; * If CD4<50, CHOP w/o R. - CNS prophylasix: see diagnostic section for LP 4) Relapsed or Refractory DLBCL - Tx: R-ICE, followed by auto-sct for chemo-sensitive patients or allo-sct for primary refractory dz. - If not a transplant candiate, second line therapy (Bendamustine +/-R, CEPP-R, DA-EPOCH, CEOP, GDP, Lenalidomide +/-R, single agent Rituximab) B. Mantle Cell Lymphoma (MCL): chemo; surgery has no role except bowel obstrcution. 1) Indolent MCL: follow CLL/SLL or FL pathway. 2) Aggressive MCL (blastic variant): stage II, III, IV - R-CHOP or R-CVP, followed by Auto-SCT; or - R-Hyper-CVAD alone (w/o transplant): reserved for high risk pt (high MIPI score) - Selection of tx: * > 65yrs R-CHOP w/o transplant; * <65 yrs either CHOP or Hyper-CVAD. - Post-tx therapy: controvertial, * no routine maintenance tx. 3) Aggressive MCL: stage I/II (local disease) - R-CHOP +/- RT 4) Relapsed or refractory MCL: - Salvage chemo (R-ICE, R-DHAP, R-HyperCVAD), followed by auto-sct - New drugs: * Bortezomib (FDA approved for refractory MCL who received at leat one prior tx. * Bendamustine +/-R. * Ibrutinib (new) C. Primary Mediastinal Large B-Cell Lymphoma (PMBCL) - Sx: * young female (35yr), * bulky anterior mediastinal mass w/o distant spread or BM involvement, * different from nodal DLBCL, similar to classical HL (GEP), * Pos for CD30 and B-cell markers (>30%pts), * origin from thymus B cells. - Tx: R-CHOP x 6 cycles plus RT ( * for bulky disease, pleural effusion or pericardial effusion, R-CHOP x 8 cycles). D. Burkitt Lymphoma - Tumor lysis prophylasix: Hydration, alkalinization, allopurinol, rasburicase (uric acid oxidase) - CNS prophylasix after each cycle of chemo for all patients. Page 4 of 5
5 - Tx: CHOP is inadequate * Low-risk (single extra-abd mass <10cm, nl LDH): CODOX-M x 3 cycles (cyclophosphamide, vincristine, doxorubicin, and MTX) * High-risk (CNS and/or BM involvement, high LDH): CODOX-M alternating with IVAC (ifosfamide, etoposide, cytarabine) x a total of 4 cycles. - Relapse or Refractory BL: Clinical trial or Auto-SCT. Follow-Up: A. Follow-up for aggressive lymphoma other than burkitt) after CR: - H&P and labs q3-6 months x 5 yrs, then yearly. - CT scan, q 6 months x 2 yrs, then as clinical indicated. B. Follow-up for Burkitt: q2-3 months for 1 y, then q3 months for 1 y, then q 6 months. Page 5 of 5
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