Epidemiology Lymphoma (both NHL and HL) is the most common hematological cancer (5% of all cancer cases). The annual incidence of \200\230lymphoma \200\231 in Western countries is 1 5 \200\22320 cases per 100,000. Incidence i with age. \231\202: \231\200 ratio 3:2. The la st decades have seen an increase; i incidence is in part due to i mean age of the populatio n, improvements in diagnosis, the HIV pan- demic, and immunosuppressive therapy and diagnos is (including HIV). Etiology The rearrangement and mutation of immunoglobulin genes that occur in B-cell diff e rentiation and the response to antigen off ers an opportu- nity for genetic accidents such as translocations or mutations involving immunoglobulin gene loci that have been characteri zed in many lym- phomas. Most translocations involve genes associated with either prolif- e ration (e.g. c-MYC) or apoptosis (e.g. BCL-2). Other factors associated with NHL are: \200 Congenital immunodefi ciency: ataxia telangie ctasia, Wiskott \200\223Aldrich syndrome, X-linked combined immunodefi ciency. Acquired immunodefi ciency: immunosuppressive drugs, transplantation, HIV infection. Infection: HTLV-I (ATLL); EBV (Burkitt lymphoma, HL); Helicobacter pylori (gastric mucosa-associated lymphoid tissue (MALT) lymphomas). Environmental toxins: agricultural pesticides, herbicides, and fertilizers, solvents and hair dyes. Familial: risk i 2 \200\2233-fold in close relatives (?environmental). Classi \201 cation The World Health Organization (WHO) classifi cation of lymphoid neoplas ms superseded the previous Revised European American Lymphoma (REAL) classifi cation. The m ost recent 2008 WHO classi- fi cation (E Table 5.1) lists over 80 diff erent clinical-patho logical lym- phomas using morphology, immunophenotype, genotype, cell of origin, and clinic al behavior. 85% of lymphomas are B-cell type, the remaining lymphomas are of T/NK-cell ori gin. The extensive list includes all entities and also includes provisional enti- ties for which the WHO Working Group felt there was insuffi cient evi- dence to recognize as distinct dis eases at this time. The most common and least rare lymphomas are discussed in this chapter. Clinical behavior of lymphomas most often determines management strategies in clinical prac tice; treatment protocols remain largely based on classifi cation systems that group diagno ses into indolent (low-grade) and aggressive (high-grade) NHL. 183 NON-HODGKIN LYMPHOMA (NHL) The more biologically relevant classifi cation of lymphoma diagnosis using the WHO classifi cation, together with emerging therapeutic options based on immunological and molecular ch aracteristics will increase the diagnosis-specifi c nature of therapy in the future. Table 5.1 WHO classifi cation of lymphoid neoplasms1,2 Mature B-cell neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Sple nic B-cell marginal zone lymphoma Hairy cell leukemia Splenic B-cell lymphoma/leukemia, unc lassifi able Splenic diff use red pulp small B-cell lymphoma Hairy cell leukemia-variant Ly mphoplasmacytic lymphoma Waldenstr m macroglobulinaemia Heavy chain diseases Alpha heavy c hain disease Gamma heavy chain disease Mu heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone lymphoma of mucosa- associated lymphoid tissue (MALT lymphoma) Nodal marginal zone lymphoma Pediatric nodal mar ginal zone lymphoma Follicular lymphoma Pediatric follicular lymphoma Primary cutaneous fol licle center lymphoma Mantle cell lymphoma Diff use large B-cell lymphoma (DLBCL), NOS T-ce ll/histiocyte rich large B-cell lymphoma Primary DLBCL of the CNS Primary cutaneous DLBCL, leg type EBV-positive DLBCL of elderly DLBCL associated with chronic infl ammation Lymphoma toid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma ALK positive large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymp homa arising in HHV8-associated multicentric Castleman disease Primary eff usion lymphoma B urkitt lymphoma B-cell lymphoma, unclassifi able, with features intermediate between diff u se large B-cell lymphoma and Burkitt lymphoma B-cell lymphoma, unclassifi able, with featur es intermediate between diff use large B-cell lymphoma and classical Hodgkin lymphoma (Continued) 184 CHAPTER 5 Lymphoma Table 5.1 WHO classifi cation of lymphoid neoplasms1,2 (Continued) Mature T-cell and NK-cel l neoplasms T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphopro liferative disorder of NK-cells Aggressive NK cell leukemia Systemic EBV positive T-cell ly mphoproliferative disease of childhood Hydroa vacciniforme-like lymphoma Adult T-cell leuke mia/lymphoma Extranodal NG/T cell lymphoma, nasal type Enteropathy-associated T-cell lympho ma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fun goides S zary syndrome Primary cutaneous CD30-positive T-cell lymphoproliferative disorder s Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Primary cutaneous gamma-delta T-cell lymphoma Primary cutaneous CD8 positive aggressive epidermotropic cytot oxic T-cell lymphoma Primary cutaneous CD4 positive small/medium T-cell lymphoma Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, AL K positive Anaplastic large cell lymphoma, ALK negative Hodgkin lymphoma Nodular lymphocyte predominant Hodgkin lymphoma Classical Hodgkin lymphoma: Nodular scleros is Hodgkin lymphoma Lymphocyte-rich classical Hodgkin lymphoma Mixed cellularity Hodgkin ly mphoma Lymphocyte depleted Hodgkin lymphoma The italicized histological types are provisional entities, for which the WHO Working Group felt there was insuffi cient evidence to recognize as distinct diseases at this time. 185 NON-HODGKIN LYMPHOMA (NHL) Presentation The features at presentation refl ect a spectrum from \200\230low-grade \200 \231 lym- phoma (typically, widely disseminated at diagnosis but with indolent course) to \200\230high-grade \200\231 lymphoma (short history of localized rapidly enlarging lymphade nopathy constitutional symptoms ( \200\230B-symptoms \200\231: drenching night sweats, > 10% weight loss and/or fevers). Almost 75% of adults present with nodal disease, usually superfi cial pain- less lymphadeno pathy. 25% are extranodal (750% in the Far East) and may present with oropharyngeal involve ment (5 \200\22310%), GI involvement (15%), CNS involvement (5 \200\22310%), skin involveme nt (mainly T-cell lym- phomas). Patients with GI involvement have a higher frequency of oropharyngeal involvement (Waldeyer \200\231s ring) and vise versa. Hepatosplenomegaly is common in advanced disease. Diagnostic and staging investigations \200 Histological diagnosis by expert haematopathol ogist: excision biopsy of lymph node or extranodal mass with immunohistochemistry molecu lar analysis. NB Fine needle aspirate (FNA) is inadequate for reliable diagnosis and grading. Detailed history including B symptoms. \200 Physical examination and performance status. \200 FBC and blood fi lm. \200 LDH. \200 CRP/ESR. \200 Serum 2-microglobulin. \200 U&E, uric acid, LFTs. \200 DAT screen. \200 Serum protein electrophoresis. \200 Plasma viscosity can be considered. \200 BM aspirate and trephine biopsy. \200 CXR. \200 Imaging: whole-body CT neck, chest, abdomen, and pelvis or PET/ CT scan; CT or MRI he ad/spine for patients with CNS symptoms; other imaging as indicated. LP also for high-grade disease with BM, testicular, paranasal sinus, parameningeal, peri-orbital or paravertebral involvement. HIV serology recommended in all patients. \200 Helicobacter pylori serology (gastric MALT lymphoma). \200 Echocardiogram pre-treatment with anthracyclin containing regimen. Staging defi nes prognosis and helps in selecting therapy. The Ann Arbor staging system dev eloped for Hodgkin lymphoma is also used in NHL (see E Table 5.9, p.217). 186 CHAPTER 5 Lymphoma (Possible) Laboratory features \200 Normochromic normocytic anemia common. \200 Leucoer ythroblastic fi lm if extensive BM infi ltration pancytopenia. \200 Hypersplenism (occ asionally). \200 PB may show circulating lymphoma cells (MCL; cleaved \200\230buttock \200\231 cells in FL and blasts in high-grade disease) \200 LFTs abnormal in hepatic infi ltration. \200 Serum LDH and 2-microglobulin are useful prognostic factors. LDH often raised in high-grade lymphomas. 20% of patients with SLL or FL have a serum paraprotein, usually IgM and usually low level. Prognostic factors \200 Histological grade. \200 Performance status. \200 Constitutio nal ( \200\230B \200\231) symptoms unfavorable. \200 Gene expression profi le in DLBCL (G CB favorable; ABC poor). Unfavorable \200 Age >60 years. \200 Disseminated disease (stage III \200\223IV). \200 Extranodal disease. \200 Bulky disease (>10cm). \200 Raised serum LDH. \200 Raised serum 2-microglobulin. \200 High proliferation rate by Ki-67 immunochemistry. \200 P5 3 mutations. \200 T-cell phenotype. \200 High-grade transformation from low-grade NHL. Various international prognostic systems are used to predict prognosis and tailor treatment . The IPI, Revised IPI (R-IPI), FLIPI, and MIPI score are discussed on E pp.187 \200\223188 . References 1. Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoieti c and Lymphoid Tissues, 4th ed. Lyon: IARC. 2. Campo, E. et al. (2011). The 2008 WHO classifi cation of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood, 117, 5019 \200\22332. 187 INTERNATIONAL PROGNOSTIC INDEX International Prognostic Index Validated in all clinical grades of NHL as a predictor of re sponse to therapy, relapse, and survival (see Table 5.2). The IPI1 was validated in the pre -rituximab era. 1 point is awarded for each of the following char- acteristics to identify 4 risk groups: \200 Age >60 years. \200 Stage III or IV. \200 \211 2 extranodal site s of disease. \200 Performance status (ECOG) \211 2. \200 Serum LDH raised. Table 5.2 IPI1 Score IPI risk group % CR 5-year CR-DFS 5-year OS 0 or 1 Low 87% 70% 73% 2 Low/intermediate 67% 50% 51% 3 Intermediate/high 55% 49% 43% 4 or 5 High 44% 40% 26% Age-adjusted IPI4 Used for patients aged >60 years who may be eligible for more intensive t herapy (see Table 5.3). 1 point is awarded for each of the following characteristics: \200 Stage III or IV. \200 Raised serum LDH. \200 Performance status \211 2. Table 5.3 Age-adjusted IPI1 Score IPI risk group (patients \211 60) % CR 5-year CR-DFS 5-year OS 0 Low 92% 86% 83% 1 Low/intermediate 78% 66% 69% 2 Intermediate/high 57% 53% 46% 3 High 46% 58% 32% Revised International Prognostic Index (R-IPI)2 has been developed for patients with DLBCL treated with R-CHOP as the addition of rituximab has altered the survival of IPI prognostic groups (see Table 5.4). R-IPI uses the same risk factors as the IPI to identify 3 distinct groups. Table 5.4 R-IPI2 Score R-IPI risk group % patients 4-year PFS 4-year OS 0 Very good 10% 94% 94% 1 or 2 Good 45% 80% 79% 3, 4, or 5 Poor 45% 53% 55% 188 CHAPTER 5 Lymphoma Follicular Lymphoma Prognostic Index (FLIPI)3 Provides better prognostic information in pat ients with follicular lym- phoma as only 711% are high risk on IPI (see Table 5.5). The FLI PI can be used to assess the need for early treatment and its likely outcome. 1 point is aw arded for each of the following risk factors to identify 3 risk groups: \200 Age >60 year s. \200 Stage III or IV. \200 Hemoglobin <120g/L. \200 Raised serum LDH. \200 Numbe r of nodal sites \211 5. Table 5.5 FLIPI3 Score FLIPI risk group % patients 5-year OS 10-year OS 0 or 1 Low 36 91% 71% 2 Intermediate 37 78% 51% \211 3 High 27 52% 36% MCL International Prognostic Index (MIPI) Applies to advanced stage MCL (III-IV). The full MIPI is calculated using the following formula: [0.03535 \227 age (years)] + 0.6978 (if ECOG >1) + [1.367 \227 log10(LDH/ULN)] + [0.9393 \227 log10(WBC count)] A score <5.7 indicates low-risk disease, 5.7 \200\2236.2 indicates intermediate risk, and > 6.2 high risk (see Tables 5.6 and 5.7). Table 5.6 Calculating the simplifi ed MIPI4 Score Age PS LDH/ULN WCC 0 <50 0 \200\2231 <0.67 <6.7 1 50 \200\22359 \200\223 0.67 \200\2230.99 6.7 \200\2239.9 2 60 \200\22369 2 \200\2234 1.0 \200\2231.49 10.0 \200\22314.9 3 \211 70 \200\223 \211 1.50 \211 15.0 LDH/ULN: LDH relative to the upper limit of normal Table 5.7 Simplifi ed MIPI4 Score Risk % patients Median OS (months) 0 \200\2233 Low 44 >90 4 \200\2235 Intermediate 35 58 6 \200\22311 High 21 37 189 INTERNATIONAL PROGNOSTIC INDEX References 1. Anonymous (1993). A predictive model for aggressive non-Hodgkin lymphoma. The international Non-Hodgkin Lymphoma Prognostic Factors. N Engl J Med, 329, 987 \200\22394. 2. Sehn, L.H. et al. (2007). The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diff use large B-cell lymphoma treated with R-CHOP. Blood, 109, 1857 \200\22361. 3. Solal-Celigny, P. et al. (2004). Follicular lymphoma international prognostic index. Blo od, 104, 1258 \200\22365. 4. Hoster, E. et al. (2008). A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood, 111, 558 \200\22365. Further reading Romaguera, J.E. et al. (2010). Ten-year follow-up after intense chemoimmuno therapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabi ne (R-MA) and without stem cell transplantation in patients with untreated aggressive mantl e cell lymphoma. Br J Haematol, 150, 200 \200\2238. Van Oers, M.H. et al. (2006). Rituximab maintenance improves clinical outcome of relapsed/ resistant follicular non-Hodgkin lympho ma in patients both with and without rituximab during induction: results of a prospective r andomized phase 3 intergroup trial. Blood, 108(10), 3295 \200\223301. 190 CHAPTER 5 Lymphoma Indolent lymphoma Clinical features Up to 40% of cases; typically slowly progressive disorders. Follicular lymphoma Most common in middle and old age (median age 55 years); can present wi th painless lymphadenopathy at \211 1 sites (most common), eff ects of BM infi ltration or constitutional symptoms (15 \200\22320%). Median sur- vival 710 years; 725% may transform to high-grade DLBCL. OS 5 years 72 \200\22377%. BM shows typical paratrabecular follicular infi ltration. PB can show minor lymphocytosis. At diagnosis \200 70% stage IV disease with BM involvement. \200 15 \200\22320% localiz ed stage I or II disease. Grading FL is graded histologically based on the average number of centroblasts in 10 neopl astic follicles at high power fi eld (HPF) examination ( \227 40). \200 Grade 1: 0 \200 \2235 centroblasts/HPF. \200 Grade 2: 6 \200\22315 centroblasts/HPF. \200 Grade 3a: >15 centroblasts/HPF with many residual small cells. \200 Grade 3b: >15 centroblasts/HPF in monotonous sheets. Note: cases of FL with a high proportion of centroblasts on histology follow a more aggress ive clinical course and are treated as aggressive lymphomas. Grade 3b FL is generally clinically treated as DLBCL. Small lymphocytic lymphoma (SLL) Nodal form of CLL and treated similarly; More common with age (>60 years); disseminated peripheral lymphadenopathy and splenomegaly possible; lymphoc yte count <4.5 \227 109/L; BM involvement in 80%; con- stitutional symptoms <20%; serum pa raprotein (usually IgM) in 30%; median survival 8 \200\22310 years; If the WCC is raised th e diagnosis is CLL rather than SLL. Marginal zone lymphoma (MZL) \200 MALT lymphomas: local invasion at site of origin, e.g. stomach, small bowel, salivary gland, or lung. Gastric MALT lymphomas present with long his tory of dyspepsia, abdominal pain GI bleeding; diagnosis by endoscopy and biopsy; locali zed in 80 \200\22390% and respond to antibiotic treatment for H. pylori; good prognosis (>8 0% 5-year survival). \200 Nodal marginal zone lymphoma: rare; associated with Sj gren \200\231s syndrome and Hashimoto \200\231s thyroiditis; usually localized to ocular adnexae, thyroid, parotid, lung, or breast. Splenic marginal zone lymphoma (SMZL) \200 Median age at diagnosis 765 years; rare <50. R are (<1% NHL). \200 Formerly \200\230splenic lymphoma with villous lymphocytes \200\231 (SLVL). 191 INDOLENT LYMPHOMA >50% survival at 5 years. Over 10% may require no treatment. Median survival >10 years from diagnosis. Transformation to diff use large B-cell NHL occur s in 710% in a median of 2 \200\2234 years. Clinical \200 Non-specifi c symptoms (fatigue, abdominal discomfort), moderate- to-massive splenomegaly, hepatomegaly in 50%, peripheral lymphadenopathy rare (splenic hila r LN frequently i). Auto-immune phenomena in 10%: AIHA, cold agglutinins, ITP, lupus anticoagulant, acquired von Willebrand \200\231s syndrome. Symptoms of cryoglobulinaemia in rare patients with concomitant hepatitis C infection. Diff erential diagnosis: MCL (especially 20% CD5+ SMZL) CLL, PLL, HCL, and hairy cell variant. Laboratory \200 Anemia and thrombocytopenia in 25 \200\22330% usually due to hypersplenism. Total WBC i due to lymphocytosis 95%; not grossly elevated. Intermediate size lymphocytes, larger than typical CLL cells, round/ oval nuclei; clumped c hromatin, indistinct nucleoli, usually with villous cytoplasmic projections at one/both pol es; monocytopenia not a feature (cf. HCL). Monoclonal serum paraprotein in up to 30%; usually IgM. \200 LDH usually normal; i serum 2-microglobulin. \200 BM aspirate may show lymphocytosis with typical immunophenotype; biopsy may be normal (10%) but usually shows moderate patchy/nodular lymphoid infi ltration ; some interstitial or diff use; intrasinusoidal CD20+ lymphoma cells characteristic of SMZ L. \200 Cytogenetic/molecular abnormalities in 80% but none specifi c. \200 Spleen hist ology: characteristic with nodular infi ltration involving the white pulp (cf. HCL). Lymphoplasmacytic lymphoma (LPC-L)/Waldenstr m macroglobulinaemia Median age 60 \200\22365 years. Median survival 6.5 years. Usually presents with isolated lymphadenopathy serum paraprotein, usually IgM (Waldenstr m). Depending on level of paraprotein symp- toms of hyperviscosity (if markedly i). BM in fi ltration common with small to medium-sized lymphocytes with lymphoplasmacytoid diff eren - tiation. International Prognostic Scoring System (IPSS) for Waldenstr m macroglobulinaemia (IPSSWM) Includes 5 (adverse) covariates: age >65 years, hemoglobin \211 115g/L, platelet count \211 100 \227 109/L, B2-microglobulin >3mg/L, serum mono- clonal protein concentration >70 g/L. The risk categories are of prognostic value (low: \211 1 adverse variable except age; inte rmediate: 2 adverse characteristics or age >65 years; high: >2 adverse characteristics) wit h 5-year OS 87%, 68%, and 36% respectively. 192 CHAPTER 5 Lymphoma See E Waldenstr m macroglobulinaemia, pp.368 \200\223377 for more details. Immunohistochemical and cytogenetic features Follicular lymphomas Pan-B markers; CD5 \210\222, CD10+, BCL \210\2222+. t(14;18)(q32;q21) in 90% (cf. reactive lymphoid hyperplasia with normal follicles BCL-2 \210\222). Small lymphocytic lymphoma Pan-B markers (CD20+, CD79a+); CD5+, weak sIg, CD23+, cyclin- D1 \210\222 (cf. MCL). Marginal zone lymphoma Pan-B markers; CD5 \210\222, CD10 \210\222, BCL-2 \210\222. MALT t(1 1,18)(q21;q21) 50%; t(1;14)(p22;q32) rare, overexpress BCL-10 and poor response to H. pylor i eradication; SMZL allelic loss at 7q21 \200\22332 in up to 40%. Splenic marginal zone lymphoma CD19+, CD20+, CD79b+, FMC7+, moderate-to-strong SmIg+; CD10 \210\222; most CD23 \210\222; usually CD5 \210\222 CD25 \210\222; 20% CD25+ but CD11c \210 \222 & CD103 \210\222 diff erentiating from HCL; NB some DBA44+; 20% CD5+ but CD23 \210\222 CD79b+ diff erentiating from CLL; cyclin D1 \210\222 dif- ferentiates CD5+ SMZL from MCL. Further reading Arcaini, L. et al. (2006). Splenic marginal zone lymphoma. Blood, 107, 4643 \200\2239. Johansson, B. et al. (1995). Waldenstrom \200\231s macroglobulinemia with the A ML/MDS-associated t(1;3)(p36;q21). Leukemia, 9(7), 1136 \200\2238. Kastritis, E. et al. (20 10), Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom \200 \231s macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH). Leuke mia Res, 34(10), 1340. Morel, P. et al (2007). International Prognostic Scoring System for Waldenstr m \200\231s Macroglobulinemia. XIth International Myeloma Workshop & IVth Intern ational Workshop on Waldenstrom \200\231s Macroglobulinemia. Haematologica, 92(6 suppl 2), 1 \200\223229. Oscier, D. et al. (2005). Splenic marginal zone lymphoma Blood Rev, 19, 39 \200\22351. Seiter, K. et al. (2012). Waldenstrom macroglobulinemia. M http://emedicine.med scape.com/ article/207097-overview 193 INDOLENT LYMPHOMA 194 CHAPTER 5 Lymphoma Treatment of indolent lymphoma Clinical trial entry where possible. FL and SLL comprise the majority of patients. Both diseases are usually responsive to chemo therapy and radiotherapy but unless truly localized, incurable with inevitable recurrence. There is no fi rm evidence of a cura- tive therapy for advanced disease. Many patients are asymptomatic and require no treatment initially. The decision to initiate treatment and the treatment chosen must take account of individual quality of life issues. At each stage, pr os and cons of treatment options should be shared with the patient to reach an agreed treat ment decision. Median OS with tra- ditional treatment 8 \200\22310 years. Initial treatment of localized FL and SLL (stage I/II) Involved fi eld radiotherapy (35 \200\22340Gy) may be curative in the 15 \200\22330% of patients with truly localized diseas e. 5-year DFS >50% may be expected. Recurrence generally occurs outside radiation fi eld. L ate relapses occur. OS 780% at 5 years, 760% at 10 years. Addition of chemotherapy improves DFS but not OS. Initial management of advanced FL and SLL (stage III/IV) Note histological grade 3b FL is u sually treated like DLBCL. Management of newly diagnosed patients involves a decision between \200\230watchful waitin g \200\231 or conventional chemotherapy and/or radiotherapy. Symptomatic patients require t reatment at diagnosis. \200\230Watchful waiting \200\231 is appropriate in asymptomatic pa tients, based on studies showing similar overall survival but better \200\230quality of li fe \200\231 in asymptomatic patients in whom therapy was deferred until indicated, compared to those in whom therapy was initiated at diagnosis. \200\230Watchful waiting \200\231 Therapy may be deferred for many months/years after diag nosis in asymptomatic patients with low bulk disease until clinical symptoms or complicatio ns develop. Patients may have better QoL and avoid expo- sure to cytotoxic agents but must be monitored closely (every 3 months for 1 year then every 3 \200\2236 months) to identify progression or complica- tions promptly. OS >80% at 5 years. Indications for treatment (patient speci \201 c) \200 B symptoms: unexplained weight los s, fever, or night sweats. \200 Cytopenia. \200 Bulky disease. \200 Steady progressio n or threatened end-organ function. \200 Evidence of transformation. \200 Other patient -specifi c features such as local compression. Therapy Established treatments: \200 Chemoimmunotherapy: standard treatment includes a co mbination of rituximab (humanized monoclonal anti-CD20 antibody) with chemotherapy. \200 \230R-chemo \200\231 regimens (R-CVP, R-CHOP, R-FC, R-MCP) 195 TREATMENT OF INDOLENT LYMPHOMA enhance OR and CR rates, DFS, and OS in newly diagnosed patients with indolent NHL compared to chemotherapy. R-CVP: addition of rituximab to CVP improves responses (OR 81% vs 57%; CR 41% vs 10%; OS 83% vs 77%).1 R-Chlorambucil (CBL): possibly superseded as 1st choice in FL but still has a place in elderly patients; remains widely used in SLL in UK. Convenient oral re gimen, well tolerated but prolonged or repeated use can cause myelosuppression. Rituximab monotherapy: Suitable for patients who cannot tolerate chemotherapy. 375mg/m2 inf usion weekly \227 4 achieves 72% OR, 36% CR rates in untreated patients and median TTP 2 y ears.2 Toxicity is mild. Risk of anaphylaxis with 1st infusion. High-grade lymphoma regimens/R-CHOP: high CR rates (760%), but the continuous pattern of relapse and OS not convincingly improved in indolent FL (histolog ical grades I and II). FL histological \200\230grade 3b \200\231 treated as \200\230high- grade \200\231 with R-CHOP; achieves responses equivalent to DLBCL but higher relapse rate. R-CHOP is widely used in USA as 1st-line therapy for FL. Purine analogs combinations (R-FC, FMD): fl udarabine has OR rate of 775% (740% CRs) in unt reated patients with FL. Combinations with rituximab and cyclophosphamide increases respons e rates (>90% CRs) and response duration. Combinations with mitoxantrone achieve similar re sponse rates. In SLL fl udarabine combinations achieve higher response rates and durations. Prophylaxis of PCP (Pneumocystis jirovecii) is required (e.g. co-trimoxazole) during and f or 6 months after therapy as well as aciclovir prophylaxis. Cellular blood products must be irradiated. FCR is widely used for SLL in USA as well as the UK. Maintenance rituximab: a number of maintenance schedules demonstrate prolonged DFS after R-chemotherapy as induction. Median PFS 51.5 months vs 14.9 months with observation. R maintenance also improved OS: 85% at 3 years vs 77% with observ ation. Standard 375mg/m2 every 2 months in fi rst response; every 3 months in 2nd response for a duration of 2 years. Bendamustine (R-bendamustine): Generally well tolerated. Similar OS rated but prolonged DFS compared to other regimens. Fast increasing in \200\230popularity \200\231, though an older drug. Radiotherapy may be useful for treatment of local problems due to bulky disease, e.g. cord compression. Used with curative intent in truly localized FL/SLL. Radioimmunotherapy: tositumomab,131I-radiolabelled murine anti- CD20 monoclonal antibody; high response rates (95% OR and 75% CR) in untreated patients wit h median PFS >6 years;3 up to 68% OR and 38% CR in treated patients. Current role only in e arly \200\230salvage \200\231 in chemo- or rituximab-resistant patients. Ibritumomab tiuxe tan 90Yt-labeled murine anti-CD20 monoclonal antibody; OR 74%, CR 15%. Role in relapsed FL refractory to rituximab. 196 CHAPTER 5 Lymphoma Treatment of relapsed FL/SLL Relapsed asymptomatic disease is not necessarily an indication for further treatment. When indolent lymphoma progresses after partial or complete respons e to initial therapy, it is important to rule out trans- formation to DLBCL (esp. if LDH i, LN rapidly enlarging, constitu- tional symptoms, extranodal disease). Therapy should be ch osen in the context of the patient \200\231s goals (palliative vs potentially curative), pe rfor- mance status and previous treatment(s) used, and their response(s). Treatment options are similar as for 1st-line treatments. Generally a chemotherapy treatment given before is not used again; excep- tions might be where a very durable remission was achieved). Furthe r responses are seen mainly in patients who achieved a previous durable response (>12 month s). Resistance to treatment ultimately develops. Autologous SCT Considered in 2nd remission in young and otherwise fi t patients. Auto-SCT a chieves improved DFS at 5 years. Continuing risk of relapse. Risk of myelodysplasia and 2nd malignancy. Only recommended in 2nd (complete) remission; 1st CR auto-SCT remains investig ational. Auto-SCT may off er younger patients with relapsed FL a survival advan- tage with a 4-year OS 71 \200\22377% vs 46%.4 Not curative. Allogeneic SCT Potential cure though i mo rbidity and mortality. Most evidence on the use of TBI-containing conditioning. CR rates >8 0% and relapse rates lower than after autograft (12% vs 55% at 5 years) and very few after 2 years. Some patients may indeed be cured. The benefi t of better disease control is off s et by a higher treatment-related mortality. Reduced-intensity conditioning ( \200\230mini \200\231-allogeneic SCT) reduces toxicity, preserves the GvL eff ect, and widens the availa bility of this treatment. Allo-SCT should be considered in appropriate patients with poor p rog- nosis disease, e.g. 1 refractory or early relapse after R-chemo. Allo-SCT using redu ced intensity conditioning has achieved 73% OS and 65% PFS at 3 years.5 High-grade transformation 725% may transform to high-grade DLBCL. All low-grade NHLs can tr ansform to high-grade lymphoma. Clinical suspicion if LDH i, LN rapidly enlarging, constitu tional symptoms, or presence of extranodal disease. 73.5 years median time to transformation in FL; 15% risk at 10 years, 22% risk at 15 years. i risk with grade 3 histology and high-risk FLIPI score.6 Other risk factors are low album in, high 2-microglobulin, and absence of CR with initial therapy. Course is progressive, response to treatment poor, and survival short (median 1.2 year). Treatment is dependent on prior therapy. Generally high-grade NHL treatment schedules used high-dose therapy and auto-SCT (750% CR rate). Prognosis is generally poor and palliation may be appropriate. 197 TREATMENT OF INDOLENT LYMPHOMA Treatment of MZL and SMZL Gastric MALT lymphoma (extranodal MZL) \200 Generally stage IE; eradication of H. pylori (as per local guidelines. An often used regimen includes clarithr omycin, amoxicillin, and omeprazole for 2 weeks): achieves CR in up to 80% of patients with 80% OS at 10 years. Regression of lesions can take 3 \200\22318 months so restaging should be done with this in mind. Re-staging at appropriate intervals (yearly once remission achi eved). Regimen should be repeated if still H. pylori +ve and no progression. Late relapses can occur. Chlorambucil rituximab or local radiotherapy can achieve CR in non-responders (frequent in t(11;18) +ve), those who progress and H. pylori \210\222ve pat ients. For more widespread disease with symptoms, non-responders, or recurrence post RT, treat as for stage III/IV indolent NHL. Non-gastric MALT lymphomas Simple combination regimens, chlorambucil or local radiotherapy (20 \200\22330 Gy) generally achieve good responses; otherwise manage as for FL. Nodal MZL: therapy similar to FL. Splenic MZL \200 Asymptomatic patients with modest splenomegaly and no signifi cant cytopenias can be observed. Splenectomy is recommended for bulky enlargement or hypersplenism (and/or to confi rm diagnosis in some cases) and can correct cytopenias and a ssociated symptoms for >5 years. Splenic irradiation is a safe and eff ective alternative to splenectomy in some cases and may be repeated. Progression after splenectomy may respond to chlorambucil (44% response rate; no CRs), fl udarabine (very high response rates in small studies), and/or ri tuximab (very high response rates in small studies). Toxic eff ects with purine analogs may be marked in elderly patients; all patients should receive prophylactic co-trimoxazole and irradiated blood products. Treatment of transformation should follow that of DLBCL. References 1. Marcus, R.E. et al. (2005). CVP chemotherapy plus rituximab compared with CVP as fi rst- line treatment for advanced follicular lymphoma. Blood, 105, 1417 \200\22323. 2. Witzig, T.E. et al. (2005). Rituximab therapy for patients with newly diagnosed, advance d stage, follicular grade I non-Hodgkin \200\231s lymphoma: a phase II trial in North Centr al Cancer Treatment Group. J Clin Oncol, 23, 1103 \200\2238. 3. Kaminski, M.S. et al. (2005). 131I-Tositumomab therapy as initial treatment for follicul ar lymphoma. N Engl J Med, 352, 441 \200\2239. 4. Schouten, H.C. et al. (2003). High dose therapy improves progression-free survival and s urvival in relapsed follicular non-Hodgkin \200\231s lymphoma: results from the randomized European CUP trial. J Clin Oncol, 21, 3918 \200\22327. 5. Morris, E. et al. (2004). Outcomes after alemtuzumab-containiing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin \200\231s lympho ma. Blood, 104, 3865 \200\22371. 6. Gine, E. et al. (2006). The Follicular Lymphoma Prognostic Index (FLIPI) and the histolo gical subtype are the most important factors to predict histological transformation in foll icular lymphoma. Ann Onc, 17, 1539 \200\22345. 198 CHAPTER 5 Lymphoma Aggressive lymphomas 750% of cases of lymphoma; rapidly progressive if untreated. Patients require immediate treatment if appropriate. IPI can be used for prog- nostication. B-cell lymhomas Diff use large B-cell lymphoma (DLBCL): most common lymphoma world- wide; 7 30% of all lymphomas; occurs at all ages, generally >40 years; presents with localized stag e I or II disease in 50% of patients but dissem- inated extranodal disease is not uncommon; constitutional symptoms in 33%; extranodal sites in 30-40%. CNS involvement more frequent in patients with testicular or BM involvement. Ascites and pleural eff usions are common en d-stage symptoms. T-cell rich B-cell lymphoma: subtype of DLBCL; occurs in younger patients; more aggressive with early BM involvement. Mediastinal large B-cell lymphoma: typically occurs in women <30 years; Anterior mediastina l mass sometimes causes superior vena cava obstruction; tendency to disseminate to other ex tranodal sites including CNS; cure rate with R-CHOP therapy similar to DLBCL. Mantle cell l ymphoma (MCL): 4 \200\2238% of NHL; median 63 years; \231\202: \231\200 ratio 4:1; B sympt oms 50%; commonly advanced disease at presenta- tion with generalized lymphadenopathy (57%) , splenomegaly (47%), hepatomegaly (18%); extranodal involvement, particularly in GI tract is common (18%). Stage IV disease at diagnosis in 70%. \200 Lymphocytosis in peripheral b lood common (38%). Intermediate size lymphocytes; nucleus often has clefts and indentations ; smear cells unusual. BM trephine biopsy demonstrates involvement in >70% with nodular, paratrabecular, interstitial, or diff use patterns. Lymph node biopsy: mantle zone expansion or diff use eff acement of nodal architecture by uniform \200\230centrocytes \200\231. Most patients have elevated LDH and serum 2-microglobulin. Up to 30% have detectable paraprotein band, usually IgM. Poor therapeutic outcome: partial responses and eventual chemoresistance. Median survival 3 \200\2234 years. \200 Improved remission rates and OS with schedules co ntaining high-dose cytarabine and auto-SCT in 1st remission in younger patients. In some patients an indolent course is observed. T-cell lymphomas Peripheral T-cell lymphomas (PTCL): several subtypes. Mature T-cell lym- p homas; median age 56; \231\202: \231\200 ratio 2:1; variable clinical behavior; nodal form more common in the West; more aggressive and less responsive to therapy than DLBCL. Hetero geneous group but poor prognosis overall; 80% stage III \200\223IV at diagnosis; constituti onal symptoms, BM and skin involvement common; 30 \200\22340% 5-year OS with combination th erapy; IPI has predictive value, though more specifi c T-cell prognostic scoring systems ex ist. PTCL-unspecifi ed most common form; extranodal 199 AGGRESSIVE LYMPHOMAS forms specifi ed (common in Asia, particularly EBV+ nasal type with nasal obstruction, disc harge, and facial swelling). Enteropathy type T-cell lymphoma: PTCL subtype; occurs in gluten-sensi- tive enteropathy; a bdominal pain, weight loss, small bowel obstruction and perforation; poor prognosis, median OS 7.5 months. Angio-immunoblastic T-cell lymphoma (AITL): median 57 \200\22368 years; consti- tutional sy mptoms, generalized lymphadenopathy, hepatosplenomegaly, pruritic skin rash, arthritis, pol yclonal hypergammaglobulinaemia, DAT+ve haemolytic anemia, cryoglobulinaemia, cold agglutin ins, and eosinophilia common; 33% progress to immunoblastic lymphoma; poor prognosis. Anaplastic large cell lymphoma (ALCL): 3 subtypes. Systemic ALK+ ALCL: usually younger pati ents and children; typically lymphadenopathy at single site; (median age <30 years and chem osensitive); systemic ALK- ALCL: median age 50 \200\22360; unfavorable; 1 cutaneous ALK \210\222 ALCL: better prognosis, may spontaneously resolve. Mycosis fungoides: mature T-cell lymphoma; presents as localized or gen- eralized plaque or erythroderma; lymphadenopathy in 50%; median sur- vival 10 years but prognosis poor with l ymphadenopathy. Once PB/BM involvement: S zary syndrome. S zary syndrome: leukaemic phase of a low-grade 1 cutaneous mature T-cell lymphoma (myco sis fungoides). See next section. S zary syndrome Occurs in up to 20% of cases of 1 cutaneous T-cell lymphoma (mycosis fun goides); median age 52 years; \231\202: \231\200 ratio 2:1. Leukaemic phase of a low-grade 1 cutaneous mature T-cell lymphoma (mycosis fungoides). Clinical \200 Generally diagnosed as a result of FBC in a patient with exfoliative erythr oderma; not necessarily end stage and may present de novo. \200 MF classically progresses through eczematoid plaque stage, infi ltrative plaque stage, and overt tumor stage and has characteristic histology on skin biopsy (epidermotropism and Pautrier microabscesses). Investigations and diagnosis \200 FBC: generally moderate leucocytosis (WBC rarely >20 \227 109/L); Hb and platelets usually normal. Blood fi lm: typically reveals large numbers of large lymphoid cells with characteristic \200\230cerebriform \200\231 folded nucleus (see Fig. 5.1). Prognosis Patients with S zary syndrome have a poor prognosis. High S zary cell count, lo ss of CD5 and CD7, and chromosomal abnormalities associ- ated with poor outcome. Median sur vival 6 \200\2238 months. 200 CHAPTER 5 Lymphoma (a) (b) Fig. 5.1 Blood fi lm in S zary syndrome showing typical cerebriform nuclei. Image (b) is r eproduced with permission from Souhami, R.L. et al. (2002). Oxford Textbook of Oncology, 2e . Oxford University Press, Oxford (E see color plate section). Very aggressive lymphomas 75 \200\22310% cases of NHL; require immediate and aggressive tre atment. Endemic Burkitt lymphoma: presents in childhood/adolescence; mainly seen in Africa with lar ge extranodal tumors in jaw or abdominal viscera; 90% associated with EBV infection; aggres sive but curable disease. Sporadic Burkitt lymphoma: median age 31 years; presents with rapidly growing lymphadenopat hy, often intra-abdominal mass; BM, CNS, and blood involvement frequent; 30% associated wit h EBV infection; associ- ated with HIV infection; aggressive but curable disease. Lymphoblastic lymphoma: median age 15 years; >50% of childhood lym- phomas; share features with ALL; T-cell LBL more frequent (85%) and usually associated with thymic mass; 33 \200 \22350% present with BM involve- ment; CNS involvement common; commonly progresses to ALL; aggres- sive but potentially curable in children. Treatment the same as for ALL.